Overview Taiwanese Journal of Psychiatry (Taipei) Vol. 31 No. 2 2017 • 115 •

Developing Drugs for Negative Symptoms of Schizophrenia

Chih-Min Liu, M.D., Ph. D.1,2

Negative symptoms in schizophrenia represent a clinically important target for drug development due to their profound effect on an individual’s ability to function normally. The lack of effective medications for this domain of psychopa- thology is a major unmet medical need in schizophrenia. Earlier clinical trials for negative symptoms have been criticized mixing primary and secondary negative symptoms as treatment target and lack of standard protocols for clinical trial de- sign. In the fi rst part, The author is reviewing the methodological issues on defi n- ing and measuring negative symptoms and on developing the consensus for clini- cal trial design for negative symptoms. Defi cit symptoms and persistent negative symptoms, instead of broadly defi ned negative symptoms, have been advocated as the treatment target of clinical trial. There were fi ve commonly used interview- based negative symptom scales with satisfactory psychometric profi les. The con- sensus has been achieved for the design of clinical trials for negative symptoms. In the second part, the treatment effi cacy of different class of drugs on negative symptoms is reviewed. Some second-generation antipsychotics, antidepressants, psychostimulants, glutamate pathway molecules, serotonin receptor antagonists, and anti-infl ammatory agents have modest effects on improving negative symp- toms than placebo. Although some statistically signifi cant effects on negative symptoms are evident, none has reached the threshold for clinically signifi cant. Several new molecules with potentials in treating negative symptoms are still in development.

Key words: schizophrenia, negative symptoms, medication, clinical trials (Taiwanese Journal of Psychiatry [Taipei] 2017; 31: 115-27)

Negative symptoms are substantially more resis- Introduction tant to current pharmacological treatments than positive symptoms [2]. With the exception of ami- The negative symptoms of schizophrenia sulpride [3] in some European countries, no phar- have been receiving much clinical attention for a macological agents have been approved for the long time because of its signifi cant correlation treatment of negative symptoms. The National with poor functional and long-term outcomes [1]. Institute of Mental Health (NIMH) Measurement

1 Department of Psychiatry, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan 2 Graduate Institute of Brain and Mind Sciences, National Taiwan University College of Medicine, Taipei, Taiwan Received: May 22, 2017; accepted: May 23,2017 *Corresponding author. No. 1, Changde Street, Taipei 100, Taiwan E-mail: Chih-Min Liu • 116 • Drugs for Negative Symptoms of Schizophrenia

and Treatment Research to Improve Cognition in current improvement of positive, depressive, and/ Schizophrenia (MATRICS) has turned its atten- or extrapyramidal symptoms. These are the major tion to negative symptoms [4]. The United States sources of secondary negative symptoms, and Food and Drug Administration (FDA) has en- other sources of secondary symptoms are usually dorsed negative symptoms of schizophrenia as a not even assessed. Thus, the use of broadly de- legitimate drug target for a labeling indication and fi ned negative symptoms as treatment target is un- has offered guidelines for development [5]. The likely to lead to the development of effective European Medicines Agency has also offered treatments for those negative symptoms, which guidelines for claiming effects on negative persist during clinical stability and are associated symptoms. with impaired rôle function performance [10]. There are two alternative approaches for de- Methodological Issues fi ning negative symptoms in the context of clini- cal trials. The fi rst approach is termed as “defi cit Defi nition of negative symptoms symptoms,” which restrict negative symptoms to Negative symptoms of schizophrenia contain primary enduring negative symptoms, which re- the following features: affective fl attening, alogia, quired clinicians to rule out any secondary causes avolition, asociality, and anhedonia [4]. Factor of negative symptoms and confi rm the persistence analyses have isolated two separate but related of these symptoms during clinical stable period subdomains, diminished expression (e.g., affec- [11]. The second approach is termed as “persistent tive fl attening), and amotivation (e.g., avolition/ negative symptoms” to include both primary neg- apathy) [6]. ative symptoms and those secondary negative Heterogeneous clinical manifestations exist symptoms, which are persistent presented during with different causes and longitudinal stability. clinical stable period and have not responded to Considering their causes and longitudinal stabili- appropriate treatments [12]. Both those approach- ty, secondary negative symptoms are referred to es have advantages over negative symptoms negative symptoms occurring presumably caused broadly defi ned for isolating those negative symp- by positive symptoms, affective symptoms, medi- toms that are the most relevant treatment target. cation side effects, environmental deprivation, or Researchers proposed that primary enduring other treatment- and illness-related factors [7], negative symptoms, named as defi cit symptoms, while primary enduring negative symptoms refer- may defi ne a separate disease entity, i.e., the defi - ring to the ones, from which other secondary cit syndrome, which is characterized by a distinct causes have been ruled out, persistently present- etiopathophysiology [13]. The defi cit form of ing for a long duration and with a stable degree of schizophrenia is defi ned by the following criteria severity. The term broadly defi ned negative symp- [11]: toms are negative symptoms without considering ‧ At least 2 of the following 6 features must be their causes, longitudinal stability, or duration. present and of a clinically signifi cant severity: Earlier studies showed negative symptoms im- (A) restricted affect, (B) diminished emotional prove during fi rst- and second-generation antipsy- range, (C) poverty of speech, (D) curbing of in- chotic drug treatment [8, 9]. But in most of these terest, (E) diminished sense of purpose, and (F) studies, this effect has been correlated with con- diminished social drive. Liu CM • 117 •

