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International Journal of Neuropsychopharmacology (2014), 17, 823832.

doi:10.1017/S1461145713001417

CINP 2013

REVIEW

5-HT2A receptor antagonists for the treatment of


neuroleptic-induced akathisia: a systematic review
and meta-analysis
Zacharias G. Laoutidis and Christian Luckhaus
Department of Psychiatry and Psychotherapy, Medical Faculty of the Heinrich Heine University, Bergische Landstrasse 2, 40629
Dsseldorf, Germany

Abstract

Received 5 August 2013; Reviewed 23 September 2013; Revised 15 October 2013; Accepted 24 October 2013;
First published online 29 November 2013
Key words: Akathisia, extrapyramidal side effects, serotonin receptor antagonists.

Introduction
Hascovec rst used the term akathisia in 1901 in order to
describe the inability of two patients with hysteria and
neurasthenia, respectively, to remain sitting down for
any length of time (Mohr and Voavka, 2002). Today,
this term is used to describe a common extrapyramidal
side-effect (EPS), which results mainly from the use of
antipsychotics. Antidepressants (Koliscak and Makela, 2009)
and dopamine receptor antagonists other than antipsychotics (e.g. metoclopramide) (Pasricha et al., 2006) are
also associated with akathisia. We will focus here solely
on neuroleptic-induced akathisia (NIA). Traditionally,
only rst generation antipsychotics are dened as neuroleptic medication (Stahl, 2008); however, atypical antipsychotics can also cause akathisia, albeit frequently
(Rosenheck et al., 2003; Haddad et al., 2012). The available data on the frequency of NIA in rst- and secondgeneration antipsychotics are not unequivocal and some
studies (among them the CATIE study; Lieberman
et al., 2005) detected no difference between them
(Peluso et al., 2012). Thus, the term antipsychotic
induced akathisia (AIA) has been proposed recently

Address for correspondence: Zacharias G. Laoutidis, Department of


Psychiatry and Psychotherapy, Medical Faculty of the Heinrich Heine
University, Bergische Landstrasse 2, 40629 Dsseldorf, Germany.
Tel.: 0049 176 931 22026 Fax: 0049 211 922 3498
Email: Zacharias.Laoutidis@lvr.de

(Poyurovski, 2010) and seems to be more appropriate.


Nevertheless, we use here the established term NIA in accordance with the majority of the existing literature.
According to DSM-IV-TR, akathisia is characterized by
a subjective feeling of restlessness and by objectively
observed typical movements such as shufing of the
legs, pacing, rocking from foot to foot, or the inability
to sit down or stand still. (American Psychiatry
Association [APA], 2000). These movements are typically
bilateral and relatively symmetrical. Reports on the
prevalence of NIA vary between 20 and 35% (Braude
et al., 1983; Halstead et al., 1994). The onset of symptoms
is usually rapid. Crane et al. (1971) reported akathisia developing within an hour after receiving droperidol or
metoclopramide. The majority of affected patients develop their symptoms within the rst days after the
onset of antipsychotic medication. Age and gender do
not seem to inuence the occurrence of NIA. Increasing
the dose in the rst days of treatment, rather than a
high dose per se seems to be the main risk factor for the
development of akathisia (Miller et al., 1997). A genetic
predisposition may also play a role (Bakker et al., 2012).
NIA is described as a very unpleasant experience and
can inuence adherence to the medication. Furthermore,
it is associated with an increase in the risk for suicide in
schizophrenic (Seemueller et al., 2012) and depressive
patients (Koliscak and Makela, 2009). This fact stresses
the importance of an accurate diagnosis and immediate
treatment. It is often reported that clinicians tend to

