Le Traitement Pharmacologique Des Déficits Neurocognitifs Associés À La Schizophrénie Et Aux Troubles Psycho,Tiques Apparentés

KARINELÉTOURNEAU

LE TRAITEMENT PHARMACOLOGIQUE DES DÉFICITS NEUROCOGNITIFS ASSOCIÉS À LA SCHIZOPHRÉNIE ET AUX TROUBLES PSYCHO,TIQUES APPARENTÉS

Thèse présentée à la Faculté des études supérieures de l'Université Laval dans le cadre du programme de doctorat en Psychologie pour l'obtention du grade de Philosophiae Doctor (Ph.D.)

ÉCOLE DE PSYCHOLOGIE FACULTÉ DES SCIENCES SOCIALES UNIVERSITÉ LAV AL QUÉBEC

2009

Divers déficits neurocognitifs s'ajoutent à la symptomatologie clinique de la schizophrénie (SZ) et des troubles psychotiques apparentés à la schizophrénie (TPSZ). En plus d'être très prévalents, ils sont maintenant considérés comme des manifestations à part entière de ces psychopathologies. Ceux-ci sont observés au niveau de différentes fonctions attentionelles, mnésiques, et exécutives. Ces déficits revêtent une importance particulière car ils ne sont pas corrigés. par les traitements pharmacologiques antipsychotiques, et sont intimement liés au fonctionnement global des gens qui en souffrent. Diverses avenues de traitement sont à l' étude afin de les enrayer, et ultimement, de normaliser le fonctionnement des individus souffrant de SZ ou d'un TPSZ. Cette thèse s'inscrit dans une perspective neuropsychopharmacologique du traitement des déficits cognitifs de la SZ et des TPSZ.

Cette thèse doctorale en psychologie comporte cinq chapitres, chacun rédigés de manière à répondre à un objectif particulier. Le chapitre premier a pour visée d'introduire les principales connaIssances relatives aux particularités cliniques, neuropathophysiologiques, et neurocognitives de la SZ et des TPSZ. L'impact fonctionnel des déficits neuropsychologiques y est discuté, puis les objectifs généraux et particuliers de la thèse y sont énoncés. Le deuxième chapitre est pour sa part constitué d' un premier article scientifique dont l'objectif général est de faire état des résultats découlant des premiers essais pharmacologiques visant à traiter les déficits neuropsychologiques dans la SZ et les TPSZ. Le chapitre 3 traite pour sa part, sous le format d'un second article scientifique, des résultats obtenus dans le cadre d'une étude-pilote s'intéressant au modafinil comme adjuvant cognitif potentiel chez des individus souffrant d'une SZ d'apparition récente. Le chapitre 4 est constitué d'un troisième article scientifique. Il a pour objectif la présentation des résultats découlant d' un essai clinique randomisé utilisant le modafinil afin de traiter les déficits neuropsychologiques chez des individus souffrant de SZ ou d'un. TPSZ, et présentant des contre-performances à diverses tâches attentionnelles. Enfin, le chapitre 5 se veut une conclusion générale des résultats des études neuropsychopharmacologiques disponibles dans la littérature, de même que ceux découlant des deux études réalisées dans le cadre de la présente thèse doctorale. 11

THESIS ABSTRACT

Various neurocognitive irnpairments are now considered as being core features of the schizophrenia (SZ) and schizophrenia spectrum psychotic disorders (SZSPD). These very prevalent syrnptorns are prirnarily affecting attention, rnemory, and executive functions. Neurocognitive deficits are particularly important because they are related to global functioning of people suffering from schizophrenia and because they resist toantipsychotic treatments. Several treatrnent avenues are currently under study in order to deal with these irnpairements, and, ultimately, to normalize the functioning of the SZ and SZSPD patients. This thesis has been realized in a neuropsychopharmacological perspective for the treatment of cognitive impairments in patients with SZ and SZSPD.

This Ph.D. thesis includes 5 chapters. The goal of the first chapter is to introduce the CUITent state of knowledge regarding the clinical, neuropathophysiological, and neurocognitive characteristics of SZ and SZSPD. The functional impact of neuropsychological impairments is then discussed, and the general and specific objectives of the thesis are expressed as weIl. The second chapter systematically and critically reviews the results of trials on cognitive enhancing drugs adjunct to second generation aritipsychotics for the treatment of neurocognitive deficits in SZ and SZSPD. This systematic literature review is written as a scientific article. Chapter 3 presents the second article of the thesis which reports the results of an open-label pilot study of modafinil used as a potential cognitive enhancer in recent-onset SZ patients. The fourth chapter (third article) presents the results of a randomized-double-blind cross-over clinical trial of modafinil administered to patients suffering from SZ or SZSPD and exhibiting impairments on attentional tasks. FinaIly, the Chapter 5 presents a general conclusion in which the available scierttific results (from the literature review), as weIl as those obtained following the two empirical studies included in the present thesis are discussed.

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AVANT-PROPOS

L'auteure de la thèse a activement participé à toutes les étapes du travail scientifique précédant la rédaction des trois articles scientifiques inclus dans le corps de cette thèse doctorale: relevé de littérature, préparation et mise sur pied du protocole, cueillette des données, analyses statistiques, et interprétation des données.

Les articles ont été rédigés par son auteure, avec la collaboration de professionnels et d'étudiants gradués ayant contribué au travail scientifique. Ils sont tous trois destinés à la publication dans des périodiques scientifiques appropriés. L'ensemble de la thèse est rédigé de manière à respecter les normes de présentation en vigueur à la Faculté des Études Supérieures de l'Université Laval.

L'article 1, s'intitule «Adjunct cognitive enhancers to second generation antipsychotics for cognitive impairments in schizophrenia : a review ». Son objectif est de regrouper les études pharmacologiques ayant employé un adjuvant neurocognitif potentiel chez des individus souffrant d'une trouble psychotique. Pour des fins de publication, cette revue de littérature sera mise à jour, et incluera les études pour lesquelles quelques participants étaient traités à l'aide d'un antipsychotique de première génération.

L'article 2, est titré « Modafinil as adjunct treatment in recent-onset psychosis : five case reports ». Cet article présente les résulats obtenus dans le cadre d'une première étude neuropsychopharmacologique menée afin de vérifier la sécurité de l'emploi, de même que l'efficacité du modafinil à titre d'adjuvant neurocognitif potentiel, auprès de cinq individus souffrant de schizophrénie d'apparition récente.

L'article 3, s'intitule: «A 1O-week , double-blind, placebo controlled, cross-over trial of adjunctive modafinil for neurocognitive impairrnents in schizophrenia ». Dans cet article sont rapportés les résultats provenant d'une deuxième étude portant sur l'utilisation du modafinil comme adjuvants neurocognitif potentiel chez des individus souffrant d'un IV

trouble psychotique. L'étude de cas faisant l'object du deuxième article ayant permis de conclure que le modafinil peut être utilisé de façon sécuritaire chez des individus souffrant d'un trouble psychotique d'apparition récente, en plus de montrer que son utilisation peut mener à des bénéfices neuropsychologiques, cette deuxième étude a été mise sur pieds. Elle a été réalisée à l'aide d'un devis permettant de dégager des conclusions scientifiques fiables, considérant que les conclusions de la première étude devaient être validées à l'aide

d'une étude expéri~entale. L'article scientifique sera soumis pour publication dans un périodique destiné à l'avancement des connaissances sur la schizophrénie et les troubles du spectre. v

REMERCIEMENTS

J'arrive à peine à le croire, je suis à écrire mes remerciements en vue du dépôt de ma thèse. Il n'y a pas si longtemps, je me demandais si cela arriverait un jour ... Il faut dire que mes premiers cheveux blancs sont apparus au cours de la réalisation de cette thèse, ce qui n'est pas peu dire ... J'entends déjà mes collègues et directeurs répondre qu'il est impossible d'établir une relation causale entre la réalisation d'un doctorat et l'apparition des premiers cheveux blancs, surtout en présence d'une variable confondante comme l'âge. Personnellement, je suis certaine que mon explication est très plausible ... © Heureusement pour moi, j 'ai été très bien entourée au cours des dernières années, ce qui m'a aidé à mener à terme ce travail.

Je tiens tout d'abord à remercier sincèrement mes co-directeurs, Marc-André Roy et Martine Simard, sans qui cette thèse n'aurait été. Marc-André, depuis le tout début de ma maîtrise, vous avez su me transmettre votre passion pour la recherche clinique auprès de la clientèle psychotique. Vous demeurerez pour moi l'exemple par excellence du praticien chercheur, pour qui le patient demeure toujours la priorité. Merci! Martine, j'ai beaucoup apprécié travailler avec vous et je Clois vous dire que j'ai particulièrement apprécié votre efficacité en période de « rush », on faisait vraiment toute une équipe! Je vous remercie également pour l'encouragement que vous m'avez fourni tout au long des dernières années.

Je remerCIe aussi tout particulièrement meSSIeurs Sébastien Tremblay et Louis Laplante, membres de mon comité de thèse. J'ai beaucoup apprécié votre contribution à cette thèse, vos précieux conseils m'ont permis d'élargir mes perspectives, ce qui, je le souhaite, se réflète dans ce travail.

Merci également aux membres externes de mon jury de thèse, messieurs Jacques Y. Montplaisir et Philip Jackson. Votre vision extérieure aura sans aucun doute pour effet de me permettre d'approfondir ma réflexion sur mon travail des dernières années. VI

Durant ces 5 dernières années, j 'ai été particulièrement bien accueillie, tant au Centre de Recherche Université Laval Robert-Giffard qu'à la Clinique Notre-Dame des Victoires. Je souhaite remercier les équipes de ces deux milieux de travail pour leur accueil chaleureux et leur aide à divers niveaux. À la clinique, je souhaite particulièrement remercier Marie-France Demers et Chantale Vallières. Marie-France, merci beaucoup pour ton implication dans cette thèse, et particulièrement pour m'avoir fait bénéficier de ton expérience en m'aidant à mettre sur pied cet essai pharmacologique. Chantale, tu as toi aussi beaucoup facilité la réalisation de ce travail, par ton travail de coordination bien sûr, mais surtout par ta simple présence. J'ai passé de très bons moments en ta compagnie, on se dit à bientôt. J'aimerais également remercier Audrey et Caroline, deux infirmières en or qui ont participé à la collecte des données, de même qu'à Jacinthe, qui a été d'une aide précieuse lors de la réalisation de l'étude pilote.

Merci aux différents médecins ayant participé au recrutement des participants, Dr Roy, Dr Bouchard, Dre L'Heureux, Dre Brochu-Blain, Dre Quintal, Dr Fulicea, et Dre Pelchat. Merci également à chacun des participants. J'ai grandement apprécié votre générosité, et je garde un très bon souvenir de chacun de vous.

Tout au long de mon parcours doctoral, j'ai eu la chance de bénéficier de l'aide technique de certaines personnes. Merci aux assistantes de recherche, qui m 'ont, à un moment ou à un autre, offert leur aide; Rosalie Ouellet, Marie .. Pier Lehoux, Hélène Marcaurelle, Shakti Lafontan, et Catherine St-Charles Bernier. Merci aussi à l'équipe de biostatistiques, et plus particulièrement à Claudia Émond, Annie Labbé, et Chantal Mérette.

Je tiens à remercier à nouveau la Fondation du Centre Hospitalier Robert-Giffard, de même que monsieur Michel Verreault pour leur soutien financier au cours des deux dernières années.

Merci à mes collègues-étudiants et amis, Julie, Catherine, Andrée-Anne, Caroline, Rosalie, Marie-Josée, Sâsse, Marie-Claire et Sandra. Vous m'avez tous, à un moment ou à vu un autre, aidé concrètement dans ma thèse. Par contre, c'est bien plus en partageant avec moi les hauts et les bas du doctorat, et en m'offrant votre amitié que vous m'avez aidé. Merci à chacun d'entre vous, qui êtes tous à votre façon une personne importante pour moi.

Merci aussi à mes amis de longue date, ainsi qu'à ma famille et ma belle-famille. À vous qui vous demandiez ce que je pouvais bien faire de mes journées, et à qui je répondais souvent évasivement ... ce n'est pas que je ne souhaitais pas vous parler de mes études, mais, plus égoïstement, c'était tout simplement pour préserver ces moments entre nous qui sont si chers et qui font que le travail devient secondaire. Merci à mes amis Chantale,

Nathalie, Pete, Audrey, Julie, et à mes collègues et amies de la SRIC, Caroline, Julie, et Michèle. Un merci plus particulier à ma mère Johanne, mon père Denis, et mon frère Dave. Je sais que peu importe mes choix de vie et mes ambitions, vous croirez toujours en moi et serez toujours présents pour moi.

Enfin, je ne peux passer sous silence le support indéfectible et la patience de mon cher Pass dans cette aventure. Tu pourras dire que tu es toi aussi passé par les hauts et les bas du doctorat, et je pourrai confirmer le tout. À la blague, on aimait bien faire des projets pour « quand on allait être grands »... eh bien je pense qu'on peut maintenant dire qu'on l'est tous les deux, et réaliser tous les projets qui nous tiennent à coeur.

Karine VIll

TABLE DES MATIÈRES

RÉSUMÉ DE LA THÈSE ...... 1 THESIS ABSTRACT ...... II A V ANT -PROPOS ...... III REMERCIEMENTS ...... V TABLE DES MATIÈRES ...... VIII LISTE DES T ABLEAUX PAR CHAPITRE ...... XII LISTE DES FIGURES PAR CHAPITRE ...... XIII LISTE DES ABBRÉVIATIONS ...... XIV CHAPITRE 1 : INTRODUCTION GÉNÉRALE ...... 1 INTRODUCTION GÉNÉRALE ...... 2 SCHIZOPHRÉNIE ET TROUBLES PSYCHOTIQUES; DESCRIPTION GÉNÉRALE ...... 4 NEUROPATHOPHYSIOLOGIE DE LA SCHIZOPHRÉNIE ...... 5 SCHIZOPHRÉNIE ET FONCTIONNEMENT NEUROPSYCHOLOGIQUE ...... 8 IMPACT FONCTIONNEL DES DÉFICITS NEUROCOGNITIFS DANS LA SCHIZOPHRÉNIE ...... 9 TRAITEMENT DES DÉFICITS NEUROCOGNITIFS DE LA SCHIZOPHRÉNIE ...... 10 TRAITEMENT PSYCHOLOGIQUE DES DÉFICITS NEUROCOGNITIFS DE LA SCHIZOPHRÉNIE ...... 12 TRAITEMENT PHARMACOLOGIQUE DES DÉFICITS NEUROCOGNITIFS DE LA SCHIZOPHRÉNIE ... 14 OBJECTIFS DE LA THÈSE PAR CHAPITRE ...... 14 Chapitre 2 ...... 14 Chapitres 3 et 4 ...... 15 Chapitre 3 ...... 17 Chapitre 4 ...... 17 Choix des épreuves neuropsychologiques ...... :...... 18 Chapitre 5 ...... 22 CHAPITRE 2: PREMIER ARTICLE ADJUNCT COGNITIVE ENHANCERS TO SECOND GENERATION ANTIPSYCHOTICS FOR COGNITIVE IMP AIRMENTS IN SCHIZOPHRENIA : A REVIEW ...... 23 RÉSUMÉ ...... 25 ABSTRACT ...... 26 RA TIONALE ...... 27 OBJECTIVES ...... 28 METHODS ...... 28 RESULTS ...... 29 Acetylcholine as a target for cognition ...... 30 Acetylcholine and schizophrenia ...... 31 Donepezil ...... 32 Rivastigmine ...... 34 IX

Galantamine ...... 35 Glutamate as a targetfor cognition ...... 36 Glutamate and schizophrenia ...... 3 7 Glycine ...... 38 Lamotrigine ...... 38 Ampakine CX516 ...... 39 Memantine ...... 41 Norepinephrine as a targetfor cognition .:...... 42 Norepinephrine and schizophrenia ...... 42 Atomoxetine ...... 43 Guanfacine ...... 44 Serotonin as a target for cognition ...... 45 Serotonin and schizophrenia ...... 45 Buspirone ...... 46 Other neurotransmission systems and schizophrenia ...... 47 Dehydroepiandrosterone ...... 47 CONCLUSIONS ...... 48 REFERENCES ...... 56 TABLES ...... 70 CHAPITRE 3: SECOND ARTICLE MODAFINIL AS ADJUNCT TREATMENT IN RECENT ONSET PSYCHOSIS: FIVE CASE REPORTS ...... 80 RESUME ...... 82 ABSTRACT ...... 83 RATIONALE ...... 84 OBJECTIVES ...... ~ ...... 88 METHODS ...... 88 Participants ...... " ...... ,... 88 Drug administration procedure ...... 88 Cognitive Assessments ...... 89 Clinical Assessments ...... 89 STATISTICAL ANALYSES ...... ~ ...... 89 RESULTS ...... ~ .. ~ ...... 90 Case 1 ...... 90 Case 2 ...... 91 Case 3 ...... 91 Case 4 ...... 92 Case 5 ...... 93 CONCLUSION ...... 93 REFERENCES ...... 97 TABLES ...... 104 x

CHAPITRE 4: TROISIÈME ARTICLE A 10-WEEK, DOUBLE-BLIND, PLACEBO CONTROLLED, CROSS-OVER TRIAL· OF ADJUNCTIVE MODAFINIL FOR NEUROCOGNITIVE IMPAIRMENTS IN SCHIZOPHRENIA ...... 107

RÉSUMÉ ...... 109 ABSTRACT ...... 110 INTRODUCTION ...... 111 GENERAL AND SPECIFIC OBJECTIVES ...... ~ ...... 115 A SECOND OBJECTIVE W AS TO ASSESS THE EFFECT OF A COMBINATION OF A SGA AND MODAFINIL ON GLOBAL FUNCTIONNING, CLINICAL CHANGE, AND NEGATIVE SYMPTOMS. IT WAS HYPOTHESIZED THA T MODAFINIL WILL SIGNIFICANTL y IMPROVE GLOBAL FUNCTIONNING, CLINICAL CHANGE, AND NEGATIVE SYMPTOMS, IN COMPARISON TO PLACEBO ...... 116 METHODS ...... 116 Participants, screening and recruitment ...... 116 Randomisation and Drug Administration Procedure ...... 11 7 Neuropsychological Assessment ...... 118 Clinical Assessments ...... 120 STATISTICAL ANALYSES ...... 124 RESULTS ...... 125 Participants' Characteristics ...... 125 Baseline Characteristics ...... 126 Completers versus drop-outs ...... 126 Completers ...... 127 Comparative Effects ofModafinil and Placebo on Neuropsychological Variables ...... 128 Comparative Effects ofModafinil and Placebo on Clinical Variables ...... 130 DISCUSSION ...... 131 Methodological issues ...... :...... 135 REFERENCES ...... 13 8 TABLES ...... 148 FIGURES ...... 159 CHAPITRE 5 : DISCUSSION ET CONCLUSION GÉNÉRALES DISCUSSION GÉNÉRALE...... 164

RÉSUMÉ DU PREMIER ARTICLE: "ADJUNCT COGNITIVE ENHANCERS TO SECOND GENERATION ANTIPSYCHOTICS FOR COGNITIVE IMPAIRMENTS IN SCHIZOPHRENIA: A REVIEW" ...... 164 RÉsuMÉ DU SECOND ARTICLE: "MODAFINIL AS ADJUNCT TREATMENT IN RECENT-ONSET PSYCHOSIS: FIVE CASE REpORTS" ...... 166 RÉsuMÉ DU TROISIÈME ARTICLE: "A 10-WEEK, DOUBLE-BLIND, PLACEBO CONTROLLED, CROSS-OVER TRIAL OF ADJUNCTIVE MODAFINIL FOR NEUROCOGNITIVE IMPAIRMENTS IN SCHIZOPHRENIA" ...... 167 DISCUSSION GÉNÉRALE ...... 168 Littérature disponible; considérations méthodologiques générales ...... 168 Difficultés liées au recrutement et à l'attrition, et recommandations ...... 169 Xl

Hétérogénéité des mesures neuropsychologiques employées, et recommandations .171 Utilité des études de cas portant sur les adjuvants neurocognitifs ...... 173 Utilité des mesures neuropsychologiques dans les essais pharmacologiques ...... 177 Modafinil et troubles psychotiques; état des connaissances ...... 180 Bénéfices sur le plan neurocognitif ...... 181 Fluidité verbale sémantique ...... 181 Attention sélective ...... 182 Flexibilité cognitive ...... 183 Mémoire de travail auditivo-verbale ...... 183 Autres bénéfices notés ...... 185 Bénéfices neurocognitifs mesurés à l'aide d'instruments cliniques ...... 185 Bénéfices sur le plan clinique ..... ~ ...... 186 A quand un remède efficace des déficits neurocognitifs ...... 187 associés aux troubles psychotiques? ...... 188 Contributions de la présente thèse doctorale ...... 190 CONCLUSION GÉNÉRALE ...... 192 RÉFÉRENCES ...... 193 ANNEXE ...... 204 XlI

LISTE DES TABLEAUX PAR CHAPITRE

CHAPITRE 1 AUCUN TABLEAU

CHAPITRE 2 TABLE 2.1 STUDIES TARGETING THE ACETYLCHOLINERGIC SYSTEM IN SCHIZOPHRENIA ...... 70 'TABLE 2.2 STUDIES T ARGETING THE GLUTAMINERGIC SYSTEM IN SCHIZOPHRENIA ...... 74 TABLE 2.3 STUDIES TARGETING EPINEPHRlNE AND NOREPINEPHRINE IN SCHIZOPHRENIA .... 77 TABLE 2.4 STUDIES TARGETING THE SEROTONERGIC SYSTEM IN SCHIZOPHRENIA ...... 78 TABLE 2.5 STUDIES TARGETING OTHER SYSTEMS IN SCHIZOPHRENIA ...... 79

CHAPITRE 3 TABLE 3 .1 PATIENTS AND TREATMENT CHARACTERISTICS ...... 104 TABLE 3.2 RESPONSE TO MODAFINIL ON NEUROPSYCHOLOGICAL TESTS ...... 105 TABLE 3.3 SUBSCALES CHANGES FOLLOWING MODAFINIL TREATMENT ...... 106

CHAPITRE 4

TABLE 4.1 MAIN CHARACTERISTICS AND RESUL TS FROM CONTROLLED NEUROPSYCHOLOGICAL STUDIES USING MODAFINIL IN SCHIZOPHRENIC SAMPLES ...... 149 TABLE 4.2 EXPERIMENTAL DESIGN ...... 150 TABLE 4.3 THE NEUROPSYCHOLOGICAL BATTERY ...... 151 TABLE 4.4 COMPARISON OF BASELINE CHARACTERISTICS AND PERFORMANCES FOR COMPLETERS AND UNCOMPLETERS, IN RA W SCORES ...... 153 TABLE 4.5 NEUROPSYCHOLOGICAL CHANGES FOLLOWING MODAFINIL AND PLACEBO TREATMENTS; COMPARISON OF EFFECTS ACCORDING TO THE VAN ZOMEREN & SPIKMAN'S CATEGORIZATION (2003) ...... 155 TABLE 4.6 POST-HOC CATEGORIZATION ACCORDING TO NEUROPSYCHOLOGICAL IMPROVEMENT, OR MEDICATION CONTINUING ...... ;...... 157 TABLE 4.7 CLINICAL CHANGES FOLLOWING MODAFINIL AND PLACEBO TREATMENTS; COMPARISON OF EFFECTS ...... 158

CHAPITRES AUCUN TABLEAU Xl11

LISTE DES FIGURES PAR CHAPITRE

CHAPITRE 1 AUCUNE FIGURE

CHAPITRE 2 AUCUNE FIGURE

CHAPITRE 3 AUCUNE FIGURE

CHAPITRE 4 FIGURE 4.1. CATEGORIZATION OF NEUROPSYCHOLOGICAL MEASURES OF ATTENTION ACCORDING TO VAN ZOMEREN, AND SPIKMAN, 2003 ...... 160 FIGURE 4.2. BASELINE NEUROPSYCHOLOGICAL PERFORMANCES (IN Z SCORES), COMPLETE SAMPLE ...... 161 FIGURE 4.3. BASELINE NEUROPSYCHOLOGICAL PERFORMANCES (IN Z SCORES), COMPLETERS (N = 20) ...... 162

CHAPITRES AUCUNE FIGURE XIV

LISTE DES ABBRÉVIATIONS

5-HT Sérotonine/Serotonine ACC Anterior Cingulate Cortex Ach Acetylcholine AchE Acetylcholinesterase ACT Auditory Consonants Trigram ADHD Attention-Deficit/Hyperactivity Disorder AMPA Alpha-amino-3-hydroxy-5-methyl-4-isoxasole propionic acid ANCOVA Covariance Analysis AP A American Psychiatric Association APG Antipsychotiques de Première Génération ASG Antipsychotiques de Seconde Génération BACS Brief Assessment of Cognition in Schizophrenia BChE Butyrylcholinesterase CANTAB Cambridge Neuropsychological Test Automated Battery CATIE Clinical Antipsychotic Trials of Intervention Effectiveness CFQ Cognitive Failure Questionnaire CGI Clinical Global Impressions ChEI Cholinesterase Inhibitor CIGT Category Instance Generation Test CNDV Clinique Notre-Dame des Victoires CNS Central Nervous System COWAT Controlled Oral Word Reading Test CPT -II Continuous Performance Test - 2nd edition CPT -IP Continuous Performance Test - Identical Pair version CVLT Califomia Verbal Leaming Test DA Dopamine DAI-IO Drug Attitude Inventory -10 item version DHEA Déhydroépiandrostérone D-KEFS Delis-Kaplan Executive Function System xv

DLPC Dorsolateral Prefrontal Cortex DS-CPT Degraded Stimulus - Continuous Performance Test DSM-III Diagnostic·and Statistical Manual of Mental Disorders, 3rd edition DSM-IV Diagnostic and Statistical Manual of Mental Disorders, 4th edition EPO Erythropoietin EPS Extrapyramidal Symptom ESRS Extrapyramidal Symptom Rating Scale FGA First Generation Antipsychotics !MRI Functional Magnetic Resonance Imaging GABA Garnma-Arninobutyric Acid GAF Global Assessment of Functioning Scale GAS Global Assessment Scale GDS Gordon Diagnostic System GLU Glutamate HVLT Hopkins Verbal Leaming Test LOCF Last Observation Carried Forward MATRICS Measurement And Treatment Research to Improve Cognition ln Schizophrenia MCCB MATRICS Consensus Cognitive Battery MGIDAY Milligrams per day MRI Magnetic Resonance Imaging/lmagerie par Résonance Magnétique MWCT Mesulam and Weintraub Cancellation Test N Number of participants NA N oradrénaline/Noradrenaline NIMH National Institute of Mental Health OC Observed Cases OMMT Object Matching Memory Test PANSS Positive And Negative Syndrome Scale PCP Phencyclidine PFC Prefrontral Cortex/Cortex prefrontal PVT-192 Psychomotor Vigilance T XVI

RBANSS Repeatable Battery for the Assessment ofNeuropsychological Status RAVL T Rey Auditory Verbal Leaming Test R-DB-PC-P Randomized, double-blind, placebo-controlled, parallel RT Reaction Time SD Standard Deviation SDMT Symbol Digit Modalities Test SDS Schedule for the Deficit Syndrome SGA Second Generation Antipsychotics SKT Short Cognitive Performance Test SOFAS Social and Occupational Functioning Assessment Scale SZ Schizophrénie; Schizophrenia SZSPD Schizophrenia Spectrum Psychotic Disorders TMT Trail Making Test TOT Tower Of Toronto TPSZ Troubles Psychotiques Apparentés à la Schizophrénie UKU U dvald for Kliniske U nders0gelser side effect rating scale UOA U nirhinal Olfactory Acui ty test, USA United States of America VWMT Visuospatial Working Memory Test WAIS-III Weschler Adult Intelligence Scale - Third edition WCST Wisconsin Card Sorting Test WMS-III Weschler Memory Scale - Third edition WRAT-R Wide Rande Achievement Test - Revised CHAPITRE 1 : INTRODUCTION GÉNÉRALE Introduction 2

INTRODUCTION GÉNÉRALE

Depuis quelques dizaines d'années, le traitement des principaux symptômes cliniques de la schizophrénie (SZ) et des troubles psychotiques apparentés à la schizophrénie (TPSZ), les hallucinations et les idées délirantes, s'est considérablement amélioré. En plus d'accroître le bien-être des individus qui en souffrent, ceci a fait en sorte que les spécialistes ont pu porter davantage attention à d'autres manifestations associés à ces psychopathologies, notamment, les déficits neurocognitifs. En effet, ceux-ci sont maintenant au centre des préoccupations des cliniciens et des .chercheurs qui s'intéressent à la SZ et aux TPSZ. Bien que les symptômes neurocognitifs soient observés depuis fort longtemps, et à l'instar d'autres manifestations associées aux troubles psychotiques (par ex. symptômes négatifs), ces déficits ont longtemps été considérés comme découlant des symptômes cliniques, qui sont généralement les plus saillants et donc, en avant-plan. L' amélioration du traitement des symptômes cliniques a donc permis de constater que les symptômes neurocognitifs persistent malgré des thérapies pharmacologiques et psychologiques efficaces des hallucinations et des idées délirantes chez plusieurs individus.

L'accroissement de l'intérêt pour ces déficits de la SZ et des TPSZ a mené à la mise sur pied de nombreuses études de groupe, spécifiquement intéressées à les qualifier et les quantifier. Les résultats de ces études ont ainsi montré l'importante prévalence ainsi que la magnitude des différents déficits neuropsychologiques au sein de cette population. Il est alors apparu qu'en tant que groupe, les individus psychotiques réussissent significativement mOIns bien que des participants-contrôles sur de nombreuses épreuves neuropsychologiques, et que .les déficits sont observables au niveau de domaines et de sous domaines neurocognitifs variés. Par la suite, quelques équipes de recherche se sont intéressées à l'impact de ces déficits sur la vie quotidienne des individus qui en souffrent. Les études ont ainsi permis de mettre en lumière que les déficits neuropsychologiques chez les individus psychotiques ont un impact non-négligeable sur leur fonctionnement global. De fait, de manière générale, il existe une forte corrélation négative entre le fonctionnement neuropsychologique, et leur fonctionnement général chez cette population. Ainsi, plus sévères sont les déficits neuropsychologiques d'un individu souffrant d'un trouble Introduction 3

psychotique, moins bon est son fonctionnement global (Green, 1996; Green, Kern, Braff, & Mintz, 2000).

Cette prise de conscience générale de l'impact des déficits neuiopsychologiques a eu pour conséquence d'accroître l'importance qui leur était accordée. Il était alors de mise d'étudier l'impact différentiel des divers agents antipsychotiques. disponibles sur ces déficits, de manière à guider le choix des cliniciens en fonction de la présence des déficits neuropsychologiques chez les patients. Bien que les attentes envers les antipsychotiques de

seconde génération (ASG) aient été relativement élevées (Sharma, & Mockler, 1998), il a été constaté que, bien que certains de ces agents puissent être bénéfiques pour le fonctionnement neurocognitif, aucune des molécules antipsychotiques ne le normalise

(Bowie, & Jaga, 2007). Conséquemment, depuis les années 1990, l'intérêt de plusieurs spécialistes de la SZ et des TPSZ s' est tourné vers l'étude de traitements potentiels des troubles neurocognitifs associés à ces problématiques de santé mentale. Alors que certains étudient les effets de traitements psychologiques (en particulier, la remédiation cognitive; voir McGurk, Twamley, Sitzer, McHugo, & Mueser, 2007), la plus grande partie des efforts de recherche est mise à l'identification d'agents pharmacologiques pouvant possiblement traiter les déficits neuropsychologiques liés à la SZ et aux TPSZ. L'ampleur qu'a pris ce champ d'étude est tel que la National Institute of Mental Health (NIMH), la plus grande organisation scientifique mondiale dédiée à la recherche sur les prQblématiques de santé mentale, a initié divers programmes dont les principaux objectifs sont d'augmenter la quantité et la qualité des essais cliniques visant le traitement des déficits neurocognitifs dans les troubles psychotiques (Marder, & Fenton, 2004). L'instauration de ces initiatives démontre bien l'importance que revêt le développement d'éventuels traitements spécifiques pour ces symptômes.

La présente thèse doctorale s'inscrit dans cette perspective du traitement des déficits neurocognitifs associés à la SZ et au TPSZ. Elle a comme premier objectif général de regrouper les différentes connaissances actuelles et d'offrir un regard critique sur les résultats des études disponibles portant sur les traitements pharmacologiques adjuvants aux traitements antipsychotiques pour les déficits neuropsychologiques en SZ et ~PSZ. Son Introduction 4

second objectif consiste à accroître les connaIssances quant à l'utilisation d'un des adjuvants neurocognitifs potentiels, le modafinil. Cette thèse comporte ainsi cinq chapitres rédigés en fonction de ces visées générales. Leurs objectifs respectifs précis seront explicités en fin d'introduction. Au préalable, voici une brève section d'introduction permettant d'approfondir les différentes notions présentées plus haut, et précisant les considérations sous-jacentes aux travaux empiriques réalisés dans le cadre de la thèse.

Schizophrénie et troubles psychotiques; description générale Selon la revue de littérature effectuée par Goldner, Hsu, Waraich, & Somers (2002), la prévalence-vie, ou le nombre d'individus vivants souffrant de SZ ou d'un TPSZ (trouble schizoaffectif, trouble schizophréniforme, trouble délirant, épisode psychotique bref) à un moment précis, varierait de 0.12% à 2.200/0 de la population selon les régions étudiées, la plupart des études rapportant des prévalences entre 0.5 et 1.0%. Ces psychopathologies donnent lieu à une symptomatologie complexe et hétérogène mais sont surtout connues pour les symptômes dits psychotiques, soit les idées délirantes et les hallucinations. Ces symptômes sont également connus sous le vocable de symptômes positifs (Crow, 1980), puisqu'ils consistent en « un ajout» par rapport à l'état pré-morbide. Des symptômes qualifiés de négatifs, par opposition aux symptômes positifs (Crow, 1980), sont aussi fréquemment notés. Leur appellation a été introduite dans le vocabulaire psychiatrique du fait que ces symptômes consistent en une « perte» ou une diminution par rapport à l'état pré-morbide (Crow, 1980). Ils se traduisent généralement par de l'apathie ou de l'avolition (manque ou perte d'initiative), de l'alogie (réduction du discours), de l'anhédonisme (perte d'intérêt) et/ou de l'émoussement affectif (American Psychiatric Association [APA], 1994; Roy, & DeVriendt, 1994). De même, des symptômes de désorganisation peuvent être observés (Liddle, 1987). Les symptômes de désorganisation se manifestent par diverses particularités au niveau du discours et du comportement, par exemple un relâchement associatif du discours, un affect inapproprié, ou des bizarreries au niveau du comportement et de l'habillement (APA, 1994). La durée des symptômes, la présence de dysfonctionnement dans différentes sphères, ainsi que la co-occurence de symptômes thymiques permettent quant à eux de préciser la nature du trouble psychotique (AP A, 1994). Introduction 5

Puisque les études dont il sera question tout au long de cette thèse ont le plus souvent été effectuées à l'aide de données recueillies auprès d'un échantillon dont la totalité ou la grande majorité des participants souffraient de schizophrénie, les sections subséquentes traiteront plus spécifiquement de la schizophrénie. Lorsque nécessaire, une description précise des diagnostics des participants inclus dans les échantillons sera toutefois fournie.

N europathophysiologie de la schizophrénie D'abondantes données permettent de mettre en évidence des anomalies cérébrales dans la SZ, et celles-ci pourraient expliquer les nombreux déficits neuropsychologiques observés. La neurobiologie des psychoses est un domaine de recherche très prolifique, et depuis plusieurs années, les techniques de neuro-imagerie structurale et fonctionnelle aident à mieux connaître et localiser les atteintes cérébrales. De manière générale, il apparaît que les gens souffrant de SZ présentent des anomalies cérébrales variées. En 2001 , Shenton, Dickey, Frumin, et McCarley ont présenté une revue de littérature visant à résumer les résultats observés dans 193 études utilisant des techniques d'imagerie par résonance magnétique (Magnetic Resonance Imaging [MRI]) afin de caractériser les principales anomalies cérébrales observées dans la SZ. Les auteurs y font état des résultats les plus consistants à travers les études répertoriées et publiées entre 1988 et 2000. Les anomalies structurales volumétriques les plus souvent observées sont les suivantes: une augmentation du volume des ventricules latéraux (80% des études répertoriées), et du troisième ventricule (73%), une réduction du volume des lobes frontaux (60%), temporaux (61 %), pariétaux (60%), et occipital (440/0), de même que de la taille du cervelet (31 %), et du volume global du cerveau (22%), une atrophie du complexe amygdale-hippocampe (74%), et du thalamus (42%), et une hypertrophie des ganglions de la base (68%), et un corps calleux plus épais (63%). Ces différences volumétriques seraient conséquentes à divers processus pathologiques menant à une diminution de la taille des neurones, de même que de la densité des synapses et des dendrites (Arnold, 1999). De même, des particularités ont été notées au plan de la cytoarchitecture des neurones à l'intérieur de certaines régions corticales et sous corticales, des patrons aberrants des connexions neuronales ont été observés, et il appert que l'émondage synaptique diffère de celui observé dans le cadre d'un développement Introduction 6 normal (Arnold, 1999). À l'heure actuelle, l'interprétation la plus probante de ces diverses particularités neuroanatomiques est neurodéveloppementale, suggérant que diverses étapes du développement du cerveau sont entravées, tant au cours de la gestation, qu'au cours de la vie.

Dans une récente revue de littérature, Antonova, Sharma, Morris, et Kumari (2004) ont exposé les relations les plus prépondérantes entre le volume de structures cérébrales et le niveau de performance neuropsychologique des individus souffrant de SZ. Alors que le volume total du cerveau apparaît relié de manière non-spécifique à divers· déficits neuropsychologiques chez les gens souffrant de SZ, une certaine consistance émerge en ce qui concerne un certain nombre d'associations structure/fonction cognitive. Au plan de l'attention (par ex., vitesse de traitement, attention soutenue), des relations ont été trouvées avec le volume de matière blanche, particulièrement au niveau du cortex pré-frontal, avec des anomalies thalamiques, ainsi qu'avec un plus grand volume des ventricules latéraux et du troisième ventricule. En ce qui concerne les tâches impliquant le langage ou des processus nécessitant l'abstraction ou la catégorisation de matériel verbal, la qualité de la performance serait associée au volume du gyrus temporal supérieur et du gyrus parahippocampique. Enfin, les performances déficitaires des patients SZ aux tâches dites · exécutives seraient entre autres associées à une diminution du volume de différentes structures du cortex pré-frontal. Le gyrus temporal supérieur, l'hippocampe antérieur, le gyrus parahippocampique, le striatum, ainsi que le gyrus cingulé antérieur pourraient également être mis en cause. Les interactions entre ces structures, principalement la circuiterie fronto-hippocampique est mise en évidence.

Les avancées technologiques ont également permIS de mettre au point des techniques de neuro-imagerie par résonance magnétique fonctionnelle (fMRI). Ces techniques d'imagerie cérébrale sont appliquées chez des individus alors qu'ils réalisent diverses activités sollicitant un traitement cognitif. Dans l'étude de la SZ et des TPSZ, ces méthodes complémentaires permettent la mesure de l'activation de diverses zones cérébrales lors de la réalisation d'épreuves neuropsychologiques, dont l'intensité est comparée avec celle de participants témoins. Elles permettent ainsi de statuer sur les Introduction 7

anomâlies d'activation cérébrale qUI semblent être en cause dans les déficits neuropsychologiques. En 2007, Ragland, Y oon, Minzenberg, et Carter ont publié une revue de littérature faisant état des résultats les plus congruents découlant de ce type d'études en SZ, cette littérature étant particulièrement difficile à résumer, compte-tenu de la complexité inhérente à la réalisation de ces études (par ex. choix de la tâche, définition du niveau de base, etc). En ce qui concerne les déficits en mémoire à long terme, ils apparajssent plus spécifiquement liés à un recrutement défaillant de l 'hypothalamus associé à une modulation anormale de l'activité frontale, qui est supérieure à celle observée chez des participants contrôles. Pour ce qui est des déficits de mémoire de travail, ils apparaissent être sous- . tendus par des dysfonctions au niveau ' du cortex préfrontal dorsolatéral dans lequel une hypoactivité est notée, de même qu'au niveau du cortex cingulé antérieur, et du cortex frontal gauche .. Enfin, en ce qui concerne le contrôle cognitif, tel que mesuré par diverses tâches exécutives et attentionnelles, les déficits observés chez les individus souffrant de SZ seraient aussi particulièrement associés à une activité réduite du gyrus cingulé antérieur. Lors de la réalisation de ce type de tâche, il est aussi noté que l'activation du cortex cingulé antérieur est diminuée che~ les individus SZ par rapport aux contrôles sains.

Différentes théories ont été développées pour intégrer les nombreuses données relatives aux atteintes cérébrales observées, et pour expliquer les déficits neuropsychologiques associés à la SZ. Entre autres, Andreasen et ses collaborateurs (1996, 1998, 1999) postulent que la caractéristique fondamentale de la SZ est une « dysmétrie cognitive», soit une déficience dans le traitement, la priorisation, la récupération, et la coordination de l'information. Bien qu'un parallèle puisse être dressé avec les fonctions exécutives telles que conceptualisées en neuropsychologie, ces auteurs font toutefois l'hypothèse que les difficultés associés à la dysmétrie cognitive découlent d'un dysfonctionnement plus étendu et plus complexe, incluant également des troubles aux niveaux émotif et moteur. Une perturbation des circuits cortico-cerebello-thalamo-corticaux serait à la base de cette dysmétrie, qui jouerait un rôle autant dans la coordination des processus cognitifs et émotifs, que dans l'activité motrice. Par l'inclusion de structures corticales et sous-corticales, cette théorie rendrait ainsi compte de plusieurs symptômes cliniques et neurocognitifs associés à la SZ. Introduction 8

De même, de nombreuses . données empIrIques permettent de démontrer que plusieurs systèmes de neurotransmission présentent des anomalies dans la SZ. Ces dysfonctions peuvent également être à l'origine des symptômes cliniques de cette pathologie, de même que de la symptomatologie cognitive. C'est notamment le cas des systèmes dopaminergique, glutamatergique, cholinergique, noradrénergique, et sérotonergique. Puisque ces anomalies neurochimiques constituent les principales considérations ayant guidé le choix des molécules adjuvantes à étudier dans les études neuropsychopharmacologiques, elles seront discutées dans le Chapitre 2.

Schizophrénie et fonctionnement neuropsychologique En plus des symptômes cliniques et des anomalies anatomo-physiologiques, les syndromes psychotiques se voient fréquemment compliqués par des perturbations au niveau du fonctionnement neurocognitif. En effet, bien que la présence de déficits neuropsychologiques ne soit pas nécessaire pour porter les différents diagnostics (AP A, 1994), leur prévalence est très importante au sein de la population psychotique. Dès le début du 20ième siècle, Bleuler et Kraepelin, des psychiatres intéressés par les manifestations de la SZ et pionniers dans ce domaine, notaient dans leurs descriptions de cette pathologie la présence de défaillances au plan de l'attention (Bleuler, 1911 ; Kraepelin, 1919). Depuis plusieurs années déjà, il a effectivement été démontré empiriquement, à l'aide d'épreuves neuropsychologiques standardisées, que des déficits neurocognitifs sont présents chez une grande proportion d'individus qui souffrent de SZ, et ce lorsque leurs performances sont comparées à celles d'individus de la population générale. Bien que la proportion des gens souffrant d'un trouble psychotique et présentant des déficits neuropsychologiques demeure difficile à quantifier, leur prévalence est telle que les spécialistes les considèrent maintenant comme étant des symptômes à part entière des troubles psychotiques. En effet, certains auteurs qualifient maintenant la SZ de psychopathologie cognitive (Green, & Nuechterlein, 1999), ou souhaitent qu'un critère référant aux particularités neuropsychologiques soit considéré pour le diagnostic (Keefe, 2008). Introduction 9

Des altérations sont notamment observées sur le plan de trois grandes sphères du fonctionnement neurocognitif soit l'attention, la mémoire, et le fonctionnement exécutif. De même, des performances diminuées sont notées au niveau de la motricité. Les déficits les plus souvent mis en évidence et aussi les plus prononcés chez les patients SZ et TPSZ comparés à des participants témoins se trouvent donc au niveau des processus spécifiques suivants: attention sélective, attention soutenue, apprentissage et mémoire en modalité verbale, inhibition, flexibilité cognitive, fluidité verbale, formation de concepts, et

coordination bimanuelle (Fioravanti, Carlone, Vitale, Cinti, & Clare, 2005; Heinrichs and Zakzanis, 1998; Hoff, & Kremen, 2003; Keefe, et al. , 2006; Lehoux et al., 2003).

Les déficits neuropsychologiques liés à la SZ et aux TPSZ sont maintenant considérés comme un aspect central de ces psychopathologies et non comme des épiphénomènes ou des phénomènes secondaires à d'autres facteurs. De nombreuses données empiriques permettent en effet de les considérer comme tels. Premièrement, les défi~its neuropsychologiques apparaissent tôt au cours de la maladie et parfois même avant les premiers symptômes psychotiques (Bilder, et al. , 2000; Hambrecht, Lammertink,

Klosterkotter, Matushek, & Pukrop, 2002; Saykin, et al. , 1994; Townsend, & Norman, 2004). Deuxièmement, ils ne peuvent être entièrement attribués à la chronicité ou à la symptomatologie, puisqu'ils sont présents lors des périodes où les symptômes aigüs sont atténués, et ne sont pas conséquents au traitement antipsychotique (Hill, Beers, Kmiec,

Keshavan, & Sweeney, 2004; Hugues, et al. , 2002). Enfin, troisièmement, ils sont observés de manière atténuée chez les enfants à risque' de développer un trouble psychotique (enfant dont un parent en est atteint), ainsi que chez leurs apparentés sains (parents, frères/sœurs 1 non-atteints) (Kremen et al., 1994; Maziade, et al., 2008 ; Sitskoom, Aleman, Ebisch, Appels, & Kahn, 2004; Snitz, Macdonald, & Carter, 2006).

Impact fonctionnel des déficits neurocognitifs dans la schizophrénie La présence des déficits neurocognitifs dans le tableau clinique des troubles psychotiques revêt une importance capitale. D'abord, en clinique, les troubles

1 L'étudiante a participé à la réalisation de cette recherche. Un des articles scientifiques en découlant est présenté en Annexe. Introduction 10

neurocognitifs font l'objet de plaintes courantes de la part des gens qui en souffrent. Leurs proches observent aussi couramment les manifestations de ces déficits et les rapportent au personnel traitant car ils en perçoivent les impacts quotidiens. D'autre part, de nombreuses études ont mis en évidence un lien positif important entre les déficits neuropsychologiques et de nombreuses sphères du fonctionnement global, notamment le fonctionnement dans les activités quotidiennes, le fonctionnement social, et le fonctionnement vocationnel (Green, 1996; Green, Kern, Braff, and Mintz, 2000; Green, Kern, and Heaton, 2004; Lehoux, et al. ; 2003). Les études montrent que les difficultés cognitives associées aux troubles psychotiques sont de bons prédicteurs du fonctionnement général et de l'autonomie des individus psychotiques. Ainsi, de manière générale, plus un individu souffrant d' un trouble psychotique présente de troubles neuropsychologiques, plus son fonctionnement global est altéré. D'après les résultats de plusieurs études, dont celles revues par Green et ses collaborateurs (1996, 2000, 2004), la valeur prédictive fonctionnelle des déficits neuropsychologiques serait supérieure à celle des symptômes cliniques positifs et négatifs de ces psychopathologies. Bien que certaines données indiquent pour leur part que les déficits neurocognitifs et les symptômes cliniques influencent différemment les sphères du fonctionnement sans toutefois valider la prépondérance de l'impact des déficits neuropsychologiques (Mohamed et al., 2008), ces derniers demeurent d'excellents prédicteurs du niveau fonctionnel. Le piètre fonctionnement des individus présentant des déficits neuropsychologiques les voue fréquemment à une prise en charge par leurs proches ou par la société. Cette prise en charge fait appel à une importante quantité de ressources humaines et financières. Certaines recherches ont en effet démontré que les difficultés fonctionnelles peuvent "entraîner, au cours d'une vie, des coûts de société plus

élev~s que ceux relevant des soins directs offerts aux patients (Andrews, et al., 1985; Hall, Andrews, & Goldstein, 1985; Wu, 2002).

Traitement des déficits neurocognitifs de la schizophrénie Depuis l'avènement de la chlorpromazine au début des années 1950, le traitement pharmacologique des symptômes cliniques de la SZ et des TPSZ constitue le traitement de première intention. Alors que les premières molécules antipsychotiques (antipsychotiques typiques ou Antipsychotiques de Première Génération [APG]) permettaient principalement Introduction Il de contrôler les symptômes positifs, les ASG (ou antipsychotiques atypiques; clozapine, risperidone, olanzapine, quétiapine, et ziprasidone) ont l'avantage d' avoir un impact plus favorable sur les symptômes négatifs, en plus de posséder un profil d'effets indésirables plus favorable (Stahl, 1999). En ce qui concerne l' effet des antipsychotiques sur le fonctionnement neuropsychologique, les études s'y étant intéressé montrent que les APG, lorsqu' administrés à faible dose, ainsi que les ASG, peuvent améliorer légèrement les déficits neuropsychologiques (Harvey, & Keefe, 2001 ; Keefe 2007; Keefe, Silva, Perkins, & Lieberman, 1999; Meltzer, & McGurk, 1999; Mishara, & Goldberg, 2004; Purdon, et al., 2000; Weiss, Bilder, Wolfgang Fleischhacker, 2002). Dans l'ensemble, lorsqu'ils ont un impact positif sur la cognition, les antipsychotiques contribuent à l'amélioration du fonctionnement de processus attentionnels, des habiletés motrices, de la mémoire épisodique verbale, des habiletés visuo-spatiales, ainsi que de divers domaines du fonctionnement exécutif (Hoff, et al., 1996; Harvey, 2003;-Mishara, and Goldberg, 2004;

Weiss, Bilder, & Wolfgang Fleischhacker, 2002). Par contre, tel que mentionné, leurs effets sur le plan neurocognitif apparaît modeste et ces molécules ne permettent donc pas de normaliser le fonctionnement neuropsychologique. L'efficacité clinique, au niveau neurocognitif, s'en trouve donc limitée.

Puisque les déficits neuropsychologiques persistent fréquemment malgré un traitement pharmacologique antipsychotique optimal et un suivi intensif à plusieurs niveaux, il importe maintenant de rechercher des moyens efficaces d'y remédier. Considérant l'impact fonctionnel des altérations cognitives, un traitement optimal de ces déficits devrait ultimeme,nt mener à une amélioration du fonctionnement quotidien des gens qui souffrent d'un trouble psychotique (Harvey, Green, Keefe, & Velligan, 2004). Ainsi, cliniquement, un traitement efficace des déficits neurocognitifs présents dans la SZ pourrait notamment se traduire par une plus grande autonomie des gens qui en souffrent, ou la reprise de leur travail ou de leurs études. Dans cette expectative, le traitement symptomatique de la SZ ser~it grandement bonifié. Différentes avenues de traitement des déficits neuropsychologiques sont étudiées depuis la fin des années 1990, notamment l'avenue psychologique et l'avenue pharmacologique. Introduction 12

Traitement psychologique des déficits neurocognitifs de la schizophrénie La remédiation cognitive, une approche psychologique visant à traiter les déficits neurocognitifs, fait l'objet de nombreuses recherches. Cette approche est née de la constatation que plusieurs psychopathologies entraînent des déficits neuropsychologiques et que ceux-ci ont généralement un impact fonctionnel majeur. La logique sous-tendant cette approche postule que l' entraînement des processus neurocognitifs affectés et impliqués dans les activités quotidiennes devrait améliorer le fonctionnement des gens atteints s'il y a généralisation des améliorations cognitives obtenues (Bellack, Gold, & Buchanan, 1999). Le mécanisme neurophysiologique qui permettrait une amélioration des fonctions cognitives suite à une thérapie de remédiation cognitive n'est toutefois pas bien établi (Wykes, et al., 2002). Cette technique soulève beaucoup de discussions quant à son efficacité, autant en ce qui concerne la SZ que les pathologies découlant de lésions neurologiques acquises (Hoff, & Kremen, 2003). En effet, bien que l'entraînement neurocognitif ait démontré une certaine efficacité, du moins en laboratoire, dans certains troubles tels que la maladie d'Alzheimer (Grandmaison, & Simard, 2003), la principale question soulevée quant à son utilité a trait à la possibilité que les acquis neuropsychologiques de l'entraînement puissent éventuellement se généraliser aux activités et situations de la vie quotidienne, ce qui constitue l'objectif ultime de leur traitement.

Chez la population psychotique, les premières études menaient à des résultats significatifs. Plusieurs de ces études ont été présentées et analysées dans la méta-analyse réalisée par Kurtz, Moberg, Gur, et Gur (2001). Cependant, la méthodologie de ces études présente des limites importantes, ce qui a pour effet d'en diminuer la validité. Par exemple, certains résultats positifs ont été obtenus sur des paramètres tirés d' épreuves neuropsychologiques évaluant des fonctions exécutives, notamment le Wisconsin Card Sorting Test (WCST). Puisque les épreuves exécutives sont, par définition, complexes et

évaluent la réaction à la nouveauté (Van der Linden, et al., 2000), le fait d'avoir évalué les participants à plus d'une reprise, causant ainsi un effet de pratique, peut à lui seul expliquer les résultats positifs obtenus. Par ailleurs, ces premières études limitaient généralement les évaluations pré-post entraînement au domaine neurocognitif, sans égard au fonctionnement global. Considérant l'objectif premier de la remédiation cognitive, l'amélioration du Introduction 13

fonctionnement global par le biais d'une amélioration des déficits cognitifs, la généralisation des acquis demeurait alors incertaine.

Toutefois, par la suite, les chercheurs ont eu le souci d'inclure également des mesures permettant de refléter une potentielle généralisation des bénéfices de la remédiation ou de l'entraînement cognitif. Plusieurs des résultats de ces mesures ont d'ailleurs été inclus dans une récente méta-analyse incluant 26 études réalisées à l'aide de devis randomisés, pour un total de 1151 participants (McGurk, et al., 2007). Au plan neuropsychologique, six domaines neurocognitifs ont été étudiés dans suffisamment d'études pour être représentés dans l'analyse: attention/vigilance, vitesse de traitement de l'information, mémoire de travail en modalité verbale, apprentissage et mémoire en modalité verbale, apprentissage et mémoire en modalité visuelle, et raisonnement/résolution de problème. Les analyses statistiques ont été réalisées de manière à comparer les changements neurocognitifs chez les individus traités à ceux de participants randomisés dans les différents groupes témoins, ce qui permet de considérer les potentiels effets de pratique. Les résultats de cette méta-analyse montre~t que tous les domaines cognitifs, à l'exception de l'apprentissage et de la mémoire en modalité visuelle, ont significativement bénéficié de la remédiation cognitive, tel que démontré par de petites et moyennes tailles d'effet (d = 0.28 à 0.52). La remédiation cognitive était également associée à un effet statistiquement significatif sur les différentes variables permettant de mesurer le fonctionnement global dans les études (d = 0.35). Ces résultats permettent de conclure que la remédiation cognitive appliquée chez des individus souffrant de SZ peut avoir des effets sur les déficits cognitifs, et que ceux-ci peuvent se traduire en une amélioration du fonctionnement global. Cependant, la magnitude de plusieurs des effets cognitifs, ainsi que celui associé au fonctionnement, montrent que la transposition des acquis à des activités de la vie quotidienne, lorsqu'elle se produit, s'effectue suite à des progrès substantiels obtenus au plan cognitif. En effet, les améliorations observées sur les variables spécifiquement incluses afin d'apprécier les changements fonctionnels sont moins importantes que celles notées sur les variables neurocognitives, et sont observées dans les études montrant les plus importantes améliorations neurocognitives. Ainsi, à l'heure actuelle, les résultats suivant les thérapies de remédiation neurocognitive sont Introduction 14

encourageants, quoi qu'il soit nécessaire d'en pourSUIvre l'étude afin d'améliorer la transposition des acquis neurocognitifs au fonctionnement dans la vie quotidienne.

Traitement pharmacologique des déficits neurocognitifs de la schizophrénie Une seconde avenue pour le traitement des déficits cognitifs présents dans la SZ est l'avenue pharmacologique. Depuis quelques années déjà, des groupes de chercheurs travaillent spécifiquement à la découverte de nouvelles molécules pouvant minimiser les déficits neuropsychologiques chez cette population. Ce courant de recherche est entre autres inspiré des résultats prometteurs obtenus chez les gens souffrant d'une démence, chez qui la symptomatologie neurocognitive est en avant-plan, et pour lesquels les traitements pharmacologiques sont maintenant courants (Simard, & Sampson, 2008).. Trois champs d'études pharmacologiques sont particulièrement prolifiques en SZ. D'abord, l'industrie pharmaceutique tente de développer de nouveaux agents antipsychotiques qui pourraient, en plus de traiter les symptômes cliniques, avoir un impact positif sur la neurocognition. Ensuite, de nombreuses études animales sont en cours afin de tester d'éventuelles molécules qui pourraient être prescrites en concomitance avec les antipsychotiques et ce, afin de traiter spécifiquement les déficits cognitifs (voir, à titre d'exemple; Cincotta, 2008). Ces molécules seraient alors utilisées à titre d'adjuvants cognitifs. Enfin, des équipes de recherche clinique travaillent à l'identification d'agents pharmacologiques existants qui pourraient être bénéfiques au plan des fonctions cérébrales supérieures, et pourraient être utilisés comme adjuvants cognitifs.

Objectifs de la thèse par chapitre Chapitre 2 Tel que mentionné plus haut, cette thèse a entre autres pour objectif de revoir et d'analyser les résultats obtenus dans le cadre des études disponibles portant sur le traitement pharmacologique de~ déficits neuropsychologiques à l'aide d'adjuvants neurocognitifs. Le champ d'étude portant sur l'identification de molécules existantes pouvant possiblement améliorer la neurocognition dans la SZ et les TPSZ est particulièrement effervescent à l'heure actuelle. Ainsi, quelques dizaines d'articles étayant les résultats d'essais cliniques sont à ce jour parus et de nombreuses recherches sont en Introduction 15 cours. Dans le cadre de la présente thèse doctorale, un relevé exhaustif de la littérature scientifique, sous forme de revue systématique, a été réalisé concernant l'emploi de potentiels adjuvants cognitifs auprès d'individus· souffrant d'un trouble psychotique. Ainsi, la revue de littérature intitulée: «Adjunct Cognitive Enhancers to Second Generation Antipsychotics for Cognitive Impairments in Schizophrenia: A Review », répertorie, commente, et analyse de manière critique les résultats des essais cliniques publiés jusqu'en mars 2008 et permettant de quantifier les impacts cognitifs de divers agents pharmacologiques à l'aide d'au moins une tâche neuropsychologique ou issue de la psychologie cognitive expériméntale. Pour être incluses dans cette revue de littérature, les études devaient être menées auprès d'individus souffrant ,de SZ ou d'un TPSZ traités à l'aide d'un ASG. Cet article constitue le Chapitre 2 de la présente thèse doctorale en psychologie.

Chapitres 3 et 4 La présente thèse doctorale vise également à accroître les connaissances concernant l'utilité d'un adjuvant neurocognitif potentiel, par la.présentation de résultats originaux de recherche. Les Chapitres 3 et 4 de la thèse sont donc dédiés à la présentation des résultats obtenus dans le cadre de deux essais pharmacologiques utilisant le modafinil auprès d'individus psychotiques, sous la forme d'articles empiriques. Étant donné le nombre élevé de substances pouvant être testées pour remédier aux problèmes cognitifs dans la SZ et un TPSZ, le choix de la molécule à utiliser dans le cadre de ces deux études a été fait sur la base de deux principales considérations. En premier lieu, la molécule à tester devait avoir déjà été administrée à des participants souffrant de SZ ou d'un TPSZ, et les résultats publiés dans la littérature scientifique devaient suggérer qu'elle puisse être utilisée de façon sécuritaire auprès d'individus psychotiques. En effet, puisqu'une grande proportion des participants des études réalisées dans le cadre de la présente thèse sont des individus dont les symptômes psychotiques sont d'apparition récente, et pour lesquels le maintien de la stabilité clinique est un enjeu constant, la molécule à l'étude se devait d'être sécuritaire.

