Newer Antidepressants and Panic Disorder A.5

Review article 33
Newer antidepressants and panic disorder: a meta-analysis

Costanza Andrisanoa, Alberto Chiesaa,b and Alessandro Serrettia
Selective serotonin reuptake inhibitors and venlafaxine are reboxetine and fluvoxamine, all drugs were associated
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currently considered as first-line agents for patients with with significantly lower dropout rates as compared with
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panic disorder (PD). However, a systematic comparison placebo. Several clinical variables moderated clinical
of newer antidepressants for the treatment of PD is lacking outcomes. However, because of some inconsistencies
thus far. Eligible studies focusing on PD patients treated across the studies and limited evidence for some
with newer antidepressants were entered in the Cochrane drugs under investigation, further head-to-head
Collaboration Review Manager. Our primary outcome comparisons are required. Int Clin Psychopharmacol
measure was the mean change in panic symptoms from 28:33–45 c 2012 Wolters Kluwer Health | Lippincott
the baseline to the endpoint in patients treated with Williams & Wilkins.
antidepressants as compared with those treated with International Clinical Psychopharmacology 2013, 28:33–45
placebo. Secondary outcome measures included the mean
change in the overall anxiety scores and dropout rates. Keywords: antidepressants, mirtazapine, panic disorder, reboxetine,
selective serotonin reuptake inhibitors, venlafaxine
Sensitivity analyses were also carried out. Fifty studies
a
focusing on 5236 patients were included. The following Institute of Psychiatry, University of Bologna, Bologna, Italy and bSection
of Pharmacology, Department of Clinical and Experimental Medicine and
antidepressants were significantly superior to placebo Pharmacology, University of Messina, Messina, Italy
for PD patients with the following increasing order of
Correspondence to Alberto Chiesa, MD, Institute of Psychiatry, University
effectiveness: citalopram, sertraline, paroxetine, fluoxetine, of Bologna, Viale Carlo Pepoli 5, 40123 Bologna, Italy
and venlafaxine for panic symptoms and paroxetine, Tel: + 39 051 6584233; fax: + 39 051 521030; e-mail: albertopnl@yahoo.it
fluoxetine, fluvoxamine, citalopram, venlafaxine, and Received 26 April 2012 Accepted 12 September 2012
mirtazapine for overall anxiety symptoms. Aside from
Introduction Nardi, 2010; Zobel and Maier, 2010; Batelaan et al.,

Pharmacological options approved by current guidelines 2011; Freire et al., 2011), a systematic comparison of
for the treatment of panic disorder (PD) include tricyclic newer antidepressants (Cipriani et al., 2009) for the
antidepressant, benzodiazepines, monoamine oxidase treatment of PD on the basis of a quantitative meta-
inhibitors, selective serotonin reuptake inhibitors analytic approach is lacking thus far. Therefore, the
(SSRIs), and serotonin–norepinephrine reuptake inhibi- extent to which different antidepressants vary in terms of
tors (Pollack et al., 2003a; Royal Australian and New efficacy and acceptability is unclear. However, such
Zealand College of Psychiatrists Clinical Practice Guide- information could provide clinicians with a useful tool
lines Team for Panic Disorder and Agoraphobia, 2003; for guiding clinical choices on the basis of rigorous
Baldwin et al., 2005; Bandelow et al., 2008; American empirical evidence and for possibly enhancing treatment
Psychiatric Association, 2009). With little differences outcomes.
among guidelines, SSRIs and the serotonin–norepine-
Accordingly, the aim of this meta-analysis is to compare
phrine reuptake inhibitor venlafaxine are currently
the short-term efficacy and tolerability of newer anti-
considered as first-line agents for PD patients because
depressants for the treatment of PD. In addition, we aim
of their favorable balance of efficacy and side effects’
to investigate whether the main outcomes of interest are
profile. Tricyclic antidepressants and monoamine oxidase
moderated by a number of easily available clinical
inhibitors should be considered as alternative choices
variables such as the duration of illness, the age of the
only when patients do not seem to respond to or tolerate
patient, and the comorbidity with other psychiatric
first-line treatments (Bandelow et al., 1995; Bandelow and
disorders.
Ruther, 2004; Bakker et al., 2005).
A critical evaluation of current guidelines, however, points
to the dearth of information as to which pharmacological Methods
compound can be best tailored to the specific needs of Literature research
each individual patient. Furthermore, although several A literature research was carried out using MEDLINE,
reviews have been published recently that deal with the ISI Web of Science, the Cochrane database, and
pharmacological approaches of PD (e.g. Mochcovitch and references of retrieved articles. The research included
articles written in English published up to January 2012.
All supplementary digital content is available directly from the corresponding In line with a recent meta-analysis focusing on the
author. efficacy and tolerability of newer antidepressants for
0268-1315
c 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/YIC.0b013e32835a5d2e
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
34 International Clinical Psychopharmacology 2013, Vol 28 No 1
patients with major depression (Cipriani et al., 2009), Of note, in case of overlapping samples, the decision to
we focused on the same drugs for patients with PD. include a given study was made on the basis of the
The main keywords were bupropion, citalopram, duloxetine, following algorithm: (i) when no difference existed
escitalopram, fluoxetine, fluvoxamine, milnacipran, mir- between two studies in terms of outcome measures, we
tazapine, paroxetine, reboxetine, sertraline, and venlafax- considered the study with the largest sample size and
ine in combination with ‘panic disorder’. (ii) when the studies provided different outcomes, we
chose the study whose outcomes were more in line with
the criteria of the present meta-analysis.

Selection of trials
Two reviewers independently searched eligible articles
for inclusion (A.C. and C.A.). The studies included had
Data extraction and analysis
to: (a) focus on patients with PD (age > 18) with or
Data were independently extracted from original reports
without further psychiatric comorbidities; (b) use one or
by two reviewers (A.C. and C.A.). The quality of the
more antidepressants mentioned above; (c) provide
included article was assessed independently by the
information about the efficacy of the antidepressant(s)
two reviewers using validated quality scales [the Jadad
under investigation on anxiety symptoms and/or on panic
Scale (Jadad et al., 1996) for controlled studies and the
symptoms; and (d) have a minimum duration of 6 weeks.
Newcastle–Ottawa Scale (Wells et al., 2005) modified for
The following articles were excluded: (a) case reports and
uncontrolled studies for the remaining studies].
case series; (b) review articles and meta-analyses; (c)
For controlled trials, a score of more than or equal to 3
long-term studies (lasting >12 weeks) that did not
was considered to be indicative of a high quality (Jadad
provide information about the improvement in anxiety
et al., 1996), whereas for uncontrolled ones, a score of
levels or panic symptoms in the short term (6–12 weeks);
more than or equal to 4 was considered as indicative of
(d) studies investigating samples of patients treated with
high quality (Wells et al., 2005). All disagreements were
different antidepressants but that did not provide
resolved through discussion and, in case of persistent
separate information about each specific antidepressant;
disagreement, with the involvement of a third reviewer
(e) studies focusing on PD patients in remission at study
(A.S.). No final disagreement was observed. All data were
entry; and (f) studies focusing on the combination of a
referred to the intention-to-treat populations, when
pharmacological treatment with a nonpharmacological
available. Otherwise, the completers’ sample was ana-
therapy of any kind. Studies with different methodolo-
lyzed. In addition, when one study included two (or
gical designs were included. However, sensitivity analyses
more) treatment arms of patients treated with the same
were carried out to estimate the impact of study design
antidepressant at different dosages, we separately con-
on the outcomes of interest (see below).
sidered each treatment arm as if they were two (or more)
independent studies.
Outcome measures
Effect sizes of improvement were calculated by Hedges’s
Our primary outcome measure was the mean change in
g (Hedges and Olkin, 1985). Because many studies
panic symptoms from the baseline to the endpoint in
included more than one assessment scale for the
patients treated with antidepressants as compared with
symptoms’ categories under investigation (panic symp-
those treated with placebo. Secondary outcome measures
toms and anxiety), we first calculated one effect size for
included the mean change in the overall anxiety scores
each scale. Then, we calculated one weightened effect
and dropout rates in patients treated with antidepres-
size for each type of measure (panic symptoms and
sants as compared with those treated with placebo.
anxiety symptoms) for each study (Mullen, 1989; Cohen,
Scales specifically designed to measure panic symptoms 1992; Shieh, 2012).
(e.g. the Panic Disorder Severity Scale; Shear et al., 1997)
In addition, because better estimates can be derived
were entered into the analysis specifically dealing with
when there are many samples and reasonable sample sizes
the severity of PD symptoms (primary outcome mea-
(Hunter and Schmidt, 1990), in accordance with previous
sure). Anxiety scales that were not specific for the
meta-analyses (e.g. Reger et al., 2004; Lopez-Leon et al.,
assessment of PD symptoms [e.g. the Hamilton Rating
2008), we focused only on drugs investigated in at least
Scale for Anxiety (Hamilton, 1959)] were included in the
three independent studies. Indeed, although there are no
analysis focusing on overall anxiety levels.
clear guidelines on this topic, there are no statistical
Whenever it was possible, we referred to the 8-week procedures to detect publication bias when the number
treatment outcomes. If 8-week data were not available, of primary studies is low. Data for drugs investigated in at
we used data ranging between 6 and 12 weeks (we gave least three independent studies were entered into the
preference to the time-point considered in the original Cochrane Collaboration Review Management Software
study as the endpoint). Patients who terminated the (RevMan version 5.1; Cochrane Collaboration, Oxford,
study before the endpoint for any reason were considered UK) and analyzed by RevMan analysis 1.01. For dichoto-
as dropouts. mous outcomes, odds ratios and their 95% confidence
Antidepressant and panic Andrisano et al. 35
intervals (CIs) were calculated, whereas for continuous inclusion and the exclusion criteria were applied to the
outcomes, the standardized mean differences and their remaining 136 studies, 86 studies were excluded and 50
95% CIs were calculated. For both dichotomous and studies could be included in the present meta-analysis
continuous outcomes, a random-effect model was used, (10 concerning citalopram, seven fluoxetine, eight
which takes into account possible differences in the fluvoxamine, five mirtazapine, 15 paroxetine, three
implementation of intervention and the characteristics reboxetine, four sertraline, and six venlafaxine; Fig. 1).
of the participants included. Among the studies included, 26 studies used a rando-
mized-controlled design, three studies used a nonrando-

