Clinical Psychopharmacology Seminar
Original Author: Paul Perry, Ph.D, BCPP
Latest Revisers: Paul Perry, Ph.D, BCPP, Brian C. Lund,
Pharm.D.
Creation Date: 1996
Last Revision Date: April 2004
Peer Review Status: Internally Peer Reviewed
Panic attacks are sudden discrete periods of intense fear or discomfort usually lasting for a few minutes to an hour. Recent epidemiologic data suggest that the worldwide lifetime prevalence of panic disorder with or without agoraphobia is 1.6-2.2% while the one-year prevalence rate is 1-2% (APA 1998). Retrospective studies of the general population have found greater than 90% of patients with agoraphobia to have a history of panic attacks (Breier et al 1986, Uhde et al 1985). Pharmacologic management of panic disorder and agoraphobia with panic attacks was first investigated in the early 1960s with monoamine oxidase inhibitors (MAOIs) and later with tricyclic antidepressants (TCAs) and benzodiazepines (BZDs) (Ballenger 1986, Jann and Kurtz 1987, Noyes et al 1989). Panic disorder is not associated with dysfunction of a single neurotransmitter system. Instead, the etiology of the disorder is related to abnormalities of serotonin, norepinephrine, gamma-aminobutyric acid, dopamine, and cholecystokinin (Johnson et al 1995).
Treatment goals in panic disorder have been divided into two categories, specific and general. Specific treatment goals include preventing panic attacks, reducing intensity of attacks, decreasing anticipatory anxiety and eliminating agoraphobic avoidance. General goals include restoration of functioning and quality of life, preventing relapses and recurrences, and preventing complications (Starcevic 1998).
The initial treatment goal is to prevent panic attacks with pharmacotherapy. However, anxiety disorder patients tend to be sensitive to medication and often experience exacerbation of their symptoms with medication, especially if the initial dose is too large. Thus the clinician is advised to "start low, go high, and persist." Once this goal is accomplished patients are encouraged to re-enter phobic situations to help extinguish the avoidance behavior. Exposure therapy eventually ought to result in a disappearance of the anticipatory anxiety. Recently, there has been a shift from exposure to phobic situations, to exposure to panic-like sensations, in an attempt to prevent catastrophizing (Hollander et al 1990).
Pharmacotherapy should be continued for one year following remission of the panic attacks to prevent relapse (APA 1998). Patients continue to improve with regard to avoidance for approximately 6-12 months. After 12 months the medication can be tapered. Two-thirds of patients will not relapse immediately after cessation of pharmacotherapy (Hollander et al 1990). As a general rule, regardless if the patient has been successfully treated with an antidepressant or BZD, approximately 50% to 95% of patients will relapse (Coryell et al 1983, Wheeler et al 1953). A review of 16 outcome studies with at least one year of follow-up found that 17-70% of patients (mean, 46%) still had panic attacks and between 36 and 82% had phobic avoidance (mean, 69%) (Roy-Byrne and Cowley 1995). Swoboda et al (2003) followed up 24 patients who participated in a treatment trial 11 years later. The data were encouraging. At baseline all patients had suffered from panic attacks and were severely disabled. At follow-up 67% had no panic attack during the year before follow-up. During the month before follow-up 88% had no panic attacks, and 54% showed no or only mild phobic avoidance. In the areas of work and family life mild or disability was observed in 90%. In the area of social life the disability rate was 67%. The a-priori definition of remission was meet in 33% of the patients. Panic disorder is not a uniformly chronic and progressing disorder. Over a period of 11 years there is a good chance of recovery from panic attacks and disabilities, and full remission is also possible. Some authors have proposed that there are multiple patterns in the course of panic disorder (Katschnig and Amering 1998). These include a remitting course (single episode, with no relapse or recurrence ~ 31% of patients), episodic course (recurrent, but periods of remission ~ 24%) and persistent course (waxing and waning course, but disorder is chronically present ~ 45%). Together, these studies emphasize that patients should be given a trial off medication after 1-2 years of successful pharmacotherapy.
