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. A review of its use in the management of schizophrenia

Quetiapine (Seroquel), a dibenzothiazepine derivative, is an atypical antipsychotic with demonstrated efficacy in acute schizophrenia. In short-term, randomised, double-blind trials, it was usually more effective than placebo, and was generally effective against both positive and negative symptoms. Overall, quetiapine (up to 750 mg/day) was at least as effective as chlorpromazine (up to 750 mg/day) and had similar efficacy to haloperidol (up to 16 mg/day) in patients with acute schizophrenia in randomised, double-blind trials; it was at least as effective as haloperidol 20 mg/day in patients with schizophrenia unresponsive or partially responsive to previous antipsychotic treatment. Improvements in overall psychopathology and positive and negative symptoms with quetiapine (up to 800 mg/day) were similar to those with risperidone (up to 8 mg/day) or olanzapine (15 mg/day) [interim analysis]. Efficacy was maintained for at least 52 weeks in open-label follow-up studies in adult and elderly patients. Quetiapine improved cognitive function versus haloperidol, and depressive symptoms and hostility/aggression versus placebo. Quetiapine is well tolerated. It is associated with placebo-level incidence of extrapyramidal symptoms (EPS) across its entire dose range, appears to have a low risk for EPS in vulnerable patient groups (e.g. the elderly, adolescents or patients with organic brain disorders) and has a more favourable EPS profile than risperidone. Irrespective of dose, quetiapine, unlike risperidone and amisulpride, does not elevate plasma prolactin levels compared with placebo, and previously elevated levels may even normalise. Quetiapine appears to have minimal short-term effects on bodyweight and a favourable long-term bodyweight profile. Preliminary studies indicate that there is a high level of patient acceptability and satisfaction with quetiapine. In conclusion, quetiapine has shown efficacy against both positive and negative symptoms of schizophrenia, and has benefits in improving cognitive deficits, affective symptoms and aggression/hostility. The beneficial effects of quetiapine have been maintained for at least 52 weeks. Quetiapine was effective and well tolerated in hard-to-treat patients, and may be of particular use in these individuals. It is at least as effective as standard antipsychotics and appears to have similar efficacy to risperidone and olanzapine. The relative risk/benefit profile of quetiapine compared with other atypical antipsychotics requires further research in head-to-head trials, although quetiapine's relatively benign tolerability profile distinguishes it from other commonly used atypical agents, particularly with respect to bodyweight, EPS and plasma prolactin levels. Overall, quetiapine has an excellent risk/benefit profile and is a suitable first-line option for the treatment of schizophrenia.     

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.     

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.     

Quetiapine fumarate (Seroquel): a new atypical antipsychotic

The goal of antipsychotic drug development efforts over the past 10 years has been to develop agents with increased efficacy and safety and fewer of the side effects commonly associated with the older antipsychotic medications. The newer agents, often called atypical antipsychotics, are effective in treating both the positive and negative symptoms of schizophrenia and are associated with fewer neurological- and endocrine-related side effects compared to the older agents. As a result, patients are likely to remain on therapy longer, preventing relapses and costly hospitalizations. Quetiapine fumarate (Seroquel) is the most recently introduced atypical antipsychotic and is indicated for the management of the manifestations of psychotic disorders and schizophrenia. Quetiapine, like clozapine (the archetypal atypical antipsychotic), interacts with a broad range of neurotransmitter receptors and has a higher affinity for serotonin (5-HT(2A)) receptors relative to dopamine (D(2)) receptors in the brain. Further, quetiapine's pharmacological effects appear selective for the mesolimbic and mesocortical dopamine systems, which are believed to be the areas of the brain responsible for the therapeutic effects of antipsychotics. In contrast to most standard antipsychotics and some atypical antipsychotics, quetiapine's effects on the nigrostriatal dopamine system, which is responsible for the extrapyramidal (or motor) side effects, are minimal. Quetiapine also has minimal activity on dopamine receptors in the tuberoinfundibular dopamine system, thereby avoiding the problem of hyperprolactinemia, common with the standard antipsychotics and some atypical antipsychotics. Because of these properties, quetiapine is an effective antipsychotic agent with a relatively benign side effect profile. Several large, placebo- and active-controlled, multicenter trials have shown quetiapine to be effective against both positive (e.g., hallucinations, delusions) and negative symptoms (e.g., emotional withdrawal, apathy) and to have benefits in reducing hostility, aggression and affective symptoms. Patients on long-term treatment report high compliance, good satisfaction, increased ability to function and improvements consistent with a better quality of life. Because of quetiapine's excellent tolerability profile, its use is particularly appropriate in patients especially sensitive to adverse effects, e.g., elderly patients with psychotic symptoms and other neurological disorders such as Parkinson's and Alzheimer's disease.     

