Intersecting evidence of bipolar and panic pathophysiology
Investigations into the causes of both disorders suggest an intriguing possible explanation that may account for similarities in the course of illness (episodicity, latent risk, potential for recovery vs residual impairment) as well as unique symptoms of bipolar and panic disorders. The evidence can be summarized as follows.
- Stress and glucocorticoid regulation. Abnormally high cortisol levels have been associated with bipolar disorder23 and with the enhanced risk for experimentally provoked panic attacks.24 Experimental response to corticotropin-releasing factor has been shown to be reduced in the presence of panic disorder and depression,25 but elevated in individuals with bipolar disorder during the onset of a manic episode.26
- Monoaminergic neurotransmission. Increased noradrenergic activity is thought to presage both panic attacks27 and switches into mania.28 Allelic variants of catechol-O-methyltransferase have been associated with panic disorder29 and rapid- cycling subtypes of bipolar disorder.30 Serotonin transporter (SERT) polymorphism has been associated with bipolar disorder31 and with experimentally induced panic.32
- Amygdala and related structures. Some overlap of anatomical evidence in bipolar and panic disorder can be observed from studies that show structural abnormalities33,34 and functional deficits35,36 in the amygdala and related structures.
The functional system that links these observations together and to the clinical phenomena of bipolar and panic disorder is the amygdala-centered process of emotional conditioning for threat-related37 and reward-related38 cues in the environment. Briefly, the amygdala is thought to be a structure in which the capacity for plasticity (ie, experience-induced alterations of neuronal structure) makes possible the ongoing process of threat and reward detection.39 Adaptive emotional functioning requires that one be able to link the present perception of an object to previous conditioning about the object's emotional salience, to present autonomic signals of emotional arousal, and to autonomic outputs that, in turn, either reinforce or diminish the conditioned association going forward. The emotional salience of an object must also be subject to revision once autonomic conditions change or new contextual information emerges. The characteristic features of panic and mood disorder can be derived from a breakdown in this model.
Emotional conditioning and psychopathology
Bipolar and panic disorders are both episodic disorders in which symptoms may occur suddenly, resolve quickly or over time, signal high risk of recurrence, and leave residual impairment in some cases but not others. Purely structural, developmental, degenerative, and biochemical processes cannot adequately account for these features. Emotional conditioning, or the process by which threats and opportunities in the environment change the structure of the brain, can account for these features (Figure).
Core symptoms that differentiate bipolar disorder from panic disorder can be accounted for by the 2 major kinds of emotional conditioning that occur via the amygdala. Outputs from the amygdala to cortical and subcortical structures, intrinsic to the normal, adaptive fear response, account for all the autonomic symptoms of a panic attack.40 The pathology in panic attacks, it can be argued, is not in the output but in the disconnection of the conditioned response from any real environmental threat. A panic attack thus may be seen as a more or less normal, albeit intense, conditioned fear response that occurs without a relevant stimulus.
By similar reasoning, one can posit that some of the core features in depression—anhedonia, inertia, inattentiveness, diminished drives—occur because of a deficit in the ability to condition the amygdala to appraise objects in the environment as having potential value as rewards. Not only is a person who is depressed unable to experience reward as before but many report that they cannot even imagine anything rewarding. In mania the deficit that accounts for excessive drive, distractibility, and racing thoughts may occur in the mechanism that would normally serve to extinguish the conditioned attention to objects with potential salience as sources of reward.