Medications have been known to be useful in the treatment
of panic disorder for more than 40 years. Most studies have focused
on their ability to stop or reduce the frequency of panic attacks,
but many have also addressed the effect of medication on anticipatory
anxiety, agoraphobic avoidance, limited symptom attacks, associated
depression, and global function. Medications from several classes
have been shown to be effective. When interpreting results from
trials of pharmacological interventions, it is important to consider
the study design and methods for measuring treatment outcome (see Section
V.A) and the funding source of the study.
1. Selective serotonin
Numerous clinical trials indicate that the SSRIs are effective for
the acute and long-term treatment of panic disorder, although there
is no clear evidence of differential efficacy among agents in this
class. Whereas an early meta-analysis (586) suggested
that the effect size for improvement with SSRIs in panic disorder
was significantly greater than for alprazolam or imipramine, subsequent
meta-analyses incorporating a larger number of SSRI studies demonstrated comparable
efficacy for the SSRIs and TCAs, with mixed results regarding the
question of whether dropout rates were lower in studies in which
patients received SSRIs, compared to those for TCAs (587, 588).
Data from a number of large randomized controlled trials demonstrate
the acute and long-term efficacy of fluoxetine for panic disorder
(74, 80, 83). Results from
one multicenter, double-blind, placebo-controlled study demonstrated
that doses of both 10 mg/day and 20 mg/day were
effective, although the 20 mg/day dose was more consistently
effective across a variety of measures (74).
Results for a number of large randomized
controlled trials demonstrate the efficacy of sertraline for the
acute and long-term treatment of panic disorder (76–78, 82, 85).
Results from a fixed-dose randomized controlled trial of 50 mg/day, 100
mg/day, or 200 mg/day of sertraline showed significantly
greater reduction for the SSRI, compared to placebo, on measures
of panic and anxiety, without evidence of a dose-response relationship
Paroxetine, both in its immediate-release and controlled-release
formulation, has demonstrated efficacy for the acute and long-term
(immediate-release formulation) treatment of panic disorder in several
large randomized controlled trials (69, 70, 72, 73, 79, 87).
Ballenger and associates (73) compared placebo to three
doses of paroxetine; the percentages of patients given paroxetine
at daily doses of 40 mg, 20 mg, and 10 mg and patients given placebo
who were subsequently panic free were 86%, 65%,
67%, and 50%, respectively. Only the difference
between 40 mg/day of paroxetine and placebo was statistically
Several randomized controlled trials of fluvoxamine for panic
disorder have also been published, with most (66–68, 84),
although not all (256, 589), demonstrating
efficacy of this agent for panic disorder. In one study (66),
a greater proportion of patients who had been given fluvoxamine
became panic free, compared with those who received placebo (61% vs. 36%).
Fluvoxamine has been shown to be effective in doses from 100 mg/day
to 300 mg/day (84).
Citalopram has also demonstrated acute and long-term efficacy
for panic disorder in large randomized controlled trials (71, 75, 81, 86).
In one double-blind trial in which 475 patients were randomly assigned
to receive citalopram (10–15 mg/day, 20–30
mg/day, or 40–60 mg/day), clomipramine (60–90
mg/day), or placebo, citalopram at 20–30 mg/day
or 40–60 mg/day was significantly superior to
placebo; citalopram at 20–30 mg/day was more effective
than 40–60 mg/day and comparable to clomipramine (71).
In one 10-week, double-blind, randomized controlled trial of escitalopram
and citalopram, administration of escitalopram led to a significantly
greater reduction in panic frequency, compared to placebo, and had
comparable overall efficacy to citalopram (86).
The concerns and debate regarding the relationship between antidepressants
and increased suicidality have already been reviewed (see Section II.H).
There is accruing evidence for a discontinuation syndrome caused
by the abrupt discontinuation of SSRIs (85, 258, 259). Although
most evidence comes from studies of patients who are being treated
with SSRIs for depression, Black and colleagues (67)
studied the effect of abrupt withdrawal of fluvoxamine from patients
with panic disorder after 8 months of treatment. A discontinuation
syndrome characterized by dizziness, incoordination, headache, irritability,
and nausea began within 24 hours, peaked at day 5 after withdrawal,
and was generally resolved by day 14.
