An analysis of safety and tolerability data from controlled, comparative studies of quetiapine in patients with schizophrenia, focusing on extrapyramidal symptoms

AIM: This analysis evaluated the tolerability profile of quetiapine using data from all comparative controlled studies in patients with schizophrenia or related disorders in the AstraZeneca clinical trials database, focusing on extrapyramidal symptoms (EPS). METHODS: Adverse event (AE) data from randomised, double-blind, controlled studies in the AstraZeneca clinical trials database were pooled, allowing comparison of quetiapine (mean daily doses 357-496 mg/day) with placebo, haloperidol (10.4 mg/day), risperidone (5.5 mg/day) or chlorpromazine (552 mg/day). Incidence of EPS-related AEs in relation to quetiapine dose was also analysed using a subset of data from fixed-dose studies. RESULTS: Data from 4956 patients were analysed. Quetiapine was well tolerated, and did not increase EPS-related AEs when compared with placebo (9.6 vs. 10.6%, respectively). The incidence of EPS-related AEs with quetiapine was consistent across the dose range (4.2-13.2% vs. 11.1% with placebo). Patients receiving haloperidol, risperidone and chlorpromazine experienced significantly higher levels of EPS-related AEs than those on quetiapine. The most common quetiapine- associated AEs, with significantly higher incidence than placebo, were sedation, somnolence and orthostatic hypotension. CONCLUSION: Quetiapine is generally well tolerated in patients with schizophrenia or related disorders, with placebo-level EPS-related AEs. Quetiapine has a more favourable EPS profile than haloperidol, chlorpromazine or risperidone.     

Review of quetiapine and its clinical applications in schizophrenia

Preclinical studies have shown that quetiapine (Seroquel, AstraZeneca) is an atypical antipsychotic with many similarities to clozapine. Both placebo-controlled and comparative studies in patients with schizophrenia have demonstrated that quetiapine has long-term efficacy in both positive and negative domains, as well as beneficial effects on affective and cognitive symptoms. Comparative clinical studies confirm that quetiapine is at least as effective as the standard antipsychotics, chlorpromazine and haloperidol and response rates with quetiapine are similar to those reported with other atypical antipychotics. Quetiapine has also demonstrated superior efficacy to haloperidol in partially responsive patients, who can be particularly difficult to treat. Quetiapine has a wide clinical dosing range (150-750 mg/day), although doses of 400 mg or above should be used in patients who do not fully respond to lower doses of the drug. Quetiapine is generally well tolerated with no requirement for routine ECG or blood monitoring and it has minimal effects on weight. Uniquely among other first-line atypical antipsychotics, quetiapine is associated with a placebo-level incidence of EPS and an indistinguishable effect from placebo on plasma prolactin at all doses. Thus, clinicians can confidently increase the dose of quetiapine, without increasing the risk of EPS or hyperprolactinaemia. A number of studies have also shown that quetiapine is well-tolerated and effective in patients who are particularly susceptible to EPS, including elderly and adolescent patients and those with pre-existing dopaminergic pathology, such as Alzheimer's disease and Parkinson's disease. The consistent efficacy in treating all schizophrenic domains and good tolerability, particularly placebo-level EPS, make quetiapine acceptable to patients, as demonstrated in a survey of patient satisfaction. Thus quetiapine is a suitable first-line therapy for the treatment of schizophrenia and psychosis.     

Combined treatment of quetiapine with haloperidol in animal models of antipsychotic effect and extrapyramidal side effects: comparison with risperidone and chlorpromazine

Rationale Quetiapine, an atypical neuroleptic, has beneficial antipsychotic effects in schizophrenic patients, but with a lower incidence of extrapyramidal symptoms (EPS) compared with typical antipsychotics. While typical antipsychotics are often switched to atypical agents when adverse effects become limiting, there is little preclinical information to support this strategy, both in terms of efficacy and side effects.Objectives The antipsychotic effects and EPS during concomitant administration of quetiapine with haloperidol, a typical antipsychotic agent, were evaluated in mice and compared with chlorpromazine and risperidone.Methods We first investigated the antipsychotic effects and EPS liability of quetiapine, risperidone, chlorpromazine, and haloperidol when administered alone to select optimal doses for subsequent combination studies. The second study was designed to evaluate the antipsychotic efficacy and EPS profile of concomitant administration of quetiapine, risperidone, or chlorpromazine with haloperidol. Antipsychotic effects were evaluated with the methamphetamine-induced hyperlocomotion test, and EPS liability was evaluated in a catalepsy-induction model.Results Quetiapine, risperidone, chlorpromazine, and haloperidol dose-dependently reduced methamphetamine-induced hyperlocomotion, with ED₅₀ values of 5.6, 0.020, 1.8, 0.035 mg/kg, respectively. In the catalepsy test, quetiapine only weakly induced catalepsy at the highest dose of 100 mg/kg, whereas risperidone, chlorpromazine, and haloperidol dose-dependently induced catalepsy with ED₅₀ values of 0.25, 4.6, and 0.10 mg/kg, respectively. While the combination of quetiapine (6 mg/kg) and haloperidol (0.04 mg/kg) significantly reduced methamphetamine-induced hyperlocomotion in comparison with haloperidol alone, quetiapine (10, 32 mg/kg) plus haloperidol did not potentiate the cataleptogenic activity of haloperidol. In contrast, risperidone (0.1, 0.32 mg/kg) or chlorpromazine (3.2 mg/kg) significantly augmented catalepsy induced by haloperidol. Catalepsy induced by co-administration of quetiapine (10 mg/kg) and haloperidol (0.1 mg/kg) was significantly potentiated by WAY100635, a 5-HT_1A antagonist, and catalepsy induced by co-administration of risperidone (0.1 mg/kg) and haloperidol (0.1 mg/kg) was significantly antagonized by 8-OH-DPAT, a 5-HT_1A agonist.Conclusion The present study demonstrated that the combined administration of quetiapine with haloperidol did not aggravate EPS, possibly because of its affinity for 5-HT_1A receptors. This finding may have the clinical implication that quetiapine could provide a successful regimen in switching from typical antipsychotic agents in the symptom management of schizophrenia, or even in adjunctive therapy with other antipsychotic agents.     