Cowley et al (1997) defined the predictors of a poor response to pharmacotherapy in a group of 106 panic disorder patients. Thirty-eight percent had panic disorder alone and 62% had panic disorder with agoraphobia. Seventy percent had at least two Axis I diagnosis and 40% had at least one comorbid Axis II diagnosis. Ninety-one had been treated with at least one effective anti-panic medication prescribed regularly rather than on a prn basis. Forty-three of these received an adequate trial while 48 did not. The most common reason for treatment failure was intolerable side effects (52%). Patients who discontinued treatment due to ADRs had higher HAMA scores and were less likely to have a history of substance abuse. Treatment resistant patients (24%, 14/59 trials) were younger and had a higher lifetime rate of major depression. Predictors of poor general outcome have also been described (Noyes et al 1993). These included higher symptom severity at baseline, longer duration of illness, history of major depression, high interpersonal sensitivity, and low social class.
COGNITIVE BEHAVIORAL THERAPY
Although outside the scope of this discussion, psychotherapy, specifically panic-focused cognitive behavioral therapy (CBT), has been shown to be an effective treatment for panic disorder (APA 1998). However, at least one direct comparison study found fluvoxamine to be significantly more effective than cognitive therapy in the treatment of panic disorder (Black et al 1993). More recently, Bakker et al (1999) conducted a 12-week, placebo-controlled study comparing the relative efficacy of paroxetine 20-60 mg/d, clomipramine 50-150 mg/d, and cognitive therapy (12 sessions) in the treatment of 131 patients with panic disorder with or without agoraphobia (DSM-IIIR). Comparisons with placebo revealed significant superiority of paroxetine and clomipramine on nearly all outcome measures e.g., CGI, MADRS, HAMA, etc. On most measures, paroxetine also showed higher efficacy than cognitive therapy. With few exceptions, cognitive therapy did not differ significantly from placebo. The number of subjects becoming panic-free favored paroxetine (66%), clomipramine (53%), cognitive therapy (40%), and placebo (34%). The differences between paroxetine and cognitive therapy and placebo were significant. The onset of action was faster in the paroxetine-treated group. Treatment with cognitive therapy yielded the highest drop-out rate (26%). It has been suggested that the combination of CBT and pharmacotherapy may prove more effective than either treatment modality alone (APA 1998, Mavissakalian 1983). However, it is becoming evident that CBT cannot be used by itself to treat panic disorder.
Below a large body of evidence is presented that supports the effectiveness of pharmacotherapy in the treatment of panic disorder.
PHARMACOTHERAPY
Boyer (1995) performed a meta-analysis contrasting the effectiveness of the SSRIs (paroxetine, zimelidine, fluvoxamine and clomipramine) to imipramine and alprazolam in the treatment of panic disorder (DSM-III or DSM-III-R). All treatments were superior to placebo in alleviating panic. Additionally, the SSRIs plus were superior to both imipramine and alprazolam. However, Gould et al (1995) determined the overall global effect size and panic frequency effect size for the tricyclics versus placebo in panic disorder patients. Later, the same group determined the overall global effect size and panic frequency effect size for the five SSRIs versus placebo (Otto et al 2001). There was no difference in the effect size on either parameter between imipramine and the SSRIs, fluoxetine, fluvoxamine, citalopram, paroxetine, and sertraline. The effect sizes in the SSRIs studies ranged from 0.23 to 0.89 (Otto et al 2001). The most recent meta-analysis of the literature also concludes that there is no apparent difference between the efficacy of the TCAs and SSRIs in the treatment of panic disorder. Based on the data from 34 randomized and 9 open trials Bakker et al (2002) concluded that there was no difference between the two antidepressant classes in the effect size or outcome on variables that included panic symptoms, agoraphobic avoidance, depressive symptoms, and anxiety symptoms. The percentage of patients free of panic attacks at study end were similar, SSRIs, 60% and TCAs, 55%. The only apparent difference between the groups was the TCA dropout rate of 31% was significantly greater than the SSRI rate of 18%.
