Alternatives to benzos for GAD.

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The Place of Antipsychotics in the Therapy of
Anxiety Disorders and Obsessive-Compulsive
Disorders
Article in Current Psychiatry Reports · December 2017
DOI: 10.1007/s11920-017-0847-x
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2. ANXIETY DISORDERS (A PELISSOLO, SECTION EDITOR)
The Place of Antipsychotics in the Therapy of Anxiety Disorders
and Obsessive-Compulsive Disorders
Baptiste Pignon1,2,3,4,5
& Chloé Tezenas du Montcel1
& Louise Carton6,7
&
Antoine Pelissolo1,2,3,4
# Springer Science+Business Media, LLC 2017
Abstract
Purpose of Review The purpose of this review was to assess
and present the findings up to this date on the efficacy of
antipsychotics in the treatment of generalized anxiety disor-
ders (GAD), social anxiety disorders (SAD), panic disorders
(PD), and obsessive-compulsive disorders (OCD), mostly
based on published randomized controlled trials (RCTs) or
on open-label studies when RCT were lacking.
Recent Findings Quetiapine could be recommended in pa-
tients with GAD. The efficacy of aripiprazole in two open-
label studies on patients with antidepressant-refractory GAD
should be assessed in RCTs. Despite preliminary positive re-
sults in open studies, there are currently no strong evidence for
the effectiveness of antipsychotics in refractory SAD and in
refractory PD. Conversely, risperidone and aripiprazole can be
used for the treatment of refractory OCD as augmentation
agents to antidepressants.
Summary Contrary to SAD and PD, this review found evi-
dence for the use of second-generation antipsychotics in GAD
and OCD. Otherwise, first-generation antipsychotics cannot
be recommended in anxiety disorders and OCD.
Keywords Generalized anxiety disorders . Social anxiety
disorders . Panic disorder . Obsessive-compulsive disorders .
First-generation antipsychotics . Second-generation
antipsychotics
Introduction
Anxiety disorders are a group of psychiatric disorders char-
acterized by pathological feelings of anxiety and fear.
Major anxiety disorders are generalized anxiety disorder
(GAD), social anxiety disorder (SAD), and panic disorder
(PD). Obsessive-compulsive disorders (OCD) share symp-
toms with anxiety disorders, but, according to DSM-5, they
are considered as separate entities [1]. Anxiety disorders are
the most common psychiatric disorders, affecting between
20 and 40% of the population [2, 3]. Many patients will
present more than one anxiety disorder at the same time,
which can complicate treatment. Anxiety disorders are as-
sociated with reduced quality of life and social functioning,
as well as higher morbidity and mortality [4].
Psychotherapy and antidepressants, especially selective
serotonin reuptake inhibitors (SSRIs) and serotonin-
norepinephrine reuptake inhibitors (SNRIs), have shown
efficiency in the treatment of anxiety disorders, and are
now considered as first-line treatment, followed by a switch
to other drugs such as benzodiazepines, mirtazapine,
This article is part of the Topical Collection on Anxiety Disorders
* Baptiste Pignon
baptistepignon@yahoo.fr
1
AP-HP, DHU PePSY, Hôpitaux Universitaires Henri-Mondor, Pôle
de Psychiatrie, 94000 Créteil, France
2
INSERM, U955, team 15, 94000 Créteil, France
3
Fondation FondaMental, 94000 Créteil, France
4
Faculté de médecine, UPEC, Université Paris-Est,
94000 Créteil, France
5
Hôpital Albert Chenevier, Groupe Hospitalier Henri-Mondor, CHU
de Créteil, Assistance Publique-Hôpitaux de Paris (AP-HP), 40 rue
de Mesly, 94 000 Créteil, France
6
Département de Pharmacologie Médicale, Univ.Lille, Inserm U1171,
CHU Lille, 59000 Lille, France
7
Service d’addictologie, CHU Lille, 59000 Lille, France
Curr Psychiatry Rep (2017) 19:103
https://doi.org/10.1007/s11920-017-0847-x

3. pregabalin, or buspirone [5–7]. However, responses to
these treatments are often incomplete, and new strategies
have to be developed to address this resistance [8].
