Review

New approaches to the

pharmacological management of
generalized anxiety disorder
1. Introduction
Massimiliano Buoli†, Alice Caldiroli, Elisabetta Caletti,
2. Methods
Riccardo Augusto Paoli & Alfredo Carlo Altamura
3. Pharmacodynamic models for University of Milan, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico,
innovative pharmacological Department of Psychiatry, Milan, Italy
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Notre Dame Australia on 05/21/13

approaches
4. New pharmacological options Introduction: Selective serotonin reuptake inhibitors (SSRIs) and serotonine
and evidence-based data reuptake Inhibitors (SNRIs) together with pregabalin are actually considered
by international guidelines as the first-line choice for generalized anxiety dis-
5. Conclusions
order (GAD) treatment. However, 50% of GAD patients have poor response to
6. Expert opinion first-line treatments and different molecules, such as atypical antipsychotics and
mood stabilizers, have been used for treating this condition. Purpose of the
present article is to provide an overview of the most recent pharmacological
approaches for the treatment of GAD and the rationale for their use.
Areas covered: A research in the main database sources has been conducted
to obtain an overview of the new pharmacological approaches in GAD
(anticonvulsants, atypical antipsychotics, agomelatine, memantine, ondansetron
and riluzole).
For personal use only.

Expert opinion: Among unlabelled molecules, quetiapine seems to have the

most robust evidence of efficacy in GAD. Valproic acid and agomelatine
appear to be effective in GAD patients, but the data are preliminary and
need to be confirmed by future studies. Quetiapine is a promising molecule
for GAD treatment but its use would be complicated by long-term metabolic
side effects. Future research will have the objective to find more targeted
molecules for the treatment of this disorder in light of its specific etiology.

Keywords: antipsychotics, atypical, generalized anxiety disorder, pharmacotherapy,

unmet needs

Expert Opin. Pharmacother. (2013) 14(2):175-184

1. Introduction

Generalized anxiety disorder (GAD) is a condition with a 12-month prevalence of

2% in European population [1]. If not promptly treated, GAD tends to become
chronic with high disability and financial burden [2]. Till date, available data do
not seem to be reassuring; GAD patients, in fact, commonly have a delayed diagno-
sis and treatment associated with poor treatment response and outcome [3,4]. Fur-
thermore, the outcome of GAD is often complicated by the comorbidity with
other psychiatric conditions [2], such as major depressive disorder (MDD), panic
disorder and alcohol/substance abuse [5]. Of note, depressive symptoms usually
appear after GAD onset, so that early diagnosis and prescription of an adequate
treatment could prevent comorbidity and ameliorate the outcome of GAD
patients [6]. In this sense, primary prevention (identification of subjects at high
risk) and secondary prevention (early recognition) strategies can reduce the duration
of untreated illness and consequently improve the course of GAD [7]. Of note, a
family history of GAD, behavioral inhibition, childhood separation, parental over-
protection and dysfunctional family functioning were all found as risk factors for
developing GAD [8].

