Antipsychotic treatment in schizophrenia: atypical options and NICE guidance

European Psychiatry 18 (2003) 209–219 www.elsevier.com/locate/eurpsy

Original article

Antipsychotic treatment in schizophrenia: atypical options and NICE guidance Ann M. Mortimer *,1 The Department of Psychiatry, University of Hull, East Riding Campus Willerby, Hull HU10 6NS, UK Received 19 August 2002; accepted 16 January 2003

Abstract Following the reintroduction of clozapine, several atypical antipsychotics have become available for the treatment of schizophrenia. These drugs are at least as effective as conventional treatment. Although each has an individual pattern of affinities, new work suggests that the hallmark of atypicality is fast dissociation at the dopamine-2 receptor. Numerous novel drugs are in development, but it is not clear how these conform to this theory of therapeutic effect. Atypical antipsychotics cause less extrapyramidal side effects than conventional treatment, but other effects such as hyperprolactinaemia, weight gain, glucose dysregulation and prolonged QTc interval remain problematic for some. Current antipsychotic prescribing practice is far from ideal: the NICE guidance stresses that atypical treatments should be considered unless symptoms are well controlled and side effects are acceptable, or depot formulation is indicated. There is a welcome emphasis on drug treatment as part of an integrated package of care negotiated with patients and their carers. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. Keywords: Atypical antipsychotic; Schizophrenia; Novel drug discovery; Side effects; NICE guidance

1. Introduction Antipsychotic treatment remains mandatory for patients with an established diagnosis of schizophrenia. However, conventional antipsychotics cause a wide range of unpleasant side effects, typically extrapyramidal side effects (EPS) in most patients [7]. They are ineffective in a significant minority, with at least 30% of patients fitting treatment-resistance criteria [33]. All have the same mechanism of action, i.e. the antagonism of the dopamine-2 (D2) receptor [44,115] and no drug is any more effective in the individual patient than any other [33]. The impetus to search for alternatives to conventional antipsychotics began after the reintroduction of clozapine in 1990. Clozapine has little apparent affinity for the D2 receptor (and therefore almost no EPS) yet has efficacy in schizophrenia resistant to conventional treatment [17,65,144]. * Correspondance author. E-mail address: [email protected] (A.M. Mortimer). 1 Prof. Mortimer trained in medicine at the University of Leicester and in psychiatry at York and Leeds. After her first consultant appointment in Huddersfield, she became a Senior Lecturer at Imperial College, London, prior to taking up her Foundation Chair at Hull in 1996.

© 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. doi:10.1016/S0924-9338(03)00060-9

Since then, several other ‘atypical’ antipsychotics have been introduced: in June 2002, the National Institute for Clinical Excellence (NICE) released guidance on their use [8].

2. What is atypicality? In general, an atypical drug should not induce EPS at therapeutic doses, and it should, of course, be at least as effective as conventional treatment. Other properties, such as having little or no effect on serum prolactin, are common to some new drugs (notably clozapine, olanzapine and quetiapine) but not others. The affinities of current atypical drugs are not limited to the D2 receptor (see Table 1). All except amisulpride have much greater affinity for serotonin 5HT-2A receptors than they do for D2 receptors. This was thought to confer atypicality: however, recent work [67] suggests that D2 receptor ‘off time’ is the most powerful predictor of atypicality. It is proposed that while all antipsychotics bind quite avidly to D2 receptors, there are marked differences in time to dissociation: for instance clozapine would bind to and be released by the D2 receptor 100 times during the time that haloperidol would take to be released. Indeed, all conventional antipsy-

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Table 1 Receptor affinities of atypical antipsychotics compared with haloperidol Atypical antipsychotic Haloperidol Clozapine Olanzapine Quetiapine Zotepine Risperidone Ziprasidone Amisulpride

D1 + + ++ – ++ + – –

D3 – – – – – ++ – +++

D2 +++ + ++ + ++ ++ ++ ++

5-HT2A + +++ +++ + +++ +++ +++ –

chotics bind to the dopamine receptor more strongly than dopamine itself, while all atypical drugs bind more loosely [116]. It is proposed that this combination of rapid binding and dissociation is physiological, i.e. it has the same effect on overall brain function as endogenous ligand dopamine in healthy people. Furthermore, affinity for other receptors including the serotonin receptor may be irrelevant to the therapeutic actions of antipsychotics [66]. The dopamine off-time hypothesis is able to explain the phenomenon of limbic selectivity, in which a drug seems to prefer binding sites in the limbic cortex rather than those in the striatum. Limbic binding is thought to be therapeutic, while striatal binding produces EPS. Because there is much more endogenous dopamine in the striatum, this will compete effectively for D2 sites in the presence of antipsychotics with short off times. Endogenous dopamine has far more opportunities to bind to the receptor when an atypical drug dissociates frequently, than in the presence of a conventional drug which does not let go so easily. By contrast, there is much less endogenous dopamine in limbic cortex: this allows an atypical drug to bind to D2 receptors without too much competition, despite the drug’s tendency to dissociate easily. The atypical antipsychotics clozapine, quetiapine and amisulpride all exhibit short off times.

3. Atypical antipsychotics currently available 3.1. Risperidone Risperidone is superior to conventional treatment for positive and negative symptoms [34,86,119] and is effective and very safe in drug-naïve and first-episode patients [73–75]. Most patients can tolerate complete cessation of current treatment with an immediate switch to risperidone, although anticholinergic medication should be tapered gradually [72]. At the daily optimal dose of 6 mg, risperidone causes no more EPS than placebo [86]. It does, however, cause hyperprolactinaemia. Other side effects include orthostatic hypotension, sedation, sexual dysfunction and weight gain. In clinical practice many patients, particular the elderly [43,67,74,114,153] and children, can be managed on doses smaller than 6 mg, even acute relapsing patients [77].

5-HT2C – ++ ++ – ++ ++ +++ –

Alpha1 +++ +++ ++ + ++ +++ + –

Alpha2 – ++ – – + +++ – –

Musc – ++ ++ + ++ – – –

NA – – – – +++ – – –

Hist – +++ +++ + – +++ + –

Sigma +++ – – – – – – –

3.2. Olanzapine Olanzapine is at least equivalent to conventional treatment for positive symptoms, and is clearly superior to conventional treatment for negative symptoms [9,10,137] although some evidence suggests pseudonegative i.e. secondary negative symptom relief only [76]. Olanzapine is markedly superior in patients within 5 years of onset [113]. It is superior to haloperidol in depressive symptoms in schizophrenia [138], and there is preliminary evidence to suggest that it improves quality of life more than haloperidol [87]. It may be useful for patients who do not respond to clozapine, or who discontinue clozapine owing to adverse events [141]. The most common side effects of olanzapine are sedation, dizziness and weight gain. EPS are unusual, apart from occasional akathisia at doses up to 15 mg/d. Other aspects of EPS are limited to doses greater than 15 mg/d [121]. Olanzapine does not induce hyperprolactinaemia. Cardiac safety appears highly satisfactory [31]. However, clinical doses tend to be greater than the 10 mg recommended: in one trial, in which variable doses were allowed according to clinical response, the average dose was 16.7 mg/d [140]. 3.3. Quetiapine Quetiapine has a broad, mild receptor profile. It is at least as effective as haloperidol for positive symptoms [4,14,15]. Evidence for better efficacy than conventional treatment in negative symptoms is more equivocal [71,80,101]. The outstandingadvantages of quetiapine are its placebo-level induction of EPS across the dosage range [4] and that it does not affect prolactin levels. This makes it particularly suitable for first-episode patients. Typically, most clinicians find maximal doses necessary in chronic patients. Side effects are infrequent and include somnolence, dry mouth, abdominal pain and weight gain. Quetiapine has been used successfully to treat psychosis in Parkinson’s disease without inducing motor deterioration [99] and in the elderly with psychotic disorder [90]. There are very high levels of patient satisfaction, efficacy in partially responsive patients (those with clinically significant symptoms despite good compliance), and efficacy in hostile aggressive patients [42,56,57]. Overall, quetiapine is probably the best tolerated atypical antipsychotic [37].