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Akathisia is a common and distressing extrapyramidal side-effect, which usually results from the use of antipsychotic medication. Previous reviews and meta-analyses have demonstrated a lack of evidence for the effectiveness of treatment strategies, which are traditionally used against neuroleptic-induced akathisia (NIA), i.e.
beta-blockers, anticholinergic agents and benzodiazepines. In the last fteen years, randomized trials have studied the effect of drugs with antiserotonergic properties on NIA. We conducted a systematic review of randomized
control trials and used meta-analytic methods to quantify the overall effect size. PubMed and the Cochrane
libraries were searched for eligible trials. Six randomized controlled trials were found, ve of which included
a placebo control group and qualied for our meta-analysis. The overall effect size in the analysis is RR = 7.10
with 95% CI 3.0816.40 (p < 0.0001). Our ndings suggest that 5-HT2A antagonists are effective in the treatment
of NIA.

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Z. G. Laoutidis and C. Luckhaus

Method
Search strategy
The aim of the present study was to determine whether
serotonin antagonists are effective in the treatment of
neuroleptic-induced akathisia (NIA). The inclusion
criteria for the studies were:
1 Double blind randomized controlled trials (RCTs),
either placebo-controlled or head-to-head trials. For
the purposes of the meta-analysis only placebocontrolled trials were used.
2 The drug used in the active arm of the trials should
have antagonist properties at serotonin receptors (i.e.
at the 5-HT2A receptors). Second generation antipsychotics were not included.
We searched for studies in the electronic databases
PubMed and the Cochrane Library. The only search
term was akathisia. We aimed towards higher sensitivity and lower precision in this rst selection in order
not to miss an appropriate study. In particular, we omitted any search term for therapy or treatment, which could

2,085 potential relevant references


identified according to the search criteria

2,073 excluded (as irrelevant)

12 articles retrieved in full text


for detailed evaluation

6 excluded (reviews, uncontrolled


studies- see list in the Appendix B)

6 studies included in the review

Fig. 1. Flow diagram of the study.

reduce the search sensitivity. This approach is suggested


by the Cochrane Handbook for systematic Reviews of
Interventions (Higgins and Green, 2006). The applied
limits of the search were that articles should be written
in English and that the search term appeared in the title
or abstract of the articles. The search was performed on
28 February 2013 and no time limits were applied. We
further searched through the reference lists of reviews
and relative articles to identify any additional studies.
Article selection and review strategy
The selection of studies involved an initial screening of
the title and the abstract in order to nd studies, which
were appropriate according to the inclusion criteria stated
above. If it was not clear from the title or the abstract that
the study should be rejected, the full text was obtained.
Both authors conducted the process independently in
order to reduce the possibility of rejecting a relevant
article.
Both authors extracted the data independently. In case
of disagreement, a clinician experienced in schizophrenia
and psychopharmacology could be involved to mediate
consensual decisions. A structured format was used,
as presented for the individual studies in Appendix A.
Dichotomous data were collected for the primary outcomes of this review (responders and non-responders to
treatment). Secondary outcomes were the risk ratios for
remission, dropouts, adverse effects and the impact of
the outcome on psychotic symptoms.
Statistical methods (meta-analysis)
A random effects model was applied in the meta-analysis
on the assumption that the true effect size was not the
same in all studies. The risk ratio (RR with 95% condence intervals) was preferred to the odds ratio for the
computation of effect size because it has the advantage
of being more intuitive (Borenstein et al., 2009).
Calculations were performed using standard formulas
(Borenstein et al., 2009) in Microsoft Excel (Excel 2003

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overlook akathisia (Weiden et al., 1987). But even after an