D(2) and 5HT(2A) receptor occupancy of different doses of quetiapine in schizophrenia: a PET study.

OBJECTIVE: Quetiapine is a novel antipsychotic agent with many atypical features, including low D(2) and higher 5HT(2A) affinity in vitro, low propensity to induce extra-pyramidal side effects and minimal effects on prolactin levels. The purpose of this study was to investigate, using positron emission tomography (PET), the relationship between plasma concentrations of different doses of quetiapine and occupancy of D(2) and 5HT(2A) receptors in schizophrenic patients. METHODS: Five patients were treated with quetiapine (titrated to 750 or 450 mg/day) for 28 days, subsequently reduced weekly in a descending-dose schedule. Dopamine D(2) and 5HT(2A) occupancies were determined using [(11)C] raclopride and [(11)C] N-methylspiperone as ligands, respectively, and PET imaging. RESULTS: Mean D(2) receptor occupancies of 41 and 30% were observed at quetiapine doses of 750 and 450 mg/day. At lower dose levels no occupancy could be determined. Quetiapine induced a consistently higher degree of 5HT(2A) receptor occupancy, with mean occupancies of 74 and 57% at doses of 750 and 450 mg/day, respectively. No EPS emerged during the trial and most of the pre-trial EPS resolved during the study. CONCLUSIONS: In clinically effective doses, quetiapine induced low occupancy at D(2) receptors, which is consistent with atypical antipsychotics such as clozapine, and probably explains the lack of EPS observed in this trial. Correlations between receptor occupancy and plasma concentrations of quetiapine could not be calculated, although receptor occupancy increased with higher plasma concentrations for the 450 and 750 mg doses.     

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.     

Atypical antipsychotics in mood disorders

Bipolar disorder is ranked as the sixth most important worldwide cause of disability. Current treatment is based chiefly on lithium and/or anticonvulsants, of which sodium valproate is the most widely used. A significant minority of patients fail to respond fully to current treatments, particularly those with mixed mania and/or rapid cycling. Many patients are unable to tolerate the side-effects of current therapy in the long term, and adverse effects may contribute to the high rate of noncompliance observed in bipolar disorder. The shortcomings of current treatments are reflected in poor outcomes: two-thirds of patients with bipolar disorder require hospitalization on more than one occasion; employment and social functioning are significantly lower than in control groups; 93% of carers suffer at least moderate distress; and 25-50% of patients are believed to attempt suicide at least once. Bipolar disorder shares some features with schizophrenia, and several atypical antipsychotics have demonstrated efficacy in bipolar disorder. Quetiapine has a particularly favourable tolerability profile, with placebo-level extrapyramidal symptoms and prolactin levels across the entire dose range combined with a neutral effect on weight during long-term use, and may be a valuable treatment option in acute mania and bipolar disorder.     

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.     

Choosing an atypical antipsychotic

The atypical antipsychotics vary in terms of their pharmacological profiles, particularly in relation to their tolerability, effects on safety parameters and patient acceptability. Olanzapine, risperidone and ziprasidone are associated with extrapyramidal symptoms (EPS) in a dose-dependent manner, whereas quetiapine has been shown to produce a significantly lower incidence of substantial EPS effects than haloperidol, and less EPS requiring treatment than risperidone. Similarly, unlike risperidone and haloperidol, quetiapine treatment has been associated with a significant reduction in serum prolactin levels, and has normalized raised prolactin levels after discontinuation of previous treatment. Weight gain is also one of the major unwanted adverse effects of treatment with many antipsychotic drugs but, in contrast, quetiapine has demonstrated a neutral or 'normalizing' effect on body weight. In comparison with other antipsychotics, quetiapine has been shown to possess a favourable safety profile, with no requirement for routine blood, thyroid, or liver monitoring during treatment. Overall, quetiapine therapy has produced high levels of patient satisfaction and compliance and this, coupled with its efficacy in reducing psychoses of various origins, has made it an attractive treatment option in both patients at increased risk of EPS, and the general population.     