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3.4. Zotepine Zotepine has been available in other countries, notably Japan, since 1982. Its broad receptor profile includes strong noradrenaline reuptake inhibition. The theoretical implication that it should be effective as an antidepressant has neither been apparent clinically nor tested in trials. Zotepine is as effective as haloperidol in the treatment of positive symptoms [106] and is at least as effective for negative symptoms [6,100]. It is more effective than chlorpromazine for symptoms overall [26]. One small double-blind randomized controlled trial (RCT) reported symptomatic improvement equivalent to clozapine [91]. Agitation and assaultativeness may be problematic, but a combination of zotepine and nefazadone has been found useful in patients who stopped clozapine owing to neutropenia [78]. Other side effects of zotepine are insomnia, somnolence, anxiety, headache, constipation, weight gain, dyspepsia and dry mouth. The incidence of EPS is lower than all comparator conventional drugs in trials, although weight gain and tachycardia may be more of a problem than with haloperidol [60]. In one long-term study, EPS were not significantly greater than placebo [25]: a post-marketing surveillance study has suggested that akathisia may decrease [69]. Tardive dyskinesia is rare. 3.5. Amisulpride Amisulpride is at least as effective for positive symptoms as conventional treatment [27,46,95,96] and substantially reduces negative symptoms compared with placebo in methodologically near-ideal studies [16,32,83]. Similar evidence from active comparator studies is generally convincing [12,24,95,103,112,120]. Amisulpride induces far less EPS than haloperidol, with placebo levels up to the dose of 300 mg daily [27]. It does, however, cause hyperprolactinaemia. Other side effects are uncommon, but can include agitation, anxiety and insomnia.

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acutely agitated patients. Two double-blind studies comparing i.m. olanzapine with i.m. haloperidol and placebo demonstrated that olanzapine-treated patients showed a significant reduction in acute agitation at 15 min compared with a minimum of 30 min for haloperidol, and fewer patients experienced EPS [150,151]. This suggests that it is now possible to transfer patients smoothly from hyperacute care to a period of stabilization, followed by maintenance treatment using a single antipsychotic. Liquid risperidone has efficacy and tolerability advantages over intramuscular haloperidol [30]. Oral olanzapine is also safe and effective for rapid tranquillization [68]. For the dubiously compliant but observable patient, olanzapine ‘velotabs’ which disintegrate orally and so cannot be disposed of later, may present advantages. 4.3. When monotherapy is inadequate Up to 20% of atypical treated patients may respond inadequately [121]. Overall it is agreed that the results of high dose treatment, and of the addition of a second antipsychotic, are disappointing. The rationale for switching to an atypical antipsychotic with a different affinity pattern is unclear, given recent work on dopamine receptor off times: this would indicate amisulpride, quetiapine or clozapine if the patient was not currently taking one of these drugs and had not had a previous unsuccessful trial. There is a small literature on the use of adjunctive treatment. For the patient with problematic negative symptoms, adding a specific serotonin reuptake inhibitor (SSRI) may be of benefit [36,62,81,118]. Further strategies include adding a mood stabilizer or antidepressant for affective components, and adding benzodiazepines such as clonazepam for agitation and anxiety. The evidence base for these strategies is limited: even when used appropriately these drugs may have little effect on unresolved symptoms [18]. Divalproex may be useful in the management of poorly controlled positive symptoms [146]. Overall it makes clinical sense to offer clozapine before exhausting every other therapeutic possibility.

4. Atypical antipsychotics in special situations

4.4. Treatment resistance

4.1. Relapse prevention

Clozapine remains the only drug licensed for the indication of treatment-resistant schizophrenia. The three best double-blind RCTs involving treatment-resistant patients reported response rates, based on a Brief Psychiatric Rating Scale (BPRS) score reduction, of 30% at 6 weeks [65], 44% at 10 weeks [17] and 42% at 29 weeks [144] on clozapine. The relative response rates on either chlorpromazine or haloperidol were 4%, 8% and 6%, respectively. Evidence to challenge clozapine from studies with other atypical antipsychotics in treatment-resistant illness is scarce, and of variable quality. Despite claiming equivalence of clozapine with risperidone, one double-blind RCT of only 4-weeks’ duration involved acutely ill patients and increasing the clozapine dose far more rapidly than recommended by the manufacturers [13].

Evidence is accruing that relapse rates for compliant patients maintained on atypical drugs are substantially lower than rates for those maintained on conventional drugs [23,28,85,147]. 4.2. Rapid tranquillization The withdrawal of droperidol, one of the mainstays of rapid tranquillization, and cautions regarding the cardiac and other side effects of intramuscular haloperidol, have led to recommendations that intramuscular benzodiazepines, particularly lorazepam, should be used instead [89]. However, intramuscular olanzapine is a promising treatment for

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A review of other atypical antipsychotics compared to clozapine suggested that newer atypical drugs ‘seemed to be broadly similar to clozapine’, but concluded that there was insufficient evidence to demonstrate equal effectiveness and tolerability [142]. An open study of treatment-resistant patients, comparing risperidone with haloperidol [3] demonstrated superiority for risperidone over haloperidol (24% vs. 10% responded, respectively), with risperidone was much better tolerated. An RCT reported similar results [153]. Olanzapine was superior to chlorpromazine in one treatment-resistant double-blind RCT [22]. The NICE guidance estimates that 37,000 patients ought to be established on clozapine in the UK, assuming (conservatively) a 60% response rate. There are currently only 13,500 such patients. Even patients commenced on clozapine may be discontinued for unclear or unacceptable reasons [97]. 5. Drugs in development 5.1. Risperidone long acting microspheres (Risperdal Consta) This is a sustained release intramuscular formulation of risperidone. The drug is encapsulated into microspheres made from a medical grade polymer commonly used in surgical sutures. The microspheres are dried to a powder, which is mixed with water for fortnightly injection. Less than 4% of active drug is released on injection: the microspheres are completely eliminated by the body. In a 3-month, doubleblind placebo-controlled randomized trial with 400 patients, this formulation proved superior to placebo, with no more withdrawals due to side effects than on placebo [45,51].

other antipsychotics, although this is significantly less than that caused by thioridazine and sertindole: there is no evidence of harmful clinical consequences [52]. However, the Swedish Summary of Product Characteristics advises against administration with any other drug which can produce this effect, alongside other safeguards [54]. Ziprasidone is now available in the USA, Scandinavia and several EEC countries. A licence application in the UK is imminent, following the termination of this procedure in 2001 for reasons related to safety concerns: new data are to be submitted in this regard. 5.3. Aripiprazole Aripiprazole is a dopamine partial agonist [126]: it acts as a pre-synaptic dopaminergic agonist and a post-synaptic antagonist [79]. It may be capable of modulating or stabilizing dopaminergic neurotransmission depending on the functional status of the synapse i.e. increasing hypofunction and decreasing hyperfunction. This may confer therapeutic effect without the EPS consequences of unrelieved antagonism [122,123]. Aripiprazole acts as a striatal antagonist in preclinical studies [88] which would indicate at least the possibility of EPS in patients. However, it has less cardiovascular effects than haloperidol in dogs [124]. 5.4. Iloperidone Iloperidone is currently in Phase III development. It is a dopaminergic–serotonergic drug with additional alphaadrenergic activity, which may confer benefits for mood and cognition. Iloperidone appears to be relatively well tolerated, with low EPS and weight gain, and no clinically relevant effects on ECG parameters: pre-clinical work suggests superiority over haloperidol for an animal model of positive symptoms [61].

