Postgraduate Medicine

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Considerations when selecting an antidepressant:

a narrative review for primary care providers
treating adults with depression

C. Brendan Montano, W. Clay Jackson, Denise Vanacore & Richard Weisler

To cite this article: C. Brendan Montano, W. Clay Jackson, Denise Vanacore & Richard Weisler
(2023) Considerations when selecting an antidepressant: a narrative review for primary
care providers treating adults with depression, Postgraduate Medicine, 135:5, 449-465, DOI:
10.1080/00325481.2023.2189868

To link to this article: https://doi.org/10.1080/00325481.2023.2189868

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POSTGRADUATE MEDICINE
2023, VOL. 135, NO. 5, 449–465
https://doi.org/10.1080/00325481.2023.2189868

REVIEW

Considerations when selecting an antidepressant: a narrative review for primary

care providers treating adults with depression
C. Brendan Montanoa, W. Clay Jacksonb, Denise Vanacorec and Richard Weislerd,e
a
Montano Wellness LLC, CT Clinical Research, University of Connecticut Medical School, Farmington, CT, USA; bWest Cancer Center, Department of
Family Medicine and Department of Psychiatry, University of Tennessee College of Medicine, Memphis, TN, USA; cSchool of Nursing, Eastern
University, St. Davids, PA, USA; dP.A. & Associates; Department of Psychiatry, Duke University, Durham, NC, USA; eDepartment of Psychiatry,
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

ABSTRACT ARTICLE HISTORY

Major depressive disorder (MDD) is a debilitating mental disorder that can be treated with Received 16 December 2022
a number of different antidepressant therapies, each with its own unique prescribing considera­ Accepted 8 March 2023
tions. Complicating the selection of an appropriate antidepressant for adults with MDD is the
KEYWORDS
heterogeneity of clinical profiles and depression subtypes. Additionally, patient comorbidities,
MDD; primary care;
preferences, and likelihood of adhering to treatment must all be considered when selecting an treatment selection;
appropriate therapy. With the majority of prescriptions being written by primary care practi­ antidepressant; partial
tioners, it is appropriate to review the unique characteristics of all available antidepressants, response; comorbidities;
including safety considerations. Prior to initiating antidepressant treatment and when patients tolerability; adherence;
do not respond adequately to initial therapy and/or exhibit any hypomanic or manic symptoms, guidelines; measurement-
bipolar disorder must be ruled out, and evaluation for psychiatric comorbidities must be con­ guided care
sidered as well. Patients with an inadequate response may then require a treatment switch to
another drug with a different mechanism of action, combination, or augmentation strategy. In this
narrative review, we propose that careful selection of the most appropriate antidepressant for
adult patients with MDD based on their clinical profile and comorbidities is vital for initial
treatment selection.
Strategies must be considered for addressing partial and inadequate responses as well to help
patients achieve full remission and sustained functional recovery. This review also highlights data for
MDD clinical outcomes for which gaps in the literature have been identified, including the effects of
antidepressants on functional outcomes, sleep disturbances, emotional and cognitive blunting, anxiety,
and residual symptoms of depression.

PLAIN LANGUAGE SUMMARY

Major depressive disorder (MDD) is a leading cause of disability worldwide and can affect each patient
differently. Antidepressants play a critical role in treatment; however, with multiple antidepressant options
available, it is important that providers select the best fit for each patient. Rather than use a “one size fits all”
approach, it is important to consider each patient’s symptoms, medical and psychiatric comorbidities, as
well as their treatment preferences. A clear summary of each antidepressant’s distinctive characteristics is
essential for providers to select antidepressants to best match each patient’s needs.
This narrative review aims to discuss the latest information on available antidepressants, including
their risks and benefits and how they impact symptoms of MDD such as sleep disturbances, anxiety,
emotional blunting, and changes in cognition, as well as different treatment goals, such as the ability to
function in everyday life. This information can guide clinical practice recommendations and further
enable shared decision-making between the provider and patient, incorporating individual treatment
needs and preferences.
In addition, many patients do not reach their treatment goals with the first antidepressant or may
continue to have symptoms of depression after treatment. This review discusses strategies to increase
the likelihood of symptom improvement and creates awareness of patient-specific considerations.
Overall, careful, personalized selection of antidepressant treatment is critical for finding the right
balance of maximized antidepressant effect with minimized side effects, leading to the best possibility
for patients to tolerate the medication and ultimately helping patients reach their treatment goals.

CONTACT C. Brendan Montano docmontano@aol.com Montano Wellness LLC, 160 West St., Ste. 1A, Cromwell, CT 06416, USA
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
450 C. B. MONTANO ET AL.

1. Introduction especially for moderate to severe MDD [8]. This multidisciplin­

ary approach may include pharmacotherapy, psychotherapy,
Depression, or major depressive disorder (MDD), is recognized as
a combination of medications and psychotherapy, or other
an important mental health concern in the United States (US)
somatic therapies such as electroconvulsive therapy, transcra­
and global populations. The devastating impact depression has
nial magnetic stimulation or light therapy, and alternative
on individuals and society is well documented [1,2]. The 2020
therapies [3,5,8]. Pharmacotherapy for depression has been
National Survey on Drug Use and Health reported that an esti­
available for more than 50 years, since the first antidepressants
mated 14.8 million adults in the US had a major depressive
targeting multiple monoaminergic pathways became available
episode with severe impairment in the past year. Globally, the
in the 1950s, and remains the mainstay of treatment [9].
12-month prevalence of MDD is 6%, and the risk of MDD over
Nevertheless, a healthy diet and exercise are also important
a lifetime is approximately 11.1%–14.6% [2,3]. With the emer­
factors in the global treatment of MDD [10,11]. An increase in
gence of the SARS-CoV-2 virus and the COVID-19 pandemic in
our understanding of the neurobiology of depression has
2020, the COVID-19 Mental Disorders Collaborators estimate that
provided a more complex picture beyond monoaminergic
throughout 2020, the pandemic led to a clinically significant
transmission, with MDD now thought to involve a complex
27.6% increase in cases of depression. The exacerbation of
interplay of various genes, neural networks, structural neuro­
MDD as a global burden highlights an urgent need to strengthen
biological changes, and neurotransmitters including serotonin,
mental healthcare systems, which includes prioritizing promo­
norepinephrine, dopamine, glutamate, GABA-ergic systems,
tion of well-being and development of depression mitigation
and histamine at certain brain regions [12–15]. This complexity
strategies [4]. Optimizing the management of depression in
is further reflected by the different subtypes of depression
primary care settings represents a critical strategy for addressing
that can occur, such as anxious depression. Furthermore, psy­
the burden of depression, as approximately 60% of mental
chiatric and medical comorbidities including sleep disorders,
healthcare is provided in primary care settings and almost 80%
anxiety disorders, attention deficit/hyperactivity disorder
of antidepressant prescriptions are written by providers who are
(ADHD), obesity and eating disorders, as well as pain and
not mental health care specialists [5]. This narrative literature
cardiovascular disease are now regarded as important risk
review aims to differentiate available antidepressants by present­
factors for the development of depression that can also influ­
ing a comprehensive examination of their risks and benefits in
ence treatment [3,8,13,16]. As our understanding of the neu­
order to support personalized treatment selection and help
robiology of depression has advanced, so too has the number
patients with MDD reach their treatment goals.
of treatments available, with more than 35 US Food and Drug
Administration (FDA)-approved antidepressant medications
[3,17]. This understanding provides both an opportunity and
2. Treatment options for adults with MDD
a challenge – an opportunity to tailor treatment to the
Depression is highly heterogeneous in its clinical presentation patient’s specific clinical and pharmacogenomic profile,
and is associated with a constellation of symptoms across comorbidities, and preferences, and a challenge, especially in
a wide range of different emotional, physical, functional, and primary care, because clinicians who do not specialize in
cognitive domains depending on each individual patient pre­ psychiatry have limited exposure to the nuances of the differ­
sentation [5–7]. For this reason, a multidisciplinary approach ent compounds and their risk-benefit profiles [12,18].
to the management of adult patients with MDD is increasingly The abundance of pharmacotherapeutic options for MDD
considered to provide them with the best chance of achieving has coincided with a consistent increase in the number of
remission, often defined as the absence of clinical levels of patients being prescribed antidepressants (Figure 1) [19]. As
depressive symptoms, and sustained functional recovery, many as 1 in 10 people in the US are currently prescribed an
 POSTGRADUATE MEDICINE 451

