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Second generation antipsychotics

Last reviewed dd mmm yyyy. Last edited dd mmm yyyy

Authoring team

  • the term 'atypical' is applied to antipsychotics that cause no or minimal extrapyramidal effects in animal models or when given in therapeutic doses to humans
  • the distinction of atypicals (also known as second generation antipsychotics) from traditional antipsychotics is not, however, absolute
    • several different pharmacological actions may be important in determining 'atypical' characteristics, and atypical antipsychotics differ from one another significantly in their pharmacodynamic and unwanted effects (1)
  • various atypical antipsychotic agents are available in the UK:
    • amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole and zotepine
    • the use of clozapine is restricted to patients with schizophrenia who are resistant to, or intolerant of, other antipsychotic therapy, because of the risk of agranulocytosis, which occurs in 0.7-0.8% of patients in the first year of treatment with the drug
    • sertindole is only available, direct from the manufacturer, for named patients in clinical studies who are intolerant of other antipsychotic drugs - this is because it can cause significant prolongation of the QTC interval on ECG, an abnormality associated with potentially fatal arrhythmias

Choice of atypical antipsychotic drug (1):

  • a 'prolactin-sparing' drug, such as quetiapine, olanzapine or aripiprazole, may help to avoid symptoms due to hyperprolactinaemia
  • in situations where daytime sedation has to be avoided, amisulpride and quetiapine seem good choices
  • atypical antipsychotics with alpha1 adrenoceptor-blocking properties (e.g. clozapine, olanzapine, quetiapine, risperidone, sertindole, zotepine) are less suitable for those elderly patients in whom postural hypotension could be dangerous
  • amisulpride and risperidone appear to be atypical antipsychotics with a lower tendency to cause or aggravate weight gain, glucose intolerance or dyslipidaemia, in patients with, or at risk of developing, diabetes or cardiovascular disease
  • because of the risk of stroke, compelling reasons are needed before prescribing any antipsychotic for elderly patients with risk factors for cerebrovascular events

Aripiprazole for the treatment of schizophrenia in people aged 15 to 17 years

  • NICE state "..aripiprazole is recommended as an option for the treatment of schizophrenia in people aged 15 to 17 years who are intolerant of risperidone, or for whom risperidone is contraindicated, or whose schizophrenia has not been adequately controlled with risperidone..." (2)


  • traditional ('typical', 'conventional', 'first generation') antipsychotic drugs, such as chlorpromazine and haloperidol, ameliorate psychotic symptoms in around 75% of patients with acute schizophrenia, but are relatively ineffective for negative symptoms (1)
  • traditional antipsychotic drugs are believed to work mainily via blockade of dopamine D2 receptors in the brain. The blockade of dopamine D2 receptors is also thought to account for unwanted effects that often undermine adherence to therapy, notably extrapyramidal effects (e.g. parkinsonism, acute dystonia, akathisia, tardive dyskinesia) and symptoms of hyperprolactinaemia (e.g. galactorrhoea, amenorrhoea or oligomenorrhoea, and female or male infertility) (1)
  • a meta-analysis comparing first and second generation antipsychotics (3):
    • the study showed that four of these drugs were better than first-generation antipsychotic drugs for overall efficacy (overall change in symptoms, and positive and negative symptoms), with small to medium effect sizes (amisulpride -0·31 [95% CI -0·44 to -0·19, p<0·0001], clozapine -0·52 [-0·75 to -0·29, p<0·0001], olanzapine -0·28 [-0·38 to -0·18, p<0·0001], and risperidone -0·13 [-0·22 to -0·05, p=0·002])
    • second-generation antipsychotic drugs induced fewer extrapyramidal side-effects than did haloperidol (even at low doses)
    • with the exception of aripiprazole and ziprasidone, second-generation antipsychotic drugs induced more weight gain, in various degrees, than did haloperidol but not than low-potency first-generation drugs
    • the study authors concluded "...Because the second-generation antipsychotic drugs differ in many properties, including efficacy, side-effects, cost (some are now generic), and pharmacology (amisulpride is not a serotonin receptor blocker), they do not form a homogeneous class and neither do first-generation antipsychotic drugs. Improper generalisation creates confusion and as a result the classification might be abandoned..."


  1. Drug and Therapeutics Bulletin (2004); 42(8):57-60.
  2. NICE (January 2011). Aripiprazole for the treatment of schizophrenia in people aged 15 to 17 years
  3. Leucht S et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis.Lancet. 2009 Jan 3;373(9657):31-41.

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