Molecular Psychiatry (2012) 17, 1206 -- 1227 & 2012 Macmillan Publishers Limited All rights reserved 1359-4184/12 www.nature.com/mp

FEATURE REVIEW Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents

S Miyamoto1, N Miyake1, LF Jarskog2,3, WW Fleischhacker4 and JA Lieberman5

Since the introduction of chlorpromazine and throughout the development of the new-generation antipsychotic drugs (APDs) beginning with clozapine, the D2 receptor has been the target for the development of APDs. Pharmacologic actions to reduce neurotransmission through the D2 receptor have been the only proven therapeutic mechanism for psychoses. A number of novel non-D2 mechanisms of action of APDs have been explored over the past 40 years but none has definitively been proven effective. At the same time, the effectiveness of treatments and range of outcomes for patients are far from satisfactory. The relative success of antipsychotics in treating positive symptoms is limited by the fact that a substantial number of patients are refractory to current medications and by their lack of efficacy for negative and cognitive symptoms, which often determine the level of functional impairment. In addition, while the newer antipsychotics produce fewer motor side effects, safety and tolerability concerns about weight gain and endocrinopathies have emerged. Consequently, there is an urgent need for more effective and better-tolerated antipsychotic agents, and to identify new molecular targets and develop mechanistically novel compounds that can address the various symptom dimensions of schizophrenia. In recent years, a variety of new experimental pharmacological approaches have emerged, including compounds acting on targets other than the dopamine D2 receptor. However, there is still an ongoing debate as to whether drugs selective for singe molecular targets (that is, ‘magic bullets’) or drugs selectively non-selective for several molecular targets (that is, ‘magic shotguns’, ‘multifunctional drugs’ or ‘intramolecular polypharmacy’) will lead to more effective new medications for schizophrenia. In this context, current and future drug development strategies can be seen to fall into three categories: (1) refinement of precedented mechanisms of action to provide drugs of comparable or superior efficacy and side-effect profiles to existing APDs; (2) development of novel (and presumably non-D2) mechanism APDs; (3) development of compounds to be used as adjuncts to APDs to augment efficacy by targeting specific symptom dimensions of schizophrenia and particularly those not responsive to traditional APD treatment. In addition, efforts are being made to determine if the products of susceptibility genes in schizophrenia, identified by genetic linkage and association studies, may be viable targets for drug development. Finally, a focus on early detection and early intervention aimed at halting or reversing progressive pathophysiological processes in schizophrenia has gained great influence. This has encouraged future drug development and therapeutic strategies that are neuroprotective. This article provides an update and critical review of the pharmacology and clinical profiles of current APDs and drugs acting on novel targets with potential to be therapeutic agents in the future.

Molecular Psychiatry (2012) 17, 1206--1227; doi:10.1038/mp.2012.47; published online 15 May 2012 Keywords: add-on treatment; antipsychotics; cognition; mechanism of action; negative symptoms; schizophrenia

INTRODUCTION third-generation antipsychotics (SGAs, TGAs) were developed and dramatic growth of research in the area of pharmacological Schizophrenia is a chronic and debilitating disorder with a lifetime treatment of schizophrenia has advanced our understanding of prevalence near 1%.1 It is characterized by positive, negative, the neurobiology and neuropharmacology of the illness.5,6 cognitive and affective symptoms, and may arise from neurode- However, the precise etiology of schizophrenia, including genetic velopmental and neurodegenerative pathophysiologic pro- and environmental diatheses, remains poorly understood.1 cesses.2,3 The serendipitious discovery of chlorpromazine in the Although existing antipsychotic medications are often effective early 1950s and development of clozapine in the late 1960s (with for treating positive symptoms, they have little impact on negative its reintroduction in the United States in 1989) represented two symptoms and cognitive deficits.7,8 These symptom domains major milestones in the pharmacotherapy of schizophrenia.4 are recognized as core features of schizophrenia and their lack During the past half century, numerous first- (FGAs), second- and of responsiveness to treatment contribute to poor functional

1Department of Neuropsychiatry, St Marianna University School of Medicine, Kawasaki, Japan; 2Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 3Department of Psychiatry, North Carolina Psychiatric Research Center, Central Regional Hospital---Raleigh Campus, Raleigh, NC, USA; 4Department of Psychiatry and Psychotherapy, Medical University Innsbruck, Innsbruck, Austria and 5Department of Psychiatry, Columbia University and New York State Psychiatric Institute, New York, NY, USA. Correspondence: Professor JA Lieberman, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York State Psychiatric Institute, Lieber Center for Schizophrenia Research, New York Presbyterian Hospital and Columbia University Medical Center, 1051 Riverside Drive, Unit #4, New York, NY 10032, USA. E-mail: [email protected] or [email protected] Received 8 September 2011; revised 7 February 2012; accepted 19 March 2012; published online 15 May 2012 Pharmacological treatment of schizophrenia S Miyamoto et al 1207 9 23 outcome. Furthermore, in a substantial number of patients, et al. hypothesized that a high ratio of affinities for 5-HT2A positive symptoms are resistant to currently available medica- receptors and D2 receptors was the critical feature of atypical tions.10 Consequently, there is an urgent need for more effective drugs, while Kapur and Seeman24 proposed that low affinity for and better-tolerated antipsychotic agents, and to develop and fast dissociation from D2 receptors may be the critical mechanistically novel compounds that possess pharmacological property for ‘atypicality’. FGAs such as chlorpromazine and activity for novel targets which address the various symptom haloperidol bind more tightly than dopamine itself to the D2 dimensions of schizophrenia. receptor, and dissociate from it slowly.25 In contrast, SGAs such In recent years, a variety of new experimental pharmacological as clozapine and quetiapine bind more loosely than dopamine to approaches have emerged and compounds acting on targets the D2 receptor, with dissociation constants (expressed as ‘koff’) other than the dopamine D2 receptor for which clinical testing has that are higher than those for dopamine. Preliminary evidence begun.11,12 Moreover, there has been a rapidly growing body of suggests that other SGAs, including amisulpride, aripiprazole research on approaches for enhancing cognition and for and paliperidone, also have higher koff values, (that is, faster improving negative symptoms in schizophrenia, either as mono- dissociation rates) than do FGAs, while asenapine, olanzapine, therapies or as adjunctive treatments added to currently available risperidone, sertindole and ziprasidone dissociate relatively slowly 13,14 26 antipsychotics. To assess progress in the development of from the D2 receptor. Thus, this ‘fast-off-D2’ theory may not treatments for schizophrenia, this article will provide a critical represent a general mechanism of ‘atypicality’.27 Moreover, it review of the pharmacology and clinical profiles of current remains uncertain how long an SGA needs to bind to D2 receptors antipsychotic drugs (APDs) and on novel targets for future to provide maximum therapeutic efficacy with minimal EPS.11 therapeutic agents. Although more research is required to identify optimum D2 receptor occupancy levels for SGAs, it appears that continuous high levels of occupancy are not critical for maximum anti- psychotic efficacy.28 THEORIES OF MECHANISMS OF ACTION OF APDS Regionally selective binding of SGAs to dopamine tracts Dopamine receptor modulation projecting to cortico-limbic areas has been proposed as another The mechanism of action of APDs is based on the hypothesis that contributor to ‘atypicality’. Many animal studies have found schizophrenia involves a dysregulation of neurotransmission in preferential effects of SGAs on ventral tegmental area (A10) as brain dopaminergic circuits with excess dopaminergic activity in compared with substantia nigra pars compacta (A9) dopamine the mesolimbic pathway and reduced dopaminergic signaling in neurons. In humans, PET and SPECT studies have demonstrated 15 29--33 the mescortical pathway. Based on this model, the antagonism this cortico-limbic D2 receptor specificity for some SGAs. of D2 receptors in the mesolimbic pathway will produce However, the finding cannot be replicated with different ligands reductions in dopamine activity and psychotic symptoms.16 The for several SGAs. A recent meta-analysis of PET and SPECT studies dopamine D2 receptor is regarded as the primary target associated supports the hypothesis that cortical D2/D3 receptors are likely to with therapeutic antipsychotic effects, as well as with the be an important site of antipsychotic action.34 However, this does induction of extrapyramidal side effects (EPS) and prolactin not exclude the involvement of other brain regions including elevation. All clinically approved and currently used APDs have striatum. Further research is needed to clarify the neurochemical nanomolar affinity for the D2 receptor and fully or partially block basis of ‘regional specificity’, as it raises the possibility of spatial 11 4 the actions of dopamine. D2 receptors mediate their physiolo- targeting of APDs in the future. gical actions through both G-protein-dependent and independent Partial D2 agonists represent another strategy of attempting to (the scaffolding protein b-arrestin 2-dependent) signaling.17 Masri normalize dopaminergic imbalance in schizophrenia, without 18 et al. have recently suggested that both FGAs and SGAs may the side effects associated with full D2 antagonists. These agents share a common molecular mechanism of blocking dopamine- have lower intrinsic activity at D2 receptors than full agonists, mediated interaction of the D2 long isoform with b-arrestin 2. allowing them to act as either functional agonists or antagonists, 35 PET (positron emission tomography) and single photon depending on synaptic dopamine levels. Partial D2 agonist emission computed tomography (SPECT) studies support the activity as reported for aripiprazole appears to inhibit endogenous importance of in vivo D2 receptor occupancy as a predictor of dopamine activity where it is high and activate D2 receptors where antipsychotic response and side effects.19 Prospective studies it is low. In addition, such an agent should ideally maintain demonstrate that, for at least some FGAs, antipsychotic effect dopaminergic tone in the nigrostriatal and tuberoinfundibular requires a striatal D2 receptor occupancy of 65--70%, and D2 pathways, thereby avoiding EPS and hyperprolactinemia normally 19 occupancy 480% significantly increases the risk of EPS. associated with D2 antagonism. However, aripiprazole is not a However, brain imaging studies found that there was a wide simple partial D2 agonist; it can have partial agonist properties at variation in D2 receptor occupancy among patients on the same D3,D4, 5-HT1A, 5-HT2C and, to a much lesser extent, 5-HT2A dose of antipsychotic and within the same individual in different receptors.36,37 At present, it is unclear to what extent binding to stages (first episode vs chronic) and phases (relapse vs remission) receptors other than D2 receptors contributes to the actions of of the illness. Thus, the thresholds, although generally accurate, aripiprazole. are not invariably reliable in predicting clinical events.20 Moreover, clozapine and quetiapine exhibit o60% striatal D2 receptor occupancy at therapeutically effective doses,21,22 indicating that Serotonin receptor modulation striatal D2 receptor blockade alone cannot explain therapeutic The ‘dopamine--serotonin antagonism theory’ conceived by 38 23 efficacy. However, the low occupancy of striatal D2 receptors by Janssen et al. and popularized by Meltzer et al. assumes that clozapine and quetiapine could account for their low EPS liability. a high ratio of serotonin 5-HT2A receptor to D2 receptor blockade SGAs were termed ‘atypical antipsychotics’ because of their low confers antipsychotic ‘atypicality’. 5-HT2A antagonism can increase incidence of EPS at therapeutically effective doses. Although there dopaminergic transmission in the nigrostriatal pathway, thus is debate as to what constitutes ‘atypicality’, the defining feature reducing the risk for EPS, and could theoretically improve negative of this class medications is the separation of the dose that results symptoms and cognitive impairment in schizophrenia by increas- in a therapeutic effect from that which is associated with an ing release of dopamine, acetylcholine (Ach) or both in the increasing risk of EPS.20 The concept of ‘atypicality’ is thought to prefrontal cortex (PFC). This hypothesis appears to apply, to some be due to two properties: (1) their lower affinity for D2 receptors degree, to most SGAs, including asenapine, clozapine, iloperidone, and (2) their high affinity for serotonin (5-HT)2A receptors. Meltzer olanzapine, paliperidone, perospirone, quetiapine, risperidone,

