Chapter 7

PHARMACOLOGICAL TREATMENT
OF DEPRESSIVE DISORDERS
Liisa Hantsoo and Sarah Mathews
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The depressive disorders are among the most
commonly diagnosed psychiatric disorders in the
United States (Kessler, Chiu, Demler, & Walters,
2005), and antidepressants are among the most
prescribed drugs in U.S. outpatient medical practices
(Olfson & Marcus, 2009). The Diagnostic and
Statistical Manual of Mental Disorders (5th ed.;
DSM–5; American Psychiatric Association, 2013)
includes eight depressive disorders: major depres-
sive disorder (MDD), persistent depressive disorder
(PDD; dysthymia), premenstrual dysphoric disorder
(PMDD), disruptive mood dysregulation disorder
(a pediatric diagnosis), substance- or medication-
induced depressive disorder, depressive disorder
due to another medical condition, other specified
depressive disorder, and unspecified depressive
disorder. The DSM–5 also includes specifiers, such
as “with peripartum onset,” “with seasonal pattern,”
and “with anxious distress.” In this chapter, the
focus will be on MDD, PDD, PMDD, and peripartum
depression (PD), as these are the more prevalent
types of depression. As pharmacologic treatment of
depression becomes more widely available, allied
providers should be well-versed in psychopharmaco­
logic management of depressive symptoms. This
chapter focuses on pharmacologic treatment of
the depressive disorders, and is geared toward
nonpsychiatrists.
EPIDEMIOLOGY AND PREVALENCE
MDD’s hallmark is the major depressive episode,
a period of at least 2 weeks of low mood or
anhedonia, accompanied by neurovegetative
symptoms (e.g., changes in appetite, sleep patterns,
energy level) that causes impairment in functioning.
MDD is relatively common, with a lifetime prevalence
in the United States of 16% (Kessler et al., 2003).
Onset is often between late adolescence and the early
40s, with a median age of onset of 25 years (Bromet
et al., 2011). The disorder is chronic in many people;
50% who remitted after one episode experienced
at least one recurrence (Burcusa & Iacono, 2007).
Each additional episode has a compounding effect,
increasing the likelihood of experiencing another
episode (Solomon et al., 2000).
Less common than MDD, PDD is a DSM–5
diagnosis that consolidates DSM–IV chronic
major depressive disorder and dysthymic disorder.
PDD is defined in DSM–5 as a depressed mood
lasting most of the day, more days than not, for at
least 2 years, accompanied by at least two additional
symptoms: low self-esteem, difficulty concentrating
or decision making, hopelessness, or the neuro­
vegetative symptoms of depression. The lifetime
prevalence rate is around 2.5% (Kessler et al., 2005),
and many people with PDD also will experience a

We thank Samantha Linhares for assistance in preparing the resources toolkit, and Heather M. Pederson, PhD for constructive feedback on drafts.
We would also like to acknowledge our funding sources, including the National Institutes of Health Mentored Patient-Oriented Research Career
Development Award (K23MH107831; Hantsoo) and Brain and Behavior Research Foundation NARSAD Young Investigator Award (Hantsoo).
http://dx.doi.org/10.1037/0000133-007
APA Handbook of Psychopharmacology, S. M. Evans (Editor-in-Chief)
Copyright © 2019 by the American Psychological Association. All rights reserved.

141
 Hantsoo and Mathews
major depressive episode or other psychiatric
diagnosis (Blanco et al., 2010; Klein, Schwartz,
Rose, & Leader, 2000). Risk factors for PDD are
similar to those for MDD (Blanco et al., 2010).
Premenstrual dysphoric disorder (PMDD) is a
cyclic mood disorder, characterized by cognitive–
affective symptoms in the week before menses
(American Psychiatric Association, 2013). PMDD
affects about 3% to 8% of women (Halbreich, 2008).
Diagnosis is based on a perimenstrual pattern of
at least five physical, affective, and/or behavioral
symptoms, with at least one key affective symptom
(marked depressed mood, hopelessness, or self-
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deprecating thoughts; affective lability, tearfulness,
sensitivity to rejection; irritability or anger; or anxiety
or tension; American Psychiatric Association, 2013).
Many women experience milder premenstrual
symptoms, often referred to as premenstrual
syndrome (PMS). Organizations including the
American College of Obstetricians and Gynecologists
(ACOG) and the World Health Organization
(WHO) have published criteria for these milder
premenstrual mood changes (American College
of Obstetricians and Gynecologists, 2001; WHO,
2004). ACOG’s PMS criteria include one physical
or psychological symptom in the 5 days prior to
menses, which must occur in three consecutive
menstrual cycles and must subside within four days
of menses onset. As with PMDD, the symptoms
must cause impairment, and must be verified by
prospective rating. Of note for the clinician, PMDD
and PMS are the only depressive disorders that
require prospective symptom tracking for diagnosis.
Recommendations for prospective symptom tracking
will be presented in the Assessment section of
this chapter (see also the Tool Kit of Resources at the
end of the chapter).
PD includes antenatal depression (depression
during pregnancy) and postpartum depression. The
DSM–5 includes PD not as its own diagnosis, but
as a diagnostic specifier (“with peripartum onset”),
indicating a depressive episode occurring during
pregnancy or in the 4 weeks following delivery.
Antenatal depression affects about 7% of pregnant
women and postpartum depression occurs in roughly
10% of postpartum women (Gavin et al., 2005),
although estimates are imprecise since many studies
142
use a 3-, 6-, or 12-month postdelivery timeframe
(Kim, Epperson, Weiss, & Wisner, 2014) as opposed
to the 4 weeks predicated by the DSM–5.
HISTORIC BACKGROUND OF
PSYCHOPHARMACOLOGIC TREATMENT
Descriptions of depression date back to ancient
texts, but it was not until the 1950s that the
first medications for depression were developed
(Hillhouse & Porter, 2015; also see Chapter 1, this
volume, for more details). This first generation
of medications included tricyclic antidepressants
(TCAs, such as clomipramine [e.g., Anafranil®],
imipramine [e.g., Tofranil®], nortriptyline [e.g.,
Pamelor®], doxepin [e.g., Sinequan®], amitriptyline
[e.g., Elavil®]) and monoamine oxidase inhibitors
(MAOIs, such as phenelzine [e.g., Nardil®], tranyl­
cypromine [e.g., Parnate®], and selegiline [e.g.,
Emsam®]). These medications were developed in
the era of the monoamine hypothesis of depression,
which held that deficiencies in serotonin, epineph-
rine, norepinephrine, and dopamine underpinned
depression. MAOIs inhibit monoamine oxidase,
the enzyme that catabolizes monoamine neuro­
transmitters in the synapse. By preventing the
breakdown of monoamines, their availability in the
synaptic cleft is increased. The tricyclics, so named
for their three-ring chemical structure, acted as
serotonin and norepinephrine reuptake inhibitors
(SNRIs), similarly increasing the length of activity
of these monoamines, with antimuscarinic, anti-
histamine, and anticholinergic effects as well. The
MAOIs and tricyclics had a number of undesirable
side effects. For instance, MAOI users had to avoid
consuming the amine tyramine, found in common
foods, to avoid a potentially lethal hypertensive
crisis. Tricyclics could produce dry mouth, blurry
vision, altered gastrointestinal motility, urinary
retention, or cognitive side effects, as well as
cardiovascular side effects or seizures.