Figure 1. Growth in number of patients prescribed antidepressants for MDD: 1996–2015 [19].
Reproduced from Luo Y, Kataoka Y, Ostinelli EG, Cipriani A and Furukawa TA. National prescription patterns of antidepressants in the treatment of adults with major depression in the US
between 1996 and 2015: a population representative survey based analysis. Front Psychiatry. 2020;11:35. doi: 10.3389/fpsyt.2020.00035; under the terms of the Creative Commons
Attribution License (CCBY). https://creativecommons.org/licenses/by/4.0/. The SE of number of adults with MDD is shown by error bars.aPatients with multiple antidepressants: referring to
patients who were prescribed >1 antidepressant during that year, i.e. both patients with combination therapy and patients who changed previous monotherapy into a new drug in
that year. MDD: major depressive disorder.

antidepressant, reflecting possible overtreatment of patients
with subsyndromal MDD or adjustment disorders; however,
only half of patients diagnosed with MDD receive an adequate
prescription, suggesting that overprescribing and inadequate
prescribing must be addressed [12]. It is possible that the array
of antidepressants is not well differentiated and understood
by some primary care providers, who frequently contend with
time constraints and large caseloads, not to mention the dis­
ruption to healthcare delivery in primary care settings caused
by the COVID-19 pandemic. As a result, physicians in primary
care may default to 1 or 2 different antidepressants for all
adult patients, thus applying a “one size fits all” approach to
a disease with a highly individualized clinical profile. This is
consistent with the observation that inadequate responses to
initial antidepressants are common, and clear guidance is
lacking for primary care providers concerning how partial
responses may be addressed [10]. Just as with initial antide­
pressant selection, the choice of medication in cases of partial
response should be guided by the patient’s clinical profile or
depression subtype and comorbid conditions. Additionally,
some antidepressants are associated with emotional and cog­
nitive blunting, which may add to the burden of illness for
patients so affected [20].
3. Addressing literature gaps
There are few review articles aimed at educating a primary
care audience about the factors to consider when choosing an
antidepressant, as well as about general principle-guided
algorithms to follow for treatment initiation or switch. In this
article, we review some of the latest data for antidepressants
to treat adults with MDD and revisit the latest clinical practice
recommendations, highlighting the importance of tailoring
treatment to the clinical profile and comorbidities of the
patient. Additionally, when emotional blunting is secondary
to antidepressant selection, guidelines for diagnosis and stra­
tegies for treatment modification must be developed [21,22].
We propose that careful selection of the most appropriate
antidepressant for adult patients with MDD is the best way
to counter both inadequate prescribing of antidepressants
and address partial and inadequate responses to antidepres­
sant therapy. This article also highlights data for MDD clinical
outcomes for which gaps in the literature have been identified
that may influence response to treatment, including the
effects of antidepressants on functional outcomes, sleep dis­
turbances, anxiety, emotional and cognitive blunting, and any
residual symptoms of depression.
4. Overview of antidepressant therapies by class
Acute-phase pharmacotherapies for MDD include selective sero­
tonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reup­
take inhibitors (SNRIs), tricyclic antidepressants (TCAs),
monoamine oxidase inhibitors (MAOIs), N-methyl-D-aspartate
(NMDA) receptor antagonists, atypicals, and serotonin modulators
that have more complex mechanisms of action and cannot be
easily categorized (Table 1) [8,12,13,23–26]. The efficacy of these
treatments compared with placebo has been established in
452 C. B. MONTANO ET AL.
Table 1. Antidepressant profiles by class.
Mechanism of antidepressant
Class effect
SSRIs ● Targeted and selective
serotonin reuptake
inhibition [32]
SNRIs ● Dual inhibition of serotonin
and norepinephrine
reuptake
● May have an effect on
other neurotransmitters
[12,37]
Serotonin ● Multimodal SSRI and
modulator a partial 5-HT1A receptor
agonist [52,53]
● Partial agonist activity at 5-
HT1A receptors [48,109]
● Multimodal; thought to be
mediated through antago­
nist effect on the 5-HT3, 5-
HT7, and 5-HT1D receptors;
partial agonist activity on
the 5-HT1B receptor; ago­
nist effect on the 5-HT1A
receptor; and inhibition of
the 5-HT transporter [51]
● Also enhances the extra­
cellular concentration of
dopamine, histamine, nore­
pinephrine, and acetylcho­
line [109]
Symptoms/Clinical
Examples profilea AEs Additional considerations
● Fluoxetine Some are also ● Headaches, GI distress, ● Avoid many of the
● Paroxetine specifically approved insomnia, fatigue, anxiety, anticholinergic and
● Fluvoxamine to treat [32]: sexual dysfunction, weight cardiac AEs of the TCAs
● Panic disorder
● Sertraline gain, falls/fractures, [32]
● Social anxiety
● Citalopram coagulopathy [32,34–36] ● Do not require dietary
● Escitalopram [32] disorder ● Prolongation of QT interval and drug-related restric­
● OCD
with citalopram and escita­ tions [32]
● PTSD
lopram [32,35] ● Often prescribed first-line
● Bulimia nervosa
because of a more tar­
● Premenstrual dys­
geted MOA and safer AE
phoric disorder profile. Subtle AE differ­
ences must be weighed
by the prescriber
● May not be suited for
patients with sleep dis­
turbances [8,12,32]
● Risk of GI bleeding may
be doubled with conco­
mitant NSAID use [32,36]
● May be associated with
increased risk of falls and
fractures with long-term
use (may be less suited
to elderly patients)
[8,34,107,108]
● Associated with emo­
tional blunting [20,22]
● Associated with disconti­
nuation syndrome [12]
● Venlafaxine ● Venlafaxine may be ● Nausea, insomnia, dry ● Side effects are similar
● Desvenlafaxine suitable for mouth, headache, to SSRIs, but may reflect
● Duloxetine comorbid anxiety increased blood pressure, noradrenergic activity
● Levomilnacipran ● Duloxetine may be sexual dysfunction, weight [8]
[37] suited to treat gain [12,33,37] ● May not be suited for
depression with pain patients with sleep dis­
[33,37] turbances [33]
● Vilazodone ● Nausea, diarrhea, ● Better side-effect profile
headache, insomnia [48,53] than most
antidepressants with
lower risk of sexual
dysfunction or weight
gain [12,52,53]
● Vortioxetine ● Older patients (aged ● Nausea, diarrhea, dizziness ● Better side-effect profile
64–88 years) [52,55] than most
● TESD antidepressants with
● Deficits in cognitive lower risk of sexual
processing speed
dysfunction or weight
● Comorbid anxiety
gain [55]
[106] ● Excellent for avoiding
emotional blunting and
cognitive blunting in
most patients. Enhances
speed of cognitive pro­
cessing [54,55]
(Continued )

