Quetiapine: a review of its safety in the management of schizophrenia.

Quetiapine, a dibenzothiazepine derivative, is a atypical antipsychotic which has greater in vitro binding affinity for serotonin 5-HT2 receptors than for dopamine D2 receptors. Quetiapine effectively treats both the positive and the negative symptoms of schizophrenia and is also associated with an incidence of extrapyramidal symptoms no greater than placebo across the entire dose range. In addition, it does not cause persistent hyperprolactinaemia. Quetiapine is associated with high levels of patient acceptability and satisfaction, which may result from its combination of efficacy and relatively benign adverse effect profile. The drug is well tolerated and has a low propensity to cause adverse events both during acute and long term treatment in the adult populations. The adverse effect profile of quetiapine makes the drug advantageous for patient populations who are susceptible to the adverse effects of drugs. Indeed, preliminary data show quetiapine to be very well tolerated in the elderly. Overdoses of quetiapine of up to 20g have been reported; however, with appropriate management in an intensive care setting there have been no reported fatalities. Quetiapine is metabolised by the cytochrome P450 3A4 isoenzyme, and the dose may need to be adjusted if quetiapine is co-administered with drugs which affect the activity of this isoenzyme. Overall, quetiapine has a favourable risk-benefit profile that should make it a valuable first-line agent in the treatment of schizophrenia.

Zotepine in the prevention of recurrence: a randomised, double-blind, placebo-controlled study for chronic schizophrenia.

RATIONALE: Zotepine is an antipsychotic drug with proven efficacy for treatment of acute episodes of schizophrenia. Antipsychotic drugs also require to be effective in prevention of recurrence. OBJECTIVE: This trial was designed to compare the effects of zotepine and placebo in the prevention of recurrence of acute episodes in a population of patients with chronic schizophrenia. METHODS: The study was a double-blind, parallel group, 26-week comparison of zotepine (300 mg daily, with fall back to 150 mg if necessary) versus placebo in 121 patients with chronic schizophrenia and a history of recurrence in the previous 18 months. The primary outcome measure was the time to recurrence. Other evaluations included the brief psychiatric rating scale (BPRS), the scale for the assessment of negative symptoms (SANS), the clinical global impression (CGI) severity and improvement scales, and the Simpson and Angus scale for extrapyramidal symptoms (EPS). RESULTS: Fewer zotepine patients experienced recurrence over 26 weeks than placebo patients (4 versus 21, respectively). The estimated 26-week risk of recurrence was six times lower for zotepine than placebo (8.7% versus 52.8%; hazard ratio 0.16, 95% CI 0.053, 0.484; P<0.001). Scores on the BPRS and CGI supported the efficacy of zotepine. There was no difference between the treatments with respect to EPS. CONCLUSIONS: Zotepine is effective in preventing recurrence in patients with chronic schizophrenia. The level of EPS was not different between zotepine and placebo.

A comparison of the effects of quetiapine ('seroquel') and haloperidol in schizophrenic patients with a history of and a demonstrated, partial response to conventional antipsychotic treatment. PRIZE Study Group.

