Early use of clozapine for poorly responding first-episode psychosis

Although most patients treated for first-episode schizophrenia will experience considerable improvement with initial antipsychotic therapy, a subgroup experiences significant ongoing positive symptoms. Clozapine has unique efficacy in improving treatment-resistant patients with chronic schizophrenia, but its role in the treatment of first-episode patients remains unclear. A standardized treatment algorithm was implemented in our First Episode Psychosis Program, with patients receiving 2 trials with 2 second-generation antipsychotics (olanzapine, quetiapine, or risperidone at low, medium, and high doses), followed by a trial of clozapine as early as 25 weeks into the start of their treatment. Patients progress along the algorithm according to their response as defined by clinical rating scales. To date, 123 patients with first-episode schizophrenia have been treated according to the algorithm. Of these, 93 (76%) responded to the first trial of an antipsychotic. Only 7 (23%) of the remaining 30 patients responded to a second antipsychotic trial; 13 of the remaining 23 individuals agreed to a trial of clozapine. We compared the clozapine-treated group with a group of 9 patients who refused clozapine and chose to continue the same antipsychotic treatment as before. Subjects who received clozapine experienced a mean Brief Psychiatric Rating Scale change of 19 points (from 53.5 to 34.5) and a change in the Clinical Global Inventory severity rating from 5.4 to 3.5 (from severely ill to mildly ill); those who refused clozapine had a 2-point increase in mean Brief Psychiatric Rating Scale (from 53 to 55) and a 0.6-point increase in the mean Clinical Global Inventory severity rating from 5.4 to 6 (remaining markedly to severely ill). In clinical practice, there is a hesitancy to switch individuals to clozapine given its side effect profile and position as treatment of "last resort." The present findings suggest that clozapine may have an important role in the early treatment of first-episode patients whose psychosis does not remit with other second-generation antipsychotics during the first months of treatment.     

Beneficial effect of olanzapine in schizophrenic patients with obsessive-compulsive symptoms

Some studies suggest that obsessive-compulsive symptoms may be common (7.8-46%) in schizophrenic patients and seem to be poorly responsive to drug therapy. Conventional neuroleptics are of limited value, but adjunctive anti-obsessive agents (clomipramine, fluvoxamine) may be an option. Although novel atypical antipsychotics (clozapine, risperidone) reportedly aggravate the obsessive-compulsive symptoms, a recent trial has shown that olanzapine did not induce new-onset obsessive-compulsive symptoms in schizophrenic patients. We report our experience with three schizophrenic patients with obsessive-compulsive symptoms who were unsuccessfully treated with various conventional neuroleptics in combination with anti-obsessive agents and subsequently showed resistance or intolerance to clozapine. All of them were switched to olanzapine (10-20 mg/ day). All patients demonstrated a significant improvement in both schizophrenic and obsessive-compulsive symptoms as measured by the Brief Psychiatric Rating Scale (BPRS) and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Within 5-8 weeks of initiation of olanzapine, the BPRS scores of the three patient decreased by 53%, 51% and 48%, and the Y-BOCS scores by 68%, 73% and 85%. Olanzapine was well tolerated. These preliminary results suggest that olanzapine may be a therapeutic option in schizophrenic patients with obsessive-compulsive symptoms.     

A comparison of olanzapine with haloperidol in cannabis-induced psychotic disorder: a double-blind randomized controlled trial.

Little controlled data exist on the treatment of substance induced psychotic disorders. In this study, 30 patients meeting DSM-IV criteria for cannabis induced psychotic disorder were randomly allocated to receive either olanzapine or haloperidol in a 4-week double-blind clinical trial. There were no significant outcome differences between the two groups on any of the primary outcome measures, the Brief Psychiatric Rating Scale (haloperidol 25.7; olanzapine 27.1; P = 0.70); Clinical Global Impression (CGI) severity scale (haloperidol 1.8, olanzapine 2.3; P = 0.21) or the CGI improvement scale (haloperidol 1.3, olanzapine 1.7; P = 0.16). The haloperidol group however, developed significantly more extrapyramidal side-effects as measured by the Simpson Angus Scale (haloperidol 11.4, olanzapine 2.5; P = 0.014). Significantly (P = 0.027) more biperidin was used for extrapyramidal side-effects in the haloperidol (7.143 mg) than in the olanzapine (0.357 mg) group. Olanzapine appears to be as effective as haloperidol in the treatment of cannabis induced psychotic disorder, but is associated with a lower rate of extrapyramidal side-effects.     