En second lieu, la molécule à tester devait avoir un potentiel à améliorer le fonctionnement cognitif, tel que démontré par la littérature scientifique. Mis à part la Introduction 16 nicotine, guanfacine, les hormones déhydroépiandrostérone (DHEA) et l'érythropoïétine (EPO), ainsi que le modafinil, les différentes molécules étudiées jusqu' à maintenant pour améliorer le fonctionnement cognitif des individus souffrant de SZ ou d'un TPSZ n'apparaissent pas procurer de bénéfices substantiel,s (Létourneau, Simard, & Roy, article en préparation, voir Chapitre 2). Pour ce qui est de la nicotine, bien qu'elle puisse être profitable au plan de l'attention et des processus inhibiteurs chez des patients psychotiques qui ne fument pas (Barr, et al., 2008), ses effets sont limités et peuvent être délétères chez ceux qui fument (Harris, et al, 2004), sans mentionner les effets néfastes de la nicotine sur la santé cardio-vasculaire. Ceci peut s'expliquer par le fait que les récepteurs nicotiniques sont désensibilisés par la nicotine de la cigarette. Puisqu'une importante proportion des individus psychotiques fume, jusqu'à 88% selon l'étude de Hughes, Hatsukami, Mitchell,

& Dahlgren (1986), et que notre cohorte comprend aussi un grand nombre de fumeurs, cette option a été écartée. En ce qui concerne la guanfacine, cette molécule n'est pas homologuée au Canada. Son investigation dans le cadre des études réalisées pour la présente thèse n'a donc pu être envisagée. En ce qui a trait aux hormones DHEA et EPO, les études à leur sujet sont très récentes et aucun résultat n'était disponible dans la littérature au moment de l'élaboration de la présente thèse.

Ainsi, sur la base des premières études non-contrôlées et disponibles au moment de la conceptualisation des protocoles, le modafinil apparaissait quant à lui être une molécule présentant un potentiel pour l'amélioration du fonctionnement cognitif chez des individus psychotiques, en plus d'être bien toléré chez cette population. Notons par ailleurs que le. fait que le modafinil soit indiqué pour le traitement de l'hypersornnolence diurne associée à diverses conditions médicales (Kumar, 2008) a contribué au choix de cette molécule. En effet, à la différence des autres molécules pouvant être étudiées en tant qu'adjuvants neurocognitifs, le modafinil présentait l'avantage de pouvoir traiter, du moins partiellement, la sédation et/ou la fatigue chez les participants. Considérant que les troubles psychotiques, et/ou leur traitement pharmacologique peuvent engendrer de la fatigue découlant de troubles du sommeil (Monti, & Monti, 2004) et/ou de la sédation suivant le traitement antipsychotique (Kane, 2008), cet apport potentiel du modafinil lui conférait un Introduction 17

intérêt supérieur. Ainsi, le potentiel d'un impact combiné sur des fonctions cognitives spécifiques et sur la sédation rend l'utilisation du modafinil particulièrement intéressante.

Chapitre 3 Le Chapitre 3 présente donc les résultats d'une première étude à devis ouvert utilisant le modafinil comme adjuvant neurocognitif potentiel chez cinq individus souffrant de SZ d'apparition récente. Plus précisément, cette étude avait pour but, en plus de vérifier l'effet neurocognitif de modafinil, d'établir la sécurité de son utilisation chez des participants dont la symptomatologie psychotique est d'apparition récente. Cette étude préliminaire a donc pris la forme d'une étude de cas multiples à laquelle cinq participants souffrant de schizophrénie ont participé. Une analyse des changements cliniques et neuropsychologiques observés entre le début et la fin de leur participation a été effectuée et est présentée dans l'article scientifique qui constitue le corps du Chapitre 3, et qui s'intitule: «Modafinil as Adjunct Treatment in Recent-Onset Psychosis: Five Case Reports ».

Chapitre 4 Le Chapitre 4 est quant à lui destiné à la présentation de résultats obtenus à l'aide de cette même molécule, dans une seconde étude, menée cette fois-ci à l'aide d'un devis expérimental. Considérant les critères énumérés plus haut pour la sélection de la molécule à ) l'étude, de même que les impacts positifs non-négligeables observés chez quatre des cinq participants de la première étude (à devis ouvert), le choix de modafinil comme molécule à tester dans ·le cadre de la présente thèse doctorale a été maintenu pour cette dernière étude. Afin de dégager des résultats d'une pertinence scientifique supérieure, la méthodologie a été bonifiée, et le nombre de participants à recruter a été établi suite à la réalisation d'une analyse de puissance. Ainsi, les effets d'une administration prolongée de modafinil y ont également été étudiés, cette fois-ci à l'aide d'un devis randomisé en double-aveugle, en chassé-croisé, et avec contrôle placebo, qui permettra de distinguer des effets de pratique ou d'évolution spontanée des effets spécifiques de la molécule. Cette étude et les résultats en découlant sont donc présentés au quatrième chapitre. Introduction 18

Choix des épr~uves neuropsychologiques Pour ce qui est du choix des mesures neuropsychologiques à employer dans cette étude expérimentale, il a lui aussi été fait en tenant compte de divers aspects cliniques, pratiques, et théoriques. D'abord, considérant la prévalence importante des déficits neuropsychologiques chez la population psychotique et l'impact non-négligeable qu'ils peuvent avoir au cours d'une séance d'évaluation, celle-ci doit être adaptée et ne peut s'échelonner sur de nombreuses heures. Ainsi, afin de maximiser la validité des résultats de recherche de même que le recrutement et le maintien des participants dans l'étude, le choix des outils à employer revêt une importance particulière. Puisque les connaissances sur les effets neuropsychologiques de modafinil chez la population souffrant de SZ sont actuellement limitées, les mesures à employer doivent être choisies de manière à pennettre de dégager des conclusions fiables en limitant l'impact potentiel de variables non-mesurées. Ainsi, dans l'élaboration du présent protocole de recherche, il a été choisi de caractériser le plus précisément possible un seul domaine neuropsychologique, l'attention.

Tel que mentionné précédemment, le domaine de l'attention fait partie des domaines cognitifs les plus fréquemment et fortement affectés par les psychoses, à l'instar de la mémoire épisodique en modalité verbale et de la mémoire de travail (Fioravanti, et al. ,

2005 ; Heinrichs, & Zakzanis, 1998). De plus, en clinique, les déficits attentionnels font l'objet de plaintes subjectives fréquentes chez la population psychotique. Les déficits d'attention soutenue, qui est l'aptitude à discriminer des cibles panni des distracteurs sur une longue période de temps, sont parmi les dysfonctions neurocognitives les plus souvent retrouvées dans la population souffrant de SZ. Ils sont par ailleurs associés à des difficultés plus prononcées dans la résolution de problèmes à caractère social, ainsi que dans l'acquisition d'habiletés dans des programmes d'entraînement (Green, 1996). Enfin, l'attention constitue une fonction de base impliquée dans toute activité cognitive, ce qui fait que l'impact des déficits attentionnels peut se traduire au niveau d'activités faisant appel à tout type d'aptitudes neurocognitives (Bowie, & Harvey, 2005). De fait, son amélioration pourrait mener à des progrès dans d'autres domaines tels la mémoire, et le fonctionnement exécutif, qui sont eux aussi altérés dans la SZ. Introduction 19

Malgré l'existence de plusieurs modèles cognitifs de l'attention, le problème du choix des tests attentionnels à utiliser dans le cadre d'une évaluation neuropsychologique se pose fréquemment selon la population à l' étude, mais également en raison de la pléthore de tâches disponibles. En 200 1, Spikman, Kiers, Deelman, et van Zomeren ont étudié la validité de construit de trois des principaux concepts utilisés lorsqu'il est question d'attention: l'attention sélective, l' attention partagée, et le contrôle attentionnel. La principale question à laquelle ils souhaitaient répondre à l'aide des résultats de leur étude était la suivante: Est-ce que ces différents construits relatifs aux mécanismes de l 'attention sous-tendent à eux seuls les performances aux tests d 'attention? Dans le cas d'une réponse positive, ceci impliquerait qu'un même processus attentionnel déterminerait la performance d'une personne à différents tests évaluant théoriquement le même construit, sans prendre en considération les caractéristiques propres aux tâches en question. Des analyses factorielles ont donc été appliquées aux scores obtenus par des participants sains à différents tests connus pour évaluer ces différents processus attentionnels. Les résultats ne permettent pas d'établir la validité de construit des trois aspects attentionnels à l'étude. Au lieu de cela, deux facteurs, aussi récurrents dans d'autres études statistiques, ont été obtenus: la vitesse ou la capacité de traitement, et le contrôle ou la mémoire de travail. Alors que le premier réfère à l'importance de la rapidité d'exécution dans certaines tâches, le second a plutôt trait aux habiletés à travailler dans des contextes ou les tâches sont moins structurées et pour lesquelles la vitesse d'exécution a peu ou pas d'importance. Ces concepts ne sont pas complètement indépendants l'un de l'autre. En effet, les aptitudes liées au contrôle peuvent être appliquées à une certaine vitesse et la vitesse peut affecter le contrôle, notamment si elle est trop rapide, dans le cas de l'impulsivité par exemple. L'importance relative des ces caractéristiques sur les épreuves peut alors varier d'une tâche attentionnelle à une autre.

Ces composantes s'apparentent de près à la conception bien connue des processus automatiques et contrôlés de l'attention. En effet, plusieurs études ayant porté sur l'attention permettent de conclure que cette fonction est limitée en termes de capacité. L'étude des conditions qui influencent la performance lors de l'exécution de deux tâches simultanées suggère une distinction entre les processus automatiques et les processus contrôlés. Alors que les processus automatiques s'exécutent rapidement et sans effort, les Introduction 20

processus contrôlés requièrent du temps et une grande quantité d'attention (Schneider, &

Shiffrin, 1977). Ainsi, dans une publication subséquente, van Zomeren, & Spikman (2003) ont présenté une façon de catégoriser les tâches dites attentionnelles sur un continuum prenant en considération ces deux facteurs. Les tâches identifiées à titre d' exemple par van Zomeren et Spikman (2003) nécessitant davantage de vitesse solliciteraient les processus automatiques, alors que celles recrutant plus le contrôle feraient appel aux processus contrôlés. L'apport de ces auteurs, en plus de montrer que la nature des épreuves neurocognitives a une incidence non-négligeable sur la performance, proposent une catégorisation des tests d'attention qui offre aux évaluateurs une logique utile pour le choix des tâches à employer. .

Le continuum sur lequel peuvent se situer les tâches inclut trois niveaux; le niveau opérationnel, le niveau tactique, et le niveau stratégique. Au niveau opérationnel, la vitesse est le principal déterminant alors que le contrôle est minimal. La pression temporelle est très élevée et le répondant doit répondre aussi rapidement que possible, et/ou les stimuli sont présentés rapidement. Il sait clairement ce qu'il doit faire et ne pas faire. De plus, les tâches de niveau opérationnel sont hautement structurées et les stimuli et les réponses à . fournir sont simples. Ces tâches sont dites « gouvernées par les stimuli ». L' attention peut être testée à ce niveau où la latence de réponse est la principale variable d'intérêt. Tel que le mentionnent van Zomeren et Spikman (2003), les tâches les plus représentatives de ce niveau sont les épreuves de temps de réaction simples. En effet, lors de la réalisation d'une telle tâche, la consigne est très simple, et la vitesse de latence constitue le principal indicateur de performance; le répondant doit réagir le plus rapidement possible à toutes les stimulations présentées.

Au niveau tactique, autant la pression temporelle que la structure de la tâche sont intermédiaires. Pour bien réussir les tâches qui s'inscrivent à ce niveau sur le continuum, les répondants doivent allier la vitesse et le contrôle. Dans ce type de tâches, la nature du contrôle à exercer est clairement spécifiée dans les instructions. Ces tâches sont «gouvernées par la mémoire» puisque les règles et les instructions doivent demeurer actives en mémoire de travail pour une réalisation optimale. Les épreuves de barrage de Introduction 21 cibles pour lesquelles les stimuli sont représentés de façon organisée (par ex. en rangées) consituent un exemple de tâche pouvant s'inscrire au niveau tactique (van Zomeren, & Spikman, 2003). Effectivement, au cours de la réalisation d'une telle tâche, le répondant doit garder en mémoire la cible à repérer, mais il doit également réaliser l'épreuve le plus rapidement possible.

Enfin, le niveau stratégique regroupe les tâches qui impliquent une composante temporelle minimale, voire absente. Ici, les répondants doivent utiliser une approche personnelle compte tenu que les instructions n'expliquent pas complètement ce qui doit être fait, ou comment s 'y prendre pour bien réussir. Les tâches de ce niveau sont donc des tâches « gouvernées par les stratégies ». Elles sont, de manière générale, des tâches connues pour évaluer l'état des fonctions exécutives. Dans leur écrit de 2003, van Zomeren et Spikman donnent comme exemples les tâches de la Tour de Londres, et la tâche de tri de cartes du Wisconsin pour illustrer ce niveau. Ces deux épreuves neuropsychologiques font principalement appel aux stratégies personnelles des évalués, sans tenir compte, ou très peu, au temps de réalisation.

Étant donné que le niveau stratégique sollicite davantage les fonctions exécutives et que les épreuves y faisant appel sont très multidéterminées ~ leur emploi dans ce devis exploratoire semble inapproprié à ce stade-ci des connaissances. Par ailleurs, l'évaluation des fonctions exécutives doit par définition être effectuée à l'aide d'épreuves nouvelles et complexes. Bien que divers outils permettent l'évaluation pré-post de certaines fonctions exécutives à l'aide de versions alternatives, le fait d'évaluer les participants à quatre reprises limite la possibilité d'inclure ce type d'épreuves. Enfin, d'un point de vue plus pratique, l'utilisation de nombreuses tâches de niveaux opérationnel et tactique limite la possibilité d'inclure des tâches additionnelles, puisque ceci aurait pour effet d'allonger les séances d'évaluation.

Le chapitre 4 présente ainsi les changements observés sur des mesures attentionnelles de niveaux opérationnel et tactique (van Zomeren, & Spikman, 2003) chez Introduction 22 des individus souffrant de SZ ou d'un TPSZ suite à l'administration prolongée de . modafinil, et en comparaison à un placebo. L'article empirique intitulé: «A double-blind, placebo controlled, cross-over trial of adjunctive modafinil for neurocognitive impairments in schizophrenia », constitue le corps de ce chapitre.

Chapitre 5 Le cinquième et dernier chapitr,e de cette thèse doctorale, il se veut d'abord une. discussion portant sur les trois articles rédigés en regard des objectifs généraux de la thèse.

Une conclusion générale sera également prés~ntée et permettra de résumer les principaux résultats obtenus jusqu'à maintenant dans les études disponibles portant sur l'amélioration du fonctionnement neurocognitif des individus souffrant de SZ ou d'un TPSZ par le biais de thérapeutiques pharmacologiques. Leurs forces et limites seront également discutées. Ce sera alors l'occasion d'offrir certaines recommandations en vue de la poursuite des recherches dans ce champ d'étude. Traitements adjuvants: Revue 23

CHAPITRE 2: PREMIER ARTICLE

Adjunct cognitive enhancers to second generation antipsychotics for cognitive impairments in schizophrenia : a review Traitements adjuvants: Revue 24

Adjunct Cognitive Enhancers to Second Generation Antipsychotics for Cognitive Impairments in Schizophrenia: A Review

Karine Létoumeau, MPs, Ph.D. Candidate in Psychology 1, 2 1 Martine Simard, PhD , 2 l Marc-André Roy, MD, MSc (epidemiology), FRCp , 3

1. Centre de Recherche Université Laval Robert-Giffard, Québec, Québec, Canada, G1J 2G3 2. Laval University, School of Psychology, Local 1116, Pavillon F. -A. Savard 2325 rue des Bibliothèques, Québec, Québec, Canada, Gl V OA6 3. Laval University, Department ofPsychiatry , Québec, Québec, Canada, G1 V OA6

[email protected], phone: (418) 663-5741 ext. 4764, Fax: (418) 663- 5971

Aknowledgments: This study was not sponsored and therefore, there IS no financial relationship to disclose. Traitements adjuvants: Revue 25

Résumé Le traitement des déficits cognitifs associés à la schizophrénie et aux troubles psychotiques du spectre est devenu un enjeu clinique crucial depuis qu'il est bien démontré que ces déficits constituent une caractéristique centrale de ces psychopathologies et un bon prédicteur du fonctionnement général. Cependant, il n'est toujours pas clair, à l'heure actuelle, quelles molécules, administrées en concommitance avec les antipsychotiques de seconde génération, sont les plus efficaces pour améliorer le fonctionnement neurocognitif des patients souffrant de SZ. L'objectif de la présente revue systématique était ainsi de procurer une évaluation systématique des données disponibles au sujet des traitements adjuvants administrés afin d'améliorer le fonctionnement cognitif des individus souffrant de schizophrénie ou d'un troubles psychotiques y étant apparenté, et de formuler des recommandations pour les essais cliniques futurs. Une recherche systématique de la littérature scientifique a été effectuée dans les bases de données Pubmed et Psychlnfo afin d'identifier les articles d'intérêt rédigés en langues anglaise ou française, et publiés entre janvier 1996 et le 4 mars 2008. Seuls les essais cliniques randomisés, réalisés en double insu, contrôllés à l'aide d'un placebo, et impliquant uniquement des participants traités à l'aide d'un adjuvant cognitif et d'antipsychotiques de seconde génération ont été revus. Une analyse qualitative des résultats a été réalisée. Vingt études intéressées par Il différentes molécules ont rencontré les critères d' inclusion, et ont donc été revues. Les résultats les plus probants ont été obtenus à l'aide d'agents glutamatergiques et noradrénergiques, alors que les moins probants ont été notés pour les inhibiteurs de la cholinestérase, particulièrement donepezil. Les études revues étaient limités par de petits échantillons, et possiblement par un manque de sensibilité de certaines des mesures neuropsychologiques utilisées. D'autres études sont nécessaires afin d'approfondir le problème du traitement des déficits neurocognitifs des troubles psychotiques du spectre de la schizophrénie. Traitements adjuvants: Revue 26

Abstract The treatment of cognitive impairments associated with schizophrenia (SZ) and SZ spectrum disorders (SZSPD) had become a crucial clinical question since it is weIl demonstrated that these impairments are a core feature of these disorders and good predictors of functional outcome. However, it is not clear yet which compounds, administered in combination with second generation antipsychotics (SGA), are the most efficacious to improve cognition in patients with SZ. The goal of the present systematic review was thus to provide a critical appraisal of the available data about the adjunct treatments administered to enhance cognitive functions in SZ and SZSPD, and to provide recommendations for future trials. A systematic literature search of Pubmed and PsychInfo databases was conducted on English and French papers published from January 1996 until March 4 2008. We reviewed randomized double-blind piacebo-controlled trials using cognitive measures, and involving participants treated with second-generation antipsychotics and adjunct cognitive enhancers. A qualitative analysis of the data was performed. Twenty studies focusing on eleven differents compounds met the inclusion criteria, and were reviewed. The best results were obtained by glutamatergic and noradrenergic agents, whereas the cholinesterase inhibitors, especially donepezil, yielded consistent negative results. The reviewed studies were limited by small sample sizes, and possibly by a lack of sensitivity of sorne cognitive measures. Further research is needed to clarify sorne issues related to the treatment of cognitive impairments in SZSPD.

Keywords : Schizophrenia, cognition, treatment, pharmacology, second-generation an tipsych 0 tic, placebo-controlled study, review Traitements adjuvants: Revue 27 .

Rationale Cognitive impairments are a core feature of schizophrenia (SZ) and SZ spectrum disorders (SZSPD) even if these impairments are not included in the diagnostic criteria of these disorders (American Psychiatric Association 1994). Indeed, it has been demonstrated that cognitive deficits precede the onset of positive symptoms, and that they persist in periods of remission (Bilder et al. , 2000; Townsend and Norman 2004). Almost every domains of cognition have already been found impaired in studies comparing SZ patients with control participants. However, specific cognitive functions, such as sustained and selective attention, verbal fluency, verbal episodic memory, working memory, abstraction and bilateral motor skills, yield the most robust effect sizes in studies comparing SZ subjects to controls, and were most consistently found impaired (Heinrichs and Zakzanis 1998; Hoff and Kremen 2003; Fioravanti et al., 2005). Several studies showed that second generation antipsychotics (SGA), compared to first generation antipsychotics (FGA), have a more positive impact on cognitive impairments yet they. do not normalize cognitive functions (Keefe et al., 1999; Meltzer and McGurk 1999; Harvey and Keefe 2001 ; Woodward et al., 2005).

In this context, cognitive impairments became a preferential target for treatment over the past few years (Friedman et al., 1999; Krebs et al., 2006; Marder 2006). This is particularly relevant since many studies suggest that cognitive impairments may be a more important determinant of global and social functioning than positive or even negative symptoms (Breier et al., 1991; Green 1996; Green et al., 2000; Lehoux et al., 2003). Therefore, the rationale underlying the development of effective treatments for cognitive impairments in SZ posits that improvements in cognition will result in improvements in the daily functioning of patients. Although research on cognitive remediation therapy is still . active, the pharmacological intervention is currently the favourite approach under investigation. Since even SGA do not normalize cognition, a growing body of clinical trials assess the impact of adjunct nootropics to antipsychotic compounds specifically tested for their potential effect on neurocognition in SZ. Traitements adjuvants: Revue 28

Objectives This paper alms at reviewing clinical trials uSlng adjunct nootropics to treat cognitive impairments in SZ and SZSPD treated with SGA. We chose to focus on studies including exclusively SGA-treated subjects (and not FGA-treated) because those compounds are currently the most widely used and because the inclusion of patients treated with FGA and SGA could have induced a confounding variability in participant characteristics. Considering the different assessment tools used from one study to another, a qualitative systematic review was performed instead of a meta-analysis. This paper will thus provide a critical and systematic overview of the current literature and available data, and will make recommendations for future clinical trials.

Methods Relevant studies were identified by conducting a literature search using Pubmed and PsychInfo databases from January 1996 until March 4, 2008. Key words systematically combined the generic name of the molecule with, respectively, "schizophrenia" and "psychosis". The following generic names were thus investigated: donepezil, rivastigmine, galantamine, huperzine A, 10 (-3) M eserine, DMXBA (GTS 21), nicotine, physostigmine, tacrine, xanomeline, velnacrine, eptastigmine, metrifonate, ipidacrine, pilocarpine, arecoline, choline, lecithin, 7-methoxyacridine , cevimeline, deanol, meclofenoxate, citicoline, RS86, CDD 0102, DI 101 7, YM 796, glycine, d-cycloserine, glutamic acid, lamotrigine, memantine, ampakine, D-Serine; sarcosine, glycyldo de cylam ide, ORG24461, ORG24598, SSR504734, modafinil, armodafinil, atomoxetine, guanfacine, clonidine, buspirone, tandospirone, perospirone, fenfluramine, ketanserine, D-amphetamine, metylphenidate, pergolide, L-dopa, bromocriptine, dehydroepiandrosterone, erythropoietin (EPO) , celecoxib and mifepristone. A cross-reference search, manual search of bibliographies of published articles, and of psychiatric joumals, were also performed to identify the broadest range of compounds. To be included in the current review, the studies should met the following inclusion criteria: 1) providing a comparison of a cognitive enhancer to a placebo in a randomized double-blind experimental design, 2) including at least one neuropsychological task (involving experimental paradigms), 3) as previously mentioned, including patients exclusively treated with a SGA. The last criterion is included Traitements adjuvants: Revue 29

for two major reasons. Studies were first grouped according to the neurotransmitter targeted by the nootropics. In each table, studies were then ordered according to the number of participants considered in statistical analysis for each trial, from the biggest to the smallest sample size.

In order to draw useful conclusions, we summarized the evidence taking into account the degree to which results have been replicated in independent studies. By doing so, we paid particular attention also to evidence of an advantage of placebo over the active compound, which could suggest deleterious effects of the latter. Even if our relatively stringent inclusion criteria ensured a certain d~gree of methodological rigor in the trials included, we also considered the following methodological aspects in assessing the strength of the evidence: i) to the number of subjects, and thus to power, in assessing studies not showing advantage of an active compound over placebo; ' ii) to the scope of the neuropsychological battery used to determine their degree of overlap across studies.

Results Twenty studies focussing on the following eleven compounds met our inclusion criteria: donepezil (n=4) (Friedman et al., 2002; Fagerlund et al. , 2007; Keefe et al., 2007; Kohler et al., 2007), rivastigmine (n=3) (Aas en 2005; Kumari 2006; Sharma 2006), galantamine (n=2) (Dyer et al., 2008; Schubert et al. , 2006), glycine (n=l) (Evins et al. , 2000), lamotrigine (n=3) (Goff et al 2007 (two studies); Zoccali et al., 2007), ampakine CX516 (n=2) (Goff et al. , 2001, 2008), memantine (n=l) (Cerullo et al., 2007), atomoxetine (n=l) (Friedman et al., 2008), guanfacine (n=l) (Friedman et al., 2001), buspirone (n=l) (Sumiyoshi et al. , 2007), and dehydroepiandrosterone (n=l) (Strous et al., 2007). A number of studies using sorne of the above-mentioned compounds or other compouilds were excluded because a proportion or aIl of their participants received FGA instead of SGA: donepezil (n=3) (Erickson et al., 2005; Freudenreich et al. , 2005; Mazeh et al. , 2005), rivastigmine (n=l) (Chouinard et al., 2007), galantamine (n=l) (Buchanan 2008), nicotine (n=7) (Dépatie et al., 2002; Smith et al. , 2002; Harris et al., 2004; Jacobsen et al., 2004; Sacco et al. , 2005; Barr et al., 2008; Smith et al. , 2006), DMXBA (GTS 21) (n=l) (Olincy et al., 2006), modafinil (n=6) (Turner et al. , 2004; Sevy et al. , 2005 ; Spence et al., 2005; Traitements adjuvants: Revue 30

Farrow et al. ; 2006; Hunter 2006; Pierre et al. , 2007; ), glycine (n=2) (Heresco-Levy et al. , 1996; Buchanan et al. , 2007), D-serine (n=l) (see Tsai et al. , 1998), D-cycloserine (n=4) (Duncan et al., 2004; Goff et al., 2005; Yurgelun-Todd et al., 2005; Buchanan et al. , 2007), dehydroepiandrosterone (n=l) (see Ristner et al. , 2006), EPO (n=l) (Ehrenreich et al. , 2007), amantadine (n=l) (Silver et al. , 2005), and mifepristone (n=l) (Gallagher et al. , 2005).

Trials testing the following compounds, and studying cognition, were also identified but did not match our inclusion criteria, mainly because they were tested in open label design: nicotine, DMXBA (GTS 21), physostigmine, tacrine, xanomeline, huperzine A, 10 (- 3) M eserine, velnacrine, eptastigmine, metrifonate, ipidacrine, pilocarpine, · arecoline, choline, lecithin, 7-methoxyacridine, arecoline, cevimeline, deanol, meclofenoxate, RS86, CDD 0102, DI 1017, YM 796, memantine, D-cycloserine, D-Serine, sarcosine, glycyldodecylamide, ORG24461, ORG24598, SSR504734, D-amphetamine, metylphenidate, pergolide, L-dopa, bromocriptine, armodafinil, guanfacine, clonidine, tandospirone, perospirone, fenjluramine, ketanserine, erythropoietin (EPO) , celecoxib, and amantadine (references available on request).

Acetylcholine as a target for cognition In the brain, eight cholinergic, cell groups projecting through the central nervous system (CNS) are classically identified (Mesulam 1995). Two are especially relevant to cognition. First, neurons originating from the nucleus basalis of Meynert mainly project to the cortex and play an important role in leaming and memory. Second, cholinergie neurons from the brainstem project to the midbrain and thalamus, 'and are involved in the sleep wake rhythrns. The nicotinic and muscarinic receptors are the two major classes of acetylcholine (ACh) receptors. The muscarinic receptors (M1-M5) are highly expressed in the neocortex, hippocampus, striatum, basal forebrain, thalamus, brainstem, and substantia nigra. The nicotinic receptors (alpha 2-9, beta 2-4) are present throughout the brain; however, they are especially abundant in the cortex, the ventral tegmental area, the hippocampus, the substantia nigra, the locus coeruleus, the amygdala, and the brainstem (Hyde and Crook 2001). In addition to their implication in the neurobiology of reward and Traitements adjuvants: Revue 31

their modulating effect on the release of other neurotransmitters, nicotinic receptors may mediate attention/vigilance, speed of processing, working memory, verbal and visual leaming and memory, reasoning and problem solving, and verbal comprehension (Lucas Meunier et al. , 2003).

Acetylcholine and schizophrenia Interest for studying the muscarinic and nicotinic receptor systems in relation to SZ mainly derived from the observations that: 1) the ACh muscarinic system is involved in many functions altered in SZ such as memory, motor activity, and sleep, and 2) the ' prevalence of cig~rette smoking is elevated among schizophrenie patients (up to 88%; Hughes et al., 1986) which suggests that smoking may be an attempt to self medicate an ACh receptor dysfunction. There is also more direct evidence for an ACh dysfunction in SZ. First, it has been observed that nicotine normalizes electrophysiological measures related to sensory gating, and this abnormality is related to the alpha-7 nicoiinic receptor gene (Adler et al. , 1993). Second, sorne post-mortem studies have implicated both muscarlnlC and nicotinic receptors dysfunctions. Early post-mortem studies using a muscarinic agoni st found increased receptor binding in the orbital frontal cortex and putamen, and decreased binding in frontal, parietal, and temporal areas of patients with SZ (Bennett et al., 1979; Owen et al. , 1981; Watanabe et al. , 1983). Other post-mortem studies lJsing muscarinic antagonists showed a decrease in ACh binding in the striatum, hippocampus, and prefrontal cortex (Dean et al., 1996, Crook et al., 2000, 2001 ; Dean et al. , 2002). These observations suggest a down-regulation in muscarinic receptors secondary to an increased ACh liberation or a more basic change in receptor production (Hyde and Crook 2001). Post-mortem studies on nicotinic receptors in SZ are more recent. Essentially, they report that patients with SZ present a lower density of nicotinic receptors in the hippocampus (Freedman 1995), and a decreased level of alpha-7 nicotinic' receptors in the frontal cortex (Ouan 1999). Furthermore, a decrease in choline acetyltransferase, a precursor of ACh, was described, post-mortem, in brains of SZ patients. This depletion was found to ,be related to the severity of antemortem cognitive impairments compared to normal controls (Karson et al. , 1996). Altogether, those observations suggest an alteration Traitements adjuvants: Revue 32 in the cholinergic system of patients suffering from SZ, and a relation of this alteration with cognitive impairments observed in this population.

The ACh nootropics used in the 10 papers reviewed below principally inhibit the action of acetylcholinesterase (cholinesterase inhibitor or ChEI). Acetylcholinesterase (AChE) is an enzyme that degrades ACh at the synaptic cleft. The inhibiting action of ChEI on this enzyme enhances the cholinergic function by increasing the biodisponibility of ACh in the synaptic cleft. The papers reviewed below deal with the following three ChEls: donepezil, rivastigmine, and galantamine.

Insert table 2.1 about here

Donepezil Donepezil or (E2020; 2-3-dihydro-5, 6-dimethoxy-2[[(1-(phenylmethyl)-4- piperidinyl]methyl]-lH-inden-1-one hydrochloride), is a high-affinity, noncovalent inhibitor that has competitive and noncompetitive properties. It is a reversible, short-acting, specific piperidine-based derivativeand is chemically distinct from other ChEI (Cardozo et al., 1992; Sugimoto et al., 1992). Preclinical studies have shown donepezil to be highly selective for AChE in the CNS (Rogers et al., 1992; Yamanishi et al., 1990). Its lack of peripheral activity is demonstrated by the fact that whilst it significantly inhibits brain cholinesterase, it has no effect on either cardiac muscle or smooth muscle in the small intestine and has only a limited effect on AChE in pectoral (striated) muscle (Krall et al. , 1999; Nordberg and Svensson, 1998; Rogers et al. , 1991).

Table 2.1 shows the results of four studies testing donepezil as a potential cognitive enhancer adjunct to SGA. (Fagerlund et al. , 2007; Friedman et al., 2002; Keefe et al., 2007; Traitements adjuvants: Revue 33

Kholer et al. , 2007). A11 of theses studies used a placebo para11el group design and a comprehensive neuropsychological battery. While Keefe et al. , (2007) included participants treated with any of the SGA available, Friedman et al., (2002) and Fagerlund et al. , (2007) recruited patients taking only, respectively, risperidone and ziprasidone. Kholer et al. , (2007) included participants treated with a11 available SGA except clozapine. One of these

studies used a multicenter rec~itment strategy (Keefe et al ~, 2007) which provided a large sample size (N=226). The size of the other samples ranged from Il to 36 participants. Fina11y, the studies of Friedman et al. (2002), and Keefe et al. (2007) were conducted over 12 weeks, and studies of Faberlund et al. (2007) and Kholer et al. (2007) were realized in 16 weeks.

The four studies altogether assessed verbal (n=4) and visuospatial (n=2) learning and memory, verbal (n=2) and visuospatial working memory (n=3), lexical (n=l) and semantic (n=2) verbal fluency, speed of information processing (n=l), sustained (n=4) and selective (n=3) attention, abstraction (n=3) and planning (n= 1) abilities, cognitive flexibility (n=4), praxis ski11s (n=2), and manual dexterity (n=l). The results were congruent across studies: donepezil did not offer any advantage over placebo on any of the cognitive measures that were administered in the trials. There were, however, sorne significant results in favour of placebo on a global cognitive composite score (Keefe et al. , 2007), on an immediate verbal memory measure (Fagerlund et al., 2007) and, using more conservative statistical analysis (LOCF), on lexical and semantic fluency tasks (Keefe et al., 2007).

In regards to safety and tolerability of donepezil in these trials, the results indicated that donepezil was safe and relatively we11 tolerated. Two patients terminated early in the study of Friedman et al. (2002) because of an increased agitation and uncooperativeness fo11owing titration to 10mg. One patient was excluded in another study (Fagerlund et al., 2007), fo11owing the onset of important extrapyramidal symptoms (EPS) related in time to the increase of the donepezil dosage. In the same study, two other participants experienced EPS, but these symptoms abated with a dose reduction. In the study conducted by Kohler et al. (2007), no serious adverse events were reported. Actua11y, two drop-outs occurred in Traitements adjuvants: Revue 34

both donepezil and placebo groups and were due to no specific reason (n=2), agitation, and dizziness. In general, the adverse events (headache, digestive system, CNS) occurred as frequently in placebo as in donepezil groups (Keefe et al. , 2007).

Rivastigmine Rivastigmine or (SDZ ENA 713; (S)-N-ethyl-3-[(I-dimethylamino)ethyl]-N methyl-phenyl carbamate hydrogen-tartrate.( -)-m-[ (S)-1 (dimethylamino )ethyl] phenyl ethylmethylcarbamate), is a carbamylating, intermediate-acting, pseudo-irreversible and non-competitive carbamate AChE inhibitor (Jann 1998). Rivastigmine also inhibits butyrylcholinesterases (BChE), but in a variable and less predictable manner than AChE (Jann 1998; Krall et al., 1999; Nordberg and Svensson 1998). BChE are present in the brain where they originate . from glial ceIls, which metabolize hormones as weIl as active metabolites that affect neuronal function (Garcia-Segura and McCarthy 2004).

Among the three piacebo-controlled randomized studies (Table 2.1) using rivastigmine as a potential cognitive enhancer (Aasen et al. , 2005; Kumari et al., 2006; Sharma et al., 2006), two were primarily designed to assess neural correlates of cognitive functions changes following the administration of modafinil, using functional magnetic resonance imaging (fMRI) (Aas en et al., 2005; Kumari et al., 2006). Participants in these three studies, conducted by a single group, were treated with olanzapine, quetiapine, or risperidone. Sample sizes ranged from 20 to 21 participants and a proportion of the participants of Sharma et al. (2006) were also part of the samples of the other two studies. While the study by Sharma et al. (2006) lasted 24 weeks, the study by Kumari et al. (2006) lasted 12 weeks, whereas that of Aasen et al. (2005) lasted from 12 to 14 weeks.

The neuropsychological tasks used by Sharma et al. (2006) assessed verbal leaming and memory (CVL T), verbal and visuospatial working memory (letter number and digit symbol subtests from the WAIS-IIII, and the Dot test), alphabetic and semantic verbal fluency (FAS and animais), sustained and selective attention (CPT, TMT A), abstraction (WCST), cognitive flexibility (TMT B), and psychomotor speed (Finger Tapping Test). Traitements adjuvants: Revue 35

The experimental paradigms in papers of Aasen et al. (2005) and Kumari et al: (2006) were designed to respectively assess selective attention and visuospatial working memory. These three studies showed no positive effect of rivastigmine compared with placebo on cognitive function. However, on the contrary to donepezil trials, there was no positive result in favour of placebo.

Rivastigmine was weIl tolerated in aIl the trials; the addition of rivastigmine to the pharmacological treatment of the participants did not produce any serious adverse event. lndeed, there was no significant change in symptoms or side effects as compared to placebo (Aasen et al. , 2005 ; Kumari et al. , 2006; Sharma et al. , 2006).

Galantamine Galantamine or (4aS, 6R, 8aS)-4a, 5, 9, 10.11 , 12-hexahydro-3-methoxy-l1-methyl- 6H-benzofuro-[3a, 3, 2-ef][2]benzazepin-6-01) is a competitive ChEl and an allosteric modulator of nicotinic receptors. Galantamine is a phenanthrene alkaloid similar to codeine that, unlike conventional ChEls, has a dual mechanism of action. Galantamine is a selective and reversible inhibitor of AChE with a competitive action which may further enhance cholinergic function by increasing the release of ACh. Galantamine is thought to pro duce this effect through allosteric m~dulation , an interaction with presynaptic nicotinic receptors. Galantamine binds to a site on the nicotinic receptor that is distinct from the ACh binding site. The binding of galantamine to this receptor site alters membrane ion channels, which makes the cholinergic neuron more excitable and enhances the response of the neuron to ACh. This creates an amplification effect, whereby even more ACh is released (Krall et al. , 1999; Nordberg and Svensson 1998).

Table 2.1 shows the principal features of the two studies investigating this compound (Dyer et al. , 2008; Schubert et al. ,- 2006). Both studies were conducted using a parallei group design. While the first trial (Dyer et al. , 2008) included patients treated with any SGA, the second trial (Schubert et al. , 2006) included only patients treated with risperidone. The sample sizes were of 20 (Dyer et al., 2008) and 14 (Schubert et al. , 2006) participants and were 8 weeks in both studies. Traitements adjuvants: Revue 36

The neuropsychological battery used by Dyer et al. (2008) spanned verbal working memory, sustained attention, inhibition processes and manual dexterity. Those used by Schubert et al. (2006) spanned immediate memory, delayed memory, visuospatial/constructional abilities, language, attention, measures of associative memory, sustained attention and planning abilities.

The results of these two studies were conflicting since one concluded to the superiority of galantamine over placebo while the other concluded the opposite. On one hand, Schubert and colleagues (2006) observed that compared to placebo-treated patient, galantarnine-treated patients were more improved on the total score, attention, and delayed memory indexes from the RBANS. On the other hand, Dyer et al observed that galantarnine-treated patients worsened on selective attention (d' index of the Continuous Performance .Test - Identical Pairs), inhibition (Stroop interference T-score), and verbal working memory (letter-number sequencing, forward span) compared to the placebo group.

As donepezil and rivastigmine, galantamine was generally well tolerated. Indeed, there was no drop-out and no serious adverse event reported in the study of Schubert et al. (2006), although one galatamine-treated participant withdrew consent due to muscle cramps in feet and abdomen in the study.ofDyer et al. (2008).

Glutamate as a target for cognition Glutamate is the most comrnon and widespread excitatory neurotransmitter in the CNS. Glutamate, which is derived from glucose and glutamine, rnediates most excitatory neurotransmission in the brain by its action on two types of receptors; the ionotropic receptors (iGluRs: N-Methyl-D-Aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4- isoxasole prQpionic acid (AMPA), and kainate) and the metabotropic receptors (mGluRs) coupled to G proteins (Hollmann and Heinemann 1994). Glutamatergic neurons in the pre frontal cortex and amygdala project to the mesolimbic network, from where sorne dopaminergic projections originate. There are also glutamatergic projections from the prefrontal cortex to the ventral tegmental area and to the nucleus accumbens. The glutamatergic neurotransmission system plays a crucial role in neuronal plasticity and in Traitements adjuvants: Revue 37

memory formation and information processing. Indeed, NMDA and AMP A are involved in the three main processes of episodic memory, namely encoding, consolidation, and retrieval. There is also evidence that glutamatergic transmission plays a key role in more complex cognitive functions such as executive functions (Robbins and Murphy 2006). The recent evidence on the involvement of glutamate receptors in cognition raised the question of how new agents modulating this neurotransmitter system might be used for improving memory and cognitive function in various neuropsychiatrie conditions.

Glutamate and schizophrenia A dopaminergic system dysregulation is still though to play a major role in the pathophysiology of SZ (Kapur, 2003). The numerous interactions between the glutamatergic and dopaminergic systems and evidence for a glutamate system dysregulation in SZ have lead to a "glutamate hypothesis" of SZ (Erhardt et al. , 2007; Javitt 2007). The interest in the role of the glutamate system in SZ first increased following the observation that phencyclidine (PCP), a glutamate receptor antagonist, produces a broad range of SZ-like positive symptoms as well as cognitive symptoms in healthy subjects (Luby et al. , 1959; Malhotra et al. , 1996; Jentsch and Roth 1999; Javitt 2007), and not only positive symptoms as observed following the administration of amphetamines, which are mainly dopaminergic enhancers (Hoffman and Lefkowitz 1995). Furthermore, several genetic risk factors converge on NMDA receptors (Harrison and Weinberger, 2005). Recently, sorne studies also demonstrated that SGA could alleviate symptoms (Malhotra et al. , 1996) and neurotransmission changes produced by glutamate antagonists (Amarg6s Bosh et al. , 2006). Current knowledge about glutamatergic system in SZ suggests that there is possibly a NMDA hypofunction which leads to dopaminergic dysfunctions and then, to positive, negative, and cognitive symptoms of the illness (Stahl 2007).

Insert table 2.2 about here Traitements adjuvants: Revue 38

Glycine

Glycine or (H02CCH2NH2) is a non-essential aminoacid biosynthesized in the body from the amino acid serine. 1t is also an inhibitory neurotransmitter in the CNS, particularly in the spinal cord, brainstem, and retina. Glycine is a glutamate agonist of NMDA receptors. While it has an inhibiting effect in the spinal cord, glycine has an excitatory effect on the NMDA glutamatergic receptors.

Table 2.2 displays the results obtained by Evins et al. (2000) who used a parallel group design to test over an 8-week period the effect of 60 gram/day dose of glycine in 30 clozapine treated patients. They observed no difference between glycine and placebo treated patients on a neuropsychological battery spanning language and general knowledge, verbal working memory, verbal leaming and memory, inhibition processes, visual perceptual and praxis skills, and motor speed. Of the two participants who dropped-out during glycine treatment, no adverse events were imputed to the compound.

Lamotrigine Lamotrigine or (6-(2, 3-dichlorophenyl)-I, 2, 4-triazine-3, 5-diamine) is a glutamate antagonist. 1t acts on sodium channels to stabilize neuronal membranes and to inhibit the glutamate release.

Table 2.2 summarizes the three studies that studied lamotrigine to placebo using a parallel placebo-controlled design (Goff et al., 2007 (two studies); Zoccali et al. , 2007). The two multi-center studies by Goff et al. (2007(N = 209; N = 210)) used similar methods; they included participants treated with any available SGA and lasted 12 weeks. The 24 week long Zoccali et al. 's study (2007) included 51 clozapine-treated patient recruited from a single university hospital.

Goff et al.' striais (2007) used tthe Brief Assessment of Cognition in Schizophrenia (BACS) which spans verbal working and episodic memory, alphabetic and semantic verbal fluency, speed of information processing, planning abilities and motor dexterity and speed Traitements adjuvants: Revue 39

as weIl as measures of verbal episodic memory and of inhibition processes added to the BACS. Zoccali et al. (2007) assessed lexical verbal fluency, inhibition processes and abstraction.

Two of the three studies revealed a positive effect of lamotrigine on cognition in SZ when compared with placebo. Indeed, lamotrigine significantly improved the BACS composite score (Goff et al. , 2007) as well as the Stroop and verbal semantic fluency performances (Zoccali et al., 2007). However, the Stroop effect was no longer significant when a Bonferroni correction was applied to statistics. Taken together, theses results indicate that lamotrigine could improve cognitive functions, particularly verbal fluency, in patients with SZ.

Comparable rates of participants experienced adverse events in lamotrigine and placebo groups as reported by Goff et al. (2007). Sorne serious adverse events occurred in both studies of Goff, with an equivalent frequency in the lamotrigine and the placebo groups. Serious adverse events were almost exclusively a worsening of psychiatrie symptoms. N evertheless, one suicide attempt occurred in study 1 of Goff et al. (2007), and was considered by the investigator as possibly related to lamotrigine. On the other hand, Zoccali et al. (2007) reported 4 drop-outs, one ofthem occurred following the apparition of a rash. However, taken together, these studies included more than 450 participants; thus, lamotrigine can be considered as a relatively safe compound when co-administered with SGA to psychotic patients.

Ampakine CX516 The "ampakines" are a family of compounds that act as positive modulators at the AMP A receptors' sites by increasing the peak and duration of glutamate-induced receptor gated inward currents (Goff et al., 2001). Ampakine CX516 or (L-(quinoxalin-6- ylcarbonyl)piperidine) is thus a modulator of the AMP A receptors. Traitements adjuvants: Revue 40

Methodological details and results obtained in the two studies reviewed using ampakine CX516 as putative adjunct treatment for cognitive impairments in SZ are presented in Table 2.2 (Goff-et al. , 2001 ; 2008). The study of Goff et al. (2008) used a parallel-group design to compare the effect of ampakine CX516 900 mg/day, with placebo in clozapine-, olanzapine-, and risperidone-treated SZ patients. One hundred five patients were randomised to ampakine CX516 and placebo conditions, and 95 of them completed this 8-week trial. A comprehensive neuropsychological battery was used to assess several cognitive functions: verbal and visual episodic memory (CVLT, WMS-III faces and family pictures subtest), verbal working memory (letter-number span), verbal lexical and semantic fluency (FAS and animaIs), sustained attention (DS-CPT), cognitive flexibility (TMT), abstraction abilities (WCST), and manual dexterity (grooved pegboard).

The second study about ampakine CX516 was a pilot study (Goff et al. , 2001). A parallel-group design was also used in this study, but the participants were exclusively treated with clozapine. Eighteen participants completed this 6-week trial, in which a daily dose of 2700 mg/day of ampakine CX516 was tested. Several neuropsychological tasks were used in this pilot study that are known to assess verbal and visuospatial working and episodic memory (WMS-III, Randt 5-item acquisition test, complex figures tests), speed of information processing (SKT), sustained attention (GDS), cognitive flexibility (TMT), abilities in reading, spelling, and arithmetic (WRA T -R), abstraction abilities (WCST), as weIl as verbal fluency, and motor speed (finger tapping test).

The findings obtained in these two studies were controversial. In the recent study (Goff et al., 2008), observed cases (N=95) and LOCF (N=105) statistical analyses were used to detect differences between the groups. The results indicated that there was no difference between groups in terms of cognitive improvement on any of the cognitive composite scores at week 4, and at week 8 of the trial. However, results from the study of Goff et al. (2001) were more promising. Indeed, Cohen' s d calculations revealed sorne large and moderate effects in favour of ampakine CX516, compared to placebo. Thus, a large effect was observed on a measure of verbal episodic memory, and moderate effects Traitements adjuvants: Revue 41

were observed on tasks measurlng sustained attention, visual episodic memory, and cognitive flexibility.

Regarding safety and tolerability of ampakine CX516, results are different according to the study. In the study of Goff et al., (2008) a comparable number of participants dropped-out in both treatment conditions. However, ampakine-treated patients reported significantly more insomnia, fatigue, heartbum and abdominal discomfort than , patients under placebo. Furthermore, four serious adverse events' occurred in the placebo group while only one occurred in the ampakine group. This last adverse event was due to a cessation of antipsychotic treatment which led to hospitalisation. Therefore, safety and tolerability of ampakine, were not optimal. However, in the study of Goff et al. , (2001), one out of the 19 participants dropped-out due to hypertension, and no other ampakine imputable effect were observed on laboratory tests or electrocardiograms.

Memantine Memantine or (3 , 5-dimethyl-1-adamantanamine) or 3, 5-dimethyl-tricyclo[3, 3, 1, 3 1 , 7]decan-1-amine) is an uncompetitive NMDA receptor antagonist. Memantine has moderate affinity for the receptor, and fast blocking-unblocking kinetics (Parsons 1999). Memantine rapidly leaves NMDA channel upon transient physiological activation but blocks receptor under pathological conditions, thus preventing glutamate toxicity (Danysz et al., 2000).

One study using this compound was reviewed (Cerullo et al. , 2007). Methodological details of this study are presented in Table 2.2. This study, using fMRI, was primarily designed to verify if memantine normalizes the brain activity in SGA-treated SZ patients. This study also included age and education-matched healthy controls. This pilot study was part of a multicenter double-blind clinical trial of memantine augmentation. Seven SZ participants, three receiving memantine, and four receiving placebo, took part in the fMRI testing. No adverse events were reported. Memantine was adjunct to olanzapine, risperidone and ziprazidone. fMRI image acquisition occurred at three different moments Traitements adjuvants: Revue 42

(baseline, week 1, and week 8) while participants were performing a working memory task (n-back paradigm). The results indicated that there was no difference between SZ participants taking memantine and those taking placebo in reaction times and accuracy, in all the experimental conditions (0-, 1-, 2-, 3-back) of the n-back task.

Norepinephrine as a targetfor cognition N orepinephrine (also called noradrenaline) is a catecholamine acting as neurotransmitter and hormone. In the CNS, the noradrenergic cells principally originate from the lateral reticular formation (lateral tegmentum), and from the locus coerulus. The reticular formation innervates the hypothalamus, amygdaloid body and sorne other areas, related to the limbic system via the medial forebrain bundle. The locus coerulus innervates the forebrain, cerebellum, and spinal cord (Heimer 1983). Norepinephrine binds to four families of receptors: alpha 1, alpha 2, beta 1 and beta 2 receptors (a-l , a-2, ~-1 , ~.-2). Projections originating from the ventrolateral tegmental area are principally associated with sexual and feeding behaviors. Fibers originating from the locus coerulus, and projecting mainly to the pre fro ntal cortex are associated with cognitive functioning. Indeed, norepinephrine is associated with leaming and memory, as well as with selective attention. Actually; the role of norepinephrine in selective attention seems particularly important in the prevention of distractibility by irrelevant stimuli (Coull 1994, 1998). Alpha- and beta adrenergic receptors appear to have a distinct role in cognition. The a-2 adrenergic receptors are reported to be dense in the prefrontal cortex (Goldman-Rakic et al. , 1990).

Animal studies, using a-2 adrenergic receptors agonists, demonstrated that these receptors are involved in visuospatial'working memory, and visuospatial episodic memory (Amsten and Goldman-Rakic 1990). On the other hand, ~-adrenergic receptors might be involved in the long term potentiation of hippocampus (Ikegaya et al. , 1996), and are influenced by the amygdala. This potentiation is a facilitating mechanism underlying leaming and memory.

Norepinephrine and schizophrenia ln addition to dopamine, which was the neurochemical focus for several years in SZ, norepinephrine seems to be an important neurotransmitter in the pathophysiology and cognitive impairments associated with this disease (van Kammen and Kelley 1991). It is Traitements adjuvants: Revue 43 now weIl established that norepinephrine has a powerfull influence on the dopaminergic system via alpha-adrenoceptors (Li and Mei, 1994). However, as mentioned by Friedman (2002), the noradrenergic dysfunction in schizophrenia may not be homogenous in the CNS. First, sorne studies demonstrated a general (Kemali et al., 1982) and localized (Crow 1979) increased level of norepinephrine in the nucleus accumbens of SZ patients. However, this depletion was not related to cognitive function in these studies. On the other hand, Powchik et al. (1998) found a significant decrease in norepinephrine concentration in the frontal cortex of SZ patients presenting cognitive impairrnents. This last finding suggested that norepinephrine could play a role in the cognitive deficits observed in schizophrenia. Therefore, pharrnacological strategies for augmenting prefrontal norepinephrine levels may pro duce cognitive enhancement in SZ.

Insert table 2.3 about here

Atomoxetine Atomoxetine or ((-)-N-methyl-3-( o-methylphenoxy)-3-phenylpropylamine) is an unconventional psychostimulant that primary acts by a selective norepinephrine reuptake inhibition through the brain, particularly in the occipital cortex, lateral hypothalamus, dorsal hippocampus, and cerebellum (Swanson, et al. , 2006). It also increases dopamine levels in the prefrontal cortex, as a secondary mechanism of action (Bymaster et al. , 2002). Atomoxetine is indicated for the treatment of Attention Deficit/Hyperactivity Disorder (ADHD).

Currently, thete is only one placebo-controlled study available using atomoxetine in SGA-treated SZ patients (Friedman et al., 2008, see Table 2.3). In this 8-week study, 20 participants were administered atomoxetine from 40 to 80mg/day. Eight subjects in the placebo group and seven subjects in the atomoxetine group completed the post drug Traitements adjuvants: Revue 44

assessments. Neuropsychological measures included the BACS and a n-back task. As mentioned above, the BACS allowed the assessment of verbal working and episodic memory (digit sequencing, list leaming), lexical and semantic verbal fluency (COW AT and category instances), speed of information processing (symbol coding), planning abilities (Tower of London), and motor dexterity and speed (Token motor task). The n-back task was performed during an fMRI acquisition. When statistical analyses were applied on data, no significant difference was observed between the atomoxetine and the placebo groups.

Two placebo-group, and one atomoxetine-group participants withdrew their consent. Two patients discontinued atomoxetine treatment consequently to adverse side effects; one patient registered an increase in heart rate and blood pressure, and the other patient, a urinary hesitancy. Therefore, except for the cardiovascular effects reported in one patient, atomoxetine was generally weIl tolerated.

Guanfacine Guanfacine is an agoni st of alpha-2A adrenoceptors. This agent stimulates central alpha(2)-adrenergic receptors, resulting in inhibition of sympathetic nervous system outflow, reduction of peripheral and renal vascular resistance, and lowering of blood pressure and heart rate. Guanfacine is generally used as an antihypertensive agent. Its pharmacological mechanism, known to increase norepinephrine, led sorne research groups to test it as a cognitive enhancer.

ln the SZ literature, there is one report on the effect of guanfacine treatment for cognitive impairments (Friedman et al., 2001 , see Table 2.3). This parallei group study, involving 40 patients with SZ, measured the effect of guanfacine with doses up to 2mg/day. Participants were assessed at baseline and after 4 weeks of treatment with placebo or guanfacine. The neuropsychological battery included measures of verbal and visuospatial working memory (digit span distraction test, simple spatial working memory task), verbal episodic memory (RA VL T), selective and sustained attention (digit span distraction test, TMT A, CPT), cognitive flexibility (TMT B) and semantic verbal fluency (animaIs). This study was primarily designed to assess the cognitive impact of guanfacine on cognition in Traitements adjuvants: Revue 45

FGA- and SGA-treated SZ, but a separate statistical analysis was realized on the data from eleven participants treated exclusively with the help of risperidone. The results indicated that in risperidone-treated SZ, guanfacine significantly improved performance of the visuospatial wO'rking memory. No serious adverse events were reported and 38 out of 40 participants completed the trial.

Serotonin as a target for cognition Serotonin (5-HT) fibers originate from the brainstem raphe nuclei and project to a large number offorebrain structures (Heimer 1983). Sorne ofthem are involved in the sleep cycle, pain perception, mood and emotional regulation. Serotonin also plays a role in cognition. The cerebral cortex, the hippocampus, septum and amygdala, are densely innerved by serotonergic fibers (Azmitia 2001; William et al. , 2002; Wilson et al. , 1991). Serotonin has interactions with various families and subtypes of 5-HT receptors. Studies with healthy volunteers suggest that several cognitive processes are influenced by levels of serotonin in the brain. Indeed, serotonin could be involved in leaming and memory (Ogren et al., 2008), and attentional processes (Winger et al., 2008). Furthermore, different subtypes of 5-HT receptors are associated with different cognitive functions. For exemple, the 5-HT1A receptors, which are concentrated in the hippocampus, lateral septum, and the cortex (particularly the cingulate and enthorhinal areas), seem to be important for memory, and attentional processes (Roth et al., 2004). The 5-HT2A re'ceptors are concentrated in the cortical layer V of pyramidal neurons, and seem to be involved in the integration of perceptual information (William et al., 2002) .

.Insert table 2.4 about here

Serotonin and schizophrenia Even if the serotonergic system is not primarily known to play an important role in the pathogenesis of SZ and SZSPD, sorne evidence conceming a serotonergic dysfunction are available. Post-mortem studies reported an increased number of 5-HT lA in frontal and Traitements adjuvants: Revue 46 temporal cortices of SZ patients (Bumet et al., 1996; Gurevich and Joyce 1997). Because augmentation of the density of receptors may represent an up-regulation subsequent to a decreased concentration of a neurotransmitter, subsequent studies investigated the binding of serotonin on 5-HT1A receptors in these areas. Kasper's (2002) and Tauscher's (2002) groups used positron emission tomography technique to study the 5-HT1A in vivo, in drug naive patients with SZ. The results of both studies revealed an increased cortical 5-HT1A binding in patients, when compared to healthy controls. Taken together, the previous findings suggest that SZ pathophysiology could include decreased serotonin liberation in cortex, which results in an up-regulation of 5-HT receptors. Because serotonin is associated with memory and attention, pharmacological strategies to improve serotonin neurotransmission in cortex could result in improvements in these cognitive functions.

Buspirone Buspirone or (8-[ 4-[ 4-(2-pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[ 4, 5]decane-

7, 9-dione (hydrochloride)), is an azapirone derivate and 5-HT1A partial agonist. It is also a weak dopaminergic antagonist.

Sumiyoshi and colleagues (2007, see Table 2.4) studied the cognitive impact of buspirone, using a parallei group design, in a sample of SZ participants. Buspirone was titrated up to 30mg/day and participants were cognitively assessed at baseline, and at 3 and 6 months following baseline. Neuropsychological assessments included measures of verbal working and episodic memory (ACT, CVLT), speed of information processing (digit symbol substitution WAIS-R subtest), abstraction processes (WeST), and alphabetic and semantic verbal fluency (COWAT, category instances). In comparison to placebo, buspirone significantl y improved speed of information processing at month 3, but not at month 6. Other measures did not reach significance at 3 and 6 months post-test. Of the 73 participants involved at baseline, 14 dropped-out after baseline. Among the 14 cases who discontinued the trial, three patients withdrew consent because of headaches, while the other reasons are not related to side effects (e.g. incarcerations, refusaI to have further cognitive testing or to continue the research, non-compliance to treatment). Buspirone could then be considered as safe and weIl tolerated. Traitements adjuvants: Revue 47

Other neurotransmission systems and schizophrenia

Insert table 2.5 about here

Dehydroepiandrosterone Dehydroepiandrosterone (DHEA) or prasterone is a hormone available in the organism and a precursor of androgenic and oestrogenic steroids. Experimental studies demonstrated its beneficial effects on obesity, anti-aging, diabetes, osteoporosis and its utility in the management of mood (Cormier, Souverbielle, and Kahan, 2001 ; Flynn, Weaver-Osterholtz, Sharpe-Timms, Allen, and Krause, 1999; Herbert 1998; Zhang, et al. , 1999). Since studies demonstrated that DHEA blood levels in SZ are different, sometimes below normal, sometimes above normallevels (Harris et al. , 2001 ; Ristner et al. , 2005), the interest for this hormone has grown. In a placebo-controlled augmentation study, DHEA 100 mg/day was found to be effective for the treatment ofnegative, depressive, and anxious symptoms in inpatients schizophrenie patients (Strous et al., 2003). The same group of researchers then got interested in the effect of this hormone on cognitive functioning in SZ (Strous et al., 2007). In the study of Strous et al. (2007) presented in Table 2.5 , placebo and DHEA were administered orally, with doses from 50 mg/day up to 150mg/day. Participants were assessed at baseline and after 12 weeks of DHEA treatment. Nine drop-outs occurred, five in the placebo, and four in the DHEA groups. On two occasions, the discontinuation was due to clinical deterioration not considered to be related with the study compound. Patients, were assessed with alternate forms of a computerized cognitive battery, the Mindstreams Computerized Cognitive Test Battery and also with other tasks. The cognitive battery allowed the measurement of verbal and visuospatial episodic memory, inhibiting processes (go-no go response inhibition, Stroop test), and speed of information processing (staged information processing speed test). A statistical analysis revealed no significant difference between placebo and DHEA groups on post-test cognitive functioning. Traitements adjuvants: Revue 48

Conclusions There is a growing body of pharmacological trials for the treatment of cognitive impairments associated with SZ and psychotic disorders. This paper reviewed the results of randomized double-blind placebo-controlIed clinical trials published from January 1996 to March 4th 2008, in patients treated exclusively with SGA, and an adjunct·nootropic.

