REVIEW
Pharmacotherapy for Anxiety Disorders: From First-Line
Options to Treatment Resistance
Andrew J. Melaragno, M.D., M.S
In this review, the author examines the evidence for psy-
chopharmacologic treatments among adults for general-
ized anxiety disorder, panic disorder, and social anxiety
disorder derived from clinical trials. For each disorder,
major categories of drugs are reviewed, and then the
evidence-based medications in each category are dis-
cussed. The author reviews key safety and tolerability
considerations for each of the medications or classes.
Evidence-based dosing for most specific agents is dis-
played in a comprehensive reference table. Subsequently,
the author synthesizes the available information to suggest
a pragmatic stepwise approach to treatment that accounts
for patient-specific factors. To inform the guidance, the
Anxiety disorders are frequently encountered conditions
that historically have been underrecognized and under-
treated; moreover, they can be associated with consider-
able morbidity and suicide risk (1). In this review, I
examine the wide array of evidence for pharmacologic
treatments for the primary anxiety disorders, including
generalized anxiety disorder, panic disorder, and social
anxiety disorder. Subsequently, I synthesize the available
evidence to create a structured and pragmatic approach
to medication trials for these disabling disorders when
first-line treatments alone are insufficient. Table 1 sum-
marizes all the drugs discussed with recommended dos-
ing schedules.
GENERALIZED ANXIETY DISORDER
Generalized anxiety disorder is a syndrome of prominent
anxiety and worries about several components of one’s
life, accompanied by symptoms of hyperarousal that may
include disturbed sleep, irritability, muscle tension, rest-
lessness, and associated fatigue and lack of concentration.
This condition carries a high burden of morbidity via
impairment of social and occupational functioning and is
often associated with comorbid depression. It has been
estimated that more than 100 million disability days per
year can be attributed to generalized anxiety disorder.
Thus, effective treatment of these individuals is of para-
mount importance (1).
Focus Vol. 19, No. 2, Spring 2021
author incorporates and refines perspectives from treat-
ment guidelines already written by clinical professional
organizations. The author also briefly reviews the relatively
new quantitative systematic review methodology of net-
work meta-analysis (NMA) and discusses how NMA may
help guide pharmacologic treatment sequencing decisions
in the future by way of ranking treatments according to
effect size and the relative amount of study to which treat-
ments have been subject. Caveats of NMA studies are
briefly discussed, as are results of recent NMAs regarding
the pharmacologic treatment of anxiety disorders.
Focus 2021; 19:145–160; doi: 10.1176/appi.focus.20200048
Review of Specific Agents and Their Efficacy
and Tolerability in Treatment of Generalized
Anxiety Disorder
Selective serotonin reuptake inhibitors (SSRIs) and seroto-
nin-norepinephrine reuptake inhibitors (SNRIs). SSRIs and
SNRIs (referred to collectively as SRIs hereafter) are the
treatment of choice for pharmacologic management of gen-
eralized anxiety disorder. SRIs increase overall serotonergic
transmission via selective blockade of presynaptic serotonin
transporters (SERTs) that normally transport serotonin
(5-HT) back into the neuron for recycling, causing a gener-
alized increase in 5-HT neurotransmission. This process
leads to a variety of downstream changes hypothesized to
play a role in treating anxiety and depression, including
desensitization of postsynaptic 5-HT1A receptors in the
raphe nucleus of the brainstem (2); central nervous system
(CNS) anti-inflammatory effects (3); and induction of
increased neuroplasticity and subsequent neurogenesis in
key brain circuitry that is mediated by serotonin-induced,
brain-derived neurotrophic factor signaling (4). SNRIs simi-
larly inhibit the SERT and increase synaptic concentrations
of 5-HT; additionally, SNRIs increase norepinephrine (NE)
levels by interfering with the activity of the NE transporter
(NET). Of note, the SNRIs vary significantly in their binding
affinity for SERT compared with NET; these variations
range from functioning predominantly as SSRIs (venlafax-
ine, desvenlafaxine, and duloxetine at low doses) to having
a 2:1 ratio of noradrenergic to serotonergic activity
focus.psychiatryonline.org 145
PHARMACOTHERAPY FOR ANXIETY DISORDERS

TABLE 1 Clinically studied medications for anxiety disordersa

Starting dosage Target dose Anxiety disorder FDA
Medication (brand name) (mg/day) range (mg) indications Specific notes
SSRIs
Escitalopram (Lexapro) 5–10 10–30 Generalized anxiety May prolong QT interval
disorder similarly to citalopram
Sertraline (Zoloft) 25 50–200 Panic disorder, social
anxiety disorder
Citalopram (Celexa) 10 20–40 None FDA warning for QT
prolongation at doses.40
mg/day; FDA recommended
dose limit 20 mg/day in
older adults
Fluoxetine (Prozac) 10 20–80 Panic disorder Very long elimination half life;
CYP2D6 strong inhibitor
Paroxetine (Paxil) 10 20–60 Panic disorder, Anticholinergic and
generalized anxiety antihistaminergic side
disorder, social effects; strong CYP2D6
anxiety disorder inhibitor; difficult
discontinuation, taper slowly
Paroxetine CR (Paxil CR) 12.5 25–75 Panic disorder, Same as paroxetine
generalized anxiety
disorder, social
anxiety disorder
Fluvoxamine (Luvox) 25 100–300 CYP1A2 strong inhibitor;
inhibits own metabolism;
increases serum levels of
clozapine, caffeine
SNRIs
Venlafaxine XR (Effexor XR) 37.5 75–300 Panic disorder, Monitor BP for patients at
generalized anxiety doses$225mg/day; difficult
disorder, social discontinuation, taper slowly
anxiety disorder
Duloxetine (Cymbalta) 20 60–120 Generalized anxiety FDA-approved for fibromyalgia
disorder and chronic pain
Milnacipran (Savella) 25 BID 50 BID FDA-approved for fibromyalgia;
may be useful for panic
disorder
Novel serotonin-modulating antidepressants
Vilazodone (Viibryd) 10 20–40 Mechanism is SSRI15-HT1A
partial agonist (like
SSRI1buspirone)
Vortioxetine (Trintellix) 5 5–20 Improves cognitive processing
speed
TCAs
Imipramine (Tofranil) 10 100–300 Target serum levels 110–140
ng/ml
Clomipramine (Anafranil) 10 50–250 Strongest evidence for panic
disorder; consider in
comorbid refractory
obsessive-compulsive
disorder
Despiramine (Norpramin) 10 100–300 Consider in comorbid
attention-deficit hyperactivity
disorder
MAOIs
Phenelzine (Nardil) 15 60–90 divided Low-tyramine diet; wash out
BID–TID prior antidepressant 5 half
lives
Tranylcypromine (Parnate) 10 30–60 divided See above
BID
continued

146 focus.psychiatryonline.org Focus Vol. 19, No. 2, Spring 2021

 MELARAGNO

TABLE 1 continued
Starting dosage Target dose Anxiety disorder FDA
Medication (brand name) (mg/day) range (mg) indications Specific notes
Other antidepressants
Bupropion (Wellbutrin) 100 SR; 150 XL 150 SR BID; Lowers seizure threshold; no
300 XL daily sexual side effects
Mirtazapine (Remeron) 7.5–15 QHS 15–30 QHS May cause significant weight
gain
Nefazodone (Serzone) 50 BID 200–600 Rare liver toxicity, can be fatal
divided BID
Trazodone (Desyrel) 50 QHS 200–400 Metabolite MCPP can cause