10.1517/14656566.2013.759559 © 2013 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 175
All rights reserved: reproduction in whole or in part not permitted
 M. Buoli et al.
Article highlights.
. About 50% of GAD patients do not achieve full
response to first-line treatments.
. The effectiveness of combined treatments (e.g., SSRIs/
SNRIs plus atypical antipsychotic) is controversial.
. Quetiapine appears to be the unlabelled molecule with
the most robust evidence of efficacy in GAD patients
but it is associated with metabolic side effects in
long-term treatment.
. Agomelatine and valproic acid could be valid alternatives
to first-line agents and quetiapine but further studies are
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needed for definitive conclusions.
. Future researches have the objective of finding more
targeted molecules for GAD in light of its specific
etiology ‘specific treatments for specific diagnoses’.
This box summarizes key points contained in the article.
Pharmacological treatment has the objective not only to
reduce acute symptoms but also to prevent relapses in the
long term [9,10]. An ideal pharmacological treatment should
therefore have fast efficacy and good tolerability. Till date,
international guidelines for GAD treatment recommend
selective serotonin reuptake inhibitors (SSRIs), serotonin
For personal use only.
and noradrenaline reuptake inhibitors (SNRIs) and pregaba-
lin as first-line options [10,11]. These therapies are safe and
efficacious, but present a long latency of action (with the
exception of pregabalin) and they are frequently associated
with troublesome side effects, such as nausea and sexual dys-
function for SSRIs and SNRIs [12] and dizziness and sedation
for pregabalin [13]. In addition, about 50% of GAD patients
do not respond to first-line treatment for different reasons
including the involvement of different neurotransmitters in
the pathophysiology of the disorder or scarce compliance [14].
The rates of remission are even more discouraging: low
remission rates were reported for venlafaxine (37%) [15] and
paroxetine (36%) [16].
These unmet needs have stimulated the introduction of
new pharmacological approaches for the treatment of GAD,
as for example mood stabilizers and atypical antipsychotics
in monotherapy or in augmentation to standard treatment
with SSRIs/SNRIs [17,18].
Aim of the article is a critical overview of the most innova-
tive pharmacological approaches for the treatment of GAD
patients and the rationale for their use.
2. Methods
A careful search of articles on MEDLINE, PsycINFO, Isi
Web of Knowledge and Medscape was performed in order
to obtain a comprehensive review of the new pharmacological
approaches for GAD treatment. In particular, the word
‘generalized anxiety disorder’ has been associated with
‘neurobiology’, ‘pharmacological treatment’, ‘atypical antipsy-
chotics’, ‘anticonvulsants’ and ‘beta-blockers’. No restriction
176 Expert Opin. Pharmacother. (2013) 14(2)
criteria were established in relation to study design so that the
present review includes researches with different methodologies
(e.g., open-label or controlled studies). On the contrary,
studies with GAD patients and comorbid mood conditions
(e.g., MDD or bipolar disorder) were excluded.
3.Pharmacodynamic models for innovative
pharmacological approaches
Till date, the most accepted pathophysiological model
of GAD asserts that acute symptoms would be the result of
neurotransmitter dysregulation and the negative effects of
illness in the long-term would be mediated by brain changes
and endocrine-immune abnormalities [19]. Pharmacological
treatment, through neurotransmitter-rebalance, would favor
a higher transcription of neurotrophic factors (e.g., brain-derived
neurotrophic factor) and would improve immune profiling of
GAD patients [20].
3.1 Neurotransmitters involved in GAD
Neurotransmitters primarily involved in ‘over-worrying’ and tar-
geting pharmacological intervention are gamma-aminobutyric
acid (GABA), serotonin and noradrenalin [21]. The GABAergic
dysfunction is actually thought to be responsible for anxious
symptoms in GAD patients [22]. Of note, GABAergic receptors
type A are channels which regulate chlorine entrance in nervous
cells: when an agonist activates the receptors, it induces cell
membrane hyperpolarization with subsequent inhibition of
nervous impulse transmission [23]. Benzodiazepines and other
experimental molecules bind to a site into the GABAA receptor
