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DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition

Chapter 88: Depressive Disorders

Amy M. VandenBerg

CHAPTER SUMMARY FROM THE PHARMACOTHERAPY HANDBOOK

For the Chapter in the Schwinghammer Handbook, please go to Chapter 69, Depressive Disorders.

KEY CONCEPTS

KEY CONCEPTS

Multiple guidelines are available to guide the treatment of major depressive disorder (MDD), including medication management. Clinicians
treating individuals with MDD should be familiar with key tenets of these guidelines.

Other potential causes of symptoms such as medical conditions, medications, and other substances must first be ruled out when evaluating
a patient for a diagnosis of MDD.

The goals of treatment for MDD are the resolution of current symptoms (ie, remission) and the prevention of further episodes of depression
(ie, relapse or recurrence).

When counseling patients with MDD who are receiving traditional antidepressant medications, the patient should be informed that
transient adverse medication reactions might occur initially, while the symptoms of depression may take 2 to 4 weeks to improve and up to 3
months for full resolution. Adherence to the treatment plan is essential for a successful outcome, and tools to help increase medication
adherence should be discussed with each patient.

Since available antidepressants are considered equally efficacious for MDD, factors such as comorbid medical conditions, age, adverse
effect profile, and past history of response are used to guide medication selection.

When determining if a particular medication is ineffective for a patient, it is essential to evaluate the dose and duration of treatment as well
as patient adherence to the medication.

Novel antidepressants that target GABA and glutamate systems may have a more rapid and transient effect on symptoms. They are typically
used in conjunction with traditional antidepressants for refractory symptoms.

Pharmacogenetic tests are now commercially available. Resources are available to guide their use when clinicians are presented with testing
results as it relates to antidepressant treatment of MDD.

When evaluating antidepressant response, the clinician must consider quality­of­life issues, such as social, and occupational functioning in
addition to target signs and symptoms. The tolerability of the agent should also be assessed due to the occurrence of adverse medication
reactions that may lead to medication nonadherence. This is especially important in cases of recurrent episodes and long­term medication
management.

PATIENT CARE PROCESS

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Patient Care Process for Major Depressive Disorder
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 addition to target signs and symptoms. The tolerability of the agent should also be assessed due to the occurrence of adverse medication
reactions that may lead to medication nonadherence. This is especially important in cases of recurrent episodes andUniversity
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management.

PATIENT CARE PROCESS

Patient Care Process for Major Depressive Disorder

Watch the video of the Patient Care Process for Major Depressive Disorder.

Collect

Patient characteristics (eg, age, sex, gender identity, race, pregnancy status)

Current and past medical/psychiatric history (including information on first­degree family members)

Past medication history, including medications not tolerated and any medication allergies (also collect on first­degree family members)

Social history (eg, tobacco, ethanol, and other substance use as well as social supports and/or stressors)

Current medications including over­the­counter (OTC), herbal products, dietary supplements, and medical or recreational cannabis use

Objective data

Blood pressure, heart rate, weight

Labs including thyroid function tests, serum creatinine, complete blood count (CBC), liver function tests, urine toxicology screen, blood
alcohol level, medication serum concentrations, and pharmacogenomics testing if available

Reported symptoms of depression or other rating scale assessment (eg, Patient Health Questionnaire 9 [PHQ­9], Beck Depression
inventory [BDI]) (Tables 88­1 and 88­2 and Chapter e81, “Evaluation of Psychiatric Illness”)

Assess

Suicidality (eg, Columbia­Suicide Severity Scale)

Severity of illness/need for hospitalization

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physical conditions that may overlap with depression symptoms (eg, pain resulting in insomnia or limited activity, gastrointestinal
symptoms resulting in weight loss) or medications that may be contributing to depressive symptoms (Table 88­1)
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Suicidality (eg, Columbia­Suicide Severity Scale)

Severity of illness/need for hospitalization

Impact of substance use on symptoms and whether a substance use disorder is contributing to symptoms

Presence of physical conditions that may overlap with depression symptoms (eg, pain resulting in insomnia or limited activity, gastrointestinal
symptoms resulting in weight loss) or medications that may be contributing to depressive symptoms (Table 88­1)

Past response and adherence (personal or family) to antidepressant medications

Ability/willingness to follow up with psychiatry services including antidepressant medication management, cognitive behavioral therapy (CBT),
outpatient groups

Barriers to participation in medication management or CBT

Barriers to adjunctive treatments (eg, exercise, stretching, yoga)

Pharmacogenomics testing results

Plan*

Medication therapy regimen including specific agent(s), dose, frequency, and titration plan if applicable (Table 88­3)

Monitoring parameters including efficacy (looking for some improvement in 2­4 weeks), safety (change in suicidality), and adverse medication
reactions (may be seen in first 1­2 weeks of treatment) (Table 88­11)

Patient education (eg, purpose of treatment, medication­specific information, medication adherence, and review of
laboratory/pharmacogenomics results)

Patient education regarding self­monitoring, when to call the clinic with questions or concerns, and when to seek emergency medical attention
(eg, suicidality)

Obtain release of information to gather collateral information (eg, family members, therapists, medical providers)

Nonpharmacological interventions (eg, diet, exercise, mindfulness)

Make referrals to other providers when appropriate (eg, neurologist, pain specialist, substance use disorder treatment)

Potential for medication interactions (Tables 88­5, 88­9, and 88­10)

Implement*

Provide patient education regarding all elements of the treatment plan

Use motivational interviewing and coaching to maximize adherence

Schedule follow­up to monitor and assess medication effectiveness (eg, PHQ­9, BDI) and adherence to treatment plan, including therapeutic
medication monitoring when appropriate.

Follow­up: Monitor and Evaluate

Resolution of depressive symptoms using standardized rating scales

Presence of adverse medication reactions (Table 88­11)

Laboratory follow­up when indicated (eg, sodium, liver function tests)

Patient adherence to treatment plan based in multiple sources of information (eg, medication refill records, patient/caregiver report)

Consider scheduling early or more frequent (every 1­2 weeks) follow­up visits after initiating therapy to monitor response and behavioral risks
such as suicidality. Reevaluate initial response at 2 to 4 weeks and again at 8 to 12 weeks. Reevaluate treatment plan quarterly and reevaluate
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Collaborate with patient, caregivers, and other healthcare professionals.
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Patient adherence to treatment plan based in multiple sources of information (eg, medication refill records, patient/caregiver report)

Consider scheduling early or more frequent (every 1­2 weeks) follow­up visits after initiating therapy to monitor response and behavioral risks
such as suicidality. Reevaluate initial response at 2 to 4 weeks and again at 8 to 12 weeks. Reevaluate treatment plan quarterly and reevaluate
duration of therapy after patient achieves remission.

*
Collaborate with patient, caregivers, and other healthcare professionals.

BEYOND THE BOOK

BEYOND THE BOOK

Watch the TED talk entitled Depression the Secret We Share by Andrew Solomon. This talk provides an engaging patient perspective on the
experience of depression including Solomon’s own experiences and that of others he interviewed.

Alternatively, watch “Pharmacology – Antidepressants – SSRIs, SNRIs, TCAs, MAOIs, lithium (Made Easy)” at [Link]
v=T25jvLC6X0w. This 19­minute video provides a brief visual narrated overview of the monoamine theory of depression and mechanisms of
commonly used antidepressant medications.

INTRODUCTION
Major depressive disorder (MDD) is diagnosed when an individual experiences one or more major depressive episodes without a history of mania or
hypomania. A major depressive episode and MDD are defined by the criteria listed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM­5).1 Depression is associated with significant functional disability, morbidity, and mortality. Antidepressants, such as the selective
serotonin reuptake inhibitors (SSRIs), are equally effective and better tolerated than older agents, such as the tricyclic antidepressants (TCAs) and the
monoamine oxidase inhibitors (MAOIs). While depressive episodes also occur in bipolar disorder, this chapter focuses exclusively on the diagnosis and
treatment of MDD.

Three key evidence­based guidelines on the assessment and management of MDD are available to assist the clinician. The American Psychiatric
Association Practice Guideline for the Treatment of Patients with Major Depressive Disorder, Third Edition (2010) (available at [Link]) is a
practical guide to the management of MDD based on both available data and clinical consensus.2 The updated British Association of
Psychopharmacology (BAP) evidence­based guidelines for treating depressive disorders with antidepressants (2015) provide recommendations for
antidepressant treatment of MDD.3 Finally, the Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the
management of adults with major depressive disorder outline evidence­based pharmacological treatments for MDD.4 These three guidelines have
many similarities in recommendations.

EPIDEMIOLOGY
While the actual prevalence of depressive disorders, including undiagnosed cases, is unknown, the estimated rate has increased over the past 25
years, with additional increases since 2020.5­8 Overall, the lifetime prevalence of depression is estimated at 7% to 15% with rate in females 1.5­ to 2.5­
fold higher than males.2,3 In looking at non­sex factors, the prevalence of depression is highest in those less than 60 years of age, within non­White
populations, and in individuals at high poverty levels compared to White populations over the age of 60 without poverty.9 Intersectionality, or the study
of how different social classes intersect, and its relationship to depression epidemiology is becoming a high priority field of study. Adolescent
depression is increasingly common with an annual prevalence (2015) of 19.4% in females and 6.4% in males between 12 and 17 years of age (up from
13.1% and 4.5%, respectively, in 2004).2,10 In addition, transgender and non­gender conforming individuals are also at risk for increased mental health
issues. In particular adolescents in these groups with poor social support report a higher degree of suicidal ideation and attempts.11

Depressive disorders and suicide tend to occur within families. Approximately 8% to 18% of patients with MDD have at least one first­degree relative
(father, mother, brother, or sister) with a history of depression, compared with 5.6% of those without depression.12 First­degree relatives of patients
with depression are 1.5 to 3 times more likely to develop depression than those without the family history.4,12 The heritability of liability for MDD has
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been estimated at 37%, with the remaining 63% of the variance in liability due to individual­specific environment (eg, high stress, trauma).12 Therefore,
Chapter 88: Depressive Disorders, Amy M. VandenBerg Page 4 / 53
MDD
©2025is relatively common,
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• Notice is influenced by both genetic and environmental
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factors.
13.1% and 4.5%, respectively, in 2004).2,10 In addition, transgender and non­gender conforming individuals are also at risk for increased mental health
University
issues. In particular adolescents in these groups with poor social support report a higher degree of suicidal ideation and attempts. 11 of the West Indies
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Depressive disorders and suicide tend to occur within families. Approximately 8% to 18% of patients with MDD have at least one first­degree relative
(father, mother, brother, or sister) with a history of depression, compared with 5.6% of those without depression.12 First­degree relatives of patients
with depression are 1.5 to 3 times more likely to develop depression than those without the family history.4,12 The heritability of liability for MDD has
been estimated at 37%, with the remaining 63% of the variance in liability due to individual­specific environment (eg, high stress, trauma).12 Therefore,
MDD is relatively common, and occurs more frequently in females than in males, and prevalence is influenced by both genetic and environmental
factors.

ETIOLOGY
The etiology of depressive disorders is too complex to be explained by a single social, developmental, or biologic theory. Several factors appear to
work together to cause or precipitate depressive disorders. Interactions between important factors such as individual’s sex, gender identity, race,
ethnicity, culture, social status, genetics, and environment are at the heart of understanding the role of intersectionality on the etiology of depression.

PATHOPHYSIOLOGY
The monoamine hypothesis that depression is caused by decreased brain levels of serotonin (5­HT), dopamine (DA), and norepinephrine (NE) has
been supported for over 50 years. However, the actual chemical basis for depression remains elusive.13 This biogenic amine hypothesis evolved as a
result of several observations made in the early 1950s that the antihypertensive medication reserpine depleted neuronal storage of NE, 5­HT, and DA
and produced clinically significant depression in 15% or more of patients.14 Subsequently, the hypothesis was supported by the mechanism(s) of
antidepressant medications. Additionally, recurrence of depression has been induced by acute depletion of tryptophan (precursor of 5­HT) and 5­HT
metabolite levels in cerebrospinal fluid are lower in some patients with MDD.15 Evidence reveals the complexities of the monoamine systems in the
brain. These systems are mediated by gamma aminobutyric acid (GABA), neuroactive steroids, endogenous opioids, and nutritional imbalances.16­22
For the purposes of this chapter, the focus of medication mechanism of action will be the monoamine hypothesis unless otherwise specified (Figs. 88­1
and 88­2).