Antipsychotic drugs could be considered as an option in
the indication of refractory anxiety disorders. These drugs
have been developed since the 1950s originally for the
treatment of psychotic disorders [9, 10]. Since decades,
their use has exceeded the management of psychotic disor-
ders, and now concerns for instance mood disorders [11].
The fact that anxiety and psychotic disorders are often as-
sociated [12] (likewise anxiety disorders and psychotic
symptoms [13, 14]) and the effectiveness of antipsychotic
medication on anxiety symptoms in patients with psychotic
disorders [15, 16] argue for the use of antipsychotic medi-
cation in anxiety disorders.
Prior to the 1980s, clinical studies compared first-
generation antipsychotics (FGAPs) to benzodiazepines, tri-
cyclic antidepressants (TCAs), and/or placebo in the treat-
ment of anxiety symptoms. In these studies, FGAPs were
superior to placebo, but results of comparisons to benzodi-
azepines and TCA were conflicting [17]. However, these
results were tempered by the side effects of these drugs—
including extrapyramidal symptoms (EPS) and irreversible
tardive dyskinesia [18, 19]. The entry of second-generation
antipsychotics (SGAPs) into the marketplace led to a resur-
gence of interest [20]. Indeed, SGAPs are characterized by
less EPS and tardive dyskinesia side effects [21]. Moreover,
in addition to D2 dopamine receptor antagonism, SGAPs
are characterized by an action on the serotonin system, es-
pecially (i) an 5HT2A serotonin receptor antagonism action
and (ii) an 5HT1A serotonin receptor agonism action [22].
Involvement of other serotoninergic receptors had also been
mentioned like 5HT7 and 5HT2 antagonism, as well as
histamine H1 receptor antagonism [23]. Since fear and wor-
ry are partly linked to serotonin and dopamine pathways,
especially in the cortico-striato-thalamo cortical loop [24],
SGAPs could be interesting for anxiety disorders.
A recent American study showed that between 30 and
50% of patients received off-label antipsychotic medication
[8]. Moreover, a recent systematic review has listed the
different off-label antipsychotic prescription among chil-
dren, adult, and elderly patients. Anxiety disorders ap-
peared as one of the main indications of this off-label pre-
scription [25]. However, off-label prescriptions need scien-
tific support, and the risk/benefit ratio needs to be consid-
ered [26], especially considering the cardiometabolic side
effects of SGAPs [27].
In this comprehensive review, our aim was to present the
current research findings on the efficacy of antipsychotics
in the treatment of anxiety disorders, i.e., GAD, SAD, and
PD, and in the treatment of OCD, mostly based on pub-
lished randomized controlled trials (RCTs), or, in absence
of RCT, on open-label studies.
Generalized Anxiety Disorder
GAD is characterized by excessive and uncontrolled anxiety
or worry about numerous activities or events for a minimum
period of 6 months [1, 28]. This maladaptive fear, considered
as an intolerance of uncertainty, is associated with autonomic
arousal and somatic symptoms (fatigability, impaired concen-
tration, irritability, sleep disorders, etc.). GAD is associated
with significant impairment and disability [29]. Lifetime prev-
alence rate for GAD has been estimated between 4.1 and 8.6%
[2, 30, 31]. GAD is a highly chronic disorder. In an 8-year
longitudinal follow-up, about one half of patients achieved
remission, and more than a third party demonstrated relapse
in that time [32]. Thus, the economic burden of GAD is high,
due to disability and healthcare costs [33, 34].