Olanzapine compared to lithium in mania: a double-blind randomized controlled trial

Neuroleptics are of established efficacy in mania. Controlled data on the use of olanzapine in mania is however, absent. In this study, 30 patients meeting DSM-IV criteria for mania were randomly allocated to receive either olanzapine or lithium in a 4 week double-blind randomized controlled design. There were no significant outcome differences between the two groups on any of the primary outcome measures, the Brief Psychiatric Rating Scale (lithium 28.2; olanzapine 28.0; P = 0.44); Clinical Global Impression (CGI) improvement scale (lithium 2.75, olanzapine 2.36; P = 0.163) or the Mania Scale (lithium 13.2, olanzapine 10.2; P = 0.315). Olanzapine was however, significantly superior to lithium on the CGI-severity scale at week 4 (lithium 2.83, olanzapine 2.29; P = 0.025). Olanzapine did not differ from lithium in terms of treatment emergent extrapyramidal side-effects as measured by the Simpson-Angus Scale. Olanzapine appears to be at least as effective as lithium in the treatment of mania.     

Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia in routine clinical care: a randomized, controlled trial

This multisite study was conducted to compare the efficacy and tolerability of combination treatment with clozapine plus aripiprazole versus combination treatment with clozapine plus haloperidol in patients with schizophrenia who do not have an optimal response to clozapine. Patients continued to take clozapine and were randomly assigned to receive daily augmentation with aripiprazole or haloperidol. Physicians prescribed the allocated treatments according to usual clinical care. Withdrawal from allocated treatment within 3 months was the primary outcome. Secondary outcomes included severity of symptoms on the Brief Psychiatric Rating Scale and antipsychotic subjective tolerability on the Liverpool University Neuroleptic Side Effect Rating Scale. A total of 106 patients with schizophrenia were randomly assigned to treatment. After 3 months, we found no difference in the proportion of patients who discontinued treatment between the aripiprazole and haloperidol groups (13.2% vs 15.1%, P = 0.780). The 3-month change of the Brief Psychiatric Rating Scale total score was similar in the aripiprazole and haloperidol groups (-5.9 vs -4.4 points, P = 0.523), whereas the 3-month decrease of the Liverpool University Neuroleptic Side Effect Rating Scale total score was significantly higher in the aripiprazole group than in the haloperidol group (-7.4 vs -2.0 points, P = 0.006). These results suggest that augmentation of clozapine with aripiprazole offers no benefit with regard to treatment withdrawal and overall symptoms in schizophrenia compared with augmentation with haloperidol. However, an advantage in the perception of adverse effects with aripiprazole treatment may be meaningful for patients.     

The effects of clozapine and high-dose olanzapine on brain function in treatment-resistant schizophrenia: a case study

Although demonstrating superior efficacy in people with treatment-resistant schizophrenia, clozapine may cause serious side effects, requires blood monitoring and is costly to administer. Olanzapine is similar to clozapine in molecular structure and pharmacologic action but has not demonstrated as robust results as clozapine at routine doses (10-25 mg). Here we present a case study measuring blood flow by positron emission tomography (PET) imaging for a patient treated sequentially with a high dose of olanzapine (50 mg/day) followed by clozapine each for 8 weeks in a double-blind design. During a task, clozapine produced more brain activation patterns than during treatment with olanzapine or during the drug free condition (2 week washout). Clozapine resulted in recruitment of frontal, parietal and cingulate regions that did not appear to be active during olanzapine in this 44 year old right handed male. Additionally, a more robust decrease in symptoms was noted on the Brief Psychiatric Rating Scale (BPRS) score than with olanzapine treatment. These findings suggest that high doses of olanzapine do not produce similar brain activation patterns as clozapine in people with treatment-resistant schizophrenia.     

