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Author/s: John Mcgrath Summary points Drug treatment is effective in managing acute psychosis and in reducing the risk of relapse Newer antipsychotics, apart from clozapine, seem to be as effective in treating positive symptoms as traditional antipsychotics but have fewer, less severe side effects Clozapine is more effective than traditional antipsychotics and should be offered to patients who have not responded to other antipsychotic drugs Health services and community agencies need to collaborate to reduce the amount of time that patients with psychosis remain untreated General practitioners are playing increasingly prominent roles in new models of delivering services to people with schizophrenia This selective review on the treatment of schizophrenia provides an update on two important issues. Firstly, new antipsychotic drugs have improved the quality of life for people with schizophrenia. This review outlines some practical issues surrounding the use of these drugs. Secondly, evidence suggests that the prompt identification and treatment of people with psychoses (including schizophrenia and affective psychoses) results in improved clinical outcomes.[1] The important role that general practitioners can play in reducing the duration of untreated psychosis is also discussed. Methods In writing this review, we collated the advice given in clinical practice guidelines for the management of schizophrenia that had been published in the past three years.[2-6] Relevant reviews in the Cochrane Library were inspected. What is schizophrenia? The schizophrenic disorders are a group of illnesses characterised by various combinations of neuropsychiatric symptoms. Modern diagnostic classifications also include criteria related to the duration of symptoms, declines in functioning, and an absence of comorbid neurological disease. Problems with attention and memory may be prominent in psychoses, for example some patients have difficulties with novel tasks that require flexibility and planning. The so called positive symptoms of schizophrenia include hallucinations, delusions, and disorganised communication. The so called negative symptoms of schizophrenia include blunted affect and poor motivation. The nature of the neurobiological lesions or the dysfunctions that cause schizophrenia remains elusive and will until our understanding of neuroscience advances considerably. There are no biological markers for schizophrenia. Review articles in journals such as Current Opinion in Psychiatry enable practitioners to keep up to date with the substantial amount of new research into schizophrenia that is published each year.[7] Do the new antipsychotics make a difference? Although most individuals with psychosis show a moderate to substantial reduction in their positive symptoms after treatment with antipsychotic drugs, about 30% of patients do not respond to psychopharmacology. The negative symptoms of schizophrenia are even less responsive to drug treatment. Once an individual is in remission, antipsychotic drugs substantially reduce the risk of relapse. During one year, 55% of those on placebo have a relapse compared with 20-25% of those on antipsychotic drugs.[8] |
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The greatest limitation of treatment with traditional antipsychotic drugs has been their side effects. In particular, people with schizophrenia have had to tolerate disabling and distressing extrapyramidal side effects such as parkinsonism, akathisia (restlessness in the legs and body), acute dystonia, and tardive dyskinesia (involuntary movements, often of the tongue and face but also of the fingers, hands, legs, and trunk). The recommended doses for acute and maintenance treatment with traditional antipsychotics can be found in guidelines such as those published by the Patient Outcomes Research Team.[4] Several new antipsychotic drugs have been introduced recently. Of these, risperidone, olanzapine, and clozapine are available in most countries. At the time of writing quetiapine was available in some countries but sertindole has been withdrawn pending review of data on cardiac safety. Ziprasidone is awaiting approval in many countries, but may be introduced in the next year or so. These drugs are sometimes called atypical antipsychotics. There is a substantial body of evidence that shows that the new antipsychotic drugs are effective in treating positive symptoms.[9] Data from trials and clinical experience also suggest that they are effective in reducing the risk of relapse during maintenance treatment, although the evidence is less extensive. In the past it was commonly thought that all traditional antipsychotics were equally effective.[10] A recently published Cochrane review comparing clozapine with traditional antipsychotics has shown that clozapine has greater clinical efficacy than traditional antipsychotics.[11] It has been claimed that some of the other new antipsychotics have statistically significant advantages on various measures of clinical outcome when compared with traditional antipsychotics; however, it remains to be seen whether these differences are clinically relevant in daily practice. There is evidence to suggest that patients on the new antipsychotic drugs have superior performance on neurocognitive measures (for example, working memory) compared with patients on traditional antipsychotics.[12 13] The table summarises selected data on the efficacy and side effects of the new antipsychotics. Clozapine, olanzapine, and quetiapine have a wide range of receptor affinities and the other products have more selective dopamine and serotonergic properties. Because of the increased risk of agranulocytosis associated with clozapine, it should not be the first choice treatment. Updated sources of evidence based recommendations should be consulted regularly. Some of these sources are given in the box.