divided BID agitation
Beta blockers (for performance-only
social anxiety disorder)
Propranolol (Inderal) 10 PRN 10–40 PRN Test dose before performance
situation; monitor BP, HR
Atenolol (Tenormin) 25 PRN 25 Test dose before performance
situation; monitor BP, HR
Azapirones
Buspirone (Buspar) 5 BID–TID 10–20 BID–TID Generalized anxiety No efficacy as monotherapy
disorder except in generalized anxiety
disorder
Antihistamines
Hydroxyzine (Vistaril, Atarax) 25 QHS 12.5–50 Evidence for efficacy in
BID–TID generalized anxiety disorder
at total daily dose of 50 mg
Benzodiazepines
Lorazepam (Ativan) 0.5 QD–TID 0.5–2 QD–TID Anxiety disorders Not reliant on CYP450-
mediated hepatic
metabolism
Clonazepam (Klonopin) 0.25–0.5 BID 0.5–1 BID Panic disorder No proven increased efficacy
(maximum 4 advantage but increased side
daily) effects at doses.2mg/day
Alprazolam (Xanax) 0.25 TID–QID 2–6 mg divided Anxiety disorders Prone to rebound anxiety;
TID–QID most misuse liability
Alprazolam XR 0.5–1 2–6 daily or Panic disorder Less risk of rebound anxiety;
divided BID slow onset
Diazepam (Valium) 2–5 40 divided Anxiety Accumulates active metabolites
BID–QID with very long half life
Anticonvulsants, including gabapentinoids
Gabapentin (Neurontin) 100–300 QHS 900–3,600 Best evidence for social anxiety
divided TID disorder; likely requires near-
maximal doses
Pregabalin (Lyrica) 75–150 QHS 300–600 Social anxiety disorder requires
divided BID higher doses (450–600)
Valproic acid (Depakote) 250 QHS 500–2,500 No target therapeutic serum
daily or divided level; requires periodic
BID monitoring of CBC, LFTs,
and drug levels
Second-generation antipsychotics
Quetiapine (Seroquel) 25 QHS 50–150 QHS Mostly studied in XR
formulation
Risperidone (Risperdal) 0.25 daily 0.25–1 daily Best evidence for panic
disorder
Olanzapine (Zyprexa) 2.5 QHS 5–10 QHS Very high risk of metabolic
adverse effect
Aripiprazole (Abilify) 2–2.5 daily 2–15 mg daily Less likely to cause metabolic
effects
a
BID, twice a day; BP, blood pressure; CBC, complete blood count; FDA, U.S. Food and Drug Administration; HR, heart rate; LFT, liver function test;
MAOI, monoamine oxidase inhibitor; MCPP, meta-chlorophenylpiperazine; PRN, as needed; QD, once a day; QHS, before bed; QID, four times a day;
SNRI, serotonin-norepinephrine reuptake inhibitor; SR, sustained release; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; TID,
three times a day; XL, extra long; XR, extended release.

Focus Vol. 19, No. 2, Spring 2021 focus.psychiatryonline.org 147

PHARMACOTHERAPY FOR ANXIETY DISORDERS
(levomilnacipran) (5). A subset of SRIs have U.S. Food and
Drug Administration (FDA) indications for generalized anxi-
ety disorder, including escitalopram and paroxetine among
the SSRIs and venlafaxine and duloxetine among the SNRIs.
Nevertheless, randomized controlled trial (RCT) evidence
supports the use of other medications from these classes in
generalized anxiety disorder, including sertraline and fluoxe-
tine (6).
Recommended starting doses and target therapeutic
ranges for each medication as per the FDA are notated in
Table 1. An adjustment period on the order of 2 months is
often needed to see the full clinical response; however, com-
piled data from multiple trials suggest that partial response
is common in the first 2–4 weeks and is a good prognostic
sign (7, 8). Expert consensus supports starting at lower doses
than in depression and titrating slowly. Despite lower initial
doses, ultimately patients tend to require doses at the higher
end of the therapeutic range for a significant response,
although dose-response studies have not yielded consistent
results. The forgoing recommendations also apply to other
patients with anxiety disorders, particularly patients with
panic disorder. These higher doses will subject patients to
increased risk of dose-dependent side effects, especially sex-
ual dysfunction (9) and the poorly quantified, but clinically
described, apathy syndrome (10). There is also a risk of
dose-dependent prolongation of the cardiac QT interval,
especially in citalopram (which carries a related FDA warn-
ing) and escitalopram, although the clinical significance of
this effect remains controversial (11). Thus, careful monitor-
ing of side effects is warranted; moreover, treatment goals
may favor doses that do not achieve full remission but suffi-
ciently reduce symptoms to improve quality of life and func-
tioning. In this case, concomitant psychotherapy may help
the patient approach full remission.
Buspirone. Buspirone, an azapirone class 5-HT1A receptor
partial agonist, is FDA approved for use in generalized anxi-
ety disorder and may prove useful among patients who do
not respond to or who are unable to tolerate SRIs. RCT evi-
dence also exists for its usefulness as an adjunct to first-line
treatment with antidepressants in the case of partial
response (12). Buspirone is generally a well-tolerated medi-
cation, is not habit forming, and notably is not associated
with sexual side effects. Like the SRIs, buspirone has a
delayed onset of anxiolytic effects on the order of weeks.
The pharmacokinetics of buspirone require dividing the
dose at least twice daily, which may present adherence chal-
lenges. For patients with mild to moderate generalized anxi-
ety disorder with hesitance about taking SRIs, buspirone
may be tried as a first-line agent.
Anticonvulsants. The gamma-aminobutyric acid (GABA)–
analog pregabalin (trade name Lyrica) has approval from
the European Medicines Agency for use in generalized anxi-
ety disorder; it also has FDA indications for fibromyalgia,
neuropathic pain, and epilepsy. Several trials have
148 focus.psychiatryonline.org
demonstrated good efficacy and tolerability of pregabalin for
generalized anxiety disorder (13). Until recently, cost bar-
riers have prevented widespread prescribing of pregabalin
in the United States, but the drug has become more afford-
able after the recent introduction of multiple generic ver-
sions. Although structurally related to GABA, pregabalin
does not work by modulating GABA neurotransmission.
Instead, the drug binds the alpha-2-delta subunit of voltage-
gated calcium channels in a state-dependent fashion in
hyperexcited neurons, resulting in CNS inhibition (14). On
the basis of the evidence supporting pregabalin, it has been
suggested that gabapentin, an older GABA analog with simi-
lar structure and mechanism of action, may also effectively
treat generalized anxiety disorder. However, only case report
evidence exists to suggest efficacy of gabapentin in general-
ized anxiety disorder (15). Noting its other clinical uses, pre-
gabalin occasionally may be considered as a first-line agent
among patients whose anxiety is comorbid with the other
FDA-approved indications. The most common side effects of
pregabalin are sedation and dizziness, although weight gain,
peripheral edema, and visual changes may occur. Both
pregabalin and gabapentin require dose adjustment for
renal impairment.
Benzodiazepines (BZDs). BZDs may play a role in treatment
of generalized anxiety disorder for appropriate patients who
fail to respond to or tolerate multiple trials of SRIs and bus-
pirone. They potentiate the CNS inhibitory effects of endog-
enous GABA by allosteric modulation of the GABA receptor.
