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ThePlaceofAntipsychoticsintheTherapyofAnxietyDisordersandObsessive-CompulsiveDisorders

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DOI:10.1007/s11920-017-0847-x

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ANXIETY DISORDERS (A PELISSOLO, SECTION EDITOR)

The Place of Antipsychotics in the Therapy of Anxiety Disordersand 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

AbstractPurpose of Review The purpose of this review was to assessand present the findings up to this date on the efficacy ofantipsychotics in the treatment of generalized anxiety disor-ders (GAD), social anxiety disorders (SAD), panic disorders(PD), and obsessive-compulsive disorders (OCD), mostlybased on published randomized controlled trials (RCTs) oron open-label studies when RCTwere 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 GADshould be assessed in RCTs. Despite preliminary positive re-sults in open studies, there are currently no strong evidence forthe effectiveness of antipsychotics in refractory SAD and inrefractory PD. Conversely, risperidone and aripiprazole can be

used for the treatment of refractory OCD as augmentationagents to antidepressants.Summary Contrary to SAD and PD, this review found evi-dence for the use of second-generation antipsychotics in GADand OCD. Otherwise, first-generation antipsychotics cannotbe recommended in anxiety disorders and OCD.

Keywords Generalized anxiety disorders . Social anxietydisorders . Panic disorder . Obsessive-compulsive disorders .

First-generation antipsychotics . Second-generationantipsychotics

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, theyare considered as separate entities [1]. Anxiety disorders arethe most common psychiatric disorders, affecting between20 and 40% of the population [2, 3]. Many patients willpresent 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 selectiveserotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), have shownefficiency in the treatment of anxiety disorders, and arenow considered as first-line treatment, followed by a switchto other drugs such as benzodiazepines, mirtazapine,

This article is part of the Topical Collection on Anxiety Disorders

* Baptiste Pignonbaptistepignon@yahoo.fr

1 AP-HP, DHU PePSY, Hôpitaux Universitaires Henri-Mondor, Pôlede Psychiatrie, 94000 Créteil, France

2 INSERM, U955, team 15, 94000 Créteil, France3 Fondation FondaMental, 94000 Créteil, France4 Faculté de médecine, UPEC, Université Paris-Est,

94000 Créteil, France5 Hôpital Albert Chenevier, Groupe Hospitalier Henri-Mondor, CHU

de Créteil, Assistance Publique-Hôpitaux de Paris (AP-HP), 40 ruede 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

pregabalin, or buspirone [5–7]. However, responses tothese treatments are often incomplete, and new strategieshave to be developed to address this resistance [8].Antipsychotic drugs could be considered as an option inthe indication of refractory anxiety disorders. These drugshave been developed since the 1950s originally for thetreatment 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 psychoticsymptoms [13, 14]) and the effectiveness of antipsychoticmedication on anxiety symptoms in patients with psychoticdisorders [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 weresuperior to placebo, but results of comparisons to benzodi-azepines and TCA were conflicting [17]. However, theseresults were tempered by the side effects of these drugs—including extrapyramidal symptoms (EPS) and irreversibletardive dyskinesia [18, 19]. The entry of second-generationantipsychotics (SGAPs) into the marketplace led to a resur-gence of interest [20]. Indeed, SGAPs are characterized byless EPS and tardive dyskinesia side effects [21].Moreover,in addition to D2 dopamine receptor antagonism, SGAPsare characterized by an action on the serotonin system, es-pecially (i) an 5HT2A serotonin receptor antagonism actionand (ii) an 5HT1A serotonin receptor agonism action [22].Involvement of other serotoninergic receptors had also beenmentioned like 5HT7 and 5HT2 antagonism, as well ashistamine 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 and50% of patients received off-label antipsychotic medication[8]. Moreover, a recent systematic review has listed thedifferent 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 sideeffects of SGAPs [27].

In this comprehensive review, our aim was to present thecurrent research findings on the efficacy of antipsychoticsin the treatment of anxiety disorders, i.e., GAD, SAD, andPD, and in the treatment of OCD, mostly based on pub-lished randomized controlled trials (RCTs), or, in absenceof RCT, on open-label studies.

Generalized Anxiety Disorder

GAD is characterized by excessive and uncontrolled anxietyor worry about numerous activities or events for a minimumperiod of 6 months [1, 28]. This maladaptive fear, consideredas an intolerance of uncertainty, is associated with autonomicarousal and somatic symptoms (fatigability, impaired concen-tration, irritability, sleep disorders, etc.). GAD is associatedwith 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-yearlongitudinal follow-up, about one half of patients achievedremission, and more than a third party demonstrated relapsein 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 CareExcellence (NICE) [35], the World Federation of Societiesof Biological Psychiatry (WFSBP) [5], and the CanadianNetwork for Mood and Anxiety Treatments (CANMAT)[36] guidelines, first-line treatment is psychotherapy and anti-depressant treatment. The efficacy of cognitive behavioraltherapies (CBT) has been widely assessed in the treatment ofGAD. CBT for GAD consists of anxiety self-monitoring, re-laxation training, or cognitive restructuring [37]. Overall, ap-proximately 50% of patients with GAD achieve significantclinical improvement with CBT [38]. Concerning pharmaco-logical treatment, the different international guidelines recom-mend SSRIs and SNRIs in monotherapy [5, 35, 36]. TheWFSBP guidelines also consider pregabalin as a first-linetreatment [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 treatmentfor patients with antidepressant-refractory GAD.

Risperidone was one of the first SGAPs investigated in thetreatment of refractory GAD. In 2005, a double-blind RCT ofrisperidone vs. placebo combined with antidepressant and/oranxiolytic among 40 patients with refractory GAD showed asignificantly greater reduction in symptoms [41]. However,rates of patients that were considered as responders did notsignificantly differ in the two groups, and the same occurred inanother RCT [42]. Thus, further studies are needed to studythe efficacy of risperidone in adjunctive treatment of refracto-ry GAD [43]. Moreover, risperidone has not been investigatedin monotherapy [20]. Concerning olanzapine, the only avail-able RCT of adjunctive therapy at a mean dose of 8.7 mg/dayvs. placebo among 24 patients showed that the responders’rate was significantly higher in the olanzapine group [44].However, weight gain caused by olanzapine represents animportant clinical concern [21]. Regarding aripiprazole, twounrandomized studies in small groups of patients (N = 6 andN = 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

and 2.5 mg/day for the second, led to significant improvementin anxiety symptoms, without significant differences in remis-sion rate [45, 46]. Finally, a RCTof ziprasidone monotherapyor in adjunctive treatment vs. placebo in refractory GAD pa-tients did not show any significant difference in reduction ofanxiety symptoms [47•].