Table 1. (Continued).
Mechanism of antidepressant
Class effect
Atypical ● Norepinephrine-dopamine
reuptake inhibitor [8,12]
● No direct effects on sero­
tonin, histamine, acetyl­
choline, or adrenaline
receptors [50]
● Targets both melatonin and
serotonin receptors
[43,110]
● Inhibits norepinephrine
alpha-2 autoreceptors,
allowing more norepi­
nephrine to be released
from presynaptic nerve
terminals [12]
● Potent agonist of histami­
nergic H1 receptors [43]
● Also blocks serotonergic 5-
HT2A/2C and 5-HT3 receptors
[42,43]
● Serotonin antagonist and
reuptake inhibitor; com­
bined effect on serotonin
reuptake pumps and 5-
HT2A/2C receptors via both
receptor agonist and
antagonist activities [44]
MAOIs ● Inhibit the activity of the
enzyme monoamine
oxidase, preventing the
breakdown of monoamine
neurotransmitters [8,27,28]
TCAs ● Elevate extracellular
serotonin and
norepinephrine levels via
uptake inhibition [12]
● Antagonize muscarinic
acetylcholine receptors
POSTGRADUATE MEDICINE 453
Symptoms/Clinical
Examples profilea AEs Additional considerations
● Bupropion ● Fatigue ● Headache, agitation, ● Increased seizure risk in
● Anxious distress [8] insomnia, loss of appetite, patients with epilepsy
weight loss, sweating, ● No sexual dysfunction or
hypertension [8] weight gain
● Contraindicated in eating
disorder due to weight
loss
● May also help patients
quit smoking [8]
● Commonly used for aug­
mentation [50]
● Agomelatineb ● Comorbid insomnia ● Toxic hepatitis (rare, ● The first melatonergic
[48] sporadic) [48] antidepressant designed
to restore perturbed
biological rhythms
[47,110]
● Requires monitoring of
liver function [48]
● Possibly lower risk of
sexual side effects [110]
● Mirtazapine ● Comorbid insomnia, ● Sedation, increased ● Reduced sexual
GAD, OCD, PTSD, appetite, weight gain [8] dysfunction compared
social anxiety ● Potential increase in cho­ with SSRIs/SNRIs [42]
disorder, headaches/ lesterol [8,43] ● Some risk of reduced
migraine [42] WBC count [42]
● May have fast onset of
action compared with
SSRIs [41]
● Trazodone ● Comorbid insomnia ● Sedation, nausea, priapism ● Reduced risk of sexual
● Nefazodone or GAD [44,45] (rare), orthostatic dysfunction, but may
hypotension [8] cause priapism [44]
● Often used to induce
sleep as a positive effect;
slow-release formulation
may be less sedating
[8,46]
● Concerns with hepato­
toxicity and liver function
monitoring limit the use
of nefazodone [12,44]
● Isocarboxazid ● MDD with atypical ● Weight gain, fatigue, ● Generally, not
● Phenelzine features, or patients orthostatic hypotension, prescribed first-line due
● Tranylcypromine with poor response sexual side effects [8] to food and drug-drug
● Selegiline to other interactions that may
● Moclobemide antidepressants cause serotonin
[8,12,28] [8,28,29] syndrome and
hypertensive crises
[8,12,28,29]
● Selegiline and moclobe­
mide may be considered
safer and more suitable
for use earlier in treat­
ment
● Imipramine ● Amitriptyline for ● Weight gain, sedation, dry ● Generally, not
● Amitriptyline pain, melancholia mouth, nausea, blurred prescribed first-line due
● Doxepin (psychomotor vision, constipation, to increased
● Desipramine slowing, diurnal tachycardia, orthostatic anticholinergic and
● Nortriptyline mood variation) hypotension [8,19] cardiotoxic side effects,
● Amoxapine ● Comorbid insomnia risk of falls [8]
● Clomipramine ● Pain
● Maprotiline ● Social anxiety
● Trimipramine disorder
● Protriptyline ● Severely depressed
[3,8,12] with melancholic
features [8,19]
(Continued )
454 C. B. MONTANO ET AL.

Table 1. (Continued).
Mechanism of antidepressant
Class effect
NMDA receptor ● Ketamine is
antagonists a noncompetitive NMDA
and glutamate receptor
antagonist, predicted to
mediate its effect by
a secondary increase in
structural synaptic
connectivity [111]
● Esketamine, like ketamine,
is postulated to inhibit
NMDA receptor on gamma-
aminobutyric acid inter­
neurons to restore synaptic
function [112]
● Dextromethorphan/bupro­
pion increases norepi­
nephrine availability by
inhibiting reuptake and
acting as alpha-4-beta-2
nicotinic antagonists [56]
Dextromethorphan is an
uncompetitive antagonist
of the NMDA receptor and
a sigma-1 receptor agonist.
Bupropion increases
plasma levels of dextro­
methorphan by inhibiting
CYP2D6, and may be
related to noradrenergic
and/or dopaminergic
mechanisms [56,59]
a
Not all are on-label. Consult the prescribing guide for the specific antidepressant.
b
Not currently available for use in the United States.
5-HT: serotonin, AE: adverse event, GAD: generalized anxiety disorder, GI: gastrointestinal, CYP2D6: cytochrome P450 2D6, MAOI: monoamine oxidase inhibitor,
MDD: major depressive disorder, MOA: mechanism of action, NMDA receptor: N-methyl-D-aspartate receptor, NSAID: nonsteroidal anti-inflammatory drug, OCD:
obsessive-compulsive disorder, PTSD: posttraumatic stress disorder, REMS: Risk Evaluation and Mitigation Strategy, SNRI: serotonin-norepinephrine reuptake
inhibitor, SSRI: selective serotonin reuptake inhibitor, TCA: tricyclic antidepressant, TESD: treatment-emergent sexual dysfunction, TRD: treatment-resistant
depression, WBC: white blood cell
Symptoms/Clinical
Examples profilea AEs
● Ketamine ● Ketamine and ● Ketamine and esketamine: ●Ketamine
● Esketamine esketamine: TRD Treatment-emergent
● Dextromethorphan/ with ≥2 failed adverse events generally
bupropion antidepressants include, but are not limited ● Intranasal esketamine
treatment, or for to, psychiatric
MDD patients with (psychotomimetic effects
acute suicidality and dissociation),
[23,57] neurologic/cognitive
(dizziness, drowsiness and
light-headedness),
hemodynamic,
genitourinary, and abuse
liability [23]
● Dextromethorphan/ bupro­
pion: Dizziness, nausea,
headache, diarrhea, som­
nolence, dry mouth [24]
Additional considerations
and esketamine:
Have rapid-onset efficacy
in TRD [23]
and intravenous keta­
mine are effective routes
of administration [23]
● To be administered only
in settings with multidis­
ciplinary trained person­
nel [23]
● Esketamine administra­
tion may require REMS in
some countries (e.g. the
United States) [23]
● Some treatment-
emergent adverse events
with ketamine are dose
dependent
● In cases of discontinua­
tion, a transitions-of-care
plan is necessary for
ongoing surveillance of
depressive symptoms
[23]
Dextromethorphan/
bupropion:
● Rapid efficacy compared
to antidepressant mono­
therapy [56]
● May increase seizure risk
in patients taking higher
doses, and with certain
other medicines and
medical conditions [59]
● To be avoided for
patients who have or had
seizure disorder or eating
disorder, and if a MAOI is
used in the last 14 days
[59]
● May increase risk of
hypertension [59]

randomized controlled trials (RCTs) [12,23–26]. Below we discuss
some of the key safety and prescribing considerations for each.
4.1. TCAs and MAOIs
TCAs and MAOIs were the first antidepressants to be introduced
following the discovery of their antidepressant properties in the
1950s [27,28]. TCAs act primarily by elevating extracellular ser­
otonin and norepinephrine levels via uptake inhibition [12].
TCAs are prone to anticholinergic side effects (e.g. dry mouth,
blurry vision, constipation, urinary retention), which often limit
their utility. TCAs can cause significant weight gain and
sedation, resulting in relatively high discontinuation rates.
They can also block cardiac sodium channels, which in the
case of overdose can lead to sudden cardiac death [12]. Once
SSRIs and SNRIs became available, there was generally less use
of TCAs, but they continue to be of use for patients with
comorbid insomnia, pain, and social anxiety disorder, and in
severe or resistant MDD with melancholia [8,19].
The broad mechanism of action (MOA) of MAOIs means
that they have significant adverse events, such as weight gain,
fatigue, and sexual side effects, making them now used almost
exclusively in patients who have not responded to other anti­
depressant classes or those with MDD with atypical features,

