Bipolar disorder (BP) is a chronic, debilitating illness that affects 0.4% to 4% of the US population.1,2 The first nosological efforts describing BP appeared in the early 2nd century ad and culminated in Kraepelin’s eloquent description of its phenomenology in his 1921 textbook on manic-depressive insanity.3 Nevertheless, the course and underlying pathophysiology of BP remain elusive.
The disorder is frequently unrecognized, misdiagnosed, and not optimally managed. Moreover, no agent has been specifically developed on the basis of an understanding of the pathophysiology of the illness or mechanism of action of effective treatments.
The current gold standard treatment for BP is lithium, whose mood-stabilizing effects are believed to occur via distinct cellular signaling pathways/targets, such as glycogen synthase kinase 3 inhibition (considered to regulate cellular apoptosis), and other potential downstream cellular mechanisms. In addition to lithium, valproate, and carbamazepine, several atypical antipsychotics (including asenapine) are FDA-approved for the treatment of acute bipolar mania (Table).
While these drugs have certainly provided relief for many individuals with BP, significant issues with tolerability and efficacy remain. For instance, clinicians may find themselves in situations in which better-tolerated agents are less effective, and vice versa. In addition, balancing efficacy with adverse effects that affect adherence, such as sedation and weight gain, underscore the urgent need to develop novel and more effective treatments.
Recent clinical findings
Findings from a meta-analysis indicate that the following agents were more effective than placebo for mania: aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone).4 Limited data suggest large effect sizes for carbamazepine, cariprazine, haloperidol, risperidone, and tamoxifen.
Another large meta-analysis evaluated the comparative efficacy of aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, quetiapine, risperidone, topiramate, and ziprasidone at therapeutic doses for treatment of acute mania.5 The study concluded that antipsychotic drugs were significantly more effective than mood stabilizers; olanzapine, risperidone, and quetiapine were better tolerated than haloperidol. Risperidone, olanzapine, and haloperidol were particularly efficacious. Most of the trials were short (typically 3 weeks), and therefore caution is needed when extrapolating the results to clinical practice. It is also important to note that because of informed consent and general enrollment issues with manic patients, more severe cases were invariably excluded.
Because strong evidence exists for the use of lithium—and to a somewhat lesser extent, lamotrigine and valproate—as a maintenance treatment for BP, antipsychotics may be increasingly used to treat the acute manic phase of the disorder and mood stabilizers (particularly lithium) may be used for long-term treatment. Nivoli and colleagues6 reviewed the major guidelines for the treatment of manic/hypomanic and mixed episodes and found that all guidelines agreed that concurrent antidepressants should be stopped during a manic/mixed episode.
1. Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication [published correction appears in Arch Gen Psychiatry. 2005;62:709]. Arch Gen Psychiatry. 2005;62:
2. Merikangas KR, Jin R, He JP, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry. 2011;68:241-251.
3. Mondimore FM. Kraepelin and manic-depressive insanity: an historical perspective. Int Rev Psychiatry. 2005;17:49-52.
4. Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology. 2011;36:375-389.
5. Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378:1306-1315.
6. Nivoli AM, Murru A, Goikolea JM, et al. New treatment guidelines for acute bipolar mania: a critical review. J Affect Disord. 2012;140:125-141.
7. Ekins S, Williams AJ. Finding promiscuous old drugs for new uses. Pharm Res. 2011;28:1785-1791.
8. DiazGranados N, Zarate CA Jr. A review of the preclinical and clinical evidence for protein kinase C as a target for drug development for bipolar disorder. Curr Psychiatry Rep. 2008;10:510-519.
9. Baum AE, Akula N, Cabanero M, et al. A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry. 2008;13:197-207.
10. Amrollahi Z, Rezaei F, Salehi B, et al. Double-blind, randomized, placebo-controlled 6-week study on the efficacy and safety of the tamoxifen adjunctive to lithium in acute bipolar mania. J Affect Disord. 2011;129:327-331.
11. Gao Y, Payne RS, Schurr A, et al. Memantine reduces mania-like symptoms in animal models. Psychiatry Res. 2011;188:366-371.
12. Keck PE Jr, Hsu HA, Papadakis K, Russo J Jr. Memantine efficacy and safety in patients with acute mania associated with bipolar I disorder: a pilot evaluation. Clin Neuropharmacol. 2009;32:199-204.