According to the National Institute for Health and Care
Excellence (NICE) [35], the World Federation of Societies
of Biological Psychiatry (WFSBP) [5], and the Canadian
Network for Mood and Anxiety Treatments (CANMAT)
[36] guidelines, first-line treatment is psychotherapy and anti-
depressant treatment. The efficacy of cognitive behavioral
therapies (CBT) has been widely assessed in the treatment of
GAD. CBT for GAD consists of anxiety self-monitoring, re-
laxation training, or cognitive restructuring [37]. Overall, ap-
proximately 50% of patients with GAD achieve significant
clinical improvement with CBT [38]. Concerning pharmaco-
logical treatment, the different international guidelines recom-
mend SSRIs and SNRIs in monotherapy [5, 35, 36]. The
WFSBP guidelines also consider pregabalin as a first-line
treatment [5]. The remission rate for SSRI- and SNRI-
treated GAD was about 30% [39, 40]. In sum, rates of resis-
tance to first-line treatment were quite high, and antipsy-
chotics should be used in monotherapy or add-on treatment
for patients with antidepressant-refractory GAD.
Risperidone was one of the first SGAPs investigated in the
treatment of refractory GAD. In 2005, a double-blind RCT of
risperidone vs. placebo combined with antidepressant and/or
anxiolytic among 40 patients with refractory GAD showed a
significantly greater reduction in symptoms [41]. However,
rates of patients that were considered as responders did not
significantly differ in the two groups, and the same occurred in
another RCT [42]. Thus, further studies are needed to study
the efficacy of risperidone in adjunctive treatment of refracto-
ry GAD [43]. Moreover, risperidone has not been investigated
in monotherapy [20]. Concerning olanzapine, the only avail-
able RCT of adjunctive therapy at a mean dose of 8.7 mg/day
vs. placebo among 24 patients showed that the responders’
rate was significantly higher in the olanzapine group [44].
However, weight gain caused by olanzapine represents an
important clinical concern [21]. Regarding aripiprazole, two
unrandomized studies in small groups of patients (N = 6 and
N = 13) with refractory GAD showed that adjunctive therapy,
at flexible dosages starting from 10 mg/day for the first study
103 Page 2 of 11 Curr Psychiatry Rep (2017) 19:103

4. and 2.5 mg/day for the second, led to significant improvement
in anxiety symptoms, without significant differences in remis-
sion rate [45, 46]. Finally, a RCT of ziprasidone monotherapy
or in adjunctive treatment vs. placebo in refractory GAD pa-
tients did not show any significant difference in reduction of
anxiety symptoms [47•].
Thus, levels of evidence concerning the efficacy of these
SGAPs in refractory GAD (in monotherapy or adjunctive
treatment) seem insufficient to be recommended in this disor-
der. The case of quetiapine is different. Although studies of
quetiapine as adjunctive treatment to SSRI antidepressant in
refractory GAD did not provide evidence of efficacy [48, 49•,
50], several RCTs suggested that quetiapine in monotherapy
was associated with significantly higher rates of responders
than placebo [51–53]. These studies were recently pooled in a
meta-analysis [54••]. Results showed that the quetiapine-
treated group had (i) significantly higher improvement in anx-
iety symptoms, (ii) significantly higher rates of responders
(RR = 1.24, 95% CI [1.16; 1.32]), and (iii) significantly higher
rates of remission (RR = 1.27, 95% CI [1.13; 1.42]) than
placebo. Comparisons with SSRIs on the same outcomes
showed non-significant differences. Other studies showed that
quetiapine improved daily life function and quality of life
[55•, 56]. Quetiapine also appears to be particularly effective
on sleep disorders of patients with GAD [55•]. Moreover,
quetiapine showed to be effective in reduction of risk of re-
lapse, i.e., as maintenance treatment [57]. Thus, quetiapine
(50–300 mg/day) is now recommended as first-line option
for acute treatment of GAD by the British Association for
Psychopharmacology and the WFSBP guidelines [5, 58].
Categories of evidence [59] based on the current knowl-
edge of the indication of the different antipsychotic drugs in
GAD are available in Table 1.