‧ Two or more of these features must have been ‧ No (or low level of) extrapyramidal symptoms present for the preceding 12 months and must on an accepted and validated rating scale. have always been present during periods of ‧ Demonstrated clinical stability for an extended clinical stability (including chronic psychotic period of time prior to the start of the study. states). Persistent negative symptoms differ from ‧ Two or more of these enduring features are also broadly defi ned negative symptoms by the re- idiopathic, i.e., not secondary to factors other quirement for persistence of the symptoms. than the disease process. Such factors include Persistent negative symptoms differ from defi cit (A) anxiety, (B) drug effects (especially, extra- symptoms in several aspects: pyramidal side effects), (C) suspiciousness, (D) ‧ The defi nition of duration: defi cit symptoms formal thought disorder, (E) hallucinations or need to be present for at least 12 months, delusion, (F) mental retardation, and (G) whereas persistent negative symptoms may be depression. present for any predefi ned time period, though ‧ The patient meets the Diagnostic and Statistical usually a minimum of 6 months. Manual of Mental Disorders, Fourth Edition ‧ Their severity is defi ned by a clinical need for criteria for schizophrenia. therapeutic intervention. The most challenging issue for the defi cit ‧ They are defi ned through a number of temporal syndrome is that information about the longitudi- and scalar criteria easily applicable within the nal course of the symptoms required to make the clinical trial context. primary/secondary distinction may not always be In light of the estimated 15% - 20% preva- readily available. In addition, the differentiation lence of the defi cit syndrome, the prevalence of of primary and secondary negative symptoms re- persistent negative symptoms is probably higher quires a level of clinical sophistication above and because persistent negative symptoms also include beyond what is usually available in clinical raters. unresponsive secondary negative symptoms [12]. Also, the prevalence of defi cit syndrome of schizophrenia has been estimated only 15% - 20% Measurement of negative symptoms of patients [4, 14], which cause diffi culty recruit- Instruments for measuring negative symp- ing adequate number of patients for clinical trial toms suitable for use in the clinical trial should and limited the generalizability of the drugs. have the following characteristics: (A) the scale The concept of persistent negative symptoms should measure all of the domains of negative represents a broader concept than the defi cit syn- symptoms and not be contaminated by other do- drome. The criteria of persistent negative symp- mains; (B) it should be sensitive to change; (C) toms [12] are described: the instrument should demonstrate good reliabili- ‧ At least moderate severity of negative symp- ty in the settings where the trials will be carried toms, defi ned on an accepted and validated rat- out; (D) it should be relatively brief; and (E) it ing scale. should be an instrument that can measure negative ‧ A defi ned threshold level of positive symptoms symptoms in international trials that include di- on an accepted and validated rating scale. verse languages and cultures [15]. ‧ No (or low level of) depressive symptoms on An NIMH consensus statement has charac- an accepted and validated rating scale. terized the domains of negative symptoms as • 118 • Drugs for Negative Symptoms of Schizophrenia

