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Treatment-Resistant Anxiety Disorders: Neurotrophic Perspectives

(PSYCHIATRIC TIMES) - Anxiety disorders are the most prevalent psychiatric disorders in the United States. Although effective treatments are available, such as the SSRIs and cognitive-behavioral therapy (CBT), it is estimated that in about 40% of patients, anxiety disorders are partially or completely resistant to first-line treatment.1 The underlying causes of such high rates of treatment resistance are unclear, but these patients are likely to pose a major challenge for psychiatrists, since most first-line treatments are administered by nonpsychiatric physicians, whereas refractory anxiety disorders are the domain of psychiatrists.

A large overlap between major depression and anxiety disorders has been noted, both in terms of phenomenology and treatment response.2 Thus, tricyclic antidepressants and monoamine oxidase inhibitors are each effective in generalized anxiety disorder (GAD) and panic disorder. SSRIs are effective antidepressants that have also been found to be efficacious in GAD, panic disorder, social anxiety disorder, and obsessive-compulsive disorder.3

It is important to recognize which forms of depressive disorders are resistant to antidepressants. Some examples include bipolar depression4 and childhood depression.5 Anxiety disorders, when comorbid with mood disorders, are as likely to be comorbid with bipolar disorder as with unipolar disorders.6 It has been hypothesized that childhood depression and anxiety may represent a variant in presentation of an underlying bipolar disorder.7 Therefore, a precedent is suggested whereby anxiety disorders may mimic certain variants of mood disorders and become treatment resistant.

A recent neurobiologic substrate has been identified for treatment resistance in anxiety disorders. Findings from a study by Stein and colleagues8 suggest that patients with generalized social anxiety disorder (GSAD) who had the "short"arm of the serotonin transporter gene were significantly less likely to respond (40% nonresponders) to maximally titrated SSRIs than patients with the "long"arm of this gene. Similar genetic variants relating to SSRI treatment resistance have been noted for panic disorder.9 It is not clear what the functional consequences of possession of the short versus long arm of the serotonin transporter imply; however, we posit that treatment-resistant anxiety disorders result from both an excess and a deficit of synaptic serotonin.
Management of treatment-resistant anxiety disorders associated with unipolar and bipolar disorders

Only 1 in 5 physicians diagnosed bipolar disorder correctly using the Mood Disorder Questionnaire.10 The remaining 80% of psychiatrists incorrectly diagnosed anxiety disorder, mood disorders, and personality disorder. We would argue that an anxiety disorder, when comorbid with bipolar mood disorder, should not be subsumed under the bipolar diagnosis, but rather the term "bipolar anxiety disorders"may encompass both the mood and anxiety disorder components simultaneously. Anxiety disorders were highly prevalent in bipolar subjects compared with controls (49 [61%] vs 7 [14%]).11

Bipolar I disorder is usually readily recognized, whereas bipolar II disorder comorbid with anxiety disorders can represent a clinical challenge for even the experienced psychiatrist.12 The patient with a treatment-resistant anxiety disorder is only likely to fully respond to treatment when pharmacotherapy that is also effective for bipolar disorder is instituted. Perhaps the most difficult challenge is the diagnosis of subtle forms of bipolar spectrum disorder, in which hypomania may present as maladaptive versus adaptive.13 Red flags include racing thoughts, irritability, late-night multitasking, and insomnia. Psychosomatic conditions, including fibromyalgia and migraine headache, appear to be associated with bipolar anxiety.

Posttraumatic stress disorder (PTSD). An examination of mood response to occupational and recreational activities in the patient who has treatment-resistant anxiety disorder is warranted. We cite the example of 3 firefighters who survived ground zero on September 11, 2001. Exposure to extreme trauma led to PTSD in each firefighter. Treatment with SSRIs, adjunctive benzodiazepines, and skilled ad- ministration of CBT failed to achieve a treatment response.

Only after several months of treatment resistance did we specifically inquire, and integrate into our treatment plan, the occurrence of manic symptoms. None of the 3 firefighters had had any prior history of bipolar disorder. One firefighter reported a frank manic episode for 2 weeks after 9/11, followed by the full syndrome of PTSD. All 3 patients endorsed a similar state of profound mood alteration following the dousing of a fire--a state of euphoria, elation, and perception of omnipotence. Each of the 3 responded markedly well to the addition of lamotrigine to their SSRI regimen, with clear reductions in PTSD symptomatology.

Panic disorder. Another example is of a young man who presented with classic panic disorder, and failed to respond to treatment with either sertraline or paroxetine, along with benzodiazepines. His mother reported that the patient had been very moody as a child, alternating between periods of several weeks of elevated mood and depression. An online gambling addiction developed precipitously, causing the patient to incur excessive debt.

During nocturnal gambling periods, the patient experienced racing thoughts, elation, a sense of omnipotence, and a sense of possessing special faculties. Once he had finally acknowledged his gambling losses, he plummeted, over a period of minutes, into a severe state of despondent mood, eventually experiencing severe depression and suicidal ideation and intent. He responded to addition of lamotrigine to his regimen of paroxetine and clonazepam.

GAD. A further example is of a middle-aged woman with GAD, who was intolerant of most SSRIs. She had responded to fluvoxamine several years previously but had gradually become increasingly symptomatic. She reported severe generalized anxiety, which was accompanied by irritability, racing thoughts, and increased distractibility. She had begun to pursue nocturnal hobbies, which induced a marked hedonic response and frantic multitasking. She was not tired, and could not bring herself to go to sleep. She believed she had bipolar disorder and raised her concerns with the treating psychiatrist who instead stated that her diagnosis was a unipolar disorder. Eventually, she responded well to the addition of quetiapine and lamotrigine.

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