Quetiapine ('Seroquel'); an effective and well-tolerated atypical antipsychotic	Abstract Introduction Preclinical Studies Neuroreceptor Affinity Antipsychotic drugs Animal Models of EPS Prolactin effects Clinical Efficacy Placebo-controled trials Trials comparing quetiapine with other antipsychotics Dose Frequency Studies Meta-analysis Safety and tolerability Overall tolerability Conclusions Key points References
PHIL MEATS Department of Psychiatry, Millbrook Unit, Sutton-in-Ashfield Correspondence Address Dr P Meats, Department of Psychiatry, Millbrook Unit, King's Mill, Sutton-in-Ash- field, Nottinghamshire NG17 4JT, UK Tel: +44 1623 784 709 Fax: +44 1623 636 029	First published in The International Journal of Psychiatry In Clinical Practice - Received 4 July 1997; accepted for publication 14 August 1997. Re-published Pharmacy On-line July 1998

Abstract

(Int J Psych Clin Pract 1997; 1: 231 - 239)

INTRODUCTION

Antipsychotic drugs reduce hallucinations, delusions, and psychomotor excitation in patients with schizophrenia and other psychoses. They differ more in their side-effects than in their therapeutic effects, which are broadly comparable. Approximately 75% of patients experience complete or worthwhile improvement in symptoms,^1,2with the remainder proving resistant to treatment. Standard antipsychotic drugs produce a range of side-effects, of which the most problematic are extrapyramidal symptoms (EPS)^.3,4 It has been suggested that EPS increase the risk of depression ⁵ and of poor compliance with treatment, and may also contribute to the high incidence of suicide in schizophrenia. ^6,7 In community settings, non-adherence to treatment and subsequent relapse have been found to be associated with EPS in up to 60% of cases. ^8-10

• there is a substantial minority of `treatment-resistant' patients for whom an effective antipsychotic would be most welcome; and
• in addition, the majority of treatment-responsive patients would welcome newer agents with fewer side-effects.

Inspired by the unique properties of clozapine, a new generation of `atypical' antipsychotic drugs is being developed, which may offer significant improvements over standard antipsychotics. This article reviews findings regarding a novel and promising `atypical' antipsychotic, quetiapine (`Seroquel', ICI 204,626). It looks briefly at the preclinical work that first drew attention to the compound's potential, and then concentrates on its clinical efficacy and tolerability, the areas of most concern to psychiatrists who await new and better drugs for schizophrenia.

PRECLINICAL STUDIES

The search for new drugs for the treatment of schizophrenia has been directed largely by the dopamine hypothesis, which is based on the observation that standard antipsychotic agents share the property of dopamine antagonism. Potential antipsychotic drugs have been identified principally by their ability to antagonize the effects of the dopamine agonists amphetamine and apomorphine. However, drugs selected by this means alone are often found to cause EPS because all share the ability to block postsynaptic D2 receptors. One exception to this is clozapine, a drug withdrawn in the 1970s because of its propensity to cause agranulocytosis. Although clozapine has recently been rehabilitated because it was found to be clinically effective in treatment-resistant schizophrenia, ¹¹a condition of licensing was the requirement for weekly monitoring of white blood-cell counts, which severely restricts its acceptability. This has provoked an intensive search for new `atypical' antipsychotic drugs, which resemble clozapine in their activity in animal models and in their receptor-binding affinities. Quetiapine is one such candidate compound. Preclinical work with quetiapine has involved an extensive range of tests in a wide variety of animal models (see reviews by Goldstein ¹² and Casey ¹³), which have provided evidence that quetiapine has a preclinical profile distinct from those of standard antipsychotics but closely resembling that of clozapine, which suggests that its clinical properties may also be similar.

NEURORECEPTOR AFFINITY

Like clozapine, quetiapine binds to a range of receptors including dopamine D1 and D2, serotonin 5-HT2A and 5-HT1A, histamine, and adrenergic a1 and a2 sites. Again like clozapine, but unlike standard agents, quetiapine has a relatively weak affinity for dopamine D2 receptors, and a much higher affinity for serotonin 5-HT2 receptors.

