Comorbidity of Bipolar and Panic Disorders and Its Consequences

Panic disorder occurs in about 1 in 5 individuals who have bipolar disorder. Anxiety amplifies the distress caused by depression and mania, but pharmacological approaches are tricky and under-studied. Frequent comorbidity and evidence of a possible genetic relationship of bipolar and panic disorders are suggestive of a causal relationship between the 2. Thus, it may be fruitful to look more closely at evidence for common biological abnormalities in both disorders to find a pathophysiological mechanism that links mania, depression, and panic attacks. Mood episodes and panic attacks can both be modeled as the result of deficits in amygdala-mediated emotional conditioning.¹ From this model, some insight may be gained for potentially helpful treatment strategies for the 2 disorders when they occur together.

Evidence for comorbidity
In nearly every study, substantial numbers of individuals who meet criteria for bipolar disorder-between 15% and 20%, or 10 to 20 times the rate in the general population-also meet criteria for panic disorder.^2-5 Others have found more modest elevations in the rate of panic disorder in persons with bipolar disorder.⁶ A relationship between bipolar and panic disorders has also been recorded when looking from the opposite direction. Anxiety disorder specialists have long noticed high rates of bipolar spectrum disorders in their patients who have panic disorder.⁷

Clinical presentation and consequences of comorbidity
Symptoms of panic disorder have been associated with greater suicidality in patients who have bipolar disorder.^8-10 Panic disorder has predicted a slower treatment response in bipolar disorder,^9,11 as well as greater likelihood of substance dependence and other anxiety disorders.⁴ Panic disorder is associated with more unstable forms of bipolar illness-namely, mixed, rapid-cycling, or rapid-switching states.^12,13 Findings from a study of intraepisodic panic attacks in hospitalized patients with bipolar disorder suggest that panic attacks are extremely common-affecting as many as 60% of patients-in bipolar, depressed, and mixed states but are relatively uncommon in patients with pure mania.¹⁴

Early-age-at-onset samples tend to have more panic comorbidity than average,¹⁵ although elevated bipolar and panic comorbidity is documented throughout the life cycle, including in geriatric populations.¹⁶ There is less information on other clinical patterns of comorbidity. The question remains whether panic attacks in individuals with bipolar disorder are identical in form to panic attacks in others. It is also unknown whether panic attacks take a different form when they occur in the context of active mood symptoms or when they occur between mood episodes.

Family/genetic aspects of bipolar and panic comorbidity
The rate of panic comorbidity in family samples with bipolar disorder resembles the rate in population studies.^17-18 In these studies, risk for panic disorder is elevated only in family members with a mood disorder. The results from analyses of 2 genetic databases reveal a specific familial risk for panic in some individuals with bipolar disorder.^17,19

Molecular evidence of a common genetic risk factor for bipolar and panic disorders remains sparse. A stratified reanalysis of bipolar linkage data from 28 families, which had supported a genetic locus for bipolar disorder on the long arm of chromosome 18,²⁰ revealed that the evidence for the link was carried almost exclusively by the families that had an elevated risk for panic disorder.²¹ This result remains in doubt, however, since it has not been replicated in other studies. A later study of 3 genes of possible functional relevance to bipolar disorder revealed that panic comorbidity enhanced the evidence of association for individuals with bipolar disorder but without panic disorder.²² This finding also awaits positive replication.

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 abnormalities^33,34 and functional deficits^35,36 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.

Evidence for the model
Glucocorticoids and related neurohormones, as well as monoaminergic neurotransmitters, have both direct and indirect effects on neuronal plasticity-some positive, some negative. For example, cortisol is known to inhibit the growth of new neurons in the hippocampus in humans⁴¹ and, based on animal studies,⁴² presumably in the amygdala as well. High cortisol tone, whether a primary deficit, a secondary result of the stress response, or externally induced by prednisone, may thus result in deficient cellular substrate in the amygdala (and possibly in the hippocampus) with which to form and revise conditioned responses. Factors that diminish available serotonin (such as low-functioning alleles of SERT) also diminish the salutary effects of brain-derived neurotrophic factor,⁴³ again impinging on plasticity and emotional conditioning.

Treatment of panic disorder and bipolar disorder
In clinical settings, mania and depression are generally more pressing clinical problems than panic and thus more likely to receive therapeutic attention⁴⁴; however, patients suffer severely from panic attacks. Treatment of panic disorder using conventional methods is perilous in the context of bipolar disorder. In patients with bipolar disorder, it appears that antidepressants commonly used to prevent panic attacks may exacerbate cycling.⁴⁵ On the other hand, drugs used to relieve anxiety when panic occurs (eg, benzodiazepines) may become abused or foster dependency in a population of patients whose mood disorder puts them at high risk for chemical dependency.⁴⁶ Although there is a role for these treatments, they must be used with caution. One possible solution would be using medications proved effective for both disorders independently. However, the only antimanic agent with reported efficacy in controlling panic is divalproex.⁴⁷

Since there are no placebo-controlled trials of treatment for panic attacks with bipolar disorder,⁴⁸ it is prudent to make mood stabilization the first priority. There is reason to hope that one can address both problems with 1 treatment. If the root of both problems is a deficit in emotional conditioning, as described in the model, the same neurotrophic factors most useful in treating bipolar disorder, such as lithium,⁴⁹ may have benefit in treating panic disorder in the context of bipolar disorder. At least one study has found that anxiety comorbidity increases the likelihood of bipolar response to lithium relative to anticonvulsants,⁵⁰ while in another, panic comorbidity was a robust predictor of bipolar response to lamotrigine.⁵¹

When patients who are acutely manic or depressed demand treatment for ongoing panic attacks, it is reasonable to offer lithium or other antimanic agents supplemented by benzodiazepines as needed to suppress attacks when they emerge. Because of the risk of habituation, it is prudent to replace benzodiazepines with definitive treatment of panic attacks if they persist after the mood is stabilized.

Thinking beyond pharmacology, if one is open to the idea that the distress from panic and bipolar disorders is often caused as much by their residual, conditioned effects as by their acute symptoms, then one will keep in focus the goal of improving a patient's global functioning through rehabilitative, or reconditioning, therapies while optimizing the pharmacological regimen.

References:

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