For the most part, since the establishment of SRIs as first
line, most experts have recommended using BZDs in the
short term only, citing concerns about tolerance and depen-
dence and the lack of established efficacy for comorbid
depression. Chemical dependence after long-term use of
BZDs is well-established; however, the common assertion
that they lead to tolerance and dose escalation has not been
observed in studies following patients taking them for up to
2 years (16, 17). BZDs should be avoided among patients
with active substance use disorders and history of misuse of
BZDs. However, clinicians should carefully weigh the bene-
fits and risks in prescribing BZDs to patients with more
remote history of disordered use of alcohol or other sub-
stances such as cannabis or stimulants. The majority of
patients misusing BZDs tend to have disordered use of other
substances as well (18). Increased risk of death from coad-
ministration of BZDs and opioids, even at typical prescribed
doses, may occur because of synergistic respiratory depres-
sive effects (19). BZDs also have a strong relative contraindi-
cation in elderly patients owing to increased fall risk and
potential for cognitive impairment.
Among the BZDs, four are most-commonly used for anx-
iety: low-potency diazepam, mid-potency lorazepam, and
the high-potency alprazolam and clonazepam. All of these
BZDs are used in the treatment of generalized anxiety disor-
der, although only alprazolam has an FDA indication for
generalized anxiety disorder. Alprazolam remains one of the
Focus Vol. 19, No. 2, Spring 2021

most widely prescribed drugs in the United States. Neverthe-
less, the literature suggests that alprazolam has the highest
misuse liability among the BZDs because of its reinforcing
pharmacokinetic and pharmacodynamic properties as well
the way it has been shown to enhance dopamine (DA)
release in the striatum similarly to stimulants (18). Other dis-
advantages of alprazolam include very fast onset and offset of
therapeutic effect, indicating a need for 3–4 times daily dos-
ing, potential for interdose rebound anxiety, and risk of life-
threatening withdrawal in abrupt cessation (20).
Lorazepam lends itself well to use as a short-term,
as-needed agent for anxiety because of its medium potency
and moderately short clearance half life. Another unique
property of lorazepam is that its metabolism bypasses
hepatic CYP450 enzymes and only involves direct glucuro-
nidation. Thus, it can be used among patients with impaired
liver and renal function. Meanwhile, clonazepam tends to be
favored as a standing agent among patients with anxiety
because of longer duration of action and half life, typically
allowing for twice daily dosing without significant interdose
anxiety (20). Diazepam is the oldest of the aforementioned
BZDs and is less commonly used at present. It has a fast
time to onset and duration of therapeutic effect similar to
that or lorazepam or clonazepam; however, it is notable for
very slow clearance, with elimination half life of diazepam
and its active metabolites varying from 30 to 100 hours.
This trait raises concern for accumulation-related side
effects, especially fall risk among older adults. Diazepam is
relatively unique in having a rectal suppository gel formula-
tion, which has very fast onset and obviates the need for
enteral or parenteral access.
Tricyclic antidepressants (TCAs). A few TCAs have demon-
strated efficacy in generalized anxiety disorder. They work
by binding and inhibiting both the SERT and NET as well
as directly modulating specific 5-HT receptors. Unfortu-
nately, they are particularly nonselective in their receptor
affinities, leading to a broad range of adverse effects. Antag-
onist effects of TCAs at muscarinic acetylcholine receptors
can lead to prominent dry mouth, constipation, urinary
retention, blurred vision, tachycardia, and impaired cogni-
tion. Patients may have significant weight gain or sedation
because of strong histamine-1 receptor blockade by TCAs.
Alpha-1 adrenergic blockade often leads to significant ortho-
static hypotension and dizziness. Finally, the SSRI-like inhi-
bition of the SERT may lead to long-term sexual side
effects. TCAs also have a narrow therapeutic index and may
be lethal in overdose via hypotension, cardiac arrhythmias,
anticholinergic poisoning, and neurologic compromise rang-
ing from seizures to coma. Thus, TCAs should be used with
care among patients with a history of suicide attempts by
medication overdose (21, 22).
Imipramine, the prototypical TCA, has undergone multi-
ple RCTs against placebo and other established treatments
supportive of efficacy for symptoms of generalized anxiety
disorder (23, 24). Clomipramine has preliminary evidence
Focus Vol. 19, No. 2, Spring 2021
MELARAGNO
for use in generalized anxiety disorder from a small open-
label trial (25), and nortriptyline showed evidence of efficacy
in a small, merged analysis of three placebo-controlled trials
among patients with generalized anxiety disorder after a
stroke (26). Whether TCAs have equivalent or superior effi-
cacy to SRIs is an important question in the context of con-
sidering next steps for patients with conditions that are
treatment resistant. Unfortunately, head-to-head data com-
paring drugs from the two classes are limited. One such
study showed similar efficacy between imipramine and par-
oxetine, with a higher proportion of patients dropping out
in the imipramine group (27). Although evidence of superior
efficacy to SRIs is lacking, TCAs are a heterogeneous group
of antidepressants with very divergent pharmacodynamic
profiles from both each other and the SRIs. This feature
allows these medications to play niche roles in treating
other conditions besides anxiety (e.g., obsessive-compulsive
disorder for clomipramine, attention-deficit hyperactivity
disorder for desipramine, headache for amitriptyline, and
chronic pain for both amitriptyline and nortriptyline). Thus,
both by being sufficiently different from the first-line agents
and by having more potential to address comorbid condi-
tions, TCAs may be useful among patients who can titrate
to therapeutic doses without intolerable side effects.
Miscellaneous antidepressants. A variety of other antide-
pressants with unique mechanisms of action have shown
promise for off-label treatment of generalized anxiety disor-
der, although they have been subject to limited study. A pilot
study (N524) found bupropion extra long (XL), which has
the advantage of not being associated with sexual side
effects, to be noninferior to escitalopram among patients
with generalized anxiety disorder (28). An open-label trial
of mirtazapine 30 mg daily for generalized anxiety disorder
showed a high response rate of almost 80% (29). A meta-
analysis of four RCTs supports the efficacy of the novel anti-
depressant vortioxetine, which acts as an SRI in addition to
modulating a few specific 5-HT receptors; furthermore, effect
size was more robust among patients with more severe anxi-
ety at baseline (Hamilton Anxiety Rating Scale score.25)
(30). Notable limitations of the studies include lower dosages
(2.5–10 mg vs. usual maximum for depression of 20 mg, and
short duration of 8 weeks). Vortioxetine has demonstrated
cognitive-enhancing effects among patients with major
depressive disorder, which may also be advantageous in the
population with generalized anxiety disorder because concen-
tration difficulties are part of the core symptom cluster (31).
A meta-analysis of three RCTs using 20–40 mg daily of
vilazodone, a combined SRI and 5-HT1A partial agonist,
achieved statistical significance for efficacy but with a small
effect size and increased dropout for adverse events (32).
Nefazodone, which acts as a 5-HT2A and 5-HT2C receptor
antagonist, has preliminary support from a small open trial
among adults with generalized anxiety disorder (33). This
drug was temporarily withdrawn from market in the United
States because of association with rare cases of fulminant
focus.psychiatryonline.org 149
PHARMACOTHERAPY FOR ANXIETY DISORDERS
FIGURE 1. Generic example of a network grapha
A
Placebo
B all at bedtime. A few small trials have provided support for
E (40–44). With all antipsychotics, major risks include weight
C
D gain, metabolic syndrome and associated sequelae, corrected
a tardive dyskinesia, and akathisia. Given these risks, trials of
The circles (“nodes”) represent treatment interventions including
placebo and active treatments (letters A–E). The size of the circles
conveys the relative number of study participants receiving each
intervention. The lines between the circles (“edges”) represent
comparative studies between different interventions, and their
relative thickness conveys the number of studies available directly
comparing the treatments.
and sometimes fatal hepatic failure, but it was later rein-
stated (34). Close monitoring for hepatotoxicity by liver
function tests and education about hepatitis symptoms
should be used if nefazodone is prescribed. In a placebo-
controlled study mentioned earlier in the section on TCAs,
trazodone demonstrated similar efficacy to diazepam and
imipramine for generalized anxiety disorder. It should be
noted that patients taking trazodone titrated to a mean dose
of 255 mg daily for anxiolytic effect (24). Trazodone is rarely
used in such high doses in contemporary practice because
of often prohibitive sedation.
