Pharmacotherapy for panic disorder

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Pharmacotherapy for panic disorder Author Peter P Roy-Byrne, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Oct 2013. | This topic last updated: Ago 30, 2013. INTRODUCTION Panic disorder is a chronic illness characterized by recurrent panic attacks, at least some of which are unexpected, accompanied either by anxiety about having future attacks or about the implications of attacks (eg, undiscovered medical illness, possible sudden death or insanity), or by a change in behavior due to attacks (eg, avoidance of certain situations, recurrent requests for medical tests) [1]. With the revision of DSM-IV to DSM-5, agoraphobia is diagnosed independently of panic disorder [1]. Agoraphobia frequently but not always accompanies panic disorder. While up to a third of the population will have a panic attack in their lifetime, only about 10 percent of this group (about 3 percent of the population) will go on to develop panic disorder [2]. Clinical trials have found that both pharmacologic and psychotherapeutic approaches are efficacious for panic disorder. Pharmacotherapy for panic disorder is discussed here. The epidemiology, pathogenesis, clinical manifestations, course and diagnosis of panic disorder are discussed separately, as is psychotherapy for panic disorder. (See "Panic disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis" and "Psychotherapy for panic disorder".) MEDICATIONS Several classes of medication have shown comparable efficacy for panic disorder, including the selective serotonin reuptake inhibitors (SSRIs), the serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCADs), monoamine oxidase inhibitors (MAOIs), and benzodiazepines. However, these drugs differ in the extent of supporting evidence, side effect profile, and in the case of benzodiazepines, their potential for abuse. These issues are discussed below [3-6]. In general, a somewhat poorer response to pharmacologic treatment of panic disorders is seen with more severe illness at baseline, whether severity is characterized by more severe symptoms, longer duration of illness, presence of psychiatric comorbidity (depression, other anxiety disorders, personality disorders), or the presence of social disadvantage [7,8]. (See "Panic disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis", section on 'Course' and "Panic disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis", section on 'Epidemiology'.) Selective serotonin reuptake inhibitors A systematic review and meta-analysis of 12 trials of acute treatment for panic disorder found the SSRIs to be efficacious compared to placebo, with a medium effect size [4]. Randomized trials have shown fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram to be effective for panic disorder compared to placebo. In general, trials have shown SSRIs to reduce the frequency of panic attacks, severity of anticipatory anxiety, and degree of phobic avoidance the core components of panic disorder. As an example, 168 patients with panic disorder with or without agoraphobia were randomly assigned to receive sertraline or placebo in a 10-week trial. Patients receiving sertraline experienced a greater mean reduction in the number of panic attacks per week compared to patients receiving placebo (88 versus 53 percent) [9]. The onset of therapeutic effect of SSRIs is somewhere between 2 and 4 weeks, but clinical response can take up to 8 to 12 weeks for some patients [10,11]. Trials have shown that therapeutic effects, particularly on anticipatory anxiety and phobic avoidance, can continue to increase over the first 6 to 12 months of treatment in many patients Section Editor Murray B Stein, MD, MPH Deputy Editor Richard Hermann, MD

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[12,13]. Virtually every clinical trial of SSRIs for panic disorder that measured phobic avoidance has found a reduction in agoraphobic symptoms in patients treated with the antidepressant compared to placebo. A number of trials have shown that panic attacks improve before anticipatory anxiety and phobic avoidance; however, other, naturalistic analyses suggest this sequence of response is not always the case [14]. Within class differences There is no evidence for superior efficacy in panic disorder among the SSRIs [15]. Selection of a particular medication should be guided by differences in side effect profile, propensity for medication interactions, half-life, and availability of less expensive, generic preparations. Fluoxetine has a longer half-life (mitigating the effect of missing doses), may be more stimulating for some patients, and can significantly affect blood levels of some medications (eg, clopidogrel). Paroxetine has a short half-life (though it is often dosed once-a-day), some anticholinergic effects, and may be more sedating for some patients (which can be useful at bedtime). Fluvoxamine is uncommonly used to treat panic disorder because its very short half-life requires dosing more than once a day. Sertraline is more likely to cause diarrhea, has fewer drug interactions than the SSRIs above, and has an intermediate half-life enabling once a day dosing. Citalopram and escitalopram are intermediate