There are few data on the optimum length of treatment following
response. Gergel and associates (342) selected patients
who had responded to paroxetine in an acute-phase trial and randomly
assigned them to receive placebo or 10 mg/day, 20 mg/day,
or 40 mg/day of paroxetine for a 12-week maintenance period.
After the maintenance phase, the rate of relapse was significantly
higher among the responders who had crossed over to placebo than
among those whose paroxetine treatment had been maintained (30% vs.
LeCrubier and associates (70) evaluated the efficacy
of paroxetine, clomipramine, and placebo for patients who completed
a 12-week double-blind trial and then chose to continue receiving
the randomly assigned treatment for an additional 36 weeks. Compared
with the placebo-treated patients, the patients who received paroxetine
experienced significantly greater reductions in panic symptoms,
and a larger proportion remained free of panic attacks throughout
the long-term study. There were no significant differences in efficacy
between paroxetine and clomipramine.
Rapaport and associates (85) examined the long-term
efficacy of sertraline in the treatment of panic disorder. Patients received
52 weeks of open-label sertraline treatment followed by a 28-week,
double-blind, placebo-controlled discontinuation trial. Compared
to those blindly tapered and switched to placebo, patients who continued
to receive sertraline were less likely to have an exacerbation of
panic symptoms (13% vs. 33%) or discontinue the
study because of insufficient clinical response (12% vs.
Three large, international, randomized controlled trials have
been performed that together provide support for the efficacy and
safety of venlafaxine ER for panic disorder. In a multicenter study
of 361 individuals with panic disorder without co-occurring depression,
the intent-to-treat population consisted of 160 participants who
were randomly assigned to receive a 10-week course of venlafaxine
ER flexibly dosed from 75 mg/day to 225 mg/day
(initiated at 37.5 mg/day for 4 days) and 168 participants
who were randomly assigned to receive matched placebo (88).
Although this study failed to find a statistically significant difference between
venlafaxine ER and placebo on the a priori primary endpoints (CGI
severity rating and proportion of participants free of panic attacks
at study endpoint), there was a significantly greater reduction
in panic attacks, with overall improvement as rated by the CGI improvement
rating and remission at endpoint (defined as a CGI improvement rating
of 1 or 2 and no panic attacks) for the venlafaxine ER group. In
a second multicenter randomized controlled trial, which included
664 individuals with panic disorder without co-occurring depression,
participants were randomly assigned to receive venlafaxine ER at
fixed doses of 75 mg/day or 150 mg/day, paroxetine
at 40 mg/day, or placebo for 12 weeks after a 2-week placebo
lead-in period (89). All active treatments were found
to be significantly more effective than placebo, with no significant
difference between the venlafaxine ER doses or paroxetine and somewhat
less sedation with the venlafaxine ER doses (3% and 4%)
than with paroxetine (13%). In a third multicenter randomized controlled
trial, which included 653 individuals with non-co-occurring panic
disorder, participants were randomly assigned to receive 225 mg/day
of venlafaxine ER, 75 mg/day of venlafaxine ER, 40 mg/day
of paroxetine, or placebo for 12 weeks after a single-blind placebo
lead-in (590). In this study, a significantly greater
proportion of patients receiving the active medications were panic
free and in remission (defined as a CGI severity score of 1 or 2
or zero panic attacks) at endpoint and had greater response from
weeks 2 or 3 onward as measured by the CGI improvement rating. All active
treatments were generally well tolerated.
An additional study examined the ability of venlafaxine ER
to prevent relapse in individuals whose panic disorder symptoms
had responded to a 12-week course of flexibly dosed (75–225
mg/day) venlafaxine ER (344). Of the 89 individuals
who had been randomly assigned to receive venlafaxine ER, time to
relapse was significantly longer than in the 80 individuals assigned
to receive placebo. During the 26-week follow-up period, secondary
measures of therapeutic efficacy, including quality of life and
disability, also showed a significant benefit for venlafaxine ER
treatment, relative to placebo.