such as reactive moods or sensitivity to rejection [8,28,29].
Early, nonselective MAOIs had potentially lethal interactions
with food, particularly foods rich in tyramine, and with other
medications, which can precipitate fatal serotonin syndrome
or hypertensive crises [12]. Because of this, MAOIs should not
be used in antidepressant augmentation with SSRIs because of
a potentially lethal increase in serotonin in the central nervous
system (CNS) [29,30]. There is some evidence that the risk and
severity of adverse dietary reactions with MAOIs may be less
severe than previously thought, especially when proper mon­
itoring by clinicians and adherence by patients are followed
[29,31].
4.2. SSRIs and SNRIs
SSRIs are the most widely used antidepressants in contempor­
ary treatment for MDD and include fluoxetine, sertraline, par­
oxetine, fluvoxamine, citalopram, and escitalopram [8,12,32].
A large body of literature supports the efficacy of SSRIs com­
pared with placebo for the treatment of MDD, and their
relative safety has driven a sharp increase in the prescribing
of pharmacotherapy for MDD [8,12,32]. Within the class, SSRIs
have noteworthy yet nuanced differences in their pharmaco­
logic profiles that may impact their clinical application, of
which prescribers should be aware [12]. A slower emergence
of the therapeutic effects of fluoxetine compared with other
SSRIs is one example. Further, some SSRIs are also specifically
approved to treat panic disorder, social anxiety disorder,
obsessive-compulsive disorder (OCD), posttraumatic stress dis­
order (PTSD), bulimia nervosa, and/or premenstrual dysphoric
disorder. Sertraline and paroxetine have several FDA approvals
and indications to treat a myriad of psychiatric disorders [12].
All SSRIs may cause nausea, headaches, gastrointestinal (GI)
issues, insomnia, fatigue, weight gain, anxiety, dizziness, dry
mouth, and sexual side effects and have been associated with
increased risk of falls and fractures [8,27,33,34]. Paroxetine
eventually may cause more weight gain, and paroxetine and
citalopram may be the most sedating. Sertraline may have
more adverse GI effects, and paroxetine and fluoxetine have
more drug-drug interactions via the cytochrome P450 (CYP)
2D6 hepatic enzyme inhibition [12]. SSRIs, particularly citalo­
pram, have the potential to prolong the QT interval, which can
lead to torsade de pointes, a rare but potentially fatal arryth­
mia [32,35]. SSRIs have also been associated with coagulopa­
thy, and use in combination with pain relievers such as aspirin,
naproxen, and blood thinners may increase the risk of bleed­
ing [32,36]. In addition, SSRIs may cause the syndrome of
inappropriate antidiuretic hormone secretion, with the great­
est risk among elderly patients.
SNRIs include venlafaxine, desvenlafaxine (the active meta­
bolite of venlafaxine), duloxetine, milnacipran, and levomilna­
cipran [37]. Each of these medications is efficacious (superior
to placebo in controlled studies and meta-analyses), and ven­
lafaxine (75–150 mg/day) and duloxetine (60 mg/day) showed
comparable efficacy in a pair of similarly designed RCTs
directly comparing these 2 antidepressants [8,38]. Side effects
most common to the class of SNRIs include nausea and vomit­
ing, dizziness, and sweating. Duloxetine and venlafaxine, in
POSTGRADUATE MEDICINE 455
particular, may cause sexual dysfunction [33,37]. Other side
effects include fatigue, insomnia, and headache [33].
Antidepressants, and in particular SSRIs and SNRIs, are also
associated with emotional blunting or indifference [20,22].
This may be underrecognized by both patients and clinicians
and poses a challenge for effective treatment because it is
frequently a cause for treatment discontinuation [20,22]. Later
in this review, we have a dedicated section on treatment
strategies for emergent emotional blunting in MDD.
Another issue associated with the use of SSRIs and SNRIs is
the emergence of withdrawal symptoms of varying severity
following discontinuation or interruption of treatment [33,39].
Symptoms of this so-called “discontinuation syndrome” can
include tremors, sweating, tachycardia, agitation, neuralgia,
sleep disturbances, vivid dreams, GI symptoms, worsening
anxiety, and mood instability [33,39]. Symptoms can be unpre­
dictable and may affect everyone differently, emerging within
a few days to weeks and potentially persisting for months or
even years [33,39]. In particular, sertraline and paroxetine of
the SSRIs, and venlafaxine and its active metabolite, desvenla­
faxine, of the SNRIs, have been associated with significant
withdrawal symptoms, which may be due to their shorter half-
lives [12,33,37,39,40]. Tapering of the treatment over weeks to
months may help to mitigate symptoms related to disconti­
nuation of SSRIs and SNRIs [33].
4.3. Atypicals
4.3.1 Mirtazapine: A pooled analysis showed fast onset of
antidepressant effect with mirtazapine, and a meta-analysis
has confirmed accelerated onset of efficacy of mirtazapine
but equal efficacy by week 8 compared with SSRIs (fluoxetine,
citalopram, paroxetine, and sertraline) [41]. Mirtazapine has
significant sedation properties, tends to promote weight gain
and causes dry mouth, but has a low rate of sexual dysfunc­
tion [8,12]. The sedative, antiemetic, anxiolytic, and appetite-
stimulating effects of mirtazapine suggest that it can also be
prescribed off-label for insomnia, panic disorder, PTSD, OCD,
generalized anxiety disorder (GAD), social anxiety disorder,
headaches, and migraines [42,43]. Mirtazapine will generally
be prescribed for MDD after an SSRI, or in depressed adults
with comorbid insomnia or those who are underweight [42].
4.3.2 Trazodone: Trazodone was an early second-generation
antidepressant whose low side-effect and toxicity profile made
it a popular alternative to MAOIs and TCAs in the early 1980s;
it is still relatively widely used [8,12]. It is considered a sedating
antidepressant, making it suited to patients with comorbid
insomnia or GAD [44,45]. A slow-release preparation is avail­
able that lowers plasma levels and tends to minimize the
sedating side effects relative to the standard formulation
[46]. Nefazodone has a structure analogous to trazodone but
has different pharmacologic properties. It has largely fallen out
of use because of concerns about hepatotoxicity and the need
for periodic liver function monitoring [12,44].
4.3.3 Agomelatine: Agomelatine was first marketed in
Europe in 2009 and has been available in Australia since
2010 but is not currently available in the United States [47].
Agomelatine has a unique MOA, targeting both melatonergic
and serotonergic receptors, with demonstrated superior
456 C. B. MONTANO ET AL.
effects on subjective or objective sleep measures, in addition
to being an effective antidepressant [48]. In countries where it
is available, it is often recommended for individuals with MDD
and sleep disturbances [48]. While agomelatine has been
demonstrated to be safe and effective, there is potential for
drug interactions mediated via CYP1A2, and it is also asso­
ciated with liver damage with longer-term use and is contra­
indicated in patients with impaired liver function [47].
4.3.4 Bupropion: Bupropion was initially approved in the
United States in the 1980s as an antidepressant but sub­
sequently removed from the market because of induction
of seizures in patients with MDD. It was remarketed after
lower doses were noted to be safer [12,49]. A meta-analysis
of 7 RCTs demonstrated comparable efficacy between
bupropion and the SSRIs fluoxetine, sertraline, and parox­
etine [41]. The side-effect profile of bupropion reflects its
unique MOA, having no sexual dysfunction or weight gain
tendencies [12], yet it is also more activating with regard
to insomnia and anxiety, causing agitation, mild cognitive
dysfunction, and GI upset, and should be avoided in indi­
viduals with comorbid eating disorders because of the
increased risk of seizures [8]. It is frequently prescribed as
a combination antidepressant, often added to an initially
partially effective SSRI [50].
4.4. Serotonin modulators
4.4.1 Vilazodone and vortioxetine: Vilazodone and vortioxe­
tine are more recent entries to the antidepressant space,
and each may be considered a “serotonin modulator and
stimulator” or multimodal antidepressant [12,51]. Vilazodone
appears to have a lower risk of weight gain and sexual side
effects than the SSRIs or SNRIs based on noncomparative
trials [12,52,53]. Vilazodone should be taken with food to
ensure adequate absorption, and a titrated dosing schedule
is recommended to minimize GI effects that are frequently
observed [48,53].
Vortioxetine has demonstrated suitability for patients with
MDD aged 18 to 88 years, including those experiencing treat­
ment-related sexual dysfunction with other antidepressants,
and those with deficits in cognitive processing speed [54,55].
GI symptoms, which were dose dependent, were the most
common adverse events in clinical trials. Vortioxetine can be
taken with or without food [52,55].
4.5. NMDA receptor antagonists
4.5.1 Ketamine and esketamine: The delayed onset of effect
seen with most traditional antidepressants has led to great
interest in the use of agents with a rapid onset of effect
[56]. NMDA receptor antagonists [23], such as ketamine
and esketamine, have demonstrated a rapid and robust
antidepressant effect in adults with treatment-resistant
depression (TRD), defined as lack of response to at least
2 adequate antidepressant treatments from different phar­
macological classes [57], with esketamine also approved
for MDD with suicidality [23]. However, both ketamine
and esketamine carry potential for clinically significant
adverse effects, abuse, and misuse, and have limited [23]
evidence of long-term efficacy. Patient selection for these
agents should involve thorough evaluation of treatment
history and other physical and psychological factors [58],
and it is recommended that a psychiatrist or other health­
care provider with expertise in the treatment of patients
with mood disorders conduct a psychiatric assessment
before and after treatment [23]. In addition, clinicians
must exercise caution when prescribing, factoring in rele­
vant regulatory requirements, such as the Risk Evaluation
and Mitigation Strategy drug safety program [23].
4.5.2 Dextromethorphan-bupropion: Similar to ketamine,
dextromethorphan is an NMDA receptor antagonist with
multimodal activity [56]; however, its clinical use has been
limited by the difficulty in achieving therapeutic plasma
levels due to its rapid metabolism via cytochrome P450
2D6 (CYP2D6) [56]. An oral tablet combining dextromethor­
phan with bupropion, a known antidepressant and inhibitor
of CYP2D6 that increases the bioavailability and half-life of
dextromethorphan and leads to sustained therapeutic con­
centrations [24,56], has shown promising results in a 6-week
randomized, double-blind, placebo-controlled, phase 3
study [24]; significant improvements in depressive symp­
toms compared to placebo were demonstrated as early as
1 week after treatment initiation [24]. Notably, dextro­
methorphan-bupropion was not associated with psychomi­
metic effects. The FDA granted approval for its use in MDD
in August 2022 [59]; however, additional data investigating
long-term efficacy and safety will help define its role in the
MDD treatment landscape [60].
5. Assessment of suicide risk in patients starting
antidepressant therapy
When initiating patients on antidepressant therapy, suicide
risk must be monitored, as some antidepressants have been
associated with an increased risk of suicidal thoughts and
behaviors, particularly in children, adolescents, and young
adults [48,61,62]. In 2004, the FDA directed manufacturers
of all antidepressants to revise their labeling as the result of
an increase in suicidality among children and adolescents
being treated with antidepressants. This warning was based
on a combined analysis of 24 short-term (up to 4 months),
placebo-controlled trials of 9 antidepressant drugs among
more than 4400 children and adolescents with MDD or
other psychiatric disorders. A greater risk of suicide during
the first few months of treatment was observed in patients
receiving antidepressants (4% vs. 2% in patients receiving
placebo) [62]. In 2007, the FDA revised the warning, chan­
ging the target period from childhood and adolescence to
young adulthood (aged 18–24 years) during initial treat­
ment [62]. However, clinicians should continue to monitor
for suicidality in all patients being treated for depression
with or without antidepressant medication.

