Anxiety Disorders ____________________________________________________________________________
A substantial number of patients fail to achieve substantive symptom relief from exposure-based therapies or experience fear relapse following exposure therapy. This results from deficits in the mechanisms considered central to extinction learning (e.g., poor medial prefrontal cortex inhibition of amygdala-generated fear impulses) that contributed to the development of pathologic anxiety and avoidance in the first place. Because of this, effort is underway to optimize exposure therapies to improve significant and durable patient response [167]. This effort includes the therapeutic alliance as a potential prognostic indicator [168]. PHARMACOTHERAPY: OVERVIEW The first-generation antidepressants monoamine oxidase inhibitors (MAOIs) and TCAs were introduced in the late 1950s and early 1960s, and the first report of antidepres- sant use in anxiety treatment was published in 1962. In this account, patients with agoraphobia who were given the TCA imipramine showed reductions in panic attacks and improved exposure to feared situations [169]. The benzodiazepine chlor- diazepoxide (Librium) was introduced to the U.S. market in 1960. This was followed by diazepam (Valium) in 1963, which became the most prescribed drug in the United States from 1969 to 1982; in 1978, more than 2.3 billion diazepam doses were sold in the United States [170]. Panic disorder was first formalized as a psychiatric disorder in the 1980 DSM-III, and alprazolam (Xanax) became the first U.S. Food and Drug Administration (FDA)-approved drug for panic disorder treat- ment in 1981, remaining the most-prescribed benzodiazepine to date [171]. In the past two decades, antidepressant drugs, specifically SSRIs, have displaced benzodiazepines as the most widely prescribed and recommended anxiety disorder pharmaco- therapy. Efforts to improve safety, efficacy, and tolerability led to introduction of the second-generation antidepressants, with trazodone (Oleptro) in 1982, bupropion (Wellbutrin) in 1985, and fluoxetine (Prozac)—the first domestically marketed SSRI—in 1987. Antidepressants are generally recommended as first-line therapy for panic disorder because, unlike benzodiazepines, antidepressants treat comorbid depression and lack abuse risk and potential side effects of excessive sedation, cognitive impairment, and ataxia. All major antidepressant classes are comparably effective, but SSRIs and, increasingly, SNRIs are recommended over TCAs and MAOIs due to better safety and tolerability [172]. Tricyclic Antidepressants Norepinephrine, serotonin (5-HT), and dopamine are termed monoamines. Monoamine reuptake transporters retrieve monoamines released into the synaptic cleft to terminate their activation of post-synaptic monoamine receptors. TCAs act by inhibiting norepinephrine and 5-HT reuptake transporters. This increases synaptic levels of norepinephrine and 5-HT
by preventing their clearance, which increases post-synaptic receptor activation and signaling. TCAs generally have greater norepinephrine than 5-HT reuptake transporter potency. TCAs also act as histamine H1/H2, muscarinic acetylcholine, and alpha-adrenergic receptor antagonists, resulting in a range of undesirable side effects associated with patient intolerance and discontinuation, including [173]: • Anticholinergic: Dry mouth, blurred vision, constipation, urinary hesitancy and retention, confusion, precipitation of glaucoma, delayed ejaculation, sweating • Alpha-1-adrenoceptor antagonism: Postural hypotension, increased heart rate, dizziness • Antihistaminergic: Sedation, psychomotor slowness, weight gain • Cardiac sodium channel blockade: QTc prolongation, decreased cardiac conduction, fatal cardiac arrest in overdose TCAs have comparable efficacy to SSRIs in panic disorder and GAD [174; 175]. TCAs are lethal in overdose and, compared to SSRIs, have a markedly broader, more problematic, and less tolerable side effect profile [172]. Nonetheless, TCAs may work when first-line agents do not [136]. Also, some patients with panic disorder are sensitive to both beneficial and adverse effects of TCAs, so they cannot tolerate imipramine doses >10 mg/day but may still experience panic blockade [172]. Monoamine Oxidase Inhibitors MAOIs inhibit MAO, an enzyme that degrades and inactivates 5-HT, norepinephrine, and dopamine, thereby increasing monoamine levels and activity. The earlier MAOIs—phenelzine (Nardil) and tranylcypromine (Parnate)—are characterized by irreversibility and nonselectivity. Irreversibility refers to tena- cious drug binding to the MAO enzyme for the 14- to 28-day lifespan of the drug molecule. Nonselectivity refers to phenel- zine and tranylcypromine binding to both A and B isoenzymes of MAO. While tyramine and dopamine are metabolized by both MAO-A and MAO-B, MAO-A inhibition is established as the precursor to hypertensive crises [176]. During phenelzine or tranylcypromine therapy, dangerous and potentially fatal hypertensive reactions can result from co-ingestion of drugs with monoamine activity or foods high in tyramine content (e.g., cheese, beer, wine). Concurrent use of serotonergic agents or supplements such as St. John’s wort can cause potentially lethal serotonin syndrome. Common side effects include orthostatic hypotension, weight gain, sexual dysfunction, sedation, headache, and insomnia. To avoid drug interactions, washout periods are required before an MAOI is started (≥5 days) or stopped before switch to another medica- tion (≥14 days) [136].
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