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)
Efficacy
Single-Drug Treatment. Numerous trials (two open, one double-blind, and thirteen double-blind placebo-controlled) were reviewed to determine the efficacy of SSRIs in the treatment of panic disorder (Ballenger 1998, Black 1993, DenBoer 1988, DenBoer 1990, Gorman 1987, Hoehn-Saric 1993, Lecrubier 1997a, Lecrubier 1997b, Londborg 1998, Michelson 1998, Oehrberg 1995, Pollack 1998, Pohl 1998, Sandmann 1998, Schneier 1990, and Wade 1997). The data consistently demonstrate that the SSRIs are effective anti-panic and anti-phobic agents.
Combination Treatment. Goddard et al (2001) contrasted the effectiveness of a single SSRI, sertraline approximately 100 mg/d to the combination therapy of sertraline plus clonazepam 0.5 mg po tid in the treatment of 50 panic disorder patients. Using a double-blind placebo controlled design patients were randomized to either sertraline alone or the sertraline-clonazepam combination or sertraline-placebo for the 4 weeks. According the clinician rating scale and the 7-item panic disorder severity scale, the patients receiving combination treatment were rated as doing better on the two scales for the first three weeks of the study. By week four the combination effect disappeared. It would seem the explanation of this effect is a combination of the antipanic effect of the clonazepam, and the ability of the benzodiazepine to reduce the transient jitteriness adverse effect associated with the use of SSRIs and TCAs in panic disorder patients. Utilizing paroxetine rather sertraline, Pollack et al (2003) replicated this finding.
Dosage
Primarily due to the "jitteriness syndrome", a substantial number of patients cannot tolerate a fluoxetine starting dose of 20 mg/d. Louie et al (1993) studied a group of 133 depressed outpatients with and without concurrent panic disorder. Patients were instructed to titrate their dose to the maximum tolerable dose, but not exceeding 20 mg/d, over a 4-week period. Sixty-five percent described themselves as "wired and hyper", 32% complained of headache, 24% sedation, and 22% insomnia. Importantly, 22 patients (17%) could not tolerate the drug and dropped out, while 15 others (11%) did well on a fluoxetine dose < 20mg/d. Approximately half the patients who discontinued the drug usually were comorbid for MDD. The 1998 American Psychiatric Association guidelines recommend the following starting doses for the SSRIs: fluoxetine, 10 mg/d or less; sertraline, 25 mg/d; paroxetine, 10 mg/d; fluvoxamine, 50 mg/d (APA 1998). The guidelines recommend maintaining this dose for several days then increasing to more "standard doses." Patients who fail to respond or have an incomplete response after several weeks may have an improved response with further dose escalation. Although citalopram does not have a FDA indication for panic disorder, a randomized, double-blind, placebo controlled trial of 475 patients found the drug beneficial in the treatment of panic disorder (Wade et al 1997). Citalopram was initiated at 10mg/d and titrated per protocol. Similarly, escitalopram was found minimally effective in the treatment of panic disorder using an initial dose of 5 mg /d and titrated to as high as 20 mg/d Stahl et al (2003).
Conclusion
For most patients, the SSRIs are likely to have the best balance of efficacy and adverse effects. Although they carry the risk of sexual adverse effects, they lack the cardiovascular and anticholinergic side effects as well as the morbidity and mortality risks resulting from tricyclic overdoses. The SSRIs should be initiated at a low dose to minimize the risk of the "jitteriness syndrome."
TRICYCLIC ANTIDEPRESSANTS
Efficacy
There are numerous trials that have investigated the efficacy of TCAs in the treatment of panic disorder and/or agoraphobia (Andersch et al 1991, Charney et al 1986, CNC Panic Study 1992, Deltito et al 1991, Gloger et al 1981, Mavissakalian and Perel 1985, Modigh et al 1992, Munjack et al 1985, Rizley et al 1986, Rosenberg et al 1991, Sheehan et al 1980, Uhlenhuth et al 1989, and Zitrin et al 1983). Response was typically defined as either the complete remission of panic attacks or an 80% reduction in the number of attacks. The mean percent of people who responded to the treatment of panic attacks was approximately 65%. Only two studies failed to find the TCAs to be significantly more effective than placebo in reducing the severity of agoraphobia in the patients self-rating scale of severity (Sheehan et al 1980, Uhlenhuth 1989). Imipramine and clomipramine were both found to be effective in the treatment of panic attacks with or without agoraphobia. Contrasting of the effect sizes suggests that clomipramine, a more potent SSRI than imipramine, is a more effective anti-panic drug.