Olanzapine as alternative therapy for patients with haloperidol-induced extrapyramidal symptoms: results of a multicenter, collaborative trial in Latin America

Conventional antipsychotic agents can induce extrapyramidal symptoms (EPS) that may be alleviated by switching patients to novel agents such as olanzapine. Patients with schizophrenia and related disorders (ICD-10) who were taking haloperidol (N = 94; mean dose = 12.7 mg/day) and had EPS (Simpson-Angus Scale [SAS] > 3) were directly switched to 6 weeks of open-label olanzapine treatment (mean dose = 11.4 mg/day). There were significant mean improvements (p <0.001 for all measurements) from baseline to endpoint on the SAS (-9.69+/-5.33; percentage change, 87.2%), the Barnes Akathisia Scale (-1.00+/-1.19; percentage change, 82.5%), and the Abnormal Involuntary Movement Scale (-1.48+/-2.89; percentage change, 81.1%), and anticholinergic use decreased from 47.9% to 12.8% (mean baseline to endpoint change: -1.52+/-1.91-mg equivalents of benztropine; p < 0.001). Significant mean baseline to endpoint improvements (p < 0.001 for all measurements) were observed on the Positive and Negative Syndrome Scale (PANSS; -25.28+/-18.67; percentage change, 30.3%), the PANSS-extracted Brief Psychiatric Rating Scale (0-6 scale, -13.41+/-10.16; percentage change, 54.4%), and the Clinical Global Impressions Severity scale (-1.16+/-1.19; percentage change, 26.4%). Spontaneously reported treatment- emergent adverse events with a greater than 5% incidence were somnolence (16.0%), increased appetite (14.9%), weight gain (11.7%), headache (8.5%), anxiety (7.4%), dizziness (6.4%), and insomnia (5.3%). Criteria for a successful switch were met by 90.5% of patients. Psychotic symptom exacerbation was experienced by 30.9% of patients at any time during the study and by 11.7% of patients at endpoint. Results suggest that a direct switch to olanzapine is a therapeutic option when patients with haloperidol-induced EPS are unable to tolerate a more gradual switch.     

Treatment of severely psychotic inpatients with schizophrenia: olanzapine versus other antipsychotic drugs

Nine hundred and ten schizophrenic inpatients suffering from acute psychotic episodes were included in a naturalistic study. Patients were prescribed treatment with olanzapine (OLZ) or with typical antipsychotic (TYP) drugs. Patients receiving another atypical antipsychotic were excluded. Of the whole sample, 483 (53.4%) were treated with olanzapine and 421 (46.6%) with typical antipsychotics. Three specific subpopulations of greater severity were defined: patients with prominent psychotic symptoms, agitated patients, and patients initially treated with intramuscular (i.m.) medication because of their acute clinical condition. Severity of illness was assessed using the Clinical Global Impression (CGI) scale for severity, the Brief Psychiatric Rating Scale (BPRS) and the Nursing Observational Scale for Inpatient Evaluation. Baseline differences were adjusted per data analysis. The mean change from baseline to endpoint of overall symptomatology (total BPRS score) was significantly greater in the olanzapine group compared to the typical antipsychotic-treated group, both in the sample of patients with prominent positive symptoms (P < 0.001) and in the sample of agitated patients (P =0.015). Significant differences were also found in BPRS positive scores, BPRS negative scores and CGI scores in these two populations. Patients who had received previous i.m. drugs showed no statistically significant differences in symptomatic improvement between both treatments groups, except for a more favourable response of BPRS negative subscores in the olanzapine group (P =0.015). The results suggest that olanzapine may be considered as a first line treatment for severely psychotic inpatients with schizophrenia.     