Social Anxiety Disorder
SAD (also known as social phobia) is characterized by fear of
social situation and of portraying anxiety symptoms that will
be socially negatively evaluated (i.e., will be humiliating, will
lead to rejection or offend others, etc.). The fear, anxiety, or
avoidance is persistent, typically lasting 6 months or more [1,
60, 61]. SAD is associated with comorbid alcohol use disor-
ders, sleep disorders, impairment of social functioning, and
overall impairments in well-being [62–66]. Lifetime preva-
lence has been estimated between 5.0 and 12.1% [67, 68].
As for GAD, according to NICE, WFSBP, and CANMAT
guidelines [5, 36, 69], either CBT and SSRIs are currently
recommended as first-line treatment [65, 70]. Within NICE
guidelines, CBT has to be the first option proposed to the
patients [69]. However, the choice to start with one modality
rather than another, or to use combined treatment, often relies
on clinical judgment about individual patients [71] and
patients’ preferences. Venlafaxine (i.e., a SNRI antidepres-
sant) is also recommended as possible first-line pharmacother-
apy by the WFSBP and CANMAT guidelines [5]. Less infor-
mation is available regarding the optimal length of treatment,
although individuals who discontinue treatment after 12–
20 weeks appear to be more likely to relapse than those who
continue on medication. The recommended duration of treat-
ment after therapeutic response is at least 3–6 months, with
longer periods considered in individuals’ cases. After
12 weeks of treatment without any response or just with partial
response, the patient is considered as resistant, and new med-
ication should be used to try improving his response [72].
Few studies have evaluated the effect of SGAPs on small
groups of patients with SAD: two involved quetiapine, one
risperidone, and one olanzapine. To our knowledge, no one
concerned FGAPs. Olanzapine was the first SGAP investigat-
ed in the treatment of SAD. In a pilot RCT (N = 12), mono-
therapy of olanzapine (5–20 mg/day) during 8 weeks showed
significantly better results than placebo [73]. Risperidone was
also evaluated among seven refractory SAD patients in a non-
controlled study [74]. They received flexible doses of risper-
idone (0.25–3 mg/day) for 8 weeks, and symptoms were also
significantly improved. One RCT evaluated first-line
quetiapine treatment (150–250 mg/day) vs. placebo during
8 weeks in 15 individuals with SAD. No significant difference
was found [75]. In an open-label pilot study, quetiapine (mean
dose 250 mg/day) during 12 weeks was found to be effective
in reducing symptoms in 13 individuals with SAD [76].
According to NICE and WFSBP guidelines [5, 69]), the
level of evidence of SGAP efficacy is not sufficient to recom-
mend these drugs for patients with SAD [36]. However, ac-
cording to CANMAT guidelines, olanzapine is recommended
as a third-line option. In these recommendations, aripiprazole
and risperidone are considered in third-line adjunctive thera-
pies [36]. Additional studies of olanzapine, risperidone, and
quetiapine as a treatment for SAD are warranted, too few data
being available to come up with any conclusion [77]. Future
research may particularly consider higher and/or chronic dos-
ing of quetiapine and whether quetiapine in combination with
CBT is better than each treatment separately [78].
Categories of evidence [59] based on the current knowl-
edge of the indication of the different antipsychotic drugs in
SAD are available in Table 1.
Panic Disorder
Panic attacks are acute anxiety and fear reactions to internal or
external stimuli that may include palpitations, sweating, trem-
or, or numbness. PD is defined by recurrent panic attacks
associated with other symptoms following the occurrence of
panic attacks, i.e., anticipatory anxiety and maladaptive
changes in behavior (e.g., avoidant behavior). Most subjects
Curr Psychiatry Rep (2017) 19:103 Page 3 of 11 103

5. with PD display agoraphobia, which is fear or avoidance of
situations in which panic attacks can occur [1]. The lifetime
prevalence of PD in the general population ranges from 3.5 to
5% [79, 80]. Patients with PD show significant socio-
professional impairment, such as higher unemployment rate
[81]. According to the NICE, WFSBP, and CANMAT guide-
lines, first-option treatment for PD is CBT and/or antidepres-
sant pharmacotherapy [5, 36, 82]. SSRIs and SNRIs are as
effective as TCA, but have less side effects [58].
