Using antipsychotic medication

Dr Kit Wa Chan and Professor Peter Jones look at the use of drugs for the management of psychosis.

PET scan showing the areas of the brain active during hallucination
PET scan showing the areas of the brain active during hallucination

About half of prescriptions for antipsychotic drugs are used to treat schizophrenia and related disorders, such as psychotic mania and depression.

Althoughtheir use is reviewed here for these conditions, the information regarding side-effects pertains to all uses.

The management of schizophrenia and related conditions focuses on managing a diverse group of symptoms and impairments, including both positive and negative symptoms.

This management should be a partnership between primary and secondary care.

First and second generation
Antipsychotic medications represent the most effective intervention in the acute stage of the illness. Antagonism at the D2 dopamine receptor remains central to the antipsychotic action.

Until recently, clinicians have accepted the classification of antipsychotic drugs into typical, or first generation antipsychotics (FGAs), versus atypical or second generation antipsychotic drugs (SGAs), including clozapine, on the basis that the latter tend to cause fewer extrapyramidal motor side-effects, probably due to their serotonergic blocking effects that ameliorate the effects of D2 antagonism in nigro-striatal circuits.1

SGAs have been assumed to be more effective given their greater tolerability.

However, the Clinical Antipsychotic Trials of Intervention Effectiveness and the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study, large randomised controlled trials in the USA and UK, respectively, indicate no great advantage to SGA.2,3

This, together with accumulating evidence of the considerable burden of metabolic side-effects, such as weight gain and glucose and lipid disturbances which many of these drugs are associated with, has led to a reappraisal of policy guidance.

It is important to recommend careful prescribing of whichever antipsychotic drug is used, with ambitious targets for efficacy and vigilance, and low tolerance of side-effects on behalf of patient and prescriber.

Interestingly, this re-appraisal comes as some atypical drugs, such as risperidone, come off patent with a resulting decrease in cost, and newer compounds such as aripiprazole, a partial D2 (and other) receptor antagonist, are becoming more widely used.

Clozapine is probably the most efficacious antipsychotic and is reserved as an intervention for treatment-resistant schizophrenia because of its propensity to cause blood dyscrasias in a minority (2-3 per cent) of patients.

Symptom management
With considerable between-patient differences, all anti-psychotics are, on average, very effective for attenuating the psychotic symptoms (positive symptoms) such as hallucinations and delusions, but comparatively ineffective for other symptoms.

These other features include negative symptoms such as blunted affect, emotional withdrawal, and lack of social or vocational interest, and cognitive symptoms including impairments in memory, attention and executive functions that are closely linked to negative features and to disease outcome.

These tend to improve as positive psychotic symptoms improve.

However, patients often continue to demonstrate negative and cognitive symptoms even after they have achieved a remission of psychotic symptoms. There is evidence that clozapine is more effective for poor responders, and that risperidone, olanzapine and amisulpride may have small advantages, which need to be balanced against their side-effects.4

Monotherapy vs polytherapy
There is a current trend to recommend monotherapy, if only to avoid the accumulation of high doses and side-effect burdens that can accompany polypharmacy.4

The counter argument is that multiple drug regimens are effective in other areas, such as cancer chemotherapy or complex hypertension.

While this may be useful for some patients, such as for careful augmentation in treatment-resistant cases where clozapine is ineffective, this cannot be logically supported in antipsychotic therapy.

Nearly all antipsychotic drugs, from the widespread effects of chlorpromazine, through to the complex pharmacology of more recent compounds, have effects on multiple receptor systems so are all, to a degree, polypharmacy in themselves.

Embarking on complex regimens must be coupled with a willingness to step back in the face of side-effects or lack of a satisfactory response.

The majority of polypharmacy should be restricted to judicious slow cross tapering when changing drugs, or limited augmentation strategies. This is an area where the evidence base is particularly thin.

How to initiate and switch treatments is further discussed in next week's issue.

Dr Chan is a specialist registrar and Professor Jones is professor of psychiatry and head of department at the University of Cambridge


  • GAs, apart from clozapine, should be considered as the first-line treatment for most patients.
  • Polypharmacy should be avoided except during changeovers of medication.
  • FGA medication can be used when the side-effects of SGA medication are intolerable.
  • Depot preparations should be used where there is reason to suspect that a patient may be unlikely to adhere to prescribed oral therapy.
  • Clozapine should be given when a patient has failed to respond to two different antipsychotic medications (at least one SGA) at sufficient dosage and duration.
  • Extra care should be taken when using antipsychotics in special patient groups, such as the elderly, pregnant women and patients with other physical disorders.


1. Stahl S. Essential Psychopharmacology, CUP, Cambridge, 2007.

2. Jones P, Barnes T, Davies L, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63: 1,079-87.

3.berman J. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia: efficacy, safety and cost outcomes of CATIE and other trials. J Clin Psychiatry 2007; 68: e04.

4. Taylor D, Paton C, Kerwin R. The Maudsley 2005-2006 Prescribing Guidelines, 8th ed 16-19.

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