Valnoctamide. Valproic acid is widely used to treat BP; however, its teratogenicity limits its use in women of childbearing potential. Valnoctamide is an analogue of valproic acid, but it does not undergo biotransformation to the corresponding free acid. It also lacks key structural groups (eg, free carboxylic groups) implicated in valproic acid’s teratogenicity. In preclinical studies, valnoctamide was markedly less teratogenic than valproic acid, with no significant changes regarding embryolethality.14 The drug has anticonvulsant properties similar to those of valproate and has been marketed as an anxiolytic and sedative in several European countries.
A recent double-blind, 5-week, add-on (with risperidone up to 6 mg/d), controlled trial (N = 32) of valnoctamide was conducted to measure its efficacy in treating mania.15 Patients were given valnoctamide 600 mg/d, increased to 1200 mg/d after 4 days, or placebo. Valnoctamide was significantly more effective than placebo across all efficacy measures beginning at week 3 through week 5. Adverse events included abnormal liver function test results (less than 3 times normal) in 1 patient; the test results normalized after the patient was switched back to valproate.
No other clinical trials with valnoctamide have been conducted to date, nor are any such trials currently pending. Nevertheless, valnoctamide may be a promising alternative to valproate for treating mania in women of childbearing age. Additional surveillance data in humans are required to make definitive claims regarding this agent.
Pentazocine. Opiates that primarily target μ-opiate receptors have been given in the past to patients with BP16; however, specific κ-opiate receptor (KOR) agonists have not been tested in patients with mania. In animal studies, direct activation of KORs caused depressogenic or dysphoric effects, while blockade of the same receptors produced antidepressant-like effects.17,18 Although no specific KOR agonist is currently approved for human use, the analgesic agent pentazocine functions as a partial KOR agonist, with weaker affinity for μ- and σ-opiate receptors.
In a recent proof-of-concept, open-label, add-on, 3-day, acute-dose study, 10 inpatients with BP-I who were hospitalized for mania received two 50-mg doses of pentazocine 2 hours apart.19 Manic symptoms were reduced 1 hour after each dose (44% after the first dose, and 41% after the second dose). Participants initially received standard treatment for BP. Efficacy measures used in the 3-day trial included the Young Mania Rating Scale (YMRS) and the Mania Acute Change Scale7—scored at hourly intervals for 6 hours.
No psychotomimetic, dysphoric, or adverse events occurred. Patients’ vital signs were stable throughout the study, and light-headedness and sedation were noted to be minimal. Limitations included the design and small number of patients in the study and questions as to whether the effects of this agent were sustained or transient. Nevertheless, these promising initial results may provide the impetus to conduct larger trials. An ongoing study is currently evaluating the effects of pentazocine versus those of lorazepam or placebo on manic symptoms.20
Allopurinol. Kraepelin was the first to associate manic symptoms with hyperuricemia, uric acid excretion, and gout. (Machado-Vieira and colleagues21 provide a thorough review of purinergic dysfunction in mania.) Allopurinol is a xanthine oxidase inhibitor approved for the treatment of gout. Results from initial add-on studies with allopurinol in refractory mania were positive; however, sample sizes were small and allopurinol was used in conjunction with a variety of medications, including antipsychotics.22,23
A recent 4-week, randomized, placebo-controlled, double-blind study (N = 180) evaluated the efficacy of allopurinol (600 mg/d) or dipyridamole (a nucleoside inhibitor; 200 mg/d) in combination with lithium.24 A linear model analysis found that allopurinol resulted in greater mean reductions in YMRS scores from baseline to day 21 (P < .001) and day 28 (P = .003) compared with placebo. Remission rates were also more favorable for persons who received allopurinol than for those who received dipyridamole or placebo (P = .008). Furthermore, decreased plasma uric acid levels were significantly positively associated with antimanic effects in the allopurinol group. Overall, allopurinol was well tolerated; the most common adverse effects were dizziness and diarrhea. An ongoing clinical trial is evaluating allopurinol as a maintenance strategy for mania in BP.25