6. Selecting pharmacotherapy for the treatment of
MDD: what do the guidelines say? Factors to
consider when initiating antidepressant treatment in
primary care settings
6.1. Efficacy
Given that depression is a heterogeneous illness with multiple
clinical presentations, antidepressant selection should be
based on patient profile and tolerability, especially considering
any comorbidities (for example, ADHD) [12,63]. Clinical prac­
tice guidelines for the treatment of MDD generally emphasize
the importance of tailoring the selected therapy to the patient
based on their clinical profile and individual preferences
(Figures 2 and 3) [3,8,48]. For example, the 2020 Royal
Australian and New Zealand College of Psychiatrists (RANZP)
clinical practice guidelines for major depression note that
there is a modest hierarchy with respect to efficacy of anti­
depressants. These guidelines state that, generally, the medi­
cations with a broader spectrum of action, such as TCAs,
appear to be more clinically efficacious than those that are
more selective [3]. Although TCAs and MAOIs may exert effec­
tiveness in treating depression, their safety profiles are of
significant concern [12]. Hence, more selective may mean
less effective in some patients. However, the 2010 American
Psychiatric Association (APA) Practice Guideline for the
Treatment of Patients With Major Depressive Disorder states
that the effectiveness of antidepressants is generally compar­
able between and within classes of medications [8]. The
Canadian Network for Mood and Anxiety Treatments
(CANMAT) 2016 Clinical Guidelines for the Management of
Adults With Major Depressive Disorder provide evidence of
superiority of some antidepressants over others. However,
they also emphasize the importance of tailoring pharmacolo­
gic treatment to the patient’s symptoms and preferences,
similarly stressing that there are no absolutes [48].
A comprehensive and relatively recent network meta-analysis
by Cipriani et al. consisting of 522 clinical trials and 116,477
participants with acute MDD reported that in head-to-head
studies, agomelatine, amitriptyline, escitalopram, mirtazapine,
paroxetine, venlafaxine, and vortioxetine were more effective
than other antidepressants, whereas fluoxetine, fluvoxamine,
reboxetine, and trazodone were the least efficacious drugs [64].
Figure 2. Treating MDD in primary care: factors influencing initial antidepressant selection [3,8,84].
POSTGRADUATE MEDICINE 457
For acceptability (defined as treatment discontinuations due to
any cause), agomelatine, citalopram, escitalopram, fluoxetine,
sertraline, and vortioxetine were more tolerable than other anti­
depressants, whereas amitriptyline, clomipramine, duloxetine,
fluvoxamine, reboxetine, trazodone, and venlafaxine had the
highest dropout rates [64]. The authors noted that the results
should inform guideline and policy developers on the relative
merits of the different antidepressants available [64]. Until there
is consensus regarding the superiority of one class of antide­
pressant over another, initial selection of an antidepressant will
be based largely on cost, patient preference and previous
responses, anticipated side effects, nuances of patient’s clinical
profile including comorbidities, and their specific and most
severe/dominant symptoms (Figure 2) [3,8]. Additionally, phar­
macologic properties of the medication (e.g. half-life, actions on
CYP enzymes, other drug interactions) must be considered [49].
7. Patient clinical profile and comorbidities
It is logical that an initial antidepressant is selected based on
the most prominent/severe depressive symptoms experienced
by the patient (e.g. suicide risk, sleep disturbances, cognitive
disturbances, anxiety, somatic symptoms, or atypical features
such as oversleeping and overeating) [28,48]. Clinical practice
guidelines address the different depression subtypes that can
be an important modifier of antidepressant efficacy, such as
depression with melancholic features (psychomotor slowing,
diurnal mood variation), depression with anxious distress, or
depression with psychotic or catatonic features [3,48]. The
Korean Medication Algorithm Project for Depressive Disorder
provides first- and second-line recommendations for nonpsy­
chotic depression, psychotic depression, and specific depres­
sion subtypes [62]. Other patient-related factors, such as cost,
age, level of sexual activity, comorbid conditions, preferences,
use of concomitant medications, response to prior antidepres­
sants, and pregnancy status, all become necessary considera­
tions as well [8,48]. In addition, pharmacogenetic testing can
sometimes guide providers in choosing potential pharma­
cotherapy, and patients may qualify for enrollment in clinical
trials, as multiple neurotransmitter and receptor targets are
currently under investigation and may help guide and
458 C. B. MONTANO ET AL.
Figure 3. Summary algorithm for selecting an antidepressant [3,8,48,88].
improve patient outcomes, including time to response and
complete remission of depression [65,66].
8. Tolerability and adherence
The 2010 APA guideline states that ”the optimal regimen is
the one that the patient prefers and will adhere to [8].”
Tolerability and patient preference therefore become critical
because they relate directly to medication adherence, which
has implications for response and remission, and antidepres­
sants differ in their potential to cause certain side effects (as
described in the previous section and Table 1) [8,67]. Indeed,
an important part of patient satisfaction with MDD treatment
comes from adequately addressing concerns about side
effects such as weight gain and sexual dysfunction. In
a study of 180 patients receiving treatment for MDD, key
concerns expressed by patients included weight gain, with­
drawal effects, and sexual dysfunction [68]. However, other
side effects commonly associated with antidepressants, of
which patients may be less aware, include hypertensive crises,
serotonin syndrome, and cardiovascular and neurological
effects, all of which are important for the prescriber to con­
sider [8]. Other factors that can influence adherence include
the patient’s clinical profile, sociocultural background, finan­
cial factors, and beliefs regarding the effectiveness of the
treatment. This is where physician expertise and a strong
doctor-patient relationship become vital [67].
9. Patient preference and shared decision-making
From the perspective of the primary care provider, physician
expertise can help guide the patient to select the
antidepressant that suits their preferences while also being
best suited to their clinical profile [3]. The concept of the
“therapeutic alliance” between the patient and provider is
important in primary care settings, with the aim being to
establish an effective partnership, taking into consideration
the patient’s preferences and ensuring that they adhere to
treatment and do not discontinue due to issues with toler­
ability without first speaking with their provider. This gives
patients the greatest chance of achieving response, remission,
and sustained functional recovery while on therapy [8].
Measurement-guided care, which uses validated screening
and monitoring tools, is encouraged for use by clinicians to
quantify the presence and severity of depressive symptoms
and track improvements in functional outcomes and adverse
events following initiation of an antidepressant. The incor­
poration of measurement-guided care increases the likelihood
of remission, treatment adherence, and sustained functional
recovery [8,69].
10. Guideline recommendations for antidepressants
There is considerable variability among clinical practice guide­
lines. The 2010 APA guideline describes the different classes of
antidepressants but does not make prescriptive recommenda­
tions concerning their selection [8]. The 2016 CANMAT guide­
lines list SSRIs, SNRIs, agomelatine, bupropion, mirtazapine,
and vortioxetine as first-line recommendations [48]. Second-
line recommendations include TCAs, quetiapine, and trazo­
done (owing to higher side-effect burden); moclobemide and
selegiline (potential serious drug interactions); levomilnacipran
(lack of comparative and relapse-prevention data); and vilazo­
done (lack of comparative and relapse-prevention data and