ANTIPSYCHOTIC DRUGS

Quetiapine is active in a range of behavioural tests commonly used to predict antipsychotic efficacy, including the conditioned avoidance test in squirrel monkeys and the normalization of apomorphine-induced behaviours in monkeys, mice and cats (a full review has been provided by Goldstein ¹²). Although it is extremely difficult to model negative symptoms in animals, it appears that the effects of amphetamine on social behaviour in Java monkeys have some degree of predictive validity in this respect.

Quetiapine was able to reverse such effects, and this offers encouragement that the compound may have enhanced clinical efficacy in combating the negative symptoms of schizophrenia.

ANIMAL MODELS OF EPS

The selectivity of quetiapine for the limbic system is indicated by a reversal of amphetamine-induced inhibition of cell firing at lower doses in limbic A10 dopamine cells than in motor-related A9 dopamine cells. ¹⁴ In addition, quetiapine selectively depolarizes limbic A10 dopamine cells. These effects predict a relative lack of EPS in man. Most drugs that cause EPS in man also produce catalepsy in rats at doses predicted to give antipsychotic efficacy. However, in the case of quetiapine, the dose that produces antipsychotic effects, that is 5 - 20 mg/kg, is much lower than the 80 mg/kg dose required to produce catalepsy equivalent to that seen with 4 mg/kg haloperidol.¹⁵ Antipsychotic drugs produce distinct patterns of expression of early gene products, such as c-fos, in the forebrain. Haloperidol and other conventional antipsychotic drugs with EPS liability are associated with c-fos expression in both limbic and motor-related regions, whereas c-fos expression with clozapine is confined to the limbic areas. Quetiapine behaves similarly to clozapine in this model, which would predict low EPS liability in clinical practice.¹⁶ Perhaps the most compelling fact is that quetiapine has a minimal tendency to cause dystonias in both haloperidol-sensitized and drug-naive monkeys. This is considered to predict a reduced liability to induce EPS and, upon prolonged exposure, tardive dyskinesia in man.¹⁴ Overall, these results suggest that, in clinical practice, quetiapine, along with clozapine, will be less likely to cause EPS than standard antipsychotics.

EFFECTS ON SERUM PROLACTIN

Unlike standard antipsychotics such as haloperidol,  quetiapine produces only a minor and transient elevation of serum prolactin following administration to rodents. In this respect also, quetiapine is similar to clozapine, which produces little or no stimulation of prolactin. ¹⁷ The preclinical results for quetiapine, particularly its similarity to the atypical antipsychotic clozapine, strongly suggest that it will be effective against both the positive and negative symptoms of schizophrenia, and will be relatively free from EPS. The remaining sections of this review examine whether these expectations are borne out in practice.

CLINICAL EFFICACY

To date, over 3000 patients have been treated with quetiapine. Summary information on completed, controlled clinical trials is shown in Table 1. A key criterion for entry to all studies was a DSM-III-R diagnosis of acute exacerbation of chronic or subchronic schizophrenia. Patients treated in these studies were acutely ill, typically with a long history of illness, multiple hospitalizations and previous exposure to antipsychotic medication. They are therefore likely to represent patients routinely encountered in clinical practice. The clinical studies have used the Brief Psychiatric Rating Scale (BPRS), ¹⁸ Positive and Negative Symptom Scales (PANSS), ¹⁹ the Scale for Assessment of Negative Symptoms (SANS), ²⁰ and Clinical Global Impression (CGI) ²¹scores to compare the efficacy of quetiapine against both placebo and active (standard antipsychotic) control drugs.

PLACEBO-CONTROLLED TRIALS: EFFICACY AGAINST BOTH POSITIVE AND NEGATIVE SYMPTOMS

A Phase II clinical study compared quetiapine at doses of up to 750 mg/day with placebo in acutely ill patients with schizophrenia. ²² In terms of BPRS score, CGI severity of illness, and SANS score, patients on quetiapine generally showed a greater degree of improvement at every timepoint than did those on placebo. Together, these data suggest that quetiapine is effective against both the positive and negative symptoms of schizophrenia.

Table One Clinical trials investigating the use of quetiapine in the treatment of schizophrenia. All studies lasted 6 weeks.