Heterogeneity across the studies was assessed by the w2
mized-controlled design, and 21 studies used an
and I2 statistics and by visual inspection of the results.
uncontrolled design. A summary of the studies included
A w2 statistic P less than 0.05 as well as an I2 statistic
is shown in Tables 1 and 2. Twenty-five out of 29
higher than 50% were considered to indicate hetero-
controlled studies and 10 out of 21 uncontrolled studies
geneity. Moreover, for studies that did not include a
were considered to have a high-quality design (supple-
placebo control group, we calculated the weighted mean
mentary data 1). Bupropion, duloxetine, escitalopram,
of the placebo samples for the considered variable from
and milnacipran were excluded from the analyses because
placebo-controlled studies that investigated the same
they were investigated in less than three studies.
variable and applied it to studies not including a placebo
group (Durrleman and Chaikin, 2003; Serretti and
Mandelli, 2010). In such cases, the sample size of the Primary outcome measure
virtual placebo group was considered as equal to the All antidepressants under investigation, with the excep-
number of patients treated with antidepressants in the tion of mirtazapine, reboxetine, and fluvoxamine, were
specific studies that did not include a placebo group to significantly more efficacious than placebo on panic
avoid inflation of the estimate. Also, for studies that did symptoms with the following increasing order of effec-
not provide the SD for continuous variables, we tiveness: citalopram, sertraline, paroxetine, fluoxetine,
calculated the weighted mean of SDs provided by studies and venlafaxine (Fig. 2 and supplementary data 2).
investigating the same measure and providing SD and we
applied it to studies not providing such measures Secondary outcome measures
(Furukawa et al., 2006). In terms of secondary outcomes, we found that, aside from
reboxetine, and sertraline which were found not to sig-
Additional sensitivity analyses were carried out on nificantly different from placebo, all drugs were effective in
randomized-controlled studies, placebo-controlled stu- reducing anxiety levels (Fig. 2 and supplementary data 2).
dies, antidepressant monotherapy studies, nonsponsored More in detail, we observed that paroxetine, fluoxetine,
studies (studies were considered as sponsored if they fluvoxamine, citalopram, venlafaxine and mirtazapine had
were funded, at least in part, by a pharmaceutical an increasing effect on the reduction of anxiety symptoms,
company or if at least one of the authors was a member paroxetine being the drug with the smallest effect and
of a pharmaceutical company), and studies focusing on mirtazapine the drug with the largest effect.
PD patients without comorbidity to determine whether
efficacy measures and dropout rates varied as a function In terms of dropout rates, we found that they were
of these variables. Moreover, the influence of several key significantly higher in patients treated with placebo as
variables on the main outcomes of interest, including (a) compared with patients treated with antidepressants,
the mean dosage of antidepressants, (b) time considered with the only exception of fluvoxamine and reboxetine
as the endpoint in the present meta-analysis, (c) mean (Fig. 2). More in detail, the following drugs were
age of the sample, (d) percentage of female patients, (e) associated with decreasing dropout rates: venlafaxine,
duration of illness, and (f) study’s quality, was calculated fluoxetine, sertraline, paroxetine, citalopram, and mirta-
using the meta-regression model within the statistics zapine (supplementary data 2). Note, however, that
environment R, version 2.8.1 (http://www.R-project.org), a significant heterogeneity was observed in the analyses,
package ‘metaphor’. The existence of a possible publica- indicating that clinical improvement and dropout rates
tion bias was assessed by visual inspection of the funnel showed large variations across the studies (supplementary
plots and by calculating quantitatively the influence of data 2).
the publication bias by Egger’s analysis (Egger et al.,
1997). Sensitivity analyses
Improvement in panic symptoms
When we focused on randomized-controlled studies and
Results on placebo-controlled studies separately, sertraline was no
Search result longer superior to placebo. In antidepressant monother-
The original search identified 5169 papers. Five thousand apy studies, we found that only fluoxetine and venlafaxine
and thirty-three studies were excluded because they did were significantly more effective than placebo. More-
not examine the use of antidepressants in PD. After the over, paroxetine was the only drug superior to placebo in
Fig. 1
Total number of citations retrieved from

literature researches (N = 5169)
Articles not investigating

antidepressants for PD (N = 5033)
Articles retrieved and evaluated in full for

inclusion (N = 136)
Articles included (N = 50) Articles excluded (N = 86)
Reason for exclusion:
- Insufficient clinical data (N = 37)
- Long-term study (lasting more than 12 weeks) not

providing information about the improvement on
anxiety levels in the short term (N = 11)
- Lack of information about improvement on anxiety

levels (N = 10)
- Insufficient duration of the study (N = 8)
- Studies focusing on PD patients in remission at study

entry (N = 6)
- The drug is associated with a non pharmacological

therapy (N = 6)
- Data referred to more SSRIs joined together (N = 3)
- Same sample of another study (N = 3)
- Clinical endpoint data concern only drug responders

(N = 1)
- Patients’ age<18 (N = 1)
Flow diagram of the review process.
studies without a sponsor. Finally, with the only ex- treatment of PD. In particular, when randomized-
ception of reboxetine, all antidepressants under investi- controlled studies were considered separately, we ob-
gation were more effective than placebo in treating served that mirtazapine, paroxetine, and sertraline were
PD patients without comorbidities (supplementary no longer superior to placebo. However, when we focused
data 3). only on placebo-controlled studies, paroxetine was
associated with a higher improvement in anxiety levels
from the baseline to the endpoint compared with that
Improvement in anxiety levels observed in the general analysis, whereas the same was
The use of different study designs had a significant not true for sertraline (see supplementary data 3). When
impact on the efficacy of several antidepressants in the studies allowing only antidepressant monotherapy were
Table 1 Main characteristics of the studies included

Drug range or Study Time considered in Number of
mean dosage Concomitant duration our study as the patients %
References Drug (mg) anxiolitics (weeks) endpoint (ITT) women Mean age Comorbidities Sponsor
Amore et al. Fluoxetine 10–50 Yes 8 + 24 T8 14 58 37.0±7.1 No No

(1999)
Ballenger et al. Paroxetine 10 No 10 T10 67 70 36.1±9.1 No Yes
(1998)
Paroxetine 20 No 10 T10 70 66 35.9±10.1 No –

