This review article examines the evidence for using atypical antipsychotics as adjunctive therapy or monotherapy to treat generalized anxiety disorder (GAD). The most evidence has been collected for quetiapine, which approximately 50% of participants tolerated, most commonly experiencing sedation and fatigue. Among those who continued treatment, significant reductions in anxiety were demonstrated when used as adjunctive therapy or monotherapy. While atypical antipsychotics show promise based on evidence from other disorders, their use for GAD remains off-label and careful consideration of risks and benefits is needed, especially regarding long-term use.

1. REVIEW ARTICLE
Role of Atypical Antipsychotics in the Treatment of Generalized
Anxiety Disorder
Rachel Hershenberg • Daniel F. Gros •
Olga Brawman-Mintzer
Published online: 5 May 2014
Ó Springer International Publishing Switzerland (outside the USA) 2014
Abstract Evidence-based treatment approaches for gen-
eralized anxiety disorder (GAD) comprise psychotherapy,
pharmacotherapy, or a combination of the two. First-line
pharmacotherapy agents include selective serotonin reup-
take inhibitors, selective serotonin-norepinephrine reuptake
inhibitors, and, in certain European guidelines, pregabalin,
which gained European Commission approval. Although
short- and long-term efficacy have been established for
these agents in controlled trials, response rates of 60–70 %
are insufficient, remission rates are relatively modest, and
relapse rates considerable. Moreover, questions increas-
ingly arise regarding tolerability and side-effect profiles.
As an alternative, antipsychotics have long been of interest
for the treatment of anxiety disorders, but investigation had
been tempered by their potential for irreversible side
effects. With the improved side-effect profiles of atypical
antipsychotics, these agents are increasingly being inves-
tigated across Axis I disorders. Atypical antipsychotics
such as quetiapine, aripiprazole, olanzapine, and
risperidone have been shown to be helpful in addressing a
range of anxiety and depressive symptoms in individuals
with schizophrenia and schizoaffective disorders, and have
since been used in the treatment of a range of mood and
anxiety disorders. In this article, we review the efficacy and
tolerability of atypical antipsychotics as adjunctive therapy
and/or monotherapy for individuals with GAD, a currently
off-label indication. The most evidence has accumulated
for quetiapine. Findings suggest that approximately 50 %
of participants tolerate the side effects, most commonly
sedation and fatigue. Among this subset, those who con-
tinue treatment demonstrate significant reductions in anx-
iety when used as adjunctive therapy or monotherapy. The
appropriateness of the use of antipsychotics in the treat-
ment of GAD is discussed.
Key Points
In this article, we review the efficacy and tolerability
of atypical antipsychotics as adjunctive therapy and/
or monotherapy for individuals with generalized
anxiety disorder (GAD), a currently off-label
indication.
Approximately 50 % of participants tolerate the side
effects, most commonly sedation and fatigue.
Those who continue treatment demonstrate
significant reductions in anxiety when used as
adjunctive therapy or monotherapy.
Careful assessment of risks and benefits of these
agents, particularly with regard to long-term use, is
needed when considering their use in GAD patients.
R. Hershenberg
VISN 4 Mental Illness Research, Education and Clinical Center
at Philadelphia VA Medical Center, 3900 Woodland Ave,
Philadelphia, PA 19104, USA
e-mail: rhersh@mail.med.upenn.edu
R. Hershenberg
Department of Psychiatry, Perelman School of Medicine,
University of Pennsylvania, Philadelphia, PA, USA
D. F. Gros Á O. Brawman-Mintzer
Mental Health Service, Ralph H. Johnson VA Medical Center,
Charleston, SC, USA
D. F. Gros Á O. Brawman-Mintzer (&)
Department of Psychiatry and Behavioral Sciences, Medical
University of South Carolina, Charleston, SC, USA
e-mail: mintzero@musc.edu
CNS Drugs (2014) 28:519–533
DOI 10.1007/s40263-014-0162-6

2. 1 Introduction
Generalized anxiety disorder (GAD) is characterized by
excessive worry and anxiety. The diagnosis was introduced
in the Diagnostic and Statistical Manual of Mental Dis-
orders, 3rd Edition (DSM-III) [1], conceptualized as a
residual category for persistent anxiety that was not char-
acteristic of another anxiety disorder. In DSM-III, Revised
Edition (DSM-III-R) [2], GAD emerged independent of
other anxiety disorders. Pathological worry became the
distinguishing feature, characterized by worry over daily
circumstances across domains such as work, school,
finances, and health of family members. To warrant a
diagnosis, anxiety or worry needed to be considered
‘unrealistic or excessive’, be about two or more life cir-
cumstances, last 6 months or longer, and be accompanied
by 6 of 18 symptoms marked by motor tension, autonomic
hyperactivity, vigilance and scanning, difficulty sleeping,
mood (irritability) and/or difficulty concentrating. The
emergence of DSM, 4th Edition (DSM-IV) [3] led to
revised diagnostic criteria, although pathological worry
remained the core of the diagnosis. The 6-month duration
was retained, but criteria were reduced for greater speci-
ficity, requiring three or more of six symptoms, including
restlessness or keyed up/on edge, fatigue, difficulty con-
centrating, irritability, muscle tension, and sleep distur-
bance. In the recently published DSM, 5th Edition (DSM-5)
[4], the criteria have remained consistent. Based on the
available treatment trials, the present review centers on the
DSM-IV/(5) definition of GAD.
In the general population, 12-month prevalence esti-
mates of GAD are 2.1 %, and lifetime prevalence estimates
are 4.1 % [5]. Estimates are higher specifically in primary
care settings (approximately 8 %) [6, 7] and even higher
among veterans [8–10]. Being female, middle-aged,
widowed/separated/divorced, and low income increases
risk [5]. Typical onset is in early adulthood [11], with men
in their early 20s and women in their late 20s [12]. Genetic
factors in GAD may be shared with major depressive dis-
order (MDD) [13]. GAD is a highly chronic disorder. In
longitudinal follow-up, approximately 46 % of women and
56 % of men achieved remission over the course of
8 years; approximately 36 % of women and 43 % of men
demonstrated relapse in that time [12]. Evidence suggests
that deteriorations in psychosocial functioning negatively
impact the course of GAD [14].
In addition to high chronicity, GAD also evidences high
comorbidity. Estimates suggest that 66 % of patients with
GAD have a comorbid disorder, and 90 % have a lifetime
history of another disorder [15]. GAD typically co-occurs
with MDD, social phobia, specific phobia, panic disorder,
and post-traumatic stress disorder (PTSD) [7].
Furthermore, without prior history, individuals with GAD
are at risk for subsequent development of mood disorders
[16, 17].
GAD is associated with significant impairment and
disability. Even without comorbidity, GAD is associated
with disability in social relationships, physical health, and
work that is comparable to impairment from MDD [17,
18]. Thus, cost to society is high, particularly due to lost
days at work, frequent utilization of healthcare services,
and chronicity of the disorder [17, 19–21]. Indeed, con-
trolling for the presence of physical illness, individuals
with GAD utilize twice the primary care visits as individ-
uals with depression [22]. Moreover, there is also financial
burden due to frequent misdiagnosis and treatment of
individuals with GAD, especially driven by laboratory
analyses and emergency services [23]. Primary evidence-
based treatment approaches for GAD comprise psycho-
therapy, pharmacotherapy, or a combination of the two
approaches.
1.1 Psychological (Non-Pharmacological) Treatment
Cognitive behavioral therapies (CBT) have been most
widely investigated for the treatment of GAD [24]. Core
components typically involve self-monitoring of anxiety,
relaxation training, cognitive restructuring, and imagery
rehearsal of coping skills [25]. Newer CBT approaches,
such as Acceptance and Commitment Therapy, are more
focused on the function rather than the content of the
thoughts [26], typically utilizing acceptance and defusion
exercises to increase psychological and attentional flexi-
bility and behaving consistent with valued life directions
[27, 28]. Overall, approximately 50 % of individuals
achieve clinically significant improvement with CBT [29].
To improve outcome, recent efforts for more comprehen-
sive approaches addressing maintaining variables such as
emotional avoidance and interpersonal dysfunction [30]
and meta-cognitive processes [31] have been investigated.
1.2 Traditional Pharmacological Treatment
Pharmacological agents that have been examined include
selective serotonin reuptake inhibitors (SSRIs; e.g. par-
oxetine, escitalopram), serotonin-norepinephrine reuptake
inhibitors (SNRIs; e.g. duloxetine, venlafaxine), benzodi-
azepines (e.g. lorazepam), tricyclic antidepressants (e.g.
imipramine), anticonvulsant medications (e.g. pregaba-
lin—a calcium channel modulator, valproate) and buspi-
rone. Consistent with international guidelines for the long-
term management of GAD (e.g. World Federation of
Societies of Biological Psychiatry, National Institute for
Health and Care Excellence) [32], first-line
520 R. Hershenberg et al.