complex, and they carry out their inhibitory function both at a
presynaptic level, through the decrease of intracellular calcium
concentration and subsequent decrease of neurotransmitter
release, and at a postsynaptic level, with cell membrane
hyperpolarization and subsequent increase of the excitability
threshold of nerve cells [24]. From an anatomic point of view,
the potentiation of GABA firing exerts its anxiolytic effects
due to the inhibition of monoamine turnover in limbic areas,
stimulated by stressful situations and projections to locus
coeruleus noradrenergic neurons and raphe nuclei serotonergic
neurons, involved in hypervigilance situations [25]. In addition,
in GAD patients, a downregulation of benzodiazepine receptors
was found with consequent dysfunction of GABAergic recep-
tors [26]. Anxiolytic GABAergic drugs have two mechanisms of
action: they potentiate the opening of GABAergic receptor
channels (benzodiazepines and barbituric acids) or they are
GABA reuptake inhibitors (e.g., gabapentin).
Serotonin neurons of raphe nuclei, which project to several
cerebral areas including limbic system and hypothalamus, are
involved in modulation of stress response [27]. Serotonergic
receptors (5-HT), involved in anxiety are represented by the
presynaptic 5-HT1 located on terminals as well as on soma/
dentrites and by the post-synaptic 5-HT1A/5-HT2 [28]. Specif-
ically, 5-HT2C is thought to mediate both anxiety
and anxiolytic responses. In light of a hyperactivation of
 New approaches to the pharmacological management of GAD
serotonin system, reported in GAD patients, molecules that
are expected to be efficacious on anxious symptoms include
agonists of 5-HT1 autoreceptors, with consequent decrease
of synaptic serotonin release, or 5-HT2 receptors antagonists
as for example atypical antipsychotics [29]. SSRIs lead to
chronic serotonin synaptic increase and to desensibilization
of 5-HT2 receptors [30] and their mechanism of action
explains the delayed onset of action (3 -- 4 weeks) and
the worsening of anxious symptoms at the beginning of
treatment, known as ‘jittering syndrome’ [31].
Noradrenergic system, through the noradrenergic projections
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to sensory neurons of spinal cord, plays an important role in
the etiology of somatic and painful anxious symptoms [32]. It is
also involved in the development of psychic anxiety through
central a1 and b1 postsynaptic receptors and a2 presynaptic
autoreceptors [33]. Furthermore, noradrenergic and serotonergic
systems are closely connected, as a1 receptor agonism on
serotonergic neurons increases synaptic serotonin release [32].
As anxiety disorders are caused by noradrenergic system hyperac-
tivation, possible pharmacological treatments consist of a2
receptors agonists with inhibition of synaptic noradrenaline
release (clonidine) or noradrenaline reuptake inhibitors (norque-
tiapine, SNRIs) [12,33] which would desensitize postsynaptic
receptors through chronic synaptic noradrenaline increase.
For personal use only.
Finally, recent biological data show that an excessive action
of the excitatory glutamate neurotransmitter, resulting in an
imbalance between inhibitory (e.g., GABA) and excitatory
systems, could contribute to the pathophysiology of GAD [34].
3.2 Physiopathology of GAD
The imbalance of neurotransmitters in GAD patients is
responsible for amygdala hyperactivation resulting in
psychic and somatic anxious symptoms [35]. This area receives
projections from frontal and prefrontal cortex, activated by
serotonergic projections of raphe nuclei and noradrenergic
projections of locus coeruleus [36]. Amygdala hyperactivation
would lead to typical GAD symptoms through projections to:
. orbitofrontal cortex (apprehension and emotional lability);
. hippocampus (cognitive symptoms);
. lateral hypothalamus -- sympathetic system (tremor and
tachycardia);
. hypothalamic paraventricular nucleus (hypercortisolemia);
. parabrachial nucleus (dyspnea);
. caudal pontine reticular nucleus (increased arousal) [37].
Prefrontal cortex seems to be involved in the reduction of
fear associated with the repetition of harmless stimuli. In
GAD patients, this structure seems to be always activated
with overstimulation of amygdala neurons and onset of
anxious symptoms [38].
Studies with magnetic resonance confirmed the enlarge-
ment of amygdala, dorsomedial prefrontal cortex and orbital
cortex in comparison with healthy controls [39,40], and more
pronounced alterations of white matter in right hemispheric