Amantadine for weight gain associated with olanzapine treatment.

Patients with schizophrenia (Sch), schizoaffective, schizophreniform, or bipolar (BP) I disorders [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)]; not manic or acutely psychotic [Brief Psychiatric Rating Scale (BPRS) total score < or =45]; treated with olanzapine for 1-24 months; and who had gained > or =5% of their initial body weight were examined to determine whether amantadine could attenuate weight gain or promote weight loss. Olanzapine (Olz; 5-20 mg/day) was co-administered with double-blind treatment of 100-300 mg/day amantadine (Olz+Amt, n=60) or placebo (Olz+Plc, n=65). Visit-wise analysis of weight showed that weight change from baseline [last-observation-carried-forward (LOCF)] in the Olz+Amt group was significantly different from the Olz+Plc group at weeks 8 (P=0.042), 12 (P=0.029), and 16 (primary endpoint, mean+/-S.D.: -0.19+/-4.58 versus 1.28+/-4.26 kg, P=0.045). Mean BPRS total score, positive subscale, and anxiety-depression scores improved comparably in both groups, and Montgomery-Asberg Depression Rating Scale (MADRS) total score improved in the Olz+Amt group. Overall, amantadine was safe, was well tolerated, and attenuated weight gain or promoted weight loss in some patients who had gained weight during olanzapine therapy.     

A placebo-controlled study of extract of ginkgo biloba added to clozapine in patients with treatment-resistant schizophrenia

The focus of this study was the systematic evaluation of the clinical effects of the extract of ginkgo biloba (EGb) as an adjunct to the atypical antipsychotic clozapine in the treatment of refractory schizophrenia. In a placebo-controlled study, 42 patients with chronic, treatment-resistant schizophrenia, who were maintained on optimal doses of clozapine, were administered either 120 mg/day of EGb (N=20) or placebo (N=22) for 12 weeks. Clinical evaluations with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, and the Scale for the Assessment of Negative Symptoms were completed biweekly. The use of EGb as an adjunct to clozapine was effective in decreasing negative symptoms, but not positive and overall psychopathology symptoms. EGb produced a mean 7.9+/-7.0 point reduction in the total Scale for the Assessment of Negative Symptoms score compared with a mean 1.8+/-3.5 point reduction in the placebo group (P=0.034). These preliminary data suggested that EGb was found useful for enhancing the effect of clozapine on negative symptoms in patients with treatment-resistant schizophrenia.     

The efficacy and safety of olanzapine for the treatment of geriatric psychosis

Elderly psychiatric patients often present with psychotic symptoms that need antipsychotic treatment. Olanzapine is one of the atypical antipsychotics with efficacy for psychotic symptoms and a safer side-effect profile than typical antipsychotics. This study was conducted to assess the efficacy and safety of olanzapine for treatment of geriatric psychosis. The sample population comprised 94 acute-ward patients who were 65 years of age or older. Clinical assessment was conducted at baseline and also at 4 weeks after commencement of olanzapine treatment, with use of the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression Improvement (CGI-I) instruments. A 4-week therapeutic evaluation was completed for 80 patients, 73 of whom (91.3%) experienced mild to substantial improvement as determined from the CGI-I. A mean 52.6% reduction from baseline was also determined from the BPRS. The mean daily dosage of olanzapine in the fourth week was 10.1 +/- 5.3 mg/d (range, 2.5-20.0). Higher olanzapine dosages were administered for patients with functional psychoses than for an analogous group with organic mental disorders. Adverse effects were monitored for all 94 patients, the most common of which were somnolence (18.1%), dizziness (18.1%), and weakness of legs or bradykinesia (16.0%). Body weight and fasting triglyceride and sugar levels were significantly elevated after olanzapine treatment (2.2, 39.9, and 8.9% from baseline, respectively). It seems reasonable to suggest that olanzapine is efficacious for geriatric patients with psychosis and that the dosage should be diagnosis-dependent.     