Thus, levels of evidence concerning the efficacy of theseSGAPs in refractory GAD (in monotherapy or adjunctivetreatment) seem insufficient to be recommended in this disor-der. The case of quetiapine is different. Although studies ofquetiapine as adjunctive treatment to SSRI antidepressant inrefractory GAD did not provide evidence of efficacy [48, 49•,50], several RCTs suggested that quetiapine in monotherapywas associated with significantly higher rates of respondersthan placebo [51–53]. These studies were recently pooled in ameta-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 higherrates of remission (RR = 1.27, 95% CI [1.13; 1.42]) thanplacebo. Comparisons with SSRIs on the same outcomesshowed non-significant differences. Other studies showed thatquetiapine improved daily life function and quality of life[55•, 56]. Quetiapine also appears to be particularly effectiveon 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 optionfor acute treatment of GAD by the British Association forPsychopharmacology and the WFSBP guidelines [5, 58].

Categories of evidence [59] based on the current knowl-edge of the indication of the different antipsychotic drugs inGAD are available in Table 1.

Social Anxiety Disorder

SAD (also known as social phobia) is characterized by fear ofsocial situation and of portraying anxiety symptoms that willbe socially negatively evaluated (i.e., will be humiliating, willlead to rejection or offend others, etc.). The fear, anxiety, oravoidance 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, andoverall 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 CANMATguidelines [5, 36, 69], either CBT and SSRIs are currentlyrecommended as first-line treatment [65, 70]. Within NICEguidelines, CBT has to be the first option proposed to thepatients [69]. However, the choice to start with one modalityrather than another, or to use combined treatment, often relieson 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 whocontinue on medication. The recommended duration of treat-ment after therapeutic response is at least 3–6 months, withlonger periods considered in individuals’ cases. After12weeks of treatment without any response or just with partialresponse, 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 smallgroups of patients with SAD: two involved quetiapine, onerisperidone, and one olanzapine. To our knowledge, no oneconcerned 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 showedsignificantly better results than placebo [73]. Risperidone wasalso 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 alsosignificantly improved. One RCT evaluated first-linequetiapine treatment (150–250 mg/day) vs. placebo during8 weeks in 15 individuals with SAD. No significant differencewas found [75]. In an open-label pilot study, quetiapine (meandose 250 mg/day) during 12 weeks was found to be effectivein reducing symptoms in 13 individuals with SAD [76].

According to NICE and WFSBP guidelines [5, 69]), thelevel 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 recommendedas a third-line option. In these recommendations, aripiprazoleand risperidone are considered in third-line adjunctive thera-pies [36]. Additional studies of olanzapine, risperidone, andquetiapine as a treatment for SAD are warranted, too few databeing available to come up with any conclusion [77]. Futureresearch may particularly consider higher and/or chronic dos-ing of quetiapine and whether quetiapine in combination withCBT 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 inSAD are available in Table 1.

Panic Disorder

Panic attacks are acute anxiety and fear reactions to internal orexternal stimuli that may include palpitations, sweating, trem-or, or numbness. PD is defined by recurrent panic attacksassociated with other symptoms following the occurrence ofpanic attacks, i.e., anticipatory anxiety and maladaptivechanges in behavior (e.g., avoidant behavior). Most subjects

Curr Psychiatry Rep (2017) 19:103 Page 3 of 11 103

with PD display agoraphobia, which is fear or avoidance ofsituations in which panic attacks can occur [1]. The lifetimeprevalence of PD in the general population ranges from 3.5 to5% [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 aseffective as TCA, but have less side effects [58].Benzodiazepines should not be considered as a first-optiontreatment, 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 antidepressanttreatment [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 dopamineand 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 theprescription of olanzapine in augmentation to SSRI or inmonotherapy 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-labelaugmentation 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 disorderspatients (including 7 PD) showed significant improvement[74]. Moreover, in a single-bind RCT of 56 patients withnon-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

Antipsychoticdrug

Indication Daily dose Monotherapy or add-on Category of evidencea

GAD

Aripirazole Refractory GAD 2.5–30 mg Add-on to antidepressantand/or to anxiolytic

C: two unrandomized trials showed significant results

Olanzapine Refractory GAD 2.5–20 mg Add-on to antidepressantand/or to anxiolytic

B: one RCT showed significant results

Quetiapine Refractory GAD 25–400 mg Add-on to SSRIantidepressant

D: inconsistent results

GAD 50–300 mg Monotherapyand add-on

A: meta-analysis of RCT showed significantly positive results

Risperidone Refractory GAD 0.25–3 mg Add-on to antidepressantand/or to anxiolytic

D: inconsistent results

Ziprasidone Refractory GAD 20–80 mg Monotherapyand add-on

E: negative evidence: a RCT showed an absence of differencewith 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 antidepressantand/or to anxiolytic

C: one open-label study showed significant higher rate ofimprovement

PD

Aripirazole Refractory PD 5–15 mg Add-on to antidepressantand/or to anxiolytic

E: one open-label study did not show significant improvement

Olanzapine Refractory PD 2.5–30 mg Add-on to SSRIantidepressant andmonotherapy

C: two open-label studies showed significant higher rate ofimprovement and response

Quetiapine Refractory PD 50–400 mg Add-on to SSRIantidepressant

E: one placebo-controlled did not show significant improvement

Risperidone Refractory PD 0.25–3.00 mg Add-on to antidepressantand/or anxiolytic

C: one open-label studies showed significant improvement

Non-refractory PDor depression withpanic 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 panicdisordera According to Bandelow et al. [59]

103 Page 4 of 11 Curr Psychiatry Rep (2017) 19:103

risperidone (0.125–1.0 mg/day) and the reference treatment,i.e., an SSRI antidepressant [86]. Sulpiride in monotherapyshowed 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 refractoryPD, the group with quetiapine in addition to an SSRI treat-ment did not reach better outcome than the patients who werein the SSRI and placebo group [91•]. However, according toanxiolytic properties of quetiapine [54••, 92], RCTs on largergroups should be conducted. To our knowledge, as for GADand 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]), antipsychoticdrugs are not recommended for the treatment of PD. A recentreview of SGAP studies in PD, some involving patients withcomorbid bipolar disorders, confirmed a general lack of effi-cacy of quetiapine, risperidone, and ziprasidone on panicsymptoms [94]. However, some findings, especiallyconcerning risperidone and olanzapine, should be consideredfor future RCT conducted on refractory PD.