Currently, ChEI are the compounds for which there is the largest volume of literature available. Several preliminary studies and case· reports found that these molecules could be beneficial for the treatment of cognitive dysfunction in SZ (Bora et al. , 2005 ; Buchanan et al., 2003; Lenzi et al., 2003; Raguraman et al., 2005). However, the results of subsequent randomized double-blind placebo-controlIed trials were, as reviewed herein, less promising. Indeed, of the nine studies reviewed, only one demonstrated an improvement folIowing galantamine administration in comparison with placebo (Schubert et al., 2006). The other study using galantamine led, on the other hand, to negative results involving deteriorations on several cognitive measures (Dyer et al., 2008).

Regarding donepezil, aIl results were negative or in favour of placebo. Although almost two out of five studies were probably underpowered, the studies of Friedman and colIeagues (2002, 2007) respectively included data of 36 and 226 participants in the statistical analyses. Two out of these four studies included more than 15 participants in each treatment, with one of them included a total of 226 participants (Friedman et al. , 2007). AlI of them reported negative results or results in favour of placebo, what alIow to conclude that donepezil is not efficacious for the treatment of cognitive impairments in SZ, and that there is no need for further studies about this compound.

Regarding 'rivastigmine, the three studies reviewed herein also led to negative findings. Two out of three trials were principalIy interested in the neural correlates of cognitive functions, using fMRI, folIowing the administration of rivastigmine. Only one study reported the effects of rivastigmine on a comprehensive neuropsychological battery. The sample sizes were relatively modeste Considering a possible role of underpowered Traitements adjuvants: Revue 49 statistical analyses for negative results, further studies using larger samples are needed to determine the potential efficacy of rivastigmine for the treatment of neurocognitive impairments in SZ and SZSPD.

Regarding galantamine, the results of the two studies were conflicting. Improvements were noted on composite scores of general cognitive functioning, attention, and delayed memory, whereas deteriorations were observed on tasks of working memory and inhibition. However, these two studies used small samples what indicates that further studies must be designed using larger samples.

The last findings are coherent with the results reported in mild-to-moderate Alzheimer' s disease where measures of working memory did not register significant . improvement following the administration of ChEI (Simard and van Reekum 1999; for a review). Catecholamines in general, and espécially dopamine, are more associated than acetylcholine with the functioning of working memory (Cools et al., 2008; Robbins and Roberts 2007), whereas acetylcholine is more associated than catecholamines in episodic memory functions (Gron et al. , 2005; Hasselmo 2006). Therefore, a biological rationale could perhaps explain the lack of efficacy of the ChEI on sorne tasks used in the trials for SZ described in the present review. In addition, it is possible that a compound may impact differently on various cognitive functions, and it may also impact differently on various tasks measuring the same cognitive function, depending on the respective sensitivity of these tasks. Therefore, the use of cognitive composite scores, although appealing to avoid multiple testing in small sample, might alter the capacity to observe and explain subtle cognitive changes following the administration of a cognitive enhancer. Future placebo controlled trials using galantamine and other ChEI in SZ will benefit from the inclusion of large samples, the utilization of specific neurocognitive measures sensitive to episodic memory, and allowing independent observations to as certain the efficacy of ChEI for treatment of cognitive impairments in SZ. Traitements adjuvants: Revue 50

Since the beginning of the second millennium, glutamatergic compounds have led to a growing interest as putative cognitive enhancers in SZ. In this paper, six trials were reviewed that assessed the effects of glycine, lamotrigine, memantine, and ampakine CX516 on cognition.

Regarding glycine, there were sorne papers available reporting its clinical effects, but only one article reported the impact of glycine on cognition in clozapine-treated patients. Although the authors of the study administered a comprehensive neuropsychological battery, the results were negative. The small sample size of this trial, may have induced a lack of power, and thus the negative results. Furthermore, only clozapine-treated patients were included; clozapine together with olanzapine are the only SGA blocking ACh muscarinic receptors (Shiloh et al. , 2000). This action might be deleterious for cognition and perhaps could not be compensated by the action of cognitive enhancers such as glycine. Consequently, these results were possibly not representative of the effects of glycine in aIl SGA-treated patients with SZ.

Lamotrigine was tested in three studies involving over 50 participants. Noteworthy, two of them included more than 200 participants. Two out of these three trials revealed positive effects of lamotrigine on a composite score of general cognitive functioning, as weIl as on verbal fluency. These results justify the pursuit of clinical trials about the use of lamotrigine for neurocognitive dysfunctions in SZ and SZSPD.

The trial on memantine (Cerullo et al., 2007) and the trial on ampakine CX516 (Goff et al., 2008) both registered negative findings. While the results of the memantine study could have been caused by . a lack of power due to sm aIl sample size, the negative findings of the ampakine CX516 could be due to. suboptimal dose. lndeed, in the study of Goff et al (2001), results was positive on several neuropsychological tasks but the dose was of 2700 mg/day instead of 900 mg/day as in Goff et al .(2008) study. Furthermore, positive results were obtained in a sample including exclusively clozapine-treated patients, which could indicate a positive interaction between clozapine and ampakine CX516 for the Traitements adjuvants: Revue 51 treatment of neurocognitive impairments. Because the effects of memantine were not assessed in large groups, further studies are needed. Regarding ampakine, even if negative results were obtained in a large sample (Goff, et al. , 2008), the susmentionned considerations about dosage and antipsychotic treatment following results from Goff et al. (2001) should encourage future studies using ampakine in order to confirm its effect on cognition in SZ patient~.

Studies interested in putative noradrenergic cognitive enhancers and meeting the selection criteria of the present review were scarce. Only one study on atomoxetine and another study on guanfacine were reviewed herein. Friedman et al. (2008) conducted the first randomized double-blind placebo-controlled trial on atomoxetine in SZ patients, which revealed no significant advantage of atomoxetine over placebo. However, the sample size was small, and the participants involved in this study were taking different SGA, whereas the cognitive battery was extensive, allowing the measurement of several cognitive functions. Possibly, the heterogeneity of the sample in terms of antipsychotic treatement, combined with a lack of statistical power led to negative results between the atomoxetine treated and placebo groups on the cognitive measures. Since the efficacy of this molecule to treat cognitive impairments associated with ADHD is known, it will doubtless lead to a growing research interest for this compound in SZ. Indeed, cognitive impairments described in SZ and ADHD are frequently related to alteration of the prefrontal areas, and could be at least partially due to decreased concentrations of norepinephrine and dopamine in these particular areas of the brain (Goldman-Rakic et al., 2004; Levy 2008; Powchick et al., 1998). Because atomoxetine mainly acts as an agoni st of norepinephrine and dopamine in the prefrontal cortex, there is a strong biological rationale for its efficacy on SZ patients. ln the future, studies involving larger samples than that involved in the Friedman et al' s trial should be performed using atomoxetine and measures of working memory and attention.

The study on another noradrenergic · cognitive enhancer, guanfacine, was not primarily designed to test the impact of this agent on SGA-treated patients. This fact perhaps explains the small sample size; However, despite the possible lack of statistical Traitements adjuvants: Revue 52 power, the results indicated that, compared with placebo, the guanfacine-treated patients registered an improvement in visuospatial working memory functions. Considering the small nurnber of participants and the positive results obtained, further studies using a comparable design and a largest sample are strongly recommended.

Serotonergic adjunct treatments are not, for the moment, weIl studied, perhaps because the biological rationale for its utilization in schizophrenia is not as strong as it is with norepinephrine. Sumiyoshi et al. (2007) conducted the only clinical trial meeting the selection criteria of the present review, and investigating the effect on cognition of a serotonergic adjunct, buspirone. This study involved a large nurnber of participants treated with various SGA, and assessed with several cognitive measures. The authors found a positive impact of buspirone on speed of information processing at three months post baseline. However, the patients did not maintain this improved level of functioning until the end of the study. Other trials using this compound will be necessary to better understand the effect of buspirone on speed of information processing, and on other cognitive functions.

Finally, Strous et al. (2007) investigated the impact of DHEA, a hormone, on cognition in SZ patients. As other studies included in this review, this study was weIl designed, but the neuropsychological assessment was restricted to sorne episodic memory and executive functions. Furthermore, the sample size was relatively small. This trial did not reveal any positive effect of DHEA over placebo on the cognitive measures. The negative results were perhaps caused by the lack of cognitive measures sensitive to the effects ofDHEA. A recent study conducted in 295 women, from community, and aged 21-

77 yearsold, revealed that women with a DHEA sulphate level in the ~ighest tertile and who had more than 12 years of education performed better than other women on Digit Span Forward and Digit Span Backward tests which are measures of attention and working memory (Davis et al. , 2008). This compound will have to be studied in future trials including more participants and cognitive tasks, which will allow, in case of positive results, to better understand the implication of DHEA in SZ and cognition. Traitements adjuvants: Revue 53

To date, and despite sorne positive results obtained with sorne compounds on a few cognitive functions, there is no powerful evidence in favour of sorne adjunct cognitive enhancers for the treatment of cognitive impairments in schizophrenia. AlI the studies reviewed had in common important strengths that validated these clinical trials. Pirst, the duration of the titration and treatment phases was always established according to the known mechanisms of action of each compound. Second, the participants included in the samples were generally aged from 18 to 60 years old. This particularity allowed the generalization of data to a larger demographic SZ population and, at the same time, prevented the inclusion of participants suffering from neurodegenerative and/or other neurological conditions invoiving a cognitive deterioration. Third, almost an studies included a graduaI titration lasting from 4 to 6 weeks, as opposed to the usual 2-week titration phase adopted in most clinical settings. This procedure prevented excessive drop outs due to the occurrence of side effects. It is thus very much unlikely that the negative findings reported in the reviewed studies were due to a lack of safety of the cognitive enhancer or to dangerous drug interactions with the SGA, since very few drop-outs occurred due to adverse events related to the compounds.

On .the other hand, several papers reviewed presented limitations that could potentially explain the lack of positive effects of the agents. Several of these studies were underpowered due to small sample sizes, and were short lasting (from 4 to 24 weeks). It is very well-known that treatment protocols involving two and more compoundsare clinically and technically challenging in the SZ population, in terms of recruitment, drug interactions, co-morbid medical conditions, monitoring and compliance to the protocol. The usefulness of a. cross-over design shall be considered in the future in this kind of studies. This design allows the recruitment of a modest number of participants and limits the impact on statistical power (Létourneau, et al., 2008, paper in preparation, see Chapter 4; Senn 2002).

Furthermore, while sorne of the studies reviewed used a comprehensive neuropsychological battery, many trials rather used a limited number of cognitive tests. Tasks with good sensitivity/specificity for the cognitive function known to be impaired in SZ and/or known to be associated with the neurotransmitter targeted by the compound Traitements adjuvants: Revue 54

under study shall be included in trials aimed at investigating the efficacy of adjunct cognitive enhancers. In this perspective, the recent MATRICS Consensus Cognitive Battery (MCCB) (Nuechterlein and Green, 2006) was developped to standardize the cognitive assessment in SZ research. This battery includes well-validated sensitive tasks to evaluate the main cognitive functions known to be altered in SZ, i.e. speed of information processing, attention/vigilance, verbal and non-verbal working memory, verbal and visual learning, reasoning and problem solving, and social cognition with well-validated sensitive tasks. Beside · the MATRICS battery, other validated batteries are available to assess schizophrenic patients (BACS, RBANSS). Relying on su ch cognitive assessment guidelines in future studies will ease the comparison and the pooling of results across studies

One should also mention that due to the inherent heterogeneity of schizophrenia (Hill et al. , 2002; Roy et al., 2001; Seaton et al., 2001), variability will inevitably occur in the way patients will respond to treatments. In addition, it is very difficult to control aIl the confounding parameters. However, sorne variables, such as the baseline level of cognitive impairment, tobacco smoking and the type of antipsychotic prescribed should always be controlled for. lndeed, many reports suggest that results could vary according to these characteristics in the SZ population. Considering the severity of the baseline level of impairment could allows to conclude that a compound is more efficient · in patients for whom deficits are more important, as observed by Spence et al. (2005). Furthermore, statistically controlling .for tobacco use is especially recommended when SZ patients are treated with ChEls, since tobacco use can interact with these nootropics by disentitizing ACh nicotinic receptors (Friedman et al., 2002). Regarding the control of the prescribed antipsychotic, it is important to keep in mind that even if SGA have common chemical properties, their individual modes of action remain relatively different from one compound to another. For example, sarcosine seems to be ineffective in clozapine-treated patients in comparison to other antipsychotics (Javitt 2008).

Even if aIl compounds used in the reviewed studies were selected using a biological rationale, sorne of them seem more promising than others for treatment of cognitive Traitements adjuvants: Revue 55

impairments in SZ, as buspirone and lamotrigine for example. However, most compounds reviewed herein rather fall into a second category, the category of eompounds for which the majority of the trials seemed underpowered, indicating that further trials using larger samples are needed. This is the case of cholinergie (rivastigmine and galantamine), glutamatergic (glycine, memantine and ampakine) and noradrenergic (atomoxetine, guanfacine) compounds. Onthe other hand, results obtained with the ChEls were much less promising. Perhaps rivastigmine and galantamine could register positive results should they be investigated in studies using larger samples and the most sensitive measures of episodic memory. However, donepezil was tested in well-designed studies using large samples and led·to negative results.

Cognitive enhancement in patients with SZ rernains a critical and clinieal challenge. The results of the studies reviewed in this paper provide sorne crucial discoveries. These findings will allow the clinicians to achieve an important goal in the future treatment of SZ, the improvement of global functioning of their patients. Traitements adjuvants: Revue 56

References

Aasen , I. , Kumari, V. , Sharma, T. (2005). Effects of rivastigmine on sustained attention in schizophrenia: an FMRI study. Journal of Clinical Psychopharmacology.25, 31 1-317.

Adler, L. E., Hoffer, L. J., Wiser, A., Freedman, R. (1993). Normalization of auditory physiology by cigarette smoking in schizophrenic patients. American Journal of Psychiatry, 150, 1856-1861.

Amarg6s-Bosh, M., L6pez-Gil, X. , Artigas, F. , Adell, A. (2006). Clozapine and olanzapine, but not haloperidol, suppress serotonin efflux in the medial prefrontal cortex elicited by phencyclidine and ketamine International Journal of Neuropharmacology, 9, 565-573.

American Psychiatric Association (1994). Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association.

Arnstein, A. F. , Goldman-Rakic, P. S. (1990). Analysis of alpha-2 adrenergic agonists effects on the delayed nonmatch-to-sample performance in aged rhesus monkeys. Neurobiology ofAging 11, 583-590.

Azmitia, E. C. (2001). Modem views on an ancient chemical: serotonin effects on cell proliferation, maturation, and apoptosis.Brain Research Bulletin, 56, 413-424.

Barr, R. S., Culhane, M. A., Jubelt, L. E. , Mufti, R. S., Dyer, M. A. , Weiss, A. P., Deckersbach, T., Kelly, J. F., Freudenreich, O., Goff, D. C., Evins, A. E. (2008). The effects of transdermal nicotine on cognition in nonsmokers with schizophrenia and nonpsychiatric controls. Neuropsychopharmacology 33, 480-490.

Bennett, J. P., Enna, S.1., Bylund, D. B., Gillin, C., Wyatt, R. J., Snyder, S. H. (1979). N eurotransmitter receptors in frontal cortex of schizophrenics. Archives of General Psychiatry, 36, 927-934.

Bilder, R. M., Goldman, R. S., Robinson, D., Reiter, G., Bell, L., Bates, J. A. , Pappadopulos, E., Wilson, D. F., Alvir, J. M., Woemer, M. G., Geisler, S., Kane, J. M., & Lieberman, J. A. (2000). Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates. American Journal of Psychiatry, 157, 549-559.

Bora, E., Veznedaroglu, B., Cayahan, B. (2005). The effect of galantamine added to clozapine on cognition in five patients with schizophrenia. Clinical Neuropharmacology, 28, 139-141. Traitements adjuvants: Revue 57

Breier, A. , Schreiber, J., Dyer, J" Pickar, D. (1991). NIMH longitudinal study of chronic schizophrenia: prognosis and predictors of. outcome. Archives of General Psychiatry, 48, 239-246.

Buchanan, R. W., Conley, R. R. , Dickinson, D., BaIl, M. P. , Feldman, S. , Gold, J. M. , McMahon, R. P. (2008). Galantamine for the treatment of cognitive impairments in people with schizophrenia. American Journal ofPs ychiatry, 165, 82-89.

Buchanan, R. W., Javitt, D. C. Marder, S. R. , Schooler, N. R., Gold, J. M., McMahon, R. P. , Heresco-Levy, D., Carpenter, W. T. (2007). The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. American Journal ofP sychiatry, 164, 1593-1602.

Buchanan, R. W., Summerfelt, A., Tek, C., Gold, J. (2003). An open-Iabeled trial of adjunctive donepezil for cognitive impairment patients with schizophrenia. Schizophrenia Research, 59, 29-33.

Bumet, P. W. J., Eastwood, S. L., Harrison, P.J. (1996). 5-HT1A and 5-HT2A receptor mRNAs and binding site densities are differentially altered in schophrenia. Neuropsychopharmacology, 15, 442-455.

Bymaster, F. P., Katner, J. S., Nelson, D. L. , Hemrick-Luecke, S. ' K. , Threlkeld. P. G. , He~ligenstein , J. H., Morin, S. M., Gehlert, D. R. , Perry, K. W. (2002). Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology, 27, 699-711.

Cardozo, M. G., Kawai, T., Iimura, Y., Sugimoto, H. , Yamanishi, Y., Hopfinger, A. J. (1992). Conformational analysis and molecular shape comparisons of a series of indanone-benzylpiperidine inhibitors of acetylcholinesterase. Journal of Medicinal Chemistry, 35, 590-601.

Cerullo, M. A. , Adler, C. M., Strakowski, S. M. (2007). Memantine normalizes brain activity in the inferior frontal gyrus: a controlled pilot fMRI study. Schizophrenia Research, 97, 294-296.

Chouinard, S., Stip, E., Poulin, J. , Melun, J. P., Godbout, R., Guillem, F., Cohen, H. (2007). Rivastigmine treatment as an add-on to antipsychotics in patients with schizophrenia and cognitive deficits. Current Medical Research and Opinion, 23, 575-583.

Cools, R. , Gibbs, S. E., Miyakawa, A., Jagust, W., D'Esposito, M. (2008). Working memory capacity predicts dopamine synthesis capacity in the human striatum. Journal ofNeurosciences , 28, 1208-1212. Traitements adjuvants: Revue 58

Cormier, C., Souberbielle, J. C., & Kahan, A. (2001). DHEA in bone and joint deseases. Joint Bane Spine, 68, 291-297.

Coull, J. T. (1994). Pharmacological manipulations of the alpha 2-noradrenergic system. Effects on cognition. Drugs Aging, 5, 116-126.

Coull, J. T. (1998). Neural correlates of attention and arousal: insights from electrophysiology, functional neuroimaging and psychopharmacology. Progress in Neurobiology, 55, 343-361. .

Crook, J. M., Tomaskovic-Crook E, Copolov, D. L., Dean, B. (2000). Decreased muscarinic receptor binding in subjects with schizophrenia: a study of the human hippocampal formation. Biological Psychology, 48, 381-388.

Crook, J. M., Tomaskovic-Crook, E. , Copolov, D. L. , Dean, B. (2001). Decreased muscarinic receptor binding in pre frontal cortex from subj ects with schizophrenia: a study of Brodmann' s areas 8, 9, 10, and 46, and the effects of neuroleptic drug treatment. American Journal ofPsychiatry , 158, 918-925.

Crow, T. J., Baker, H. F. , Cross, A. J. , Joseph, M. H., Lofthouse, R., Longden, A. , Owen, F. , Rileu, G. J. , Glover, V., Killpack, W. S. (1979). Monoamine mechanisms in chronic schizophrenia:post-mortem neurochemical findings. British Journal of Psychiatry, 134, 249-256.

Danysz, W., Parsons, C. G. , Mobius, H. J. , Stoffler, A. , Quack, G. (2000). Neuroprotective and symptomatological action of memantine relevant for Alzheinier' s disease- a unified glutamatergic hypothesis on the mechanism of action. Neurotoxicity Research, 2, 85-97.

Davis, S. R., Shah, S. M., McKenzie, D. P., Kulkami, J., Davison, S. L. , Bell, R. J. (2008). Dehydroepiandrosterone sulphate levels are associated with more favourable cognitive function in women. Journal of ClinicaJ Endocrinology and Metabolism, 93, 801-808.

Dean, B., Crook, J. M., Opestkin, K., Hill, C., Keks, H., Copolov, D. L. (1996). The density of muscarinic Ml receptors is decreased in the caudate-putamen of subjects with schizophrenia. Molecular Psychiatry,l, 54-58.

Dean, B., Crook, J. M., Pavey, G., Opeskin, K., Copolov, D. (2000). Muscarinic1 and 2 receptor mRNA in the juman caudate-putamen: no change in ml mRNA in schizophrenia. Molecular Psychiatry, 5, 203-207.

Dépatie, L. , O'Driscoll, G. A., Holahan, A.-L. V., Atkinson, V., Thavundayil, J. Z. , Ng Ying Kin, N., LaI, S. (2002). Nicotine and behavioural markers of risk for schizophrenia: a double-blind, placebo-contolled, cross-over study. Neuropsychopharmacology, 27, 1056-1070. Traitements adjuvants: Revue 59

Duncan, E. J. , Szilagyi, S. , Schwartz, M. P. , Bugarski-Kirola, D., Kunzova, A. , Negi, S., Stephanides, M., Efferen, T. R., Angrist, B., Peselow, E. , Corwin, J. , Gonzenbach, S. , Rotrosen, J. P. (2004). Effects of D-cycloserine on negative symptoms in schizophrenia. Schizophrenia Research, 71, 2-3.

Dyer, M. A. , Freudenreich, O., Culhane, M. A. , Pachas, G. N., Deckersbach, T. , Murphy, E. , Goff, D. C., Evins, A. E. (2008). High-dose galantamine augmentation inferior to placebo on attention, inhibitory control and working memory performance in nonsmokers with schizophrenia. Schizophrenia Research, 102, 88-95.

Ehrenreich, H., Hinze-Selch, D., Stawicki, S. , Aust, C. , Knolle-Veentjer, S. , Wilms, S. , Heinz, G. , Erdag, S. , Jahn, H. , Degner, D., Ritzen, M., Mohr, A., Wagner, M., Schneider, U., Bohn, M., Huber, M., Czemik, A., Pollmacher, T., Maier, W., Siren, A. L., Klosterkotter, J., Falkai, P. , Ruther, E., Aldenhoff, J. B., Krampe, H. (2007). Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Molecular Psychiatry, 12, 206-220.

Erhardt, S., Schwieler, L. , Nilsson, L., Linderholm, K. , Engberg, G. (2007). The kynurenic acid hypothesis of schizophrenia. Physiology and Behavior, 92, 203-209.

Erickson, S. K. , Schwarzkopf, S. B., Palumbo, D., Badgley-Fleeman, J. , Smimow, A. M. , Light, G. A. (2005). Efficacy and ' tolerability of low-dose donepezil in schizophrenia. Clinical Neuropharmacology, 28, 179-184.

Evins, A. E., Amico, E., Posever, T. A., Toker, R. , Goff, D. C. · (2002). D-Cycloserine added to risperidone in patients with primary negative symptoms of schizophrenia. Schizophrenia Research, 56, 19-23.

Evins, A. E., Fitzgerald, S. M. , Wine, L. , Rosselli, R., Goff, D. C. (2000). Placebo controlled trial of glycine added to clozapine in schizophrenia. American Journal of Psychiatry, 157, 826-828.

Fagerlund, B., Soholm, B. , Fink-Jensen, A., Lublin, H., Glenthoj, B. Y. (2007). Effects of donepezil adjunctive treatment to ziprasidone on cognitive deficits in schizophrenia: a double-blind, placebo-controlled study. Clinical Neuropharmacology, 30, 3-12.

Farrow, T. F., Hunter, M. D., Haque, R., Spence, S. A. (2006). Modafinil and unconstrained motor activity. in schizophrenia: double-blind crossover placebo controlled trial. British Journal ofPsychiatry , 189, 461-462.

Fioravanti, M., Carlone, O., Vitale, B., Cinti, M. E., Clare, L. (2005). A meta-analysis of cognitive deficits in adults with a diagnosis of schizophrenia. Neuropsychology Review, 15, 73-95. Traitements adjuvants: Revue 60

Flynn, M. A., Weaver-Osterholtz, D., Sharpe-Timms, K. L. , Allen, S. , Krause, G. (1999). Dehydroepiandrosterone 'replacement in aging humans. The Journal of Clinical Endocrinology and Metabolism, 84, 1527-1533. '

Freedman, R. , Hall, M., Adler, L. E. , Leonard, S. (1995). Evidence in post mortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biological psychiatry, 38, 22-33. in adults with a diagnosis of schizophrenia. Neuropsychology Review, 25, 73-95.

Freudenreich, O. , Herz, L. , Deckers~ach , T., Evins, A. E. , Henderson, D. C., Cather, C. , Goff, D. C. (2005). Added donepezil for stable schizophrenia: a double-blind, placebo-controlled trial. Psychopharmacology, 181, 358-363. .

Friedman, J. 1. , Adler, D. N., Howanitz, E. , Harvey, P. D. , Brenner, G. , Temporini, H. , White, L. , Parella, M., Davis, K. L. (2002). A double-blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia. Biological Psychiatry, 51, 349-357.

Friedman, J. 1. , Adler, D. N., Temporini, H. D., Kemether, E., Harvey, P. D. , White, L. , Parrella, M., Davis, K. L. (2001). Guanfacine treatment of cognitive impairment in schizophrenia. Neuropsychopharmacology, 25, 402-409.

Friedman, J. 1., Carpenter, D. , Lu, J. , Fan, J. , Tang, C. Y. , White, L. , Parrella, M., Bowler, S., Elbaz, Z., Flanagan, L., Harvey, P. D. (2008)~ A Pilot Study of Adjunctive Atomoxetine Treatment to Second-Generation Antipsychotics for Cognitive Impairment in Schizophrenia. Journal ofClinical Psychopharmacology, 28, 59-63.

Friedman, J. L, Temporini, H. , Davis, K. L. (1999). Pharmacologic strategies for augmenting cognitive performance in schizophrenia. Biological Psychiatry, 45, 1- 16.

Gallagher, P. , Watson, S. , Smith, M. S., Ferrier, 1. N., Young, A. H. (2005). Effects of adjunctive Mifepristone (RU -486) administration on neurocognitive function and symptoms in schizophrenia. Biological Psychiatry, 57, 155-161.

Garcia-Segura, L. M., McCarthy, M. M. (2004). Minireview: role of glia in neuroendocrine function. Endocrinology, 145, 1082-1086.

Goff, D. C., Herz, L. , Posever, T., Shih, V. , Tsai, G., Henderson, D. C., Freudenreich, O. , Evins, A. E. , Yovel, L, Zhang, H., Schoenfeld, D. (2005). A six-month, placebo controlled trial of D-cycloserine co-administered with conventional antipsychotics in schizophrenia patients. Psychopharmacology (Ber!), 179, 144-150.

Goff, D. C., Keefe, R., Citrome, L., Davy, K. , Krystal, J. H., Large, C. , Thompson, T. R., Volavka, J., Webster, E. L. (2007). Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials. Journal of Clinical Psychopharmacology, 27, 582-589. Traitements adjuvants: Revue 61

Goff, D. C., Lamberti, 1. S. , Leon, A. C., Green, M. F., Miller, A. L. , Patel, J. , Manschreck, T. , Freudenreich, O. , Johnson, S. A. (2008). ~ placebo-controlled add-on trial of the ampakine, CX516, for cognitive deficits ln schizophrenia. Neuropsychopharmacology, 33, 465-472.

Goff, D. C., Leahy, L., Berman, L, Posever, T. , Herz, L. , Leon, A. C., Johnson, S.A., Lynch, G. (2001). A placebo-controlled pilot study of the ampakine, CX516, added to clozapine in schizophrenia. Journal of Clinical Psychopharmacology, 21 , 484- 487.

Goldman-Rakic, P. S. , Castner, S. A. , Svensson, T. H. , Siever, L. J. , Williams, G. V. (2004). Targeting the dopamine Dl receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl), 174, 3-16.

Goldman-Rakic, P. S., Lidow, M. S. , Gallager, D. W. (1990). Overlap of dopaminergic, adrenergic and serotonergic receptors and complementary of their subtypes in primate prefrontal cortex. Journal ofNeurosciences , 10, 2125-2138.

Green, M. F. (1996). What are the functional consequences of neurocognitive deficits in schizophrenia? AmericanJournal ofPsychiatry, 153, 321-330.

Green, M. F., Kem, R. S., Braff, D. L. , Mint, J. (2000). Neurocoghitive Deficits and Functional Outcome in Schizophrenia: are We Measuring the« Right Stuff»? Schizophrenia Bulletin, 26, 119-136.

Gron, G. , Kirstein, M., Thielscher, A., Riepe, M. W., Spitzer, M. (2005). Cholinergic enhancement of episodic memory in healthy young adults. Psychopharmacology (Berl), 182, 170-179.

Guan, Z-Z., Zhang, X., Blonnoww, K., Nordberg, A.(1999). Decreased protein level of nicotinic receptor alpha7 subunit in the frontal cortex from schizophrenic brain. Neuroreport, 10, 1779-1782.

Gurevich, E. V., Joyce, J. N. (1997). Alterations in the cortical serotonergic system in schizophrenia: apost-mortem study. Biologica/ Psychiatry, 42, 529-545.

Harris, D. S. , Wolkowitz, O. M., Reus, V. 1. (2001). Movement disorder, memory, psychiatric symptoms and serum DHEA levels in schizophrenic and schizoaffectve patients. WorldJourna/ ofBiological Psychiatry, 2, 99-102.

Harris, J. G. , Kongs, S., Allensworth, D., Martin, L., Tregellas, 1., Sullivan, B., Zerbe, G. , Freedman, R. (2004). Effects of nicotine on cognitive deficits in schizophrenia. Neuropsychopharmac%gy, 29, 1378-1385.

Harrison, P. J., Weinberger, Dr. (2005). Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mo/ecular PsychiatrYJ 10, 40- 68. Traitements adjuvants: Revue 62

Harvey, P. D. , Keefe, R. S. (2001). Studies of cognItIve change in patients with schizophrenia following novel antipsychotic treatment. American Journal of Psychiatry, 158, 176-184.

Hasselmo, M. E. (2006). The role of acetylcholine ln leaming and memory. Current Opinion in Neurobiology, 16, 710-715.

Heimer, L. (1983). The human brain and spinal cord. Functional neuroanatomy and dissection guide. New-York: Springer-Verlag.

Heinrichs, R. W., Zakzanis, K. K. (1998). Neurocognitive review in schizophrenia: a quantitative review of the evidence. Neuropsychology, 12, 426-445.

Herbert, J. (1998). Neurosteroids, brain damage, and mental illness. Experimental Gerontology, 33, 713-727.

Heresco-Levy, D. , Javitt, D. C., Ermilov, M. , Mordel, C. , Horowitz, A. , Kelly, D. (1996). Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia. The British Journal ofPsychiatry , 169, 610-617.

Hill, S. K. , Ragland, J. D. , Gur, R. C. , Gur, R. E. (2002). Neuropsychological profiles delineate distinct profiles of schizophrenia, an interaction between memory and executive function, and uneven distribution of clinical subtypes. Journal of Clinical and Experimental Neuropsychology, 24, 765-780.

Hoff, A. L., Kremen, W. S. (2003). Neuropsychology in schizophrenia: an update. Current Opinion in Psychiatry, 16, 149-155.

Hoffman, B. B., Lefkowitz, R. J. (1996). Catecholamines, sympathomirnetie drugs, and adrenergie reeeptor antagonists. In: Goodman and Gilman' s (eds), The pharmacological basis oftherapeutics (pp. 199-242). New-York: The MeGraw-Hill Cornpanies.

Hollmann, M., Heinemann, S. (1994). Cloned glutamate reeeptors. Annual Review of Neuroscience, 17,31-108.

Hughes, J. R., Hatsukami. D. K., Mitchell, J. E., Dahlgren, L. A. (1986). Prevalenee of smoking among psychiatrie outpatients. American Journal of Psychiatry, 143, 993- 997.

Hunter, M. D. , Ganesan, V. , Wilkinson, 1. D. , Spence, S. A. (2006). Impact ofmodafinil on prefrontal exeeutive funetion in schizophrenia. American Journal of Psychiatry, 163, 2184-2186.

Hyde, T. M., Crook, J. M. (2001). Cholinergie systems and sehizophrenia: primary pathology or epiphenomena? Journal ofChemical Neuroanatomy, 22, 53-63. Traitements adjuvants: Revue 63

Ikegaya,.Y. , Nakanishi, K. , Saito, H. , Abe, K. (1996). Amygdala ~-noradrenergic influence on hippocamp~llong-term potentiation in vivo. Neuroreport, 8, 3143-3146.

Jacobsen, L. K. , D'Souza, D. C., Mencl, W. E., Pugh, K. R. , Skudlarski, P. , Krystal, J. H. (2004). Nicotine effects on brain function and functional connectivity in schizophrenia. Biological Psychiatry, 55, 850-858.

Jann, M. W. (1998). Pharmacology and clinical efficacy of cholinesterase inhibitors. American Journal ofHealth-System Pharmacy, 55, 22-25.

Javitt, D. C. (2007). Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate . receptors, and dopamine-glutamate interactions. International Review of Neurobiology, 8, 69-108.

Javitt, D. C. (2008). Glycine transport inhibitors and the treatment of schizophrenia. Biological Psychiatry, 63, 6-8.

Jentsch, J. D. & Roth, R. H. (1999) .. The neuropsychopharmacology ofphencyclidine: from NMDA receptor hypofuriction to the dopamine hypothesis of schizophrenia. Ne uropsychopharmacology, 20, 201-225.

Kapur, S. (2003). Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. American Journal of Psychiatry, 160, 13-23.

Karson, C. N. , Mrak, R. E., Husain, M. M., Griffin, W. S. (1996). Decreased mesopontine choline acetyltransferase levels in schizophrenia. Correlations with cognitive functions. Molecular and Chemical Neuropathology, 29, 181-191.

Kasper, S., Tauscher, J., Willeit, M., Stamenkovic, M., Neumeister, A. , Fufferle, B., Barnas, C. , Stasny, J., Praschak-Rieder, N., Pezawas, L. , de Zwaan, M. , Quiner, S. , Pirker, W., Asenbaum, S., Podreka, L, Brucke, T. (2002). Receptor and transporter imaging studies in schizophrenia, depression, bulimia and Tourette's disorder - implications for psychopharmacology. World journal of biological Psychiatry, 3, 133-146.

Keefe, R. S., Malhotra, A. K. , Meltzer, H. Y., Kane, J. M., Buchanan, R. W., Murthy, A. , Sovel, M., Li, C. , Goldman, R. (2007). Efficacy and Safety of Donepezil in Patients with Schizophrenia or Schizoaffective Disorder: significant Placebo/Practice Effects in a 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial. Neuropsychopharmacology, 33, 1217-1228.

Keefe, R. S., Malhotra, A. K. , Meltzer, H. Y., Kane, J. M., Buchanan, R. W., Murthy, A. , Sovel, M., Li, C., Goldman, R. (2007). Efficacy and Safety of Donepezil in Patients with Schizophrenia or Schizoaffective Disorder: significant Placebo/Practice Effects in a 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial. Neuropsychopharmacology, 33, 1217-1228. Traitements adjuvants: Revue 64

Keefe, R. S. E. , Silva, S. G. , Perkins, D. O. , Lieberman, J. A. (1999). The effects ofatypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophrenia bulletin, 25, 201-222.

Kemali, D., Del-Vecchio, M., Maj, M. (1982). Increased noradrenaline levels in CSF and plasma of schizophrenic patients. Biological Psychiatry, 1 7, 711-717.

Kholer, C. G. , Martin, E. A. , Kujawski, E. , Bilker, W. , Gur, R. E. , Gur, R. C. (2007). No effect of donepezil on neurocognition and social cognition in young persons with stable schizophrenia. Cognitive Neuropsychiatry, 12, 412-421.

Krall, W. J., Sramek, J. J. , Cutler, N. R. (1999). Cholinesterase inhibitors: a therapeutic strategy for Alzheimer disease. The Annals ofPharmacotherapy , 33, 441-450.

Krebs, M. , Leopold, K., Hinzpeter, A. , Schaefer, M. (2006). Neuroprotective agents in schizophrenia and affective disorders. Expert Opinion on Pharmacotherapy, 7, 837- 848.

Kumari, V., Aasen, I. , Ffytche, D., Williams, S. C. , Sharma, T. (2006). Neural correlates of adjunctive rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double-blind fMRI study. Neuroimage, 29, 545-556.

Lehoux, C., Everett, J., Laplante, L., Émond, C., Trépanier, J., Brassard, A. , René, L. , Cayer, M., Mérette, C., Maziade, M., Roy, M -A. (2003). Fine motor dexterity is correlated to social functioning in schizophrenia. Schizophrenia Research, 62, 269- 273.

Lenzi, A., Maltinti, E., Poggi, E., Fabrizio, L. , Coli, E. (2003). Effects of 'fivastigmine on cognitive function and quality of life in patients with schizophrenia. Clinical Neuropharmacology, 26,317-321.

Létoumeau, K. , Simard, M., Demers, M-F., Émond, C., Mérette, C., Bouchard, R-H., & Roy, M-A. A 10-week, double-blind, placebo controlled, cross-over trial of adjunctive modafinil for neurocognitive impairments in schizophrenia. Paper in preparation.

Levy, F. (2008). Pharmacological and therapeuticdirections in ADHD: specificity in the PFC. Behavioral Brain Functions, 4, 12.

Luby, E. D., Cohen, R. C., Rosenbaum, B., Gottlied, J S. , Kelly, R. (1959). Study of a new schizophrenomimetic drug: Semyl. Archives of Neurological Psychiatry, 81 , 363- 369.

Lucas-Meunier, E., Fossier, P., Baux, G., Amar, M. (2003). Cholinergie modulation of the cortical neuronal network. Pflugers Archiv : European Journal of Physiology, 446, 17-29. Traitements adjuvants: Revue 65

Malhotra, A. K. , Pinals, D. A., Weingartner, H. , Sirocco, K. , Missar, C. D. , Pickar, D. , Breier, A. (1996). NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers. Neuropsychopharmacology, 14, 301-307.

Marder, S. R. (2006). Drug initiatives to improve cognitive function. Journal of Clinical Psychiatry, 67, 31 S-35S.

Mazeh, D., Zemishlani, H. , Barak, Y. , Mirecki, I. , Paleacu, D. (2005). Donepezil for negative signs in elderly patients with schizophrenia: an add-on, double-blind, crossover, placebo-controlled study. International Psychogeriatrics, 18, 429-436.

Meltzer, H. Y. , McGurk, S. R. (1999). The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophrenia Bulletin, 25, 233-255.

Mesulam, M. M. (1995). Structure and function of cholinergic pathways in the cerebral cortex, limbic system, basal ganglia, and thalamus in the human brain. In: Bloom FE, Kupfer DJ (eds). Psychopharmacology: the fourth generation of progress (pp.135-146). New York: Raven Press.

Nordberg, A., Svensson, A. L. (1998). Cholinesterase inhibitors in the treatment of Alzheimer's disease: a comparison of tolerability and pharmacology. Drug Safety 19, 465-480.

Nuechterlain, K. , Green, M. F. (2006). MATRICS Consensus Cognitive Battery (MCCB). Los Angeles: MATRICS Assessments Inc. .

Ogren, S. O., Eriksson, T. M. , Elvander-Tottie, E. , D'Addario, C., Ekstrom, J. C. , Svenningsson, P., Meister, B., Kehr, J. , Stiedl, O. (2008). The role of 5-HT1A in leaming and memory. Behavioural Brain Research, 195, 54-77.

Olincy, A., Harris, J. G. , Johnson, L. L. , Pender, V., Kongs, S., Allensworth, D. , Ellis, J. , Zerbe, G. O., Leonard, S. , Stevens, K. E., Stevens, J. O., Martin, L. , Adler, L. E. , Soti, F., Kem, W. R., Freedman, R. (2006). Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Archives ofGeneral Psychiatry, 63, 630-638.

Owen, F., Cross, A. J., Lofihouse, R., Plulter, M. (1981). Neurotranmitter receptors in brain in schizophrenia. Acta psychiatrica Scandinavica. Supplementum, 3, 20-27.

Parsons, C. G., Danysz, W., Quack, G. (1999). memantine is a clinically weIl tolerated N nethyl-D-aspartate (NMDA) receptor antagonist ~a review of preclinical data. Neuropharmacology, 38, 735-767.

Pierre, J. M., Peloian, J. H., Wirshing, D. A. , Wirshing, W. C., Marder, S. R. (2007). A randomized, double-blind, placebo-controlled trial of modafinil for negative symptoms in schizophrenia. Journal ofClinical Psychiatry, 68, 705-710. Traitements adjuvants: Revue 66

Powchik, P. , Davidson, M., Haroutunian, V. , Gabriel, S. M. , Purohit, D. P. , Perl, D. P., Harvey, P. D., Davis, K. L. (1998). Post-mortem studies in schizophrenia. Schizophrenia Bulletin, 24, 325-341.

Psychopharmacology: The fourth generation ofprogress (pp 135-146). New-York: Raven press.

Raguraman, J. , Sagar, J. V. , Chandrasekaran, R. (2005). Effects of rivastigmine in a case redidual schizophrenia. Canadian Journal ofPsychiatry " 50, 243-244.

Ristner, M. , Gibel, A. , Maayan, R. , Ratner, Y. , Ram, E. , Biadsy, H. , Modai, L, Weizman, A. (2005). Cortisol/dehydroepiandrosterone ratio and responses to antipsychotic treatment in schizophrenia. Neuropsychopharmacology, 30, 1913-1922.

Ristner, M. S., Gibel, A. , Ratner, Y. , Tsinovoy, G. , Strous, R. D. (2006). Improvement of sustained attention and visual and movement skills, but not clinical symptoms, after dehydroepiandrosterone augmentation in schizophrenia. Journal of Clinical Psychopharmacology, 26, 495-499.

Robbins, T. W., Murphy, E. R. (2006). Behavioral pharmacology: 40+ years of progress,. with a focus on glutamate receptors and cognition. Trends in Pharmacological Sciences, 27, 141-148. .

Robbins, T. W., Roberts, A. C. (2007). DifferentiaI regulation of fronto-executive function by the monoamines and acetylcholine. Cerebral Cortex, 17, 151 S-160S.

Rogers, S. L., Walters, E. J., Friedhoff, L. T. (1992). The pharmacokinetics (PK) and pharmacodynamies (PD) of E2020 ((R,S,)-I-bezyl-4-((5,6-dimethoxy-I-indanon)-2- yl)-methylpiperidine hydrochloride) a novel inhibitor of acetylcholinesterase (AChE): implications for use in the treatment of Alzheimer' s disease. Neurobiology ofAging, 13, 125S-126S.

Rogers SL, Yaminishi Y, Yamatsu K (1991) E2020- The pharmacology of a piperidine cholinesterase inhibitor. In Becker Rand Giacobini E (eds). Cholinergie Basis for Alzheimer Therapy, vol 3, (pp 314-120). Boston, MA: Birkhauser.

Roth, B.L., Hanizavareh, S. M., Blum,.A. E. (2004). Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology, 174, 17-24.

Roy, M. A., Mérette, C., Maziade, M. (2001). Subtyping schizophrenia according to outcome or severity: a search for homogeneous subgroups. Schizophrenia Bulletin, 2 7, 115-138.

Sacco, K.A., Termine, A., Seyal, A., Dudas, M. M., Vessicchio, J. C., Krishnan-Sarin, S., Jatlow, P. L, Wexler, B. E., George, T. P. (2005). Effects of cigarette smoking on Traitements adjuvants: Revue 67

spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. Archives of General Psychiatry, 62, 649-659.

Schubert, M. H., Young, K. A., Hicks, P. B. (2006). Galantamine Improves Cognition in Schizophrenic Patients Stabilized on Risperidone. Biological Psychiatry, 60, 530- 533.

Seaton, B. E. , Goldstein, G. , Allen, D. N. (2001). Sources of heterogeneity in schizophreni':l: the role of neuropsychological functioning. Neuropsychology Review, 11, 45-67.

Senn, S. (2002). Cross-over trials in clinical research, 2nd ed. London: John Wiley & Sons.

Sevy, S., Rosenthal, D. O., Alvir, J. , Meyer, S. , Visweswaraiah, H. , Gunduz-Bruce, H. , & Schooler; N. R. (2005). Double-blind, placebo-controlled study of modafinil for fatigue and cognition in schizophrenia patients treated with psychotropic medications. Journal of Clinical Psychiatry, 66, 839-843.

Sharma, T., Reed, C. , Aasen, L, Kumari, V. (2006). Cognitive effects of adjunctive 24- weeks rivastigmine treatment to antipsychotics in schizophrenia: a randomized, placebo-controlled, double-blind investigation. Schizophrenia Research, 85, 73-83.

Shiloh R, Nutt D, Weizman A (2000) Atlas of Psychiatric Pharmacotherapy, 2nd edition . . Martin Dunitz: London

Silver, H. , Goodman, C. , Isakov, V., Knoll, G. , & Modai, 1.(2005). A double-blind, cross over comparison of the effects of amantadine or placebo on visuomotor and cognitive function in medicated schizophrenia patients. International Clinical Psychopharmacology, 20, 319-326.

Simard, M., Van Reekum, R. (1999). Memory assessment in studies of cognition enhancing drugs for Alzheimer' s disease. Drugs Aging, 14, 197-230.

Smith, R. C., Singh, A., Infante, M., Khandat, A., Kloos, A. (2002). Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia. Neuropsychopharmacology, 27, 479-497.

Smith, R. C., Warner-Cohen, 1., Matute, M., Butler, E. , Kelly, E., Vaidhyanathaswamy, S. , Khan, A. (2006). Effects of nicotine nasal spray on cognitive function in schizophrenia. Neuropsychopharmacology, 31,637-643.

Spence, S. A. , Green, R. D., Wilkinson, 1. D., Hunter, M. D. (2005). Modafinil modulates anterior cingulate function in chronic schizophrenia. British Journal of Psychiatry, 187, 55-61.

Stahl, S. M. (2007). Beyond the dopamine hypothesis to the NMDA glutamate receptor hypofunction hypothesis of schizophrenia. CNS Spectrums, 12, 265-268. .Traitements adjuvants: Revue 68

Strous, R. D., Maayan, R. , Lapidus, R. , Stryjer, R. , Lustig, M., Kotler, M. , Weizman, A. (2003). Dehydroepiandrosterone (DHEA) augmentation in the management of negative, depressive and anxiety symptoms in schizophrenia. Archives of General Psychiatry, 60, 133-141.

Strous, R. D. , Stryjer, R. , Maayan, R. , Gal, G. , Viglin, D., Katz, E. , Eisner, D., Weizman, A. (2007). Analysis of clinical symptomatology, extrapyramidal symptoms and neurocognitive dysfunction following dehydroepiandrosterone (DHEA) administration in olanzapine treated schizophrenia patients: a randomized, double blind placebo controlled trial. Psychoneuroendocrinology, 32, 96-105.

Sugimoto, H. , Iimura, Y. , Yamanishi, Y. , Yamatsu, K. (1992). Synthesis and acetylcholinesterase activity of l-benzyl-4-[(5,6,-dimethoxy-I-indanon)-2-yl] methyl piperidine hydrochloride (E2020) and related compounds. Bioorganic and Medicinal Chemistry, 2, 871-876.

Sumiyoshi, T., Park, S., Jayathilake, K. , Roy, A. , Ertugrul, A. , Meltzer, H. Y. (2007). Effect of buspirone, a serotonin1 A partial agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophrenia Research, 95, 158-168. .

Swanson, C. J. , Perry, K. W. , Koch-Krueger, S., Katner, J. , Svensson, K. A. , & Bymaster, F. P. (2006). Effect of the attention deficit/hyperactivity disorder drug atomoxetine on extracellular concentrations of norepinephrine and dopamine in several brain regions of the rat. Neuropharmacology, 50, 755-770.

Tauscher, J. , Kapur, S. , Verhoeff, P. L. G. , Hussey, D. F. , Daskalakis, Z. J. , Tauscher Wisniewski, S. , Wilson, A. A., Houle, S., Kasper, S., Zipursky, R. B. (2002) Brain serotonin 5-HT1A receptor binding in schizophrenia measured by positron emission tomography and [llC]WAY-100635. Archives of General Psychiatry, 59, 514-520.

Townsend, L. A. & Norman, R. M. (2004). Course of cognitive functioning in first episode schizophrenia spectrum disorders. Expert Review ofNeurotherapeutics, 4, 61-68.

Tsai, G., Yang, P., Chung, L. C., Lange, N., Coyle, J. T. (1998). D-serine added to antipsychotics for the treatment of schizophrenia. Biological Psychiatry, 44, 1081- 1089.

Turner, D. C. , Clark, L. , Pomarol-Clotet, E., McKenna, P., Robbins, T. W. , Sahakian, B. J. (2004). Modafinil Improves Cognition and Attentional Set Shifting in Patients with Chronic Schizophrenia. Neuropsychopharmacology, 29, 1363-1373.

Van Kammen, D. P., Kelley, M. (1991). Dopamine and norepinephrine activity ln schizophrenia. An integrative perspective. Schizophrenia Research, 4, 173 -191. Traitements adjuvants: Revue 69

Watanabe, S., Nishikawa, T. , Takashima, M. , Toru, M. (1983). Increased muscarlnlC cholinergic receptors in p!efrontal cortices of medicated schizophrenics. Life Sciences, 33, 2187-2196.

Wilson, M. A. , Mollicer, M. E. (1991). The organization of serotonergic projections to cerebral cortex in primates: regional distribution ofaxon terminaIs. Neuroscience, 44, 537-553.

Woodward, N. D. , Purdon, S. E. , Meltzer, H. Y. , Zald, D. H. (2005). A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. The International Journal of Neuropsychopharmacology, 8, 457- 472.

Yamanishi, Y. , Ogura, H., Kosasa, T. , Araki, S. , Sawa, Y. , Yamatsu, K. (1990). Inhibitory action of donepezil, a novel acetylcholinesterase inhibitor, on cholinesterase. Comparison with other inhibitors. In: Nagatsu T, Fisher A, Yoshida M (eds) Basic clinical, and therapeutic aspects of Alzheimer' s and Parkinson' s diseases, vol 2 (pp 409-413). Plenum Press: New York.

Yurgelun-Todd, D. A. , Coyle, J. T. , Gruber, S. A. , Renshaw, P. F. , Silveri, M. M. , Arnico, E., Cohen, B., Goff, D. C. (2005). Functional magnetic resonance imaging studies of schizophrenic , patients during word production: effects of D-cycloserine. Psychiatry Research, 138, 23-31.

Zhang, Z., Araghi-Niknam, M. , Liang, B., Inserra, P. , Ardestani, S. K., Jiang, S. , Chow, S., Watson, R. R. (1999). Prevention of immune dysfunction and vitamin E loss by dehydroepiandrosterone and melatonin supplementation during murine retrovirus infection. Immunology, 96, 291-297.

Zoccali, R. , Muscatello, M. R. , Bruno, A., Cambria, R. , Mico, U. , Spina, E. , Meduri, M. (2007). The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: a double-blind, placebo-controlled study. Schizophrenia Research, 93, 109-116. Traitements adjuvants: Revue 70

Tables

Table 2.1 Studies targeting the acetylcholinergic sJ!..stem in schizophrenia Authors Molecule & Study Design Duration Na Diagnosis and Measures Results Dosage (weeks) antipsychotic ~m~da~} treatment Keefe et Donepezil R-DB-PC-P 12 226 Schizophrenia The CATIE Using OC analysis al. , 2007 5 up to10 & neurocognitive battery; (N=187), there is a . Schizoaffecti ve comprises COWAT significant improvement letter fluency, Category of the placebo group Aripiprazole, instances, WISC-III comparatively to the olanzapine, Mazes, HVLT, WAIS-R donepezil group on the quetiapine, Digit Symbol Test, CATIE neurocognitive risperidone, letter-number test of battery composite score and/or auditory working (p=0.04). ziprasidone memory, grooved Using LOCF analysis pegboard, CPT, VWMT, (N=226), there is a and WCST 64 significant improvement of the placebo comparing to the donepezil group on the letter (p=0. 02) and semantic (p~0.001) fluency tasks Friedman Donepezil R-DB-PC-P 12 36 Schizophrenia Simple Spatial Working- Using OC (N=34) or et al., 2002 5 up to 10 Memory Test, CPT, LOCF (N=36) analysis, Risperidone TMT A & B, WCST, there is no significant only RAVLT , and Digit Span differences between donepezil and placebo groups found on the cognitive measures using Traitements adjuvants: Revue 71

Kohler et Donepezil R-DB-PC-P 16 26 Schizophrenia The Penn Computerized No significant al. , 2007 5 up to 10 & Neurocognitive Scan. differences between Schizoaffective Includes tests of donepezil and placebo abstraction, attention, groups found on the Second- verbal and spatial cognitive measures. generation memory, and spatial antipsychotics abilities except cloza.Qine Fagerlund Donepezil R-DB-PC-P 16 Il Schizophrenia CANTAB, Buschke There is a significant et al., 2007 5 up to 10 selecti ve reminding task, improvement of the Zi prasidone Rey Complex Figure placebo group only Task, verbal semantic comparatively to the fluency (animaIs), donepezil group on the SDMT, and TMT A & B Buschke selective reminding task (immediate verbal recall : E=0.02) Sharma et Rivastigmine R-DB-PC-P 24 21 Schizophrenia CYLT , WCST, verbal No significant al.,2006 3 up to 12 AH participants category and differences between the were on Olanzapine, phonological fluency ri vastigmine and the placebo for one quetiapine, or test, letter number and placebo groups found on week before risperidone digit symbol subtests the cognitive measures randomization from W AIS-III, Dot Test, CPT, TMT A &.13, and F inger tapping test Traitements adjuvants: Revue 72

Kumari et Rivastigmine R-DB-PC-P 12 21 Schizophrenia A "n-back" task No significant al., 2006 3 up to 12 AlI participants implying non-verbal differences between the were on Olanzapine, stimuli. Accuracy and ri vastigmine and the placebo for one quetiapine, or latency were recorded placebo groups found on week before risperidone the cognitive measures randomization Aasen et Rivastigmine R-DB-PC-P 12 to 14 20 Schizophrenia Experimental No significant al. , 2005 3 up to 12 AlI participants & computerized paradigm differences between the were on Schizoaffective of selective attention ri vastigmine and the placebo for one Accuracy and latency placebo groups on the week before Olanzapine, are recorded cognitive measure randomization quetiapine, or risQeridone Dyer et al., Galantamine R-DB-PC-P 8 20 Schizophrenia CPT- IP, Three-card Using LOCF analysis, 2008 4 up to 32 & stroop, W AIS-III letter- there is a significant Schizoaffecti ve number subtest, Grooved worsening of the depressed type pegboard galantamine group (non-smoking comparatively to the

outpatients) placebo group on ·d J parameter of the CPT-IP Aripiprazole, (p=0.04), inhibition clozapine, condition of the Stroop olanzapine, (p=0.04), and the forward quetiapine, condition of the Letter- risperidone, number span (p

Schubert Galantamine "R-DB-PC-P 57 days 14 Schizophrenia RBANS, CPT, OMMT, Using LOCF analysis, et al. , 2006 8 up to 24 & TOT, and UOA there is a significant Schizoaffective improvement of the (depressed galantamine type) comparativel y to the placebo group on Risperidone RBANS total (p=0.04), only. attention (p=0.02), and delayed memory scores (p=0.03) CANTAB: Cambridge Neuropsychological Test Automated Battery, CATIE: Clinical Antipsychotic Trials of lntervention Effectivness, COW AT: Controlled Oral Word Association Task, CPT: Continuous Performance Test, CPT-IP : Continuous Performance Test - Identical Pairs, CVLT : Califomia Verbal Leaming Test, HVLT: Hopkins verballeaming test-Revised, LOCF : Last Observation Carried Forward, OC : Observed Cases, OMMT : Object Matching Memory Test, RA VLT: Rey Auditory Verbal Leaming Test, RBANS: Repeatable Battery for the Assessment of Neuropsychological Status, R-DB-PC-P: Randomized Double-Blind Placebo-Controlled Parallel trial, SDMT : Symbol Digit Modalities Test, TMT: Trail Making Test, TOT: Tower of Toronto Puzzle Test, UOA : Unirhinal Olfactory Acuity test, VWMT: Visuospatial Working Memory Test, WAIS-III : Weschler Adult Intelligence Scaie-III. a: Numbers of subjects reported are the ones used in statistical analysis

)- Traitements adjuvants: Revue 74

Table 2.2

Studies tar~eting the glutaminergJc system in schizophrenia Authors Molecule & Study Design Duration N Diagnosis & Measures Results Dosage (weeks) Antipsychoti ~mg/dal:~ c treatment Evins et Glycine R-DB-PC-P 8 27 Schizophrenia Stroop, W AIS Using LOCF analysis, al., 2000 60 grams/day AlI participants vocabulary, information, there is no significant were on 2 week Clozapine digit span & block design differences between the single-blind only subtests, CVLT, finger glycine and the placebo placebo before tapping test and . groups on the cognitive randomiza-tion judgment of line measures. orientation. Lamotrigine R-DB-PC-P 12 210 .Schizophrenia BACS (list leaming, digit Using LOCF analysis, Goff et sequencing task, token there is a significant al., 25 up to a Aripiprazole, motor task, COWAT & improvement of the 2007 range of 100 clozapine, category instances, tower lamotrigine group to 400 olanzapine, of London, symbol comparatively to the "Study 2" quetiapine, coding), a delayed verbal placebo group on the risperidone memory task and a BACS composite score and/or Stroop test (p<0.01) zi~rasidone. Goff et Lamotrigine R-DB-PC-P 12 209 Schizophrenia BACS (list leaming, digit Using LOCF analysis, al.~ 2007 sequencing task, token there is no significant 25 up to a Aripiprazole, motor task, COWA T & differences between "Study 1" range of 100 clozapine, category instances, tower lamotrigine and placebo to 400 olanzapine, of London, symbol groups found on any of quetiapine, coding), a delayed verbal the cognitive measures. risperidone memory task and a and/or Stroop test ziprasidone. Traitements adjuvants: Revue 75

Zoccali et Lamotrigine R-DB-PC-P 24 51 Schizophrenia WCST, COWAT and the Using OC analysis, there al., 2007 . 25 up to 200 (treatment- Stroop test. is a significant resistant improvement of the outpatients) lamotrigine groups comparatively to the Clozapine placebo group on the only Stroop and the phonemic verbal fl uency task After the Bonferroni correction, only verbal fluency remained significant

Cerullo et Memantine R-DB-PC-P 8 7 Schizophrenia A n-back paradigm There is no significant al., 2007 difference between the o lanzapine , memantine and the risperidone, or placebo groups on the n- ziprasidone. back task at 0, 1, or 8 weeks.

Goff et Ampakine R-DB-PC-P 8 105 Schizophrenia TMT, DS-CPT, CVLI, Using LOCF (N=105) or a1. ~ 2008 CX516 WMS-III faces and OC analysis (N=95), 900 Clozapine, family pictures subtest, there is no significant olanzapine, or WCST, verbal category difference between risperidone and phonological fluency ampakine and placebo test, letter-number span, groups on the cognitive and grooved pegboard. composite scores at week 4 and week 8. Goff et Ampakine R-DB-PC-P 6 18 Schizophrenia Randt memory test, SKI, Using Cohen's d al. , 2001 CX516 GDS distraction test, calculation, there is 2700 Clozapine figer tapping test, WMS- effects in favour of the Traitements adjuvants: Revue 76

only III, WRAT-R, Rey ampakine at week 4. A Osterrieth and Taylor large effect (d> 0.8) is complex figure tests, observed on the Randt verbal fluency, TMT, and memory test. Moderate weST effects (d> 0.5) are observed on the GDS distraction test, Rey and Taylor complex figures, and TMT part B. BACS: Brief Assessment of Cognition in Schizophrenia, COWAT: Controlled Oral Word Association Test, CVLT: Califomia Verbal Learning Test, DS-CPT: Degraded Stimulus Continuous Performance Test, GDS: Gordon Diagnostic System, LOCF: Last Observation Carried Forward, OC: Observed Cases, R-DB-PC CO: Randomized Double-Blind Placebo-Controlled Cross-Over trial, R-DB-PC-P: Randomized Double-Blind Placebo-Controlled Parallel trial, SKT: Short Cognitive Performance Test, TMT: Trail Making Test, WAIS: Weschler Adult Intelligence Scale, WCST: Wisconsin Card Sorting Test, WMS-III: Weschler Memory Scale, third edition, WRAT-R: Wide Range Achievement Test-Revised. Traitements adjuvants: Revue 77

Table 2.3 Studies targeting ep,/nephrine and norepJnephrine in schizophrenia Authors Molecule & Study Design Duration N Diagnosis & Measures Results Dosage (weeks) Antipsychotic {m&da~l treatment Friedman Atomoxetinea R-DB-PC-P 8 15 Schizophrenia BACS (list leaming, digit Using LOCF analysis, et al., 40 up to 80 sequencing task, token there is no significant 2008 Aripiprazole, motor task, COWAT & difference between olanzapine, category instances, tower atomoxetine and placebo quetiapine or of London, symbol found on the cognitive risperidone. coding) and a "n-back" measures.

task implying verbal 1 stimuli. - Friedman Guanfacine R-DB-PC-P 4 ' Il Schizophrenia Simple spatial working There is a significant et al., 0.5 up to 2 memory test, CPT, TMT improvement of the 2001 Risperidone A & B, RAVLT , digit guanfacine comparing to span distraction test, the placebo group on the verbal fluency. reaction time on the visuospatial working memory task (p=0.03). BACS: Brief Assessment of Cognition in Schizophrenia, CPT: Continuous Performance Test, R-DB-PC-P: Randomized Double-Blind Placebo-Controlled Parallel trial, RA VLT: Rey Auditory Verbal Leaming Test, TMT A & B: Trail Making Test, part A & B. Traitements adjuvants: Revue 78

Table 2.4 Studies targeting the serotonergic system' in schizophrenia Authors Molecule & Study design Duration N Diagnosis & Measures Results dosage (weeks) antipsychotic (mglday) treatment Sumiyoshi Buspirone R-DB-PC-P 26 59 Schizophrenia Digit Symbol In comparison with et al., 2007 10 up to 30 Substitution Test (WAIS placebo, buspirone Clozapine, R), COWAT, CIGT, significantly improves olanzapine, CVLT, ACT, and WCST. performances on Digit . risperidone, Symbol Substitution Test or at 3 months from ziprazidone. baseline but not at 6 months.