As the serotonin hypothesis of depression took
hold in the 1970s, the second generation of anti­
depressants, selective serotonin reuptake inhibitors
(SSRIs), were introduced. These medications bound
postsynaptic serotonin receptors, allowing more
serotonin to accumulate in the synaptic cleft.
Fluoxetine (e.g., Prozac®, Sarafem®) was the first

SSRI approved by the U.S. Food and Drug Adminis­
tration (FDA), and went on the U.S. market in 1988
(Hillhouse & Porter, 2015). This was followed by
other SSRIs including paroxetine (e.g., Paxil®),
sertraline (e.g., Zoloft®), citalopram (e.g., Celexa®),
and escitalopram (e.g., Lexapro®). In 1989, bupro-
pion (e.g., Wellbutrin®), a dopamine-norepinephrine
reuptake inhibitor, was approved by the FDA.
The first of the SNRIs, venlafaxine (e.g., Effexor®),
was introduced in 1993, followed by duloxetine
(e.g., Cymbalta®) and milnacipran (e.g., Savella®).
With more specific mechanisms of action, the SSRIs
and SNRIs had more acceptable side effect profiles
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than the MAOIs and tricyclics. SSRIs are still the
most commonly prescribed antidepressants, given
their good safety and tolerability profiles (Dupuy,
Ostacher, Huffman, Perlis, & Nierenberg, 2011).
For more detail on the history of antidepressant
medications, Hillhouse and Porter (2015) provide
a thorough review.
DIAGNOSING DEPRESSIVE DISORDERS
When diagnosing a depressive disorder, a thorough
clinical assessment by a mental health provider
should evaluate symptoms, past depressive episodes,
comorbid disorders, and medication trials and
responses. Assessment should rule out medical
conditions that mimic depressive symptoms, such
as hypothyroidism, a sleep disorder, or treatment
side effects from a medication. Brief screenings,
including self-report or those administered by a
provider, may serve as a starting point for more
detailed assessment. Here, we describe well-
validated tools that can be used to assess
depressive symptoms, aiding in diagnosis of
MDD, PDD, PMDD, or PD.
Assessment of Major Depression
and Persistent Depressive Disorder
Clinician administered scales.  The Hamilton
Depression Rating Scale (HAM-D) is a 21- or
17-item measure administered by a health care
professional (Hamilton, 1960). A structured interview
guide is available to foster reliable administration
(Williams, 1988). The scoring range suggests
absence of depression (score 0–6), mild depression
Pharmacological Treatment of Depressive Disorders
(score 7–17), moderate depression (score 18–24),
or severe depression (score >24). The Inventory of
Depressive Symptomatology (IDS) was developed
as an alternative to the HAM-D, with a 16-item
Quick IDS (QIDS; Rush et al., 2003) available.
The Montgomery-Åsberg Depression Rating Scale
(MADRS) is a 10-item clinician-administered scale
that is more focused on the psychological symptoms
of depression than the neurovegetative symptoms
(Montgomery & Åsberg, 1979).
Self-report scales.   The Beck Depression Inventory
(BDI) is a well-established 21-item self-report
measure assessing depressive symptoms in the past
2 weeks (Beck, Steer, Ball, & Ranieri, 1996). The
freely available Patient Health Questionnaire–9
(PHQ-9; Kroenke, Spitzer, & Williams, 2001)
similarly assesses depressive symptoms over the
past 2 weeks and provides cutoffs for likely mild,
moderate, or severe depression.
Assessment of Premenstrual
Dysphoric Disorder
To be diagnosed with PMDD, symptoms must
be confirmed with at least two menstrual cycles
of prospective daily ratings. The Daily Record of
Severity of Problems (DRSP) is the gold standard
tool for prospectively assessing PMDD symptoms
(Endicott, Nee, & Harrison, 2006). A scoring
rubric guides the clinician in diagnosing PMDD via
comparison of number and severity of symptoms
in the follicular (asymptomatic) versus luteal
(premenstrual) phase of the menstrual cycle. An
alternative, the Carolina Premenstrual Assessment
Scoring System (C-PASS), was published in 2016
(Eisenlohr-Moul et al., 2016) and assesses whether
the individual meets full PMDD criteria versus
another menstrually-related mood disorder,
providing a more dimensional approach than the
Endicott scoring rubric for the DRSP (Epperson
& Hantsoo, 2017).
Assessment of Peripartum Depression
Rating scales used to assess depression in the
general population may not be appropriate for
assessing PD. Pregnancy and postpartum include
physical symptoms that are considered normal
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 Hantsoo and Mathews
perinatally, yet overlap with depressive symptoms,
such as changes in energy, weight, appetite, and
sleep. The clinician-rated Pregnancy Depression
Scale (PDS) is a 7-item scale derived from the HAM-D
(Altshuler et al., 2008). The Edinburgh Postnatal
Depression Scale (EPDS; Cox, Holden, & Sagovsky,
1987) is a well-established 10-item self-report scale
that assesses symptoms of postpartum depression
occurring in the past week. While initially developed
for use in the postpartum period, studies have
established its validity during pregnancy as well
(Flynn, Sexton, Ratliff, Porter, & Zivin, 2011). The
Perinatal Depression Inventory (PDI) is a 14-item
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scale that, unlike the EPDS, assesses depressive
symptoms in the antenatal or postpartum period
(Brodey et al., 2016). When assessing PD, the clinician
should ask the patient about depressive symptoms
during or following other pregnancies, as this is a
risk factor for subsequent episodes. The provider may
also ask about whether the pregnancy was planned,
whether it was desired, how the patient feels about
motherhood, support from her partner, and whether
she has any concerns about the transition to mother­
hood, as these factors may influence depressive
symptoms or risk.
EVIDENCE-BASED PHARMACOLOGICAL
TREATMENTS OF DEPRESSIVE DISORDERS
Pharmacologic treatment is recommended for
moderate to severe MDD (Fournier et al., 2010),
and is also an option for PMDD or PD that has not
responded to nonpharmacologic treatments. When
deciding whether psychopharmacologic treatment
is appropriate, severity of symptoms should be
considered, along with the potential for side effects,
treatment history, patient preference, and medical
comorbidities.
Major Depression and
Persistent Depressive Disorder
As mentioned, SSRIs are the most commonly
prescribed medications for depression. At a
general level, SSRIs exert their therapeutic effect
by inhibiting reuptake of synaptic serotonin
(5-HT) by the presynaptic neuron. With serotonin
remaining in the synapse for a longer period of
144
time, the neurotransmitter is able to repeatedly
stimulate its postsynaptic receptors. There are
more than 15 different serotonin receptor subtypes
(e.g., 5-HT1A) found throughout the brain and
an SSRI may have more or less affinity for a partic-
ular receptor subtype. In addition, SSRIs impact
muscarinic, adrenergic, serotonergic, and cholinergic
receptors to various degrees (Owens, Morgan,
Plott, & Nemeroff, 1997). This can influence a
patient’s response to or side effects experienced
with a particular SSRI. Pharmacokinetics, such
as half-life and metabolites produced, are also an
important consideration when selecting an anti-
depressant due to potential for discontinuation
symptoms if doses are missed. There is typically
a lag between SSRI initiation and improvement in
symptoms, which can be 1 to 6 weeks (van Calker
et al., 2009). This is generally understood to be due
to effects on postsynaptic function, consistent with
a reformulation of the monoamine hypothesis that
proposed depression was not due to a serotonin
deficit, but to dysregulated serotonergic post­
synaptic receptor function (Hindmarch, 2002).