Categories of evidence [58] based on the current knowl-edge of the indication of the different antipsychotic drugs inPD are available in Table 1.

Obsessive-Compulsive Disorder

OCD is characterized by recurrent and persistent thoughtsconsidered as intrusive and unwanted (obsessions), and/or repetitive behaviors or mental acts performed in responseto an obsession in the objective of decreasing anxiety(compulsions) [1]. OCD is a debilitating pathology causingsevere functional impairment [95], with a lifetime prevalenceof about 1.9 to 2.5% [96].

A large body of evidence showed that CBT with exposureand response prevention techniques can be considered as afirst-line therapy [58]. Concerning psychopharmacology, theNICE, WFSBP, and CANMAT guidelines consider SSRIs asthe first-line treatment of OCD [5, 36, 58]. When treatingOCD, SSRIs should be used with optimal doses exceedingthe one used in depressive disorders, and one should wait 8to 12 weeks before concluding on its possible efficacy. Asthey 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 giventhe 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 treatmentresponse. OCD is considered severe when the score is above16, and response to treatment is defined by a decrease of 35%ofY-BOCS score [99]. Resistance to two SSRI trials as well asresistance to an adequate clomipramine trial define refractoryOCD [58, 100].

As 40 to 60% of the patients do not respond sufficiently tothese lines of treatment, the search for efficient add-on treat-ment to SSRIs is an important issue [101]. In 1994,McDouglepursued the first double-blind RCT (N = 34) adding haloper-idol to an SSRI antidepressant (fluvoxamine) in refractoryOCD and that resulted in significantly higher response ratesthan placebo [102]. In 2005, a double-blind placebo-con-trolled cross-over study confirmed the effect of haloperidoland showed greater effect compared to risperidone and toplacebo [103]. However, in the same trial, almost 42% ofthe patients treated displayed important EPS induced by hal-operidol. Therefore, as for other FGAPs, haloperidol is notconsidered as an eligible choice for antipsychotic add-on torefractory OCD, except for patients with comorbid Tourettesyndrome [104], since various studies evaluated the efficacyof 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 highdose of SSRIs showed significant decrease in Y-BOCS scoreswith various doses of risperidone of 0.5 to 6 mg/day [105••].

Aripiprazole drew specific attention given its partial agonistactivity at the dopamine D2 and serotonin 5HT1A receptors aswell as antagonistic activity at the 5HT2A receptors [106]. In adouble-blind RCT, in comparison to placebo, proportions ofresponders were significantly higher among 12-weekaripiprazole 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••]. Itshowed 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 smallsamples (N = 12 andN = 16), these results should be consideredwith 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 toaripiprazole, with a greater decrease in Y-BOCS total score after8 weeks of treatment (with 50% of response in the aripiprazolegroup, 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 ofthe compulsion subscale. Finally, quetiapine and olanzapineeffect did not significantly differ from placebo.

So far, risperidone seems to be the first SGAP recommend-ed by international guidelines [109], but small evidence bringsus to consider aripiprazole as efficient add-on treatment ofsevere refractory OCD. Further large-scale studies should beconducted to assess this efficiency and highlight the existenceof potential specific effects of these drugs. It should also benoted that SGAPs, especially clozapine, olanzapine, and ris-peridone, have been repeatedly implicated in the de novoemergence and exacerbation of obsessive-compulsive symp-toms in patients with schizophrenia [110]. Therefore, thispoint may need specific attention in at-risk patients.

Curr Psychiatry Rep (2017) 19:103 Page 5 of 11 103

Categories of evidence [58] based on the current knowl-edge of the indication of the different antipsychotic drugs inOCD are available in Table 2.

Discussion

According to the current scientific knowledge, only three an-tipsychotics can be recommended for the treatment of anxietydisorders and OCD, in two specific situations: quetiapine forGAD, and aripiprazole and risperidone in augmentation forrefractory OCD.

As they gave promising results, some other SGAPs shouldbe reviewed in further studies: olanzapine and aripiprazole forrefractory 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 toleranceprofile, FGAPs cannot be recommended.

The present review considered the background treatment ofanxiety disorders and OCD, and not the acute treatment ofanxiety symptoms. Although they are not recommended as aspecific treatment for such disorders, certain FGAPs, likecyamemazine [111], display anxiolytic effects, and are usedin acute treatment of serious anxiety symptoms, especially insome countries like France [112]. Quetiapine appeared to haveacute anxiolytic effects on patients with specific phobia [113].Compared to benzodiazepine drugs, they offer the advantageof the absence of abuse potential and dependence, but theirbenefit-risk ratio in these indications is not well established[20, 114].

As in schizophrenia, the monitoring and managing of sideeffects associated with the prescription of SGAPs—weightincrease, 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 ourknowledge on SGAPs’ role in anxiety disorders, because theavailable data are relatively rare and not always based onsufficiently robust methodologies (open-label trials, small

sample sizes, etc.). Specifically, the following critical issuesshould be addressed: treatment response criteria, especiallyconcerning overall severity or specific symptoms (such aspoor insight in OCD, or even psychotic symptoms), choiceof associated antidepressants for augmentation strategies, andduration of treatment. It is important to also take into accountthe case of bipolar disorder comorbidity in patients with anx-iety disorders, considering the risk of triggering the start of amanic episode or the course of illness being destabilized withthe use of antidepressants. SGAPs are generally suggested asalternatives to antidepressants in this indication, but data arecurrently insufficient to make a clear recommendation on thisissue [119].