Review of quetiapine and its clinical applications in schizophrenia

Preclinical studies have shown that quetiapine (Seroquel?, AstraZeneca) is an atypical antipsychotic with many similarities to clozapine. Both placebo-controlled and comparative studies in patients with schizophrenia have demonstrated that quetiapine has long-term efficacy in both positive and negative domains, as well as beneficial effects on affective and cognitive symptoms. Comparative clinical studies confirm that quetiapine is at least as effective as the standard antipsychotics, chlorpromazine and haloperidol and response rates with quetiapine are similar to those reported with other atypical antipychotics. Quetiapine has also demonstrated superior efficacy to haloperidol in partially responsive patients, who can be particularly difficult to treat. Quetiapine has a wide clinical dosing range (150 - 750 mg/day), although doses of 400 mg or above should be used in patients who do not fully respond to lower doses of the drug. Quetiapine is generally well tolerated with no requirement for routine ECG or blood monitoring and it has minimal effects on weight. Uniquely among other first-line atypical antipsychotics, quetiapine is associated with a placebo-level incidence of extrapyramidal side-effects (EPS) and an indistinguishable effect from placebo on plasma prolactin at all doses. Thus, clinicians can confidently increase the dose of quetiapine, without increasing the risk of EPS or hyperprolactinaemia. A number of studies have also shown that quetiapine is well-tolerated and effective in patients who are particularly susceptible to EPS, including elderly and adolescent patients and those with pre-existing dopaminergic pathology, such as Alzheimer’s disease and Parkinson’s disease. The consistent efficacy in treating all schizophrenic domains and good tolerability, particularly placebo-level EPS, make quetiapine acceptable to patients, as demonstrated in a survey of patient satisfaction. Thus quetiapine is a suitable first-line therapy for the treatment of schizophrenia and psychosis.     

Quetiapine or haloperidol as monotherapy for bipolar mania--a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial.

METHODS: Patients (n=302) with bipolar I disorder (manic episode) were randomised to 12 weeks' double-blind treatment with quetiapine (flexibly dosed up to 800 mg/day), placebo, or haloperidol (up to 8 mg/day). The primary efficacy outcome variable was change from baseline to Day 21 in Young Mania Rating Scale (YMRS) score. RESULTS: YMRS score improved with quetiapine at Day 21 (-12.29 versus -8.32 for placebo; P<0.01). The difference in favor of quetiapine increased by Day 84 (-17.52 versus -9.48; P<0.001). Haloperidol also showed an advantage over placebo at Days 21 and 84 (P<0.001). There was no significant difference in efficacy measures between quetiapine and haloperidol groups at any assessment except Day 21. The only common adverse event with quetiapine was somnolence (12.7%). Extrapyramidal symptoms (EPS), including akathisia, occurred at 59.6% with haloperidol, 12.7% with quetiapine, 15.8% with placebo. Most quetiapine responders (84%) received a dose of 400-800 mg/day. CONCLUSIONS: Quetiapine was effective and well tolerated. The efficacy and tolerability profile of haloperidol (including its propensity for EPS) supported study validity.     

