Dr. Shah is a PGY-2 Psychiatry Resident, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, Kentucky. Dr. Elsayed is a Post-doctoral Research Fellow, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, Kentucky. Dr. El-Mallakh is Professor and Director, Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, Kentucky.
Disclosures Dr. Shah and Dr. Elsayed report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products. Dr. El-Mallakh is a speaker for Axsome, Intra-Cellular Therapies, Janssen, Lundbeck, Myriad, Noven, Otsuka, and Teva, and has received research grants/funding from Sunovion.
Carbamazepine is an anticonvulsant FDA-approved for treating BD.7 Like valproate, it acts by inhibiting voltage-gated sodium channels in an activity-dependent manner,72 which means it preferentially inhibits the most active neurons and those with higher intracellular sodium.43
Benzodiazepines, which have shown to be effective for treating acute mania,73 potentiate synaptic GABA receptors accruing an elevation in intracellular chloride influx.74 Despite acute efficacy, benzodiazepine use is limited because these agents are associated with worsening long-term, substance use–related outcomes.75,76
Antipsychotics are effective for treating mood disorders,60,76 and their use has been rising dramatically.12 The antimanic effect of all antipsychotics is believed to be mediated through dopamine D2 blockade, since use of a dose sufficient to block D2 receptors is required, and haloperidol, which acts exclusively on the D2 receptor, is equal to SGAs in its antimanic effect.77 Blockade of the D2 receptor will increase the activity of the sodium pump (sodium and potassium-activated adenosine triphosphatase) thus reducing intracellular sodium and calcium concentrations.37 When antipsychotics are used as antidepressants, they are generally used at doses lower than those used to treat mania.78
Antipsychotics are effective for treating BD, and may work more quickly than other agents for treating acute mania.79 However, maintenance or prevention trials tend to favor mood stabilizers.35,60,80 Several add-on studies have found the combination of a mood stabilizer plus an antipsychotic is superior to a mood stabilizer alone or an antipsychotic alone.81
An argument for mood stabilizers
Evidence suggests mood stabilizers and other approaches, such as antipsychotics, are almost equivalent for treating acute mania, with a small clinical advantage of mood stabilizers for preventing relapse. In general, current treatment guidelines do not distinguish mood stabilizers from antipsychotics as the first-line treatment.82 Over the past 20 years, antipsychotic use has increased while mood stabilizer use has decreased, so that presently a patient with BD is more likely to be prescribed an antipsychotic than a mood stabilizer.12 Over the same time, dysfunction among patients with BD has increased.33 Antipsychotics are appealing because they appear to be equally effective and generally well tolerated. But these agents cause problems that are difficult to see in routine visits, such as metabolic27-31 and cardiovascular adverse effects29 as well as reductions in brain volume.23-26 Mechanistic research suggests that mood stabilizers directly correct known pathophysiologic anomalies with additional protective effects, whereas antipsychotics appear to create new abnormalities and contribute to medical problems. Clinicians need to look beyond the similarities in acute efficacy and make a more broadly supported, evidence-based choice for managing BD, which clearly places mood stabilizers as the first-line agent and antipsychotics as reasonable alternatives. At a minimum, mood stabilizers should be viewed as the foundation to which antipsychotics can be added.
Bottom Line
Traditional mood stabilizers—lithium and some anticonvulsants—are the only agents that directly address physiologic abnormalities associated with both mania and bipolar depression, including mood state–associated elevations of intracellular sodium. Because of their specificity, these agents maximize mood stabilization and minimize adverse effects.