Discomfort with antipsychotic medication in patients withanxiety disorders should be studied. As they excluded lesspatients 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 indicationsof antipsychotics, beyond the categorical approach of anxietydisorders. The potential target of personality disorders couldfor 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 instancebe relevant in the efficacy of antipsychotics for certain anxietydisorders. Indeed, in a 10-year prospective study, Keuroghlianet al. showed that the evolution of BPD symptoms predicts theevolution of GAD [124]. Moreover, aripiprazole (15 mg/day)is effective on anxiety symptoms in patients with BPD (incomparison to placebo, standardized mean difference on theHamilton 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 withBPD (e.g., American Psychiatric Association (APA) [127],National Health and Medical Research Council (NHMRC)[128]).Weber et al. have also shown that BPD was associatedto off-label prescriptions of antipsychotics for patients withanxiety 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 inhibitorsa According to Bandelow et al. [59]

103 Page 6 of 11 Curr Psychiatry Rep (2017) 19:103

antipsychotic drugs could be particularly useful in comorbidpsychiatric disorders (e.g., associated mood or psychotic dis-orders to anxiety disorders or OCD), or for the treatment ofserious anxiety symptoms as part of such disorders, with adimensional 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 inthese indications because of their tolerability profile and oflimited data. Therefore, further larger studies are needed forprecision of the place of SGAPs in treatment algorithms ofanxiety disorders and OCD.

Acknowledgements The authors thank Yasmina Frem for assistanceand proofreading. The authors thank Dr. Friedel for reviewing themanuscript.

Compliance with Ethical Standards

Conflict of Interest Baptiste Pignon and Chloé Tezenas du Montceleach 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 doesnot contain any studies with human or animal subjects performed by anyof the authors.

References

Papers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. American Psychological Association. DSM-5: diagnostic and sta-tistical manual of mental disorders. Washington: AmericanPsychiatricl Publishing; 2013.

2. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR,Walters EE. Lifetime prevalence and age-of-onset distributionsof DSM-IV disorders in the National Comorbidity SurveyReplication. Arch Gen Psychiatry. 2005;62:593–602.

3. Leray E, Camara A, Drapier D, Riou F, Bougeant N, Pelissolo A,et al. Prevalence, characteristics and comorbidities of anxiety dis-orders in France: results from the “Mental Health in GeneralPopulation” survey (MHGP). Eur Psychiatry J Assoc EurPsychiatr. 2011;26:339–45.

4. Bruce SE, Yonkers KA, Otto MW, Eisen JL, Weisberg RB,PaganoM, et al. Influence of psychiatric comorbidity on recoveryand recurrence in generalized anxiety disorder, social phobia, and

panic disorder: a 12-year prospective study. Am J Psychiatry.2005;162:1179–87.

5. Bandelow B, Sher L, Bunevicius R, Hollander E, Kasper S, ZoharJ, et al. Guidelines for the pharmacological treatment of anxietydisorders, obsessive-compulsive disorder and posttraumatic stressdisorder in primary care. Int J Psychiatry Clin Pract. 2012;16:77–84.

6. Bandelow B, Reitt M, Röver C, Michaelis S, Görlich Y,WedekindD. Efficacy of treatments for anxiety disorders: a meta-analysis.Int Clin Psychopharmacol. 2015;30:183–92.

7. Perna G, Alciati A, Riva A, Micieli W, Caldirola D. Long-termpharmacological treatments of anxiety disorders: an updated sys-tematic review. Curr Psychiatry Rep. 2016;18:23.

8. Weber SR,Wehr AM, DucheminA-M. Prevalence of antipsychot-ic prescriptions among patients with anxiety disorders treated ininpatient and outpatient psychiatric settings. J Affect Disord.2016;191:292–9.

9. Delay J, Deniker P, Hari J. Utilisation en thérapeutiquepsychiatrique d’une phénothiazine d’action centrale sélective(4560 PR). Ann Med Psychol. 1952:112–7.

10. Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G,et al. Antipsychotic drugs versus placebo for relapse prevention inschizophrenia: a systematic review and meta-analysis. Lancet.2012;379:2063–71.

11. Miura T, Noma H, Furukawa TA, Mitsuyasu H, Tanaka S,Stockton S, et al. Comparative efficacy and tolerability of phar-macological treatments in the maintenance treatment of bipolardisorder: a systematic review and network meta-analysis. LancetPsychiatry. 2014;1:351–9.

12. Young S, Pfaff D, Lewandowski KE, Ravichandran C, CohenBM, Öngür D. Anxiety disorder comorbidity in bipolar disorder.Schizophr SchizoaffectiveDisord Psychopathol. 2013;46:176–85.

13. Saha S, Scott J, Varghese D, McGrath J. Anxiety and depressivedisorders are associated with delusional-like experiences: a repli-cation study based on a National Survey of Mental Health andWellbeing. BMJ Open. 2012;2

14. Pignon B, Schürhoff F, Szöke A, Geoffroy PA, Jardri R, RoelandtJ-L, et al. Sociodemographic and clinical correlates of psychoticsymptoms in the general population: findings from the MHGPsurvey. Schizophr. Res. 2017. Available from: http://www.sciencedirect.com/science/article/pii/S0920996417303924

15. Garay RP, Samalin L, Hameg A, Llorca P-M. Investigationaldrugs for anxiety in patients with schizophrenia. Expert OpinInvestig Drugs. 2015;24:507–17.

16. Marques TR, Levine SZ, Reichenberg A, Kahn R, Derks EM,Fleischhacker WW, et al. How antipsychotics impact the differentdimensions of schizophrenia: a test of competing hypotheses. EurNeuropsychopharmacol J Eur Coll Neuropsychopharmacol.2014;24:1279–88.

17. Gao K, Muzina D, Gajwani P, Calabrese JR. Efficacy of typicaland atypical antipsychotics for primary and comorbid anxietysymptoms or disorders: a review. J Clin Psychiatry. 2006;67:1327–40.

18. Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F,Kissling W, et al. Second-generation antipsychotic drugs and ex-trapyramidal side effects: a systematic review andmeta-analysis ofhead-to-head comparisons. Schizophr Bull. 2012;38:167–77.

19. van Os J, Fahy T, Jones P, Harvey I, Toone B, Murray R. Tardivedyskinesia: who is at risk? Acta Psychiatr Scand. 1997;96:206–16.

20. Hershenberg R, Gros DF, Brawman-Mintzer O. Role of atypicalantipsychotics in the treatment of generalized anxiety disorder.CNS Drugs. 2014;28:519–33.