3. pharmacological treatment includes SSRIs and SNRIs [33],
particularly those approved for GAD treatment, including
escitalopram, paroxetine, duloxetine, and venlafaxine, with
evidence supporting pregabalin as a potential first-line
agent in countries where it has been approved for use in
GAD [34]. Interestingly, a recent meta-analysis comparing
the efficacy and tolerability of various medication options
for GAD found the most support for SSRIs [35]. Fluoxetine
was ranked first for clinically significant treatment
response (62.9 %) and achieving remission (60.6 %), and
sertraline was ranked first for tolerability (49.3 %) [35].
However, the methodological rigor of this study has been
questioned. Notably, only one fluoxetine trial, which was
conducted in comorbid patients, was included in the
review; thus, the positive effects of fluoxetine are clearly
not representative. Nevertheless, these analyses do under-
score the utility of SSRIs as first-line treatment in this
patient population. In contrast, in an effect-size analysis of
pharmacological treatments for GAD, Hidalgo and col-
leagues [36] demonstrated the highest effect size for pre-
gabalin. However, the authors noted that the short duration
of 4 weeks for pregabalin trials included in their analyses
may have affected results. As reviewed by Katzman and
colleagues [32, 37], these first-line treatments typically
demonstrate about 60–70 % response rate, with 30–60 %
of patients experiencing residual symptoms and 10–20 %
experiencing relapse. Moreover, not only is there latency in
response (typically 2–4 weeks before initial onset of relief
and 6–12 weeks before significant improvements), but side
effects also may limit their favorability. For example,
SSRIs and SNRIs are associated with sexual dysfunction,
gastrointestinal side effects, and weight gain [38, 39].
Pregabalin is associated with dizziness and sedation [40].
Although fast-acting, benzodiazepines have a risk of
dependency, which limits their long-term therapeutic use
[41]. Together, considerable rates of non-response coupled
with tolerability issues decrease patient compliance, which
may further compound difficulty of achieving long-term
remission.
1.3 Antipsychotics as Pharmacological Treatment
for Depression and Other Anxiety Disorders
One class of medicine that has been considered more
recently in the treatment of GAD is antipsychotics. Anti-
psychotics have long been of interest for the treatment of
anxiety disorders, but investigation was tempered by risk of
irreversible side effects associated with the ‘typicals’.
However, there has been a resurgence of interest over the
past decade because of decreased concern about extrapy-
ramidal symptoms and tardive dyskinesia associated with
the next-generation atypical antipsychotics. Atypical anti-
psychotics such as quetiapine, ariprazole, olanzapine, and
risperidone have been shown to be helpful in addressing a
range of anxiety and depressive symptoms in individuals
with schizophrenia and schizoaffective disorders [42, 43]
and have since been used in the treatment of a range of
mood and anxiety disorders such as PTSD, obsessive
compulsive disorder, and treatment-resistant MDD [44–
48]. In the US, aripiprazole and quetiapine have received
approval by the Federal Drug Administration as an adjunct
to antidepressant medication to treat depression [49].
Mechanisms of action on symptoms of depression and
anxiety have not been established, but it has been
hypothesized that it may be due to blocking 5-HT2a
receptors [50, 51]. One benefit may be that blocking of the
receptors could increase slow-wave sleep, which might
improve sleep quality [52]. Other purported mechanisms
may involve partial agonism at 5-HT1A receptors and/or
antagonism at central histamine receptors. Moreover, nor-
quetiapine, the active metabolite of quetiapine, acts as a
norepinephrine reuptake inhibitor [53].
2 Antipsychotics as Pharmacological Treatment
for Generalized Anxiety Disorder
Given their demonstrated effectiveness in the treatment of
mood and other anxiety disorders [44–48], the use of
atypical antipsychotics in the treatment of GAD has
increased, with several initial investigations focused on the
potential for antipsychotics to improve treatment outcome
for non-responders from other first-line treatments. The
purpose of the present article is to review the existing lit-
erature for atypical antipsychotics as adjunctive therapy
and/or monotherapy for individuals with GAD. Although
varying by country, note that the use of atypical antipsy-
chotics is currently considered off-label for treatment of
GAD in the US and Europe.
The terms ‘generalized anxiety disorder’ and ‘anti-
psychotic’ were searched in MEDLINE and PsycINFO to
obtain a comprehensive sample of treatment studies. No
date or language restrictions were applied. In addition,
reference searches were completed within treatment
studies and past review articles on pharmacological
approaches to GAD [53, 54]. No restriction criteria were
established in relation to study design, and we included
both open-label trials (no control/comparison group) and
controlled outcome studies with individuals with primary
diagnoses of GAD. Studies recruiting participants with
multiple anxiety disorders were included if they provided
secondary analyses specifically on the GAD group [55],
but excluded if they only provided data for the entire
sample [56]. We focus our review on efficacy and toler-
ability. Unless otherwise noted, efficacy is based on sta-
tistically significant reductions in anxiety symptoms on
Atypical Antipsychotics and GAD 521

4. the Hamilton Rating Scale for Anxiety (HAM-A). Tol-
erability refers to frequency of side effects and rates of
dropout. Our review focuses on five atypical antipsy-
chotics: risperidone, olanzapine, aripiprazole, ziprasidone,
and quetiapine. It should be noted that new atypical an-
tipsychotics, specifically asenapine, iloperidone and pali-
peridone, are not reviewed in this article as there are
currently no data on their role in the treatment of GAD. A
summary of results can be found in Table 1.
2.1 Risperidone
Risperidone was one of the first atypical antipsychotics
investigated in individuals with GAD. A hypothesized
mechanism of action is its anxiolytic effect via modulation
of the 5-HT system. Risperidone has been used effectively
with individuals with schizophrenia, schizoaffective dis-
order, bipolar disorder, PTSD, and irritability associated
with autism [57–60].
An open-label, flexible-dose trial of adjunctive risperi-
done was conducted on individuals with GAD (n = 16),
panic disorder (n = 7), or social anxiety disorder (n = 7)
continuing to demonstrate symptoms despite pharmaco-
therapy with a traditional anxiolytic [61]. All participants
were initiated on adjunctive risperidone at 0.25 mg/day and
flexibly titrated up to a maximum of 3 mg/day (average
endpoint dose 1.12 mg/day). Symptoms of anxiety signif-
icantly decreased among GAD participants. Tolerability
was reported for the entire sample. Thirty percent of the
sample discontinued treatment, and the most common side
effects included sedation/fatigue (46.7 %), increased
appetite and weight gain (36.7 %), dizziness (26.7 %),
nausea/gastrointestinal distress (23.3 %), dry mouth
(20.0 %), headache (16.7 %), and blurred vision (16.7 %).
The average weight gain was 3.9 pounds.
In a double-blind adjunctive trial, Brawman-Mintzer
and colleagues investigated risperidone in individuals with
GAD who remained symptomatic despite at least 4 weeks
of anxiolytic treatment [62]. All participants continued to
take their medication and received adjunctive risperidone
(n = 19; 0.5–1.5 mg/day) or placebo (n = 20). At the end
of 5 weeks, the risperidone group evidenced significantly
greater reductions in anxiety symptoms, and 58 % of ris-
peridone participants compared with 35 % of placebo
participants were considered ‘much’ or ‘very much’
improved. Common side effects included somnolence (47.4
% risperidone; 15 % placebo) and blurred vision (15.8 %
risperidone; 0.0 % placebo). Dizziness was common in
both groups (21.1 % risperidone; 15.0 % placebo), and the
average weight increase was approximately 2.7 pounds
across conditions. Although participants discontinued
treatment equally between conditions (21.1 % risperidone;
20.0 % placebo), 75 % of risperidone participants
compared with 25 % of placebo participants discontinued
treatment due to side effects.
Finally, a large double-blind adjunctive trial examined
risperidone in GAD individuals with no other diagnostic
comorbidity [63]. The sample involved individuals who
continued to present with significant GAD symptoms
despite treatment with an antidepressant, benzodiazepine,
buspirone, or a combination thereof for at least 8 weeks.
Participants were randomly assigned to receive placebo
(n = 194) or adjunctive risperidone (n = 196), building up
to 1 mg/day for those on fluoxetine or paroxetine and up to
2 mg/day for all others. At the end of 4 weeks, participants
in both groups demonstrated significant improvement in
the four symptoms that they indicated were most trouble-
some at baseline (as indicated on the Patient-Rated Trou-
bling Symptoms for Anxiety scale). Although no
significant group differences were observed in the top four
symptoms, the risperidone group evidenced significantly
greater improvement in specific symptoms of muscle ten-
sion, trouble sleeping, and fatigue. Participants completed
the study equally across the risperidone (84.7 %) and pla-
cebo (86.6 %) conditions and reported an equal incidence
of side effects (57.2 % risperidone; 52.1 % placebo).
However, twice the risperidone participants (11.2 %) dis-
continued the study due to side effects. The most common
side effects across conditions were headaches and
increased weight, and the average weight increase was
approximately 0.83 pounds. Specific to risperidone, par-
ticipants also reported increased appetite (4.6 % risperi-
done; 1.0 % placebo), peripheral edema (2.6 %
risperidone; 1.0 % placebo), and galactorrhea (2.0 % ris-
peridone; 1.0 % placebo). The number of serious side
effects were rare, rated as in doubtful relation to the study,
and found equally across conditions.
2.2 Olanzapine
Olanzapine, an atypical antipsychotic that evidences mixed
effects at the serotonergic (5-HT2) and dopaminergic (D2)
receptors [64], has also been investigated in individuals
with GAD. Olanzapine has demonstrated efficacy in indi-
viduals with schizophrenia, bipolar disorder, as adjunctive
therapy in treatment-resistant MDD, PTSD [65] and social
anxiety disorder [66] with partial responses to an SSRI.
One double-blind trial has investigated the use of
adjunctive olanzapine in individuals with GAD who
remained symptomatic following 6 weeks of an SSRI [67].
Study participants with primary GAD diagnoses received
up to 20 mg/day of fluoxetine for the first 6 weeks of the
study, and those who remained symptomatic (n = 26) and
agreed to the next phase were randomly assigned to the
olanzapine (n = 12; received up to 20 mg/day) or placebo
(n = 12) condition for the next 6 weeks. Efficacy data are
522 R. Hershenberg et al.