There are currently no systematic data available on the use of
duloxetine in panic disorder, although its similar mechanism of
action to venlafaxine suggests it could be a potentially effective
3. Tricyclic antidepressants
The first controlled study documenting the efficacy of the TCA
imipramine in blocking panic attacks was conducted by Klein and
published in 1964 (90). In this study, imipramine was superior to
placebo for antipanic effect and for change in the CGI. Since then,
numerous controlled trials have shown that imipramine is effective
in reducing panic attacks (91, 92, 94–102, 104, 105, 107, 108, 111).
After treatment with imipramine, 45%–70% of
patients were found to be panic free, compared to 15%–50% of
those receiving placebo. In addition, patients with panic disorder
who were treated with imipramine had less agoraphobic avoidance
and anticipatory anxiety than those receiving placebo.
A number of placebo-controlled randomized trials have documented
the acute and long-term efficacy of clomipramine for panic disorder
(70, 72, 79, 103, 109, 110). Clomipramine
appears at least as effective as imipramine for panic disorder (93);
in the one double-blind, placebo-controlled study addressing this
issue, clomipramine (mean dose of 109 mg/day) was superior
to both imipramine (mean dose of 124 mg/day) and placebo
in panic reduction and decrease in score on the Hamilton anxiety
scale (102). Most placebo-controlled studies comparing
clomipramine to an SSRI demonstrate equivalent efficacy, although
with a less favorable side effect profile for the TCA.
The few studies that have evaluated other TCAs for panic disorder
support the efficacy of desipramine (106) and nortriptyline
(112). However, randomized trials comparing desipramine
with clomipramine (591) and maprotiline with fluvoxamine
(272) both found the more noradrenergic TCA to be less
effective than the serotonergic comparator.
Several research studies have shown that some patients with panic
disorder are sensitive to both the beneficial and adverse effects
of TCAs (91, 106). For example, Zitrin
and associates (91) found that 20% of the
patients in their study could not tolerate doses of imipramine higher
than 10 mg/day but still experienced panic blockade. Higher
doses of TCAs are associated with a higher dropout rate in research
studies. For example, Mavissakalian and Perel (108)
reported that among subjects treated with an average of 35 mg/day,
99 mg/day, and 200 mg/day of imipramine, the dropout
rates because of drug side effects were 6%, 15%,
and 36%, respectively.
Few studies have rigorously addressed the optimum dose of TCAs
for panic disorder. In most research studies, the mean final dose
is approximately 150 mg/day of imipramine and the maximum
final dose is up to 300 mg/day. Mavissakalian and Perel
(108) randomly assigned patients with panic disorder
to low-dose (mean, 35 mg/day), medium-dose (mean, 99 mg/day),
and high-dose (mean, 200 mg/day) imipramine. They found
that both the medium and high doses were superior to placebo in
reducing panic and not significantly different from each other;
the low dose was no more effective than placebo.
There is a suggestion in the literature that clomipramine
may be effective in somewhat lower doses than imipramine. Clomipramine
can generally be used effectively with doses less than 150 mg/day.
Given the results of the studies by Modigh and associates (102)
and Cassano and colleagues (93), it may be reasonable
to administer clomipramine in a dose range of 25–150 mg/day.
Most controlled trials of TCAs for the treatment of panic
disorder were for a minimum of 8 weeks, and time to patients' response
has not always been reported. There are few long-term studies of
TCA treatment for panic disorder in the literature. Cassano and
colleagues (99) continued to treat patients with imipramine
or placebo for 6 months after an acute-phase 8-week study and found
that imipramine remained superior to placebo for panic reduction.
Curtis and associates (104) also maintained patients
on a regimen of placebo or imipramine for up to 8 months after acute
8-week treatment and found that the placebo-treated patients had
more panic attacks and agoraphobic avoidance and were more likely
to drop out of treatment during the maintenance phase. The limited
available data are mixed about whether patients who remit during
treatment benefit more from over a year of subsequent treatment, compared
with 6 months of continued pharmacotherapy prior to discontinuation
(343, 592, 593). In one study
that examined the impact of longer-term treatment with imipramine on
relapse, relapse rates for a combined group of patients who were
randomly assigned to receive placebo discontinuation or open discontinuation
after 12–30 months of remission were compared with relapse
rates for patients randomly assigned to placebo discontinuation
after 6 months of remission (592). The rates of reported
relapse were nearly identical for the two groups (37%)
during the follow-up period after discontinuation, suggesting that
the achievement of remission prior to treatment discontinuation
may be a more critical determinant in preventing relapse than the
subsequent duration of maintenance therapy.