Paroxetine 40 No 10 T10 72 60 36.3±10.8 No –
Placebo – No 10 T10 69 68 37.3±10.4 – –
Bandelow Paroxetine 48.1±11.2 Yes 12 T12 113 66 38.1±11.7 No Yes
et al. (2004)
Sertraline 84.5±39.1 Yes 12 T12 112 60 39.6±11.7 – –
Bertani et al. Paroxetine 40 No 12 T12 30 50 32.2±9.3 No No
(2004)
Reboxetine 8 No 12 T12 27 56 29.3±10.1 – –
Black et al. Fluvoxamine 230 No 8 T8 23 60 35.1±10.4 MD Yes
(1993)
Placebo – – 8 T8 23 64 37.0±9.9 – –
Boshuisen Mirtazapine 36.3 Yes 12 T12 19 63 43.2±11.5 No Yes
et al. (2001)
Coplan et al. Fluoxetine 17.7±16. Yes 12 T8 13 59 – No No
(1995)
Carli et al. Mirtazapine 30 No 12 T12 15 47 41.13±9.71 MD No
(2002)
Dannon et al. Reboxetine 8 No 6 T6 24 58 38.8±12.81 No No
(2002)
Den Boer and Fluvoxamine 150 No 6 T6 20 75 37.3±10.6 No No
Westenberg
(1988)
Den Boer and Fluvoxamine 150 No 8 T8 20 75 36.8±7.3 No No
Westenberg
(1990)
Placebo – No 8 T8 19 74 37.3±6.8 – –
Ferguson et al. Venlafaxine 172.1±53.2 No 12 + 26 T12 291 68 37.2±11.3 No Yes
(2007)
Goddard et al. Sertraline 100 Yes 12 T8 22 54 38.8±7.0 No Yes
(2001)
Sertraline 100 No 12 T8 25 56 37.6±11.0 – –
Gulsun et al. Paroxetine 20 Yes 6 T6 35 57 33.1±6.1 GAD, MD, dysthymia, No
(2007) OCD
Humble and Citalopram 41 Yes 8 + 56 T8 17 85 34.8 No No
Wistedt
(1992)
Hoehn-Saric Fluvoxamine 206.8 No 8 T8 18 – 38±9.6 No No
et al. (1993)
Placebo – – 8 T8 18 – 38±9.6 – –
Kamijima et al. Sertraline 82.7±26.6 Yes 8+8 T8 393 64 36.1±8.9 No Yes
(2005)
Kim and Yu Paroxetine 20–40 Yes 12 T12 28 54 34.2±6.9 No No
(2005)
Kindler et al. Fluoxetine 20 No 8 T8 10 0 35 No No
(1997)
Lepola et al. Citalopram 41.74 No 8 T8 23 62 35 No No
(1994)
Liebowitz et al. Venlafaxine 188.3±49.1 Yes 10 T10 155 72 36±12.4 MD, GAD Yes
(2009)
Placebo – Yes 10 T10 155 59 36.7±12.0 – –
Michelson Fluoxetine 10 Chloral 10 + 24 T10 84 70 37.5±10.7 Depressive disorder or Yes
et al. (1998) hydrate other anxiety disorders
Fluoxetine 20 Chloral 10 + 24 T10 81 70 35.8±10.3 – –
hydrate
Placebo – – 10 + 24 T10 78 68 37.9±11.5 – –
Michelson Fluoxetine 29.8 No 12 T12 90 52 36.5±10.3 No Yes
et al. (2001)
Placebo – No 12 T12 90 59 34.8±9.8 – –
Montanes- Mirtazapine 30 Yes 8 T8 24 69 43.7±13.9 GAD, MD, dysthymia, No
Rada et al. obsessive personality
(2005) disorder traits
Paroxetine 23.84 Yes 8 T8 31 46 43.5±17.8 – –
Nair et al. Fluvoxamine 171.4 No 8 T8 43 56 34.5 No Yes
(1996)
Placebo – No 8 T8 47 45 35.5 – –
Nardi et al. Paroxetine 38.4±3.7 No 8 T8 50 68 33.7±8.8 No No
(2011)
Neuger et al. Citalopram 36.6±7.7 Yes 6–8 + 26 T8 28 76 34.5±10 No No
(2000)
Table 1 (continued)
Drug range or Study Time considered in Number of

mean dosage Concomitant duration our study as the patients %
References Drug (mg) anxiolitics (weeks) endpoint (ITT) women Mean age Comorbidities Sponsor
Oehrberg et al. Paroxetine 20–60 No 12 T12 60 80 37.7 No Yes

(1995)
Placebo – No 12 T12 60 72 37 – –
Papp et al. Venlafaxine 93.4 No 10 T10 9 77 34±9.7 Dysphoria, hystory of Yes
(1998) substance use disorder

Pecknold et al. Fluoxetine 20 Yes 8 T8 28 73 36.9 Dysthymia, GAD, MD No

(1995)
Pelland et al. Paroxetine 40 No 12 + 12 T12 13 46 40±13 No No
(2010)
Perna et al. Citalopram 40.7±6.8 No 8 T8 27 74 30.5±10.6 No No
(2001)
Paroxetine 33.6±9.5 No 8 T8 25 56 32.2±9.1 – –
Perna et al. Citalopram 40 No 6 T6 15 73 27.4±9.3 No No
(2003)
Perna et al. Paroxetine 30.2±8.4 No 12 T12 90 57 34.2±12.6 No No
(2005)
Pollack et al. Venlafaxine 166±39.2 No 8 T8 12 – 36.7±11.2 No Yes
(1996)
Placebo – No 8 T8 11 – 36.7±11.2 – –
Pollack et al. Sertraline 118.1±62.9 Chloral 10 T10 88 69 37.8±11.6 Dysthymia, personality Yes
(1998) hydrate disorder, other anxiety
disorder
Placebo – Chloral 10 T10 88 61 34.9±9.6 – –
hydrate
Pollack et al. Paroxetine 39 No 12 T8 22 – 34.5–37.3 MD, GAD, social anxiety Yes
(2003b) disorder, dysthymia,
PTSD
Paroxetine 37 Yes 12 T8 18 – – – –
Paroxetine 38.6 Yes 12 T8 20 – – – –
Pollack et al. Paroxetine 40 Yes 12 T12 151 67 37.5±11 No Yes
(2007a)
Venlafaxine 75 Yes 12 T12 156 65 35.8±9.97 – –
Placebo – – 12 T12 157 70 35.1±9.48 – –
Pollack et al. Paroxetine 40 Yes 12 T12 161 64 37.6±10.5 MD, GAD Yes
(2007b)
Placebo – – 12 T12 156 69 37.7±11.3 – –
Pols et al. Fluvoxamine 159±20.2 Yes 6 T6 11 82 35.6±10.9 Dysthymia No
(1996)
Rampello et al. Citalopram 20 No 8 T8 18 35 70.5 No No
(2006)
Ribeiro et al. Fluoxetine 14.0±1.0 No 8 T8 13 62 36.4±10.1 No No
(2001)
Mirtazapine 18.3±1.3 No 8 T8 14 86 36.1±10.9 – –
Sarchiapone Mirtazapine 30 No 12 T12 45 64 36.4±9.45 MD No
et al. (2003)
Seedat et al. Citalopram 31.7±9.4 No 8+2+8 T8 9 – 35.5 Dysthymia and other No
(2003) anxiety disorder
Reboxetine 6.3±1.9 No 8+2+8 T8 8 – 35.5 – –
Sharp et al. Fluvoxamine 150 No 12 T6 29 82 36.62 No Yes
(1996)
Placebo – No 12 T6 28 81 42.28 – –
Shlik et al. Citalopram 20–40 Yes 8 T8 8 62 28.6 No Yes
(1997)
Sim et al. Paroxetine 27 Yes 12 T12 5 40 42.6±7 No No
(2010)
Stahl et al. Citalopram 21.3 Yes 10 T10 112 62 37.1 No Yes
(2003)
Placebo – Yes 10 T10 114 55 38.6 – –
van Vliet et al. Fluvoxamine 150 Yes 12 + 12 T12 15 – 35±7.46 No No
(1996)
Wade et al. Citalopram 13 Yes 8 T8 97 – 38 No No
(1997)
Citalopram 24 Yes 8 T8 95 – 38 – –
Citalopram 48 Yes 8 T8 89 – 38 – –
Placebo – Yes 8 T8 96 – 38 – –
Note that the table does not report the antidepressants not included in the study.
GAD, general anxiety disorder; ITT, intent-to-treat population; MD, major depression; OCD, obsessive compulsive disorder; PTSD, post-traumatic stress disorder.
Table 2 Main characteristics of the studies included

Drug range or mean Used scales for Hedge’s g Used scale for panic Hedge’s g panic Number of
References Drug dosage (mg) anxiety anxiety symptoms symptoms dropouts
Amore et al. (1999) Fluoxetine 10–50 HAMA 3.816±1.24 – – 1

Ballenger et al. (1998) Paroxetine 10 HAMA 1.296±0.66 – – 22
Paroxetine 20 – 1.269±0.62 – – 23
Paroxetine 40 – 1.66±0.63 – – 22
Placebo – – 1.124±0.65 – – 23
Bandelow et al. (2004) Paroxetine 48.1±11.2 HAMA 1.555±2.65 PAS 1.874±0.47 32

