Adjunctive Aripiprazole, Olanzapine, or Quetiapine for Major Depressive Disorder: An Analysis of Number Needed to Treat, Number Needed to Harm, and Likelihood to be Helped or Harmed

Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
Postgraduate Medicine (Impact Factor: 1.7). 07/2010; 122(4):39-48. DOI: 10.3810/pgm.2010.07.2174
Source: PubMed


To describe the efficacy and safety of adjunctive aripiprazole, olanzapine, and quetiapine for major depressive disorder.
Published registration study reports, supplemented by clinical trial synopses as disclosed by manufacturers and product labeling.
All available reports of studies were identified.
Descriptions of the principal results and calculation of number needed to treat (NNT) for response and remission and number needed to harm (NNH) for relevant dichotomous adverse outcomes were extracted. Likelihood to be helped or harmed (LHH) was subsequently calculated.
Three registration studies of adjunctive aripiprazole, 5 for olanzapine-fluoxetine combination, and 2 for quetiapine extended-release reveal NNT for response and remission to range from 7 to 14 and 7 to 13, respectively, for adjunctive antipsychotic versus antidepressant monotherapy, depending on the antipsychotic and/or dose. Adverse event profiles for the 3 different adjunctive antipsychotics are more diverse, with adjunctive aripiprazole more strongly associated with akathisia (NNH, 6), adjunctive olanzapine with weight gain (NNH, 3), and adjunctive quetiapine with somnolence (NNH, 5 for 300 mg/d and NNH, 6 for 150 mg/d).
Number needed to treat and NNH can be used to quantify efficacy and tolerability outcomes and help place various therapeutic options into clinical perspective. Likelihood to be helped or harmed can illustrate to the clinician and the patient the trade-offs between obtaining potential benefits versus harms. In the case of the adjunctive second-generation antipsychotics approved for treating major depressive disorder, these trade-offs vary greatly among the choices available and require careful, individualized, patient-centered clinical decision making.

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    • "Clinicians and teachers find them to be an appealing, easy-toremember integer that can be readily translated into clinical practice. Among these constructs are: the number needed to treat (NNT) (Citrome, 2012, 2010; Popovic et al., 2011), number needed to harm (NNH), and the likelihood to be helped or harmed (the ratio of NNH to NNT) (Citrome and Katrowitz, 2008; Citrome, 2012). Recently, Popovic et al. (2012) have proposed the polarity index (PI) as another descriptor for categorizing profiles of drugs used for maintenance treatment of bipolar disorder. "
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    ABSTRACT: The medical community increasingly supports the use of simplifying constructs or ratios to facilitate incorporation of evidence-based medicine into clinical practice such as number needed to treat (NNT) and polarity index (PI). Clinicians and teachers find them to be an appealing, easy-to remember integer that can be readily translated into clinical practice. However, serious questions have been raised with respect to the validity, reliability and value of these descriptors of response. This commentary identifies some of the specific limitations of the NNT and PI constructs when applied to treatments of bipolar disorder.
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    ABSTRACT: Addition of atypical antipsychotics to the therapeutic regimen of patients with unipolar major depressive disorder not responding adequately to their treatment has become a common intervention. With all these agents the observation that low doses that are ineffective in schizophrenia, and thus not blocking dopamine D2 receptors effectively, indicate that their beneficial action is attributable to their action at other receptors. Preclinical research has shown that atypical antipsychotics can reverse the suppression of firing of norepinephrine neurons produced by selective serotonin reuptake inhibitors through their antagonism of 5-HT₂(A) receptors. In the case of aripiprazole, three large placebo-controlled studies in more than 1,000 patients individually concluded to significant antidepressant responses and remissions after a six-week treatment. Aripiprazole addition did not produce more discontinuations due to adverse events than placebo. The most frequently encountered adverse events were akathisia and restlessness. Weight gain was minimal but significant in two of the three studies, suggesting that this side effect is not major problem. There was no significant laboratory abnormalities noted with this strategy. It is proposed that because of its long half-life (approximately 3 days), the doses of aripiprazole were escalated too rapidly in these controlled trials. More gradual titration may lead in routine clinical practice to better outcomes, minimizing side effects and improving remission rates.
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