the need to titrate and take with food) [48]. Third-line recom­
mendations include MAOIs (owing to higher side-effect bur­
den and potential serious drug and dietary interactions) and
reboxetine (lower efficacy) [48]. The 2020 RANZP guidelines
for major depression list 7 molecules with different MOAs that
they recommend as “Choice” antidepressants, which is
a unique approach to treatment recommendations (escitalo­
pram, vortioxetine, agomelatine, venlafaxine, mirtazapine,
bupropion, amitriptyline) [3]. The RANZP guidelines also pro­
vide guidance on selecting these molecules according to the
patient’s clinical profile and to minimize side effects [3]. While
many if not all recommendations provided by the guidelines
discussed may continue to be applicable, updates are needed,
particularly for inclusion of newer agents such as NMDA recep­
tor antagonists.
11. Partial or inadequate response to initial
antidepressant
Regardless of the intervention used, a substantial proportion
of patients do not adequately respond or achieve remission
after initial treatment. For example, about 40% of patients
treated with second-generation antidepressants do not
respond, and approximately 70% do not achieve remission
[10]. Partial or inadequate response is important to address
because a lack of early improvement in symptoms (defined in
RCTs as a 20%–30% reduction from baseline in a depression
rating scale after 2–4 weeks) is a predictor of later antidepres­
sant nonresponse/nonremission. However, there is only low-
quality evidence to support early switching at 2 or 4 weeks for
nonresponders to an initial antidepressant [48]. Inadequate
responses to antidepressants can also prompt nonadherence,
which can be an important driver of poor response to an
antidepressant therapy [3,67]. In primary care settings where
defining partial or inadequate response may be ambiguous,
measurement-guided care using time-efficient patient- and
clinician-completed rating scales may help with patient mon­
itoring following initiation of an antidepressant (Figure 3). This
can assist both the patient and provider in tracking and clin­
ical management of symptoms and functioning over time,
identifying factors influencing inadequate response, and
understanding if treatment adjustments are needed [8,69].
11.1. Increasing the dose/duration of antidepressants
Almost all approved antidepressants have an initial dose that
can be incrementally increased depending on the patient’s
response and tolerability [8]. Partial responses to antidepres­
sants can be addressed by first increasing the dosage at 2 to
4 weeks if tolerated [3,48]. In addition, the 2010 APA guideline
suggests doing this after 4–8 weeks of treatment and provides
guidance for the starting dose of the different classes of anti­
depressants and the usual daily dosage, which should be
increased incrementally [8]. Prescribing information for each
antidepressant can also be consulted for the most up-to-date
dosing information.
POSTGRADUATE MEDICINE 459
11.2. Assessing treatment adherence and reevaluating
diagnosis: bipolar disorder (BPD) and comorbid ADHD as
examples
Unipolar depression is a diagnosis of exclusion, as bipolar
depression, or BPD, must first be ruled out. Often the first
presentation of BPD is a major depressive episode (MDE),
which may be indistinguishable from that of unipolar depres­
sion [70]. Up to 25% of patients presenting with an MDE may
in fact have BPD [71]. Screening tools are available for eva­
luation of BPD in primary care, such as the Rapid Mood
Screener, a validated scale, and the Mood Disorder
Questionnaire; both are time-sensitive and extremely helpful
for ruling out BPD [70]. It is also important to rule out BPD
because there is evidence suggesting that antidepressant
monotherapy in individuals with BPD can induce states of
hypomania, mood destabilization, and potential increase in
suicidality [72,73]. The consensus is that individuals diag­
nosed with BPD should not be treated with antidepressant
monotherapy as a first-line strategy, as mood stabilizers
and second-generation antipsychotics are considered to be
more appropriate and are less likely to cause mood cycling
[72,74]. Once BPD is excluded, the APA guideline suggests
that if at least moderate improvement in symptoms of uni­
polar depression is not observed within 4–8 weeks of treat­
ment initiation, the diagnosis should be reassessed.
Antidepressant side effects should be taken into considera­
tion, complicating co-occurring conditions and psychosocial
factors reviewed, and the treatment plan adjusted accord­
ingly [8,75,76]. Other factors to consider include pharmaco­
kinetic or pharmacodynamic influences on efficacy, as blood
levels of antidepressants can help determine if dosage
adjustments are needed [8]. Treatment adherence should
also be evaluated [8], as there is evidence that up to 20%
of patients may have poor adherence [48]. This should be
done before moving on to a different antidepressant.
ADHD is frequently comorbid with both BPD and MDD, and
a mean prevalence of 7.8% of comorbid ADHD in individuals with
depression has been reported, complicating identification and
management of each disorder [16,63,77]. Depressive symptoms
in adults with ADHD may manifest as a result of coping with
lower hedonic tone, and in one study, up to 28% of individuals
referred to a tertiary clinic for mood and anxiety disorders had
undetected ADHD [16,78]. Symptoms of ADHD may also be
masked by substance use disorder, as individuals with ADHD
have double the risk of substance abuse and dependence com­
pared with the general population [79]. Symptoms of ADHD
respond best to catecholaminergic agents such as psychostimu­
lants or norepinephrine-dopamine reuptake inhibitors such as
bupropion, which has shown potential off-label use for treat­
ment of ADHD [80]. In addition, viloxazine, an SNRI previously
used for treatment of MDD in Europe, was recently approved by
the FDA for treatment of ADHD and has shown promise as
a nonstimulant option [27,81,82]. Serotonergic agents alone do
not improve symptoms of ADHD; thus, initiation of treatment
with an SSRI alone for MDD in an individual with comorbid ADHD
is likely to yield unsatisfactory response to treatment for either
MDD or ADHD [16].
460 C. B. MONTANO ET AL.
In primary care settings where depressive symptoms may
be more frequently reported by adults and therefore more
easily diagnosed, clinicians may benefit from asking adult
patients presenting with depressive symptoms questions
about previous diagnosis or family history of ADHD, or
whether they had difficulty in school. This may help to identify
comorbid ADHD in their patients [77].
11.3. Combination, switching, and augmentation
strategies
In clinical practice guidelines, there is no consistent evidence
supporting switching within or between antidepressant classes.
Switching within a class has been noted as acceptable if the
antidepressant was not taken as prescribed because of poor
adherence or side effects; however, there is limited guidance on
how to switch to a different antidepressant in the same class
[3,48]. There are few RCTs comparing a switch strategy to continu­
ing the same antidepressant, and thus the value of switching
between or within classes remains controversial [48]. One theory
regarding why patients often respond suboptimally to their initial
antidepressant is that receptor tolerance to drug action precipi­
tates antidepressant nonresponse, so treatment switching to
a different class could be considered a reasonable strategy [83].
There is limited information about which treatments may be best
suited as second-line therapies in patients who have not achieved
an adequate response with their initial antidepressant, but the
selection of the subsequent therapy should account for the class/
MOA and response to initial antidepressant [84].
Combination and augmentation strategies are additional
approaches to consider if the patient continues to have
a partial or inadequate response at the maximally tolerated
dose of initial therapy after an adequate duration of treatment
[3,62,76]. The combination of 2 antidepressants with different
MOAs may have synergistic effects that enhance response in
inadequate responders, and there is some evidence support­
ing the addition of bupropion to an SSRI [8,76]. Further, pre­
scribers must be aware of the risk for serotonin syndrome
when combining antidepressants.
Augmentation typically involves the addition of a non-
antidepressant to a current antidepressant. As we have men­
tioned, multiple comorbidities can drive the patient to experi­
ence symptoms of depression, which must be kept in mind
when approaching augmentation and combination strategies.
Augmentation with lithium and atypical antipsychotics (e.g.
aripiprazole, cariprazine [85], brexpiprazole, risperidone, que­
tiapine, or olanzapine) may be appropriate strategies to con­
sider for non- or partial responders who may have mixed
features, TRD, or BPD, for example [3,8,48]. For adults with
MDD who have comorbid ADHD, most antidepressants can be
combined (with monitoring) with long- or short-acting stimu­
lants to treat ADHD symptoms [16,63,77,79]. Long-acting pre­
parations are preferred when using psychostimulants.
12. Antidepressant therapy for MDD: filling the
literature gaps
There is heightened awareness of the ability of antidepressants
to aid patients with MDD struggling to achieve full functional
recovery, as well as of the impact of comorbid symptoms such as
distractibility, sleep disturbance/apnea, emotional blunting, and
anxiety. This section aims to highlight recently published data on
antidepressant effectiveness for these specific issues where lit­
erature gaps have been identified. We conducted a search of
articles in English from 2013 to the present pertaining to use of
antidepressants for functional recovery, and comorbid symp­
toms such as sleep disturbances, emotional blunting, and anxi­
ety. Data continue to emerge on a range of antidepressants that
may be prescribed to address these specific challenges in indivi­
duals with MDD, and longer-term and real-world studies are
providing insights into which antidepressants may be best suited
for patients experiencing specific symptoms. Of note is that
distinguishing symptoms such as sleep disturbances or emo­
tional blunting with antidepressant therapy from residual symp­
toms of MDD remain a challenge.
12.1. Antidepressant therapy, cognitive dysfunction, and
functional outcomes
In 2015, CANMAT published recommendations for assessment
of functional outcomes in individuals with MDD, which high­
lighted the critical impact of depressive symptoms on social,
occupational, and physical functioning [48,86]. Functional sta­
tus relates to an individual’s ability to “perform the tasks of
daily life and to engage in mutual relationships with other
people in ways that are gratifying and that meet the needs of
the individual and the community in which they live” [86]. The
CANMAT guidelines emphasized that recovery from depres­
sion must involve both relief of symptoms and improvement
of functioning, but systematic reviews show that functional
outcomes are only modestly correlated with symptom out­
comes, and functional improvement may lag behind symptom
improvement, which is prioritized as an outcome in the major­
ity of RCTs [48,86,87].
Symptoms of cognitive impairment may have a particularly
adverse effect on functional outcomes and have been linked to
psychosocial dysfunction, patient employment status, and ability
to functionally recover [88–91]. Further, antidepressants that are
best suited to treat cognitive symptoms may lead to improve­
ments in functional outcomes for patients, but there are few
studies that address this subject. PERFORM-J, a 6-month, non­
interventional, prospective, longitudinal study, investigated the
relationship among cognitive disturbances, severity of depres­
sive symptoms, and social functioning in patients with MDD in
Japan. Notably, improvement of depressive symptoms in the
early stages of antidepressant treatment was associated with
a reduced risk of residual cognitive symptoms after 6 months
in patients with MDD, highlighting the importance of early
improvements in depressive symptoms for long-term remission
and the need for early and aggressive monitoring and treatment
modifications with measurement-guided care [91,92]. Also, resi­
dual cognitive disturbances have been demonstrated in indivi­
duals with MDD even after achieving remission from mood
symptoms, which can have an impact on long-term outcomes
including remission, relapse, and social functioning [92]. In
a 3-year follow-up study, approximately 44% of individuals with
MDD who reported partial/full remission with treatment contin­
ued to experience impairments in cognitive function despite the
 POSTGRADUATE MEDICINE 461

