Pharmacotherapy of Acute Bipolar Depression in Adults: An Evidence Based Approach

Abstract

In the majority of cases of bipolar disorder, manic episodes are usually brief and typically responsive to currently available psychopharmacological agents. In contrast, depressive manifestations are more prevalent and persistent, and can present as major depressive/mixed episodes or residual interepisode symptoms. The depressive phase is often associated with other neuropsychiatric conditions, such as anxiety spectrum disorders, substance use disorders, stressor-related disorders, and eating disorders. It is viewed as a systemic disease with associated ailments such as metabolic syndrome, diabetes mellitus, and cardiovascular disease. There is an increased rate of mortality not only from suicide, but also from concomitant physical illness. This scenario is made worse by the fact that depressive symptoms, which represent the main disease burden, are often refractory to existing psychotropic drugs. As such, there is a pressing need for novel agents that are efficacious in acute depressive exacerbations, and also have applicable value in preventing recurrent episodes. The rationale of the present review is to delineate the pharmacotherapy of the depressive phase of bipolar disorder with medications for which there is evidence in the form of observational, open-label, or double-blind randomized controlled studies. In the treatment of acute bipolar depression in adults, a comprehensive appraisal of the extant literature reveals that among mood stabilizers, the most robust proof of efficacy exists for divalproex sodium; while atypical antipsychotics, which include olanzapine, quetiapine, lurasidone, and cariprazine, are also effective, as demonstrated in controlled trials.

Keywords: Anticonvulsants; Atypical Antipsychotics; Bipolar Depression; Drug Therapy; Mood Stabilizers.

Figure 1. In bipolar disorder, affective symptoms act in a vicious cycle causing exacerbation of the illness, leading to adverse biopsychosocial sequelae.

Figure 2. Bipolar depression is difficult to treat with refractoriness to conventional mood stabilizers like lithium.

Figure 3. The distributed action of lithium ions and anticonvulsants in the regulation of mood. Anticonvulsant mood stabilizers have a pharmacodynamic advantage over lithium in normalizing abnormal manifestations of mood in bipolar disorder. Much like lithium, these inhibit the enzyme GSK-3β, but additionally act through fibroblast growth factors, histone deacetylation, and astrocyte attached proteins to stabilize mood. VPA, valproic acid; CBZ, carbamazepine; GPT, gabapentin; LTG, lamotrigine; TPM, topiramate; Li, lithium; GSK-3β, glycogen synthase kinase-3 beta; FBF-1B, fibroblast growth factor-1B.

Figure 4. Purported mechanism of biased signaling by novel antipsychotics. Biased ligands are presumed to act in a functionally discriminating manner at G-protein coupled receptors, e.g., D2-type dopamine receptors. One method of functional selectivity may be the favored binding to diverse conformations of the receptor, activating different downstream pathways according to the local milieu and the neuronal sub-types in which these are expressed. Postsynaptic scaffolding proteins, adaptors and effectors may be affected differentially by each receptor conformationrelated cascade differentially stimulated by the ligand. cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; Akt, protein kinase B; GSK-3, glycogen synthase kinase-3; MAPK, mitogen activated protein kinase.