21. Leucht S, Cipriani A, Spineli L, Mavridis D, Örey D, Richter F,et al. Comparative efficacy and tolerability of 15 antipsychoticdrugs in schizophrenia: a multiple-treatments meta-analysis.Lancet. 2013;382:951–62.

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22. Yatham LN, Goldstein JM, Vieta E, Bowden CL, Grunze H, PostRM, et al. Atypical antipsychotics in bipolar depression: potentialmechanisms of action. J Clin Psychiatry. 2005;66(Suppl 5):40–8.

23. Roberts RJ, Lohano KK, El-Mallakh RS. Antipsychotics as anti-depressants. Asia-Pac Psychiatry Off J Pac Rim Coll Psychiatr.2016;8:179–88.

24. Stahl SM. Stahl’s essential psychopharmacology: neuroscientificbasis and practical applications. 4 edition. Cambridge: CambridgeUniversity Press; 2013.

25. Carton L, Cottencin O, Lapeyre-Mestre M, Geoffroy PA, Favre J,Simon N, et al. Off-label prescribing of antipsychotics in adults,children and elderly individuals: a systematic review of recentprescription trends. Curr Pharm Des. 2015;21:3280–97.

26. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribingamong office-based physicians. Arch Intern Med. 2006;166:1021–6.

27. Keltner NL. Biological perspectives.Metabolic syndrome: schizo-phrenia and atypical antipsychotics. Perspect Psychiatr Care.2006;42:204.

28. Tyrer P, Baldwin D. Generalised anxiety disorder. Lancet LondEngl. 2006;368:2156–66.

29. Weisberg RB. Overview of generalized anxiety disorder: epidemi-ology, presentation, and course. J Clin Psychiatry. 2009;70(Suppl2):4–9.

30. Grant BF, Hasin DS, Stinson FS, Dawson DA, June Ruan W,Goldstein RB, et al. Prevalence, correlates, co-morbidity, andcomparative disability of DSM-IV generalized anxiety disorderin the USA: results from the National Epidemiologic Survey onAlcohol and Related Conditions. Psychol Med. 2005;35:1747–59.

31. Kessler RC, Gruber M, Hettema JM, Hwang I, Sampson N,Yonkers KA. Co-morbid major depression and generalized anxi-ety disorders in the National Comorbidity Survey follow-up.Psychol Med. 2008;38:365–74.

32. Yonkers KA, Bruce SE, Dyck IR, Keller MB. Chronicity, relapse,and illness—course of panic disorder, social phobia, and general-ized anxiety disorder: findings in men and women from 8 years offollow-up. Depress Anxiety. 2003;17:173–9.

33. Bereza BG, Machado M, Einarson TR. Systematic review andquality assessment of economic evaluations and quality-of-lifestudies related to generalized anxiety disorder. Clin Ther.2009;31:1279–308.

34. Hoffman DL, Dukes EM, Wittchen H-U. Human and economicburden of generalized anxiety disorder. Depress Anxiety. 2008;25:72–90.

35. National Institute for Health and Clinical Excellence (NICE).Generalised anxiety disorder overview—NICE Pathways[Internet]. 2012 [cited 2017 Jan 25]. Available from: https://pathways.nice.org.uk/pathways/generalised-anxiety-disorder

36. Katzman MA, Bleau P, Blier P, Chokka P, Kjernisted K, VanAmeringen M. Canadian clinical practice guidelines for the man-agement of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14:S1.

37. Bagby RM, Quilty LC. Review: cognitive behavioural therapy ismore effective than control and similarly effective to pharmaco-therapy for generalised anxiety disorder. Evid Based Ment Health.2006;9:43.

38. Hunot V, Churchill R, Silva de LimaM, Teixeira V. Psychologicaltherapies for generalised anxiety disorder. Cochrane DatabaseSyst. Rev. 2007;CD001848.

39. Rickels K, Zaninelli R, McCafferty J, Bellew K, Iyengar M,Sheehan D. Paroxetine treatment of generalized anxiety disorder:a double-blind, placebo-controlled study. Am J Psychiatry.2003;160:749–56.

40. Stein MB, Pollack MH, Bystritsky A, Kelsey JE, Mangano RM.Efficacy of low and higher dose extended-release venlafaxine in

generalized social anxiety disorder: a 6-month randomized con-trolled trial. Psychopharmacology. 2005;177:280–8.

41. Brawman-Mintzer O, Knapp RG, Nietert PJ. Adjunctive risperi-done in generalized anxiety disorder: a double-blind, placebo-controlled study. J Clin Psychiatry. 2005;66:1321–5.

42. Pandina GJ, Canuso CM, Turkoz I, Kujawa M, Mahmoud RA.Adjunctive risperidone in the treatment of generalized anxietydisorder: a double-blind, prospective, placebo-controlled, random-ized trial. Psychopharmacol Bull. 2007;40:41–57.

43. Patterson B, Van Ameringen M. Augmentation strategies fortreatment-resistant anxiety disorders: a systematic review and me-ta-analysis. Depress Anxiety. 2016;33:728–36.

44. Pollack MH, Simon NM, Zalta AK, Worthington JJ, Hoge EA,Mick E, et al. Olanzapine augmentation of fluoxetine for refracto-ry generalized anxiety disorder: a placebo controlled study. BiolPsychiatry. 2006;59:211–5.

45. Menza MA, Dobkin RD, Marin H. An open-label trial ofaripiprazole augmentation for treatment-resistant generalized anx-iety disorder. J Clin Psychopharmacol. 2007;27:207–10.

46. Hoge EA, Worthington JJ, Kaufman RE, Delong HR, PollackMH, Simon NM. Aripiprazole as augmentation treatment of re-fractory generalized anxiety disorder and panic disorder. CNSSpectr. 2008;13:522–7.

47.• Lohoff FW, Etemad B, Mandos LA, Gallop R, Rickels K.Ziprasidone treatment of refractory generalized anxiety disorder:a p l acebo -con t ro l l ed , doub le -b l i nd s tudy. J Cl inPsychopharmacol. 2010;30:185–9. This RCT of ziprasidone inmonotherapy or adjunctive treatment vs. placebo in refracto-ry GAD patients did not show any significant difference inreduction of anxiety symptoms.

48. Simon NM, Connor KM, LeBeau RT, Hoge EA, Worthington JJ,ZhangW, et al. Quetiapine augmentation of paroxetine CR for thetreatment of refractory generalized anxiety disorder: preliminaryfindings. Psychopharmacology. 2008;197:675–81.