The newer generation antidepressants include
SNRIs (e.g., venlafaxine, desvenlafaxine [e.g.,
Pristiq®], duloxetine), norepinephrine-dopamine
reuptake inhibitors (NDRIs, e.g., bupropion),
α2-adrenergic receptor antagonists (e.g., mirtazapine
[e.g., Remeron®]), and serotonin antagonist and
reuptake inhibitors (e.g., trazodone [e.g., Desyrel®]).
While serotonin has been linked to depressive
symptoms including anxiety, dopamine has been
linked with symptoms related to motivation,
pleasure, and reward, and norepinephrine has been
linked with alertness and energy (Nutt, 2008).
Thus, these medications that impact dopamine
and norepinephrine may address a wider range of
symptoms than those impacting serotonin alone.
Meta-analyses have found that SSRIs have similar
efficacy to tricyclics (Anderson, 2000; Geddes,
Freemantle, Mason, Eccles, & Boynton, 2000), but
that SSRIs have superior acceptability and tolerability
(Guaiana, Barbui, & Hotopf, 2007). There are fewer
studies comparing SSRIs with newer generation
antidepressants. One meta-analysis concluded that
while there were no significant differences among
newer generation antidepressants in terms of efficacy

or effectiveness, there were differences in side
effect profiles that should be considered in treatment
planning (Gartlehner et al., 2008). For instance,
paroxetine had greater mean weight gain and sexual
dysfunction than some other drugs, and venlafaxine
had a higher mean incidence of nausea and vomiting
than SSRIs. A meta-analysis in The Lancet compared
12 newer generation antidepressants (bupropion,
citalopram, duloxetine, escitalopram, fluoxetine,
fluvoxamine [e.g., Luvox®], milnacipran, mirtazapine,
paroxetine, reboxetine [e.g., Edronax®], sertraline,
and venlafaxine) and included six SSRIs (citalopram,
escitalopram, fluoxetine, fluvoxamine, paroxetine,
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sertraline; Cipriani et al., 2009). It found that
mirtazapine, escitalopram, venlafaxine, and sertraline
were significantly more efficacious than duloxetine,
fluoxetine, fluvoxamine, paroxetine, and reboxetine.
The meta-analysis concluded that sertraline may
be the best first-line treatment for moderate to
severe major depression, considering its efficacy,
acceptability, and cost. However, this recommendation
was not without controversy, with some researchers
pointing out that there may have been methodo-
logic issues (e.g., failure to account for potential
confounders such as psychiatric comorbidity,
starting dose, titration schedule, or concomitant
benzodiazepine use) or publication bias (Seyringer
& Kasper, 2009). There is no one-size-fits-all treat-
ment for MDD, making broad recommendations
such as these challenging. However, insights from
large-scale treatment studies such as the Sequenced
Treatment Alternatives to Relieve Depression
(STAR*D) trials, discussed in a following section
of this chapter, can provide useful information on
treatment approaches. While there is less literature
on the pharmacologic treatment of PDD, it is treated
similarly to MDD, with SSRIs being a common
treatment choice (Meister et al., 2016).
Premenstrual Dysphoric Disorder
ACOG (American College of Obstetricians and
Gynecologists, 2001) and the International Society
for Premenstrual Disorders (Ismaili et al., 2016)
recommend pharmacotherapy as a first-line treatment
for PMDD and severe mood-related PMS. A meta-
analysis of randomized placebo-controlled trials
found that daily SSRI is an effective treatment for
Pharmacological Treatment of Depressive Disorders
PMDD (Marjoribanks, Brown, O’Brien, & Wyatt,
2013). In addition to such “continuous” pharmaco-
therapy, PMDD may be treated with dosing schemes
restricted to the luteal phase (Marjoribanks et al.,
2013). Intermittent dosing refers to administering
the medication only during the luteal phase (ovulation
to menstruation onset; Freeman, 2004), while
symptom-onset treatment initiates medication each
cycle when the patient notices symptoms (usually a
week or so before menses onset) and continues daily
until menstruation (Steinberg, Cardoso, Martinez,
Rubinow, & Schmidt, 2012). Interestingly, PMDD
symptoms respond to SSRIs within days, as opposed
to the weeks required for symptom reduction in
MDD, and at lower doses (Landén & Thase, 2006;
Steinberg et al., 2012), allowing luteal phase dosing
regimens. The rapid onset of action is likely due
to the SSRIs’ interaction with enzymes involved
in neurosteroid synthesis, as opposed to purely
serotonergic mechanisms (Griffin & Mellon, 1999).
Meta-analyses indicate a moderate to large effect
size for both continuous and luteal phase SSRI
treatment (Marjoribanks et al., 2013; Shah et al.,
2008), and no clear difference in symptom
response between the two dosing regimens
(Marjoribanks et al., 2013). Luteal phase dosing
with a shorter half-life SSRI, such as sertraline,
paroxetine controlled release (CR), or citalopram,
may most benefit women who experience SSRI
side effects such as nausea, decreased libido, or
drowsiness.
However, more than one third of women with
PMDD do not respond to an SSRI (Halbreich, 2008).
For these women, hormonal treatment (e.g., an
oral contraceptive) for PMDD may be an option,
but findings are mixed (Cunningham, Yonkers,
O’Brien, & Eriksson, 2009). Combined oral contra-
ceptives (COCs) are a daily pill used for pregnancy
prevention that include a combination of estrogen
and progestogen (a synthetic equivalent to proges-
terone). There are numerous generic and brand-
name formulations of COCs containing different
amounts of these hormones. COCs have been
shown to somewhat reduce PMDD symptoms, but
often with a large placebo effect (Eisenlohr-Moul,
Girdler, Johnson, Schmidt, & Rubinow, 2017;
Freeman et al., 2012; Lopez, Kaptein, & Helmerhorst,
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 Hantsoo and Mathews
2012). Progesterone monotherapy for PMS was
not supported by strong evidence in a Cochrane
review (Ford, Lethaby, Roberts, & Mol, 2012).
Gonadotropin-releasing hormone (GnRH) agonists
or inhibitors induce postmenopausal levels of ovarian
hormones (Pincus, Alam, Rubinow, Bhuvaneswar,
& Schmidt, 2011). GnRH drugs are typically used
only when women with PMDD have failed multiple
trials of SSRIs, as extended hypoestrogenism in
premenopausal women may have negative health
effects. A last-resort option for severe treatment-
resistant PMDD is oophorectomy, or surgical meno-
pause (Wyatt, Dimmock, Ismail, Jones, & O’Brien,
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2004). As this treatment induces sudden menopause
and prohibits further childbearing, it is only used in
the most severe cases.