5. Table1Selectedcharacteristicsofcompletedstudiesidentifiedbyreview
Study(year)Treatmentmodality
Medication/dose(n)
[randomization]
TreatmenteffectsSEs/tolerability
Risperidone
Brawman-
Mintzer
etal.(2005)
[62]
5-weekadjunctivetherapy
0.5–1.5mgrisperidone(19)
Placebo(20)
[randomized]
Risperidoneledtosignificantlygreaterreductioninsymptoms
comparedwithplacebo.Althoughnumericallysuperior,
treatmentresponsewasnotsignificantlygreaterinthe
risperidonegroup(58%)comparedwithplacebo(35%)
LimitedreportsofSEsinbothconditions.MostcommonSEsfor
risperidoneweresomnolenceandblurredvision.21%of
risperidoneparticipantsand20%ofplaceboparticipants
discontinued,although75%ofdiscontinuationsinthe
risperidonegroupwereduetoSEscomparedwith25%inthe
placebogroup
Pandinaetal.
(2007)[63]
4-weekadjunctivetherapy
0.25–2mgrisperidone(196)
Placebo(194)
[randomized]
Overallimprovementnotsignificantlydifferentbetweengroups,
althoughtherisperidonegroupperformedsignificantlybetteron
specificsymptomsofmuscletension,troublesleeping,and
tiringeasily
15.3%ofrisperidoneparticipantsand13.4%ofplacebo
participantsdiscontinued.SEswereequalacrossgroups(57%
risperidone,52%placebo)buttwicetherisperidone
participantsdiscontinuedduetoSEs.MostcommonSEsfor
bothgroupswereheadacheandweightgain;specificto
risperidonewereincreasedappetite,drymouth,peripheral
edema,andgalactorrhea
Simonetal.
(2006)[61]
8-weekadjunctivetherapy
0.25–3mgrisperidone(30total
sample,characterizedas16GAD,7
panicdisorder,7socialanxiety)
[norandomization]
TheGADgroupsignificantlyimprovedinanxietysymptoms30%ofallparticipantsdiscontinued.Sideeffectsoccurringin
10%ormoreofthesampleincludedsedation/fatigue,increased
appetite/weightgain,dizziness,nausea/gastrointestinaldistress,
drymouth,headache,blurredvision,musclecramps,urinary
urgency/incontinence,sexualdysfunction,andvividdreaming
Olanzapine
Pollacketal.
(2006)[67]
6-weekadjunctivetherapy(following
6weeksof20mgfluoxetine)
2.5–20mgolanzapine(12)
Placebo(12)
[randomized]
Althoughinexpecteddirection,improvementinsymptomswas
notsignificantlygreaterintheolanzapinegroupcomparedwith
theplacebogroup.Olanzapineparticipants(41.7%)were
significantlymorelikelytobeconsideredrespondersthan
placeboparticipants(8.3%)
41.7%ofolanzapineparticipantsand17%ofplacebo
participantsdiscontinuedtreatment.Weightgainwas
significantlygreaterforolanzapine(averageincrease11
pounds)comparedwithplacebo(averagelossof0.7pounds).
OtherSEsacrossbothgroupsincludedsedation,gastrointestinal
distress,increasedappetite,andsexualdysfunction
Aripiprazole
Hogeetal.
2008[55]
8-weekadjunctivetherapy
2.5–30mgaripiprazole(23total
sample,characterizedas13GAD,
10panicdisorder)
[norandomization]
GADparticipantssignificantlyimprovedinanxietysymptoms.
23%ofGADparticipantsachievedremission
Threeofthe23participants(13%)discontinuedduetosedation
(n=1),chestdiscomfort(n=1),andrestlessness(n=1).
MostcommonSEsoverallincludedsedation/fatigue,insomnia,
jitteriness,dyspepsia,andnausea.Averageweightincreasewas
2.5pounds
Menzaetal.
(2007)[71]
6-weekadjunctivetherapy
Flexibledoseinitiatedat10mg,
averagedose13.9mg(9)
[norandomization]
Participantssignificantlydecreasedinsymptomsofanxiety.One
patient(11%)achievedremission
Oneparticipant(11%)discontinuedduetoakathisia.OtherSEs
includedheadache,nausea,dizziness,tiredness,blurredvision,
andincreasedanxiety.Oneparticipant(11%)gained10pounds
Atypical Antipsychotics and GAD 523

6. Table1continued
Study(year)TreatmentmodalityMedication/dose
(n)[randomization]
TreatmenteffectsSEs/tolerability
Ziprasidone
Lohoffetal.
(2010)[76]
8-weekmonotherapy(44)or
adjunctivetherapy(18)
20–80mgziprasidone(41)
Placebo(21)
[randomized]
Reductioninanxietysymptomswasnotsignificantlydifferent
betweenziprasidoneandplaceboparticipants.Trend-level
findingssuggestedthatmonotherapyziprasidoneparticipants
producedlargerimprovementsthanaugmentedziprasidone
patients
31.7%ofziprasidoneparticipantsdiscontinued.Attrendlevel,
morefrequentSEsamongziprasidoneparticipantswere
drowsiness,stimulation,insomnia,anddrymouth.Theaverage
weightgain,1.8pounds,didnotsignificantlydifferbetween
groups
Snyderman
etal.(2005)
[75]
7-weekmonotherapy
29–80mgziprasidone(13)
[norandomization]
Symptomsofanxietysignificantlyimproved.38.5%of
participantswereconsideredremitted
38.5%ofparticipantsdiscontinuedtreatment.CommonSEs
includedsedation,difficultyconcentrating,dizziness,and
insomnia.Theaverageweightgainwas0.2pounds
Quetiapine
Altamura
etal.(2011)
[84]
8-weekadjunctivetherapy
25–150mgquetiapineIR(10)
Placebo(10)
[randomized]
Significantlybettersymptomimprovementsinthequetiapine
groupcomparedwiththeplacebogroup.Althoughnumerically
superior,thenumberofremittersdidnotsignificantlydiffer
betweenthequetiapine(40%)andplacebo(20%)groups
LimitedreportsofSEsinbothconditions(sedationinone
participantonquetiapine).Noparticipantsdiscontinued
treatmentduetoSEsineithergroup
Bandelow
etal.(2010)
[85]
10-weekmonotherapy
50mgquetiapineXR(221)
150mgquetiapineXR(218)
20mgparoxetine(217)
Placebo(217)
[randomized]
Allactiveagentsproducedsignificantimprovementsinanxiety
symptomscomparedwithplacebo.Significantlyhigherratesof
remissionin150mgquetiapine(42.6%)andparoxetine
(38.8%)comparedwithplacebo(27.2%).Quetiapine
improvementsasearlyasday4
OverallincidenceofSEswashigherinactiveagents(50mg
quetiapine,70.9%;150mgquetiapine,76.1%;paroxetine,
72.6%)comparedwithplacebo(55.8%).Discontinuationrates
were25.8%(50mgquetiapine),25.2%(150mgquetiapine),
20.3%(paroxetine),and18.9%(placebo).MostcommonSEs
forquetiapineweresomnolence(21.8;25.2%),drymouth
(15.9;25.7%),andfatigue(15.0;16.5%)for50and150mg,
respectively
Gabriel(2011)
[83]
12-weekadjunctivetherapy
50–150mgquetiapine(16)
200–400mgquetiapine(7)
[norandomization]
Participantssignificantlyimprovedinsymptomsofanxiety.No
differencesemergedforparticipantswhoreceivedthesmalleror
higherdose.47.8%wereconsideredremitted
Oneparticipantdiscontinuedtreatmentduetoexcessive
drowsinessanddizziness(4.2%).Mostcommonsideeffects
weredrowsiness,dizziness,headaches,andnervousness.The
averageweightgainwas1.76pounds
Katzmanetal.
(2008)[81]
12-weekadjunctivetherapy
25–800mgquetiapine(40)
[norandomization]
Participantssignificantlydecreasedinanxietysymptoms.72%
wereconsideredremitted
20%ofparticipantsdiscontinuedtreatment.MostcommonSEs
weresedationanddrymouth.Averageweightgainwas1.1
pounds
Katzmanetal.
(2011)[86]
4–8weekopen-labeltrial(1,224)
followedby12?weekstabilization
Stableparticipantsbeganupto52
weeks’maintenancemonotherapy
50–300mgquetiapineXR(216)
Placebo(216)
[randomized]
Amongparticipantswhowererandomized,quetiapine
significantlydelayedthetimetorecurrenceofanxiety
symptoms,anddelayedthetimetodiscontinuationcompared
withtheplacebogroup
66.6%oftheinitialsamplediscontinued.MostcommonSEs
weresedation,somnolence,fatigue,dizziness,irritability,
constipation,restlessness,akathisia,andtremor.Following
randomization,discontinuationsduetoSEswerelowanddid
notdifferbetweenconditions.Themeanweightincreasefor
quetiapineparticipantswas2.87pounds
524 R. Hershenberg et al.

7. Table1continued
Study(year)TreatmentmodalityMedication/dose
(n)[randomization]
TreatmenteffectsSEs/tolerability
Khanetal.
(2011)[87]
10-weekmonotherapy
50mgquetiapineXR(234)
150mgquetiapineXR(241)
300mgquetiapineXR(241)
Placebo(235)
[randomized]
Anxietysymptomssignificantlydecreasedinthe50and150mg
groups(butnotthe300mggroup)comparedwithplacebo.
Symptomimprovementsbeganasearlyasweek1forallactive
agents.Remissionrateswere36.1%(50mg),37.2%
(150mg),28.6%(300mg),and27.6%(placebo)
Discontinuationwashighestinthe300mggroup(56.9%),
followedbythe150mg(51.5%),50mg(49.2%),andplacebo
(45.5%)groups.ThemostcommonSEsleadingto
discontinuationweresedationandsomnolence.Averageweight
gainwaslessthantwopounds
Meridethetal.
(2012)[88]
10-weekmonotherapy
150mgquetiapineXR(219)
300mgquetiapineXR(207)
10mgescitalopram(213)
Placebo(215)
[randomized]
Allthreeactivetreatmentssignificantlyimprovedanxiety
symptomscomparedwithplacebo.150mgquetiapine
outperformedescitalopram.Rateofremissionwashighestfor
150mgquetiapine(37.3%),whichwassignificantlygreater
thanplacebo(27.4%).Ratesofremissionof300mgquetiapine
(28.4%)andescitalopram(31.5%)werenotsignificantly
betterthanplacebo.Symptomimprovementsinquetiapine
participantswereevidentasearlyasday4
Discontinuationwashighestinthe300mgquetiapinegroup
(51.2%)followedbythe150mgquetiapine(44.75%),
escitalopram(41.8%),andplacebo(38.6%)groups.Overall
incidenceofSEswashigherinactiveagents(150mg
quetiapine,84.3%;300mgquetiapine,86.9%;escitalopram,
69.9%)comparedwithplacebo(58.9%).Themostcommon
SEsweredrymouth,somnolence,andsedationforquetiapine,
andheadacheandnauseaforescitalopram.5.7–6.8%of
participantsinactiveconditionsexperiencedextrapyramidal
symptomscomparedwith4.2%ofplacebopatients.The
averageweightincreaseinbothquetiapinegroupswas2.2
pounds,andchangeinweightwaslessthanaquarterofapound
intheplaceboandescitalopramgroups
Simonetal.
(2008)[82]
8-weekadjunctivetherapy(following
10weeksofopen-labelparoxetine
CR,flexiblydosed12.5–62.5mg)
25–200mgquetiapinebid(11)
Placebo(11)
[randomized]
Reductionsinanxietywerenotsignificantlygreaterinthe
quetiapinegroupcomparedwiththeplacebogroup.Remission
rateswere26.4%quetiapineand18.2%placebo
45%ofquetiapineparticipantscomparedwith9%ofplacebo
participantsdiscontinuedtreatment.ThemostcommonSEsfor
quetiapineweresedation,drymouth,diarrhea,sexual
dysfunction,andnausea
Mezhebovsky
etal.(2012)
[89]
11-weekmonotherapy
50–300mgquetiapineXR(223)
Placebo(227)
[randomized]
Samplecomprisedofolderadultsage
66?years
Participantsinthequetiapinegroupsignificantlydecreased
symptomsofanxietycomparedwithplacebo.Ratesof
remissioninthequetiapinegroup(40.1%)weresignificantly
greaterthanplacebo(12.8%).Symptomimprovementshownas
earlyasweek1
30.5%ofquetiapineparticipantsand38.3%ofplacebo
participantsdiscontinuedtreatment.Themostfrequently
reportedSEwassomnolence(65%quetiapine,50%placebo),
whichwashigherinparticipantsolderthan75yearsofage.The
averageweightgaininthequetiapinegroupwas1.32andthere
wasnoaverageweightchangefortheplacebogroup
bidtwicedaily,CRcontrolledrelease,GADgeneralizedanxietydisorder,IRimmediaterelease,SEssideeffects,XRextendedrelease
Atypical Antipsychotics and GAD 525