Risperidone: a review of its use in the management of the behavioural and psychological symptoms of dementia

Risperidone is a benzisoxazole derivative which has proven efficacy against the positive and negative symptoms of schizophrenia. It has more recently been investigated and shown efficacy as a treatment for the behavioural and psychological symptoms associated with dementia in the elderly. Risperidone has pharmacological properties resembling those of the atypical antipsychotic clozapine and an improved tolerability profile compared with the conventional antipsychotic haloperidol. Risperidone has antagonistic activity primarily at serotonin 5-HT2A and dopamine D2 receptors. In the first 2 large, well controlled trials of an antipsychotic agent used in the treatment of elderly patients with Alzheimer's dementia, vascular dementia or mixed dementia, risperidone 1 mg/day was at least as effective as haloperidol and superior to placebo, as assessed by the rating scales for global behaviour, aggression and psychosis. In extension phases of the 2 trials, clinical benefits were maintained for treatment periods of up to 1 year, with an incidence rate of tardive dyskinesia (2.6%) one-tenth of that seen with conventional antipsychotics. Risperidone, administered at a low dosage of 1 mg/day was associated with fewer extrapyramidal symptoms compared with haloperidol in elderly patients. Risperidone was well tolerated with no clinically relevant abnormalities in laboratory tests, vital signs or electrocardiogram results. Conclusion: The efficacy of risperidone has been demonstrated in the treatment of the behavioural and psychological symptoms associated with dementia in the elderly. Preliminary results from 1-year extension studies confirm the favourable efficacy and tolerability profile of risperidone 1 mg/day. Although head to head studies with other atypical antipsychotic agents are required and the long term use of the drug requires clarification, risperidone represents a generally well tolerated and effective treatment in the management of dementia-associated behavioural and psychological symptoms in the elderly.     

Aripiprazole

Aripiprazole is a quinolinone derivative and the first of a new class of atypical antipsychotics. The drug has partial agonist activity at dopamine D(2) and serotonin 5-HT(1A) receptors, and is also an antagonist at 5-HT(2A) receptors. In patients with acute relapse of schizophrenia or schizoaffective disorder, aripiprazole 15 to 30 mg/day was at least as effective as haloperidol 10 mg/day and had similar efficacy to risperidone 6 mg/day in well designed, 4-week, placebo-controlled trials. Negative symptoms improved earlier in the aripiprazole than the risperidone group. Efficacy of aripiprazole was observed at week 1 in several trials and was sustained throughout the study periods. Aripiprazole was superior to placebo in a 26-week trial in patients with stable, chronic schizophrenia. In a 52-week trial involving patients with acute relapsing disease, aripiprazole was similar to haloperidol as assessed by time to failure to maintain response and was superior in ameliorating negative and depressive symptoms. The incidence of extrapyramidal symptoms during aripiprazole therapy was similar to that with risperidone and placebo but lower than with haloperidol. Compared with placebo, the proportion of patients with increased plasma prolactin levels and QTc prolongation was similar in patients treated with aripiprazole 15 to 30 mg/day but was significantly increased with haloperidol and risperidone.     

Amisulpride: a review of its use in the management of schizophrenia.

Amisulpride, a substituted benzamide derivative, is a second-generation (atypical) antipsychotic. At low doses, it enhances dopaminergic neurotransmission by preferentially blocking presynaptic dopamine D2/D3 autoreceptors. At higher doses, amisupride antagonises postsynaptic dopamine D2 and D3 receptors, preferentially in the limbic system rather than the striatum, thereby reducing dopaminergic transmission. In patients with acute exacerbations of schizophrenia, the recommended dosage of amisulpride is 400 to 800 mg/day, although dosages < or =1200 mg/day may be administered. In comparative trials, amisulpride administered within this range (400 to 1200 mg/day) was as effective as haloperidol 5 to 40 mg/day, flupenthixol 25 mg/day and risperidone 8 mg/day in patients with acute exacerbations of schizophrenia with predominantly positive symptoms. Amisulpride was more effective than haloperidol but equally effective as risperidone in controlling negative symptoms. Amisulpride 400 to 800 mg/day was more effective than haloperidol, risperidone and flupenthixol in controlling affective symptoms in these patients. In randomised, double-blind trials involving patients with predominantly negative symptoms of schizophrenia, amisulpride 50 to 300 mg/day was more effective than placebo. Amisulpride is effective as maintenance therapy in patients with chronic schizophrenia. Long-term treatment with amisulpride was associated with improvements in quality of life and social functioning. Amisulpride is generally well tolerated. In well-controlled trials, the neurological tolerability profile (including ratings on extrapyramidal symptom scales) of amisulpride 400 to 1200 mg/day was superior to that of the conventional antipsychotics (haloperidol or flupenthixol), but was similar to that of the atypical antipsychotic risperidone. At low dosages of amisulpride (< or =300 mg/day), the incidence of adverse events (including extrapyramidal symptoms) reported with amisulpride was similar to that with placebo. CONCLUSION: In comparative trials, amisulpride 400 to 1200 mg/day showed efficacy in reducing overall symptomatology and positive symptoms similar to that of conventional antipsychotics and newer atypical antipsychotics in patients with acute exacerbations of schizophrenia. Moreover, its effective alleviation of negative and affective symptoms, its lower association with extrapyramidal symptoms and loss of cognitive function than conventional antipsychotics and its long-term efficacy justifies consideration of the use of higher dosages of amisulpride in this group of patients. Consequently, the dosage of amisulpride that is recommended in patients with acute exacerbations of schizophrenia is 400 to 800 mg/day, although dosages < or =1200 mg/day may be administered. Lower dosages of amisulpride (50 to 300 mg/day) should be considered for the management of patients with negative symptoms of schizophrenia. Amisulpride is a first-line treatment option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.     