Benzodiazepines should not be considered as a first-option
treatment, because of high dosages needed and risks of depen-
dence and withdrawal syndrome [83].
However, a large proportion (between 20 and 40%) re-
mains symptomatic after psychotherapy and/or antidepressant
treatment [43, 84]. Although the considered definition of re-
fractory PD has varied (one or two antidepressants trials, du-
ration of treatment, etc.) [85], SGAP treatment could be
discussed in this indication. In fact, their action on dopamine
and especiallyserotonin could have an anti-panic effect [86,
87].
Several SGAPs have been tested in the indication of refrac-
tory PD. Two small-effective open-label studies tested the
prescription of olanzapine in augmentation to SSRI or in
monotherapy in patients with resistant PD. Both showed sig-
nificant improvement in efficacy measures [88, 89]. The aug-
mentation study resulted in response among 81% of the pa-
tients, and in remission in 58% [89]. In another open-label
augmentation study, aripiprazole led to unsignificant improve-
ment, and to only 10% of remission [46]. Concerning risper-
idone, an open-label study on 30 refractory anxiety disorders
patients (including 7 PD) showed significant improvement
[74]. Moreover, in a single-bind RCT of 56 patients with
non-refractory PD or depression with panic attack patients,
there was no significant difference between very low-dose
Table 1 Antipsychotics for anxiety disorders: the categories of evidence
Antipsychotic
drug
Indication Daily dose Monotherapy or add-on Category of evidencea
GAD
Aripirazole Refractory GAD 2.5–30 mg Add-on to antidepressant
and/or to anxiolytic
C: two unrandomized trials showed significant results
Olanzapine Refractory GAD 2.5–20 mg Add-on to antidepressant
and/or to anxiolytic
B: one RCT showed significant results
Quetiapine Refractory GAD 25–400 mg Add-on to SSRI
antidepressant
D: inconsistent results
GAD 50–300 mg Monotherapy
and add-on
A: meta-analysis of RCT showed significantly positive results
Risperidone Refractory GAD 0.25–3 mg Add-on to antidepressant
and/or to anxiolytic
D: inconsistent results
Ziprasidone Refractory GAD 20–80 mg Monotherapy
and add-on
E: negative evidence: a RCT showed an absence of difference
with the placebo
SAD
Olanzapine SAD 5–20 mg Monotherapy B: one RCT showed significant results
Quetiapine SAD 50–300 mg Monotherapy D: inconsistent results
Risperidone Refractory SAD 0,25–3 mg Add-on to antidepressant
and/or to anxiolytic
C: one open-label study showed significant higher rate of
improvement
PD
Aripirazole Refractory PD 5–15 mg Add-on to antidepressant
and/or to anxiolytic
E: one open-label study did not show significant improvement
Olanzapine Refractory PD 2.5–30 mg Add-on to SSRI
antidepressant and
monotherapy
C: two open-label studies showed significant higher rate of
improvement and response
Quetiapine Refractory PD 50–400 mg Add-on to SSRI
antidepressant
E: one placebo-controlled did not show significant improvement
Risperidone Refractory PD 0.25–3.00 mg Add-on to antidepressant
and/or anxiolytic
C: one open-label studies showed significant improvement
Non-refractory PD
or depression with
panic attack(s)
0.125–1 mg Monotherapy B: one RCT showing no difference with the reference treatment,
i.e., SSRI antidepressant
Sulpiride Refractory PD 100–200 mg Monotherapy C: one open-label studies showed significant improvement
GAD generalized anxiety disorder, RCT randomized controlled trials, SSRI selective serotonin reuptake inhibitors, SAD social anxiety disorder, PD panic
disorder
a
According to Bandelow et al. [59]
103 Page 4 of 11 Curr Psychiatry Rep (2017) 19:103

6. risperidone (0.125–1.0 mg/day) and the reference treatment,
i.e., an SSRI antidepressant [86]. Sulpiride in monotherapy
showed promising results in an open-label study on 19 pa-
tients with refractory PD (significant improvement) [90•].