Alprazolam has been studied more extensively than any other
benzodiazepine for the treatment of panic disorder and is approved
by the FDA for the treatment of panic disorder. Eleven trials of
alprazolam IR for treatment of panic disorder have been published,
including the Cross-National Collaborative Panic Study, which involved
more than 1,000 patients randomly assigned to receive imipramine,
alprazolam, or placebo (594). Nine of the trials were
double-blind, and seven were placebo-controlled. Two meta-analyses
of studies on alprazolam treatment for panic disorder are also available
In six of the seven double-blind,
placebo-controlled trials, alprazolam was found to be superior to
placebo in the treatment of panic attacks (104, 116, 118, 122, 123, 126),
although the remaining trial did not assess panic attacks as an outcome
measure (276). The percentage ranges of patients who
were panic free (generally assessed over a 1-week period) at endpoint
were 55%–75% for alprazolam (at doses
of 5–6 mg/day) and 15%–50% for
placebo. These percentages represent the intent-to-treat proportions
(i.e., the panic-free proportion of patients who were originally
assigned to receive active treatment or placebo at the start of
the trial); the differences between the completers were less striking
or nonsignificant because of higher dropout rates for the nonresponders
in the placebo groups. Alprazolam was superior to placebo in reducing
agoraphobic avoidance in five of the six studies in which it was
assessed, disability in five of five studies, anticipatory anxiety
in three of three studies, and Hamilton anxiety scale scores in
six of seven studies. In most of the studies, patients with primary
current major depression were excluded and the level of agoraphobic
avoidance was moderate.
Four of the 11 trials compared alprazolam to imipramine (104, 126, 221, 594).
Three of these trials were double-blind. Alprazolam and imipramine
were comparable in efficacy as measured by reduction of panic attacks
and phobias, Hamilton anxiety scores, disability ratings, and CGI
ratings. More dropouts occurred in the imipramine group in three
of the four studies.
These data support the efficacy of alprazolam (especially in
the 5–6 mg/day range) in treating multiple dimensions
of illness in patients with panic disorder who do not have primary
current major depression. A sustained-release form of alprazolam
is FDA-approved for once-daily dosing based on two placebo-controlled
studies (125, 129).
Fourteen studies regarding other benzodiazepines have also
been published (113–117, 119–122, 124, 127, 128, 130–132).
These studies support the short-term efficacy of other benzodiazepines
for panic disorder. The agents studied include clonazepam (effective
in the three double-blind, placebo-controlled trials and the only
other FDA-approved benzodiazepine besides alprazolam), diazepam
(effective in two of two trials, both double-blind and one placebo-controlled),
and lorazepam (equivalent to alprazolam in three of three double-blind
trials). One study showed superiority of imipramine over chlordiazepoxide.
Three controlled trials have established that the short-term
(4–6 week) addition of benzodiazepines (alprazolam and
clonazepam) to antidepressants produces a more rapid therapeutic
response (100, 222, 223).
Whereas no discontinuation problems were reported in the two studies
using the longer half-life clonazepam added to an SSRI and a 3-week taper
(222, 223), 10 of 17 patients in the alprazolam
study were unable to taper from 1.5 mg/day to discontinuation
in 2 weeks after 4–6 weeks of treatment added to imipramine (100).
The adverse effects of benzodiazepines in patients with panic disorder
appear similar to those reported when benzodiazepines are used for
other indications. They include primarily sedation, fatigue, ataxia,
slurred speech, memory impairment, and weakness. Some sedation or
drowsiness occurred in 38%–75% of alprazolam-treated
subjects and 11%–21% of those taking
placebo. In addition, an increased risk of motor vehicle accidents
in association with benzodiazepine use has been reported (288).