resolution of their depressed mood [90]. The precise mechanisms 12.2. Antidepressant therapy and sleep disturbances
for the lasting cognitive impairment, even in remitters from
Sleep disturbance is a prominent symptom in patients with
mood symptoms, are unclear, but it is possible that neurobiolo­
MDD, and depressed patients with sleep disturbance are more
gical insults due to recurring depressive episodes may be respon­
likely to present with more severe symptoms and difficulties
sible (some patients with MDD show atrophy of the
with treatment [94,95]. Insomnia is a predisposing factor for
hippocampus, which may be associated with lingering cognitive
the development of new or recurring depression in young and
symptoms) [92].
older adults [94]. Persistent insomnia is the most common
Baune and colleagues conducted a systematic review of 35
residual symptom in depressed patients, is considered a vital
studies evaluating pharmacologic and nonpharmacologic
predictor of depression relapse, and may contribute to
treatments of cognitive impairment primarily in the domains
adverse clinical outcomes [94]. There are several different
of memory, attention, processing speed, and executive func­
proposed mechanisms involved in sleep disturbances and
tion in clinical depression [89]. The results showed that various
MDD; most notably for patients with MDD, there may be
classes of antidepressants exert improving effects on cognitive
a disruption to circadian rhythm, specifically rapid eye move­
function across several cognitive domains. Specifically, SSRIs,
ment (REM) sleep disturbances and dysfunction of the mono­
the selective serotonin reuptake enhancer tianeptine, the SNRI
aminergic and cholinergic systems [94,95]. Improving sleep
duloxetine, vortioxetine, and other antidepressants such as
outcomes in patients with MDD should be prioritized in pri­
bupropion and moclobemide may exert specific positive
mary care; however, some antidepressants can worsen sleep
effects on cognitive function in depression, such as learning,
quality due to their role in modulating levels of neurotrans­
memory, and executive function [89]. In addition to their
mitters involved in the sleep-wake cycle. These include the
positive effects on cognitive function, sertraline, citalopram,
SNRIs, MAOIs, SNRIs, SSRIs, and TCAs [94,96].
and nortriptyline or paroxetine improved overall psychosocial
Polysomnography studies have reported that SSRIs, SNRIs,
functioning, and duloxetine improved overall social function­
and activating TCAs increase REM sleep latency, suppress
ing and enjoyment of life, which may be due in part to its
REM sleep, and impair sleep continuity. Sedating antidepres­
pain-alleviating effect [89]. Further, in a separate analysis, Pan
sants, such as mirtazapine and trazodone, decrease sleep
and colleagues note that while most antidepressants exert
latency, ameliorate sleep efficiency, and increase slow-wave
procognitive effects, vortioxetine and duloxetine are the only
sleep, with little effect on REM sleep. In this regard, sedating
antidepressants that have established these effects when
antidepressants are favorable for patients with comorbid
a rigorous methodology is used [90].
depression and sleep disturbance [94]. In a meta-analysis of
A recent publication reported on the real-world effective­
276 RCTs exploring insomnia and somnolence associated
ness of vortioxetine for functional outcomes in patients with
with second-generation antidepressants, 10 of 14 antidepres­
MDD. In this 24-week observational study of outpatients initi­
sants showed significantly higher rates of insomnia than pla­
ating MDD treatment with vortioxetine, the Sheehan Disability
cebo, with the following increasing order of incidence:
Scale (SDS) was used as the main outcome measure to evalu­
escitalopram, duloxetine, venlafaxine, paroxetine, reboxetine,
ate patient functioning. Significant improvements in function­
fluoxetine, fluvoxamine, sertraline, desvenlafaxine, and bupro­
ing were observed, and the proportion of patients with severe
pion. Agomelatine was the only antidepressant that had
functional impairment decreased substantially [93]. Sustained
a lower likelihood of inducing insomnia than placebo.
improvements in functioning were seen over the 24 weeks of
Mirtazapine, milnacipran, and citalopram did not differ from
treatment irrespective of vortioxetine treatment line [93].
placebo in terms of insomnia rates [96].
In one of the few studies directly assessing antidepres­
sant effects on functional outcomes, a meta-analysis of 17
RCTs exploring occupational (workplace) impairment in
12.3. Emotional blunting
MDD reported a small positive effect versus placebo of
duloxetine, desvenlafaxine, venlafaxine, paroxetine, escitalo­ Limited evidence-based information exists on how emotional
pram, levomilnacipran, and vortioxetine on occupational blunting, or “numbness” of both positive and negative emo­
impairment in the short term as measured by the SDS- tions caused by antidepressant therapy, may be addressed in
work subscale. However, the authors questioned the overall individuals with MDD [22]. Patients with MDD who suffer from
clinical significance of the findings due to a small effect size emotional blunting are subject to a reduction in a broader
[87]. While the ability of antidepressants to exert positive range of emotions, including love, affection, fear, and anger,
effects on cognition is relatively well studied, more large- which is distinct from anhedonia and apathy, and may lead to
scale, longer-term studies that directly assess their impact reduced quality of life or reduced social responsibilities [22].
on functional outcomes are needed to be able to provide Emotional blunting is frequently reported by patients receiv­
more robust treatment recommendations for one antide­ ing antidepressant treatment for MDD, particularly SSRIs, and
pressant over another [48,87,89]. From a primary care per­ is considered to be one of the most prominent side effects
spective, sustained functional recovery in patients with MDD leading to treatment discontinuation [21,22,97].
should be considered an important treatment goal [91], and Approximately 40%–60% of patients who suffered from MDD
providers should maintain a partnership with their patients and were treated with either SSRIs, SNRIs, and TCAs experi­
to monitor functional outcomes with antidepressant therapy enced some degree of emotional blunting [97,98]. Some stu­
over time. dies suggest that emotional blunting is not simply a side effect
462 C. B. MONTANO ET AL.