Peripartum Depression
Pharmacologic treatment of PD including during
pregnancy, postpartum, or while breastfeeding
requires special considerations. During pregnancy,
many women are reluctant to take medication due
to fear of causing harm to the fetus. However, the
potential risks to the fetus from medication must
be considered with the potential risks to the fetus
of untreated depression (Nulman et al., 2012).
There are few randomized controlled trials (RCTs)
of antidepressants during pregnancy, given potential
ethical issues. In a report on psychopharmaco-
therapy during pregnancy, the American Psychiatric
Association and ACOG published practice guide-
lines regarding medication use during pregnancy
(Yonkers et al., 2009). These guidelines review
potential risks of antidepressant use during preg-
nancy and weigh these against the risks of untreated
depression.
Among women with a previous episode of post-
partum depression, antidepressants are sometimes
started prophylactically to prevent recurrence
(Wisner et al., 2004). SSRIs are generally considered
safe during breastfeeding (Davanzo, Copertino,
De Cunto, Minen, & Amaddeo, 2011). Citalopram,
venlafaxine, and fluoxetine may not be the first
choice for breastfeeding mothers due to their maternal
milk to plasma ratio and relative infant dose (Berle
& Spigset, 2011; Davanzo et al., 2011). However,
the patient’s history of medication response should
146
be considered when selecting pharmacotherapy.
If a patient who is breastfeeding has had a favorable
response to these agents in the past, they may be a
treatment option. Due to altered drug metabolism
postpartum (Sit, Perel, Helsel, & Wisner, 2008),
antidepressant dosages should start low and be
titrated slowly in the postpartum period (Kim,
Epperson et al., 2014).
There are few placebo-controlled antidepressant
treatment studies in postpartum women specifically.
An open-label prospective study of escitalopram
in nonbreastfeeding depressed postpartum women
found a 93% response rate (Misri, Abizadeh, Albert,
Carter, & Ryan, 2012). A small pilot study of
bupropion sustained release (SR) in women with
MDD onset within 3 months of childbirth found a
75% response rate (Nonacs et al., 2005). One placebo-
controlled RCT of paroxetine found a significantly
greater proportion of remissions in the active
medication group, but no significant difference
between paroxetine and placebo in responder rate
(Yonkers, Lin, Howell, Heath, & Cohen, 2008).
Sertraline produced similar improvement in symp-
toms compared with nortriptyline (Wisner et al.,
2006). An RCT of sertraline in women with post-
partum depression found better response and
remission rates than placebo, particularly in women
who had developed postpartum depression within
4 weeks of childbirth (Hantsoo et al., 2014).
PD may result from atypical response of the
central nervous system to hormonal fluctuations
during or following pregnancy. However, there
are few studies assessing hormonal treatment of
PD symptoms. Women who received a medroxy­
progesterone acetate injection following delivery
did not have significantly lower EPDS scores at
6 weeks postpartum compared with women who
did not receive the hormonal injection (Tsai &
Schaffir, 2010). Women who received an intra-
muscular injection of norethisterone enanthate, a
progestogen-only contraceptive, within 2 days post-
delivery actually had worse depressive symptoms
than a placebo group at 6 weeks postpartum, and
no difference at 3 months postpartum (Lawrie et al.,
1998). A recent double-blind RCT suggested that
an intravenous formulation of allopregnanolone,
a progesterone metabolite, may be an emerging

option for treating severe postpartum depression
(Kanes et al., 2017). Women with severe post-
partum depression who received intravenous allo-
pregnanolone treatment over the course of 60 hours
had a significant reduction in depression scores
(based on the HAM-D) compared with placebo.
Further work is needed to determine whether other
formulations (e.g., oral) are as effective.
BEST APPROACHES FOR ASSESSING
TREATMENT RESPONSE AND
MANAGING SIDE EFFECTS
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Major Depression and
Persistent Depressive Disorder
Symptoms should be monitored regularly to
assess treatment response during the initial weeks
of treatment. It is recommended that providers
administer a standardized depression rating tool
to augment their clinical judgment when assessing
treatment response. Otherwise, they may fail to
detect patients’ lack of improvement or symptom
worsening (Hatfield, McCullough, Frantz, &
Krieger, 2010). The PHQ-9 is well-suited to assess
depression treatment response, as it measures the
cardinal symptoms of major depression, is sensitive
to change over time, and provides easily interpretable
score ranges (Fortney et al., 2017). A suggested
guideline is to assess the patient 4 to 6 weeks after
medication initiation. If the PHQ-9 score is five or
more points lower than the pretreatment baseline,
the individual is responding and current medication
should be continued (Bentley, Pagalilauan, &
Simpson, 2014). For a score reduction of two to
four points, the provider may consider continuing
this medication at a higher dosage. For score reduc-
tions of less than two points, the provider should
consider initiating a trial of a second medication,
alone or in combination with the initial medication
prescribed. Cross-tapering may be used to simul-
taneously wean the patient off of one medication
while titrating up the other, especially if the
medications are of different neurochemical classes
(Keks, Hope, & Keogh, 2016).
Thirty-eight percent of more than 700 patients
taking citalopram, escitalopram, fluoxetine, parox-
etine, or sertraline reported at least one side effect
Pharmacological Treatment of Depressive Disorders
(Cascade, Kalali, & Kennedy, 2009). The most
commonly reported side effects were sexual dysfunc-
tion, sleepiness, and weight gain (Cascade et al., 2009).
Nausea, insomnia, and headache are other common
short-lived side effects of SSRIs (Marjoribanks
et al., 2013), while weight gain and sexual dysfunc-
tion are longer term side effects (Deshmukh &
Franco, 2003; Montgomery, Baldwin, & Riley,
2002). Other common side effects of the SSRIs and
newer generation antidepressants include head-
ache, dry mouth, insomnia, and dizziness (Mackay
et al., 1999). Some of these may be mitigated by
reducing the dose (Sienaert, 2014). Hepatotoxicity
and cardiovascular changes are rare but serious
side effects of some antidepressants. A 2014 review
includes useful tables of antidepressant side effects
and the associated neurotransmitter systems
(Bentley et al., 2014).
Premenstrual Dysphoric Disorder
Unlike MDD, treatment response to SSRIs often
occurs rapidly in PMDD, within a few days
(Steinberg et al., 2012). In order to monitor treat-
ment response, patients should continue to rate
their menstrual mood symptoms daily throughout
their menstrual cycle using the DRSP or C-PASS.
Response is often operationalized as a 50% reduction
in symptoms from pretreatment luteal phase to
treated luteal phase (Steinberg et al., 2012).
Peripartum Depression
Experts recommend administering the EPDS monthly
to monitor treatment response (Kim, Epperson et al.,
2014). As the items on the EPDS are geared toward
the perinatal period, they are more sensitive to
month-to-month changes in perinatal depressive
symptoms than a more general measure, such as
the PHQ-9.