5.2. Ziprasidone

5.5. Other potential antipsychotics

Studies to date report that, like risperidone, ziprasidone’s strongest affinity is for the 5-HT2 receptor, with slightly reduced affinity for the D2 receptor. Unlike risperidone, it has significant affinities for the 5-HT1A and 5-HT1C receptors. It has an early onset of action, and is as effective as conventional treatment for positive symptoms [50]. There is limited evidence of better efficacy for negative symptoms compared with conventional treatment [52,53], although it is better than placebo. It appears to have some antidepressant/anxiolytic effect [108]. EPS liability is small, but dose related, with an EPS incidence of approximately 10% at the standard dose of 160 mg daily, which does not exceed placebo rates. Only somnolence [108] and gastrointestinal side effects [70] are more common than with placebo. Ziprasidone does not cause hyperprolactinaemia. An intramuscular formulation is available: preliminary data indicate that it has efficacy and tolerability advantages compared with intramuscular haloperidol [125]. Ziprasidone is associated with more QTc interval prolongation than most

Other drugs in development include a fixed-dose olanzapine and fluoxetine formulation for bipolar depression, treatment-resistant depression and psychotic depression. Tricyclic antidepressant/conventional antipsychotic preparations were used widely in the 1970s and early 1980s, but preferred practice was to use monotherapy if possible, with adjuncts given separately to preserve flexibility of dosing. Safety and efficacy data on the new combination are awaited. Regarding schizophrenia, adding fluoxetine to olanzapine to control weight gain in first-episode schizophrenic patients was ineffective in one study, possibly hampering the resolution of positive symptoms [104]. There are several entirely novel drugs in development: 1. ORG-5222 (Organon), a D2/5HT2c antagonist [109]; 2. S-16924 and SR-46349 (Sanofi), clozapine-like drugs with potent 5HT affinities [93]; 3. M-100907 (Aventis), a highly selective 5-HT2A antagonist with NMDA glutamatergic affinity, potentially useful in chronic schizophrenia [35];

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4. DU127090 (Lundbeck), a D2 ‘modulator’ (may agonize or reverse agonize receptor according to receptor status) and 5HT1A agonist; 5. DTA201 (Novartis), a D3 antagonist; 6. Sonepiprazole (Pharmacia), a D4 antagonist; 7. Osanetant (SR-142801, Sanofi), a neurokinin-3 antagonist; 8. Eplivanserin (Sanofi), a 5HT2A antagonist; 9. Ampalex (Organon), a neuroprotective AMPA (glutamate) receptor modulator [5,49,63]; 10. OSU6162, a D2 modulator [40,41,131,132]. It remains to be seen whether these drugs will demonstrate efficacy and safety: even so there are issues regarding whether they represent a further advance in schizophrenia treatment. Given the interest in dopamine receptor off times, there is an obvious rationale for the development of a new drug with dopamine binding kinetics similar to clozapine, but without neutropenia, weight gain, sedation, hypersalivation, glucose dysregulation, tachycardia and all the other serious side effects associated with this drug. It is of considerable interest whether short dopamine off times equate to stabilization, modulation and partial agonism of dopamine receptors in this regard.

6. New concerns: weight gain, diabetes and QTc prolongation 6.1. Weight gain Marked bodyweight gain has been observed with atypical antipsychotics, although it is also a problem with conventional treatment. Histamine receptor affinity, and dopamine relative to 5-HT2 receptor affinity, both seem to be robust correlates of weight increase. Induction of leptin secretion may also be relevant. Clozapine and olanzapine appear to be associated with more weight gain than other atypical antipsychotics: low pre-treatment body mass index, young age and female gender increase liability. There are some reports of an association between weight gain and clinical improvement [110]. It remains unclear as to how much weight gain contributes to diabetes and hyperlipidaemia. One review quoted weight gain associated with atypical antipsychotics as follows: zotepine and olanzapine 2.3 kg/month, quetiapine 1.8 kg/month, clozapine 1.7 kg/month, risperidone 1.0 kg/month and ziprasidone 0.8 kg/month [148]. This was said to occur mainly in the first 12 weeks of treatment, with underweight patients most likely to gain weight. Another review quoted mean weight gains of 3.19 kg with thioridazine, 4.45 kg with clozapine, 4.15 kg with olanzapine, 2.92 kg with sertindole, 2.1 kg with risperidone and 0.04 kg with ziprasidone [2]. A large systematic review of weight gain ranked clozapine as presenting the highest risk, followed by olanzapine, quetiapine, risperidone, sertindole, zotepine and amisulpride: ziprasidone had not been associated with weight gain [130].

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6.2. Diabetes The World Health Organization has estimated that the worldwide prevalence of diabetes will more than double between 1995 and 2025 [19]. Schizophrenic populations are known to have a two to threefold increased risk for Type II diabetes: it is even possible that the glycaemic state of patients contributes to their symptoms, and that part of the therapeutic effects of antipsychotics stem from their effects on glucose metabolism [39]. It has been pointed out that treatment-emergent diabetes may be an observational artefact of clinical trials, resulting from undiagnosed diabetes or impaired glucose tolerance at baseline [19]. However, the strength of the association between antipsychotics and diabetes varies across individual medications, with the largest number of reports for chlorpromazine, clozapine and olanzapine [55,58,94]. A small study looking at glucose tolerance testing [98] demonstrated that glucose levels in patients receiving clozapine and olanzapine were significantly greater than those of patients receiving risperidone, conventional treatment or nothing (healthy volunteers). Furthermore, a retrospective comparison involving 94 inpatients reported far greater increases in fasting glucose and lipids on olanzapine compared to risperidone [92]. However, a post-marketing surveillance exercise of nearly 9000 patients on olanzapine yielded only eight reports of diabetes [11]. A study comparing 552 patients on clozapine and 2461 on conventional antipsychotics found clozapine to be associated with a significantly increased relative risk of diabetes of 2.5 when compared to the risk to patients aged 20–34 years on conventional antipsychotics [84]. There were no differences when all age groups were pooled. However, one naturalistic study of 82 patients on clozapine reported that over a third had diabetes 5 years later [59]. A large study of 38,600 patients with schizophrenia [117] suggested that patients on atypical treatment (clozapine, olanzapine, quetiapine and risperidone) were 9% more likely to have diabetes than conventional treated patients: risperidone, however, was not associated with an increased risk across the entire age group, just in patients under 40 years old. Zotepine and amisulpride were not available to the patients and so could not be examined. The largest study is a pharmacoepidemiological examination of the prescription records of nearly six million people [21]. Those receiving any antipsychotic de novo, followed by receipt of antidiabetic medication (including insulin) de novo, were identified during a 2 year period. Hazard ratio analysis indicated that the risk of developing diabetes was the same for conventional and atypical antipsychotics (again zotepine and amisulpride were unavailable). The only outliers were clozapine, with a ratio of 1.3 compared to conventional treatment, and lower doses of quetiapine, with a ratio of 0.7 compared to conventional treatment. Overall there is little evidence to suggest that atypical antipsychotics are worse for glucose regulation and diabetes