FIGURE 88­1

Monoamine neurotransmitter (NT) regulation at the neuronal level. NTs carry messages between cells. Each NT generally binds to a specific receptor,
and this coupling initiates a cascade of events. NTs are reabsorbed back into nerve cells by reuptake pumps (ie, transporter molecules) at which point
they may be recycled for later use or broken down by enzymes. For their primary mechanism of action, most antidepressants are thought to inhibit the
transporter molecules and allow more NT to remain in the synapse. (Reprinted from Mind Over Matter: The Brain’s Response to Drugs—Teacher’s
Guide Revision. NIH Publication No. 05­3592. Office of Science Policy and Communications, National Institutes of Health. Revised May 2005.
[Link]

Monoamine
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Chapter
enhances88:
NEDepressive
transmissionDisorders, Amy [Link]
may secondarily both 5­HT and DA activity.23,24
VandenBerg Page 5 / 53
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Although increase in synaptic monoamines (eg, NE, DA, and 5­HT) occurs rapidly after initiation of an antidepressant, the clinical effects (ie,
measurable symptom improvement) are generally delayed by weeks.15,23 This delay may be the result of a cascade of events from receptor occupancy
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Monoamine systems do not function independently, but serve as feedback mechanisms for each other. Therefore, a medication that preferentially
enhances NE transmission may secondarily alter both 5­HT and DA activity.23,24

Although increase in synaptic monoamines (eg, NE, DA, and 5­HT) occurs rapidly after initiation of an antidepressant, the clinical effects (ie,
measurable symptom improvement) are generally delayed by weeks.15,23 This delay may be the result of a cascade of events from receptor occupancy
to gene transcription, downregulation of presynaptic feedback mechanisms, and secondary effects on other neurotransmitter symptoms or
neuroplasticity.13,15,25 This led researchers to focus on the adaptive changes induced by antidepressants. In the mid­1970s, chronic, but not acute,
administration of antidepressants to animals caused desensitization of NE­stimulated cyclic adenosine monophosphate synthesis. In fact, for most
antidepressants, downregulation of β­adrenergic receptors accompanies this desensitization.26,27 Studies of many antidepressants have
demonstrated that either desensitization or downregulation of NE receptors corresponds the time course for antidepressant effects.27 Other studies
have revealed desensitization of presynaptic 5­HT1A autoreceptors following chronic administration of antidepressants.15 These theories based on
changes in receptor sensitivity provide a cogent explanation for the delayed onset of therapeutic response with antidepressant medications. The
dysregulation hypothesis incorporates the diversity of antidepressant activity with the adaptive changes occurring in receptor sensitization over
several weeks. In this theory, emphasis is placed on a failure of homeostatic regulation of NT systems rather than on absolute increases or decreases in
their activities. According to this hypothesis, effective antidepressant agents restore efficient regulation to the dysregulated NT system.13

Traditional explanations of the biologic basis of depressive disorders have focused largely on NE and 5­HT. However, most of the evidence that
coalesced into the biogenic amine hypothesis of depression does not clearly distinguish between NE and DA. There is an abundance of evidence
suggesting that DA transmission is decreased in depression, and agents that increase dopaminergic transmission have been found to be effective
antidepressants.23 Specifically, increased DA transmission in the mesolimbic pathway accounts for at least part of the mechanism of action of
antidepressant medications.23 The mechanisms by which antidepressant medications alter DA transmission remain unclear, but may be mediated
either directly by dopaminergic changes or indirectly by primary actions at NE or 5­HT terminals. The complexity of the interaction between 5­HT, NE,
and DA is gaining greater appreciation, but a more in­depth understanding of the precise mechanism is needed. The availability of dopaminergic­
based first­line and augmentation antidepressant strategies (eg, bupropion, high­dose venlafaxine, second­generation antipsychotics) may help
answer remaining questions.

Neuroactive steroids are a growing area of research in depression as a link between the progesterone metabolite, allopregnanolone, and depression
has been found. Allopregnanolone release is increased in the setting of acute stress and may serve a neuroprotective role. However, with chronic
stress and MDD central nervous system (CNS) concentrations of allopregnanolone may decrease. Rapid decline in allopregnanolone levels in the
postpartum period has been associated with postpartum depression.28 Furthermore, certain antidepressants have been shown to increase cerebral
spinal fluid (CSF) levels of allopregnanolone proportional to depressive symptom response.18

Another proposed pathway for depression involves a complex interplay of inflammation and overexcitation resulting in decreased neuroplasticity and
neuronal differentiation. Brain­derived neurotrophic factor (BDNF) is a primary mediator of these neuronal changes as well as synaptogenesis.
Chronic stress, associated with increased glucocorticoids such as cortisol, may lead to decreased BDNF expression. Evidence suggests this process may
be prevented, or possibly even reversed, by antidepressant medications or electroconvulsive therapy (ECT).29 Increased BDNF expression after
treatment initiation follows timeline similar to antidepressant response.29

Chronic stress and inflammation also alter glutamate and GABA transmission, changes that have been linked to depression and decreased BDNF.
Increased GABAA receptor activity is associated with decreased transmission of 5­HT and increased NE transmission while increased GABAB receptor

activation is associated with decreased 5­HT and NE transmission.24 Increased serum and extrasynaptic glutamate has been associated with MDD
symptom severity. Many available antidepressants decrease serum glutamate concentrations and are thought to increase BDNF activity.16,29 An
example of this is ketamine which inhibits extrasynaptic NMDA receptors, theoretically increasing synaptic glutamate activity, triggering BDNF release
from synaptic vesicles.30 Further, BDNF has been shown to decrease expression of GABAA receptors possibly resulting in increased 5­HT and NE

transmission linking it back to the monoamine hypothesis.29 The interaction of all of these related systems is not fully understood. However, the
complexities could partially explain differences in response to medications as there are likely distinct subtypes of depression with different
pathogenesis.

Biologic Markers
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and treatment of MDD. Although no gold­standard biologic marker has
been discovered, several biologic abnormalities have been variably identified in patients with MDD. Hypersecretion of cortisol or a lack of cortisol
suppression after dexamethasone administration (ie, a positive dexamethasone suppression test) has been positively correlated to depression as well
from synaptic vesicles.30 Further, BDNF has been shown to decrease expression of GABAA receptors possibly resulting in increased 5­HT and NE
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transmission linking it back to the monoamine hypothesis.29 The interaction of all of these related systems is not fully understood. However, the
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complexities could partially explain differences in response to medications as there are likely distinct subtypes of depression with different
pathogenesis.

Biologic Markers

Investigators continue to search for biologic markers to assist in the diagnosis and treatment of MDD. Although no gold­standard biologic marker has
been discovered, several biologic abnormalities have been variably identified in patients with MDD. Hypersecretion of cortisol or a lack of cortisol
suppression after dexamethasone administration (ie, a positive dexamethasone suppression test) has been positively correlated to depression as well
as risk of suicide.31 Although the widespread use of this test has fallen out of favor in recent decades (due to limited sensitivity and specificity), the
inability of the brain to suppress the hypothalamic–pituitary–adrenal (HPA) axis and the associated stress response could contribute to depression,
possibly due to excessive glutamate and decreased BDNF discussed above.31 According to this theory, there is a disruption somewhere in the normal
negative feedback system that controls cortisol levels.

FIGURE 88­2

The presynaptic regulation and postsynaptic actions of serotonin and norepinephrine are multifaceted and many of the steps have been implicated in
the pathophysiology of depression. Currently available oral antidepressants have mechanisms focused on presynaptic regulation. Most first­line
antidepressants target serotonin and/or norepinephrine transporters which are responsible for “reuptake” of the neurotransmitters into presynaptic
neurons (hence, selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors). Polymorphisms in these transporters
have been associated with depression and may impact efficacy of medications that target the transporters. Other medication targets include MAO,
5HT1A receptors (vilazodone, vortioxetine), and α2 receptors (mirtazapine). Due to the complexity of these systems, there are numerous other targets
at various stages of investigation. (Reproduced, with permission, from DeBattista C. Antidepressant Agents. Katzung BG, ed. Basic & Clinical
Pharmacology. 15th ed. New York, NY: McGraw­Hill; 2021.)

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Emerging evidence provides promise for both biologic and genetic markers for MDD. As previously mentioned serum levels of glutamate have
have been associated with depression and may impact efficacy of medications that target the transporters. Other medication targets include MAO,
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5HT1A receptors (vilazodone, vortioxetine), and α2 receptors (mirtazapine). Due to the complexity of these systems, there are numerous other targets
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at various stages of investigation. (Reproduced, with permission, from DeBattista C. Antidepressant Agents. Katzung BG, ed. Basic & Clinical
Pharmacology. 15th ed. New York, NY: McGraw­Hill; 2021.)

Emerging evidence provides promise for both biologic and genetic markers for MDD. As previously mentioned serum levels of glutamate have
correlated with MDD severity and rising concentrations of BDNF in the CNS have correlated to antidepressant response. The genes coding for BDNF
production have been identified with polymorphisms that result in lower levels of BDNF.29 Another focus of pharmacogenomics has been on
polymorphisms of methylenetetrahydrofolate reductase (MTHFR) as they relate to differences in rates of depression and antidepressant response
(inconsistent results to date).32 Multiple other phenotypes have been identified and are available for testing with commercially available products, but
evidence to date does not support routine testing for diagnosis or to predict treatment response.33 Nor is there enough evidence to support testing
CNS concentrations of BDNF or serum concentrations of glutamate.

CLINICAL PRESENTATION

CLINICAL PRESENTATION: Depressive Disorder

Emotional Symptoms

Diminished ability to experience pleasure

Loss of interest and pleasure in usual activities, hobbies, or work (anhedonia)

Pessimism,
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Voices (eg, auditory hallucinations) saying negative comments or suggesting suicide

evidence to date does not support routine testing for diagnosis or to predict treatment response.33 Nor is there enough evidence to support testing
CNS concentrations of BDNF or serum concentrations of glutamate. University of the West Indies
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CLINICAL PRESENTATION

CLINICAL PRESENTATION: Depressive Disorder

Emotional Symptoms

Diminished ability to experience pleasure

Loss of interest and pleasure in usual activities, hobbies, or work (anhedonia)

Pessimism, hopelessness regarding feeling better

Anxiety

Voices (eg, auditory hallucinations) saying negative comments or suggesting suicide

Physical Symptoms

Chronic fatigue resulting in decreased ability to attend to daily tasks (eg, bathing, grooming)

Fatigue does not improve with rest and is often associated with pain, headache

Changes in sleep (eg, early morning awakening, difficulty falling asleep, frequent awakening or increased sleep with associated fatigue)34

Appetite changes (eg, most common decreased appetite and unintentional weight loss; increased appetite/weight gain atypical)34,35

Gastrointestinal disturbances, genitourinary issues, cardiovascular complaints (eg, palpitations), loss of libido

Cognitive Symptoms35

Decreased concentration or slowed thinking

Poor memory for recent events (especially older adults)

Confused or indecisive

Psychomotor Disturbances

Slow physical movements, speech and thought processes (psychomotor retardation)

Restlessness (eg, pacing, wringing of hands), outbursts of anxiety or agitation (eg, crying or yelling); together known as psychomotor agitation

When a patient presents with depressive symptoms, it is necessary to investigate the possibility of a contributing medical or medication­induced
etiology. All patients evaluated for depression should have a complete physical examination, mental status examination, and basic laboratory workup,
including a complete blood count (CBC) with differential, thyroid function tests, and electrolytes, to identify any potential medical problems. While a
complete discussion of medical conditions associated with depression is beyond the scope of this chapter, multiple common medical conditions are
associated with development of depressive symptoms, such as stroke, Parkinson disease, traumatic brain injury, and hypothyroidism. Other
conditions associated with increased risk for depression include pain, diabetes, seizures, and coronary artery disease.36 The DSM­5 describes a
diagnostic category for both “Depressive Disorder Due to Another Medical Condition” and “Substance/Medication­Induced Depressive Disorder,”1
which emphasizes the importance of ruling out alternative causes of symptoms. A complete medication review should include both current and
previous medications to assess for both helpful and contributing medications. Additionally, consider the contribution of substance withdrawal (eg,
cocaine, cannabis, or alcohol) to depressive symptoms. Table 88­1 lists medications commonly associated with causing or exacerbating depressive
symptoms.37­44

Once other medical­, medication­, or substance­related causes of symptoms have been ruled out, the patient should be evaluated for MDD. According
to the DSM­5, 2025­5­6
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11:17depressive
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is is characterized by five (or more) of the symptoms described in Table 88­2​​.1 At least one of the
Chapter
symptoms 88:
is Depressive
depressed mood Disorders,
(oftenAmy mood in children or adolescents) or loss of interest or pleasure in nearly all activities.1 These
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an irritable Page 9 / 53
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symptoms must have been present nearly every day for at least 2 weeks and must represent a change from the patient’s previous level of functioning.
The diagnostic code for MDD is determined by whether this is a single or recurrent depressive episode, current severity, presence of psychotic
features, and remission status. The diagnosis can be followed by specifiers that apply to the current episode. The possible specifiers include anxious
previous medications to assess for both helpful and contributing medications. Additionally, consider the contribution of substance withdrawal (eg,
cocaine, cannabis, or alcohol) to depressive symptoms. Table 88­1 lists medications commonly associated with causing orUniversity of the
exacerbating West Indies
depressive
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symptoms.37­44

