Systematic review: which anti-psychotic medication is the best?


Schizophrenia is considered a chronic long-term debilitating condition, affecting about 1% of the population. There has been considerable debate about which of the anti-psychotic medications are the best treatments. The debate has usually been structured around typical (older) and atypical (newer) anti-psychotic medications. The revised NICE guidelines (2009) moved towards a more neutral stance between atypical (newer drugs) and typical (older drugs) anti-psychotics.


This aimed to compare fifteen antipsychotic drugs across seven domains including effectiveness/efficacy (symptom reduction PSYRATS or BPRS), and all cause discontinuation, side effects including Extrapyramidal Side Effects (EPSE), weight gain, prolactin increase, QTc prolongation, and sedation. The authors conducted a Bayesian-framework, multiple treatment meta-analysis.

The researchers combined data from studies.

The researchers combined data from 212 different studies involving 43,209 participants.


  • 212 trials containing 43,209 participants were identified, 144 (68%) had been conducted by the pharmaceutical industry.
  • All drugs included in the analysis fared better than placebo.
  • There were high rates of withdrawal across all the studies at about 35%.
  • No one drug was best across all the domains – see summary table of best/worst performers across the domains.
  • Five atypical anti-psychotics had significantly more EPSE than placebo.
  • Efficacy (symptom change) – the best performers were Clozapine, Amisulpride & Olanzapine, the worst performers were Asenapine, Lurasidone & Iloperidone.
  • All cause discontinuation – the best performers were Amisulpride, Olanzapine & Clozapine, the worst performers were Lurasidone, Sertindole & Haloperidol.
  • EPSE – the best performers were Clozapine, Sertindole & Olanzapine, the worst performers Chlorpromazine, Zotepine & Haloperidol.
  • Weight gain – the best performers were Haloperidol, Ziprasidone & Lurasidone, the worst performers Clozapine, Zotepine & Olanzapine.
  • Prolactin increase* – the best performers were Aripiprazole, Quetiapine & Asenapine, the worst performers were Haloperidol, Risperidone & Paliperidone.
  • QTc prolongation** – the best performers were Lurasidone, Aripirazole & Paliperidone, the worst performers were Ziprasidone, Amisulpride &  Sertindole.
  • Sedation – the best performers were Amisulpride, Paliperidone & Sertindole, the worst performers were Chlorpromazine, Zotepine & Clozapine.

*Not applicable Amisulpride Clozapine  Zotepine, **Not applicable Clozapine Chlopromazine Zotepine

Authors conclusions:

‘Results for our primary outcome challenge the dogma that the efficiency of all antipsychotic drugs is the same.’

‘Antipsychotics differed substantially in side-effects and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients.’



The reviewers found small but statistically significant differences between drugs.

It’s interesting to note the differences between the anti-psychotics which might help to challenge some clinician’s beliefs that certain drugs (atypicals) are better than others despite evidence to the contrary (see here). There is clearly a need for a more individualised approach to prescribing which involves negotiation and cost-benefit analysis for each individual service user/patient taking into account the potential side effect profiles and benefits of each drug. The authors suggested that cost appears to becoming a less issue, although atypical anti-psychotics are  more expensive especially when new to the market.

Dosing still appears key, although this is not really clear from this review, often trials which compare atypicals with typical anti-psychotics use typical doses above the 7.5 mg Haloperidol or less recommended for treatment of acute psychosis (see here). Some side effects are dose dependent. Further analysis needs to factor this in.

There were some limitations with the review some drugs are not currently used in the UK, others have a good evidence base underpinning them but not included in the analysis, for example, sulpiride and perphenazine. There were some potential problems with the analysis, for example, the use of all cause discontinuation as a proxy measure of acceptability.


Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel R, Geddes J, Kissling W, Stapf M, Lassig B, Salanti G, Davis J (2013) Comparative efficacy and tolerability of 15 anti-psychotic drugs in schizophrenia: a multiple-treatments meta-analysis. The Lancet, Early Online Publication, 27 June 2013


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John Baker

John Baker was appointed to Chair of Mental Health Nursing in 2015. John's research focuses on developing complex clinical and psychological interventions in mental health settings. He is particularly interested in i) acute/inpatient mental health services and clinical interventions; ii) medicines management in mental health care; iii) the attitudes and clinical skills of mental health workers, iv) the mental health workforce. The good practice manuals which he developed have been evaluated, cited as examples of good practice, and influenced clinical practice in the UK and abroad. The training package for patients, service users and carers to promote research awareness and understanding has been cited by the MHRN and NICE as an exemplar of good practice.

John is a member of the NIHR post-doctoral panel, sits on the Editorial boards for Journal of Psychiatric and Mental Health Nursing & International Journal of Mental Health Nursing. He is a Registered Nurse Teacher with the Nursing, Midwifery Council (NMC) and is active within Mental Health Nursing Academics (UK).

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