blunted affect, alogia, asociality, anhedonia, and sponding to the fi ve domains of negative symp- avolition [4]. A recent review of factor analysis toms [15]. All of them are corresponding to the studies of the SANS found that roughly the same fi ve domains of negative symptoms, except the two factors had been found with rather good con- PANSS without items corresponding to anhedo- sistency [16]. Those two factors consisted of (A) nia. The BNSS and CAINS has separated anhedo- internal experience, which includes apathy, amoti- nia into two parts: the anticipatory component and vation, asociality, and anhedonia; this factor is of- the consumatory component [15]. When using ten termed avolition/ apathy; and (B) behaviors SANS, it was suggested to remove the items in the related to the expression of emotion, specifi cally Attention subscale, as well as the Inappropriate blunted affect and alogia (poverty of speech); this Affect item from the Affective Flattening subscale factor is often termed expressivity. Subsequent [15, 25]. When using PANSS, it was suggested to studies have replicated the existence of these fac- use the PANSS negative factors derived from fac- tors when negative symptoms are rated by other tor analyses, instead of the original PANSS nega- scales as well [17, 18]. Such a fi nding would sug- tive subscale [25]. gest that in the analysis of future treatment trials, these two factors should routinely be examined Consensus on clinical trial design for separately. negative symptoms Recent studies of negative symptom patients ‧ Defi nition of negative symptoms: consensus- have suggested that it may be useful to separate based defi nitions of negative symptoms cur- the anticipatory component of anhedonia (or the rently include the following fi ve sub-domains: wanting) from the consumatory (or the liking) blunted affect, alogia, anhedonia, asociality, component [19, 20]. Studies suggest that schizo- and avolition [4]. phrenia patients have impairments in the anticipa- ‧ Assessment: negative symptoms should be as- tory aspect, but have a relatively normal ability to sessed with a validated interview-based mea- experience consumatory pleasure. sure [26]. Information from informants should There are fi ve instruments suitable for use in be included for ratings when available [27]. clinical trials for negative symptoms, including ‧ Study subjects should be under the age of 65 the Schedule for the Assessment of Negative years [27]. Symptoms (SANS) [21], the Positive and Negative ‧ Severity of negative symptoms: subjects should Syndrome Scale (PANSS) [22], the Negative have no fewer than two negative symptoms and Symptom Assessment Scale (NSA) [23], the Brief at least one should be rated as moderate or Negative Symptom Scale (BNSS) [17] and the greater [27]. Clinical Assessment Interview for Negative ‧ Negative symptoms should be stable and per- Symptoms (CAINS) [24]. All of them are consid- sistent: this may be operationally defi ned using ered to be reliable and valid measures for negative criteria for persistent negative symptoms [12] symptom trials but differ with respect to their do- or the defi cit form of schizophrenia [11]. Before main coverage, use of informants, integration of entering into a negative symptom study, sub- global scores, administration time and compre- jects should demonstrate clinical stability for a hensiveness of their structured interviews. Table 1 period of 4 to 6 months by collection of retro- summarizes the items of these instruments corre- spective information; and prior to entry, the sta- Liu CM • 119 • (to be continued) work activities relationships romantic relationships Motivation for work and school Motivation for recreational activities Motivation for close family/ spouse Motivation for close friendships and Quantity of speech Facial expression expression Vocal Expressive gestures ve domains of negative symptoms experience experience elaboration fi Avolition: behavior Avolition: internal Avolition: Asociality: behavior Asociality: internal Quantity of speech Spontaneous Facial expression expression Vocal Expressive gestures hygiene purpose interviewer quantity content gestures modulation Poor grooming and Reduced sense of Reduced daily activity Reduced social drive Poor rapport with Reduced sexual interest Restricted speech Impoverished speech Affect: reduced display Affect: Reduced expressive ow of ow fl withdrawal expression conversation and Emotional Poor rapport Passive/apathetic Social withdrawal Lack of spontaneity Blunted affect reduced Affect: ections fl SANS PANSS NSA BNSS CAINS school closeness and peers response expression movements gestures Impersistence at work of Physical anergia Ability to feel intimacy and Relationship with friends Poverty of content speech Blocking Increased latency of Unchanging facial Decreased spontaneous Paucity of expressive Poor eye contact non responsivity Affective Lack of vocal in The correspondence of detail items of SANS, PANSS, NSA, BNSS and CAINS to the The correspondence of detail items SANS, PANSS, affect domains Symptom Avolition Grooming and hygiene Asociality Sexual interest and activity Alogia Poverty of speech Blunted Table 1. Table • 120 • Drugs for Negative Symptoms of Schizophrenia Symptom Assessment Scale; (continued from the previous page) activities – past week recreational activities – next week ties – past week social activities – next week work and school activities – next week Frequency of pleasurable recreational Frequency of expected pleasurable Frequency of pleasurable social activi- Frequency of expected pleasurable Frequency of expected pleasurable distress during activities pleasurable activities ed pleasure from future activities Lack of normal Intensity of pleasure Frequency of Intensity of expect- respond interests Prolonged time to Inarticulate speech Slow movements Emotion: reduced range Reduced hobbies and culty in culty fi abstract thinking Stereotyped thinking Dif SANS PANSS NSA BNSS CAINS mental status testing activities Inattentiveness during domains Symptom Other Social inattentiveness Anhedonia Recreational interests and SANS, the Schedule for the Assessment of Negative Symptoms; PANSS, the Positive and Negative Syndrome Scale; NSA, Assessment of Negative Symptoms; PANSS, SANS, the Schedule for BNSS, the Brief Negative Symptom Scale; CAINS, the Clinical Assessment Interview for Negative Symptoms BNSS, the Brief Negative Symptom Scale; CAINS, Clinical Liu CM • 121 •