half-life compounds enabling once a day dosing, and have limited or no propensity to cause drug interactions. Dosing Because patients with panic disorder are unusually sensitive to overstimulation effects with antidepressants [16], treatment should be started at low doses (fluoxetine 5 mg, paroxetine 10 mg, sertraline 25 mg, citalopram 10 mg and escitalopram 5 mg, all once daily in the morning). If the patient is able to tolerate these doses without anxiety, jitteriness, or insomnia, the doses can be gradually titrated beginning three to seven days after initiation. The SSRI should be titrated to a therapeutic dose over two to six weeks (20 to 40 mg fluoxetine, 20 to 40 mg paroxetine, 100 to 200 mg sertraline, 20 to 40 mg of citalopram, and 10 to 20 mg of escitalopram). A trial of an SSRI should be dosed at the lower end of the therapeutic range for two to four weeks; at that point the dose can be increased if clinical improvement is not seen. Increases should occur no faster than at one to two week intervals. Although one small placebo-controlled study did not support sertraline dose increases as more effective in non-responsive panic disorder, one should move to the higher end of these dose ranges if there continue to be symptoms at the lower therapeutic doses [17]. When the decision is made to discontinue an SSRI for panic disorder, a slow taper over several months is generally recommended. In instances where more rapid taper is desired (eg, if patient becomes pregnant and if it is felt that the SSRI should not be continued during pregnancy) then this can be accomplished over several days, if necessary (eg, 150 mg sertraline to 50 mg sertraline immediately, and then discontinue completely after two to three days), acknowledging that SSRI withdrawal symptoms may ensue. (See "Antidepressant medication in adults: Switching and discontinuing medication", section on 'Discontinuation of antidepressants'.) Side effects The most common side effects are headaches, irritability, gastrointestinal distress (nausea or diarrhea), insomnia and sexual dysfunction. An increased risk of suicidality is seen in patients under age 25. A syndrome of neurologic, gastrointestinal, and psychiatric symptoms can occur if an SSRI is discontinued too quickly. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Side effects' and "Antidepressant medication in adults: Switching and discontinuing medication".) Serotonin-norepinephrine re-uptake inhibitors Venlafaxine extended release (ER) has been found in randomized trials to be an efficacious treatment of patients with panic disorder [18,19]. Venlafaxine reduces all three core components of panic disorder (attack frequency, anticipatory anxiety and phobic avoidance). Other SNRIs have not been adequately studied in panic disorder. As an example, 664 nondepressed adults with panic disorder were randomly assigned to treatment with venlafaxine ER (75 or 150 mg/day), paroxetine 40 mg/day, or placebo [18]. After 12 weeks, patients receiving venlafaxine were more likely to be free of full symptom panic attacks compared to patients on placebo (54.4 to

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59.7 versus 35.3 percent). Response rates to venlafaxine ER and paroxetine were approximately equal. Because this medication can cause hypertension, particularly at higher doses, and may also be more dangerous in overdose, venlafaxine ER is a second choice for use if SSRIs are ineffective. There is no evidence that the small and subtle advantages of SNRIs over SSRIs observed in depression studies [20] apply to panic disorder. Some experts believe that the greater noradrenergic effect with higher doses (eg, 225 mg) can be anxiogenic for some panic disorder patients, although there is no systematic study of this. Dosing Venlafaxine ER should be started at no more than 37.5 mg, taken orally in the morning. The immediate release (IR) version of venlafaxine should not be used for panic disorder because of its much greater side effect burden and the difficulty panic disorder patients have tolerating internal bodily sensations and somatic side effects. Dose should be raised to 75 mg at one week, and 150 mg by two to three weeks. This medication has a linear dose response curve in depression studies, and in one of the panic disorder studies the higher dose appeared somewhat more effective [18]. If the clinical response is inadequate after six weeks, the dose should be raised to 225 mg. Side effects Common side effects are nausea, dry mouth, constipation, anorexia, sweating, somnolence and sexual dysfunction. A small number of patients may develop hypertension, particularly at doses of 225 mg or above. Blood pressure should be monitored at regular intervals. Neurologic, gastrointestinal, and psychiatric symptoms can be seen if an SNRI is withdrawn too quickly [21]. SNRIs may have a higher risk of lethal overdose compared with SSRIs [22,23]. (See "Serotonin-norepinephrine reuptake inhibitors (SNRIs): Pharmacology, administration, and side effects".) Benzodiazepines Numerous randomized trials have found alprazolam (in standard and sustained release formulations), clonazepam, lorazepam, and diazepam to be efficacious for panic disorder [15]. Benzodiazepines reduced each of the