WAIS-R: Weschler AduIt Intelligence Scale - Revised, COWAT: Controlled Oral Word Association Test, ClOT: Category Instance Generation Test, CVLT: Califomia Verbal Leaming Test, ACT: Auditory Consonants Trigram, WCST: Wisconsin Card Sorting Test. Traitements adjuvants: Revue 79

Table 2.5 Studies targeting other systems in schizophrenia Authors Molecule & Study design Duration N Diagnosis & Measures Results dosage (weeks) . antipsychotic (mg/day) treatment Strous et Dehydroe R-DB-PC-P 12 26 Schizophrena The Mindstreams No significant al., 2007 piandrostero (inpatients) Computerized Cognitive . differences between ne Test Battery (includes a DHEA and placebo (steroid) Olanzapine Go-NoGo response found on the cognitive 50 up to 150 inhibition test, a Stroop measures. interference test & the Staged information processing speed test). Tests of verbal (associative) and non verbal memory were also administered.

Acknowledgements : This study was not sponsored, therefore, there is no financial 'relationship to disclose.

. 1

! CHAPITRE 3: SECOND ARTICLE

Modafinil as adjunct treatment in recent onset psychosis: five case reports Modafini1; étude pilote 81

Modafinil as Adjunct Treatment in Recent-Onset Psychosis: Five Case Reports

Karine Létourneau 1,3, MPs, PhD Candidate in Psychology Jacinthe Leblanc2, DPH, B Pharm Roch-Hugo BouchardI ,2,3 MD, FRCP Martine Simard 1,3, PhD l Hélène Marcaurelle , 3, B Psy l Rosalie Ouellet , MPs l Chantal Vallières , 2, B Psy Marc-Andé Royl,2,3, MD, MSc (epidemiology), FRCP

1. Centre de Recherche Université Laval Robert-Giffard, 2601 chemin de la Canardère, Québec, Québec, Canada, G1J 2G3 2. Clinique Notre-Dame des Victoires, Centre Hospitalier Robert-Giffard, 70 Dalhousie, bur. 40, Québec, Québec, Canada, G1K 4B2 3. Laval University, School ofPsych0 logy, Local 1116, Pavillon F. -A. Savard 2325 rue des Bibliothèques, Québec, Québec, Canada, G1 V OA6 4. Laval University, Department ofPsychiatry , Faculty ofMedicine , Pavillon Ferdinand- Vandry, 1050, avenue de la Médecine, Québec, Québec, Canada, G1VOA6

[email protected], phone: (418) 663-5741 ext. 4764, Fax: (418) 663- 5971

Aknowledgments: This study was not sponsored and therefore, there is no financial relationship to disclose. Shire Biochem supplied modafinil's tablets, Ville St-Laurent, Québec, Canada. These data were presented at the International Congress On Schizophrenia Research, Colorado Springs, USA, March 30, 2007. Modafinil; étude pilote 82

Résumé Modafinil (Alertec, Provigil, Modiodal) est un stimulant du système nerveux central indiqué au Canada, aux Etats-Unis, et en Europe, pour le traitement de la somnolence diurne associée à la narcolepsie et au travail sur quarts de nuits, ainsi qu'en tant qu'adjuvant au traitement standard de l'apnée du sommeil. Il est pharmacologiquement différent des psycho stimulants conventionnels, mais son mode d'action exact demeure inconnu. Modafinil est aussi utilisé dans de nombreuses autres conditions médicales qui occasionnent de la fatigue et/ou de la somnolence diurne excessive. Il est utilisé pour traiter la sédation occasionnée par certaines médications psychotropes, et afin de potentialiser l' efficacité de traitements médicaux. Les résultats de quelques études suggèrent également que le modafinil peut aider à traiter les déficits neurocognitifs associés à diverses psychopathologies. Cet article illustre, à l'aide d'une étude de cas, l'efficacité et la sécurité liées à l'utilisation prolongée de modafinil chez cinq patients souffrant d'un trouble psychotique d'apparition récente, ·et qui présentent des déficits neurocognitifs. Au plan neuropsychologique, modafinil a amélioré le fonctionnement neurocognitif chez quatre des cinq participants. L'effet positif observé chez ces patients, associé avec une bonne sécurité, justifie l'investigation future des effets de l'utilisation prolongée de modafinil chez de grands échantillons d'individus souffrant d'un trouble psychotique d'apparition récente, et ce, à l'aide de devis expérimentaux. Modafinil; étude pilote 83

Abstract Modafinil (Alertec, Provigil, Modiodal) is a central nervous system stimulant indicated to treat excessive daytime sleepiness associated with narcolepsy and chronic shift work sleep disorder, and as an adjuvant to the standard treatment of sleep apnoea syndrome in Canada, United States, and Europe. It is pharmacologically distinct from classical stimulants, but its exact mechanism of action remains unknown. Modafinil is also used in many other conditions that lead to excessive daytime sleepiness. It is utilised off-label to treat sedation caused by sorne psychotropic medications, and to potentialize efficacy of sorne medical treatments. Sorne studies also suggest that modafinil could help to treat neurocognitive impairrnents associated with psychopathologies. This paper illustrates, using a case report design, preliminary efficacy and tolerability data of a prolonged use of modafinil in five patients with recent-onset psychosis who experience neurocognitive impairments. In terms of neuropsychological evidence, modafinil enhanced neurocognitive functions in four cases out of five. The positive effects observed in patients, associated with a good tolerability, justify further investigation of prolonged use of modafinil in larger samples of recent-onset psychosis using a randomized controlled experimental design.

Keywords : schizophrenia, modafinil, neurocognition, neurocognitive enhancer Modafinil; étude pilote 84

Rationale It is now clearly demonstrated that schizophrenia (SZ) and SZ spectrum disorders are characterized by neuropsychological deficits, principally on specific attentional, memory, and executive functioning processes, and on motor abilities (Heinrichs and Zakzanis 1998; Velligan et al., 2000; Hoff and Kremen 2003; Fioravanti et al. , 2005). These deficits are present even during remissions of positive symptoms, and are more predictive of level of functioning than severity of positive or negative symptoms are (Green 1996; Harvey et al., 1998; Addington and Addington 1999; Bellack et al. , 1999; Evans et al., 2002; Fujii and Wylie 2003; Lehoux et al., 2003; McGurk et al. , 2003). Although second generation antipsychotics are more beneficial than first-generation ones on neurocognitive functions (Keefe et al., 1999; Meltzer and McGurk 1999; Harvey and Keefe 2001; Woodward et al., 2005), they do not restore or normalize these functions. Therefore, neurocognitive impairments are an important target in treating these disorders. This has led the National Institute of Mental Health (NIMH) to sponsor a series of consensus-oriented conferences about Measurement And Treatment Research to Improve Cognition in Schizophrenia [MA TRICS], focusing on the selection of molecular targets, priorization of compounds, and determination of guidelines for clinical trial designs. The goal is to optimize the quality and relevance of further studies in the field, which will in tum accelerate the discovery of effective treatments.

As presented in Chapter 2 (Létoumeau, Simard, & Roy, paper in preparation), many potential cognitive enhancers are currently tested.in SZ and related psychotic disorders. Indeed, this review of placebo controlled trials in second-generation (SGA) treated psychotic. patients demonstrated that sorne compounds led to promising results, namely galantamine (Schubert, Young, & Hicks, 2006), buspirone (Sumiyoshi et al., 2007), guanfacine (Friedman, et al., 2001), lamotrigine (Goff et al., 2007; ZoccaH, et al., 2007), as well as the ampakine CX516 (Goff et al., 2001). Furthermore, other compounds tested in placebo-controlled studies in psychotic samples treated with a SGA or a first-generation antipsychotic(FGA), and excluded from its review, appear good candidate as potential neurocognitiveenhancers in SZ, notably modafinil (Turner et al, 2004), and nicotine (Barr et al., 2008). Modafinil (Alertec, Provigil, Modiodal) appeared particularly interesting to ' , Modafinil; étude pilote 85 assess in such patients since this central nervous system (CNS) stimulant could combine a potential neurocognitive effect (Turner, et al., 2004) with an impact on fatigue and sedation, symptoms frequently noted in SZ patients (Monti and Monti, 2004; Kane, 2008).

First, regarding its potential effect on fatigue and/or sedation, modafinil has proven its effectiveness as a wake-promoting agent in the treatment of daytime sleepiness in narcolepsy (Broughton et al., 1997; United States Modafinil in Narcolepsy Multicenter Study Group, 1998, 2000). In Canada, United States and European countries, modafinil is licensed to treat excessive daytime sleepiness caused by the chrohic shift work sleep disorder and as an adjunct to the standard treatment of sleep apnoea/hypopnoea syndrome. Furthermore, its has been proven effective in treating daytime sleepiness associated with various medical conditions such as multiple sclerosis, myotonic dystrophy, Parkinson's disease, a~d major depressive disorder (Adler, et al. , 2003; DeBattista, et al. , 2003 , 2004; Fava, et al. , 2005; Kumar, 2008; Nasr, 2004; Nieves, & Lang, 2002; Ninan, et al. , 2004; Price, & Taylor, 2005; Rasmussen, et al., 2005; Talbot, et al., 2003; Zifko 2004). Moreover, modafinil has been successfully prescribed in major depression to manage sedation caused by antidepressants (Schwartz et al., 2004), and to improve hypersorimia, depressed mood, lack of energy and lack of interest as an augmentation therapy (Menza et al. , 2000; DeBattista et al., 2004; Fava et al. , 2005; Price and Taylor 2005; Rasmussen et al., 2005) or in monotherapy (Price and Taylor 2005). These results strongly suggest that modafinil could potentially help managing fatigue and/or sedation in SZ patients. Two case series involving a total of 12 patients (Makela and Cutlip 2003; Rosenthal and Bryant 2004) suggested that modafinil in dosages of 100 to 200 mg could decrease excessive sleep duration (Makela et al. , 2003) or fatigue, and improve global functioning (Rosenthal and Bryant, 2004) without significant adverse events.

Secondly, regarding its potential neurocognitive effect, controlled trials support a positive impact of modafinil on cognition in non-sleep deprived healthy volunteers, and in attention deficit hyperactivity disorder (ADHD). In placebo-controlled trials involving healthy volunteers, modafinil significantly improved seriaI reaction times, vigilance, working and episodic memory (recognition), planning skills, and accuracy in a logical Modafinil; étude pilote 86 reasonlng task. Modafinil slowed information processlng speed resulting in a better performance on cornplex tasks (Baranski, et al. , 2004; Müller, et al., 2004; Turner, et al., 2003) suggesting a positive effect on impulsivity control, with better response inhibition as a result. Moreover, participants reported feeling more alert, attentive and energetic with rnodafinil. In ADHD, two placebo-controlled studies demonstrated that modafinil significantly improved inhibiting processes, sustained attention, immediate recognition and working memory in verbal and non-verbal modalities, as well as planning and decision . making skills (Rugino and Copley 2001 ; Turner et al. , 2004b).

In SZ, the 5 published double-blind randomized placebo-controlled (DBRPC) studies testing modafinil as a cognitive enhancer have reported conflicting results. (More in Zamir, Turner, & Sahakian, 2007; Saavedra-Velez, Yusim, Anbarasan, & Lindenmayer, 2008).

First, Turner et al. (2004a) included 20 chronic high-functioning adult SZ patients, 18 of whom were taking clozapine. U sing a crossover design, subj ects were tested in two sessions one week ap art , once after a single 200 mg dose of modafinil and once after a placebo with a battery including Cambridge Neuropsychological Test Autornated Battery (CANT AB), the digit span (W AIS), and the stop-signal (STOP) task. Modafinil showed a significant positive effect on forward and backward digit span and on attentional set shifting. A slowing in latency wa~ also observed on a complex spatial planning task.

Second, Sevy et al. (2005), using a parallel group design, assessed the effect of modafinil 200 mg or placebo on sustained attention (Continuous Performance Test Identical Pair), verbal working memory (Letter-Number Span & Oculomotor Delayed Response Test), verbal fluency (COWAT) and verbal episodic memory (Delayed Matched to Sample & Rey Auditory Verbal Learning Test) at baseline and 8 weeks later. Assessrnents occured 2 hours post-drug administration. All the 20 patients were treated with a SGA, but 5 additionally received a FGA. No differences were found between modafinil and placebo. Modafinil; étude pilote 87

Third, using a cross-over design, Spence et al. (2005) assessed functional magnetic resonance imaging (fMRI) activation during a working memory task ("2-back" task) 2 . hours after a single administration of a single 100 mg modafinil or of a placebo in 17 SZ patients. Although no group differences were observed, participants presenting the greatest anterior cingulate cortex activation presented the greatest improvements between sessions on the neurocognitive task.

Fourth, the same group conducted a second study (Hunter et al., 2006) about executive functioning using a similar methodology. At baseline, subject were administered a letter fluency task and a kinaesthetic praxis task (generation of irregular motor sequences) which was performed on two occasions during prefrontal fMRI acquisition. The irregularity generated o~ the praxis task was interpreted as an indicator of cognitive control, and was shown to be associated with the activation of dorsolateral prefrontal cortex (DLPC). No significant group effects were observed, in part due to the variability between participants. However, the administration of modafinil was associated with a greater activation of the DLPC. In addition, the baseline letter fluency results were negatively correlated with change in irregularity of sequences. This led the authors to conclude that modafinil could potentially be more effective in patients with executive impairments.

Fifth, Pierre et al. (2007) used a parallel group design to compared the impact of a 200 mg modafinil dose to that of a placebo on 20 subjects, 18 of whom were taking SGA and 2 FGA. Neurocognitive assessments at baseline and 8-week later included Trail Making B, Califomia Verbal Leaming Test, and the Degraded Stimulus-Continuous Performance Test. There were no differences between groups in neurocognitive test scores.

In summary, the results regarding the effect of modafinil on neurocognition in . chronic SZ are heterogeneous and controversial. Sorne studies demonstrated promising results whereas other studies reported negative results. This situation highlights the need for additional data. The preliminary data in SZ and other populations suggest several potential Modafinil; étude pilote 88

neurocognitive targets that include verbal working memory, attentional flexibility, sustained attention, time latency or reaction in complex tasks, decision making and inhibition. While all previous studies on modafinil focussed primarily on chronic SZ patients, its use in recent-onset psychoses, may be particularly pertinent given the peak in potential for symptomatic and functional recovery occurring during the first few years of illness. Furthermore, most studies (4 out of 5) focused on single administration, rather than prolonged administration, which thus requires further studies.

Objectives Therefore the goal of the present study was to assess the security, tolerability and potential neurocognitive and functional impact of modafinil in patients with recent-onset psychosis, and using a prolonged administration.

Methods Participants Participants were recruited at the Clinique Notre-Dame des Victoires, Québec City, Canada, a clinic specialized in the treatment and follow-up of adult patients with recent onset psychosis. The five patients included presented a DSM-IV (American Psychiatric Association 1994) diagnosis of SZ and their positive symptoms were stabilized with a single second-generation antipsychotic. They were recruited on the basis of suspected neurocognitive impairments according to their subjective impression as well as those from the treating team. These impairments were ascertained using a standardized neuropsychological assessment. AlI patients were fully informed about the purposes and procedures of the study before signing informed consent. The study was approved by the

Centre de Recherche Universite Laval Robert-Giffard Ethics Committee and IS ln accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

Drug administration procedure Modafinil was initiated at 50 milligrams per day (mg/day) and was gradually increased based on its tolerability and effectiveness up to 200mg/day, taken orally in a single dose in the moming. Modafinil; étude pilote 89

Cognitive Assessments Cognitive tests, performed at baseline and 62 to 173 days later, included the Continuous Performance Test-II (CPT-II; Conner' s 2000), the Mesulam and Weintraub CanceIlation Test (MWCT; Dawes 2000),. the Color Trail test (D'Elia et al., 1996), the Stroop Color-Word test (Golden and Freshwater 1998), the digit span subtest of the W AIS (Weschler 1997), and verbal fluency tests (FAS and animaIs; Gladsjo et al., 1999). These tests assessed, respectively, parameters of sustained and selective attention, attentional flexibility, automatic processing and inhibition, verbal span and working memory, as weIl as lexical and categorical verbal fluency. These neuropsychological tests were chosen because of their well-recognized validity, the availability of large sample-normative data (Lezak et al. , 2004; Mitrushina et al., 2005), and to avoid floor and ceiling effects.

Clinical Assessments At baseline and at the end of the study, we assessed tolerability and the . clinical impact of modafinil using the Positive And Negative Syndrome Scale (PANSS; Kay et al., 1987) the Extrapyramidal Symptoms Rating Scale (ESRS; Chouinard et al., 1980), the Clinical Global Impression (CGI; Guy 1976), the Udvald for Kliniske Unders0gelser side effect rating scale (UKU; Lingjaerde et al., 1987), the Global Assessment Functioning scale (GAF; American Psyohiatric Association 1994) and the Scale for Deficit Syndrome (SDS; Kirkpatrick et al., 1989).

Statistical-Analyses Considering the exploratory goal of this study and its smaIl sample size, no group statistics using means calculations were performed. Instead, aIl parameters were taken into consideration separately, case by case. Regarding the neuropsychological results, aIl raw scores were transformed into Z scores using relevant normative data, to standardize the performances. An improvement (or deterioration) of one standard score was required to conclude that an improvement (or deterioration) significantly occurred in a specific cognitive process. Although sorne statistical methods could be applied in single cases (e.g.,

Reliable Change Index, Jacobson, & Truax, 1991), those methods could not be used in the present study since they require information on psychometric parameters (i.e., internai Modafinil; étude pilote 90 consistency and/or test-retest coefficients; standard deviation at baseline in a normative sample) for which appropriate data were not available. Indeed, we did not have normative samples sharing the demographic characteristics of our sample, and the test-retest interval often differed from ours and was obtained generally with population who may differ from the present one in terms of liability to practice effect.

Results Table 3.1 provides demographic information regarding the participants. Tables 3.2 and 3.3 illustrate, respectively, specific neuropsychological and clinical changes following treatment with modafinil.

Case 1 Case 1 had completed one year of schooling at the university level, at the beginning of the' ~ase reportstudy. However, since the onset of psychosis, he repeatedly failed in his attempts to go back to school. At baseline, he showed no signs of active psychosis, but reported an important decline in his attention since the onset of psychosis. His request of an intervention to improve his cognitive impairments motivated our first use of modafinil. However, his performances were within normative limits, suggesting that he probably presented a high premorbid cognitive functioning. He was unemployed and lived with his family. As early as Day 16, while taking modafinil 100 mg, he spontaneously reported experiencing many improvements in his daily functioning. He particularly mentioned having more facility than before to express his ideas. This assertion was supported by a very important improvement on the categorical verbal fluency at post-test, which was not paralleled by performance on the Lexical verbal fluency task. Other cognitive improvements were observed on the CPT-II and the Color Trail Test. The improved indexes were principally related to selective attention (omissions; commissions; response style) and speed of processing verbal 'information (Time Trail A), the last being congruent with his subjective report. On the PANSS , improvements spanned conceptual disorganization, blunted affect, difficulty in abstract thinking, lack of spontaneity & flow of conversation, motor retardation, poor attention, and, disturbance of volition. The ESRS and UKU revealed no worsening and improvements on concentration difficulties, Modafinil; étude pilote 91 depression, astheniallassitude/fatigability, sleepinesslsedation, and emotional indifference . . Pinally, GAP scores increased by 20 points. This increase reflected that the subject was on welfare bertefits and unable to pursue his academic training at baseline and had successfully retumed to university at the end of the study, which eventually allowed him to hold since that time a full time competitive job.

Case 2 Case 2 had completed Il years of schooling and his IQ was in the low average. He was unemployed and was living with his family. During the trial, improvements were observed on: i) CPT-II (perseverations); ii) MWCT (targets for structured letters; time for structured symbols) and iii) the Color Trail Test (false initiations; color errors), reflecting improvements in flexibility ànd in the accuracy of selective attention, in verbal as weIl as non-verbal modalities. This improvement is however restricted to tasks in which stimuli are structured, and are thus less "resource-demanding". However, we also observed an increased impulsivity (color trail near misses) and a greater susceptibility to interference in an attentional flexibility task (col or trail interference). Results on the clinical scales showed improvement on the P ANSS, particularly related on items from the general psychopathology subscale (somatie concern, guilt feelings, poor attention). However, there were also worsening on uneooperativeness, laek of judgment and insight, volition, & impulse control. Improvements were also noted on the UKU (concentration difficulties, sleepinesslsedation, astheniallassitudelinereased fatigability, failing memory, increased duration of sleep). The GAP scores did not vary and the participant maintained a poor global functioning. Case 2 tolerated weIl the titration of modafinil up to 200 mg/day. Subjectively, he reported feeling a little more attentive but he did not spontaneously mention any marked improvement in his everyday life.

Case 3 Case 3 had completed 10 years of formaI education, was unemployed and lived autonomously in an apartment. While on modafinil 200 mg/day, he experienced a very slight increase in' auditory hallucinations, as measured by the P ANSS, that quickly abated after decreasing modafinil to 100 mg/clay. Case 3 improved on several variables' from the -Modafinil; étude pilote 92

CPT-II (Hit Reaction Time 1.84 SD), MWCT (structured letters, targets; structured symbols, targets; unstructured symbols, time), Color Trail Test (Trail A time; Trail B errors), Stroop color and word test (colored words, time), on total digit span, and on the lexical verbal fluency-test. These improvements spanned speed of information processing, accuracy to complete attentional tasks including verbal and non-verbal information, inhibition, and verbal fluency compared to baseline. However, he also showed an-increase in impulsivity (CPT-II commissions) and a worsening in reaction time constancy (CPT-II Hit Reaction Time ISI Change) in comparison to baseline. Case 3 experienced clinical improvements on the PANSS (spontaneity of speech, motor retardation) and UKU (volition, duration of sleep and emotional indifference) but GAF scores did no change significantly.

Case 4 Case 4 had completed 13 years of formaI education. He was unemployed and lived with his family. He had a few friends but no productive occupation relative to school or employment. He tolerated weIl the increase of modafinil up to 200 mg/day. He reported feeling more energetic and staying awake longer than before, with a daily sleeping duration decrease from 12 hours at baseline to 9 hours at week 16. However, he did not report feeling more alert or concentrated. In contrast to his subjective report, his neuropsychological profile was improved on several parameters including CPT-II commissions, Hit RT ISI Change & Hit SE ISI Change; MWCT time for unstructured letters & time for unstructured symbols; Color Trail test time Trail B, color errors, near misses, prompts & interference; lexical fluency, suggesting improvements in selective and sustained attention, motor control, working memory, and verbal fluency. Case 4 also on several P~NSS negative and general psychopathology items (blunted affect, emotional withdrawal, poor rapport, lack ofspontaneity and jlow ofconversation , motor retardation). The UKli revealed il11provements on concentration difficulties, astheniallassitudelincreased fatigability, sleepinesslsedation, increased duration of sleep. Importantly, at the beginning of the study, this participant was considered to present a deficit syndrome, which had resolved by the end of the study. These improvements translated in a mode st 3 point improvement on the GAP in comparison to baseline. Modafinil; étude pilote 93

CaseS Case 5 had completed 12 years of education. He lived with his family and held a sheltered job. He was particularly withdrawn and did not have friends. When the modafinil dose reached 200 mg/day, he reported feeling increased anxiety which quickly abated after decreasing dosage to 100mg/day. Case 5 reported a clearly improved alertness. The clinical scales yielded improvements on abstract thinking and lack of spontaneity and jlow of conversation as weIl as on motor retardation and in lack of judgment and insight. Moreover, on the UKU, he reported improvements on concentration difficulties and that his need to sleep decreased. His treating psychiatrist noted that Case 5' s global functioning increased by 5 point with adjunct modafinil. However, the neuropsychological performance rather decreased on parameters of the CPT-II, and the MWCT related to impulsivity, and selective and sustained attention.

Conclusion The present results suggest that the use of modafinil in patients with recent-onset psychosis patients may have neurocognitive, clinical, and functional benefits. Although no between- or within-group analyses of variance were performed, an examination of the changes in Z scores revealed a cognitive enhancement in 4 out of 5 participants on cognitive tests. In one of them (Case 1), these improvements translated into an important improvement in the day to day functioning and probably to an improvement of future outcome considering that he successfully came back to university. In regards to clinical features, aIl the participants benefited of modafinil, and these changes were judged clinically si gnifi cant. The reported improvements were particularly related to awakening/alert/sedation and duration of sleep, to negative symptoms, and to neurocognitive functions as memory and attention. Regarding the global functioning, results were more inconsistent. An improvement was observed in 3 out of 5 participants, but there was no difference in two participants when post-test was compared to baseline.

In terms of safety and tolerability, only one patient (Case 3) registered a slight exacerbation of auditory hallucinations following the administration of modafinil 200 mg/day, but these symptoms quickly decreased when the dosage was decreased. There was Modafinil; étude pilote 94

no side or adverse effects reported on the ESRS and the UKU. Therefore modafinil may be considered as safe and well-tolerated in patients with recent-onset psychosis. However, it is important to emphasize that such a treatment should be accompanied by a close monitoring of psychiatric symptoms given its limited use so far with SZ patients.

Sorne of the present results are congruent with those of previous studies regarding the effect of modafinil on cognition. Our results support those of Turner et al. (2003 ; 2004a; 2004b), who found a positive impact of modafinit on cognitive flexibility and on working memory in healthy, ADHD, and SZ adults. In the present -study, the most . congruent positive results across participants were observed on selective attention, speed of processing, and on verbal fluency. Altogether, these findings suggest that modafinil could facilitate tasks requiring thinking before selecting a response. Furthermore, the present case report assessed sorne cognitive functions that were not assessed in other clinical trials involving patients with SZ (e.g., verbal fluency). This allowed to highlights that such a cognitive function could bene fit from modafinil, which emphasizes the need for further data. Future studies will bene fit from the utilization of a wide variety of neuropsychological measures, sorne more process-specific, sorne more global, before being able to conclude that modafinil has a specific cognition-enhancing pattern in SZ.

It is noteworthy that there were striking discrepancies between patients' subjective report on modafinil effect and objective changes in neuropsychological performance. Sorne of the patients did not subjectively report the positive effects that were objectively seen on neuropsychological tests, whereas other patients reported subjective amelioration that was not objectively apparent on results of the neuropsychological tests. These findings -suggest that the cog~itive tests utilized in the present study do not necessary assess aIl the important aspects that are important- in the patients' daily life, and/or, that these two domains are differently modulated by modafinil. Another possible explanation for the discrepancy between the subjective and the objective assessment of change is related to insight. A lack of insight characterizes a part of the population suffering. from SZ and SZ spectrum disorders and studies demonstrated that there is often no correlation between neuropsychological results and subjective impressions of change (Zanello and Huguelet Modafinil; étude pilote 95

2001). Indeed, participants with SZ in the study of Turner et al. (2004a) completed visual analogue scales, and reported no significant effect. However, the investigators observed significant cognitive improvement on the scales. In studies involving healthy volunteers and ADHD patients, participants generally felt and reported the improvement registered on the neuropsychological assessment following the administration of modafinil. In these populations, insight is perhaps better than in patients with SZ·or psychosis ..

The case report format of this study, as opposed to a group study, made it possible to highlight the fact that different participants ·with SZ could benefit from modafinil in different ways, and that sorne patients benefit from modafinil while others do not. The heterogeneity of cognitive impairments, clinical symptoms, antipsychotics and concomitant treatments probably play a key role in the explanation of these discrepancies. For example, the pharmacological treatment taken by the patients included in the studies conducted by Turner et al. (2004a) and Sevy ,et al. (2005) was different. In the first study, the majority of the patients (18 out of 20) were treated with clozapine, while no participant received this molecule in the second study.This could partly explain the important discrepancies . between these two studies. In our sample, 3 out of 5 participants were treated with clozapine, and 2 of these 3 patients were cognitively improved following the introduction of modafinil. In future studies, it will be very important to consider these differences as covariables. This will contribute to address the issue of whether patients have any common clinical characteristics which would enable the prediction of a therapeutic response to modafinil.

The present study led to interesting findings but presented obvious limitations. First, this was a case report and thus there was no control group. Second, the number of participants was very small, therefore analyses of variance could not be performed because of a lack of power. Third, the results cannot be generalized as weIl as the results of a study using a larger sample. Fourth, several cognitive tests were used, and many of them were multidetermined, making it difficult to identify a specifie cognitive profile of enhancement. Finally, no alternate forms of the neuropsychological tasks were used, making it difficult to control for a practice effect. Modafinil; étude pilote 96

However, this study allows to draw sorne important conclusions for further trials with modafinil in SZ. The strong positive effect observed in most patients should also encourage further experimental investigations in the subpopulation of recent-onset SZ. More importantly, our data suggested that modafinil is a safe and well tolerated molecule in such subpopulation, and contributed to establish the inocuity of this compound when used in psychotic patients. Future randomized placebo-controlled studies will help to better establish the cognition-enhancing profile of modafinil in SZ. These future trials are also mandatory to provide information on the neuropsychological improvements that really .contribute to the functional improvement following the administration of modafinil. Modafinil; étude pilote 97

References

Addington, J., Addington, D. (1999). Neurocognitive and social functionning ln schizophrenia. Schizophrenia Bulletin, 25, 173-182.

Adler, C. , Caviness, J. N., Hentz, 1. G. , Lind, M., Tiede, J. (2003). Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease. Movement Disorders, 18, 287-293.

American Psychiatric Association (1994). DSM-IV: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American psychiatric association.

Baranski, J. V., Pigeau, P. R. , Dinich, P. , Jacobs, 1. (2004). Effects of modafinil on cognitive and meta-cognitive performance. Human Psychopharmacology, 19, 323- 332.

Barr, R. S. , Culhane, M. A., Jublert, L. E., Mufti, R. S. , Dyer, M. A., Weiss, A. P., Deckersbach, T., Kelly, J. F.; Freudenreich, O., Goff, D. C. , & Evins, A. E. (2008). The effects of transdermal nicotine on cognition in nonsmokers with schizophrenia and nonpsychiatric controls. Neuropsychopharmacology, 33, 480-490.

Bellack, A. S. , Gold, J. M., Buchanan, R. W. (1999). Cognitive rehabilitation for schizophrenia : Problems, Prospects, and strategies. Schizophrenia Bulletin, -25, 257-274.

Broughton, R. J., Fleming, J. A., George, C. F., Hill, J. D., Kryger, M. H., Moldofsky, H. , Montplaisir, J. Y., Morehouse, R. L., Moscovitch, A., Murphy, W. F. (1997). Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology, 49, 444-451.

Chouinard, G., Ross-Chouinard, A., Annable, L., Jones, B. D. (1980). Extrapyramidal Symptom Rating Scale. The Canadian Journal off!eurological Science, 7, 233-239 ~

Conner's, K. (2000). Conner's CPT-II, Continuous Performance Test II. Computer Program, for WindowsTM, Technical Guide and Software Manual. Toronto, Canada: Multi Health Systems Inc (MHS).

Dawes SE, SeniorG (2000) The Mesulam and Weintraub Cancellation Test: normative data and clinical utility. http://www.usq.edu.au/users/senior/PostersINAN%202001%20MWCT.htm

DeBattista, C., Lembke, A., Solvason, B., Ghebremichael, R. , Poirier, J. (2004). A prospective trial of modafinil as an adjunctive treatment of major depression. Journal ofClinical Psychopharmacology, 24, 87-90. Modafinil; étude pilote 98

DeBattista, C., Doghramji, K., Menza, M. A. , Rosenthal, M. H., Fieve, R. R. (2003). Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind placebo-controlled study. Journal ofClinical Psychiatry, 64, 1057-1064.

D'Elia, L. F., Satz, P., Uchiyama, C. L. , White, T.r (1996). Color Trail Test, professional Manual. Odessa, FL: Psychological Assessment Ressources, inc

Evans, 1. D., Bond, G. R., Meyer, P. S., Kim, H. W., Lysaker, P. H. , Gibson, P. J. , Tunis, S. (2004). Cognitive and clinical predictors of suècess in vocational rehabilitation in schizophrenia. Schizophrenia Research, 70, 31-342.

Fava, M., Thase, M. E., DeBattista, C. (2005). A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. Journal of Clinical Psychiatry, 66, 85-93.

Fioravanti, M., Carlone, O. , Vitale, B., Cinti, M. E., Clare, L. (2005). A meta-analysis of cognitive deficits in adults with a diagnosis of schizophrenia. Neuropsychology Review, 15, 73-95.

Friedman, J. L, Adler, D. N., Temporini, H. D., Kemether, E., Harvey, P. D., White, L. , Parella, M., & Davis, K. L. (2001). Guanfacine treatment of cognitive impairment in schizophrenia. Neuropsychopharmacology, 25, 402-409.

Fujii, D. E., Wylie, A. M. (2003). Neurocognition and community outcome in schizophrenia: long-term predictive validity. Schizophrenia Research, 59, 219-223.

Ghidsjo, J. A. , Schuman, C. C., Evan, J. D., Peavy, G. M., Miller, S. W., Heaton, R. K. (1999). Norms for letter and category fluency: Demographic corrections for age, education and ethnicity.Assessment, 6, 147-178.

Golden, C. J., Freshwater, S. M. (1998). Stroop Color and Word Test, Revised Examiner's Manual. Wood Dale: Stoelting co.

Green, M. F. (1996). What are the functional consequences of neurocognitive deficits in schizophrenia. American Journal ofPsychiatry , 153, 321-330.

Goff, D. C., Keefe, R., Citrome, L., Davy, K., Krystal, J. H., Large, C., Thompson, T. R. , Volavka, J., & Webster, E. L. (2007). Lamotrigine as add-on therapy in . schizophrenia: results of 2 placebo-controlled trials. Journal of Clinical Psychopharmacology, 27, 582-589.

Goff, D. C., Leahy, L., Berman, L, Posever, T., Herz, L. , Leon, A. C., Johnson, S. A., & Lynch, G. (2001). A placebo-controlled pilot study of the ampakine, CZ516, added to clozapine in schizophrenia. Journal of Clinical Psychopharmacology, 21 , 484- 487. Modafinil; étude pilote 99

Guy, W. (1976). ECDEU assessment manual for psychopharmacology. US department health, education, and welfare publication. Rockville, MD: National institute of mental health

Heinrichs, R. W. , Zakzanis, K. K. (1998). Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology, 12, 426-445.

Hoff, A. L. , Kremen, W. S. (2003). Neuropsychology in schizophrenia: an update. Current Opinion in Psychiatry, 16, 149-155.

Harvey, P. D., Howanitz, E. , Parrella, M. , White, L., Davidson, M. , Mohs, R. C. , Hoblyn, 1., Davis, K. L. (1998). Symptoms, cognitive functioning, and adaptive skills in geriatric patients with lifelong schizophrenia: a comparison across treatment sites. American Journal of Psychiatry, 155, 1080-1086.

Harvey, P. D. , Keefe, R. S. (2001). Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. American Journal of Psychiatry, 158, 176-184.

Hunter, M. D., Ganesan, V. , Wilkinson, 1. D., Spence, S. A. (2006). Impact ofmodafinil on prefrontal executive function in schizophrenia. American Journal of Psychiatry, 163, 2184-2186.

Jacobson, N. S., and Truax, P. (1991). Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. Journal of Consulting and Clinical Psychology, 59, 12-19.

Kane, J. M. (2008). Sedation as a side effect of the treatment of mental disorders. Journal ofClinical Psychiatry, 69, 20.

Kay, S., Fiszbein, A. , Opler, L. A. (1987). The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13, 261-276.

Keefe, R. S. E., Silva, S. G. , Perkins, D. O., Lieberman, J. A. (1999). The effects ofatypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophrenia -Bulletin, 25, 201-222.

Kirkpatrick, B., Buchanan, R. W., McKenney, P. D., Alphs, L. D., Carpenter, W. T. (1989). The schedule for the deficit syndrome: an instrument for research in schizophrenia. Psychiatry Research, 30, 119-123.

Kumar, R. (2008). Approved and investigatinal uses of modafinil: an evidence-based review. Drugs, 68,1803-1839.

Lehoux, C. , Everett, :J., Laplante, L. , Émond, C., Trépanier, J. , Brassard, A. , René, L. , Cayer, M., Mérette, C., Maziade, M., Roy, M-A. (2003). Fine motor dexterity is Modafinil; étude pilote 100

correlated to social functioning in schizophrenia. Schizophrenia Research, 62, 269- 273.

Létourneau, K., Simard, M., & Roy, M-A. Adjunct cognItIve enhancers to second generation antipsychotics for cognitive impairments in schizophrenia: a review. Paper in preparation.

Lezak, M. D., Howieson, D. B., Loring, D. W. (2004). Neuropsychological assessment, fourth edition. New-York: Oxford University Press

Lingiaerde, O. , Ahlfors, U. G. , Bech, P., Dencker, S. J. , EIgen, K. (1987). A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatrica Scandinavica, 76, 1- 100.

Makela, E. H., Miller, K. , Cutlip, W. D. (2003). Three case reports of modafinil use in treating sedation induced by antipsychotic medications. Journal of Clinical Psychiatry, 64, 485-486.

Mc Gurk, S. R. , Mueser, K. T., Harvey, P. D., LaPuglia, R. , Marder, J. (2003). Cognitive and symptom predictors of work outcomes for clients with schizophrenia in supported employment. Psychiatric Services, 54, 1129-1135.

Meltzer, H. Y., McGurk, S. R. (1999). The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophrenia Bulletin, 25, 233- 255.

Menza, M. A. , Kaufman, K. R. , Castellanos, A. (2000). Modafinil Augmentation of Antidepressant Treatment in Depression. Journal of Clinical Psychiatry, 61, 378- 381. .

Mitrushina, M., Boone, K. B., Razani, 1., D'Elia, L. F. (2005). Handbook of normative data for neuropsychological assessment, second edition. New-York: Oxford University Press

Monti, J. M., & Monti, D. (2004). Sleep in schizophrenia patients and the effects of antipsychotic drugs. Sleep Medicine Reviews, 8, 133-148.

Morein-Zamir, S., Turner, D. C., & Sahakian, B. J. (2007). A review of the effects of modafinil on cognition in schizophrenia. Schizophrenia Bulletin, 33, 1298-1306.

Müller, U., Steffenhagen, N., Regenthal, R., Bublak, P. (2004). Effects of modafinil on working memory processes in humans. Psychopharmacology, 177, 161-169.

Nasr, S. (2004). Modafinil as adjunctive therapy in depressed outpatients. Annals of Clinical Psychiatry, 16, 133-138. Modafinil; étude pilote 101

Nieves, A. V., Lang, A. E. (2002). Treatment of Excessive Daytime Sleepiness in Patients with Parkinson's Disease with Modafinil. Clinical Ne uropharmacology, 25, 111- 114.

Ninan, P. T. , Hassman, H. A. , Glass, S. J. , McManus, F. C. (2004). Adjunctive modafinil at initiation of treatment with a selective serotonin reuptake inhibitor enhances the degree and onset on therapeutic effects in patients with major depressive disorder and fatigue. Journal of Clinical Psychiatry, 65, 414-420.

Pierre, 1. M., Peloian, J. H. , Wirshing, D. A. , Wirshing, W. C., Marder, S. R. (2007). A randomized, double-blind, placebo-controlled trial of modafinil for negative symptoms in schizophrenia. Journal of Clinical Psychiatry, 68, 705-710.

Price, C. S. , Taylor, F. B. (2005). A retrospective chart review of the effects of modafinil on depression as monotherapy and as adjunctive therapy. Depress Anxiety, 21, 149- 153.

Rasmussen, N-A., Schroder, P., Olsen, L. R. , Brodsgaard, M. , Bech, M. U. P. (2005). Modafinil augmentation in depressed patients with partial response to antidepressants: a pilot study on self-reported symptoms covered by the major depression inventory (MDI) and the symptom checklist (SCL-92). Nordic Journal of Psychiatry, 59, 173-178.

Rosenthal, M. H., Bryant, S. L. (2004). Benefits of adjunct modafinil in an open-label, pilot study in patients with schizophrenia. Clinical Neuropharmacology, 27, 38-43.

Rugino, T. A., Copley, T. C. (2001). Effects of modafinil in children with attention deficitlhyperactivity disorder: an open-label study. Journal of the American Academy ofChild and Adolescent Psychiatry, 40, 230-235.

Saavedra-Velez, C., Yusim, A. , Anbarasan, D., & Lindenmayer, J-P. (2008). Modafinil as an adjunctive treatment of sedation, negative symptoms, and cognition ln schizophrenia: a critical review. Journal ofClinical Psychiatry, pii: ej07m03982

Schubert, M. H., Young, K. A., Hicks, P. B. (2006). Galantamine improves cognition in schizophrenic patients stabilized on risperidone. Biological Psychiatry, 60, 530- 533.

Schwartz, T. L., Azhar, N., Cole, K., Hopkins, G. , Nihalani, N., Simionescu, M. , Husain, 1., Jones, N. (2004). An open-label study of adjunctive modafinil in patients with sedation related to serotonergic antidepressant therapy. Journal of Clinical Psychiatry, 65, 1223-1227.

Sevy, S., Rosenthal, D. O., Alvir, J., Meyer, S., Visweswaraiah, H., Gunduz-Bruce, H~ , Schooler, N. R. (2005). Double-blind, placebo-controlled study of modafinil for fatigue and cognition in schizophrenia patients treated with psychotropic medications. British Journal ofPsychiatry , 66, 839-843. Modafinil; étude pilote 102

Spence, S. A. , Green, R. D., Wilkinson, 1. D. , & Hunter, M. D. (2005). Modafinil modulates anterior cingulate function in chronic schizophrenia. British Journal of Psychiatry, 187, 55-61 .

Sumiyoshi, T., Park, S. , jayathilake, K. , Roy, A. , Ertugrul, A. , & Meltzer, H. Y. (2007). E ffe ct of buspirone, a serotoninlA partial agonist, on cognitive function in schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophrenia Research, 95, 158-168.

Talbot, K. , Stradling, J. , Crosby, J. , Hilton-Jones, D. (2003). Reduction in excess daytime sleepiness by modafinil in patients with myotonic dystrophy. Neuromuscular Disorders, 13, 357-364.

Taylor, F. B., Russo, J. (2000). Efficacy of modafinil compared to dextroamphetamine for the treatment of attention deficit hyperactivity disorder in adults. Journal of Child and Adolescent Psychopharmacology, 10, 311-320.

Turner, D. C. , Robbins, T. W. , Clark, L. , Aron, A. R., Dowson, J. , Sahakian, B. J. (2003). Cognitive enhancing effects of modafinil ln healthy volunteers. Psychopharmacology, 165, 260-269.

Turner, D. C., Clark, L. , Pomarol-Clotet, E., McKenna, P., Robbins, T. W., Sahakian, B. 1. (2004a). Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharmacology, 29, 1363-1373.

Turner, D. C. , Clark, L. , Dowson, J., Robbins, T. W. , Sahakian, B. J. (2004b). Modafinil improves cognition and response inhibition in adult attention de fi cit/hyperactivity disorder. Biological Psychiatry, 55, 1031-1040.

United States Modafinil in Narcolepsy Multicenter Study Group. (1998). Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Annals of Neurology, 43, 88-97.

United States Modafinil in Narcolepsy Multicenter Study Group. (2000). Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology, 54, 1166-1175.

Velligan, D. L, Bow-Thomas, C. C., Mahurin, R. K. , Miller, A. L. , Halgunseth, L. C. (2000). Do specific neurocognitive deficits predict specific do mains of community function in schizophrenia? The Journal of Nervous and Mental Disease, 188, 518- 524.

Wechsler, D. (1997). Wechsler Adult Intelligence Scale - III, Technical Manual. USA: The Psychological Corporation.

Woodward, N. D., Purdon, S. E., Meltzer, H. Y., Zald, D. H. (2005). A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in Modafinil; étude pilote 103

schizophrenia. The international Journal of Neuropsychopharmacology, 8, 457- 472.

Zanello, A. , Huguelet, P. (2001). Relationship between subjective cognitive symptoms and frontal executive abilities in chronic schizophrenie outpatients. Psychopathology, 34, 153-158.

Zifko, U. A. (2004). Management of fatigue in patients with multiple sclerosis. Drugs, 64, 1295-1304.

ZoccaH, R. , Muscatello, M. R. , Bruno, A. , Cambria, R. , Mico, U. , Spina, E. , & Meduri, M. (2007). The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenie patients: a double-blind, placebo-controlled study. Schizophrenia Research, 93, 109-116. Modafinil; étude pilote 104

Tables

Table 3.1 Patients and Treatment Characteristics

Pharmacolo gical Time with Modafinil' s final Case Age/Sex DSM-IV Diagnoses Treatments and modafinil (optimal) dosage dosage per day (days) per day

1 24/male U ndifferentiated SZ Clozapine 500mg 138 100mg Undifferentiated SZ 2 Quetiapine 300mg 19/male Social phobia 173 200 mg Citalopram 80mg OCD Paranoïd SZ 3 24/male Social phobia Clozapine 225mg 63 100 mg (probable) SZ 4 Olanzapine 15mg 26/male Social pho bia 115 200 mg Citalopram 40mg (probable) Clozapine 350mg 5 Paranoïd SZ 22/male Citalopram 60mg 62 200 mg Social phobia

SZ = Schizophrenia; OCD = Obsessive-compulsive disorder Modafinil; étude pilote 105

Table 3.2 Resl!.0nse to Modafinil on Neur0l!.sJ:,.cholosJcal Tests (Standard Deviation change) Case CPT-II MWCT Color Trail Stroop Digit span Verbal fluency Omissions + 1.21 Time part A + 1.20 1 NIA Commisions + 1.5 NIA NIA AnimaIs +2.60 Response stY le + 1.16 Near misses -2.00 Structured letters Near misses +4.09 targets + 1.35 Part B, errors +3.80 2 Perseverations + 1. 92 Structured symbols No change No change No change time + 1.71 Prompts -2.28 Interference -1.1 7 Structured letters targets + 1.11 Reaction times + 1. 84 Time part A + 1.10 Colored 3 Structured symbols, Total +1 .33 FAS +1 .95 Part B, errors + 1.21 words + 1.10 · Commissions -1.55 targets + 1.33 Rit RT ISI -1.02 Unstructured symbols, Time +1.12 Time part B + 1.50 U nstructured letters, Commisions +1.29 Part B, errors + 1.37 4 time +1.92 Rit RT ISI + 1.00 Near misses +1.54 No change No change FAS +1.20 Unstructured symbols, Rit SE ISI + 1.54 Prompts + 1.54 time +1.07 Interference + 1.15 Structured letters, Omissions -6.32 time +1.19 d' -1.23 5 Perseverations -6.04 Structured letters, No change No change No change No change Rit SE ISI -1.58 targets -3.33 Structured symbols, targets -1.33

CPT -II: Continuous Performance Test-II; Hit RT ISI : Hit Reaction Time, Inter-Stimulus Interval; HIT SE ISI : Hit Reaction Time Standard Error, Inter-Stimulus Interval; MWCT: Mesulam and Weintraub Cancellation Test; SD : Standard Deviation Modafinil; étude pilote 106

Table 3.3 SubscaZes ChanB,.es (exe.ressed in raw scores) Following Modall.nil Treatment Case PANSS ESRS UKU GAF CGI Subseale Pre Post Subseale Pre Post Subseale Pre Post Pre Post Effieaey & Side effeets 12 9 Psyehie 15 6 Marked. Vast improvement. Positive Parkinsonism 1 1 1 14 8 Neurologie 2 2 Complete of nearly complete Negative Dystonia 0 0 51 71 26 18 Autonomie 4 4 remission of an symptoms. General Dyskinesia 0 0 Total 52 35 Other 0 0 No side effeet. 17 16 Psyehie 17 4 Minimal. Slight improvement Positive Parkinsonism 2 2 2 26 26 Neurologie 3 7 whieh doesn't alter status of eare Negative Dystonia 0 0 40 40 43 39 Autonomie 4 1 of patient. General Dyskinesia 2 1 Total 86 81 Other 2 1 No side effeet. Marked. Vast improvement. Positive 10 Psyehie 5 3 Il Parkinsonism 3 2 Complete of nearly complete 3 Negative 16 14 Neurologie 0 0 Dystonia 0 0 55 55 remission of an symptoms. General 27 24 Autonomie 3 1 Dyskinesia 0 0 Side effeets do not signifieantly Total 53 49 Other 0 0 interfere with funetioning.

Positive 9 8 Psyehie 17 12 Moderate. Deeided Parkinsonism 14 7 4 Negative 21 16 Neurologie 4 3 improvement. Partial remission Dystonia 0 0 45 48 General 34 29 Autonomie 1 1 of symptoms. Dyskinesia 1 0 Total 64 53 Other 0 0 No side effeet.

Positive 11 · 10 Psyehie 6 4 Moderate. Deeided Parkinsonism 3 3 Negative 28 21 Neurologie 1 1 improvement. Partial remission 5 Dystonia 22 13 50 55 General 25 20 Autonomie 5 4 of symptoms. Dyskinesia 0 '0 Total 64 51 Other 2 2 No side effeet. CHAPITRE 4: TROISIÈME ARTICLE

A lO-week, double-blind, placebo controlled, cross-over trial of adjunctive modafinil for neurocognitive impairments in schizophrenia A 10-week, double-blind, placebo controlled, cross-over trial of adjunctive modafinil for neurocognitive impairments in schizophrenia

Karine Létoumeau 1, 3, MPs, Ph.D. Candidate in Psychology Martine Simard 1, 3, PhD Marie-France Demersl ,2, B Pharm, MSc Claudia Emond, , 1 , MSc Chantal Mérette, l , PhD Roch-Hugo Bouchard, 1,2,4, MD, FRCP Marc-Andé Royl,2,4, MD, MSc (epidemiology), FRCP

1. Centre de Recherche Université Laval Robert-Giffard, 2601 chemin de la Canardère, Québec, Québec, Canada, G1J 2G3 2. Clinique Notre-Dame des Victoires, Centre Hospitalier-Robert-Giffard, 70 Dalhousie, bur. 40, Québec, Québec, Canada, G1K 4B2 3. Laval University, School ofPsychology , Local 1116, Pavillon F.-A. Savard 2325 rue des Bibliothèques, Québec, Québec, Canada, G1 V OA6 4. Laval University, Department ofPsychiatry , Faculty ofMedicine , Pavillon Ferdinand- Vandry, 1050, avenue de la Médecine, Québec, Québec, Canada, G1VOA6

[email protected], phone: (418) 663-5741 ext. 4764, Fax: (418) 663- 5971

Aknowledgments: This study was not sponsored and therefore, there is no financial relationship to disclose. Modafinil; étude expérimentale 109

Résumé Bien que quelques études de cas, dont celle présentée au chapitre précédent, suggèrent que le modafinil puisse être un adjuvant cognitif efficace dans le traitement de la schizophrénie, les résultats des études contrôlées sont contradictoires, et l'étendue des domaines cognitifs y étant étudiée est limitée. La présente étude a ainsi pour but de vérifier les effets de modafinil sur le fonctionnement neurocognitif d'individus souffrant d'un trouble du spectre de la schizophrénie, et présentant des· déficits neuropsychologiques sur des tâches ·évaluant le fonctionnement attentionnel. Sa méthodologie, différente de celle de la première étude, de même que la taille de l'échantillon, confèrent à cette deuxième étude une valeur scientifique accrue, en permettant de distinguer les effets de pratique ou d'évolution spontanée des effets spécifiques de la molécule. Des individus étant traités à l'aide d'un antipsychotique de seconde génération et présentant des déficits attentionnels ont complété cette étude expérimentale, d'une durée de dix semaines, réalisée en double aveùgle, avec contrôle placebo, et menée en chassé-croisé. Les participants ont été évalués à quatre reprises à l'aide d'épreuves neuropsychologiques permettant l'évaluation de la vitesse de traitement de l'information, de l'attention sélective en modalité visuelle, de l'attention soutenue, de l'inhibition et de la flexibilité, de la mémoire à court terme en modalités verbale et visuelle, ainsi que de la flui~ité verbale lexicale et sémantique. Diverses échelles cliniques ont aussi été administrées afin de détailler l'effet de modafinil au plan de la symptomatologie psychotique, des effets indésirables, de l'amélioration clinique globale, et du fonctionnement. Trente et un participants ont complété l'évaluation de base, ~8 ont été randomisés aux deux conditions expérimentales, et 20 d'entre eux ont complété leur participation. Au plan neuropsychologique, le modafinil s'est montré supérieur au placebo pour améliorer la fluidité verbale sémantique, la mémoire à court terme en modalité verbale, de même que l'aptitude à repérer des cibles présentées visuellement parmI des distracteurs. Sur le plan clinique, le modafinil a mené à une amélioration subjective de la mémoire, de même que de l'asthénie, ou fatigue. En conclusion, le modafinil semble faciliter l'initiation de la réponse dans des domaines neurocognitifs variés, en plus de diminuer la fatigue vécue par les participants. Il demeure ainsi une alternative en tant qu'éventuel adjuvant neurocognitif, et pour le traitement de la fatigue chez les gens souffrant d'un trouble du spectre de la schizophrénie. Modafinil; étude expérimentale 110

Abstract

Although so~e open-label studies, including the one presented in the preVlOUS chapter, suggested that modafinil could be an effective cogn,itive enhancer in schizophrenia, results from controlled studies were contradictory whereas the scope of the cognitive domains that they assessed was limited. Therefore, the aim of the present study was to assess the effects of modafinil on neurocognition in participants suffering from a schizophrenia spectrum disorder. Themethod and sample size of the present trial differed from that of the previous study which confers an increased scientific value to this second study, by allowing to distinguish practice and spontaneous improvements from the compound's effects. The participants who showed atlentional impairments were treated with a second-generation antipsychotic and completed this 10-week double-blind, placebo controlled cross-over study. The participants were assessed on four occasions with neuropsychological tests assessing information processing speed, visual selective attention, sustained attention, inhibition, cognitive flexibility, verbal and visual working memory, as weIl as lexical and semantic verbal fluency. Clinical scales were also used to assess psychotic symptoms, side effects, clinical global improvement, and global functioning. Thirty-one participants took part in the initial assessment, 28 were randomized in the two experimental conditions, and 20 out of them completed the entire assessments. In regards to the neuropsychological variables, modafinil compared to placebo significantly improved semantic verbal fluency, verbal working memory, and the ability to detect visual targets among distractors. ClinicaIly, modafinil significantly improved subjective memory, as weIl as fatigue. In conclusion, modafinil does not seem to lead to specific improvements in processing speed, but rather, to facilitate response initiation in various neurocognitive domains. Therefore, modafinil remalns an interesting alternative as a potential neurocognitive enhancer and a treatment for sorne negative symptoms of the schizophrenia spectrum disorders. Modafinil; étude expérimentale 111

Introduction Many studies over the last decades have established that schizophrenia (SZ) and SZ spectrum psychotic disorders (SZSPD) are characterised by cognitive deficits in various cognitive domains such as attention, memory, and executive functioning, as weIl as in motor functions (Fioravanti, Carlone, Vitale, Cinti, & Clare, 2005; Heinrichs & Zakzanis, 1998; Hoff & Kremen, 2003; Lehoux, et al. , 2003). These deficits are inherent to the iIlness since they often precede the onset of positive symptoms, are present in the early phases of the illness, persist in periods of remission, and are also present, although to a lesser severity, in non-psychotic relatives (Bilder, et al. , 2000; Hambrecht, Lammertink,

Klosterkotter, Matushek, & Pukrop, 2002; Saykin, et al., 1994; Townsen, and Norman, 2004). Moreover, the severity of cognitive deficits is often found to better predict functioning than the severity of symptom does (Green, 1996; Green, Kem, Braff, & Mintz, 2000), which may suggest that improving cognitive deficits could improve functioning

(Harvey, Green, Keefe, & Velligan, 2004). Consequently, the development of effective treatments for cognitive impairments associated with SZ becomes a crucial issue .

. A first group of studies have assessed the impact of available antipsychotics on cognitive performance, and have suggested that second generation antipsychotics (SGA), as weIl as low-dose first-generation antipsychotics (FGA; e.g. perphenazine) can improve global cognition and sorne specific cognitive functions. However, these medications did not normalize cognition (Harvey, & Keefe, 2001; Keefe 2007; Keefe, Silva, Perkins, & Lieberman, 1999; Meltzer, & McGurk, 1999; Mishara and Goldberg, 2004; Purdon, et al., 2000; Weiss, Bilder, & Wolfgang Fleischhacker, 2002; Woodward, Purdon, Meltzer, & Zald, 2005). This finding led to clinical trials testing the efficacy of various compounds to especially deal with neurocognitive impairments in SZ and SZSPD. The molecules generally target the neurotransmitter' s systems believed to be dysfunctionnal in SZ or known to modulate cognitive domains typically impaired in SZ. As such, many clinical trials were conducted since the end of the 1990s (Létoumeau, Simard, & Roy, paper in preparation, see Chapter 2). Modafinil; étude expérimentale 112

Modafinit2 is among the compounds tested for their possible effects on cognition in psychotic disorders. It is a central nervous system (CNS) stimulant, currently indicated in United States of America (USA), Canada, and Europe for the treatment of daily sleepiness associated to narcolepsy, sleep apnea, and shift wor~ disorders (Bittencourt, et al. , 2008; Morgenthaler, et al. , 2007; Nishino, 2007)3. Modafinil has also been studied since the mid nineties for its psychostimulant properties in other medical conditions. Many data suggest the efficacy of modafinil for treating tiredness associated with various conditions, such as Parkinson's disease, multiple sclerosis, muscular dystrophy, major depressive disorder, and the chronic fatigue syndrome, fibromyalgia, and Lyme' s disease (Adler, et al. , 2003 ;

Menza, Kaufman, & Castellanos, 2000; Nieves & Lang, 2002; Talbot, et al., 2003; Zifko, 2004).

The stimulating effect of modafinil is dose-dependant (Chapotot, Pigeau, Canini,

Bourdon, & Buguet, 2003; Touret, Sallanon-Moulin, & Jouvet, 1995). The first studies comparing the effect of modafinil to that of conventional psycho stimulants showed that unlike conventional psychostimulants, it does not modify the wake-sleep cycle, and it does not lead to a compensatory augmentation of paradoxical sleep, i.e. sleep rebound (Saletu, et al., 1989; Touret, Sallanon-Moulin, and Jouvert, 1995). Furthermore, its potential of abuse is inferior to that of the conventional stimulants, based on subjective, behavioural, and physiological responses from polysubstance abusers (Jasinski, 2000; Jasinski, & Kovacevié-Ristanovié, 2000).