Once other medical­, medication­, or substance­related causes of symptoms have been ruled out, the patient should be evaluated for MDD. According
to the DSM­5, a single major depressive episode is characterized by five (or more) of the symptoms described in Table 88­2​​.1 At least one of the
symptoms is depressed mood (often an irritable mood in children or adolescents) or loss of interest or pleasure in nearly all activities.1 These
symptoms must have been present nearly every day for at least 2 weeks and must represent a change from the patient’s previous level of functioning.
The diagnostic code for MDD is determined by whether this is a single or recurrent depressive episode, current severity, presence of psychotic
features, and remission status. The diagnosis can be followed by specifiers that apply to the current episode. The possible specifiers include anxious
distress, mixed features (ie, presence of manic/hypomanic features), melancholic features, atypical features, mood­congruent or incongruent
psychotic features, catatonia, peripartum onset, and seasonal pattern. The clinician must consider presenting symptoms, their duration, and the
patient’s current level of social, occupational, or other important areas of functioning. Significant stressors or life events may trigger depression in
some individuals; however, not all patients will have a clear precipitant.1

TABLE 88­1
Select Medications Associated with Depressive Symptoms

Medication Class Individual Agents Comments

Acne treatment Isotretinoin REMS program iPledge recommends monitoring psychiatric symptoms

Antiseizure All FDA­approved antiseizure medications Specific warning added to labeling under Warnings and Precautions
medications (including clorazepate and clonazepam) regarding increased risk of suicidal thoughts or behavior
Not all agents with warning have demonstrated increased risk
Controversial

Cardiovascular Reserpine Rarely used due to historical reports of depression due to depletion of
medications monoamines

Angiotensin receptor blockers Conflicting data for most agents

β­Blockers β­Blockers classically linked to depression; however, most evidence
Calcium channel blockers supports only physical symptoms of fatigue and low energy
Clonidine Link between cardiovascular disease and depression must be considered
Methyldopa

Central nervous Deutetrabenazine Deplete synaptic monoamines via decreasing vesicular transport in
system agents Tetrabenazine presynaptic neurons
Valbenazine Deutetrabenazine and tetrabenazine have boxed warning for depression
and suicidality

Hormonal Gonadotropin­releasing hormone Linked to alterations in progesterone and estrogens and possible link to
therapy Oral contraceptives monoamine oxidase activity

Steroids (eg, prednisone) Possible association with inflammation and HPA axis changes in
depression

Immunologic Interferons Labeled warning

agents

Smoking Varenicline Reports to FDA MedWatch after release

cessation Large postmarketing study does not support increased risk
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REMS, Risk Evaluation and Mitigation Strategy; FDA, Food and Drug Administration.
distress, mixed features (ie, presence of manic/hypomanic features), melancholic features, atypical features, mood­congruent or incongruent
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psychotic features, catatonia, peripartum onset, and seasonal pattern. The clinician must consider presenting symptoms, their duration, and the
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patient’s current level of social, occupational, or other important areas of functioning. Significant stressors or life events may trigger depression in
some individuals; however, not all patients will have a clear precipitant.1

TABLE 88­1
Select Medications Associated with Depressive Symptoms

Medication Class Individual Agents Comments

Acne treatment Isotretinoin REMS program iPledge recommends monitoring psychiatric symptoms

Antiseizure All FDA­approved antiseizure medications Specific warning added to labeling under Warnings and Precautions
medications (including clorazepate and clonazepam) regarding increased risk of suicidal thoughts or behavior
Not all agents with warning have demonstrated increased risk
Controversial

Cardiovascular Reserpine Rarely used due to historical reports of depression due to depletion of
medications monoamines

Angiotensin receptor blockers Conflicting data for most agents

β­Blockers β­Blockers classically linked to depression; however, most evidence
Calcium channel blockers supports only physical symptoms of fatigue and low energy
Clonidine Link between cardiovascular disease and depression must be considered
Methyldopa

Central nervous Deutetrabenazine Deplete synaptic monoamines via decreasing vesicular transport in
system agents Tetrabenazine presynaptic neurons
Valbenazine Deutetrabenazine and tetrabenazine have boxed warning for depression
and suicidality

Hormonal Gonadotropin­releasing hormone Linked to alterations in progesterone and estrogens and possible link to
therapy Oral contraceptives monoamine oxidase activity

Steroids (eg, prednisone) Possible association with inflammation and HPA axis changes in
depression

Immunologic Interferons Labeled warning

agents

Smoking Varenicline Reports to FDA MedWatch after release

cessation Large postmarketing study does not support increased risk
medications

REMS, Risk Evaluation and Mitigation Strategy; FDA, Food and Drug Administration.

Data from References 2 and 37­44.

TABLE 88­2
Diagnostic Criteria for Major Depressive Episode

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Suicidal P Your IP or
with is without plan, suicide attempt; recurrent thoughts of death
Chapter 88: Depressive Disorders, Amy M. VandenBerg Page 11 / 53
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anhedonia

G Guilt—inappropriate or excessive in nature; feelings of worthlessness

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Data from References 2 and 37­44.

TABLE 88­2
Diagnostic Criteria for Major Depressive Episode

S Suicidal ideation with or without plan, suicide attempt; recurrent thoughts of death

I Interest—loss of interest or pleasure in activities; anhedonia

G Guilt—inappropriate or excessive in nature; feelings of worthlessness

E Energy decreased

C Concentration decreased; difficulty making decisions

A Appetite changes; typically decreased; resulting in 5% change in weight from baseline

P Psychomotor agitation or retardation

S Sleep impairment; typically insomnia but may be hypersomnia

At least five symptoms must be consistently present over a 2­week period.

Symptoms must include depressed mood or anhedonia.
Symptoms must cause substantial distress or impairment in functioning.
Other medical conditions or substance use do not account for symptoms.

Data from Reference 1.

Depression Rating Scales

Instruments to assess the severity of depressive symptoms can be used for both clinical and research purposes. For example, the Montgomery­Åsberg
Depression Rating Scale (MADRS) is a clinician­administered scale that is commonly used in clinical trials given its sensitivity to change.45 Some
depression rating scales are self­administered such as the Beck Depression Inventory (BDI) that takes only 5 to 10 minutes to complete by the
respondent.46 The PHQ­9 is another brief scale that has been validated for use.47 For a more detailed explanation of these instruments, as well as other
rating scales and evaluation approaches, refer to Chapter e81.

Emotional Symptoms

A major depressive episode is characterized by a persistent, diminished ability to experience pleasure, and as such a loss of interest and pleasure in
usual activities, hobbies, or work is common. Patients appear sad or depressed, and they are often pessimistic and believe that nothing will help them
feel better. The occurrence of guilty feelings that are unrealistic is common, and these may reach delusional levels where patients feel that they
deserve punishment and may view their present illness as a punishment. A patient suffering from MDD with psychotic features may hear voices, usually
auditory hallucinations saying that they are a bad person or should try to die by suicide. Depression with psychotic features may require
hospitalization, especially if the patient becomes a danger to self or others. Additionally, anxiety symptoms are present in almost 90% of outpatients
with depression, which may have treatment implications.

Additional Symptoms of Depression

Physical symptoms, rather than emotional symptoms, often motivate patients, especially older adults, to seek medical attention. Chronic fatigue, with
a decreased ability to perform normal daily tasks is a common presenting symptom. The fatigue seen in patients with depression often appears worse
in the morning, does not improve with rest, and is frequently accompanied by pain, especially headache.
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Sleep disturbances
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88: Depressive presentAmy
Disorders, as early morning awakening with difficulty returning to sleep. This may coexist with difficulty falling Page
M. VandenBerg asleep12and
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sleep) is less common. Recognition and management of sleep
disturbances among patients with depression are crucial, as approximately 60% to 90% of patients experiencing MDD report sleep disturbances.34
 University of the West Indies
Additional Symptoms of Depression
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Physical symptoms, rather than emotional symptoms, often motivate patients, especially older adults, to seek medical attention. Chronic fatigue, with
a decreased ability to perform normal daily tasks is a common presenting symptom. The fatigue seen in patients with depression often appears worse
in the morning, does not improve with rest, and is frequently accompanied by pain, especially headache.

Sleep disturbances generally present as early morning awakening with difficulty returning to sleep. This may coexist with difficulty falling asleep and
frequent nighttime awakening, daytime exhaustion or fatigue. Hypersomnia (increased sleep) is less common. Recognition and management of sleep
disturbances among patients with depression are crucial, as approximately 60% to 90% of patients experiencing MDD report sleep disturbances.34

Appetite disturbances, specifically decreased appetite, often result in substantial weight loss, especially in older adults.34,35 Some patients lose 2 lb (0.9
kg) or more per week without dieting. Other patients may overeat and gain weight, although they typically do not enjoy eating.

Patients may present with a variety of other symptoms such as gastrointestinal (GI) issues (eg, pain, nausea, diarrhea, constipation), genitourinary
issues (eg, incontinence, pain), cardiovascular complaints (eg, palpitations), cognitive impairment (especially older adults), or muscle fatigue. Lastly,
patients frequently present with a loss of sexual interest or libido.

In addition to physical symptoms patients with MDD frequently experience cognitive and psychomotor disturbances noted in the Clinical Presentation
box.

Suicide Risk Evaluation and Management

As of 2018, the Centers for Disease Control and Prevention listed death by suicide as the tenth leading cause of death among Americans and the second
leading cause of death among 10­ to 44­year­olds.6 Suicide rates increased between 6% and 58% in 49 of 50 states between 1999 and 2016 and the
rates in adolescents in particular are rising in the face of the COVID pandemic.8,48 All patients diagnosed with MDD should be assessed for suicidal
thoughts and factors associated with increased risk for suicide including other psychiatric disorders, substance use disorders, adolescents and
younger adults, physical illness, recent stressful life event, childhood trauma, hopelessness, and male gender.49 Those with a higher level of risk often
have high degree of suicidal intent and describe more specific plans, in particular, plans that are violent and irreversible.49 The risk of death by suicide
in those recovering from MDD may increase as they develop the energy and capacity to act on a plan made earlier in a course of illness. Despite factors
to help identify those at greatest risk, it remains very difficult to predict suicidality in any given individual. Therefore, when suicidal intent is suspected,
it is important to ask, “Are you thinking about harming or killing yourself?” (See Chapter e81 for more information.) If the risk is significant, the patient
must be referred immediately to an appropriate healthcare professional. Certain depression rating scales, such as the MADRS and PHQ­9 discussed
above, include questions that target suicidality, which may help identify those patients at risk. Additionally, the Columbia­Suicide Severity Rating Scale
is widely accepted in clinical practice as a validated assessment of suicide risk.50

In September 2004, the FDA required manufacturers of antidepressants to add a boxed warning stating that all antidepressants increase the risk of
suicidal thinking and behavior in short­term studies in children and adolescents with depressive disorders. These risks have become a new source of
concern among those treating their patients with antidepressants. In order to help deal with the confusion these warnings have caused, experts have
recommended the following51:

1. It is especially important to closely monitor patients for suicidal ideation and behavior at the beginning of treatment and among younger patients.

2. Discuss the possibility that adverse medication reactions may occur, including behavioral agitation or anger, and encourage patients to seek help
should this occur.

3. Deal with the subject of suicide directly.

Withholding antidepressant treatment may not decrease the risk of suicide and may actually increase the risk. Furthermore, it may be that longer­term
medication is needed for any protective effects against suicidality.51

In May 2007, the FDA expanded the boxed warning regarding suicidality to include young adults 18 to 24 years of age, during the initial stages of
treatment. The warning also applies to any medication with either monotherapy or adjunct treatment of depression as an FDA­approved indication
even if not classified as an “antidepressant” (eg, aripiprazole, quetiapine).

Assessment of actual suicide risk has proven to be difficult as there are differences in coding of events in clinical trials and complete case data from
trials is often not available. Additionally, there appears to be an increased risk of suicidality in the 30 days after antidepressant discontinuation, which
is not routinely evaluated in clinical trials. 52
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population88:should
Depressive Disorders,
be evaluated Amy upon
carefully M. VandenBerg Page 13 / 53
initiation or discontinuation of antidepressant treatment. The complex relationships between
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antidepressant use and suicidality will continue to be explored with the hopes of more unequivocal recommendations.
treatment. The warning also applies to any medication with either monotherapy or adjunct treatment of depression as an FDA­approved indication
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even if not classified as an “antidepressant” (eg, aripiprazole, quetiapine).
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Assessment of actual suicide risk has proven to be difficult as there are differences in coding of events in clinical trials and complete case data from
trials is often not available. Additionally, there appears to be an increased risk of suicidality in the 30 days after antidepressant discontinuation, which
is not routinely evaluated in clinical trials.52 An increased risk of suicidality in children and adolescents has been found in multiple studies and this
population should be evaluated carefully upon initiation or discontinuation of antidepressant treatment. The complex relationships between
antidepressant use and suicidality will continue to be explored with the hopes of more unequivocal recommendations.