Remission in schizophrenia: the relationship to baseline symptoms and changes in symptom domains during a one-year study

The concepts of partial recovery and remission have become increasingly important for the evaluation of the effectiveness of schizophrenia therapeutics. The relationship of baseline symptoms and changes in symptoms to remission of psychosis was evaluated. Fifty-six outpatients with residual schizophrenia completed a double-blind trial of olanzapine versus haloperidol and were then enrolled into a one-year open-label trial of olanzapine. Out of these 56 subjects, 13 (23%) met remission criteria at the beginning of the open-label treatment and were excluded. During the one-year study, 7/43 (16%) subjects met remission criteria. These subjects had significantly lower baseline ratings for tardive dyskinesia (TD) than subjects who did not achieve remission (1.8 +/- 1.5 vs. 4.2 +/- 4.6, P = 0.03). As expected, remitted subjects had significantly greater improvements in Brief Psychiatric Rating Scale total scores, positive subscale scores and scale for the Assessment of Negative Symptoms total scores. Remitted subjects also experienced a significantly greater improvement in depressive symptoms (P = 0.001), activation (P = 0.005), and Clinical Global Impressions scores (P < 0.001), as well as greater improvements in extrapyramidal symptoms (P = 0.007) and TD (P < 0.001). These results suggest that the relationship of depressive symptoms and improved side effects to the construct of remission in schizophrenia may deserve special attention. Future studies should aim to relate remission criteria to functional outcomes, cognition, and other important symptom domains.     

Practical issues with amisulpride in the management of patients with schizophrenia

Amisulpride is an atypical antipsychotic with a significantly greater effect size than first-generation, typical antipsychotics, and efficacy at least similar to that of olanzapine and risperidone in large-scale clinical trials in schizophrenia. Amisulpride provides greater improvement in positive and negative symptoms of schizophrenia, a better long-term outcome than typical antipsychotics, and distinct tolerability advantages over typical antipsychotics, which are reported to cause extrapyramidal symptoms (EPS) in 20-50% of patients. In addition, amisulpride is associated with significantly less weight gain than olanzapine and risperidone, does not increase body mass index, and favourably influences lipid profiles. In many patients with schizophrenia, adverse events impair adherence to treatment, and switching from typical or atypical antipsychotic therapy to amisulpride may be clinically appropriate. Observational drug-utilization studies suggest that many physicians switch to amisulpride because of fewer EPS and/or less weight gain and improved patient adherence. Cross-tapering (over 4 weeks), rather than abrupt cessation of pre-switch treatment, is preferred. Amisulpride has a low risk of drug-drug interactions, and, during cross-tapering, patients can remain on concurrent treatments (e.g. anticholinergics and antiparkinsonian agents) until the effective dosage has been reached. An appropriate amisulpride starting dose is 800 mg/day for patients with acute psychotic exacerbations, 400-800 mg/day for patients with predominantly positive symptoms, and 100-300 mg/day for predominantly negative symptoms. Amisulpride may be particularly suitable for clozapine-augmentation therapy in patients with refractory schizophrenia. Indeed, amisulpride is more effective than quetiapine as augmentation therapy in patients partially responsive to clozapine, and several prospective open-label studies and case series have reported promising results for amisulpride/clozapine combination therapy. In three prospective studies, addition of amisulpride 200-800 mg/day to clozapine significantly reduced mean scores on the Brief Psychiatric Rating Scale (BPRS) total (-33% to -35%), Clinical Global Impression (CGI)-Severity scale (-31%), Positive and Negative Syndrome Scale total (-22%), and Scale for the Assessment of Negative Symptoms (-34%). The proportion of responders (CGI score > or =3 or BPRS improvement >20%) was 71-86%. Retrospective case-series analyses have also reported improved psychopathological state, reduced adverse events, and lower clozapine dosage requirement with use of this combination. The pharmacological and clinical profiles of amisulpride suggest that this agent is a viable clinical option when a change of antipsychotic therapy is required in patients with schizophrenia because of lack of efficacy, adverse events and poor adherence to treatment, or for augmentation of clozapine in treatment-resistant illness.     