Expert Opin. Pharmacother. (2013) 14(2)
regions [41], mainly involved in mentalization and emotion
control [42]. However, these preliminary data have to be
confirmed by future research.
Some studies found immunity system dysregulation in
GAD patients. A lower expression of interleukin-2 receptors
with higher risk of contracting respiratory tract infections
has been observed in patients with respect to controls [43].
Finally, one study showed that immune alterations are
not the result of an unspecific stress stimulus but are the
consequence of a long duration of illness [44].
In light of these considerations, GAD treatment is not
limited to the remission of acute symptoms but it also helps
in the prevention of relapses with the objective to avoid
possible cerebral and immunological alterations, associated
with a long duration of illness (e.g., several years) [45].
4.New pharmacological options and
evidence-based data
According to current guidelines, SSRIs, SNRIs and pregabalin
are considered as first-line drugs for GAD treatment [10]. As men-
tioned above, SSRIs and SNRIs are well tolerated and effective
compounds, but they show the disadvantage of having a long
latency of action and even worsening of anxious symptoms in
the first days of treatment as a consequence of the increase of
serotonin synaptic concentration. Furthermore, SNRIs less
than SSRIs are associated with troublesome side effects, such as
sexual dysfunction [12]. Finally, about 50% of GAD patients do
not obtain full response after standard treatment, so that in the
past few years different pharmacological approaches have been
used in clinical practice, in monotherapy or augmentation [46].
4.1 Anticonvulsant drugs
As mentioned above, anticonvulsant drugs are administered to
GAD patients for their action on cell membrane channels:
they cause hyperpolarization by blocking the nerve impulse
transmission and decrease the calcium presynaptic concentra-
tions by reducing the monoamine release [47].
Pregabalin is a structural derivative of the GABA that binds
to the a2-subunit of the voltage-dependent calcium channels,
decreasing the presynaptic calcium currents and consequently
the release of excitatory neurotransmitters [48]. Its latency of
action is about 1 week [48]. A number of data have shown
the effectiveness of pregabalin in GAD treatment, both in
the acute phase and in the long-term treatment: this is the
only molecule with a specific recommendation for this disor-
der [49]. In contrast, one of the disadvantages of this molecule
is the increasing evidence of a potential abuse and of an asso-
ciated withdrawal syndrome [50]. The most common symp-
toms of discontinuation syndrome include sweating, unrest,
arterial hypertension, tremor and craving [51].
The effectiveness of pregabalin on GAD symptoms opened
the testing of other anticonvulsants.
Although gabapentin has similar action and is widely used
off-label in GAD treatment, evidences of its efficacy are
177
 M. Buoli et al.
surprisingly missing in literature. The only study consists of
two GAD treatment-resistant cases, which were effectively
treated with gabapentin [52].
Treatment with tiagabine, a GABA reuptake inhibitor, has
shown contrasting results about its effectiveness on GAD
symptoms. In one study, tiagabine (4 -- 16 mg/day) showed
the same efficacy of paroxetine (20 -- 60 mg/day) in improv-
ing acute GAD symptoms [53]. In contrast, in another study
tiagabine was superior in terms of efficacy with respect to
placebo only in patients who had been taking flexible doses
of the molecule for 10 weeks [54]. Furthermore, patients
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with anxious symptoms, resistant to SSRIs and benzodiaze-
pines, have shown improvement after augmentation with
tiagabine (mean dose 13 mg/day) [55].
Specific studies about the efficacy of lamotrigine in GAD
patients are lacking. In literature, cases of effectiveness are
reported in patients with unspecific anxious symptoms and
medical comorbidity [56].
Finally, a double-blind study with a sample of 80 GAD
patients has shown that valproic acid (1,500 mg/day) is
effective in the acute phase [57].
4.2 Atypical antipsychotics
Atypical antipsychotics have a large spectrum of action, involv-
For personal use only.
ing neurotransmitters (e.g., serotonin or noradrenalin) which
are implicated in the pathophysiology of GAD, so that these
molecules are expected to be more efficacious on GAD
symptoms with respect to first-generation antipsychotics that