In geriatric patients, the risk of falls and fractures appears to
be greater in individuals taking a benzodiazepine, regardless of
the medication half-life or duration of use (283–287, 295, 458, 595, 596).
Memory problems were reported by up to 15% of patients taking
alprazolam and 8.5% of patients taking placebo in the Cross-National
Collaborative Panic Study (101). However, patients
may not recognize their own cognitive impairment, which limits spontaneous
reporting of this side effect and has prompted several controlled
studies to more systematically investigate the cognitive effects
of these agents in people with panic disorder. Two placebo-controlled
studies have examined the effects of alprazolam on short-term memory
at baseline and in the acute (8–12 week) treatment phase
in small samples of patients with panic disorder (about 20 patients
per group). In one study using alprazolam IR at a mean dose of 5.5
mg/day, some evidence of memory impairment was found (292),
whereas no evidence of memory impairment was found in another study
using alprazolam extended release at a mean dose of 4 mg/day
(293). A follow-up of the positive study found that,
3.5 years after discontinuation, there were no long-term memory
deficits, suggesting that there is no carryover effect after medication
has been discontinued (597). Two other reports, one
meta-analysis (598) and one review (296),
do not provide convincing evidence of long-term cognitive effects
of benzodiazepines in mixed groups of patients because of the spotty
nature of the findings and because many studies have serious methodologic
Major concerns about benzodiazepine tolerance and withdrawal
have been raised. However, according to the report of the APA Task
Force on Benzodiazepine Dependence, Toxicity, and Abuse, "There
are no data to suggest that long-term therapeutic use of benzodiazepines
by patients commonly leads to dose escalation or to recreational
abuse" (294). The studies of long-term alprazolam
treatment for panic disorder show that the doses patients use at
32 weeks of treatment are similar to those used at 8 weeks, indicating
that, as a group, patients with panic disorder do not escalate alprazolam
doses or display tolerance to alprazolam's therapeutic
effects, at least in the first 8 months of treatment. Furthermore,
data in the more severely ill Medicaid population with a mix of mostly
mood and anxiety disorder diagnoses show that long-term use of benzodiazepines
(at least 2 years) does not typically result in dose escalation,
with the incidence of escalation to a high dose being 1.6% (346).
Nevertheless, studies of dose escalation following longer periods
of benzodiazepine use, especially in specific cohorts of patients
with panic disorder, are lacking, making it difficult to draw definitive
conclusions about the potential for benzodiazepine tolerance in the
clinical treatment of panic disorder.
In terms of the occurrence of benzodiazepine withdrawal symptoms,
studies of alprazolam discontinuation in patients with panic disorder
demonstrated that significant numbers (ranging from 33% to
100%) are unable to complete a taper of the medication
after 6 weeks to 22 months of treatment. Another study showed that,
compared with imipramine, alprazolam causes significantly more withdrawal
symptoms, recurrent panic attacks, and inability to discontinue
the medication (351). An additional study suggested
that patients with panic disorder have more difficulty during tapering
of alprazolam than do those with generalized anxiety disorder, even when
the patients in both groups are treated with similar doses (599).
Difficulties during alprazolam tapering seem most severe during
the last half of the taper period and the first week after the medication
is discontinued. In many instances, it is difficult to determine
the extent to which symptoms are occurring because of withdrawal,
rebound, or relapse.
The one study comparing diazepam to alprazolam for panic disorder
indicated that both are no different from placebo during gradual
tapering of the first half of the dose (600). With
abrupt discontinuation of the remaining dose, however, alprazolam
caused significantly more anxiety, relapse, and rebound. This finding
is consistent with reports of the APA Task Force on Benzodiazepine
Dependence, Toxicity, and Abuse (294), which suggest
that there are more difficulties with short half-life, high-potency
compounds. However, apart from this one study, the issue of discontinuation
of benzodiazepines with short versus long half-lives or high versus
low potency has not been adequately addressed in relation to panic
disorder. In addition, studies by Schweizer, Rickels, and associates
(126, 351) of benzodiazepine-treated patients
with other psychiatric disorders show no significant effect of half-life
on the results of a gradual taper, but greater withdrawal severity
after abrupt discontinuation with compounds that have shorter half-lives
and with higher daily doses. Taken together, these studies suggest
that half-life is less of a factor, or in fact may not be important, given
a gradual taper schedule.