Sertraline 84.5±39.1 – 1.551±0.56 – 2.016±0.46 27
Bertani et al. (2004) Paroxetine 40 – – PASS 2.29±0.35 4
Reboxetine 8 – – – 1.266±0.52 7
Black et al. (1993) Fluvoxamine 230 CAS 1.641±0.79 PASS 0.638±3.3 4
Placebo – – 0.656±0.89 – 0.572±2.55 7
Boshuisen et al. (2001) Mirtazapine 36.3 HAMA 1.016±1.15 – – 7
Coplan et al. (1995) Fluoxetine 17.7±16 HAMA 1.606±1.3 – – 4
Carli et al. (2002) Mirtazapine 30 HAMA, ZUNG 5.47±0.94 PDSS 5.326±0.05 0
Dannon et al. (2002) Reboxetine 8 HAMA 1.473±1.45 PSQ 3.858±0.19 5
Den Boer and Fluvoxamine 150 HAMA 1.850±1.03 – – 0
Westenberg (1988)
Den Boer and Fluvoxamine 150 HAMA, STAI 1.82±1.63 – – –
Westenberg (1990)
Placebo – – 0.29±2.62 – – 1
Ferguson et al. (2007) Venlafaxine 172.1±53.2 – – PDSS 2.958±0.19 96
Goddard et al. (2001) Sertraline 100 – – PDSS 2.135±0.63 6
Sertraline 100 – – – 1.615±0.85 10
Gulsun et al. (2007) Paroxetine 20 – – PAS 1.765±0.8 0
Humble and Wistedt Citalopram 41 CAS 3.121±0.50 – – 3
(1992)
Hoehn-Saric et al. (1993) Fluvoxamine 206.8 CAS 2.064±0.61 – – 6
Placebo – – 0.619±0.8 – – 7
Kamijima et al. (2005) Sertraline 82.7±26.6 HAMA 1.321±0.29 PDSS 1.759±0.16 77
Kim and Yu 2005 Paroxetine 20–40 HAMA, STAI, ASI 1.48±1.48 API 1.142±1.28 10
Kindler et al. (1997) Fluoxetine 20 HAMA 2.686±1.87 PS 2.640±2.86 0
Lepola et al. (1994) Citalopram 41.74 HAMA 2.377±0.96 – – 1
Liebowitz et al. (2009) Venlafaxine 188.3±49.1 HAMA 1.463±0.40 PDSS 2.064±0.28 65
Placebo – – 1.117±0.42 – 1.667±0.55 53
Michelson et al. (1998) Fluoxetine 10 HAMA 1.004±0.61 – – 35
Fluoxetine 20 – 1.196±0.639 – – 42
Placebo – – 0.663±0.74 – – 46
Michelson et al. (2001) Fluoxetine 29.8 HAMA 1.816±0.62 PDSS 2.267±0.38 15
Placebo – – 1.191±0.92 – 1.573±0.37 10
Montanes-Rada et al. Mirtazapine 30 BAI 1.742±1.37 – – 5
(2005)
Paroxetine 23.84 – 1.5±1.43 – – 2
Nair et al. (1996) Fluvoxamine 171.4 CAS 1.034±0.55 – – 31
Placebo – – 0.871±0.5 – – 29
Nardi et al. (2011) Paroxetine 38.4±3.7 HAMA 0.347±0.33 – – 9
Neuger et al. (2000) Citalopram 36.6±7.7 CAS, BAI 1.71±1.05 – – 1
Oehrberg et al. (1995) Paroxetine 20–60 ZUNG 0.746±0.73 – – 5
Placebo – – 0.591±0.67 – – 8
Papp et al. (1998) Venlafaxine 93.4 HAMA 3.676±0.81 – – 4
Pecknold et al. (1995) Fluoxetine 20 HAMA, SPRAS 1±0.9 – – 10
Pelland et al. (2010) Paroxetine 40 ASI 0.881±2.09 PAS 1.922±1.39 2
Perna et al. (2001) Citalopram 40.7±6.8 – – PASS 1.627±0.46 3
Paroxetine 33.6±9.5 – – 1.197±0.68 3
Perna et al. (2003) Citalopram 40 STAI 0.852±2.51 PASS 1.069±0.71 0
Perna et al. (2005) Paroxetine 30.2±8.4 – – PASS 1.794±0.3 2
Pollack et al. (1996) Venlafaxine 166±39.2 HAMA 0.419±2.78 – – 2
Placebo – – 0.658±2.14 – – 8
Pollack et al. (1998) Sertraline 118.1±62.9 HAMA 2.008±0.51 PDSS 0.213±0.22 17
Placebo – – 2.247±0.5 – 0.153±0.23 15
Pollack et al. (2003b) Paroxetine 39 HAMA 0.823±1.05 PDSS 1.273±0.1 11
Paroxetine 37 – 1.422±1.38 – 1.561±0.12 6
Paroxetine 38.6 – 0.761±1.35 – 1.086±0.13 9
Pollack et al. (2007a) Paroxetine 40 – – PDSS 2.379±0.25 35
Venlafaxine 75 – – – 2.310±0.24 24
Venlafaxine 225 – – – 2.482±0.24 29
Placebo – – – 1.831±0.25 43
Pollack et al. (2007b) Paroxetine 40 HAMA 1.895±0.38 PDSS 2.605±0.24 30
Venlafaxine 75 – 1.805±0.38 – 2.499±0.24 32
Venlafaxine 150 – 1.894±0.38 – 2.704±0.24 35
Placebo – – 1.277±0.43 – 1.907±0.25 42
Pols et al. (1996) Fluvoxamine 159±20.2 STAI, ZUNG 1.03±2.15 – – 0
Rampello et al. (2006) Citalopram 20 HAMA 2.96±1.12 – – 2
Ribeiro et al. (2001) Fluoxetine 14.0±1.0 HAMA 2.359±1.42 – – 3
Table 2 (continued)
Drug range or mean Used scales for Hedge’s g Used scale for panic Hedge’s g panic Number of
References Drug dosage (mg) anxiety anxiety symptoms symptoms dropouts
Mirtazapine 18.3±1.3 1.375±2.03 – 2

Sarchiapone et al. (2003) Mirtazapine 30 HAMA 2.667±0.69 PDSS 0.455±0.44 3
Seedat et al. (2003) Citalopram 31.7±9.4 HAMA 0.404±3.44 PDSS 0.886±1.77 5
Reboxetine 6.3±1.9 – 0.418±3.38 – 0.199±2.31 5
Sharp et al. (1996) Fluvoxamine 150 HAMA 1.981±0.9 – – 7

Placebo – – 1.029±1.04 – – 9
Shlik et al. (1997) Citalopram 20–40 HAMA, STAI 5.12±1.3 MC-PAS 4.342±0.92 0
Sim et al. (2010) Paroxetine 27 HAMA 3.120±0.91 PDSS 3.936±0.64 0
Stahl et al. (2003) Citalopram 21.3 HAMA 0.687±0.51 P&A 0.446±0.7 38
Placebo – – 0.627±0.59 – – 79
van Vliet et al. (1996) Fluvoxamine 150 HAMA 1.890±1.05 – – 0
Wade et al. (1997) Citalopram 13 HAMA 1.503±0.49 – – 26
Citalopram 24 – 1.606±0.49 – – 20
Citalopram 48 – 1.757±0.51 – – 19
Placebo – – 1.01±0.55 – – 25
Note that the table does not report the antidepressants not included in the study.
API, Acute Panic Inventory; ASI, Anxiety Sensitivity Index; BAI, Beck Anxiety Inventory; CAS, Clinical Anxiety Scale; HAMA, Hamilton Rating Scale for Anxiety;
MC-PAS, Multicenter Panic and Agoraphobia Scale; P&A, Panic and Agoraphobia; PAS, Panic and Agoraphobia Scale; PASS, Panic-Associated Symptoms Scale;
PDSS, Panic Disorder Severity Scale; PS, Panic Score; PSQ, Panic Self-Questionnaire; SPRAS, Sheehan Patient-Rated Anxiety Scale; STAI, State Trait Anxiety
Inventory; ZUNG, Zung Self-Rating Anxiety Score.
considered separately, venlafaxine and paroxetine were no Meta-regression analyses