MEDICATION MANAGEMENT ISSUES
There are a number of potential challenges in
the pharmacologic treatment of depression,
including medication adherence, partial symptom
response, unsupervised medication discontinu-
ation, and relapse. Medication adherence refers
to taking the medication as prescribed by the
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 Hantsoo and Mathews
provider—the appropriate dose at the appropriate
time. Individuals who are adherent with their
medication over the long term have better outcomes
than nonadherent patients (Åkerblad, Bengtsson,
von Knorring, & Ekselius, 2006). Numerous factors
can influence medication adherence, including side
effects, comorbidity, age, and availability of follow-up
care, to name a few (Akincigil et al., 2007). Data
from chart reviews and insurance claims have found
antidepressant adherence ranging from 12% to 72%,
suggesting that many individuals discontinue their
antidepressant before the recommended 6 months
following symptom remission (Keyloun et al., 2017;
Copyright American Psychological Association. Not for further distribution.
Mårdby et al., 2016).
The STAR*D study, which ran at multiple sites
across the United States from 2001 to 2006, assessed
pharmacologic treatment approaches for individuals
whose symptoms had not responded to the initial
medication trial. The study found that more than half
of the participants achieved remission after multiple
medication trials (Rush et al., 2006). Generally,
if a patient fails two antidepressants from different
neurochemical classes at therapeutic doses, she or he
is considered to have treatment-resistant depres-
sion (M. Fava & Davidson, 1996). With severe
depression, approaches may include augmentation
of antidepressant with an atypical antipsychotic
(Han et al., 2015) or high-dose antidepressant
treatment (e.g., rapidly doubling or tripling the
dose; Jakubovski, Varigonda, Freemantle, Taylor,
& Bloch, 2016). For perinatal treatment-resistant
depression, including partial response to SSRI, experts
recommend three trials of different antidepressants
or augmenting agents; for a thorough review see
Robakis and Williams (2013).
Relapse is common, as MDD is considered a
chronic condition. Individuals with a history of
a major depressive episode have a significantly
elevated risk of experiencing additional episodes
(Burcusa & Iacono, 2007). Antidepressant main-
tenance therapy is often used to prevent relapse.
However, some patients relapse despite remaining
on an antidepressant (Gueorguieva, Chekroud, &
Krystal, 2017). Reasons for this are unclear, but
could include pharmacokinetic tolerance. If the
clinician is able to rule out treatment nonadherence
or inadequate dose as causative factors, she or he
148
could consider approaches including dosage change,
switching to another antidepressant, or augmentation
with another medication (Targum, 2014).
Once remission is achieved, tapering off of an
antidepressant should occur under the guidance
of a clinician, who can determine readiness to
discontinue medication based on length of symptom
remission, and monitor for emergent symptoms
such as self-harm, suicidal ideation, or panic attacks.
When creating a tapering schedule, the prescribing
provider will consider the medication dose, half-life,
and withdrawal potential. If a patient has been on
the medication for more than 1 month, it is recom-
mended that the taper occur over at least 4 weeks
(Ogle & Akkerman, 2013), as more abrupt cessation
of an SSRI or SNRI is associated with “withdrawal”
or discontinuation symptoms including insomnia,
headache, nausea, dizziness, or mood changes
(Black, Shea, Dursun, & Kutcher, 2000). However,
some contend that discontinuation symptoms may
occur regardless of length of taper (G. A. Fava,
Gatti, Belaise, Guidi, & Offidani, 2015). Providers
should discuss potential withdrawal effects with
the patient before tapering begins.
When treating perinatal depression, there are
special considerations regarding medication manage-
ment. A woman who is taking antidepressants and
learns she is pregnant should discuss options with
her clinician before self-tapering or abruptly stop-
ping medication on her own. This will allow the
provider and patient to weigh the risks of potential
discontinuation symptoms or relapse, and the impact
of untreated depression during pregnancy versus
prenatal exposure of the fetus to an antidepressant.
Some women who discontinue antidepressants
around the time of conception opt to reinitiate
the medication at some point during pregnancy
(Cohen, Altshuler, Stowe, & Faraone, 2004).
EVALUATION OF PHARMACOLOGICAL
APPROACHES ACROSS THE LIFESPAN
Childhood and Adolescence
The prevalence of depression is around 2% to 11%
in children and in adolescents (Kashani et al., 1983;
Merikangas et al., 2010). The American Academy
of Child and Adolescent Psychiatry (AACAP)

practice parameters for children and adolescents
with depressive disorders recommend that treatment
is initiated with psychoeducation on depression
for the child and caregivers, supportive manage-
ment or psychotherapy, and family and school
involvement (Birmaher & Brent, 2007). In mild
to moderate depression, these measures, cognitive
behavioral therapy (CBT), or interpersonal psycho-
therapy (IPT) are often efficacious (Birmaher &
Brent, 2007). However, if a patient does not respond
to these measures or has significant impairment,
suicidality, or agitation, then pharmacologic treat-
ment should be considered. The AACAP practice
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parameters note that there may be limited avail-
ability of pediatric mental health providers, and that
some families may have objections to medication
use in children. Fluoxetine and escitalopram are
FDA approved for treatment of pediatric depression
(U.S. Food and Drug Administration, 2014). Other
SSRIs are commonly used, but considered off-label
for pediatric patients. The tricyclics are not recom-
mended as a first-line pediatric treatment, as they
have not been shown to be more efficacious than
placebo and have a greater number of side effects
and potential for fatality after overdose (Birmaher
& Brent, 2007). Antidepressant dosing in children
is similar to that in adults, although initial doses
should be lower in children; see Birmaher and
Brent (2007) for basic dosage guidelines. Because
the half-life of some medications may be shorter in
children than in adults, the AACAP recommends
that pediatric patients are monitored for withdrawal
symptoms if they are taking medication only once
per day (Birmaher & Brent, 2007). They recommend
that patients are seen weekly for the first month,
and that symptoms are assessed at 4-week inter-
vals to monitor treatment response. The Children’s
Depression Rating Scale (CDRS; Poznanski, Cook,
& Carroll, 1979) or Children’s Depression Inventory
(CDI; Kovacs, 1992) are options for monitoring
treatment response in children ages 6 to 12 years
and 7 to 17 years, respectively. For adolescents,
scales used with adults, such as the Center for
Epidemiologic Studies Depression Scale (CES-D),
may be used (Stockings et al., 2015). If response
is not achieved by 8 to 12 weeks of treatment, the
guidelines suggest that other treatment options be
Pharmacological Treatment of Depressive Disorders
considered. Once response is achieved, it is recom-
mended that the patient remain on medication
for 6 to 12 months to prevent relapse. When the
patient does discontinue medication, tapering
should occur very slowly. For those who develop
depression in childhood, particularly in adolescence,
there is an increased risk of having additional
depressive episodes in adulthood (Birmaher,
Arbelaez, & Brent, 2002).
Adulthood
As this chapter is already focused on treatment of
depressive disorders in adulthood, we will highlight
here only a few key points in the adult lifespan that
are particularly relevant to consider in treatment.
First, during childhood the prevalence of depressive
disorders is similar in boys and girls; however, with
puberty, the prevalence in adolescent and adult
females is double that of males (Burt & Stein, 2002).