& 2012 Macmillan Publishers Limited Molecular Psychiatry (2012), 1206 -- 1227 Pharmacological treatment of schizophrenia S Miyamoto et al 1208 sertindole, ziprasidone and zotepine. There are, however, critical administration.11 Inconsistent and often conflicting findings limitations to this concept.20 For example, amisulpride has no have been reported for NMDA-R subunit gene expression meaningful affinity for the 5-HT2A receptor, and aripiprazole and following long-term treatment with FGAs or SGAs. Differences blonanserin have higher D2 than 5-HT2A affinity, and yet clinically in treatment regimens, brain regions examined and methods they have atypical profiles.35,39 In addition, chlorpromazine and of assessment likely contribute to many of these discrepancies. A loxapine have relatively higher 5-HT2A than D2 affinity, but they do preclinical study showed that clozapine inhibits synaptosomal not have an atypical profile.23 Furthermore, risperidone and glycine transport through system A amino-acid transporters.53 olanzapine exhibit high 5-HT2A receptor occupancy at doses that Regulation of synaptic glycine levels represents a potential are not antipsychotic, and as doses of these drugs are increased indirect mechanism for clozapine to potentiate NMDA-R function beyond their usual therapeutic ranges, the risk for EPS increases (Figure 1). 40 123 despite maximal 5-HT2A receptor blockade. Thus, high 5-HT2A The development of [ I]CNS-1261 as the first usable SPECT affinity may contribute to the modulation of dopamine in the ligand for the NMDA-R intra-channel PCP-binding site permitted 54 striatum and PFC, but high 5-HT2A occupancy does not protect the direct estimation of NMDA-R activity in living humans. 55 against the risk of EPS if D2 receptor occupancy is greater than the Bressan et al. found that schizophrenia patients treated with 20 EPS threshold. The 5-HT2A/D2 hypothesis, therefore, does not clozapine had significantly reduced NMDA-R binding in all the satisfactorily explain ‘atypicality’.41 Furthermore, the apparent lack brain regions. A trend in the same direction for FGAs was also of efficacy of monotherapy with the selective 5-HT2A receptor observed. Further studies are needed to determine whether antagonist M-100907 indicates that 5-HT2A antagonism alone does inhibition of the effects of NMDA-R antagonists by SGAs involves not account for the efficacy of SGAs.42,43 molecular modifications in glutamate receptors and/or other Some but not all SGAs are 5-HT2C, 5-HT6 and 5-HT7 receptor neurotransmitter--glutamate interactions. 44 antagonists as well as direct or indirect 5-HT1A receptor agonists. It has been suggested that partial agonism of 5-HT1A receptors, Other receptor modulation resulting in activation and blockade of pre- and postsynaptic Most APDs interact with adrenergic, histaminergic and muscarinic receptors, respectively, contributes to the mechanism of action of neurotransmitter systems as well as with monoamine transporters. some SGAs and TGAs, including aripiprazole, clozapine, perospir- Interactions with these receptor systems contribute to many one, quetiapine and ziprasidone.45 5-HT receptors are located 1A common antipsychotic-induced side effects but emerging data presynaptically in the raphe nuclei, where they act as cell body also indicate the potential for previously unrecognized therapeutic autoreceptors to inhibit the firing rate of 5-HT neurons, and are benefits.11 For example, the blockade of H receptors by APDs is located postsynaptically in limbic and cortical regions, where they 1 probably related to weight gain and sedation, and a -adrenergic also attenuate firing activity. 5-HT partial agonist activity is 1 1A receptor (AR) blockade is believed to contribute to orthostatic thought to improve negative symptoms and cognitive impairment hypotension and sedation.4 M antagonist actions may cause by enhancing dopamine release in the PFC. In addition, 5-HT 1 1A central (for example, cognitive impairment) and peripheral (for receptor agonists have been reported to possess antidepressant example, constipation and dry mouth) anticholinergic adverse and anxiolytic properties, and to attenuate the EPS liability of D 2 effects. In contrast, as will be mentioned later, M receptor antagonists.11 However, this remains to be proven in clinical 1 agonism might be beneficial in treating the cognitive dysfunction studies. as well as the psychotic symptoms in schizophrenia.56 Muscarinic M1 receptor agonism is relatively unique to clozapine and has NMDA receptor modulation been suggested as one mechanism that might underlie its superior efficacy.57 However, there is no definitive evidence that The ability of non-competitive N-methyl-D-aspartate receptor any neuroreceptors other than the D receptor play a significant (NMDA-R) antagonists, such as phencyclidine (PCP) and ketamine, 2 role in their therapeutic efficacy. to induce a spectrum of positive, negative and cognitive schizophrenia-like symptoms has led to the hypothesis that NMDA-R hypofunction can contribute to the pathophysiology of Neuroprotection schizophrenia.46--48 Structural neuroimaging studies have demonstrated that patho- A wide range of preclinical studies have demonstrated that morphological brain changes, such as ventricular enlargement acute treatment with some SGAs, but not FGAs, selectively and reduction in gray- and white-matter volumes, may be present antagonizes the consequences of experimentally induced NMDA- at the first psychotic episode of schizophrenia and possibly in the R hypofunction at cellular and behavioral levels.49,50 For example, prodromal and premorbid phase.58,59 Longitudinal studies have clozapine and olanzapine, but not haloperidol or raclopride, also found that cortical gray-matter loss may be progressive--- inhibit electrophysiological effects of PCP in sectioned brain tissue, especially early in the course of illness---and is associated with and attenuate NMDA-R antagonist-induced deficits in PPI functional decline.60,61 These findings raise the question of (prepulse inhibition), social behavior and neurotoxicity. In addi- whether APDs could mitigate such pathophysiological progres- tion, ketamine-induced brain metabolic activation is blocked by sion in the early stages of illness. A number of investigators have acute administration of clozapine and olanzapine, but not found that APDs produce neuroplastic changes at structural and haloperidol.51 In contrast, chronic administration of haloperidol molecular levels in the brain.62--65 For example, Lieberman et al.66 blocks PCP-induced deficits in PPI and ketamine-induced brain reported that long-term treatment with olanzapine, but not metabolic activation.52 Thus, adaptive changes elicited by both haloperidol, prevented progressive gray-matter volume reductions FGAs and SGAs appear to attenuate the effects of NMDA-R in patients with first-episode psychosis. Studies with similar results antagonists.11 have been reported by the Utrecht group, indicating the specific The well-documented effects of SGAs on responses to NMDA-R neuroprotective value of APD treatment and particularly with antagonists raise the possibility that the therapeutic action of clozapine and olanzapine.67,68 Although the precise mechanisms these agents may involve a correction of NMDA-R hypofunction. by which APDs may arrest or delay the pathomorphological However, since none of the SGAs demonstrate direct affinity for process remain unknown, there is growing evidence that some NMDA-R, the mechanism by which these effects might be SGAs, both in vitro and in vivo, may have neuroprotective effects, mediated is poorly understood. Animal studies have reported including the production of neurotrophic factors, the attenuation variable effects (increases, decreases, no change) on NMDA-R of glutamate excitotoxicity, oxidative stress and apoptosis and the density in various brain regions after chronic antipsychotic enhancement of neurogenesis and connectivity, all of which could

Molecular Psychiatry (2012), 1206 -- 1227 & 2012 Macmillan Publishers Limited Pharmacological treatment of schizophrenia S Miyamoto et al 1209 GlyT1 Inhibitor Glial cell Presynaptic mGluR2/3 (glycinergic) GlyT2 GlyT1 Glycine cAMP Inhibitory transmission Cl– Kainate Postsynaptic Ampakines

mGluR2/3 Na+ mGluR4/8 AMPA BDNF Synaptic mGluR2/3 CREB Plasticity agonist Neurotrophins 2+ (-) NMDA Ca Presynaptic Glutamate Excitatory transmission (glutamatergic) (Glu) IP3/DAG mGluR5 PAM Glycine Gln Glu VGluT site PAM NAC (+) mGluR1/5 Glu EAAT Cystine NAC mGluR1/5 Cystine – Cystine Glial cell Glutamine(Gln) Glu (astrocyte) glutamate exchange Glu Cystine Glutathione Cystine

Figure 1. Glutamatergic synaptic transmission and treatment targets. In the central nervous system, glutamate (Glu) is released from pre- synaptic neurons and acts with postsynaptic glutamate receptors, including N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid (AMPA) and kainate receptors. These ionotropic glutamate receptors are responsible primarily for fast synaptic transmission. Released glutamate is taken up by the excitatory amino-acid transporter (EAAT) on astrocytes, where it is converted to glutamine (Gln) and transported back to the presynaptic neurons. Glutamine is reconverted to glutamate and packaged into vesicles via the vesicular glutamate transporter (VGluT). Glycine is an inhibitory amino acid and obligatory co-agonist at the NMDA receptor (NMDA-R) complex. Positive allosteric modulators (PAM) on the glycine site potentiate the effect of NMDA-R-mediated transmission. Glycine is taken up by glycine transporters (GlyT). GlyT1 inhibitors increase NMDA-R-mediated transmission. Ampakines allosterically enhance AMPA receptors and facilitate synaptic plasticity. Glutamate signaling also occurs through metabotropic glutamate receptors (mGluRs). Group I mGluRs (mGluR1/5) induce inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). These excitatory Ca2 þ flows activate cAMP-response element- binding protein (CREB), and neurotrophins such as brain-derived neurotrophic factor (BDNF), to regulate synaptic plasticity. mGluR5 PAMs can enhance such excitatory transmission. Group II mGluRs (mGluR2/3) regulate glutamate on presynaptic neurons and mGluR2/3 agonists inhibit glutamate release. Low extrasynaptic concentrations of glutamate are maintained in part by a transport system that mediates the exchange of glutamate for cystine. This cystine-glutamate antiporter produces glutathione, the primary endogenous antioxidant, for which N-acetyl- cysteine (NAC) is a precursor. provide a rationale for pharmacological intervention with SGAs phenothiazines (for example, chlorpromazine) and a heteroge- during the initial stages of schizophrenia.65,66 However, a recent neous third group.74 large-scale longitudinal observational study of first-episode The ability of FGAs to reduce positive symptoms and risk for schizophrenia reported that APDs had a slight but significant relapse markedly improved clinical outcomes for many patients association with brain tissue volume loss over time.69 This finding with schizophrenia. However, B30% of patients with acutely is further supported by a controlled study in macaque monkeys in exacerbated symptoms have little or no response to FGAs, and up which chronic administration of both olanzapine and haloperidol to 50% have only a partial response.75,76 Moreover, FGAs offer induced frontoparietal volume reductions associated with de- little benefit for negative symptoms or cognitive impairment. creased astrocyte numbers.70--72 Thus, further well-designed FGAs produce a variety of side effects including acute EPS, clinical studies in first-episode patients are required to determine hyperprolactinemia, as well as TD (tardive dyskinesia) associated whether specific APDs may produce neuroprotective or possibly with long-term exposure, which are caused by the blockade of neurotoxic effects. Also, the clinical relevance of subtle changes in dopaminergic nigrostrial pathways.4 Low-potency FGAs possess white and gray matter remains to be determined. high affinities for muscarinic M1 Ach, histaminergic H1 and a1 norepinephrine receptors, which can result in partially distinctive and overlapping side-effect profiles (for example, cognitive PHARMACOLOGICAL AND CLINICAL PROFILES OF APDS deficits and sedation).77 Largely because of the side-effect risks First-generation APDs of EPS, some have argued that the only patients for whom FGAs FGAs, also known as typical APDs, possess high affinity for and act are clearly preferable are those with a history of good response 73 78 as full antagonists at D2 receptors, and are associated with a and tolerable side effects during treatment with an FGA. high incidence of EPS and hyperprolactinemia.4 FGAs can be classified as either high- or low-potency medications with the former having a greater affinity for D2 receptors than the Second- and third-generation APDs latter.73 Based on their chemical structure, FGAs may be divided Clozapine, the prototypical SGA or atypical antipsychotic, was into three groups: butyrophenones (for example, haloperidol), found to be an effective antipsychotic and did not cause EPS.