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than conventional drugs, apart from clozapine. It would seem prudent to monitor patients’ weight, glucose and lipid levels, whatever antipsychotic they are prescribed. 6.3. QTc prolongation It is likely that all antipsychotics have electrophysiological properties which in theory should increase the risk of sudden cardiac death [152]. Indeed, numerous reports suggest that patients with schizophrenia suffer an excess of sudden fatal cardiac events [107]. It is generally considered that the ventricular arrhythmia, torsade de pointes, which is associated with syncope and sudden death, is a likely explanation [48]. A prolonged QTc interval (especially longer than 500 ms) is a risk factor for torsade de pointes, but is not the direct cause. Thioridazine, pimozide, sertindole, droperidol and haloperidol have all been documented to cause torsade de points and sudden death: the greatest risk is with thioridazine. This has resulted in the withdrawal of droperidol and sertindole, the virtual withdrawal of thioridazine, and subsequently some difficulties in the licensing of ziprasidone in the UK. Pimozide should not be prescribed without extensive precautions around ECG monitoring and the exclusion of other drugs which affect QT intervals, the metabolism of pimozide, or electrolyte balance. Olanzapine, quetiapine and risperidone have not been associated with torsade de pointes: there are no data on amisulpride and zotepine. Individual antipsychotics, whether conventional or atypical, are associated with differing degrees of QTc prolongation: it is not likely that one class or the other will prove more unsafe. Assessing risk is fraught with confounding issues. QTc prolongation is not the only factor in precipitation of torsades de pointes: haloperidol has been associated with torsade de pointes despite prolonging QTc by a mere 5 ms. As a rare event, sudden death is more likely to be observed with widely prescribed drugs than those which are not widely prescribed. ECG anomalies are likely to surface with closely monitored drugs in clinical trial development, but their relevance cannot be assessed without widespread prescription. Furthermore, data on QTc prolongation in stable patients cannot be reliably extrapolated to intramuscular use in acutely disturbed patients. Pharmacokinetic properties are also of relevance: with some drugs there is a dose related QTc interval, or serum level and QTc prolongation vary together when relevant enzyme inhibitors are inadvertently coprescribed. This does not apply to ziprasidone [52]. Overall it is recommended that antipsychotics are not used in patients for whom their benefit is marginal, and they should be used with caution in patients with established cardiovascular disease. 7. Current antipsychotic prescribing practices Both government policies [133,134] and influential guidelines on antipsychotic prescribing in schizophrenia [29,128] generally favour the use of atypicals, although there are some

detractors [1,47]. There are especially strong arguments for the use of atypicals in first-episode schizophrenia patients, up to 40% of whom have intrinsic EPS [20,82]. Despite these factors, to which can be added the widening choice and lengthening duration of availability, only 18% of antipsychotic prescriptions in the UK currently are for atypical drugs [135]. By contrast in Italy the percentage is 42% and in the USA it is 62%. There are parliamentary constituencies in the UK in which less than 13% of prescriptions are for atypical drugs, and in no constituency is the percentage more than 44%. It has been suggested that the majority of patients are still denied access until they have failed to respond to or tolerate conventional treatments: 21% of health authorities actively restrict access to atypical drugs [135]. Despite this evidence, it has been reported that in the year April 2001–April 2002 numbers of prescriptions for oral atypical treatment grew by 55%, amounting to 2.3 million prescriptions, a 37% share of the market [102]. The recent discontinuation of droperidol and virtual withdrawal of thioridazine, owing to their prolongation of QTc interval with the risk of cardiac arrhythmia [54] may have affected prescribing patterns. However, in primary care the familiarity of GPs with conventional antipsychotics and benzodiazepines may result in the substitution of a conventional alternative, a benzodiazepine or nothing: this issue has not been addressed. There is still a widespread tendency for the prescription of antipsychotics in high doses, with a prevalence of up to 44% in samples of inpatients [145]. Similarly, more than one antipsychotic is often prescribed, for instance 28% in newly discharged patients [105]. There is no theoretical rationale or clinical evidence base to support the co-prescription of conventional and atypical drugs [129]. High dose antipsychotics are recognized as presenting substantial physical risk, and there are cumbersome guidelines regarding their use [136]. Multiple antipsychotics clearly increase the overall dose and the probability of side effects and interactions. Even in a service with a low (4%) prevalence of high dose prescribing, guidelines were not being followed: the prevalence of multiple prescribing was 28% [143]. 8. The NICE guidance: a summary A more collaborative, holistic approach to treatment planning is recommended: choice of antipsychotic should follow an informed discussion with the patient (and their carer or advocate if appropriate) covering relative benefits and sideeffect profiles. Advance directives regarding choice of treatment should be developed whenever possible. Antipsychotic therapy should form part of a comprehensive package of care that addresses the individual’s clinical, emotional and social needs: progress should be monitored particularly following change of drug. Atypical antipsychotics should be considered as first-line treatment for new patients, for relapsing patients and for

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patients suffering from unacceptable side effects even if symptom control is acceptable. It is recommended that the definition of unacceptable side effects be determined by discussion between patient and doctor. For patients in whom such discussion is not possible, the matter should be discussed with the carer or advocate: atypical drugs should be considered as the treatment options of choice owing to the lower risk of side effects. If more than one atypical treatment is indicated, that with the lowest acquisition cost should be prescribed. Patients with good symptom control and acceptable side effects should not be changed onto an oral atypical drug, and depot medications should be prescribed if a risk assessment indicates that this is appropriate. If there is evidence of treatment-resistant schizophrenia, clozapine should be introduced at the earliest opportunity. Such evidence is defined as a lack of satisfactory clinical improvement despite the sequential use of two antipsychotics, one an atypical, in recommended doses for 6–8 weeks. Finally, the guidance prohibits co-prescription of conventional and atypical drugs except for short periods to cover changeover of medication. 8.1. Comments on the NICE guidance The guidance has been generally well received in the author’s view. The emphasis on involvement of patients and carers, a comprehensive package of care and review of therapeutic progress is laudable, but really formalizes what should be going on in any case. For many, the crucial word in the guidance is ‘consider’. There is no directive to prescribe atypical treatment in the circumstances described (except for clozapine). However, neither are there specified limitations on prescribing atypicals, such as having to use low dose conventional treatment first. The guidance on clozapine is particularly radical: at the Maudsley Hospital, patients were prescribed, on average, six antipsychotics before clozapine. The mean delay between the failure of the second drug and the prescribing of clozapine was over 2 years [127]. Outside centres of excellence the situation may be far less acceptable in terms of the NICE guidance. NICE recognizes only the EPS and cost benefits of atypical treatment: it does not accept that atypical treatment may be superior to conventional treatment for both symptom efficacy and relapse prevention. The reason given is the quality of available data. As a whole the data do, however, tend to point in the same direction in very much the same way as the pharmacoeconomic data. Regarding EPS, NICE has nothing to say on the chronic use of anticholinergic antidotes, although it is well established that this is harmful [38,64,139,149]. This is a surprising omission given NICE guidance on unacceptable side effects. Furthermore, the guidance fails to comment on other well-documented atypical tolerability advantages such as the lack of hyperprolactinaemia with some options. Neither does it recognize the differing side-effect profiles of individual atypicals, which

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are becoming well established for instance with regard to EPS liability and hyperprolactinaemia. This is particularly relevant to the guidance on prescribing the cheapest of alternatives which are equivalent in other respects. Neither does NICE address the huge issue of the use of antipsychotic treatment long-term outside its licensed indication of psychosis, particularly in primary care [111]. However, the guidance on polypharmacy is particularly welcome.

