Other predictors of favorable response to lithium prophylaxis include a family history of bipolar disorder, illness course characterized by maniadepression-euthymia episode sequence, and few prior mood episodes.21 Conversely, co-occurring alcohol or substance use disorder, multiple prior mood episodes, and familial negative affective style have been associated with poor response to lithium maintenance treatment.
Tentative predictors of response to divalproex maintenance treatment include mixed episodes, rapid cycling, and absence of co-occurring personality disorder. In one lithium comparison trial, patients with mixed episodes, bipolar II, and NOS disorders and mood-incongruent symptoms appeared to have a better response to carbamazepine.10
The dosage and relevant plasma concentrations of maintenance agents may also affect long-term efficacy. Gelenberg et al observed that the risk of relapse in bipolar patients maintained on low (0.4-0.6 mmol/L) serum concentrations was 2.6 times higher than for patients maintained on high (0.8-1.0 mmol/L) serum concentrations.23 However, there was a tradeoff in tolerability. Patients treated at the higher concentrations experienced significantly more and often treatment-limiting side effects.
No data are available regarding a possible plasma concentration-response relationship between maintenance treatment with divalproex or carbamazepine, but based on data from acute treatment trials, concentrations well within the therapeutic range of each drug appear essential.
The problem of subsyndromal symptoms
Evidence from a number of long-term outcome studies in bipolar disorder indicates that many patients spend protracted periods of time neither well nor in syndromal manic or depressive episodes, but rather experiencing chronic subsyndromal symptoms.24,25 In these studies, depressive symptoms were twice as prevalent as hypomanic symptoms between acute episodes of illness. Furthermore, persistent subsyndromal depressive symptoms were strongly associated with an increased risk for relapse and poor occupational functioning.
Keller et al26 found that patients maintained on low lithium serum concentrations (0.4-0.6 mmol/L) were more likely to experience subsyndromal symptoms and that their symptoms were more likely to worsen at any time than were symptoms of patients maintained at higher serum concentrations (0.8-10 mmol/L). The first occurrence of subsyndromal symptoms increased the risk of fullepisode relapse fourfold. These findings indicate that the optimal pharmacological maintenance treatment of bipolar disorder requires titration of mood-stabilizer medications to eradicate subsyndromal symptoms. Eliminating these residual or recurrent symptoms, in turn, substantially decreases the risk of relapse and of enduring functional impairment.
Conventional wisdom, in part supported by limited data from a small number of studies, suggests that antidepressants be used sparingly and for limited periods of time in conjunction with mood-stabilizers for bipolar depression. However, new data indicate that this strategy may significantly increase the risk of recurrence of depressive symptoms and episodes.27 Thus, combined treatment with mood-stabilizing agents and antidepressants for patients without rapid cycling and with recurrent depressive episodes may be indicated more often than previously thought.
In practice, perhaps the majority of patients with bipolar disorder require treatment with more than one mood-stabilizing medication to suppress subsyndromal symptoms as well as to prevent full episode recurrence. The use of combinations has been very poorly studied in randomized, controlled trials. In a pilot study of 12 patients with bipolar I disorder, Solomon et al compared the efficacy of lithium alone versus the combination of lithium and divalproex for 1 year.28 Not surprisingly, the combination significantly reduced the risk of recurrence of mania and depression but was also associated with more bothersome side effects.
Clinical practice has greatly outstripped the limited data available from formal studies. Recently reported as useful maintenance treatment strategies are combinations of:
- lithium and divalproex
- lithium and carbamazepine
- divalproex and carbamazepine
- lithium, divalproex, and carbamazepine
- lithium and/or divalproex with atypical antipsychotics, antidepressants, and lamotrigine.
Related resources
- Nathan PE, Gorman JM, eds. A Guide to Treatments that Work. 2nd ed. New York: Oxford University Press, 2001.
- Buckley PF, Waddington JL, eds. Schizophrenia and Mood Disorders: the New Drug Therapies in Clinical Practice. Boston: Butterworth-Heiman, 2000.
- Goldberg JF, Harrow M. Bipolar Disorders. Clinical Course and Outcome. Washington, DC: American Psychiatric Press, 1999.
- Sachs GS, Thase ME. Bipolar disorder therapeutics: maintenance treatment. Biol Psychiatry 2000;48:573-81.
- Hirschfeld RMA, Bowden CL, Gitlin MJ, et al. Practice guideline for the treatment of bipolar disorder (revision). Am J Psychiatry, in press.
Drug brand names
- Clozapine • Clozaril
- Divalproex • Depakote, Depakote Sprinkle
- Lamotrigine • Lamictal
- Mirtazapine • Remeron, Remeron Soltab
- Nefazodone • Serzone
- Olanzapine • Zyprexa
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Trazodone • Desyrel
- Valproate sodium • Depacon
- Ziprasidone • Geodon
Disclosure
Dr. Keck reports that he receives grant/research support from and serves as a consultant to Abbott Laboratories, AstraZeneca, Pfizer Inc., and Eli Lilly and Co. He also receives grant/research support from Merck and Co. and Otsuka America Pharmaceutical, and serves as a consultant to Bristol-Myers Squibb Co., GlaxoSmithKline, and Janssen Pharmaceutica.