Selected features of new antipsychotic drugs ECG=electrocardiography |
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Acutely ill patients who have behavioural disturbances may refuse oral treatment. Until parenteral forms of the newer antipsychotic medications become available, the parenteral administration of a traditional antipsychotic (for example, haloperidol 5-10 mg) plus a benzodiazepine for sedation may be required. Who should receive the new antipsychotics? Patients experiencing their first episode of schizophrenia should be considered for treatment with the new antipsychotic drugs (except clozapine). The comparative lack of side effects of these drugs makes them the first choice for drug treatment in patients with schizophrenia of recent onset. Hopefully, this advantage will translate into improved compliance with drug treatment during maintenance and reduce the risk of relapse. For those patients who do not respond to treatment with the new antipsychotics, a trial of a traditional antipsychotic should be offered. Patients who have responded to traditional antipsychotics but who have persistent extrapyramidal side effects should also be offered a trial of a new antipsychotic. Patients who have not responded to other antipsychotics should be offered a trial of clozapine. Points to consider when prescribing Switching between antipsychotics When switching a patient to a newer antipsychotic, it is important to educate patients and their caregivers about the risks (for example, the risk of relapse and temporary exacerbation of side effects) and potential benefits (for example, a reduction in symptoms and side effects). A crossover phase of one to two weeks is recommended, during which the dose of the first drug is reduced (or, in the case of depot preparations, ceased) and the dose of the second drug is gradually increased. During the crossover, patients, their clinicians, and caregivers should look for early signs of breakthrough psychosis. It is also helpful to set predetermined goals for treatment (such as a reduction in the severity or number of symptoms or a decrease in the severity or number of side effects) to help in deciding whether to continue.[18] Dosage strategies To reduce the severity and number of side effects, it is important to start new drugs at a low dose and increase the dose slowly. The new drug should be started at as low a dose as possible and then be increased over several weeks in response to changes in symptoms and side effects. Doses in the lower part of the recommended range may be adequate for patients in the early phases of their illness and very young or elderly patients. In acutely ill patients, agitation usually resolves within days, but it may be several weeks before the positive symptoms respond to treatment. Evidence shows that giving higher doses of antipsychotics than recommended increases side effects without increasing relief from symptoms[19] Maintenance treatment needs to be continuous and if possible at the lower end of the reference range. Intermittent treatment is not recommended. |
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Duration of maintenance treatment After one to two years of treatment, those patients who have had only one acute psychotic episode and who have had a good response to drug treatment--that is, their symptoms are in remission--may be suitable for a trial of time without drug treatment. For those patients who have had two or more acute episodes, treatment should be continued for at least five years; many of these patients, however, Mil require prolonged treatment. For patients undergoing withdrawal from drug treatment or a reduction in dose, a review by a psychiatrist is recommended, as is frequent clinical review. Coprescription of psychotropic agents Ideally, the newer antipsychotic drugs should be used alone. Short term use of benzodiazepines may assist agitated or anxious patients and can be particularly useful during acute episodes. Depression is common in schizophrenia, with a lifetime prevalence of up to 80%, and antidepressants may need to be added to treatment with antipsychotics. The depressed patient needs to be monitored closely for any risk of self harm. Those with extrapyramidal symptoms, whose symptoms persist despite a lowered dose and trying newer antipsychotics, may require treatment with anticholinergic drugs. Prompt diagnosis and treatment Recently there has been a growing awareness of the association between a longer duration of untreated psychosis and worse outcomes in the medium term and the long term.