Finally, in a RCT conducted in 26 patients with refractory
PD, the group with quetiapine in addition to an SSRI treat-
ment did not reach better outcome than the patients who were
in the SSRI and placebo group [91•]. However, according to
anxiolytic properties of quetiapine [54••, 92], RCTs on larger
groups should be conducted. To our knowledge, as for GAD
and SAD, FGAPs have not been tested in PD.
In sum, according to the current knowledge and to guide-
lines (NICE, WFSBP, or CANMAT [5, 36, 93]), antipsychotic
drugs are not recommended for the treatment of PD. A recent
review of SGAP studies in PD, some involving patients with
comorbid bipolar disorders, confirmed a general lack of effi-
cacy of quetiapine, risperidone, and ziprasidone on panic
symptoms [94]. However, some findings, especially
concerning risperidone and olanzapine, should be considered
for future RCT conducted on refractory PD.
Categories of evidence [58] based on the current knowl-
edge of the indication of the different antipsychotic drugs in
PD are available in Table 1.
Obsessive-Compulsive Disorder
OCD is characterized by recurrent and persistent thoughts
considered as intrusive and unwanted (obsessions), and/
or repetitive behaviors or mental acts performed in response
to an obsession in the objective of decreasing anxiety
(compulsions) [1]. OCD is a debilitating pathology causing
severe functional impairment [95], with a lifetime prevalence
of about 1.9 to 2.5% [96].
A large body of evidence showed that CBT with exposure
and response prevention techniques can be considered as a
first-line therapy [58]. Concerning psychopharmacology, the
NICE, WFSBP, and CANMAT guidelines consider SSRIs as
the first-line treatment of OCD [5, 36, 58]. When treating
OCD, SSRIs should be used with optimal doses exceeding
the one used in depressive disorders, and one should wait 8
to 12 weeks before concluding on its possible efficacy. As
they have been shown to be more effective than SSRIs [97],
the WFSBP and CANMAT guidelines considers also TCA,
e.g., clomipramine, as a first-line treatment [5, 36], but given
the worse tolerance, it is now used as a second-line treatment
[98]. The Yale-Brown Obsessive Compulsive Scale (Y-
BOCS) evaluates the severity of the disorder and treatment
response. OCD is considered severe when the score is above
16, and response to treatment is defined by a decrease of 35%
of Y-BOCS score [99]. Resistance to two SSRI trials as well as
resistance to an adequate clomipramine trial define refractory
OCD [58, 100].
As 40 to 60% of the patients do not respond sufficiently to
these lines of treatment, the search for efficient add-on treat-
ment to SSRIs is an important issue [101]. In 1994, McDougle
pursued the first double-blind RCT (N = 34) adding haloper-
idol to an SSRI antidepressant (fluvoxamine) in refractory
OCD and that resulted in significantly higher response rates
than placebo [102]. In 2005, a double-blind placebo-con-
trolled cross-over study confirmed the effect of haloperidol
and showed greater effect compared to risperidone and to
placebo [103]. However, in the same trial, almost 42% of
the patients treated displayed important EPS induced by hal-
operidol. Therefore, as for other FGAPs, haloperidol is not
considered as an eligible choice for antipsychotic add-on to
refractory OCD, except for patients with comorbid Tourette
syndrome [104], since various studies evaluated the efficacy
of adding SGAPs to SSRIs in severe refractory OCD.
Considering risperidone, a meta-analysis of four double-
blind and placebo-controlled RCTs concerning add-on to high
dose of SSRIs showed significant decrease in Y-BOCS scores
with various doses of risperidone of 0.5 to 6 mg/day [105••].