& 2012 Macmillan Publishers Limited Molecular Psychiatry (2012), 1206 -- 1227 Pharmacological treatment of schizophrenia S Miyamoto et al 1210 Moreover, clozapine proved to be superior to chlorpromazine in of speech, anhedonia and apathy. They may be divided into three treatment-resistant schizophrenia. However, clozapine also was subtypes that are often difficult to distinguish: (1) primary associated with an elevated risk of potentially lethal hematotoxi- enduring (or deficit), (2) primary non-enduring and (3) negative city (agranulocytosis).79 Consequently, additional SGAs were symptoms that are secondary to other causes, such as depression, introduced including risperidone, olanzapine, quetiapine and positive symptoms, EPS, substance abuse or iatrogenic effects ziprasidone in an effort to provide the therapeutic benefits of such as understimulation during long-term hospitalization.88,89 clozapine without the associated risk of blood dyscrasias.11,80 Approximately 70% of schizophrenic patients develop primary Aripiprazole is another pharmacologically different agent that is negative symptoms before the onset of positive symptoms.90 To sometimes termed a TGA.81 Lower incidence of EPS is the major date, there are no effective treatments for primary negative advantage of NGAs (new-generation antipsychotics) compared symptoms. with most FGAs.8 However, most SGAs have an increased risk of In a meta-analysis by Leucht et al.,8 four SGAs (amisulpiride, causing weight gain and disturbances in glucose and lipid clozapine, olanzapine and risperidone) were more efficacious than metabolism. FGAs for treatment of negative symptoms. However, the other five During the past decade, additional SGAs, including paliper- SGAs (aripiprazole, quetiapine, sertindole, ziprasidone and zote- idone, asenapine, iloperidone and lurasidone, have been ap- pine) were only as efficacious as FGAs. It should be noted that proved by the United States (US) Food and Drug Administration few of the studies included have specifically examined the effect (FDA).82 The pharmacology of these drugs is similar to other SGAs of SGAs on primary negative symptoms. Thus, a direct bene- except that lurasidone is notable for its high affinity for the ficial effect of SGAs on primary negative symptoms has not 83 5-HT7 receptors. However, the comparative effectiveness of been established with the possible exception of low doses of these agents to existing FGAs and NGAs has yet to be determined. amisulpride.91 Some SGAs may be effective for secondary negative symptoms, since they have been proposed to show greater effects Efficacy on psychotic symptoms. In a recent meta-analysis of on symptoms of depression and anxiety and have lower risk randomized controlled trials (RCTs) comparing SGAs with FGAs, of EPS. four SGAs (amisulpiride, clozapine, olanzapine and risperidone) Phase 2 of the CATIE trial provides a notable opportunity to were more efficacious than FGAs for treatment of positive compare the effectiveness of multiple SGAs in the treatment of symptoms, with small-to-medium effect sizes.8 However, the negative symptoms. Patients who had discontinued their phase 1 other SGAs (aripiprazole, quetiapine, sertindole, ziprasidone APD due to lack of efficacy were randomized either to clozapine or and zotepine) were only as efficacious as FGAs. Thus, there may to another SGA. There were no significant differences in PANSS be a modest advantage for some, but not all SGAs compared negative symptom subscores either between or within treatment with FGAs. groups at baseline, 3 and 6 months.92 At 6 months, however, There have been three large long-term pragmatic studies, clozapine showed a trend toward greater reduction in negative which compared the effectiveness of SGAs with FGAs. The Clinical symptom scores, as compared with other SGAs. Patients who Antipsychotic Trials of Intervention Effectiveness (CATIE) study had discontinued their phase 1 APD due to intolerable side compared the effectiveness of the FGA perphenazine with the effects were randomized to olanzapine, quetiapine, risperidone or SGAs olanzapine, quetiapine, risperidone and ziprasidone in 1493 ziprasidone. There were similarly no significant differences in chronic schizophrenic outpatients for up to 18 months of PANSS negative symptom subscores among treatment groups at treatment.80 Results from the first phase of this study demon- 12 months.93 Thus, the results of the CATIE study suggest only strated that olanzapine had a significant advantage regarding all slight efficacy for SGAs in the treatment of negative symptoms of cause discontinuation, the primary study outcome measure. The chronic schizophrenia, with a probable small advantage for time to the discontinuation of treatment for lack of efficacy was clozapine. significantly longer in the olanzapine group than in the FGA perphenazine group (hazard ratio, 0.47), the quetiapine group Efficacy on cognition. Patients with schizophrenia typically per- (hazard ratio, 0.41), the risperidone group (hazard ratio, 0.45) or form one to two standard deviations below healthy volunteers on the ziprasidone group (hazard ratio, 0.59). However, the other SGA a variety of neuropsychological measures, particularly those that drugs did not differ from perphenazine on the primary outcome assess attention, verbal skills, processing speed and executive measure and all five medications displayed comparable changes function.94 Given that cognitive deficits are among the strongest in Positive and Negative Syndrome Scale (PANSS) positive scores. predictors of functional outcome in schizophrenia,95 treatments In the CUtLASS (Cost Utility of the Latest Antipsychotic Drugs in for these symptoms are currently considered to be the most Schizophrenia Study), in which FGAs and SGAs were compared as urgently needed. classes (most patients in the first group were treated with sulpiride In a meta-analysis of 14 controlled studies with random and most in the second group with olanzapine), no significant assignment to treatment with either FGA or SGA (clozapine, differences in positive symptoms were observed between patients olanzapine, quetiapine or risperidone), SGAs were superior to treated with FGAs and those with SGAs.84 FGAs, haloperidol in particular, for ameliorating overall cognitive In a third large pragmatic trial, the EUFEST (European First- function, and specific improvements were noted in learning and Episode Schizophrenia Trial)85,86 close to 500 first-episode patients processing speed.94 In another meta-analysis focusing on long- were randomly allocated to open-label treatment with either low- term memory measures, SGAs showed benefits over FGAs, with an dose haloperidol or one of four SGAs (amisulpride, olanzapine, effect size for differential improvement of o0.20.96 It is unclear, quetiapine or ziprasidone) for 1 year. Compared with haloperidol, however, whether the improvements observed with SGAs in these all SGAs showed a significantly lower risk for early study studies represent true cognitive enhancement or only a relative discontinuation, the primary outcome variable but there were reduction in EPS- and anticholinergic-related cognitive effects, as no group differences in PANSS total scores. In summary, CATIE, compared with FGAs.97,98 Also, it is possible that the improve- CUtLASS and EUFEST did not provide unequivocal evidence to ments may, at least in part, be due to practice effects.99 support the superiority of SGAs over FGAs or of any individual There has been a debate as to whether lower doses of FGAs non-clozapine antipsychotic over another on positive or overall might show comparable efficacy to SGAs for cognitive symptoms symptoms.87 of schizophrenia.100 Several studies with improved methodology suggest that low doses of haloperidol can produce cognitive Efficacy on negative symptoms. Negative symptoms of schizo- outcomes that approximate the SGA comparator.101--105 Other phrenia include affective blunting, emotional withdrawal, poverty studies have also found mild benefits in cognitive performance

Molecular Psychiatry (2012), 1206 -- 1227 & 2012 Macmillan Publishers Limited Pharmacological treatment of schizophrenia S Miyamoto et al 1211 with certain FGAs.106 The most compelling of these is the CATIE strategy commonly employed in the management of such trial, in which perphenazine yielded more improvement in patients is to augment clozapine with other psychotropic cognition after 18 months than any of the phase 1 SGAs.107 medications. However, the evidence supporting this practice is Notably, the magnitude of cognitive improvement was small and very limited, and no drug has consistently demonstrated efficacy probably not clinically meaningful for all APDs assessed in this as an adjuvant to clozapine in treatment-resistant schizophrenia.4 analysis. Taken together, FGAs and SGAs, when dosed properly, Efficacy on disease-related complications and behavioral distur- may yield at most modest improvements in cognitive deficits of bances (suicide, violence, substance abuse). Suicidal behavior is schizophrenia. Neither class appears to be clearly superior to the common in schizophrenia. Approximately 50% of patients with other. As described later, the use of adjunctive pharmacological schizophrenia or schizoaffective disorder have suicidal beha- agents might offer a viable approach, because they can be used to vior,116 and about 5% ‘succeed’ in taking their own lives.117 The modulate specific neurotransmitter systems (for example, gluta- InterSePT (International Suicide Prevention Trial), a double-blind mate, Ach) hypothesized to be associated with particular cognitive RCT, compared suicidal behavior in 980 patients at relatively high functions. risk for suicide, who were randomized to clozapine or olanzapine treatment and followed for up to 2 years.116 Suicidal behavior was Efficacy on mood symptoms. Mood symptoms, depression in significantly less common in patients treated with clozapine. particular but also mania, can occur in schizophrenia. Depressive Although the InterSePT study has been criticized for certain symptoms are particularly common in all phases of the illness, and methodological limitations, such as lack of blinding among are associated with poorer outcomes, impaired social and patients and clinicians, the results were compelling enough to vocational functioning, lower quality of life and an increased risk garner the US FDA’s approval of an indication unique to clozapine: of relapse and suicide.108 The modal rate of comorbid depression reduction of the risk of recurrent suicidal behavior in patients with in schizophrenia has been reported to be 25%.109 schizophrenia or schizoaffective disorder. In a secondary analysis A meta-analysis demonstrated that five SGAs (amisulpride, of a large-scale safely study, the authors describe a lower suicide aripiprazole, clozapine, olanzapine and quetiapine) were more attempt risk for patients treated with sertindole compared with efficacious than FGAs for treatment of depressive symptoms, risperidone.118 whereas risperidone was not.8 However, it needs to be noted that Violent behavior is observed in a minority of patients with most of the studies included were not primarily designed to schizophrenia. It is etiologically heterogeneous (for example, evaluate depressive symptoms. Therefore, prospective trials with positive symptoms, impaired impulse control, comorbid person- change in depression as the primary outcome are needed. ality disorders).119 Current treatment of persistent violence in schizophrenia relies on APDs and mood stabilizers. The evidence Efficacy for treatment-resistant schizophrenia. One-fifth to one- of efficacy is relatively strong for clozapine120,121 and olanza- third of patients with schizophrenia who receive an adequate trial pine,122 but inconsistent for other SGAs.119 In the CATIE trial, SGAs fail to respond to prescribed APDs, and are considered ‘treatment- did not reduce violence more than perphenazine.123 The resistant’.110,111 Additional subsets of patients may be treatment- antihostility and/or antiaggressive effects of clozapine appear to intolerant, treatment-non-compliant, slow to respond or only be independent of general antipsychotic effects. partial responders.111 Nearly 50% of patients with schizophrenia have a lifetime Clozapine has been most extensively studied in treatment- history of substance use disorder and substance abuse is a potent resistant schizophrenia patients, and it is the only APD approved determinant for poor outcome in schizophrenia.124 To date, by the US FDA for this indication.79,111 The drug’s singular effi- preliminary research has been conducted in patients with cacy in treatment resistance was first conclusively demon- schizophrenia and co-occurring substance use disorders, and has strated in a pivotal study in which 30% of patients receiving suggested possible beneficial effects for aripiprazole, clozapine, clozapine responded at 6 weeks, compared with 7% treated with olanzapine, risperidone and quetiapine.125 However, all of these chlorpromazine.79 A meta-analysis of seven controlled trials drugs require further research with RCTs to fully assess their comparing clozapine to an FGA in treatment-resistant schizo- impact on such population in schizophrenia. phrenia found clozapine to be superior to FGAs in terms of overall psychopathology reduction, EPS and compliance, although the Safety. In general, SGAs offer the advantage of fewer acute EPS magnitude of the drug’s therapeutic effect was not consistently and reduced likelihood of TD, but produce greater metabolic side robust.112 effects than FGAs.126 A meta-analysis demonstrated that all SGAs In the past decade, a number of double-blind RCTs have were associated with fewer EPS than haloperidol (even at low reported the short-term (4--18 weeks) efficacy of clozapine to be doses).8 However, with the exception of clozapine, olanzapine and comparable or greater than the other SGAs in treatment-resistant risperidone, SGAs were not more effective than low-potency FGAs. schizophrenia.113 The second phase of the CATIE study found that Among SGAs, amisulpride, paliperidone and risperidone have switching to open-label treatment with clozapine was more the potential to increase serum prolactin levels to an extent effective than to another SGA drugs in patients with schizophrenia comparable to FGAs.4 In contrast, quetiapine, and clozapine, do who failed to improve after initial treatment with an SGA.92 In the not elevate serum prolactin levels, while aripiprazole actually CUtLASS 2 trial comparing the effectiveness of clozapine with that suppresses prolactin. Olanzapine causes hyperprolactinemia only of other SGAs (amisulpride, olanzapine, quetiapine and risper- at high doses.127 idone) in patients with schizophrenia with clinician-defined poor Marked differences in liability for metabolic side effects are seen response to 2 or more APDs, clozapine showed a statistically between the different SGAs. A meta-analysis by Leucht et al.8 significant advantage with respect to total PANSS score, but not found that with the exception of aripiprazole and ziprasidone, quality of life, over 1 year.114,115 SGAs differentially induced more weight gain than haloperidol but Because of clozapine’s superior efficacy relative to FGAs and not the low-potency FGAs. In another recent meta-analysis of 48 probably other SGAs, clozapine monotherapy represents the ‘gold studies, clozapine and olanzapine produced the greatest elevation standard’ for treatment of patients with refractory schizophrenia. in weight, cholesterol and glucose followed by quetiapine, Unfortunately, the risk of serious side effects and the need for risperidone and sertindole with intermediate elevations. Amisul- regular blood monitoring render it unsuitable as a first-line medi- pride and aripiprazole demonstrated lower elevations and cation. Even with clozapine treatment, a considerable number of ziprasidone the lowest.128 These safety concerns are associated patients do not respond or are only partially responsive. Thus, one with potential long-term health risks for patients as well as