The other available TCAs have not been as widely studied as imipramine or clomipramine. Clinical experience suggests that desipramine, nortriptyline, doxepin, and amitriptyline are effective (Ballenger 1986, Hollister 1986, Liebowitz 1985, Muskin and Fyer 1981). However, the norepinephrine dominant agonist TCAs, such as desipramine and nortriptyline, are less potent in the treatment of panic disorder. However, there may be a subgroup of patients with primarily norepinephrine dysfunction that will benefit from these TCAs.
Dosage
Several reports indicated that though some patients may respond to imipramine doses of 25 mg/d, most patients require greater than 150 mg/d to achieve a response. Some patients may require up to 200-400 mg/d. Imipramine doses should be initiated at 10-25 mg/d and can be increased to 150-200 mg/d over a 2- to 4-week period. If a response is not seen in 4-6 weeks, the dose may be increased to 400 mg/d. Doses of antidepressants other than imipramine in the management of panic disorder are typically in the antidepressant range.
Mavissakalian and Perel (1989) found the anti-panic effect of imipramine was achieved with a 1.5 mg/kg/d whereas the anti-phobic effect occurred with a higher dose of 3.0 mg/kg/d (Mavissakalian and Perel 1989). More recently, the same group concluded that a total imipramine (imipramine + desipramine) plasma concentration of 110-140 ng/ml and a target imipramine dose of 2.25 mg/kg/d are optimal in the acute treatment of patients with panic disorder with agoraphobia (Mavissakalian et al 1995). This group further showed that the plasma concentration of imipramine (or its logarithm) to be the most statistically significant predictor for predicting panic severity. Total plasma concentration (desipramine + imipramine) was the next best predictor, with desipramine being the weakest predictor (Mavissakalian et al 1995). One possible neurobiochemical explanation is that the parent compound is essentially serotonergic and active metabolite mostly noradrenergic. It has been thought that this increase in noradrenergicity reduces the drug's potency, particularly its anti-phobic effects in panic disorder with agoraphobia.
Adverse Effects
Large dropout rates were consistently observed in the panic disorder TCA treatment trials (mean, 25%) although these rates did not differ from the SSRIs (Gould et al 1995, Otto et al 2001). Many of the dropouts were due to an inability to tolerate the TCAs. The main adverse effects that were noted were anticholinergic effects, including blurred vision, dry mouth, constipation, and difficulty urinating. Unfortunately, less safety and efficacy data is available for the less anticholinergic TCAs, nortriptyline and desipramine. TCAs may also cause paradoxical aggravation of some of the symptoms of panic disorder. Charney et al (1986) found that a small number of patients had an increase in anxiety and insomnia after taking TCAs. Gloger et al (1981) found that 40% of the subjects had their clinical condition aggravated initially with clomipramine, but changes in dose of 10 mg in either direction could make the difference between exacerbation and amelioration. Finally, dropouts were also attributed to the slow onset of actions of the TCAs. Most studies found that imipramine requires 3-4 weeks before it is effective.
A reaction that appears almost exclusively in panic patients is the "jitteriness syndrome" or "hypersensitivity" reaction (Pohl et al 1988). Forty-nine of 158 patients (30%) with panic disorder developed this reaction in one retrospective study. Symptoms included jitteriness, shakiness, increased anxiety, and insomnia. Though TCA doses were most often started at 10 mg/d symptoms still occurred. It appeared with initial doses and tolerance develops over 7 to 10 days (Pohl et al 1988, Zitrin et al 1983). If patients do not develop this within 7 to 10 days of initiation of treatment it is unlikely it will occur. Desipramine was reported to be more likely to produce this adverse effect than imipramine, based on retrospective data (Pohl et al 1988).