Other data suggest that certain personality traits may increase
the likelihood of discontinuation effects in panic disorder patients.
In one study of 123 patients with panic disorder, after accounting
for the effects of dose and duration of alprazolam use, as well
as pretreatment anxiety and panic frequency, measures of anxiety
symptom sensitivity and avoidance predicted difficulty discontinuing
alprazolam during a tapered, gradual withdrawal process (353).
Very few studies have empirically evaluated dosing of benzodiazepines
for panic disorder. Two studies compared alprazolam doses of 6 mg/day
and 2 mg/day (95, 278). One of
the studies showed a significant advantage for the higher dose in reducing
frequency of panic attacks (95). The other study showed very little
difference between the higher and lower doses; absence of panic
attacks at study end was found for 65% of patients taking
the higher dose, 50% of those taking the lower dose, but
only 15% of those taking placebo (278). However,
the rates of surreptitious benzodiazepine use for the lower-dose
(23%) and placebo (35%) patients were considerably
greater than the rate for the patients taking the higher alprazolam
dose (4%) (278), perhaps suggesting that the
patients did not find the lower dose or placebo clinically effective.
In addition, adverse side effects were more pronounced at the higher
dose than at the lower dose of alprazolam in that study.
In one multicenter dose-ranging trial, patients with panic disorder
were randomly assigned to placebo or one of five fixed doses (0.5
mg/day, 1 mg/day, 2 mg/day, 3 mg/day,
or 4 mg/day) of clonazepam (601). During 6
weeks of treatment, the minimum effective dose was 1 mg/day,
and daily doses of 1 mg/day and higher were equally effective
in reducing the number of panic attacks.
The dosing of other benzodiazepines in the treatment of panic
disorder is less well established. In controlled studies, lorazepam
has been given at doses of about 7 mg/day, usually two
or three times daily (119, 128). Diazepam
doses ranged from 5 mg/day to 40 mg/day in two
published trials (115, 116).
Very few data indicate the optimum length of maintenance therapy
for responders to benzodiazepines. Two published trials have compared
maintenance imipramine, alprazolam, and placebo treatment, and both
suggested that imipramine may be superior. In the study by Cassano
and colleagues (99), patients who received imipramine
and those who received alprazolam fared equally well in terms of
panic reduction during a 6-month maintenance phase, but the imipramine-treated
patients had less agoraphobic avoidance. There were more dropouts
in the alprazolam group during the maintenance phase than during
the 8-week acute treatment phase, whereas the number of dropouts
in the imipramine group did not differ between the two phases. Curtis
and associates (104) found that from month 4 through
the end of an 8-month maintenance phase patients taking imipramine
had virtually no panic attacks, whereas alprazolam-treated patients
continued to experience infrequent panic attacks. On all other measures,
however, the two medications performed equally well. In a third
investigation by Lepola and colleagues (602), 27 patients
who had been treated with alprazolam and 28 patients who had been
treated with imipramine in a 9-week trial were then followed for
3 years in a naturalistic study. Significantly more alprazolam users
than imipramine users were found to still be using their original medication
after 3 years (74% vs. 32%). The authors pointed out
that it is difficult to know whether this difference is attributable
to a better long-term response among the imipramine users than among
the alprazolam users, a greater degree of intolerable side effects
for the imipramine users, or greater difficulty in discontinuing
treatment among the alprazolam users because of physiologic dependence.
a. Monoamine oxidase
No studies of the nonselective MAOIs phenelzine and tranylcypromine
have been performed since the diagnosis of panic disorder was introduced
in DSM-III. The most modern and rigorous study (603)
involved the use of phenelzine for the treatment of "phobic
neurosis" (604). This study included patients
with what would now be called panic disorder and found phenelzine
to be effective (297).
Four studies have examined the effectiveness of moclobemide,
a reversible inhibitor of monoamine oxidase A, in panic disorder,
and the results are only modestly encouraging. Although two studies
with active comparators, but no placebo, showed comparable efficacy
to both fluoxetine (298) and clomipramine (299),
respectively, the only two published placebo-controlled studies
of this medication failed to show an effect greater than placebo
(300, 301). Although the MAO-B inhibitor
selegiline is available in the United States, there are no data
to support its efficacy for the treatment of panic disorder.