bility of negative symptoms should be con- lowed except when the antipsychotic has a fi rmed prospectively for four weeks or longer potential pharmacokinetic or pharmacodynam- [27]. ic interaction with the experimental medication ‧ Secondary negative symptoms: Subjects with [26]. notable extrapyramidal side effects from anti- ‧ Monotherapy trials: an experimental medica- psychotic medications should be excluded. tion being considered for broad spectrum anti- Scales measuring the extrapyramidal syn- psychotic effi cacy (e.g., improving both posi- dromes should be included in negative symp- tive and negative symptoms) should initially be tom trials. Subjects should be excluded for demonstrated as effective in treating positive symptoms of depression that do not overlap symptoms. It can then be tested in a comparator with negative symptoms. For those subjects trial against another antipsychotic that does not with positive symptoms, the positive symptoms have effects on negative symptoms, while care- should not be so severe to hinder the assess- fully assessing potential confounders (e.g., de- ment of negative symptoms and should be con- pression, EPS, etc.) to show improvements are fi rmed persistently stable for a period and not specifi c for primary negative symptoms [26]. responsive to current treatment [26, 27]. ‧ Cognitive function assessment: Negative Overview of the Effects of symptom trials should include an assessment Different Classes of Drugs on battery to measure cognition [27]. Negative Symptoms ‧ Functional measures should not be required as a co-primary in negative symptom trials [27]. There have been several meta-analyses and ‧ Subjects currently treated with clozapine systematic reviews about the treatment effects of should not be excluded in negative symptom various classes of drugs on the negative symp- trials of co-medication [27]. toms. Some of those studies have included the ‧ Trial duration: clinical trials evaluating treat- clinical trials in which negative symptoms were ments for negative symptoms should be of lon- not the primary target and all of them have includ- ger duration than those targeting positive symp- ed those clinical trials which did not strictly defi ne toms. The extra time is necessary because negative symptoms as defi cit syndrome or persis- negative symptoms do not improve at the same tent negative symptoms. Therefore, the medica- rate as do positive symptoms [28]. tion effects upon negative symptoms revealed by Preregistration trials should be at least 6 months these meta-analyses and reviews should be viewed in duration, not including prospective assess- as treatment effects upon broadly defi ned negative ment of clinical stability. A briefer duration of symptoms, not defi cit syndrome or persistent neg- treatment is acceptable for proof-of-concept tri- ative symptoms. Because the consensus of meth- als. Phase 2 negative symptom trials should be odological issue about clinical trial on negative 12 weeks and 26 weeks is preferred for Phase 3 symptoms has been achieved several years ago, trials [27]. there may not be enough data accumulating for ‧ Adjunctive agents in clinical trials: In trials ad- meta-analysis of treatment effects upon persistent dressing the use of co-medications to treat neg- negative symptoms using data of clinical trials ative symptoms, all antipsychotics, may be al- meeting the standard consensus. Therefore, I will • 122 • Drugs for Negative Symptoms of Schizophrenia