One study allowed concurrent use of low-dose BZDs during the trial (Modigh et al 1992). This may have an effect on the results. However, the study had significantly fewer dropouts. Thus the BZDs may partially counteract the paradoxical aggravation often observed in the initial phases of treatment with TCAs which leads to TCA discontinuation.
Summary
MONOAMINE OXIDASE INHIBITORS (MAOIs)
Five placebo-controlled trials with phenelzine have reported that MAOIs are effective in 65-70% of patients (Mountjoy et al 1977, Sheehan et al 1980, Solyom et al 1973, Solyom et al 1981, Tyrer et al 1973).
Dosage
Treatment is usually initiated at 15 mg/d and increased to 15 mg/d every 3 to 4 days until 90 mg/d is reached. Tranylcypromine is begun at 10 mg in the morning. The dose may be raised by 10 mg every 3-4 days to a maximum dose of 80 mg/d.
Summary
OTHER ANTIDEPRESSANTS
Venlafaxine
In a double-blind, placebo-controlled trial a significant difference was seen in global improvement scales in panic disorder patients which received venlafaxine compared to those in the placebo group (Pollack et al 1996). One additional open study of venlafaxine found low doses (mean, 47 mg/d) to yield substantial reductions in panic attacks and anxiety symptoms (Papp et al 1998).
Trazodone
Trazodone has been associated with limited anti-panic activity (Mavissakalian et al 1987), and appears less efficacious than either TCAs or BZDs (Charney et al 1986).
Bupropion
In a single-blind, placebo-controlled trial bupropion failed to demonstrate a significant anti- panic effect (Sheehan et al 1983).
Maprotiline
Maprotiline has been reported to be effective in open trials. A double-blind trial reported maprotiline was ineffective in preventing panic attacks (Den Boer and Westenberg 1988).
Reboxetine
Reboxetine, a norepinephrine reuptake inhibitor, has been found effective in the treatment of panic disorder in a double-blind placebo controlled trial (Versiani et al 2002).
Mirtazepine
GABA AGONISTS
Benzodiazepines
Efficacy. Early experience with benzodiazepines (BZDs) suggested they were only partially effective for panic disorder. However, the findings controlled trials argue that lorazepam, diazepam, alprazolam, and clonazepam are equally effective as anti-panic and anti-phobic agents when taken regularly and in sufficient doses (Andersch et al 1991, Ballenger et al 1988, Charney et al 1986, Chouinard et al 1982, CNC Panic Study 1992, Deltito et al 1991, Dunner et al 1986, Noyes et al 1984, Noyes et al 1996, Rizley et al 1986, Rosenbaum et al 1997, Rosenberg et al 1991, Schweizer et al 1988, Sheehan et al 1993, Sheehan et al 1984, Swinson et al 1987, Tesar et al 1987, Uhlenhuth et al 1989). BZDs proved effective on all of the assessment scales employed in these various studies, and were also ranked high in subjective evaluations.
Symptoms responding included anxiety, frequency and severity of panic attacks, and phobic fear and avoidance. In trials with alprazolam, the number of panic attacks decreased by an average of 81%, and were sometimes eliminated completely. More patients experienced moderate to marked improvement with BZDs than with any other class of drugs. A decrease in anticipatory anxiety and disability in work, family life and social life was reported. Somatic complaints including cardiovascular, respiratory, gastrointestinal and muscular also responded (Sheehan and Raj 1990).
Other factors supporting the effectiveness of BZDs included greater compliance with this treatment group, fewer dropouts due to ineffectiveness, smaller proportion of non-responders, and the return of symptoms when doses are tapered.
In the 14 BZD efficacy studies, when compared to other classes of drugs, buspirone was found to be no more effective than placebo; propranolol was somewhat more efficacious than placebo, but had the undesirable adverse effects of hypotension, bradycardia, and sedation and imipramine proved effective but had several disadvantages, including slower onset and more adverse effects.