accurate diagnosis, the majority of available medications
for the treatment of NIA have not proven to be sufciently effective.
Propranalol, anticholinergic agents and benzodiazepines have been traditionally used for the treatment of
NIA. Propranolol is a non-selective beta-blocker and is
considered to be a rst-line agent against NIA. Side effects (e.g. hypotension, bradycardia), contraindications
(e.g. diabetes mellitus, bronchial asthma) and drug interactions (propranolol is an inhibitor at cytochrome P450 2D6)
set limitations in its use. In a review, Barnes et al. (2004)
could identify only three trials, which reported on the effectiveness of beta-blockers on NIA. No rm conclusions
could be drawn from this small data set. Anticholinergic
agents seem to be less effective against NIA than against
other extra-pyramidal symptoms (EPS) (dystonia, parkinsonism). Rathbone and Soares-Weiser (2006) performed a
review and mentioned the lack of evidence for the
efcacy of anticholinergic agents against NIA. Similarly,
another meta-analysis included only two trials, which
tested the effectiveness of benzodiazepines on NIA
(Resende Lima et al., 1999). The positive-effect size lacked
statistical signicance. Miller et al. (1990) studied the effectiveness of ritanserin, a 5-HT2A receptor antagonist,
against NIA in a single-blind trial without a control
group. Since then, the effect of agents with serotonin antagonistic properties has been studied in several trials,
based on the assumption that the antagonism of the
atypical antipsychotics at 5-HT2A receptors accounts for
their low incidence of EPS. Here, we give an overview
of the current evidence for the effectiveness of these
agents in the treatment of akathisia and use meta-analytic
methods in order to quantify this effect.

Table 1. Overview of studies

Author

Year

A. Head-to-head trials
Fischel
2001

Drug

Cyprohe-ptadine vs.
propranolol

Duration

Antipsychotic
medication

n = 30

7 d. (4 d on medication
and 3 d drug-free)

n = 30

5d

Evaluation tools

Results

haloperidol,
perphenazine

BARS, SAS, BPRS

No signicant difference between cyproheptadine


and propranolol. After discontinuing medication
symptoms worsened more in the cyproheptadine
group than in the propranolol group.

haloperidol,
perphenazine,
uphenazine
haloperidol,
perphenazine

BARS, LAS, SAS,


BPRS, HAM-D

The differences between the two groups were


signicant (6/15 vs. 1/15 responders; p = 0.04 by
Fishers exact test, log odds ratio = 2.23)
Response rate of 53.8% (7/13) in the mirtazapine
group and only 7.7% (1/13) in the placebo group
(t = 8.3, df = 1, p = 0.004)
The number of responders was signicantly
greater in the vitamin B6 group (13/23, 56%) and
in the mianserin group (13/20, 65%) than in the
placebo group (1/17, 6%; 22 = 14.976, p<0.0005)
13 (43.3%) of 30 patients in the mirtazapine group
and 9 (30.0%) of 30 patients in the propranolol
group were considered responders vs. only 2
(6.7%) of 30 patients in the placebo group
(2 = 10.57, df = 2, p = 0.0051). The difference in the
responder rate between the two active treatment
groups was not statistically signicant (2 = 1.15,
df = 1, p = 0.28).
At the end of the rst phase, 4 of 8 patients who
started with trazodone had a response; there were
no responders in the placebo group.

Poyurovski

2003

Mirtazapine vs. Placebo

n = 26

5d

BARS, SAS,
PANSS, HAM-D

Miodownik

2006

Mianserin vs. vitamin B6


vs. placebo

n = 60

5d

39 patients on FGA, 21
patients on SGA

BARS, BPRS, CGI

Poyurovski

2006

Mirtazapine vs.
propranolol vs. placebo

n = 90

7d

haloperidol,
perphenazine,
clothiapine

BARS, SAS, BPRS,


HAM-D

Stryjer

2010

Trazodone vs. Placebo

n = 13

6 d in 2 phases of 3 d
each (crossover trial)

Not reported

BARS, SAS,
PANSS, HAM-D

BARS, Barnes akathisia rating scale; BPRS, brief psychiatric rating scale; CGI, clinical global impression; df, degrees of freedom; FGA, rst generation antipsychotics; HAM-D, Hamilton rating
scale-depression; LAS, Leeds anxiety scale; PANSS, positive and negative symptoms scale; SAS, Simpson-Angus scale; SGA, second generation antipsychotics.