Aripiprazole drew specific attention given its partial agonist
activity at the dopamine D2 and serotonin 5HT1A receptors as
well as antagonistic activity at the 5HT2A receptors [106]. In a
double-blind RCT, in comparison to placebo, proportions of
responders were significantly higher among 12-week
aripiprazole augmentation to the SSRI group (53 vs. 17%)
[107•]. Another RCT concerning aripiprazole was published,
and both results were pooled in a meta-analysis [105••]. It
showed significant efficacy of aripiprazole on symptom reduc-
tion in severe refractory OCD, either on obsessions or compul-
sions. However, as these two studies were performed on small
samples (N = 12 and N = 16), these results should be considered
with caution. A single-blind RCTcompared the effect of risper-
idone and aripiprazole as add-on treatment to SSRI [108•].
Results showed superior effect of risperidone compared to
aripiprazole, with a greater decrease in Y-BOCS total score after
8 weeks of treatment (with 50% of response in the aripiprazole
group, compared to 72% in the risperidone group). Moreover,
they highlighted a specific effect of risperidone on the obses-
sion subscale, with no significant difference on the decrease of
the compulsion subscale. Finally, quetiapine and olanzapine
effect did not significantly differ from placebo.
So far, risperidone seems to be the first SGAP recommend-
ed by international guidelines [109], but small evidence brings
us to consider aripiprazole as efficient add-on treatment of
severe refractory OCD. Further large-scale studies should be
conducted to assess this efficiency and highlight the existence
of potential specific effects of these drugs. It should also be
noted that SGAPs, especially clozapine, olanzapine, and ris-
peridone, have been repeatedly implicated in the de novo
emergence and exacerbation of obsessive-compulsive symp-
toms in patients with schizophrenia [110]. Therefore, this
point may need specific attention in at-risk patients.
Curr Psychiatry Rep (2017) 19:103 Page 5 of 11 103

7. Categories of evidence [58] based on the current knowl-
edge of the indication of the different antipsychotic drugs in
OCD are available in Table 2.
Discussion
According to the current scientific knowledge, only three an-
tipsychotics can be recommended for the treatment of anxiety
disorders and OCD, in two specific situations: quetiapine for
GAD, and aripiprazole and risperidone in augmentation for
refractory OCD.
As they gave promising results, some other SGAPs should
be reviewed in further studies: olanzapine and aripiprazole for
refractory GAD, olanzapine for SAD and risperidone for re-
fractory SAD, risperidone for PD, and olanzapine, risperi-
done, and sulpiride for refractory PD. Due to their tolerance
profile, FGAPs cannot be recommended.
The present review considered the background treatment of
anxiety disorders and OCD, and not the acute treatment of
anxiety symptoms. Although they are not recommended as a
specific treatment for such disorders, certain FGAPs, like
cyamemazine [111], display anxiolytic effects, and are used
in acute treatment of serious anxiety symptoms, especially in
some countries like France [112]. Quetiapine appeared to have
acute anxiolytic effects on patients with specific phobia [113].
Compared to benzodiazepine drugs, they offer the advantage
of the absence of abuse potential and dependence, but their
benefit-risk ratio in these indications is not well established
[20, 114].
As in schizophrenia, the monitoring and managing of side
effects associated with the prescription of SGAPs—weight
increase, metabolic syndrome, type 2 diabetes, QT prolonga-
tion, sexual dysfunction, hyperprolactinemia, etc.—are abso-
lutely necessary [115–118]. Since SSRI and SNRI antidepres-
sants display a better tolerance profile than antipsychotics,
they should remain as first-line drug treatment.
Other studies are now needed to further improve our
knowledge on SGAPs’ role in anxiety disorders, because the
available data are relatively rare and not always based on
sufficiently robust methodologies (open-label trials, small
sample sizes, etc.). Specifically, the following critical issues
should be addressed: treatment response criteria, especially
concerning overall severity or specific symptoms (such as
poor insight in OCD, or even psychotic symptoms), choice
of associated antidepressants for augmentation strategies, and
duration of treatment. It is important to also take into account
the case of bipolar disorder comorbidity in patients with anx-
iety disorders, considering the risk of triggering the start of a
manic episode or the course of illness being destabilized with
the use of antidepressants. SGAPs are generally suggested as
alternatives to antidepressants in this indication, but data are
currently insufficient to make a clear recommendation on this
issue [119].