9. Summary There are now several atypical antipsychotics available, all of which differ in side effect and efficacy profile. New understanding of the mechanism of action of these drugs implies exciting potential for drug development, but incomplete concordance remains between neuroscience and the direction in which drug development is being pursued by the pharmaceutical industry. One result of this may be the launch of additional atypical antipsychotics of little if any extra value. Choice of antipsychotic treatment is a complex issue. The clinical state of the patient, their treatment history and their individual side-effect profile are all of relevance. There is an increasing awareness of weight gain, glucose dysregulation and cardiac conduction anomalies in patients prescribed antipsychotics whether conventional or atypical: these effects should not be ignored. Following the NICE guidance, atypical antipsychotics are now a legitimate option in the management of psychosis. However, the guidance is unlikely to lead to a wholesale switch to atypical treatment, and several important issues in clinical practice remain unaddressed.

10. Multiple choice questions 1. Atypical antipsychotics except clozapine should be considered first-line when The patient has unacceptable side effects on conventional treatment The patient is known to be non-compliant The patient has well-controlled symptoms but unacceptable side effects The patient is antipsychotic naïve or in first episode The patient is treatment resistant

T F T T F

2. Mood stabilizers may be a useful adjunct in schizophrenia with Comorbid substance abuse Comorbid personality disorder Comorbid learning disability Unresolved positive symptoms Unresolved negative symptoms

F F F T F

3. The following are sensible antipsychotic regimes High dose oral antipsychotics of any type Co-prescription of conventional and atypical antipsychotics Long-term anticholinergic antidote treatment for EPS

F F F

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1. Atypical antipsychotics except clozapine should be considered first-line when An atypical antipsychotic with an SSRI for negative symptoms Clozapine for treatment-resistant patients 4. Try clozapine if The patient fails to respond to depot You have not tried 5 other antipsychotics yet The patient has a history of neutropenia The patient fails to respond to 2 antipsychotics, one an atypical antipsychotic The patient is drug naïve in first episode 5. QTc interval prolongation may be a serious side effect of the following Thioridazine Pimozide Quetiapine Sertindole Olanzapine

T T

F F F T F

T T F T F

References [1]

Adams C, The Cochrane Schizophrenia Group. Drug treatments for schizophrenia, 5. NHS Centre for Reviews and Dissemination; 1999 Effective Health Care [report]. [2] Allison DB, Mentmore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156(11):1686–96. [3] Ames D, Wirshing WC, Marshall BD. Risperidone versus haloperidol in treatment resistant schizophrenia. Schizophrenia Res 1997;24:193–4. [4] Arvanitis LA, Miller BG, the Seroquel Trial Study Group. Multiple fixed doses of ‘Seroquel’ (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. Biol Psychiatry 1997;42:233–46. [5] Bahr BA, Bendiske J, Brown QB, Munirathinam S, Caba E, Rudin M, et al. Survival signaling and selective neuroprotection through glutamatergic transmission. Exp Neurol 2002;174(1):37–47. [6] Barnas C, Stuppack CH, Miller C, Haring C, Sperner-Unterweger B, Fleischhacker WW. Zotepine in the treatment of schizophrenic patients with prevailingly negative symptoms, a double blind trial versus haloperidol. Int Clin Psychopharmacol 1992;7:23–7. [7] Barnes TRE, Edwards J. Antipsychotic drugs and their side effects. London: Academic Press; 1993. [8] Barnett D. Guidance on the use of newer (atypical) antipsychotic drugs for the treatment of schizophrenia, 43. London: National Institute for Clinical Excellence; 2002 Technology Appraisal Guidance [report]. [9] Beasley CM, Hamilton SH, Crawford AM. Olanzapine versus haloperidol: acute-phase results of the international double-blind olanzapine trial. Eur Neuropsychopharmacol 1997;7:125–37. [10] Beasley CM, Tollefson G, Tran P. Olanzapine versus haloperidol and placebo: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology 1996;14:111–24. [11] Biswasl PN, Wilton LV, Pearcel GL, Freemantle S, Shakir SA. The pharmacovigilance of olanzapine: results of a post-marketing surveillance study on 8858 patients in England. J Psychopharmacol 2001; 15(4):265–71. [12] Blin O. Which role for amisulpride in rehabilitation of schizophrenic patients with acute exacerbation? Encephale 2000;26(Spec No 1): 7–11.

[13] Bondolfi G, Baumann P, Dufour H. Treatment resistant schizophrenia: experience with new antipsychotics. Eur Neuropsychopharmacol 1996;6(Suppl 2):2–25. [14] Borison RL, Arvanitis LA, Miller BG. A comparison of five fixed doses of ‘Seroquel’ (ICI 204,636) with haloperidol and placebo in patients with schizophrenia. Schizophrenia Res 1996;18(2,3):132. [15] Borison RL, Arvanitis LA, Miller BG, et al. ICI 204,636, an atypical antipsychotic: efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. J Clin Psychopharmacol 1996;16: 158–69. [16] Boyer P, Lecrubier Y, Peuch AJ. Treatment of negative symptoms in schizophrenia with amisulpiride. Br J Psychiatry 1995;166:68–72. [17] Breier A, Buchanan JR, Kirkpatrick B. Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry 1994;151:20–6. [18] Buchanan RW, Kreyenbuhl J, Zito JM, Lehman A. Relationship of the use of adjunctive pharmacological agents to symptoms and level of function in schizophrenia. Am J Psychiatry 2002;159(6):1035–43. [19] Buse JB. Metabolic side effects of antipsychotics: focus on hyperglycaemia and diabetes. J Clin Psychiatry 2002;63(Suppl 4):37–41. [20] Caliguiri M, Lohr JB, Jeste DV. Parkinsonism in neuroleptic naive schizophrenic patients. Am J Psychiatry 1993;150(9):1343–8. [21] Cavazzoni P, Baker RW, Kwong K, Hornbuckle K, Hutchins D, Jovanovic L, et al. A pharmacoepidemiological study of diabetes mellitus and antipsychotic treatment in the United States [pamphlet]. 2002. [22] Clark O, O’Carroll R. An examination of the relationship between executive function and rehabilitation status in schizophrenia. Neuropsycholog Rehabilitat 2003 (in press). [23] Conley R, Love R, Kelly DL, Bartko JJ. Rehospitalisation rates of patients recently discharged on a regimen of risperidone or clozapine. Am J Psychiatry 1999;156:863–8. [24] Conley R, Tamminga CA, Bartko JJ, Richardson C, Peszke M, Lingle J, et al. Olanzapine compared with chlorpromazine in treatment-resistant schizophrenia. Am J Psychiatry 1998;155(7): 914–20. [25] Cooper SJ, Butler A, Tweed J, Welch C, Raniwalla J. Zotepine in the prevention of recurrence: a randomised, double-blind, placebocontrolled study for chronic schizophrenia. Psychopharmacology 2000;150(3):237–43. [26] Cooper SJ, Tweed J, Raniwalla J, Butler A, Welch C. A placebocontrolled comparison of zoptepine versus chlopromazine in patients with acute exacerbation of schizophrenia. Acta Psychiatr Scand 2000; 101(3):218–25. [27] Coukell AJ, Spencer CM, Benfield P. Amisulpiride: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of schizophrenia. CNS Drugs 1996;6(3): 237–56. [28] Csernansky JG. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med 2002;346(1):16–22. [29] Cummins C, Stevens A, Kisely C. In: Milne R, Stein K, editors. The use of olanzapine as a first and second choice treatment in schizophrenia, 84. 1998. p. 1–50 The South and West Development and Evaluation Service [report]. [30] Currier GW, Simpson GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry 2001;62(3):153–7. [31] Czekalla J, Kollach-Walker S, Beasley CM. Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics. J Clin Psychiatry 2001;62(Suppl 2):35–40. [32] Dannion J, Rein W, Fleurot O. Improvement of schizophrenic patients with primary negative symptoms treated with amisulpiride. Am J Psychiatry 1999;156:610–6. [33] Davis JM, Schaffer CB, Killian GA. Important issues in the drug treatment of schizophrenia. Schizophrenia Bull 1980;6:70–87.