present the treatment effects of medication on antipsychotics has shown no signifi cant treatment broadly defi ned negative symptoms according to effect [35]. A commentary on the collective work these meta-analyses and systemic reviews and concluded that the evidence is not strong enough highlight some recent clinical trials of which tar- to support their use [36]. get is persistent negative symptoms and which meet the standard consensus in different class of Psychostimulants drugs. An earlier systematic review of psychostim- ulants for negative symptoms has revealed im- Antipsychotics provement of negative symptom scores with vari- A systematic meta-analysis of 168 unique ous agents such as methylphenidate, amphetamine, and independent placebo-controlled trials for neg- and modafi nil or armodafi nil. The literature points ative symtpoms, including 6,503 patients in the to evidence that, used adjunctively, DA agonists treatment arm and 5,815 patients in the placebo may improve negative symptoms without worsen- arm revealed second-generation antipsychotics ing of positive symptoms in selected patients who had signifi cant effect on negative symptoms, are stable and treated with effective antipsychotic while the effect of fi rst-generation antipsychotics medications [37]. A recent meta-analysis has re- is non-signifi cant [29]. But, the effects of second- ported signifi cant differences with modafi nil or generation antipsychotics are modest and not to armodafi nil in treating negative symptoms, but the the level of clinical meaningfulness. A novel anti- effect size was small, and the advantage disap- psychotics, cariprazine, a dopamine D3 and D2 re- pears when chronically ill patients or those with ceptor partial agonist with preferential binding to high negative symptom burden are treated [38].

D3 receptors, have shown superior effects over risperidone on treating the schizophrenia with Glutamate pathway related molecules predominant negative symptoms in a double-blind Evidence continues to grow supporting a rôle randomized controlled trial containing a relative for glutamate in processes critical to schizophre- large sample (230 patients for cariprazine and 231 nia [39]. Two meta-analyses, not specifi c to nega- patients for risperidone) [30]. tive symptoms, have suggested a favorable, albeit small, signal supporting the effi cacy of drugs en- Antidepressants hancing NMDA receptor function (e.g., d-serine, Antidepressants have been used in treating sarcosine, N-acetylcysteine, D-cycloserine), al- negative symptoms for a long time. Two earlier though the effect was different between agents meta-analyses provided equivocal evidence [31] [40, 41]. A relative large scale double-blind ran- and a lack of support [32], respectively, while the domized placebo controlled proof-of-concept trial two recent reports have supported some evidence of bitopertin, a glycine transporter 1 inhibitor, has of benefi ts that differs between agents [29, 33]. successfully demonstrated treatment effects on One recent double-blind randomized controlled persistent negative symptoms of schizophrenia trial using duloxetine add-on risperidone revealed [42]. But a larger scale international phase III trial signifi cant effect of duloxetine in improving nega- for bitopertin has been discontinued due to lack of tive symptoms of schizophrenia [34], while an- effi cacy [43]. The development of molecules with other similar clinical trial using citalopram add-on mGluR2/3- positive allosteric modulation (e.g., Liu CM • 123 •

LY2140023) has also failed eventually [44]. A trials using 5-HT3 antagonists, including six stud- double-blind randomized placebo controlled trial ies (total N = 311). Those study drugs included using another novel molecule, AMG 747, also a one granisetron plus risperidone study, one ondan- glycine transporter 1 inhibitor, has been found to setron plus risperidone study, one ondansetron have signifi cant treatment effects of 15 mg AMG plus haloperidol, and three tropisetron plus ris-