three components of panic disorder (attack frequency, anticipatory anxiety, and phobic avoidance). Meta-analyses have found the effect sizes in these trials to be similar to those seen for SSRIs or tricyclic antidepressants [5,6]. Onset of the anti-panic effects of benzodiazepines is very rapid, beginning within the first week of treatment. This may be a distinct advantage in severely symptomatic and functionally impaired patients who require rapid relief in order to avoid further clinical deterioration. Within class differences All agents in this class appear to be equally effective with trials showing comparability among alprazolam, clonazepam, lorazepam, and diazepam [24]. Only alprazolam and clonazepam are approved by the US FDA for the treatment of panic disorder. Clonazepam has several advantages over alprazolam for panic disorder. Clonazepams longer half-life allows dosing once to twice daily, versus the three to four times daily required for alprazolam. Alprazolam XR, an extended-release formulation of alprazolam, demonstrated to be effective in a controlled trial [25], requires twice daily dosing according to most clinical experts [15]. Alprazolam is associated with more inter-dose anxiety, as effects can wear off rapidly in some patients, causing more anxiety before the next dose [26]. When alprazolams faster onset of action, due to greater lipid solubility and brain penetration, is combined with its short half-life, these effects can strongly reinforce pill-taking to alleviate anxiety, can enhance potential for abuse, and may reduce self-efficacy (ie, patients confidence that they can manage their anxiety on their own). Clonazepam has less intensive symptoms on discontinuation than alprazolam [27]. Dosing The starting dose of clonazepam is typically 0.5 mg/day taken orally at bedtime; however, divided doses can be prescribed if there is breakthrough anxiety. The initial dose should be maintained for three to five days to assess for side effects of sedation, psychomotor impairment or concentration difficulties. Increases should be guided by both side effects and therapeutic effects. Most patients will respond to a dose of 1 to 3 mg/day, though some older patients or those with reduced body weight may respond to a lower dose. Alprazolam can be started at 0.25 mg three to four times daily. After three to five days to assess for side effects, alprazolam can be increased to 2 mg/day in divided doses. Despite the labeling, which supports use of alprazolam up to 10 mg, most patients should respond to total doses between 2 and 6 mg/day [28]. Higher doses should only be considered after a careful search for other factors maintaining panic (eg, medical or

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psychosocial stress), and after ruling out the possibility of escalating tolerance due to a personal or familial history of substance abuse [29]. Our clinical experience suggests that the majority of patients with continued anxiety on 3 mg of clonazepam would be unlikely to improve at higher doses. Taper and discontinuation of these medications needs to take place gradually over a course of three to six months, with not more than 10 percent of the dose reduced every two weeks. Physiologic dependence, which occurs with chronic use of benzodiazepines, is described below. (See 'Side effects' below.) Side effects Adverse effects of benzodiazepines include abuse and addiction as well as withdrawal if stopped abruptly. Side effects consist of sedation, fatigue, psychomotor impairment and reduced memory and concentration. Reported concerns about long-term cognitive impairment with chronic use are not supported by the literature [30]. Benzodiazepines are usually well-tolerated, particularly compared to other medications for panic disorder [24]. Side effects can usually be limited by careful dose adjustment. Patients should be cautioned against operating motor vehicles or heavy machinery during initiation or dose increases. The risk of abuse of benzodiazepines is largely confined to individuals with a substance abuse history or problem; though a family history of substance abuse may be a risk factor for some individuals [29]. (See "Prescription drug abuse and addiction: Clinical features, epidemiology, and contributing factors".) Treating patients who are no longer currently abusing substances with benzodiazepines is not absolutely contraindicated, but would require increased prescription monitoring, increased visit frequency, and the use of more long acting benzodiazepines with slower absorption and onset of action (eg, clonazepam). Treatment lasting months or more is likely to lead to physiological dependence and consequent withdrawal symptoms if discontinued too quickly. (See 'Dosing' above.) Tricyclic antidepressants Sixteen randomized trials (11 for imipramine and 5 for clomipramine) have found tricyclic antidepressants (TCADs) to be superior to placebo in reducing the frequency of panic attacks; their effects on anticipatory anxiety and phobic avoidance has been found to be more variable and, in some cases, less robust [3]. Smaller trials have suggested that other agents in this class are also effective. Most studies of TCADs do not show drug placebo differences until week four with