There is minimal support for the use of trazodone in panic disorder.
Although a single-blind study of 11 patients with panic disorder
treated with trazodone found significant improvement in panic symptoms
compared to a baseline period of placebo treatment (307),
a double-blind study in which 74 patients with panic disorder were
assigned to trazodone, imipramine, or alprazolam showed trazodone
to be less effective than either imipramine or alprazolam (221).
Further, a study of trazodone flexibly dosed from 50 mg/day
to 300 mg/day (mean, 178 mg/day) alone and as
augmentation to CBT failed to show greater efficacy with trazodone
or combination therapy than with CBT alone, and patients who took trazodone
had greater rates of side effects and study discontinuation (308).
c. Bupropion and
bupropion sustained release
Bupropion has been found to be effective in the treatment
of depression, but there is little systematic study of its efficacy
in panic disorder, and the available data are contradictory. Two small
uncontrolled trials have been published, one positive and one negative.
In the positive trial, which included 20 patients, bupropion sustained
release flexibly dosed at 200 mg b.i.d. was effective and well tolerated
(313). In the negative trial, which included 12 patients,
bupropion immediate release at high doses of 300–700 mg/day
was associated with significant side effects, including myoclonus
and one seizure (314).
Although there are a few small, positive open-label reports examining
nefazodone in panic disorder, large randomized controlled trials
are lacking (605), and there are concerns about liver
Although there are a few open short-term studies supporting the
potential efficacy of mirtazapine for panic disorder (315–319)
and a very small randomized controlled trial (involving 27 patients)
of mirtazapine compared with paroxetine suggesting similar efficacy
(320), substantial side effects have been noted, and
no data from large randomized controlled trials are available.
Reboxetine, a norepinephrine reuptake inhibitor, is currently not
available for use in the United States or Canada. Reboxetine has
been studied with preliminary support for its efficacy and safety
in a small randomized controlled trial involving 42 patients in
Europe and Brazil (606) and an open-label trial for resistant
patients (607), with mixed support in single-blind comparison
with SSRIs (608, 609).
There are limited data concerning the use of anticonvulsant medications
in the treatment of panic disorder. One randomized controlled trial
of gabapentin in 103 patients with panic disorder provided partial
support for its efficacy and safety (321). The only
other randomized study, a small placebo-controlled trial, suggested
that carbamazepine was not effective for panic disorder (328).
Data from small open-label studies support the efficacy of valproic
acid (322–324) and levetiracetam
(326), and very preliminary case report data support
the efficacy of tiagabine (327) and vigabatrin (327), but
more rigorous studies of these medications are needed.
There is minimal evidence that first-generation antipsychotic medications
are effective for panic disorder. In small open-label trials, significant
reductions in symptoms were observed in patients with treatment-resistant
panic disorder treated with olanzapine (329) and adjunctive
risperidone (330). Double-blind, randomized controlled
trials are needed.
A limited number of trials of antihypertensive medications have
been conducted in panic disorder. Results with beta-adrenergic blocking
agents are mixed but suggest that propranolol offers peripheral
blockade but is ineffective and/or less effective than
benzodiazepines (115, 332, 333).
A single small, 4-week, randomized controlled trial that included
25 patients supported the potential efficacy of pindolol, dosed
2.5 mg t.i.d., as augmentation for patients with panic disorder
resistant to 8 weeks of treatment with an SSRI (334).
Data are even more limited for calcium channel blockers (335)
and clonidine (336, 337) and suggest only
mild and/or transient effects, if any, for panic disorder.
Although inositol is rarely used clinically for panic disorder, two
small studies have supported its potential efficacy in treatment
of panic disorder (216, 217).
Minimal data are available
on the use of buspirone in panic disorder, and no systematic controlled
trials support its efficacy. Two reports suggest that buspirone
monotherapy is not effective for panic disorder (338, 339),
and a randomized controlled trial examining augmentation of CBT
does not suggest additional efficacy with buspirone (340).