act predominantly on dopaminergic system.
In particular, atypical antipsychotics are:
. partial 5-HT1A receptors agonists: aripiprazole, asenapine;
. 5-HT2C receptor antagonists: olanzapine, ziprasidone,
asenapine;
. a2 receptors antagonists: quetiapine, asenapine;
. SNRIs: quetiapine (through its metabolite norquetia-
pine) and ziprasidone;
. antihistamines: risperidone, olanzapine, quetiapine [58].
Two double-blind randomized trials documented risperi-
done efficacy (0.5 -- 3 mg/day) in augmentation to antidepres-
sants or benzodiazepines in GAD patients with poor response
to first-line treatments [59,60].
In a double-blind study olanzapine (mean dose 8.7 mg/day)
in augmentation to fluoxetine showed efficacy in patients who
had not responded to a first antidepressant treatment [61].
Quetiapine was used in monotherapy or in augmentative
strategies for GAD treatment with positive results but there
was no consensus about the effective doses. A double-blind,
multicentric study with GAD patients compared the efficacy
of quetiapine extended-release (XR) at the doses of 50 and
150 mg/day with respect to paroxetine (20 mg/day) and
placebo. All doses of active agents showed superiority with
respect to placebo in improving global GAD symptoms;
however, significant separation from placebo in remission rates
178 Expert Opin. Pharmacother. (2013) 14(2)
and somatic anxiety improvement was observed only in patients
treated with paroxetine or quetiapine at 150 mg/day [62].
In contrast, a more recent study with 951 GAD patients showed
that low quetiapine XR doses (50 and 150 mg/day) were more
effective in comparison with a dose of 300 mg/day in improving
anxious symptoms and somatic correlates [63]. A further
escitalopram-controlled study confirmed these results with a
statistical significant improvement with respect to placebo at
fourth day of quetiapine treatment [64]. Efficacy of low quetia-
pine doses (50 mg/day) was also confirmed in an augmentation
study with GAD patients who were partial responders or total
non-responders to first-line SSRIs [65]. This finding was
replicated in a more recent study [66]. In contrast, an open-
label study found that quetiapine was effective only at higher
mean dosage (386 mg/day) [67], while another report demon-
strated that quetiapine (25 -- 400 mg/day) in augmentation to
a first treatment with paroxetine was not more effective com-
pared to placebo [68]. Finally, a recent study demonstrated that
quetiapine XR (50 -- 300 mg/day) is effective both during the
acute phase and in the long-term treatment [69]. Similar to pre-
gabalin, but with less evidence, the risk of quetiapine abuse and
withdrawal syndrome have been described in case reports [70].
The most common withdrawal symptoms include nausea,
dizziness, headache and anxiety [71].
A preliminary study with nine treatment-resistant GAD
patients demonstrated that augmentative aripiprazole to
antidepressant treatment is effective for at least 50% of treated
patients, with a reduction ‡ 50% of anxiety psychometric
scores [72]. Another search confirmed the efficacy of low-dose
aripiprazole augmentation (10 mg/day), but the sample
included patients with panic disorder [73].
An open-label study with 13 refractory GAD patients showed
that augmentative ziprasidone (20 -- 80 mg/day) is associated to
a rate of response equal to 54% [74]. This finding was not
replicated in a following double-blind, placebo-controlled
study with 62 refractory GAD patients [75].
4.3 Other drugs
Other molecules with a favorable pharmacodynamic profile
for GAD treatment are actually the object of the study.
Agomelatine, blocking 5-HT2C receptors, is a promising
antidepressant for GAD treatment. A double-blind study showed
the efficacy of agomelatine (25 -- 50 mg/day) compared to
placebo in the acute treatment of GAD with an improvement
of patients’ disability. The active treatment group showed
statistical significant improvement at week 6 [76]. A very recent
6-month follow-up paper demonstrated the efficacy and
tolerability of agomelatine in the long-term GAD treatment [77].
The Alzheimer’s disease medication, memantine, blocks
the excitatory action of glutamate at the N-methyl-D aspar-
tate receptor, which is thought to be activated under patho-
logical conditions such as GAD. In an open-label trial, seven
GAD patients showed a mean 22.4% reduction on Hamilton
Anxiety Rating Scale (HAM-A) scores after a 12-week
memantine treatment (20 mg/day) [78].
 New approaches to the pharmacological management of GAD