5-HT2A receptor antagonists for the treatment of neuroleptic-induced akathisia

B. Placebo-controlled trials
Poyurovski
1999 Mianserin vs. Placebo

Participants
(n)

825

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Z. G. Laoutidis and C. Luckhaus

Table 2. Relative risk ratios for response in each trial and mean effect size
Drug-group

Placebo-group

Study

Drug

Responders

Responders

Poyurovsky et al. (1999)


Poyurovsky et al. (2003)
Miodownik et al. (2006)
Poyurovsky et al. (2006)
Stryjer et al. (2010)

Mianserin
Mirtazapine
Mianserin
Mirtazapine
Trazodone

15
13
20
30
8

6
7
13
13
4

15
13
17
30
5

1
1
1
2
0

86

43

80

Total

Author

RR

95% CI

P-Value

6.00

0.82-44.00 0.0780

Poyurovski, 2003

7.00

1.00-49.16 0.0504

Miodovnik, 2006

11.05 1.61-76.01 0.0146

Poyurovski, 2006

6.50

1.60-26.36 0.0088

Stryjer, 2010

5.82

0.38-88.21 0.2039

Total

7.10

3.08-16.40 <0.0001

Lower limit

Upper limit

6.00
7.00
11.05
6.50
5.82

0.82
1.00
1.61
1.60
0.38

44.00
49.16
76.01
26.36
88.21

0.0780
0.0504
0.0146
0.0088
0.2039

7.10

3.08

16.40

<0.0001

p-value

RR and 95% CI

0,1
0,5
favours placebo

10
favours drug

Fig. 2. Forest plot.

Edition, Microsoft, USA). The forest plot was also created


in Microsoft Excel according to a guide published by
Higgins and Green (2008).
Heterogeneity I2 was computed in order to assess the
percentage of the overall variability attributable to the
between-studies variability. The risk of bias in individual
studies was evaluated using the Cochrane Collaborations
domain-based tool, which assesses allocation concealment, sequence generation, blinding, selective outcome
reporting and other sources of bias. The risk of publication bias was assessed using a funnel plot and the
Egger regression method (Egger et al., 1997).
In the case of crossover studies, we included only the
rst phase of the trial in our meta-analysis. Crossover
trials are most appropriate for symptomatic treatment of
chronic or relatively stable conditions or disorders
(Elbourne et al., 2002). Akathisia is an acute condition;
thus, the treatment or the non-treatment of akathisia
alters the condition and on entry to subsequent phases
patients may systematically differ from their initial state.
In the case of zero events trials (in one or in both arms),
the standard continuity correction of 0.5 was applied
(Friedrich et al., 2007).
Results
Search results
The electronic searches provided 1515 references from
MEDLINE and 570 references (clinical trials) from the

Cochrane Library. The initial scanning of the abstracts


excluded all but 12 reports. These reports were further
screened and assessed for eligibility and six of them
were rejected. The remaining 6 RCTs fullled the inclusion criteria for the review. From these 6 citations
there was one head-to-head trial (Fischel et al., 2001),
i.e. active drugs were compared with each other; and
ve randomized placebo-controlled studies (Poyurovsky
et al., 1999, 2003, 2006; Miodownik et al., 2006; Stryjer
et al., 2010) (see ow diagram in Fig. 1). Details of each
trial are presented in Table 1 and Appendix A. The complete list of assessed trials is presented in Appendix B.

Overview of all studies


Head-to-head trials
Fischel et al. (2001) studied 30 patients with akathisia.
Propranolol (80 mg/day, n = 12) was not found to be superior to the serotonin receptor antagonist cyproheptadine (16 mg/day, n = 18). The efcacy of propranolol in
the treatment of NIA has already been demonstrated
in other trials (Adler et al., 1986; Reiter et al., 1987;
Kramer et al., 1988) and it is traditionally considered as
a rst line option. However, other studies failed to replicate these positive ndings (Irwin et al., 1988; Sachdev
and Loneragan, 1993a). The results of Fischel et al.
(2001) suggest that cyproheptadine is as effective as propranolol. Both drugs were well tolerated. The authors