TREATMENT
Desired Outcomes

The goal of treating depression is resolution of depressive symptoms and return to previous level functioning. Initial treatment may occur in the
hospital or in outpatient treatment settings. Hospitalization is more likely when there is a high risk of suicide, poor physical health, limited social
support or psychotic symptoms. Response, typically defined as 50% decrease in symptoms and is achieved in 40% to 50% of patients 8 to 12 weeks
after medication initiation. Remission (absence of symptoms) is achieved in 25% to 30% of patients within 8 to 12 weeks after medication initiation.3

General Approach to Treatment

There are three treatment phases for patients with MDD: (a) the acute phase lasting approximately 6 to 12 weeks in which the goal is remission; (b) the
continuation phase lasting 4 to 9 months after remission is achieved, in which the goal is to eliminate residual symptoms or prevent relapse (ie, return
of symptoms within 6 months of remission); and (c) the maintenance phase lasting at least 12 to 36 months in which the goal is to prevent recurrence
(ie, a separate episode of depression).2,53 The duration of antidepressant therapy depends on the risk of recurrence which increases with each
depressive episode. Some guidelines recommend lifelong maintenance therapy for persons at greatest risk for recurrence (younger than 40 years of
age with two or more prior episodes or any age with three or more prior episodes).2 An alternative guideline is to treat for at least 2 years in patients
considered to be at high risk for relapse.3 The decision as to “when” and “how” to taper/discontinue an antidepressant regimen is always going to
depend on patient­ and medication­specific variables. Both SSRIs and SNRIs have an idiosyncratic discontinuation syndrome that may occur;
therefore, it is recommended to slowly taper these agents over weeks to months to minimize risk. However, a slow taper is not always effective in
preventing discontinuation symptoms.54

Educating the patient and their support system (eg, family and friends) regarding the delay in antidepressant effects and the importance of
medication adherence should occur before and during the entire course of treatment. The treatment of MDD generally includes both
nonpharmacologic and pharmacologic strategies.

Nonpharmacologic Therapy

In addition to pharmacologic interventions, psychotherapy (“talk therapy”) should be employed whenever the patient is able and willing to participate.
Traditionally, psychotherapy alone is recommended only for mild to moderately severe cases of MDD. However, evidence supports the benefit of
cognitive behavioral therapy (CBT) for even severe MDD.55 Psychotherapy should not be the primary treatment modality for patients with psychotic
features. The effects of psychotherapy and antidepressant medications are considered to be additive, thus combined treatment may be advantageous
for patients with partial responses to either treatment alone and for those with a chronic course of illness. In practice, CBT as primary treatment is
limited significantly by cost and logistics (eg, need for more frequent appointments and time off work). Additionally, many insurance plans do not
adequately cover the cost of psychotherapy, the availability of providers may be limited in certain areas, and patients may be more reluctant to spend
the time in therapy versus taking medication. In the Sequenced Treatment Alternatives to Relieve Depression study (STAR*D), evaluation of the
psychotherapy arm was limited by low participation rates.56

Electroconvulsive therapy (ECT) is a safe and effective treatment for severe MDD. Ideally it is used when a rapid response is needed (eg, severe
suicidality, nutritional deficiency, catatonic symptoms), risks of other treatments outweigh potential benefits, symptoms refractory to two
antidepressant trials, or there is history of good response to ECT, and the patient expresses a preference for ECT. Another nonpharmacologic
approach is repetitive transcranial magnetic stimulation (rTMS), which has demonstrated efficacy in treating MDD symptoms without the anesthesia
required for ECT.57

The health benefits of physical activity have long been recognized for many medical conditions, and data suggest benefits in depressed patients. The
Treatment with Exercise Augmentation for Depression (TREAD) study demonstrated that 16 kcal (67 kJ) per kilogram per week (KKW) exercise was
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MDD remission is compared with 4 KKW, when both were used as augmentation to an SSRI.58 According to APA Task Force,
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integrating
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[Link] the MDD
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of Use • Privacy Policyand confers
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Pharmacologic Therapy
antidepressant trials, or there is history of good response to ECT, and the patient expresses a preference for ECT. Another nonpharmacologic
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approach is repetitive transcranial magnetic stimulation (rTMS), which has demonstrated efficacy in treating MDD symptoms without the anesthesia
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required for ECT.57

The health benefits of physical activity have long been recognized for many medical conditions, and data suggest benefits in depressed patients. The
Treatment with Exercise Augmentation for Depression (TREAD) study demonstrated that 16 kcal (67 kJ) per kilogram per week (KKW) exercise was
associated with greater MDD remission rates compared with 4 KKW, when both were used as augmentation to an SSRI.58 According to APA Task Force,
integrating exercise into the MDD treatment plan is medically appropriate and confers many well­accepted health benefits.59

Pharmacologic Therapy

Antidepressants are considered first­line treatment for a moderate­to­severe depressive episode.2­4 They can be classified in several ways, including
by chemical structure and the presumed mechanism of antidepressant activity. Although the link between the presumed mechanism of action and
antidepressant response is tenuous, this classification has the advantage of being based on established pharmacology and clearly explains some of
the common, but expected, adverse medication reactions. The knowledgeable clinician can use these antidepressant properties to tailor treatment to
individual patient needs optimizing treatment outcomes. Currently available antidepressants, including dosing guidance, are provided in Table 88­
3.2,3,53,60­62

TABLE 88­3
Adult Dosing Guidance for Currently Available Antidepressant Medications

Medication (Brand Initial Usual Comments (eg, Maximum Daily Dosage, Suggested Therapeutic Plasma
Name) Dose Dosage Concentration)
(mg/day) Range
(mg/day)

Selective Serotonin Reuptake Inhibitors (SSRIs)

Patients with significant anxiety should start with lower initial dose to improve tolerability; however, target dose does not differ.

Citalopram 10­20 20­40 Doses >40 mg/day not recommended due to QTc prolongation risk; maximum 20 mg/day for
(Celexa) CYP2C19 poor metabolizers, coadministration with CYP2C19 inhibitors or patients older than
60 years of age

Escitalopram 5­10 10­20 Maximum 20 mg/day; dose may be increased to maximum daily dose after 1 week
(Lexapro)

Fluoxetine 10­20 20­60 Maximum 80 mg/day; dose may be increased in 20­mg increments
(Prozac)

Fluvoxamine 25­50 50­ Maximum 300 mg/day; daily doses >100­mg total dose should be divided twice daily, with the
(Luvox) 300 larger dose given at night
Maximum 300 mg/day (ER formulation)

Paroxetine (Paxil) 10­20 20­50 Maximum 50 mg/day (IR formulation); titrate 10 mg/day increments weekly
Maximum 62.5 mg/day (CR formulation); titrate 12.5 mg/day increments weekly

Sertraline 25­50 50­ Maximum 200 mg/day; titrate 25 mg/day increments weekly
(Zoloft) 200

Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs)

Newer­generation SNRIs
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Depressive Disorders,
50Amy M. VandenBerg
100
Page 15 / 53
Doses up to 400 mg/day have been studied; however, tolerability decreases with doses >50
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(Pristiq) mg. Dose reductions or discontinuation may be required if sustained hypertension occurs
 Sertraline 25­50 50­ Maximum 200 mg/day; titrate 25 mg/day increments weekly
(Zoloft) 200 University of the West Indies
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Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs)

Newer­generation SNRIs

Desvenlafaxine 50 100 Doses up to 400 mg/day have been studied; however, tolerability decreases with doses >50
(Pristiq) mg. Dose reductions or discontinuation may be required if sustained hypertension occurs

Duloxetine 30 30­90 Maximum 120 mg/day (given once or twice daily); doses >60 mg/day not shown to provide
(Cymbalta) increased efficacy for the treatment of MDD

Venlafaxine 37.5­ 75­ Maximum 375 mg/day (IR); maximum 225 mg/day (ER); may increase in increments up to 75
(Effexor) 75 225 mg/day at a minimum of every 4 days. Dose reductions or discontinuation may be required if
sustained hypertension occurs

Levomilnacipran 20 40­ Initial dose (20 mg) for 2 days before dose increases is recommended at intervals of 2 or more
(Fetzima) 120 days. Dose adjustment or discontinuation may be required if sustained elevated heart rate or
hypertension occurs

Tricyclic antidepressants (TCAs)

Amitriptyline 25 100­ Maximum 300 mg/day for MDD; as single daily dose at bedtime or divided doses; therapeutic
(Elavil) 200 serum level 80­200 ng/mL (mcg/L; ~300­740 nmol/L); parent medication plus metabolite
(nortriptyline)

Desipramine 25 100­ Maximum 300 mg/day; suggested therapeutic concentration range for combined imipramine +
(Norpramin) 200 desipramine: 100­300 ng/mL (mcg/L; ~370­1,100 nmol/L)

Doxepin 25 100­ Maximum 300 mg/day as a single daily dose at bedtime (if tolerated) or in divided doses; a
(Sinequan) 200 single dose should not exceed 150 mg

Imipramine 25 100­ Maximum 300 mg/day as single daily dose at bedtime (if tolerated) or divided doses;
(Tofranil) 200 suggested therapeutic concentration range for combined imipramine + desipramine: 150­300
ng/mL (mcg/L; ~550­1,100 nmol/L)

Nortriptyline 25 50­ Maximum 150 mg/day as single daily dose (if tolerated) or divided doses; therapeutic serum
(Pamelor) 150 level 50­150 ng/mL (mcg/L; 190­570 nmol/L)

Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)

Bupropion 150 150­ Maximum 450 mg/day (IR, ER), 400 mg/day (SR); ER dosed once daily; SR dosed once or twice
(Wellbutrin) (75 450 daily; IR may be dosed up to three times daily. Adhering to labeled maximum daily and
mg maximum single doses minimizes effect on seizure threshold
given
twice
daily)

Mixed Serotonergic Effects (Mixed 5­HT)

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Nefazodone 100
IP is 200­ Maximum 600 mg/day; daily doses should be divided twice daily; boxed warning
Chapter 88: Depressive Disorders, Amy M. VandenBerg Page 16 / 53
(Serzone) 400 hepatotoxicity
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Trazodone 50 150­ Maximum 600 mg/day

 twice
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daily)
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Mixed Serotonergic Effects (Mixed 5­HT)

Nefazodone 100 200­ Maximum 600 mg/day; daily doses should be divided twice daily; boxed warning
(Serzone) 400 hepatotoxicity

Trazodone 50 150­ Maximum 600 mg/day

(Desyrel) 300

Vilazodone 10 20­40 Target dose 20­40 mg/day unless coadministered with CYP3A4 inhibitor (dose not to exceed
(Viibryd) 20 mg/day). Dose titration: 10 mg/day for 7 days, 20 mg/day for 7 days, and then may increase
to 40 mg/day. Dose must be taken with food to ensure adequate absorption

Vortioxetine 10 20 Maximum 20 mg/day

(Trintellix)

Serotonin and α 2 ­Adrenergic Antagonist

Mirtazapine 15 15­45 Maximum 45 mg/day

(Remeron)

Monoamine Oxidase Inhibitors (MAOIs)

Phenelzine 15 30­90 Maximum 90 mg/day; divided dosing; increase by 15 mg at 1­ to 3­week intervals

(Nardil)

Selegiline 6 6­12 Not to exceed 12 mg/24 hours; dose may be increased by 3 mg/day increments every 2 weeks;
(transdermal) site of application should be rotated
(Emsam)

Tranylcypromine 10 20­40 Maximum 60 mg/day; divided dosing; increase by 10 mg at 1­ to 3­week intervals

(Parnate) 10­20 30­60

Isocarboxazid 10­20 30­60 Maximum 60 mg/day; divided dosing

(Marplan)

Second­generation Antipsychotics (SGA) as Augmentation (5HT2 A a n d D2 modulators)

Aripiprazole 2 2­15 FDA­approved for augmentation; CANMAT Level 1 evidence, 1st line
(Abilify)

Brexpiprazole 1 1­3 Not FDA­approved for augmentation; CANMAT Level 1 evidence, 2nd line
(Rexulti)

Olanzapine 2.5 2.5­10 Not FDA­approved for augmentation; CANMAT Level 1 evidence, 2nd line
(Zyprexa)

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Olanzapine/fluoxetine 3/25 6­12/25­50 FDA­approved for treatment­resistant depression
Chapter 88: Depressive Disorders, Amy M. VandenBerg Page 17 / 53
(Symbyax)
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Quetiapine 50 150­ FDA­approved for augmentation; CANMAT Level 1 evidence, 1st line
 (Rexulti)
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Olanzapine 2.5 2.5­10 Not FDA­approved for augmentation; CANMAT Level 1 evidence, 2nd line
(Zyprexa)

Olanzapine/fluoxetine 3/25 6­12/25­50 FDA­approved for treatment­resistant depression

(Symbyax)

Quetiapine 50 150­ FDA­approved for augmentation; CANMAT Level 1 evidence, 1st line
(Seroquel) 300

Risperidone 1 1­3 Not FDA­approved for augmentation; CANMAT Level 1 evidence, 1st line
(Risperdal)

Alternative Augmentation Agents (Not FDA­Approved for Antidepressant Augmentation)

Buspirone 10 10­60 Divided dosing 2 to 3 times daily

(Buspar) 5HT1A partial agonist

Lithium 300 600­ Dose based on therapeutic levels (target 0.6­1 mEq/L [mmol/L])
1,200 Mechanism in depression not fully understood

Triiodothyronine 0.025 0.025­ Once daily dosing; monitor free T3 levels

(Cytomel) 0.05

CANMAT, Canadian Network for Mood and Anxiety Treatments; CR, continuous release; ER, extended release; IR, immediate release; MDD, major depressive disorder;
SR, sustained release.