longer superior to placebo. Paroxetine was also not Improvement in panic symptoms
significantly different from placebo in nonsponsored We found that citalopram was more effective in alleviat-
studies. In addition, a sensitivity analysis focusing on ing panic symptoms if the duration of illness was shorter.
studies including PD patients without comorbidities Furthermore, paroxetine and sertraline showed a higher
showed that mirtazapine, paroxetine, and venlafaxine efficacy in studies with a longer duration. In addition,
were no more effective than placebo for the improvement older age was significantly associated with higher clinical
in anxiety levels in this group of patients. For specific improvement in patients treated with sertraline. Finally,
details, see supplementary data 3. higher quality was positively correlated with PD symp-
toms’ improvement in patients treated with citalopram
and negatively correlated with improvement in PD
Dropout rates symptoms in patients taking venlafaxine.
When data derived from randomized-controlled trials
were analyzed separately, we observed that only venlafax- Improvement in anxiety levels
ine and paroxetine were associated with significantly We found that fluoxetine was more effective in alleviating
lower dropout rates as compared with placebo. Further- anxiety levels when patients had a shorter duration of
more, the sensitivity analysis including only placebo- illness. Older age was significantly associated with higher
controlled studies showed that the number of dropouts clinical improvement in patients treated with fluvoxa-
did not differ significantly between patients treated with mine. Moreover, we observed that sertraline was more
antidepressants and those treated with placebo, with the beneficial at lower doses. Finally, the efficacy of
only exception of venlafaxine. Moreover, in studies paroxetine and venlafaxine increased with increasing
allowing only antidepressant monotherapy, the dropout duration of treatment.
rates did not change significantly between patients
treated with placebo and those treated with the following Dropout rates
antidepressants: fluoxetine, fluvoxamine, and reboxetine. We observed that higher doses of sertraline were strongly
Also, when nonsponsored studies were considered associated with a greater number of dropouts. Moreover,
separately, we found that all antidepressants under we found that women were more likely to drop out when
investigation were associated with significantly lower taking venlafaxine or paroxetine. In addition, patients
dropout rates as compared with placebo. In addition, the treated with venlafaxine who had a longer duration of
analysis focusing on PD patients without comorbidities illness were more likely to discontinue the trial as
showed that no significant difference was observed compared with those with a shorter duration of illness.
between fluoxetine, fluvoxamine, mirtazapine, and pla- However, patients treated with paroxetine were more
cebo in terms of dropout rates, whereas citalopram, likely to drop out if they had a shorter duration of illness.
paroxetine, reboxetine, venlafaxine, and sertraline were Finally, we found that patients were more likely to drop
associated with a lower likelihood of dropout as compared out in shorter term studies using venlafaxine and in longer
with placebo (supplementary data 3). term studies using fluoxetine (see supplementary data 4).
Fig. 2
Clinical improvement on panic symptoms

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Continuous and dichotomous outcomes. PD, panic disorder; SSRI, selective serotonin reuptake inhibitors
Publication bias Discussion

The publication bias was investigated by visual inspection The findings of our work lend support to the higher efficacy
of the funnel plots (supplementary Figs 1–3) as well of most antidepressants under investigation over placebo for
through Egger’s analysis (supplementary data 5). A the reduction of panic symptoms and anxiety levels.
significant publication bias was detected only in the Reboxetine was the only drug that was found to be
analysis focusing on the usefulness of venlafaxine for the ineffective for the treatment of both panic symptoms and
improvement in panic symptoms (b = 0.98, P = 0.0004, anxiety levels and mirtazapine as well as fluvoxamine were
intercept = – 15.01, 95% CI = – 21.35 to – 8.67). How- found not to be useful in alleviating panic symptomatology.
ever, this publication bias is not entirely reliable because Overall, our findings are in agreement with those reported in
only a small number of studies provided information previous reviews and meta-analysis (van Balkom et al.,
about the effects of venlafaxine on the improvement in 1997; Otto et al., 2001; Bakker et al., 2002; Mitte, 2005).
panic symptoms. However, our meta-analysis is the first to provide information
about a clear ranking of antidepressants’ efficacy for overall Our results also indicate that mirtazapine was no more
anxiety and PD symptoms investigated separately. effective than placebo for the reduction of panic
symptoms. However, this newer antidepressant was
Of note, no clear advantage of any SSRIs over the others
associated with the highest improvement in anxiety
has been established definitely so far (Bakker et al., 2005).
levels. A possible explanation for such a discrepancy could
Therefore, our results strengthen current evidence by
be related to the fact that mirtazapine could be more
showing that paroxetine, fluoxetine, fluvoxamine, and
effective for general anxiety symptoms such as worries,
citalopram could be associated with increasingly higher

insomnia, and muscle tension, possibly because of its

effectiveness in lowering anxiety levels. Of note,
sedative profile, but less effective on specific panic
paroxetine was found to be the less effective antidepres-
symptoms. However, this explanation remains speculative
sant in the general analysis focusing on anxiety levels.
thus far. Furthermore, no placebo-controlled trials of
However, this was not true in the analysis including only
mirtazapine for the treatment of PD have been published
placebo-controlled studies. The discrepancy observed
thus far. Therefore, these results should be considered
between these two analyses could be related to the large
with extreme caution pending further replications
variety of methodological designs of the studies included
in properly powered double-blind placebo-controlled
focusing on paroxetine. Indeed, several of these studies
studies.
used an uncontrolled design that has required the
implementation of several virtual placebo samples. This
could also explain why further sensitivity analyses focus- Moreover, when studies allowing only antidepressants
ing, as an example, on nonsponsored and monotherapy monotherapy were considered separately, only venlafaxine
studies showed that paroxetine did not differ significantly and fluoxetine were associated with a significant im-
from placebo. It should be noted, however, that in the provement in panic symptoms compared with placebo,
sensitivity analysis of placebo-controlled studies specifi- indicating that patients treated with the other antide-
cally focusing on panic symptoms, paroxetine was pressants could achieve higher benefits when such
associated with the highest improvement. This finding antidepressants are associated with anxiolytic drugs.
can be explained by the fact that paroxetine seems to Our results also suggested that paroxetine, mirtazapine,
have the highest affinity for the serotonin transporter as and venlafaxine did not significantly differ from placebo
compared with other SSRIs (Owens and Nemeroff, in terms of clinical improvement in anxiety when PD
1994; Owens et al., 2008). patients with comorbid psychiatric disorders were ex-
cluded. A possible explanation for these findings could be
In terms of reboxetine, the only antidepressant that was that clinical improvement in PD patients treated with
found to be ineffective in treating both panic and anxiety these drugs could be largely because of the effects of
symptoms in the general analysis, it is worth mentioning these antidepressants on comorbid psychiatric disorders
that only one study has been published so far that such as major depression that frequently occurs in
examined the efficacy of reboxetine in comparison with comorbidity with PD. However, further in-depth studies
placebo for PD treatment (Versiani et al., 2002). The are required to investigate this hypothesis.
results of this study suggested that reboxetine was
significantly more effective than placebo in reducing In terms of the dropout rates, we found that a large
the final mean number of panic attacks and phobic number of antidepressants were associated with signifi-
symptoms. A significant limitation of this study was, cantly lower dropout rates than placebo, fluvoxamine and
however, the concomitant use of benzodiazepines that reboxetine being notable exceptions. Furthermore, our
did not allow us to understand to what extent reboxetine data suggest that patients treated with mirtazapine were
alone was effective for PD patients. In addition, in the less likely to drop out as compared with patients treated
present meta-analysis, we found that reboxetine was with other drugs. It should be noted, however, that our
ineffective for the treatment of PD patients not only in data indicating that no significant difference was
the general analysis but also in the sensitivity analysis observed between reboxetine and placebo in terms of
focusing on antidepressant monotherapy. One possible dropout rates are in conflict with some studies focusing
explanation for this finding could be the fact that the on reboxetine (Dannon et al., 2002; Versiani et al.,
serotonergic dysfunction is believed to play a more 2002; Seedat et al., 2003) showing that less than 5% of
significant role in the etiology of PD as compared with patients treated with reboxetine discontinued the trial.
the noradrenergic dysfunction (Maron and Shlik, 2006). Moreover, our results differ from those reported
Therefore, because reboxetine acts only on the noradre- by Wagner et al. (1994, 1996), who point to the good
nergic system (Brunello and Racagni, 1998; Hajos et al., safety and tolerability profile of fluvoxamine. Similar to
2004), it might not be as effective for the treatment of efficacy measures, however, it is worth mentioning that
PD patients as dual-acting antidepressants or as drugs the discrepancy observed between our findings and those
inhibiting only the reuptake of serotonin. We underscore, reported in earlier studies might be attributed to the
however, that evidence deriving from high-quality studies large variety of methodological designs of the studies
on reboxetine is too little to draw definitive conclusions. included.
Of note, the sensitivity analysis focusing on a placebo- preferred to also include studies using different metho-
controlled study found that there were no significant dological designs to collect a larger number of studies.
differences in terms of the dropout rates between This could explain why a high heterogeneity was
patients treated with placebo and those treated with observed across the studies included in the present
most antidepressants. A possible explanation for this meta-analysis.
finding could be that patients taking placebo may be
Second, for studies that did not include a placebo control
more likely to drop out because of lack of efficacy,
group, we calculated a virtual placebo. The virtual control