Modafinil' s mode of action is not perfectly understood although it likely involves interactions between several neurotransmitter systems as adrenaline (Duteil, et al., 1990; Lin, et al. , 1992, 1996; Mignot, et al., 1994; Stone, et al. , 2002), serotonin (de Saint-Hilaire, et al., 2001; Ferraro, et al., 2002), dopamine (Mignot, et al., 1994; Ferraro, et al., 1996; Nishino, et al., 1998; Sebban, et al., 1999, de Saint-Hilaire, et al., 2001), glutamate (Touret, et al., 1994; Ferraro, et al., 1999), and histamine. Modafinil also seems to modulate orexins

2 Alertec, Attenace, Modavigil, Modiodal, Provigil, Sparlon, and Vigil 3 Armodafmil, the R-enantiomer of modafmil, that has a comparab1e mode of action from the one of modafinil, is approved for the same indications since june, 15 2007 in USA. Modafinil; étude expérimentale 113

(hypocretins) (Chemelli, et al. , 1999; Scammel, et al., 2000), neuropeptides originating exclusively from lateral hypothalamic neurons. This system may be complementary to moaminergic and cholinergic systems for generation of the sleep/wake cycle regulation (Espana, et al., 2001; Hungs and Mignot, 2001). However, as mentionned by Minzenberg and Carter (2008), and as suggested by a recent animal study (Mitchell, et al. , 2008), the only two neurotransmitters currently known to be directly involved in its mechanism of action are noradrenaline and dopamine (DA). According to the available data, the neurochemical variations occurring in the systems of adrenaline, serotonin, gamma aminobutyric acid, glutamate, and orexines, would depend at least in part from variations in the noradrenaline and DA systems. A possible explanation for the differences observed between the effects of modafinil and conventional psycho stimulants may lie in the fact that the DA promoting effect of low dosages of modafinil is mainly observed in the neocortex, and minimally in subcortical areas (Minzenberg, & Carter, 2008).

Only a few open-label and randomized studies tested the impact of modafinil in individuals with SZ. Because of its indications for sleepiness following various medical conditions, the first two studies conducted in psychotic patients focussed on antipsychotic associated fatigue and/or sedation (Makela, Miller, & Cutlip, 2003; Rosenthal, & Bryant, 2004), and showed positive effects of modafinil on these targets. Rosenthal and Bryant (2004) also assessed verbal working memory using the letter-number sequencing subtest from the Weschler Adult Intelligence Scale, third edition (WAIS-III). This open-label study yielded improvements of performance on this subtest suggesting that modafinil might be a potential cognitive adjunct in SZ, as tested in 5 published randomized, placebo controlled clinical trials of modafinil in SZ (see Table 4.1). Although aIl these studies used cognitive measures, only three of them were mainly interested in the neuropsychological impact of modafinil (Turner, et al., 2004; Pierre, et al., 2007; Sevy, et al., 2005). The other two studies were designed to verify the neurophysiological effects of modafinil in SZ patients, using functional magnetic resonance imaging (Hunter, Ganesan, Wilkinson, & Spence, 2006; Spence, Green, Wilkinson, & Hunter, 2005). It is noteworthy that, among the three neuropsychopsychological studies, only that using a more robust design (i.e., a cross-over design) and the m,ost comprehensive test battery (Turner, et al., 2004) revealed a significant Modafinil; étude expérimentale 114 advantage of modafinil over placebo on a verbal working memory task (digit span subtest from the W AIS-III - forward & backward), and on a test of cognitive flexibility (Cambridge Neuropsychological Test Automated Battery [CANTAB] intra dimensional/extradimensional shift). Further data from weIl designed, placebo-controlled studies are clearly needed to further test the usefulness of modafinil for treating neurocognitive impainnents in SZ attempts at replicating Turner et al. (2004) results have yet to be published. The present study was thus designed to provide additional data on one of the most impaired function in SZ, attention, using the categorisation of vanZomeren & Spikman (2003) for the selection of neuropsychological tests.

Insert Table 4.1 about here

We chose to particularly focus on attention because: i) this domain typically yields sorne of the largest effect sizes in studies comparing SZ patients with controls; ii) impainnents in these domains are among the principal subjective complaints expressed by patients; iii) attention is among the most robust detenninants of social functioning in patients (Green 1,996; 2000); IV) attention is a precondition to other higher-order cognitive domains in SZ (e.g., verbal memory, Brébion, David, Bressan, & Pilowsky, 2006; Holthausen, et al., 2003; working memory; Hartman, Steketee, Silva, Lanning, & McCann, 2002; executive functioning, Bowie, and Harvey, 2005); thus, improvement in attention is likely to improve other cognitive functions as weIl; v) attention and vigilance tasks are less prone to practice effect than memory and executive function tasks (Szoke, et al. , 2008); vi) the evidence cited above suggest that modafinil may be especially effective in improving attention, and attentional tasks.

Designing a battery 'to assess attention requires choosing among a large number of potentially interesting tasks. Our choice was guided by the categorization of van Zomeren, and Spikman (2003) whose factor analyses challenged the usual categorization of attention Modafinil; étude expérimentale 115

tasks into selective attention, divided attention, and attentional control. They rather proposed two major dimensions for the realisation of attentional tasks, i.e., spe.ed of processing and control, and they proposed to categorize attentional tasks on a continuum taking these two characteristics into consideration, as shown in Figure 4.1.

Insert Figure 4.1 about here

Three levels are included: operational, tactical, and strategical. At the operational level, the speed is the main determinant while control is minimal. The temporal pressure is very high and the individual is pro~ided clear instructions to respond as rapidly as possible, and/or ~timuli are presented rapidly. Moreover, operational tasks are highly structured and stimuli and responses are simple. Thus, response latency is the main variable of interest. Therefore, alertness tasks involving simple reaction times are the best paradigms to illustrate the operationallevel. Tasks from the tacticallevel are intermediate between those from the operational and the strategicallevels. Indeed, in tactical tasks, temporal pressure is as important as the task structure. Moreover, the control to apply is clearly explained in the instructions. Thus, a good performance requires combining speed and control. Cancellation tasks illustrate the tactical level. In these tasks, examinees know which targets are to be cancelled. These tasks are «memory govemed » because rules and instructions must be active in working memory for an optimal realization. FinaIly, the strategic level combines tasks involving a minimum level or no speed compoIient at aIl. Individuals must use a personal approach because the instructions do not entirely explain what must be done to properly realize the tasks. GeneraIly, strategic level tasks assess executive functions.

General and Specifie Objectives The aim of the present study was to assess, using a cross-over double-blind placebo controlled design and prolonged administration of the molecule, the impact of modafinil in SGA-treated patients with SZ or SZSPD on attentional functions at the operational and Modafinil; étude expérimentale 116 tactical levels (van Zomeren, & Spikman, 20'03). Available evidence on the effect of modafinil does not justify the extensive use of strategic level attention tasks at this moment.

The primary hypothesis was that modafinil will significantly improve alertness and speed of processing, and this will translate into improvements in operational and tactical tasks. This way, reaction time and processing speed diminutions shall be significantly improved during the modafinil treatment phase compared to the placebo phase. This hypothesis was guided by the "processing speed hypothesis" of neuropsychological impairments in SZ which stipulates that a slowing in processing speed underlies various neurocognitive-impairments, as observed in several studies (Brébion, David, Bressan, & Pilowsky, 2006; Hartman, Steketee, Silva, Lanning, & McCann, 2002; Holthausen, et al. , 2003; Rodriguez-Sânchez, Crespo-Facorro, Gonzalez-Blanch, Pérez-Iglesias, & Vasquez Barquero, 2007).

A second objective was to assess the effect of a combination of a SGA and modafinil on global functionning, clinical change, and negative symptoms. It was hypothesized that modafinil will significantly improve global functionning, clinical change, and negative symptoms, in comparison to placebo.

A third objective was to assess the safety and tolerability of a combination of a SGA and modafinil. The hypothesis was that modafinil will not significantly worsen psychosis, as well as side effects in comparison with placebo.

Methods Participants, screening and recruitment Participants were recruited at the clinics specialized in the treatment of SZ and SZSPD adult outpatients at the Institut Universitaire de Sant'é Mentale de Québec, Québec City, Canada. These clinics are. Participants were referred by their treating psychiatrist to the research team. Criteria to consider inclusion in the trial were: 1) a diagnosis of SZ or SZSPD (schizoaffective disorder, schizophreniform disorder, delusional disorder, brief Modafinil; étude expérimentale 117 psychotic disorder) according to the DSM-IV criteria (American Psychiatric Association [APA] , 1994); 2) being aged 18 or more; 3) stabilization of psychotic symptoms with a single SGA administrated at a fixed dose for at least four weeks (cl?zapine, quetiapine, risperidone, or ziprasidone), as reflected by scores of:s 4 on aIl items of the Positive And Negative Syndrome Scale (PANSS); and 4) attentional impairments had to be suspected by the referring treating team.

Exclusion criteria were: 1) a diagnosis of mental retardation (APA, 1994); 2) presence of a neurological disease that could account for neurocognitive impairments ; 2) a diagnosis of panic disorder (AP A, 1994) and suffering from moderate to severe anxiety according to the treating psychiatrist; 3) important suicidaI potential according to the psychiatrist; 4) high blood pressure or a cardiac disorder (e.g. arhythmia); 5) taking other medications than SGA or street drugs, or natural products having psychostimulant effects and, 6) for women, being pregnant or breast feeding, or not using an effective contraceptive method (modafinil could decrease the effectiveness of oral contraceptives).

After being contacted by the research team, potential participants were informed about the purpose and methods of the trial, and signed an informed written consent. The study was approved by the institute Ethical Committee and Health Canada. After the initial interview, the suspected attentionnal impairments were ascertained using the neurocognitive battery. Patients were included in the trial if at least one main parameter of the battery reached a critical value of Z ~ -1.00, which is accepted as reflecting counter performances or "midI y impaired" function (Bowie, & Harvey, 2005; Ehrenreich, et al., 2007). Participants were then randomly assigned to one of the two trial sequences: 1) modafinil first, then placebo, OR, 2) placebo first, then modafinil:

Randomisation ·and Drug Administration Procedure Table 4.2 illustrates the design of the study. Modafinil and placebo tablets were over-encapsulated to be indistinguishable and packages containing sequences of modafinil/placebo and placebo/modafinil were prepared. Packages were identified using Modafinil; étude expérimentale 118

computer-generated randomised numbers. Participants were then allocated to either sequences according to their order of entry in the trial. The randomization was concealed using opaque envelopes to keep assessors and patients blind to the group condition. The treatment was initiated with one tablet per day of either modafinil 100 mllIigrams (mg) or of placebo. After the second week, participants were met by the research team and they completed a second clinical assessment to ensure that they tolerated the treatment. The dose was then increased to a maximum of two tablets daily of modafinil 100mg or of placebo. The dose of 200mg was chosen as a compromise between efficacy and safety given the risk of psychotic exacerbation documented in previous studies of higher dosages. This dosage was maintained for another 2 weeks during which it could be titrated down to one tablet daily of either modafinil or placebo in the event of tolerability/safety issues. This first treatment phase lasted a total of 4 weeks after which a two-week wash-out period followed to avoid a carry-over effect of modafinil. During the second cross-over treatment phase, the patient was administered the treatment that was not administered during the first stage, using a procedure identical to that of the first stage. Thus, participants who completed the whole trial were involved for a total qf 10 weeks and were clinically assessed six times and received cognitive assessments on 4 occasions. AlI participants received 5.00$ (CAN) for each study visit as a transportation fee to attend assessment sessions. There was no folIow up after the 10-week trial period.

Insert Table 4.2 about here

Neuropsychological Assessment One subjective questionnaire on neurocognition and eight neuropsychological tasks were used to compare the effects between modafinil and placebo on neurocognition. While six out of the eight tasks were included to assess the operationnal and tactical levels of the van Zomeren and Spikman's categorization (2003), two tasks were included because they have yielded important improvement in our open-label study of modafinil in SZ subj ects (Létoumeau, et al., paper in preparation, see Chapter 3). Modafinil; étude expérimentale 119

The neuropsychological seSSIons started with Cognitive Failures Questionnaire . ([CFQ]; Broadbent, Cooper, FitzGerald, & Parkes, 1982) which was used to assess the participant's subjective impression about the effect of modafinil, as self-observed during daily life activities. This self-report includes 25 items concerning various daily life attentionnal and memory failures occurring in the last weeks (during the trial, since implementing treatment) for which the participants chose one out of 5 degrees of occurrence from "never" (score = 0) to "very often" (score = 4; worst possible total score = 100). The CFQ is validated to emphasize cognitive difficulties associated with various conditions such as attention deficitlhyperactivity disorder (Wallace, Kass, & Stanny, 2002). AlI items are positively inter-correlated to each other and internaI consistency was found to be good (Cronbach's alpha = 0.91). It has very good test-retest reliability (correlation = 0.82 over a two month interval; Vom Rofe, Mainemarre, & Vannier, 1998). This instrument was translated into French language for the purpose of the study.

As previously stated, the neuropsychological tasks were chosen to assess operational and tactical levels from the categorization of van Zomeren, & Spikman (2003) and to further test the hypotheses raised by our pilot study (Létoumeau, et al., paper in preparation, see Chapter 3). The tasks included: 1) the Psychomotor Vigilance Task ([PVT-

192]; Dinges, & Powell, 1985), 2) the Continuous Performance Test - second edition ([CPT-II]; Conners, 2000), 3) the Mesulam and Weintraub Cancellation Test ([MWCT]; Mesulam, 1985), 4) the Syrnbol Digit Modalities Test ([SDMT]; Smith, 1982), 5) the Delis

Kaplan Executive function System battery ([D-KEFS]; Delis, Kaplan, & Kramer, 2001) Color-Word Interference Test, 6) Trail Making Test (TMT), 7) and verbal fluency subtests, 8) the Wechsler Adult Intelligence Scale - third edition ([WAIS-III]; Wechsler, 1997a) digit span subtest, and 9), the Wechsler Memory Scale - third edition ([WMS-III] ; Wechsler, 1997b) spatial span subtest. Details on the cognitive battery are presented in the Table 4.3. Table 4.5 presents the variables used in the statistical analysis as well as the classification according to van Zomeren & Spikman (2003). Modafinil; étude expérimentale 120

Insert Table 4.3 about here

Clinical Assessmenls Safety, tolerability and clinical status were assessed at baseline and post-test in the modafinil and placebo phases, as weIl as in the middle of each phase, after two weeks of treatment with each of the two compounds. The four pre-post assessments measured changes following treatment, whereas the two "middle-phases" assessments were done to ensure safety before dose increase. The clinical scales assessed psychosis related symptoms, side effects, adherence, attitude towards medication, global functioning and global clinical improvement.

Psychotic symptoms were assessed using the Positive And Negative Syndrome

Scale ([PANSS]; Kay, Opler, & Fiszbein, 1987), and the Schedule for the Deficit Syndrome ([SDS]; Kirkpatrick, Buchanan, McKenney, Alphs, & Carpenter, 1989). The P ANSS is a thirty-item clinical scale that was developed following a data collection on 101 participants aged from 20 to 68 years old. It contains 18 items adaptated from the Brief

Psychiatric Rating Scale (Overall, & Gorham, 1962), and 12 items from the Psychopathology Rating Schedule (Singh, & Kay, 1975). Seven items assess positive symptoms, seven assess negative symptoms, and 16 assess general psychopathology (e.g., anxiety, depression). A complete definition of the intensity of aIl symptoms allows the rating on the seven-point rating scale in which 1 means absent, and 7, extreme. The validated french version of the P ANSS was used in the present study (Lépine, Piron, & Chapotot, 1989). The internaI consistency from the positive, negative, and general psychopathology subscales, respectively 0.73, 0.83, and 0.79, are satisfactory. Concerning the PANSS test-retest reliability, the coefficients are relatively good after three to six months, considering the inevitable clinical variations (0.80, 0.68, and 0.60) (Kay, Fizbein,

& Opler, 1987). Modafinil; étude expérimentale 121

The second scale used for the assessment of clinical symptoms is the French version

(Ribeyre, Dollfus, Lesieur, Ménard, & Petit, 1994) of the SDS (Kirkpatrick, Buchanan, McKenney, Alphs, & Carpenter, 1989). This scale was particularly designed to assess the presence of negative symptoms and deficit syndrome. This syndrome is characterized by two or more primary negative symptoms since at least 12 months, to a specific intensity (at least 2/4), and rated as primary, i.e., as direct manifestations of the trouble, and not as reactions to other symptoms. The symptoms assessed by the scale are the following:

\ restricted affect, diminished emotional range, poverty of speech, curbing of interests, diminished sense of purpose, and diminished social drive. The SDS has a good inter-rater reliability, with a range of 80% to 90% of agreement for the final categorization cleficit/non-deficit (Kirkpatrick, et al., 1989; Ribeyre, et al., 1994). Since the deficit syndrome appears very stable over time, the agreement of categorization after 3.8 years is 83% for the deficit items, and 88% for the non-deficit items (Amador, et al., 1999).

The Udvald for Kliniske Unders0gelser side effect rating scale ([UKU]; Lingjaerde,

Ahlfors, Bech, Dencker, & EIgen, 1987) and the Extrapyramidal Symptom Rating Scale ([ESRS]; Chouinard, Ross-Chouinard, Annable, & Jones, 1980) were used to assess psychic, neurologic, autonomic, motor, and other unspecific side effects. They were both conceived to assess si de effects related to psychopharmacological treatment. The UKU includes 48 items rated in four degrees of intensity and three levels of imputability to the drug (improbable, not excluded/possible, probable). It also allows the report of si de effects not explicitly included in the scale. The scoring is done by a trained examiner during a structured clinical interview. At the end of the questionnaire, the examiner and the examinee evaluate separately the impact of the reported side effects on daily life activities. For the purpose of the study, the whole questionnaire was administrated but only pertinent side effects in accordance with the putative effect of modafinil were included in the statistical analyses. ActuaIly, as proposed by its authors, " .. .it does not seem meaningfull to add aIl the items of the UKU into a total score, as it is unlikely that there is an additive interaction between the individual items" (Lingjaerde, et al., 1987). The psychometrics properties of the UKU were assessed in three independent studies, and were reported in the paper of Lingjaerde, et al. (1987). The face, content, concurrent, and construct validity Modafinil; étude expérimentale 122 appears satisfactory. The intra-class correlation coefficients used to evaluate inter-observer reliability ranged from 0.62 to 0.82 for the following subscales: psychic side effects, autonomic side effects, and other side effects. The intra-class correlation coefficient for the neurological side effects was 0.40. Inter-rater reliability for individual items chosen for the present study is generally high.

The ESRS was especially developed to assess antipsychotic-related motor side effects. Although the UKU includes sorne motor items, the ESRS is more detailed and thus allows a shrewd assessment. Even if there is no report suggesting a negative effect of modafinil on motor function, potential pharmacokinetic interactions with sorne antipsychotic treatments (e.g. clozapine, DeQuardo, 2002), may lead to motor disturbances. The ESRS includes 12 motor items related to, for example, parkinsonism, dyskinesia, and dystonia, aIl rated on a six-point severity scale, assessing symptom severity according to frequency and amplitude. The inter-rater reliability of the ESRS, verified in two different studies, is high for aIl subscales, ranging from r = 0.80 to r = 0.97 (Chouinard, Ross-Chouinard, Annable, & Jones, 1980; Chouinard, Ross-Chouinard, Gauthier, Annable, & Mercier, 1984). The sensitivity of the ESRS was also studied in clinical trials, in which this scale permitted to differentiate between placebo-, and antipsychotic-treated patients (Chouinard, et al., 1993; Marder, & Meibach; 1994), or placebo-, and anticholinergic-treated patients with drug-induced parkinsonism (Chouinard,

Annable, Mercier, & Turnier, 1987).

The Drug Attitude Inventory, 10-item verSIon ([DAI-10]; Hogan, Awad, & Eastwood, 1983) was also used. OriginaIly, the DAI included 30 items, and has been developed to assess how the attitude of SZ patients towards their medications could influence their compliance to treatment. The items of the short version were chosen according to the comments repeated by patients in clinical settings. Ihternal consistency of this first version was high (0.93; Hogan, et al., 1983), and discriminated correctly 88.7% of compliant and noncompliant patients (Awad, 1993). The 10-item version contains ten out of the 30 initial items, for which six were among the most discriminant between compliant and noncompliant subjects (Awad, 1993). Participants must answer "true" or "false" to Modafinil; étude expérimentale 123 each sentence ~ Each response reflecting a good attitude gives one point, and in case of a negative response, 1 point is substracted. Therefore the total scoring may range from -lOto 10.

The Social and Occupational Functioning Assessment Scale (SOFAS), is a DSM axis V global rating scale. The SOFAS is a 1-to-100 point rating scale, and is a DSM-IV experimental scale. The SOFAS focuses exclusively on the patient social and occupational functioning, notwithstanding the severity of symptoms (APA, 1994). It exhibits very high level of interrater reliability. In a validation study interested in the reliability, and convergent as weIl as discriminant validity of the DSM-IV axis V scales, the SOFAS obtained the highest corrected intraclass correlation coefficient (0.94) (Hilsenroth, et al. , 2000). Furthermore, its French version demonstrated high correlation with a French version of the Strauss and Carpenter Revised Outcome Criteria Scale (Poirier, et al. , 2004). The SOF AS was included in the present study to assess potential improvements in functioning following the treatment with modafinil. Furthermore, to assess the compliance to medication, a visual analog scale was completed during each clinical assessment in order to assess the compliance to medication.

FinaIly, the Clinical Global Impressions scale ([CGI]; Guy, 1976), is a clinical scale widely used in pharmacological trials for the assessment of the clinical improvement following treatment. It includes three subscales: severity of illness, global improvement, and efficacy index. The first subscale rates pathology severity according to seven degrees. A score of zero corresponds to the absence of pathology, and a score of seven represents the highest degree of severity. The second subscale assesses the global improvement, also on a seven-point scale. A score of one indicates a high degree of improvement, and a score of seven indicates a high degree of deterioration. The efficacy index requires a single scoring summarizing the therapeutic effect, as weIl as the side effect occurrence. For the purpose of the study, only the global improvement scale was included in the statistical analyses. The CGI is one of the most widely used outcome measures ln psychopharmacology trials and has a good sensitivity to change over time (Guy, 1976). Modafinil; étude expérimentale 124

Statistical Analyses Three sets of statistical analyses were carried out. First, frequency analyses and mean and standard deviation calculations were performed to describe the sample at baseline on scores of clinical and neuropsychological measures. Regarding the neuropsychological variables, when normative data were available (presented in the Table 4.2), raw scores were converted into Z scores (mean = 0, SD = 1) to provide a comparison with normal population. Regarding the other measures, mean and SD were calculated on the raw scores. A second set of statistical analyses using t-tests were conducted to compare the completers with the drop-outs on demographic data, clinical and neuropsychological raw scores.

A third set of statistical analyses were carried out to specificaIly address the question of comparative effects of modafinil and 'placebo on neurocognitive and clinical variables. The cross-over design has features of randomized block and Latin square designs (Kirk, 1995), and it can be analysed in different manners according to its characteristics ..In the present case, each treatment phase of the design included its own baseline and post-test. Thus, covariance analyses (ANCOV A) for randomized blocks were applied, with baseline level of variables and sequences in which molecules were administered as covariables, as proposed by Senn (2002). Furthermore, effect sizes (d) adjusted for the same covariables were calculated to provide an interpretable measure of the magnitude of the difference between the modafinil and placebo effects (Cohen, 1988). Because the principal focus of this study was on the neurocognitive effects, several neuropsychological variables and only few clinical variables were computed in the ANCOV A analyses.

AIl tests applied were two-tailed, and a p-value of 5% or less was considered statisticaIly significant. Despite the high number of statistical analyses that were performed on the data, no statistical correction was applied due to the exploratory nature of this study. Modafinil; étude expérimentale 125

ResuUs Participants' Characteristics From December 2005 to March 2008, 48 participants meeting DSM-IV diagnostic criteria for SZSPD were approached to participate in the study. Thirty-seven patients agreed to meet the research team, whereas Il (22.9%) refused. The majority of patients who refused to participate did not provide reasons or clearly mentioned that they were not interested to take a new medication, or to take part in the placebo phase. Of the 37 (77.1 0/0) patients interested in the study, six (16.2%) did not meet inclusion or exclusion criteria. Thus, 31 (83.8%) participants completed the baseline assessments, among whom three withdrew consent before randomization. Among the remaining 28 randomized participants, 20 (71.4%) completed the study. Among the eight participants who did not complete the study, 5 were premature dropouts (17.9%; 3 on modafinil - 2 on placebo), and 3 were excluded (10.7%). Three among the drop-outs were subjects who did not comply with the assessments and two presented emergence of psychotic symptoms. Among the latter two patients, one patient reported a relapse of positive symptoms at 100mg/day although further interviewing revealed that these symptoms were already present but concealed at baseline; thus, a causal link with modafinil is difficult to assess. A second patient showed a clear psychotic exacerbation after increasing dosage to 200mg/day which quickly abated following modafinil discontinuation.

Eighteen participants tolerated well the 200mg/day and were then tested at this maximum dosage. However, one participant was assessed on 100mg/day, and another patient, on 50mg/day for sensitivity issue with clozapine. It is known that moclafinil could inhibit P450 cytochrome (CYP1A2, CYP2B6, CYP2C9, CYP2CI9, & CYP3A4/5) (Robertson, DeCory, Madan, & Parkinson, 2000), which is involved in the metabolism of clozapine, and could 'interfere with clozapine clearance (DeQuardo, 2002). For this reason and considering the sensitivity issue, a special protocol was implemented for this participant. Indeed, instead of following the planned titration, this participant began, in modafinil and placebo phases, with 50 mg/day, to terminate with 100 mg/day. Regarding the second participant who exhibited residual positive symptoms at baseline, an increase of auditory hallucinations was noted at 200mg/day, due to which dosage was firstly reduced to Modafinil; étude expérimentale 126

100mg/day, and finally to 50mg/day, which was well tolerated. These two modifications were done blind to the treatment conditions by a clinician not involved in the research. During the placebo phase, all patients were tested with the maximum dosage of 2 tablets per day.

Baseline Characteristics Twenty-seven men and four women, with a mean age of 27.9 (6.6) years old completed the baseline assessements. DSM-IV diagnoses were SZ for 24 patients and schizoaffective disorders for 3. Patients were treated with either quetiapine (n = 10), clozapine (n = 9), risperidone (n = 8), or olanzapine (n = 4). The mean P ANSS total score at baseline were 64.97 (SD = 15.04); positive symptom score = 14.03 (SD = 3.5), negative symptom score = 19.19 (SD = 6.8), and general psychopathology score = 31.94, (SD =

6.97). On the CGI, the majority of the participants (n = 16) were rated as "moderately ill", Il were "midly ill", two were "borderline mentally, ill", and two were "markedly ill". The mean CFQ score (subjective rating of cognition) was 33.16 (SD = Il.52). Finally, the sample presented Z scores ranging from -1.93 to 0.60 on neuropsychological variables (see Figure 4.2). Regarding the PVT-192, the mean and standard scores were calculated on the basis of raw scores because there is no available normative data allowing the computing of standardized scores. In this manner, the available baseline data for 29 participants demonstrated that, as a group, the sample had a mean visual simple reaction time of 292.56 ms (SD = 65.93 ms).

Insert Figure 4.2 about here

Completers versus drop-outs Table 4.4 presents comparisons between completers and drop-outs on the neuropsychological variables. With the exception of one variable from the CPT-II which provides too small variability and thus was converted into Z scores, all variables were analysed on the basis of raw scores. As shown in this table, completers and drop-outs were Modafinil; étude expérimentale 127 mostly comparable on neuropsychological variables, although there was a trend for better performance of completers in the semantic verbal fluency task (p = 0.05). However, completers were older than uncompleters (p = 0.02), had a lower PANSS total score (p = 0.01) following trends on all PANSS subscales, and had a greater DAI total score (p < 0.0 1), the later indicating a more positive attitude towards medication for the completers group.

Insert Table 4.4 about here

Completers Twenty participants completed the entire protocol, lOin the modafinil-placebo sequence, and lOin the placebo-modafinil sequence. Eighteen were men, and two were women. Half of the sample had no occupation, 4 were students (2 part-time, 2 full-time), 3 were involved part-time in a supported employment program, 2 had a full-time competitive job, and one had only occasional positions. Eighteen participants were diagnosed per the DSM-IV as having SZ, and two participants were treated for a schizoaffective disorder. In average, the onset of positive symptoms occurred at 23.35 (SD = 7.64) years -old. The completers required, in the past, 2.7 (SD = 2.39) hospitalizations, and antipsychotic trials using an average of 2.6 (SD = 1.05) different SGA. The baseline total P ANSS mean score was 60.20 (SD = 13.79). AlI patients were treated with a SGA (quetiapine n = 7; clozapine n = 7; risperidone n = 3, and olanzapine n = 3). Figure 4.3 presents the means of baseline neuropsychological results, expressed in Z scores. The baseline scores ranged from 0.55 for the motor speed condition of the D-KEFS TMT, to -1.20. for the semantic verbal fluency task (animaIs) with 23 out of the 27 variables in the -1.00 to +1.00 Z-score range.

Insert Figure 4.3 about here Modafinil; étude expérimentale 128

Comparative Effects of Modafinil and Placebo on Neuropsychological Variables Table 4.5 presents the results of the comparative analyses between the modafinil and placebo conditions on the neuropsychological variables. Positive d values indicate a beneficial effect of modafinil over placebo, whereas negative d values indicate superiority of placebo over modafinil.

Insert Table 4.5 about here

At the operational level, modafinil was significantly superior to placebo on the composite score representing the trade-off for time and efficacy in the completion of the Symbols-Structured condition from the MWCT, d = 0.56, F(l, 16) = 6.00, p = 0.03. In addition, a trend for a more positive effect of modafinil over placebo was observed for the

D-KEFS word reading condition completion time, d = 0.46, F(l, 16) = 4.03 , p = 0.06. Finally, there was a trend for statistical significance favouring the placebo for a greater decrease in the mean reaction time, as measured by the PVT-192, d = -0.59, F(l , 10) = 4.56, p = 0.06.

Regarqing the variables of the tactical level, a significant difference favoured the placebo on the mean number of commissions during the CPT-II completion, d = -0.68, F(l , 15) = 8.24,p = 0.01.

Finally, regarding the other neuropsychological variables, modafinil was statistically superior to placebo on the number of correct responses on the semantic verbal fluency task, d = 0.64, F(l, 17) = 8.29, p = 0.01, and on the WAIS-III digit span total, d = 0.51, F(l, 17) = 5.25, p = 0.04. Modafinil; étude expérimentale 129

Two supplementary sets of post hoc statistical analyses were carried out. The first one assessed the effect of potential moderating variables such as compliance on the differences observed on neuropsychological variables (MWCT, correct targets/time in the Symbols-Structured condition; CPT-II, commission errors; "Digit span, total correct; and semantic verbal fluency, total correct). To this end, the post-test results (at the end of each 2 treatment condition phases) on the visual .analog adherence scale were entered in the ANCOV A as co-variables. Results showed that there was no statistically significant difference, r < 0.4; therefore compliance had no impact on the cognitive results. Furthermore, the relation between the type of treatment (modafinil or placebo), and the compliance was analysed. This analysis demonstrated that during the modafini1 phase, participants were significantly less compliant than during the placebo phase (p = 0.03).

A second post hoc set of analyses was conducted to determine whether improvers differed from non-improvers on baseline characteristics. To this end, two improver/non improver categorizations were done: 1) the neuropsychological profiles for placebo and modafinil phases were submitted to three neuropsychologists who had to respond to the following question: "In a clinical context, would you say that this patient neuropsychologically responded to modafinil, in comparison to placebo?". The agreement between the three assessors was 100% for Il out of the 20 participants, and 66.6%. for the remaining 9 participants. U sing this method, 10 participants were categorized as improvers, and 10, as non-improvers. 2) In the second categorization method the improvers and non improvers were distinguished according to the the decision made by the treating psychiatrist, in consultation with the research team, to either continue or not treatment with modafinil following the end of the study. · This was decided according to the subjective impressions of improvement, by the participant and treating psychiatrist. Thus, 14 participants were maintained on modafinil' s treatment at the end of the study. Nine out of the ten patients rated as improvers on the neuropsychologist' s judgment basis were among those continuing to be treated with modafinil following the end of the study. The remaining improver was a participant for which a subjective impression of improvement was noted, ,but the neuropsychological data did not show any objective improvement. The results of the categorization of patients according to the two methods are presented in Table 4.6. In both Modafinil; étude expérimentale 130

categorizations, T and Chi-square tests were applied to distinguish potential participant characteristics regarding treatment response. The following variables, as observed at baseline, were entered in the analyses: age, duration of illness, PANSS total score, antipsychotic treatment, involvement in an occupation or not, and baseline scores of the neuropsychological variables found improved in the cross-over analyses.

Insert Table 4.6 about here

The results following the statistical analyses according to both categorizations were \ consistent. Only one variable accounted for the response to treatment in the sample: the baseline total score of the digit span subtest. When the grouping was done according to the

continuation of treatment, the result was statistically significant (p = 0.02), whereas when it was done according to the neuropsychologists' judgment of improvement, it did not reach

statistical significance (p = 0.08). Both results suggest that the baseline digit span total score of the improvers was lower than that of the non-improvers.

Comparative Effects ofModafinil and Placebo on Clinical Variables Table 4.7 illustrates the results obtained on the clinical measures. No difference emerged on the P ANSS and SDS variables. In addition, the degree of improvement on the

CGI did not statistically differ, d = 0.20, F(l , 16) = 1.69, P = 0.21 between the two treatment conditions. However, there were sorne statistically significant differences between the side effects reported by patients in the modafinil and placebo conditions. Indeed, the UKU showed a significant superiority of modafinil on improving

asthenia/fatigability (d = 0.52, F(l , 17) = 5.41 , p = 0.03) and memory (d = 0.58, F(l , 17) =

6.67, p = 0.02). There was also a trend for superiority of modafinil decreasing psychic

subscale of the UKU (d = 0.52, F(l, 17) = 3.48, p = 0.08). No differences were found on the neurologic or motor side effects as measured by the UKU and ESRS. Modafinil; étude expérimentale 131

Insert Table 4.7 about here

Discussion The main goal of this study was to verify the potential efficacy of modafinil as a neurocognitive enhcancer in SZ and SZSPD using a randomized double-blind placebo cross-over design, and a prolonged administration of modafinil. Neuropsychological tasks were chosen to specifically assess the operational and tactical levels of attention from the van Zomeren, & Spikman categorization (2003). The corresponding hypothesis was that modafinil would significantly improve alertness and speed of proéessing, which would translate in improvements on operational and tactical tasks. This hypothesis was not confirmed in the present study. Indeed, while sorne results offered partial support for this hypothesis (Le. , improved processing speed according to time/correct targets ratio from MWCT, Symbols-Structured; trend for improvement on D-KEFS word reading condition from the Color-Word task, a highly automated process), the global results were conflicting. Indeed, a trend for deterioration (PVT mean reaction tirne [RT]) demonstrated that modafinil could possibly deteriorate simple R T, which is the purest operational variable used. When looking at the rnean changes following rnodafinil and placebo treatments, the results obtained by only one participant seemed to underly this trend. Indeed, when these odd results were excluded, the changes appeared comparable between the two treatmerit groups, which suggests that modafinil and placebo impacted cornparably on simple RT.

Conceming the variables of the t~ctical level, no improvement occurred during the modafinil treatment. There was, however, a significant difference suggesting anegative effect of modafinil, i.e., commissions errors during the CPT-II task. This difference reached a medium size effect and did not seem related to a significant faster hit R t , since this parameter remained stable. However, when looking at the mean changes following modafinil and placebo, it seems like the statistical difference could be attributed to a decrease of commissions during the placebo phase and a stable performance during the modafinil phase. Regarding the other variables, modafinil significantly iniproved verbal Modafinil; étude expérimentale 132 working memory and semantic fluency, with medium effect sizes, confirming our previous observation during an open-trial (Létourneau, et al., paper in preparation, see Chapter 3).

Although the current neuropsychological results do not support our neurocognitive hypothesis inspired by Van Zomeren and Spikman, they are mainly congruent with the findings of the Turner and colleagues' (2004) cross-over, single-dose trial. Indeed, in this study, modafinil had a positive impact on verbal working memory, and slowed reaction latency in a computerized planning task. We also observed a slowing in latency using a simple RT task. This slowing in latency did not seem to result from a simple psychomotor effect of drug since we observed an improvement on a visuo-motor scanning task and a stability of the CPT-II hit RT, and because comparable results were obtained by Turner et al. (2004). Concerning the positive results obtained on visual scanning and verbal fluency tasks, they are mainly consistent with those observed in our previous pilot study (Létourneau, et al. , paper in preparation, see Chapter 3) which mainly indicated an improvement on these tasks. However, while Turner observed a significant effect of modafinil on a precision measure from a cognitive flexibility task, we did not observe any change in tasks involving this cognitive process (D-KEFS TMT Number-Letter Switching and Color-Word InhibitionlSwitching). Although statistical analyses on the total errors were not performed, the errors commirted in these two tasks generally translated in prolonged completion times, which were the scores entered in the analyses.

Given the overall consistency in results between the present study and Turner et al' s trial and given also that the designs of these studies were similar (except for the duration of modafinil administration), it is interesting to compare the two patient samples. A priori, they seemed relatively comparable. Indeed, the sample of Turner, et al. (2004) was composed of high-functioning patients with SZ, and our sample was also relatively neuropsychologically preserved. Actually, when looking at Figure 4.3, completers were within the normal range of performance for the majority of the cognitive variables. It is also interesting to note that, 0,11 the three significant improvements observed, two were obtained on variables for which counter performances (Z < -1.00) were measured at baseline. Modafinil; étude expérimentale 133

ClinicaIly, this suggests that a more impaired cognitive function could potentially benefit more from treatment than a less impaired cognitive function (ceiling effect).

On the contrary to the results of Turner, et al. (2004) and those of the present study, Pierre et al. (2007), and Sevy et al. (2005), did not find any difference between modélfinil and placebo. Two facts can account for these discrepancies. First, Turner' s trial and the present study used a cross-over design, while Pierre and Sevy used parallei designs. Even if numbers of subjects are roughly equal between aIl these studies, the use of a cross-over design has the advantage to increase statistical power (Senn, 2002). Second, Turner' sand the present study used a broad array of neuropsychological tasks as opposed to the studies of Pierre et al. (2007) and Sevy et al.(2005) which included only a limited number of cognitive tasks.

Our positive results was spanned over various cognitive processes. We had hypothesized that tasks at the operational and tactical levels of the categorisation of attentional tasks proposed by van Zomeren, & Spikman (2003) would benefit from modafinil, which was not supported. Indeed, our results as those from Turner, et al. (2004) rather suggested that modafinil could impact high-ordered processes at the strategic level which essentially encompasses executive functioning.

When looking for a common process necessary for an optimal realisation of the tasks improved, although we cannot provide a definite answer, we can speculate about these mechanisms based on three patterns of results possibility pointing towards an improvement in initiation of verbal responses. First, when treated with modafinil, participants initiated their responses more .easily, as reflected by improvement in semantic verbal fluency. Indeed, in this tasks, the first response frequently facilitates the next one, and so on. For example, if an examinee first provides the name of a domestic animal, the subsequent responses are frequently domestic animaIs as weIl, as if the initial response allows the individual to develop a stategy. The semantic condition is more prone to the initiation effect than the lexical one, for which responses cannot be combined. Second, Modafinil; étude expérimentale 134 initiation can also play a role in the realisation of verbal working memory tasks like digit span. Indeed, good responses are generally given relatively rapidly while errors often occur when the responder spends more time to rememorate the digits before answering. If the initiation of response is facilitated by modafinil, it is possible that responders succeed more easily in retrieving subsequent digits after having said the first one. Third, except for the result observed on MWCT, our findings about modafinil advantages mainly favoured tasks involving verbal responses. In addition to the results cited above, we obtained trend for a modafinil advantage on the word reading condition from the Color-W ord test, which is consistent with this pattern. Moreover, we observed no advantage of modafinil on many visuomotor tasks (e.g. TMT alphabetic, and alphabetical tracking, MWCT motor control), nor on the visual working memory task, which is roughly comparable to the digit span subtest, but with a visual input, and a motor output. Thus, these three patterns of results may suggest that modafinil exerts its positive effects through a facilitation effect of verbal initiation. However, this hypothesis could not explain the slowing in the latency observed on simple RT. Additional studies are needed to further test this hypothesis, and to replicate deteriorations in latency. /

When the present results are compared with those obtained in neuroimaging studies, sorne parallels can be drawn. Spence, Green, Wilkinson, & Hunter (2005) recorded brain activity of SZ during the realisation of a working-memory task presenting similarities with the backward condition of the digit span subtest administered in modafinil- and placebo treated patients. The main finding of Spence's study is that modafinil-treated participants presented a significantly greater activation in the anterior cingulate cortex (ACC) in comparison to those on placebo. Furthermore, even if there was no significant group improvement on the working memory task under modafinil, there was a relationship between the degree to which the ACC activation was modulated during the task, and the performance on the task. Thus, it seems like modafinil could activate the ACC, a structure involved in the realisation ofworking memory tasks (Bush, Luu, & Posner, 2000). We can even speculate that it is possible that modafinil could improve diffusion in neuronal networks, such as those involving the ACC. This hypothesis is particularly consistent with the results observed on the digit span test assessing the temporary storage and manipulation · Modafinil; étude expérimentale 135 of verbal information. Furthermore, the baseline performance of this neurocognitive task appears to discriminate the improvers and non-improvers following . a treatment with modafinil.

Regarding our second hypothesis postulating that modafinil could improve clinical parameters, the results indicated that it was not the case. However, the results on the PANSS , SDS and CGI suggest that participants did not exhibit change in their clinical symptoms, and in their global psychiatric status. This could reflect a ceiling effect at baseline since patients were required to be stabilized on their SGA in order to be included in the trial. However, when measuring side effects as a manner to assess tolerability and safety, the results confirmed the third hypothesis. This hypothesis stipulated that treatment with modafinil would not generate more side effects than with placebo. In addition, modafinil subjectively improved asthenia/fatigability and memory, as measured by one of the side effect rating scale. However, regarding safety, it is important to remind that one patient withdrew in the context of a psychotic symptom exacerbation, for which modafinil could be responsible, and also. that one patient needed a dosage lower than 200 mg due to an exacerbation of psychotic symptoms. These observations justify a close monitoring of patients when introducing modafinil.

Methodological issues The design had many strengths to notice. First the use of a cross-over design contributed to improve power, and thus, to recruit a relatively small number of participants, considering that each of them participated in both treatment phases. Indeed, even if the sample was comparable to that from other studies resulting in negative findings (Pierre, et al. , 2007; Sevy, et al., 2005; Spence, et al. , 2005), the positive results obtained herein suggest that the use of this design optimized the detection of changes, while this is not the / case in parallel designs. Second, this design had the advantage to control for a variety of individual factors that might underlie, at least in part, the results. In addition, it allows the control for practice effects, which are frequent in neuropsychological multiple testing. lndeed, if practice effects occurred, for example, at the second neuropsychological assessment, the fact that half of the patients were on modafinil and the other half on Modafinil; étude expérimentale 136 placebo, ensures that the practice effect was equally di stributed. Second, the neuropsychological battery had the advantages to include tasks frequently used in SZ studies, and to coyer a broad range of attentional subprocesses, as well as sorne indexes of working memory and executive functions. Ihdeed, . the three papers reporting negative results assessed a very limited range of neuropsychological domains (Hunter, et aL ,·2006 ; Spence, et al., 2005; Pierre, et al. , 2007) contrasting with the comprehensive battery used in the present study, which probably contributed to our detecting significant differences. Third, considering that the vast . majority of the participants were recent-onset psychotic patients, these results are the first to be obtained using an experimental study with a prolonged administration of modafinil in this psychotic subpopulation. This fact contributes to establish the inocuity ofthis compound in SZ and SZSPD.

However, sorne limitations must be taken into consideration. First, we performed numerous statistical analyses. While it is possible that sorne positive findings resulted from multiple analyses, the congruence between the present results and those observed by Turner et al. (2004) indicates that it is probably not the case. Second, considering that the subsamples of patients taking the same antipsychotic treatment were small, this study probably did not allow the detection of different effects of modafinil according to the specific SGA used. Third, the assessment of daily functioning was restricted to the SOFAS score, which could underlie the negative findings. Indeed, the single score provided by this scale reflects the functioning in various daily life spheres. Because specific neurocognitive domains are correlated with different measures of outcome in SZ (Green, 1996), the use of more specific functional outcome measures could help to characterize functional changes. However, it is also possible that the occurrence of significant changes in daily life (e.g. return to school or work) may require a longer period of time than the 4-week treatment period of the current study.

In conclusion, this study demonstrated that, in a relatively young and neuropsychologically preserved sample of patients with SZ and SZSPD, modafinil improved verbal working memory, semantic verbal fluency, and non-verbal visual scanning abilities. Furthermore, it seems like modafinil could potentially improve reading speed, but Modafinil; étude·expérimentale 137 also decrease simple RT. Many of these changes could potentiaIly be due to a facilitation of initiation, mainly when verbal responses are required, an effect of modafinil on the ACC, an area known to be involved in working memory and executive task, or both. Modafinil also improved the participant's subjective impressions about their memory and fatigue, which are side effects frequently mentioned by SZ patients, and could account for the lack of compliance to antipsychotic medications. Regarding safety of the SZ treatment with modafinil, it seems relatively weIl established. However, the fact that one participant had to withdraw from the proto col because of an exacerbation of psychotic symptoms underlines the importance of a . close monitoring of symptoms during trials or treatment with compounds for which knowledge is not yet sufficient. These results were obtained in participants for whom positive and anxious symptoms were weIl stabilized. Therefore, they cannot be generalized to the whole SZ population. Thus, even if further data are needed, these results suggest that modafinil could be an alternative treatment to improve sorne neurocognitive impairments and fatigue in SZSPD patients. Modafinil; étude expérimentale 138

References

Adler, C. , Caviness, J. N., Hentz, 1. G. , Lind, M., & Tiede, J. (2003). Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson's disease. Movement Disorders, 18, 287-293.

Amador, X. F., Kirkpatrick, B., Buchanan, R. W., Carpenter, W. T. , Marcinko, L. , & Yale, S. A. (1999). Stability of the diagnosis of deficit syndrome in schizophrenia. American Journal ofPsychiatry , 156, 637-639.

Arnerican Psychiatric Association (1994). Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: Arnerican Psychiatric Association.

Awad, A. G. (1993). Subjective response to neuroleptics in schizophrenia. Schizophrenia Bulletin, 19, 609-618.

Bilder, R. M., Goldman, R. S. , Robinson, D., Reiter, G. , Bell, L. , Bates, J. A. , Pappadopulos, E. , Will son, D. F. , Alvir, J. M. J. , Woemer, M. G. , Geisler, S. , Kane, J. M., & Lieberman, J. A.(2000). Neuropsychology of first-episode schizophrenia: Initial characterization and clinical correlates. American Journal of Psychiatry, 157, 549-559.

Bittencourt, L. R. , Lucchesi, L. M., Rueda, A. D., Garbuio, S. "A., Palombini, L. O., Guilleminault, C., & Tufik, S. (2008). Placebo and modafinil on sleepiness in obstructive sleep apnea. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 32, 552-559.

Bowie, C. R., & Harvey, P. D. (2005). Cognition in schizophrenia: impairments, determinants, and functional importance. Psychiatric Clinics of North America, 28, 613-633.

Brébion, G., David, A. S. , Bressan, R. A., & Pilowsky, L. S. (2006). Processing speed: a strong predictor of verbal ' memory performance in schizophrenia. Journal of Clinical and Experimental Neuropsychology, 28, 370-382.

Broadbent, D. E. , Cooper, P. F., FitzGerald, P., & Parkes, K. R. (1982). The cognitive failures questionnaire (CFQ) and its correlates. British Journal of Clinical Psychology, 21, 1-16.

Bush, G., Luu, P., & Po.sner, M. 1. (2000). Cognitive and emotional influences in anterior cingulated cortex. Trends in Cognitive Sciences, 4, 215-222.

Chapotot, F., Pigeau, R., Canini, F., Bourdon, L. , & Buguet, A. (2003). Distinctive effects of modafinil and d-amphetamine on the homeostatic and circadian modulation of the human waking EEG. Psychopharmacology (Ber!), 166, 127-138. Modafinil; étude expérimentale 139

Chemelli, R. M. , Willie, J. T. , Sinton, C. M. , Elmquist, 1. K. , Scammell, T. , Lee, C. , Richardson, 1. A., Williams, S. C., Xiong, Y. , Kisanuki, Y. , Fitch, T. E. , Nakazato, M. , Hammer, R. E. , Saper, C. B., Yanagisawa, M. (1999). Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Ce Il, 98, 437-451.

Chouinard, G. , Annable, L., Mercier, P. , & Turnier, L. (1987). Long-term effeets of L-dopa and procyclidine on neuroleptic-induced extrapyramidal and schizophrenie symptoms. Psychopharmacology Bulletin, 23, 221-226.

Chouinard, G. , Jones, B., Remington, G. , Bloom, D. , Addington, D., MacEwan, G. W. , Labelle, A., Beauclair, L. , Arnott, W. (1993). A Canadian multicenter placebo controlled study of fixed doses of risperidone and haloperidol in the in the treatment of chronic schizophrenic patients. Journal of Clinical Psychopharmacology, 13, 25- 40.

Chouinard, G, Ross-Chouinard, A. , Annable, L. , & Jones, B. (1980). The extrapyramidal symptoms rating seale. Canadian Journal ofNeurology Science, 7, 233.

Chouinard, G. , Ross-Chouinard, A. , Gauthier, S. , Annable, L., & Mercier, P. (1984). An extrapyramidal rating scale for idiopqthic and neuroleptic-induced Parkinsonism and dyskinesia. Collegium Internationale Neuro-Psychopharmacologicum (C.LN.P.) 14th congress, book of abstracts, p. 16.

Cohen, J. (1988). Statistical power analysis for the behavioral sciences (Second ed.). Hillsdale, NJ: Erlbaum Associates.

Conners, C. K. (2000). Conner 's Continuous Performance Test II, New-York: Multi-Health Systems inc.

Dawes, S., & Senior, G. (2001 , October-November). Australian normative data and clinical utility of the Mesulam and Weintraub Cancellation' Test. Poster presented at the 21 st annual conference of the National Aeademy of Neuropsychology, San Francisco, California, USA.

Delis, D.C., _Kaplan, E., & Kramer, J.H. (2001). The Delis-Kaplan Executive Function System. San Antonio: The psychological corporation.

De Saint Hilaire, Z., Orosco, M., Rouch, C., Blanc, G. , Nicolaidis, S. (2001). Variations in extracellular monoàmines in the prefrontal cortex and medial .hypothalamus after modafinil administration: a microdialysis study in rats. Neuroreport, 12, 3533-3537.

DeQuardo, J. R. (2002). Modafinil-associated clozapine toxicity. American Journal of Psychiatry, 159, 1243-1244.

Dinges, D. F. , & Powell, J. W. (1985). Microcomputer analyses of performance on a portable, simple visual R T task during' sustained operations. Behavior Research Me th 0 ds, Instuments, & Co mputers, 17, 652-655. Modafinil; étude expérimentale 140

Duteil, 1., Rambert, F. A. , Pessonnier, J. , Hermant, J. F., Gombert, R. , Assous, E. (1990). Central alpha 1-adrenergic stimulation in relation to the behaviour stimulating e ffe ct of modafinil; studies with experimental animaIs. European Journal of Pharmacology, 180, 49-58.

Ehrenreich, H. , Hinze-Selch, D., Stawicki, S. , Aust, C. , Knolle-Veentjer, S. , Wilms, S.,Heinz, G. ,Erdag, S. ,Jahn, H. , Degner, D. , Ritzen, M. , Mohr, A. , Wagner, M., Schneider, U. , Bohn, M., Huber, M. , Czemik, A. , Pollmacher, T., Maier, W. , Siren, A. L. , Klosterkotter, J. Falkai, P., Ruther, E., Aldenhoff, J. B., Krampe, H. (2007). Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Molecular Psychiatry, 12, 206-220.

Espana, R. A. , Baldo, B. A. , Kelley, A. E. , Berridge, C. W. (2001). Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action. Neuroscience, 106, 699-715.

Ferraro, L. , Antonelli, T. , Tanganelli, S., O'Connor, W. T. , Perez de la Mora, M. , Mendez Franco, J. , Rambert, F. A. , Fuxe, K. (1999). The vigilance promoting drug modafinil increases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: prevention by local GABAa receptor blockade. Neuropsychopharmacology, 20, 346-356.

Ferraro, L. , Fuxe, K. , Tanganelli, S., Tomasini, M. C., Rambert, F. A. , Antonelli, T. (2002). DifferentiaI enhancement of dialysate serotonin levels in distinct brain regions of the awake rat by modafinil: possible relevance for wakefulness and depression. Journal ofNeuroscience Research, 68, 107-112.

Ferraro, L., Tanganelli, S., O'Connor, W. T., Antonelli, T., Rambert, F. , Fuxe, K. (1996). The vigilance promoting drug modafinil increases dopamine release in the rat nucleus acc:umbens via the involvement of a local GABAergic mechanism. European Journal ofPharmacology , 306, 33-39

Fioravanti, M., Carlone, O., Vitale, B., Cinti, M. E. , & Clare, L. (2005). A meta-analysis of cognitive deficits in adults with a diagnosis of schizophrenia. Neuropsychology Review, 15, 73-95.

Gladsjo, J. A. , Schuman, C. C., Evan, J. D., Peavy, G. M., Miller, S. W., & Heaton, R. K. (1999). Norms for letter and category fluency: demographic corrections for age, education, and ethnicity. Assessment, 6, 147-178.

Green, M. F. (1996). What are the functional consequences of neurocognitive deficits in schizophrenia. American Journal ofPsychiatry, 153, 321-330.

Green, M. F., Kem, R. S., Braff, D. L., & Mintz, J. (2000). Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the "right stuff'? Schizophrenia Bulletin, 26, 119-136. Modafinil; étude expérimentale 141

Guy, W. (1976). Clinical Global Impressions: In ECDEU Assessment Manual for Psychopharmacology, pp. 218 -222. Revised DHEW Pub. (ADM). Rockville, MD: National Institute for Mental Health.

Hambrecht, M., Larnrnertink, M., Klosterkotter, J. , Matuschek, E. , & Pukrop, R. (2002). Subjective and objective neuropsychological abnorrnalities in a psychosis prodrome. British Journal ofPsychiatry , 43, 30-37.

Hanly, J. G. , Fisk, J. D., Sherwood, G., & Eastwood, B. (1994). Clinical course of cognitive dysfunction in systemic lupus erythematosus. Journal of Rheumatology, 21 , 1825- . 1831.

Hartman, M., Steketee, M. C., Silva, S., Lanning, K., & McCann, H. (2002). Working memory and schizophrenia: evidence for slowed encoding. Schizophrenia Research, 59, 99-113.

Harvey, P. D., Green, M. F., Keefe, R. S. E., & Velligan, D. 1. (2004). Cognitive functioning in schizophrenia: a consensus statement on its role in the definition and evaluation of effective treatments for the illness. Journal of Clinical Psychiatry, 65, 361-372.

Harvey, P. ' D., & Keefe, R. S. (2001). Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. The American Journal of Psychiatry, 158, 176-184.

Heinrichs, R. W., & Zakzanis, K. K. (1998). Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology, 12, 426-445.

Hilsenroth, M. J. , Ackerman, S. J., Blagys, M. D., Baumann, B. D., Baity, M. R. , Smith, S. R. , Price, J. L., Smith, C. L ~, Heindselman, T. L. , Mount, M. K., Holdwick, D. J., Jr. (2000). Reliability and validity of DSM-IV axis V. American Journal ofPsychiatrY J 157, 1858-1863.

Hoff, A. L., & Kremen, W. S. (2003). Neuropsychology in schizophrenia: An Update .. Current Opinion in Psychiatry, 16, 149-155.

Hogan, T. P., Awad, A. G., & Eastwood, M. R. (1983). A self-report scale predictive of drug compliance in schizophrenies: Reliability and discriminative ability. Psychological Medicine, 13, 177-183.

Holthausen, E. A. E., Wiersma, D., Sitskoom, M. M., Dingemans, P. M., Shene, A. H., & van den Bosch, R. J. (2003). Long-terrn memory deficits in schizophrenia: primary or secondary dysfunction? Neuropsychology, 17, 539-547.

Hungs, M., Mignot, E. (2001). Hypocretinlorexin, sleep and narcolepsy. BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology, 23, 397-408. Modafini1; étude expérimentale 142

Hunter, M. D. , Ganesan, V. , Wilkinson, 1. D., & Spence, S. A.(2006) Impact of modafinil on prefrontal executive function in schizophrenia. American Journal of Psychiatry, 163, 2184-2186.

Jalan, R. , Gooday, R. , o 'Carroll, R. E. , Redhead, D. N. , Elton, R. A. , & Hayes, P. C. (1995). A prospective evaluation of changes in neuropsychological and liver function tests following transjugular intrahepatic portosystemic stent-shunt. Journal ofHepatology, 23, 697-705.

Jasinski, D. R. , (2000). An evaluation of the abuse potential of modafinil uSlng methylphenidate as a reference. Journal ofPsychopharmacology , 14, 53-60.

Jasinski, D. R. , & Kovacevié-Ristanovié, R. (2000). Evaluation of the abuse liability of modafinil and other drugs for excessive daytime sleepiness associated with narcolepsy. Clinical Neuropharmacology, 23, 149-156.

Kay, S. R. , Fiszbein, A. , & Opler, L. A. (1987). The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin, 13, 261-276.

Keefe, R. S., Bilder, R. M. , Davis, S. M., Harvey, P. D., Palmer, B. W. , Gold, J. M., Meltzer, H. Y., Green, M. F., Capuano, G., Stroup, T. S., McEvoy, J. P., Swartz, M. S., Rosenheck, R. A. , Perkins, D. O., Davis, C. E., Hsiao, J. K. , Lieberman, J. A. ; CATIE Investigators; Neurocognitive Working Group. (2007). Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Archives ofGeneral Psychiatry, 64, 631-632.

Keefe, R. S., Silva, S. G., Perkins, D. O., & Lieberman, J. A. (1999). The effects ofatypical antipsychotic drugs on neurocognitive impairment ·in schizophrenia: a review and meta-analysis. Schizophrenia Bulletin, 25, 201~222.

Kirk, R. E. (1995). Experimental design: Procedures for the behavioral sciences - third edition. Roger E. Kirk Pacific Grove, CA: Brooks/Cole.

Kirkpatrick, B., Buchanan, R. W., McKenney, P. D., Alphs, L. D., Carpenter, W. (1989). The schedule for the deficit syndrome: An instrument for research in schizophrenia. Psychiatry Research, 30, 119-123.

Lehoux, C. (2006). Dans quelle mesure les déficits neuropsychologiques sont-ils liés au fonctionnement social des personnes atteintes de schizophrénie ou de psychose apparentée à la schizophrénie? Doctoral thesis, Laval University, Québec, Can~da.

Lehoux, C., Everett, J. , Laplante, L., Émond, C. , Trépanier, J., Brassard, A. , René, L. , Cayer, M. , Mérette, C., Maziade, M. & Roy, M-A. (2003). Fine motor dexterity is correlated to social functioning in schizophrenia. Schizophrenia Research, 62, 269- 273. . Modafinil; étude expérimentale 143

Lépine, 1. P. , Piron, 1. 1., & Chapotot, E. Factor analysis of t~e PANSS in schizophrenia patients. In: Stefanis C. N., Soltados, C. R. , Rabavilas, A. D. Ed. Psychiatry Today: accomplishments and promises. Amsterdam: Experta Medica.

Létoumeau, K. , Leblanc, J. , Bouchard, R-H., Simard, M., Marcaurelle, H., Ouellet, R., Vallières, C. , & Roy, M-A. Modafinil as Adjunct Treatment in Recent-Onset Psychosis: Five Case Reports. Paper in preparation.

Létoumeau, K. , Simard, M., & Roy, M-A. Adjunct Cognitive Enhancers to Second Generation Antipsychotics for Cognitive Impairments in Schizophrenia: A Review. Paper in preparation.

Leucht, S. , Kane, J. M., Kissling, W., Hamann, J. Etschel, E. , & Engel, R. R. (2005). What does the PANSS mean? Schizophrenia Research, 79, 231-238. '

Lezak, M. D., Howieson, D. B., & Loring, D. W. (2004). Neuropsychological assessment, (Fourth Eds). Oxford: Oxford University Press.

Lin, J. S., Roussel, B., Akaoka, H. , Fort, P., Debilly, G. , Jouvet, M. (1992). Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat. Brain research, 591, 319-326.

Lin, J. S., Hou, Y. , Jouvet, M. (1996). Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. Proceedings of the National Academy of Sciences ofthe United States ofAmerica , 93, 14128-14133.

Lingjaerde, O., Ahlfors, U. G. , Bech, P., Dencker, S. J. , EIgen, K. (1987). A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatrica Scandinavica, 334, 1- 100.

Makela, E. H., Miller, K. , & Cutlip, W. D. (2003). Three case reports of modafinil use in treating sedation induced by antipsychotic medications. Journal of Clinical Psychiatry, 64, 485-486.

Marder, S. R., & Meibahc, R. C. (1994) Risperidone in the treatment of schizophrenia. American Journal ofPsychiatry , 151, 825-835.