Adverse Effects. Adverse effects were reported more frequently with BZDs than with placebo, but were usually mild and rarely required discontinuation. The most frequently reported adverse effect was drowsiness. Patients need to be warned about the effects of benzodiazepines on driving. They cannot be used on a prn basis. Van Laar et al (1992) administered diazepam 5 mg po tid for 4 weeks to 12 anxious patients. He tested their driving skills weekly with a 100 km highway driving test. Diazepam impaired their speed control during the 1st week and lateral position control during the 1st three weeks. Ataxia and impaired cognition have also been reported. Tolerance to side effects usually develops, so it may be that recommended doses not be adjusted upward until after a few weeks of treatment.
A common clinical complaint with the BZDs in panic disorder is that it is difficult to taper patients off these agents. Slow BZD tapers result in a re-emergent symptom rate that varies from 20-38%. Of patients successfully tapered 50% relapse within 6 months of discontinuation. Spiegel et al (1994) tapered 21 patients off alprazolam (mean dose = 2.2 mg/d) using a slow flexible taper schedule in which the dose was changed every 1-2 weeks. Half of the subjects were randomly assigned to cognitive behavioral therapy. The investigators were equally successful in discontinuing the drug in 80% of the alprazolam alone group and 90% of the alprazolam plus cognitive behavioral therapy group. However, on 6 month follow-up 50% of the alprazolam alone group had relapsed while none of the combined treatment group relapsed. Thus CBT is useful in tapering subjects off medication. Whether this is also true for the SSRIs, TCAs, and MAOIs remains to be seen.
Summary (Sheehan and Raj 1990)
Valproic Acid
BZDs have anticonvulsant activity which is attributed to their GABA agonist effects. Valproic acid (VPA) also enhances the GABA transmission. Animal studies suggest VPA has anxiolytic activity. There are four studies that have examined the effectiveness of VPA in the treatment of panic disorder (Baetz and Bowen 1998, Keck et al 1993, Primeau et al 1990, and Woodman and Noyes 1994). Unfortunately all trials were open designs. Although the drug may be effective, controlled trials contrasting valproic acid to BZDs, TCAs and placebo are required. The ability to tolerate the ADRs, especially the GI ADRs produced by VPA, may limit its usefulness in the treatment of panic disorder.
BETA-BLOCKING AGENTS
Three studies have examined the effectiveness of beta-blockers in a total of 73 patients having panic disorder with or without phobic avoidance, or agoraphobia with panic attacks (Munjack et al 1985, Noyes et al 1984, Ravaris et al 1991). Propranolol was compared to imipramine, alprazolam, and diazepam. Response to the treatments was judged by decrease in the number of panic attacks, avoidance of phobic situations, decrease of phobic symptoms, and by the HAM-A. The trials resulted in a 46% overall mean decrease of panic attacks with propranolol usage, 79% with imipramine, and 67% with diazepam and alprazolam. The overall average decrease in phobic avoidance and phobic symptoms was 41% with propranolol, 48% for imipramine, and 45% for the two BZDs. The HAM-A scale was utilized in only one study. The scores decreased by 68% with propranolol, and 60% with alprazolam. Table 5 suggests that the TCAs and BZDs are better anti-panic drugs but propranolol seems approximately equally effective as an anti-phobia drug.
Summary
Buspirone
One controlled trial comparing buspirone, imipramine, and placebo reported buspirone to be less effective than imipramine and equal to placebo in panic disorder (Sheehan 1987). A second study reported imipramine and buspirone were no better than placebo in a double-blind trial (Pohl et al 1989). The studies were criticized by the manufacturer because they claimed the maximal dose of the drug, 60 mg/d, was not utilized. The most recent study (Sheehan et al 1993) utilized a 60 mg/d dose in comparing the drug's efficacy to alprazolam and placebo. Once again buspirone was less effective than alprazolam and no more effective than placebo in the treatment of panic disorder.
