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J Affect Disord. 2001 Aug;65(3):281-7.

Long-term naturalistic treatment of depressive symptoms in bipolar illness with divalproex vs. lithium in the setting of minimal antidepressant use.

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Psychopharmacology Program, Cambridge Hospital, Consolidated Department of Psychiatry, Harvard Medical School, Cambridge, MA, USA.



Risks have been associated with the long-term use of antidepressant in the treatment of bipolar disorder. We review our naturalistic experience with divalproex versus lithium in treating depressive symptoms of bipolar illness.


All patients with bipolar disorder treated with lithium or divalproex were identified in a university outpatient psychiatry clinic sample over one year (n=38 patients, 41 treatment trials). Treatment response was based on standard prospective symptom rating scales. Mean duration of follow-up was 90 weeks.


Lithium and divalproex were equally effective and tolerated in the total sample. Antidepressant effects were noted despite sparing use of standard antidepressant agents (19% received them). Lithium non-responders responded well to divalproex (50%), and vice versa (44%). Divalproex monotherapy (24%) was more common than lithium monotherapy (7%, P=0.07) and was notably effective in treating depressive symptoms, with a 7/10 response on the CGI-BP and improvement on the HDRS (14.8+/-9.2 to 7.6+/-7.8, P=0.003, duration of prospective follow up 26.7 weeks).


Lithium and divalproex were equally effective and tolerated in this naturalistic sample, but responders may represent distinct subgroups. Both agents, but particularly divalproex, demonstrated long-term antidepressant effects, with limited adjunctive standard antidepressant use.

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