Antihistamines. The histamine blocking medication hydroxy-
zine has support from double-blind RCTs with placebo and
active comparators, such as BZDs or buspirone, and has dem-
onstrated comparable efficacy with these established general-
ized anxiety disorder treatments (35, 36). A Cochrane review
in 2010 (37) characterized hydroxyzine as having support for
use in generalized anxiety disorder but could not recommend
it as a first-line treatment because of limited studies and sam-
ple size along with high risk of bias in the available trials.
Usual daily dosing per the trials is 50 mg, divided twice a day
to three times a day, and the most prominent adverse effect
is sedation (37).
Neuroleptics. Finally, RCT evidence has been found for the
use of second-generation antipsychotics in generalized anxi-
ety disorder, particularly quetiapine. However, citing signifi-
cant cardiovascular and metabolic risks, an FDA panel
denied approval for this indication. A meta-analysis in 2016
found quetiapine to be efficacious as a monotherapy for gen-
eralized anxiety disorder at doses between 50 and 150 mg
daily, with discontinuation and drop-out rates similar to
150 focus.psychiatryonline.org
those in clinical trials of antidepressants (38). Specifically,
two studies found quetiapine to have essentially equivalent
effects on generalized anxiety disorder to standard doses of
10 mg of escitalopram and 20 mg of paroxetine, respectively.
Although the studies were performed with quetiapine
extended release (XR), pharmacokinetic studies showed no
significant difference in side-effect profile between the
immediate release and XR formulations; however, the XR
version did show decreased sedation in the initial few hours
after dosing (39), which is easily circumvented with dosing
adjunctive use of risperidone, ziprasidone, and aripiprazole
QT prolongation, drug-induced extrapyramidal symptoms,
antipsychotics should be reserved for failure of several prior
adequate trials of safer agents.
Rational Pharmacologic Approach to Generalized
Anxiety Disorder
Comprehensive, evidence-based guides to direct treatment
of generalized anxiety disorder are limited, with one note-
worthy exception being the “Canadian Clinical Practice
Guidelines for the Management of Anxiety, Posttraumatic
Stress and Obsessive-Compulsive Disorders” (45). In this
sizeable review, the authors stratified treatment interven-
tions according to established efficacy, quality of evidence,
and tolerability and safety considerations; furthermore, they
proposed a hierarchy of first-, second-, and third-line mono-
therapy options as well as ranked adjunctive treatment
options. The authors concluded that SSRIs and SNRIs along
with pregabalin should be considered first-line treatments.
They characterized TCAs, BZDs, vortioxetine, bupropion
XL, buspirone, quetiapine, and hydroxyzine as second-line
treatments. They qualified miscellaneous antidepressants
and valproic acid (VPA) in rare formulations as third-line
treatments. Finally, for adjunctive treatment, they favored
pregabalin over second-generation antipsychotics (45).
Investigators have devised evidence-based algorithms to
guide sequencing of medication trials in generalized anxiety
disorder on the basis of estimates of treatment effect size
from meta-analyses (46). Traditional pairwise systematic
review and meta-analysis has the limitation of only being
able to compare two interventions with each other at once
and fails to account for the relative amount of study that dif-
ferent interventions have received. Network meta-analysis
(NMA) is a novel approach to ranking the efficacy of various
interventions by using data from a systematic review of the
literature and drawing on both direct and indirect compari-
sons. An important part of a NMA is the network graph
(Figure 1), which displays a network of circular nodes of
varying sizes with lines called edges of varying thickness
between the nodes. The nodes represent interventions, and
the size of the nodes indicates the number of participants
in each intervention. The edges between nodes represent
Focus Vol. 19, No. 2, Spring 2021

studies directly comparing two interventions, with the thick-
ness proportional to the number of such trials. This visuo-
spatial mapping of the literature gives context to the
quantitative analysis of effect size, which uses complex sta-
tistical methods to identify the effect sizes of various inter-
ventions relative to each other and to placebo (47).
For instance, one NMA comparing various psychophar-
macologic and psychological interventions for generalized
anxiety disorder reported bupropion and mirtazapine as
more efficacious than all other treatments, even though they
have a paucity of data backing them. The network plot
clearly displays this contradiction by showing the nodes rep-
resenting bupropion and mirtazapine as small dots in com-
parison with the much more studied first-line treatments
(6). Using traditional pairwise meta-analysis, clinicians inter-
preting the research may have (probably falsely) concluded
that they should resort to bupropion and mirtazapine as
first-line agents. Another network analysis in 2019 showed
significant positive effects combined with good tolerability
relative to placebo for escitalopram, duloxetine, venlafaxine,
and pregabalin. This same study also measured quetiapine
as having the strongest effect size, although poorly tolerated
(48). As the methodology of NMA continues to advance, the
results of such studies will have more clinical utility. Of
course, even with the additional dimensions added by
NMAs, no method has been established to computationally
incorporate additional factors such as side-effect profile and
cost. Eventually choice of agents comes down to a human
integrating available quantitative evidence for efficacy with
other qualitative considerations.
On the basis of the data presented earlier, the following
is one of multiple possible models for rational stepwise
pharmacologic treatment of patients with generalized anxi-
ety disorder. At all stages, proper informed consent and
shared decision making should be incorporated into the pro-
cess. In this model, and at points throughout this review,
the concept of an “incomplete” or “partial” response is ref-
erenced; for the reader, these terms may be defined as a
roughly 50% improvement but with residual symptoms con-
tinuing to distress the patient or impair functioning.
First line: Treatment should typically begin with an SSRI;
one might choose the initial antidepressant on the basis of
characteristics of the agent rather than presence or
absence of FDA approval. Sertraline and escitalopram are
often strong choices on the basis of demonstrated efficacy
in generalized anxiety disorder, along with lower poten-
tial than the FDA-approved agents for drug-drug interac-
tions or idiosyncratic adverse effects. Among patients
with certain comorbid conditions such as fibromyalgia or
chronic pain, an SNRI such as duloxetine would be a logi-
cal first choice. Among patients with significant hesitation
about sexual side effects with SSRIs, consider buspirone
monotherapy as first line.
Second line: In most cases, clinicians may resort to SSRIs
and SNRIs for the first several medication trials because
Focus Vol. 19, No. 2, Spring 2021
MELARAGNO
the SSRIs each exhibit idiosyncratic effects in different
patients; moreover, the SNRIs are clinically a heteroge-
nous group of medications in terms of their differential
effects on 5-HT and NE signaling. Because of its benign
side-effect profile, buspirone may be the rational next
step, either as monotherapy or as augmentation to an anti-
depressant that achieved an incomplete response. Prega-
balin as monotherapy or in combination with another
drug should also be considered at this stage. Finally, for
patients without contraindications, BZDs warrant a trial.
Third line: TCAs are relegated to this stage because of toler-
ability and safety concerns, although available evidence
shows that they may have equal efficacy to the first-line
treatments. Despite efficacy, quetiapine as monotherapy
or augmentation similarly should be reserved for patients
with conditions that are truly treatment refractory
because of the previously mentioned significant risk of
long-term adverse effects from antipsychotics.