Olanzapine and sulpiride: a preliminary study of combination/augmentation in patients with treatment-resistant schizophrenia

Coadministration of olanzapine, an atypical neuroleptic, with sulpiride, a selective D2 antagonist, is suggested as an efficient strategy for treating patients with resistant unremitting schizophrenia. The psychopharmacologic rationale that may account for the enhanced clinical efficacy of combining sulpiride with olanzapine and vice versa is the difference in affinity of the two drugs to brain receptors. Olanzapine affinity is related more to serotonin 5-HT2 than to dopamine-2, whereas sulpiride is considered a selective D2 blocker. The adjunction of a selective D2 antagonist to olanzapine may act as the olanzapine's augmentor by enhancing D2 blockage. This mode of treatment was introduced to six patients with chronic schizophrenia who showed noteworthy and rapid clinical improvement, supported by a decrease in their scores on the Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale. No bothersome side effects were noticed. This clinical approach is in accordance with the findings of previous reports assessing the efficacy of the combined treatment of clozapine and sulpiride. The grounds for this treatment regimen using olanzapine rather than clozapine are discussed, calling for further studies to affirm the hypothesis and clinical results.     

A double-blind,randomised comparative trial of amisulpride versus olanzapine in the treatment of schizophrenia: short-term results at two months

OBJECTIVE: To compare the efficacy and safety of the atypical antipsychotics amisulpride and olanzapine in the treatment of acute psychotic exacerbations of schizophrenia. DESIGN AND SETTING: A multinational, double-blind randomised clinical trial. PATIENTS AND TREATMENT: Three hundred and seventy-seven patients with predominantly positive symptomatology were treated for six months with either amisulpride (200-800 mg/d) or olanzapine (5-20 mg/d). MAIN OUTCOME MEASURES: Short-term results were analysed after two months of treatment. The primary efficacy measure was the change of score on the Brief Psychiatric Rating Scale (BPRS). Other measures of efficacy and safety were also evaluated. RESULTS: Psychotic symptoms, as measured on the BPRS score, improved with both treatments, amisulpride being equivalent to olanzapine. All BPRS factor scores, as well as depressive symptoms, improved to a similar extent with both treatments. Less than five per cent of patients withdrew for adverse events, and there was no evidence for the emergence of extrapyramidal symptoms with either treatment. Statistically significant greater weight gain (2.7 +/- 3.9 kg) was observed during the study in the olanzapine group, compared with the amisulpride group (0.9 +/- 3.2 kg, p < 0.0001). CONCLUSIONS: Amisulpride and olanzapine show equivalent efficacy at 2 months in the treatment of acute psychotic exacerbations of schizophrenia. Amisulpride offers a significant advantage in preserving body weight.     

Olanzapine versus chlorpromazine in the treatment of schizophrenia: a pooled analysis of four 6-week, randomized, open-label studies in the Middle East and North Africa

