Do Anti-depressants Cause Mood Switching in Bipolar Patients?

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Leverich et al. Risk of Switch in Mood Polarity to Hypomania or Mania in Patients with Bipolar Depression During Acute and Continuation Trials of Venlafaxine, Sertraline, and Buproprion as Adjuncts to Mood Stabilizers. Am J Psychiatry 2006; 163: 232-239.

Clinical Question on Harm:

Does the use of antidepressants with mood stabilizers increase the risk of switching to hypomania or mania?

Background Info:

There is controversy as to the response rate to antidepressants and risk of switch into hypomania or mania when these agents used in adjunct to mood stabilizers.

Harm/Risk:

Showed similarity in possible determinants of outcome. Each type of antidepressant analyzed separately. Groups were not treated similarly WRT mood stabilizer(s) but threshold switching reported to be unrelated. Outcomes measured in the same way in the groups being compared. Follow-up weekly for first 2 wks, then at least biweekly during 10-wk phase, and at least monthly during continuation phase with PRN visits. Reasonable temporal relationship between exposure and outcome. Unclear dose-response gradient.

Randomized Controlled Trial

Blinding: Outcome measures were blindly assessed by clinicians.

Duration: 10-week acute treatment phase followed by continuation study for up to 1 year.

Setting: Patients from Stanley Foundation Bipolar Network

Patients/Population: Total N = 159 of 184 included bec/ had life chart: 115 (72.3%) BP I patients, 40 (25.2%) w/ rapid cycling. 52.2% Male. 87 patients with response to antidepressant entered continuation treatment for up to 1 year.

Intervention/drug exposure: Patients with BP depression receiving at least 1 mood stabilizer at clinically therapeutic levels were randomly assigned to buproprion, sertraline, and venlafaxine. If pt did not respond acutely to initial antidepressant, they were offered blind re-randomization 1 of the other 2 drugs.

Outcome measures: Monitor antidepressant response with the Clinical Global Impression BP Version (CGI-BP). Occurrence of sub-threshold brief mania (emergence of brief hypomania as least 1 but <7 days or recurrent brief hypomania) or threshold switches (emergence of full duration hypomania or mania) were blindly assessed by clinician-rated daily reports of continuum mood-associated dysfunction on the NIMH Life Chart Method.

Main Results:

111 (48.7%) of 228 acute antidepressant trials a/w rating of much improved/very much improved on CGI-BP. 11.4% hypomania and 7.9% mania threshold switches occurred in acute treatment trials; 21.8% hypomania and 14.9% mania, respectively, in the continuation trials. Rate of threshold switches was higher in the 169 trials in BP I patients (30.8%) than 59 trials with BP II patients (18.6%). Ratio of threshold switches to subthreshold brief hypomania was higher in both acute (3.60) and continuation trials (3.75) of venlafaxine than in the trials of buproprion (ratios 0.85, 1.17), sertraline (1.67, 1.66). Only 23.3% of patients (37 of 228 acute antidepressant trials) had sustained antidepressant response in continuation phase without threshold switch.

Conclusions:

In patients with bipolar depression, I would take caution in prescribing an adjunctive antidepressant to mood stabilizer as there is increased risk in switching to hypomania or mania. This study used a scale to rate a continuum of mood rather than a single-threshold or dichotomous measures. However, patients could be on different types of mood stabilizers that were held constant.

Synopsis:

Adjunctive treatment with antidepressants in BP depression was associated with increased risks of threshold switches to full-duration hypomania or mania in both acute and continuation trials. Highest relative risk of such switching: Venlafaxine > Sertraline > Buproprion

Presented by Johnny Lee, MD on 3/26/07

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