Spotlight on amisulpride in schizophrenia

Amisulpride, a substituted benzamide derivative, is a second-generation (atypical) antipsychotic. At low doses, it enhances dopaminergic neurotransmission by preferentially blocking presynaptic dopamine D(2)/D(3) autoreceptors. At higher doses, amisulpride antagonises postsynaptic D(2) and D(3) receptors, preferentially in the limbic system rather than the striatum, thereby reducing dopaminergic transmission. In patients with acute exacerbations of schizophrenia, the recommended dosage of amisulpride is 400 to 800 mg/day, although dosages < or = 1200 mg/day may be administered. In comparative trials, amisulpride administered within this range (400 to 1200 mg/day) was as effective as haloperidol 5 to 40 mg/day, flupenthixol 25 mg/day and risperidone 8 mg/day in patients with acute exacerbations of schizophrenia with predominantly positive symptoms. Amisulpride was more effective than haloperidol but equally effective as risperidone in controlling negative symptoms. Amisulpride 400 to 800 mg/day was more effective than haloperidol, risperidone and flupenthixol in controlling affective symptoms in these patients. In randomised, double-blind trials involving patients with predominantly negative symptoms of schizophrenia, amisulpride 50 to 300 mg/day was more effective than placebo. Amisulpride is effective as maintenance therapy in patients with chronic schizophrenia. Long-term treatment with amisulpride was associated with improvements in quality of life and social functioning. Amisulpride is generally well tolerated. In well-controlled trials, the neurological tolerability profile (including ratings on extrapyramidal symptom scales) of amisulpride 400 to 1200 mg/day was superior to that of the conventional antipsychotics (haloperidol or flupenthixol), but was similar to that of the atypical antipsychotic risperidone. At low dosages of amisulpride (< or = 300 mg/day), the incidence of adverse events (including extrapyramidal symptoms) reported with amisulpride was similar to that with placebo. Conclusion: In comparative trials, amisulpride 400 to 1200 mg/day showed efficacy in reducing overall symptomatology and positive symptoms similar to that of conventional antipsychotics and newer atypical antipsychotics in patients with acute exacerbations of schizophrenia. Moreover, its effective alleviation of negative and affective symptoms, its lower association with extrapyramidal symptoms and loss of cognitive function than conventional antipsychotics and its long-term efficacy justifies consideration of the use of higher dosages of amisulpride in this group of patients. Consequently, the dosage of amisulpride that is recommended in patients with acute exacerbations of schizophrenia is 400 to 800 mg/day, although dosages < or = 1200 mg/day may be administered. Lower dosages of amisulpride (50 to 300 mg/day) should be considered for the management of patients with negative symptoms of schizophrenia. Amisulpride is a first-line treatment option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.     

Differential effect of quetiapine on depressive symptoms in patients with partially responsive schizophrenia

While atypical antipsychotics appear to be effective in reducing depressive symptoms in the acute phase of schizophrenia, little is known about their efficacy in patients with ongoing symptoms. The present study assessed whether quetiapine (Seroquel) is more effective than haloperidol in treating depressive symptoms in patients with persistent positive symptoms, and investigated whether this effect is independent, or secondary to, reductions in other symptoms such as positive, negative or extrapyramidal symptoms. Patients with schizophrenia and a history of partial refractoriness to conventional antipsychotics who had not responded to 4 weeks of fluphenazine treatment (20 mg/day) were randomized to receive either quetiapine (600 mg/day) or haloperidol (20 mg/day) for a further 8 weeks. Change in the Positive and Negative Syndrome Scale depression factor score from baseline to endpoint was calculated and path analyses were performed on data from 269 patients. Quetiapine produced a greater reduction in depressive scores than haloperidol (-1.60 versus -0.54; p = 0.006). The path analyses indicated that this was a direct effect on depressive symptoms. These findings extend the evidence for an antidepressant effect for the novel antipsychotics in schizophrenia, and suggest that this is not limited to acutely psychotic patients.     