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Poyurovski, 1999

RR

5-HT2A receptor antagonists for the treatment of neuroleptic-induced akathisia

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Table 3. Relative risk ratios for remission in each study


Drug-group

Placebo-group

Study

Drug

Remission

Remission

RR

Lower limit

Upper limit

p-value

Poyurovsky et al. (1999)


Poyurovsky et al. (2003)
Miodownik et al. (2006)
Poyurovsky et al. (2006)
Stryjer et al. (2010)

Mianserin
Mirtazapine
Mianserin
Mirtazapine
Trazodone

15
13
20
30
8

4
5
4
10
3

15
13
17
30
5

1
1
0
2
0

4.00
5.00
7.68
5.00
4.53

0.50
0.67
0.44
1.19
0.29

31.74
37.12
132.99
20.92
71.73

0.19
0.12
0.16
0.02
0.28

86

26

80

4.95

2.01

12.22

Total

0.0005

Table 4. Relative risk for dropouts


Placebo-group

Study

Drug

Dropouts

Dropouts

RR

Lower limit

Upper limit

p-value

Poyurovsky et al. (1999)


Poyurovsky et al. (2003)
Miodownik et al. (2006)
Poyurovsky et al. (2006)
Stryjer et al. (2010)

mianserin
mirtazapine
mianserin
mirtazapine
trazodone

15
13
20
30
8

0
3
0
6
0

15
13
17
30
5

4
3
0
10
0

0.11
1.00
0.85
0.60
0.65

0.01
0.25
0.02
0.25
0.01

1.89
4.07
40.83
1.44
28.08

0.13
1.00
0.94
0.25
0.82

86

80

17

0.62

0.31

1.25

0.18

Total

Table 5. Relative risk for adverse effects (sedation)


Drug-group
Study

Drug

Poyurovsky et al. (1999)


Poyurovsky et al. (2003)
Miodownik et al. (2006)
Poyurovsky et al. (2006)
Stryjer et al. (2010)

Mianserin
Mirtazapine
Mianserin
Mirtazapine
Trazodone

15
13
20
30
8
86

Total

Remission

Placebo-group
n

Remission

RR

Lower limit

Upper limit

p-value

8
5
0
6
0

15
13
17
30
5

3
1
0
10
0

2.67
5.00
0.85
0.60
0.65

0.87
0.67
0.02
0.25
0.01

8.15
37.12
40.83
1.44
28.08

0.09
0.12
0.94
0.25
0.82

19

81

14

1.42

0.54

3.73

0.55

Table 6. Impact on psychotic symptoms


Drug-group

Placebo-group

Study

Scale

Mean change

SD

Mean change

SD

Hedges g

Poyurovsky et al. (1999)


Poyurovsky et al. (2003)
Miodownik et al. (2006)
Poyurovsky et al. (2006)

BPRS
PANSS
BPRS
BPRS

6.5
9.7
0.5
0.3

7.0
13.6
4.55
6.30

1.5
0.1
0.7
0.07

1.4
5.90
3.08
6.44

0.98
0.91
0.05
0.04

Total

0.42

p-value

0.07

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Drug-group

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Z. G. Laoutidis and C. Luckhaus

Domain

Assessment

Sequence generation
Allocation concealment
Blinding
Missing data
Slective reporting
Other bias

Yes

Unclear

No

Fig. 3. Risk of bias graph. The semaphore colours provide a visual impression of the quality of the study reports for meta-analysis;
green: condition is fullled; yellow: condition is questionable and red: condition is not fullled and risk of bias is present. The
overall risk of bias is low.