& 2012 Macmillan Publishers Limited Molecular Psychiatry (2012), 1206 -- 1227 Pharmacological treatment of schizophrenia S Miyamoto et al 1212 decreased adherence to treatment regimens that may lead to Preclinical studies have suggested that its propensity for EPS is relapse. low and that it may have pro-cognitive properties. While modest, dose-dependent QTc prolongation has been With the exception of aripiprazole and cariprazine, develop- reported with many antipsychotics; several FGAs (for example, ment of D2 partial agonists for schizophrenia has been de- haloperidol, mesoridazine, pimozide, thioridazine) and SGAs emphasized due to their inferior therapeutic profile as compared (sertindole, ziprasidone) can increase the QTc interval consider- with other marketed APDs. The intrinsic activity of D2-like receptor ably, and all of these have been associated with fatal or potentially agonism may be critical in determining the efficacy and fatal arrhythmias.129,130 In 2005, the US FDA issued a black box tolerability of such agents, and on which symptom dimen- warning regarding an increased risk of mortality associated with sions.151,152 the use of SGAs in elderly patients with dementia. On the basis of SSR-181507 is a new partial D2 agonist and displays antagonist 131,132 further observational research, the FDA extended this activity at D2 receptors as well as agonist activity at 5-HT1A warning to FGAs in 2008. A large retrospective cohort study receptors.153 Preclinical studies suggest that SSR-181507 has demonstrated that current users of FGAs and SGAs had a similar, antipsychotic-like activity in the absence of extrapyramidal signs dose-related increased risk of sudden cardiac death.133 The and cognitive deficits, with the additional benefit of apparent 154 evidence for other clinically relevant adverse events, such as antidepressant and anxiolytic activities. OPC-34712 is a novel D2 sedation, sexual disturbances, hepatotoxic effects and orthostatic partial agonist and exhibits enhanced affinity for 5-HT1A, 5-HT2A, 155 hypotension is limited and variable, especially with regard to 5-HT7 serotonin receptors. It is in phase III testing for differential risks between the different APDs.4 schizophrenia.

D3 receptor antagonist. The D3 receptor has cortico-limbic distri- CURRENT AND FUTURE DRUG DEVELOPMENT STRATEGIES bution and is of interest because most APDs have high affinity for this receptor and it represents a promising target for enhancing Dopaminergic agents 156 cognition. Selective D3 antagonists have been developed D1 receptor antagonist or agonist. Earlier preclinical studies (S33084, S33138, SB-277011-A, AVE5997),157--159 but there are demonstrated that selective D1-like antagonists are active in most limited animal behavioral data at this time. As aforementioned, conventional rodent models predictive of antipsychotic-like 150 134 cariprazine has B10-fold higher affinity for D3 vs D2 receptors. activity. However, clinical trials of the selective D1-like antago- 135,136 137 In a preliminary study, ( þ )-UH232, a D3 antagonist, actually nist SCH39166 and NNC 01-0687 failed to demonstrate worsened psychotic symptoms in drug-free patients with schizo- antipsychotic properties (Table 1). 160 phrenia. In a recent 6-week double-blind RCT, a selective D3 Dopamine D1 receptors play an important role in cognitive antagonist ABT-925, used as monotherapy, failed to demonstrate function such as working memory. It is postulated that either any significant benefits for psychopathological symptoms in insufficient or excessive D1-like receptor stimulation is deleterious patients with acute exacerbation of schizophrenia, although the to cognitive function of the PFC, thus an ‘optimal’ level of D1-like doses of ABT-925 used might have been too low to produce a receptor activation is necessary for normal cognitive func- 161 138,139 measurable antipsychotic effect. Further controlled trials of D3 tion. Low doses of selective full D1-like receptor agonists, antagonists will help clarify the differential contributions of the D2 such as dihydrexidine (DAR-0100), A77636 and SKF81297, have and D receptor in the mediation of antipsychotic effect (Table 1). been reported to have cognitive-enhancing actions in rodents 3 and non-human primates.140--143 In a pilot study, a single D4 receptor antagonist.D4 receptor antagonism has been propo- subcutaneous dose of dihydrexidine was well tolerated in patients sed as a novel target and possibly contributes to the superior with schizophrenia, but did not produce delayed clinical or neuro- 144 efficacy and atypical profile of clozapine. However, negative psychological improvements. However, it induced a signi- 162 studies for the highly selective D4 antagonist L-745,870, the ficant increase in prefrontal brain activity (perfusion) compared 5-HT /D antagonist finanserin163 and sonepiprazole164 suggest with placebo, suggesting that dihydrexidine and other full 2A 4 that the selective D4 receptor antagonist mechanism is ineffective, D1-like receptor agonists may be able to modulate prefrontal at least as monotherapy.11 dopaminergic function in schizophrenia.145 It should be noted, however, that chronic administration of full D1-like receptor agonists may lead to down-regulation of D1 receptors, which Serotonergic agents 56 could exacerbate cognitive dysfunction in schizophrenia. Con- 5-HT1A receptor agonist. Preclinical studies suggest that 5-HT1A sequently, the dosing strategy of low and intermittent adminis- agonists may potentiate the antipsychotic activity of dopamine 165 tration has been proposed as an alternative to conventional antagonists. Further, 5-HT1A receptors are up-regulated in 146 dosing. postmortem PFC in schizophrenia, suggesting a deficit in 5-HT1A 166,167 function. Interestingly, the 5-HT1A partial agonists tandospir- one and buspirone can enhance certain domains of cognition in D2 receptor partial agonist. Several clinical studies with selective patients receiving FGAs or SGAs.168,169 Based on these data, D2-like receptor partial agonists, including talipexole, preclamol, roxindole and pramipexole, failed to demonstrate a clear thera- compounds that possess 5-HT1A agonism combined with D2-like peutic effect on positive symptoms of schizophrenia, although receptor antagonism, including SLV-313, SSR-181507, F-15063, S-16924, BSF 190555 (BTS 79018) and RGH-188, are being the results suggested possible beneficial activity against 148,170 negative symptoms.147,148 In addition, the use of higher doses of developed as potential APDs. It is suggested that the balance between D2-like receptor antagonism and 5-HT1A recep- partial D2 agonists is associated with worsening of positive symptoms, probably related to the activation of postsynaptic tor agonism may be critical in determining the efficacy of these compounds.170 D2-like receptors. Cariprazine (RGH-188), a novel putative APD, is currently in phase III clinical trials. It exhibits partial agonism at D2/D3 recep- 5-HT2A receptor antagonist. As already described, 5-HT2A antago- 171 tors, with preferential binding to D3 receptors, and partial agonism nists may contribute to ‘normalizing’ levels of dopamine release 149,150 at 5-HT1A receptors. It showed lower affinity for D2 or higher and theoretically possess antipsychotic activity, and also improve 150 172 affinity for D3 receptors compared with aripiprazole. Cariprazine negative symptoms of schizophrenia. Three RCTs have demon- displayed partial agonist activity at D2/D3 receptors, with similar strated that addition of ritanserin, a relatively selective 5-HT2A/2C intrinsic activity but higher potency than those of aripiprazole.150 antagonist, to an FGA, produced significant reductions in negative

Molecular Psychiatry (2012), 1206 -- 1227 & 2012 Macmillan Publishers Limited Pharmacological treatment of schizophrenia S Miyamoto et al 1213 Table 1. Benefits and limitations of agonism or antagonism at dopamine and serotonin receptors

Receptors Mechanisms Benefits Limitations

D1 Agonism Pro-cognitive, modulates prefrontal dopamine Could exacerbate psychotic symptoms and lead function to cognitive impairment with chronic administration Antagonism Antipsychotic-like activity (rodent models) No antipsychotic effect (in clinical trials) D2 Partial agonism Reduced EPS and hyperprolactinemia Insufficient antipsychotic effect? Antagonism Antipsychotic, antimanic, antiaggression effect EPS, hyperprolactinemia, cognitive impairment D3 Agonism Reduced EPS Worsens psychotic symptoms? Antagonism Pro-cognitive, antipsychotic effect? Improves Limited effect on psychotic symptoms? negative symptoms? D4 Antagonism Pro-cognitive? No antipsychotic effect (at least in monotherapy) 5-HT1A Agonism or Antidepressant, anxiolytic, pro-cognitive, Cognitive impairment? partial agonism reduced EPS Antagonism Anxiolytic 5-HT2A Antagonism or Antidepressant, improves negative symptoms? No antipsychotic effect (in monotherapy) inverse agonism Reduced EPS 5-HT2C Agonism Antipsychotic-like activity (rodent models), Worsens cognition and cause EPS anorexic Antagonism Pro-cognitive? Weight gain 5-HT3 Antagonism Pro-cognitive, improves negative symptoms Does not improve global cognitive function and positive symptoms 5-HT4 Agonism Pro-cognitive (with cholinesterase inhibitors)? 5-HT6 Antagonism Pro-cognitive, improves negative symptoms? 5-HT7 Antagonism Antidepressant, pro-cognitive, antipsychotic-like activity (rodent models) Abbreviations: D, dopamine; EPS, extrapyramidal symptoms; 5-HT, serotonin.

symptoms and depressed mood in chronic schizophrenia.173--175 placebo and olanzapine controlled phase II study with the full Moreover, ritanserin potentiated the clinical efficacy of risperi- agonist vabicaserin showed a significant improvement over done on negative symptoms.176 However, the development placebo for the 200 mg dose on PANSS total and positive scores of M-100907, a selective 5-HT2A antagonist, was discontinued as well as on the Clinical Global Impression Scale (CGI), but 400 mg after two phase III clinical trials demonstrated lower antipsychotic per day did not separate from placebo.185 efficacy compared with haloperidol.42,43 A phase II trial of the 5-HT2A/2C antagonist SR-46349B also demonstrated efficacy 5-HT3 receptor antagonist. The 5-HT3 receptors tonically inhibit the superior to placebo but inferior to haloperidol.177 Current data release of Ach and also inhibit g-aminobutyric acid (GABA) 186 are insufficient to adequately judge the efficacy of 5-HT2A inhibitory interneurons. In preclinical models, 5-HT3 antagonists antagonists, but monotherapy with such agents may not be a have been shown to have a broad spectrum of psychotropic viable treatment strategy (Table 1). effects, including correcting psychotic-like behavior, improving cognitive deficits and antagonizing locomotor hyperactivity 187 5-HT2A receptor inverse agonist. It has been recently recognized induced by dopamine stimulants. Adjunctive treatment with that many SGAs are inverse agonists at the 5-HT2A receptor rather ondansetron, a highly selective 5-HT3 antagonist, was shown to be than neutral antagonists.178 In contrast to antagonists, inverse effective for auditory P50 deficits,188 negative symptoms and agonists lack negative intrinsic efficacy and can attenuate basal cognitive impairments (visual memory) in patients with chronic constitutive signaling activity and block only agonist-induced schizophrenia on stable antipsychotic therapy.189--191 However, 179 responses. Pimavanserin tartrate (ACP-103) is the first 5-HT2A ondansetron did not improve global cognitive functioning or inverse agonist to enter clinical trials as a treatment for schizo- positive symptoms.190 Replication with larger sample sizes will be phrenia. In phase II clinical trials, pimavanserin seemed to be safe, necessary before endorsing a role for adjunctive ondansetron in well tolerated and potentiated the therapeutic effects of low-dose schizophrenia. risperidone, and reduced haloperidol-induced akathisia.180 5-HT4 receptor agonist. 5-HT4 receptors, expressed in nigrostriatal 5-HT2C receptor agonist. The 5-HT2C receptor possesses a unique and mesolimbic systems, can modulate the release of Ach, 181 192 ability to tonically regulate dopamine release and play a critical dopamine, GABA and 5-HT. 5-HT4 receptor agonists (for role in mediating the interaction between serotonergic and example, BIMU1, RS67333, RS17017) were shown to enhance 182 193 dopaminergic systems. 5-HT2C receptor agonists inhibit dopa- memory in several animal models. The combined administra- 181 mine release in the mesolimbic dopamine pathways. Animal tion of partial 5-HT4 receptor agonists (for example, RS67333, studies of the 5-HT2C receptor agonists WAY-163909 and CP- SL65.0155) with cholinesterase inhibitors may enhance cognition 809,101 showed that they can attenuate psychostimulant- or to a greater extent than either treatment alone.194,195 Although 183,184 NMDA-R antagonist-induced behaviors. Furthermore, CP- there have been no clinical trials of 5-HT4 receptor agonists as 809,101 was active in novel object recognition, an animal model add-on therapy in patients with schizophrenia, 5-HT4 receptors 184 of cognitive function. Thus, 5-HT2C receptor agonists appear to may be an attractive target for improving cognition in schizo- have a pharmacological profile similar to that of the SGAs and may phrenia, since currently available SGAs generally lack significant 193,196 be a novel approach in the treatment of schizophrenia. However, affinity for 5-HT4 receptors. there is a concern that 5-HT2C receptor agonists may worsen cognition and cause EPS by reducing dopaminergic transmission 5-HT6 receptor antagonist. 5-HT6 receptors are almost exclusively in the mesocortical and nigrostriatal pathways.27 A 6-week expressed in the central nervous system (CNS), particularly in areas