Fourth line: Augmentation with other second-generation
antipsychotics and use of the miscellaneous antidepres-
sants fall into this category because of limited supportive
data and significant adverse effects.
PANIC DISORDER
The hallmark of panic disorder is anxiety and pathological
avoidance surrounding recurrent panic attacks, which are
brief episodes of intense fear associated with unpleasant phys-
ical symptoms. Treatment emphasizes reducing frequency
and severity of panic attacks, with the goal of reversing
learned patterns of avoidance that interfere with functioning
and quality of life, often through psychotherapy. Panic disor-
der has been characterized as a relapsing-remitting chronic
disorder for which the severity of symptoms varies over
time. Psychotherapy, particularly cognitive-behavioral therapy
(CBT), can promote lifelong remission in some. However,
indefinite pharmacologic treatment is indicated among many
patients because of the nature of the disorder (1).
Review of Specific Agents and Their Efficacy and
Tolerability in Treatment of Panic Disorder
SRIs. As in generalized anxiety disorder, first-line (and sec-
ond- and sometimes third-line) pharmacotherapy for panic
disorder uses SRIs. The specific SSRIs that have FDA
approval for panic disorder include fluoxetine, sertraline,
and paroxetine (regular and controlled release). Venlafaxine
XR is the sole SNRI with an FDA indication for panic disor-
der. Nevertheless, placebo-controlled and more preliminary
clinical trial evidence supports off-label use of the other
SSRIs (escitalopram, citalopram, fluvoxamine) (49–51) and
SNRIs for panic disorder (duloxetine and milnacipran) (52,
53). The evidence base supports dosing of SSRIs and SNRIs
within the usual FDA-approved dosing ranges.
BZDs. Before the establishment of SRIs as first-line treat-
ment for panic disorder, the high-potency BZDs (HPBs)
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PHARMACOTHERAPY FOR ANXIETY DISORDERS
clonazepam and alprazolam were preferred treatments
because of their rapid onset of effect, tolerability, and sus-
tained antipanic efficacy over time. For reasons already dis-
cussed, these medications have fallen out of favor. However,
HPBs remain a valuable second-line option among appropri-
ate patients who are resistant to or cannot tolerate the SRIs.
Clonazepam is the preferred HPB for panic disorder, and
clear efficacy has been demonstrated for doses ranging from
1 to 4 mg daily, usually divided twice daily (54, 55). A dose-
finding trial indicated that dose-dependent sedation and
ataxia became more problematic when exceeding 2 mg total
daily; in addition, 1–2 mg daily of clonazepam provided the
best tradeoff of therapeutic efficacy and tolerability (56).
Alprazolam XR, although rarely used in practice, may also
be used to address the frequent dosing and interdose anxi-
ety associated with immediate-release alprazolam (57). At
high doses, the XR form does not eliminate the misuse lia-
bility of the drug (18). The midpotency BZD lorazepam was
shown in a head-to-head, double-blind trial with alprazolam
to have equivalent efficacy for panic disorder (58). A study
comparing the low-potency benzo diazepam with alprazolam
found similar antipanic efficacy (59). Interestingly, a 2019
Cochrane meta-analysis comparing BZDs with placebo for
treatment of panic disorder slightly favored BZDs; however,
the authors took care to point out the low quality of evidence
and high risk of bias across most reviewed studies (55).
TCAs. TCAs have well-demonstrated efficacy for panic dis-
order. Imipramine has the most supportive clinical trial evi-
dence (24, 60–62). It was found to have equivalent antipanic
efficacy in a head-to-head RCT with sertraline among
patients with comorbid panic disorder and major depressive
disorder (63). This medication may cause high levels of ini-
tial jitteriness and anxiety among patients with panic disor-
der, so a low starting dose of 10 mg daily is recommended,
with slow titration in 25-mg increments to the ultimate tar-
get dose (64). Serum levels may be useful for guiding treat-
ment, with one trial showing that levels of 110–140 ng/ml
yielded optimal results (61). The other two TCAs that have
been validated for panic disorder are clomipramine and
desipramine, with multiple RCTs supporting the antipanic
efficacy of each (65–68).
Monoamine oxidase inhibitors (MAOIs). MAOIs block the
activity of enzymes involved in the breakdown of serotonin
(5-HT) and the catecholamine neurotransmitters DA and
NE by oxidative deamination, thereby leading to increased
levels of these neurotransmitters in the synaptic cleft. The
monoamine oxidase (MAO) enzymes include MAO-A and
MAO-B. The catecholamines are metabolized by both
MAO-A and MAO-B, whereas 5-HT is metabolized only
by MAO-A. The four irreversible MAOIs marketed in the
United States include the nonselective MAOIs phenelzine
and tranylcypromine and the MAO-B selective drugs sele-
giline and isocarboxazid ((2)). Presumably because they
increase 5-HT transmission in addition to DA and NE,
152 focus.psychiatryonline.org
only the nonselective MAOIs phenelzine and tranylcypro-
mine have demonstrated significant efficacy for anxiety
disorders, specifically panic disorder and social anxiety
disorder (69–72).
Despite sufficient evidence for their efficacy, MAOIs
should be reserved for patients with anxiety disorders that
are severely treatment resistant because of their heavy side-
effect burden and risk of dangerous complications. Roughly
half of patients taking MAOIs will experience significant
orthostatic dizziness. Other very common side effects
include sexual dysfunction, insomnia or sedation, headache,
constipation, and dry mouth (73). Patients taking irreversible
MAOIs must adhere to dietary restrictions to avoid the
dreaded tyramine-induced hypertensive crisis, sometimes
called the “cheese effect” because it can be triggered by
eating foods such as certain aged cheeses that have high
tyramine content (74). Furthermore, coadministration of
MAOIs with other medications that increase serotonergic
or catecholaminergic neurotransmission may lead to life-
threatening drug interactions such as serotonin syndrome or
dangerous hypertension. Thus, before starting an MAOI,
patients must allow at least five half-lives time for their pre-
vious antidepressant to wash out. This gap may vary from 1
to 2 weeks in the case of most antidepressants and from 4
to 5 weeks in the case of fluoxetine. Similarly, because the
effects of irreversible MAO inhibition can persist for 2–3
weeks, a washout period of the same length is recom-
mended before switching to another class of antidepressant
to prevent problematic drug interactions (75).
Although the decision to start an MAOI should not be
taken lightly for all the reasons discussed earlier, risk-benefit
calculation may yet favor prescribing these medications in
subpopulations of patients with panic or social anxiety dis-
order with severe, disabling symptoms and failure to
respond to or tolerate several adequate trials of lower-risk
medications. Dietary restrictions are the most common rea-
son for hesitancy; however, it is worth noting that the tyra-
mine content of foods has decreased over time and that
after reexamination, earlier low-tyramine diets have been
deemed unnecessarily expansive. With advances in food sci-
ence and the usual tyramine content of different foods,
researchers have developed less-restrictive, more user-
friendly diets for patients taking MAOIs (75).
The reversible inhibitors of MAO-A (RIMAs) have been
targets of interest for the treatment of panic disorder
because of the toxicity and drug-interaction concerns raised
by phenelzine and tranylcypromine. In the presence of sub-
strates such as tyramine or monoamine neurotransmitters,
RIMAs are easily displaced from the MAO enzyme, making
major adverse events such as tyramine-associated hyperten-
sive crisis or serotonin syndrome very unlikely. Thus, limited
to no dietary adjustments are required to take these medica-
tions (74). The most widely used RIMA is moclobemide,
which is not marketed in the United States but is commer-
cially available in Canada and many European countries.