Data from References 2, 3, 53, and 60­62.

Antidepressants are of equivalent efficacy when administered in comparable doses. Because one cannot predict which antidepressant will be the
most effective in an individual patient, the initial choice is made empirically. Factors that often influence antidepressant choice include the patient’s
history of response, history of familial antidepressant response, concurrent medical illnesses and medications, presenting symptoms (eg, insomnia vs
hypersomnia), potential for medication interactions, adverse medication reactions, patient preference, and medication cost. Although the precise
pathophysiology of MDD remains elusive, clinicians can now select from multiple approved medications with different mechanisms of action (Tables
88­3 and 88­8).2­4,63 Failure to respond to one antidepressant class or one antidepressant agent within a class does not predict a failed response to
another class or another agent within the same class (Fig. 88­3). Approximately 50% to 60% of patients with MDD improve with acute medication
therapy, compared with about 30% to 40% who improve with placebo.3,64

Selective Serotonin Reuptake Inhibitors

The efficacy of SSRIs is superior to placebo and comparable to other antidepressant classes in treating patients with MDD.2,53 They are generally
chosen as first­line due to relative safety in overdose and improved tolerability over TCAs and MAOIs. The decision of which SSRI to use is typically
based on the nuances of each medication, such as differences in interaction profile and pharmacokinetic (PK) parameters (eg, half­life). These
concepts will be discussed in greater detail later in this chapter. The STAR*D trial demonstrated that nonresponse to one SSRI does not predict
nonresponse to an alternative SSRI and a recent meta­analysis found no differences in efficacy between agents.56,65

The SSRIs, as the name implies, have a low affinity for other receptors including alpha1­adrenergic (α1), histaminic (H1), and muscarinic (M1)
receptors. Given this pharmacology, they are associated with lower rates of orthostatic hypotension, sedation, weight gain, and anticholinergic effects
compared to TCAs.2­4,63 The most common dose­dependent tolerability issues with SSRI use, which generally are mild and limited to 1 to 2 weeks after
initiation or dose increases, are GI symptoms (eg, nausea, vomiting, and diarrhea), anxiety, and headache.66 Both somnolence and insomnia have been
Downloaded all SSRIs.67
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Additionally IP isSSRIs may cause clinically relevant impairment in all three stages of the human sexual response (arousal,
Chapter 88: Depressive Disorders, Amy M. VandenBerg Page 18 / 53
libido, orgasm)68; however, it is important to note that depression itself may be associated with sexual dysfunction. A discontinuation or withdrawal
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syndrome may occur if SSRIs are abruptly discontinued (see details below with SNRIs). Paroxetine has more anticholinergic and antihistaminergic
activity that has been linked with increased sedation and weight gain compared to other SSRIs.2­4,63 The FDA released a safety announcement linking
The SSRIs, as the name implies, have a low affinity for other receptors including alpha1­adrenergic (α1), histaminic (H1), and muscarinic
University (M1)
of the West Indies
receptors. Given this pharmacology, they are associated with lower rates of orthostatic hypotension, sedation, weight gain,Access
and Provided
anticholinergic
by: effects
compared to TCAs.2­4,63 The most common dose­dependent tolerability issues with SSRI use, which generally are mild and limited to 1 to 2 weeks after
initiation or dose increases, are GI symptoms (eg, nausea, vomiting, and diarrhea), anxiety, and headache.66 Both somnolence and insomnia have been
reported with all SSRIs.67 Additionally the SSRIs may cause clinically relevant impairment in all three stages of the human sexual response (arousal,
libido, orgasm)68; however, it is important to note that depression itself may be associated with sexual dysfunction. A discontinuation or withdrawal
syndrome may occur if SSRIs are abruptly discontinued (see details below with SNRIs). Paroxetine has more anticholinergic and antihistaminergic
activity that has been linked with increased sedation and weight gain compared to other SSRIs.2­4,63 The FDA released a safety announcement linking
citalopram to a dose­dependent increase in QT interval, with recommended, age­dependent dose limits.69 There has since been controversy regarding
this safety warning and potential unintended consequences (eg, underdosing, discontinuation leading to relapse).69,70 Dose­dependent increase in QT
interval may also be associated with escitalopram; however, clinical significance of the QT increase is questionable with both agents.69

Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs)

Tricyclic Antidepressants

Although TCAs are effective in treating MDD, use has diminished greatly due to the availability of equally effective therapies that are better tolerated
and much safer in overdose. All TCAs potentiate the activity of NE and 5­HT by blocking their reuptake. However, the potency and selectivity of TCAs for
the inhibition of NE and 5­HT reuptake vary greatly among these agents (see Table 88­4). Nortriptyline is most commonly used and may be selected in
patients with comorbid migraine headaches, neuropathic pain, or fibromyalgia.

TABLE 88­4
Relative Potencies of Norepinephrine and Serotonin Reuptake Blockade and Select Receptor Antagonism Profile of Antidepressants

Reuptake Antagonism M1 H1 α1

NE 5­HT

Selective Serotonin Reuptake Inhibitors (SSRIs)

Citalopram 0 ++++ 0 + 0

Escitalopram 0 ++++ 0 0 0

Fluoxetine + ++++ 0 0 0

Fluvoxamine 0 ++++ 0 0 0

Paroxetine ++ ++++ ++ + 0

Sertraline 0 ++++ 0 0 +

Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs)

Duloxetine +++ ++++ 0 0 0

Levomilnacipran ++++ +++ + 0 0

Venlafaxinea and desvenlafaxine +++ ++++ 0 0 0

Tricyclic Antidepressants (TCAs)

Amitriptyline ++ ++++ ++++ ++++ +++

Desipramine ++++ ++ + ++ ++
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Doxepin ++ ++ +++ ++++ +++
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Imipramine ++ ++++ +++ ++++ +++

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Tricyclic Antidepressants (TCAs)
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Amitriptyline ++ ++++ ++++ ++++ +++

Desipramine ++++ ++ + ++ ++

Doxepin ++ ++ +++ ++++ +++

Imipramine ++ ++++ +++ ++++ +++

Nortriptyline ++++ ++ ++ +++ ++

Mixed Serotonergic (Mixed 5­HT)

Nefazodone 0 ++ 0 +++ +++

Trazodone 0 ++ 0 ++ +++

Vilazodone 0 ++++ 0 + 0

Vortioxetine 0 ++++ 0 + 0

Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)

Bupropionb + 0 + 0 0

Serotonin and α 2 ­Receptor Antagonist

Mirtazapine 0 0 0 +++ +

M1, antimuscarinic/anticholinergic adverse reactions; H1, antihistamine, sedation; α1 antiadrenergic, hypotension.

++++, high; +++, moderate; ++, low; +, very low; 0, absent or not adequately studied.

aVenlafaxine: primarily 5­HT at lower doses, NE at higher doses, and DA at very high doses.

b Bupropion: also blocks dopamine reuptake.

Data from References 2­4, 53, and 63.

The TCAs affect other neurotransmitters and produce a wide range of pharmacologic actions, including several unwanted, but expected, adverse
medication reactions. The most commonly occurring dose­related adverse reactions are anticholinergic in nature and include dry mouth,
constipation, blurred vision, urinary retention, dizziness, and tachycardia (see Table 88­8). In older adult patients or with very high doses, memory
impairment or delirium may occur.71 Although some tolerance does develop, these reactions have the potential to impact patient adherence,
particularly in older adults and those receiving long­term maintenance therapy. Additional tolerability issues that decrease TCA adherence include
weight gain and sexual dysfunction.71

Orthostatic hypotension is a common, dose­related reaction attributed to the affinity of the TCAs for α1 receptors.63 In patients with history of
myocardial infarction, TCAs should be avoided due to risk of severe arrhythmias (QTc prolongation, torsades de pointes) thought to be associated with
their class IA antiarrhythmic effects.72 Additionally, TCAs can cause cardiac conduction delays, may induce heart block in patients with a preexisting
conduction disorder, and overdose is associated with severe arrhythmias.71 Desipramine’s prescribing information reflects an increased risk of death
in patients receiving the medication who have a family history of sudden cardiac death, cardiac dysrhythmias, and cardiac conduction disturbances.
More on this reaction can be found at the FDA’s MedWatch Website. Caution should be exercised when prescribing these agents, especially in higher
doses, to patients with clinically significant cardiac disease, and to patients with a family history of a cardiac event.

Newer­Generation SNRIs
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Venlafaxine
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low doses, and NE reuptake at higher doses, whereas duloxetine
equally inhibits both 5­HT and NE reuptake inhibition across all doses. This difference in receptor binding has not been associated with significant
differences in efficacy. According to some studies, the SNRIs may be associated with higher rates of response and remission than other
conduction disorder, and overdose is associated with severe arrhythmias.71 Desipramine’s prescribing information reflects an increased risk of death
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in patients receiving the medication who have a family history of sudden cardiac death, cardiac dysrhythmias, and cardiac conduction disturbances.
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More on this reaction can be found at the FDA’s MedWatch Website. Caution should be exercised when prescribing these agents, especially in higher
doses, to patients with clinically significant cardiac disease, and to patients with a family history of a cardiac event.

Newer­Generation SNRIs

Venlafaxine and its primary active metabolite, desvenlafaxine, inhibit 5­HT reuptake at low doses, and NE reuptake at higher doses, whereas duloxetine
equally inhibits both 5­HT and NE reuptake inhibition across all doses. This difference in receptor binding has not been associated with significant
differences in efficacy. According to some studies, the SNRIs may be associated with higher rates of response and remission than other
antidepressants; however, most of these studies involved venlafaxine, and not all studies support this conclusion.65 The BAP guidelines discuss the
possibility of a slight efficacy advantage (ie, lower number needed to treat; NNT) for venlafaxine (as well as escitalopram and sertraline) compared to
other antidepressants.3

The most recent SNRI to be FDA­approved for MDD is levomilnacipran. This is a single­isomer, extended­release formulation of milnacipran which is
FDA­approved only for the treatment of fibromyalgia. It is too soon to determine its place in therapy for MDD; however, pharmacologically it is relatively
unique among the SNRIs given its greater potency at inhibiting NE reuptake compared to 5­HT reuptake.63,73 One NE selective reuptake inhibitor,
reboxetine, available in non­US markets, was not FDA­approved due to poor tolerability and lack of efficacy.

The most commonly reported tolerability issues with SNRIs, similar to those of SSRIs, may be dose­related and include nausea, sexual dysfunction, and
activation.2­4 Hyperhidrosis (excessive sweating) occurs primarily with SNRIs. Dose­related increases in blood pressure have been reported more with
venlafaxine and levomilnacipran but may also occur with duloxetine and desvenlafaxine.2 Blood pressure should be monitored at baseline and
regularly during therapy, especially after dose increases. The discontinuation or withdrawal syndrome that can occur when treatment is stopped
appears to be more severe with SNRIs than SSRIs. Common withdrawal symptoms include headache, fatigue, sweating, musculoskeletal pain, electric
shock sensations, and anxiety. While slowly tapering off the medication may help to reduce the risk of the withdrawal syndrome, it may not fully
prevent.54 Duloxetine has also been associated with idiosyncratic hepatotoxicity (1 per 100,000 case exposures) with enzyme elevations more than
three times upper limit of normal in 1% of patients, but does not carry the boxed warning associated with nefazodone.74

Mixed Serotonergic Medications (Mixed 5­HT)

Trazodone and nefazodone have dual actions on serotonergic neurons, acting as both postsynaptic 5­HT2 antagonists and presynaptic 5­HT reuptake

inhibitors. They may also enhance 5­HT1A­mediated neurotransmission.63 Trazodone blocks α1 and H1 receptors leading to adverse reactions (eg,
dizziness and sedation) that limit its use as an antidepressant. Use of nefazodone declined after reports of hepatotoxicity and the FDA­approved
labeling includes a boxed warning describing rare cases of fulminant liver failure (1 case per 300,000 treatment years) and hepatic impairment (29
cases per 100,000 treatment years).74 Trazodone and nefazodone are effective agents in treating MDD; however, both carry risks that limit their
usefulness. Immediate­release trazodone is most often used adjunctively (in low doses) with other antidepressants to treat insomnia associated with
MDD.67

