Panic comorbidity with bipolar disorder: what is the manic–panic connection?

Context:  Bipolar/panic comorbidity has been observed in clinical, community and familial samples. As both are episodic disorders of affect regulation, the common pathophysiological mechanism is likely to involve deficits in amygdala‐mediated, plasticity‐dependent emotional conditioning. Evidence:  Neuronal genesis and synaptic remodeling occur in the amygdala; bipolar and panic disorders have both been associated with abnormality in the amygdala and related structures, as well as in molecules that modulate plasticity, such as serotonin, norepinephrine, brain‐derived neurotrophic factor (BDNF) and corticotrophin releasing factor (CRF). These biological elements are involved in behavioral conditioning to threat and reward. Model:  Panic attacks resemble the normal acute fear response, but are abnormally dissociated from any relevant threat. Abnormal reward‐seeking behavior is central to both manic and depressive syndromes. Appetites can be elevated or depressed; satisfaction of a drive may fail to condition future behavior. These dissociations may be the result of deficits in plasticity‐dependent processes of conditioning within different amygdala subregions. Conclusions:  This speculative model may be a useful framework with which to connect molecular, cellular, anatomic and behavioral processes in panic and bipolar disorders. The primary clinical implication is that behavioral treatment may be critical to restore function in some bipolar patients who respond only partially to medications.