Discover how to minimize the serious side effects of mood stabilizers.

Long-term tolerability is a key feature of the ideal drug therapy; evidence shows how mood stabilizers meet this standard of care - Foundational treatment - Journal of Family Practice, March, 2003 by Sanjay Gupta

Lifetime maintenance treatment is recommended for patients with bipolar disorder, somewhat akin to managing chronic medical illnesses such as diabetes or hypertension. Because maintenance therapy must be both safe and effective, ideal medications for bipolar disorder should have three characteristics:

1. long-term tolerability
2. patient-friendly administration and monitoring
3. minimal risk of drug-drug interactions.

This article reviews the tolerability of mood stabilizers used in maintenance treatment of bipolar disorder and offers helpful strategies to maximize their safety.

Tolerability

When treating bipolar disorder, psychiatrists often use divalproex or lithium as foundational therapy because of these agents' beneficial effects, which include control of manic symptoms and predictable response based on serum levels. At the same time, however, divalproex and lithium have potentially serious side effects:

• Divalproex has black-box warnings of hepatotoxicity; pancreatitis, and teratogenicity(1)--its use essentially is contraindicated in pregnant women.

• Long term lithium use has been associated with hypothyroidism, possible renal impairment, and cardiac abnormalities on ECG. (1) It also may have teratogenic potential involving the fetal cardiovascular system, although the risk appears much less than with divalproex. (2)

Antipsychotics also are used in treating bipolar disorder, especially to control manic and psychotic symptoms, to augment lithium or divalproex, and when lithium and divalproex are contraindicated, as in pregnancy; Common side effects of typical antipsychotics include parkinsonism, extrapyramidal symptoms (EPS), hyperprolactinemia, and tardive dyskinesia (TD). (3) Atypical antipsychotics are less likely to cause EPS, and most do not cause sustained prolactin elevation. (3)

Tardive dyskinesia Atypical antipsychotics also are associated with a lower risk of TD than typical antipsychotics. TD risk varies among the atypicals; clozapine does not appear to increase TD risk, risperidone (4) and quetiapine show low risk in shun-term studies, (5) and the risk with ziprasidone has not been assessed. No case of TD has been reported in randomized, controlled trials using olanzapine in patients with bipolar disorder.

A recent controlled trial (6) suggests a palliative effect of olanzapine in patients with TD, similar to that seen in open trials using clozapine. (7) When 92 patients with a 5-year history of moderate to severe TD received olanzapine, 5 to 20 mg/d, 70% no longer met diagnostic criteria for TD after 8 months. No significant TD worsening was noted when dosages were reduced by 75% at weeks 14 and 24.

Hyperprolactinemia. Chronic hyperprolactinemia is associated with reduced bone mineral density, menstrual irregularities such as amenorrhea, galactorrhea, and sexual dysfunction, particularly in men. (8) Typical antipsychotics elevate serum prolactin levels two to three times greater than normal. (9) Among the atypical antipsychotics, clozapine and quetiapine do not appear to elevate serum prolactin; olanzapine and ziprasidone produce transient prolactin elevation; and risperidone can cause sustained prolactin elevation. (10)

Hyperglycemia and diabetes

Hyperglycemia. Newcomer et al (11) compared serum glucose levels in 48 patients taking antipsychotics for schizophrenia with those of 31 untreated healthy controls. In this study, which was limited by a small sample size, they found that patients treated with olanzapine, clozapine, or risperidone had elevated fasting and post-load serum glucose levels, compared with healthy controls.

Patients taking risperidone in this study had serum glucose levels similar to those seen in patients receiving typical antipsychotics anti less than those of patients receiving olanzapine or clozapine. A follow-up trial using the euglycemic clamp to assess peripheral glucose use found no statistically significant differences among patients receiving typical antipsychotics, risperidone, or olanzapine. (12) Based on these results, the effects of the various antipsychotics on insulin secretion and peripheral glucose utilization do not appear to differ significantly.

In a placebo-controlled study in normal subjects using the hyperglycemic clamp, Sowell et al found no evidence that risperidone or olanzapine directly impaired insulin secretion. They did find that insulin response to hyperglycemia increased and insulin sensitivity decreased--which were thought to be indirect effects related to increased body mass index in study subjects taking either antipsychotic. (13)

These studies do not indicate that any of the atypical antipsychotics directly cause diabetes, but it may be that associated weight gain is an indirect risk factor for glycemic dysregulation.

Diabetes. In patients with bipolar disorder, the relative risk of diabetes has been reported to be two to three times higher than that of the general population. (14)

Koller et al identified cases of new-onset diabetes associated with clozapine, risperidone, and olanzapine in a review of the FDA's MedWatch data. (15-17) They suggested atypical antipsychotics may unmask or precipitate diabetes in susceptible patients. Although more new-onset diabetes cases were associated with clozapine and olanzapine than with risperidone, these authors cautioned against drawing conclusions in the absence of direct prospective studies.

A large unpublished epidemiologic study by Cavazonni et al suggested that diabetes may be more common in patients receiving antipsychotics than in the general U.S. population (Figure 1). Diabetes incidence was similar among the antipsychotics that were studied. (18)

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