Another placebo-controlled study compared the efficacy and safety of quetiapine at high (up to 750 mg/day) and low doses (up to 250 mg/day) with placebo. ²³ With the low dose of quetiapine, there were no differences from placebo for any of the rating scales. However, in patients receiving quetiapine at up to 750 mg/day there were significant improvements compared with placebo in BPRS score, CGI severity of illness and SANS score, again showing quetiapine to be effective in the treatment of both positive and negative symptoms of schizophrenia. A seven-arm dose-response study involved five fixed doses of quetiapine (75, 150, 300, 600 and 750 mg/day), a placebo arm, and a haloperidol (12 mg/day) arm.²⁴ With the exception of 75 mg/day, all the doses of quetiapine gave significantly (P <0.05) larger reductions than placebo in both BPRS total score and CGI severity of illness score.

As might be expected, the haloperidol group also showed a mean reduction from baseline significantly greater than placebo (P50.05). Reductions in the SANS scores, which imply an improvement in the negative symptoms of schizophrenia, were seen in all quetiapine treatment groups. These appeared to show a U-shaped distribution, with the 300 mg group showing the greatest improvement (P <0.05 versus placebo). These data suggest that quetiapine is effective over a wide dose range, from 150 to 750 mg/day, which offers the clinician flexibility to tailor the dose to the individual patient, although the most appropriate dose in clinical practice is likely to lie in the middle of this range. The above three placebo-controlled trials were designed to demonstrate differences between groups with respect to changes from baseline in BPRS total score. On this primary measure, quetiapine was consistently more effective than placebo. The magnitude of improvement with quetiapine was consistent across the trials, was clinically meaningful (a mean reduction of 6 - 10 points), and was comparable to improvements reported in the literature for other anti-psychotic agents.^{25 - 27}In all three trials quetiapine also performed significantly better than placebo when clinical improvement was measured using change from baseline in the CGI score for severity of illness. The CGI is an indicator of the patient's overall psychiatric state and is thus a useful guide to the value of an antipsychotic drug in improving overall psychopathology.

TRIALS COMPARING QUETIAPINE WITH OTHER ANTIPSYCHOTIC AGENTS

Peuskens and Link compared flexible dosing of quetiapine (up to 750 mg/day) with chlorpromazine (up to 750 mg/ day),²⁸ and showed that quetiapine is at least as effective as chlorpromazine in the treatment of the positive and negative symptoms of schizophrenia. The magnitude of reductions from baseline for BPRS, CGI severity of illness, and PANSS(N) scores was significant for both drugs, and the reductions were numerically greater with quetiapine (though not reaching statistical significance). The suggestion that quetiapine may be more effective than chlorpromazine gains further support from the analysis of treatment response in the two groups. Using a relatively strict criterion of at least 50% improvement in BPRS total score at any timepoint in the trial, 65% of patients in the quetiapine group could be classified as `treatment responders' compared with 53% in the chlorpromazine group, a statistically significant difference (P=0.04). In the second comparative study, quetiapine, at a mean daily dose of 450 mg/day, was compared with haloperidol 8 mg/day. ²⁹

Both treatment groups showed marked reductions in PANSS total score: 18.7+1.63 for quetiapine and 22.1+1.63 for haloperidol. The magnitude of these reductions was clinically significant, although the difference between the treatment groups was not. Response to treatment was defined a priori as a reduction of at least 30% in PANSS total score at any time during the study. Thus 44% of individuals in the quetiapine group and 47% of those receiving haloperidol were classified as treatment responders. This difference was not statistically significant. These findings suggest that the efficacy of quetiapine is similar to that of haloperidol in the treatment of schizophrenia.

DOSE FREQUENCY STUDIES: SUPPORT FOR TWICE DAILY DOSING WITH QUETIAPINE

The simpler the dosing schedule, the easier patients find it to adhere to treatment. ³⁰ Hence it is more convenient to give a drug twice daily (bd) rather than three times a day (tid). The studies described above used three times daily dosing, based on an estimated plasma half-life for quetiapine of 6 - 8 h. However, the half-life of receptor occupancy is more relevant to clinical effect and may be longer than the plasma half-life. In order to investigate this, a PET scan study by Gefvert et al compared the plasma elimination half-life of quetiapine with the occupancy half-lives at dopamine D2 and serotonin 5-HT2 receptors. ³¹ The ratio of D2 : 5-HT2 receptor occupancy was 1:2, which is similar to that seen with clozapine. The results showed that while the plasma half-life was 5.3 h, the D2-receptor occupancy declined more slowly (half-life, 6 - 6.4 h) and serotonin 5-HT2 occupancy fell even more slowly (half-life, 20 - 27 h). These results support the possibility of twice daily administration. A study reported by Fleischhacker et al compared the efficacy of two dosing regimens of quetiapine 450 mg/day (225 mg bd and 150 mg tid). 32 There was no placebo group, although a group of patients received a dose of quetiapine considered to be subtherapeutic (25 mg bd). Both of the 450 mg/day groups did significantly better than the 50 mg/day group in terms of improvement of BPRS and CGI scores. The responses in the bd group were marginally better than for the tid group. Moreover, the bd group performed better on the SANS scale of negative symptoms than the tid group, and significantly better than the 50 mg/day group. This study therefore suggests that bd dosing is likely to be at least as effective as a tid regimen, and offers additional flexibility and convenience of administration.