Olanzapine: an updated review of its use in the management of schizophrenia

Olanzapine, a thienobenzodiazepine derivative, is a second generation (atypical) antipsychotic agent which has proven efficacy against the positive and negative symptoms of schizophrenia. Compared with conventional antipsychotics, it has greater affinity for serotonin 5-HT2A than for dopamine D2 receptors. In large, well controlled trials in patients with schizophrenia or related psychoses, olanzapine 5 to 20 mg/day was significantly superior to haloperidol 5 to 20 mg/day in overall improvements in psychopathology rating scales and in the treatment of depressive and negative symptoms, and was comparable in effects on positive psychotic symptoms. The 1-year risk of relapse (rehospitalisation) was significantly lower with olanzapine than with haloperidol treatment. In the first double-blind comparative study (28-week) of olanzapine and risperidone, olanzapine 10 to 20 mg/day proved to be significantly more effective than risperidone 4 to 12 mg/day in the treatment of negative and depressive symptoms but not on overall psychopathology symptoms. In contrast, preliminary results from an 8-week controlled study suggested risperidone 2 to 6 mg/day was superior to olanzapine 5 to 20 mg/day against positive and anxiety/depressive symptoms (p < 0.05), although consistent with the first study, both agents demonstrated similar efficacy on measures of overall psychopathology. Improvements in general cognitive function seen with olanzapine treatment in a 1-year controlled study of patients with early-phase schizophrenia, were significantly greater than changes seen with either risperidone or haloperidol. However, preliminary results from an 8-week trial showed comparable cognitive enhancing effects of olanzapine and risperidone treatment in patients with schizophrenia or schizoaffective disorder. Several studies indicate that olanzapine has benefits against symptoms of aggression and agitation, while other studies strongly support the effectiveness of olanzapine in the treatment of depressive symptomatology. Olanzapine is associated with significantly fewer extrapyramidal symptoms than haloperidol and risperidone. In addition, olanzapine is not associated with a risk of agranulocytosis as seen with clozapine or clinically significant hyperprolactinaemia as seen with risperidone or prolongation of the QT interval. The most common adverse effects reported with olanzapine are bodyweight gain, somnolence, dizziness, anticholinergic effects (constipation and dry mouth) and transient asymptomatic liver enzyme elevations. In comparison with haloperidol, the adverse events reported significantly more frequently with olanzapine in > or = 3.5% of patients were dry mouth, bodyweight gain and increased appetite and compared with risperidone, only bodyweight gain occurred significantly more frequently with olanzapine. The high acquisition cost of olanzapine is offset by reductions in other treatment costs (inpatient and/or outpatient services) of schizophrenia. Pharmacoeconomic analyses indicate that olanzapine does not significantly increase, and may even decrease, the overall direct treatment costs of schizophrenia, compared with haloperidol. Compared with risperidone, olanzapine has also been reported to decrease overall treatment costs, despite the several-fold higher daily acquisition cost of the drug. Olanzapine treatment improves quality of life in patients with schizophrenia and related psychoses to a greater extent than haloperidol, and to broadly the same extent as risperidone. CONCLUSIONS: Olanzapine demonstrated superior antipsychotic efficacy compared with haloperidol in the treatment of acute phase schizophrenia, and in the treatment of some patients with first-episode or treatment-resistant schizophrenia. The reduced risk of adverse events and therapeutic superiority compared with haloperidol and risperidone in the treatment of negative and depressive symptoms support the choice of olanzapine as a first-line option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.     

A comparison of extrapyramidal symptoms in older outpatients treated with quetiapine or risperidone

OBJECTIVE: To compare the tolerability of quetiapine with risperidone in older outpatients. RESEARCH DESIGN AND METHODS: Post hoc analysis of a subset of older patients (aged 60-80; n = 92) from a randomized, 4-month, multicenter, open-label trial comparing quetiapine and risperidone in an outpatient setting. Participants had various neuropsychiatric disorders associated with psychosis as defined by criteria from the Diagnostic and Statistical Manual of Mental Disorders (4th edn). MAIN OUTCOME MEASURES: The main outcome measure was an extrapyramidal symptoms (EPS) checklist, used to assess motor symptoms, including parkinsonism, at baseline and after treatment. The Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression scale were used to assess therapeutic efficacy. RESULTS: Substantial EPS (defined as EPS requiring a dosage adjustment or use of medication to reduce EPS) occurred less often with quetiapine (median dosage, 200 mg/day) than with risperidone (median dosage, 3 mg/day); odds ratio, 0.31 (P < 0.03). Quetiapine was also less likely than risperidone to cause akathisia or hypertonia. Both compounds produced comparable reductions in PANSS scores. CONCLUSIONS: Interpretation of findings in this report is limited by the open-label design of the study and the post hoc nature of this analysis. However, the results suggest that quetiapine, when given within the recommended dosage range, has a benign EPS profile, with potentially greater tolerability and comparable efficacy to risperidone in older outpatients with psychotic disorders.     