Discomfort with antipsychotic medication in patients with
anxiety disorders should be studied. As they excluded less
patients than in RCTs, naturalistic studies could give impor-
tant insight, particularly on dropout rates of patients with an-
tipsychotic medication [120, 121].
Finally, further research should also specify the indications
of antipsychotics, beyond the categorical approach of anxiety
disorders. The potential target of personality disorders could
for instance be considered. Borderline personality disorder
(BPD), which displays a high rate of comorbid anxiety disor-
ders, including GAD and SAD [122, 123], could for instance
be relevant in the efficacy of antipsychotics for certain anxiety
disorders. Indeed, in a 10-year prospective study, Keuroghlian
et al. showed that the evolution of BPD symptoms predicts the
evolution of GAD [124]. Moreover, aripiprazole (15 mg/day)
is effective on anxiety symptoms in patients with BPD (in
comparison to placebo, standardized mean difference on the
Hamilton Anxiety Rating scale = − 0.73, 95% CI [− 1.29;
− 0.17]) [125], as well in low dose of quetiapine (150 mg/
day) on overall BPD symptomatology [126]. Several guide-
lines recommend the use of antipsychotics in patients with
BPD (e.g., American Psychiatric Association (APA) [127],
National Health and Medical Research Council (NHMRC)
[128]). Weber et al. have also shown that BPD was associated
to off-label prescriptions of antipsychotics for patients with
anxiety disorders [8]. It is important to note that, in the differ-
ent RCTs of antipsychotics on anxiety disorders and OCD,
BPD did not count as an exclusion criterion. Moreover,
Table 2 Antipsychotics for OCD: the categories of evidence
Antipsychotic drug Indication Daily dose Monotherapy or add-on Category of evidencea
Aripiprazole Refractory OCD 10–15 mg Add-on to SSRI antidepressant A: meta-analysis of RCT
Haloperidol Refractory OCD 3–10 mg Add-on to SSRI antidepressant B: one RCT showed significant results
Olanzapine Refractory OCD 5–20 mg Add-on to SSRI antidepressant D: inconsistent results
Quetiapine Refractory OCD 160–400 mg Add-on to SSRI antidepressant D: inconsistent results
Risperidone Refractory OCD 0.5–10 mg Add-on to SSRI antidepressant A: meta-analysis of RCT
OCD obsessive-compulsive disorder, RCT randomized controlled trials, SSRI selective serotonin reuptake inhibitors
a
According to Bandelow et al. [59]
103 Page 6 of 11 Curr Psychiatry Rep (2017) 19:103

8. antipsychotic drugs could be particularly useful in comorbid
psychiatric disorders (e.g., associated mood or psychotic dis-
orders to anxiety disorders or OCD), or for the treatment of
serious anxiety symptoms as part of such disorders, with a
dimensional approach [7, 17].
Conclusion
We found limited but promising evidence of SGAP prescrip-
tions for specific disorders, in monotherapy or in augmenta-
tion strategies, in particular for GAD and OCD. However,
these drugs cannot be considered as first-line treatment in
these indications because of their tolerability profile and of
limited data. Therefore, further larger studies are needed for
precision of the place of SGAPs in treatment algorithms of
anxiety disorders and OCD.
Acknowledgements The authors thank Yasmina Frem for assistance
and proofreading. The authors thank Dr. Friedel for reviewing the
manuscript.
Compliance with Ethical Standards
Conflict of Interest Baptiste Pignon and Chloé Tezenas du Montcel
each declare no potential conflicts of interest.
Antoine Pelissolo is a section editor for Current Psychiatry Reports.
Louise Carton reports personal fees from AstraZeneca, Indivior, and
Lundbeck for talks.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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