META-ANALYSIS

In order to discover more about the efficacy of quetiapine in the treatment of schizophrenia, the studies reported by Borison et al, ²² Small et al, ²³ Fleischhacker et al ³² and Arvanitis et al ²⁴ were included in a meta-analysis. The aim was to estimate the benefit of quetiapine compared with placebo, as measured by changes in BPRS total and SANS score. To do this, all the doses of quetiapine from the studies of Small et al ²³ and Arvanitis et al ²⁴ were aggregated and included in the quetiapine group. In the study reported by Fleischhacker et al, ³² which did not have a placebo group, the low dose (25 mg bd) was included in the placebo group. In both cases, this is likely to have given a more conservative estimate of the true effect of treatment with quetiapine.

For each study, the magnitude and direction of the estimated treatment effect indicate that quetiapine is beneficial.  The clear separation of the estimated treatment effect from zero, together with the narrow confidence interval, provide further support for the beneficial treatment effect of quetiapine. A similar meta-analysis, conducted on the change from baseline in SANS score, also confirmed that quetiapine treatment was associated with greater improvement than placebo (P<0.05), providing the clinician with further evidence of the potential value of quetiapine in clinical practice.

LONG-TERM EFFICACY OF QUETIAPINE

The above studies, conducted with patients undergoing acute exacerbation of chronic schizophrenia, demonstrate the effectiveness of quetiapine in the acute treatment of schizophrenia. After completing the short-term studies, a number of patients continued to take quetiapine in an open-label extension (OLE) phase. While this is not a controlled clinical trial, it does allow comparison with other published studies. Therefore, to examine the effectiveness of quetiapine in maintaining clinical response, the progress of patients who had initially responded to quetiapine and who entered an OLE phase was examined. In total, of the patients who entered the OLE phase of the studies reported by Fleischhacker et al ^29,32 and Arvanitis et al, ²⁴ 265 were eligible for one year's treatment and could also be classified as initial responders to quetiapine, either by showing a 40% reduction from baseline in BPRS score or by scoring 18 or less on BPRS at the end (day 42) of double-blind treatment. Of these 265 patients, 88 (33%) of the total were still taking quetiapine after one year. This one-year completion rate is comparable with the published completion rates for long-term extension trials with the other recently intro- duced antipsychotic agents, olanzapine (35%) ²⁶ and sertindole (34%). ³³ Mean changes from OLE baseline over time were small and did not approach the levels seen before the initiation of double- blind treatment, which suggests continued utility over a sustained period of time.

CLINICAL SAFETY AND TOLERABILITY

Tolerability data are available for the 3726 patients who participated in the completed efficacy, tolerability and pharmacokinetic studies (JS Helliwell, personal communication). The total exposure to quetiapine now exceeds 1103 patient-years. In particular, 640 patients were exposed to quetiapine for more than 6 months, 378 patients for more than 1 year, and 137 for more than 2 years. Most patients were exposed to daily doses within the effective dose range of 150 - 750 mg/day.

GENERAL ADVERSE EVENTS

As in any investigative drug programme, a range of adverse events was reported with quetiapine. Those occurring with a frequency greater than 10% were somnolence, headache, agitation and insomnia, some of which may have been related to the underlying illness rather than to the treatment. Events which occurred with an incidence statistically significantly greater than with placebo were somnolence, dry mouth, increased alanine aminotransfer- ase (ALT) and aspartate aminotransferase (AST) activities, abdominal pain and weight gain. Adverse events were associated with few withdrawals: a post hoc analysis of data from all controlled Phase II/III trials showed no significant difference between the numbers of withdrawals due to adverse events in the quetiapine and the placebo groups. The tolerability aspects of quetiapine which are particularly relevant to its use as an antipsychotic agent are discussed below.