Standard error

0,50

1,00

1,50
3,00 2,00 1,00 0,00 1,00 2,00 3,00 4,00 5,00 6,00 7,00

Log odds ratio

Fig. 4. The funnel plot shows no gap at bottom left, which


would be indicative of selective non-reporting of negative
ndings in studies with few participants and thus larger
standard error. Because of the small number of studies, the
ndings from the funnel plot are not conrmatory.

attributed the positive effect of cyproheptadine on NIA to


its 5-HT2A antagonistic properties.
Placebo-controlled studies
Poyurovsky et al. (1999) and Miodownik et al. (2006)
compared the tetracyclic antidepressant mianserin
(15 mg/d in both studies) with placebo in 30 and
37 patients with NIA, respectively. Both publications
reported a signicant effect of mianserin on akathisia in
comparison to placebo. The anticholinergic properties of
mianserin are minimal, so that its effect on NIA can be
attributed solely to its antagonism at the 5-HT2A
receptors.
Poyurovsky et al. (2003) found in another trial with
26 participants that mirtazapine (15 mg/d) is effective in
the treatment of NIA. Poyurovsky et al. (2006) replicated
these positive results in a trial with a larger sample (n = 60,
mirtazapine dose = 15 mg/d). A third group with propranolol (80 mg/d) was included in this latter study
(Poyurovsky et al., 2006). Both drugs were equally

effective, but mirtazapine was better tolerated.


Mirtazapine is structurally and pharmacologically similar
to mianserin and exhibits marked 5-HT2A antagonism.
Finally, Stryjer et al. (2010) found in a crossover trial
that trazodone (100 mg/d) was more effective than
placebo in the treatment of NIA. Trazodone is a weak
serotonin reuptake inhibitor with potent antagonism at
5-HT2A and 5-HT2C receptors. In the rst phase of the
study, which lasted 3 days, 8 patients were treated with
trazodone and 5 with placebo. There was no washout period between the rst and the second phase. As mentioned
above, we included only the rst phase in our analysis.
Meta-analysis
Effect size
All studies used the Barnes Akathisia Rating Scale (BARS)
to quantify the symptoms of NIA and the response was
dened as a reduction of the BARS score by at least
two points. The overall effect size in the analysis is
RR = 7.10 with 95% CI 3.0816.40 (p < 0.0001).Thus, with
the 5-HT2A antagonists, a therapeutic response (as
dened in the considered studies) is about seven times
more likely than in the placebo group (see Table 2 and
forest plot in Fig. 2). As can be seen in the forest plot,
the error bars of the effect size for the rst and fth
study cross the y-axis, which means that these results
lack statistical signicance. This discrepancy between
the results presented here and the ones presented in the
original studies results from using a different measure
of effect size. Poyurovsky et al. (1999) found a signicant
odds ratio of responders in their trial (log odds ratio =
2.23, p = 0.04). Stryjer et al. (2010) reported a statistically
signicant score reduction in the BARS, but did not report
an effect size for responders.
Heterogeneity
The computed heterogeneity I2 was 14.07. Values less
than zero make no sense and heterogeneity is considered

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0,00

5-HT2A receptor antagonists for the treatment of neuroleptic-induced akathisia

829

Egger regression method


3,00
y = 1,9614x 0,0007

Standardised estimate

2,50
2,00
1,50
1,00
0,50

0,20

0,00
0,00

0,20

0,40

0,60

0,80

1,00

1,20

1,40

1,60

0,50

Precision (1/SE)
Fig. 5. The Egger regression method is used to quantify the risk of publication bias. An intercept near zero is indicative of a low
probability for bias. In our study the intercept was 0.0007.

the reliability of these results. The estimated intercept in


Eggers regression was 0.0007 (Fig. 5). Values near
zero indicate no publication bias.

