Baseline manic symptoms, even if minimal, signal problems with mood
switch after an antidepressant regimen is initiated for patients with bipolar
Psychiatrists must watch for subtle symptoms of mania before prescribing
antidepressants for bipolar patients during a depressive episode because of a
significant risk of inducing mania in this particular subgroup of patients, a
new study suggests.
In the clinical trial conducted by the Bipolar Collaborative Network
(formerly the Stanley Foundation Bipolar Network), 176 adult patients with
bipolar depression were treated with adjunctive antidepressants for 10 weeks.
The authors found that patients who experienced treatment-emergent
mania—a rapid mood switch from depression to mania or
hypomania—had significantly higher levels of motor activity, speech, and
language-thought disorder on the Young Mania Rating Scale (YMRS) at baseline,
compared with patients who did not have this adverse outcome.
The patients who experienced treatment-emergent mania also had a
significantly higher total YMRS score at baseline than patients who did not
have treatment-emergent mania. By analyzing YMRS items that are found to
relate to each other, the authors identified a significant correlation between
treatment-emergent mania and higher scores for motor/verbal activation at
Forty-six patients had treatment-emergent mania, specifically defined as a
mania severity score of 4 or greater (moderate to severe) on the Clinical
Global Impression scale for bipolar disorder (CGI-BP) or a change in score of
6 or 7 (much worse or very much worse) during the 10-week trial.
The authors conducted post hoc analyses on data from a randomized,
controlled clinical trial that had compared the efficacy and safety among
three antidepressants—venlafaxine, sertraline, and bupropion—as an
adjunct to a mood stabilizer. The trial was conducted at six sites in the
United States, the Netherlands, and Germany. The same group of authors
previously reported in the February 2006 American Journal of
Psychiatry that venlafaxine was linked to the highest risk of mood
switch, and bupropion with the lowest risk.
The causes of rapid mood switch associated with antidepressant treatment
are not completely understood. Some antidepressants such as tricyclics are
known to pose a higher risk for inducing mood switch. Past studies also
indicate that patients with the rapid-cycling type of disorder and in mixed
episodes are more likely to have a mood switch when they take
“It is important to emphasize that large, placebo-controlled studies
suggest that antidepressant treatment [as adjunct to mood stabilizers] is no
more efficacious than placebo for bipolar patients treated with
mood-stabilizing medications,” said Roy Perlis, M.D., M.Sc., in an
interview. He is the medical director of the Bipolar Clinical and Research
Program and Center for Human Genetic Research at Massachusetts General
Hospital and an assistant professor of psychiatry at Harvard Medical
“So, before we talk about the risk of mood switch, we need to
consider whether any amount of risk is worthwhile,” added
Perlis, who served as an investigator in the National Institute of Mental
Health's Systematic Treatment Enhanced Program for Bipolar Disorder (STEP-BD)
Data from the STEP-BD trial indicated that in bipolar patients with
simultaneous manic symptoms and full-blown depression, adjunctive
antidepressants were not significantly more effective than placebo and may
exacerbate mania (Psychiatric News, September 21, 2007).
“What the current study makes clear is that, among previously
suggested clinical features, few are useful for predicting mood switch. The
one set of features... significantly associated with switch were manic
symptoms,” said Perlis. In other words, when a patient is depressed,
having more manic symptoms is a sign that he or she is closer to a manic or
mixed state. “The closer you are to mania, the more likely you are to
become manic after [antidepressant] treatment; this is not a big surprise.
However, this finding underscores the important point that all depressed
patients need to be carefully evaluated for manic/hypomanic symptoms prior to
initiating or changing treatment,” he emphasized.
The current study was funded by the Stanley Medical Research Institute and
published online in AJP in Advance on November 17, 2008.
Combined with other similar findings, the authors concluded that“
short-term use of antidepressants may have liabilities—induction
of mania or hypomania or persistence of manic or hypomanic symptoms—in
bipolar depressed patients who have minimal manic symptoms at
“A careful examination for... specific symptoms of mania is warranted
prior to antidepressant treatment for bipolar depression,” they
“Correlates of Treatment-Emergent Mania Associated With
Antidepressant Treatment in Bipolar Depression” is posted at<ajp.psychiatryonline.org/cgi/reprint/appi.ajp.2008.08030322v1>.▪