RCT evidence for using moclobemide to treat panic disorder
Focus Vol. 19, No. 2, Spring 2021

has been supportive of efficacy and improved safety and tol-
erability in comparison with other MAOIs or TCAs (74,
76–80). Similarly, the MAO-B selective inhibitor selegiline
has drawn growing interest because of the availability of a
transdermal patch for treatment of major depressive disor-
der, which at the lowest dose form of 6 mg does not require
dietary modifications. Unfortunately, no studies have sup-
ported its use for panic disorder.
Other antidepressants. A handful of the unclassified antide-
pressants are supported by multiple small RCTs. A small,
open-label, flexibly-dosed trial of vortioxetine was sugges-
tive of benefit for panic disorder (81). Mirtazapine has dem-
onstrated efficacy for panic disorder in multiple open-label
trials and in one double-blind, head-to-head study with flu-
oxetine, with effective dosing ranging from 15 to 30 mg daily
(82–84). Bupropion has been studied with mixed results
(85). Nefazodone has multiple open trials supportive of effi-
cacy for panic disorder at doses between 200 and 600 mg
daily (86, 87). The evidence for trazodone is weak, with pos-
itive results in a small open-label trial; however, high attri-
tion and low response rate were found in an 8-week,
double-blind trial comparing it with the established agents
imipramine and alprazolam (60).
Anticonvulsants. VPA has preliminary evidence for efficacy
in treating panic disorder from small open trials in doses
from 500 to 2,250 mg daily. Generally, VPA is well tolerated,
but it may cause weight gain, tremor, and hair loss. Because
of the potential for cytopenias, hepatic injury, and buildup
of toxic levels, patients taking VPA require periodic moni-
toring of complete blood counts, liver function tests, and
serum VPA levels (88, 89). Trials with carbamazepine and
gabapentin have been negative and equivocal, respectively
(90, 91).
Second-generation antipsychotics. An 8-week, single-blind
RCT (N556) of moderately-dosed paroxetine against low-
dose risperidone among patients with panic disorder either
alone or comorbid with major depressive disorder showed
significant antipanic efficacy that was not different between
treatment groups. Moreover, presumably because of the low
doses used, risperidone was generally well tolerated (92).
However, a double-blind, placebo-controlled trial (N5111) of
risperidone 0.5–4.0 mg daily monotherapy for patients with
comorbid bipolar disorder and generalized anxiety disorder
or panic disorder failed to show significant improvements in
anxiety symptoms (93). In a 12-week, open-label study
(N531) of SSRI augmentation with olanzapine 5 mg daily,
57.7% of patients achieved remission (94).
Rational Pharmacologic Approach to Panic Disorder
As with generalized anxiety disorder, studies informing
rational sequencing of medication trials for panic disorder
are limited. The American Psychiatric Association has devel-
oped treatment guidelines that are relatively nonspecific
Focus Vol. 19, No. 2, Spring 2021
MELARAGNO
(95). Katzman and colleagues (45) sorted the available inter-
ventions into first line (SSRIs and SNRIs), second line
(BZDs, TCAs, and the miscellaneous antidepressants rebox-
etine and mirtazapine), and third line (MAOIs and RIMAs,
second-generation antipsychotics, assorted antidepressants,
and a few anticonvulsants). For adjunctive therapy, they
supported BZDs, the beta blocker pindolol, and second-
generation antipsychotics. They also discussed the strength
of the various medications for maintenance treatment of
panic disorder (45). In 2009, a three-phase, 24-week RCT
did provide an interesting comparison of various commonly
pursued pathways all starting at the same first-line SSRI
therapy. The trial began with an open-label, 6-week SSRI
(sertraline or escitalopram) targeted to a usual therapeutic
dose (i.e., 100 mg sertraline) (96). Of the patients, 20%
achieved remission status after phase 1 and terminated the
study at this point. Next phases, in succession, included
increased dose of SSRI or same dose as phase 1 plus pla-
cebo; subsequent phases included “medication optimization”
with flexibly dosed clonazepam or psychotherapy with CBT.
The end results tended to favor allowing adequate time for
standard therapeutic doses of SSRI to take effect and using
combination with CBT (96).
NMA studies were discussed in the section on general-
ized anxiety disorder as a novel method of ranking treat-
ment interventions. Unfortunately, although NMAs have
been published comparing various psychological treatments
for panic disorder, review of the literature yielded no pub-
lished NMAs of psychopharmacologic therapies. The addi-
tion of high-quality NMAs would add significantly to the
current evidence base for stratifying treatments.
The following hierarchy of treatments on the basis of the
evidence presented earlier is proposed:
First line: Begin with SRIs with particular consideration of
specific drug characteristics and comorbid conditions.
Second line: For panic disorder, a standing high-potency
benzo (usually clonazepam) should be considered sooner
in appropriate patients because of its well-demonstrated
track record of efficacy and tolerability. If SRIs were not
tolerated and the patient has only panic disorder, mono-
therapy with HPBs would be reasonable. Otherwise, espe-
cially with comorbid conditions treated by SRIs, HPBs
should be used in combination with the SRI.
Third line: As in generalized anxiety disorder, TCAs are
arguably third line despite strong data for efficacy in
treating panic disorder because they have a formidable
side-effect burden and potential for toxicity. Another dis-
advantage is lack of efficacy in treating comorbid social
anxiety disorder. At this stage, other antidepressants such
as mirtazapine and nefazodone should also be considered,
given their moderately strong clinical evidence coupled
with low-moderate adverse effect risks.
Fourth line: At this point, the remaining studied interven-
tions can all be considered, including adjunctive second-
generation antipsychotics, MAOIs, and VPA. Although
focus.psychiatryonline.org 153
PHARMACOTHERAPY FOR ANXIETY DISORDERS
any of these medications may prove efficacious among
patients with conditions that are treatment resistant,
these medications should be end-of-the-line options
because of either paucity of data or mixed results of stud-
ies, dangerous or highly intolerable adverse effect poten-
tial, or some combination of the two.
SOCIAL ANXIETY DISORDER
Social anxiety disorder involves pathological levels of anxi-
ety in social or performance situations in which intense
scrutiny by others is perceived or anticipated. Patients tend
to altogether avoid the feared social situations; only
approach them with a companion; or endure them with dis-
tress and physical symptoms that can approach the intensity
of full panic attacks, such as flushing, sweating, palpitations,
and tremor. Social anxiety disorder includes both a
“performance-only” variant and generalized social anxiety
disorder, which extends to a variety of social interactions (1).
Review of Specific Agents and Their Efficacy and
Tolerability in Treatment of Social Anxiety Disorder
SRIs. Pharmacologic treatment aims to decrease anticipatory
anxiety and avoidance behaviors before, and distress during,
essential social activities to improve social and occupational
functioning. As with the other anxiety disorders, SRIs are
the pharmacologic treatment of choice for generalized social
anxiety disorder. Performance-only social anxiety disorder is
generally not treated with maintenance medications because
most people infrequently encounter the feared performance
situations. The drugs in these classes that carry the FDA
indication for social anxiety disorder include the SSRIs ser-
traline, paroxetine, and paroxetine CR as well as the SNRI
venlafaxine XR. Data from RCTs also support the use of the
SSRIs fluvoxamine, citalopram, and escitalopram (97–100).