8. reported on nine olanzapine participants who provided
sufficient post-trial data. No differences were observed
between conditions on reductions in clinician-rated anxiety
symptoms. However, olanzapine participants were more
likely to be considered ‘responders’, demonstrating 50 %
or more reduction in anxiety symptoms (55.6 % olanza-
pine; 8.3 % placebo). More participants in the olanzapine
(41.7 %) compared with placebo (16.7 %) condition dis-
continued treatment. The most common side effects were
sedation (90.9 % olanzapine; 41.7 % placebo), weight gain
(54.6 % olanzapine; 16.7 % placebo), gastrointestinal dis-
tress (36.4 % olanzapine; 25.0 % placebo), increased
appetite (27.3 % olanzapine; 16.7 % placebo), and sexual
dysfunction (18.2 % olanzapine; 25.0 % placebo). Extra-
pyramidal symptoms did not significantly elevate. Of par-
ticular note, average weight gain was significantly greater
in the olanzapine (11.0 pounds) compared with the placebo
(-0.7 pounds) condition.
2.3 Aripiprazole
Aripiprazole has been used effectively in schizophrenia,
schizoaffective disorder, bipolar disorder [68], as adjunc-
tive treatment for MDD [69], and to treat irritability
associated with autism [59, 70]. Aripiprazole has partial
agonist activity at D2 and 5-HT1A receptors, and antagonist
activity at 5-HT2A receptors. Compared with other anti-
psychotic agents, its side-effect profile tends to include a
lower risk of metabolic effects, sedative effects, movement
disorders, and weight gain.
An open-label trial was conducted on adjunctive ari-
piprazole in nine individuals with primary GAD diagnoses
who continued to evidence significant GAD symptoms
after 6 weeks of antidepressant treatment [71]. Partici-
pants’ medications were augmented with aripiprazole,
beginning with 10 mg/day and adjusted at each visit over
the 6-week study period (average dose 13.9 mg/day).
Participants significantly decreased in symptoms of anxi-
ety. Furthermore, at study completion, 89 % of participants
reported a rating of ‘much improved’ or ‘very much
improved’. Fifty-six percent evidenced greater than 50 %
reduction in anxiety symptoms, and 11.1 % evidenced
‘remission’. 33.3 % of participants had akathisia within the
first week (two resolved; one terminated treatment as a
consequence). Other side effects, which resolved by the
end of the study, included headache (11.1 %), nausea
(11.1 %), dizziness (11.1 %), tiredness and blurred vision
(11.1 %), and increased anxiety (11.1 %). Weight gain was
reported by one participant (10 pounds), which did not
resolve by study completion.
An 8-week, open-label, flexible dose trial of adjunctive
aripiprazole was completed on individuals with GAD
(n = 13) or panic disorder (n = 10) who continued to
evidence significant symptoms following adequate treat-
ment with an anxiolytic [55]. All participants’ medications
were augmented with aripiprazole, beginning with 2.5 mg/
day, increased to 5 mg/day for the first week, and then
titrated flexibly up to a maximum of 30 mg/day. In GAD
participants, symptoms of anxiety significantly decreased,
and 23.1 % achieved remission. Tolerability was reported
for the entire sample. Thirteen percent of participants dis-
continued treatment, and the most common side effects
included sedation or fatigue (73.9 %), insomnia (34.8 %),
jitteriness (30.4 %), dyspepsia (21.7 %), and nausea
(21.7 %). The average weight increase was 2.5 pounds.
2.4 Ziprasidone
Research has been conducted on ziprasidone, an atypical
antipsychotic with serotonergic properties as well as
antagonist activity at the dopamine D2 receptor. Because it
has not been associated with changes in weight or prolactin
levels, its side-effect profile has been considered somewhat
mild [72]. Ziprasidone has been used to treat schizophrenia
and bipolar disorder [73, 74].
In the first examination of ziprasidone, an open-label
trial was conducted with 13 participants with a primary
GAD diagnosis who continued to evidence significant
symptoms following at least 8 weeks of a first-line anxio-
lytic [75]. Participants began the 7 weeks of the study at
20 mg/day and the maximum dosage at study completion
was 80 mg. Ziprasidone was treated as a monotherapy,
although 23.1 % of participants continued on concomitant
low-dose benzodiazepines. Fifty-four percent evidenced a
50 % or greater reduction in symptoms, and 38.5 % were
considered remitted. Sixty-one percent completed the
study, with 23.1 % discontinuing treatment due to side
effects (sedation or persistent insomnia). Overall, common
side effects included sedation (53.9 %), difficulty concen-
trating (30.8 %), dizziness (15.4 %), and insomnia
(15.4 %). Major adverse events such as development of
movement disorder, extrapyramidal symptoms, and pro-
longation of the QTc interval did not occur. The mean
change in weight was 0.2 pounds.
A randomized, double-blind, placebo-controlled trial
was conducted with 62 individuals diagnosed with GAD
[76]. All participants had a treatment failure of at least one
adequate trial of an anxiolytic. Twenty-one participants
received placebo and 41 participants received a daily
dosage of 20 mg/day of ziprasidone, which was titrated
throughout the course of the 8-week study (maximum
dosage 80 mg/day). Seventy-one percent discontinued
prior psychotropic medications (non-augmented/mono-
therapy condition), and the remaining 29 % continued with
their current medication (augmented condition). The main
treatment effect of reductions in anxiety symptoms was not
526 R. Hershenberg et al.

9. significant; however, there was a statistical trend suggest-
ing that monotherapy ziprasidone evidenced more
improvement than the ziprasidone adjunctive group.
Thirty-two percent in the ziprasidone condition discontin-
ued the trial in contrast to 9.5 % in the placebo condition.
At trend level, side effects that were more frequent among
ziprasidone participants included drowsiness (51.2 %
ziprasidone; 28.6 % placebo), stimulation (43.9 % zipr-
asidone; 19.0 % placebo), insomnia (29.3 % ziprasidone;
9.5 % placebo), and dry mouth (31.7 % ziprasidone; 9.5 %
placebo). The average weight gain was approximately 1.8
pounds across groups.
2.5 Quetiapine
Quetiapine had demonstrated efficacy across a range of
mood and anxiety disorders [45–47, 77]: schizophrenia,
bipolar disorder, and adjunctive treatment (quetiapine
extended release [XR]) in MDD [78]. Quetiapine and
norquetiapine (active metabolite) demonstrate a moderate
to high affinity for serotonin, 5HT2A and dopamine D2
receptors, and norquetipaine may be an inhibitor of the
norepinephrine transporter [NET; 79], which may in part
contribute to its efficacy [80]. Due to the larger amount of
research on quetiapine, studies were separated into
adjunctive and monotherapy subsections.
2.5.1 Adjunctive Quetiapine
In one of the first investigations, an open-label trial was
conducted with 40 participants with a primary GAD
diagnosis who continued to endorse symptomatology after
8-weeks of a traditional anxiolytic [81]. For the 12-week
study, all participants received adjunctive quetiapine
immediate release (IR), beginning with 25 mg/day and
titrated up to a maximum of 800 mg/day (mean dose
386 mg/day). Participants significantly decreased in anxi-
ety and worry symptoms, and 72 % were considered
remitted. Eighty percent completed the study. Common
side effects were sedation (72.5 %) and dry mouth (30 %).
No clinically significant changes in vital signs or laboratory
assessments were reported. The body mass index signifi-
cantly increased with an average weight gain of 1.1
pounds.
A two-phase, prospective treatment trial was conducted
on individuals with a primary GAD diagnosis [82]. In
phase one, subjects received 10 weeks of open-label par-
oxetine controlled release (between 12.5 mg and 62.5 mg/
day). Of the 86.0 % who completed phase one, 55.8 %
continued to evidence significant symptoms of GAD. Of
the 22 non-responders who elected to participate, 11 were
assigned to receive adjunctive quetiapine at flexible dosing
25–400 mg/day (average dose 120.5 mg), and 11 were
assigned to placebo for 8 weeks. Following treatment,
reductions in anxiety were not significantly greater in the
quetiapine group compared with the placebo group.
Although rates of remission were higher for quetiapine
(36.4 %) than placebo (18.2 %), again this was not a sta-
tistically significant difference. Forty-five percent discon-
tinued in the quetiapine condition compared with 9.1 % in
the placebo condition. The most common side effects for
quetiapine were sedation (54.6 %), dry mouth (27.3 %),
diarrhea (27.3 %), sexual dysfunction (18.2 %), and nausea
(18.2 %).
In an open-label trial, 24 individuals with GAD who
failed to respond to 8 weeks or more of a first-line anxio-
lytic received 12 weeks of adjunctive quetiapine XR [83].
Remaining on their existing medication, 66.7 % received a
maximum dose of 50–150 mg/day, and 29.2 % received a
maximum dose of 200–400 mg/day. After 12 weeks, par-
ticipants significantly improved in symptoms of anxiety,
and there was no significant effect for dose. Of the 95.8 %
who completed treatment, 21.7 % were considered ‘very
much improved’, 56.5 % were rated as ‘much improved’,
and 47.8 % were considered remitted. The most common
side effects were drowsiness (12.5 %), dizziness (8.6 %),
headaches (4.3 %), and nervousness (4.3 %). There was no
evidence of extrapyramidal symptoms. Average weight
gain was 1.76 pounds.
Low doses of quetiapine were investigated in 20 indi-
viduals with primary GAD diagnoses showing partial or no
response to at least 8 weeks of an SSRI [84]. Participants
remained on their SSRI at stable doses and were randomly
assigned to receive adjunctive quetiapine IR (n = 10;
beginning at 25 mg/day, up to 150 mg) or placebo
(n = 10). Both groups improved over the course of
8 weeks, but the quetiapine group showed significantly
greater reductions in anxiety symptoms and illness sever-
ity. At the end of the study, 40 % of the quetiapine group,
compared with 20 % of the placebo group, were considered
remitted. With regard to tolerability, 10.0 % in the que-
tiapine group reported sedation, and no participants dis-
continued due to side effects.
2.5.2 Quetiapine as Monotherapy
In a large, double-blind study, individuals with a primary
GAD diagnosis were randomly assigned to an 8-week
active monotherapy and 2-week treatment discontinuation
phase or placebo condition [85]. Of the 873 participants
meeting the inclusion criteria, 221 received 50 mg que-
tiapine XR (initiated and maintained at this dose), 218
received 150 mg quetiapine XR (beginning at 50 mg on
day 1 and increased to 150 mg on day 3), 217 received
20 mg paroxetine (initiated and maintained at this dose),
and 217 received placebo. At 8 weeks, anxiety symptoms
Atypical Antipsychotics and GAD 527

