Drug Can Benefit Severely Depressed Patients

By Sean Henahan
The Medical Post, May 16, 1995

SAN DIEGO - The anticonvulsant agent valproate has recently become a useful therapy for patients with severe manic depression.

New data now suggest that valproate can also provide significant benefits for patients with less severe mood disorders, and at much lower doses.

That's according to a study presented at the annual meeting of the American Society for Clinical Pharmacology and Therapeutics.

The new data come from an open label, prospective longitudinal study involving 121 patients with bipolar II disorder, a more mild form of manic depression, or cyclothymia, a disorder also characterized by alternating depression and high moods, but less severe in nature.

The trial compared the effects of lithium, valproate and placebo during a mean treatment period of 18 months. The dosing of valproate began at 125 to 250 mg and was increased incrementally until symptoms were controlled.

Patients receiving valproate show virtually the same symptomatic improvement as those receiving lithium. The patients with cyclothymia achieved symptom stabilization with significantly lower doses of valproate than required by the bipolar II patients.

Cyclothymic patients required a mean dose of 277 mg/day compared with bipolar II patients, who required a mean of 377 mg/day. The bipolar II patients also needed to achieve a higher serum level of valproate than did cyclothymia patients to achieve a therapeutic response, said Dr. Fred Jacobsen, medical director, Transcultural Mental Health Institute, Washington, D.C.

Dr. Jacobsen also evaluated a parallel group of 33 patients with bipolar I disorder, the most severe form of manic depression. These patients required significantly higher doses of valproate - mean of 1168 mg/day and serum levels, 69.5ug/mL - than either the cyclothymic or bipolar II patients, he said.

"The study confirms that a majority of patients with cyclothymia or bipolar disorder II show stabilization of symptoms with valproate in doses below 500 mg/day.

"Moreover, we observed a relationship between the severity of bipolar illness and the dose of valproate required for stabilization of symptoms with cyclothymia requiring the lowest doses, bipolar disease slightly higher doses, and bipolar I patients the highest dose. This is the first time such a dose/severity relationship has been demonstrated in the field of psychopharmacology," he added.

A common problem encountered in the treatment of manic depression with lithium is that, while it is often possible to control the manic symptoms, all too often the depressive symptoms remain.

In the current study, a third of the patients responded to lowdose valproate alone without requiring antidepressants later. This suggests valproate may be the only psychotropic agent needed for treating some patients with the more mild mood disorders, Dr. Jacobsen said.

"Lithium is still considered the first line of therapy for bipolar I disorder, except in patients with rapid cycling. Those patients clearly respond better to an anticonvulsant such as valproate or carbamazepine.

"For the milder cycling disorders, low-dose valproate may be a reasonable first line treatment before adding anything else."

Lithium has been a mainstay of therapy for severe depression and bipolar disease since the 1950s, but up to one-third of patients fail to respond to lithium and side effects limit its utility in many others.

The data supporting the use of valproate are important for patients because it may work when lithium does not. Moreover, it is useful to have an alternative to lithium, since some physicians hesitate to prescribe lithium out of concern for its high side effect profile, Dr. Jacobsen said.

The current study is also the first to show the affect of specific treatments in patients with cyclothymia. In the past, the cyclothymia symptoms were often attributed to psychodynamic factors, as were the symptoms of other, more severe forms of depression and mood instability. This study provides strong evidence that cyclothymia has physiologic underpinnings, he added.

Copyright 1995 Maclean Hunter Publishing Limited
Reprinted with permission.

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