maximal responses by the end of the trial (weeks 8 to 12) [24]. Continued improvement has been observed with open label treatment through six months [31]. Dosing Imipramine or clomipramine can be started at 10 mg/day, gradually increased to 25 mg/day within the first week, and thereafter increased in 25 mg weekly increments to 100 mg/day. If there is no response after two to four weeks, the dose can be raised higher in 25 to 50 mg increments up to a total dose of 200 mg/d. Side effects TCADs have a substantial side effect burden and studies have clearly documented poor tolerability compared to SSRIs. The most common side effects are anticholinergic effects, sweating, sleep disturbance, orthostatic hypotension, fatigue and weakness, weight gain, modest blood pressure increases, and sexual dysfunction. (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects", section on 'Side effects'.) Other antidepressants The irreversible MAO inhibitors (MAOIs) have efficacy against panic disorder, but are infrequently used due to dietary restrictions and side effects. Phenelzine 45 mg/day was found to be effective compared to placebo in a randomized trial of patients with multiple elements of panic disorder (panic attacks, anxiety, and phobias). The trial did not study patients with the formal diagnosis of panic disorder as later defined in the DSM [32]. Based on clinical experience, we use a dose of 60 mg per day. There are no empirical data to support the perception among some clinicians that phenelzine may be especially useful in treatment resistant cases. The irreversible MAOIs require a restricted diet and avoidance of certain medications. MAOIs should not be taken concurrently with serotonergic antidepressants. The use and adverse effects of these agents is discussed separately. (See "Monoamine oxidase inhibitors (MAOIs) for treating depressed adults" and "Serotonin syndrome".) The newer, reversible MAOI agents (brofaromine and moclobemide) have been shown to be superior to placebo in some, but not all, studies [15]. Neither of these drugs is available in the US.

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Randomized trials have not generally supported the efficacy of trazodone, bupropion, nefazodone, or buspirone [15,24]. Other medications No randomized trials support the use of anticonvulsants for panic disorder, with negative trials for carbamazepine [33], tiagabine [34], and gabapentin [35]. A post-hoc analysis suggested that gabapentin may have efficacy in more severe forms of the disorder [35], but this remains to be determined. Trials have found monotherapy with beta-blockers or clonidine, an alpha-2 noradrenergic agonist, to be no more effective than placebo for panic disorder [36,37]. (See 'Medication combinations' below.) The absence of randomized trials of second-generation antipsychotics for panic disorder, combined with growing concern about the side effects of these agents, suggests that they should not be used as monotherapy for the disorder. The role of these drugs in combination with other antipanic drugs for treatment refractory cases remains to be determined. Duration of treatment There are no studies that systematically address the optimal duration of treatment, but available evidence suggests that effective pharmacotherapy for panic disorder should be continued for at least one year after symptom control has been attained. Studies have found that symptoms continue to improve over the first 6 months of treatment with an SSRI, SNRI, or TCAD; many studies suggest that improvement continues between months 6 and 12 [12,31,38]. A meta-analysis of six randomized discontinuation trials with 796 patients treated for panic disorder with an SSRI, SNRI, or TCAD strongly favored antidepressant continuation over replacement with a placebo during the first year of treatment (odds ratio=0.35, 95% CI 0.23-0.51) [39]. Relapse rates following antidepressant discontinuation were approximately 25 to 50 percent [12,40,41]. Relapse rates following discontinuation of benzodiazepine treatment for panic disorder have been much higher (70 percent) [42]. These results are more difficult to validate because symptoms that follow discontinuation can reflect either transient withdrawal symptoms or re-emergence of panic anxiety. Patients with more severe panic disorder should receive treatment at the longer end of the one to two year range, whether severity is characterized by duration of illness, intensity of symptoms, or the presence of Axis I or II comorbidities, residual symptoms, or medical or psychosocial stressors [15]. MEDICATION COMBINATIONS There are little data on combining medications to treat panic disorder. Two placebo controlled trials have demonstrated that augmenting acute-phase antidepressant treatment with four to six weeks of clonazepam or alprazolam results in more rapid symptom resolution compared to placebo augmentation, but no difference in outcome by 8 to 12 weeks [43,44]. Use of the short half-life alprazolam produced expected worsening of anxiety symptoms during fairly rapid, two week discontinuation. Discontinuation and taper with clonazepam was more easily tolerated. A small randomized trial found that adding the beta-blocker pindolol to the treatment of patients