This pooled analysis of four 6-week, randomized, open-label, parallel trials of patients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) compared the efficacy and tolerability of olanzapine (5-20 mg/d) with those of chlorpromazine (200-800 mg/d). Of the 123 patients randomly allocated to olanzapine (n = 83) or chlorpromazine (n = 40), 109 completed the study (olanzapine, n = 77; chlorpromazine, n = 32). Olanzapine-treated patients showed significantly greater baseline-to-end point mean improvements in the primary efficacy measure, Brief Psychiatric Rating Scale total, compared with chlorpromazine-treated patients (least-squares means: olanzapine, -21.1; chlorpromazine, -10.4; P < 0.001). Response rate was significantly higher in the olanzapine group (66.3% vs. 32.4%; P = 0.001). Baseline-to-maximum changes in the UKU scores for akathisia were significantly different between the groups (P = 0.018). A decrease (improvement) in these scores was observed in 6/74 (8.1%) of olanzapine- and 1/36 (2.8%) chlorpromazine-treated patients. Weight gain was the only common (> or =10%) adverse event that occurred more frequently, although not significantly differently, in the olanzapine group (27.7%) than the chlorpromazine group (12.5%), whereas postural hypotension was the only common adverse event whose occurrence was significantly different between the groups (olanzapine, 0.0%; chlorpromazine, 10.0%; P = 0.010). Both the incidence of > or =7% weight gain from baseline (olanzapine, 26.3%; chlorpromazine, 24.3%) and baseline-to-end point changes in weight (mean +/- SD, kg: olanzapine, 3.41 +/- 3.14; chlorpromazine, 2.81 +/- 2.65) were not significantly different between the treatment groups. Baseline-to- end point changes in nonfasting glucose differed significantly between the groups (mean +/- SD, mmol/L: olanzapine, 0.09 +/- 1.11; chlorpromazine, 0.72 +/- 2.04; P = 0.042).This analysis suggests that, compared with chlorpromazine, olanzapine may be more efficacious and have a more favorable tolerability profile in treating patients with schizophrenia.     

Controlled, double-blind investigation of the clozapine discontinuation symptoms with conversion to either olanzapine or placebo. The Collaborative Crossover Study Group.

The abrupt appearance of clozapine discontinuation symptoms represents a particularly unique situation that has not been characterized in a double-blind, placebo-controlled trial. A randomized, double-blind comparison of placebo (N = 53) and olanzapine 10 mg (N = 53) for 3 to 5 days following the abrupt discontinuation of clozapine (< 300 mg/day) was carried out. Subjects were assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale of Severity, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Mini-Mental State Evaluation. Subsequently both groups received open-label olanzapine (10-25 mg/day) for an additional 9 weeks. Statistically significantly more placebo-treated (24.5%) than olanzapine-treated (7.5%) patients experienced clozapine discontinuation symptoms (p = 0.017). Core symptoms included delusions, hallucinations, hostility, and paranoid reaction and translated into a significantly higher worsening from baseline on the PANSS total, PANSS General Psychopathology subscale, and MADRS among subjects randomly assigned to receive placebo. After open-label treatment with olanzapine for 9 weeks, both groups were clinically stable, suggesting that the discontinuation symptoms were transient. However, subjects who had been randomly assigned to the 3- to 5-day placebo discontinuation segment achieved somewhat less global clinical improvement. Although a pharmacologic interpretation is speculative, evidence of a clozapine discontinuation syndrome was apparent. In most cases, the direct substitution of a pharmacologically similar agent (olanzapine) prevented the syndrome. Clozapine discontinuation or noncompliance should be considered in the differential assessment of an acutely emergent psychosis. The possibility that subjects who experience a clozapine discontinuation syndrome may take longer or are less likely to clinically restabilize warrants further investigation.     

Augmentation with a second antipsychotic in patients with schizophrenia who partially respond to clozapine: a meta-analysis

OBJECTIVES: To conduct a meta-analysis of randomized placebo-controlled trials (RCTs) of clozapine augmentation with another antipsychotic drug in patient with schizophrenia who partially respond to clozapine and compare the results with the findings of relevant open studies. METHODS: A systematic literature search was conducted to identify eligible RCTs. All baseline, posttreatment, and change scores in these trials were included in the meta-analysis. For change in Brief Psychiatric Rating Scale/Positive and Negative Syndrome Scale total scores, the effect size was calculated, and for the proportion of patients with a reduction in Brief Psychiatric Rating Scale/Positive and Negative Syndrome Scale scores of 20% or more, the relative risk was calculated. RESULTS: There was a total of 166 participants in the 4 eligible RCTs. Pooling effect sizes across these studies revealed clinically important heterogeneity (I = 63.5%). Analyzing by duration accounted for the heterogeneity (I = 0%), whereas analyzing by drug did not (I = 57.5%). The 2 RCTs lasting 10 weeks or more gave an odds ratio of response to treatment of 4.41 (95% confidence interval, 1.38 to 14.07). In 8 open studies identified, the same pattern of response was seen. The main treatment-emergent side effects reported were extrapyramidal side effects and raised serum prolactin. CONCLUSIONS: Augmentation of clozapine with another antipsychotic drug in patients with schizophrenic illness that has partially responded to clozapine is worthy of an individual clinical trial. This trial may need to be longer than the 4 to 6 weeks usually recommended for acute antipsychotic monotherapy.     