McCaffrey, R. J., Duff, K., & Westervelt, H. J. (2000). Practitioner 's guide to evaluating change with neuropsychological assessment intruments. N ew-York: Kluwer Academic/Plenum Press. Meltzer, H. Y., & McGurk, S. R. (1999). The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophrenia Bulletin, 25, 233- 255. Modafinil; étude expérimentale 144

Menza, M. A., Kaufman, K. R. , & Castellanos, A., (2000). Modafinil augmentation of antidepressant treatment in depression. Journal ofclinical psychiatry, 61 , 378-381.

Mesulam, M. M. , (1985). Principles of Behavioural Neurology. Philadelphia: F. A. Davie Company.

Mignot, E. , Nishino, S., Guilleminault, C., Dement, W. C. (1994). Modafinil binds to the dopamine uptake carrier site with low affinity. Sleep, 1 7, 436-437.

Minzenberg, M. J. , & Carter, C. S. (2008). Modafinil : a review of neurochemical actions and effects on cognition. Neuropsychopharmacology, 33, 1477-1502.

Mishara, A. L. , & Golberg, T.E. (2004). Conventional neuroleptic treatment on cognition in schizophrenia: opening a closed book. Biological Psychiatry, 55, 1013-1022.

Mitchell, H. A. , Bogenpohl, J. W., Liles, L. C., Epstein, M. P., Bozyczko-Coyne, D., Williams, M., Weinshenker, D. (2008). Behavioral responses of dopamine beta hydroxylase knockout mice to modafinil suggest a dual noragrenergic-dopaminergic mechanism of action. Pharmacology, doi: 1 0.1 0 16/j.pbb. 2008.07. 014

Morgenthaler, T. I. , Lee-Chiong, T. , Alessi, C., Friedman, L., Aurora, N., Boehlecke, B., Brown, T., Chesson, A. L. , Kapur, V., Maganti, R. , Owens, J. , Pancer, J. , Swick, T. J., & Zak, R. , Standards of practice cornrnittee of the AASM. (2007). Practice parameters ' for the clinical evaluation and treatment of circadian thythrn. sleep disorders. An Arnerican Academy ofSleep Medicine Report. Sleep, 30, 1445-1459.

Nieves, A. V. , & Lang, A. E. (2002). Treatment of excessive daytime sleepiness in patients with Parkinson's Disease with modafinil. Clinical Neuropharmacology, 25, 111- 114.

Nishino, S. (2007). Narcolepsy: pathophysiology and pharrnacology. Journal of Clinical Psychiatry, 68,9-15.

Nishino, S., Mao, J., Sampathkumaran, R., Shelton, J. (1998). Increased dopaminergic transmission mediates the wake-promoting effects of CNS stimulants. Sleep Research Online, 1, 49-61.

Overall, J. E., & Gorham, D. R. (1962). Brief Psychiatric Rating Scale. Psychological Reports, 10, 799-812.

Pierre, J. M., Peloian, J. H., Wirshing, D. A., Wirshing, W. C., & Marder, S. R. (2007). A randomized, double-blind, placebo-controlled trial of modafinil for negative symptoms in schizophrenia. Journal ofClinical Psychiatry, 68, 705-710.

Poirier, S., Bureau, V., Lehoux, C., Bouchard, R-H., Maziade, M., Pelletier, S., René, L., Trépanier, J., Émond, C., Mérette, C., & Roy, M-A. (2004). A factor analysis of the Modafinil; étude expérimentale 145

Strauss and Carpenter Revised Outcome Criteria Scale : a validation of the French translation. Journal on Nervous and Mental Disease, 192, 864-867.

Purdon, S. E., Jones, B. D., Stip, E., Labelle, A., Addington, D., David, S. R. , Breier, A. , & Tollefson, G. D. (2000). Neuropsychological change in early phase schizophrenia during 12 months of treatment with olanzapine, risperidone, or haloperidol. The Canadian Collaborative Group for research in schizophrenia. Archives of Genreral Psychiatry, 57, 249-258.

Ribeyre, J. M., Dollfus, S. , Lesieur, P. , Ménard, J. F. , & Petit, M. (1994). Schedule for evaluation of the deficit syndrome in schizophrenia : Schedule for deficit syndrome (SDS) (Kirkpatrick et al.). Importance pertinence of the SDS. Introduction of the French version. Encéphale, 20, 413-419.

Roberston, P., DeCory, H. H. , Madan, A., & Parkinson, A. (2000). In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. Drug Metabolism and Disposition: the Biological Fate ofChemicals, 28, 664-671.

Rodrîguez-Sanchez, J. M., Crespo-Facorro, B., Gonzalez-Blanch, C. , Pérez-Iglesias, R., & Vasquez-Barquero, J. (2007). Cognitive dysfunction in first-episode psychosis: the processing speed hypothesis. British Journal ofPsychiatry , 191, 107-110.

Rosenthal, M. H. , & Bryant, S. L. (2004). Benefits of adjunct modafinil in an open-label, , pilot study in patients with schizophrenia. Clinical Neuropharmacology, 27, 38-43.

Saavedra-Velez, C. , Yusim, A., Anbarasan, D., & Lindenmayer, J-P. (2008). Modafinil as an adjunctivè treatment of sedation, negative symptoms, and cognition ln schizophrenia: a critical review. Journal ofClinical Psychiatry, pii: ej07m03982

Saletu, B., Fery, R., Krupka, M., Anderer, P., Grünberger, J. , & Barbanoj, M. J. (1989). DifferentiaI effects of a new central adrenergic agonist - modafinil- and D amphetamine on sleep and early moming behaviour in young healthy volunteers. 11Jternational Journal of Clinical Pharmacology Research, 9, 183-195.

Saykin, A. J. , Shtasel, D. L., Gur, R. E. , Kester, D. B., Mozley, L. H., Stafiniak, P., & Gur, R.C. (1994). Neuropsychological deficits in neuroleptic naive patients with first episode schizophrenia. Archives ofGeneral Psychiatry, 51, 124-131.

Scammell; T. E., Estabrooke, 1. V., McCarthy, M. T., Chemelli, R. M., Yanagisawa, M., Miller, M. S. , Saper, C. B. (2000). Hypothalamic arousal regions are activated during modafinil-induced wakefulness. Journal ofNeuroscience, 20, 8620-8628.

Sebban, C. , Tesolin-Decros, B., Millan, M. J., Spedding, M. (1999). Contrasting EEG profiles elicited by antipsychotic agents in the prefrontal cortex of the conscious rat: antagonism of the effects of clozapine by modafinil. British Journal of Pharmacology, 128,1055-1063. Modafinil; étude expérimentale 146

Senn, S. (2002). Cross-over trial in clinical research (Statistics in practice). John Wiley & Sons (Ed). West Sussex, U.K. : Wiley.

Sevy, S., Rosenthal,D.O., Alvir, J. , Meyer, S. , Visweswaraiah, H. , Gunduz-Bruce, H. , & Schooler, N.R. (2005). Double-blind, placebo-contr611ed study of modafinil for fatigue and cognition in schizophrenia patients treated with psychotropic medications. Journal ofClinical Psychiatry, 66, 839-843.

Singh, M. M. , & Kay, S. R. (1975). A comparative study of haloperidol and chlorpromazine in terms of clinical effects and therapeutic reversaI with benztropine in schizophrenia: Theoretical implications for potency differences among neuroleptics, Psychopharmacologia, 43, 103-113.

Smith, A. (1982). Symbol Digit Modalities Test (SDMT). Manual (revised). Los Angeles: Western Psychological Services.

Spence, S. A. , Green, R. D., Wilkinson, 1. D. , & Hunter, M. D. (2005). Modafinil modulates anterior cingulate function in chronic schizophrenia. British Journal of Psychiatry, 187, 55-61.

Szoke, A. , Trandafir, A. , Dupont, M-E., Méary, A. , Schürhoff, F. , & Leboyer, M. (2008). Longitudinal studies of cognition in schizophrenia: meta-analysis. British Journal of Psychiatry, 192, 248-257.

Stone, E. A., Cotecchia, S., Lin, Y. , Quartermain, D. (2002). Role of brain alpha 1B- . adrenoceptors in modafinil-induced behavioral activity. Synapse, 46, 269-270.

Strauss, E., Sherman, E. M. S., & Spreen, o. (2006). A compendium ofneuropsychological tests. Administration, norms, and commentaty (Third Edition). New-York : Oxford University Press.

Talbot, K. , Stradling, J., Crosby, J. , & Hilton-Jones, D. (2003). Reduction in excess daytime sleepiness by modafinil in myotonic dystrophy. Neuromuscular Disorders, 13, 357-364.

Touret, M. , Sallanon-Moulin, M., Fages, C., Roudi'er, V. , Didier-Bazes, M., Roussel, B., Tardy, M., Jouvet, M. (1994). Effects of modafinil-induced wakefulness on glutamine synthetase regulation in the rat brain. Brain Research. Molecular Brain Research, 26, 123-128.

'Touret, M. , Sallanon-Moulin, M., & Jouvet, M. (1995). Awakening properties ofmodafinil without paradoxical sleep rebound: comparative study with amphetamine in the rat. Neuroscience Letters, 189, 43-46.

Townsend, L. A., & Norman, R. M. (2004). Course of cognitive functioning in first episode schizophrenia spectrum disorders. Expert Review ofNe urotherape utics, 4, 61-68. Modafinil; étude expérimentale 147

Turner, D. C., Clark, L. , Pomarol-Clotet, E. , McKenna, P., Robbins, T. W. Sahakian, B. J. (2004). Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharmacology, 29, 1363-1373.

Van Zomeren, E. , & Spikman S. (2003). Assessment of attention dans Hallington, P.W., Kischka, U. , & Marshall, J. C. (Eds.). Handbook ofclinical psychology. New-York: Oxford Université Press.

Vom Hofe, A. , Mainemarre, G. , & Vannier, L. (1998). Sensitivity to everyday failures and cognitive inhibition: are the y related? European Review of Applied Psychology, 48, 49-55. .

Wallace, J. C., Kass, S. J. , & Stanny, C. J. (2002). The cognitive failures questionnaire revisited: Dimensions and correlates. Journal o/General Psychology, 129, 238-256.

Weiss, E. M., Bilder, R. M., & Fleischhacker, W. W. (2002) The effects of second generation antipsychotics on cognitive functioning and psychosocial outcome in schizophrenia. Psychopharmacology (Berl), 162, 11-17 .

. Weschler, D. (2001). Weschler Adult Intelligence Scale (3 rd Ed), (WAIS-III), Canadian Technical Manual. Toronto, Ontario: Harcourt Canada.

Weschler, D. (1997a). Weschler Adult Intelligence Scale (3 rd Ed), (WAIS-III). USA: The Psychological Corporation.

Weschler, D. (1997b). Weschler Memory Scale. III. San Antonion : Harcourt, Brace & Co.

Woodward, N. D., Purdon, S. E., Meltzer, H. Y., & Zald, D. H. (2005). A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. International Journal ofNeuropsychopharmacology, 8, 457-472.

Zifko, U. A. (2004). Management of fatigue in patients with multiple sclerosis. Drugs, 64, 1295-1304. Modafinil; étude expérimentale 148

Tables Modafinil; étude expérimentale 149

Tàble 4.1 Main characteristics and results from control/ed neuropsychological studies using modafinil in schizophrenie samples

ATTENTION MEMORY EXECUTIVE FUNCTIONING LANGAGE Sustained . Working Episodic Inhibition Planning Flexibility Fluency Turner, DB-PC, CO Digit span PRM (CANTAB) STOP SWM (CANTAB) IDED (CANTAB) N=20 et al., -Forward* DMTS (CANTAB) NTOL (CANTAB)* -Total EDS 200mg 2004 -Backward * * (CANTAB) errors*

Spatial span (CANTAB) Sevy, DB-PC CPT-IP Letter-number Delayed COWAT et al., N=20 span matched (CFL & PRW) 100 to 200 mg 2005 Oculomotor to sample Delayed RAVLT Response Test Spence, DB-PC, CO 2-back et al., 100mg 2005 N=17 Hunter, DB-PC, CO Generation of et al., 100mg variable motor 2006 N=12 sequences Pierre, DB-PC Degraded CPT CVLT Trail B et al., 100 to 200 mg 2007 N=17 * P <0.05 ** P <0.01 CANTAB: Cambridge Neuropsychological Test Automated Battery; CO: Cross-Over ; CVLT: California Verbal Leaming Test; COWAT: Controlled Oral Word Association Test; CPT: Continuous Performance Test; CPT-IP: Continuous Performance Test-Identical Pairs version; DB: Double Blind ; DMTS: Delayed Matching To Sample; EDS errors : Extra-Dimensional Shift errors; IDED: Intra-Dimensional/Extra-Dimensional set-shifting task; N: Number of participants; NTOL: New Tower Of London; PC: Placebo Controlled; PRM: Pattern Recognition Memory; RA VLT: Rey Auditory Verbal Learning Test; STOP: Stop signal task; SWM: Spatial Working Memory. Modafinil; étude expérimentale 150

Table 4.2 Experimental design Days AssessmentslInstructions Dosage Treatment (weeks)

Clinical & Day 0 neuropsychological NA NA (Phase 1 pre-test) Days 1 to 14 1 capsule every moming 100 mg Placebo or Modafinil (Weeks 1 & 2) Clinical Day 14 100 mg Placebo or Modafinil (follow-up before titration) Days 15 to 28 2 capsules every moming 200 mg Placebo or Modafinil (Weeks 3 & 4) Clinical & Day 28 neuropsychological 200 mg Placebo or Modafinil (Phase 1 post-test) Days 29 to 42 No medication, wash-out NA NA (Weeks 5 & 6) Clinical & Day 42 neuropsychological NA NA (Phase 2 pre-test) Days 43 to 56 1 capsule every moming 100 mg Modafinil or Placebo (Weeks 7 & 8) Clinical (follow-up before Day 56 100 mg Modafinil or Placebo titration) Days 57 to 72 2 capsules every moming 200 mg Modafinil or Placebo (Weeks 9 & 10) Clinical & Day 72 neuropsychological 200 mg Modafinil of Placabo (Phase 2 post-test) Modafinil; étude expérimentale 151

Table 4.3 The neuropsychological battery Neuropsychological Tasks & normative data used to Description Psychometrie properties standardize baseline scores PVT-192 4-minutes visual-motor portable Visual Simple RT are very (Dinges, & Powell, 1985) simple R T test. Provides visual stable after a 1 month feedback about each reaction interval in controls (- 2 Performances were not time. Inter-stimuli intervals milliseconds, J alan, et al. , standardized ranging from 2 to 10 seconds. 1995). The split-half reliability for 14-minutes visuo-motor the seven main indexes CPT-II computerized task. Examinees (reaction time, commissions, (Conners, 2000) must respond as quickly as omissions, standard error, possible to aIl targets, pseudo- variability, d', and Beta) Normative data: 1920 healthy randomly presented letters, with ranges from 0.73 to 0.95, and participants ranging from 6 to the exception of the X. Inter- the test-retest correlations over 55 years. stimuli intervals are 1, 2, or 4 from 0.55 to 0.84 (Conners, seconds. 2000). Four visual scanning conditions MWCT for which completion time and (Mesulam, 1985) errors can be recorded. An Practice effect is observed experimental motor control after one year, healthy Normative data: 228 condition was also included. participants significantly community volunteers ranging 1. Letters-Structured completed conditions rapidly from 18 to 49 years old 2. Letters-U nstructured (Dawes, and Senior, 2001). (Dawes, & Senior 2001). 3. Symbols-Structured 4. Symbols-Unstructured Comparable to the "coding" One month oral form test- subtest from the W AIS. retest correlation = 0.76 However, the examinee must (Smith, et al., 1982). SDMT complete with the digit rather (Smith, 1982) than with the code. The verbal While Smith (1982) administration was chosen, the o bserved a small gain after a Normative data: 420 healthy participant gives its responses mean of29,4 days in healthy persons ranging from 18 to 74 verball y. A first form is nd participants, another study years old. administered for the 1st and 2 did not demonstrated it sessions, and the alternative one, th (McCaffrey, Duff, & for the 3 rd and 4 to prevent for Weservelt, 2000). memory effects. CPT-II: Continuous Performance Test-second edltlon;.. MWCT: Mesulam and Wemtraub Cancellatlon Test; PVT-192: Psychomotor Vigilance Task-192; RT: Reaction Time; SDMT: Symbol Digit Modalities Task; W AIS: Weschler Adult Intelligence Scale Modafinil; étude expérimentale 152

Table 4.3 (continue) Five conditions for which The 5 conditions present completion time anq errors can different test-retest reliability D-KEFS TMT be recorded, as well as contrast ranging from marginal (0.60- , (Delis, Kaplan, & Kramer, measures. 0.69) to adequate (0.70-0.79) 2001) 1. Visual Scanning (Strauss, Sherman, & Spreen, 2. Digital Visuomotor Tracking 2006). In the flexibility Normative data: 1750 3. Alphabetical Visuomotor conditions, controls participants ranging from 8 to Tracking generally improve more than 89 years old. 4. Cognitive Flexibility SZ at retest (Szoke, et al., 5. Motor speed 2008). F our conditions for which completion time and errors can D-KEFS Color-Word Satisfactory reliability be recorded, as well as contrast Interference Test (Lezak, Howieson, Loring, measures. & 2004). In SZ, studies 1. Color N aming N ormati ve data: 1750 measuring practice effect 2. Word Reading participants ranging from 8 to reported heterogeneous 3. Inhibition 89 years old. results (Szoke, et al. , 2008). 4.InhibitioniSwitching

Lexical and semantic conditions. In SZ samples, the lexical The number of words named in condition, an improveinent is D-KEFS Verbal Fluency Test one minute as well as errors can generally observed at retest. nd be recorded. For the 1st and 2 . However, in the Szoke, et al. , Normative data: 768 sessions, FAS and ,animaIs were (2008) review, the semantic rd th participants ranging from 20 employed. For the 3 and 4 , the condition is, among all the to 101 years old (Gladsjo, et PRT (not from the D-KEFS), 31 variables of interest, the al. , 1999). and the boys name conditions only one remaining stable were uses, in order to avoid from baseline to retest in the memory impact. SZ samples. Forward and backward digit W AIS-III digit span span conditions. A slight improvement is (Weschler, 1997a) The format most commonly used generally observed in the SZ in the assessment of span of population at retest, but it is Normative data: from 1123 irnrnediate verbal recall and lower than the one observed participants ranging from 16 verbal working memory (Lezak, in controls (Szoke, 2008). to 89 years (Weschler, 2001). Howieson, & Loring, 2004). WMS-III spatial span In controls, forward score is (Weschler, 1997b) not improved and backward F orward and backward spatial score is slightly improved at span conditions. Normative data: from 1250 post-test (Hanly, Fisk, participants ranging from 16 Sherwook, & Eastwood, to 89 years. 1994). D-KEFS: Delis-Kaplan Executive Functions System; TMT: Trail Making Test; WAIS-III: Weschler Adult Intelligence Scale-third edition Modafinil; étude expérimentale . 153

Table 4.4 Comparison of baseline characteristics and performances for completers and uncompleters, in raw scores

.Completers Uncompleters TasklScale Variable p mean (sd) n mean (sd) n value

Age 29.55 (7.27) 20 24.82 (3.82) Il 0.02 Positive subscale total 13.15 (2.76) 20 15.64 (4.25) Il 0.06 Negative subscale total 17.50 (7.34) 20 22.27 (4.52) Il 0.06 PANSS General subscale total 29.55 (5.64) 20 34.82 (8.96) Il 0.05

Total score 60.20(13.79) 20 73.64 (13.74) Il 0.01

CGI Illness gravity 3.45 (0.76) 20 3.82 (0.60) Il 0.18 SOFAS Total 56.65 (12.77) 20 51.64 (12.09) Il 0.30 DAI Total 6.70 (3.01) 20 2.00 (4.54) 8 < 0.01 . CFQ Total on 100 32.85 (11.92) 20 33.73 (11.30) Il 0.93 Omissions 1.5.00 (40.02) 20 14.00 (15.88) Il 0.59 Commissions 17.50 (8.83) 20 21.45 (6.31) Il 0.94 CPT-II Hit RT (in ms) 388.40 (92.58) 20 356.64 (65.29) Il 0.09 Hit-R T block changea -0.72 (0.83) 20 -0.82 (1.10) Il 0.31 Color naming 34.85 (14.31) 20 31.27 (6.8'1) Il 0.89 Stroop' Word reading 22.80 (5.52) 20 22.73 (6.84) Il 0.34 ( completion time Inhibition 65.1 0 (38.53) 20 58.27 (14.19) Il 0.43 in seconds) Inhibition/Switching 67.15 (19.08) 20 69.09 (20.27) Il 0.55

Digit span Total score 16.00 (3.21) 20 15.09 (2.98) Il 0.89 Spatial span Total score 14.45 (3.32) 20 16.18 (3.22) Il 0.96 Mean reaction timme 291.14 (50.67) 18 294.89 (88.30) Il 0.54 PVT-192 (in ms) Median reaction time 258.00 (45.72) 18 272.91 (92.05) Il 0.62 Verbal Lexical 34.15 (15.45) 20 30.18 (13.06) Il 0.67 fluency (correct Semantic 18.10 (6.75) 20 17.00 (4.56) Il 0.05 words) CFQ: Cognitive Failures Questionnaire; CGI: Clinical Global Impression; CPT-II: Continuous Performance Test-second edition; DAI: Drug Attitude Inventory; PANSS: Positive And Negative Syndrome Scale; PVT- 192: Psychomotor Vigilance Task-192; SOFAS: Social and Occupational Functioning Assessment Scale a This variable was the only one converted into Z score due to its small variability in raw score. Modafinil; étude expérimentale 154

Table 4.4 (continue)

Completers Uncompleters Task/Scale Variable p Mean (sd) n Mean (sd) n value

Visual scanning 21.55 (5.90) 20 21.82 (8.35) Il 0.38 Number sequencing 37.30 (10.20) 20 36.36 (10.32) Il 0.95 TMT Letter sequencing 36.30 (11.53) 20 36.45 (12.56) 0.90 ( completion Il time Letter-number in seconds) 84.80 (24.49) 20 80.91 (32.26) Il 0.58 switching Motor speed 22.75 (9.35) 20 17.80 (6.18) 10 0.20 Letters-structured 82.79 (17.89) 19 72.63 (19.71) Il 0.48 MWCT Letters-unstructured 97.16 (30.58) 19 74.55 (18.62) 0.14 ( completion Il time Symbols-structured 82.84 (21.80) 19 64.09 (23.28) Il 0.57 in seconds) S ymbols-unstructured 74.11 (22.26) 19 58.00 (27.48) Il 0.99 SDMT Total correct 50.35 (9.88) 20 51.45 (6.39) Il 0.75 MWCT: Mesulam and Weintraub Cancellation Test; SDMT: Symbol Digit Modalities Test; TMT: Trail Making Test Modafinil; étude expérimentale 155

Table 4.5 Neuropsychological changes following modafinil and placebo treatments; comparison of effects according to the van Zomeren & Spikman 's categorization (2003) Level Task Variable n F tr p Mean reaction time (RT) 13 4.56 -0.59 0.06 PVT-192 R T standard deviation 13 1.79 -0.37 0.21 Color-Word W ord, reading 19 4.03 0.46 0.06 Interference Test Color naming 19 0.23 0.11 0.64 (Completion time) TMT Operational Motor speed 19 0.03 0.04 0.86 (ComQletion time) Letters-Structured 19 0.38 -0.14 0.55 MWCT Symbols-Structured 19 6.00 0.56 0.03* (Correct targetltime) Motor speedb 19 0.32 0.13 0.58 SDMT Total correct 20 0.38 0.14 0.55

Visual scanning 20 0.42 -0.14 0.53 TMT Number sequencing 20 1.07 -0.23 0.31 (Completion time) Letter sequencing 20 0.49 0.16 0.49 Letters-U nstructured 19 0.95 0.22 0.34 MWCT (Correct target/time) Symbols-Unstructured 19 0.56 0.17 0.46

Hit reaction time 18 0.54 0.17 0.48 Tactical Omissions errors 18 0.58 0.18 0.46 CPT-II Commissions errors 18 7.13 -0.63 0.02* Detectability 18 2.86 0.40 0.11 Hit RT block change 18 0.00 0.02 0.95

TMT Number-Letter Switching 20 0.76 0.20 0.39 (ComQletion time) Inhibition 19 0.77 0.20 0.39 Color-Word Interference Test InhibitioniSwitching 19 0.71 0.19 0.41

* p < 0.05 CPT-II: Continuous Performance Test-second edition; MWCT: Mesulam and Weintraub Cancellation Test; . PVT- 192: Psychomotor Vigilance Test-192; SDMT: Symbol Digit Modalities Test; TMT:, Trail Making Test a : When positive, the d value indicates a superior effect of modafinil in comparison to placebo. When negative, its indicated a superior effect of placebo; b: This is an experimental condition Modafinil; étude expérimentale 156

Table 4.5. (continue)

Level Task Variable N F tf1 P CFQ Total on 100 20 1.01 0.22 0.33 Total, forward 20 1.73 0.29 0.21

Digit span Total, backward 20 2.89 0.38 0.11 Total 20 5.25 0.51 0.04* Total, forward 20 0.01 0.02 0.92 Others variables Spatial span Total, backward 20 0.07 0.06 0.79 Total 20 0.36 0.13 0.56 Total correct, lexical 20 0.27 0.12 0.61 condition Verbal fi uency Total correct, semantic 20 8.29 0.64 0.01 * condition.

* p < 0.05 CFQ: Cognitive Failures Questionnaire a : When positive, the d value indicates a superior effect of modafinil in comparison to placebo. When negative, its indicated a superior effect of placebo Modafinil; étude expérimentale 157

Table 4.6 Post-hoc categorizationaccording to neuropsychological improvement, or medication continuing

Categorization method Participant Neuropsychological response Modafinil continuation (according to 3 neuropsychologists) aCter study 1002 Improver, 100% agreement Yes 1004 Non-improver, 66.6% agreement Yes 1008 Improver, 100% agreement Yes 1009 Non-Improver, 66.6% agreement No 1010 Improver, 100% agreement Yes 1012 Improver, 66.6% agreement Yes 1013 Improver, 100% agreement Yes 1016 Non-Improver, 66.6% agreement Yes 1019 Improv'er, 100% agreement No 1020 Improver, 66.6% agreement Yes 1025 Non-Improver, 100% agreement Yes 1027 Improver, 66.6% agreement Yes 2015 Non-Improver, 66.6% agreement No 2017 Non-Improver, 66.6% agreement Yes 2018 Non-Improver, 66.6% agreement Yes 2021 Non-Improver, 100% agreement No 2022 Non-Improver, 100% agreement No 2023 Improver, 100% agreement Yes 2026 Improver, 100% agreement Yes 2029 Non-Improver, 100% agreement No Modafinil; étude expérimentale 158

Tabie 4.7 Clinical changes following modafinil and placebo treatments; comparison of effects

Clinical Variable n F Adjusted p Scale value if value SOFAS Total 20 0.13 0.08 0.72 Positive subscale total 20 0.09 0.07 0.77 Negative subscale total 20 0.09 0.07 0.76 PANSS General subscale total 20 0.03 0.04 0.85 Total 20 0.00 0.01 0.97 Restricted affect item 20 0.85 0.21 0.37

Diminished emotional range item 20 0.85 0.21 0.37

Poverty of speech itemb 20 NA NA NA SDS Curbing of interests itemb 20 NA NA NA

Diminished sense of purpose item 20 1.67 -0.29 0.21 Diminished social drive itemb 20 NA NA NA

CGI Global improvement subscale 20 1.69 0.21 0.20 Psychic subscale total 20 3.48 0.52 0.08 -Concentration difficulties 20 0.66 0.18 0.43 -Asthenia/F atigability 20 5.41 0.52 0.03*

-S leepiness/Sedati on 20 3.36 0 ~ 41 0.08 UKU -Failing memory 20 6.67 0.58 0.02 N eurologic subscale total 20 0.14 0.09 0.71 Other symptoms subscale total 20 2.21 -0.33 0.16 -Headhache 20 1.15 -0.23 0.30 Dystonia subscale total 20 0.89 0.21 0.36 ESRS Parkinsonism subscale total 20 0.07 0.06 0.79 Dyskinesia subscale total 20 0.01 -0.02 0.93 CGI: Clinical Global Impressions; ESRS: Extrapyramidal Symptom Rating Scale; PANSS: Positive And Negative Syndrome Scale; SDS: Schedule for the Deficit Syndrome; SOF AS: Social and Occupational Functioning Assessment Scale; UKU: Udvald for Kliniske Unders0gelser side effect rating scale a : When positive, the d value indicates a superior effect of modafinil in comparison to placebo. When negative, its indicated a superior effect of placebo b: There were no difference on these measures what prevented for statistics calculations Modafinil; étude expérimentale 159

Figures Modafinil; étude expérimentale 160

Operationallevel

Tacticallevel

Strategicallevel

Control or Working memory

Level Time pressure Structure of the task

Operational High Highly structured, stimulus-driven

Tactical Intermediate Partially structured, memory-driven

Strategical Low U nstructured, strategy-driven

Figure 4.1. Categorization ofneuropsychological measures ofattention according to van Zomeren, and Spikman, 2003. Modafini1; étude expérimentale 161

1 V") 0 f- t- ~ . ~ :::;E u . ~ ~ CI) ~ CI) 0::: . ~ ·Ë co co f- 00 . ~ 00 t- C'î ..0 != . ~ lS lS ~ ·Ë E 0::: f- lS M~ ...... ~ N~ -~ -~ 0 8 ::r:: u ~ "

=~ -1 ~ ~ -1.5

-2 ~------~ Operational • Tactical Il Others -2.5 -'------' Neuropsychological variables

Figure 4.2. Baseline neuropsychological performances (in Z scores), complete sample (N = 31)

CPT-II: Continuous Performance Test-second edition; SDMT: Symbol Digit Modalities Test; MWCT: Mesulam and Weintraub Cancellation Test; TMT: Trail Making Test. Modafinil; étude expérimentale 162

0.5 -+----1

- N 0.. 0.. o 0 o 0 b b C/) C/)

N = ~ -0.5 ~

-1

Operational • Tactical Il Others -1.5 Neuropsychological variables

Figure 4.3. Baseline neuropsychological performances (in Z scores), completers (n = 20)

CPT-II: Continuous Performance Test-second edition; SDMT: Symbol Digit Modalities Test; MWCT: Mesulam and Weintraub Cancellation Test; TMT: Trail Making Test. Discussion générale 163

CHAPITRE 5 : DISCUSSION ET CONCLUSION GÉNÉRALES Discussion générale 164

DISCUSSION GÉNÉRALE La présente thèse doctorale en psychologie poursuivait deux objectifs généraux. D'abord, elle visait à regrouper les différentes connaissances et à offrir un regard critique sur les résultats empiriques disponibles portant sur les traitements pharmacologiques adjuvants aux traitements antipsychotiques des déficits neurocognitifs en SZ et TPSZ. Son second objectif était de contribuer à l ' accro ~ ssement des connaissances quant à l'utilisation d'un des adjuvants neurocognitifs potentiels, le modafinil. Dans ce contexte, une revue de littérature systématique, ainsi que deux essais cliniques ont été réalisés. Leurs objectifs respectifs précis, de même que les conclusions qui en découlent seront résumés dans les prochaines lignes. Par la suite s'en suivra une section destinée à offrir une vue d'ensemble des connaissances actuellement disponibles en ce qui a trait au traitement pharmacologique des déficits neurocognitifs associés à la SZ et aux TPSZ. Ce sera alors l'occasion de traiter de diverses considérations méthodologiques pouvant sous-tendre les résultats obtenus, et certaines recommandations seront alors formulées. Cette section permettra également une réflexion portant sur l'utilité des outils neuropsychologiques dans les essaIS pharmacologiques, de même que ce qui peut être attendu pour le futur dans ce domaine de recherche. Subséquemment, une section portant plus spécifiquement sur l'état actuel des connaissances quant à l'utilisation du modafinil chez les individus psychotiques suivra. Enfin, les principales contributions empiriques, théoriques et cliniques de la thèse seront mentionnées, et ce chapitre se terminera sur une conclusion générale.

Résumé du premier article: "Adjunct Cognitive Enhancers to Second Generation Antipsychotics for Cognitive Impairments in Schizophrenia: A Review" L'objectif de cette revue systématique de la littérature était de regrouper les essais cliniques évaluant les effets de diverses molécules pharmacologiques sur le fonctionnement neurocognitif d'individus souffrant de SZ ou d'un TPSZ. Plus spécifiquement, les études répertoriées devaient avoir été réalisées en double-aveugle, avec un comparatif placebo, et ce, exclusivement auprès d'individus traités avec un antipsychotique de seconde génération (ASG). La recherche dans la littérature a été effectuée pour 59 molécules différentes. Vingt études correspondant aux critères d'inclusion et rapportant les résultats obtenus à l'aide de

Il molécules différentes ont été identifiées. Bien que certaines molécules soient testées en Discussion générale 165

SZ suite à l'observation d'améliorations neurocognitives avec d'autres populations présentant des déficits neurocognitifs, la plupart d'entre elles sont plutôt choisies en fonction de considérations neurochimiques. En effet, bien que 1' hypothèse dopaminergique pour l'explication des symptômes de la SZ et des TPSZ a prévalu pendant de très nombreuses années et qu'elle permet, toujours à ce jour, d'expliquer certains d'entre eux (Alves, Figee, Vamelsvoort, Veltman, & Haan, 2008), plusie,urs neurotransmetteurs apparaissent maintenant sous-tendre les divers symptômes qui y sont associés (Létoumeau, Simard, & Roy, article · en préparation, voir Chapitre 2). Ainsi, les molécules étudiées présentent des modes d'action variés, ayant pour cibles quatre grands systèmes de neurotransmission, en l'occurrence les systèmes cholinergique, glutamatergique, noradrénergique, et sérotonergique. D'autres molécules agissant plutôt sur des voies hormonales et modulant les systèmes de neurotransmission ont également été étudiées. Les molécules cholinergiques sont celles pour lesquel~es les toutes premières études ont été réalisées, et, de fait, pour lesquelles la plus importante quantité de données empiriques est disponible. Les autres molécules ont pour leur part été étudiées dans le cadre d'un nombre plus restreint d'études. Considérant la quantité d'études, la qualité des devis utilisés, la variété des épreuves neuropsychologiques employées, de même que la puissance stat~stique des études, les conclusions qui peuvent actuellement être tirées sur l'emploi d'adjuvants pharmacologiques pour le traitement des· déficits neurocognitifs associés à la SZ et aux TPSZ sont les suivantes:

1) Le buspirone, un agent sérotonergique, ·a procuré des bénéfices n'eurocognitifs dans une étude utilisant un devis robuste et impliquant un nombre élevé de participants. Ainsi, il serait important d'en prioriser l'étude dans un futur rapproché. 2) Les résultats suivant l'utilisation de lamotrigine suggèrent que cette molécule peut avoir un effet positif sur la neurocognltion chez les individus psychotiques. Cependant, il n'y a pas suffisamment de· données probantes permettant de conclure définitivement sur son utilité. Des études additionnelles sont donc nécessaires. 3) Pour une majorité de molécules étudiées (rivastigmine, galantamine, glycine, memantine, ampakine, atomoxétine, guanfacine, et qehydropiandostérone), et malgré la qualité des devis, les échantillons étaient relativement petits. Ainsi, pour Discussion générale 166

ces molécules, des études supplémentaires incluant un nombre supérieur de participants sont nécessaires afin de pouvoir dégager des conclusions fiables. Il est toutefois important de noter que malgré cette limite, certains résultats positifs ont été dégagés pour l' ampakine CX516 et la guanfacine, ce qui devrait avoir pour effet une priorisation des études sur ces molécules. 4) Le donepezil ne procure pas de bénéfices neuropsychologiques, ainsi, son étude n'apparaît plus nécessaire pour vérifier son potentiel de traitement à cet effet

Résumé du second article: "Modafinil as Adjunct Treatment in Recent-Onset Psychosis: Five Case Reports" L'objectif de cette première étude était d'évaluer la sécurité de l'utilisation, de même que l'impact neurocognitif et fonctionnel potentiel du modafinil chez des individus souffrant d'une SZ d'apparition récente. Pour ce faire, cinq hommes ont été évalués au plan clinique, neuropsychologique, et fonctionnel avant et après un traitement prolongé avec cette molécule. Au plan clinique, bien que tous les participants aient toléré la médication, le dosage a dû être réduit pour l'un d'entre eux, suivant une exacerbation de ses symptômes psychotiques. Bien qu'il n'ait pu être confirmé que l'utilisation de modafinil était en cause, cette possibilité n'a pas pu être écartée, considérant qu'une réduction de la dose a entraîné . une diminution des symptômes psychotiques. Le modafinil apparaissait donc pouvoir être utilisé sécuritairement chez cette clientèle, quoiqu'un suivi étroit des symptômes cliniques s'avère nécessaire. Les échelles cliniques pharmacologiques ont révélé une amélioration de l'impression subjective d'éveil, de la sédation, et de la vigilance, ainsi qu' une réduction de certains symptômes négatifs, de même que la durée du sommeil quotidien. Sur le plan neuropsychologique, quatre des cinq individus se sont améliorés sur plusieurs des mesures employées. Ce fût particulièrement le cas pour les mesures typiquement utilisées pour évaluer l' attention sélective, la vitesse de traitement de l'information, de même que la fluidité verbale. Enfin, en ce qui concerne le fonctionnement global, il s'est trouvé amélioré chez trois des individus impliqués dans le protocole. Les résultats découlant de cette étude, associés à ceux obtenus par une autre équipe de recherche (Turner, et al., 2004), encouragaient ainsi la poursuite des études portant sur l'utilisation du modafinil auprès des Discussion générale 167 individus psychotiques, et la possi~ilité de le faire chez ceux dont la symptomatologie psychotiques est d'apparition récente.

Résumé du troisième article: "A lO-week, double-blind, placebo controlled, cross-over trial of adjunctive modafinil for neurocognitive impairments in schizophrenia" La première étude ayant permis de conclure que le modafinil pouvait être utilisé de manière sécuritaire chez des individus souffrant de SZ d'apparition récente, en plus de montrer que cette molécule pouvait potentiellement améliorer leur fonctionnement neurocognitif, la deuxième étude a été conçue pour tester plus rigoureusement l'impact de modafinil chez les gens souffrant de SZ ou d'un TPSZ. Ainsi, 20 participants, souffrant de

SZ ou d'un TPSZ, qui, pour la majorité, était d'apparition récente, ont participé à cette étude expérimentale utilisant un devis chassé-croisé randomisé, avec contrôle placebo. Les participants étaient évalués aux plans neuropsychologique, clinique, et fonctionnel. Considérant l'importante prévalence des déficits attentionnels et leur association avec le fonctionnement global chez cette population, de même que l'importance de l'attention dans le fonctionnement neurocognitif en général, ce domaine a fait l'objet d'un intérêt particulier dans l'étude. La catégorisation des épreuves attentionnelles proposée par van Zomeren & Spikman (2003) a · été utilisée afin de choisir les tâches neuropsychologiques. De même, certaines mesures utilisées dans les études menées antérieurement et ayant montré un effet de modafinil ont été incluses. La catégorisation de van Zomeren, & Spikman (2003) a permis de formuler l'hypothèse principale, qui était à l'effet que les principaux bénéfices neuropsychologiques notés après le traitement avec modafinil se retrouveraient au niveau des tâches dont la principale composante constituait la vitesse de traitement de l'information. Au plan neurocognitif, le modafinil a eu un effet positif sur la fluidité verbale sémantique, la mémoire de travail en modalité verbale, et sur l' aptitude à repérer rapidement et efficacement des cibles parmi des distracteurs visuels. L'emploi du modafinil a aussi été associé à une plus importante propension à faire des erreurs de commission dans une épreuve typiquement utilisée pour l'évaluation de l'attention soutenue et de l'attention sélective. Bien que les résultats obtenus ne permettent pas de retenir l 'hYP9thèse primaire, les changements observés sont cohérents avec ceux obtenus par d' autres équipes de. recherche, qui ont, pour la majorité, employé une dose unique de modafinil. Les résultats · Discussion générale 168

suggèrent que le modafinil pourrait, chez la clientèle psychotique, faciliter l'initiation de la

réponse lors de la réalisation de tâches neuropsychologiques va~iées. Sur le plan clinique, le traitement avec modafinil s'est traduit par une amélioration subjective de la mémoire, de même que celle de la fatigue vécue par les participants. D'un point de vue fonctionnel, le traitement avec le modafinil ne s'est pas traduit par une amélioration du· fonctionnement global, tel que mesuré avec un outil unique.

Discussion générale Littérature .disponible; considérations méthodologiques générales Le souci de traiter efficacement les déficits neurocognitifs associés à la SZ et aux TPSZ s'est récemment traduit par la mise sur pied de nombreux essais pharmacologiques. Les résultats provenant de nouvelles études expérimentales sont évidemment attendus avec impatience, mais, à ce stade-ci, diverses limites inhérentes aux études réalisées se doivent d'être soulignées. Bien entendu, la réalisation de protocoles de recherche dédiés au traitement pharmacologique des déficits neurocognitifs en SZ comporte son lot de difficultés. Certaines d'entre elles semblent particulièrement en cause pour l'observation de nombreux résultats négatifs, ou, du moins, de résultats mitigés. Voici donc certaines particularités relatives à l'étude des adjuvants neurocognitifs auprès de la population psychotique qui peuvent être en cause pour les difficultés rencontrées, de même que certaines pistes de solution pouvant aider à les contourner dans le futur. Leur prise en considération pour la poursuite des études dans ce champ pourrait donner lieu à une amélioration de leur qualité, et, conséquemment, à accroître leur apport clinique.

Par la suite suivra une réflexion portant sur les standards expérimentaux attendus dans ce type de recherche. Plus précisément, cette section traitera de la pertinence de l'emploi des études de cas, et de celle des mesures neuropsychologiques dans le cadre des essais pharmacologiques liés au traitement des déficits neurocognitifs chez la population psychotique. Discussion générale 169

Difficultés liées au recrutement et à l'attrition, et recommandations Un premier constat a trait au fait que plusieurs études ont été réalisées avec de trop petits nombres de participants pour qu'il soit possible de statuer sur la valeur thérapeutique des molécules étudiées, la puissance statistique s'en trouvant limitée. Ceci peut en partie être dû au fait qu'il est difficile de .recruter les personnes psychotiques afin qu'elles participent à des études de traitement. D'un point de vue clinique, le fait qu'une certaine proportion de la population psychotique présente un manque d'autocritique diminue leur

intérêt à recevoir et maintenir un traitement (Loffler, Kilian, Toumi, & Angermeyer, 2003 ; Mintz, Dobson, & Romney, 2002). De même, ce manque d'autocritique peut les amener à minimiser l' ampleur de leurs difficultés neurocognitives, ceci, même si elles sont observées par leurs proches et le personnel traitant, et/ou qu'elles sont objectivées grâce à une évaluation neuropsychologique exhaustive. Ce manque d'autocritique se traduit fréquemment par un refus de participer à des études de traitement, ou, dans le cas où les patients s'y impliquent volontairement, d'un manque d'observance à la médication adjuvante ou aux rencontres prévues au protocole. Tout ceci se solde habituellement par un retrait' précoce de l'étude. Par ailleurs, d'un point de vue pharmacologique, l'utilisation de médications concomitantes au traitement antipsychotique requiert un suivi étroit des effets indésirables et de la formule sanguine. Ce suivi augmente le fardeau pour les participants, et peut donc nuire à leur observance au protocole. À titre d'exemple, alors que 48 individus ont été sollicités pour participer à l'étude expérimentale présentée au Chapitre 4 (Létoumeau, et al., article en préparation), 37 ont accepté d'y prendre part (77.0%), et de ceux -ci, 8 ont retiré leur consentement en cours de participation. Étant donné que la difficulté de recruter des participants psychotiques résulte en grande partie de caractéristiques inhérentes à la clientèle ou à leur traitement, il est important d'utiliser des stratégies visant à a) maximiser la puissance statistique obtenue, et b) maintenir un maximum de participants impliqués dans le protocole.

a) Pour optimiser la puissance statistique obtenue avec un nombre limité de participants, l'utilisation d'un devis en chassé-croisé présente un avantage certain. En effet, puisque chacun des participants reçoit les deux traitements comparés, chaque groupe de traitement comporte ainsi un plus grand nombre d'individus. À titre comparatif, si 20 , Discussion générale 170 individus sont recrutés pour participer à une étude utilisant un devis mené en parallèle, dix participants recevront la molécule à l'étude, et les dix autres, le placebo. Dans un devis mené en chassé-croisé, 20 participants recrutés feront plutôt en sorte que 20 reçoivent le traitement adjuvant, et 20 reçoivent le placebo. En plus de cet avantage, le devis en chassé croisé permet un contrôle des variables individuelles qui pourraient être en cause pour les changements observés dans un devis mené en parallèle, car chaque participant est son propre témoin. Par ailleurs, son utilisation permet de répartir également entre les groupes de traitement d'éventuels effets de pratique qui pourraient sous-tendre une partie de la variation neuropsychologique observée en post-test. En effet, dans ce type de devis, chaque participant est généralement évalué à quatre reprises à l'aide des mêmes mesures, ou de versions alternatives, lorsque disponibles. Cependant, les deux moitiés de l'échantillon reçoivent les traitements dans un ordre inversé, ce qui fait en sorte que les effets de pratique sont distribués également entre les groupes de traitement, qui sont constitués des phases identiques de chaque condition expérimentale. Enfin, lorsqu'une période de sevrage est incluse entre les différentes phases de traitement en fonction de la durée d'élimination de ,la molécule de l'organisme, le dèvis chassé-croisé contrôle efficacement l'impact d'une potentielle superposition des effets pharmacologiques (Senn, 2002). Par ailleurs, à l'instar de ce qu'ont fait Turner et ses collaborateurs (2004) pour l'étude du modafinil, le devis en chassé-croisé peut être réalisé sans que les participants aient à entreprendre une utilisation prolongée de la molécule à l'étude. Dans ce cas précis, le modafinil ou le placebo étaient administrés aux participants environ deux heures avant la réalisation des tâches neurocognitives. Cette option peut être envisagée avec toute molécule présentant une assimilation et une action . rapides, quoique la vérification de l'inocuité nécessite probablement une plus longue période d'utilisation.

b) Une fois les participants recrutés, l'optimisation de la pUIssance nécessite également qu'ils demeurent impliqués dans l'étude jusqu'à la fin. Encore ici, il semble possible de pallier au problème de l'attrition par retrait du consentement. En effet, les résultats obtenus dans le cadre de l'étude empirique présentée au Chapitre 4 (Létourneau, et al., article en préparation) laissent croire que dès la sollicitation, il peut être possible d'anticiper le retrait de certains participants. En effet, il apparaît clairement que l'attitude Discussion générale 171

des p~rticipants face à la prise de médications psychotropes est un bon prédicteur de leur prédisposition à compléter ou non toutes les étapes du protocole auquel ils prennent part. Dans ce cas précis, elle a été mesurée à l'aide de la DAI-IO, qui est un outil permettant de mesurer l'attitude à l'égard de la prise de médicaments en quelques minutes. Les résultats de cette étude montrent une importante différence d'attitude entre les individus ayant complété leur participation, et ceux qui ne l'ont pas complétée. Effectivement, ces derniers présentent, en moyenne, une opinion très négative de l'utilisation d'une médication, en comparaison avec celle de ceux l'ayant complétée. Ainsi, afin de maximiser les probabilités de maintenir les participants impliqués dans le protocole, ceci pour optimiser l'utilisation des ressources de recherche, un critère d'inclusion relatif à cette échelle pourrait être utilisé dans des essais pharmacologiques ultérieurs. Par exemple, selon nos propres données le fait d'obtenir un score égal ou supérieur à 5 à la DAI pourrait constituer un critère d'inclusion des participants.

Hétérogénéité des mesures neuropsychologiques employées, et recommandations Une deuxième considération méthodologique apparaissant être en cause dans le peu de résultats probants actuellement publiés a trait au fait que les différentes études incluaient des mesures neuropsychologiques très variées, ce qui limite la reproduction des résultats. De plus, alors que certaines études ont ciblé quelques processus spécifiques à l' aide d'outils expérimentaux, d'autres ont priorisé l'inclusion d'épreuves normalisées permettant de mesurer de nombreux processus neurocognitifs, ce qui ajoute au problème de la reproduction des résultats A priori, ce choix repose généralement sur les connaissances concernant le mode d'action de la molécule (considérations biologiques), ou de celles découlant de son utilisation antérieure (considérations neuropsychologiques, ou neurocognitives). Cependant, cela occasionne une difficulté à dégager des conclusions générales sur l'effet des molécules étudiées. En effet, bien que chaque étude, lorsque considérée seule, permette d'en apprendre davantage sur l'utilité d'un adjuvant potentiel, il s'avère plus ardu de dégager des conclusions sur la base de l'ensemble de la littérature disponible. En effet, dans ce cas précis, soit des résultats contradictoires obtenus sur des mesures évaluant théoriquement le même construit demeurent difficiles à interpréter, soit cela empêche de connaître l'impact de la médication sur des processus particuliers 'qui Discussion générale 172 n'ont pas fait l'objet des études. Au stade actuel des connaissances liées à l'utilité des adjuvants neurocognitifs en SZ, un effort particulier devrait être fourni pour uniformiser davantage les mesures employées.

Afin de résoudre, entre autres choses, les problèmes relatifs à l'utilisation de mesures différentes dans ces études, des représentants du NIMH, de la· Food and Drug Administration, de même que ceux de l'initiative Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) se sont réunis au printemps 2004. Durant cette séance de travail, des directives relatives à la méthodologie étant destinées aux chercheurs ont été dégagées consensuellement, sur la base des résultats empiriques les plus probants. Ces directives ont entre autres trait au diagnostic des participants, à leur état clinique et la sévérité de leurs symptômes, ainsi qu'au traitement antipsychotique et à la polypharmacie (Buchanan, et al., 2005), qui est courante dans le traitement des troubles psychotiques. De plus, cette séance de travail a donné lieu à la décision de créer une batterie neuropsychologique permettant l '·évaluation des changements relatifs à l'emploi de médications adjuvantes. Les épreuves neuropsychologiques incluses dans cette batterie ont été choisies pour leur qualité à mesurer les déficits neurocognitifs fréquemment observés dans la SZ et les TPSZ, de même qu'en fonction de leur sensibilité, et de leur spécificité à l'égard des ces déficits (Green, Kem, & Heaton, 2006). Actuellement, la standardisation, l'accumulation des données normatives ainsi que les propriêtés de cette batterie d'évaluation sont suffisamment étayées pour qu'elle puisse être utilisée aisément (Kem, et al., 2008 ; Nuechterlein, et al., 2008).

U ne utilisation étendue de cette b(:ltterie consensuelle (MATRICS Consensus Cognitive Battery, [MCCB]) dans les prochaines études devrait avoir pour effet de prévenir les nombreux problèmes qui limitaient jusqu'ici la comparaison des résultats entre eux. Des résultats plus facilement comparables d'une étude à l'autre pourront ainsi découler de cet effort d'uniformisation. Il est toutefois important de mentionner que les tâches incluses dans la MCCB sont des tâches couramment utilisées en neuropsychologie, et qu' çlles n'ont pas été spécifiquement développées afin d'étudier l'évolution des déficits neurocognitifs liés à la SZ et aux TPSZ. Ainsi, cette batterie comporte certaines limites, entre autres celle Discussion générale 173

liée à l'utilisation de quelques sous-tests multidéterminés dont les résultats peuvent être sous-tendus par diverses aptitudes autres que celles pour lesquels ils ont été inclus. Par exemple, certains tests «papier-crayon» sont inclus pour permettre l'évaluation de processus neurocognîtifs comme la vitesse de traitement de l'information et les aptitudes de planification, mais ils nécessitent que les évalués écrivent (i.e., sous-test Symbol-Coding de

la Brief As~essment of Cognition in Schizophrenia; sous-test Labyrinthes de la Neuropsychological Assessment Battery). De fait, et considérant les dysfonctions psychomotrices observées chez une importante proportion d'individus psychotiques

(Delevoye-Turrell, Giersch, & Danion, 2003 ; Delevoye-Turrell, Giersch, Wing, & Danion, 2001 ; Lehoux, et al., 2003), l'emploi d' autres épreuves permettant de mesurer plus spécifiquement ces processus sans faire appel aux processus moteurs aurait dû être privilégié. Ainsi, le principal apport de son utilisation sera de permettre de dégager des conclusions sur la base de plusieurs études présentant une méthodologie plus uniforme.

Suite à l' «ère MATRICS », il sera toutefois justifié de tester des hypothèses plus précises en relation avec les résultats les plus congruents. En effet, des études plus ciblées en termes de sous-processus neurocognitifs pourront alors être mises sur pied, ce qui raffinera la compréhension de l'impact des diverses molécules adjuvantes. De cette manière, les données actuellement disponibles demeurent pertinentes, mais auront sans doute une valeur .scientifique accrue dans quelques années.

Utilité des études de cas portant sur les adjuvants neurocognitifs De manière générale, en neuropsychologie, les études de cas ont eu un impact considérable sur le développement des connaissances. Dans le domaine plus particulier des troubles psychotiques, ce type d'études a entre autres permis de mieux comprendre les défaillances du système attentionnel superviseur (Shallice, Burgess, & Frith, 1991). Mais qu'en est-il de leur utilité dans le domaine précis de la découverte d'agents pharmacologiques pour le traitement des déficits neurocognitifs associés à la SZ et' aux TPSZ? Certains aspects inhérents aux troubles psychotiques peuvent sans doute militer en faveur de l'utilité des études de cas, lorsque réalisées en parallèle avec les études de groupes. Discussion générale 174

La variété des profils neuropsychologiques qui peuvent être observés chez les individus psychotiques peut constituer un premier argument favorable à l'utilisation des études de cas. En effet, même s'il est bien admis, et tel qu'explicité en introduction, que certaines fonctions neurocognitives sont plus fréquemment altérées dans les troubles psychotiques, il n'en demeure pas moins qu'une importante hétérogénéité inter-individuelle existe dans la population SZ. À titre d'exemple, Brazo et al. (2002) se sont intéressés à caractériser le profil neuropsychologique d'un groupe d'individus selon le sous-type de SZ auquel ils apparaissaient appartenir (prédominance de symptômes positifs, de symptômes négatifs, ou de désorganisation). Un groupe de participants sains était inclus dans leur étude à titre comparatif. Leurs résultats indiquent que les patients présentant davantage de symptômes positifs offrent un rendement neuropsychologique relativement normal par rapport aux témoins, alors· que ceux à prédominance de symptômes négatifs et de désorganisation réalisent plus difficilement les tâches faisant appel aux aptitudes attentionnelles, mnésiques, et exécutives. Les performances des deux derniers groupes se distinguent toutefois par la nature des tâches affectées. De plus,. outre la possibilité de regrouper les individus en fonction de la prépondér~nce de certains sous-types de symptômes cliniques, l'hétérogénéité propre aux troubles psychotiques fait en sorte que de nombeux sous-groupes de SZ ont été proposés à travers le temps, et ce, en fonction de diverses autres variations (par ex. âge d'apparition, réponse au traitement, qualité de l'évolution, etc.) (Murray, et al., 1991; Roy, Mérette, & Maziade, 2001). Certains auteurs suggèrent d'ailleurs que la SZ et les TPSZ pourraient constituer divers syndromes distincts.

Ainsi, à l'instar de l'étude empirique réalisée dans le cadre de la présente thèse doctorale, et pour laquelle une majorité de participants souffraient d'un trouble psychotique d'apparition récente, les études de groupes sont généralement effectuées auprès de patients présentant une ou des caractéristiques communes. Malheureusement, les nombreuses variations de leurs caractéristiques neuropsychologiques et cliniques font en sorte qu'il est impossible de constituer un groupe SZ homogène. Ces fluctuations constituent l'un des facteurs pouvant être en cause pour expliquer les nombreux résultats négatifs jusqu'ici obtenus, le manque de réponse au traitement d'une majorité de participants ayant pu obscurcir des résultats positifs chez certains d'entre eux. C'est ce qui a pu se produire lors Discussion générale 175 de l'étude des différents inhibiteurs de l'acétylcholinestérase. Effectivement, au départ, plusieurs études de cas rapportaient des améliorations importantes sur le plan des variables neurocognitives investiguées (Bora, Veznedaroglu, & Kayahan, 2005; Howard, Thomton, Altman, & Honer, 2002; Lenzi, et al., 2003; MacEwan, Ehmann, Kanbhai, & Wrixon, 2001; Mazeh, Mirecki, Paleacu, & Barak, 2003; Raguraman, Sagar, & Chandrasekaran, 2005; Risch, et al., 2001). Par contre, les études de groupe réalisées subséquemment ne sont pas parvenues à les reproduire (Létoumeau, Simard, & Roy, 2008, article en préparation, voir Chapitre 2). D'un point de vue méthodologique, diverses considérations peuvent être avancées pour expliquer les contradictions notées entre les résultats des études de groupe et ceux provenant d'études de cas. Pour ne nommer que ceux-là, les phénomènes du biais de sélection ou de celui provenant des attentes de l' expérimentateur, peuvent tendre à favoriser les résultats positifs découlant des études de cas. D'un point de vue clinique par contre, les études de groupe rapportant des résultats négatifs font en sorte qu'il devient impossible de connaître les caractéristiques des participants qui ont bénéficié du traitement.

Dans l'éventualité où les participants bénéficient de façon différente des molécules investiguées, la réalisation d'études de cas et la diffusion des résultats peuvent jouer un rôle important dans la découverte de traitements efficaces, et ce, principalement de deux manières ~ D'abord, tel que mentionné précédemment, la publication de résultats positifs obtenus chez quelques individus peut susciter l'intérêt scientifique et mener à la mise sur pied de devis plus puissants, ciblant plus spécifiquement les processus ayant bénéficié de la molécule à l'étude. Deuxièmement, la réalisation de telles études perni.et généralement aux auteurs, lors de la publication de leurs résultats, de détailler les caractéristique du ou des patients impliqués, de même que la qualité de leur réponse au traitement expérimental. D'un point de vue clinique, ceci peut s'avérer fort utile pour le praticien, qui peut ainsi identifier lesquels, parmi ses patients, rencontrent les caractéristiques mentionnées et pourraient être de potentiels candidats à bénéficier de la molécule à l'étude. L'objectif ultime étant d'améliorer le traitement des patients, cette application des connaissances scientifiques a l'avantage d'être plus personnalisée, mais également plus prometteuse et diligente. De plus, comme le soulignent Kurtz, Moberg, Gur, et Gur (2001), certains devis plus sophistiqués et comportant des niveaux de base multiples peuvent être appliqués sur Discussion générale 176 une base · individuelle et présentent l'avantage de favoriser des inférences quant à l'efficacité du traitement.

Une alternative au fait de choisir entre l'une ou l'autre des procédures peut également être envisagée. En effet, puisqu'ils présentent des avantages différents, les devis de groupe et les études de cas peuvent également être réalisés de manière séquentielle; à l' instar, entre autres, de ce qui a été fait dans le cadre de l'étude empirique présentée dans cette thèse (Létourneau, et al., article en préparation, voir Chapitre 4). En effet, alors que les résultats de groupe ont d'abord été dégagés, des analyses subséquentes ont permis de vérifier si les participants s'étant amélioré sur le plan neuropsychologique partageaient des caractéristiques que les « non-répondants» ne présentaient pas. Une troisième étape aurait pu consister à détailler les cas individuels des meilleurs répondants afin de fournir des précisions relatives à leur profil clinique. Cette façon de faire allierait ainsi les forces des différents devis, et serait aisément réalisable si l'évaluation des participants est effectuée de manière suffisamment exhaustive pour que des descriptions individuelles puissent être dégagées. Enfin, cette façon de faire pourrait par ailleurs permettre de diminuer certaines contraintes d'inclusion et d'exlusion, tels que fixées au départ. Par exemple, dans cette optique, des individus traités avec des molécules variées, par exemple des antipsychotiques de première génération et des ASG pourraient ainsi être inclus afin que les données de groupe et de sous-groupes puissent être analysées. C'est d'ailleurs ce qui a été fait par

Friedman et ses collaborateurs (2001), qui s'intéressaient à l'effet de guanfacine en tant que potentiel adjuvant cognitif chez la population psychotique. Leur échantillon initial était composé de 29 individus traités à l'aide d'un APG ou d'un ASG, et les analyses statistiques prenant en considération tous les participants n'ont révélé ni effet significatif, ni tendance statistique. Toutefois, lorsque seuls les Il participants traités à l'aide de la rispéridone, un ASG, ont été considérés, les analyses post-hoc ont révélé une amélioration des performances sur des tâches mesurant la mémoire de travail en modalité non-verbale, des temps de réaction au CPT-II, de même qu'au plan de la flexibilité cognitive, telle que mesurée à l'aide du Trail Making Test, partie B. De même, toujours en comparaison avec le placebo, la guanfacine, lorsqu'administrée en concomitance avec la rispéridone, tend à améliorer la mémoire d'informations présentées visuellement. Ces résultats, de même que Discussion générale 177 ceux découlant de nos propres analyses a posteriori, démontrent bien de quelle manière certaines caractéristiques des participants ou de leur traitement peuvent être impliquées dans l'effet pharmacologique des adjuvants neurocognitifs. De même, ils soulignent l'importance d'aller au-delà des résultats de groupe pour optimiser les conclusions pouvant être tirées. Cette façon de faire présente sans contredit des avantages au plan empirique, de même qu'au plan clinique.