Managing acute exacerbations of schizophrenia: focus on quetiapine

In this commentary article we describe our clinical experience and provide our views on the use of quetiapine in the treatment of patients with acute exacerbations of schizophrenia. Some patients with acute schizophrenia may require parenteral medication; however, we believe that oral antipsychotics, either alone or in combination with other medications, have a key role to play as an initial and/or subsequent pharmacotherapeutic intervention. Quetiapine has beneficial calming properties and successfully treats the symptoms of aggression, anxiety and hostility that can accompany acute exacerbations of schizophrenia. Based upon a review of published findings, data presented at recent international psychiatric congresses and our clinical experience, we propose that a more rapid initiation schedule (for example, 400 mg by Day 2, increasing to 600 mg/day by Day 3 and often up to 800 mg/day by Day 4, or in severe cases 300 mg on Day 1, 600 mg on Day 2 and 900 mg on Day 3) than that currently described in quetiapine prescribing information can be used to provide safe, effective treatment in hospitalised patients with acute schizophrenia. (Note that lower doses are used in patients with first-episode schizophrenia.) Furthermore, while current prescribing information recommends that quetiapine be administered at doses up to 750 mg/day (800 mg/day in the USA and Canada), there is growing evidence that dosing up to 1600 mg/day of quetiapine has been well tolerated in some patients. In general, newer antipsychotics have superior tolerability profiles compared with conventional agents; however, clear differences in tolerability exist among the new generation antipsychotics. Quetiapine has an excellent tolerability profile offering high patient acceptability that, in turn, may promote patient adherence to medication and an improved quality of life. As such, we consider quetiapine to be a first-choice antipsychotic for the treatment of acute exacerbations of schizophrenia.     

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.     

The effects of concomitant phenytoin administration on the steady-state pharmacokinetics of quetiapine

Quetiapine fumarate ('Seroquel') is a newly introduced atypical antipsychotic with demonstrated efficacy in the treatment of positive and negative symptoms of schizophrenia. It is extensively metabolized, predominantly by cytochrome P450 3A4. Therefore, concurrent administration of drugs that induce or inhibit this enzyme may affect quetiapine pharmacokinetics. This study demonstrated that the potent cytochrome P450 enzyme-inducer phenytoin did indeed have a marked effect on the metabolism of quetiapine, resulting in a 5-fold increase in clearance when administered concomitantly to patients with DSM-IV-diagnosed schizophrenia, schizoaffective disorder, or bipolar disorder. These results indicate that dosage adjustment of quetiapine may be necessary when the two drugs are given concurrently and that caution may be required when administering other drugs that inhibit or induce cytochromes, particularly P450 3A4.     

Managing acute exacerbations of schizophrenia: focus on quetiapine

SUMMARY

In this commentary article we describe our clinical experience and provide our views on the use of quetiapine in the treatment of patients with acute exacerbations of schizophrenia. Some patients with acute schizophrenia may require parenteral medication; however, we believe that oral antipsychotics, either alone or in combination with other medications, have a key role to play as an initial and/or subsequent pharmacotherapeutic intervention. Quetiapine has beneficial calming properties and successfully treats the symptoms of aggression, anxiety and hostility that can accompany acute exacerbations of schizophrenia. Based upon a review of published findings, data presented at recent international psychiatric congresses and our clinical experience, we propose that a more rapid initiation schedule (for example, 400?mg by Day 2, increasing to 600mg/day by Day 3 and often up to 800mg/day by Day 4, or in severe cases 300?mg on Day 1, 600?mg on Day 2 and 900?mg on Day 3) than that

currently described in quetiapine prescribing information can be used to provide safe, effective treatment in hospitalised patients with acute schizophrenia. (Note that lower doses are used in patients with first-episode schizophrenia.) Furthermore, while current prescribing information recommends that quetiapine be administered at doses up to 750mg/day (800mg/day in the USA and Canada), there is growing evidence that dosing up to 1600mg/day of quetiapine has been well tolerated in some patients. In general, newer antipsychotics have superior tolerability profiles compared with conventional agents; however, clear differences in tolerability exist among the new generation antipsychotics. Quetiapine has an excellent tolerability profile offering high patient acceptability that, in turn, may promote patient adherence to medication and an improved quality of life. As such, we consider quetiapine to be a first-choice antipsychotic for the treatment of acute exacerbations of schizophrenia.     

Dose response and atypical antipsychotics in schizophrenia

Based on information from clinical trials, both the efficacy and adverse effects of conventional antipsychotics in the treatment of schizophrenia are dose related. The overlapping nature of these dose-response profiles limits the use of these agents. Atypical antipsychotics provide greater relief across the comorbid symptom domains of schizophrenia, but dose-response studies and clinical experience have revealed that some of these drugs also have dose limitations. This article reviews the dose-response relationships of the atypical antipsychotics as presented predominantly in pivotal, randomised studies (double-blind and otherwise).Limited data indicate that clozapine shows dose-related efficacy up to 600 mg/day in patients with treatment-resistant schizophrenia. However, higher dosages of clozapine may be associated with the risk of seizures. Risperidone demonstrates dose-related adverse events that compromise efficacy. The dose-response relationships for ziprasidone, quetiapine and aripiprazole are less well established. The efficacy of olanzapine appears to be dose related within the recommended dosage range of 10-20 mg/day, but clinical trials that have explored higher dosages suggest improved efficacy. Furthermore, the higher doses are not associated with a significantly increased incidence of adverse events.Further studies are clearly needed to fully characterise the dose-response relationships of atypical antipsychotics.     