[20 21] Obviously, there will be a greater impact on the psychosocial networks (including those of work, family, education, and friends) of people who are psychotic and who remain untreated; one school of thought suggests that prolonged, untreated psychosis can result in a poorer long term prognosis because of altered neurobiological mechanisms.[1] Just as prolonged coma and lengthy periods of post-traumatic amnesia are associated with poorer clinical outcomes, so is prolonged psychosis. As a consequence, many agencies providing mental health services are attempting to reduce the duration of untreated psychosis. For example, health education programmes can teach the general public about psychosis and the need for prompt self referral and the prompt referral of potential patients by caregivers. Close ties need to be developed between key agencies in contact with adolescents and young adults (for example, teachers and healthcare workers) to facilitate the pathway to care for those experiencing psychosis of recent onset. In particular, general practitioners have an important role in the prompt identification of psychosis. General practitioners should monitor closely patients who are at risk to identify the onset or evolution of frank psychosis. Prodromal features of psychosis may include depression, anxiety, suspiciousness, social isolation, and bizarre behaviour. Those with a family history of psychosis or with a schizoid or schizotypal personality are at an increased risk of psychosis. Specialised services for patients with recent onset psychoses have been developed by many centres (see box for information).[22] |
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Psychosocial interventions Although it is outside the scope of this review, the treatment of schizophrenia should include psychosocial interventions in addition to drugs. For example, providing education to patients and caregivers about the illness and teaching practical ways of coping with the illness results in a reduced risk of relapse.[23 24] At each phase of the illness, the clinician must provide education about the illness, assist with access to support and rehabilitation in the community, and generally foster an alliance between the patient and the team providing treatment. Clinicians and disability support workers can assist those patients with persistent cognitive impairment by providing help with problem solving, budgeting, and activities of daily living. Interventions based on cognitive behavioural programmes or more finely tuned cognitive rehabilitation can also help improve clinical outcomes.[25] Consumer and caregiver support groups can play an important role in education, support, and advocacy. Additionally, several Cochrane reviews have assessed developments in the delivery of mental health services including case management and the use of assertive community outreach teams.[26-29] These reviews suggest that newer models of care, if used appropriately, can reduce the costs of hospital care and improve both outcomes and the satisfaction of patients. Conclusions The introduction of new antipsychotic drugs has alleviated many of the problems of side effects for people with psychoses and resulted in obvious improvements in their quality of life. Hopefully, use of the new antipsychotics in combination with optimal education and community support, will improve compliance with treatment and reduce the chance of relapse. It is necessary for those involved in planning the delivery of services to devise ways to reduce the duration of untreated psychosis. Evaluations carried out over the next few years will determine whether these interventions are associated with improvements in clinical outcomes in the medium term and the long term. The optimal goal of treatment must be the immediate, complete, and sustained remission of all symptoms of psychosis in all individuals being treated. Although we are still a long way from achieving this goal, the new antipsychotic drugs have narrowed the gap between current and optimal practice. Regularly updated sources of evidence-based recommendations http://som.flinders.edu.au/FUSA/COCHRANE/
cochrane/health.htm http://home.vicnetmet.au/~eppic Competing interests: JM and WBE have been investigators in clinical trials of several of the products mentioned in this paper; JM is a member of advisory boards to companies involved in the manufacture of several of the products mentioned in this paper. These products are clozapine, quetiapine, risperidone, olanzapine, and ziprasidone. JM and WBE have accepted travel costs to attend scientific meetings from the manufacturers of products mentioned in this paper. |
