Do the New Antipsychotics
Make A Difference?

British Medical Journal - Oct 16, 1999

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.

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, aripiprazole (Abilify) has been approved in the U.S., quetiapine was available in some countries but sertindole has been withdrawn pending review of data on cardiac safety.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.

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.

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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
Drug (dose)                  Study           Findings
Clozapine (200-800mg/day)    Cochrane        Effective
  versus traditional         review[11]      antipsychotic, fewer
  antipsychotic drugs        29 studies      relapses, greater
                             based 2490      reduction in
                             participants    symptoms, fewer
                                             drop-outs greater
                                             patient satisfaction
                                             satisfaction
Risperidone (2-6mg/day)      Cochrane        Effective
  versus traditional         review[14]      antipsychotic,
  antipsychotic drugs        14 studies      greater clinical
                             based on 3401   improvement little
                             participants    no additional effect
                                             positive or negative
                                             symptoms, fewer
                                             drop-outs
Olanzapine (10-20mg/day)     Cochrane        Effective
  versus traditional         review[17] 5    antipsychotic, fewer
  antipsychotic drugs        studies based   drop-outs, lower
                             on 2911         depression scores,
                             participants    less sedation,
                                             fewer extrapyramidal
                                             side effects
Sertindole (12-20mg/day)     Randomised      Effective
  versus traditional         controlled      antipsychotic, fewer
  antipsychotic drugs        trials[9]       extrapyramidal side
                                             effects
Ziprasidone (80-160mg/day)   Randomised      Effective
  versus traditional          controlled     antipsychotic, fewer
  antipsychotic drugs         trials[6]      extrapyramidal side
                                             effects
Quetiapine (300-450mg/day)   Cochrane        Effective
  versus traditional         review[17]      antipsychotic, fewer
  antipsychotic drugs        6 trials        extrapyramidal side
                             based on 1417   effects
                             participants
Drug (dose)                  Selected side effects
Clozapine (200-800mg/day)    Sedation, hypersalivation, weight
  versus traditional         gain, increased risk of
  antipsychotic drugs        convulsions at higher doses, 1%
                             risk of agranulocytosis
Risperidone (2-6mg/day)      Weight gain, hyperprolactinaemia
  versus traditional         (leading to amenorrhoea,
  antipsychotic drugs        galactorrhea, impotence),
                             postural hypotension
Olanzapine (10-20mg/day)     Sedation, weight gain, dizziness
  versus traditional
  antipsychotic drugs
Sertindole (12-20mg/day)     Increased risk of QT interval
  versus traditional         prolongation (1.7% of patients)
  antipsychotic drugs
Ziprasidone (80-160mg/day)   Sedation
  versus traditional
  antipsychotic drugs
Quetiapine (300-450mg/day)   Dizziness, dry mouth, sedation
  versus traditional
  antipsychotic drugs
Drug (dose)                  Comments
Clozapine (200-800mg/day)    Patients require regular
  versus traditional         haematological monitoring, 31% of
  antipsychotic drugs        patients with schizophrenia
                             previously resistant to drug
                             treatment have clinical improvement
Risperidone (2-6mg/day)      Lacks anticholinergic properties,
  versus traditional         patients switched from older
  antipsychotic drugs        antipsychotics (which often required
                             the coprescription of
                             anticholinergics to reduce
                             extrapyramidal side effects to
                             risperidone can undergo cholinergic
                             rebound (flu-like symptoms)
Olanzapine (10-20mg/day)     Transient elevation of hepatic
  versus traditional         transaminases, lower incidence of
  antipsychotic drugs        tardive dyskinesia compared with
                             haloperidol
Sertindole (12-20mg/day)     Baseline and regular ECG monitoring
  versus traditional         recommended, should be avoided in
  antipsychotic drugs        patients taking drugs known to
                             prolong the QT interval,
                             contraindicated in patients with
                             clinically significant
                             cardiovascular disease, now under
                             review because ECG changes noted in
                             some patients
Ziprasidone (80-160mg/day)   Weight gain has not been a prominent
  versus traditional         feature of treatment with
  antipsychotic drugs        ziprasidone as compared with
                             clozapine, risperidone, and
                             olanzapine
Quetiapine (300-450mg/day)   High drop-out rates in the trials
  versus traditional         limit interpretation
  antipsychotic drugs

continued

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