It is also at this time that females may begin to
experience PMS, PMDD, or premenstrual worsening
of a depressive disorder; however, this often does
not present until a woman’s 20s or 30s. Women
with a history of depressive episodes are at risk for
perimenopausal depression, although even women
with no history of depression are two to three times
more likely to develop depression perimenopausally
(Bromberger et al., 2011; Freeman, Sammel, Lin,
& Nelson, 2006). Recent research suggests that
women who experienced significant stress during
adolescence are more likely to have incident depres-
sion in the menopausal transition (Epperson et al.,
2017). SSRIs are the first-line treatment for peri-
menopausal depression, particularly in women with
a past history of depression, and emerging evidence
suggests adjunct estradiol treatment may also be
an option (Soares, 2017).
Older Adulthood
Depressive disorders are more prevalent among
those aged 85 and older or among those in nursing
homes (Luppa et al., 2012; Seitz, Purandare, &
Conn, 2010), but depression is often undertreated
in older adults (Barry, Abou, Simen, & Gill, 2012).
Older patients with depression may present
with complaints including fatigue, weight loss,
or unexplained physical symptoms; cognitive
149
 Hantsoo and Mathews
complaints; social withdrawal; refusal to eat or
engage in self-care; or use of alcohol or sedatives
(Kok & Reynolds, 2017). Diagnosis may be
more challenging if there are cognitive or medical
comorbidities. If a patient is experiencing cognitive
difficulties, it is recommended that a caregiver
report on the patient’s symptoms, and a cognitive
assessment such as the Mini-Mental State Examina­
tion should be performed (Kok & Reynolds, 2017).
A 2017 JAMA review suggested the Geriatric
Depression Scale Short Form, a 15-item measure
that can be administered by a provider or completed
as self-report (Kok & Reynolds, 2017). Meta-analyses
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indicate that SSRIs, SNRIs, and TCAs may be effica-
cious for depression in older adults (Calati et al.,
2013; Kok, Nolen, & Heeren, 2012). Side effects
and tolerability are a concern, particularly if the
patient is taking other medications for physical
illness, in which case it is also important to consider
whether cognitive or functional capacity will
influence ability to be adherent to medication
(Kok & Reynolds, 2017).
CONSIDERATION OF POTENTIAL
SEX DIFFERENCES
In adulthood, women are twice as likely as men to
have MDD (Bromet et al., 2011). Reasons for this are
complex, and likely include a combination of social
and biological contributors (Derry, Padin, Kuo,
Hughes, & Kiecolt-Glaser, 2015; Nolen-Hoeksema,
Larson, & Grayson, 1999). Women may present
with different symptomatology than men; for
instance, increased tearfulness or appetite (Romans,
Tyas, Cohen, & Silverstone, 2007). The STAR*D
studies found that women had less suicidal ideation
but more past suicide attempts than men; men were
more likely to have substance or alcohol abuse
comorbidity, while women had more comorbid
anxiety and eating disorders (Marcus et al., 2008).
In a study of 1,401 opposite-sex dizygotic twin pairs
who met criteria for MDD, the females reported
increased fatigue, hypersomnia, and psychomotor
retardation, while the males reported more insomnia
and agitation (A. A. Khan, Gardner, Prescott, &
Kendler, 2002). In a sample of older adults, women
more commonly had changes in appetite and expe-
150
rienced joylessness during depression, while men
more often experienced agitation (Kockler &
Heun, 2002). Another important sex difference
in depressive disorders is postpartum depression,
which has traditionally been understood to occur
only in women. There is some evidence that men
may also experience depression following the
birth of a child, although this is distinct from the
hormonally-mediated changes in mood that women
may experience perinatally (Paulson & Bazemore,
2010). In men, these symptoms of depression are
more likely to be associated with psychosocial factors.
Women and men may also differ in their response
to treatments. This may be due in part to pharmaco­
kinetics, which can be influenced by factors including
gut transit time, stomach pH (a measure of acidity),
body fat, fluid distribution, metabolism, and renal
function, all of which vary between the sexes
(Damoiseaux, Proost, Jiawan, & Melgert, 2014).
Women may require a lower dose of some medica-
tions, such as sertraline (Thiels, Linden, Grieger,
& Leonard, 2005), while other medications show
no difference in therapeutic dose between men and
women (A. Khan, Brodhead, Schwartz, Kolts, &
Brown, 2005; Young et al., 2009). In the STAR*D
studies, women had a better treatment response to
open-label citalopram than men, with no significant
differences in dose or side effects (Young et al.,
2009). Response rates were similar between women
and men for placebo and SNRIs, but there were
significantly more female responders to SSRIs than
males (A. Khan et al., 2005). However, other studies
have failed to find sex differences in treatment
response for fluoxetine (Quitkin et al., 2002),
sertraline (Thiels et al., 2005), clomipramine, cita-
lopram, paroxetine, and moclobemide (e.g., Amira;
Hildebrandt et al., 2003). All studies mentioned
in this section were designed to specifically assess
sex differences. However, some of these studies
were open label, providing weaker evidence than
a placebo-controlled study would. While sex
differences may be modified by age, there is little
research on this. Women were more responsive to
sertraline, but only among those age 40 years and
older (Morishita & Kinoshita, 2008). Women aged
50 years or older taking an SSRI had a lower chance
of remission compared with women under 50 and

men (Thase, Entsuah, Cantillon, & Kornstein, 2005).
It may not be age or sex per se that causes differences,
but hormonal status, although more research is
needed in this area.
INTEGRATION OF PHARMACOTHERAPY
WITH NONPHARMACOLOGICAL
APPROACHES: BENEFITS
AND CHALLENGES
Major Depression and
Persistent Depressive Disorder
Pharmacologic treatment of depressive disorders is
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often combined with nonpharmacologic treatments,
such as psychotherapy. In depressive disorders,
CBT targets dysfunctional cognitions and behaviors,
while IPT targets an individual’s interpersonal
environment. CBT combined with antidepressant
medication had better recovery rates for MDD than
antidepressants alone, but only in individuals with
severe or nonchronic MDD (Hollon et al., 2014).
This result is similar to a meta-analysis that found
that individuals with milder depression had similar
response rates to combined medication and psycho-
therapy versus psychotherapy alone (CBT or IPT),
but those with more severe, recurrent depression
had significantly better outcomes when on the
combined treatment (Thase et al., 1997). The
Cognitive Behavioural Therapy as an Adjunct to
Pharmacotherapy for Treatment Resistant Depression
in Primary Care (CoBalT) trial assessed CBT as an
adjunct to treatment as usual for individuals with
treatment-resistant depression in a primary care
setting. The study recruited more than 400 partici-
pants who continued to meet criteria for depression
after being on an antidepressant for at least 6 weeks
from 73 primary care practices in the United Kingdom.
CoBalT found that CBT significantly improved
treatment response among pharmacotherapy non-
responders (Wiles et al., 2013). Combined treatment
may produce more durable response (Karyotaki et al.,
2016) and be more effective in preventing relapse
(Guidi, Tomba, & Fava, 2016) than pharmaco­
therapy alone.