Utilité des mesures neuropsychologiques dans les essais pharmacologiques Depuis déjà plusieurs années, et à la lumière de leur valeur prédictive à l'égard du fonctionnement global, les outils neuropsychologiques font généralement partie intégrante de l'évaluation systématique des individus souffrant d'un TPSZ. Conséquemment, les études de traitement mises sur pied récemment incluent généralement quelques épreuves neuropsychologiques. Si l'objectif de ces études est principalement le traitement des déficits neuro co gnitifs , les épreuves neuropsychologiques sont habituellement plus nombreuses et variées. Jusqu'à maintenant, ces mesures ont permis de mettre en évidence l'utilité potentielle de certains adjuvants neurocognitifs. C'est le cas de quelques-unes des molécules pour lesquelles des études ont été revues dans l'article constituant le Chapitre 2

(Létoumeau, Simard, & Roy, article en préparation, voir Chapitre 2), de même que, celui du modafinil (voir Chapitres 3, et 4), et de la nicotine (données non-revues dans le cadre de la thèse). Puisque les connaissances actuelles ayant trait à l'efficacité des adjuvants neurocognitifs pour les TPSZ sont plutôt limitées, l'utilité de ces mesures est incontestable. En effet, les résultats dégagés à ce stade-ci permettent d'orienter les recherches futures en identifiant quels processus neurocognitifs seraient les plus enclins à profiter de l'ajout des molécules adjuvantes étudiées, tel que c'est le cas pour chacune des études mentionnées ci haut. Néanmois, certaines lacunes semblent inhérentes à l'utilisation des mesures neuropsychologiques dans de telles études.

D'abord, la recension de la littérature portant sur l'utilisation d'adjuvants neurocognitifs potentiels (Létoumeau, Simard, & Roy, article en préparation, voir Chapitre 2) a permis de constater que, dans les études incluant diverses évaluations cliniques et neuropsychologiques, les mesures cliniques apparaissaient parfois plus sensibles aux Discussion générale 178 changements que' les mesures neuropsychologiques. C'est notamment ce qui a été observé dans les études réalisées par Keefe et al. (2008), et Zocalli, et al. (2007), portant respectivement sur l'impact de donepezil et de lamotrigine sur le fonctionnement neurocognitif d'individus souffrant de SZ ou de TPSZ. En effet, dans ces cas précis, les bénéfices ont été mis en évidence à l'aide de mesures cliniques mesurant les symptômes cliniques de ces psychopathologies, alors que les outils neuropsychologiques n'ont pas montré d'amélioration. De même, la réalisation de l'essai clinique expérimental de la thèse a permis de constater que dans plusieurs cas, les résultats neuropsychologiques individuels ne permettaient pas de mettre en évidence des améliorations, pourtant clairement notées de manière subjective, par exemple, une production verbale plus spontanée, ou une alerte générale plus importante. La poursuite de la prise du modafinil par certains participants pour lesquels des améliorations ont été notées subjectivement a d'ailleurs permis de confirmer leur utilité à la suite du protocole. En effet, pour la majorité d'entre eux, ceux-ci se sont traduit par un bien-être supérieur et une nette impression de leur part que cette molécule favorise leur fonctionnement dans la réalisation ,des activités quotidiennes.

Ce constat soulève un questionnement quant à la sensibilité des mesures neuropsychologiques utilisées dans ce type d'études. La majorité des épreuves neuropsychologiques utilisées dans les études susmentionnées ont démon~ré leur sensibilité

à différentes lésions cérébrales (Lezak, Howieson, & Loring, 2004), et donc, a priori, l'hypothèse d'un manque de sensibilité devrait être écartée. Une autre hypothèse explicative est plutôt à l'effet que, bien qu'elles soient conçues en vue de dégager des conclusions sur un nombre restreint de processus neurocognitifs à la fois, les mesures neuropsychologiques demeurent toujours essentiellement multidéterminées. Une partie de -la réponse pourrait effectivement avoir trait à cette multidétermination, qui a tendance à faire en sorte que les résultats obtenus sur une tâche précise utilisée pour la mesure d"un ,processus particulier peuvent être sous-tendus par des habiletés différentes de celles d'intérêt. Dans cette optique, l'utilisation des mesures les moins multidéterminées possibles présentent l'avantage de faire appel à un nombre plus restreint d'habiletés, et donc, à permettre une mesure plus efficiente de processus neurocognitifs précis. À la manière des tâches issues de la psychologie cognitive expérimentale, les concepteurs des ' outils Discussion générale 179 neuropsychologiques contemporains ont souvent le souci d'inclure plusieurs sous-tâches pour la mesure d'un seul processus. En effet, l'exemple de la batterie D-KEFS illustre bien de quelle façon il est possible d'isoler un processus spécifique en permettant d'extraire l'influence d'autres processus par le biais de leur mesure indépendante. Dans l'exemple précis de la D-KEFS, les différentes conditions d'un meme sous-test sont ainsi conçues pour fairè appel à un seul processus nouveau d'une condition à l'autre (e.g. Mots colorés, Trail Making Test). Cela permet le calcul d'index dégageant l'apport d'un seul processus. L'utilisation de tels outils, de même que de ceux développés sur mesure (mesures expérimentales) pourrait éventuellement présenter l'avantage d'être plus révélatrice des bienfaits neurocognitifs mesurés. Il n'en demeure toutefois pas moins que l'impression subjective d'un bienfait, soit par le participant, soit par l'évaluateur, est peut-être plus globale, et ne fait pas nécessairement appel à un ou des processus neurocognitif(s) précis.

Deuxièmement, il est apparu à l'observation des profils neurof'sychologiques individuels, et malgré la stabilité relative des épreuves utilisées lorsqu'employées chez des individus sains, qu'une grande variabilité intra-individuelle était observable chez plusieurs participants. Cette variabilité a en effet été observée, tant lors de la phase de traitement avec le modafinil, que lors de la phase 'placebo, durant laquelle les variations devraient, théoriquement, être dûes à un t:ffet de pratique ainsi qu'à l'effet placebo. Les variations « à la baisse» sont notamment les plus difficilement interprétables, principalement lorsqu'elles sont notées au cours de la phase de traitement avec le placebo. Bien que la qualité du devis expérimental utilisé, de même que l'emploi d'analyses statistiques appropriées aient pour effet d'accroître la confiance pouvant être accordées aux résultats, ces variations demeurent surprenantes. Dans la population à l'étude, elle,s pourraient être imputables à divers facteurs individuels, notamment à la motivation des participants à se prêter aux évaluations neuropsychologiques. Sachant qu'elle joue effectivement un rôle important dans les résultats de toute évaluation neuropsychologique, pourrait-elle être à l'origine des fluctuations observées dans l'étude? Malheureusement, les outils inclus dans le protocole ne permettent pas de répondre à cette question. Toutefois, considérant que le manque de motivation constitue un symptôme 'négatif fréquemment rapporté par les indivi'dus psychotiques, des performances non-optimales à certaines séances cl' évaluation pourraient Discussion générale 180 effectivement en rendre compte. Ainsi, a posteriori, il appert qu'une simple question portant sur l'état de la motivation des participants à chaque évaluation, et étant par exemple cotée sur une échelle visuelle analogue, aurait pu être utile afin de mieux comprendre les résultats observés, et les facteurs les sous-tendant. La motivation pourrait ainsi être considérée à titre de co-variable dans les analyses statistiques.

Modafinil et troubles psychotiques; état des connaissances En ce qui concerne spécifiquement le modafinil, son utilisation pour le traitement des déficits neurocognitifs inhérents aux troubles psychotiques est, encore à ce jour, plutôt rare. Alors que cette molécule fait l'objet d'un intérêt grandissant pour son utilité dans le traitement de nombreuses conditions médicales auxquelles sont associées de la fatigue ou de la sédation, de même que des déficits neurocognitifs (Kumar, 2008), son investigation dans le traitement des troubles psychotiques est plus restreinte (Morein-Zamir, Turner, &

Sahakian, 2008; Saavedra-Velez, Yusim, Anbarasan, & Lindenrnayer, 2008). Diverses raisons peuvent être évoquées afin d'expliquer pourquoi son emploi est limité chez cette clientèle. Notamment, deux des premières publications concernant son utilisation auprès d'individus psychotique faisaient respectivement état d'une recrudescence des symptômes psychotiques (Narendran, et al., 2002) et d'une augmentation substantielle du taux sanguin de clozapine (DeQuardo, 2002). Cependant, il faut noter que ces deux patients étaient traités respectivement à l'aide de doses de 800 et 400 milligrammes quotidiennement, qui sont nettement plus élevées que celles utilisées dans la présente thèse . .Deuxièmement , la compréhension du mode d'action de modafinil se raffine et les études plus récentes indiquent qu' il comporte un effet sur la dopamine, qui est un neurotransmetteur 'connu pour sous-tendre les symptômes positifs des troubles psychotiques (Stahl, 2007). Bien -que les constats énumérés précédemment se doivent d'être sérieusement considérés au moment de commencer l'utilisation du modafinil auprès d'individus ou de populations psychotiques, il semble qu'elle puisse tout de même être envisagée. En effet, à la lumière des résultats publiés dans la littérature et de ceux découlant des deux études réalisées dans le cadre de la présente thèse doctorale, il semble, à ce stade-ci des connaissances, que son utilisation puisse présenter des bénéfices chez cette population. Ainsi, le rapport coûtlbénéfices tend pour le moment à favoriser son emploi auprès de cette clientèle . . Discussion générale 181

Bénéfices sur le plan neurocognitif D'une part, le modafinil semble pouvoir mener à une amélioration de fonctions · neurocognitives variées chez la population psychotique. Jusqu'à maintenant, la fluidité verbale sémantique, l'attention sélective, la flexibilité cognitive, la latence lors de la réalisation d'une tâche faisant appel aux aptitudes de planification, ainsi que la mémoire de travail auditivo-verbale, paraissent pouvoir en bénéficier (Létourneau, et al. , article en préparation, voir Chapitre 4; Turner, et al., 2004).

Fluidité verbale sémantique La fluidité verbale sémantique constitue un bon indicateur de la manière dont un individu organise sa pensée (Estes, 1974). Elle est une fonction fréquemment trouvée atteinte chez les individus souffrant de SZ ou d'un TPSZ (Bozikas, Kosmidis, & Karavatos, 2005 ; Henry, & Crawford, 2005). Certaines études démontrent d'ailleurs qu'il pourrait s'agir d'un des plus puissants endophénotypes neurocognitifs de ces psychopathologies. En effet, les performances dans les tâches de fluidité sémantique demeurent stables dans le temps alors que la. plupart des autres fonctions tendent à s'améliorer progressivement (Sz6ke, et al., 2008). De même, les apparentés sains d'individus psychotiques tendent à présenter des performances déficitaires relativement à celle de participants contrôles (Chen, Chen, & Lieh-Mak, 2000). Le déficit de fluidité verbale sémantique chez la population psychotique est fortement corrélé aux difficultés dans le fonctionnement communautaire (Green, et al. , 2000). Sur le plan de la symptomatologie, il apparaît sous-tendre l'alogie (Joyce, Collinson, & Crichton, 1996; Sumiyoshi, et al. , 2005), un symptôme négatif fréquemment noté chez cette population. Il a été démontré que, chez les individus psychotiques, les mêmes stratégies de recrutement du réseau sémantique que celles déployées par des individus sains sont mises en branle lors de la réalisation d'une tâche de fluidité verbale. Ce serait une difficulté d'accès au bagage sémantique qui sous-tendrait les déficits observés (Joyce, Collinson, & Crichton, 1996). La fluidité verbale est mise à contribution dans toute conversation, et constitue un pré-requis pour une communication effective. Son intégrité permet notamment d'exprimer précisément une idée, et à participer activement à une discussion. Puisque le modafinil semble pouvoir influencer positivement Discussion générale 182 les résultats sur ce type de tâches, il semble qu'il permette d'améliorer l'efficacité de l'accès au réseau sémantique et donc d'initier plus facilement la production verbale. Au quotidien, ceci pourrait se traduire par une amélioration de la quantité du discours, de même que de sa qualité, ce qui est d'une grande importance pour l'acquisition et le maintien de relations sociales satisfaisantes. Rappelons par ailleurs que le premier participant de l'étude pilote a présenté une amélioration considérable de sa fluidité verbale, ce qui nous a ~onvaincus de poursuivre l'étude des effets cognitifs de ce médicament. Selon ses dires, le modafinil lui a permis de formuler verbalement ses pensées, ce qu'il arrivait difficilement à faire avant le traitement. .

Attention sélective L'attention sélective ou focale fait référence à la capacité d'un sujet à investir ses ressources de traitement sur les éléments pertinents à la situation ou à la tâche dans laquelle il est engagé, tout en inhibant les éléments distracteurs (Leclercq, & Zimmermann, 2000). Autant lors de l'évaluation neuropsychologique de la population psychotique que celle d'autres populations, les outils d'évaluation de l'attention sont principalement de nature visuo-motrice. Les épreuves de « tracking » de même que les tâches de barrage de cibles sont effectivement celles dont l'utilisation est la plus répandue. Chez la population psychotique, l'attention , sélective est une autre des nombreuses fonctions atteintes

(Heinrichs, & Zakzanis, 1998). Par ailleurs, elle peut, du moins en partie, découler de la présence d'hallucinations, . qui agissent en tant que distracteurs (Hatashita-Wong, & Silverstein, 2003). Selon les études réalisées par Green et ses collaborateurs (1996 ; 2000), les déficits d'attention sélective sont en cause dans le dysfonctionnement social. Bien que son amélioration par le modafinil ne soit observée que sur une seule variable permettant son évaluation dans notre étude empirique, le fait que l'échantillon soit petit peut avoir nui à la détection d'autres effets. Actuellement, le résultat observé suggère que le modafinil peut améliorer les aptitudes lors de la détection de cibles visuelles « non-verbalisables » parmi des distracteurs du même type. Puisque c'est le ratio entre la vitesse d'exécution et la précision des réponses qui a été utilisé à titre comparatif, ce résultat démontre que ces deux aptitudes ont bénéficié du traitement. Des données supplémentaires devront être recueillies afin de valider ce résultat, mais" à l'heure actuelle, il appert que l'amélioration de Discussion générale 183

l'attention sélective puisse figurer parmi les cibles neurocognitives du modafinil chez les individus psychotiques.

Flexibilité cognitive La flexibilité cognitive est reconnue comme faisant partie des fonctions exécutives et consiste en la capacité à déplacer l'attention d'une classe de stimuli à une autre (van Der Linden, et al., 2000). Chez les individus psychotiques, une difficulté à alterner entre divers

stimuli, ou même une franche persévération sont souvent mises ~n évidence (Bonilha, et al. , 2008 ; Heinrichs, & Zakzanis, 1998). Divers outils neuropsychologiques permettent de quantifier l'état de la flexibilité cognitive. Les plus souvent utilisés sont probablement le TMT B, le Wisconsin Card Sorting Test, de même que certaines conditions d'alternance découlant de la tâche de Stroop. Selon la littérature, lorsque présents chez des. individus souffrant de SZ, les déficits de flexibilité seraient fortement liés à des défaillances dans le fonctionnemept communautaire, de même qu'à des difficultés dans la réalisation des activités de la vie quotidienne (Green, et al., 1996; 2000). À ce stade-ci, l'effet du modafinil sur la réalisation de tâches faisant appel à la flexibilité cognitive a été évalué dans trois études, dont la nôtre (Létourneau, et al., 2008, article en préparation, voir Chapitre 4; Pierre, et al., 2007; Turner,' et al. 2004). Ces derniers sont les seuls à avoir mis en évidence un impact positif de la molécule, à l'aide d'une épreuve tirée de la batterie CANTAB. Si ce résultat est reproduit et que le modafinil influence positivement la flexibilité cognitive, des bénéfices subséquents liés entre autres à l'autonomie communautaire de même qu'à l'autonomie résidentielle pourraient potentiellement être envisagés.

Mémoire de travail auditivo-verbale La mémoire de travail permet l'encodage et la manipulation temporaire d'informations - dans ce cas-ci, verbales - utiles à des fins immédiates (van Der Linden,

Meulemans, Belleville, & Collette, 2000). Le modèle cognitif le plus connu de la mémoire dé travail a été décrit par Baddeley et Hitch (1974; Baddeley, 1986). Il comporte différentes composantes et sous-composantes. Trois d'entre elles ont davantage été étudiées; la boucle phonologique et le registre visuo-spatial, ainsi que l'administrateur

Discussion générale 185

Considérant que plusieurs de ces fonctions sont fréquemment altérées chez les individus psychotiques (Fioravanti, Carlone, Vitale, Cinti, & Clare, 2005; Heinrichs and Zakzanis, 1998; Keefe, et al., 2006), leur traitement, du moins partiel, pourrait se traduire par une amélioration du fonctionnement ou de la qualité de vie des gens traités. C'est du moins ce qui a pu être observé chez trois des cinq participants traités sur une période prolongée lors de l'étude pilote réalisée dans le cadre de la présente thèse (Létourneau, et al., article en préparation, voir Chapitre 3).

Autres bénéfices notés D'autre part, le modafinil semble pouvoir avoir un impact positif au plan clinique chez cette population. En effet, un impact significatif positif a pu être observé sur des mesures permettant de mettre en évidence une amélioration de la ·mémoire, de même qu'une diminution de la fatigue, tels que subjectivement rapportés par les participants lors des entrevues cliniques (Létourneau, et al., article en préparation, voir Chapitre 4). Puisque les plaintes relatives à la mémoire et à la sédationlfatigue sont fréquemment mentionnées par les patients, leur amélioration subjective constitue en soi un apport du traitement pharmacologique avec le modafinil.

Bénéfices neurocognitifs mesurés à l'aide d'instruments cliniques En ce qui concerne plus spécifiquement la mémoire, il s'agit de la première étude faisant état de son amélioration subjective suivant un traitement avec le modafinil. Cette amélioration a été mise en évidence à l'aide d'une échelle permettant de quantifier les effets indésirables suivant la prise d'une médication psychotrope. Parmi les effets indésirables

évalués par la sous-échelle des «symptômes psychiques», un 1 item ayant trait à des difficultés mnésiques est inclus. Lors des visites de suivi au protocole, les participants avaient à apprécier l'intensité de leurs troubles de mémoire sur une échelle en quatre points, ce qui a donné lieu à une amélioration significative lors du traitement avec le modafinil. D'une part, ce résultat apparaît cohérent avec celui observé sur l'épreuve de mémoire de travail utilisant des stimuli verbaux. Cependant, il apparaît contradictoire avec celui que nous avons observé sur la mesure subjective de défaillances cognitives, incluses spécifiquement afin de dégager les impressions subjectives des participants à l'égard de Discussion générale 186 leur fonctionnement neurocognitif, le CFQ, qui ne met en évidence aucune différence. Les récents écrits de Medalia et ses collaborateurs (Medalia, & Thysen, 2008 ; Medalia, Thysen, & Freilich, 2008) peuvent toutefois amener un peu d'éclairage sur cette apparente contradiction entre les résultats obtenus avec la UKU, et le CFQ. D'abord, à l'instar de nombreux autres chercheurs, ils ont mis en évidence le fait que malgré la présence de déficits neurocognitifs objectivés à l'aide de mesures neuropsychologiques, une grande proportion des individus souffrant de SZ ou d'un TPSZ n'en a qu'une conscience limitée. De même, lorsque comparés avec des participants contrôles, et bien qu'ils rapportent globalement plus de dysfonctions neurocognitives, les patients ont davantage tendance à endosser les «énoncés extrêmes» stipulant qu'ils ne rencontrent jamais telle ou telle situation. Les participants témoins présentent pour leur part un patron de réponse plus nuancé, utilisant plus fréquemment les « énoncés intermédiaires », par exemple: « une fois par semaine ou moins ». Puisque le CFQ est également élaboré à l' aide d'une échelle de type likert pour laquelle il est possible de répondre «jamais », un manque de nuance de la part des participants de l'étude a pu contribuer à l'égalité des effets subjectifs du modafinil et du placebo. Enfin, il est possible que le résultat obtenu sur l' item lié à la mémoire mette en évidence une amélioration plus étendue du fonctionnement neurocognitif. En effet, le concept de mémoire po.uvant être interprété différemment d'un participant à un autre, ce résultat positif suggère qu'un bienfait a été observé sur plan de la cognition, et possiblement sur celui de la mémoire.

Bénéfices sur le plan clinique En ce qui concerne la sédationlfatigue, elle constitue un effet indésirable fréquent lors de la prise d'une médication antipsychotique (Marinkovic, Timotijevic, Babinski,

Totic, & Paunovic, 1994; Tandon, 2002 ; Woods, Martin, Spector, & McGlashan, 2002). Considérant que la moitié des individus SZ traités à l'aide d'un antipsychotique évoquent que les effets indésirables liés à leur traitement sont principalement en cause pour l'arrêt de leur médication, une amélioration.de la fatigue par le modafinil constitue une amélioration clinique importante (Loffler, Kilian, Toumi, & Angermeyer, 2003). Qui plus est, cette sédation, qui est associée à un niveau d' activité réduit, peut contribuer à une augmentation du poids, une dyslipidémie, et une tension artérielle élevée, qui constituent des facteurs de Discussion générale 187 rIsque pour les troubles cardiovasculaires, le diabète, et le syndrome métabolique

(Henderson, & Doraiswamy, 2008), pour lesquels les patients psychotiques sous traitement à l'aide d'un ASa présentent un risque accru (Curtis, Bartolomei, & Merlo, 2008) .

De cette manière, il apparaît que les bénéfices pouvant éventuellement découler de l'utilisation du modafinil chez la population psychotique soient suffisants pour justifier la mise sur pied d'autres études de groupe. Évidemment, dans cette optique, les rapports d'effets indésirables sérieux auront intérêt à être considérés de manière à instaurer des mécanismes cliniques permettant d'assurer la sécurité des participants.

Il va de soi que l'instauration de protocoles pharmacologiques ngoureux et sécuritaires ne peut se concrétiser dans tous les milieux cliniques. Que ce soit en raison de caractéristiques précises de la clientèle (e.g. instabilité clinique), ou en raison de la disponibilité limitée des ressources professionnelles, l'instauration d'un traitement pharmacologique dédié à l'amélioration du fonctionnement neurocognitif chez quelques patients seulement peut s'avérer plus facilement réalisable et mener à des améliorations considérables. Bien que les bienfaits de l'utilisation du modafinil chez la population psychotique nécessitent encore à ce stade-ci d'être étayés par de nouvelles études de groupe, l'apport d'études de cas n'est pas à négliger dans le futur. C'est du moins ce que démontre l'historique des investigations portant sur l'utilisation du modafinil auprès de cette clientèle. En effet, dans leur étude ouverte, Rosenthal et Bryant (2003; 2004) avait observé l'effet positif de cette molécule pour réduire la fatigue. et améliorer le fonctionnement de la mémoire à court terme en modalité verbale, ce qui s'est vérifié par la suite dans les études de groupe. En plus de susciter l'intérêt pour le modafinil, la diffusion de ces résultats a également eu pour effet de guider le choix des outils à employer dans les études subséquentes. Par ailleurs, qu'elles soient réalisées pour étudier le modafinil ou une autre molécule adjuvante, les études de cas présentent certains avantages par rapport aux études de groupes.

A quand un remède efficace des déficits neurocognitifs Discussion générale 188

associés aux troubles psychotiques? Bien que l' accumulation de résultats empiriques permette d'identifier quelques molécules pouvant potentiellement influencer positivement le fonctionnement neurocognitif des individus psychotiques, la communauté scientifique n'a pas identifié la panacé à ce jour. Les résultats des études de groupes ultérieures, dont plusieurs seront sans doute réalisées en accord avec les directives de MATRICS , et à l'aide de la batterie consensuelle MCCB, auront sans doute pour effet de permettre ' l'identification des molécules profitables pour un grand nombre d'individus. Malgré cela, et considérant certains états de faits relatifs aux pathologies psychotiques, il apparaît plus probable que les praticiens du corps médical auront à personnaliser leur approche de traitement .en fonction des caractéristiques particulières de leurs patients. C'est du . moins ce que suggère l'importante hét~rogénéité inter-individuelle notée tant dans les symptômes cliniques, que celle des profils neuropsychologiques et fonctionnels des gens atteints de SZ ou d'un TPSZ. À l'instar du traitement antipsychotique, qui offre actuellement diverses options thérapeutiques, le traitement des déficits neurocognitifs aura fort probablement avantage à être choisi au cas par cas, et donc à être « taillé sur mesure» en fonction de la présentation clinique du patient. À ce stade-ci, la littérature scientifique permet déjà de faire des constats quant ·à l'efficacité de certains traitements en fonction de caractéristiques personnelles. Celles-ci concernent entre autres la nature du traitement antipsychotique, l'évolution de la pathologie, la prépondérance de symptômes positifs ou négatifs, de même que la nature et l'intensité des déficits neurocognitifs. Une variété de traitement pour une variété d'individus est donc à envisager dans l'avenir. D'ici là, et à la lumière des différents . constats dégagés dans la thèse, il apparaît qu'une séquence logique de travaux empiriques pourrait être établie, ceci afin de découvrir le plus rapidement possible des traitements pharmacologiques efficaces.

Dans un premier temps, et tel que mentionné préalablemènt, l'initiative MATRICS devrait avoir pour effet d'uniformiser les différents protocoles de recherche, ce qui maximisera la confiance pouvant être portée dans les résultats en découlant. De manière concomitante toutefois, il sera important d'inclure différentes mesures cliniques permettant l'évaluation des symptômes cliniques, des effets . indésirables, de même que de la Discussion générale 189 motivation, ou d'autres caractéristiques cliniques particulières aux participants. En ce qui concerne l'évaluation du fonctionnement global, ou de l'évaluation dans différente sphères plus précises telles le fonctionnement social ou le fonctionnement vocationnel, les variables à l'étude bénéficieront d'être mesurées de manière adéquate et exhaustive. En effet, tel que nous l'avons observé, l'utilisation d'une mesure unique n'apparaît pas particulièrement utile. De fait, il y aura lieu d'innover dans la façon de mesurer le fonctionnement. À titre d'exemples, des mesures fonctionnelles issues de l'ergothérapie, ou d'autres permettant une cotation parallèle par un proche pourraient être des avenues intéressantes à envisager dans la réalisation d'études futures.

Lorsque des résultats plus consènsuels auront été dégagés, l'usage des adjuvants neurocognitifs pour la SZ et les TPSZ sera probablement plus . courant. Toutefois, considérant que les outils inclus dans la MCCB sont issus de la neuropsychologie conventionnelle, il sera encore nécessaire d'approfond.ir les connaissances. C'est alors, au cours de «l'après-MATRICS », que l'emploi d'outils neurocognitifs taillés sur mesure permettra de mieux comprendre les mécanismes cognitifs qui sous-tendent leurs effets.

Suite à cela, la littérature scientifique permettra sans doute aux cliniciens d'identifier plus facilement les options de traitement qui s'offrent pour leurs patients, de même que les bénéfices pouvant être attendus.

Par ailleurs, rappelons que les résultats d"une récente méta-analyse portant sur les effets de la remédiation neurocognitive en SZ (McGurk, Twamly, Sitzer, McHugo, & Mueser, 2007) montrent des améliorations significatives au plan de plusieurs fonctions neurocognitives, de même que du fonctionnement global. Cette alternative de traitement constitue ainsi une thérapeutique potentielle dont l'étude se poursuit, et pour laquelle l'accumulation de données scientifiques permettra de mieux établir quels sont les ingrédients thérapeutiques qui sous-tendent ses effets positifs. De même, il pourra être intéressant de comparer les effets de diverses méthodes de remédation neurocognitives à ceux des molécules adjuvantes les plus prometteuses en termes d'efficacité. De même, en plus d'en comparer les effets, des études visant à étudier l'effet de ces deux types d'interventions combinés pourront être utiles d'un point de vue clinique. Discussion générale 190

Contributions de la présente thèse doctorale La présente thèse a contribué à l'avancement des connaissances portant sur l'utilisation des adjuvants neurocognitifs pour la SZ et les TPSZ. Dans un premier temps, la réalisation de la revue systématique de la littérature portant sur leur emploi chez cette population constitue le premier écrit regroupant les études randomisées avec contrôle placebo, et ayant trait aux molécules ciblant les divers systèmes de neurotransmission probablement sous-jacents aux déficits. Lorsqu'elle sera publiée, cette revue de littérature pourra permettre aux chercheurs d'obtenir une vue d'ensemble sur l'état actuel des connaissances à ce sujet. Les chercheurs intéressés à mener un essai pharmacologique pourront également cibler les molécules présentant un potentiel de traitement supérieur, ceci, dans le but ultime de faire bénéficier la communauté scientifique et clinique de nouvelles données concernant les molécules les plus susceptibles de pouvoir exercer un bénéfice chez les individus psychotiques. Cette revue de littérature pourra également être d'un grand intérêt pour les cliniciens oeuvrant auprès de la clientèle psychotique. En effet, les conclusions qui découlent permettent de constater qu'actuellement, quelques molécules peuvent être profitables au plan neurocognitif chez la population psychotique. Cet article, de même que les deu~ articles ayant trait à l'utilisation du modafinil, pourront amener les cliniciens à considérer l' emploi de ces traitements pharmacologiques chez certains de leurs patients.

En ce qui concerne plus spécifiquement l'utilisation du modafinil chez la population psychotique, la présente thèse doctorale fournit un appui supplémentaire au fait que cette molécule peut être utilisée auprès d'individus souffrant de SZ ou d'un TPSZ. En plus de démontrer qu'elle peut être utilisée de manière sécuritaire, ces études procurent des données supplémentaires permettant de statuer qu'elle peut leur procurer certains bénéfices neurocognitifs. En effet, puisque les résultats concordent en grande partie avec ceux obtenus par une autre équipe de recherche, leur valeur sçientifique apparaît élevée. Ainsi, cette thèse permet de valider que le modafinil peut se montrer utile pour ,améliorer la fluidité verbale, de même que la mémoire de travail en modalité verbale, et l'efficience de l'attention lors de la réalisation de tâches en modalité visuelle. De même, elle démontre que Discussion générale 191 suivant une utilisation prolongée, le modafinil peut être bénéfique pour améliorer le fonctionnement global des individus psychotiques. Enfin, elle souligne l'importance de maintenir une vigilance accrue de l'état clinique des patients psychotiques lors de l'emploi du modafinil, ou de toute molécule adjuvante, qui sont, dans le cas présent, font l'objet d'une utilisation non approuvée par les instances gouvernementales de la santé. Notons par ailleurs qu'actuellement, très peu de molécules semblent pouvoir exercer un tel effet, et donc, ces résultats renouvelleront sans doute l'intérêt porté à cette molécule.

D'un point de vue méthodologique, l'étude empirique réalisée dans le cadre de la présente thèse doctorale constitue un exemple de devis expérimental pouvant être mené afin de dégager des conclusions fiables concernant l'emploi d'un adjuvant neurocognitif potentiel. Effectivement, puisque des résultats positifs en ·découlent malgré le nombre

~elativement restreint de participants, la publication de cet article pourra encourager des chercheurs-cliniciens à mettre sur pied de tels protocoles de recherche. De plus, le fait d'avoir réalisé des analyses statistiques permettant a posteriori de dégager les caractéristiques des participants ayant bénéficié du traitement avec le modafinil pourra inciter les chercheurs à documenter davantage leurs données.

Enfin, l'utilisation de la catégorisation d~ van Zomeren et Spikman (2003) pour le choix des mesurse à employer dans le cadre de l'étude empirique présentée dans la thèse, bien qu'elle ait été utile pour la conception du protocole, s'est montré d'une utilité limitée au moment d'interpréter les résultats. En effet, les différents niveaux inclus dans cette catégorisation n'ont pas été représentatifs des améliorations observées, et des processus sous-jacents aux ·changements notés. Bien que les explications des auteurs quant à leur catégorisation soient des plus claires, il n'est pas aisé de classifier une tâche dans un des trois niveaux proposés. La nature de cette catégorisation, présentée sous la forme d'un continuum, fait en sorte que toutes les tâches imputées au même niveau ne requièrent pas nécessairement une « quantité» comparable de vitesse et/ou de contrôle. Ceci a, dans le cas présent, fait en sorte que les hypothèses ont été posées en termes de niveaux, ce qUI n'apparaît pas nécessairement viable au moment d'interpréter les résultats. Discussion générale 192

Conclusion générale En terminant, l'importance de traiter spécifiquement les ' déficits neurocognitifs associés à la schizophrénie et aux troubles psychotiques y étant apparentés demeure un enjeu de premier ordre. Bien que de nombreux chercheurs consacrent actuellement un effort de recherche considérable afin de développer ou d'identifier des molécules en permettant un traitement efficace, aucun traitement universel n'a .. été identifié. Puisqu'il semble déjà évident qu'aucune panacé ne sera identifiée dans un futur rapproché, un traitement individualisé devra être envisagé, à l'instar du traitement antipsychotique. Dans cette optique, la poursuite des études sur les molécules actuellement investiguées, de même que de nombreux autres produits pharmaceutiques s'avère nécessaire. Toutes les conditions semblent maintenant réunies afin de favoriser la découverte rapide de thérapeutiques pharmacologiques. En effet, les initiatives MATRICS et TURNS promues par le NIMH constitueront sans doute un soutien appréciable pour les chercheurs intéressés . à contribuer aux prochaines avancées scientifiques sur le sujet. Des recherches de qualité

supérieure devraient ainsi être mises sur pied au cours des prochai~es années. Pour les individus souffrant de schizophrénie ?u d'un trouble psychotique apparenté, l'effervescence observée dans ce domaine de recherche devrait se concrétiser par une amélioration de leur traitement et, espérons-le, de leur fonctionnement quotidien de même que de leur qualité de ·vIe. - 1

Discussion générale 193

Références

Alves, F. S. , Figee, M., Vamelsvoort, T. , Veltman, D., & Haan, L. (2008). The revised dopamine hypothesis of schizophrenia: evidence from pharrnacological MRI studies with atypical antipsychotic medication. Psychopharmacology Bulletin, 41, 121-132.

Arnerican Psychiatric Association (1994). Diagnostic and statistical manual of mental disorders, 4th ed. (pp. 321-372). Washington, DC : Arnerican Psychiatric Association.

Andreasen, N. C., Nopoulos, P. , O'Leary, D. S. , Miller, D. D., Wassink, T., & Flaurn, M. (1999). Defining the phenotype of schizophrenia: cognitive dysmetria and its neural mechanisms. Biological Psychiatry, 46, 908-920.

Andreasen, N. C., O'Leary, D. S. , Cizadlo, T., Arndt, S. , Rezai, K., Ronto, L. L. , Watkins, G. L. & Hichwa, R. D. (1996). Schizephrenia and cognitive dysmetria: a positron emission tomography study of dysfunctional prefrontal-thalamic-cerebellar circuitry. Proceedings ofthe National Academy ofSciences , 93, 9985-9990.

Andreasen, N. C., Paradiso, S., & O'Leary, D. S. (1998). "Cognitive dysmetria" as an integrative theory of schizophrenia: a dysfunction in cortical-subcortical-cerebellar circuitry? Schizophrenia Bulletin, 24, 203-218.

Andrews, G., Hall, W., Goldstein, G. , Lapsey, H., Bartels, R., & Silove, D. (1985). The economic costs of schizophrenia. Implications for pul?lic policy. Archives of General Psychiatry, 42, 537-543.

Antonova, E, Sharrna, T, Morris, R. , & Kumari, V. (2004). The relationship between brain structure and neurocognition in schizophrenia: a selective review. Schizophrenia Research, 70, 117-145.

Arnold, S. E. (1999). Neurodevelopmental abnorrnalities in schizophrenia: insights from neuropathology. Development and Psychopathology, 11, 439-456.

Baddeley, A. D. (1986). Working Memory. Oxford: Clarendon Press.

Baddeley, A. D. (2000). The episodic buffer: a new. component of working memory? Trends in Cognitive Science, 4, 417-423.

Baddeley, A. D., & Hitch, G. (1974). Working memory. In G. Bower (Ed). The psychology ofleaming and motivation. New-York: Academic Press.

Barr, R. S., Culhane, M. A., lubelt, L. E., Mufti, R. S., Dyer, M. A., Weiss, A. P., Deckersbach, T., Kelly, 1. F., Freudenreich, O., Goff, D. C., & Evins, A. E. (2008). The effects of transderrnal nicotine on cognition in nonsmokers with schizophrenia and nonpsychiatric controis. Neuropsychopharmacology, 33, 480-490. Discussion générale 194

Bellack, A. S. , Gold, 1. M., & Buchanan, R. W. (1999). Cognitive rehabilitation for schizophrenia: problems, prospects, and strategies. Schizophrenia Bulletin, 25, 257- 274.

Bilder, R. M., Goldman, R. S., Robinson, D., Reiter, G., Bell, L. , Bates, J. A., Pappadopulos, E., Will son, D. F. , Alvir, J. M., Woerner, M. G., Geisler, S. , Kane, 1. M., & Lieberman, J. A. (2000). Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates. American Journal of Psychiatry, 157, 549-559.

Bleuler, E. (Eds.) (1911). Dementia praecox; or the group of schizophrenias. New-York: International Universities Press.

Bonilha, L. , Molnar, C., Homer, M. D., Anderson, B., Forster, L., George, M. S., & Nahas, z. (2008). Neurocognitive deficits and prefrontal cortical atrophy in patients with schizophrenia. Schizophrenia Resedrch, 101 , 142-151.

Bora, E., Veznedaroglu, B, & Kayahan, B. (2005). The effect of galantamine added to clozapine on cognItIon of five patients with schizophrenia. Clinical Neuropharmacology, 28, 139-141.

Bowie, C. R., & Harvey, P. D. (2005). Cognition in schizophrenia: impairments, determinants, and functional importance. Psychiatrie Clinics of North America, 28, 613-633.

Bowie, C. R., & Jaga, K. (2007). Methods for treating cognitive deficits in schizophrenia. Expert Review and Neurotherapeutics, 7,281-287.

Bozikas, V. P., Kosmidis, M. H., & Karavatos, A. (2005). Disproportionate impairment in semantic verbal fluency in schizophrenia: differential deficit in clustering. Schizophrenia Research, 74, 51-59.

Brazo, P., Marié, R. M., Halbecq, L, Benali, K., Segard, L., Delamillieure, P., 'Langloi Thiéry, S., Van Der Elst, A., Thibaut, F., Petit, M., & Dollfus, S. (2002). Cognitive patterns in subtypes of schizophrenia. European Psychiatry, 17, 155-162.

Buchanan, R. W., Davis, M., Goff, D., Green, M. F., Keefe, R. S. E., Leon, A. C., Nuechterlein, K. H., Laughren, T., Levin, R., Stover, E., Fenton, W., & Marder, S. R. (2005). A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophrenia Bulletin, 31, 5-19.

Chen, Y. L., Chen, Y. H., & Lieh-Mak, F. (2000). Semantic verbal fluency deficit as a familial trait marker in schizophrenia. Psychiatry Research, 95, 133-148.

Cincotta, S. L., Yorek, M. S., Moschak, T. M., Lewis, S. R., & Rodefer, J. S. (2008). Selective nicotinic acetylcholine receptor agonists: potential therapies for Discussion générale 195

neuropsychiatric disorders with cognitive dysfunction. Current Opinion in Investigational Drugs, 9, 47-56.

Curtis, L. , Bartolomei, J., & Merlo, M. C. G. (2008). Le syndrome métabolique chez le patient sous traitement antipsychotique: un défi pour le psychiatre psychothérapeute. Archives Suisses de Neurologie et de Psychiatrie, 159, 7-15.

Crow, T. J. (1980). Positive and negative schizophrenic symptoms and the role of dopamine. British Journal ofPsychiatry , 137, 383-386.

Delevoye-Turrel, Y. , Giersch, A., & Danion, J. M. (2003). Abnormal sequencing of motor actions in patients with schizophrenia: evidence from grip force adjustments during objects manipulation. American Journal ofPsychiatry , 160, 134-141.

Delevoye-Turrel, Y. , Giersch, A. , Wing, A. M., & Danion, 1. M. (2007). Motor fluency . deficits in the sequencing of actions in schizophrenia. Journal of Abnormal Psychology, 116, 56-64.

Dequardo, J. R. (2002). Modafinil-associated clozapine toxicity. American journal of psychiatry, 159, 1243-1244.

Estes, W. K. (1974). Leaming theory and intelligence. American Psychologist, 29, 740-749.

Fioravanti, M., Carlone, O., Vitale, B., Cinti, M. E., & Clare, L. (2005). A meta-analysis of cognitive deficits in adults with a diagnosis of schizophrenia. Neuropsychology Review, 15, 73-95.

Food and Drug Administration (FDA), 2007. Modafinil (rriarketed as Provigil): Serious skin reactions. FDA drug safety newsleuer, 1.

Goldman-Rakic, P. S. (2001). Working memory dysfunction in schizophrenia. In: Salloway, S. P., Malloy, P. F:, Duffry, J. D., eds. The frontal lobes and neuropsychiatric illness. Washington DC : American Psychiatric Publishing.

Goldner, E. M., Hsu, L., Waraich, P., & Somers, J. M. (2000). Prevalence and incidence studies of schizophrenic disorders: a systematic review of the literature. Canadian Journal ofPsychiatry , 47, 833-843.

Grandmaison, E., & Simard, M. (2003). A critical review ofmemory stimulation programs in Alzheimer' s disease. Journal ofNeuropsychiatry and Clinical Neurosciences, 15, 130-144.

Green, M. F. (1996). What are the functional consequences of neurocognitive deficits in schizophrenia. American Journal ofPsychiatry, 153,321-330. Discussion générale 196

Green, M. F. , Kem, R. S. , Braff, D. L., & Mintz, J. (2000). Neurocognitive deficits and functional outcome in schizophrenia: are we mea~uring the "right stuff'? Schizophrenia Bulletin, 26, 119-136. Green, M. F. , Kem, R. S., and Heaton, R. K. (2004). Longitudinal studies of cognition and funcitional outcome in schizophrenia: implications for MATRICS. Schizophrenia Research, 72, 41-51.

Green, M. F. , & Nuechterlain, K. H. (1999). Should schizophrenia be treated as a . neurocognitive disorder? Schizophrenia Bulletin, 25, 309-318.

Gur, R. E. , Calkins, M. E. , Gur R. C., Horan, W. P., Nuechterlein, K. H., Seidman, L. 1., & Stone, W. S. (2007). The consortium on the genetics of schizophrenia: neurocognitive endophenotypes. Schizophrenia Bulletin, 33, 49-68.

Hall, C. , Andrews, G. , & Goldstein, G. (1985). The costs of schizophrenia. Australian and New Zealand Journal ofPsychiatry , 19, 3-5.

Hambrecht, M., Lammertink, M. , Klosterkotter, J. , Matuschek, E., & Pukrop, R. (2002). Subjective and objective neuropsychological abnormalities in a psychosis prodrome. British Journal ofPsychiatry , 43, 30-37.

Harris, J. G. , Kongs, S., Allensworth, D., Martin, L., Tregellas, J., Sullivan, B., Zerbe, G. , & Freedman, R. (2004). Effects of nicotine on cognitive deficits in schizophrenia. Neuropsychopharmacology, 29, 1378-1385.

Harvey, P. D., (2003). Ziprasidone and cognition: the evolving story. Journal of Clinical Psychiatry, 64, 33-39.

Harvey, P. D., Green, M. F., Keefe, R.S.E., & Velligan, D.I. (2004). Cognitive funcitoning in schizophrenia: a consensus statement on its role in the definition and evaluation of effective treatments for the illness. Journal ofClinical Psychiatry, 65, 361-372.

Harvey, P. D., & Keefe, R. S. (2001). Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. American Journal of Psychiatry, 158,176-184.

Hatashita-Wong, M., & Silverstein, S. M. (2003). Coping with voices: selective attention training for persistent auditory hallucinations in treatment refractory schizophrenia. Psychiatry, 66, 255-261.

Heinrichs, R. W., & Zakzanis, K. K. (1998). Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology, 12, 426-445.

Henderson, D. C., & Daraiswamy, P. M. (2008). Prolactin-related and metabolic adverse effects of atypical antip~ychotic agents. Journal of Clinical Psychiatry, 69, 32-44. Discussion générale 197

Hemy, 1. D. , & Crawford, J. R. (2005). A meta-analytic review of verbal fluency deficits in schizophrenia relative to other neurocognitive deficits. Cognitive Ne uropsychiatry, 10, 1-33. Hill, S. K. , Beers, S. R. , Kmiec, J. A. , Keshavan, M. S. , & Sweeney, 1. A. (2004). Impairment of verbal memory and leaming in antipsychotic-naive patients with . first-episode schizophrenia. Schizophrenia Research, 68, 127-136.

Hoff, A. L. , & Kremen, W. S. (2003). Neuropsychology in schizophrenia: an update. Current Opinion in Psychiatry, 16, 149-155.

Horan, W. P. , Braff, D. L., Nuechterlein, K. H., Sugar, C. A. , Cadenhead, K. S. , Calkins, M. E. , Dobie, D. J. , Freedman, R. , Greenwood, T.A., Gur, R. E. , Gur, R. C., Light, G. A. , Mintz, J. , Olincy, A., Radant, A. D. , Schork, N. J. , Seidman, L. 1., Siever, L. J. , Silverman, J. M., Stone, W. S. , Swerdlow, N. R. , Tsuang, D. W. , Tsuang, M. T. ~ Turetsky, B. 1. , Green, M. F. (2008). Verbal working memory impairments in individuals with schizophrenia and their first-degree relatives: findings from the Consortium on the Genetics of Schizophrenia. Schizophrenia Research, 103, 218- 228.

Howard, A. K. , Thomton, A. E. , Altman, S., & Hone~ , W. G. (2002). Donepezil for memory dysfunction in schizophrenia. Journal of Psychopharmacology, 16, 267- 270.

Hughes, J. R., Hatsukami, D. K. , Mitchell, J. E. , & Dahlgren, L. A. (1986) Prevalence of smoking among psychiatric outpatients. American Journal of Psychiatry 143, 993- 997

Hugues, C. , Kumari, V., Soni, W. , Das, M. , Binneman, B., Drozd, S. , O'Neil, S. , Mathew, V., Sharma, T. (2002). Longitudinal study of symptoms and cognitive function in chronic schizophrenia. Schizophrenia Research, 59, 137-146.

Joyce, E. M., Collinson, S. L. & Crichton, P. (1996). Verbal fluency in schizophrenia: relationship with executive function, semantic memory and clinical alogia. Psychological Medicine, 26, 39-49.

Kane, J. M. (2008). Sedation as a side effect of the treatment of mental disorders. Journal ofClinical Psychiatry, 69, 20.

Keefe, R.S. (2008). Should cognitive impairment be included in the diagnostic criteria for schizophrenia? World Psychiatry, 7, 22-28.

Keefe, R. S., Bilder, R. M., Davis, S. M., Harvey, P. D., Palmer, B. W., Gold, J. M., Meltzer, H. Y., Green, M. F., Capuano, G. , Stroup, T. S. , McEvoy, J. P. , Swartz, M. S., Rosenheck, R. A., Perkins, D. O., Davis, C. E., Hsiao, J. K. , Lieberman, J. A.; CATIE Investigators; Neurocognitive Working Group. (2007). Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Archives of General Psychiatry, 64, 631-632. Discussion générale 198

Keefe, R.S.E., Bilder, R.M., Harvey, P.D., Davis, S.M., Palmer, B.W., Gold, J.M., Meltzer, H.Y., Green, M.F., Miller, D.D., Canive, J.M., Adler, L.W., Manschreck, T.C., Swartz, M. , Rosenhech, R. , Perkins, D.O., Walker, T.M., St!OUP, T".S., McEvoy, " J.P., and Lieberman, J.A. (2006). Baseline neurocognitive deficits in the CATIE schizophrenia trial. Neuropsychopharmacology, 31 ~ 2033-2046.

Keefe, R. S. E., Malhotra, A. K. , Meltzer, H. Y., Kane, J. M., Buchanan, R. W., Murthy, A. , Sovel, M. , & Li, C. (2008). Efficacy and safety of donepezil in patients with schizophrenia or schizoaffective disorder. Significant placebo/practice effects in a 12-week, randomized, double-blind, placebo-controlled trial. Ne uropsychopharmacology, 33, 1217-1228.

Keefe, R. S. , Silva, S. G. , Perkins, D. O., & Lieberman, J. A. (1999). The effectsof atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review of and meta-analysis. Schizophrenia Bulletin, 25, 201-222.

Kem, R. S., Nuechterlein, K. H. , Green, M. F., Baade, L. E., Fenton, W. S. , Gold, J. M., Keefe, R. S. , Mesholam-Gately, R. , Mintz, J. , Seidman, L. J. , Stover, E. , & Marder, S. R. (2008). The MATRICS Consensus Cognitive Battery, part 2: co-norming and standardization. American Journal ofPsychiatry , 165, 214-220.

Kraepelin, E. (Eds.) (1919). Dementia praecox and paraphrenia. Edingurgh (UK) : E. & S. Livingstone.

Kremen W. S., Seidman, L. J., Pepple, J. R. , Lyons, M. J. , Tsuang, M. T. , & Faraone, S. V. (1994). Neuropsychological risk indicators for schizophrenia: a review of family studies. Schizophrenia Bulletin, 20, 103-119.

Kumar, R: (2008). Approved and investigatinal uses of modafinil: an evidence-based review. Drugs, 68, 1803-1839.

Kurtz, M. M., Moberg, P. J., Gur, R. C., & Gur, R. E. (2001). Approaches to cognitive remediation of neuropsychological deficits in schizophrenia: A review and meta analysis. Neuropsychology Review, 11, 197-210.

Leclercq, M. , & Zimmermann, P. (2000). L 'évaluation des fonctions attentionnelles. Traité de Neuropsychologie Clinique, Tome 1 (pp. 95-114). Marseill~s : SolaI.

Lehoux, C., Everett, J., Laplante, L., Émond, C., Trépanier, J., Brassard, A., René, L., Cayer, M., Mérette, C., Maziade, M. & Roy, M-A. (2003). Fine motor dexterity is correlated to social functioning in schizophrenia. Schizophrenia Research, 62, 269- 273.

Lenzi, A., Maltinti, E., Poggio E., Fabrizio, L. , & Coli. E. (2003). Effects of rivastigmine on cognitive function and quality of life in patients with schizophrenia. Clinical Neuropharmacology, 26, 317-321. Discussion générale 199

Létoumeau, K. , Leblanc, J. , Bouchard, R-H., Simard, M., Marcaurelle, H., Ouellet, R. , Valliè~es , C. , & Roy, M-A. Modafinil as Adjunct Treatment in Recent-Onset Psychosis: Five Case Reports. Article en préparation

Létoumeau, K. , Simard, M., Demers, M-F., Émond, C., Mérette, C., Bouchard, R-H., & Roy, M-A. A double-blind, placebo coptrolled, cross-over trial of adjunctive modafinil for neurocognitive impairments in schizophrenia. Article en préparation.

Létoumeau, K. , Simard, M., & Roy, M-A. Adjunct cognitive enhancers to second generation antipsychotics for cognitive impairments in schizophrenia: a review. Article en préparation.

Liddle, P. F. (1987). The symptoms of chronic schizophrenia. A re-examination of the positive-negative dichotomy. British Journal ofPsychiatry , 151, 145-151.

Laffler, W. ; Kilian, R., Toumi, M., & Angermeyer, M. C. (2003). Schizophrenic patient's subjective reasons for compliance and noncompliance with neuroleptic treatment. Pharmacopsychiatry, 36, 105-112.

MacEwan, G.W., Ehmann , T.S., Kanbhai, I. , & Wrixon, C. (2001). Do~epezil in schizophrenia - is it helpful? An experimental design case study. Acta Psychiatrica Scandinavica, 104, 469-472.

Marder, S. R., & Fenton, W. (2004). Measurement and treatment research to improve cognition in schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition in schizophrenia. Schizophrenia Research, 72, 5- 9.

Marinkivic, D., Timotijevic, I. , Babinski, T. , Totic, S., & Paunovic, V. R. (1994). The side effects of clozapine: a four year follow-up study. Progress in neuro psychopharmacology and biological psychiatry, 18, 537-544.

Mazeh, D., Mirecki, I. , Paleacu, D., & Barak, Y. (2003). Donepezil for the treatment of a schizophrenia patient with frontal lobotomy. Journal of Clinical Psychopharmacology, 23, 522.

Maziade, M., Rouleau, N., Gingras, N., Boutin, P., Paradis, M-È., Jomphe, V., Boutin, J. , Létoumeau, K., Gilbert, E., Lefèbvre, A-A., Doré, M-C., Marino, C., Battaglia, M., Mérette,- C., & Roy, M-A. (2008). Shared neurocognitive dysfunctions in young offspring at extreme risk for schizophrenia or bipolar disorder in eastern Quebec multigenerational families. Schizophrenia Bulletin, doi: 10.1 093/cchbul/sbn058

McGurk, S. R., Twamley, E. W., Sitzer, D. I., McHugo, G. 1., & Mueser, K. T. (2007). A meta-analysis of cognitive remediation in schizophrenia. American Journal of Psychiatry, 164,1791-1802. Discussion générale 200

Medalia, A., & Thysen, J. (2008). Insight into neurocognitive dysfunction in schizophrenia. Schizophrenia Bulletin, doi: 10.1 093/schbullsbm144

Medalia, A., Thysen, J. , & Freilich, B. (2008). De people with schizophrenia who have objective cognitive impairment identify cognitive deficits on a self report measure? Schizophrenia Research, doi: 10.1 016/j.schres.2008.07.007

Meltzer, H. Y. , & Mc Gurk, S. R. (1999) The ·effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophrenia Bulletin, 25, 233- 255.

Mintz, A. R. , Dobson, K. S. , & Romney, D. M. (2002). Insight in schizophrenia: a meta analysis. Schizophrenia Research, 61 , 75-88.

Mishara, A. L. , & Golberg, T. E. (2004). Conventional neuroleptic treatment on cognition in schizophrenia: opening a closed book. Biological Psychiatry, 55, 1013-1022.

Mohamed, S., Rosenheck, R. , Swartz, M., Stroup, S., Lieberman, J.A., & Keefe, R. S. E. (2008). Relationship of cognition and psychopathology to functional impairment in . schizophrenia. American Journal ofPsychiatry , 165, 978-987.

Monti, J. M., & Monti, D. (2004). Sleep in schizophrenia patients and the effects of antipsychotic drugs. Sleep Medicine Reviews, 8, 133-148.

Morein-Zamir, S., Turner, D. C. , & Sahakian, B. J. (2007). A review of the effects of modafinil on cognition in schizophrenia.Schizophrenia Bulletin, 33, 1298-1306.

Murray, R. M., Castle, D., O'Callaghan, E., Lewis, S. W. , Sham, P., & Wilkins, S. (1991). The neurodevelopmental and adult schizophrenias: Kraepelin lost and kraepelin found. Schizophrenia Research, 4, 282-283.

Narendran, R., Young, C. M., Valenti, A. M., Niskolova, M. K., & Pristach, C. A. (2002). Is psychosis exacerbated by modafinil? Archives ofgeneral psychiatry, 59,292-293.

Nuechterlein, K. H., Green, M. F., Kern, R. S., Baade, L. E. , Barch, D. M., Cohen, J. D., rd Essock, S., Fenton, W. S., Frese, F. J., 3 , Gold, J. M., Goldberg, T., Heaton, R. K. , Keefe, R. S., Kraemer, H. , Mesholam-Gately, R., Seidman, L. J., Stover, E., Weinberger, D. R., Young, A. S., Zalcman, S., & Marder, S. R. (2008). The MATRICS Consensus Cognitive Battery, Part 2: Co-norming and standardization. American Journal ofPsychiatry , 165, 214-220.

Purdon, S. E., Jones, B. D., Stip, E., Labelle, A., Addington, D., David, S. R., Breier, A., & Tollefson, G. D. (2000). Neuropsychological change in early phase schizophrenia Discussion générale 201

during 12 months of treatment with olanzapine, risperidone, or haloperidoL The Canadian Collaborative Group for research in schizophrenia. Archives of General Psychiatry, 57, 249-258.

Ragland, J. D. , Yoon, 1., Minzenberg, M. J. , & Carter, C. S. (2007). Neuroimaging of cognitive disability in schizophrenia: search for a pathophysiological mechanism. Internationel Review ofPsychiatry , 19, 419-429.

Raguraman, J., Sagar, J. V., & Chandrasekaran, R. (2005). Effects ofrivastigmine in a case tesidual schizophrenia. Canadianjournal ofPsychiatry , 50, 243-244.

Risch, S. C. , McGurk, S. , Homer, M. D., Nahas, Z., Owens, S. D. , Molloy, M. , Gilliar, C., Christie, S. , Markowitz, J. S. , DeVane, C. L. , Mintzer, J. , & George, M. S. (2001). A double-blind placebo-controlled case study of the use of donepezil to improve cognition in a schizoaffective disorder patient : Functional MRI correlates. Neurocase, 7, 105-110.

Rosenthal, M. H., & Bryant, S. (2003, Marsh). Modafinil as adjunct treatment in schizophrenia: results from an open-label, pilot study. Poster presented to the International Congress on Schizophrenia Research, Colorado Springs, Colorado, USA.

Rosenthal, M. H., & Bryant, S. (2004). Benefits of adjunct modafinil in an open-label, pilot study in patients with schizophrenia. Clinical Neuropharmacology, 27, 38-43.

Roy, M-A., & DeVrient, X. (1994). Positive and negative symptoms in schizophrenia: a current overview. Canadian Journal ofPsychiatry , 39, 407-414.

Roy, M-A., Mérette, C., & Maziade, M. (2001). Subtyping schizophrenia according to outcome or severity : a search for homogeneous subgroups. Schizophrenia Bulletin, 27, 115-138.

Saykin, A. 1., Shtasel, D. L., Gur, R. E. , Kester, D. B., Mozley, L. H., Stafiniak, P., & Gur, R.C. (1994). Neuropsychological deficits in neuroleptic naive patients with first episode schizophrenia. Archives of General Psychiatry, 51 , 124-131.

Schneider, W., & Shiffrin, R. M. (1977). Controlled and automatic human informatiori processing : I. Detection, search, and attention. Psychological Review, 84, 1-66.

Senn, S. (2002). Cross-over trial in clinical research (Statistics in practice). John Wiley & Sons (Ed). West Sussex, U.K. : Wiley.

Shallice, T., Burgess, P. W., & Frith, C. D. (1991). Can the neuropsychological case-study approach be applied to schizophrenia? Psychological Medicine, 21 , 661-673.

Sharma, T., & Mockler, D. (1998). The cognitive efficacy of atypical antipsychotics in schizophrenia. Journal ofClinical Psychopharmacology, 18, 12-19. Discussion générale 202 ,

Shenton, M. E. , Dickey, C. C. , Frumin, M. , & McCarley, R. W. (2001). A review of MRI , findings in schizophrenia. Schizophrenia Research, 49, 1-52.

Simard, M. , & Sampson, E. (Tyrer and K. Silk Eds.) (2008) Dementia: Pharmacological and Non-Pharmacological Treatments and Guideline Review. Cambridge Textbook of Effective Treatments in Psyehiatry (pp. 217-243). Cambridge: Cambridge University Press.

Sitskoorn, M. M., Aleman, A., Ebisch, S. J. , Appels, M. C. , & Kahn, R. (2004). Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis. Schizophrenia Research, 71 , 285-295.

Snitz, B. E., Macdonald, A. W. , 3rd, & Carter, C. S. (2006). Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. Schizophrenia Bulletin, 32, 179-194.

Szoke, A. , Trandafir, A., Dupont, M-E., Méary, A. , Schürhoff, F., & Leboyer, M. (2008). Longitudinal studies of cognition in schizophrenia: meta-analysis. British Journal of Psyehiatry, 192, 248-257.

Spikman, J. M. , Kiers, H. A. L., Deelman, B. G. , & van Zomeren, A. H. (2001). Construct validity of concepts of attention in healthy controls and patients with CHI. Brain and Cognition, 47, 446-460.

Stahl, S. M. (1999). Selecting an atypical antipsychotic by combining clinical experience with guidelines from clinical trials. Journal of Clinieal Psyehiatry, 60, 31-41.

Stahl, S. M. (2007). Beyond the dopamine hypothesis to the NMDA glutamate receptor hypofunction hypothesis of schizophrenüi. CNS Spectrums, 12, 265-268. .

Sumiyoshi, C. , Sumiyoshi, T., Nohara, S., Yamashita, 1., Matsui, M., Kurachi, M. & Niwa, S. (2005). Disorganization of semantic memory underlies alogia in schizophrenia: an alalysis of verbal fluency performance in Japanese subjects. Schizophrenia Researeh, 74, 91-100.