whereas patients taking active drugs could be more likely

groups that we used to contrast drugs’ effectiveness could
to drop out because of the occurrence of adverse effects.
have been different from the population studied. Never-
This explanation is consistent with observations reported
theless, it is worth mentioning that in a previous meta-
in a large number of placebo-controlled studies focusing
analysis, an analysis aimed at comparing the results
on the efficacy of antidepressants under investigation for
observed in placebo-controlled trials separately analyzed
patients with PD (e.g. Nair et al., 1996; Michelson et al.,
with those derived including virtual placebo samples, no
1998).
significant differences were found (Serretti and Mandelli,
In addition to the findings mentioned above, our meta- 2010). Furthermore, our strategy has the advantage to
analysis suggested that several variables moderated the allow for the inclusion of more data that would otherwise
clinical outcomes and dropout rates. For example, we be excluded. Third, we did not use a uniform measure to
observed that sertraline was more beneficial on anxiety calculate the clinical improvement in panic and anxiety
levels at lower doses, possibly because lower doses are levels from the baseline to the endpoint. However,
better tolerated and less associated with activation efficacy measures were analyzed by Hedge’s g. Hedge’s g
symptoms. Indeed, we also found that higher doses of standardizes the results of studies employing different
sertraline were strongly associated with a greater number assessment measures to a uniform scale so that they can
of dropouts. Moreover, as reviewed by Pollack et al. be combined.
(2000), the rate of dropouts because of adverse effects Fourth, we calculated missing SDs by calculating the
was higher in the fixed-dose studies (Gorman and weighted mean of SDs provided by studies investigating
Wolkow, 1994; Londborg et al., 1998), in which the initial the same measure and we applied them to studies not
dose level was higher and the titration schedule did not providing this measure. Note, however, that this method
allow dose adjustments in response to emergent side has been validated empirically and seems adequate and
effects, as compared with the flexible-dose studies (Pohl reliable (Furukawa et al., 2006). Fifth, we included studies
et al., 1998; Pollack et al., 1998). with a small sample size, which limits their power to
In sum, our results preliminary suggest a possible detect differences among different treatment options.
specificity profile for drugs under investigation that In any case, this critical issue is partially compensated by
require further investigation in properly powered placebo the weights of the sample size that reduce the weight of
randomized-controlled trials. In case of replication, our small trials. Then, an artificial inflation of the effect could
results could have important clinical implications because be because of the use of the same normative control
they could allow us to match each patient to his/her most sample scores. Also, we did not include bupropion,
appropriate drug during the short-term treatment of PD duloxetine, escitalopram, and milnacipran because they
and possibly enhance treatment outcomes. were investigated in very few studies (Hunter and
Schmidt, 1990). Finally, our analyses focused only on
Although the reviewed findings are noteworthy and could the acute-phase treatment of PD and cannot be general-
have important clinical implications, we emphasize that ized to very short-term periods (< 6 weeks) or to periods
they should be considered with caution because of the longer than 12 weeks. Selecting the studies in the short-
following limitations. First, we included both controlled term treatment allowed us to include a greater number of
and uncontrolled studies. Furthermore, we included both pharmacological trials in our work. Moreover, it is worth
double-blind, single-blind, and open trials, even though mentioning that the majority of studies in the literature
double-blind randomized-controlled studies showed investigating the acute PD treatment report the eighth
superiority to other study designs and are usually week as the endpoint.
preferred for meta-analytic purposes (Colditz et al.,
1989; Schulz et al., 1995). Note, however, that several
analyses were carried out and that, with the only Conclusion
exception of citalopram and venlafaxine, our meta- The results of the present meta-analysis indicate that the
regression analysis focusing on the impact of study majority of antidepressants under investigation are
quality on clinical and safety outcomes did not provide effective and safe for the short-term treatment of PD.
evidence to suggest that it significantly affected the Also, our meta-analysis is the first to provide information
results. Moreover, it would be methodologically more on a clear ranking of antidepressants’ efficacy for overall
rigorous to select only head-to-head trials, but we anxiety and PD symptoms investigated separately and
to provide information on the possible moderators of Dannon PN, Iancu I, Grunhaus L (2002). The efficacy of reboxetine in the
outcome. However, considering the several limitations treatment-refractory patients with panic disorder: an open label study.
Hum Psychopharmacol 17:329–333.
stated above, our results should be considered with Den Boer JA, Westenberg HG (1988). Effect of a serotonin and noradrenaline
caution and point to the strong need for more rigorous uptake inhibitor in panic disorder; a double-blind comparative study with
and properly powered double-blind head-to-head com- fluvoxamine and maprotiline. Int Clin Psychopharmacol 3:59–74.
Den Boer JA, Westenberg HG (1990). Serotonin function in panic disorder: a
parison trials that could provide more reliable data on how double blind placebo controlled study with fluvoxamine and ritanserin.
different drugs differ in terms of efficacy and tolerability Psychopharmacology (Berl) 102:85–94.
Durrleman S, Chaikin P (2003). The use of putative placebo in active control

for the treatment of PD.