A.M. Mortimer / European Psychiatry 18 (2003) 209–219 [34] Davis R, Janicak PG. Risperidone: a new, novel (and better?) antipsychotic. Psychiatric Ann 1996;26:78–87. [35] de Paulis T. M-100907 (Aventis). Curr Opinion Investigation Drugs 2001;2(1):123–32. [36] Decina P, Mukherjee S, Bocola V. Adjunctive trazodone in the treatment of negative symptoms of schizophrenia. Hosp Community Psychiatry 1994;45:1220–3. [37] Dev V, Raniwalla J. Quetiapine: a review of its safety in the management of schizophrenia. Drug Safety 2000;23(4):295–307. [38] Dose M, Tempel HD. Abuse potential on anticholinergics. Pharmacopsychiatry 2000;33(Suppl 1):43–6. [39] Dwyer DS, Bradley RJ, Kablinger AS, Freeman 3 AM. Glucose metabolism in relation to schizophrenia and antipsychotic drug treatment. Ann Clin Psychiatry 2001;13(2):103–13. [40] Ekesbo A, Andren PE, Gunne LM, Tedroff J. (–)-OSU 6162 inhibits levodopa-induced dyskinesias in a monkey model of Parkinson’s disease. Neuroreport 1997;8(11):2567–70. [41] Ekesbo A, Torstenson R, Hartvig P, Carlsson A, Sonesson C, Waters N, et al. Effects of the substituted (S)-3-phenylpiperidine (–)-OSU6162 on PET measurements of [11C] SCH23390 and [11C] raclopride binding in primate brains. Neuropharmacology 1999;38(3):331–8. [42] Emsley RA, Raniwalla J, Bailey PJ, Jones AM. 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. Int Clin Psychopharmacol 2000;15:121–31. [43] Falsetti AE. Risperidone for control of agitation in dementia patients. Am J Health-System Pharmacy 2000;57(9):862–70. [44] Farde L, Wiesel FA, Halldin C. Central dopamine-2 occupancy in schizophrenic patients treated with antipsychotic drugs. Arch General Psychiatry 1988;45:71–6. [45] Finn C. Risperdal long acting microspheres. In: Mortimer AM, editor. 2001 26-9-2001 [personal communication]. [46] Freeman HL. Amisulpiride compared with standard neuroleptics in acute exacerbations of schizophrenia: three efficacy studies. Int Clin Psychopharmacol 1997;12(Suppl 2):11–7. [47] Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. Br Med J 2000;321:1371–6. [48] Glassman AH, Bigger JT. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001; 158(11):1774–82. [49] Goff DC, Leahy I, Berman I, Posever T, Herz L, Leon AC, et al. A placebo-controlled study of the ampakiine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol 2001;21(5):484–7. [50] Goff DC, Posever T, Herz L, Simmons J, Kletti N, Lapierre K, et al. An exploratory haloperido-controlled dose-finding study of ziprasidone in hospitalised patients with schizophrenia or schizoaffective disorder. J Clin Psychopharmacol 1998;18(4):296–304. [51] Green B. Focus on risperidone. Curr Med Res Opinion 2000;16(2): 57–65. [52] Gunasekara NS, Spencer CM, Keating GM. Ziprasidone: a review of its use in schizophrenia and schizoaffective disorder. Drugs 2002; 62(8):1217–51. [53] Gunn KP. Ziprasidone: safety and efficacy. Schizophrenia Res 1996; 18:132–3. [54] Haddad P. QTc prolongation and schizophrenia: managing the risks. Progr Neurology Psychiatry 2001(Suppl):2–11. [55] Haupt DW, Newcomer J. Hyperglycaemia and antipsychotic medications. J Clin Psychiatry 2001;62(Suppl 27):15–26. [56] Hellewel JSE. Efficacy of quetiapine in aggression and hostility in schizophrenia. Presented at the Association of European Psychiatry Congress, 1998. 1998. [57] Hellewel JSE, Kalali A, Langham S, McKellar J. Patients’ satisfaction and acceptability of long-term treatment with ‘seroquel’: results of an international study. Presented at the ECNP, 1997. 1997.

217

[58] Henderson DC. Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? CNS Drugs 2002;16(2):77–89. [59] Henderson DC, Cagliero E, Gray C, Nasrallah HA, Hayden DL, Schoenfeld DA. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study. Am J Psychiatry 2000; 157:975–81. [60] Hwang TJ, Lin SK, Lin H-N. Efficacy and safety of zotepine for the treatment of Taiwanese schizophrenic patients: a double-blind comparison with haloperidol. J Formosan Med Assoc 2001;100(12):811–6. [61] Jain KK. An assessment of iloperidone for the treatment of schizophrenia. Expert Opinion Investigation Drugs 2000;9(12):2935–43. [62] Joffe G, Appelberg B, Rimon R. Adjunctive nefazodone in neuroleptic-treated schizophrenic patients with predominantly negative symptoms: an open prospective pilot study. Int Clin Psychopharmacol 1999;14:233–8. [63] Johnson SA, Luu NT, Herbst TA, Knapp R, Lutz D, Arai A, et al. Synergistic interactions between ampakines and antipsychotic drugs. J Pharmacol Exp Ther 1999;289(1):392–7. [64] Johnstone EC, Crow TJ, Ferrier IN, Frith CD, Owens DGC, Bourne RC, et al. Adverse effects of anticholinergic medication on positive schizophrenic symptoms. Psycholog Med 1983;13(3): 513–27. [65] Kane J, Honigfeld G, Singer J. Clozapine for the treatment resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch General Psychiatry 1988;45:789–96. [66] Kapur S, Remington G. Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry 2001;50(11):873–83. [67] Kapur S, Seeman P. Does fast dissociation from the dopamine D(2) receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 2001;158(3):360–9. [68] Karagianis JL, Dawe IC, Thakur A, Raskin J, Roychowdhury SM. Rapid tranquillization with olanzapine in acute psychosis: a case series. J Clin Psychiatry 2001;62(Suppl 2):12–6. [69] Kasper S, Quiner S, Barnas C, Fabisch H, Haushofer M, Sackel C, et al. Zotepine in the treatment of acute hospitalized schizophrenic episodes. Int Clin Psychopharmacol 2001;16(3):163–8. [70] Keck P, Buffenstein A, Ferguson J, Feighner J, Jaffe W, Harrigan EP, et al. Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebocontrolled trial. Psychopharmacology 1998;140(2):173–84. [71] King DJ. Drug treatment of the negative symptoms of schizophrenia. Eur Psychopharmacology 1998;8:33–42. [72] Kirov GK, Murray RM, Seth RV, Feeney S. Observations on switching patients with schizophrenia to risperidone treatment. Acta Psychiatr Scand 1997;95:439–43. [73] Kopala LC, Fredrikson D, Good KP, Honer WG. Symptoms in neuroleptic-naive, first episode schizophrenia: response to risperidone. Biol Psychiatry 1996;39:296–8. [74] Kopala LC, Good KP, Fredrikson D, Whitehorn D, Lazier L, Honer WG. Risperidone in first-episode schizophrenia: improvement in symptoms and pre-existing extrapyramidal signs. International J Psychiatry Clin Practice 1998;2(Suppl 1):19–25. [75] Kopala LC, Good KP, Honer WG. Extrapyramidal signs and clinical symptoms in first-episode schizophrenia: response to low-dose risperidone. J Clin Psychopharmacol 1997;17(4):308–13. [76] Kopelowicz A, Zarate R, Tripodis K, Gonzalez V, Mintz J. Differential efficacy of olanzapine for deficit and nondeficit negative symptoms in schizophrenia. Am J Psychiatry 2000;157(6):987–93. [77] Lane HY, Chiu WC, Chou JC, Wu ST, Su MH, Chang WH. Risperidone in acutely exacerbated schizophrenia: dosing strategies and plasma levels. J Clin Psychiatry 2000;61(3):209–14. [78] Launer M. Zotepine and nefazadone for clozapine ‘reds’. In: Mortimer AM, editor. 2002 [personal communication].

