Treatment Options in Bipolar Disorder: Mood Stabilizers

Charles L. Bowden, MD

Medscape Psychiatry & Mental Health eJournal. 1997;2(4) 

In This Article

Mood-Stabilizing Agents: CBZ

CBZ is an anticonvulsant with antimanic and possibly antidepressant properties that can be used in patients with bipolar disorder. Although well-controlled study data are lacking, there is evidence that the drug is effective in the management of acute mania, particularly in patients who have responded inadequately or are unresponsive to Li. CBZ may have a slightly shorter onset of action than Li. It does not have an FDA-approved indication for bipolar disorder.[1,3]

Similar to the other mood-stabilizing agents, Li and VPA, CBZ appears to have multiple potential sites of action that could account for its psychotropic effects. Its anticonvulsant effects have been closely associated with several neurotransmitter and ion-channel systems. For example, it binds to voltage-sensitive sodium channels. Like phenytoin, it binds more avidly to inactive sites, decreasing sodium influx in a voltage-, frequency-, and use-dependent fashion. Like VPA, CBZ promotes potassium conductance and may also block neuromuscular dopaminergic receptor-mediated currents. However, it is unlikely that its action on type-2 sodium channels accounts for the antimanic and antidepressive effects. For example, the benzodiazepines, clonazepam and diazepam, have primary effects on the chloride channel via the central-type benzodiazepine receptor.[1,3,51]

Pooled data from uncontrolled studies indicate that a majority (mean, 53%) of acutely manic patients who received CBZ showed a moderate to marked improvement in symptoms (generally defined as a greater than 50% symptom reduction or at least partial remission).[24,52] Controlled studies also demonstrated that CBZ was superior to placebo and comparable to Li, with an average response rate of 55%. However, it should be noted that although these data are promising, their interpretation is limited by weaknesses in study designs and the narrow patient populations studied. Well-controlled, comparative studies are needed.[1,24,52]

Controlled studies comparing CBZ with placebo indicate that CBZ is superior to placebo in the treatment of bipolar disorder after 1 year.[24] In studies comparing the drug with Li, a majority of patients taking either drug required adjunctive treatment for breakthrough manic or depressive episodes. Although CBZ was effective in the reduction of affective episodes and the prolongation of euthymic periods, the effect was incomplete for most patients.[24]

Two randomized, controlled trials of CBZ in the treatment of depression have been conducted.[53,54] Similar to Li and VPA, CBZ appears to have a less pronounced effect in the treatment of acute depression than in acute mania.

Post and coworkers[55] found that rapid cycling, mixed mania, and a negative family history of mood disorder were associated with response to CBZ.

CBZ is effective as monotherapy in difficult-to-treat, acutely manic patients (eg, those with documented nonresponse or intolerance to Li). The drug is also useful as adjunctive therapy when used concomitantly with Li, VPA, neuroleptics, and thyroid hormones (Table V).[1,3,36,56,57]

Disadvantages of CBZ include its ability to autoinduce and heteroinduce drug metabolism, which complicates its own routine clinical use. Subtherapeutic blood levels may result from its half-life being cut in half (from 20 to 30 hours to 10 to 15 hours) anywhere between 3 weeks and 6 months into the treatment course. A consequent relapse into cycling may be misinterpreted as a therapeutic failure. Although serum-level monitoring of CBZ is readily available, the relationship between serum level and efficacy has not been firmly established.[1,36,57]

CBZ can be used to manage acute mania in people with a history of Li-resistant rapid cycles, Li failure/intolerance, or kidney dysfunction. It appears to be effective, either alone or in combination with Li, for the acute treatment of mixed states, which may be unresponsive to Li alone. CBZ can be used in the treatment of secondary manic states and in organic affective disorder. Because it lessens aggression, it is also an option for the patient who is suicidal. However, like other tricyclic compounds, its toxicity presents a risk of deliberate overdose. CBZ should be taken with meals, and is available as a suspension, tablet, and chewable tablet.[1,57,58]

The side effects of CBZ can loosely be categorized as dose-related, non-dose-related, and idiosyncratic. Dose-related effects include leukopenia, initial lethargy, double vision, altered cognition, increased liver function tests (LFTs), and hyponatremia. Non-dose-related effects include GI upset, nausea, and fluid retention. Idiosyncratic effects include aplastic anemia, agranulocytosis, hepatic failure, skin reactions, Stevens-Johnson syndrome, and effects on the fetus. CBZ is metabolized in the liver to a stable, active metabolite, which can be toxic when significant levels accumulate.

Untoward hematologic effects of CBZ include dose-related reductions in WBC and platelet counts. The risk of aplastic anemia and agranulocytosis is about 1 in 300,000--lower than that seen when CBZ was first introduced. Benign leukopenia occurs in 15% to 20% of patients treated with CBZ, usually during the first 6 months of therapy. If the WBC falls to 3000/mm3, the dose must be lowered, with weekly monitoring of the CBC. If the count falls below 2500/mm3, the drug must be discontinued temporarily until the count returns to above 3000/mm3.[1,36]

If CBZ and VPA are used together, a number of drug interactions are possible (Table VI). In addition to autoinducing its own metabolism (and thereby decreasing its serum level), CBZ enhances VPA metabolism, decreasing VPA levels. Because VPA displaces protein-bound CBZ, and VPA inhibits the metabolism of 10,11-epoxide CBZ, the CBZ effect will be greater even though its serum levels are not changed. Thus, if CBZ has been therapeutic, the dose should be lowered if VPA is added to the regimen. If CNS side effects occur, this occult enhanced effect should be assumed and the CBZ dose, not the VPA dose, should be lowered. When CBZ is added to VPA, mood stability may deteriorate because VPA levels may fall. Thus, the VPA dose may need to be adjusted upward concurrently with CBZ titration.

CBZ also induces the metabolism of other important drugs, including neuroleptic agents and contraceptives. Other drugs whose levels are lowered by CBZ include doxycycline (leading to decreased antimicrobial efficacy); nondepolarizing muscle relaxants (reduced duration and efficacy); acetaminophen (potentiation of acetaminophen hepatotoxicity and decreased therapeutic effects); cyclosporine; tricyclic antidepressants (TCAs); and benzodiazepine (decreased level). Li and CBZ together may cause neurotoxicity not present with either drug alone.

Treatment options for bipolar disorder have been widened with the availability of divalproex and CBZ, in addition to Li, as therapy. The expansion of therapeutic regimens has been driven by the incomplete or lack of response to Li. Open and controlled studies indicate that divalproex is at least as effective as Li for treating acute mania in patients with bipolar disorder. Li and divalproex are the only FDA-approved drugs for treatment of acute mania. Clinical trials of the use of Li, divalproex, and CBZ for maintenance therapy are less conclusive. Most studies indicate that therapy in patients with bipolar disease is less effective for acute depression than for manic episodes.

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