trials: two applications in a regulatory setting. Stat Med 22:941–952.
Egger M, Davey Smith G, Schneider M, Minder C (1997). Bias in meta-analysis
detected by a simple, graphical test. BMJ 315:629–634.
Acknowledgements Ferguson JM, Khan A, Mangano R, Entsuah R, Tzanis E (2007). Relapse
Conflicts of interest prevention of panic disorder in adult outpatient responders to treatment with
venlafaxine extended release. J Clin Psychiatry 68:58–68.
There are no conflicts of interest. Freire RC, Hallak JE, Crippa JA, Nardi AE (2011). New treatment options for
panic disorder: clinical trials from 2000 to 2010. Expert Opin Pharmacother
12:1419–1428.
References Furukawa TA, Barbui C, Cipriani A, Brambilla P, Watanabe N (2006). Imputing
American Psychiatric Association (2009). Treatment of patients with panic missing standard deviations in meta-analyses can provide accurate results.
disorder. 2nd ed. Washington, DC: American Psychiatric Association; J Clin Epidemiol 59:7–10.
Available at: http://www.psychiatryonline.com/pracGuide/pracGuideTopi- Goddard AW, Brouette T, Almai A, Jetty P, Woods SW, Charney D (2001). Early
c_9.aspx [Accessed 25 March 2012]. coadministration of clonazepam with sertraline for panic disorder. Arch Gen
Amore M, Magnani K, Cerisoli M, Casagrande C, Ferrari G (1999). Panic Psychiatry 58:681–686.
disorder. A long-term treatment study: fluoxetine vs imipramine. Hum Gorman J, Wolkow R (1994). Sertraline as a treatment for panic disorder.
Psychopharmacol 14:429–434. Neuropsychopharmacology 10:117–175.
Bakker A, van Balkom AJ, Spinhoven P (2002). SSRIs vs. TCAs in the treatment Gulsun M, Doruk A, Uzun O, Turkbay T, Ozsahin A (2007). Effect of dissociative
of panic disorder: a meta-analysis. Acta Psychiatr Scand 106:163–167. experiences on drug treatment of panic disorder. Clin Drug Investig 27:
Bakker A, van Balkom AJ, Stein DJ (2005). Evidence-based pharmacotherapy of 583–590.
panic disorder. Int J Neuropsychopharmacol 8:473–482. Hajos M, Fleishaker JC, Filipiak-Reisner JK, Brown MT, Wong EH (2004). The
Baldwin DS, Anderson IM, Nutt DJ, Bandelow B, Bond A, Davidson JR, et al. selective norepinephrine reuptake inhibitor antidepressant reboxetine:
(2005). Evidence-based guidelines for the pharmacological treatment of pharmacological and clinical profile. CNS Drug Rev 10:23–44.
anxiety disorders: recommendations from the British Association for Hamilton M (1959). The assessment of anxiety states by rating. Br J Med Psychol
Psychopharmacology. J Psychopharmacol 19:567–596. 32:50–55.
Ballenger JC, Wheadon DE, Steiner M, Bushnell W, Gergel IP (1998). Double- Hedges LV, Olkin I (1985). Statistical methods for meta-analysis. Orlando, FL:
blind, fixed-dose, placebo-controlled study of paroxetine in the treatment of Academic Press.
panic disorder. Am J Psychiatry 155:36–42. Hoehn-Saric R, McLeod DR, Hipsley PA (1993). Effect of fluvoxamine on panic
Bandelow B, Ruther E (2004). Treatment-resistant panic disorder. CNS Spectr disorder. J Clin Psychopharmacol 13:321–326.
9:725–739. Humble M, Wistedt B (1992). Serotonin, panic disorder and agoraphobia: short-
Bandelow B, Sievert K, Rothemeyer M, Hajak G, Ruther E (1995). What term and long-term efficacy of citalopram in panic disorders. Int Clin
treatments do patients with panic disorder and agoraphobia get? Eur Arch Psychopharmacol 6 (Suppl 5):21–39.
Psychiatry Clin Neurosci 245:165–171. Hunter JE, Schmidt FL (1990). Methods of meta-analysis. Correcting error and
Bandelow B, Behnke K, Lenoir S, Hendriks GJ, Alkin T, Goebel C, et al. (2004). bias in research finding. Beverly Hills, CA: Sage Publications.
Sertraline versus paroxetine in the treatment of panic disorder: an acute, Jadad AR, Moore RA, Carroll D (1996). Assessing the quality of reports
double-blind noninferiority comparison. J Clin Psychiatry 65:405–413. of randomized clinical trials: is blinding necessary? Controlled Clin Trials 17:
Bandelow B, Zohar J, Hollander E, Kasper S, Moller HJ, Zohar J, et al. (2008). 1–12.
World Federation of Societies of Biological Psychiatry (WFSBP) guidelines Kamijima K, Kuboki T, Kumano H, Burt T, Cohen G, Arano I, et al. (2005).
for the pharmacological treatment of anxiety, obsessive-compulsive and A placebo-controlled, randomized withdrawal study of sertraline for panic
post-traumatic stress disorders – first revision. World J Biol Psychiatry disorder in Japan. Int Clin Psychopharmacol 20:265–273.
9:248–312. Kim EJ, Yu BH (2005). Increased cholesterol levels after paroxetine treatment in
Batelaan NM, Van Balkom AJ, Stein DJ (2011). Evidence-based pharmacotherapy patients with panic disorder. J Clin Psychopharmacol 25:597–599.
of panic disorder: an update. Int J Neuropsychopharmacol1–13. Kindler S, Dolberg OT, Cohen H, Hirschmann S, Kotler M (1997). The treatment
Bertani A, Perna G, Migliarese G, Di Pasquale D, Cucchi M, Caldirola D, et al. of comorbid premature ejaculation and panic disorder with fluoxetine. Clin
(2004). Comparison of the treatment with paroxetine and reboxetine in panic Neuropharmacol 20:466–471.
disorder: a randomized, single-blind study. Pharmacopsychiatry 37:206–210. Lepola U, Leinonen E, Turtonen J, Pentinen J (1994). The effect of citalopram in
Black DW, Wesner R, Bowers W, Gabel J (1993). A comparison of fluvoxamine, panic disorder and agoraphobia. Nord J Psychiatry13–17.
cognitive therapy, and placebo in the treatment of panic disorder. Arch Gen Liebowitz MR, Asnis G, Mangano R, Tzanis E (2009). A double-blind, placebo-
Psychiatry 50:44–50. controlled, parallel-group, flexible-dose study of venlafaxine extended release
Boshuisen ML, Slaap BR, Vester-Blokland ED, den Boer JA (2001). The effect of capsules in adult outpatients with panic disorder. J Clin Psychiatry 70:
mirtazapine in panic disorder: an open label pilot study with a single-blind 550–561.
placebo run-in period. Int Clin Psychopharmacol 16:363–368. Londborg PD, Wolkow R, Smith WT, DuBoff E, England D, Ferguson J, et al.
Brunello N, Racagni G (1998). Rationale for the development of noradrenaline (1998). Sertraline in the treatment of panic disorder. A multi-site, double-
reuptake inhibitors. Hum Psychopharmacol 13:13–19. blind, placebo-controlled, fixed-dose investigation. Br J Psychiatry 173:
Carli V, Sarchiapone M, Camardese G, Romano L, DeRisio S (2002). Mirtazapine 54–60.
in the treatment of panic disorder. Arch Gen Psychiatry 59:661–662. Lopez-Leon S, Janssens AC, Gonzalez-Zuloeta Ladd AM, Del-Favero J, Claes SJ,
Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Oostra BA, et al. (2008). Meta-analyses of genetic studies on major
(2009). Comparative efficacy and acceptability of 12 new-generation depressive disorder. Mol Psychiatry 13:772–785.
antidepressants: a multiple-treatments meta-analysis. Lancet 373:746–758. Maron E, Shlik J (2006). Serotonin function in panic disorder: important, but why?
Cohen J (1992). A power primer. Psychol Bull 112:155–159. Neuropsychopharmacology 31:1–11.
Colditz GA, Miller JN, Mosteller F (1989). How study design affects outcomes in Michelson D, Lydiard RB, Pollack MH, Tamura RN, Hoog SL, Tepner R, et al.
comparisons of therapy. I: medical. Stat Med 8:441–454. (1998). Outcome assessment and clinical improvement in panic disorder:
Coplan JD, Papp LA, Martinez J, Pine D, Rosenblum LA, Cooper T, et al. (1995). evidence from a randomized controlled trial of fluoxetine and placebo. The
Persistence of blunted human growth hormone response to clonidine in Fluoxetine Panic Disorder Study Group. Am J Psychiatry 155:1570–1577.
fluoxetine-treated patients with panic disorder. Am J Psychiatry 152: Michelson D, Allgulander C, Dantendorfer K, Knezevic A, Maierhofer D, Micev V,
619–622. et al. (2001). Efficacy of usual antidepressant dosing regimens of fluoxetine in
panic disorder: randomised, placebo-controlled trial. Br J Psychiatry Pollack MH, Lepola U, Koponen H, Simon NM, Worthington JJ, Emilien G, et al.
179:514–518. (2007b). A double-blind study of the efficacy of venlafaxine extended-release,
Mitte K (2005). A meta-analysis of the efficacy of psycho- and pharmacotherapy paroxetine, and placebo in the treatment of panic disorder. Depress Anxiety
in panic disorder with and without agoraphobia. J Affect Disord 88:27–45. 24:1–14.
Mochcovitch MD, Nardi AE (2010). Selective serotonin-reuptake inhibitors in the Pols HJ, Hauzer RC, Meijer JA, Verburg K, Griez EJ (1996). Fluvoxamine
treatment of panic disorder: a systematic review of placebo-controlled attenuates panic induced by 35% CO2 challenge. J Clin Psychiatry 57:
studies. Expert Rev Neurother 10:1285–1293. 539–542.
Montanes-Rada F, de Lucas-Taracena MT, Sanchez-Romero S (2005). Mirtaza- Rampello L, Alvano A, Raffaele R, Malaguarnera M, Vecchio I (2006). New
pine versus paroxetine in panic disorder: an open study. Int J Psych Clin possibilities of treatment for panic attacks in elderly patients: escitalopram
Pract 9:87–93. versus citalopram. J Clin Psychopharmacol 26:67–70.