with panic disorder who had not responded to fluoxetine 20 mg/day resulted in symptom reduction compared to placebo augmentation [36]. Because pindolol also is a serotonin 1A receptor agonist, it is possible that beta-blockade is unrelated to anti-panic effects. COMPARING MEDICATION TO CBT CBT and antidepressant medication have been shown in controlled trials to be equally effective in the treatment of panic disorder [5]. (See "Psychotherapy for panic disorder", section on 'Comparing CBT to medication'.) COMBINED MEDICATION AND CBT The combination of CBT (or in some cases, behavioral therapy) and antidepressant treatment has shown a small advantage in the short term over either CBT alone or antidepressants alone for panic disorder. (See "Psychotherapy for panic disorder", section on 'Combined CBT and medication'.) TREATMENT SELECTION In the absence of evidence showing robust differences in effectiveness among medication, psychotherapy, and combined treatment in panic disorder, we suggest that the initial selection between medication and psychotherapy in panic disorder be made on the basis of patient preference and treatment availability. (See 'Comparing medication to CBT' above and 'Combined medication and CBT' above and

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"Psychotherapy for panic disorder".) When medication is used to treat panic disorder, we suggest first-line treatment with a selective serotonin reuptake inhibitor (SSRI) rather than other medications. There are little data comparing medications in the treatment of panic disorder. This suggestion is based on (see 'Selective serotonin reuptake inhibitors' above): Evidence of efficacy of SSRIs in panic disorder as well as in more commonly concurrent psychiatric disorders Their relatively benign side effect profile (compared to tricyclic antidepressants [TCADs] and monoamine oxidase inhibitors [MAOIs]) Their safety in overdose (in comparison to TCADs, MAOIs, and possibly serotonin-norepinephrine reuptake inhibitors [SNRIs]) The absence of abuse potential and physiological dependence (in contrast to benzodiazepines) The growing availability of less costly generic preparations. In patients with panic disorder that has not responded to one or more trials of an SSRI, we suggest use of venlafaxine ER, a SNRI, over other medications. A trial of a second SSRI is a reasonable alternative based on our clinical experience and in the absence of comparative trials of these approaches. (See 'Serotonin-norepinephrine re-uptake inhibitors' above.) Tricyclic antidepressants (TCADs), while effective in panic disorder, have largely been replaced by the serotonergic antidepressants. The greater side effect burden, cardiovascular effects, and morbidity and mortality in overdose of TCADs must be weighed against the potential clinical benefit. They may be an option in patients with disabling illness who fail to respond to the serotonergic agents or are unable to tolerate them. (See 'Tricyclic antidepressants' above.) Treatment of panic disorder with a benzodiazepine requires careful consideration of benefits and risk. In contrast to the weeks needed before the clinical response to SSRIs and SNRIs, benzodiazepines typically take effect within several days and patients will feel an immediate anxiolytic effect within hours. However, this benefit must be weighted against the risks of abuse, the development of physiological dependence, and the existence of a prominent discontinuation syndrome (which is less of a problem with longer acting agents). Patients appear to have more difficulty stopping benzodiazepines and tolerating the effects of discontinuation (which can include hyperarousal, rebound worsening of anxiety, insomnia, tremor and, in its extreme, seizures) compared to SSRIs, which have their own discontinuation syndrome. (See 'Benzodiazepines' above and "Benzodiazepine poisoning and withdrawal", section on 'Withdrawal'.) We suggest treatment of panic disorder with a long-acting benzodiazepine in patients with severe symptoms and associated disability that has either not responded to an SSRI or SNRI, or who cannot wait for the time required for them to work. We suggest the use of a long-acting benzodiazepine to augment a serotonergic antidepressant in the first weeks of treatment before the antidepressant takes effect in patients with marked distress or impairment from panic disorder. Benzodiazepine use should be limited to patients without active substance abuse or a history of benzodiazepine or prescription drug abuse. These medications should be prescribed carefully in patients with a history of a substance use disorder. Combined treatment with a serotonergic antidepressant and cognitive behavioral therapy is suggested in panic disorder co-occurring with other potentially responsive disorders, eg, other anxiety disorders and major depression, particularly with suicidality or in patients with panic disorder who have persistent symptoms after adequate trials of pharmacotherapy. This suggestion is based on our clinical experience; there are no trials on response to combined versus individual treatments specific to these subgroups. (See "Panic disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis", section on 'Epidemiology'.)