Focus on quetiapine

Quetiapine fumarate is a novel dibenzothiazepine antipsychotic developed by Zeneca. It is marketed under the trade name 'Seroquel'. Quetiapine is well tolerated and clinically effective in the treatment of schizophrenia. The initial hope of investigators was that quetiapine would have antipsychotic potential and that it might share some of the properties of clozapine without its toxicity to white blood cells. The effective dosage range is usually 300-450 mg/day split into two doses. The dose is titrated upwards from 25 mg twice daily from day 1 to 300 mg/day on day 4. Elderly patients or patients with liver problems should be started on lower doses. It is both superior to placebo and comparable to haloperidol in reducing positive symptoms at doses ranging from 150 mg/day to 750 mg/day, and is an effective treatment for negative symptoms. Somnolence is the most common adverse event. Abnormalities of the QT interval on ECG appear very infrequently and there is no need for a baseline ECG or blood pressure monitoring, as used to be the case with sertindole. There is no need for haematological monitoring as with clozapine. Quetiapine, across the full dosage range, is associated with no greater extrapyramidal symptoms than placebo. Quetiapine's general efficacy and side-effect profile suggest that, unless there are unforeseen post-marketing complications, it deserves a major place in the initial and long-term management of schizophreniform disorders.     

A review of the efficacy, tolerability and safety of sertindole in clinical trials

Sertindole is a non-sedating atypical antipsychotic agent with high selectivity for dopaminergic neurons in the mesolimbic system. In pivotal clinical trials, sertindole has demonstrated significantly greater efficacy than placebo against both the positive and negative symptoms of schizophrenia. In addition, sertindole has had at least similar efficacy to haloperidol and risperidone against positive symptoms, and significantly greater efficacy than haloperidol and risperidone against negative symptoms. The incidence of extrapyramidal symptom (EPS)-related adverse events and the rate of medication used to treat EPS in patients receiving clinically effective doses of sertindole in clinical trials were similar to those observed in placebo recipients and significantly less than those in haloperidol recipients. The incidence of QTc interval prolongation of 500 ms or greater with therapeutic dosages of sertindole has also been low. In general, sertindole has been well tolerated in clinical trials. Unlike other antipsychotic agents, sertindole has not been associated with cognitive impairment, and can actually improve cognitive function. Observational studies have shown that the efficacy and tolerability of sertindole observed in the clinical trial situation are emulated in a naturalistic setting. Large cohort analyses (N > 8000) have shown that all-cause and cardiovascular mortality is no greater with sertindole than with risperidone or olanzapine.     

Quetiapine: a review of its use in the management of bipolar depression

Quetiapine (Seroquel?) is an orally administered atypical antipsychotic that is indicated for the treatment of schizophrenia and bipolar disorder, including bipolar depression. An extended-release (XR) formulation of quetiapine is also available. This review summarizes the pharmacological properties, efficacy and tolerability of quetiapine and quetiapine XR in patients with bipolar depression. Quetiapine is an antagonist at both serotonin 5-HT2 and dopamine D2 receptors, and its antipsychotic effects are thought to stem from interactions at these receptors. The antidepressant effects of quetiapine are poorly understood, but may be related to antagonism of 5-HT2A receptors in cortical regions, partial agonism of 5-HT1A in the prefrontal cortex in association with increased extracellular dopamine release in the region, or to reduced synaptic reuptake of noradrenaline resulting from inhibition of the noradrenaline reuptake transporter by the quetiapine metabolite norquetiapine. The efficacy and tolerability of quetiapine was evaluated in five 8-week, randomized, double-blind, placebo-controlled, multicentre or multinational trials in patients with a major depressive episode (MDE) associated with bipolar disorder. Across trials, monotherapy with oral quetiapine 300 or 600?mg/day (or quetiapine XR 300?mg/day) produced significantly greater improvements than placebo in depressive symptoms (primary endpoint), according to the change in the Montgomery-Asberg Depression Rating Scale total score. In general, quetiapine and quetiapine XR were also associated with significantly higher MDE response and remission rates than placebo. Across trials, quetiapine and quetiapine XR produced significantly greater improvements in global severity of illness scores than placebo, according to changes in the Clinical Global Impressions scale score. There were no differences in treatment outcomes between quetiapine 300?mg/day and 600?mg/day dosage groups. Patients with bipolar depression who responded to quetiapine during two 8-week acute treatment trials also benefited from continuing quetiapine therapy for up to 52 weeks. Compared with quetiapine responders randomized to placebo, quetiapine responders who continued quetiapine 300 or 600?mg/day had a significantly reduced risk of recurrence of any mood events and of depression mood events, but not of hypomanic/manic events. In a randomized, double-blind, placebo-controlled trial, quetiapine maintenance therapy for up to 104 weeks was more efficacious than placebo or lithium in prolonging the time to recurrence of any mood event (primary endpoint). Patients in this trial had bipolar I disorder with mania, depression or a mixed episode as the index episode, and the trial included only patients who were responsive to acute phase quetiapine, which may have introduced a positive bias in favour of quetiapine over lithium during maintenance therapy. Quetiapine 300 or 600?mg/day and quetiapine XR 300?mg/day was generally well tolerated in patients with bipolar depression, with most treatment-emergent adverse events being of mild to moderate severity. The most frequent adverse events occurring during the acute treatment phase were dry mouth, sedation, somnolence, dizziness (quetiapine and quetiapine XR), constipation (quetiapine) and increased appetite (quetiapine XR). Extrapyramidal symptoms (EPS) occurred across quetiapine and placebo groups, but there were no significant differences between quetiapine and placebo recipients on objective measures of EPS and akathisia. In some trials, quetiapine recipients experienced significantly greater weight gain than placebo recipients. Across trials, some quetiapine recipients had clinically relevant increases in blood glucose or lipid parameters, although these also occurred in patients from other treatment groups. The clinical significance of these changes is uncertain. In conclusion, quetiapine and quetiapine XR are valuable additions to the first-line treatments for bipolar depression. Further head-to-head trials of quetiapine versus other drug regimens that are effective in bipolar depression would be of considerable interest.     