Table 1. Summary of evidence-based data of new pharmacological GAD treatments.

Drugs Positive studies % % Negative % %

Response Remission studies Response Remission

Tiagabine Rosenthal 2003 [53] (n = 40) Not reported Not reported None
Schwartz et al. 2005 [55], 76 59
add-on trial (n = 17)
Pollack et al. 2008 [54] (n = 1820) 40.5 20.0
Valproic acid Aliyev et al. 2008 [57] (n = 80) 72.2 Not reported None
Risperidone Brawman-Mintzer et al. 2005 [59], 58.0 35.0 None
add-on trial (n = 40)
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Pandina et al. 2007 [60], 42.0 20.2

add-on trial (n = 417)
Olanzapine Pollack et al. 2006 [61], fluoxetine 56.0 44.0 None
augmentation (n = 24)
Quetiapine Bandelow et al. 2010 [62] (n = 873) Not reported Not reported Simon et al., 54.0 36.4
Katzman et al. 2011 [69] (n = 432), Rate of relapses (quetiapine 2008
long-term study 10.2%; placebo 38.9%)
Khan et al. 2011 [63] (n = 951) 58.9 Not reported
Merideth et al. 2012 [64] (n = 854) 62.7 37.3
(150 mg/day) (150 mg/day)
Katzman et al. 2008 [67], Not reported 72.1
add-on trial (n = 40)
Altamura et al. 2011 [45], 60.0 40.0
add-on trial (n = 40)
Gabriel 2011 [66], add-on trial Not reported Not reported
Aripiprazole Menza et al. 2007 [72] (n = 9) Not reported 23.0 None
Ziprasidone Snyderman et al. 2005 [74] (n = 13) 54.0 38.0 Lohoff et al., Not Not
For personal use only.

2010 reported reported

(n = 62)
Memantine Feusner et al. 2009 [78] (n = 7) 0.0 0.0 None
Agomelatine Stein et al. 2008 [76] (n = 121) 66.7 41.3 None
Stein et al. 2012 [77] (n = 227), rate of relapses (agomelatine
long-term study 19.5%; placebo 30.7%)
Ondansetron Freeman et al. 1997 [83] (n = 54) Not reported Not reported None
Riluzole Mathew et al. 2005 [84] (n = 18) 80 53.3 None
Mathew et al. 2008 [85] (n = 14) Not reported 64.3

Beta blockers improve psychic anxiety by regulating central
noradrenergic system and they ameliorate somatic anxiety (e.
g., tachycardia) due to their action on peripheral receptors.
In a naturalistic study with a sample of patients affected by
anxiety disorders (most of them with GAD), the treatment
with the long half-life beta blocker betaxolol (5 -- 10 mg/die)
was found to be associated with rapid improvement of anxiety
symptoms [79]. In addition, preliminary data also showed the
effectiveness of propranolol and atenolol, even though the
latter was associated with important side effects such as
hypotension [80]. Studies with large samples of GAD are
needed to confirm these findings.
A preliminary double-blind study demonstrated that cloni-
dine, a hypertensive drug, is effective in GAD patients even
though this agent is not well tolerated for the troublesome
side effects (hypotension, dizziness and sleepiness) [81]. Actu-
ally the molecule is essentially used in experimental neuroim-
aging trials as marker of a2 receptors hypo-functioning in
GAD patients [82].
Ondansetron is a 5-HT3 receptors antagonist that is
supposed to be effective on gastric somatic symptoms of
GAD. A double-blind study demonstrated that ondansetron
(1 mg/day) was more effective than placebo in reducing anxious
symptoms [83]. However, this finding has not yet been replicated.
Riluzole is a presynaptic inhibitor of glutamate, an excit-
atory neurotransmitter and GABA antagonist; it is actually
used for the treatment of amyotrophic lateral sclerosis. Two
open-label studies demonstrated the efficacy of this molecule
at doses of 100 mg/day in GAD patients [84,85]. Of note, a
study found that riluzole treatment is associated with
hippocampal N-acetylaspartate increase (marker of neuronal
wellness) (Table 1) [85].
4.4 Other biological approaches
Neuromodulation techniques and other biological treatments,
such as sleep deprivation, have been successfully prescribed
for mood disorders, but in the case of GAD the data are
controversial and preliminary.
Transcranic magnetic stimulation (TMS) allows a noninva-
sive electrical stimulation of the cerebral cortex by means of
magnetic fields generated by a handheld coil, and a number
of data indicates its efficacy for MDD treatment [86]. An

