A randomized, double-blind, parallel-group multicenter study of treatment outcomes was conducted by Bowden et al in 2000 (2). Patients could be enrolled in the open-label phase while being manic, having partially recovered from the manic episode, or being euthymic after the episode, but not while depressed. Patients had to be randomized to double-blind maintenance treatment within 3 months of the onset of the index episode. Results showed that Divalproex was superior to placebo in terms of lower rates of discontinuation for either a recurrent mood episode or depressive episode. Divalproex was superior to lithium in longer duration of successful prophylaxis and less deterioration in depressive symptoms and Global Assessment Scale scores.
More recently, the results of BALANCE study, a randomised open-label trial (3) clearly showed that for people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than valproate monotherapy is. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy. The suggestion by the BALANCE group that emerging non-responders to long-term lithium treatment should be continued on lithium combined with valproate is debatable. The combination could be better than lithium alone in this subgroup of long-term lithium non-responders despite the overall study results. The BALANCE study, even without a placebo group, confirms the long-term efficacy of lithium, not only in the prevention of mania but also depression. Finally, as commented by Licht (3): “Why is BALANCE the first three-group study testing a drug combination versus each drug alone in the long-term treatment of bipolar disorder, in view of the fact that such comparisons are highly relevant? An obvious reason is that a three-group study is expensive. Additionally, no drug company is eager to do such a study, because for marketing reasons it would not be optimum if a combination of their drug and another drug was shown to be more efficacious than treatment with their drug alone. Thus, in the few company-sponsored long-term trials assessing drug combinations in bipolar disorder, the company’s drug (an atypical antipsychotic) combined with lithium or valproate was compared with lithium or valproate given alone, but not with the antipsychotic given alone”.
Lamotrigine was superior to placebo in two studies of 18 months duration, which enrolled manic or recently manic patients in one and depressed or recently depressed bipolar I patients in the other. The two studies showed that lithium alone was superior to placebo in the prevention of manic symptoms, whereas lamotrigine alone was superior to placebo in the prevention of a depressive episode (4, 5). A pooled analysis of the two studies showed that Lamotrigine but not lithium delayed time to depression compared with placebo. Both lithium and Lamotrigine delayed time to intervention for mania compared with placebo. However, the rate of relapse to mania was significantly lower with lithium than with Lamotrigine (6). In a double-blind placebo-controlled prophylaxis study in rapid cycling bipolar disorder, Lamotrigine was not superior on time to intervention for a mood episode (7). However, a secondary analysis indicated that Lamotrigine was significantly superior to placebo on time to discontinuation for any reason in bipolar II, but not bipolar I subjects. Since bipolar II disorder is characterized by full depression but milder manic features, the study results suggest that principal benefits of Lamotrigine are seen in patients whose illnesses are weighted toward depression (8).
In the last decade, a comparable efficacy of carbamazepine and lithium has been claimed with a slight superiority of lithium (9-14). These studies show a variety of shortcomings: only small samples were investigated, selected patient groups such as lithium non-responders or ‘‘rapid cyclers’’ were included, and observation periods were rather short, usually not more than one year long. Hence to date, positive results concerning the application of carbamazepine in bipolar patients cannot be generalized to the whole population. Data regarding combination therapy with Lithium have been published in the early 1980s (15), and this combination continues to be widely regarded as a useful option following unsatisfactory results with either agent given alone. More recently, Baethge et al (16) compared the outcomes of a sample of bipolar patients during combination therapy to the outcomes during the monotherapy (lithium or carbamazepine); they found that the combination therapy determined substantial benefit.
The use of Valproic Acid, Lamotrigine and Carbamazepine in bipolar disorder maintenance is not free of several adverse effects.
Valproic Acid shows teratogenic risk during the first trimester of pregnancy, pancreatitis and hepatic dysfunction, but the latter two show extremely low rates (hepatotoxicity 1 ⁄ 49,000 and pancreatitis <1%), they are idiosyncratic and more commonly seen in younger patients. Higher serum valproate levels are significantly associated with reductions in white blood cell count and platelet count in maintenance treatment.
Lamotrigine shows a high rate of benign rash (11.6% ) and a rate of serious rash (below 0.1%), both of idiosyncratic nature.
Carbamazepine induces its own metabolism. This, coupled with adverse events, particularly affecting the central nervous system in the early course of treatment, necessitates starting at low doses (100–400 mg⁄day) and titrating gradually until response or adverse events ensue or serum level exceeds 12 lg ⁄mL. Carbamazepine induces cytochrome P450 enzymes, particularly P450-3A3⁄4, leading to lowering of plasma levels of other drugs such as anticonvulsants, antidepressants, antipsychotics, and many anxiolytics and oral contraceptives. Agranulocytosis and aplastic anemia, idiosyncratic in nature, is seen in 1 ⁄ 10,000–100,000 patients, though benign leukopenia (transient 10%, persistent 2%) is more common. Thrombocytopenia is seen in 2% of patients treated with Carbamazepine and also causes mild hyponatremia, which may manifest more seriously in the geriatric or medically ill subgroup of patients.