Tandon, R. (2002). Safety and tolerability: how do newer generation "atypical" antipsychotics compare? Psychiatrie Quarterly, 73, 297-311.

Townsend, L. A., & Norman, R. M. (2004). Course of cognitive functioning in first episode schizophrenia spectrum disorders. Expert Review ofNeuroth,erapeutics, 4,61-68.

Turner, D. C., Clark, L., Dowson, J. , Robbins, T. W., & Sahakian, B. J. (2004b). Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder. Biological Psychiatry, 55, 1031-1040. Discussion générale 203

Turner, D. C., Clark, L. , Pomarol-Clotet, E. , McKenna, P., Robbins, T. W., & Sahakian, B. 1. (2004). Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharrnacology, 29, 1363-1373.

Turner, D. C., Robbins, T. W. , Clark, L., Aron, A. R. , Dowson, J. , & Sahakian, B. 1. (2003). Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology, 165, 260-269.

Van der Linden, M., Coyette, P. , & Seron, X. (Van Der Linden, Danion, J. M. & Agniel, A. Eds) (2000). La psychopathologie: Une approche cognitive et neuropsychologique. Marseille: SolaI.

Van der Linden, M., Meulemans, T., Belleville, S., & Collette, P. (2000). L 'évaluation des troubles de la mémoire. Traité de Neuropsychologie Clinique, Torne 1 (pp. 115- 155). Marseilles : SolaI.

Van der Linden, M., Meulemans, T. , Seron, X., Coyette, P. , Andrès, P, & Prairal, C. (2000). L 'évaluation des fonctions exécutives. Traité de Neuropsychologie Clinique, Tome 1 (pp. 275-300). Marseilles : SolaI.

Van Zomeren, E., & Spikman S. (2003). Assessment of attention dans Hallington, P.W., Kischka, U., & Marshall, J. C. (Eds.). Handbookofclinicalpsychology. New-York: Oxford Université Press. '

Weiss, E. M., Bilder, R. M., & Pleischhacker, W. W. (2002) The effects of second generation antipsychotics on cognitive functioning and psychosocial outcome in schizophrenia. Psychopharmacology (Berl), 162, 11-17.

Woods, S. W., Martin, A., Spector, S. G., & McGlashan, T. H. (2002). Effects of development on olanzapine-associated adverse events. Journal of the American Academy of Child and Adolescent Psychiatry, 41, 1439-1446.

Wu, E. Q., Birnbaum, H. G., Shi, L., BalI, D. E. , Kessler, R. C., Moulis, M., & Aggarwal, J. (2005). The economic burden of schizophrenia in the United States in 2002. Journal of Clinical Psychiatry, 66, 1122-1129.

Wykes, T., Reeder, C., Williams, C., Corner, J., Rice, C., & Eve ritt , B. (2002). Are the effects of cognitive remediation therapy (CRT) durable? Results from an exploratory trial in schizophrenia. Schizophrenia Research, 61, 163 -174.

Zoccali, R. , Muscatello, M. R., Bruno, A., Cambria, R. , Mico, U., Spina, E., & Meduri, M. (2007). The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: a double-blind placebo-controlled study, Schizophrenia Research, 93, 109-116. - ~- -- - l

ANNEXE Schizophrenia Bulletin Advance Access published June'11, 2008

Schizophrenia Bulletin doi: 10.109 3/sch bul/sbn058

Shared Neurocognitive Dysfunctions in Young Offspring at Extreme Risk for Schizophrenia or Bipolar Disorder in Eastern Quebec Multigenerational Families

1 2 2 3 2 Michel Maziade • , Nancie Rouleau • , Nathalie Gingras , ment. Our data suggest that the extremely high genetic 2 2 2 Pierrette Boutin , Marie-Eve Paradis , Valérie J omphe , and familial loading of these HRs May have contributed 3 3 3 Julie Boutin , Karine Létourneau , Elsa Gilbert , to a quantitatively increased magnitude of the cognitive 3 3 Andrée-Anne Lefebvre , Marie-Claire Doré , impairments in both HR subgroups, especially in memory. 4 5 2 Cecilia Marin0 , Marco Battaglia , Chantal Mérette , and These offspring at heightened risk present difficulties in Marc-André Roy2 processing information that warrant preventive research. 2Centre de recherche Université Laval Robert-Giffard, 260 l, Chemin de la Canardière, F-4500, Québec QC G 11 2G3, Canada; Key words: high risk/schizophrenia/bipolar disorder/ 3École de psychologie, Université Laval, Québec, Canada; genetics/developmental precursor/cognition 4Department of Child Psychiatry, Eugenio Medea Institute, Via Don luigi Monza, 2023842 Bosisio Parini (Lecco), Italy; 5Department of Neuropsychiatrie Sciences, San Raffaele " Vita Salute" University, 20 via Stamira d'Ancona, 20127 Milan, Italy Introduction The identification of susceptibility genes for schizophre Background: Adult patients having schizophrenia (SZ) or nia (SZ) and bipolar disorders (BPs) has been compli bipolar disorder (BP) may have in common neurocognitive cated by the role of environmental factors, genetic deficits. Former evidence suggests impairments in several heterogeneity, and uncertainty about the Diagnostic neuropsychological functions in young offspring at genetic and Statistical Manual of Mental Disorders (DSM) phe risk for SZ or BP. Moreover, a dose-response relation May notype.1 Endophenotypes, defined as rneasurable traits exist between the degree of familial loading and cognitive (biochemical, neuroanatomical, cognitive) related to an impairments. This study examines the cognitive functioning illness, may be helpful in identifying susceptibility genes of high-risk (HR) offspring of parents having schizophrenia because they are thought to have a simpler genetic etiol (HRSZ) and high-risk offspring of parents having bipolar ogy than the DSM categories. 1-3 disorder (HRBP) descending from densely affected kin Several studies have observed significant neuropsycho dreds. Methods: The sample consisted of 45 young off logical deficits in nonaffected adult relatives (NAARs ) that spring (mean age of 17.3 years) born to a parent having tended to be similar to those seen in SZ patients but with SZ or BP descending from large multigenerational families .sm aller effect sizes.4-6 For instance, the cognitive func of Eastern Québec that are densely affected by SZ or BP tions showing a decreased performance in NAARs and followed up since 1989. The offspring were adminis span attention/-9 episodic memory,IO- 12 and executive tered a lifetime best-estimate diagnostic procedure (Diag- functions 13-16 as weIl as language and spatial abilities.4-6 nostic and Statistical Manual ofMental Disorders, Fourth Fewer studies have investigated NAARs ofBP patients17 Edition (DSM-IV) and an extensive standard neuropsy and sorne reported that N AARs of BP may perform chological battery. Raw scores were compared with age worse than controls on memory,18,19 in executive func and gender-matched con trois. Results: The offspring tions;9 in executive inhibitory processes,20 and in psy displayed differences in memory and executive functions chomotor performance speed,2 1 suggesting that sorne when compared with controls. Moderate to large effect cognitive impairments might be shared by NAARs of sizes (Cohen d) ranging from 0.65 to 1.25 (for IQ and mem SZ and those of BP. As regards the direct comparison ory) were observed. Several of the cognitive dysfunctions of NAARs of SZ to those of BP, greater impairments were present in both HRSZ and HRBP, even when consid in memory have been observed among the former while ering DSM-IV cIinical status. Conclusions: HRSZ and intellectuai function, executive functions, and psychomo HRBP shared several aspects of their cognitive impair- tor performance were found similar. 22 Zalla et al20 inves tigated executive functions and attention and found no difference between NAARs of SZ and NAARs of BP ITo whom correspondence should be addressed; tel: (418) 663- 23 5744, fax: (418) 663-9540; e-mail: [email protected]. while Toulopoulou et al observed that relatives of

BP showed greater verbal-performance 1Q discrepancy the diagnosis of the spouse of the index patient was often scores compared with the SZ relatives. not assessed. Third, only 2 of the prospective studies of This would be congruent with former findings showing HRSZ, started between 1952 and 1973, included an ex similar neuropsychological deficits in patients with SZ or tensive battery and comEleted a longitudinal follow-up 33 BP,20,24-30 particularly the recent report of Schretlen until mid-adulthood. ,3 ,40 Fourth, few studies have ex et al24 who administered the same extensive battery to amined the specificity of the findings by comparing a large sample of SZ and BP patients. They obtained HRSZ to HRBP within the sa me study. Cohen d mean effect sizes of 0.97 across tests for SZ The current study addresses sorne of these limitations. patients and of 0.59 for BP patients, then suggesting We had the opportunity to focus on offspring at extreme that SZ had more severe global cognitive impairments risk having affected parents descending from densely af than BP and that both disorders presented qualitatively fected multigenerational families. These adult family similar profiles. members (ie, including spouses and relatives of affected The study of neuropsychological functioning in young parents) were extensively and directly diagnosed, fol high-risk (HR) offspring (ie, offspring of an affected par lowed up longitudinally, and had been formerly submit ent) is particularly appealing. lndeed, extensive ted to diverse family genetic studies.41 -43 HRSZ and 31 33 reviews - have confirmed the presence of a poorer per HRBP were assessed with similar methods. formance in HRs in several tasks encompassing atten We administered an extensive neuropsychological bat tion, memory, and executive functions, which may be tery to coyer several areas of cognitive functioning. Our congruent with the dysfunctions observed in NAARs. hypotheses were that (1) these young HR offspring would Byrne et al,34 using an extended battery, observed in display cognitive underperformances in memory and ex high-risk offspring of parents having schizophrenia ecutive functions, wh en compared with age- and gender (HRSZ) a poorer performance in intellectuallevel, exec matched normal controls, and that the expected effect utive functions, and memory when compared with con sizes would be considerable given the high familialload troIs. Less attention has been given to cognitive ing of the affected parent and (2) sorne of the expected functioning in high-risk offspring of parents having bipo dysfunctions would be shared by the HRSZ and the lar disorder (HRBP).35 Recently, Klimes-Dougan et al36 HRBP. We also aimed to test the effect of the presence investigated 43 adolescent offspring (average age of of a DSM nonpsychotic diagnosis on the cognitive differ 15 years) ofBP mothers from an affluent, high-achieving ences. We have indeed just reported that these young milieu, who were compared with offspring of mothers offspring, having not reached the age of incidence of psy with major depression and with controls. They found def chosis, displayed high frequency of behavior disorders as icits mainly in executive functions and attention which indexed by nonpsychotic DSM-IV diagnoses.44 The may be seen as somewhat overlapping those observed DSM defined behavior disorders were mostly shared in HRSZ studies, even though much work remains to by the HRSZ and the HRBP and, overall, resem bled be done to investigate such commonalities. the clinical profile reported for other HR offspring Sorne limitations in existing HR studies may also affect cohorts having an absent or a lesser familialloading. the interpretation of the results. First, the offspring's se lection criterion was most often based on an affected par ent without documenting the family history. Hence, the Methods HRs' parents in most former studies may either present the sporadic or the familial form of illness. Focusing on Ascertainment of Kindreds parents'with the familial form may be particularly fruitful We targeted aIl the multigenerational families densely af given the evidence that cognitive dysfunction in relatives fected by SZ or BP in the Eastern Québec (Canada) catch of SZ probands may depend on their degree of genetic ment area. Families were selected if there was at least relatedness with the probands. For example, cognitive 1 first-degree relative affected with the same disorder dysfunction in SZ may covary with genetic relatedness as the proband and if there were at least 4 affected in di such as in the affected monozygotic and dizygotic cotwins viduals with the sa me disorder. The firstwave of kindred of SZ patients.37 Congruently, in family studies of enrolment comprised 21 multigenerational families: 6 NAARs of SZ patients, more severe cognitive dysfunc had 30-50 members, 5 had 20-29, 7 had 10-20, and 3 tions were associated with a higher family genetic load had less than 10 family members. The average number ing,38,39 ie, the larger the number of relatives affected by per kindred was 26 members. The families had an average the disease, the more severe the cognitive dysfunctions in number of 6 members affected by SZ or BP. The final NAARs. A similar familial trend was also observed for sample consisted of 7 SZ kindreds (at least 85 0/0 of ill executive functions in the HRSZ study of Byrne et ae4 members affected by SZ or an SZ spectrum disorder, This body of data supports the assessment of the nature the remaining 150/0 having a BP spectrum disorder), and magnitude of cognitive dysfunctions in HR offspring 6 BP kindreds (at least 850/0 of ill members affected by having a high familialloading. A second limitation is that BP or a BP spectrum disorder, the remaining 15% having

2 Neuropsychological Functioning in High-risk Offspring an SZ spectrum disorder), and 8 mixed kindreds, ie, af (ADHD) diagnosis and because of family history of de fected almost equally by both major psychoses. The high pression and 3 because of substance use. The study was rate of mixed pedigrees may have resulted from our using explained and a signed consent was obtained, as reviewed a blind best-estimate diagnosis (BED). We have indeed by our University Ethics Committee. demonstrated that unblind diagnosis had greater conti nuit y with the most predominant diagnosis in a kindred 45 Assessment of Clinical Diagnosis in the Affected Parent than did blind diagnosis. The mean age of onset of adult and in the Parent's Relatives family members was 25.4 (SD 8.5) years for SZ and 28.8 = The affected parent and the adult relatives had the same (SD 10.3) years for BP. The mean age at evaluation was = direct BED. This lifetime BED was based on information 43.8 and 56.4 years, respectively.41 from an interview with the subjects (Structured Clinical Interview for DSM-III-R [SCID]), from other fa mil y Sample of Offspring informants, and from all available medical records across The ascertainment of kindreds was done in 2 waves, and lifetime. Based on this information, a consensus BED was the present sample of54 offspring was drawn from the first derived by a panel of 4 research psychiatrists who were 45 wave of assessment and led to the identification of off blind to diagnoses in relatives. ,46 The Global Assess spring who belonged to the most proximal generations. ment Scale (GAS)47 in the affected parents was used to measure the severity and the social functioning during Inclusion and Exclusion Criteria. The inclusion criteria the intervals between acute episodes across the entire were (1) having a parent with a definite DSM-IV SZ or life according to a method we reported elsewhere.45 BP disorder and (2) having a neuropsychological evalua tion before 23 years old. In the present cognitive study, the Instruments HRs' exclusion criteria were the presence of a diagnosis of The 45 HR offspring and 45 controls were administered DSM-IV psychotic disorder, BP or major depression, and brain and metabolic disorders known to cause neuropsy clinical and neuropsychological measures. The detailed description of the DSM-IV lifetime BED procedure in chological impairments. Out of the 54 offspring, 1 HR was 44 excluded for a recurrent major depression and 8 others the offspring in this sample is detailed elsewhere. In were excluded because they could not have their neuro summary, the methods consisted in a direct interview with the parents and the children Kiddie-Schedule for psychological assessment done by the age of 22, which 48 left 45 subjects (mean age = 17.33, SD = 4.31, table 1). Affective Disorders and Schizophrenia for subjects under 18 or the SCID49 for those over 18). A lifetime best-estimate DSM-IV diagnosis used an available infor Sample of Control Subjects mation concerning the offspring,44 as had been formerly 45 We selected, by advertisements in local newspapers and made in parents and relatives. ,46 A summary descrip in the population, the 45 unrelated normal controls tion of diagnoses among HRs is provided in table 2. (mean = 17.32, SD = 4.30) from the same population. The standard neuropsychological tests of our battery They were matched for gender and age. The exclusion cri met the following criteria: (a) well-known psychometrie teria were the same as those in HRs with the addition of properties; (b) high heritability of the performance or any axis I DSM diagnosis or a positive family history of function; (c) previous use in studies of HRs, NAARs, SZ or BP spectrum disorders. One volunteer was ex and patients, for the sake of future comparability; (d) cluded because of an attention-deficit hyperactivity dis available French versions when the tèst had a significant order (ADHD) diagnosis; another one was excluded verbal component; and (e) possible use in children, ado because of an attention-deficit hyperactivity disorder lescents, and adults.

Table 1. OfTspring Sample Characteristics

HR (N = 45) HRSZ (N = 22) HRBP (N = 23)

Mean age at evaluation (SD) 17.33 (4.31) 17.20 (4.16) 17.45 (4.54) Gender, number of males (0/0) 23 (51) 9 (41) 14 (61) Mean CGAS (SD)a 68.34 (15.97) 65.55 (18.59) 71.00 (12.90) Mother affected (%) 24 (53) 13 (59) Il (48) Mean GAS of parent (SD)b 67.63 (13.00) 60.35 (12.86) 75.72 (7.18) Socioeconomic status (Family Blishen score) (SD) 41.34 (15.50) 37.29 (15.82) 45.21 (14.48)

Note: HR, high risk; HRSZ, high-risk offspring of parents having schizophrenia; HRBP, high-risk offspring of parents having bipolar disorder; CGAS, Children Global Assessment Scale; GAS, Global Assessment Scale. aAverage COAS of primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis.44,72 47 b Average parental GAS measured during the intervals between acute episodes across life of the afTected parent.

3 M. Maziade et al.

Table 2. Proportions of Lifetime DSM-IVDiagnoses in the Total to copy a figure and then recall after 3 (immediate recall), HR Offspring Sam pie and in HRSZ and HRBP Parents at Time of and 30 min (delayed recall). They were then presented Neuropsychological Testing with 24 items (targets and distracters) and asked to iden tifY each item that was included in the initial figure (rec Lifetime Sam pie DSM-IV ognition). (6) Working memory was assessed first with Diagnosesa HR HRSZ HRBP the digit span (WISC-III or W AIS-III subtest), in which (N = 45 (N = 22 (N = 23 subjects had to recall serially sequences of digits, and sec subjects) subjects) subjects) ond, with the Corsi,57 in which the subjects had to recall Occurrences Occurrences Occurrences series of blocks. (7) Executive functions/problem-solving (%) (%) (0/0) abilities were assessed with the Wisconsin Card Sorting Test-128 cards (WCST:CV4) in which participants had Any SZ and affective 0 0 0 to classify series of cards into 3 categories, after having disorders found the experimenter's classification rule (color, Any anxiety disorders 14 (31.1) 9 (40.9) 5 (21.7) number, or forms).58 (8) Executive functions/initiation Any disruptive disorders 12 (26.7) 5 (22.7) 7 (30.4) Any personality disorders 2 (4.4) 2 (9.1) 0 executive ability was assessed with the Verbal Fluency Learning disorders 5(11.1) 4 (18.2) 1 (4.3) Test,59 in which subjects had to produce a maximum Communication disorders 2 (4.4) 2 (9.1) 0 number of words during al-min iIiterval. The first con Other disorders 23 (51.1) 8 (36.4) 15 65 .2) dition consisted in producing words from a phonological Absence of diagnosis . 17 (37.8) 8 (36.4) 9(39.1) cue (ie, words beginning with the letter " p"), and for the second condition, subjects were asked to produce as Note: DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; HR, high risk; HRSZ, high-risk many words as possible from the same semantic category offspring of parents having schizophrenia; HRBP, high-risk (ie, "animaIs"). (9) Executive functions/planning was offspring of parents having bipolar disorder. evaluated with the Tower of London (TOLDX ), 60 where aBecause several individuals had more that one lifetime disorder, subjects had to plan and reproduce models with 3 balls of the numbers of individual diagnoses does not necessarily add up different colors while respecting explicit roles. (l0) Motor to the total number of offspring in a particular sample. coordination: In the Purdue Pegboard,61 subjects were asked to in sert as many pins as possible into small holes Based on this, we assessed the following 10 cognitive simultaneously with both hands, in al-min period. domains: (1) Intelligence: A full standard intelligence In terms of procedure, subjects were individually scale (Wechsler Intelligence Scale for Children, 3rd ed. assessed in a quiet room for a period of 3--4 h. Pauses Wechsler Adult Intelligence Scale, 3rd ed. [WISC-IIII were offered when needed. Clinical assessments were WAIS-III] for HR and Wechsler Abbreviated Scale of In- conducted by an experienced nurse and supervised by telligence for con trois) was completed to assess global in a research psychiatrist (Maziade and Roy). The neuro 5 52 tellectualleve1. O- The Continuous Performance Test-II psychological assessment was made by certified psychol (CPT-Il)53 assesses different aspects of attention. Sub ogists or graduate PhD students supervised by a senior jects had to press the space bar each time they were shown neuropsychologist (Rouleau). Depending on the age of a letter on the screen (all except the X) for an uninter the subject, the children or adolescent/adult version of rupted period of 14 min. (2) Sustained attention was those tests was used. The tests were administered in assessed with sorne CPT variables "hit reaction time the same order in all subjects and analyzed and corrected block change" (increased speed over time) and " hit stan blind to parents' diagnosis. dard error block change" (variability of performance). (3) Selective attention was assessed with index of Omis- Socioeconomic Status sions (number of targets missed), of commissions (number To characterize family socioeconomic status (SES), we 62 of Xs identified as targets), and of detectability d'. The used the Blishen index based on the highest SES of the Stroop Test54 was added to more specifically assess inhi 2 parents at time of offspring upbringing. This index is bition in subjects with the use of the provided formula based on education and income and on a Canadian taking into account the individual's speed of processing census of 514 occupational categories according to the Ca in measuring resistance to interference. (4) Verbal epi nadian Classification and Dictionary of Occupations. An sodic memory (VEM) was assessed with the California advantage is that norms were available from the Canadian Verbal Learning Test,55 in which subjects had to learn generalpopulation: mean was42.74(SD= 13.3) and range a series of words presented orally over 5 trials and to im from 17.81 (low SES) to 101.74 (high SES). In our offspring mediately recall them after each presentation (total recall sarnple, me an was 41.34 (SD = 15.50) and range from 22.08 of 5 trials) or with a 20-min delay (delayed recall). They to 70.19, showing no difference with general population were also asked to recognize target words between dis (l-sample t test for the mean, P = .55). Farnily SES was tracters (recognition). (5) Visual episodic memory was not correlated with IQ (r = .18, P =.24 , NS) nor with assessed with the Rey Complex Figure. 56 Subjects had the cognitive domains of table 3 (median r of 0.12, NS).

4 Neuropsychological Functioning in High-risk Offspring

Table 3. Comparisons of HR to Controls on the Neuropsychological Tests

Adjusted for Adjusted for Age, Unadjusted Mean (SD) Age and Gender Gender, and IQ

Cognitive ANCOVA's ANCOVA's Functioning HR Controls P Value Effect Size P Value Effect Size l-Intelligence GlobalIQ 96.9 (10.9) 108.3 (9A) <.OOOl a -1.25 2-Sustained attention b CPT-hit reaction time block change 0.00 (0.03) 0.00 (0.02) A3 -.18 .05 - .52 b CPT-hit standard error block change 0.03 (0.09) 0.00 (0.06) .13 -.34 A2 -.21 3-Selective attention b CPT omissions 3.62 (5.10) 3.18 (5.55) A8 -.16 A6 -.19 CPT commissionsb 15.7 (8.5) 17.1 (7.8) .53 .14 .63 .12 CPT detectability d' 0.64 (0.44) .0.55 (OAO) A3 .18 .59 .14 Stroop interference score 1.49 (18.79) -0.93 (14.39) 1.0 .001 .85 .05 4-Verbal episodic memory CYLT total recall 52.1 (8.9) 57.6 (8.1) .0006<: -.77 .01 -.65 CYLT dela yed recall 11.2 (2.8) 13.1 (2.0) <.OOOl a -.95 .007 -.72 CYLT recognitiori 14.6 (1.6) 15.1 (1.2) .09 -.37 .60 -.13 5-Visu al episodic memory Rey immediate recall 19A (6.2) 23.6 (6.1) .0003<: -.82 .05 -.51 Rey delayed recall 19.5 (5.8) 24.2 (6.8) .0OOl c -.87 .02 -.64 Rey recognition 20.6 (1.7) 20.8 (2A) .61 -.11 .87 -.04 6-Working memory Total spatial span 16.7 (3.2) 18A (3.7) .004d -.66 .02 -.65 Total digit span 16.0 (3.5) 17.0 (3.9) .10 -.36 A3 -.20 7-Executive function/problem solving b WCST total errors 20A (17.9) 14.1 (6.8) .02 -.52 .23 -.33 WCST number of categories completed 5A7 (1.37) 5.50 (1.13) .93 -.02 .68 -.11 WCST trials first categoryb 17.6(19.9) 14.0 (4.9) .28 -.25 .21 -.34 WCST failure to maintain setb 0.97 (1.10) 0.58 (0.78) .07 -A2 ,36 -.25 WCST learning to learn -0.56 (4.58) -0.22 (3.63) .70 -.09 .53 .17 8-Executive function/initiation Letter fluency test 8A3 (4.04) 10.91 (3.92) .0()()1<: -.88 .004 -.77 Category fluency test 17.8 (4.59) 19.8 (4.60) .008 -.60 .33 -.26 9-Executive function/planning Total number of problems solved 4.74 (2.16) 5.98 (2.08) .001 d -.75 .03 -.57 in minimum moves Total time violationsb 1.05 (1.12) 0.80 (0.94) .26 -.25 .05 -.51 Total rule violation Sb 0.62 (1.21) 0.13 (0.34) .007 -.61 .14 -.38 1O--M otor coordination Purdue-both hands 12.1 (2.07) 12.3 (2.02) .24 -.26 .80 .07

Note: HR, high risk; ANCOVA, analysis of covariance; CPT, Continuous Performance Test; CVLT, California Verbal Learning Test; WCST, Wisconsin Card Sorting Test; Values are presented as raw scores for each cognitive variable, and IQ is presented as standard score. When we used an analysis of variance, without entering age and gender as covariables, the results remained similar. Bold values represent significant results according to our criterion that takes into account multiple testing (see Multiple Testing in Methods section) aSignificant at P ::; .0001 according to multilevel modeling with sibships nested in the group as a random effect. bFor these subtests, an elevated score indicates a subject's poor performance. Note that the effect sizes have been inverted for these subtests. CSignificant at P < .005 according to multilevel modeling with sibships nested in the group as a random efTect. dSignificant at P < .05 according to multilevel modeling with sibships nested in the group as a random effect.

Statistical Analysis First, we compared the total sample of HRs (N = 45) The analyses were done in 3 phases aIl including age and with the controls (N =45) on each of the cognitive tests by gender as covariables. We did so despite the matching be means of analyses of covariance (ANCOVAs) (when we tween HR and control subjects on these variables because used an analysis of variance, without entering age and such matching was lost for several of the comparisons gender as covariables, the results remained the same). reported below, such as the analyses comparing HRSZ The effect sizes coming out of the comparisons between to HRBP and those excluding HR subjects having spe the 2 groups were calculated by computing the Cohen d. 63 cifie DSM diagnoses. We also tested for the impact of a DSM-IV diagnosis of 5 M. Maziade et al.

ADHD or substance use in the offspring by excluding memory (d= -.66), and poorer performance on executive subjects presenting those diagnoses. To address the pos functions such as initiation and planning (d = - .88 sible effect of lack of independence of observations due to -.75). As mentioned earlier, the ANCOVAs' results to sorne of the 45 offspring who were siblings (9 two- and were interpreted when the-statistical threshold of .005 3 three-sibships), multilevel modeling64 was done using as was reached. When the 7 HRs with a substance-use diag the random effect, the sibships nested in the group. nosis were withdrawn from the analysis, the effect sizes Second, we examined the main effect of the group remained in the same range (d = -.66 to -1.25) as membership (HRSZ, HRBP, or controls) using ANCO weIl as when the 6 HRs with ADHD were withdrawn VAs. When the main effectwas found statisticaIly signif (d = -.58 to -1.18). To address the possible effect of icant, we examined the differences between HRBP and lack of independence of observations due to sorne of controls, HRSZ and controls, and HRBP and HRSZ, us the 45 offspring who were siblings, the analysis was re ing post hoc least significant difference (LSD) procedure done using multilevel modeling and yielded consistent based on Student t test. results in table 3, suggesting that the number of related Third, given that (1) general intelligence may affect the offspring had not affected the results. FinaIly, to assess performance at each cognitive test level and that, in turn, the possibility that the cognitive differences might a cognitive impairment in a specific domain may affect be mainly due to a subgroup being in a prodromal the general IQ performance and (2) intelligence quotient state, we stratified the HR sample into those under age was modestly associated with most neuropsychological 17 (N = 19) and those aged 17 and over (N = 26). variables in our sample (correlations of .30-.43), we Most of the differences were similar in each of the

performed the analyses (ANCOVAs and effect sizes) 2 age strata, respectively, for IQ: d = -1.03, P ANCOVA = by controlling for IQ in addition to age and gender. .003 and d = -1.40, PANCOVA < .000 1, and for visual To examine whether the neuropsychological difference episodic memory: d ::; -1.16, PANCOVA ::; .002 and between the offspring and controls might be due to the d::; -.68, PANCOVA ::; .02. presence of a DSM behavior disorder, an ANCOVA was conducted among HRs with a DSM nonpsychotic Comparisons of HRSZ, HRBP and ContraIs diagnosis, HRs without such a diagnosis, and controls. The ANCOVAs adjusted for age and gender revealed The group with a DSM behavior disorder was composed group effects significant at the .005 level for IQ, verbal of HRs with a nonpsychotic DSM clinical disorder, and visual episodic memory, and executive functions excluding DSM developmental disorder (language disor (problem solving, initiation, and planning, table 4). der, learning disorder), and axis II disorders. We ex Post hoc analyses revealed, in aIl but one of these instan cluded language and learning disorders because the ces, a significantly poorer performance in HRBP and interest here was in disturbed behavior and not in diag HRSZ compared with controls. For the WCST total nosed developmental disorder already associated with errors, the HRSZ did not differ from controls, whereas cognitive functioning. The effect sizes coming out of the HRBP did. Other potential trends (P = .01) for differ the comparisons between the groups were also calculated. ences across the 3 groups were found such as for working memory and sustained attention. Multiple Tes t ing. To take account of multiple testing, we set our criterion for detecting a significant overall Cognitive Differences Adjusted for IQ F test for ANCOVA at P = .005, while a P value found between .05 and .005 was interpreted as a possible Tables 3 and 4 also provide the ANCOVA 's results when tendency. This stringent criterion is the result of the usual adjusted for IQ, in addition to age and gender. Several of threshold for significance of .05 divided by 10, given that the differences with con troIs remained significant in the 10 neuropsychological domains were assessed and given total HR group and in the HRSZ and HRBP subgroups, that a principal component analysis confirmed that 10 in and most of the Cohen d remained moderate to large. dependent factors explained more than 800/0 of the vari Overall Neuropsychological Profiles ance (results not shown). The r:J. = .05 significance level was used for post hoc analyses adjusting for IQ and Both HRSZ and HRBP had a lower IQ than controls, for comparing groups via LSD procedures. AIl analyses respectively, 94.1, 99.6, and 108.3 (d = -1.56, P < .0001 were performed using SAS (version 9.1; PROC GLM). for HRSZ and d = -.99, P =.0002 for HRBP, table 4). Figure 1 illustrates the general cognitive profiles observed ResuUs in HRSZ and HRBP. Overall, the effect sÏzes for the different cognitive .domains suggest that (1) both Analysis in Total HR Sample and Intervening Factors HRSZ and HRBP showed a decreased cognitive func Compared with controls (table 3), the HR group (N = 45) tioning particularly in memory, (2) effect sÏzes were of showed a lower global IQ (d = -1.25), p60rer verbal and moderate to high magnitude, in the 0.5- 1.0 range, in visual episodic memory (d= -.77 to -.95), lower working measures like episodic memory and global IQ, and (3)

6 Neuropsychological Functioning in High-risk Offspring

Table 4. Comparison of HRSZ, HRBP, and Controls on Neuropsychological Tests

Unadjusted Mean (SD) ANCOV A Post Hoc Analyses

HRSZ vs. CTL HRBB vs. CTL HRSZ vs. HRBP

Effect Effect Effect b b b Cognitive Variable HRSZ HRBP Controls P Valuea P Value Size P value Size P Value Size l-Intelligence GlobalIQ 94.1 (8.1) 99.6 (12.6) 108.3 (9.4) <.0001 <.0001 -1.S6 .0002 -.99 .06 -.57 2-Sustained attention CPT-hit reaction time - 0.01 (0.03) 0.01 (0.03) - 0.001 (0.02) .10d block changeC CPT-hit standard -0.01 (0.08) 0.06 (0.09) 0.003 (0.06) .Old .61 .15 .007d -.74 .Old .89 error block changeC 3-Selective attention CPT omissionsc 3.38 (4.83) 3.81 (5.41) 3.18 (5.55) .78 CPT commissionsc 14.0 (8.8) 17.0 (8.1) 17.1 (7.8) .70 CPT detectability d' 0.79 (0.49) 0.52 (0.35) 0.55 (0.40) .20 Stroop interference score 2.06 (15.02) 1.00 (21.9) -0.93 (14.4) 1.0 4-Verbal episodic memory CYLT total recall 54.4 (7.4) 50.2 (9.7) 57.6 (8.1) .001d .04 -.S7 .OOOSe -.94 .25 .36 CYLT delayed recall 11.5 (2.9) 10.9 (2.8) 13.1 (2 .0) .0002d .003 -.86 .0002e -1.03 .60 .17 CYLT recognition 14.9 (1.45) 14.4 (1.7) 15.1 (1.2) .18 5-Visu al episodic memory Rey immediate recall 19.0 (5.2) 19.7 (7.0) 23.6 (6.1) .001 .002 -.92 .006 -.73 .56 -.19 Rey delayed recall 19.8 (4.4) 19.3 (6.8) 24.2 (6.8) .001d .003 -.86 .001d -.88 .95 .02 Rey recognition 21.1 (1.6) 20.3 (1.7) 20.8 (2.4) .41 6---Working memory Total spatial span 16.9 (2.8) 16.5 (3.5) 18.4 (3.7) .01 .04 -.60 .009 -.71 .73 .11 Total digit span 15.6 (3.7) 16.3 (3.3) 17.0 (3.9) .20 7-Executive functionlproblem solving WCST total errorsc 13.2 (6.9) 26.2 (21.8) 14.1(6.8) .001e .98 -.01 .000Sd -.98 .004Sf .98 WCST numberb of 6.01 (0.00) 5.05 (1.75) 5.50(1.13) .10 categories completed WCST trials first 13.0 (7.3) 21.3 (25.6) 14.0 (4.9) .14 categoryC WCST failure to 1.12 (1.17) 0.86 (1.06) 0.58 (0.78) .15 maintain setC WCST learning to learn 0.52 (1.66) -1.47 (5.96) -0.22 (3.63) .45 8-Executive functionlinitiation Letter fluency test 9.22 (3.93) 7.77 (4.10) 10.9 (3.9) .000Se .01 -.72 ·.0003e -1.00 .39 .28 Category fluency test 18.2 (3.9) 17.5 (5.2) 19.8 (4.6) .03 .03 -.63 .03 -.57 .85 -.06 9-Executive function/planning Total number of 4.94 (2.14) 4.59 (2.22) 5.98 (2.08) .003d .05 -.S8 .001d . -.88 .37 .30 problems solved in minimum moves Total time violationsC 0.88 (1.36) 1.18 (0.91) 0.80 (0.94) .35 Total rule violationsc 0.71 (1.57) 0.55 (0.86) 0.13 (0.34) .02 .02 -.71 .05 -.53 .58 -.18 10-Motor coordination Purdue-both hands 12.0(2.1) 12.1 (2.1) 12.3 (2.0) .20

Note: ANCOV A, analysis of covariance; HRSZ, high-risk ofTspring of parents having schizophrenia; HRBP, high-risk offspring of parents having bipolar disorder; CPT, Continuous Performance Test; CYL T, California Verbal Learning Test; WCST, Wisconsin Card Sorting Test; values are presented as raw scores for each cognitive variable, and IQ is presented as standard score. Bold values represent significant results according to our criterion that takes into account multiple testing (see Multiple Testing in Methods section). a P value of overall F test of ANCOVA adjusted for age and gender comparing HRSZ, HRBP, and controls. b P value from post hoc analyses using least significant difference (LSD) procedure. cFor these subtests, an elevated score indicates a subject's poor performance. Note that the efTect sizes have been inverted for these subtests. dSignificant at P < .05 according to analyses adjusted for age, gender, and IQ comparing HRSZ, HRBP, and controls. eSignificant at P < .01 according to analyses adjusted for age, gender, and IQ comparing HRSZ, HRBP, and controls. fSignificant at P < .001 according to analyses adjusted for age,gender, and IQ comparing HRSZ, HRBP, and controls.

7 M. Maziade et al.

1,00

0.50

0.00 c CP .:: 0 ..0 ,50 0 ~ -1 .00

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-2.00 Cl> Cl> III III Cl> c c c '0 ~ III III CIJ C Q al al e e =0 (ij en en ~ ~ Qi E ~ Cl> c e 0 $ a (j) en ~ Cl> a c e 0 0 ~ ~ ~ ! ~ ~ a. 0- e Cl> > 0 a 'oP (ij 'ii) ,~ 8 Cl> Cl> al (J) (J) al Cl> t- t- a co .0 en m 'c;; (j) 'ë j ~ 'ë , ;v C .c. .r: III 1) CI:: CI:: a:: 0) 0. ~ -' ()' >- ~ ~ ~ e 0 Ü Q) a (ij '0, E m i§ u (5 (5 ü 'Ë 19 0 '0 '0 ~ i2 c e Ô .;;,é, C1> g l Jl 0 ~ 0 Ü e 'Ë g u c S 0) Cl> Cl> 0 al co :> :> u TI E >. ~ 0- ë5 U (j) '«1 :::l :::l .Q .Q 0 ie ~ {3. iO m ~ c Q) ~ Cl> ex: (J) III ~ 'ë CL CL .ç;; 8 0.. 0 4i Ci) >. ~ .-. Q1 ~ "5 co co Cl .g .-. Q) (j') CIJ U f- ....J 0 0 {3. .9 ni ~ "0 a:: C1> t- ~ ~ 'g Cl> Cl> i= E a.. > f- :>. a:: m ~ 0 ....J ....J a E e CL ~ 1 1 Q) al ~ ....J Cl> al > U .5 U ..J {:. ~ ~ ...J ~ ~ W (.) a. U ! - ~ .2 f- 2 0 > a:: ('(1 f- (j) en .... f2 e 0 ü (j') (V ~ "E 0 i ü u... U III .g en ~ 0 "0 '0 1- ~ E en c (j) ~ (j) Q) Cl> j9 ~ :0 CI:: (j) .0 e 1 E ~ a.. J: i: :::l ë ~ ...:. z Cl. ~ .0 a.. (j') Z (,) Ü ~ ~ Attention \. .) \.... Memory ./ ...... Executive functions ./

Fig. 1. Effect Size of Cognitive Functioning Arnong High-Risk Offspring of Parents Having Bipolar Disorder and High-Risk Offspring of Parents Having Schizophrenia. Effect sizes were calculated according to the Cohen d index. HRBP values are represented by triangles, and HRSZ values are represented by sq uares. The sign ofthe effect size values was changed for sorne tests in order to have the dysfunctional poles in negative values. On this figure, the zero value indicates d = 0, ie, no difference with controls. the cognitive profiles of HRSZ and HRBP were to a cer to controls and for the comparison of HRs without a be tain degree superposed. As sorne HR subjects came from havior disorder to controls were, respectively, for IQ families (or kindreds) that were more homogeneous or (d = -1.14 and -1.15), for VEM (d = -1.02 and -0.95), that were mixed in terms of family history, we investi for visual episodic memory (d = -0.88 and -0.84), and gated whether family history could have influenced cog for executive functionlplanning (d = -0.78 and -0.67). nitive differences. When we regrouped the HRs into those having a SZ parent from a SZ kindred (n = 8 offspring), those having a BP parent from a BP kindred (n = 17 off Discussion spring), excluding those with a parent from a mixed kin Methodological Issues dred (n 20 offspring), the same pattern of lower IQ was = Our design had several strengths such as a definite high observed for both subgroups when compared with con familiality of the parent's illness, a lifetime BED of troIs (mean IQ of HRSZ from SZ kindred = 96.1, P = parents, of relatives, and of offspring, and extensive neu .002; mean IQ of HRBP from BP kindred = 101.8, = P ropsychological battery with the same methods for both .006, data not shown). HRSZ and HRBP. However, our study also had limita tions. Thefirst one is whethersuch a very HR sample and DSM Nonpsychotic Behavior Disorders and Cognitive their ill parents are representative of aIl parents with ma Functioning jor psychosis and their offspring, thus calling for cau Because 600/0 presented a DSM-IV nonpsychotic diagno tiousness before generalizing to the entirety of SZ and sis warranting a psychiatrie consultation44 (table 2), we BP. In counterpart, however, our previous reports42A5 examined whether the former .differences in cognitive have shown that the clinical and epidemiological ,charac functioning between offspring and con troIs might be teristics of the adults with SZ and BP in the se kindreds due to the presence or absence of a DSM behavior dis were quite similar to those observed in general patient order. The difference with controls remained the same samples regarding severity, age of onset, factor structure when taking into account clinical status: the effect sizes of symptoms, response to treatments, and gender differ for the comparison of HRs with a behavior disorder ences. The clinical profùe of these HRs shows a rate and

8 Neuropsychological Functioning in High-risk Offspring type of DSM nonpsychotic disorders that are similar to Interestingly, our findings differ slightly from those of those reported in HRs having an affected parent with no Klimes-Dougan et ae6 who found in their HRBP more or low family history.44 Second, the small size of the sam dysfunctions in executive functions than in memory. pIe may generate type II error especially with regards to However, the sample was from an affluent and highly the HRSZ/HRBP comparisons. Third, despite the use of educated milieu and Klimes-Dougan et al's affected an extensive neuropsychological battery, potentially mothers might have been sporadic or less familial cases meaningful areas of cognition such as language or praxia than in our sample. were not covered by our study. Fourth, we did not include an instrument specifically designed for assessing prodro Shared and Specifie Neuroeognitive Charaeteristies mal symptoms because this HR study was started 10 years To our knowledge, this is the first study having investi ago and also because the predictive value of these instru 65 gated HRSZ and HRBP concurrently with the same sam ments is still debated. However, the hypothesis that pling and assessment methods, allowing for the direct our HRs could be in a prodromal state explaining their testing of early cognitive dysfunctions that could be neurocognitive deficits remains unlikely, based on 2 sets shared by both risk groups. We observed that the of considerations: (1 ) the cognitive differences were pres HRs' differences with controls in IQ, episodic memory, ent in preadolescence as much as in postadolescence years and executive functions were present in both subgroups. in our sample and (2) the HRs were administered an Figure 1 illustrates their largely superposed neuropsycho extensive lifetime BED procedure that would have prob logical profiles. While visual inspection of effect sizes ably detected most of the known prodromal symptoms suggests sorne discrepancies, only one domain, namely (subdelusions, dysperceptual symptoms, etc.).44 executive functions/problem solving, reached our statis tical threshold for a HRBP/HRSZ difference. This again Similarities with Findings in H Rs, in N AARs, and in appears globally in continuity with the accumulating Patients evïdence that adult SZ and BP patients have many phe These young offspring at extreme risk for SZ or BP pre notypic features in common,42,68 as weIl as numerous ge sented a dysfunction in several cognitive domains as nomic susceptibility loci evidenced by linkage and 41 indexed by the observed effect sizes. Most of the HRs' association studies. ,69 Our findings in HRs are also differences with controls on this extensive neuropsycho much in continuity with the recent study of adult SZ logical battery appeared rather congruent with recent and BP patients by Schretlen et al,24 who also observed findings from other HR studies. 31,32,34 The offspring that the neurocognitive profiles were largely shared by underperformance in episodic memory and executive the 2 disorders when using a neuropsychological battery functions is also compatible with those showed in a quite comparable to ours. As suggested by the present meta-analysis of adult SZ patient studies66 and in data, the early risk mechanisms of the 2 major psychoses 70 meta-analyses of NAARs' studies.4-6,12 As in other would show several commonalities. HR studies using extended batteries,32,36,67 we observed Further studies are needed to investigate whether that differences in attentional processes might not be the the type of family history, homogeneous or mixed, of the main or only cognitive feature to focus on for future use affected parent may affect the cognitive profile of the as an endophenotype in genetic research. offspring. We did not have sufficient sample size to explore satisfactorily this issue. AIso, it is still difficult at this point Quantitative Differences in Cognition and Familial in time to have a definite interpretation of the meaning of Loading the possible specific impairments presented by the HRBP in sustained attention and in executive functions su ch as Our findings suggest that offspring with a very high planning and subtests of problem solving. More studies familiallgenetic loading have cognitive impairments in different populations and further foIlow-up of our that may be qualitatively similar to those observed in HRs may throw light on these patterns because specific HRs with mil der familiallgenetic loading and in NAARs. cognitive dysfunctions may appear later in life. However, in quantitative terms, the present effect sizes (Cohen d in the 0.6-1.0 range) approach those observed in adult patients, typically in the 0.8-1.2 range,24,66 and is Implications for a Hypothetic Mechanistic Modelof higher than those tisually reported for NAARs, which is Vulnerability in the 0.3-0.5 range.4 Our findings would then be congru Despite the methodological issues formerly raised, one ent with (1) former observations that cognitive impair can nevertheless assume that a putative model of vulner ment in NAARs of SZ tends to increase with the ability for major psycho sis wou Id have to reconcile the number of affected members38 and (2) the preliminary following empirical observations: (1) sorne of the child observation by Byrne et al34 that sorne executive func hood risk mechanisms for SZ and BP would be shared tions in HRSZ are more impaired if the familialloading by the 2 major psychoses, and the commonalities of nu is higher. merous phenotypic and epidemiological characteristics

9 M. MazÎade et al. that the 2 disorders have in adulthood would originate in 6. Szoke A, Schurhoff F, Mathieu F, Meary A, Ionescu S, sorne early mechanisms, (2) the specificity of an orienta Leboyer M. Tests of executive functions in first-degree rela tion toward SZ or BP may not come from factors strongly tives of schizophrenic patients: a meta-analysis. Psycho! Med.2005;35:771-782. related to neurocognitive functioning, ev en though cog 7. Cornblatt BA, Keilp JG. Impaired attention, genetics, and nitive differences between HRSZ and HRBP may exist, the pathophysiology of schizophrenia. Schizophr Bull. 1994; and (3) the very high genetic density in the former gen 20:31-46. erations of these HRs could have affected the severity 8. Chen WJ, Faraone SV. Sustained attention deficits as of the neurocognitive dysfunctions rather th an the spec markers of genetic susceptibility to schizophrenia. Am J ificity of impairment in a particular domain. Congruent Med Genet. 2000;97:52-57. with a multifactorial oligogenic model that is largely ac 9. Mirsky AF, Lochhead SJ, Jones BP, Kugelmass S, Walsh D, cepted for the major psychoses,7) the greater the genetic Kendler KS. On familial factors in the attentional deficit in schizophrenia: a review and report of two new subject sam loading in the extended family, the more serious the insult pIes. J Psychiatr Res. 1992;26:383-404. to brain functioning expressed in cognitive functioning. 10. Park S, Holzman PS, Goldman-Rakic PS. Spatial working In conclusion, the true test for revealing which of the memory deficits in the relatives of schizophrenic patients. developmental abnormalities better predicts the future Arch Gen P~ychiatry . 1995;52:821-828. appearance of a major psychosis and related disorders Il . Conklin HM, Curtis CE, Katsanis J, Iacono WG. Verbal will rest on 2 complementary arms of evidence: on one working memory impairment in schizophrenia patients and hand, in the demonstration of a valid relationship be their first-degree relatives: evidence from the digit span task. tween an early endophenotype and a genotype and, on Am J Psychiatry. 2000; 157:275-277. the otherhand, in the longitudinal demonstration that 12. Faraone SV, Seidman LJ, Kremen WS, Pepple JR, Lyons MJ, Tsuang MT. Neuropsychological functioning among the non such an endophenotype-genotype match can predict psychotic relatives of schizophrenic patients: a diagnostic the development of major psychosis when HR offspring efficiency analysis. J Abnorm Psychol. 1995; 104:286-304. are followed up beyond the age of incidence of the disease. 13. Gilvarry CM, Russell A, Jones P, Sham PC, Hemsley D, Murray RM. Verbal fluency in patients with schizophrenia and affective psychoses and their first-degree relatives. Psy- Funding cho! Med. 2001;31:695-704. 14. Chen YLR, Eric YH, Chen FM. Semantic verbal fluency def Canada Research Chair (#950-200810); a CIHR grant icit as a familial trait marker in schizophrenia. Psychiatry Res. (#MOP-74430); the Fonds de la recherche en santé du 2000;95:133-148. Québec (M-A.R.). 15. Laurent A, d'Amato T, Naegele B, et al. Fonctions exécutives et mnésiques d'un groupe d'apparentés de premier degré de patients schizophréniques. L'Encéphale. 2000;26:67-74. Acknowledgments 16. Laurent A, Biloa-Tang M, Bougerol T, et al. Executive/atten We are grateful to our professional research assistants tional performance and measures of schizotypy in patients with schizophrenia and their non psychotic first-degree rela Linda René and Louise Bélanger and the family tives. Schizophr Res. 2000;46:269-283. members, adults, and children, who have participated 17. Murphy FC, Sahakian BJ. Neuropsychology of bipolar disor in this study. We also thank Institut interuniversitaire der. Br J P~ychiatry. 2001;178:s120-s127. de recherches sur les populations for their 18. Keri S, Kelemen 0, Benedek G, Janka Z. Different trait collaboration regarding the BALSAC database. markers for schizophrenia and bipolar disorder: a neurocogni tive approach. Psychol Med. 2001;31:915-922. 19. Robinson LJ, Ferrier IN. Evolution of cognitive impairment References in bipolar disorder: a systematic review of cross-sectional ev idence. Bipolar disord. 2006;8: 103-116. 1. Szatmari P, Maziade M, Zwaigenbaum LZ, et al. Informative 20. Zalla T, Joyce C, Szôke A, et al. Executive dysfunctions as phenotypes for genetic studies of psychiatric disorders. Am potential markers of familial vulnerability to bipolar disorder J Med Genet B Neuropsychiatr Genet. 2007;144:581-588. and schizophrenia. Psychiatry Res. 2004; 121 :207-217. 2. Cannon TD. The inheritance of intermediate phenotypes for 21. Antila M, Tuulio-Henriksson A, Kieseppa T, .Eerola M, schizophrenia. Curr Opin Psychiatry. 2005;18:135-140. Partonen T, Lonnqvist J. Cognitive functioning in patients 3. BrafT DL, Freedman R, Schork NJ, Gottesman 1. Decon with familial bipolar 1 disorder and their unaffected relatives. structing schizophrenia: an overview of the use of endopheno Psychol Med. 2007;37:679-687. types in order to understand a complex. disorder. Schizophr 22. McIntosh AM, Harrison LK, Forrester K, Lawrie SM, John Bull. 2007;33:21-32. stone EC. Neuropsychological impairments in people with 4. Snitz BE, Macdonald A W, 3rd, Carter CS. Cognitive deficits schizophrenia or bipolar disorder and their unafTected rela in unaffected first-degree relatives of schizophrenia patients: tives. Br J Psychiatry. 2005;186:378-385. a meta-analytic review of putative endophenotypes. Schizophr 23. Toulopoulou T, Quraishi S, McDonald C, Murray RM. Bull. 2006;32: 179-194. The Maudsley Family Study: premorbid and current 5. Sitskoorn MM, Aleman A, Ebisch SJH, Appels MCM, Kahn general intellectual function levels in familial bipolar 1 disor RS. Cognitive deficits in relatives of patients with schizophre der and schizophrenia. J Clin Exp Neurop~y chol. 2006;28: nia: a meta-analysis. Schizophr Res. 2004;71 :285-295. 243-259.

10 Neuropsychological Functioning in High-risk Offspring

24. Schretlen DJ, Cascella NG, Meyer SM, et al. Neuropsycho a dense genome scan in Eastern Quebec families. Mol Psychi- logical functioning in bipolar disorder and schizophrenia. atry . 2005; 10:486-499. Biol Psychiatry . 2007;62: 179-186. 42. Maziade M, Roy M-A, Martinez M, et al. Negative, psycho 25 . Morice R. Cognitive inflexibility and pre-frontal dysfunction ticism, and the disorganized dimensions in patients with fa in schizophrenia and mania. Br J Psychiatry . 1990; 157:50-54. milial schizophrenia or bipolar disorder: continuity and 26. Goldberg TE, Gold JM, Greenberg RD, et al. Contrasts be discontinuity between the major psychoses. Am J P~y chiatry . tween patients with affective disorders and patients with · 1995;152:1458-1463. schizophrenia on a neuropsychological test battery. Am J 43. Mérette C, Roy M-A, Bureau A, et al. Replication of linkage Psychiatry . 1993; 150: 1355-1362. with bipolar disorder on chromosome 16p in the Eastern 27. McGrath J, Scheldt S, Welham J, Clair A. Performance on Quebec population. Am J Med Genet B Ne urop~ychiatr Genet. tests sensitive to impaired executive ability in schizophrenia, In press. mania and weil controls: acute and subacute phases. Schiz- 44. Maziade M, Gingras N, Rouleau N, et al. Clinical diagnoses ophr Res. 1997;26:127-137. in offspring from Eastern Québec muItigenerational families 28. Albus M , Hubmann W, Ehrenberg C, et al. Neuropsycholog densely affected by schizophrenia or bipolar disorder. Acta ical impairment in first-episode and chronic schizophrenia Psychiatr Scand. 2008 ;117:118-126. patients. Eur Arch Psychiatry Clin Neurosci. 1996;246: 45 . Roy M-A, Lanctôt G, Mérette C, et al. Clinical and method 249-255. ological factors related to reliability of the best-estimate diag 29. Albus M, Hubmann W, Wahlheim C, Sobizack N , Franz U , nostic procedure. Am J Psychiatry . 1997; 154: 1726-1733. Mohr F . Contrasts in neuropsychological test profile between 46. Maziade M, Roy MA, Fournier J-P, et al. Reliability of best patients with first-episode schizophrenia and first-episode af estimate diagnosis in genetic linkage studies of major psycho fective disorders. Acta Psychiatr Scand. 1996;94:87-93. ses: results from the Québec pedigree studies. Am J Psych ia- 30. Addington J, Addington D. Attentional vulnerability indica try. 1992; 149: 1674-1686. tors in schizophrenia and bipolar disorder. Schizophr Res. 47. Endicott J, Spitzer RL, Fleiss JL, Cohen J. The global assess 1997;23 : 197-204. ment scale: a procedure for measuring overall severity of psy 31. Niemi LT, Suvisaari JM, Tuulio-Henriksson A, L6nnqvist chiatric disturbances. Arch Gen P~y chiatry . 1976;33: JK. Childhood developmental abnormalities in schizophre 766-771. nia: evidence from high-risk studies. Schizophr Res. 2003; 48. Kaufman J, Birmaher B, Brent D, et al. Schedule for affective 60:239-258. disorders and schizophrenia for school-age children-present 32. Owens DG, Johnstone EC. Precursors and prodromata of and lifetime version (K-SADS-PL): initial reliability and schizophrenia: findings from the Edinburgh High Risk Study validity data. J Am Acad Child Adolesc Psychiatry . 1997;36: and their literature context. Psychol Med. 2006 ;36:1501-1514. 980-988: 33. Erlenmeyer-Kimling L. Neurobehavioral deficits in offspring 49. Spitzer RL, Williams JB, Gibbon M, First MB. The Struc of schizophrenic parents: liability indicators and predictors of tured Clinical Interview for DSM-III-R (SCID) I: history, illness. Am J Med Genet. 2000;97:65-71 . rationale and description. Arch Gen Psychiatry . 1992;49: 624-629. 34. Byrne M , Hodges A, Grant E, Owens DC, Johnstone EC. Neuropsychological assessment of young people at high ge 50. Weschler D. Echelle d'intelligence de Weschler pour adultes. netic risk for developing schizophrenia compared with con Troisiéme édition Recherche. Version pour francophones du trois: preliminary findings of the Edinburgh High Risk Canada. Toronto, Canada: The Psychological Corporation, Study (EHRS). Psychol Med. 1999;29:1161-1173. Harcourt Assessment, Inc; 2005. 35. Del Bello MP, Geller B. Review of studies of child and adoles 51. Weschler D. Weschler Abbreviated Scale of Intelligence. Tor cent offspring of bipolar parents. Bipolar disord. 2001 ;3: onto, Canada: The Psychological Corporation; 1999. 325-334. 52. Weschler D. Echelle d'intelligence de Weschler pour enfants. 36. Klimes-Dougan B, Ronsaville D, Wiggs EA, Martinez PE. Troisiéme édition. Version pour francophones du Canada. Neuropsychological functioning in adolescent children of Toronto, Canada: The Psychological Corporation, Harcourt mothers with a history of bipolar or major depressive disor Assessment, Inc; 1997. ders. Biol P~ychiatry. 2006;60:957-965. 53. Conners K. Continuous Performance Test Il. Odessa, FL: Psy 37. Cannon TD, Huttunen MO, Lonnqvist J, et al. The inheri chological Assessment Resources; 1999. tance of neuropsychological dysfunction in twins discordant 54. Golden C. Stroop Color and Word Test. Tampa, FL: Phycho for schizophrenia. Am J Hum Genet. 2000;67:369-382. logical Assessment Resources; 1976. 38. Faraone SV, Seidman LJ, Kremen WS, Toomey R, Pepple 55. Delis D , Kramer J, Kaplan E, Ober B. California Verbal JR, Tsuang MT. Neuropsychologic functioning among the Learning Test Manual. San Antonio, TX: Phychological nonpsychotic relatives of schizophrenic patients: the effect Corporation; 1987. of genetic loading. Biol P~ychiatry. 2000;48:120-126. 56. Meyers JE, Meyers KR. Rey Complex Figure Test and Recog- 39. Tuulio-Henriksson A, Arajarvi R, Partonen T, et al. Familial nition Trial (RCFT). Odessa, FL: Phychological Assessment loading associates with impairment in visual span among Resources; 1995. healthy siblings of schizophrenia patients. Biol Psychiatry. 57. Weschler D . WMS-III: Weschler Memory Scale. San Anto 2003;54:623-628. nio, TX: Harcourt Assessment Inc; 1997. 40. Erlenmeyer-Kimling L, Rock D , Roberts SA, et al. Attention, 58. Heaton RK, Chelune GJ, Talley JL, Kay GG, Curtiss G. memory, and motor skills as childhood predictors of schizo Wisconsin Card Sorting Test: Manual Revised and Expanded. phrenia-related psychoses: the New-York High-Risk Project. Odessa, FL: Psychological Assessment Resources; 1993. Am J Psychiatry. 2000;157:1416-1422. 59. Delis De, Kaplan E, Kramer JH. DeUs-Kaplan Executive 41. Maziade M, Roy M-A, Chagnon Y, et al. Shared and specifie Function System. San Antonio, TX: The Psychological Cor susceptibility loci for schizophrenia and bipolar disorder: poration; 2001.

Il M. Maziade et al.

60. Culbertson W, Zillmer E. TOl,ver of London-TOL DX. Tam 67. Cornblatt B, Obuchowski M, Roberts S, Pollack S, Erlen pa, FL: Psychological Assessment Resources; 2001. meyer-Kimling L. Cognitive and behavioral precursors of 61. Tiffin J. Purdue Pegboard Test. Tampa, FL: Psychological schizophrenia. Dey Psychopathol. 1999; 11:487-508. Asse~sment Resources; 1948. 68. Maier W, Zobel A, Wagner M. Schizophrenia and bipolar disor 62. Blishen B, Carroll W, Moore C. The 1981 socioeconomic in der: difTerences and overlaps. Curr Opin P~ychiatry. 2006; 19: dex for occupations in Canada. Canad Rey Sociol Anthropol. 165-170. 1987;24:465-488. 69. Berrettini W. Evidence for shared susceptibility in bipolar 63. Cohen J. Statistical Power Analysisfor the Behayioral Sciences, disorder and schizophrenia. Am J Med Genet. 2003; 123C: 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988. 59-64. 64. Goldstein H. Multilevel models. In: Armitage P, Colton T, 70. Murray RM, Sham P, Van Os J, Zanelli J, Cannon M, eds. Encyclopedia of Biosta tistics. Chichester, West Sussex, McDonald C. A developmental model for similarities and dis England: John Wiley and Sons Ltd; 1998:2725-2731. similarities between schizophrenia and bipolar disorder. 65. Olsen KA, Rosenbaum B. Prospective investigations of the Schizophr Res, 2004;71:405-416. prodromal state of schizophrenia: review of studies. Acta Psy- 71. Gottesman II, Shields J. Schizophrenia and genetics: a twin chiatr Scand. 2006;113:247-272. study yantage point. New York, NY: Academic Press; 1972. 66. Heinrichs R W, Zakzanis KK. Neurocognitive deficit in 72. Shaffer D, Gould MS, Brasic J, et al. A children's global schizophrenia: a quantitative review of the evidence. Neuro- assessment scale (CGAS). Arch Gen Psychiatry . 1983 ;40: psych%gy . 1998; 12:426-445. 1228-1231.