Trazodone and nefazodone have minimal anticholinergic effects and comparatively less 5­HT agonist adverse reactions (eg, sexual dysfunction), but
they can cause orthostatic hypotension. Sedation, cognitive slowing, and dizziness are the most frequent dose­limiting adverse reactions associated
with trazodone, although the dosage used for the treatment of depression is significantly higher than the dosage often used for the treatment of
insomnia (25­200 mg).4,67 Common adverse medication reactions associated with nefazodone include light­headedness, dizziness, orthostatic
hypotension, and somnolence. Nefazodone treatment should not be initiated in individuals with active liver disease or with elevated baseline serum
transaminases. A rare but potentially serious adverse reaction of trazodone is priapism, which is reported to occur in approximately 1 in 6,000 male
patients. Some cases have required surgical intervention (1 in 23,000), and permanent impotence may result.75 There have been no reports of priapism
associated with nefazodone use in males, but there is a published case report of nefazodone­induced clitoral priapism.75

Vilazodone and vortioxetine are combination SSRI and 5­HT1A presynaptic receptor partial agonists approved for the treatment of MDD.73 Presynaptic
5­HT1A partial agonism has previously been hypothesized as a mechanism for SSRI augmentation with pindolol, which has preferential antagonism at

the presynaptic 5­HT1A receptor.76 The primary dose­limiting adverse reaction of these two newer agents is nausea. Vortioxetine additionally
antagonizes 5­HT3 which is proposed to mitigate some of the nausea, and is also a partial agonist at 5­HT1B, and an antagonist at 5­HT1D and 5­HT7

receptors.62 Preliminary data support a linkage between the 5­HT7 receptor antagonism and lack of cognitive slowing and potential for improved
cognitive symptoms
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decreased libido (particularly among males) when compared to placebo.73 Rates of sexual dysfunction appear to be lower than with SSRIs; however, in
some trials comparator agents known to cause sexual dysfunction (eg, duloxetine) also had lower rates of sexual dysfunction.62,73
5­HT1A partial agonism has previously been hypothesized as a mechanism for SSRI augmentation with pindolol, which has preferential antagonism at
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the presynaptic 5­HT1A receptor.76 The primary dose­limiting adverse reaction of these two newer agents is nausea. Vortioxetine additionally
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antagonizes 5­HT3 which is proposed to mitigate some of the nausea, and is also a partial agonist at 5­HT1B, and an antagonist at 5­HT1D and 5­HT7

receptors.62 Preliminary data support a linkage between the 5­HT7 receptor antagonism and lack of cognitive slowing and potential for improved
cognitive symptoms with vortioxetine in patients with MDD.

Vilazodone and vortioxetine are both associated with significant dose­related GI tolerability issues (eg, diarrhea and nausea), dizziness, insomnia, and
decreased libido (particularly among males) when compared to placebo.73 Rates of sexual dysfunction appear to be lower than with SSRIs; however, in
some trials comparator agents known to cause sexual dysfunction (eg, duloxetine) also had lower rates of sexual dysfunction.62,73

Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)

Bupropion has no appreciable effect on the 5­HT reuptake, and inhibits both the NE and DA reuptake making it one of the most activating
antidepressants.63 This can be particularly helpful for decreased motivation, low energy, and fatigue, which are common symptoms in older adult
patients. It is also FDA­approved for smoking cessation and in a combination product with naltrexone for weight loss.

Adverse medication reactions associated with bupropion include nausea, vomiting, tremor, insomnia, and dry mouth. The occurrence of seizures in
patients taking bupropion appears to be strongly dose­related, and may be increased by predisposing factors such as history of prior seizure activity,
severe alcohol withdrawal, head trauma, or CNS tumor. Bupropion use is contraindicated in patients with eating disorders such as bulimia and
anorexia. In addition to risk for further appetite suppression, these patients are prone to electrolyte abnormalities and are therefore at higher risk for
seizure activity. At daily doses of 450 mg (the FDA­approved maximum dose) or less, the incidence of seizures is 0.4%, which is similar to reported rates
for clomipramine, desipramine, and citalopram.77 Bupropion is associated with minimal sexual dysfunction compared with the SSRIs and may actually
improve SSRI­induced sexual dysfunction when used as adjunctive treatment.78

Serotonin and α 2 ­Adrenergic Receptor Antagonists

Mirtazapine enhances central noradrenergic and serotonergic activity through the antagonism of central presynaptic α2­adrenergic autoreceptors and

heteroreceptors.79 Furthermore, it antagonizes postsynaptic 5­HT2, 5­HT3, and H1 receptors resulting in anxiolytic, anti­nausea, and sedative effects,
respectively.

The most common adverse medication reactions of mirtazapine are somnolence, weight gain (>7%), likely due to relatively strong antihistaminergic
properties.67 Mirtazapine is associated with minimal sexual dysfunction.

Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors increase the concentrations of NE, 5­HT, and DA within the neuronal synapse through inhibition of the MAO enzymes.
The MAOIs isocarboxazid, phenelzine, and tranylcypromine are nonselective inhibitors of MAO­A and MAO­B. A selegiline transdermal patch allows
inhibition of MAO­A and MAO­B in the brain, yet has reduced effects on MAO­A in the gut.80

The most common adverse reaction of oral MAOIs is postural hypotension, which is more likely to occur with phenelzine and may be minimized with
divided doses. Other common adverse reactions include weight gain and sexual dysfunction (eg, decreased libido and anorgasmia).2 Phenelzine has
mild­to­moderate sedating effects, while tranylcypromine and selegiline may exert a stimulating effect and insomnia due to amphetamine­like
metabolites.61

Hypertensive crisis, which is a potentially serious and life­threatening but rare adverse reaction, may occur when MAOIs are taken concurrently with
foods containing tyramine. Tyramine is usually metabolized by MAO­A in the gut and not absorbed into systemic circulation where it acts as a potent
vasoconstrictor. Oral MAOIs block gut MAO­A resulting in absorption of tyramine. In patients on MAOIs, 10 mg of tyramine can cause marked
hypertension and severe headache, and 25 mg can result in hypertensive crisis, whereas the average adult can tolerate over 500 mg of tyramine
without a significant impact on blood pressure.61,81 This may also occur when MAOIs are co­ingested with medications that increase norepinephrine
(eg, decongestants, stimulants, SNRIs). Symptoms of hypertensive crisis include occipital headache, stiff neck, nausea, vomiting, sweating, and sharply
elevated blood pressure which may culminate in cerebrovascular accident and death. For details regarding management of hypertensive emergencies,
refer to Chapter 30, “Hypertension.” The other significant risk of MAOIs is serotonin syndrome with concurrent use of other medications that increase
serotonin (eg, antidepressants other than MAOIs). Education of patients taking MAOIs regarding dietary and medication restrictions is extremely
important. Examples of potentially high tyramine foods and medications that should be avoided or used with caution are provided in Table 88­5.61,81
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Dietary and Medication Restrictions for Patients Taking Monoamine Oxidase Inhibitors
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a
without a significant impact on blood pressure.61,81 This may also occur when MAOIs are co­ingested with medications that increase norepinephrine
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(eg, decongestants, stimulants, SNRIs). Symptoms of hypertensive crisis include occipital headache, stiff neck, nausea, vomiting, of the and
sweating, Westsharply
Indies
elevated blood pressure which may culminate in cerebrovascular accident and death. For details regarding management of hypertensive
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refer to Chapter 30, “Hypertension.” The other significant risk of MAOIs is serotonin syndrome with concurrent use of other medications that increase
serotonin (eg, antidepressants other than MAOIs). Education of patients taking MAOIs regarding dietary and medication restrictions is extremely
important. Examples of potentially high tyramine foods and medications that should be avoided or used with caution are provided in Table 88­5.61,81

TABLE 88­5

Dietary and Medication Restrictions for Patients Taking Monoamine Oxidase Inhibitorsa

Foods to Avoid Completely Approximate Tyramine Content (mg) per Ounce

Aged cheeses (eg, cheddar, blue, Swiss, Camembert) 25­45

Chicken liver 60
Dry aged meats (eg, mortadella, salami, prosciutto) 2­45
Fava beans Unknown
Kim chee Unknown
Red wine Variable
Sauerkraut 1­3
Smoked or pickled fish (eg, lox, caviar, pickled herring) 0­80
Soy sauce, fermented soy, miso Varies
Tap beer 20­40
Yeast extract 2­60

Foods to Eat in Moderation

American cheese, Parmesan cheese <2

Canned, filtered beer <2 per 12 oz (355 mL)
Havarti, brie Thought to be low
Pepperoni <2
Pizza (large commercial chains generally safe; avoid gourmet with aged cheeses and meats) 2 slices
White wine <1 per 4 oz (120 mL)

Foods Without Restrictions

Fresh dairy products (cottage cheese, cream cheese, fresh milk, ice cream, ricotta, sour cream, yogurt)
Fresh meats (including fresh sausage)
Processed meats (eg, lunch meat, hot dogs, ham)
Spirits (eg, bourbon, gin, rum, vodka)
Yeast bread products

Medications to Avoid Completely

Antidepressantsa Dopamine Methylphenidate

Amphetamines Ephedrine Reserpine

Appetite suppressants Epinephrine Sympathomimetics

Asthma inhalants Guanethidine

Tramadol
Buspirone Levodopa
Tryptophan
Carbamazepine Local anestheticsb
Decongestants Meperidine
Dextromethorphan Methyldopa

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aTricyclic antidepressants may be used with caution by experienced clinicians in treatment­refractory populations.
Chapter 88: Depressive Disorders, Amy M. VandenBerg Page 23 / 53
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bThose containing sympathomimetic vasoconstrictors.

Data from References 61 and 81.

 Tryptophan
Carbamazepine Local anestheticsb
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Decongestants Meperidine
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Dextromethorphan Methyldopa

aTricyclic antidepressants may be used with caution by experienced clinicians in treatment­refractory populations.

bThose containing sympathomimetic vasoconstrictors.

Data from References 61 and 81.

Second­Generation Antipsychotics

The second­generation antipsychotics (SGAs) aripiprazole, brexpiprazole, and quetiapine have been FDA­approved for augmentation of
antidepressant treatment. The combination of olanzapine/fluoxetine is FDA­approved for treatment refractory depression. Additionally, cariprazine,
olanzapine, and risperidone have been studied and are recommended in some treatment guidelines for refractory symptoms.3,4 The specific
mechanisms for these medications in MDD is not fully understood, but is thought to involve modulation of 5­HT and DA activity as they have variable
activity at 5­HT1A, 5­HT2A, D2, and D3 receptors.60 While these medications may be useful in the treatment of depression they are associated with the
risk of metabolic complications and movement disorders. As discussed in detail in Chapter 87, “Schizophrenia,” patients taking SGAs must have
baseline and follow­up monitoring of metabolic parameters (weight, glucose, lipids, blood pressure) due to the risk of metabolic syndrome.
Additionally, patients should be assessed for treatment emergent extrapyramidal symptoms (eg, parkinsonism, akathisia, dystonia). See Chapter 87
for greater detail.

FIGURE 88­3

Suggested algorithm for treatment of uncomplicated MDD. (SSRI, selective serotonin reuptake inhibitor.) Note: Both the British Association of
Pharmacology (BAP) guidelines and the STAR*D trial suggest that switching and augmentation strategies are supported by stronger evidence
compared to dose increases (among poor antidepressant responders).

New/Investigational Agents with Novel Mechanisms

Medications with novel mechanisms have transitioned from proof of concept research to formal clinical trials and, in some cases, FDA approval (see
Table 88­10). As mentioned above, while these agents do not directly alter activity of monoamines, they likely alter activity of monoamines as a
secondary
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Ketamine, an older
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• Notice decade for treatment resistant depression (TRD). Ketamine
• Accessibility
modulates glutamate activity via extrasynaptic N­methyl­D­aspartate (NMDA) receptor antagonism that is thought to increase synaptic glutamate
activity resulting in increased BDNF activity and synaptogenesis.30 Though not FDA­approved for MDD, ketamine has demonstrated rapid
 University of the West Indies
New/Investigational Agents with Novel Mechanisms
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Medications with novel mechanisms have transitioned from proof of concept research to formal clinical trials and, in some cases, FDA approval (see
Table 88­10). As mentioned above, while these agents do not directly alter activity of monoamines, they likely alter activity of monoamines as a
secondary effect.