Secondary outcomes
Remission rates were signicantly higher in the drug
groups than in the placebo groups (RR = 4.95, 95% CI
2.0112.22, p = 0.0005; Table 3). There were no signicant
differences between patients in either group in dropouts
(RR = 0.62, 95% CI 0.311.25, p = 0.18; Table 4) and adverse
effects (RR = 1.42, 95% CI 0.543.73, p = 0.55; Table 5). Two
studies (Miodownik et al., 2006; Stryjer et al., 2010)
reported no adverse effects in either drug or placebo
groups, while two other studies (Poyurovsky et al.,
1999, 2003) reported only sedation. Poyurovsky et al.
(2006) presented a more extensive list of adverse effects.
In order to achieve comparable results, we included
only the patients with sedation from this study in the
meta-analysis. The treatment of akathisia did not inuence the severity of the psychotic symptoms (see
Table 6). Here data from four studies were available,
since the corresponding author of the fth study did
not provide us with missing data.
Risk of bias and publication bias
The risk of bias for each study can be assessed using the
following six domains: sequence generation, allocation
concealment, blinding, missing data, selective outcome
reporting and other sources of bias (Higgins and Green,
2008). The group of studies was relatively homogenous
and the overall risk for bias could be described as low
(Fig. 3). The results for each trial are presented in
Appendix C. Finally, no indication of publication bias
can be derived from the funnel plot; in particular, there
was no gap on the bottom left side, which would be indicative of unpublished studies with small to moderate
effects (Fig. 4). However, the small number of trials limits

Discussion
This is the rst meta-analysis to estimate the effect of
agents with antagonistic properties at the 5-HT2A receptor
on NIA and the rst to report a positive effect of a drug
group. The mean effect size was RR = 7.10 (95% CI
3.0816.40, p < 0.0001), which indicates a substantial
drug efcacy. There were no signicant differences between drug and placebo groups as far as adverse effects
and dropouts are concerned. A reduction in the intensity
of akathisia was not accompanied by a reduction in psychotic symptoms severity. Because of the small number of
trials, no differences in efcacy among the three agents
used (i.e. mirtazapine, mianserin and trazodone) can be
detected. Based on the existing literature, mirtazapine
seems to have a more favourable side effects prole
than the other two agents. Mianserin and trazodone
have adrenolytic properties, which can cause somnolence,
sedation, impairment of cognitive functioning and circulatory problems (Stahl, 2008). Trazodone can also cause
priapismus, an infrequent but severe adverse effect
(Fagiolini et al., 2012). In contrast, mirtazapine lacks adrenolytic properties and can thus be better tolerated when
combined with antipsychotics, which themselves exhibit
1-receptor blockade. Sedation is often observed in low
doses, owing to its antihistaminergic properties, for this
reason mirtazapine is preferentially administered before
sleep. Long-term use is associated with weight gain.
Alternative options
In addition to the medication discussed above, there are
trials that show the efcacy of other agents, e.g. vitamin
B6 (Lerner et al., 2004; Miodownik et al., 2006),

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to be equal to zero in such cases. Heterogeneity between 0


and 40% is of no importance.

830

Z. G. Laoutidis and C. Luckhaus

apomorphine (Sachdev and Loneragan, 1993b) and zolmitriptan (Avital et al., 2009). Only vitamin B6 has been
shown to be effective in more than one trial. The lack of
signicant adverse effects of vitamin B6 and its proven
efcacy justify its use in the treatment of NIA. Vitamin
B6 has already been found to be effective in the treatment
of tardive dyskinesia (Lerner et al., 2001, 2007). The exact
mechanism of action is not known; but the fact that a derivative of vitamin B6 is a coenzyme of dopa decarboxylase is suggestive (Amadasi et al., 2007). Apomorphine
has dopaminergic properties. However, it is not known
to exacerbate psychotic symptoms in schizophrenic
patients (Dpatie and Lal, 2001). Zolmitriptan is a
5-HT1A receptor antagonist and is used in the treatment
of migraine.

Acknowledgments
We thank Hara Alexandri for her help in preparing the report. We would also like to thank Vladimir Lerner for
sending us information about his study.

Statement of Interests
None.

Supplementary material
For supplementary material accompanying this paper,
visit http://dx.doi.org/10.1017/S1461145713001417.

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