Safety of olanzapine versus conventional antipsychotics in the treatment of patients with acute schizophrenia. A naturalistic study.

BACKGROUND: Conventional antipsychotics although effective in treating acute psychotic and behavioural symptoms are subject to certain limitations due to the high incidence of side effects associated, mainly extrapyramidal symptoms (EPS), and insufficient response shown in some cases. EPS are a major factor in neuroleptic non compliance and high relapse rates among patients. This study was designed to assess the safety and effectiveness of olanzapine compared to typical antipsychotics drugs in the treatment of schizophrenic inpatients at acute psychiatric in-patient units. METHOD: Data from 904 patients schizophrenic patients (F20 of ICD10, WHO) were collected in this prospective, comparative, non-randomized, open and observational study. Patients were followed during their entire hospital stay. Safety was assessed through the collection of spontaneous adverse events and a specific extrapyramidal symptoms questionnaire (EPS). Clinical status was measured through the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression of Severity (CGI-S), Patient Global Impression of Improvement (PGI) and the Nursing Observational Scale for In-patient Evaluation (NOSIE). RESULTS: A total of 483 patients received olanzapine (olanzapine group, OG), and 421 received typical antipsychotics (control group, CG). Treatment emergent EPS, or worsening of previous EPS were statistically significantly higher in the CG (P=0.001). Responder rate was statistically greater in the OG (P<0.001). Mean change in BPRS-total, BPRS-negative, BPRS-agitation subscales and PGI was significantly higher in the OG (P<0.001). Mean decrease in CGI, BPRS positive and BPRS depression sub-scales was also significantly lower (P< or =0.05). Mean change in the NOSIE scale was similar between both groups. CONCLUSION: Olanzapine has been shown to be better tolerated in comparison with conventional antipsychotics in a large unselected sample of acutely psychotic schizophrenic in-patients. Its effectiveness may be greater than that of conventional antipsychotics.     

A double-blind, randomized comparative trial of amisulpride versus olanzapine for 6 months in the treatment of schizophrenia

Atypical antipsychotics offer advantages over earlier drugs for the treatment of schizophrenia, although few data exist on the relative merits of different atypical antipsychotics. A multicentre, double-blind, randomized trial was performed to compare amisulpride and olanzapine in the treatment of acute schizophrenia. Adult schizophrenic patients with dominant positive symptomatology received amisulpride (200-800 mg/day) or olanzapine (5-20 mg/day) for 6 months. The primary efficacy variable was change from baseline of the Brief Psychiatric Rating Scale (BPRS) score, assessed with a non-inferiority analysis. The evolution of positive and negative symptomatology, depression, social functioning and quality of life were assessed. Safety evaluation included adverse event reporting, neurological status and body weight. The improvement of BPRS score was 32.7% in the amisulpride group and 33.0% in the olanzapine group; thus, the efficacy of amisulpride was not inferior to that of olanzapine. All other secondary efficacy outcome variables evolved to a similar extent in both groups. Adverse event frequency was similar in both groups. Amenorrhoea was encountered only in the amisulpride group (6.2% of patients), whereas elevations of liver transaminases were more frequent in the olanzapine group (17% versus 3.7% of patients). The incidence and mean extent of clinically relevant weight gain were higher in the olanzapine group (35.1% and 3.9 kg) than in the amisulpride group (20.6% and 1.6 kg). The efficacy of amisulpride is not inferior to that of olanzapine in the treatment of acute schizophrenia. The side-effect profile of the two drugs differed.