218

A.M. Mortimer / European Psychiatry 18 (2003) 209–219

[79] Lawler CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA, et al. Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 1999;20(6):612–27. [80] Leucht S, Pitschel-Walz G, Abraham D, Kissling W. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophrenia Res 1999;35(1):51–68. [81] Leysen JE, Gommeren W, Schotte A. Serotonin receptor subtypes: possible roles and implications in antipsychotic drug action. In: Kane JM, Moller H-J, Awouters F, editors. Serotonin in antipsychotic treatment. New York: Marcel Dekker, Inc; 1996. p. 51–75. [82] Lieberman JA. Atypical antipsychotic drugs as a first-line treatment of schizophrenia: a rationale and hypothesis. J Clin Psychiatry 1996; 57(Suppl 11):68–71. [83] Loo H, Poirer-Littre MF, Theron M. Amisulpiride versus placebo in the medium-term treatment of the negative symptoms of schizophrenia. Br J Psychiatry 1997;170:18–22. [84] Lund BC, Perry PJ, Brooks JM, Arndt S. Clozapine use in patients with schizophrenia and the risk of diabetes, hyperlipidaemia, and hypertension: a claims-based approach. Arch General Psychiatry 2001;58(12):1172–6. [85] Marder SR. Antipsychotic drugs and relapse prevention. Schizophrenia Res 1999;35(Suppl 1):87–92. [86] Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994;151(6):825–35. [87] Martin C. Impact of olanzapine on quality of life in schizophrenia. Eur Psychiatry 1996;11(Suppl 4):252 [abstract]. [88] Matsubayashi H, Amano T, Sasa M. Inhibition by aripiprazole of dopaminergic inputs to striatal neurons from substantia nigra. Psychopharmacologia 1999;146(2):139–43. [89] McAllister-Williams RH, Ferrier IN. Rapid tranquilisation: time for a reappraisal of options for parenteral therapy. Br J Psychiatry 2002; 179(485):489. [90] McManus DQ, Arvanitis LA, Kowalcyk BB. Quetiapine, a novel antipsychotic: experience in elderly patients with psychotic disorders. Seroquel Trial 48 Study Group. J Clin Psychiatry 1999;60(5):292–8. [91] Meyer-Lindenberg A, Gruppe H, Bauer U, Lis S, Krieger S. Improvement of cognitive function in schizophrenic patients receiving clozapine or zotepine: results from a double-blind study. Pharmacopsychiatry 1997;30:35–42. [92] Meyer JM. A retrospective comparison of weight, lipid, and glucose changes between risperidone and olanzapine treated inpatients: metabolic outcomes after 1 year. J Clin Psychiatry 2002;63(5):425–33. [93] Millan MJ, Schreiber R, Monneyron S, Denorme B, Melon C, Queriaux S, et al. S-16924, a novel, potential antipsychotic with marked serotonin1A agonist properties. IV. A drug discrimination comparison with clozapine. J Pharmacol Exp Ther 1999;289(1):427–36. [94] Mir S, Taylor D. Atypical antipsychotics and hyperglycaemia. Int Clin Psychopharmacol 2001;16(2):63–73. [95] Moller H-J. Amisulpride: a review of its efficacy in schizophrenia. Acta Psychiatr Scand 2000;400(Suppl):17–22. [96] Moller H-J, Boyer P, Fleurot O, Rein W. Improvement of acute exacerbations of schizophrenia with amisulpiride: a comparison with haloperidol. Psychopharmacology 1997;132:396–401. [97] Mortimer AM. A clozapine cohort: outcome and issues of concern. Human Psychopharmacol 1997;12:361–3. [98] Newcomer J, Haupt DW, Fucetola R, Melson AK, Schweiger JA, Cooper BP, et al. Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch General Psychiatry 2002; 59(4):337–45. [99] Parsa A, Bastani B. Quetiapine (Seroquel) in the treatment of psychosis in patients with Parkinson’s disease. J Neuropsychiatry Clin Neurosci 1998;10(2):216–9.

[100] Petit M, Raniwalla J, Tweed JA, Leutenegger E, Dollfus S, Kelly F. A comparison of an atypical and typical antipsychotic, zotepine versus haloperidol in patients with acute exacerbation of schizophrenia: a parallel-group double-blind trial. Psychopharmacol Bull 1996;32(1): 81–7. [101] Peuskens J, Link CGG. A comparison of quetiapine and chlopromazine in the treatment of schizophrenia. Acta Psychiatr Scand 1997; 96:265–73. [102] Pfizer LTD. Introducing new products to the schizophrenia market. In: Mortimer AM, editor. Data on file, ZEL200/0702. 2002 [personal communication]. [103] Pichot P, Boyer P. A double blind, controlled, multi-centre trial of low dose amisulpiride (Solian 50) versus low dose fluphenazine in the treatment of negative symptoms in chronic schizophrenia. Ann Psychiatry 1988;3(3):312–20. [104] Poyurovsky M, Pashinian A, Gil-Ad I, Maayan R, Schneidman M, Fuchs C, et al. Olanzpine-induced weight gain in patients with firstepisode schizophrenia: a double-blind, placebo-controlled study of fluoxetine addition. Am J Psychiatry 2002;159(6):1058–60. [105] Procyshyn RM, Zerjav S. Drug utilization patterns and outcomes associated with in-hospital treatment with risperidone or olanzapine. Clin Ther 1998;20(6):1203–17. [106] Raniwalla J, Tweed JA, Dollfus S, Petit M. A comparison of an atypical (zotepine) and classical (haloperidol) antipsychotic in patients with acute exacerbation of schizophrenia. Schizophrenia Res 1996;18(2,3):133. [107] Ray WA, Meador KG. Antipsychotics and sudden death: is thioridazine the only bad actor? Br J Psychiatry 2002;180:483–4. [108] Reeves K, Harrigan EP. The efficacy and safety of two fixed doses of ziprasidone in schizophrenia and schizoaffective disorder. Presented at the 149th annual meeting of the American Psychiatric Association, New York. 1996. [109] Richelson E, Souder T. Binding of antipsychotic drugs to human brain receptors: focus on new generation compounds. Life Sci 2000;68(1): 29–39. [110] Russell JM, Mackell JA. Bodyweight gain associated with atypical antipsychotics: epidemiology and therapeutic implications. CNS Drugs 2001;15(7):537–51. [111] Rymer M, Williets S, Shepherd CJ, Mortimer AM. An audit of antipsychotic prescribing in primary care 2002 [unpublished work]. [112] Saletu B, Kufferle B, Grunberger J. Clinical, EEG mapping and psychometric studies in negative schizophrenia: comparative trials with amisulpiride and fluphenazine. Neuropsychobiology 1994;29(3):125–35. [113] Sanger T, Lieberman JA, Tohen M, Grundy S, Beasley CM, Tollefson G. Olanzapine versus haloperidol treatment in first-episode psychosis. Am J Psychiatry 1999;156(1):79–87. [114] Sciolla A, Jeste DV. Use of antipsychotics in the elderly. Int J Psychiatry Clin Practice 1998;2(Suppl 1):27–34. [115] Seeman P. Dopamine/neuroleptic receptors in schizophrenia. In: Burrows GD, Norman TR, Rubinstein G, editors. Handbook on studies of schizophrenia. Amsterdam: Elsevier; 1986. [116] Seeman P. Atypical antipsychotics: mechanism of action. Can J Psychiatry 2002;47(1):27–38. [117] Sernyak MJ, Leslie DL, Alarcon RD, Losonczy M, Rosenheck R. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002;159(4):561–6. [118] Silver HSN. Augmentation with fluvoxamine but not maprotiline improves negative symptoms in treated schizophrenia: evidence for a specific serotonergic effect from a double-blind study. J Clin Psychopharmacol 1998;18:208–11. [119] Song F. Risperidone in the treatment of schizophrenia: a neta-analysis of randomised controlled trials. J Psychopharmacol 1997;11:65–71. [120] Speller J, Barnes TRE, Curson DA. One-year, low-dose neuroleptic study of in-patients with chronic schizophrenia characterised by persistent negative symptoms: amisulpiride v. haloperidol. Br J Psychiatry 1997;171:564–8.