10. significantly decreased for all three active conditions
compared with placebo, and remission rates were signifi-
cantly greater with 150 mg quetiapine (42.6 %) and par-
oxetine (38.8 %) compared with placebo (27.2 %); the rate
of remission in the quetiapine 50 mg group was 32.4 %. At
the close of the 8-week monotherapy, 25.2 % of quetiapine
150 mg participants dropped out, of which 58.2 % were
due to side effects, most commonly somnolence (34.4 %)
and fatigue (21.9 %). Higher mean increase in supine pulse
and ECG heart rates also were observed with this group
compared with placebo. Twenty-six percent of quetiapine
50 mg participants dropped out, of which 43.9 % were due
to side effects, most commonly fatigue (28.0 %) and
somnolence (24.0 %). Twenty percent of paroxetine par-
ticipants dropped out, of which 36.4 % were due to side
effects, most commonly insomnia (31.2 %), dizziness
(25.0 %), and fatigue (25.0 %). Nineteen percent of pla-
cebo participants dropped out, of which 42.1 % were due
to side effects, and none of which occurred for more than
one participant. Weight gain occurred specifically for
participants in the 50 mg (1.32 pounds) and 150 mg (2.42
pounds) quetiapine XR groups. By week 8, there were also
no clinically relevant mean changes in vital signs, ECG,
hematology, or clinical laboratory parameters. Moreover,
while there were no clinically meaningful changes in glu-
cose, total cholesterol, high-density lipoprotein (HDL),
low-density lipoprotein (LDL), or triglycerides, there was a
substantial amount of variability, and increases in the
quetiapine groups were significantly greater than placebo.
In another multicenter, placebo-controlled study, que-
tiapine XR was investigated as monotherapy with indi-
viduals with GAD [86]. The study consisted of several
treatment phases, including a 4–8 week open-label trial
(50–300 mg/day) and a 12-week open-label stabilization
period. Participants remaining stable during the 12 weeks
were randomized to double-blind treatment, continuing the
same dose of quetiapine XR (n = 216) or placebo
(n = 216) for 52 weeks or until they met the criteria for
significant anxiety symptoms (defined by HAM-A score or
other indicators such as markedly ill on the Clinical Global
Impression-Severity of Illness scale, hospitalization, or
initiation of prohibited medication). Overall, 1,224 partic-
ipants were included in the open-label treatment period,
66.6 % of whom discontinued. Nineteen percent of these
discontinuations were due to side effects, including seda-
tion (6.6 %), somnolence (3.4 %), fatigue (1.6 %), dizzi-
ness (1.4 %), irritability (1.0 %), and constipation (0.8 %).
During this period, the incidence of extrapyramidal
symptoms was 7.4 %, the most common of which were
restlessness (2.6 %), akathisia (2.4 %), and tremor (1.9 %).
More specifically with regard to scores on the Simpson-
Angus Scale, Barnes Akathisia Rating Scale, and Abnor-
mal Involuntary Movement Scale, no change was observed
for the majority of participants (77.4, 87.5, and 89.9.6 %,
respectively). Among those who continued in the study,
following randomization, quetiapine significantly delayed
the time to recurrence of anxiety symptoms and delayed the
time to discontinuation compared with the placebo group.
During this phase of the study, discontinuations due to side
effects were low and similar across groups (2.3 % active;
2.8 % placebo). Changes in glucose regulation were
equivalent between groups, although a higher proportion of
participants in the quetiapine group became elevated on
measures of total cholesterol, LDL cholesterol and tri-
glycerides, and reduced HDL compared with placebo.
Prolactin level changes were considered small for both the
placebo (-0.67 ng/ml) and quetiapine XR (0.69 ng/ml)
groups. The mean weight increase from open-label baseline
to the end of the randomization period was 2.87 pounds for
quetiapine and 1.98 pounds for placebo.
Multiple doses of quetiapine XR as monotherapy were
investigated in a 10-week, multicenter, randomized, dou-
ble-blind, placebo-controlled trial [87]. Individuals with
GAD were randomized to 8 weeks of once-nightly que-
tiapine XR 50 mg/day (n = 234), 150 mg/day (n = 241),
300 mg/day (n = 241), or placebo (n = 235). A 2-week
discontinuation phase followed. After 8 weeks, anxiety
symptoms significantly reduced in the 50 and 150 mg/day
groups compared with placebo. Although symptoms
reduced in the 300 mg/day group, this was not significantly
different from placebo. Remission rates followed this pat-
tern as well; rates were 36.1 % (50 mg), 37.2 % (150 mg),
28.6 % (300 mg), and 27.6 % (placebo). Study discontin-
uation rates also followed a pattern: rates were 45.5 % in
placebo (6.4 % discontinued due to side effects), 49.2 % in
50 mg (15.9 % discontinued due to side effects), 51.5 % in
150 mg (18.1 % discontinued due to side effects), and
56.9 % in 300 mg (24.4 % discontinued due to side
effects). The most common side effects leading to dis-
continuation were sedation (1 % placebo; 3.4 % 50 mg;
5.8 % 150 mg; 10.0 % 300 mg) and somnolence (1 %
placebo; 4.7 % 50 mg; 4.6 % 150 mg; 4.2 % 300 mg). The
average weight gain was less than one pound in the placebo
and 300 mg groups, and less than two pounds in the 50 and
150 mg groups. Extrapyramidal symptoms were minimal,
and the majority of participants experienced either no
change or improvement in Simpson-Angus Scales
(93.1–94.1 %) and Barnes Akathisia Ratings Scale
(95.9–98.1 %) scores. With regard to glucose regulation
and other laboratory parameters, participants with fasting
glucose of more than 126 mg/dL at the end of treatment
were 0.7 % (placebo), 2.6 % (50 mg), 0 % (150 mg), and
5.6 % (300 mg). Participants with fasting LDL cholesterol
160 mg/dL or greater and HDL 40 mg/DL or lower were
3.1 % LDL and 10.2 % HDL (placebo), 3.9 % LDL and
12 % HDL (50 mg); 5 % LDL and 7.3 % HDL (150 mg),
528 R. Hershenberg et al.

11. and 3.2 % LDL and 15.5 % HDL (300 mg). Participants
with fasting triglycerides of 200 mg/dL or more at the end
of treatment were 3.4, 4.2, 6, and 22.3 % for placebo, 50,
150, and 300 mg, respectively, and the average change in
prolactin levels (ng/mL) were 0.4, 0.8, 0.8, and 0.3,
respectively. Serious side effects were low overall across
groups (2.1 % of total).
Another 10-week, multicenter, randomized, double-
blind, placebo-controlled trial was conducted comparing
multiple doses of quetiapine XR with escitalopram and
placebo as monotherapy [88]. Individuals with GAD were
randomized to 8 weeks of quetiapine XR 150 mg/day
(n = 219), quetiapine XR 300 mg/day (n = 207), escita-
lopram 10 mg/day (n = 213), or placebo (n = 215) and a
2-week discontinuation phase. At week 8, all active treat-
ment groups significantly reduced anxiety symptoms com-
pared with placebo. Directly comparing the antipsychotic to
the antidepressant, quetiapine (specifically at 150 mg) sig-
nificantly improved anxiety symptoms, including somatic
and psychological symptoms, compared with escitalopram.
The proportion of participants considered remitted were
significantly greater in the 150 mg quetiapine group
(37.3 %) compared with placebo (27.4 %); the rates for
300 mg quetiapine (28.4 %) and escitalopram (31.5 %)
were not significantly better than placebo. Participants
completed the study at the following rates: 55 % in 150 mg,
48.8 % in 300 mg, 58.2 % in escitalopram, and 61.4 % in
placebo. A significantly greater proportion of treatment-
related side effects occurred in the active treatment groups
(84.3 % 150 mg; 86.9 % 300 mg; 69.9 % escitalopram)
compared with placebo (58.9 %). In the quetiapine groups,
common reasons for withdrawal were sedation (6.5 %
150 mg; 10.2 % 300 mg) and somnolence (5.5 % 150 mg;
9.2 % 300 mg). In the escitalopram group, sedation (1.9 %)
and anxiety (1.4 %) were common. Side effects were rare in
the placebo group, with nausea (1.4 %), anxiety, dizziness,
and headache (0.9 %). Sexual side effects were twice as
likely in the escitalopram group (8.1 %) compared with the
other three groups (4.1 % 150 mg, 3.9 % 300 mg, and
3.7 % placebo). The most common side effects related to
extrapyramidal symptoms were tremor, restlessness, and
akathisia, which occurred among 6 % (quetiapine 150 mg),
6.8 % (quetiapine 300 mg), 5.7 % (escitalopram), and
4.2 % (placebo) of the participants. At the end of treatment,
extrapyramidal scores were similar across treatment groups,
with 90.2–93.9 % evidencing no change/improvement on
the Simpson-Angus Scale, and 93.9–96.1 % evidencing no
change/improvement on the Barnes Akathisia Rating scale.
Change in weight was less than a quarter of a pound in the
placebo and escitalopram groups; the average weight
increase in both quetiapine groups was 2.2 pounds. No
mean changes in vital signs, electrocardiogram, or QTc
interval were evident across treatment conditions.
Significant increases (from normal to high) in fasting glu-
cose were observed in 3.9 % (150 mg), 1.6 % (300 mg),
0.8 % (escitalopram), and 3.0 % (placebo) of participants.
Significant increases in total cholesterol, LDLs, and tri-
glycerides were also observed across groups; rates were 7.2,
4.4, and 10.1 %, respectively in 150 mg; 1.9, 0.9, and 9.7 %
in 300 mg; 5.6, 3.6, and 6.1 % in escitalopram; and 1.6, 1.6,
8.7 % in placebo.
Finally, in a study of older adults aged 66 years and
above, once-daily quetiapine XR was compared with pla-
cebo in an 11-week, multicenter, double-blind trial [89].
Individuals with GAD were randomly assigned to a flexible
dose of quetiapine (n = 223; initiated at 50 mg/day, up to
300 mg/day, average dose 167.6 mg) or placebo (n = 227)
for 9 weeks, followed by a 2-week discontinuation period.
Participants in the quetiapine group significantly decreased
in symptoms of anxiety compared with placebo, and this
was the case for participants both over and under age 75
years. Likewise, the quetiapine group (40.1 %) demon-
strated significantly greater rates of remission than the
placebo group (12.8 %). Seventy percent of quetiapine
participants and 61.7 % of placebo participants completed
the study. The most frequently reported side effect was
somnolence (50 % placebo; 65 % quetiapine), the inci-
dence of which was higher in participants older than 75
years of age. Five percent of participants in the quetiapine
group withdrew due to side effects, compared with 1.3 %
in the placebo group. With regard to scores on the Simp-
son-Angus Scale, Barnes Akathisia Rating Scale, and
Abnormal Involuntary Movement Scale, no change or
improvement was observed for 88.2, 96.8, and 89.6 % of
quetiapine participants, respectively, and 91.2, 96.5, and
92.9 % of placebo participants. No clinically relevant
changes in laboratory or hematology parameters, vital
signs, or electrocardiogram data were reported in either
group. Significant shifts in glucose, triglycerides, choles-
terol level, and weight occurred, although these increases
did not differ between groups. The average weight gain in
the quetiapine group was 1.32 pounds, and the placebo
group, on average, did not exhibit weight change.
3 Conclusions
We provided a qualitative review of the 17 studies that
investigated the use of atypical antipsychotics for the
treatment of DSM-IV GAD. We specifically reviewed
studies that included risperidone, olanzapine, aripiprazole,
ziprasidone, or quetiapine as adjunctive therapy (in non-
responders to first-line anxiolytics) or monotherapy.
Although some atypical antipsychotics are approved for
adjunctive treatment in depression [49], none have current
approval for the treatment of GAD.
Atypical Antipsychotics and GAD 529