Additional forms of adjunct psychotherapy include
IPT and mindfulness-based techniques. However,
these trials are fewer in number and are smaller
Pharmacological Treatment of Depressive Disorders
than the CBT augmentation trials. IPT did not
provide benefit above and beyond pharmacotherapy
for patients with MDD (Souza et al., 2016), with
similar findings in adults with dysthymic disorder
(de Mello, Myczcowisk, & Menezes, 2001). There
was no difference in time to relapse or remission
in a pharmacotherapy group versus a pharmaco-
therapy plus mindfulness-based cognitive therapy
group (Kuyken et al., 2016). However, individuals
with inadequate response to antidepressants had
an improvement in depressive symptoms with an
8-week breathing-based meditation intervention
compared with a waitlist control group (Sharma,
Barrett, Cucchiara, Gooneratne, & Thase, 2017).
Other additions to pharmacotherapy may include
telephone-administered therapy, Internet-based
therapies, exercise, and bright light therapy, although
there are fewer studies on these practices, or electro-
convulsive therapy (ECT) or transcranial magnetic
stimulation (TMS) for severe, treatment-resistant
depression. Six counseling and support sessions
delivered weekly over the telephone, in addition to
pharmacotherapy, significantly reduced depressive
symptoms at 3- and 6-month follow-up compared
with pharmacotherapy alone (Tutty, Simon, &
Ludman, 2000). A larger study of individuals
starting an antidepressant found that an eight-
session telephone CBT program improved depres-
sion symptoms compared with antidepressant alone
(Simon, Ludman, Tutty, Operskalski, & Von Korff,
2004). Interpersonal and social rhythm therapy
(a form of behavioral therapy often used in bipolar
disorder that focuses on interpersonal relation-
ships and maintaining consistent patterns in daily
activities such as sleeping, eating, and exercise) or
intensive clinical management delivered once per
week over the telephone for 30 to 45 minutes in
combination with an antidepressant produced larger
percentages of responders over an 8-week trial than
an antidepressant alone (Corruble et al., 2016).
A meta-analysis of 10 randomized trials of bright
light therapy at 5000 lux or greater for at least
30 minutes combined with antidepressant suggested
an added benefit of bright light therapy over medi-
cation alone (Penders et al., 2016). Exercise as an
adjunct to pharmacotherapy may provide a small
benefit, but studies have typically used small sample
151
 Hantsoo and Mathews
sizes (Danielsson, Noras, Waern, & Carlsson, 2013).
Finally, ECT or TMS are options for severe, treatment-
resistant depression. Both are brain stimulation
therapies, meaning that currents are applied to
stimulate the brain and are administered several
times per week until response is achieved. ECT
involves applying an electrical current to induce
a brief seizure, and TMS uses magnetic fields to
induce electrical currents in specific areas of the
brain. A meta-analysis suggested that ECT alone
or in conjunction with an antidepressant provided
better symptom improvement than antidepressant
alone among individuals with treatment-resistant
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depression (Song et al., 2015). ECT may impact
some aspects of memory and executive function,
particularly in the first few days following treatment
(Semkovska & McLoughlin, 2010). Like ECT, TMS
may be used alone or in conjunction with pharmaco­
therapy (Perera et al., 2016). However, a large
randomized, double-blind, sham-controlled study
found no additional benefit of TMS beyond that
provided by antidepressant alone (Herwig et al., 2007).
Premenstrual Dysphoric Disorder
Nonpharmacologic treatments for PMDD include
psychotherapy, changes in diet or exercise, and
complementary treatments such as vitamin B6 or
calcium supplements (Yonkers & Simoni, 2018).
However, there is little evidence for efficacy of
these measures in conjunction with pharmacologic
treatment. The Royal College of Obstetricians
and Gynaecologists treatment guidelines indicate
that simple interventions should be tried prior to
pharmacotherapy, including exercise, vitamin B6
(100 mg), diet (complex carbohydrates during the
late luteal phase), or calcium (1,000 mg daily), but
there are no trials assessing these used in conjunction
with an antidepressant or hormonal treatment.
CBT is also recommended as an intervention for
milder cases of PMDD, but there are no existing
studies comparing CBT with pharmacotherapy or
in conjunction with pharmacotherapy in PMDD.
Peripartum Depression
Pregnancy and the postpartum period represent a
unique psychosocial and biological milieu. Stressors
152
such as parenting (Misri et al., 2010) and role changes
(Logsdon, Wisner, Hanusa, & Phillips, 2003) may
impact willingness to seek psychiatric care. If anti-
depressant treatment alone is not sufficient to treat
PD, psychotherapy is a common adjunct. While
meta-analysis suggests that CBT and IPT are both
beneficial for PD (Sockol, Epperson, & Barber,
2011), findings on psychotherapy as an adjunct to
medication in peripartum women are mixed. In a
pragmatic, open-label RCT, women with postpartum
depression were randomized to antidepressant
pharmacotherapy (general practitioner’s choice) or
supportive therapy with the option of antidepressant
(Sharp et al., 2010). After 4 weeks of treatment, the
pharmacotherapy group had twice the improve-
ment rate of the supportive therapy group, but
at 18 weeks, there was no statistically significant
difference between the two treatments. Postpartum
women with MDD and comorbid anxiety random-
ized to paroxetine monotherapy or paroxetine
with CBT showed significant improvement (Misri,
Reebye, Corral, & Milis, 2004). Other studies have
shown that combined treatment is equivalent to
pharmacotherapy alone (Appleby, Warner, Whitton,
& Faragher, 1997; Milgrom et al., 2015; Misri et al.,
2004). Placebo-controlled studies that compare
medication with psychotherapy in the PD popula-
tion are lacking. As the peripartum phase may involve
barriers to psychotherapy treatment, such as limited
mobility, schedule, childcare, or transportation,
another option may be computer-based therapies
such as therapy sessions via video chat, computer-
assisted therapy, or self-guided online therapy
(Hantsoo, Podcasy, Sammel, Epperson, & Kim,
2017; Kim, Hantsoo, Thase, Sammel, & Epperson,
2014). However, there are no studies looking
specifically at these treatments in combination
with pharmacotherapy.
INTEGRATED APPROACHES
FOR ADDRESSING COMMON
COMORBID DISORDERS
The depressive disorders are often comorbid with
other psychiatric disorders. In the U.S. National
Comorbidity Survey Replication, 72% of those

with a lifetime MDD diagnosis had a psychiatric
comorbidity (Kessler et al., 2003). This included
59.2% with a comorbid anxiety disorder, 30% with
comorbid impulse control disorder, and 24% with
a comorbid substance use disorder. Patients with
comorbid disorders may require higher doses of
medication or require more time for treatment
response (Silverstone & Salinas, 2001).
SSRIs and SNRIs are used not only to treat
depressive disorders, but also anxiety disorders,
making them an ideal choice for patients with
these comorbidities. Beyond SSRIs or SNRIs,
benzodiazepines with a long half-life, such as
Copyright American Psychological Association. Not for further distribution.
clonazepam, may be used for rapid control of anxiety
symptoms (Coplan, Aaronson, Panthangi, & Kim,
2015). For patients with a history of substance abuse,
atypical antipsychotics are an option instead of
benzodiazepines to manage anxiety (Coplan et al.,
2015). In terms of nonpharmacologic treatments,
the Unified Protocol for Transdiagnostic Treatment
of Emotional Disorders (UP) is a transdiagnostic
CBT protocol, meaning that it can be used across
several related diagnoses (Barlow, Allen, & Choate,
2016). Thus, for someone with a depressive disorder
and a secondary anxiety disorder diagnosis, this
may be a useful approach. UP includes standard
CBT techniques, such as cognitive reappraisal and
exposure with five core modules: emotion awareness,
cognitive flexibility, emotion avoidance, emotion-
related physical sensations, and emotion-focused
exposures.