49.• Altamura AC, Serati M, Buoli M, Dell’Osso B. Augmentativequetiapine in partial/nonresponders with generalized anxiety dis-order: a randomized, placebo-controlled study. Int ClinPsychopharmacol. 2011;26:201–5. This placebo-controlledRCT of quetiapine augmentation in refractory GAD patientsshowed a higher rate of responders among the quetiapinegroup than placebo.

50. Maher AR, Theodore G. Summary of the comparative effective-ness review on off-label use of atypical antipsychotics. J ManagCare Pharm JMCP. 2012;18:S1–20.

51. Bandelow B, Chouinard G, Bobes J, Ahokas A, Eggens I, Liu S,et al. Extended-release quetiapine fumarate (quetiapine XR): aonce-daily monotherapy effective in generalized anxiety disorder.Data from a randomized, double-blind, placebo- and active-controlled study. Int J Neuropsychopharmacol. 2010;13:305–20.

52. Khan A, Joyce M, Atkinson S, Eggens I, Baldytcheva I, ErikssonH. A randomized, double-blind study of once-daily extended re-lease quetiapine fumarate (quetiapine XR) monotherapy in pa-t i e n t s w i t h gene r a l i z ed anx i e t y d i s o rd e r. J C l i nPsychopharmacol. 2011;31:418–28.

53. Merideth C, Cutler AJ, She F, Eriksson H. Efficacy and tolerabilityof extended release quetiapine fumarate monotherapy in the acutetreatment of generalized anxiety disorder: a randomized, placebocontrolled and active-controlled study. Int Clin Psychopharmacol.2012;27:40–54.

54.•• Maneeton N, Maneeton B,Woottiluk P, Likhitsathian S, Suttajit S,Boonyanaruthee V, et al. Quetiapine monotherapy in acute treat-ment of generalized anxiety disorder: a systematic review andmeta-analysis of randomized controlled trials. Drug Des DevelTher. 2016;10:259–76.Thismeta-analysis of RCTof quetiapinein non-refractory GAD showed a significant effect (reductionof anxiety symptoms and increase of responders’ rate).

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55.• Sheehan DV, Svedsäter H, Locklear JC, Eriksson H. Effects ofextended-release quetiapine fumarate on long-term functioningand sleep quality in patients with Generalized Anxiety Disorder(GAD): data from a randomized-withdrawal, placebo-controlledmaintenance study. J Affect Disord. 2013;151:906–13. Thisopen-label study showed that sulpiride monotherapy inrefractory-PD led to significant clinical improvement. Thisplacebo-controlled RCT showed an efficacy of quetiapinemonotherapy in GAD patients which showed long-term effi-cacy of quetiapine on functioning and sleep quality.

56. Endicott J, Svedsäter H, Locklear JC. Effects of once-daily ex-tended release quetiapine fumarate on patient-reported outcomesin patients with generalized anxiety disorder. Neuropsychiatr DisTreat. 2012;8:301–11.

57. Katzman MA, Brawman-Mintzer O, Reyes EB, Olausson B, LiuS, Eriksson H. Extended release quetiapine fumarate (quetiapineXR) monotherapy as maintenance treatment for generalized anx-iety disorder: a long-term, randomized, placebo-controlled trial.Int Clin Psychopharmacol. 2011;26:11–24.

58. Baldwin DS, Anderson IM, Nutt DJ, Allgulander C, Bandelow B,den Boer JA, et al. Evidence-based pharmacological treatment ofanxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from theBritish Association for Psychopharmacology. J PsychopharmacolOxf Engl. 2014;28:403–39.

59. Bandelow B, Zohar J, Kasper S, Möller H-J. How to grade cate-gories of evidence. World J Biol Psychiatry. 2008;9:242–7.

60. Heimberg RG, Hofmann SG, Liebowitz MR, Schneier FR, SmitsJAJ, Stein MB, et al. Social anxiety disorder in DSM-5. DepressAnxiety. 2014;31:472–9.

61. Peyre H, Hoertel N, Rivollier F, Landman B, McMahon K,Chevance A, et al. Latent class analysis of the feared situationsof social anxiety disorder: a population-based study. DepressAnxiety. 2016;33:1178–87.

62. Katzelnick DJ, Kobak KA, DeLeire T, Henk HJ, Greist JH,Davidson JR, et al. Impact of generalized social anxiety disorderin managed care. Am J Psychiatry. 2001;158:1999–2007.

63. Kushnir J, Marom S, Mazar M, Sadeh A, Hermesh H. The linkbetween social anxiety disorder, treatment outcome, and sleepdifficulties among patients receiving cognitive behavioral grouptherapy. Sleep Med. 2014;15:515–21.

64. Schneier FR, Foose TE, Hasin DS, Heimberg RG, Liu S-M, GrantBF, et al. Social anxiety disorder and alcohol use disorder co-morbidity in the National Epidemiologic Survey on Alcohol andRelated Conditions. Psychol Med. 2010;40:977–88.

65. Davis ML, Smits JAJ, Hofmann SG. Update on the efficacy ofpharmacotherapy for social anxiety disorder: a meta-analysis.Expert Opin Pharmacother. 2014;15:2281–91.

66. Fehm L, Pelissolo A, Furmark T, Wittchen H-U. Size and burdenof social phobia in Europe. Eur Neuropsychopharmacol J Eur CollNeuropsychopharmacol. 2005;15:453–62.

67. Ruscio AM, Brown TA, Chiu WT, Sareen J, Stein MB, KesslerRC. Social fears and social phobia in the USA: results from theNational Comorbidity Survey Replication. Psychol Med.2008;38:15–28.

68. Grant BF, Hasin DS, Blanco C, Stinson FS, Chou SP, GoldsteinRB, et al. The epidemiology of social anxiety disorder in theUnited States: results from the National Epidemiologic Surveyon Alcohol and Related Conditions. J Clin Psychiatry. 2005;66:1351–61.