Some initial data support SNRI duloxetine for the treatment
of social anxiety disorder (101). Fluoxetine has less consis-
tent evidence (98, 102, 103). Escitalopram, paroxetine, ser-
traline, and venlafaxine were shown in a meta-analysis to
have roughly equivalent effect size and superiority to pla-
cebo (104). Principles guiding titration and dosing are simi-
lar to those applied to generalized anxiety disorder and
panic disorder.
Beta-adrenergic blockers. Beta blockers have been validated
for the treatment of performance-only social anxiety, which
generally arises in the context of public speaking or other
performative situations. Their hypothesized mechanism of
action is suppression of the physiological hyperarousal that
occurs in the fear response to such situations. This process
interrupts an escalating feedback loop in which patients
become distressed and self-conscious about physical mani-
festations such as flushing, palpitations, and sweating, which
subsequently causes them to further amplify these symp-
toms; this amplification, in turn, begets more psychic anxi-
ety about these manifestations being scrutinized by others
154 focus.psychiatryonline.org
and so on (105, 106). For reasons that are not fully under-
stood, beta blockers have not demonstrated efficacy in
treating generalized social anxiety disorder. For instance, a
head-to-head trial of beta blocker atenolol compared with
the validated treatment phenelzine and placebo found aten-
olol ineffective for generalized social anxiety (107).
The nonselective beta blocker propranolol and the
cardio-selective agent atenolol are the two primary agents
that have been studied for use in performance-only social
anxiety disorder. Recommended use is as needed 1–2 hours
before a performance situation at total daily doses of 10–80
mg propranolol and 50–150 mg atenolol. One should take a
“test” dose on a day with no performance obligations to get
accustomed to the feeling of the medication. Typical adverse
effects include orthostatic hypotension and lightheadedness,
bradycardia, sedation, and nausea; in the case of nonselec-
tive propranolol, effects include worsening of underlying air-
way obstruction among patients with asthma or chronic
obstructive pulmonary disease (105, 106, 108, 109).
BZDs. BZDs have moderate support in clinical studies for
use in treating social anxiety disorder and are associated
with a faster response than the first-line antidepressant
agents (110). Used as needed before performance situations
or occasional feared social situations, BZDs may be quite
helpful given their rapid onset of effect; however, they may
also be associated with cognitive and psychomotor impair-
ment and ataxia, which, in turn, could impair performance.
A high incidence of patients with social anxiety disorder
use alcohol to self-medicate symptoms. Thus, thorough
substance use evaluation should be undertaken with all
patients, and practitioners should carefully discuss risks and
benefits of BZD prescriptions with patients who have histo-
ries of problematic alcohol use and document these conver-
sations thoroughly. Concomitant use of alcohol with BZDs
risks synergistic CNS depression, which could result in
death (111). However, if BZDs lead to significant improve-
ment of social anxiety disorder symptoms, patients who his-
torically have used alcohol to self-medicate for social
anxiety may no longer feel compelled to do so.
The available evidence suggests minimizing use of
as-needed BZDs for generalized social anxiety disorder
because rapid relief of anxiety with medication eliminates
exposure to anxiety symptoms required for fear-extinction
learning, interfering with the efficacy of CBT interventions
(112). For patients with refractory generalized social anxiety
symptoms, standing BZD regimens may be appropriate,
preferably with a long-acting agent initiated at low dose and
titrated to the minimum dose needed for efficacy. In one
study, adding 1–2 mg per day of clonazepam to flexibly-
dosed paroxetine yielded superior results compared with
paroxetine monotherapy (110). For as-needed use, lorazepam
given 1–2 hours before the occasional feared situation is a
reasonable choice. As with beta blockers, patients naïve to
BZDs should first take a test dose in a safe setting to ensure
toleration of the medication.
Focus Vol. 19, No. 2, Spring 2021

Anticonvulsants. Gabapentin and pregabalin both have
RCTs showing efficacy over placebo for social anxiety disor-
der; however, it should be noted that improvement was
associated with higher doses than are often tolerated (e.g.,
.2,100 mg daily for gabapentin and 600 mg total daily
for pregabalin) (113–115). However, one study supported
slightly lower maintenance dosing for pregabalin (114). Small
open-label trials have raised the possibility of treating social
anxiety disorder effectively with VPA, levetiracetiram,
topiramate, and tiagabine, but these trials either were not
successfully replicated with, or not followed by, subse-
quent RCTs.
MAOIs. The MAOIs phenelzine and tranylcypromine for-
merly were regarded as the standard of care pharmacologic
treatment for social anxiety disorder before the emergence
of the safer, less complicated SSRIs and SNRIs. This practice
was based initially on the observation that MAOIs seemed
to uniquely treat patients with “atypical” depression and
prominent rejection sensitivity; this practice was subse-
quently supported by multiple positive RCTs (69, 73). The
RIMAs represent a potentially helpful and easier to adminis-
ter MAOI category for the treatment of social anxiety disor-
der, but limitations include lack of availability in the United
States and mixed evidence (79, 104, 116). Selegiline transder-
mal patch also lacks evidence for use in treating social anxi-
ety disorder.
Miscellaneous medications: other antidepressants, buspir-
one, and neuroleptics. Contrary to their well-supported use
in panic disorder and generalized anxiety disorder, TCAs
have no established role in treating social anxiety disorder
because of negative results in the few available open-label
and double-blind, placebo-controlled trials. Vilazodone
was studied in one double-blind, placebo-controlled RCT
(N539) of patients who, on average, had severe social
anxiety disorder at baseline; their symptoms significantly
improved compared with placebo, with a moderate effect
size (117). An RCT (N540) of vortioxetine against placebo
in a patient sample with comorbid major depressive disor-
der and social anxiety disorder showed marked reductions
in measures of social anxiety (118). Mirtazapine has posi-
tive evidence from open-label studies as well as a more
rigorous RCT with a sample of only women, but a larger
placebo-controlled RCT of both men and women failed to
replicate those results (119–121). At least one small open
trial suggests possible efficacy of bupropion (122). As an
adjunctive agent to SSRI therapy, buspirone has limited
evidence suggesting efficacy (123). Small trials and case
series provide preliminary evidence of efficacy for the
second-generation antipsychotics quetiapine and olanza-
pine in treating social anxiety disorder (124–126). Overall,
the body of evidence for each of these treatments is small.
The favorable outcomes in studies of vilazodone and vorti-
oxetine are not surprising given their pharmacodynamic
similarity to SSRIs.
Focus Vol. 19, No. 2, Spring 2021
MELARAGNO
Rational Pharmacologic Approach to Social
Anxiety Disorder
The Anxiety and Depression Association of America has
published a clinical practice review for social anxiety disor-
der that separates psychopharmacologic treatments into a
first-line category (essentially the SSRIs and SNRIs), fol-
lowed by a second-line category, which contains the broad
range of treatments discussed earlier; however, notable
option rankings are not included except to suggest first a
trial of a different SSRI or SNRI (127). Other important con-
clusions from this report included a recommendation
against standing beta blockers for generalized social anxiety
disorder and as-needed quetiapine for performance-only
social anxiety disorder; however, cautious optimism was
given for both quetiapine and olanzapine as adjunct treat-
ment (127). The Canadian Clinical Practice Guidelines
similarly recommend SSRIs and SNRIs and high-dose pre-
gabalin as first line. BZDs, MAOIs, and gabapentin were
recommended as second line. Finally, a variety of antide-
pressants, anticonvulsants, and second-generation antipsy-
chotics were recommended as third line (45). In 2014,
Pollack and colleagues (128) conducted a double-blind RCT
examining next-step treatment options for patients with
social anxiety disorder who did not respond to sertraline
after 10 weeks. The patients who did not respond to sertra-
line were randomly assigned to either receive continued
sertraline plus placebo, sertraline augmentation with up to
3.0 mg per day of clonazepam, or switch from sertraline to
optimally titrated venlafaxine. Augmentation with clonaze-
pam as a strategy resulted in significant reductions in
measures of social anxiety compared with maintenance ser-
traline or switch to venlafaxine, although no significant dif-
ference was found in the number of patients achieving
remission (128).