Quetiapine ('Seroquel') is a well-tolerated, novel, atypical antipsychotic with consistent efficacy in the treatment of schizophrenia. To date, no clinical studies have evaluated the effect of quetiapine in patients who only partially respond to conventional antipsychotics, yet this type of patient is most frequently seen by psychiatrists. Therefore, this international, multicentre, double-blind study was conducted to compare the efficacy and tolerability of 8 weeks' treatment of quetiapine 600 mg/day with haloperidol 20 mg/day in 288 patients who had a history of partial response to conventional antipsychotics and displayed a partial or no response to 1 month of fluphenazine (20 mg/day) treatment. Patients on quetiapine tended to have greater improvement than those on haloperidol in the primary efficacy measure, mean Positive and Negative Symptom Scale (PANSS) score, after 4 weeks' treatment (-9.05, -5.82, respectively, P = 0.061) and at study end (-11.50, -8.87, respectively, P = 0.234). Similarly, there was a trend towards patients on quetiapine demonstrating greater improvements in the secondary efficacy measures (Clinical Global Impression, PANSS subscale and Brief Psychiatric Rating Scale scores) [week 4 (baseline) to week 12 (end)], but the difference between treatments did not reach significance. Significantly more patients on quetiapine than on haloperidol showed a clinical response-patient response rates, defined as > 20% reduction in PANSS total score between weeks 4 and 12, were 52.2% for quetiapine and 38.0% for haloperidol (P = 0.043). Patients receiving quetiapine required less anticholinergic medication (P < 0.011), had greater reduction in extrapyramidal symptoms (EPS) (P = 0.005) and fewer treatment-emergent EPS-related adverse events compared to those on haloperidol (P < 0.001). Serum prolactin concentrations were elevated at the end of fluphenazine treatment in 73% of patients. Between weeks 4 and 12, elevated serum prolactin concentrations significantly decreased in quetiapine-treated patients compared to those receiving haloperidol (P < 0.001). At the end of quetiapine treatment, 83% of patients had normal prolactin levels while only 21% of patients receiving haloperidol were within the normal range. These results suggest that quetiapine may make a valuable contribution to the management of patients with a history of partial response to conventional antipsychotics.

A placebo-controlled comparison of zotepine versus chlorpromazine in patients with acute exacerbation of schizophrenia.

OBJECTIVE: The aim of this study was to evaluate the efficacy of zotepine in the treatment of acute episodes of schizophrenia. METHOD: Patients with acute exacerbation of schizophrenia (DSM-III-R criteria; n = 158) were allocated on a random, double-blind basis to receive zotepine (150 or 300 mg/day), chlorpromazine (300 or 600 mg/day) or placebo for 8 weeks. Symptoms were assessed on the BPRS, SANS and CGI scales at baseline and weeks 1, 2, 4, 6 and 8 and patients were assessed at these times for adverse effects. Analysis was by analysis of variance on the intent-to-treat population, with last observation carried forward. RESULTS: Mean BPRS scores improved statistically significantly more with zotepine than chlorpromazine (point estimate of difference -12.4, 95% CI -18.3 to -6.5) or placebo (point estimate of difference -12.7, 95% CI -18.6 to -6.8). Zotepine produced significantly fewer extrapyramidal symptoms (EPS) than chlorpromazine. CONCLUSION: Zotepine is an effective antipsychotic with low propensity for EPS.

The safety and efficacy of zotepine in the treatment of schizophrenia: Results of a one-year naturalistic clinical trial.

INTRODUCTION AND METHOD: The safety and efficacy of zotepine,75 - 450 mg/day, were evaluated in an open multicentre one-year study in patients suffering from acute exacerbation of schizophrenia; total exposure amounted to 152.78 years. RESULTS: Mean BPRS total score was reduced from 51.7 at baseline to 40.8 at end-point (P<0.05). Similar significant reductions at all study time-points were recorded for BPRS total and subscores, CGI severity and improvement, BAS total scores and SANS total and global scores. Significant improvements in EPMS and AIMS were recorded from week 12 to end-point. Clinically significant improvements in acute symptoms, detected early in the study, were maintained to end-point. CONCLUSION: Zotepine was well tolerated: weight gain, reduced serum uric acid, raised liver enzymes and increased heart rate were associated with chronic zotepine treatment. Seven patients experienced seizures during the study, although concomitant medications and a known historical predisposition to seizure are factors likely to have contributed to these events. The improvements in negative symptoms and low propensity to cause further extrapyramidal side-effects support the importance of zotepine in maintenance treatment.

A double-blind, comparative study of dothiepin and clomipramine in the treatment of major depressive illness.