& 2012 Macmillan Publishers Limited Molecular Psychiatry (2012), 1206 -- 1227 Pharmacological treatment of schizophrenia S Miyamoto et al 1214 197,198 11 associated with learning and memory. While 5-HT6 receptor compounds that increase NMDA-R transmission. Glycine is a function has not been fully elucidated, its distribution and high positive allosteric modulator (PAM) and obligatory co-agonist at affinity for certain SGAs (for example, clozapine, olanzapine) the NMDA-R (Figure 1).207 The glycine allosteric regulatory site support the hypothesis that 5-HT6 ligands may have a therapeutic agonists, including glycine, D-cycloserine, D-serine and D-alanine, role in schizophrenia.199 In fact, there is an increasing body of have been studied as potential drugs to augment NMDA-R- evidence, suggesting that 5-HT6 receptor blockade improves mediated neurotransmission and treat the symptoms of schizo- 198 memory processes. Preclinical studies indicate that 5-HT6 phrenia. In a recent meta-analysis of 26 double-blind, placebo- receptor antagonists, including SB-271046, SB-258510A, SB- controlled studies, adjuvant glycine therapy was found to be 399885, can enhance the release of cortical dopamine and cortical effective in reducing total psychopathology, which was assessed and hippocampal Ach and glutamate, and may also have longer- by PANSS total scale or BPRS (Brief Psychiatric Rating Scale), 197,198 208 term neurotrophic actions in normal rats. Moreover, 5-HT6 positive symptoms and depressive symptoms. D-cycloserine, a receptor antagonists can restore cognitive impairments in several partial glycine site agonist, was not effective in any symptom 200--202 animal models of schizophrenia. Interestingly, SB-399885 domains. D-serine, a full glycine site agonist, was found effective in can potentiate haloperidol and risperidone-induced dopamine total psychopathology, negative symptoms and cognitive symp- 203 efflux in medial PFC and hippocampus. These data suggest a toms. D-serine is more permeable than glycine at the blood--brain 209 possible therapeutic role for 5-HT6 antagonists, as an adjunct to barrier, thus requiring a lower dosage. A recent trial, however, antipsychotics, to enhance cognitive function and/or to treat failed to show beneficial effects of D-serine on any clinical 210 negative symptoms in schizophrenia (Table 1). The 5-HT6 anta- symptoms in patients with chronic schizophrenia. D-alanine, also gonist GSK (SB)-742457 is currently in phase II clinical trials.202 acting as a full agonist on the glycine site of the NMDA-R, has been reported to improve both positive and negative symptoms.211 Furthermore, these glycine site agonists added onto SGA (excluding 5-HT7 receptor antagonist. The 5-HT7 receptor exerts important 199 clozapine) were significantly better than FGA or clozapine, in roles in circadian rhythms, mood and sleep. 5-HT7 receptors are 208 found in relatively high concentrations in hippocampus, thalamus improving negative symptoms and total psychopathology. and hypothalamus, with generally lower levels in cortex and However, neither glycine nor D-cycloserine have shown 204 consistent benefits on any aspects of cognitive function in amygdala. As with 5-HT6 receptors, 5-HT7 receptors bind certain 13 SGAs (for example, amisulpride, clozapine, lurasidone, risperidone) schizophrenia. Indeed, the results of the largest 16-week RCT with high affinity and may have important roles in learning of adjunctive glycine and D-cycloserine, the CONSIST (Cognitive and memory as well as antidepressant actions.199,205 Moreover, and Negative Symptoms in Schizophrenia Trial), suggest that neither glycine nor D-cycloserine are effective for treating negative the specific 5-HT7 receptor antagonist SB-258741 produced an 212 unequivocal positive result in one animal model for positive symptoms or cognitive impairments. symptoms of schizophrenia.206 Evaluation of its therapeutic Taken together, these results suggest that while adjunctive potential is eagerly awaited in patients with schizophrenia. glycine and maybe D-alanine appear to convey some benefit against positive symptoms, this could not be demonstrated for any other of the glycine site modulators. Moreover, no Glutamatergic agents consistent benefit was seen on negative and cognitive symptoms. Glycine site allosteric modulator. The NMDA-R hypofunction D-Cycloserine was not found effective and the evidence for hypothesis of schizophrenia predicts a therapeutic effect for D-serine is not clear (Table 2).

Table 2. Benefits and limitations of agonism or antagonism at glutamate and other receptors

Receptors Mechanisms Benefits Limitations

NMDA Agonism Improves negative symptoms Neurotoxicity, epilepsy Positive allosteric modulate at Antipsychotic effect, pro-cognitive? glycine site Antagonism Neuroprotective effect, pro-cognitive, Worsens psychotic symptoms, antidepressant cognitive impairment AMPA Agonism or partial agonism Pro-cognitive? Antagonism Antiepileptic action mGluR2/3 Agonism Antipsychotic effect, decreases glutamate Cognitive impairment? release, mood stabilization Antagonism Antidepressant mGluR1/5 Positive allosteric modulation Antipsychotic-like effect, pro-cognitive? Negative allosteric modulation Antidepressant, anxiolytic? Cognitive impairment? Worsens psychotic symptoms? GABAA a2/a3 Partial agonism Pro-cognitive? Sedation, cognitive impairment? adrenergic a2 Agonism Pro-cognitive, sedative effect, pain-relieving Hypotension, sedation qualities Antagonism Antidepressant, increases alertness and blood Cognitive impairment? pressure a7 nACh Agonism or partial agonism Pro-cognitive, improves negative symptoms a4b2 nACh Agonism Pro-cognitive, relieves smoking addiction Activates psychotic or mood symptoms M1 Partial agonism Antipsychotic effect, pro-cognitive? Causes EPS? Antagonism Reduced EPS Anticholinergic effect H1 Antagonism Sedative effect Sedation, weight gain H3 Antagonism or inverse agonism Antipsychotic effect, pro-cognitive? Abbreviations: AMPA, a-amino-3-hydroxy-5-methyl-isoxazole-4-propipnic acid; EPS, extrapyramidal symptoms; GABA, g-aminobutyric acid; H, histamine; mGluR, metabotropic glutamate receptor; nACh, nicotinic acetylcholine; NMDA, N-methyl-d-aspartate.

Molecular Psychiatry (2012), 1206 -- 1227 & 2012 Macmillan Publishers Limited Pharmacological treatment of schizophrenia S Miyamoto et al 1215 Glycine transporter inhibitor. Glycine transporters, GlyT1 and GlyT2, mGluR5 are located in cerebral cortex and nucleus accumbens are expressed on both neuronal and glial cells in the CNS and are expressed postsynaptically on glial cells (Figure 1). (Figure 1). GlyT1 is thought to regulate the concentration of mGluR5 have been shown to enhance NMDA-R function in vitro, extracellular glycine at excitatory synapses containing NMDA- and activation of mGluR5 can improve learning and memory Rs.213 Thus, blockade of the GlyT1 transporter would increase in normal animals as well as reverse cognitive impairments NMDA-R-mediated transmission. To date, a number of pharma- induced by NMDA-R blockade.226 PAMs of mGluR5 include ceutical companies have been developing novel GlyT1 inhibitors. 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB)228 Sarcosine (N-methylglycine), a potent and prototype GlyT1 and ADX47273.227 Several preclinical studies have demonstrated inhibitor, when added to an existing regimen of APDs, showed that these compounds exhibit beneficial effects in preclinical efficacy for positive and negative symptoms in both chronically behavioral models that predict efficacy in the treatment of both stable210,214 and acutely ill patients with schizophrenia.215 positive symptoms and cognitive deficits in patients with schizo- However, sarcosine has not shown clinical efficacy when added phrenia. Further results from clinical populations are awaited. to clozapine.216 Lane et al.210,215 suggested that sarcosine is more efficacious than D-serine as adjuvant therapy for schizophrenia. Ampakines. Ampakines, a class of compounds that allosterically However, optimal dosing for sarcosine and D-serine may be enhance AMPA (a-amino-3-hydroxy-5-methy-isoxazole-4-propio- different.210 Sarcosine has also been studied as monotherapy in 217 nic acid) receptor function, represent another potential class of acutely symptomatic drug-free schizophrenic patients. To fully adjunctive treatments for schizophrenia (Figure 1). Ampakines assess sarcosine’s effects further placebo- or active-controlled, enhance excitatory glutamatergic transmission and facilitate long- larger-sized studies are necessary. term potentiation, learning and memory in rodents.229,230 In a In a recent large-scale double-blind phase II study of the potent small double-blind RCT of schizophrenic patients who were and non-competitive GlyT1 inhibitor RG1678 (bitopertin), the partially refractory to treatment with FGAs, the ampakine CX-516 compound significantly improved negative symptoms in the per as a sole agent did not produce significant effects on positive protocol analysis and demonstrated a trend towards functional symptoms or cognitive impairment.231 Moreover, in a placebo- improvement in schizophrenia patients with predominant nega- 218 controlled RCT of CX-516 added to clozapine, olanzapine or tive symptoms. In contrast, adding another GlyT1 inhibitor, Org- risperidone, no benefits were observed on cognition or symptoms 25935 to an SGA in a 12-week placebo-controlled study in patients of schizophrenia.232 Farampator (CX-691, ORG-24448), an AMPA with persistent negative symptoms in schizophrenia did not lead 233 219 potentiator, is currently in a phase II trial. In the case of AMPA to a significant improvement. It will be interesting to learn ligands, it remains unclear whether agonists or partial agonists/ whether these GlyT1 inhibitors are also effective in ameliorating modulators will have benefits in schizophrenia. cognitive deficits in schizophrenia.