A.M. Mortimer / European Psychiatry 18 (2003) 209–219 [121] Stahl SM. Selecting an atypical antipsychotic by combining clinical experience with guidelines from clinical trials. J Clin Psychiatry 1999;60(Suppl 10):31–41. [122] Stahl SM. Dopamine system stabilizers, aripiprazole, and the next generation of antipsychotics, part 2: illustrating their mechanism of action. J Clin Psychiatry 2001;62(12):923–4. [123] Stahl SM. Dopamine system stabilizers, aripiprazole, and the next generation of antipsychotics, part 1, “Goldilocks” actions at dopamine receptors. J Clin Psychiatry 2002;62(11):841–2. [124] Sugiyama A, SatohY, Hashimoto K. In vivo canine model comparison of cardiohemodynamic and electrophysiological effects of a new antipsychotic drug aripiprazole (OPC-14597) to haloperidol. Toxicol Appl Pharmacol 2001;173(2):120–8. [125] Swift RH, Harrigan EP, van Kammen DP. A comparison of fixed-dose, intramuscular (IM) ziprasidone with flexible-dose, IM haloperidol. Eur Neuropsychopharmacol 1998;8(Suppl 2):216. [126] Tamminga CA. Partial dopamine agonists in the treatment of psychosis. J Neural Transmission–General Section 2002;109(3):411–20. [127] Taylor D. UK prescribing of antipsychotics and clozapine. In: Kerwin RW, editor. The earlier use of clozaril: a discussion. London: The Workhouse; 2002. p. 15–20. [128] Taylor D, McConnell D, McConnell H, Kerwin RW. The Maudsley 2001 prescribing guidelines. 6th ed. London: Martin Dunitz; 2001. [129] Taylor D, Mir S, Mace S, Whiskey E. Co-prescribing of atypical and typical antipsychotics–prescribing sequence and documented outcome. Psychiatric Bull 2002;26:170–2. [130] Taylor DM, McAskill R. Atypical antipsychotics and weight gain–a systematic review. Acta Psychiatr Scand 2000;101:416–32. [131] Tedroff J, Ekesbo A, Sonesson C, Waters N, Carlsson A. Long-lasting improvement following (–)-OSU6162 in a patient with Huntingdon’s disease. Neurology 1999;53(7):1605–6. [132] Tedroff J, Torstenson R, Hartvig P, Sonesson C, Waters N, Carlsson A, et al. Effects of the substituted (S)-3-phenylpiperidiine (–)OSU6162 on PET measurements in subhuman primates: evidence for tone-dependent normalization of striatal dopaminergic activity. Synapse 1998;28(4):280–7. [133] The Department of Health. The National Service Framework for Mental Health [bill/resolution]. 1999. [134] The Department of Health HMG. Modernising Mental Health Services: White Paper [bill/resolution]. 1997. [135] The Zito Trust. The practice gap in schizophrenia: are people with schizophrenia being given the best chance in life? Eli Lilly UK [pamphlet]. 2001. [136] Thompson C. The use of high dose antipsychotic medication. Br J Psychiatry 1994;164:448–58. [137] Tollefson G, Sanger T. Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine. Am J Psychiatry 1997;154:457–65. [138] Tollefson G, Sanger T, Lu Y, Thieme M. Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol. Arch General Psychiatry 1998;55:250–8.

219

[139] Tracy JJ, Monaco C, Giovannetti T, Abraham G, Josiassen RC. Anticholinergicity and cognitive processing in chronic schizophrenia. Biol Psychiatry 2001;56(1):1–22. [140] Tran PV, Hamilton SH, Kuntz AJ, Potvin JH, Andersen SW, Beasley Jr C, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997;17(5):407–18. [141] Tran P, Shamir E, Poyorovski M, Lokshin P, Weizer N, Dorfman P, et al. Olanzapine in the treatment of patients who failed to respond to or tolerate clozapine. Psychopharmacol Bull 1997;33(3): 599. [142] Tuunainen A, Wahlbeck K, Gilbody SM. Newer antipsychotic medication versus clozapine for schizophrenia. Cochrane Database System Review 2000;2 [CD000966] [generic]. [143] Tyson PJ, Mortimer AM, Wheeler JA. High dose antipsychotic treatment in clinical practice: a review, audit and survey of consultant psychiatrist opinions. Psychiatric Bull 1999;23:661–4. [144] Umbricht D, Ames D, Wirshing WC. Predictors of response to clozapine in a long-term double blind treatment study. Schizophrenia Res 1997;24:189. [145] Warner JP, Slade R, Barnes TRE. Change in neuroleptic prescribing practices. Psychiatric Bull 1995;19:237–9. [146] Wassef AA, Dott SG, Harris A, Brown A, O’Boyle M, Meyer WJ, et al. Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic schizophrenia. J Clin Psychopharmacol 2000;20(3):357–61. [147] Weiden P, Aquila A, Standard J. Atypical antipsychotic drugs and long-term outcome in schizophrenia. J Clin Psychiatry 1996;57(Suppl 11):53–60. [148] Wetterling T. Bodyweight gain with atypical antipsychotics. A comparative review. Drug Safety 2001;24(1):59–73. [149] World Health Organisation. Prophylactic use of anticholinergics in patients on long-term neuroleptic treatment. Br J Psychiatry 1990; 156:412. [150] Wright P, Birkett M, Meehan K. A double-blind dose response study comparing intramuscular olanzapine, haloperidol and placebo in acutely agitated schizophrenic patients. Schizophrenia Res 2001; 49(Suppl 1):250–1. [151] Wright P, Birkett M, David SR, Meehan K. Double-blind, placebocontrolled comparison of intramuscular olanmzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry 2001;158:1149–51. [152] Zarate CA. Sudden cardiac death and antipsychotics. Arch General Psychiatry 2001;58(1168):1171. [153] Zhang XY, Zhou DF, Cao LY, Zhang PY, Wu GY, Shen YC. Risperidone versus haloperidol in the treatment of acute exacerbations of chronic inpatients with schizophrenia: a randomized double-blind study. Int Clin Psychopharmacol 2001;16(6):325–30.