of antidepressants, but also a residual symptom of depression one week, with dose reductions permitted based on individual
due to incomplete treatment, adding further complexity to tolerability [106].
understanding how it may be mitigated by appropriate treat­
ment selection [22,98].
Studies aimed at understanding the etiology of antidepres­
Conclusions
sant-induced emotional blunting have generally focused on
SSRIs and a possible modulating effect on frontal lobe activity The multitude of different types of antidepressants for MDD
via serotonergic signaling [22]. Other studies hypothesize represents both an opportunity and a challenge for primary care
a mutually opposed relationship between serotonergic and providers who must tailor the antidepressant to their patient.
dopaminergic systems, which may have inhibitory effects on Practitioners prescribing antidepressants in primary care can
rewarding and aversive stimuli [22,99]. Emotional blunting achieve better outcomes for their patients and help prevent
with antidepressants appears to be dose related, with several them from cycling through a range of different antidepressants
case studies noting a reduction in emotional blunting with an with inadequate response through careful selection of an initial
incremental tapering of the dose of SSRI. Thus, from a clinical antidepressant therapy. An initial therapy that fits the patient’s
perspective, dose reduction of SSRIs or other antidepressant is clinical profile and comorbidities is most likely to be successful and
a promising strategy if clinically feasible [22]. If there is any tolerated. Providers need to not only focus on relieving the symp­
question as to whether emotional blunting is still of concern, toms related to MDD, but also focus on improving functional
the Oxford Depression Questionnaire should be administered outcomes for their patients. Prioritizing the management of resi­
[100]. Another strategy is to switch to a different class of dual symptoms that can adversely impact response, remission,
antidepressant [22]. In more recent studies, emotional blunt­ and precipitate reoccurrence will help provide the patient with
ing has been found to be less frequent in patients taking the best chance of symptomatic and functional remission.
agomelatine than in those taking escitalopram (an SSRI), and
less severe when medication was switched from SSRIs/SNRIs
to vortioxetine [101,102]. Augmentation may also be consid­
List of Abbreviations
ered; however, the evidence for this as an effective strategy to
address emotional blunting is less robust [22]. 5-HT serotonin
ADHD attention deficit/hyperactivity disorder
AE adverse event
APA American Psychiatric Association
BPD bipolar disorder
12.4. MDD and comorbid anxiety CANMAT Canadian Network for Mood and Anxiety Treatments
CNS central nervous system
Few dedicated trials have been conducted in patients with CYP2D6 cytochrome P450 2D6
anxious depression, as MDD with comorbid GAD has not yet FDA US Food and Drug Administration
been recognized as a distinct disorder. Consequently, specific GAD generalized anxiety disorder
treatment guidelines and recommendations are lacking [103]. GI gastrointestinal
MAOI monoamine oxidase inhibitor
Fortunately, there is considerable therapeutic overlap between MDD major depressive disorder
agents used to treat both anxiety and depression, with many MDE major depressive episode
pharmacotherapies demonstrating efficacy for both disorders MOA mechanism of action
NMDA N-methyl-D-aspartate
[103]. Treatment selection for patients with MDD and comorbid
NSAID nonsteroidal anti-inflammatory drug
anxiety should therefore focus on antidepressants that also OCD obsessive-compulsive disorder
demonstrate efficacy for anxiety, or vice versa, such as the PTSD posttraumatic stress disorder
SSRIs, SNRIs, and serotonin modulators (e.g. vortioxetine and RANZP Royal Australian and New Zealand College of Psychiatrists
RCT randomized controlled trial
vilazodone). Goodwin provides recommendations for treatment
REM rapid eye movement
options for MDD and GAD that include off-label use of TCAs, REMS Risk Evaluation and Mitigation Strategy
agomelatine, vortioxetine, and bupropion [103]. SDS Sheehan Disability Scale
In a meta-analysis of 3 RCTs, vilazodone was found to be SIADH syndrome of inappropriate antidiuretic hormone secretion
SNRI serotonin-norepinephrine reuptake inhibitor
superior to placebo in the short-term treatment of GAD [104].
SSRI selective serotonin reuptake inhibitor
However, a later meta-analysis demonstrated poor tolerability, TCA tricyclic antidepressant
highlighting the need for additional studies to confirm overall TESD treatment-emergent sexual dysfunction
benefit [105]. Recently published data from an 8-week, open- TRD treatment-resistant depression
US United States
label study of vortioxetine in 100 adult patients with severe
WBC white blood cell
MDD and comorbid severe GAD demonstrated clinically mean­
ingful and statistically significant improvements in patient-
and clinician-assessed symptoms of depression and anxiety.
In the trial, vortioxetine was administered as a first-line ther­ Acknowledgments
apy or in patients switching to vortioxetine due to inadequate
Under the direction of the authors, medical writing assistance was provided by
response to another antidepressant [106]. Significant improve­
Katherine Price, PhD, and Leandra Dang, PharmD, on behalf of Syneos Health
ments in overall functioning and health-related quality of life Medical Communications, LLC. Takeda Pharmaceuticals U.S.A., Inc., and
were also noted [106]. In the trial, treatment with vortioxetine H. Lundbeck A/S provided funding to Syneos Health for support in writing
was initiated at 10 mg/day and titrated up to 20 mg/day after this manuscript.

Funding
This review was funded by Takeda Pharmaceuticals U.S.A., Inc., and
H. Lundbeck A/S.
Declaration of interest
C. Brendan Montano has received consulting fees from AbbVie, Acadia,
Alkermes, Arbor, Eisai, Neos, Novo Nordisk, Otsuka, Sunovion, Supernus,
and Takeda, and has also received payment/honoraria from AbbVie, Arbor,
Eisai, Otsuka, and Takeda. W. Clay Jackson has received consulting fees and
payment/honoraria from AbbVie, Alkermes, Genentech, Otsuka, and
Sunovion; has received honoraria from AbbVie, Alkermes, Genentech,
Otsuka, and Sunovion for attending meetings and/or travel; and has partici­
pated on a data safety monitoring board or advisory board for AbbVie,
Alkermes, Genentech, Otsuka, and Sunovion. Denise Vanacore has received
payment/honoraria from AbbVie. Richard Weisler has received grants or
contracts from Allergan, Alkermes, Astellas, Axsome Therapeutics,
Ironshore, Janssen, Lundbeck, Major League Baseball, Neos Therapeutics,
Otsuka America Pharmaceuticals, Sirtsei Pharmaceuticals, Shire, Supernus
Pharmaceuticals, Takeda, and Validus. The authors have no other relevant
affiliations or financial involvement with any organization or entity with
a financial interest in or financial conflict with the subject matter or materials
discussed in the manuscript apart from those disclosed.
A reviewer on this manuscript has disclosed receiving manuscript or
speaker’s fees from Astellas, Eisai, Eli Lilly, Elsevier Japan, Janssen
Pharmaceuticals, Kyowa Yakuhin, Lundbeck Japan, Meiji Seika Pharma,
Mitsubishi Tanabe Pharma, MSD, Nihon Medi-Physics, Novartis, Otsuka
Pharmaceutical, Shionogi, Shire, Sumitomo Pharma, Takeda Pharmaceutical,
Tsumura, Viatris, Wiley Japan, and Yoshitomi Yakuhin; and research grants
from Eisai, Mochida Pharmaceutical, Meiji Seika Pharma, Shionogi and
Sumitomo Pharma. Peer reviewers on this manuscript have no other relevant
financial relationships or otherwise to disclose.
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