Pharmacologic Therapy

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PD may be treated successfully with TCAs, SSRIs, SNRIs, or MAOIs, as well as benzodiazepines50,52 (Table 40-6). While all these agents are similarly effective, SSRIs have become the treatment of choice in PD. Benzodiazepines often are used concomitantly with antidepressants, especially early in treatment, or as monotherapy to acutely reduce panic symptoms. Benzodiazepines are not preferred for long-term treatment but may be used when patients fail several antidepressant trials.49'50 PD patients with comorbid depression should be treated with an antidepressant. An algorithm for pharmacologic management of PD appears in Figure 40-3.

Antidepressants

Antidepressants have a delayed onset of antipanic effect, typically 4 weeks, with optimal response at 6 to 12 weeks. Reduction of anticipatory anxiety and phobic avoidance generally follows improvement in panic symptoms. PD patients are more likely to experience stimulant-like side effects of antidepressants than patients with major depression. Antidepressants should be initiated at lower doses (Table 40-6) in PD patients than in depressed patients or those with other anxiety disorders. Target doses are similar to those used in depression. Antidepressants should be tapered when treatment is discontinued to avoid withdrawal symptoms including irritability, agitation, and dysphoria.

Tricyclic Antidepressants

Treatment with imipramine, the most studied TCA, leaves 45% to 70% of patients panic-free. Both desipramine and clomipramine have demonstrated effectiveness in PD as well. Despite their efficacy, TCAs are rendered second-line pharmacotherapy due to poorer tolerability, patient acceptance, and toxicity on overdose.49,50 TCAs are associated with a greater rate of discontinuation from treatment than SSRIs.54 PD patients taking TCAs may experience anticholinergic effects, orthostatic hypotension, sweating, sleep disturbances, dizziness, fatigue, sexual dysfunction, and weight gain. Stimulant-like side effects occur in up to 40% of patients.49,50

Table 40-6 Antidepressants Used in the Treatment of PD

Recommended Starting uiuai Tlw*p*uik Dosage Range Img.'düy)_

JdvjntügTi

SSfflvSWHfs Citalopram EstieailopfiiTi riuonetirW

riuviMamiiK1 Pa*aooetine° ^cstrfllinc* Uenlafaxine XR°

50-2W

iS/lfs On gififiujj Antidepressant acHvity

irtvgls daily diinng (all tu! Iluvosamine): law toaclclk^ same available in generic hiKk 4in gen&ab) Actrvaliont delay«J onset oF

sexual side eiiecis; Gl side effects

50-2W

Selective Serotonin Reuptake Inhibitors

SSRIs are the drugs of choice for PD. All SSRIs have demonstrated effectiveness in controlled trials, with 60% to 80% of patients achieving a panic-free state.25'49'50 With similar efficacy reported and no trials comparing different SSRIs, selection generally is based on pharmacokinetics, drug interactions, side effects, and cost differences (see Chap. 38). The most common side effects of SSRIs include headaches, irritability, nausea and other GI complaints, insomnia, sexual dysfunction, increased anxi-

49,50

ety, drowsiness, and tremor. ' Serotonin-Norepinephrine Reuptake Inhibitors

Venlafaxine is FDA approved for the treatment of PD. In doses of 75 to 225 mg/day, it reduced panic and anticipatory anxiety in short-term controlled trials, and it prevents relapse with extended treatment over 6 months.55,56 The most common side effects include anorexia, dry mouth, constipation, somnolence, tremor, abnormal ejaculation, and sweating.

Monoamine Oxidase Inhibitors

MAOIs have not been evaluated systematically for treatment of PD under the current diagnostic classification and generally are reserved for patients who are refractory to other treatments.49,50 They have significant side effects that limit adherence. Additionally, patients must adhere to dietary restriction of tyramine and avoid sympathomimetic drugs to avoid hypertensive crisis (see Chap. 38).

The reversible inhibitors of monoamine oxidase A (RIMAs) (brofaromine and me-clobemide) have been studied with mixed results.49 Neither is approved for use in the United States, but they are available in Canada.

Other Drugs

Bupropion, trazodone, and nefazodone are not recommended for treatment of PD.50 Benzodiazepines

Benzodiazepines are effective antipanic agents with significant effects on anticipatory anxiety and phobic behaviors. Alprazolam, the one studied most extensively, is associated with significant panic reduction after 1 week of therapy (e.g., 55-75% panic-free).49,50 Benzodiazepines achieve similar outcomes to antidepressants over extended treatment, but benzodiazepine-treated patients are more likely to relapse when the drug is discontinued.49,50 The risk for dependence and withdrawal and lack of efficacy for depression are significant concerns for long-term treatment of PD. There is no evidence that tolerance to therapeutic effect does occur. In fact, patients do not require dose escalation during extended treatment. Patients with PD do experience greater rebound anxiety and relapse when discontinuing benzodiazepines than do GAD patients. Tapering should be done at a slower rate and over a more extended period of time than with other anxiety disorders.25,49,50

Anxiety Treatment Algorithm

FIGURE 40-3. Algorithm for the pharmacotherapy of panic disorder. BZ, benzodiazepines; SSRIs, selective serotonin reuptake inhibitors (Adapted from Kirkwood CK, Melton ST. Anxiety disorders: I. Generalized anxiety, panic and social anxiety disorders. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:1163-1178.)

The dose of benzodiazepine required for improvement generally is higher than that used in other anxiety disorders, and this may explain why high-potency agents such as alprazolam and clonazepam generally are preferred. Lorazepam and diazepam, when given in equivalent doses, produce similar treatment benefits.49 Doses should be titrated to response (Table 40-4). The use of extended-release al-prazolam or clonazepam will minimize breakthrough panic symptoms that are some-

times observed with immediate-release alprazolam.

Side effects associated with benzodiazepines in PD patients are similar to those observed in other disorders. Sedation, fatigue, and cognitive impairment are the most commonly reported side effects.49 Benzodiazepines should be avoided in patients with current or past substance abuse/dependence or sleep apnea. Additionally, caution should be used in older adults because they have more pronounced psychomotor and cognitive effects.

P-Blockers

^ Pindolol 25 mg three times a day has been shown effective as an adjunctive treatment for PD when used with an SSRI58 Propranolol 120 to 240 mg/day has been found equivalent to alprazolam in reduction of panic attacks.59 ^-Blockers are not expected to reduce psychic anxiety or avoidance behavior. Additionally, heart rate and blood pressure reduction are dose-related adverse events that may limit use.

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