____________________________________________________________________________ Anxiety Disorders
alprazolam, clonazepam, and lorazepam were among the top 25 most frequently prescribed psychotropic medications in the United States; alprazolam ranked ninth, clonazepam ranked 12th, and lorazepam ranked 16th [220; 221]. Pharmacology and Short-Term Effects Numerous benzodiazepines are available and have similar pharmacodynamic properties and clinical actions; they mainly differ in pharmacokinetic properties (absorption, distribution, metabolism, elimination). Benzodiazepines bind to a specific receptor site in the GABA-A receptor complex. GABA is the primary inhibitory neurotransmitter in the CNS, and ben- zodiazepines cause non-selective GABA-A inhibitory effects throughout the brain that include drowsiness, cognitive impair- ment, dampening of fear and anxiety, memory impairment, anticonvulsant actions, and impairment of balance, motor control, muscle tone, and coordination. Adverse reactions to alprazolam also include amnesia, aggression, mood changes, and hostility. The newer Z drugs (e.g., zolpidem, zopiclone) have similar actions to benzodiazepines but are marketed for insomnia due to their pharmacokinetic profile, with high doses required for anxiolytic effects. There is evidence the Z drugs share similar risks to benzodiazepines [222; 223]. Meta-analyses suggest alprazolam, lorazepam, and diazepam are effective but comparable in GAD efficacy, while clonazepam shows much greater efficacy in the treatment of panic disorder than alprazolam, lorazepam, and diazepam, which all have modest efficacy [224]. Appropriate Prescribing Benzodiazepine treatment of anxiety disorders is controver- sial. While effective in rapid anxiety reduction, the potential drawbacks with long-term use are substantial. These agents are indicated when potent, short-term anxiolytic effects are necessary to permit infrequent exposure to feared stimuli and potentially severe anxiety, such as airplane travel [121; 129; 136]. Clonazepam, lorazepam, and alprazolam are effective for short-term use in panic disorder, GAD, and SAD, but ineffective for, and potentially worsening, comorbid depres- sion [28]. The rapid anxiolytic effects make benzodiazepines highly appealing to patients with anxiety, but aside from this specific context, benzodiazepine prescribing for as-needed use is discouraged [136; 225; 226]. Benzodiazepines can reinforce pill taking, serve as a safety signal that undermines self-efficacy, and become incorporated into conditioned fear responses; these concerns are heightened with as-needed use. On-demand dosing links pill taking to rapid anxiety reduction, powerfully reinforcing avoidance in anxiety-provoking situations and encouraging longer-term reliance on the drug. This iatrogenic effect also contributes to poor CBT response. The current recommended prescribing is for time-dependent use, instead of panic response-dependent use, to minimize the risks [121]. This would also seem to maximize risk of withdrawal syndrome from uninterrupted versus intermittent drug exposure.
Benzodiazepines are also useful in the initial weeks of SSRI/ SNRI initiation, to rapidly reduce anxiety and possible early anxiogenic medication side effects before the onset of SSRI/ SNRI anxiolytic effects [121; 129; 136]. However, patients may discontinue the antidepressant when co-prescribed a rapidly effective benzodiazepine, believing the benzodiazepine’s symptom relief makes the SSRI/SNRI unneeded. Supportive therapy with regular visits or phone contacts may also help patients remain adherent until the delayed onset of antide- pressant benefits appears or early antidepressant side effects lessen [227]. Another indication for benzodiazepine use is for the short-term relief (two to four weeks only) of anxiety that is severe, disabling, or subjecting the individual to unacceptable distress. Perhaps the greatest prescribing challenge with benzodiazepines is preventing short-term use from insidiously developing into long-term use. Patients with the most severe anxiety may obtain the greatest relief and become most hesitant to discontinue use [228]. In many cases, clinicians ignore the recommended two- to four-week prescribing limit, mainly because alternative options with superior anxiolytic effects are not available [229]. Clinicians intending to prescribe alprazolam should carefully consider the likelihood that its use will remain restricted to the very short term—a few days to a couple weeks—to see the patient through a crisis [228]. Benzodiazepines may be prescribed to augment SSRI/SNRI therapy for improved response in select patients with significant residual anxiety or non-response. In one study, patients with SAD and sertraline nonresponse after 10 weeks were given sertraline plus clonazepam (≤3 mg/day), venlafaxine (≤225 mg/day), or sertraline plus placebo for 12 weeks. Those with sertraline augmented by clonazepam showed greatest reduc- tion in SAD symptoms and a better overall response rate than comparator groups, although remission rates did not differ sig- nificantly [230]. These agents are third- or fourth-line treatment in patients unresponsive or intolerant to other anxiolytic drugs who remain highly symptomatic [121; 129; 136]. Generally, patients with a history of substance abuse, personality disorder, or chronic pain should not be treated with benzodiazepines because of the high risk for overuse of these medications [129]. While benzodiazepines should usually be reserved for patients lacking response to at least two treatments (i.e., non-response to an SSRI/SNRI and a psychologic treatment), concerns about potential problems in long-term use should not prevent their use in patients with persistent, severe, distressing, and impairing anxiety symptoms [231]. It seems the most appropriate guidance for benzodiazepine prescribing involves occasional, context-specific use or cautious use during SSRI/SNRI initiation [3; 231]. Otherwise, benzo- diazepines should be reserved for patients lacking response to three or more treatments, such as an SSRI, an SNRI, and a psychologic intervention, who remain highly symptomatic.
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