Bipolar Depressive Subtypes, Other Clinical Factors, and Treatment Response

Bipolar Depressive Subtypes, Other Clinical Factors, and Treatment Response

Although pharmacotherapy with lithium is an effective treatment for many patients with bipolar disorder, Maj and colleagues (1989) reported that even an initially complete response to lithium, defined as no episodes during the first 2 years of treatment, did not predict response over the next 5 years. Among the 25 patients sustaining treatment over a 5-year period, 40% relapsed and another 38% of the original sample dropped out. The range of lithium's prophylactic effectiveness, once broadly asserted, is now bounded by caveats that increasingly narrow the claims made for lithium maintenance therapy. Possible factors that may reduce the efficacy of lithium are mixed episodes, rapid cycling, comorbidity, and demographic factors.

Mixed Episodes
Several investigators (Himmelhoch and Garfinkel 1986; Prien et al. 1988; Secunda et al. 1985) reported a substantially poorer outcome for lithium therapy in patients with mixed episodes (dysphoric mania, depressive mania) compared with patients with pure affective episodes. The outcome of anticonvulsant therapy for mixed mania is also less robust than the response of patients with pure manic episodes to these agents. Patients who meet DSM-IV criteria for mixed episodes are very difficult to treat and demonstrate a similar but poor response to lithium, anticonvulsants, or placebo (Swann et al. 1997). Interestingly, however, mania associated with subsyndromal depressive features appears to respond better to anticonvulsants than to lithium.

Rapid Cycling
Rapid-cycling bipolar disorder has traditionally been defined as 4 or more episodes of mania or depression per year, although Bauer and Whybrow (1995) suggested changing the criterion to 12 or more episodes per year. Several studies demonstrated reduced efficacy of lithium in patients with rapid-cycling bipolar illness (Dilsaver et al. 1993; Dunner 1979; Kukopulos et al. 1983). As is typical of these studies, Kukopulos et al. (1983) found good response to lithium prophylaxis in only 16% of rapid-cycling patients compared with a 57% response rate in continuously cycling patients with low cycle frequency. Maj et al. (1998) reported that no rapid-cycling patients treated with lithium remained episode-free over a 5-year follow-up period.

Bowden et al. (1999a) reported the outcome of the open phase of an ongoing double-blind study in which lamotrigine was added to the treatment regimen of rapid-cycling bipolar disorder. More than 50% of the sample remained stable while taking lamotrigine monotherapy for at least 2 weeks after tapering all other concomitant treatments.

Comorbid Substance Abuse
It is estimated that more than 60% of patients with bipolar disorder meet criteria for substance abuse at some point during their lives, which exceeds even the rate for patients with unipolar depression (Regier et al. 1990). This relatively high rate of comorbid substance abuse is associated with the occurrence of mixed episodes and rapid cycling (Himmelhoch and Garfinkel 1986) and therefore with relative resistance to treatment.