EPS

The occurrence of EPS in the quetiapine clinical trial programme was recorded using the following measures: . the Simpson-Angus scale, sometimes modified to include an item for akathisia . the incidence of EPS adverse events . the use of anticholinergic medication for the treatment of EPS . the number of withdrawals from treatment due to EPS . the Barnes Akathisia Scale. In placebo-controlled studies, the incidence of EPS (including akathisia) across the entire quetiapine dose range was the same as that with placebo. In the quetiapine/ haloperidol study, Simpson-Angus scale scores in the five quetiapine groups did not differ significantly from those for patients on placebo, but all showed small reductions from their baseline values. ²⁴

When the changes from baseline values were grouped and re-analysed, the quetiapine and placebo groups tended to have more patients who improved, while the haloperidol group had more patients who deteriorated. In the placebo-controlled studies, 8.6% of patients on quetiapine needed anticholinergic drugs to control EPS, compared with 12.6% of patients on placebo. The incidences of EPS adverse events were also similar for the two groups, and were generally low (Table 2). The quetiapine/haloperidol comparative study showed that the incidence of EPS was significantly lower with quetiapine than with haloperidol. 29 In this study, 51% of patients on haloperidol had a worse score on the Simpson- Angus scale at the end of the study than at the beginning, compared with only 19% of patients taking quetiapine (P50.0001). Haloperidol was associated with more akathisia, parkinsonism and dystonia than quetiapine (Table 3). Only 13% of quetiapine patients required anticholinergic medication, compared with 49% of halo- peridol patients. No withdrawals due to EPS were reported in the quetiapine group, whereas 4.4% of patients in the haloperidol group withdrew. Likewise, data from the quetiapine/chlorpromazine comparative study suggest that quetiapine may have advantages over chlorpromazine in terms of tolerability, especially in EPS. 28 Analysis of Simpson-Angus scores and Barnes Global Clinical Assessment of Akathisia indicated trends towards greater improvement in patients taking quetiapine, and there was a significant difference in favour of quetiapine at day 42 (the end of the study). The only withdrawal from the study due to an EPS adverse event was a case of acute dystonia in a chlorpromazine patient.

ANTICHOLINERGIC DRUGS

Quetiapine has minimal intrinsic anticholinergic proper- ties, and hence a low incidence of anticholinergic effects (such as blurred vision, acute confusional state, bladder and bowel dysfunction) was recorded in schizophrenic patients entering clinical trials. The effects were mild and transient, and did not generally lead to withdrawal from treatment.

CLINICAL CHEMISTRY

Asymptomatic elevations in serum transaminase (ALT, AST) or gamma-glutamyltransferase levels have been observed in some patients taking quetiapine. These were usually reversible on continued quetiapine treat- ment. Quetiapine treatment was associated with small dose- related decreases in thyroid hormone levels, particularly total and free T4. In nearly all cases, these effects reversed on stopping treatment with quetiapine. The reduction in total and free T4 was maximal within 2 - 4 weeks of quetiapine treatment, with no further reduction during long-term treatment. These changes in thyroid function were not seen to be clinically significant.

SERUM PROLACTIN

Hyperprolactinaemia, an unwanted effect of many anti- psychotic agents, may be associated with problems such as gynaecomastia, amenorrhoea, impotence and possibly, in the long term, with osteoporosis. In the clinical trials described above, quetiapine was not associated with elevations in serum prolactin and indeed was often associated with a reduction. Reductions in serum prolactin were significantly greater during quetiapine than during chlorpromazine treatment (P=0.0035). In the seven-arm dose-response study, haloperidol was associated with an increase in serum prolactin significantly greater than that seen with placebo (P=0.0075), whereas quetiapine treatment was associated with a small reduc- tion from baseline. ²⁴

HAEMATOLOGY

Despite substantial patient exposure to quetiapine, no cases of agranulocytosis have been noted to date, nor have there been any deaths from any cause that could have been the result of undetected agranulocytosis. Therefore, there appears to be no need for the regular haematological monitoring that is essential during clozapine treatment.

