Recent drug developments in BP
Improved pharmacological strategies with pronounced and sustained effects would have an enormous impact on public health, particularly given the high mortality associated with BP. A variety of compounds are now being tested that offer mechanistically different approaches for the treatment of BP. Some of the drugs we will discuss target particular pathways specific to lithium, while others focus on more novel targets, such as N-methyl-D-aspartate (NMDA) and opiate receptors. Evidence also suggests that older agents used to treat other diseases can be “re-purposed” if they show promise in reducing manic activity.7 While the focus of these compounds is on the treatment of mania, some may also be beneficial during the depressed phase of the illness.
Tamoxifen. Tamoxifen is a protein kinase C (PKC) inhibitor and antiestrogenic drug that crosses the blood-brain barrier and is relatively well tolerated (up to 200 mg/d). Lithium is thought to regulate the PKC signaling cascade, and findings suggest that PKC activation enhances the release of dopamine, a neurotransmitter implicated in mania.8 A recent genome-wide association study also implicated diacylglycerol kinase eta (DGKH) in the pathogensis of BP; DGKH is a key protein in the lithium-sensitive phosphatidylinositol pathway and a precursor to PKC.9
A number of studies evaluated the effects of adjunctive tamoxifen treatment for mania, with encouraging results. The most recent of these was a double-blind, randomized, placebo-controlled, 6-week study (N = 40) that evaluated the efficacy and safety of tamoxifen with adjunctive lithium in the treatment of acute bipolar mania.10 Combined tamoxifen/lithium therapy was superior to lithium alone for rapidly reducing manic symptoms; results were apparent as early as day 7. In that study, all psychotropic medications except benzodiazepines were discontinued at least 48 hours before randomization.
Lorazepam (1 to 2 mg/d) was stopped after the initial 10 days and was not dispensed within 8 hours of the administration of the mania rating scale. The starting dosage of tamoxifen was 20 mg twice daily (40 mg/d). Daily doses were subsequently increased by 10 mg to achieve 80 mg/d in twice-daily divided doses. This dosage of tamoxifen was well tolerated, and no clinically significant adverse effects except fatigue were observed. Despite these clinically encouraging results, long-term safety data are limited, and tamoxifen is associated with increased risk of endometrial carcinoma and uterine sarcoma.
Memantine. This selective NMDA glutamate receptor antagonist is approved for the treatment of moderate to severe Alzheimer disease. Preclinical studies found that memantine was associated with antimanic-like properties, such as decreased locomotor hyperactivity.11
In an open-label, multisite, pilot study (N = 33), 20 to 50 mg/d of memantine as monotherapy was well tolerated, and patients with acute mania responded by day 21.12 The study evaluated 3 cohorts who received either 20 to 30 mg/d, 30 to 40 mg/d, or 40 to 50 mg/d, with an allowed increase or decrease of 10 mg/d based on tolerability and response. The greatest response occurred in the group that received 20 to 30 mg/d. The most frequently reported adverse effects were nausea, headache, and constipation.
Unfortunately, no randomized placebo-controlled trials to date have demonstrated the antimanic efficacy of memantine in either manic or mixed-state patients. However, it is interesting to note that a recent 8-week, double-blind, randomized, placebo-controlled, proof-of-concept trial found that memantine augmentation (20 mg/d) of lamotrigine conferred no statistically significant benefit to patients with bipolar depression. Nevertheless, post hoc results suggest that depressive symptoms did improve in these patients during initial titration (5 mg/wk) and for the first 4 weeks but that no sustained effects were evident at 8 weeks.13