69. National Institute for Health and Clinical Excellence (NICE).Social anxiety disorder: recognition, assessment and treatment.Clinical guideline [Internet]. 2013 [cited 2017 Apr 10].Available from: https://www.nice.org.uk/guidance/cg159?unlid=107165807620164922324

70. YoshinagaN, Niitsu T, Hanaoka H, Sato Y, Ohshima F,Matsuki S,et al. Strategy for treating selective serotonin reuptake inhibitor-resistant social anxiety disorder in the clinical setting: arandomised controlled trial protocol of cognitive behavioural ther-apy in combination with conventional treatment. BMJ Open.2013;3

71. Stein MB, Stein DJ. Social anxiety disorder. Lancet Lond Engl.2008;371:1115–25.

72. Blanco C, Bragdon LB, Schneier FR, Liebowitz MR. Theevidence-based pharmacotherapy of social anxiety disorder. Int JNeuropsychopharmacol. 2013;16:235–49.

73. Barnett SD, Kramer ML, Casat CD, Connor KM, Davidson JRT.Efficacy of olanzapine in social anxiety disorder: a pilot study. JPsychopharmacol Oxf Engl. 2002;16:365–8.

74. Simon NM, Hoge EA, Fischmann D, Worthington JJ, ChristianKM, Kinrys G, et al. An open-label trial of risperidone augmen-tation for refractory anxiety disorders. J Clin Psychiatry. 2006;67:381–5.

75. Vaishnavi S, Alamy S, Zhang W, Connor KM, Davidson JRT.Quetiapine as monotherapy for social anxiety disorder: aplacebo-controlled study. Prog Neuro-Psychopharmacol BiolPsychiatry. 2007;31:1464–9.

76. Schutters SIJ, van Megen HJGM, Westenberg HGM. Efficacy ofquetiapine in generalized social anxiety disorder: results from anopen-label study. J Clin Psychiatry. 2005;66:540–2.

77. Komossa K1, Depping AM, Gaudchau A, Kissling W, Leucht S.Second-generation antipsychotics for major depressive disorderand dysthymia. Cochrane Database Syst. Rev. 2010;12:CD008121. doi:10.1002/14651858.CD008121.pub2.

78. DonahueCB, KushnerMG, Thuras PD,Murphy TG, VanDemarkJB, Adson DE. Effect of quetiapine vs. placebo on response to twovirtual public speaking exposures in individuals with social pho-bia. J Anxiety Disord. 2009;23:362–8.

79. Kessler RC, Chiu WT, Jin R, Ruscio AM, Shear K, Walters EE.The epidemiology of panic attacks, panic disorder, and agorapho-bia in the National Comorbidity Survey Replication. Arch GenPsychiatry. 2006;63:415–24.

80. Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM,Wittchen H-U. Twelve-month and lifetime prevalence and life-time morbid risk of anxiety and mood disorders in the UnitedStates. Int J Methods Psychiatr Res. 2012;21:169–84.

81. Bystritsky A, Kerwin L, Niv N, Natoli JL, Abrahami N, Klap R,et al. Clinical and subthreshold panic disorder. Depress Anxiety.2010;27:381–9.

82. National Institute for Health and Clinical Excellence (NICE).Generalised anxiety disorder and panic disorder in adults: man-agement. Guidance and guidelines NICE [Internet]. 2011 [cited2017 Apr 16]. Available from: https://www.nice.org.uk/guidance/cg113?unlid=50950734120166612729

83. Freire RC, Machado S, Arias-Carrión O, Nardi AE. Current phar-macological interventions in panic disorder. CNS Neurol DisordDrug Targets. 2014;13:1057–65.

84. Batelaan NM, de Graaf R, Penninx BW, van Balkom AJ,Vollebergh WA, Beekman AT. The 2-year prognosis of panic ep-isodes in the general population. Psychol Med. 2010;40:147–57.

85. Freire RC, Zugliani MM, Garcia RF, Nardi AE. Treatment-resistant panic disorder: a systematic review. Expert OpinPharmacother. 2016;17:159–68.

86. Prosser JM, Yard S, Steele A, Cohen LJ, Galynker II. A compar-ison of low-dose risperidone to paroxetine in the treatment ofpanic attacks: a randomized, single-blind study. BMCPsychiatry. 2009;9:25.

87. Wang HR, Woo YS, Bahk W-M. The potential role of atypicalantipsychotics in the treatment of panic disorder. HumPsychopharmacol. 2014;29:405–13.

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88. Hollifield M, Thompson PM, Ruiz JE, Uhlenhuth EH. Potentialeffectiveness and safety of olanzapine in refractory panic disorder.Depress Anxiety. 2005;21:33–40.

89. Sepede G, De Berardis D, Gambi F, Campanella D, La Rovere R,D’AmicoM, et al. Olanzapine augmentation in treatment-resistantpanic disorder: a 12-week, fixed-dose, open-label trial. J ClinPsychopharmacol. 2006;26:45–9.

90.• Nunes EA, Freire RC, Dos Reis M, de OliveiraESilva AC,Machado S, JAS C, et al. Sulpiride and refractory panic disorder.Psychopharmacology. 2012;223:247–9. This open-label studyshowed that sulpiride monotherapy in refractory-PD led tosignificant clinical improvement.

91.• Goddard AW, Mahmud W, Medlock C, Shin Y-W, Shekhar A. Acontrolled trial of quetiapine XR coadministration treatment ofSSRI-resistant panic disorder. Ann General Psychiatry. 2015;14:26. In this RCT, among 26 patients with SSRI-resistant panicdisorder, quetiapine augmentation was not associated with asignificant clinical difference.

92. Gao K, Wu R, Kemp DE, Chen J, Karberg E, Conroy C, et al.Efficacy and safety of quetiapine-XR as monotherapy or adjunc-tive therapy to a mood stabilizer in acute bipolar depression withgeneralized anxiety disorder and other comorbidities: a random-ized, placebo-controlled trial. J Clin Psychiatry. 2014;75:1062–8.

93. National Institute for Health and Clinical Excellence (NICE).Panic disorder overview—NICE Pathways [Internet]. [cited2017 Aug 1]. Available from: https://pathways.nice.org.uk/pathways/panic-disorder

94. Giampaolo P, Alessandra A, Raffaele B, Elisa M, Giuseppina D,Paolo C, et al. Is there room for second-generation antipsychoticsin the pharmacotherapy of panic disorder? A systematic reviewbased on PRISMA guidelines. Int J Mol Sci. 2016;17:551.