12. Although there was considerable variability in study
methodology and assessments utilized across trials, and
while sample size in many of these trials was low, overall
findings suggest that atypical antipsychotics were effective
in reducing symptoms of anxiety among individuals with
primary diagnoses of GAD. More specifically, the most
research has amassed for quetiapine, and evidence suggests
that relatively low doses of XR 150 mg/day consistently
outperformed higher XR 300 mg/day doses, and initiating
at 50 mg might be sufficient to produce benefit [90]. Rates
of remission did not differ if used as adjunctive therapy or
monotherapy. Similar to benzodiazepines, antipsychotics
led to rapid change within the initial week(s), but unlike
benzodiazepines, they did not lead to difficulty with tol-
erance, withdrawal, or addiction. Serious side effects,
including extrapyramidal symptoms, were relatively rare.
Weight gain was a major concern in the one study that
examined olanzapine [67], consistent with meta-analytic
data suggesting that weight gain is most robust for olan-
zapine [91]. With quetiapine, the average weight gain was
consistently less than 3 pounds. Lastly, metabolic side
effects should be noted from the studies that reported this
data. Specifically, the larger quetiapine randomized trials
demonstrated clinically meaningful changes in fasting
glucose, cholesterol, and triglycerides.
Although efficacy findings are promising, it is essential
to include all indices of outcome in order to interpret these
findings within a larger context. Most significantly, roughly
half of the participants in these studies discontinued treat-
ment prior to study completion. Moreover, discontinuation
was often due to medication side effects, most commonly
sedation and fatigue. Thus, taking efficacy and process
findings into account, findings may suggest that, among
patients who tolerate the medication, antipsychotic medi-
cations demonstrate significantly improved reductions in
anxiety when compared with placebo and SSRI treatments,
with approximately 30–40 % of these tolerant patients
demonstrating symptom remission.
However, given the potential risk for side effects, the
use of antipsychotics must be closely monitored and uti-
lized with caution and discretion [92]. Concerns about
metabolic complications associated with the use of atypical
antipsychotics clearly remain. Indeed, recent data indicate
that atypical antipsychotics, such as olanzapine as well as
aripiprazole, which is considered metabolically sparing,
exert direct effects on insulin-sensitive tissues, and this risk
of early metabolic dysregulation is independent of weight
gain, food intake, or psychiatric presentation [93]. Fur-
thermore, reports of dose-dependent increased risk of
sudden cardiac death cannot be ignored when the use of
atypical antipsychotics in GAD is considered [94]. Toge-
ther, these concerns call into question the risk to benefit
ratio of using antipsychotics in the treatment of GAD. In
fact, despite large numbers of clinical trials conducted with
quetiapine in GAD patient populations, safety concerns
expressed both by US and European regulatory agencies
have led to the discontinuation of further development of
quetiapine for this indication.
Currently, several unanswered questions remain that
require further investigation. First, many trials excluded
individuals with multiple disorders, despite the fact that
individuals with GAD commonly present with diagnostic
comorbidity [7, 9]. Although antipsychotic medications
have evidenced symptom improvements in common
comorbid conditions [44, 46, 47], providers should use
caution prescribing these medications with these individ-
uals until trials thoroughly investigate the influence of
comorbidity. Second, the long-term efficacy and tolerabil-
ity are largely unknown; with one exception [86], the
longest study period was 12 weeks. It is also unclear if
antipsychotics are more effective for certain types of GAD
symptoms (e.g. muscle tension and sleep/fatigue), with the
majority of studies omitting specific symptom-based anal-
yses. Providers may want to use caution in individuals with
alternative presentations of GAD (e.g. restlessness, irrita-
bility, and concentration difficulties) until additional
symptom-based analyses are available. Alternatively, these
findings suggest that antipsychotics may be particularly
appropriate for individuals with difficulty falling or staying
sleeping, due to the common side effects of sedation.
Although no studies have conducted head-to-head
comparisons of the different antipsychotics, a more clini-
cally useful advance might be to include trials with med-
ication, psychotherapy, and medication plus psychotherapy
conditions [95, 96]. Indeed, it would be useful to directly
compare pharmacological and non-pharmacological
options, given that a combination approach may be bene-
ficial for the approximately 50 % of individuals who will
not demonstrate response to psychological or pharmaco-
logical intervention. Alternatively, it is also possible that
the combination approach may perform less well than
monotherapy/psychotherapy, as has been shown in other
anxiety disorders with alternative medications [97].
Moreover, within an evidence-based practice approach to
clinical care, it would be helpful for treatment studies to
move toward questions of timing and sequencing that take
into account patient characteristics (e.g. severity level,
comorbidity) and patient preferences (e.g. lack of afford-
ability of therapy; discomfort with medication).
In conclusion, a review of the initial findings suggests
that these medications could provide additional symptom
relief, especially in those who have not responded to first-
line anxiolytics. Caution is needed when prescribing these
medications due to the tolerability of these agents and
treatment discontinuation. The most evidence has accu-
mulated for quetiapine, both in terms of efficacy as a
530 R. Hershenberg et al.