Ketamine, an older anesthetic agent, has increasingly been studied and used in the past decade for treatment resistant depression (TRD). Ketamine
modulates glutamate activity via extrasynaptic N­methyl­D­aspartate (NMDA) receptor antagonism that is thought to increase synaptic glutamate
activity resulting in increased BDNF activity and synaptogenesis.30 Though not FDA­approved for MDD, ketamine has demonstrated rapid
antidepressant effects in sub­anesthetic intravenous doses (typically 0.5 mg/kg) for TRD in multiple studies.19 Esketamine, the single s­isomer of
ketamine, has a higher affinity for the NMDA receptor than the r­isomer.82 An intranasal formulation of esketamine was FDA­approved for TRD in 2019.
The intranasal formulation overcomes some of the barriers associated with intravenous ketamine use, but has logistical barriers of its own. It requires
supervised, in­clinic self­administration with two to six intranasal sprays per session and 2 hours of in­clinic observation after administration. In trials,
patients received doses twice weekly for 4 weeks and variable dosing thereafter.83 Overall both ketamine and esketamine appear to be relatively well
tolerated at the doses used in clinical trials; however, transient psychotomimetic/dissociative effects and blood pressure elevation (10­20 mm Hg)
occurred at higher rates than placebo with both agents.19,83

Based on research involving endogenous allopregnanolone levels and depression, specifically alterations in pregnancy and postpartum, brexanolone
(exogenous allopregnanolone) was developed and FDA­approved for the indication of postpartum depression in 2019. Administration involves a 60­
hour stepped dose, intravenous infusion. First­pass metabolism precludes oral administration. Brexanolone is thought to exert antidepressant effect
by allosteric modulation of GABAA receptors, which may increase 5HT and NE transmission.24,84 The most common adverse medication reactions in
brexanolone trials were headache, dizziness, and somnolence. In up to 4% of patients, the infusion was stopped due to excessive sedation or loss of
consciousness.84 It has a mandatory Risk Evaluation and Mitigation Strategies (REMS) program with Elements to Ensure Safe Use (ETASU). Analogues
of brexanolone with oral bioavailability, including zuranolone, are in development but not yet FDA­approved (Table 88­6).

TABLE 88­6
Novel Antidepressants

Medication Administration Comments

Ketaminea Not FDA­approved for MDD Sub­anesthetic dose

10 mg/mL, 50 mg/mL, and 100 Based on clinical trials Optimal duration of treatment not
mg/mL Most common dose: established

Diluted for infusion 0.5 mg/kg IV infusion Requires IV access

Dose range: Lower rate of dissociation compared
0.1­1 mg/kg IV infusion with anesthetic doses of ketamine
Frequency: Limited sites of care
Ranges from single dose up to 3 doses per week × 2­6 weeks May not be covered by insurance

Esketamine (Spravato) 28 mg FDA­approved indications: Treatment resistant depression Sub­anesthetic dose

per nasal spray device (14 mg per One spray per nostril (28 mg) Repeat in 5 minutes for 56 mg and again in 5 Optimal duration of treatment not
spray) minutes for 84 mg2×/week for 4 weeks then weekly for 4 weeks then every established
1­2 weeks Requires in office administration and
MDD with suicidality observation post­dose
84 mg 2×/week for 4 weeks Rate of dissociative symptoms
comparable to low dose IV ketamine
Limited sites of care
Costly
SPRAVATO REMS program: sedation,
dissociation, use and misuse

Brexanolone (Zulresso) 100 FDA­approved for postpartum depression only Requires hospitalization
mg/20 mL Single 60­hr stepped infusion ZULRESSO REMS program: excessive
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24 to 52 hr 90 mcg/kg/hr Effect past 30 days not established
52 to 56 hr 60 mcg/kg/hr Limited sites of care
by allosteric modulation of GABAA receptors, which may increase 5HT and NE transmission.24,84 The most common adverse medication reactions in
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brexanolone trials were headache, dizziness, and somnolence. In up to 4% of patients, the infusion was stopped due to excessive sedation or loss of
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consciousness.84 It has a mandatory Risk Evaluation and Mitigation Strategies (REMS) program with Elements to Ensure Safe Use (ETASU). Analogues
of brexanolone with oral bioavailability, including zuranolone, are in development but not yet FDA­approved (Table 88­6).

TABLE 88­6
Novel Antidepressants

Medication Administration Comments

Ketaminea Not FDA­approved for MDD Sub­anesthetic dose

10 mg/mL, 50 mg/mL, and 100 Based on clinical trials Optimal duration of treatment not
mg/mL Most common dose: established

Diluted for infusion 0.5 mg/kg IV infusion Requires IV access

Dose range: Lower rate of dissociation compared
0.1­1 mg/kg IV infusion with anesthetic doses of ketamine
Frequency: Limited sites of care
Ranges from single dose up to 3 doses per week × 2­6 weeks May not be covered by insurance

Esketamine (Spravato) 28 mg FDA­approved indications: Treatment resistant depression Sub­anesthetic dose

per nasal spray device (14 mg per One spray per nostril (28 mg) Repeat in 5 minutes for 56 mg and again in 5 Optimal duration of treatment not
spray) minutes for 84 mg2×/week for 4 weeks then weekly for 4 weeks then every established
1­2 weeks Requires in office administration and
MDD with suicidality observation post­dose
84 mg 2×/week for 4 weeks Rate of dissociative symptoms
comparable to low dose IV ketamine
Limited sites of care
Costly
SPRAVATO REMS program: sedation,
dissociation, use and misuse

Brexanolone (Zulresso) 100 FDA­approved for postpartum depression only Requires hospitalization
mg/20 mL Single 60­hr stepped infusion ZULRESSO REMS program: excessive
0 to 4 hr 30 mcg/kg/hr sedation and sudden loss of
4 to 24 hr 60 mcg/kg/hr consciousness
24 to 52 hr 90 mcg/kg/hr Effect past 30 days not established
52 to 56 hr 60 mcg/kg/hr Limited sites of care
56 to 60 hr 30 mcg/kg/hr Costly: ~$30,000 per infusion

aNot FDA­approved for treatment of MDD.

IV, intravenous; REMS, Risk Evaluation and Mitigation Strategy.

Data from References 60, 84, and 85.

Additional Adverse Events

Serotonin Syndrome

Any antidepressant that increases serotonergic neurotransmission can be associated with serotonin syndrome (SS), especially in situations where
interactions increase release or duration of serotonin activity. The typical triad of symptoms seen in SS includes mental status changes, autonomic
instability, and neuromuscular abnormalities (eg, hyperreflexia, myoclonus) which can be lethal.86 As SS is primarily a diagnosis of exclusion, other
causes of symptoms including neuroleptic malignant syndrome, anticholinergic toxicity, and malignant hyperthermia must be ruled out, with
particular attention being paid to concurrent medications to guide differential diagnosis. Prompt medical attention is needed for any patient
suspected of having
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The PK of the antidepressants is summarized in Table 88­7.60,73,87 The diversity of SSRIs is evident not only in their chemical structures but also in their
Any antidepressant that increases serotonergic neurotransmission can be associated with serotonin syndrome (SS), especially in situations where
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interactions increase release or duration of serotonin activity. The typical triad of symptoms seen in SS includes mental status of the
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autonomic
instability, and neuromuscular abnormalities (eg, hyperreflexia, myoclonus) which can be lethal.86 As SS is primarily a diagnosis
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of exclusion, other
causes of symptoms including neuroleptic malignant syndrome, anticholinergic toxicity, and malignant hyperthermia must be ruled out, with
particular attention being paid to concurrent medications to guide differential diagnosis. Prompt medical attention is needed for any patient
suspected of having SS syndrome, to discontinue all potentially causative agents, manage blood pressure and heart rate and maintain hydration.

Pharmacokinetics and Pharmacodynamics of Antidepressants

The PK of the antidepressants is summarized in Table 88­7.60,73,87 The diversity of SSRIs is evident not only in their chemical structures but also in their
PK profiles as the unique PK attributes of each SSRI can be used to guide treatment. For example, the long half­life of fluoxetine and its active
metabolite norfluoxetine may be beneficial in instances of partial nonadherence. Conversely, caution must be taken to monitor for medication
interactions prior to combining another medication with fluoxetine, fluvoxamine, or paroxetine.

TABLE 88­7
Pharmacokinetic Properties of Antidepressants

Generic Name Elimination Half­Lifea Plasma Protein Binding (%) Clinically Important Metabolites

Selective Serotonin Reuptake Inhibitors (SSRIs)

Citalopram 33 hr 80 None

Escitalopram 27­32 hr 56 None

Fluoxetine 4­6 daysb 94 Norfluoxetinec

Fluvoxamine 15­26 hr 77 None

Paroxetine 24­31 hr 95 None

Sertraline 27 hr 99d None

Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs)

Desvenlafaxine 11 hr 30 None

Duloxetine 12 hr 90 None

Levomilnacipran 12 hr 22 None

Venlafaxine 5 hr 27­30 O­Desmethyl­venlafaxine

TCAs

Amitriptyline 9­46 hr 90­97 Nortriptyline

Desipramine 11­46 hr 73­92 2­Hydroxy­desipramine

Doxepin 8­36 hr 68­82 Desmethyl­doxepin

Imipramine 6­34 hr 63­96 Desipramine

Nortriptyline 16­88 hr 87­95 10­Hydroxy­nortriptyline

Mixed Serotonergic (Mixed 5­HT)

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Nefazodone 2­4 hr meta­Chlorophenyl­piperazine
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Trazodone 6­11 hr 92 meta­Chlorophenyl­piperazine
 Imipramine 6­34 hr 63­96 Desipramine
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Nortriptyline 16­88 hr 87­95 10­Hydroxy­nortriptyline

Mixed Serotonergic (Mixed 5­HT)

Nefazodone 2­4 hr 99 meta­Chlorophenyl­piperazine

Trazodone 6­11 hr 92 meta­Chlorophenyl­piperazine

Vilazodone 25 hr >95

Vortioxetine 66 hr 98

Norepinephrine/Dopamine Reuptake Inhibitor (NDRI)

Bupropion 10­21 hr 82­88 Hydroxy­bupropion

Threohydro­bupropion

Erythrohydro­bupropion

Serotonin and α2 ­Adrenergic Antagonists

Mirtazapine 20­40 hr 85 None

aBiologic half­life in slowest phase of elimination.

bFour to 6 days with chronic dosing; norfluoxetine, 4 to 16 days.

cTake with food to increase area under the curve concentrations by greater than 60%.

dIncreases 30% to 40% when taken with food.

Data from References 60, 73, and 87.

Bioavailability is low (30%­70%) for most TCAs as a result of first­pass metabolism, which shows great interindividual variation.89 The TCAs have a large
volume of distribution and concentrate in brain and cardiac tissue in laboratory animals. They are bound extensively and strongly to plasma albumin,
erythrocytes, α1­acid glycoprotein, and lipoprotein.89 The major metabolic pathways are demethylation, aromatic and aliphatic hydroxylation, and

glucuronide conjugation, although enterohepatic cycling has been described.89 Normally, the PK of TCAs is linear within the usual dosage range;
however, the elimination half­lives can vary greatly among individual patients, which may be related to pharmacogenomic variability, primarily within
CYP2D6 and CYP2C19.89

Venlafaxine is metabolized to an active metabolite, O­desmethylvenlafaxine, which contributes to the overall pharmacologic effect, and is also FDA­
approved as an antidepressant (desvenlafaxine). Immediate release (IR) venlafaxine is generally dosed twice daily to avoid end of dose discontinuation
symptoms, while extended release venlafaxine and desvenlafaxine have a longer duration of action and can be dosed once daily.60 Bupropion is
metabolized to multiple active metabolites (Table 88­7), and there are three formulations of bupropion hydrochloride (immediate release, sustained
release, and extended release), which are equivalent on a total daily dose basis as well as a bupropion hydrobromide formulation that can be
converted to equivalent hydrochloride doses.90 The bupropion peak plasma concentrations are lower for the sustained­release formulation, which are
believed to contribute to a lower seizure risk.90 Mirtazapine undergoes biotransformation to several metabolites91,92; however, it is primarily
eliminated unchanged in the urine. The mirtazapine metabolites are present at such low plasma concentrations they minimally contribute to the
overall pharmacologic profile. Levomilnacipran is primarily metabolized via CYP3A4 with renal elimination of over 50% of the dose.60

Brexanolone undergoes extensive first­pass metabolism and is only available in intravenous formulation.80 Ketamine (IV) and esketamine (nasal)
undergo extensive oxidative metabolism and have elimination half­lives of approximately 2 hours and 7 to 12 hours, respectively.

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selegiline (FDA­approved only for Parkinson disease) and transdermal selegiline impacts their
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formulation.80 At the low CNS concentrations achieved with the oral formulation, selegiline selectively inhibits MAO­B resulting in increased DA levels
(hence, the use for Parkinson disease). Nonselective inhibition of both MAO­A (resulting in increased NE and 5HT levels) and MAO­B, which is thought
eliminated unchanged in the urine. The mirtazapine metabolites are present at such low plasma concentrations they minimally contribute to the
University
overall pharmacologic profile. Levomilnacipran is primarily metabolized via CYP3A4 with renal elimination of over 50% of the dose.60of the West Indies
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Brexanolone undergoes extensive first­pass metabolism and is only available in intravenous formulation.80 Ketamine (IV) and esketamine (nasal)
undergo extensive oxidative metabolism and have elimination half­lives of approximately 2 hours and 7 to 12 hours, respectively.