Dothiepin, a well-established antidepressant, has been compared with clomipramine in a single-blind study which demonstrated that dothiepin was better tolerated but there was no difference in efficacy. The present study was performed to recent European guidelines on good clinical practice using a randomised, double-blind, parallel-group methodology. One hundred and one patients suffering from major depressive disorder as defined by DSM-III-R were randomised to receive either clomipramine (25-150 mg daily) or dothiepin (75-150 mg daily) for up to six weeks. The clomipramine group comprised 51 patients, the dothiepin group 50 patients. At baseline, both groups had a mean age of 41-43 years and gave similar mean scores on the Hamilton Depression Rating Scale (23.5 for clomipramine, 23.6 for dothiepin). At endpoint it was reduced in both groups but there were no significant differences between the groups (mean change from baseline for the clomipramine and dothiepin groups was -14.6 and -14.1 respectively). Thirty-one clomipramine patients and 41 dothiepin patients completed six weeks' treatment. Withdrawal from treatment (20 patients for clomipramine, nine for dothiepin) was significantly different (p = 0.0105). When reasons for withdrawal were analysed, 13 clomipramine patients and two dothiepin patients withdrew because of adverse events, this difference being significant (p = 0.002). Thus both treatments were effective in treating patients suffering from major depressive disorder, but patients receiving dothiepin suffered fewer adverse events and were more likely to complete their treatment.

A comparison of an atypical and typical antipsychotic, zotepine versus haloperidol in patients with acute exacerbation of schizophrenia: a parallel-group double-blind trial.

The atypical antipsychotic zotepine was compared to haloperidol in 126 patients suffering from acute exacerbation of schizophrenia (DSM-III-R) in a randomized, double-blind study. After 8-weeks, 150 to 300 mg zotepine improved scores on the Brief Psychiatric Rating Scale (BPRS) more than 10 to 20 mg haloperidol (-17.03 versus -13.45; 95%CI for zotepine-haloperidol -9.34/2.04). BPRS subscores and Clinical Global impressions (CGI) Severity and improvement subscales showed comparable gains, but scores on the Scale for the Assessment of Negative Symptoms (SANS) improved significantly more with zotepine (-23.82) than haloperidol (-15.15; P < .05; 95%CI for zotepine haloperidol -18.03/-0.18). Adverse events were reported by 71 percent of zotepine and 78 percent of haloperidol patients. Extrapyramidal side effect (EPMS) scores decreased with zotepine (-0.34) but increased with haloperidol (+2.32; P < .05). Seven haloperidol patients reported akathisia but no zotepine patients did (p < .05). Uric acid reductions (which appear to have no clinical consequence) and transient raised liver enzymes were recorded with zotepine. Weight increased on zotepine (2.32 kg; P < .001) and a small increase in pulse rate occurred (P < .05). Both drugs were effective in reducing positive symptoms of schizophrenia; zotepine was significantly more effective against negative symptoms and reduced EPMS.

Antigen-induced non-specific suppressor factor in sheep efferent lymph is prostaglandin E2.

Efferent lymph from the popliteal node of sheep challenged with antigen was found to suppress the in vitro transformation of sheep peripheral blood lymphocytes to a variety of antigens. The suppressor factor appeared 6-20 hr after challenged of the node and was shown to be prostaglandin E2, probably complexed to albumin.

Activation of the alternative complement pathway by normal and transformed cells in homologous and heterologous sera.

A variety of both normal and viral transformed or infected cells have been tested for their ability to activate the alternative pathway of complement in either homologous or heterologous sera. Normal cell lines fail to produce alternative pathway activation in homologous sera but readily activate the alternative pathway in heterologous sera. In contrast, human cells, persistently infected with measles virus or chicken cells transformed with oncogenic avian viruses, produce a marked activation in homologous sera. It is suggested that in certain circumstances, the alternative pathway of complement can discriminate between normal and abnormal "self" cells of foreign cell surfaces.

Malignant cells isolated from Burkitt's lymphoma but not other forms of leukemia activate the alternative complement pathway in human serum.

Cells isolated directly from primary biopsies of Burkitt's lymphoma were found to activate the alternative complement pathway in hypogammaglobulinemic human serum. In contrast, cells isolated from patients with either acute lymphoblastic leukemia, chronic lymphocytic leukemia or chronic myeloid leukemia did not activate. No defects in the ability of Burkitt's lymphoma sera to support alternative pathway activation were detected.