Metabotropic glutamate receptor agonist. Metabotropic glutamate Glutathione precursor. Glutathione (GSH) is the primary endo- receptors (mGluRs), of which there are eight subtypes, are genous antioxidant and it plays a critical role in protecting cells from damage by reactive oxygen and other radical species.234 categorized into three groups: Group I (mGluR1/5), Group II 235 (mGluR2/3) and Group III (mGluR4/6/7/8).220 Group II mGluRs GSH also potentiates the NMDA-R response to glutamate. In drug-naive patients with schizophrenia, a decrease of GSH levels (mGluR2/3) are located presynaptically on glutamate terminals 236 where they may act as autoreceptors inhibiting glutamate release was observed in cerebrospinal fluid and medial PFC. As such, (Figure 1).220,221 Extensive preclinical data demonstrate that GSH supplementation could be of clinical benefit in the treatment orthosteric mGluR2/3 agonists, including LY354740, LY379268 of schizophrenia by preventing oxidative stress and enhancing neurotransmission at NMDA-Rs. However, oral administration of and LY404039, exhibit an antipsychotic-like behavioral and 234 neurochemical profile in animal models of schizophrenia.222 GSH has been shown to have little effect on brain GSH levels. However, there is a possible concern that group II mGluRs may N-acetylcysteine (NAC), a precursor of GSH, penetrates the 27 blood--brain barrier and raises brain GSH levels in animal models desensitize during chronic treatment with mGluR2/3 agonists. 234 A double-blind proof-of-concept RCT reported significantly (Figure 1). In a large-scale, double-blind, 6-month RCT of NAC as greater improvement on positive and negative symptoms after adjunctive therapy, NAC significantly improved psychopatho- treatment with LY2140023 (Methionine-LY404039) compared with logical symptoms of schizophrenia, particularly negative symp- placebo, with few side effects, suggesting that mGluR2/3 agonists toms in patients with chronic schizophrenia. Interestingly, NAC also improved akathisia, suggesting a beneficial effect of have antipsychotic properties without direct D2 antagonism and may provide a new alternative monotherapy for the treatment NAC for EPS. In an ancillary component of the primary study, 223 NAC improved auditory cortical functioning as indexed by the of schizophrenia. However, a follow-up phase II trial with 237 LY2140023 and olanzapine in acute schizophrenia patients was mismatch negativity, a marker of glutamatergic function. Taken inconclusive as both agents failed to show significant clinical together, NAC supplementation appears to be a promising improvement due to an unusually high placebo response rate.224 augmentation strategy in the treatment of schizophrenia that In a more recent 6-month open-label study, LY2140023 was warrants further investigation. inferior to the atypical antipsychotic standard of care in improve- ment on PANSS total score at the 6-month end point.225 Thus, the Adrenergic agents therapeutic effects of LY2140023 as a sole antipsychotic may not a2 AR agonist or antagonist. Norepinephrine plays an important be large enough to claim equivalence to the existing APDs. role in cognitive function of the PFC, particularly in working 238,239 Moreover, the impact of LY2140023 on cognitive dysfunction memory, by its actions at a2 ARs (Table 2). Indeed, the a2 remains to be tested (Table 2). Despite the inconclusive results of agonists (clonidine and a more selective a2A agonist guanfacine) phase II trials, phase III trials with LY2140023 have been initiated. have been shown to improve cognition in various preclinical studies.240--242 In an early clinical trial, clonidine improved PFC- Metabotropic glutamate receptor modulator. PAMs of mGluR offer mediated cognitive dysfunction in schizophrenia.243 A 4-week, an attractive alternative to the direct activation of mGluR by double-blind RCT demonstrated a cognitive-enhancing effect of orthosteric competitive agonists. PAMs have been discovered adjunctive guanfacine in patients with schizophrenia taking 226 244 for mGluR1, mGluR2 and mGluR5. These molecules offer the risperidone. The potential ability of a2 agonists to improve potential to increase the efficiency of normal glutamate transmis- cognitive performance on tasks dependent on PFC function sion without the risk of inappropriate stimulation.227 should be investigated in further large-scale RCTs.

& 2012 Macmillan Publishers Limited Molecular Psychiatry (2012), 1206 -- 1227 Pharmacological treatment of schizophrenia S Miyamoto et al 1216 On the contrary, clozapine and risperidone have potent phrenia.267 However, the sample size of this trial was small and antagonist properties at a2 ARs, which may contribute to the tropisetron was not superior to placebo on cognitive performance. ‘atypicality’ of the SGAs by enhancing frontocortical dopaminergic A phase IIa study of TC-5619, a selective a7 nAChR partial transmission.245,246 Several clinical and preclinical studies provide agonist, found that patients treated with TC-5619 performed evidence that the a2 AR antagonist idazoxan enhances the significantly better on selective cognitive tests on the Cog State antipsychotic efficacy of FGAs, olanzapine and risperidone.247--249 Schizophrenia Battery and showed improvement on the Scale for There are no current clinical trials investigating a2 AR antagonists the Assessment of Negative Symptoms, CGI-Improvement (CGI-I) in schizophrenia. In the case of a2 ARs ligands, it remains unclear and Subject Global Impression Scale of Cognition (SGI-Cog). whether agonists or antagonists will have greater potential However, this effect was predominantly in patients who were benefits in schizophrenia. tobacco smokers.268 Additional studies are required to determine the therapeutic potential of a7 nAChR agonists in schizophrenia. COMT inhibitors. Diverse evidence suggests that catechol-O- methyl transferase (COMT), a postsynaptic methylation enzyme a4--b2 nicotinic receptor agonist. The a4 b2 nAChRs are also known that metabolizes released dopamine, is primarily responsible for to be involved in cognition, and their agonists such as AZD3480 synaptic dopamine inactivation in PFC, and that variation in COMT (TC-1734), varenicline, SIB-1553A and RJR2403 have been devel- oped as adjunctive agents to APDs for the treatment of cognitive activity may affect prefrontal cortical activity, especially during 56,269 working memory and executive function tasks.250,251 Abnormal- deficits in schizophrenia. However, in a phase IIb trial of AZD3480, various domains of cognition were not improved in ities of prefrontal dopamine function associated with working 270 memory appear to be prominent features of schizophrenia, and schizophrenia. A small open-label study of varenicline, which is specific alleles of the COMT gene run in families with a high also a full agonist at a7 nAChR, showed that the agent has some 252 beneficial effects on cognition (verbal learning and memory) and incidence of the illness. 271 Tolcapone, a CNS penetrant reversible selective inhibitor of reduces smoking behavior in schizophrenia patients. Another COMT, has been reported to enhance prefrontal cognitive more recent larger study examined the effects of adjunctive function in rodents253 and in normal human subjects.254 varenicline in an 8-week randomized placebo-controlled trial. Tolcapone and a peripherally acting COMT inhibitor entacapone Antipsychotic doses remained constant through the study in are currently in phase II clinical trials to investigate whether these which varenicline was titrated up to 1 mg daily. While the primary COMT inhibitors offer a new adjunctive treatment for cognitive analyses of neurocognitive function showed no drug--placebo impairment in schizophrenia with and without the high-risk differences, some secondary analyses found advantages over 255 placebo. Treatment effects differed between smokers and non- combination of COMT alleles. However, tolcapone was with- 272 drawn from the market in Europe and Canada due to an increased smokers. While not reported in patients with schizophrenia, risk of serious hepatotoxicity,256 and in the United States, there have been case reports and an US FDA advisory about restrictive liver enzyme monitoring measures are mandated that possible psychiatric side effects of varenicline, including depres- severely limits its use.257 sion, suicidal ideation or attempts, and activation of psychotic or manic symptoms (Table 2).273,274 Further study of varenicline in patients with schizophrenia is needed to understand whether a Cholinergic agents risk of behavioral toxicity also exists in clinically stable patients a-7 nicotinic receptor agonist. Nicotinic Ach receptors (nAChRs) receiving APD. have been implicated in cognitive function and sensory proces- sing. Among the nAChRs, the a nAChR subtype is a possible 7 Muscarinic agents therapeutic target for schizophrenia, since preclinical, genetic and postmortem studies have demonstrated altered levels and Muscarinic receptor agonist. There is a large body of anatomical 258 and pharmacological evidence demonstrating the potential function associated with the illness. Selective a7 nAChR for modulation of dopamine and glutamatergic neurons by choli- agonists such as 3-2,4-dimethoxybenzylidene anabaseine 275 (DMXB-A), R3487/MEM3454, PHA-709829, PH-399733, EVP-6124 nergic muscarinic receptors. Moreover, drugs enhancing muscarinic receptor function would be expected to lead to and TC-5619 have been developed as potential candidates for 196 adjunctive treatments of cognitive impairment and negative enhancement of GABAergic interneuron function. There is symptoms in schizophrenia (Table 2).259--263 Despite early con- growing evidence that partial agonists of muscarinic receptors are active in animal models predictive of antipsychotic activity, and cerns that rapid desensitization of the a7 nAChR would limit their the SGAs clozapine and olanzapine are partial agonists for therapeutic potential, several a7 nAChR agonists have already advanced to clinical trials. A phase II trial of DMXB-A found muscarinic M1,M2 and M4 receptors. In addition, muscarinic improvement in cognition that did not separate from placebo, agonists have activity in animal models of negative symptoms, while negative symptoms improved significantly.264 DMXB-A cognitive dysfunction and affective disorders, suggesting potential usefulness of muscarinic agonists either alone or in combination reduced the activity of the hippocampus during pursuit eye 220,270,276 movement task as measured with fMRI (functional magnetic with APDs in the treatment of schizophrenia. Examples of resonance imaging), suggesting its therapeutic effect on hippo- these agents are the muscarinic M1/M4 agonist xanomeline, the 265 M2/M4 agonists PTAC and BuTAC and the M1/M3 agonists CDD- campal inhibitory interneurons. It also improved default network 179,275 function in schizophrenia.266 Continued expectations for DMXB-A 0102, CI-1017 and YM-706. as a pro-cognitive agent are reflected in ongoing clinical trials. In a In a pilot double-blind, 4-week RCT, xanomeline demonstrated phase Ib double-blind, 3-week RCT, EVP-6124 demonstrated efficacy on measures of cognition and total BPRS and PANSS scores when compared with placebo in unmedicated patients significant improvement in measures of cognition and electro- 277 physiological biomarkers of sensory processing when compared with schizophrenia. This was a small trial, and further studies with placebo in schizophrenia patients treated with SGAs.259 are necessary to determine whether xanomeline is effective for There is additional evidence from a study with tropisetron, cognitive deficits and general psychopathology in schizophrenia, either as monotherapy or as adjunctive treatment.13 a high-affinity partial agonist for a7 nAChR and a potent 5-HT3 receptor antagonist. In a recent 8-week double-blind RCT, adjunctive administration of tropisetron improved auditory Acetylcholinesterase inhibitor. Acetylcholinesterase (AchE) is an sensory gating P50 deficits and sustained visual attention enzyme responsible for catabolizing Ach in the synaptic cleft. compared with baseline in non-smoking patients with schizo- AchE inhibitors can enhance cholinergic function by increasing