95. Macy AS, Theo JN, Kaufmann SCV, Ghazzaoui RB, PawlowskiPA, Fakhry HI, et al. Quality of life in obsessive compulsive dis-order. CNS Spectr. 2013;18:21–33.

96. Fontenelle LF, Mendlowicz MV, Versiani M. The descriptive ep-idemiology of obsessive-compulsive disorder. Prog Neuro-Psychopharmacol Biol Psychiatry. 2006;30:327–37.

97. Ackerman DL, Greenland S. Multivariate meta-analysis of con-trolled drug studies for obsessive-compulsive disorder. J ClinPsychopharmacol. 2002;22:309–17.

98. Fineberg NA, Gale TM. Evidence-based pharmacotherapy ofobsessive-compulsive disorder. Int J Neuropsychopharmacol.2005;8:107–29.

99. Goodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P,Heninger GR, et al. The Yale-Brown Obsessive CompulsiveScale. II. Validity. Arch Gen Psychiatry. 1989;46:1012–6.

100. Mallet L, Polosan M, Jaafari N, Baup N,Welter M-L, Fontaine D,et al. Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N Engl J Med. 2008;359:2121–34.

101. Sugarman MA, Kirsch I, Huppert JD. Obsessive-compulsive dis-order has a reduced placebo (and antidepressant) response com-pared to other anxiety disorders: a meta-analysis. J Affect Disord.2017;218:217–26.

102. McDougle CJ, Goodman WK, Leckman JF, Lee NC, HeningerGR, Price LH. Haloperidol addition in fluvoxamine-refractory ob-sessive-compulsive disorder. A double-blind, placebo-controlledstudy in patients with and without tics. Arch Gen Psychiatry.1994;51:302–8.

103. Li X,May RS, Tolbert LC, JacksonWT, Flournoy JM, Baxter LR.Risperidone and haloperidol augmentation of serotonin reuptakeinhibitors in refractory obsessive-compulsive disorder: a crossoverstudy. J Clin Psychiatry. 2005;66:736–43.

104. Jiménez-Jiménez FJ, García-Ruiz PJ. Pharmacological options forthe treatment of Tourette’s disorder. Drugs. 2001;61:2207–20.

105.•• Dold M, Aigner M, Lanzenberger R, Kasper S. Antipsychoticaugmentation of serotonin reuptake inhibitors in treatment-

resistant obsessive-compulsive disorder: an update meta-analysisof double-blind, randomized, placebo-controlled trials. Int. J.Neuropsychopharmacol. 2015;18. This meta-analysis of 14RCTs concerning 6 different antipsychotics add-on in refrac-tory OCD patients showed significant efficacy of haloperidol,risperidone, and aripiprazole, compared to placebo.Haloperidol induced severe motor side effects. Quetiapine,olanzapine, and paliperidone did not show efficacy.

106. DeLeon A, Patel NC, Crismon ML. Aripiprazole: a comprehen-sive review of its pharmacology, clinical efficacy, and tolerability.Clin Ther. 2004;26:649–66.

107.• Sayyah M, Sayyah M, Boostani H, Ghaffari SM, Hoseini A.Effects of aripiprazole augmentation in treatment-resistant obses-sive-compulsive disorder (a double blind clinical trial). DepressAnxiety. 2012;29:850–4. This double-bind placebo-controlledRCTof aripiprazole in refractory OCD showed an efficacy ofaripiprazole in symptom reduction.

108.• Selvi Y, Atli A, AydinA, Besiroglu L, Ozdemir P, Ozdemir O. Thecomparison of aripiprazole and risperidone augmentation in selec-tive serotonin reuptake inhibitor-refractory obsessive-compulsived i so rde r : a s i ng le -b l i nd , r andomised s tudy. HumPsychopharmacol. 2011;26:51–7. This double-bind placebo-controlled RCT of aripiprazole in refractory OCD showedan efficacy of aripiprazole in symptom reduction.

109. American Psychiatric Association. Practice guideline for the treat-ment of patients with obsessive-compulsive disorder. [Internet].2007 [cited 2017 May 9]. Available from: http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm

110. Fonseka TM, Richter MA, Müller DJ. Second generationantipsychotic-induced obsessive-compulsive symptoms inschizophrenia: a review of the experimental literature. CurrPsychiatry Rep. 2014;16:510.

111. Bourin M, Dailly E, Hascöet M. Preclinical and clinical pharma-cology of cyamemazine: anxiolytic effects and prevention of alco-hol and benzodiazepine withdrawal syndrome. CNS Drug Rev.2004;10:219–29.

112. Fourrier A, Gasquet I, Allicar MP, Bouhassira M, Lépine JP,Bégaud B. Patterns of neuroleptic drug prescription: a nationalcross-sectional survey of a random sample of French psychiatrists.Br J Clin Pharmacol. 2000;49:80–6.

113. Diemer J, Domschke K, Mühlberger A, Winter B, Zavorotnyy M,Notzon S, et al. Acute anxiolytic effects of quetiapine during vir-tual reality exposure—a double-blind placebo-controlled trial inpatients with specific phobia. Eur Neuropsychopharmacol J EurColl Neuropsychopharmacol. 2013;23:1551–60.

114. O’brien CP. Benzodiazepine use, abuse, and dependence. J ClinPsychiatry. 2005;66(Suppl 2):28–33.

115. Ames D, Carr-Lopez SM, Gutierrez MA, Pierre JM, Rosen JA,Shakib S, et al. Detecting and managing adverse effects of anti-psychotic medications: current state of play. Psychiatr Clin NorthAm. 2016;39:275–311.

116. De Hert M, Dekker JM,Wood D, Kahl KG, Holt RIG,Möller H-J.Cardiovascular disease and diabetes in people with severe mentalillness position statement from the European PsychiatricAssociation (EPA), supported by the European Association forthe Study of Diabetes (EASD) and the European Society ofCardiology (ESC). Eur Psychiatry J Assoc Eur Psychiatr.2009;24:412–24.

117. De Hert M, Detraux J, Peuskens J. Second-generation and newlyapproved antipsychotics, serum prolactin levels and sexual dys-functions: a critical literature review. Expert Opin Drug Saf.2014;13:605–24.

118. Marder SR, Essock SM, Miller AL, Buchanan RW, Casey DE,Davis JM, et al. Physical health monitoring of patients withschizophrenia. Am J Psychiatry. 2004;161:1334–49.

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