13. Anand A, Gunn AD, Barkay G, et al. Early antidepressant effect of memantine during augmentation of lamotrigine inadequate response in bipolar depression: a double-blind, randomized, placebo-controlled trial. Bipolar Disord. 2012;14:64-70.
14. Radatz M, Ehlers K, Yagen B, et al. Valnoctamide, valpromide and valnoctic acid are much less teratogenic in mice than valproic acid. Epilepsy Res. 1998;30:41-48.
15. Bersudsky Y, Applebaum J, Gaiduk Y, et al. Valnoctamide as a valproate substitute with low teratogenic potential in mania: a double-blind, controlled, add-on clinical trial. Bipolar Disord. 2010;12:376-382.
16. Maremmani I, Perugi G, Pacini M, Akiskal HS. Toward a unitary perspective on the bipolar spectrum and substance abuse: opiate addiction as a paradigm. J Affect Disord. 2006;93:1-12.
17. Carlezon WA Jr, Béguin C, DiNieri JA, et al. Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats. J Pharmacol Exp Ther. 2006;316:440-447.
18. Corbett AD, Henderson G, McKnight AT, Paterson SJ. 75 years of opioid research: the exciting but vain quest for the Holy Grail. Br J Pharmacol. 2006;147(suppl 1):S153-S162.
19. Cohen BM, Murphy B. The effects of pentazocine, a kappa agonist, in patients with mania. Int J Neuropsychopharmacol. 2008;11:243-247.
20. ClinicalTrials.gov. Effects of pentazocine versus lorazepam or placebo on manic symptoms. http://clinicaltrials.gov/ct2/show/NCT00431184?term=pentazocine&rank=1). Accessed October 30, 2012.
21. Machado-Vieira R, Lara DR, Souza DO, Kapczinski F. Purinergic dysfunction in mania: an integrative model. Med Hypotheses. 2002;58:297-304.
22. Akhondzadeh S, Milajerdi MR, Amini H, Tehrani-Doost M. Allopurinol as an adjunct to lithium and haloperidol for treatment of patients with acute mania: a double-blind, randomized, placebo-controlled trial. Bipolar Disord. 2006;8(5, pt 1):485-489.
23. Machado-Vieira R, Lara DR, Souza DO, Kapczinski F. Therapeutic efficacy of allopurinol in mania associated with hyperuricemia. J Clin Psychopharmacol. 2001;21:621-622.
24. Machado-Vieira R, Soares JC, Lara DR, et al. A double-blind, randomized, placebo-controlled 4-week study on the efficacy and safety of the purinergic agents allopurinol and dipyridamole adjunctive to lithium in acute bipolar mania. J Clin Psychiatry. 2008;69:1237-1245.
25. ClinicalTrials.gov. Allopurinol maintenance study for bipolar disorder. http://clinicaltrials.gov/ct2/show/NCT00732251. Accessed October 30, 2012.
26. Schlecker C, Boehmerle W, Jeromin A, et al. Neuronal calcium sensor-1 enhancement of InsP3 receptor activity is inhibited by therapeutic levels of lithium. J Clin Invest. 2006;116:1668-1674.
27. Ferreira MA, O’Donovan MC, Meng YA, et al; Wellcome Trust Case Control Consortium. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet. 2008;40:1056-1058.
28. Sklar P, Smoller JW, Fan J, et al. Whole-genome association study of bipolar disorder. Mol Psychiatry. 2008;13:558-569.
29. Levy NA, Janicak PG. Calcium channel antagonists for the treatment of bipolar disorder. Bipolar Disord. 2000;2:108-119.
30. Berk M, Copolov DL, Dean O, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008;64:468-475.
31. Berk M, Dean O, Cotton SM, et al. The efficacy of N-acetylcysteine as an adjunctive treatment in bipolar depression: an open label trial. J Affect Disord. 2011;135:389-394.
32. Brower V. Nutraceuticals: poised for a healthy slice of the healthcare market? Nat Biotechnol. 1998;16:728-731.
33. Sarris J, Mischoulon D, Schweitzer I. Adjunctive nutraceuticals with standard pharmacotherapies in bipolar disorder: a systematic review of clinical trials. Bipolar Disord. 2011;13:454-465.