13. monotherapy and adjunctive therapy. Findings suggest that
patients who can tolerate the side effects, most commonly
sedation and fatigue, may demonstrate significant reduc-
tions in anxiety. However, careful assessment of risks and
benefits of these agents, particularly with regard to long-
term use, is needed when considering their use in GAD
patients.
Acknowledgments This material is the result of work supported
with resources and the use of facilities of the VISN 4 Mental Illness
Research, Education, and Clinical Center, Philadelphia Veterans
Affairs Medical Center, Philadelphia, PA, USA, and the Ralph H.
Johnson Veterans Affairs Medical Center. The views expressed in this
article are those of the authors and do not necessarily reflect the
position or policy of the Department of Veterans Affairs or the US
government. There were no conflicts of interest in the preparation of
this manuscript for Drs. Rachel Hershenberg or Daniel F. Gros. Dr.
Olga Brawman-Mintzer received grant support from Forest
Laboratories.
References
1. American Psychiatric Association. Diagnostic and statistical
manual of mental disorders. 3rd ed. Washington, DC: American
Psychiatric Association; 1980.
2. American Psychiatric Association. Diagnostic and statistical
manual of mental disorders. 3rd ed, rev. Washington, DC:
American Psychiatric Association; 1987.
3. American Psychiatric Association. Diagnostic and statistical
manual of mental disorders. 4th ed. Washington, DC: American
Psychiatric Association; 1994.
4. American Psychiatric Association: Diagnostic and statistical
manual of mental disorders, 5th ed. American Psychiatric Asso-
ciation: Washington, DC; 2013.
5. Grant BF, Hasin DS, Stinson FS, Dawson DA, June Ruan W,
Goldstein RB, Smith SM, Saha TD, Huang B. Prevalence, cor-
relates, co-morbidity, and comparative disability of DSM-IV
generalized anxiety disorder in the USA: results from the
National Epidemiologic Survey on Alcohol and Related Condi-
tions. Psychol Med. 2005;35(12):1747–59.
6. Kroenke K, Spitzer RL, Williams JBW, Monahan PO, Lo¨we B.
Anxiety disorders in primary care: prevalence, impairment,
comorbidity, and detection. Ann Intern Med. 2007;146(5):
317–25.
7. Wittchen HU. Generalized anxiety disorder: prevalence, burden,
and cost to society. Depress Anxiety. 2002;16(4):162–71.
8. Hoge CW, Castro CA, Messer SC, McGurk D, Cotting DI,
Koffman RL. Combat duty in Iraq and Afghanistan, mental
health problems, and barriers to care. N Engl J Med. 2004;
351(1):13–22.
9. Milanak ME, Gros DF, Magruder KM, Brawman-Mintzer O,
Frueh BC. Prevalence and features of generalized anxiety disor-
der in Department of Veteran Affairs primary care settings.
Psychiatry Res. 2013;209:173–9.
10. Phillips AC, Batty GD, Gale CR, Deary IJ, Osborn D, MacIntyre
K, Carroll D. Generalized anxiety disorder, major depressive
disorder, and their comorbidity as predictors of all-cause and
cardiovascular mortality: the Vietnam experience study. Psy-
chosom Med. 2009;71(4):395–403.
11. Brown TA, Barlow DH, Liebowitz MR. The empirical basis of
generalized anxiety disorder. Am J Psychiatry. 1994;151(9):
1272–80.
12. Yonkers KA, Bruce SE, Dyck IR, Keller MB. Chronicity, relapse,
and illness—course of panic disorder, social phobia, and gen-
eralized anxiety disorder: findings in men and women from
8 years of follow-up. Depress Anxiety. 2003;17(3):173–9.
13. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. Major
depression and generalized anxiety disorder: same genes, (partly)
different environments? Arch Gen Psychiatry. 1992;49(9):716.
14. Rodrı´guez BF, Bruce SE, Pagano ME, Keller MB. Relationships
among psychosocial functioning, diagnostic comorbidity, and the
recurrence of generalized anxiety disorder, panic disorder, and
major depression. J Anxiety Disord. 2005;19(7):752–66.
15. Wittchen H-U, Zhao S, Kessler RC, Eaton WW. DSM-III—R
generalized anxiety disorder in the National Comorbidity Survey.
Arch Gen Psychiatry. 1994;51:355–64.
16. Fava M, Rankin MA, Wright EC, Alpert JE, Nierenberg AA,
Pava J, Rosenbaum JF. Anxiety disorders in major depression.
Compr Psychiatry. 2000;41(2):97–102.
17. Wittchen HU, Carter RM, Pfister H, Montgomery SA, Kessler
RC. Disabilities and quality of life in pure and comorbid gen-
eralized anxiety disorder and major depression in a national
survey. Int Clin Psychopharmacol. 2000;15(6):319–28.
18. Kessler RC, DuPont RL, Berglund P, Wittchen H-U. Impairment
in pure and comorbid generalized anxiety disorder and major
depression at 12 months in two national surveys. Am J Psychi-
atry. 1999;156(12):1915–23.
19. DuPont RL, Rice DP, Miller LS, Shiraki SS, Rowland CR,
Harwood HJ. Economic costs of anxiety disorders. Anxiety.
1996;2(4):167–72.
20. Greenberg PE, Sisitsky T, Kessler RC, Finkelstein SN, Berndt
ER, Davidson JR, Ballenger JC, Fyer AJ. The economic burden
of anxiety disorders in the 1990s. J Clin Psychiatry. 1999;60:
427–35.
21. Woodman CL, Noyes R, Black DW, Schlosser S, Yagia SJ. A
five-year follow-up study of generalized anxiety disorder and
panic disorder. J Nerv Men Dis. 1999;187:3–9.
22. Wittchen H-U, Kessler RC, Beesdo K, Krause P, Hoyer J. Gen-
eralized anxiety and depression in primary care: prevalence,
recognition, and management. J Clin Psychiatry. 2002;63:24–34.
23. Dilbaz N, Darcin EA. Treatment of generalized anxiety disorders:
unmet needs. In: Durbano F, editor. New insights into anxiety
disorders. New York: InTech. ISBN:978-953-51-1053-8. http://
www.intechopen.com/books/new-insights-into-anxiety-disorders/
treatment-of-generalized-anxiety-disorders-unmet-needs.
24. Newman M, Borkovec T. Cognitive behaviour therapy: a guide
for the practising clinician. In: Simos G, editor. Cognitive
behavioral therapy for worry and generalized anxiety disorder.
New York: Taylor & Francis; 2002. p. 150–72.
25. Borkovec TD, Ruscio AM. Psychotherapy for generalized anxi-
ety disorder. J Clin Psychiatry. 2001;62:37–45.
26. Hayes SC, Villatte M, Levin M, Hildebrandt M. Open, aware, and
active: contextual approaches as an emerging trend in the
behavioral and cognitive therapies. Annu Rev Clin Psychol.
2011;7:141–68.
27. Orsillo SM, Roemer L, Barlow DH. Integrating acceptance and
mindfulness into existing cognitive-behavioral treatment for
GAD: a case study. Cognit Behav Pract. 2003;10(3):222–30.
28. Roemer L, Orsillo SM. An open trial of an acceptance-based
behavior therapy for generalized anxiety disorder. Behav Ther.
2007;38(1):72–85.
29. Hunot V, Churchill R, Silva de Lima M, Teixeira V. Psycho-
logical therapies for generalised anxiety disorder. Cochrane
Database Syst Rev. 2007;(1):CD001848.
30. Newman MG, Castonguay LG, Borkovec TD, Fisher AJ, Boswell
JF, Szkodny LE, Nordberg SS. A randomized controlled trial of
cognitive-behavioral therapy for generalized anxiety disorder
Atypical Antipsychotics and GAD 531

14. with integrated techniques from emotion-focused and interper-
sonal therapies. J Consult Clin Psychol. 2011;79(2):171–81.
31. Wells A, Welford M, King P, Papageorgiou C, Wisely J, Mendel
E. A pilot randomized trial of metacognitive therapy vs applied
relaxation in the treatment of adults with generalized anxiety
disorder. Behav Res Ther. 2010;48(5):429–34.
32. Katzman MA. Current considerations in the treatment of gen-
eralized anxiety disorder. CNS Drugs. 2009;23(2):103–20.
33. Reinhold JA, Mandos LA, Rickels K, Lohoff FW. Pharmaco-
logical treatment of generalized anxiety disorder. Expert Opin
Pharmacother. 2011;12(16):2457–67.
34. Bandelow B, Sher L, Bunevicius R, Hollander E, Kasper S, Zohar
J, Mo¨ller HJ. Guidelines for the pharmacological treatment of
anxiety disorders, obsessive-compulsive disorder and posttrau-
matic stress disorder in primary care. Int J Psychiatry Clin Pract.
2012;16(2):77–84.
35. Baldwin D, Woods R, Lawson R, Taylor D. Efficacy of drug
treatments for generalised anxiety disorder: systematic review
and meta-analysis. BMJ. 2011;342:1–11.
36. Hidalgo RB, Tupler LA, Davidson JR. An effect-size analysis of
pharmacologic treatments for generalized anxiety disorder.
J Psychopharmacol. 2007;21(8):864–72.
37. Katzman MA, Copeland A, Klassen LJ, Chokka P, Brawman-
Mintzer O. Pharmacotherapy for generalized anxiety disorder.
Psychiatr Ann. 2011;41(2):95–103.
38. Dell’Osso B, Buoli M, Baldwin DS, Altamura AC. Serotonin
norepinephrine reuptake inhibitors (SNRIs) in anxiety disorders:
a comprehensive review of their clinical efficacy. Human Psy-
chopharmacol Clin Exp. 2010;25(1):17–29.
39. Kennedy SH, Lam RW, Cohen NL, Ravindran AV. Clinical
guidelines for the treatment of depressive disorders. IV: medi-
cations and other biological treatments. Can J Psychiatry.
2001;46:38S–58S.
40. Dobrea C, Buoli M, Arici C, Camuri G, Dell’Osso B, Altamura
AC. Tolerability and use in co-administration of pregabalin in
affective patients: a 6-month prospective naturalistic study.
Expert Opin Drug Saf. 2012;11(6):893–9.
41. Michelini S, Cassano GB, Frare F, Perugi G. Long-term use of
benzodiazepines: tolerance, dependence and clinical problems in
anxiety and mood disorders. Pharmacopsychiatry. 1996;29(04):
127–34.
42. Buckley PF. Efficacy of quetiapine for the treatment of schizo-
phrenia: a combined analysis of three placebo-controlled trials.
Curr Med Res Opin. 2004;20:1357–63.
43. Mullen J, Jibson MD, Sweitzer D. A comparison of the relative
safety, efficacy, and tolerability of quetiapine and risperidone in
outpatients with schizophrenia and other psychotic disorders: the
quetiapine experience with safety and tolerability (QUEST)
study. Clin Ther. 2001;23(11):1839–54.
44. Bystritsky A, Ackerman DL, Rosen RM, Vapnik T, Gorbis E,
Maidment KM, Saxena S. Augmentation of serotonin reuptake
inhibitors in refractory obsessive-compulsive disorder using
adjunctive olanzapine: a placebo-controlled trial. J Clin Psychi-
atry. 2004;65:565–8.
45. Denys D, de Geus F, Van Megen HJ, Westenberg HG. A dou-
bleblind, randomized, placebo-controlled trial of quetiapine
addition in patients with obsessive-compulsive disorder refrac-
tory to serotonin reuptake inhibitors. J Clin Psychiatry.
2004;65:1040–8.
46. Doree J-P, Rosiers JD, Lew V, Gendron A, Elie R, Stip E, Vale´rie
Tourjman S. Quetiapine augmentation of treatment-resistant
depression: a comparison with lithium. Curr Med Res Opin.
2007;23(2):333–41.
47. Hamner MB, Deitsch SE, Brodrick PS, Ulmer HG, Lorberbaum
JP. Quetiapine treatment in patients with posttraumatic stress
disorder: an open trial of adjunctive therapy. J Clin Psycho-
pharmacol. 2003;23(1):15–20.
48. Li X, May RS, Tolbert LC, Jackson WT, Flournoy JM, Baxter
LR. Risperidone and haloperidol augmentation of serotonin re-
uptake inhibitors in refractory obsessive-compulsive disorder: a
crossover study. J Clin Psychiatry. 2005;66(6):736–43.
49. Patkar AA, Pae C-U. Atypical antipsychotic augmentation strat-
egies in the context of guideline-based care for the treatment of
major depressive disorder. CNS Drugs. 2013;27 Suppl 1:S29–37.
50. Shayegan DK, Stahl SM. Atypical antipsychotics: matching
receptor profile to individual patient’s clinical profile. CNS
Spectr. 2004;9(10 Suppl 11):6.
51. Yatham LN, Goldstein JM, Vieta E, Bowden CL, Grunze H, Post
RM, Suppes T, Calabrese JR. Atypical antipsychotics in bipolar
depression: potential mechanisms of action. J Clin Psychiatry.
2005;66(Suppl 5):40–8.
52. Sharpley AL, Vassallo CM, Cowen PJ. Olanzapine increases
slow-wave sleep: evidence for blockade of central 5-HT2C
receptors in vivo. Biol Psychiatry. 2000;47(5):468–70.
53. Lorenz RA, Jackson CW, Saitz M. Adjunctive use of atypical
antipsychotics for treatment-resistant generalized anxiety disor-
der. Pharmacother J Human Pharmacol Drug Ther. 2010;30(9):
942–51.
54. Buoli M, Caldiroli A, Caletti E, Paoli RA, Altamura AC. New
approaches to the pharmacological management of generalized
anxiety disorder. Expert Opin Pharmacother. 2013;14(2):175–84.
55. Hoge EA, Worthington JJ, Kaufman RE, Delong HR, Pollack
MH, Simon NM. Aripiprazole as augmentation treatment of
refractory generalized anxiety disorder and panic disorder. CNS
Spectr. 2008;13:522–7.
56. Worthington III JJ, Kinrys G, Wygant LE, Pollack MH. Aripip-
razole as an augmentor of selective serotonin reuptake inhibitors
in depression and anxiety disorder patients. Int Clin Psycho-
pharmacol. 2005;20(1):9–11.
57. Bartzokis G, Lu PH, Turner J, Mintz J, Saunders CS. Adjunctive
risperidone in the treatment of chronic combat-related posttrau-
matic stress disorder. Biol Psychiatry. 2005;57(5):474–9.
58. Conley RR, Mahmoud R. A randomized double-blind study of
risperidone and olanzapine in the treatment of schizophrenia or
schizoaffective disorder. Am J Psychiatry. 2001;158(5):765–74.
59. Zuddas A, Zanni R, Usala T. Second generation antipsychotics
(SGAs) for non-psychotic disorders in children and adolescents: a
review of the randomized controlled studies. Eur Neuropsycho-
pharmacol. 2011;21(8):600–20.
60. Nagaraj R, Singhi P, Malhi P. Risperidone in children with aut-
ism: randomized, placebo-controlled, double-blind study. J Child
Neurol. 2006;21(6):450–5.
61. Simon NM, Hoge EA, Fischmann D, Worthington JJ, Christian
KM, Kinrys G, Pollack MH. An open-label trial of risperidone
augmentation for refractory anxiety disorders. J Clin Psychiatry.
2006;67(3):381–5.
62. 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(10):1321–13235.
63. Pandina GJ, Canuso CM, Turkoz I, Kujawa M, Mahmoud RA.
Adjunctive risperidone in the treatment of generalized anxiety
disorder: a double-blind, prospective, placebo-controlled, ran-
domized trial. Psychopharmacol Bull. 2007;40(3):41–57.
64. Zhang W, Bymaster FP. The in vivo effects of olanzapine and
other antipsychotic agents on receptor occupancy and antagonism
of dopamine D1, D2, D3, 5HT2A and muscarinic receptors.
Psychopharmacology. 1999;141(3):267–78.
65. Stein MB, Kline NA, Matloff JL. Adjunctive olanzapine for
SSRI-resistant combat-related PTSD: a double-blind, placebo-
controlled study. Am J Psychiatry. 2002;159(10):1777–9.
532 R. Hershenberg et al.