In 2020, an NMA of pharmacologic treatments for social
anxiety disorder was published and yielded interesting
results (129). The authors identified paroxetine as superior
to other treatments for reducing the symptom severity of
social anxiety disorder; therefore, they recommended parox-
etine as first-line treatment. However, paroxetine is asso-
ciated with several practical problems, including an
association with weight gain, anticholinergic effects, and
drug-drug interactions via strong inhibition of the important
cytochrome P450 enzyme 2D6. On the basis of a single
included study, the authors of this analysis found olanzapine
to be considered very efficacious, which suggests a need
for higher-quality studies, especially in light of the medica-
tion’s long-term safety and tolerability profile. The authors
also identified a broad group of agents as superior to pla-
cebo for social anxiety disorder, including the SSRIs paroxe-
tine, escitalopram, fluvoxamine, and sertraline; the BZDs
bromazepam and clonazepam; and the MAOI phenelzine
(129).
The following proposed hierarchy of pharmacologic
treatments for social anxiety disorder integrates all the evi-
dence previously discussed:
focus.psychiatryonline.org 155
PHARMACOTHERAPY FOR ANXIETY DISORDERS
First line: As with the other major anxiety disorders, start
with SSRIs or SNRIs, noting idiosyncratic drug character-
istics and comorbid conditions. If the patient exhibits
performance-only social anxiety, then trial an as-needed
beta blocker, typically propranolol first.
Second line: Pursue one or more additional trials of sup-
ported SRIs, including venlafaxine. Despite the paucity of
evidence, on the basis of the quality and effect size from
available studies, one may subsequently consider a trial
of vortioxetine or vilazodone. For performance-only
social anxiety disorder that is not responsive to beta
blockers, consider as-needed, short-acting BZDs such as
lorazepam.
Third line: Consider adequacy of engagement with psycho-
therapy before additional medication trials. For general-
ized social anxiety disorder, in the event of incomplete
response of an antidepressant, one may pursue adjunctive
treatment with an HPB such as clonazepam 1–2 mg daily
in an appropriate patient for BZDs. If numerous SRIs
were not tolerated or failed to achieve even partial (e.g.,
.50%) response and the patient does not have comorbid
conditions requiring an antidepressant, one should con-
sider monotherapy with a standing HPB.
Fourth line: Depending on patient preference and other
considerations, next steps would include the anticonvul-
sants gabapentin and pregabalin or the MAOIs phenelzine
and tranylcypromine.
Fifth line: Other treatments with inconsistent trials (mirta-
zapine) or only open-label trial evidence should be con-
sidered as last resort. Even though a small trial and a
recent NMA study provide support for strong efficacy of
olanzapine, because of long-term safety and tolerability
issues, I would reserve monotherapy or adjunct second-
generation antipsychotics only for the most severe
patients with conditions that are the most treatment
refractory.
CONCLUSIONS AND FUTURE DIRECTIONS
Psychiatry has had a lack of novel pharmacologic treatments
developed specifically to target anxiety disorders for deca-
des. Nevertheless, the field continues to make incremental
progress via rigorous study of repurposing medications pri-
marily approved for other conditions to good effect for anxi-
ety. In this review, I examined the wide evidence base for
medication treatment of the primary anxiety disorders, with
updates to account for the latest studies supporting off-label
use of classes of medications such as novel antidepressants,
anticonvulsants, and second-generation antipsychotics. Addi-
tionally, I reviewed the novel systematic review methodol-
ogy of NMA, which is unique and promising for its capacity
to develop relative ranking of treatments even if they were
never studied head to head. I also critically assessed avail-
able NMAs of pharmacologic treatments for incorporation
into clinical decision making. Finally, for generalized anxiety
disorder, panic disorder, and social anxiety disorder, I
156 focus.psychiatryonline.org
constructed pragmatic and flexible hierarchies for evidence-
based sequencing of medication trials.
A few points covered in this review bear reemphasizing.
The first is the potential for wider use of pregabalin.
Because of lack of FDA approval, pregabalin is underutilized
in the United States for anxiety disorders. The drug has
recently come off patent, and new generic formulations
have become available, decreasing costs. Thus, clinicians
treating patients with anxiety should consider it earlier in
treatment algorithms, especially for generalized anxiety dis-
order, for which it has strong evidence of efficacy at moder-
ate, well-tolerated doses. A second point of emphasis is the
continued role of BZDs for pharmacologic treatment of
moderate to severe anxiety, particularly panic disorder and
more refractory generalized anxiety disorder. Effective clini-
cians should be comfortable prescribing these medications
among patients for whom they are appropriate and in situa-
tions that necessitate more rapid stabilization of symptoms
than first-line SRIs can provide. If possible, they should be
used in a time-limited manner to avoid the development of
physical dependence, but long-term use is indicated in a
subset of patients.
Another key finding from the literature is that second-
generation antipsychotics are evidence-based therapies for
anxiety disorders, especially quetiapine as monotherapy or
adjunct for generalized anxiety disorder. These drugs remain
nonpreferred treatments because of significant long-term
risks, especially weight gain and metabolic abnormalities.
However, if well informed about risks and benefits, patients
with anxiety disorders that are highly refractory warrant tri-
als of these agents. I would assert that clinicians’ hesitance
to prescribe them for anxiety disorders in the absence of
additional novel low-risk medications may reflect a tendency
to underpathologize severely disordered anxiety. Disordered
anxiety imposes substantial morbidity on society via impair-
ment of patients’ occupational and social functioning; more-
over, it is associated with suicide, as evidenced by the
epidemiological data showing an increased risk of suicide
among patients with panic disorder (130).
In this review, I did not address novel drug targets for
anxiety disorders. I also did not discuss use of psycho-
pharmacologic agents to facilitate psychotherapy, as in
psychedelic-assisted psychotherapy, which is currently the
subject of rigorous RCTs for posttraumatic stress disorder
and depression; if approved, it warrants further study in the
primary anxiety disorders. Other issues not covered include
best practices for integrating psychopharmacologic treat-
ments with evidence-based psychotherapy, such as CBT, and
the incorporation of agents from complementary and alter-
native medicine. All of the aforementioned issues warrant
additional research. With reference to optimizing the use of
the currently available drug armamentarium as discussed in
this review, next steps include development of highly
sophisticated sequenced treatment algorithms that factor
in specific patient characteristics and cost-effectiveness,
among other considerations. With ongoing refinement of
Focus Vol. 19, No. 2, Spring 2021

methodology, additional NMAs of pharmacologic treatments
will contribute significantly to the development of decision-
support tools for busy general psychiatrists. Given all these
considerations, a great deal of work remains to advance
medication treatment of anxiety disorders.
AUTHOR AND ARTICLE INFORMATION
Division of Medical Psychiatry, Brigham and Women’s Hospital, Boston;
Department of Psychiatry Harvard Medical School, Boston Send corre-
spondence to Dr. Melaragno (amelaragno@bwh.harvard.edu).
The author reports no financial relationships with commercial interests.
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