Carbamazepine
Carbamazepine produced a marked improvement in only 1 of 14 patients with panic disorder (Uhde et al 1988).
CONCLUSIONS
Drug Selection
Based on published clinical trials for the treatment of panic disorder, with or without agoraphobia, we can make the following treatment recommendations. Based on a meta-analysis of 27 controlled trials (n = 2348), SSRIs are the drugs of choice for the treatment of panic disorder, over TCAs and BZDs. MAOIs have proven efficacy, but the associated dietary and drug restrictions limit their usefulness. Based on three controlled trials (n = 95), ß-blockers are effective anti-phobic agents but are less effective than antidepressants and BZDs as anti-panic agents. Preliminary data indicate that venlafaxine and valproic acid may have some utility in panic disorder.
Some clinicians utilize a BZD during initial 4 weeks of treatment because of a more rapid onset of effect compared to the antidepressants. The BZD is then tapered over 2 weeks after a good clinical response is achieved and the antidepressant is continued. However, there is concern with the possible abuse potential and withdrawal symptoms. The data suggests that this is primarily a concern in patients with a comorbid diagnosis of alcoholism or poly-substance abuse (Sheehan and Raj 1990).
If a patient fails an adequate trial with one treatment then another, including CBT, should be tried. Though not well studied, combination treatment with various agents has been reported to succeed when individual drugs fail (Jann and Kurtz 1987).
Adverse Effects
Adverse effects with benzodiazepines include sedation, ataxia, short-term memory impairment, and withdrawal signs/symptoms with abrupt discontinuation. Propranolol leads to bradycardia, hypotension, dizziness, and lightheadedness.
In panic patients TCAs have been associated with typical adverse effects such as anticholinergic effects, orthostatic hypotension, weight gain, and sedation. These ADRs are often not well tolerated and have been reported to result in 35% of patients discontinuing treatment (Noyes et al 1989).
Maintenance Treatment
Curtis et al (1993) contrasted the long-term effectiveness of alprazolam (n=134) and imipramine (n=138) to placebo (n=139) in a group of 411 panic disorder with/without agoraphobia. More than twice as many alprazolam (37%, n=50, 6-7 mg/d) and imipramine (35%, n=48, 150-175 mg/d) than placebo (15%, n =21)) patients remained in treatment for the full eight months of the trial. These data demonstrate the long-term efficacy and safety of imipramine and alprazolam and suggest that tolerance does not develop to the therapeutic effect of either drug.
Studying a group of 51 stable patients treated for 6 months with imipramine 2.25 mg/kg/d diagnosed with panic disorder, Mavissakalian (2002) contrasted the effectiveness of 6 months of imipramine maintenance therapy versus 12 to 30 months of maintenance therapy. There were no demographic or clinical variables that predicted relapse risk. The rate of relapse after an only 6 months of maintenance treatment was (10/27, 37%) was identical to the rate of relapse after 12 to 30 months of treatment (9/24, 37.5%).
Medication Termination
It is recommended that any of the available pharmacologic treatments be tapered gradually over a 1- to 3-month period to allow early detection of a relapse. Tapering alprazolam should be done very slowly to avoid significant withdrawal symptoms, especially if higher doses are being used (Pecknold et al 1988, Rickels et al 1993).
If the patient relapses after the first taper, then reinstitution of treatment often achieves clinical control. It is recommended that tapering be tried again in 3-6 months. It appears a large percentage of patients can remain off medications during the second year of treatment, but some will require long-term treatment.
Long-Term Follow-Up
A follow-up study of 49 patients with panic disorder ± agoraphobia who initially received either alprazolam or imipramine in a 9-week study, were followed-up after a period of 6 years (Lepola et al 1996). At six years, 33 of 49 patients were receiving medication at significantly lower doses than during the 9-week study. Seventeen of 33 (52%) were receiving alprazolam, 4 of 33 (12%) imipramine and 12 were switched to an SSRI. At the end of six years, 35 (71%) had no panic attacks, although nine suffered from major depression, six from alcoholism and 18 had agoraphobia (usually mild) (Lepola et al 1996).
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