Molecular Psychiatry (2012), 1206 -- 1227 & 2012 Macmillan Publishers Limited Pharmacological treatment of schizophrenia S Miyamoto et al 1217 Ach concentrations and potential activity at both nicotinic and Cannabidiol, a cannabis constituent that does not appear to act on 13 294 muscarinic receptors. A number of studies have examined AchE CB1 receptors, may have some potential for antipsychotic effects. inhibitors, including donepezil, rivastigmine and galantamine, as potential cognitive enhancers added to APDs in schizophrenia. GABAA-positive modulator. GABA is the major CNS inhibitory The results of double-blind RCTs of donepezil and rivastigmine neurotransmitter and GABAergic interneurons inhibit neuronal suggest that these agents are not particularly effective for output of glutamatergic pyramidal cells in the PFC through 13 improving cognitive function in schizophrenia. activation of GABA type A (GABAA) receptors containing a2 Galantamine is an AchE inhibitor that also acts as an allosteric subunits.295 Agents that increase GABAergic inhibition of cortical modulator of the a4 b2 and a7 nAChRs. Of the seven double-blind, pyramidal cells have been hypothesized to improve working placebo-controlled trials in patients with schizophrenia, four have memory and other cognitive impairments in schizophrenia provided some evidence of improvements in cognitive function (Table 2). with galantamine compared with placebo on total cognitive In a small double-blind RCT, adjunctive administration of MK- battery scores and on measures of memory and processing 0777, a GABAA a2/a3 partial agonist, improved delayed memory speed.278--281 However, results from three recent studies found no performance and decreased reaction time on selected measures cognitive benefits in schizophrenia.282--284 Moreover, one double- of prefrontal cortical function in patients with chronic schizo- blind RCT of galantamine failed to show improvements in phrenia.296 However, a recent double-blind RCT of MK-0777 failed negative symptoms.285 These results provide no global support to show any significant benefits for cognitive deficits or for galantamine augmentation for cognitive and negative psychopathological symptoms in schizophrenia.297 MK-0777 is a symptoms in schizophrenia, although specific cognitive deficits relatively weak GABAA a2 partial agonist, with 10--20% of the may be responsive to adjunctive galantamine in some patients. potency of a full GABAA a2 agonist, thus a more potent partial agonist with greater intrinsic activity might be necessary. Histaminergic agents Histamine H receptor antagonist/inverse agonist. The histamine H Antiinflammatory agents (Celecoxib). In line with the findings 3 3 indicating immunological alterations in schizophrenic patients, non- receptor (H3R) is a presynaptic autoreceptor that inhibits histamine release in the brain and also regulates the release of steroidal antiphlogistic agents have been explored. In a placebo- controlled, double-blind and randomized study, Akhondzadeh numerous other neurotransmitters (for example, dopamine, ACh, 298 noradrenaline and GABA) via a parallel role as a heterorecep- et al. added 400 mg per day celecoxib, a cyclooxygenase-2 286,287 inhibitor, to risperidone in 60 acutely ill schizophrenic in-patients. tor. A number of H3R antagonists/inverse agonists have been synthesized and evaluated for their potential utility in the The cyclooxygenase-2 group outperformed the placebo group in treatment of schizophrenia.286,287 Preclinical studies suggest that terms of positive and general psychophathology symptoms as well these compounds can enhance the release of such neurotrans- as total PANSS scores although improvement was found in both groups. In another placebo-controlled, randomized, double-blind mitters simultaneously, which play important roles in cognitive 299 processes. Moreover, pitolisant (BF2.649), a high affinity and study, Mu¨lleret al. confirmed an earlier study of theirs and found an improvement of PANSS and CGI scores in first-episode selective non-imidazole H3R antagonist/inverse agonist, showed significant inhibitory activity in several mouse models of schizo- schizophrenic patients after co-administration of celecoxib to a 288 therapeutic dose of amisulpride. phrenia. As such, H3R antagonists/inverse agonists deserve attention as a possibly novel class of drugs endowed with pro- Minocycline. The therapeutic potential of minocycline, a second- cognitive properties (Table 2). Several H3R antagonists/inverse agonists, including ABT-288, pitolisant (BF2.649), GSK-239512 and generation tetracycline, was shown in several studies using animal MK-0249, are currently under clinical investigation in phase II trials models of schizophrenia. For example, minocycline attenuated for the treatment of schizophrenia.286 cognitive impairments and PPI deficits induced by NMDA-R antagonists.300--302 In addition, minocycline attenuated the increase of dopamine levels in frontal cortex and striatum induced Other agents by a NMDA-R antagonist,302 and ameliorated neurotoxicity caused Cannabinoid-1 receptor antagonist. Acute cannabis intoxication by methamphetamine.303 The mechanism by which minocycline and long-term cannabis use can induce schizophrenia-like acts is not fully understood, but it has demonstrated neuro- symptoms. In addition, cannabis is thought to be a risk factor protective effects in animal models of ischemic brain injury, for developing schizophrenia.289 Accumulating evidence suggests inflammatory-mediated neurotoxicity and classic neurodegenera- that cannabinoid-1 (CB1) receptors and their accompanying tive disorders, possibly via its inhibition of nitric oxide synthase, system of endogenous activators may be dysregulated in inhibition of, microglial activation, and antiapoptotic properties.304 290 schizophrenia, and CB1 receptors also play an important role In a recent 24-week double-blind RCT, minocycline added on to in glucose and lipid metabolism.291 Consequently, the potential SGAs showed a beneficial effect on negative symptoms and utility of CB1 receptor antagonists for the treatment of psychiatric cognitive functioning, including executive function, spatial work- symptoms and obesity in schizophrenic patients has received ing memory and spatial recognition memory, in patients with 305 considerable attention. In a double-blind RCT, a selective CB1 early-phase schizophrenia. Additional work is needed to more receptor antagonist, SR-141716, used as monotherapy, failed to fully delineate the potential of this agent. demonstrate benefits for psychopathological symptoms in schizo- phrenia, although only a single dose of the experimental agent Neurokinin-3 receptor antagonist. Neurokinin-3 (NK3) tachykinin 177 was studied. Rimonabant, another CB1 receptor antagonist that receptors are located in the brain regions implicated in schizo- had approval for weight loss in Europe, did not reduce body phrenia and appear to regulate midbrain dopamine neuronal weight or improve metabolic parameters in a small study of activity.306 Preclinical studies have demonstrated that a potent 292 overweight patients with schizophrenia and another small-scale and selective non-peptide NK3 receptor antagonist, osanetant (SR- placebo-controlled study employing the Repeatable Battery for 142801) selectively inhibits dopamine release in certain brain the Assessment of Neuropsychological Status total score as the regions.307 In a 6-week RCT, osanetant monotherapy was superior primary outcome measure found no improvement of global to placebo on global assessment of efficacy and measures of cognitive functioning.293 The agent was withdrawn from the positive symptoms in schizophrenia.177 A double-blind phase II European market in 2009 due to increased risk of psychiatric RCT of another selective NK3 receptor antagonist, talnetant adverse effects. This also led to the early termination this RCT. (SB-223412), has also shown significant improvement in positive

& 2012 Macmillan Publishers Limited Molecular Psychiatry (2012), 1206 -- 1227 Pharmacological treatment of schizophrenia S Miyamoto et al 1218 symptoms and cognitive impairment with no major side effects in favorable side-effect profiles and their potential to restore schizophrenia.308 However, both osanetant and talnetant have disturbances in the metabolism of synaptic membrane phospho- significant pharmacokinetic limitations309 and development of lipids that may be responsible for dysfunction of dopaminergic these compounds for schizophrenia has been stopped.310 Never- and serotonergic receptors. theless, NK3 antagonists have demonstrated some potential for Results of several double-blind RCTs of omega-3 fatty acids in antipsychotic and pro-cognitive effects and this mechanism schizophrenia remain inconclusive.329,330 However, a recent clearly merits further study. AZD2624 is a NK3 receptor antagonist. double-blind RCT demonstrated that 12-week administration of It has reached phase II clinical trials. omega-3 fatty acids can reduce the risk of conversion from a prodromal state into first-episode psychosis.331 Omega-3 fatty Estrogen. Epidemiological studies have shown that female acids were well tolerated, thus they could potentially represent a patients have a considerably later onset of schizophrenia, better viable and safe preventative monotherapy in people at ultra-high therapeutic responses and outcomes than males, and women are risk of psychosis. more likely to develop late-onset schizophrenia after meno- pause.311 Clinical studies have demonstrated the inverse relation- Oxytocin. The posterior pituitary hormone oxytocin is a neuro- ship between estradiol levels and positive symptoms over the peptide that plays a key role in the regulation of a number of menstrual cycle in premenopausal women with schizophrenia.312 diverse behavioral and cognitive processes, including social In preclinical studies, estrogen has been shown to modulate the attachment, affiliation and memory.332,333 In addition, preclinical sensitivity of D2 receptors in the brain and it can reduce behavioral studies have shown that oxytocin has antipsychotic-like efficacy in abnormalities induced by dopamine agonists.313 These findings several animal models of schizophrenia.334,335 In human studies, have been interpreted to provide a theoretical rationale for acute intranasal oxytocin administration increased interpersonal the antipsychotic-like effects of estrogen.314 In three double- trust, eye contact, performance on tests of face emotion blind RCTs, adjunctive estrogen showed a beneficial effect on recognition and theory of mind as well as social reciprocity in positive symptoms in women with schizophrenia.311,315,316 healthy336,337 and autistic subjects.338 Feifel et al.339 recently Although estrogen may be a useful treatment for women with reported that 3-week administration of intranasal oxytocin, given schizophrenia, its therapeutic potential in men with schizophrenia adjunctive to APDs, produced significantly greater reductions in remains unclear. schizophrenic symptoms compared with placebo. Moreover, in a preliminary double-blind RCT, 2-week daily intranasal administra- Neurosteroid agents. Accumulating evidence suggests that neu- tion of oxytocin improved measures of social cognition and roactive steroids, including pregnenolone, pregnenolone sulfate, psychotic symptoms, especially paranoia in schizophrenia.340 In allopregnanolone, dehydroepiandrosterone (DHEA) and DHEA order to characterize the antipsychotic potential of oxytocin, sulfate (DHEAS), act at inhibitory GABAA and excitatory NMDA- further trials are needed with larger sample sizes, a broader dose Rs, and have neuroprotective and neurotrophic properties.317,318 range, and longer durations of treatment. Thus, neurosteroids may be candidate modulators of the pathophysiology and therapeutics of schizophrenia.319 PDE10A inhibitor. Phosphodiesterase 10A (PDE10A) is a dual In a small double-blind RCT, pregnenolone as adjunct to SGAs specificity enzyme hydrolyzing the cyclic nucleotide messengers, significantly reduced negative symptoms, but not cognitive cAMP and cGMP.341 PDE10A is abundant only in brain tissue, with impairments, in patients with schizophrenia or schizoaffective a predominant distribution in the putamen and caudate nucleus disorder compared with placebo.320 A small double-blind RCT of in the medium spiny neurons of the striatal complex.342 PDE10A adjunctive DHEA in patients with chronic schizophrenia and inhibitors, including papaverine, TP-10 and MP-10 (PF-2545920), prominent negative symptoms found that adjunctive DHEA was demonstrate positive effects in several animal models, spanning superior to placebo in treating negative, depressive and anxiety positive, negative and cognitive symptoms of schizophrenia.341,343 symptoms, especially in women.321 In another study in olanza- However, a phase II trial of MP-10 was terminated before pine-treated patients, DHEA augmentation was associated with an completion for undisclosed reasons.341 improvement in negative symptoms, but no effect on positive symptoms.322 Interestingly, some improvement in EPS was also Secretin. Secretin is a gastrointestinal peptide increasingly recog- seen in patients receiving DHEA, consistent with a previous study nized as an important neuropeptide with extensive CNS receptor in which DHEA significantly decreased antipsychotic-induced expression and activity. Preclinical studies have demonstrated that Parkinsonism.323 Finally, in another study, DHEA augmentation systemically administered secretin is capable of modulating produced modest pro-cognitive effects while showing no effects conditioned fear344 and can partially reverse impairment in PPI on positive, negative or Parkinsonian symptoms.324 Although the induced by PCP.345 In a small pilot double-blind RCT, a single findings with neurosteroid augmentation in schizophrenia are intravenous dose of secretin produced transient improvement in somewhat inconsistent and the mechanism of action of pregne- the CGI-I scale in patients with treatment-refractory schizophrenia, nolone and DHEA requires further characterization, the possibility although no significant differences in psychiatric symptoms were that these compounds have efficacy in schizophrenia should be found between secretin- and placebo-treated patients.346 A recent further investigated in longer and larger studies with broader dose double-blind RCT showed that subcutaneous administration of ranges. secretin significantly increased eye-blink conditioning in schizo- phrenia, suggesting a possible role for secretin in modu- Omega-3 fatty acid. The two main omega-3 fatty acids in fish oil, lating cerebellar-mediated learning by classical conditioning.347 eicosapentaenoic acid and docosahexaenoic acid have important Further studies evaluating the efficacy and safety of secretin are biological functions in the CNS. Eicosapentaenoic acid can affect warranted, especially among less severely ill patients with neuronal activity and docosahexaenoic acid is a major structural schizophrenia. component of neuronal membranes.325 Moreover, omega-3 fatty acids have antiapoptotic, antioxidant and antiinflammatory effects Erythropoietin. The hematopoietic growth factor erythropoietin in the brain.326,327 A number of studies suggest that deficient (EPO) possesses multifaceted direct neuroprotective properties uptake or excessive breakdown of membrane phospholipids may such as antiapoptotic, antiinflammatory, antioxidant, neuro- be associated with schizophrenia.328 These have led to research trophic, angiogenic and synaptogenic activity.348,349 EPO was interest in the possible therapeutic benefits of adjunctive use of generally found to be clinically safe and crosses the blood--brain omega-3 fatty acids in schizophrenia, especially given their barrier.348 In a double-blind RCT, weekly intravenous administra-

