Which antipsychotics are better tolerated? The tolerability ladder for antipsychotics-Lancet. ahead of print.2013.


How do common antipsychotics compare with each other on side effects? Many antipsychotic drugs have not been compared head to head and it has been a difficult question.  Multiple metaanalysis is a methodology to synthesise data from different trials (by integrating direct and indirect comparisons) to create efficacy ladders or comparative efficacy or side effects tables. Stefan Leucht, Andrea Cipriani and team compared efficacy and side effects of the two prototypical first-generation (haloperidol and chlorpromazine) and 13 second-generation antipsychotic drugs  used in patients with schizophrenia.Efficacy table was summarised yesterday.

Studies that met the strict quality criteria were only included in the analysis. all-cause discontinuation, weight gain, use of antiparkinson drugs as a measure of extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation were the relevant secondary outcomes.Analysis included 212 studies  with 43,049 participants with mean duration of illness being 12 years.68% of studies were done by pharma. 94% were double blinded.


All-cause discontinuation: This was used as a measure of acceptability.Amisulpride , olanzapine , clozapine , paliperidone , and risperidone  had significantly lower all-cause discontinuation than several other drugs.

Weight gain: Haloperidol, ziprasidone, and lurasidone caused no weight gain. As expected Olanzapine produced significantly more weight gain than most other drugs.Clozapine, iloperidone, chlorpromazine, sertindole, quetiapine, risperidone, and paliperidone produced significantly more weight gain than halo- peridol, ziprasidone, lurasidone, aripiprazole, amisulpride, and asenapine (with the exception that asenapine did not differ significantly from paliperidone)

EPS:  Clozapine, sertindole, olanzapine, quetiapine, aripiprazole, iloperidone, amisulpride, and asenapine did not cause significantly more EPS than placebo. Clozapine produced fewer extrapyramidal side-effects than all other drugs and placebo.

Prolactin increaseAripiprazole, quetiapine, asenapine, chlorpromazine, and iloperidone did not  significantly increase prolactin concentrations compared with placebo. Paliperidone and risperidone were associated with significantly more prolactin increase than all other drugs.No usable data were available for amisulpride.

QTc prolongation: Lurasidone, aripiprazole, paliperidone, and asenapine were not associated with significant QTc prolongation compared with placebo.

Sedation: Amisulpride, paliperidone, sertindole, and iloperidone were not significantly more sedating than placebo . Clozapine,zotepine and chlorpromazine tops the table for sedation.

Separation between FGA and SGA based on EPS or weight gain ( metabolic parameters) are not supported by these results. Note that five second-generation drugs were associated with significantly more EPS than  placebo. Some FGAs cause significant weight gain.


The seven hierarchies ( efficacy, discontinuation,EPS, sedation, weight gain, prolactin effect, QTc) are useful when initiating antipsychotics, i.e. by matching patient characteristics and preferences to individual antipsychotic profile.

Summary of the article (part 2) :

Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.

Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM.Lancet. 2013 Jun 26. doi:pii: S0140-6736(13)60733-3. 10.1016/S0140-6736(13)60733-3. [Epub ahead of print]


2 thoughts on “Which antipsychotics are better tolerated? The tolerability ladder for antipsychotics-Lancet. ahead of print.2013.

    • They do.Authors report that there were no usable data available for amisulpride and agree that its high prolactin risk is well known. thanks for making this point clear.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )


Connecting to %s