Quetiapine: dose-response relationship in schizophrenia

Quetiapine is a widely used second-generation antipsychotic that is effective in the treatment of schizophrenia and bipolar mania. In recent years, various publications have suggested the possibility that, in some patients, higher than licensed dosages are necessary for full therapeutic effect. A 'high-dose' theory of quetiapine activity has developed, leading many prescribers to disregard the formal upper limit of the quetiapine dosage range (750 or 800 mg/day, depending on local labelling). In this review, we examine the clinical and neuroimaging data relating to the use of quetiapine in acute exacerbations of schizophrenia. Fixed-dose efficacy studies of immediate-release (IR) quetiapine suggest dosages of quetiapine of 150-450 mg/day are more effective than placebo and no less effective than dosages of 600 or 750 mg/day. A fixed-dose study of extended-release quetiapine indicated that dosages of 600 and 800 mg/day were equally efficacious and numerically superior to 400 mg/day. Dosages of IR quetiapine averaging between 254 and 525 mg/day have been shown to be equivalent in efficacy to standard dosages of conventional and other atypical antipsychotics. Pooled data support these findings. Effectiveness studies using quetiapine in daily doses averaging between 565 and 653 mg revealed quetiapine to be somewhat less effective than some comparator drugs. Support for the use of high-dosage quetiapine (>800 mg/day) is very limited: case reports, albeit numerous, describe quetiapine as showing therapeutic effects only at dosages above the licensed range; some data suggest widespread use of higher dosages in practice; and neuroimaging data suggest inadequate dopamine receptor occupancy at standard dosages (although these findings may reflect the low affinity of quetiapine for dopamine receptors). Overall, robust controlled data strongly suggest that the standard dosage range for quetiapine is appropriate for clinical use. The balance of evidence does not support the belief that higher dosages are required for full therapeutic effect, although higher dosage trials are ultimately required to confirm or refute this hypothesis.     

Antipsychotics – The Future of Schizophrenia Treatment

Summary

Schizophrenia is a debilitating mental disorder affecting up to five in every thousand people. Although specialist psychiatrists are initially responsible for treating patients suffering from acute schizophrenia, the current structure of mental healthcare in the UK puts the onus for the delivery of maintenance therapy of discharged patients on to the general practitioner. It is crucial, therefore, that the general practitioner is aware of all available therapies for the effective, long-term, community-based treatment of patients with schizophrenia. The so-called typical antipsychotics effectively treat the positive but not the negative symptoms of schizophrenia, and up to 40% of patients are nonresponders. These antipsychotics, however, are associated with high levels of extrapyramidal side-effects (EPS), which are the main cause of patient non-compliance and their subsequent relapse and hospital readmission. Clozapine, the first atypical antipsychotic, may cause severe agranulocytosis and patients must undergo regular haematological monitoring, which is both costly and a factor unlikely to foster patient compliance. In contrast, newly developed atypical antipsychotics, such as olanzapine and quetiapine, are not only efficacious in treating the symptoms of schizophrenia, but also give rise to fewer EPS and are generally better tolerated than clozapine. In particular, olanzapine and quetiapine are not associated with severe agranulocytosis. Atypical antipsychotics, therefore, have the potential to enhance patient compliance and thus ease the general practitioner's problems of providing long-term and effective treatment for patients with schizophrenia.     

A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation

The atypical antipsychotics risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole have become first-line treatment for schizophrenia because they reduce the positive symptoms of psychosis but do not have a high incidence of extrapyramidal symptoms. However, these agents, like other antipsychotics, may take as long as 16 or more weeks to produce a response, and even with prolonged treatment are unlikely to evoke responses greater than 50% improvement in symptoms. This has led to the experimental use of high atypical antipsychotic doses, antipsychotic polypharmacy, and augmentation with other psychotropic drugs, all of which occur commonly in clinical practice. This article reviews the current evidence for these increasingly common means of treating schizophrenia and psychosis, with particular emphasis on polypharmacy and augmentation. To date, there are only two controlled studies of antipsychotic polypharmacy involving an atypical antipsychotic; the rest of the data are uncontrolled trials and case reports that describe a mixture of positive and negative findings. One multicenter, double-blind trial shows a faster onset of action when divalproex is added to risperidone or olanzapine than with antipsychotic monotherapy. A small double-blind study demonstrates efficacy when lamotrigine is added to clozapine. The rest of the data on augmentation with anticonvulsants are uncontrolled, and most report adverse effects. With the exception of divalproex, there are currently no compelling data to justify the use of antipsychotic polypharmacy or augmentation. Existing evidence suggests that the best treatments for schizophrenia and psychosis may be long-term trials of a sequence of atypical antipsychotic monotherapies at therapeutic doses.