Mullen B (1989). Advanced BASIC meta-analysis. In: Hillsdale NE, editor. Reger MA, Welsh RK, Watson GS, Cholerton B, Baker LD, Craft S (2004).
Advanced BASIC meta-analysis. Hillsdale, NJ: Erlbaum. The relationship between neuropsychological functioning and driving ability
Nair NP, Bakish D, Saxena B, Amin M, Schwartz G, West TE (1996). Comparison in dementia: a meta-analysis. Neuropsychology 18:85–93.
of fluvoxamine, imipramine, and placebo in the treatment of outpatients with Ribeiro L, Busnello JV, Kauer-Sant’Anna M, Madruga M, Quevedo J, Busnello EA,
panic disorder. Anxiety 2:192–198. et al. (2001). Mirtazapine versus fluoxetine in the treatment of panic disorder.
Nardi AE, Valenca AM, Freire RC, Mochcovitch MD, Amrein R, Sardinha A, et al. Braz J Med Biol Res 34:1303–1307.
(2011). Psychopharmacotherapy of panic disorder: 8-week randomized trial Royal Australian and New Zealand College of Psychiatrists Clinical Practice
with clonazepam and paroxetine. Braz J Med Biol Res 44:366–373. Guidelines Team for Panic Disorder and Agoraphobia (2003). Australian and
Neuger J, Wistedt B, Sinner B, Aberg-Wistedt A, Stain-Malmgren R (2000). The New Zealand clinical practice guidelines for the treatment of panic disorder
effect of citalopram treatment on platelet serotonin function in panic and agoraphobia. Aust NZ J Psychiatry 37:641–656.
disorders. Int Clin Psychopharmacol 15:83–91. Sarchiapone M, Amore M, De Risio S, Carli V, Faia V, Poterzio F, et al. (2003).
Oehrberg S, Christiansen PE, Behnke K, Borup AL, Severin B, Soegaard J, et al. Mirtazapine in the treatment of panic disorder: an open-label trial. Int Clin
(1995). Paroxetine in the treatment of panic disorder. A randomised, double- Psychopharmacol 18:35–38.
blind, placebo-controlled study. Br J Psychiatry 167:374–379. Schulz KF, Chalmers I, Hayes RJ, Altman DG (1995). Empirical evidence of bias.
Otto MW, Tuby KS, Gould RA, McLean RY, Pollack MH (2001). An effect-size Dimensions of methodological quality associated with estimates of treatment
analysis of the relative efficacy and tolerability of serotonin selective reuptake effects in controlled trials. JAMA 273:408–412.
inhibitors for panic disorder. Am J Psychiatry 158:1989–1992. Seedat S, van Rheede van Oudtshoorn E, Muller JE, Mohr N, Stein DJ (2003).
Owens MJ, Nemeroff CB (1994). Role of serotonin in the pathophysiology of Reboxetine and citalopram in panic disorder: a single-blind, cross-over,
depression: focus on the serotonin transporter. Clin Chem 40:288–295. flexible-dose pilot study. Int Clin Psychopharmacol 18:279–284.
Owens MJ, Krulewicz S, Simon JS, Sheehan DV, Thase ME, Carpenter DJ, et al. Serretti A, Mandelli L (2010). Antidepressants and body weight: a comprehensive
(2008). Estimates of serotonin and norepinephrine transporter inhibition in review and meta-analysis. J Clin Psychiatry 71:1259–1272.
depressed patients treated with paroxetine or venlafaxine. Neuropsycho- Sharp DM, Power KG, Simpson RJ (1996). Fluvoxamine, placebo, and cognitive
pharmacology 33:3201–3212. behavioural therapy used alone and in combination in the treatment of panic
Papp LA, Sinha SS, Martinez JM, Coplan JD, Amchin J, Gorman JM (1998). Low- disorder and agoraphobia. J Anxiety Disord 10:219–242.
dose venlafaxine treatment in panic disorder. Psychopharmacol Bull 34: Shear MK, Brown TA, Barlow DH, Money R, Sholomskas DE, Woods SW, et al.
207–209. (1997). Multicenter collaborative panic disorder severity scale. Am J
Pecknold JC, Luthe L, Iny L, Ramdoyal D (1995). Fluoxetine in panic disorder: Psychiatry 154:1571–1575.
pharmacologic and tritiated platelet imipramine and paroxetine binding study. Shieh G (2012). Confidence intervals and sample size calculations for the
J Psychiatry Neurosci 20:193–198. weighted eta-squared effect sizes in one-way heteroscedastic ANOVA.
Pelland ME, Marchand A, Lessard MJ, Belleville G, Chauny JM, Vadeboncoeur A, Behav Res Methods.
et al. (2010). Efficacy of 2 interventions for panic disorder in patients Shlik J, Aluoja A, Vasar V, Vasar E, Podar T, Bradwejn J (1997). Effects of
presenting to the ED with chest pain. Am J Emerg Med 29:1051–1061. citalopram treatment on behavioural, cardiovascular and neuroendocrine
Perna G, Bertani A, Caldirola D, Smeraldi E, Bellodi L (2001). A comparison of response to cholecystokinin tetrapeptide challenge in patients with panic
citalopram and paroxetine in the treatment of panic disorder: a randomized, disorder. J Psychiatry Neurosci 22:332–340.
single-blind study. Pharmacopsychiatry 34:85–90. Sim HB, Kang EH, Yu BH (2010). Changes in cerebral cortex and limbic brain
Perna G, Alpini D, Caldirola D, Raponi G, Cesarani A, Bellodi L (2003). functions after short-term paroxetine treatment in panic disorder: an [F]FDG-
Serotonergic modulation of the balance system in panic disorder: an open PET Pilot Study. Psychiatry Invest 7:215–219.
study. Depress Anxiety 17:101–106. Stahl SM, Gergel I, Li D (2003). Escitalopram in the treatment of panic disorder: a
Perna G, Favaron E, Di Bella D, Bussi R, Bellodi L (2005). Antipanic efficacy of randomized, double-blind, placebo-controlled trial. J Clin Psychiatry
paroxetine and polymorphism within the promoter of the serotonin 64:1322–1327.
transporter gene. Neuropsychopharmacology 30:2230–2235. Van Balkom AJ, Bakker A, Spinhoven P, Blaauw BM, Smeenk S, Ruesink B
Pohl RB, Wolkow RM, Clary CM (1998). Sertraline in the treatment of panic (1997). A meta-analysis of the treatment of panic disorder with or without
disorder: a double-blind multicenter trial. Am J Psychiatry 155:1189–1195. agoraphobia: a comparison of psychopharmacological, cognitive-behavioral,
Pollack MH, Worthington JJ 3rd, Otto MW, Maki KM, Smoller JW, Manfro GG, and combination treatments. J Nerv Ment Dis 185:510–516.
et al. (1996). Venlafaxine for panic disorder: results from a double-blind, Van Vliet IM, den Boer JA, Westenberg HG, Slaap BR (1996). A double-blind
placebo-controlled study. Psychopharmacol Bull 32:667–670. comparative study of brofaromine and fluvoxamine in outpatients with panic
Pollack MH, Otto MW, Worthington JJ, Manfro GG, Wolkow R (1998). Sertraline disorder. J Clin Psychopharmacol 16:299–306.
in the treatment of panic disorder: a flexible-dose multicenter trial. Arch Gen Versiani M, Cassano G, Perugi G, Benedetti A, Mastalli L, Nardi A, et al. (2002).
Psychiatry 55:1010–1016. Reboxetine, a selective norepinephrine reuptake inhibitor, is an effective and
Pollack MH, Rapaport MH, Clary CM, Mardekian J, Wolkow R (2000). Sertraline well-tolerated treatment for panic disorder. J Clin Psychiatry 63:31–37.
treatment of panic disorder: response in patients at risk for poor outcome. Wade AG, Lepola U, Koponen HJ, Pedersen V, Pedersen T (1997). The effect of
J Clin Psychiatry 61:922–927. citalopram in panic disorder. Br J Psychiatry 170:549–553.
Pollack MH, Allgulander C, Bandelow B, Cassano GB, Greist JH, Hollander E, Wagner W, Zaborny BA, Gray TE (1994). Fluvoxamine. A review of its safety
et al. (2003a). WCA recommendations for the long-term treatment of panic profile in world-wide studies. Int Clin Psychopharmacol 9:223–227.
disorder. CNS Spectr 8:17–30. Wagner W, Hauser V, Wong LF (1996). The safety profile of fluvoxamine in elderly
Pollack MH, Simon NM, Worthington JJ, Doyle AL, Peters P, Toshkov F, et al. patients. Hum Psychopharmacol 11:267–272.
(2003b). Combined paroxetine and clonazepam treatment strategies Wells GA, Shea B, O’Connell D (2005). The Newcastle-Ottawa Scale (NOS) for
compared to paroxetine monotherapy for panic disorder. J Psychopharmacol assessing the quality of nonrandomised studies in meta-analysis. Available at:
17:276–282. http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm [Accessed 1
Pollack M, Mangano R, Entsuah R, Tzanis E, Simon NM, Zhang Y (2007a). March 2012].
A randomized controlled trial of venlafaxine ER and paroxetine in the treatment Zobel A, Maier W (2010). Pharmacogenetics of antidepressive treatment.
of outpatients with panic disorder. Psychopharmacology (Berl) 194:233–242. Eur Arch Psychiatry Clin Neurosci 260:407–417.

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Review article 33

Newer antidepressants and panic disorder: a meta-analysis

Introduction Nardi, 2010; Zobel and Maier, 2010; Batelaan et al.,

the criteria of the present meta-analysis.

mized-controlled design, three studies used a nonrando-

Total number of citations retrieved from

Articles not investigating

Articles retrieved and evaluated in full for

Articles included (N = 50) Articles excluded (N = 86)

Reason for exclusion:

- Insufficient clinical data (N = 37)

- Long-term study (lasting more than 12 weeks) not

- Lack of information about improvement on anxiety

- Insufficient duration of the study (N = 8)

- Studies focusing on PD patients in remission at study

- The drug is associated with a non pharmacological

- Data referred to more SSRIs joined together (N = 3)

- Same sample of another study (N = 3)

- Clinical endpoint data concern only drug responders

Flow diagram of the review process.

Table 1 Main characteristics of the studies included

Amore et al. Fluoxetine 10–50 Yes 8 + 24 T8 14 58 37.0±7.1 No No

Paroxetine 20 No 10 T10 70 66 35.9±10.1 No –

Drug range or Study Time considered in Number of

Oehrberg et al. Paroxetine 20–60 No 12 T12 60 80 37.7 No Yes

(1998) substance use disorder

Pecknold et al. Fluoxetine 20 Yes 8 T8 28 73 36.9 Dysthymia, GAD, MD No

Table 2 Main characteristics of the studies included

Amore et al. (1999) Fluoxetine 10–50 HAMA 3.816±1.24 – – 1

Bandelow et al. (2004) Paroxetine 48.1±11.2 HAMA 1.555±2.65 PAS 1.874±0.47 32

Mirtazapine 18.3±1.3 1.375±2.03 – 2

Sharp et al. (1996) Fluvoxamine 150 HAMA 1.981±0.9 – – 7

considered separately, venlafaxine and paroxetine were no Meta-regression analyses

Clinical improvement on panic symptoms

Publication bias Discussion

citalopram could be associated with increasingly higher

insomnia, and muscle tension, possibly because of its

group, we calculated a virtual placebo. The virtual control

whereas patients taking active drugs could be more likely

Durrleman S, Chaikin P (2003). The use of putative placebo in active control

for the treatment of PD.

Pract 9:87–93. versus citalopram. J Clin Psychopharmacol 26:67–70.

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