Expert Opin. Pharmacother. (2013) 14(2) 179

 M. Buoli et al.
open-label study assessed the effectiveness of repetitive TMS
in the treatment of GAD patients: six of ten participants
showed remission of symptoms after six sessions over the
course of 3 weeks [87].
A study found an improvement on HAM-A scores in GAD
patients who had undergone one night of sleep deprivation [88].
These results have not been replicated yet.
5. Conclusions
GAD treatment has showed more changes in the last years
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than the pharmacotherapy of other psychiatric disorders,
such as major depression. Of note, in the last 20 years,
pharmacological treatment of GAD has changed from an
acute symptomatic approach with benzodiazepines to the
use of molecules acting on biological changes associated
with the disorder. Progresses in the pharmacological field
and in neuroscience have contributed to this change.Of
note, neuroimaging studies have demonstrated a role of lim-
bic dysregulation in the pathogenesis of the disorder [89]. In
this sense a very recent study confirmed these data, demon-
strating a reduced frontolimbic structural connectivity in
patients affected by GAD [90].
Actually first-line treatments (SSRIs and SNRIs) can prob-
For personal use only.
ably reverse the biological correlates of GAD, but they have a
delayed effect and are associated with side effects which reduce
patients’ compliance [12]. In addition, clinical response and
remission of GAD symptoms is not always achieved by
patients that consequently present a high risk of chronicity
and low quality of life. Clinical research has tried to satisfy
these ‘unmet needs’ by assessing the effectiveness and tolera-
bility of other psychopharmacological classes: most of the
studies consider the use of atypical antipsychotics, but, with
the exception of quetiapine, the small sample sizes prevent
definitive conclusions about the effectiveness of these agents
in GAD patients. Among unlabelled molecules, quetiapine
(followed by risperidone) have the most robust evidence for
the treatment of this disorder probably for its ‘anxiolytic’
pharmacodynamic profile. Despite the efficacy of quetiapine
in GAD patients, some authors do not recommend this mol-
ecule for GAD treatment (at least not as first-line option) in
light of long-term metabolic side effects, associated with an
increased mortality with respect to general population [91].
If rates of response/remission are taken into account, que-
tiapine is again the most favorable molecule showing response
in 58.9 -- 62.7% and remission up to 72.1% of GAD patients.
These rates of response/remission are moderately higher with
respect to those reported for first-line agents. Treatments with
agomelatine/valproic acid are associated with higher rates of
response/remission than SSRIs/SNRIs, but further studies
are necessary for definitive conclusions.
Taken as a whole, the presented data indicate that GAD has
been traditionally treated with antidepressants in light of a
clinical/biological overlapping with MDD. However the
most recent biological evidences indicate GAD as a condition
180 Expert Opin. Pharmacother. (2013) 14(2)
with a specific etiology and requiring more targeted
pharmacological treatments. Future research will have the
objective to find molecules that can not only treat the
‘unspecific’ anxiety symptoms but also correct the biological
changes associated with the pathophysiology of the disorder.
Finally some limits of the present paper have to be shortly
mentioned. First most of the cited studies include samples
of patients attending psychiatric services and not always
representing the ‘real psychiatric world’. Second some of the
presented studies include mixed samples with patients having
diagnosis other than GAD.
6. Expert opinion
In the past, anxiety symptoms were considered as
‘transnosographic’ and unspecific and consequently they
were treated with generic agents, such as benzodiazepines,
which ameliorate acute symptoms but have negative effects
in the long term (risk of dependence, re-exacerbation of
symptoms, cognitive impairment, chronicity). Afterward, a
clinical/biological overlap between anxiety and mood symp-
toms was found so that antidepressant treatment was extended
to GAD. SSRIs and SNRIs improved outcome of GAD
patients especially in the long term treatment, but they were
unsatisfactory for 50% of the patients. These molecules, in
fact, can even worsen the anxiety symptoms in the first days
of treatment with obvious implications for patients’ compli-
ance. In addition 50% of patients experience residual
symptoms after a SSRI/SNRI trial.
Despite the scarce compliance of some GAD patients, the
lack of targeted treatments for a disorder with a specific
etiology can be thought as a possible cause for frequent poor
response to first-line agents. Of note, pregabalin is actually
the only agent to have a specific labeling for GAD. In the
past years clinical researches have differentiated anxiety symp-
toms associated with mood disorders with respect to GAD
over-worrying that result in less responsiveness to antidepres-
sant agents. At the same time, biological research identified
specific abnormalities of GAD that will be potential
target of pharmacological treatment (e.g., immunological
alterations) in the future.
In case of poor response to first-line agents, the clinicians
can switch to a different monotherapy or select augmentative
strategies. Recently, adjunctive therapy with pregabalin has
been evaluated in a randomized placebo-controlled study,
but the rate of response was again discouraging (47.5 vs
35.2% in the placebo group) [92]. In addition, an increasing
number of data suggest that pregabalin treatment can be asso-
ciated with potential abuse and discontinuation syndrome.
On the other hand, the available data of atypical antipsychotic
augmentation to first-line treatments (with the exception of
quetiapine) are contradictory and preliminary: the studies
present small sample sizes and they report the same rates of
response and remission as first-line monotherapies. The evi-
dence would not support the use of combined treatments in
 New approaches to the pharmacological management of GAD

