Review
The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology, and treatment issues

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Abstract

Background: Although symptoms of anxiety as well as anxiety disorders commonly occur in patients with bipolar disorder, the pathophysiologic, theoretical, and clinical significance of their co-occurrence has not been well studied. Methods: The epidemiological and clinical studies that have assessed the overlap of bipolar and anxiety disorders are reviewed, with focus on panic disorder and obsessive–compulsive disorder (OCD), and to a lesser extent, social phobia and post-traumatic stress disorder. Potential neural mechanism and treatment response data are also reviewed. Results: A growing number of epidemiological studies have found that bipolar disorder significantly co-occurs with anxiety disorders at rates that are higher than those in the general population. Clinical studies have also demonstrated high comorbidity between bipolar disorder and panic disorder, OCD, social phobia, and post-traumatic stress disorder. Psychobiological mechanisms that may account for these high comorbidity rates likely involve a complicated interplay among various neurotransmitter systems, particularly norepinephrine, dopamine, gamma-aminobutyric acid (GABA), and serotonin. The second-messenger system constituent, inositol, may also be involved. Little controlled data are available regarding the treatment of bipolar disorder complicated by an anxiety disorder. However, adequate mood stabilization should be achieved before antidepressants are used to treat residual anxiety symptoms so as to minimize antidepressant-induced mania or cycling. Moreover, preliminary data suggesting that certain antimanic agents may have anxiolytic properties (e.g. valproate and possibly antipsychotics), and that some anxiolytics may not induce mania (e.g. gabapentin and benzodiazepines other than alprazolam) indicate that these agents may be particularly useful for anxious bipolar patients. Conclusions: Comorbid anxiety symptoms and disorders must be considered when diagnosing and treating patients with bipolar disorder. Conversely, patients presenting with anxiety disorders must be assessed for comorbid mood disorders, including bipolar disorder. Pathophysiological, theoretical, and clinical implications of the overlap of bipolar and anxiety disorders are discussed.

Introduction

Symptoms of anxiety as well as sub-syndromal anxiety disorders often occur in patients with bipolar disorder. Indeed, Kraepelin (1921) was among the first to include anxiety as a symptom of mania. In categorizing mixed states of manic-depressive insanity, he described ‘depressive or anxious mania’ as ‘a morbid state…composed of flight of ideas, excitement, and anxiety…mood is anxiously despairing.’ He also described ‘excited depression,’ in which there was ‘great restlessness…mood is anxious, despondent, lachrymose, irritable, occasionally mixed with a certain self-irony.’ More recently, epidemiologic and clinical studies indicate that anxiety disorders are often comorbid with bipolar disorder. However, the importance of co-occurring anxiety symptoms and disorders as diagnostic and treatment issues in bipolar disorder has not received adequate study.

In this paper, we review epidemiological and clinical studies that have assessed the overlap of bipolar and anxiety disorders, with focus, on panic disorder and obsessive compulsive disorder, and to a lesser extent, social phobia and post-traumatic stress disorder. We address potential neural mechanisms to account for this co-occurrence, review relevant treatment response literature, and then discuss theoretical implications of a bipolar–anxiety disorder link. We conclude by presenting preliminary treatment guidelines for bipolar patients with various comorbid anxiety disorders.

Section snippets

Anxiety as a symptom of bipolar disorder

Although it is well established that symptoms of anxiety commonly occur in unipolar depression, the prevalence and clinical significance of anxiety symptoms in mania and bipolar depression have not been well studied (Strakowski et al., 1994, Young et al., 1993). However, when they have been specifically assessed, anxiety symptoms have been found to occur relatively frequently in both the manic and depressive phases of bipolar disorder. For example, in a recent study of 316 inpatients with

Psychobiological issues in the overlap of bipolar disorder and anxiety disorders

The psychobiology regarding the comorbidity of bipolar and anxiety disorders has not been well delineated. Most likely, a complicated interplay among various neurotransmitter systems and neuromodulator contributes to their overlap. However, the norepinephrine, dopamine, gamma-aminobutyric acid (GABA), and serotonin systems are presumably involved. Inositol, a simple isomer of glucose important in second messenger synthesis, might also play a role.

Discussion

It is imperative for clinicians to be aware of the striking comorbidity that exists between bipolar and anxiety disorders. Indeed, genetic data is now emerging to support already extensive epidemiological and clinical data suggesting that bipolar disorder and some anxiety disorders may be associated conditions. Biological mechanisms that may explain such associations are not well understood, but systems involving GABA, serotonin, norepinephrine, dopamine, and inositol may be involved. Treatment

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