Molecular Psychiatry (2012), 1206 -- 1227 & 2012 Macmillan Publishers Limited Pharmacological treatment of schizophrenia S Miyamoto et al 1219 tion of high-dose rhEPO (recombinant human EPO) over 12 weeks, identified. However, as yet there is no proven mechanism for given adjunctive to APDs, produced significantly greater improve- developing such drugs and many barriers still exist in the ment in a set of cognitive functions as compared with placebo in translation from basic science to drug discovery.356 As such, patients with chronic schizophrenia.350 Moreover, rhEPO was able developments in translational neuroscience are needed to to delay the progressive atrophy in the brain areas typically bridge from preclinical to proof-of-concept studies so that they affected in schizophrenia.351 Importantly, the gray matter protec- can, to the greatest extent possible, use similar outcome tion by rhEPO was highly associated with improvement in measures.77 Although hypotheses of cognitive deficits in schizo- attention and memory functions.351 Thus, EPO may have the phrenia separately implicate dopaminergic, cholinergic, noradre- potential to prevent progressive neuropathological changes and nergic, serotonergic, glutamatergic and/or GABAergic deficits, it is to improve cognitive function in schizophrenia. Further clinical very likely that the actual circuit dysfunction involves interactive studies are warranted with larger sample sizes, a broader dose changes across some or most of these systems.242 Accordingly, range and longer durations of treatment. such complexity may limit the potential effectiveness of agents targeting a single mechanism, and more creative approaches may Ginkgo. Ginkgo, a traditional Chinese medicine, has antioxidant be necessary.13 and immunostimulatory properties and it can improve brain From a mechanistic perspective, a more rational approach to the circulation at the microvascular level.352 In a recent meta-analysis treatment of cognitive deficits in schizophrenia would be to of six trials, adjunctive ginkgo to APDs demonstrated moderate develop compounds that specifically target the mesocortical improvement in total symptomatology and in negative symptoms system, with particular selectivity for the PFC and medial temporal 352 in patients with chronic schizophrenia. However, ginkgo lobe, while avoiding other dopaminergic pathways (for example, D1 appears to be effective only when added to FGAs. Moreover, it mediated). In order to develop such agents, it is necessary to learn remains unclear as to what properties play a therapeutic role in more about how individual compounds affect specific brain regions schizophrenia.352 in both preclinical and clinical studies.77 Several neurophysiological and non-invasive neuroimaging biomarkers, including oculomotor neurophysiology assessments, fMRI, evoked response potentials, FUTURE STRATEGIES FOR DRUG DEVELOPMENT IN MR spectroscopy and magnetoencepholography, hold great SCHIZOPHRENIA promise to enhance translational research. Reliable and sensitive Since the introduction of chlorpromazine and throughout the measures of brain function will likely prove essential for enhancing development of the new-generation APDs beginning with our ability to characterize the biological effects of novel therapeutic 77 clozapine, the D2 receptor has been the ‘Holy Grail’ for the agents in the early stages of drug development. development of APDs. Pharmacologic actions to reduce neuro- In recent years, significant progress has been made in transmission through the D2 receptor represent the only proven identifying various susceptibility genes in schizophrenia, including therapeutic mechanism for psychoses. A number of novel non-D2 dysbindin, neuregulin 1, COMT, disrupted in schizophrenia 1 mechanisms of action of APDs have been explored over the past (DISC1) and others, by genetic linkage and association studies.56 40 years but none has definitively been proven effective. Many of these genes appear to regulate synaptic plasticity and Consequently, it remains unclear as to which pharmacologic chemical neurotransmission particularly by glutamate. Research mechanism will provide the highest level of efficacy while on the products of these implicated genes will promote rational avoiding serious side effects in the treatment of schizophrenia. drug development. Indeed, investigators have pursued a number Moreover, there is still an ongoing debate as to whether drugs of genetic animal models for schizophrenia based on single genes selective for singe molecular targets (that is, ‘magic bullets’) or as etiologic agents of the illness.357 However, these animal models drugs selectively non-selective for several molecular targets (that cannot be expected to recapitulate the breadth of the clinical is, ‘magic shotguns’, ‘multifunctional drugs’ or ‘intramolecular phenotype of schizophrenia, because schizophrenia is a complex polypharmacy’) will lead to more effective new medications for multi-factorial, polygenic brain disorder involving environmental schizophrenia.3,27,152,179,353,354 Given the complexity of schizo- interactions. More sophisticated bioinformatic animal models phrenia as a disease, and the heterogeneity of the patient based on etiological considerations could produce new opportu- population, it would seem logical to develop compounds with nities to identify the molecular pathophysiology of the disease 357 at least a modicum of D2 receptor affinity that also bind one or phenotype. However, at present, we have no molecular target more favored targets such as 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, for any of the dimensions of schizophrenia. glutamatergic and/or nicotinergic receptors, while avoiding There is a great need for the development of novel methods engagement of problematic targets such as a1-adrenergic, H1, to identify optimal individualized treatment plans. In particular, 355 M1 and M3 receptor activity. Another option is to develop the efficacy and tolerability of antipsychotics could be directly single-target agents that can be used to augment multi-target influenced by genetic variations in cytochrome P450 (CYP) agents. The conundrum of single-target vs multi-target agents will enzymes that affect drug metabolism. The activity of drugs may likely remain at the forefront of drug development until the also be influenced by genetic alterations affecting the drug target pathophysiology of schizophrenia is fully elucidated. molecule, such as monoaminergic receptors, neurotransmitter In this context, current and future drug development strategies transporters and metabolizing enzymes. Further development of can be seen to fall into three categories: (1) refinement of genetic tests for the prediction of drug response and side effects, precedented mechanisms of action to provide drugs of compa- and pharmacogenetic research into genetically determined drug rable or superior efficacy and side-effect profiles to existing APDs; metabolic polymorphisms, as well as pharmacogenomic strategies (2) development of novel (and presumably non-D2) mechanism to the identification of novel factors influencing response, would APDs; (3) development of compounds to be used as adjuncts to lead to a better understanding of the rational basis for the APDs to augment efficacy by targeting specific symptom personalization of antipsychotic treatment.358 In addition, APDs dimensions of schizophrenia and particularly those not responsive may also be targeted to specific patient subgroups based on to traditional APD treatment. profiling and the identification of endophenotypes of schizo- Given that cognitive deficits in schizophrenia are widely phrenia. Clinical implementation of such practices could have a prevalent and appear to be correlated with functional outcome, strong impact in reducing adverse effects and improving much effort has been focused on developing cognitive-enhancing treatment adherence and efficacy.358 drugs. As described above, a variety of molecular targets with In recent decades, a focus on early detection and early potential pro-cognitive effects in schizophrenia have been intervention in psychosis has emerged.359 As already described,

& 2012 Macmillan Publishers Limited Molecular Psychiatry (2012), 1206 -- 1227 Pharmacological treatment of schizophrenia S Miyamoto et al 1220 various lines of evidence indicate that pathophysiological changes 9 Green MF. What are the functional consequences of neurocognitive deficits in occur in cortical and subcortical brain regions in patients with schizophrenia? Am J Psychiatry 1996; 153: 321--330. schizophrenia, which may be associated with disease progression, 10 Miyamoto S, Duncan GE, Goff DC, Lieberman JA. Therapeutics of schizophrenia. clinical deterioration and functional decline.65 If that is the case, In: Davis KL, Charney D, Coyle JT, et al. (eds). Neuropsychopharmacology: The early intervention aimed at halting or reversing progressive Fifth Generation of Progress. Lippincott Williams & Wilkins: Philadelphia, 2002, pathophysiological processes in schizophrenia could yield sub- pp 775--807. 11 Miyamoto S, Duncan GE, Marx CE, Lieberman JA. Treatments for schizophrenia: a stantial improvements in outcomes in the future. To do so, more critical review of pharmacology and mechanisms of action of antipsychotic sensitive and specific diagnostic tools as well as safe and effective drugs. Mol Psychiatry 2005; 10: 79--104. 1 interventions including novel therapeutic agents are required. 12 Gray JA, Roth BL. The pipeline and future of drug development in schizophrenia. Mol Psychiatry 2007; 12: 904--922. 13 Barch DM. Pharmacological strategies for enhancing cognition in schizophrenia. CONCLUSION Curr Top Behav Neurosci 2010; 4: 43--96. 14 Buchanan RW, Freedman R, Javitt DC, Abi-Dargham A, Lieberman JA. Recent Pharmacotherapy for schizophrenia is highly effective but at the advances in the development of novel pharmacological agents for the same time there is tremendous unmet clinical need. Over the last treatment of cognitive impairments in schizophrenia. Schizophr Bull 2007; 33: half century, there has been only limited progress in innovating 1120--1130. mechanisms of action and developing novel therapeutic agents 15 Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and for the treatment of schizophrenia. APDs have mainly been reconceptualization. Am J Psychiatry 1991; 148: 1474--1486. developed in the procrustean mold of D2 receptor antagonists. 16 Seeman P. Dopamine receptor sequences. Therapeutic levels of neuroleptics Despite refinements in this mechanism of action, the therapeutic occupy D2 receptors, clozapine occupies D4. Neuropsychopharmacology 1992; 7: effects of the NGAs are not yet sufficiently robust to claim 261--284. superiority over earlier treatments, with the possible exception of 17 Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, Caron MG. clozapine. Moreover, novel drugs in the development for An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 2005; 122: 261--273. schizophrenia have not yet been proven effective or validated 18 Masri B, Salahpour A, Didriksen M, Ghisi V, Beaulieu JM, Gainetdinov RR et al. alternative mechanisms of action. Other novel approaches to Antagonism of dopamine D2 receptor/beta-arrestin 2 interaction is a common enhance efficacy and change the ultimate course and prognosis of property of clinically effective antipsychotics. Proc Natl Acad Sci USA 2008; 105: schizophrenia need to be explored. The breadth of potential 13656--13661. targets and compounds under investigation clearly demonstrate 19 Remington G, Kapur S. D2 and 5-HT2 receptor effects of antipsychotics: bridging the interest and importance in pursuing innovative drug devel- basic and clinical findings using PET. J Clin Psychiatry 1999; 60(suppl 10): opment. The discovery of effective novel therapeutic agents for 15--19. the treatment of schizophrenia will require continued research 20 Sharif Z, Miyamoto S, Lieberman JA. Pharmacotherapy of schizophrenia. In: efforts and collaboration by both academic and industrial Sibley D, Hanin I, Kuhar M, et al. (eds). The Handbook of Contemporary laboratories to further our understanding of the molecular and Neuropharmacology. John Wiley & Sons: Hoboken, 2007, pp 369--409. 21 Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G. Positron emission functional pathophysiological mechanisms operative in schizo- tomographic analysis of central D1 and D2 dopamine receptor occupancy in phrenia. patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry 1992; 49: 538--544. 22 Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P. A positron CONFLICT OF INTEREST emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 Dr Miyamoto is a consultant for Dainippon Sumitomo Pharmaceutical. He has receptor occupancy. Arch Gen Psychiatry 2000; 57: 553--559. received advisory board honoraria from Chugai Pharmaceutical. Dr Jarskog has 23 Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical received grant support from Genentech, GlaxoSmithKline, Novartis and Sunovion. Dr Fleischhacker has received research grants from Alkermes, Janssen Cilag, Eli Lilly, antipsychotic drugs on the basis of dopamine D1, D2 and Serotonin2 pKi BMS/Otsuka and Pfizer. He has received honoraria for educational programs from values. J Pharmacol Exp Ther 1989; 251: 238--246. Janssen, Pfizer and AstraZeneca, speaking fees from AstraZeneca, Pfizer, Janssen 24 Kapur S, Seeman P. Does fast dissociation from the dopamine d(2) receptor Cilag, Roche, Lundbeck, BMS/Otsuka and advisory board honoraria from BMS/Otsuka, explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry Wyeth, Janssen Cilag Neurosearch, Amgen, Lundbeck, Endo, United Biosource, 2001; 158: 360--369. Targacept, MedAvante and AstraZeneca. Dr Lieberman has received grant/research 25 Seeman P. Atypical antipsychotics: mechanism of action. Can J Psychiatry 2002; funding from Allon, GlaxoSmithKline, Merck, Novartis, Pfizer, Sepracor and Targacept 47: 27--38. and also served on advisory boards for Bioline, Eli Lilly, GlaxoSmithKline, Intracellular 26 Seeman P. An update of fast-off dopamine D2 atypical antipsychotics. Am J Therapies, Pierre Fabre and Psychogenics. Psychiatry 2005; 162: 1984--1985. 27 Kim DH, Stahl SM. Antipsychotic drug development. Curr Top Behav Neurosci 2010; 4: 123--139. 28 Cutler A, Ball S, Stahl SM. Dosing atypical antipsychotics. 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