Emerging experimental therapeutics for bipolar disorder: clues from the molecular pathophysiology

Abstract

Bipolar affective disorder (manic-depressive illness) is a common, severe, chronic, and often life-threatening illness, associated with significant comorbidity. The recognition of the significant morbidity and mortality of patients with bipolar disorder, as well as the growing appreciation that a high percentage of patients respond poorly to existing treatments, has made the task of discovering new therapeutic agents, that are both efficacious and have few side effects increasingly more important. Most recent agents introduced into the pharmacopeia for the treatment of bipolar disorder have been anticonvulsants and atypical antipsychotics. We propose that novel treatments developed specifically for bipolar disorder will arise from (1) understanding more precisely the molecular mechanisms of treatments that are clearly efficacious or (2) developing medications based on the knowledge obtained of the underlying pathophysiology of bipolar disorder. Knowledge with regard to the underlying pathophysiology of bipolar disorder is increasing at a rapid pace, including alterations in intracellular signaling cascades as well as impairments of cellular plasticity and resilience in critical neuronal circuits. We propose that therapeutics designed to enhance cellular plasticity and resilience and that counter maladaptive stress-responsive systems may have considerable utility for the treatment of bipolar disorder. Therapeutic strategies designed to address cellular resilience and plasticity include the regulation of neurotrophic pathways, glucocorticoid signaling, phosphodiesterase activity, and glutamatergic throughput and mitochondrial function. While the task of developing novel medications for bipolar disorder is truly daunting, these and similar approaches will ultimately lead to better medications for the millions who suffer from this devastating illness.

Neural circuitry and neuroplasticity in mood disorders: Insights for novel therapeutic targets

“…Converging lines of evidence indicate that impairments of cellular plasticity and resilience may underlie the pathophysiology of mood disorders. 11,[133][134][135][136] Here, we propose that disturbances in neural plasticity and cellular resilience are critical factors in precipitating and perpetuating disruption of the affective circuits discussed above ( see FIG. 2).…”

Glycogen Synthase Kinase-3: a Putative Molecular Target for Lithium Mimetic Drugs

“…Furthermore, in a recent placebocontrolled clinical study, adjunctive treatment with Zinc had antidepressant effects (Nowak et al, 2003a). These data suggest the possibility that zinc may exert these effects through inhibition of GSK-3; however, zinc has other biological effects, including antagonism of NMDA receptors (see Quiroz et al (2004) for a review), that require consideration.…”

Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?

“…Because of the complexity of bipolar disorder and lack of an accepted animal model, researchers model therapeutic mood-stabilizing drug regimens in rodents to elucidate the causes and pathophysiology of bipolar disorder. 11 Because of the relatively long time to onset of action, it is commonly thought that effects observed after chronic mood stabilizer administration may be more relevant to their therapeutic effect. However, despite there being a number of Food and Drug Administration-approved drugs for treating the disease, the mechanisms of action of these agents are not agreed upon.…”