For those with depression and a comorbid
substance use disorder diagnosis, psychosocial
treatment is typically used to address the substance
abuse concern (Pettinati, O’Brien, & Dundon, 2013).
It may be useful to reduce the patient’s substance
use early in treatment to determine the severity of
affective symptoms in the absence of the substance
(Pettinati et al., 2013). However, if the depressive
episode is exacerbating substance use, it may make
sense to address the depressive symptoms first via
pharmacotherapy (Pettinati, 2004). While anti­
depressant medications such as SSRIs will address
the depressive symptoms, they do not necessarily
improve the substance use symptoms (Kranzler et al.,
2006; Pettinati, 2004). Further, chronic alcohol
Pharmacological Treatment of Depressive Disorders
use may affect the pharmacokinetics of prescribed
psychiatric medications, especially in patients who
have liver damage resulting from chronic alcohol
use. To address both depressive symptoms and
alcoholism, adding a medication such as naltrexone
(which reduces alcohol use) to the antidepressant
pharmacotherapy may be effective (Pettinati
et al., 2010).
EMERGING TRENDS
While the monoamine hypothesis of depression
drove drug development initially, recent efforts
have concentrated on refining the specific receptors
or transporters targeted within the monoamine
system, shifting the focus to other neurotransmitter
systems such as glutamate or gamma-aminobutyric
acid (GABA), and even moving beyond neuro­
transmitters to study inflammation or neurogenesis.
Multimodal antidepressants are designed to affect
a wider range of monoamine receptors and trans-
porters. For instance, vilazodone (e.g., Viibryd®)
is a serotonin transporter (SERT) inhibitor and
5-HT1A partial agonist approved by the FDA in
2011 (Laughren et al., 2011). Vortioxetine (e.g.,
Brintellix®) is a SERT inhibitor, 5-HT1A agonist
and 5-HT3 receptor antagonist that was approved
by the FDA in 2013 (Bang-Andersen et al., 2011).
Both medications have shown efficacy similar
to that of traditional antidepressants, but there
is little data on long-term treatment outcomes
(Citrome, 2016; Connolly & Thase, 2016).
Triple reuptake inhibitors have been another
recent area of research. These agents block 5-HT,
norepinephrine, and dopamine reuptake, hence
the acronym SNDRIs. However, there are few
successful clinical trials of these agents, and
more research is needed (Learned et al., 2012;
Zhang et al., 2014).
Ketamine, which affects the glutamate system
as an N-methyl-d-aspartate (NMDA) receptor
antagonist, produces a rapid antidepressant effect
in patients with treatment-resistant depression
(Berman et al., 2000). Ketamine was initially
developed as an anesthetic, but has been studied
off-label at low doses to produce antidepressant
153
 Hantsoo and Mathews
effects within hours of intravenous administration.
However, the antidepressant effects of ketamine
for depression only last a few days (Kishimoto et al.,
2016) so patients need to go to their treatment facility
every few days for additional ketamine infusions.
Ketamine also has abuse potential and can elicit
psychotomimetic side effects such as delirium,
disorientation, or hallucinations (Short, Fong,
Galvez, Shelker, & Loo, 2018).
There is a large body of research demonstrating
links between depression and inflammation (Kiecolt-
Glaser, Derry, & Fagundes, 2015). Thus, efforts are
emerging to develop medications that may treat
Copyright American Psychological Association. Not for further distribution.
depressive symptoms by targeting the immune
system, particularly proinflammatory cytokines such
as tumor necrosis factor-alpha (TNF-α). A trial of
infliximab (an anti-TNF-α antibody) in individuals
with depression showed that for those who started
the study with higher levels of inflammation,
infliximab improved depressive symptoms (Raison
et al., 2013). However, those who did not have
elevated inflammation before treatment did not
show improvement with infliximab over placebo.
Further work is needed in this area. Neurogenesis
stimulators are another potential avenue for depres-
sion treatment. These agents, such as NSI-189
(a benzylpiperazine-aminopyridine compound),
stimulate neurogenesis—the production of new
neurons—in the hippocampus. A preliminary
double-blind RCT in depressed outpatients showed
significant improvement in depressive symptoms
among those taking NSI-189 versus placebo
(M. Fava et al., 2016); however, more studies
are needed. Another developing treatment area
is personalized medicine. Pharmacogenomics
assesses how a person’s genes might influence
his or her response to pharmacotherapy. Among
individuals whose medication for depression was
based on pharmacogenomics testing, some had
better remission rates, but results were mixed
across studies (Rosenblat, Lee, & McIntyre, 2017).
Thus, to date there is only limited evidence for
pharmacogenomics-guided treatment. However,
these are among many potential pathways for
improvements in the pharmacologic treatment
of depression that may provide new options in
the coming decades.
154
TOOL KIT OF RESOURCES
Major Depression
Patient Resources
Anxiety and Depression Association of America (ADAA),
Screening for Depression: https://adaa.org/
iving-with-anxiety/ask-and-learn/screenings/
screening-depression
Mayo Clinic Patient Care & Health Information,
Diseases & Conditions: Depression (Major
Depressive Disorder): http://www.mayoclinic.org/
diseases-conditions/depression/home/ovc-20321449
National Institute of Mental Health (NIMH), Health
and Education, Mental Health Information:
Depression: https://www.nimh.nih.gov/health/
topics/depression/index.shtml
National Institute of Mental Health. (2015). Depression:
What you need to know (NIH Publication No. 15-3561).
Bethesda, MD: U.S. Government Printing Office.
Available at https://www.nimh.nih.gov/health/
publications/depression-what-you-need-to-know/
index.shtml
Provider Resources
American Psychiatric Association. (2010). Treating
major depressive disorder: A quick reference guide.
Washington, DC: Author. http://psychiatryonline.org/
pb/assets/raw/sitewide/practice_guidelines/guidelines/
mdd-guide.pdf
Anxiety and Depression Association of America (ADAA),
Clinical Practice Review for Major Depressive
Disorder: https://adaa.org/resources-professionals/
practice-guidelines-mdd
Gartlehner, G., Gaynes, B. N., Amick, H. R., Asher, G. N.,
Morgan, L. C., Coker-Schwimmer, E., . . . Lohr, K. N.
(2016). Comparative benefits and harms of anti­
depressant, psychological, complementary, and
exercise treatments for major depression: An
evidence report for a clinical practice guideline
from the American College of Physicians. Annals of
Internal Medicine, 164, 331–341. http://dx.doi.org/
10.7326/M15-1813
Gelenberg, A. J., Freeman, M. P., Markowitz, J. C.,
Rosenbaum, J. F., Thase, M. E., Trivedi, M. H., &
Van Rhoads, R. S. (2010). Practice guideline for the
treatment of patients with major depressive disorder,
third edition. The American Journal of Psychiatry,
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