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INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient information: Panic disorder (The Basics)") SUMMARY AND RECOMMENDATIONS We recommend initial treatment of panic disorder with an antidepressant, cognitive behavioral therapy (CBT), or a combination of the two (Grade 1A). Selection among these options can be made on the basis of patient preference and treatment availability. (See 'Comparing medication to CBT' above and 'Combined medication and CBT' above and "Psychotherapy for panic disorder".) When medication is used to treat panic disorder, we suggest first-line treatment with a selective serotonin reuptake inhibitor (SSRI) (Grade 2B). Starting doses should be low and titration gradual in order to avoid symptom exacerbation. As an example, citalopram can be started at 10 mg/day and should be advanced to the therapeutic range (20 to 40 mg/day) over two to six weeks. (See 'Selective serotonin reuptake inhibitors' above.) In patients with panic disorder that has not responded to a trial of an SSRI, we suggest use of the serotonin-norepinephrine reuptake inhibitor (SNRI), venlafaxine extended release, for panic disorder rather than other medications (Grade 2B). Venlafaxine ER can be started at 37.5 mg/day and increased to 75 mg/day after a week and to 150 mg/day over two to three weeks. If the clinical response is inadequate after six weeks, the dose can be raised to 225 mg/day. (See 'Serotonin-norepinephrine re-uptake inhibitors' above.) A trial of a second SSRI is a reasonable alternative to an SNRI based on our clinical experience and in the absence of comparative trials of these approaches. Tricyclic antidepressants are effective for panic disorder but are more poorly tolerated than SSRIs, with adverse somatic effects that may trigger these patients intolerance of internal bodily sensations, possibly exacerbating their panic. (See 'Tricyclic antidepressants' above.) For patients with severe panic disorder and associated disability that has either not responded to an SSRI or SNRI, or cannot wait for the time required for them to work, we suggest treatment with a benzodiazepine over other medications (eg, clonazepam 1 to 3 mg/day; alprazolam 0.5 to 2.0 mg tid) (Grade 2C). (See 'Benzodiazepines' above.) A long acting benzodiazepine can also be used in conjunction with a serotonergic antidepressant in the first weeks of treatment, before the antidepressant takes effect, in patients with marked distress or impairment. Benzodiazepine use should be limited to patients without active substance abuse or a history of benzodiazepine or prescription drug abuse. These medications should be prescribed carefully in patients with a history of a substance use disorder The duration of pharmacotherapy should be at least one year after symptom control has been attained. Decisions about discontinuation should be based on a prior history of relapse and the presence of risk factors for relapse, including the severity of the initial syndrome or the presence of psychiatric comorbidity (depression, agoraphobia, or personality disorder), ongoing psychosocial or medical stress, and any

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residual symptoms of phobia, anticipatory anxiety or subclinical panic. (See 'Duration of treatment' above.) The combination of an antidepressant medication and CBT is suggested for patients with panic disorder co-occurring with another anxiety disorder, depression, or suicidality as well as for patients with panic disorder who have persistent symptoms after adequate trials of pharmacotherapy. (See "Psychotherapy for panic disorder", section on 'Combined CBT and medication'.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 14630 Version 5.0

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