poor-responder GAD patients in light of the controversial
effectiveness and the higher risk of developing side effects
(e.g., sexual dysfunction in SSRI/risperidone combination).
Quetiapine monotherapy appears as a promising molecule
for GAD treatment: its efficacy has been demonstrated by large
sample controlled studies and the rates of response/
remission appear to be more favorable in comparison with
first-line agents. The disadvantage of quetiapine prescription
is long-term metabolic side effects associated with increased
mortality with respect to general population. In this sense,
studies, assessing risk:benefit ratios, could clarify the pertinence
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Notre Dame Australia on 05/21/13
quetiapine, but the favorable data are preliminary and further
studies have to b conducted for definitive conclusions.
In light of the described ‘unmet needs’ and the problems of
current treatment options for GAD, future researches should
aim to find more targeted molecules for this disorder, to
decrease the cases of treatment resistance and to ameliorate
patients’ outcome.
Declaration of interest
M Buoli is a consultant at Roche. AC Altamura is a consultant

of quetiapine prescription in GAD patients. Valproic acid and at Merck and Astra Zeneca, and is a member of the Speakers’
agomelatine could be valid alternative to first-line molecules or Bureau for Sanofi, Lilly and Pfizer.

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Affiliation
Massimiliano Buoli† MD, Alice Caldiroli MD,
Elisabetta Caletti PsyD,
Riccardo Augusto Paoli MD &
Alfredo Carlo Altamura MD
†
Author for correspondence
University of Milan,
Fondazione IRCCS Ca’Granda Ospedale
Maggiore Policlinico,
Department of Psychiatry,
Via F. Sforza 35, 20122, Milan, Italy
Tel: +39 02 55035934;

Fax: +39 02 55033190;

correlates of GAD.
E-mail: massimiliano.buoli@hotmail.it
For personal use only.

184 Expert Opin. Pharmacother. (2013) 14(2)