15. 66. Barnett SD, Kramer ML, Casat CD, Connor KM, Davidson JR.
Efficacy of olanzapine in social anxiety disorder: a pilot study.
J Psychopharmacol. 2002;16(4):365–8.
67. Pollack MH, Simon NM, Zalta AK, Worthington JJ, Hoge EA,
Mick E, Kinrys G, Oppenheimer J. Olanzapine augmentation of
fluoxetine for refractory generalized anxiety disorder: a placebo
controlled study. Biol Psychiatry. 2006;59(3):211–5.
68. Stip E, Tourjman V. Aripiprazole in schizophrenia and schizo-
affective disorder: a review. Clin Ther. 2010;32:S3–20.
69. Nelson JC, Pikalov A, Berman RM. Augmentation treatment in
major depressive disorder: focus on aripiprazole. Neuropsychiatr
Dis Treat. 2008;4(5):937–48.
70. Marcus RN, Owen R, Kamen L, Manos G, McQuade RD, Carson
WH, Aman MG. A placebo-controlled, fixed-dose study of ari-
piprazole in children and adolescents with irritability associated
with autistic disorder. J Am Acad Child Adolesc Psychiatry.
2009;48:1110–9.
71. Menza MA, Dobkin RD, Marin H. An open-label trial of ari-
piprazole augmentation for treatment-resistant generalized anxi-
ety disorder. J Clin Psychopharmacol. 2007;27(2):207–10.
72. Taylor DM, McAskill R. Atypical antipsychotics and weight
gain: a systematic review. Acta Psychiatr Scand. 2000;101(6):
416–32.
73. Greenberg WM, Citrome L. Ziprasidone for schizophrenia and
bipolar disorder: a review of the clinical trials. CNS Drug Rev.
2007;13(2):137–77.
74. Potkin SG, Keck PE Jr, Segal S, Ice K, English P. Ziprasidone in
acute bipolar mania: a 21-day randomized, double-blind, pla-
cebo-controlled replication trial. J Clin Psychopharmacol.
2005;25:301–10.
75. Snyderman SH, Rynn MA, Rickels K. Open-label pilot study of
ziprasidone for refractory generalized anxiety disorder. J Clin
Psychopharmacol. 2005;25(5):497–9.
76. Lohoff FW, Etemad B, Mandos LA, Gallop R, Rickels K. Zipr-
asidone treatment of refractory generalized anxiety disorder: a
placebo-controlled, double-blind study. J Clin Psychopharmacol.
2010;30(2):185–9.
77. Calabrese JR, Keck PE, Macfadden W, Minkwitz M, Ketter TA,
Weisler RH, Cutler AJ, McCoy R, Wilson E, Mullen J. A ran-
domized, double-blind, placebo-controlled trial of quetiapine in
the treatment of bipolar I or II depression. Am J Psychiatry.
2005;162:1351–60.
78. Srisurapanont M, Maneeton B, Maneeton N. Quetiapine for
schizophrenia. Cochrane Database Syst Rev. 2004;(2):CD000967.
79. Jensen NH, Rodriguiz RM, Caron MG, Wetsel WC, Rothman
RB, Roth BL. N-desalkylquetiapine, a potent norepinephrine re-
uptake inhibitor and partial 5-HT1A agonist, as a putative
mediator of quetiapine’s antidepressant activity. Neuropsycho-
pharmacology. 2007;33(10):2303–12.
80. Goldstein J, Christoph G, Grimm S, Liu J, Widzowski D, Brecher
M. Quetiapine’s antidepressant properties: direct and indirect
pharmacologic actions on norepinephrine and serotonin receptors.
Eur Neuropsychopharmacol. 2007;17:S401.
81. Katzman MA, Vermani M, Jacobs L, Marcus M, Kong B, Lessard
S, Galarraga W, Struzik L, Gendron A. Quetiapine as an
adjunctive pharmacotherapy for the treatment of non-remitting
generalized anxiety disorder: a flexible-dose, open-label pilot
trial. J Anxiety Disord. 2008;22(8):1480–6.
82. Simon NM, Connor KM, LeBeau RT, Hoge EA, Worthington III
JJ, Zhang W, Davidson JR, Pollack MH. Quetiapine augmenta-
tion of paroxetine CR for the treatment of refractory generalized
anxiety disorder: preliminary findings. Psychopharmacology.
2008;197:675–81.
83. Gabriel A. The extended-release formulation of quetiapine
fumarate (quetiapine XR) adjunctive treatment in partially
responsive generalized anxiety disorder (GAD): an open label
naturalistic study. La Clinica Terapeutica. 2011;162(2):113.
84. Altamura AC, Serati M, Buoli M, Dell’Osso B. Augmentative
quetiapine in partial/nonresponders with generalized anxiety
disorder: a randomized, placebo-controlled study. Int Clin Psy-
chopharmacol. 2011;26(4):201–5.
85. Bandelow B, Chouinard G, Bobes J, Ahokas A, Eggens I, Liu S,
Eriksson H. Extended-release quetiapine fumarate (quetiapine
XR): a once-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.
86. Katzman MA, Brawman-Mintzer O, Reyes EB, Olausson B, Liu
S, Eriksson H. Extended release quetiapine fumarate (quetiapine
XR) monotherapy as maintenance treatment for generalized
anxiety disorder: a long-term, randomized, placebo-controlled
trial. Int Clin Psychopharmacol. 2011;26(1):11–24.
87. Khan A, Joyce M, Atkinson S, Eggens I, Baldytcheva I, Eriksson
H. A randomized, double-blind study of once-daily extended
release quetiapine fumarate (quetiapine XR) monotherapy in
patients with generalized anxiety disorder. J Clin Psychophar-
macol. 2011;31(4):418–28.
88. Merideth C, Cutler AJ, She F, Eriksson H. Efficacy and tolera-
bility of extended release quetiapine fumarate monotherapy in the
acute treatment of generalized anxiety disorder: a randomized,
placebo controlled and active-controlled study. Int Clin Psycho-
pharmacol. 2012;27(1):40–54.
89. Mezhebovsky I, Magi K, She F, Datto C, Eriksson H. Double-
blind, randomized study of extended release quetiapine fumarate
(quetiapine XR) monotherapy in older patients with generalized
anxiety disorder. Int J Geriatr Psychiatry. 2013;28(6):615–25.
90. Gao K, Kemp DE, Fein E, Wang Z, Fang Y, Ganocy SJ, Cala-
brese JR. Number needed to treat to harm for discontinuation due
to adverse events in the treatment of bipolar depression, major
depressive disorder, and generalized anxiety disorder with atyp-
ical antipsychotics. J Clin Psychiatry. 2011;72(8):1063–71.
91. Maher AR, Maglione M, Bagley S, Suttorp M, Hu JH, Ewing B,
Wang Z, Timmer M, Sultzer D, Shekelle PG. Efficacy and
comparative effectiveness of atypical antipsychotic medications
for off-label uses in adults. JAMA. 2011;206(12):1359–69.
92. Tschoner A, Engl J, Laimer M, Kaser S, Rettenbacher M, Fle-
ischhacker WW, Patsch JR, Ebenbichler CF. Metabolic side
effects of antipsychotic medication. Int J Clin Pract. 2007;
61(8):1356–70.
93. Teff KL, Rickels MR, Grudziak J, Fuller C, Nguyen HL, Rickels
K. Antipsychotic-induced insulin resistance and postprandial
hormonal dysregulation independent of weight gain or psychiatric
disease. Diabetes. 2013;62:3232–40.
94. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical
antipsychotic drugs and the risk of sudden cardiac death. N Engl J
Med. 2009;360(3):225–35.
95. DeRubeis RJ, Hollon SD, Amsterdam JD, Shelton RC, Young
PR, Salomon RM, O’Reardon JP, Lovett ML, Gladis MM, Brown
LL. Cognitive therapy vs medications in the treatment of mod-
erate to severe depression. Arch Gen Psychiatry. 2005;62(4):
409–16.
96. Dimidjian S, Hollon SD, Dobson KS, Schmaling KB, Kohlenberg
RJ, Addis ME, Gallop R, McGlinchey JB, Markley DK, Gollan
JK. Randomized trial of behavioral activation, cognitive therapy,
and antidepressant medication in the acute treatment of adults
with major depression. J Consult Clin Psychol. 2006;74(4):658.
97. Otto MW, Smits JAJ, Reese HE. Combined psychotherapy and
pharmacotherapy for mood and anxiety disorders in adults:
review and analysis. Clin Psychol Sci Pract. 2005;12(1):72–86.
Atypical Antipsychotics and GAD 533