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[1] Expert Consensus Guideline Group. Treatment of schizophrenia. J Clin Psychiatry 1996;57:11-58. [2] American Psychiatric Association. Practice guidelines for the treatment of patients with schizophrenia. Am J Psychiatry 1997;154:1-63. [3] Lehman AF, Steinwachs DM, and the co-investigators of the PORT Project. Translating research into practice: the schizophrenia patient outcomes research team (PORT) treatment recommendations. Schizophr Bull 1998;24:1-10. [4] Pearsall R, Glick ID, Pickar D, Suppes T, Tauscher J, Jobson KO. A new algorithm for treating schizophrenia. Psychopharmacol Bull 1998;34:349-53. [5] Nathan PE, Gorman JM. A guide to treatments that work. Oxford: Oxford University Press, 1998. [6] Wyatt RJ. Neuroleptics and the natural course of schizophrenia. Schizophr Bull 1991;17:325-51. [7] Kane JM. Schizophrenia: how far have we come? Curr Opin Psychiatry 1999;12:17-8. [8] Dixon LB, Lehman AF. Family intervention for schizophrenia. Schizophr Bull 1995;21:631-43. [9] 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. Schizophr Res 1999:35;51-68. [10] Kane JM. The current status of neuroleptic therapy. J Clin Psychiatry 1989;50:322-8. [11] Wahlbeck K, Cheine M, Essali MA. Clozapine vs `typical' neuroleptic medication for schizophrenia. In: Cochrane Collaboration. Cochrane Library. Issue 4. Oxford: Update Software, 1998. [12] Green MF, Marshall BD, Wirshing WC, Ames D, Marder SR, McGurk S, et al. Does risperidone improve verbal working memory in treatment-resistant schizophrenia? Am J Psychiatry 1997;154:799-804. [13] Hagger C, Buckley P, Kenny JT, Friedman L, Ubogy D, Meltzer HY. Improvement in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenia patients receiving clozapine. Biol Psychiatry 1993;34:702-12. [14] Kennedy E, Song F, Hunter R, Clark A, Gilbody S. Risperidone versus `conventional' antipsychotic medication for schizophrenia. In: Cochrane Collaboration. Cochrane Library. Issue 4. Oxford: Update Software, 1998. [15] Duggan L, Fenton M, Dardennes RM, El-Dosoky A, Indran S. Olanzapine for schizophrenia. In: Cochrane Collaboration. Cochrane Library. Issue 1. Oxford: Update Software, 1999. [16] Fleischhacker WW. The psychopharmacology of schizophrenia. Curt Opin Psychiatry 1999;12:53-9. [17] Srisurapanont M, Disayavanish C, Taimkaew K. Quetiapine for schizophrenia. In: Cochrane Collaboration. Cochrane Library. Issue 4. Oxford: Update Software, 1998. [18] Weiden P. Switching antipsychotic medication. J Clin Psychiatry, 1997;5: 34-7. [19] Hirsch SR, Barnes TR. Clinical use of high-dose neuroleptics. Br J Psychiatry 1994;164:94-6. |
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[20] Loebel AD, Lieberman JA, Alvir JMJ, Mayerhoff DI, Geisler SH, Szymanski SR. Duration of psychosis and outcome in first-episode schizophrenia. Am J Psychiatry 1992;149:1183-8. [21] McGlashan TH, Johannessen JO. Early detection and intervention with schizophrenia: rationale. Schizophr Bull 1996;22:201-22. [22] McGorry PD, Edwards J, Mihalopoulos C, Harrigan SM, Jackson HJ. EPPIC: an evolving system of early detection and optimal management. Schizophr Bull 1996;22:305-26. [23] Mari JJ, Streiner D. Family intervention for schizophrenia. In: Cochrane Collaboration. Cochrane Library. Issue 4. Oxford: Update Software, 1998. [24] Kane JM, McGlashan TH. Treatment of schizophrenia. Lancet 1995;346:820-5. [25] Wykes T. Outcome and innovation in the psychological treatment of schizophrenia. Chichester:John Wiley, 1998. [26] Marshall M, Lockwood A. Assertive community treatment for people with severe mental disorders. In: Cochrane Collaboration. Cochrane Library. Issue 2. Oxford: Update Software, 1999. [27] Marshall M, Gray A, Lockwood A, Green R. Case management for people with severe mental disorders. In: Cochrane Collaboration. Cochrane Library. Issue 2. Oxford: Update Software, 1999. [28] Tyrer P, Coid J, Simmonds S, Joseph P, Marriott S. Community mental health teams for people with severe mental illnesses and disordered personality. In: Cochrane Collaboration. Cochrane Library. Issue 2. Oxford: Update Software, 1999. [29] Joy CB, Adams CE, Rice K. Crisis intervention for people with severe mental illnesses. In: Cochrane Collaboration. Cochrane Library. Issue 2. Oxford: Update Software, 1999. Queensland Centre for Schizophrenia Research, Wolston Park Hospital, Wacol, Q4076 Australia John McGrath director Division of Mental Health Services, Royal Brisbane Hospital and District Heath Service, Herston, Q4029 Australia W Brett Emmerson director Correspondence to: J McGrath jjm@brain.wph.uq. edu.au BMJ 1999;319:1045-83 |
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