Table 2

Incidence of acute EPS adverse events in quetiapine placebo- controlled studies. Note that a patient may have more than one type of EPS ^22-24 .

Table 3

Incidence of acute EPS adverse events with quetiapine and haloperidol. ²⁹ Note that a patient may have more than one type of EPS

CARDIOVASCULAR EFFECTS

In common with many other antipsychotic drugs, quetiapine was associated with some cardiovascular effects such as orthostatic hypotension and dizziness. These events usually occurred during the initial period of dose titration, and seldom required cessation of treatment. Blood-pressure monitoring is not routinely required, but should be conducted if there are signs of orthostatic hypotension. Many antipsychotic agents cause ECG changes, often with prolongation of the QTc interval, which is an important cause of arrhythmias. ECG recordings in clinical trials showed little mean change in QTc intervals in patients exposed to quetiapine, and there was no relation between plasma levels of quetiapine and any changes in the QTc interval. Quetiapine appears to have minimal pro- arrhythmic activity, and routine ECG monitoring is unlikely to be required in clinical practice.

SEIZURE THRESHOLD

Unlike many antipsychotic drugs, quetiapine appears to have a low propensity to cause seizures. The clinical trials all excluded patients with any history of seizures; therefore the occurrence of such adverse events during the trials, although rare, would have to be regarded as significant. The incidence of seizures in patients taking quetiapine (three events in 100 patient-years) was comparable with that for placebo (seven events in 100 patient-years), haloperidol (five events in 100 patient-years) or chlorpromazine (22 events in 100 patient-years).

SEXUAL DYSFUNCTION

It is likely that symptoms of sexual dysfunction are under- reported by patients, and such events may be unacknow- ledged or unrecognized in clinical practice. The incidence of sexual dysfunction appears to be low with quetiapine: of the patients who received quetiapine in the controlled clinical trials, only 13 reported sexual problems that might have been related to treatment. The rarity of reported sexual dysfunction may reflect the lack of sustained hyperprolactinaemia seen with quetiapine.

WEIGHT GAIN

Weight gain was reported as an adverse event by 2% of patients in placebo-controlled studies. In the first 6 weeks of treatment with quetiapine there may be a modest weight gain of about 2 kg. However, this does not appear to persist during long-term treatment, and may reflect improvements in the patient's nutrition and general well-being.

OVERALL TOLERABILITY OF QUETIAPINE

The above data show that quetiapine is generally well tolerated, particularly with respect to EPS, which are most often identified as a problem by patients, and which have frequently been reported to be associated with non- compliance. ^{8 - 10} The absence of serious haematological effects of the kind seen with clozapine is also an important aspect of the tolerability profile of quetiapine, as the risk of such serious complications places significant restrictions on the use of an antipsychotic agent, no matter how effective or well tolerated it is in other respects.

CONCLUSIONS

Quetiapine is an effective treatment for both the positive and negative symptoms of schizophrenia. Clinical trials show that it is at least as effective as standard antipsychotic agents such as haloperidol, and is better tolerated. Patients in these trials were moderately to severely affected by schizophrenia: they tended to have recurrent illness and to have been ill for a long time. This means that the trial results should be applicable to common clinical practice with patients who have acute relapses. Further work is necessary to determine if there is any benefit in patients with treatment-resistant schizophrenia. Particular advantages of quetiapine over standard antipsychotic agents are the freedom from EPS and the minimal interference with plasma prolactin. The in- cidence of other side-effects, including hepatic and cardiovascular side-effects, convulsions, and sexual dysfunction, appears no worse than with standard antipsychotics. As with all agents which act on the serotonergic system, there remains the possibility of weight gain in some patients. With its balance of good efficacy, safety and tolerability, plus the convenience of twice-daily dosing, quetiapine offers the clinician a significant advance over the standard antipsychotic drugs that have long been the mainstay of the pharmacological treatment of schizo- phrenia.

KEY POINTS .

• Quetiapine is a novel, atypical antipsychotic, and is as effective as haloperidol and chlorpromazine in the treatment of schizophrenia .
• Quetiapine, across its dose range, has demon- strated a low propensity for extrapyramidal symptoms in clinical trials in patients with relapses of moderate or severe schizophrenia .
• Quetiapine offers the clinician a significant advance over standard antipsychotic drugs in the treatment of schizophrenia

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