Efficacy and tolerability of quetiapine in patients with schizophrenia who switched from haloperidol, olanzapine or risperidone

A post hoc analysis of the SPECTRUM trial was carried out to evaluate whether the improvements in efficacy and tolerability gained on switching to quetiapine occurred consistently for patients previously treated with either: haloperidol (n = 43); olanzapine (n = 66); or risperidone (n = 55) monotherapy. Patients were initiated with quetiapine to 400 mg/day over 7 days, and then flexibly dosed (300-750 mg/day) for 11 weeks. The mean (SD) modal dose of quetiapine was 501 (138) mg/day in the haloperidol subgroup, 472 (147) mg/day in the olanzapine subgroup and 485 (141) mg/day in the risperidone subgroup at the study endpoint. Switching to quetiapine induced significant improvements from baseline in PANSS scores, with least square mean changes in total scores of -32.5, -15.4, and -18.5 for patients previously treated with haloperidol, olanzapine and risperidone, respectively, (all p < 0.001 vs baseline). Significant improvements were also noted in CDSS scores, particularly for patients clinically depressed at baseline (all p < 0.001 vs baseline). There were significant reductions in EPS on the SAS and BAS for all subgroups (all p < 0.001 vs baseline). Switching to quetiapine produced efficacy and tolerability benefits regardless of whether their previous antipsychotic was haloperidol, olanzapine or risperidone.     

Amisulpride: a review of its use in the management of schizophrenia

Amisulpride (Solian), a substituted benzamide derivative, is a second-generation antipsychotic that preferentially binds to dopamine D2/D3 receptors in limbic rather than striatal structures. High dosages preferentially antagonise postsynaptic D2/D3 receptors, resulting in reduced dopamine transmission, and low dosages preferentially block presynaptic D2/D3 receptors, resulting in enhanced dopamine transmission. Amisulpride (200-1200 mg/day) was at least as effective as haloperidol and as effective as risperidone or olanzapine, in studies of up to 1 year in patients with schizophrenia manifesting predominantly positive symptoms. Amisulpride (50-300 mg/day) was significantly more effective than placebo in studies of up to 6 months in patients manifesting predominantly negative symptoms. Quality of life was also improved significantly more in patients receiving amisulpride than in those receiving haloperidol in 4- and 12-month studies in patients with predominantly mixed symptoms. Amisulpride was generally well tolerated in clinical trials. In patients with predominantly positive symptoms, amisulpride appeared to be better tolerated than haloperidol and was tolerated as well as risperidone and olanzapine. The incidence of extrapyramidal adverse effects with amisulpride was lower than with haloperidol but was generally similar to risperidone or olanzapine. Weight gain with amisulpride was less than that with risperidone or olanzapine and, unlike these agents, amisulpride does not seem to be associated with diabetogenic effects. Plasma prolactin levels are increased during amisulpride therapy and amenorrhoea occurs in about 4% of women. The incidence of adverse events with low dosages of amisulpride (< or = 300 mg/day) in patients with predominantly negative symptoms was similar to that observed with placebo. In conclusion, oral amisulpride (200-1200 mg/day) is at least as effective as haloperidol, and as effective as risperidone or olanzapine, in the treatment of patients with schizophrenia manifesting predominantly positive symptoms. In the treatment of patients manifesting predominantly negative symptoms, low dosages of amisulpride (50-300 mg/day) are significantly more effective than placebo. Amisulpride appears to be better tolerated than haloperidol, causing a lower incidence of extrapyramidal adverse effects and an improved quality of life. Compared with risperidone or olanzapine, amisulpride is more likely to cause hyperprolactinaemia, but has a lower propensity to cause weight gain and does not seem to be associated with diabetogenic effects. Thus, amisulpride is an effective and well tolerated option for the first-line treatment of patients with acute schizophrenia as well as for those requiring long-term maintenance therapy.     

