ALAN EPPEL MB, FRCPC
Attached to the cover of a recent issue of the Canadian Journal of Psychiatry was an advertisement promoting the use of aripiprazole for the treatment of depression.

The advertisement was addressed to me personally and recommended that aripiprazole be considered early on in the treatment algorithm for depression. The advertisement implied that  adjunctive aripiprazole be considered after 2 to 4 weeks of nonresponse to an antidepressant.

The use of second-generation antipsychotics for the treatment of mood and anxiety disorders has skyrocketed in the past decade. While there is some evidence for efficacy claims are frequently made without a balanced consideration of the risks versus benefits.


The main serious side effects antipsychotic medications are 1) metabolic syndrome and 2) extrapyramidal symptoms and tardive dyskinesia. 
Metabolic Syndrome Diagnostic Criteria: International Diabetes Federation Criterion A plus two of other four items.


Waist circumference

men >37 inches; women >31.5 inches 


1. Fasting triglycerides >150 mg/dl
 2. High-density lipoprotein Men: <40 mg/dl Women: <50 mg/dl

 3. Systolic blood pressure/diastolic blood pressure >130/85 mmHg, or on antihypertensive medication 

4. Fasting glucose >100 mg/dl, or on insulin or hypoglycemic medication. 
 In a meta-analysis conducted by Spielmans et al. adjunctive aripiprazole had an effect size of only 0.35 considered, small to moderate. 

 Aripiprazole was associated with akathisia with the number needed to harm of NNH=4.  With regard to weight gain NNH= 29. Average weight gain across a number of trials was one kilogram and ranged from 0.42 1.67 kg.

Troublesome methodological deficiencies were identified in these studies. The Federal Drug Administration expressed concern about a number of protocol violations in one of the aripiprazole studies. This concerned the number of participants who used prohibited medications during the trial.

The authors note that at the time of publication there were no trials that directly compared adjunctive atypical antipsychotic medication to other treatment strategies such as such adjunctive lithium, switching the antidepressant, or adding psychotherapy.

In a study of second generation antipsychotics in 342 youth, Carbon et al found that 15.2% developed drug-induced parkinsonism. 

SGA-group drug-induced parkinsonism rates were as follows:

quetiapine = 1.5%, olanzapine = 13.8%,

risperidone = 16.1%, ziprasidone = 20.0%,
and aripiprazole = 27.3%.

Treatment-emergent dyskinesia ranged from 4.5% with aripiprazole, to 15.5% with olanzapine.
Cloud et al in a review  noted tardive dyskinesia prevalence rates of 13 % among patients on SGAs and 32 % among patients on first-generation agents. One included review of 12 trials reported  the annual incidence of TD to be 3.9 % for SGAs and 5.5 % for first-generation drugs


Contrary to early hopes, second generation antipsychotics do have significant rates of serious side effects. In the treatment of schizophrenia and related psychoses these risks may be outweighed by the potential benefits.

However the risk benefit equation provides  no justification for the use of SGAs in the  treatment of mood or anxiety as first, second or even third line agents.

1. Spielmans GI et al. Adjunctive atypical antipsychotic treatment for major
depressive  disorder: a meta-analysis of depression, quality of life, and
safety outcomes. PLoS Med. 2013;10(3):e1001403. doi: 10.1371/journal.pmed.1001403.
2. Carbon M  et al. Neuromotor Adverse Effects in 342 Youth During 12 Weeks of Naturalistic Treatment With 5 Second-Generation Antipsychotics.
J Am Acad Child Adolesc Psychiatry. 2015 Sep;54(9):718-727
                    3.Cloud LJ, Zutshi D, Factor SA. Tardive dyskinesia: therapeutic options for 
                    an increasingly common disorder. Neurotherapeutics. 2014 Jan;11(1):166-76.

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