747, but not higher or lower doses, on the im- peridone studies. The results showed 5-HT3 an- provement of PANSS negative symptom factor tagonists add-on therapy is more benefi cial on the score [45]. But the trial was terminated because psychopathology (especially negative symptoms) one patient using 40 mg AMG 747 had Stevens- than controls in patients with schizophrenia [51]. Johnson syndrome/toxic epidermal necrolysis. For NMDA receptor antagonists, a meta- Sex hormones analysis examining amantadine and memantine Pregnenolone, a neurosteroid, has been re- has not supported signifi cant effect in treating ported to have treatment effects on negative negative symptoms, although they seemed to have symptoms of schizophrenia in two randomized small effects on cognitive improvement [46]. controlled trials [52, 53]. Recently, a combination of pregnenolone and l-theanine over 8 weeks can Acetylcholine pathway related molecules decrease both negative and anxiety symptoms of Most of the clinical trials about the related schizophrenia [54]. Raloxifene, an estrogen re- drugs of this pathway have focused on cognitive ceptor modulator, has been reported to improve symptoms as the primary endpoint, instead of negative symptoms over 6 months in post-meno- negative symptoms. Many newer α7 nicotinic pausal female patients with schizophrenia with acetylcholine receptor (α7 nAChR) agonists/par- prominent negative symptoms [55]. tial agonists as well as positive allosteric modula- tors have been developed. A recent phase II trial Anti-infl ammatory agents with the α7 nAChR agonist, TC-5619 failed to Minocycline, a broad-spectrum tetracycline demonstrate any signifi cant effects in treating antibiotic with neuroprotective properties mediat- negative symptoms [47]. ed through anti-infl ammatory, anti-apoptotic, and antioxidant effects [56], has received the greatest Serotonin receptor antagonists attention. A meta-analysis, including 4 random- The notion that serotonin antagonism may ized controlled trials with 330 patients, revealed prove useful in treating negative symptoms came that minocycline is superior to placebo for de- from the early claims that second-generation anti- creasing PANSS negative subscale scores, show- psychotics are superior to fi rst-generation antipsy- ing its value on improving the psychopathology of chotics in treating negative symptoms [48]. A se- schizophrenia, especially the negative symptoms lective 5-HT2 antagonist, ritanserin, has been [57]. A 16-week, double-blind, randomized, pla- reported to have treatment effi cacy for the nega- cebo-controlled clinical trial of minocycline re- tive symptoms in two randomized controlled trials cruited 92 patients with early stage schizophrenia [49, 50]. The more recent focus has turned to se- treated with risperidone has demonstrated that the lective 5-HT3 antagonists (e.g., ondansetron, tro- addition of minocycline to second-generation an- pisetron, granisetron). A meta-analysis of clinical tipsychotic drugs in early schizophrenia has sig- • 124 • Drugs for Negative Symptoms of Schizophrenia

nifi cant effi cacy on negative symptoms [58]. toms. It is partly because heterogeneity of nega- Pioglitazone, an antidiabetic agent with anti-in- tive symptoms and our limited understanding fl ammatory and antioxidant properties, has shown regarding negative symptoms underlying etiology to have effi cacy as an augmentation therapy in and pathophysiology. Another reason is the onset reducing the negative symptoms of schizophrenia of negative symptoms, which can precede the fi rst in a clinical trial [59]. psychotic break, also means that treatments are delayed. Conclusion Based on those evidences in this overview, I hope that improved assessment tools, the develop- There have been a number of important ad- ment of performance-based measures for negative vances in search of pharmacological treatments symptoms, the discovery of biomarkers to use as for negative symptoms over the past decade. For proxies for effi cacy, and improved animal models methodological issue, consensus-based guidelines will help further the development of new thera- have been established for defi ning and measuring peutics. Studies intervening at particular stages of negative symptoms, sample inclusion/exclusion the illness (i.e., prodromal or early in course) may criteria, trial design, and duration. Controlling for also be warranted. Investigations combining spe- symptom stability and ruling out possible second- cifi c pharmacotherapies in combination with spe- ary sources of negative symptoms are the most cifi c psychosocial or psychotherapeutic interven- important for determining whether new medica- tions may also be future possibilities. With tions can treat primary negative symptoms. advances in these areas, We hope to have effective There are some evidences that second-gener- treatments in alleviating negative symptoms, and ation antipsychotics have modest benefi ts for in improving real world functioning and quality of overall negative symptoms over fi rst-generation life. antipsychotics. Those apparent benefi ts are likely largely due to improvements in secondary, rather Acknowledgements than primary, negative symptoms. A novel anti- psychotic, cariprazine, has recently shown signifi - The author declares that he does not have any cantly more improvement than risperidone in competing confl icts of interest in writing this schizophrenia with predominant negative symp- overview. toms. It is worth noting that further development and real experiences are needed in clinical prac- References tice. There is also evidence that some available medications, including antidepressants, NMDA 1. Ventura J, Hellemann GS, Thames AD, Koellner V, glutamatergic modulators, serotonin receptor an- Nuechterlein KH: Symptoms as mediators of the re- tagonists, and some anti-infl ammation agents may lationship between neurocognition and functional offer modest benefi ts as adjunctive treatments for outcome in schizophrenia: a meta-analysis. Schizophr negative symptoms. Despite all the above signifi - Res 2009; 113: 189-99. 2. Erhart SM, Marder SR, Carpenter WT: Treatment of cant fi ndings, there are still no drugs, achieving schizophrenia negative symptoms: future prospects. the level of signifi cant clinical effi cacy and indi- Schizophr Bull 2006; 32: 234-7. cating for the treatment of primary negative symp- 3. Leucht S, Pitschel-Walz G, Engel RR, Kissling W: Liu CM • 125 •

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