Efficacy of quetiapine for the treatment of schizophrenia: a combined analysis of three placebo-controlled trials

OBJECTIVE: To determine the effectiveness of quetiapine (Seroquel) against specific aspects of schizophrenic symptomatology. RESEARCH DESIGN AND METHODS: Combined data from three placebo-controlled, double-blind, randomised trials that had previously demonstrated quetiapine's overall clinical effectiveness and tolerability were analysed. Efficacy assessments evaluated were the Clinical Global Impression (CGI) Severity of Illness score, Brief Psychiatric Rating Scale (BPRS) factors I-V, BPRS positive symptom cluster score and 18 individual BPRS items. The Simpson-Angus Scale (SAS), the Abnormal Involuntary Movements Scale (AIMS), changes in weight and prolactin concentrations and the recording of adverse events comprised the main tolerability measures. RESULTS: Efficacy assessments were available for a total of 426 quetiapine patients (mean age 36.9 years) with a DSM-IIIR diagnosis of schizophrenia; 502 patients were included in the tolerability analyses. The mean quetiapine dose was 300.5 mg/day with a mean maximum dose of 686.0 mg/day. Quetiapine was efficacious across a broad range of symptoms, including depression, anxiety and hostility. Significant improvements compared with placebo were noted for CGI Severity of Illness (p < 0.001) and in 14 of the 18 individual BPRS items (p < 0.001). Positive symptoms also improved (p < 0.01 at Week 2 and p < 0.001 from Week 3); greater improvements were observed in patients who received at least 400 mg/day quetiapine. Quetiapine was generally well tolerated: 4.0% of patients withdrew from treatment due to adverse events compared with 3.0% of placebo patients. Akathisia occurred in 2.0% and 2.5% of quetiapine and placebo patients, respectively. Similar decreases in prolactin levels for quetiapine (-10.0 microg/L) and placebo (-10.9 microg/L) were noted from baseline to end of treatment. Agitation and headache, the most common adverse events, were comparable in the quetiapine and placebo groups (agitation: 19.3% vs. 20.3%, respectively; headache: 19.1% vs. 17.3%, respectively). CONCLUSIONS: The results of this combined analysis confirm the individual findings of the three pivotal studies to demonstrate that quetiapine is effective across several domains of schizophrenia, improving positive, negative and depressive symptoms and reducing agitation, aggression and hostility. Similarly, the analysis reiterated the good tolerability profile of quetiapine, particularly in terms of its placebo-like effects on prolactin levels and incidence of extrapyramidal symptoms (EPS).     

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.     

Ziprasidone: a review of its use in schizophrenia and schizoaffective disorder

Ziprasidone is a novel antipsychotic agent with a pharmacological profile distinct from that of other currently available novel or classical antipsychotics. In preclinical studies, ziprasidone was predicted to have efficacy against positive, negative and affective symptoms of schizophrenia with a favourable tolerability profile, including a low propensity to induce extrapyramidal adverse effects. The drug has been administered orally to >300 patients with an acute exacerbation of schizophrenia or schizoaffective disorder in published 4- to 6-week randomised, double-blind trials. When given twice daily, at dosages of between 80 and 160 mg/day, ziprasidone produced significantly greater improvements in overall symptomatology than placebo. In the largest study, ziprasidone 80 or 160 mg/day was also significantly more effective than placebo in reducing negative symptoms and, at 160 mg/day, was significantly more effective than placebo in improving depressive symptoms in patients with associated clinically significant depression. Data from a 4-week trial indicate that ziprasidone 160 mg/day has similar efficacy to haloperidol 15 mg/day. Ziprasidone 40 to 160 mg/day was more effective than placebo with respect to prevention of impending relapse and improvement of negative symptoms in 294 stable patients with chronic schizophrenia who were treated for up to 1 year. In addition, significantly more ziprasidone than haloperidol recipients achieved a negative symptom response in a 28-week study involving 301 stable patients with chronic or subchronic schizophrenia. In general, oral ziprasidone is well tolerated with an overall incidence of adverse events similar to placebo. Importantly, the drug has a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. Ziprasidone is associated with slight prolongation of the QTc interval; the clinical significance of this is not yet clear. The drug does not appear to be associated with sustained elevation of plasma prolactin concentrations. Preliminary data indicate that long-term oral ziprasidone treatment is well tolerated. Ziprasidone is the only novel antipsychotic currently available in a rapid-acting intramuscular formulation. Short-term treatment with intramuscular ziprasidone was effective and well tolerated in patients with acute agitation associated with psychosis. In addition, intramuscular ziprasidone reduced agitation scores by a significantly greater extent than haloperidol in a study involving patients with acute agitation associated with psychosis. CONCLUSIONS: Ziprasidone is a promising new antipsychotic that has shown significant efficacy in the oral treatment of patients with schizophrenia or schizoaffective disorder. The drug is well tolerated with a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. In addition, intramuscular ziprasidone shows efficacy and good tolerability in the treatment of acute agitation associated with psychotic disorders.