An important PK difference between oral selegiline (FDA­approved only for Parkinson disease) and transdermal selegiline impacts their
pharmacodynamic profiles. Oral selegiline undergoes extensive first­pass metabolism resulting in bioavailability of 4% versus 73% for the transdermal
formulation.80 At the low CNS concentrations achieved with the oral formulation, selegiline selectively inhibits MAO­B resulting in increased DA levels
(hence, the use for Parkinson disease). Nonselective inhibition of both MAO­A (resulting in increased NE and 5HT levels) and MAO­B, which is thought
to be important to achieve an antidepressant effect, occurs at the higher CNS concentrations only achieved with the transdermal formulation.80

Antidepressant Altered Pharmacokinetics

Antidepressants may have significantly altered PK in patients with hepatic or renal disease; however, the data regarding the altered PK parameters are
often derived from small, single­dose studies. Changes are variably reported as decreased clearance, increased area under the curve (AUC) or
increased half­life.91,92 In patients with chronic liver disease, clearance may be decreased 30% (citalopram, mirtazapine) to over 70% (duloxetine,
sertraline) and half­life may be increased twofold (citalopram, paroxetine) to threefold (duloxetine, fluoxetine). The AUC of TCAs and bupropion have
been reported to increase threefold in cirrhosis.92 Duloxetine is not recommended in patients with significant hepatic impairment.

Renal impairment and end­stage renal disease (ESRD) do not significantly alter antidepressant PK, with notable exceptions. The half­life of citalopram,
escitalopram, and paroxetine may increase 30% to 40%.91 The AUC of bupropion desvenlafaxine, duloxetine, mirtazapine, and venlafaxine may
increase twofold.91 Duloxetine labeling recommends against use in patients with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2.91
Bupropion metabolites have also demonstrated accumulation in ESRD. Renal failure does not alter nortriptyline metabolism, but the 10­hydroxy
metabolite may accumulate, and protein binding may be diminished, with resulting enhanced sensitivity to the medication.89

In patients with significant renal or hepatic impairment, it is reasonable to initiate treatment with 50% lower dose and titrate to 50% to 75% of
maximum dose based on tolerability and response. Patients should be monitored for electrolyte abnormalities and low platelets that can increase risk
of arrhythmias and bleeding. Additionally, lower doses and cautious monitoring are prudent when patients are on concomitant medications with
overlapping toxicity profiles.

Plasma Concentration and Clinical Response

For the newer antidepressants, a strong correlation between plasma concentration and clinical response or tolerability has not been established,
while this has been established for some TCAs (eg, amitriptyline, nortriptyline, desipramine, and imipramine). However, the best established
therapeutic range is for nortriptyline (50­150 ng/mL [mcg/L; 190­570 nmol/L]),89 which appears to demonstrate a curvilinear plasma concentration­
response relationship.

Clinical response, not plasma concentration, should dictate dosage adjustments, as some patients with plasma concentrations outside the suggested
therapeutic range respond to treatment, whereas others are nonresponsive even with “therapeutic” plasma concentration.

Plasma Concentration Monitoring

Because of interindividual variations in plasma concentrations achieved by a given dose, interpretation of plasma concentrations can be very difficult
for the TCAs.89 Although plasma concentration monitoring is not performed routinely, some indications include inadequate response, relapse, serious
or persistent adverse medication reactions, use of higher­than­standard doses, suspected toxicity, older adult patients, pregnant patients, cardiac
disease, suspected nonadherence, and suspected PK interactions. If plasma concentration monitoring is used to detect nonadherence, a cutoff as low
as 30 ng/mL (mcg/L; ~110 nmol/L) for the TCAs has been suggested to avoid confusion with low bioavailability or unusually rapid metabolism. Blood
samples for plasma concentration determinations should be obtained at steady state, usually after a minimum of 1 week at constant dosage. Sampling
should be performed during the elimination phase, usually in the morning, 12 hours after the last dose. Samples collected in this manner are
comparable for patients on once­, twice­, or thrice­daily regimens.89

Medication Interactions

Interactions fall into two broad categories: PK and PD medication interactions, with the PK interactions being the most common. Antidepressants are
primarily substrates for cytochrome P450 enzymes and variably act as inhibitors of the enzymes (see Table 88­8).60,88
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TABLE 88­8
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Antidepressants All Cytochrome
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Potential
comparable for patients on once­, twice­, or thrice­daily regimens.89
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Medication Interactions

Interactions fall into two broad categories: PK and PD medication interactions, with the PK interactions being the most common. Antidepressants are
primarily substrates for cytochrome P450 enzymes and variably act as inhibitors of the enzymes (see Table 88­8).60,88

TABLE 88­8
Antidepressants and Cytochrome (CYP) P450 Enzyme Inhibitory Potential

CYP Enzyme Inhibition

Medication 1A2 2C 2D6 3A4

Bupropion 0 0 +++ 0

Citalopram 0 0 + NA

Duloxetine 0 0 +++ 0

Escitalopram 0 0 + 0

Fluoxetine 0 ++ ++++ ++

Fluvoxamine ++++ ++ 0 +++

Mirtazapine 0 0 0 0

Nefazodone 0 0 0 ++++

Paroxetine 0 0 ++++ 0

Sertraline 0 ++ + +

(des)­Venlafaxine 0 0 0/+ 0

Vilazodone 0 0 0 0

Vortioxetine 0 0 0 0

++++, high; +++, moderate; ++, low; +, very low; 0, absent.

Data from References 60 and 88.

Pharmacokinetic Interactions

Interactions may occur when an antidepressant is coadministered with another medication metabolized through the cytochrome P450 system. Two of
the cytochrome P450 system isoenzymes, CYP2D6 and CYP3A4, are responsible for the metabolism of most currently marketed medications.88 The
ability of an antidepressant to inhibit the activity of these enzymes will be a significant contributory factor in determining its capability to cause a PK
interaction when administered concomitantly. Table 88­8 shows the cytochrome P450 enzyme inhibitory potential of antidepressant agents. Patients
taking substrates of these enzymes should be monitored closely if started on an antidepressant with inhibitory potential. Select examples can be
found in Table 88­9.

TABLE 88­9
Select Pharmacokinetic Interactions of Antidepressants

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Class

Selective Serotonin Reuptake Inhibitors

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TABLE 88­9
Select Pharmacokinetic Interactions of Antidepressants

Antidepressant Interacting Effect

Medication/Medication Class

Selective Serotonin Reuptake Inhibitors

Citalopram and Omeprazole Increased concentrations of citalopram and escitalopram

escitalopram

Fluoxetine Alprazolam Increased concentrations and half­life of alprazolam; increased psychomotor

impairment

Antipsychotics (eg, aripiprazole, Increased antipsychotic concentrations; increased extrapyramidal symptoms

haloperidol)

β­Adrenergic blockers Increased metoprolol concentrations; increased bradycardia; possible heart block

Carbamazepine Increased concentrations of carbamazepine; symptoms of carbamazepine toxicity

Phenytoin Increased concentrations of phenytoin; symptoms of phenytoin toxicity

Tamoxifen Decreased conversion of tamoxifen to active metabolites

TCAs Markedly increased TCA concentrations; symptoms of TCA toxicity

Thioridazine Thioridazine Cmax increased; prolonged QTc interval

Fluvoxamine Alosetron Increased alosetron AUC (sixfold) and half­life (threefold)

Alprazolam Increased AUC of alprazolam by 96%, increased alprazolam half­life by 71%; increased
psychomotor impairment

β­Adrenergic blockers Fivefold increase in propranolol concentration; bradycardia and hypotension

Carbamazepine Increased concentrations of carbamazepine; symptoms of carbamazepine toxicity

Clozapine Increased clozapine concentrations; increased risk for seizures and orthostatic
hypotension

Diltiazem Bradycardia

Methadone Increased methadone plasma concentrations; symptoms of methadone toxicity

Ramelteon Increased AUC (190­fold) and Cmax (70­fold)

TCAs Increased TCA concentration; symptoms of TCA toxicity

Theophylline and caffeine Increased concentrations of theophylline or caffeine; symptoms of theophylline or

caffeine toxicity

Thioridazine Thioridazine Cmax increased; prolonged QTc interval

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Paroxetine Antipsychotics (eg, aripiprazole, Increased antipsychotic concentrations; increased CNS and extrapyramidal symptoms
haloperidol)
 Theophylline and caffeine Increased concentrations of theophylline or caffeine; symptoms of theophylline
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Thioridazine Thioridazine Cmax increased; prolonged QTc interval

Warfarin Increased effect of warfarin

Paroxetine Antipsychotics (eg, aripiprazole, Increased antipsychotic concentrations; increased CNS and extrapyramidal symptoms
haloperidol)

β­Adrenergic blockers Increased metoprolol concentrations; increased bradycardia; possible heart block

Tamoxifen Decreased conversion of tamoxifen to active metabolites

TCAs Markedly increased TCA concentrations; symptoms of TCA toxicity

Thioridazine Thioridazine Cmax increased; prolonged QTc interval

Sertraline Methadone Increased methadone levels

Serotonin–Norepinephrine Reuptake Inhibitors

Venlafaxine and CYP3A4 inhibitors May increase levels of venlafaxine and O­desmethylvenlafaxine especially in CYP2D6
desvenlafaxine poor metabolizers

Duloxetine Metoprolol May increase metoprolol levels twofold

Tamoxifen Decreased conversion of tamoxifen to active metabolites

Thioridazine Thioridazine Cmax increased; prolonged QTc interval

Levomilnacipran CYP3A4 inhibitors Clinically relevant increases in levomilnacipran concentrations may occur

Mixed Serotonergic (Mixed 5­HT)

Vilazodone CYP3A4 inhibitors Maximum vilazodone dose 20 mg with coadministration of potent CYP3A4 inhibitor

Vortioxetine CYP2D6 inhibitors May need to reduce vortioxetine dose by half with coadministration of potent CYP2D6
inhibitor

Serotonin and α­2­Adrenergic Antagonist

Mirtazapine Carbamazepine Mirtazapine concentration decreased (60%)

Norepinephrine and Dopamine Reuptake Inhibitor

Bupropion Tamoxifen Decreased conversion of tamoxifen to active metabolites

AUC, area under the time concentration curve; Cmax, maximum concentration; MAOI, monoamine oxidase inhibitor.

Note: Any medication that augments serotonergic function may impact bleeding risk and should be used with caution in patients receiving NSAIDs or other
medications with hematologic effects.

Data from References 2, 60, 73, and 88.

Because the TCAs are metabolized in the liver through the cytochrome P450 system, they may interact with other medications that modify hepatic
enzyme activity or hepatic blood flow. TCAs are also extensively protein bound, which can result in interactions through displacement from protein­
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binding sites.
Chapter Many commonly
88: Depressive used medications
Disorders, can interact when given concurrently with TCAs.
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As nefazodone use has been severely limited due to its potential to induce liver toxicity, and trazodone is primarily used as a non­FDA­approved
hypnotic at low doses, neither of these agents is likely to be involved in clinically significant medication interactions. However, nefazodone is a potent
 Note: Any medication that augments serotonergic function may impact bleeding risk and should be used with caution in patients receiving NSAIDs or other
medications with hematologic effects. University of the West Indies
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Data from References 2, 60, 73, and 88.

Because the TCAs are metabolized in the liver through the cytochrome P450 system, they may interact with other medications that modify hepatic
enzyme activity or hepatic blood flow. TCAs are also extensively protein bound, which can result in interactions through displacement from protein­
binding sites. Many commonly used medications can interact when given concurrently with TCAs.

As nefazodone use has been severely limited due to its potential to induce liver toxicity, and trazodone is primarily used as a non­FDA­approved
hypnotic at low doses, neither of these agents is likely to be involved in clinically significant medication interactions. However, nefazodone is a potent
inhibitor of CYP3A4.88 Vilazodone is primarily metabolized via CYP3A4 and vortioxetine is primarily metabolized via CYP2D6 and both require dose
adjustment with inhibitors.60,62

Pharmacodynamic Medication Interactions

Certain PD medication interactions that may occur with antidepressants are concerning and require close monitoring. For example, concurrent use of
serotonergic antidepressants with other medications that augment serotonergic function can increase the risk of SS with some combinations
conferring a higher risk than others.86

Tramadol presents as an example of a PK interaction increasing the risk of a PD interaction. When tramadol is coadministered with strong CYP2D6
inhibitors, the decrease in metabolism may result in higher levels of tramadol, which also exhibits SNRI effects. Therefore, high doses of the
combination have been reported to cause serotonin syndrome.86,93

See Table 88­10 for key examples of PD interactions.60,86,93­96

TABLE 88­10
Select Pharmacodynamic Medication Interactions of Antidepressants

Medication/Medication Antidepressants/Antidepressant Effect and Management

Class Class

NSAIDs SSRIs, SNRIs, TCAs, trazodone, FDA warning for increased risk of bleeding
Aspirin vilazodone, vortioxetine Number needed to harm with NSAIDs = 82 vs >700 with SSRI alone
Anticoagulants Assess for baseline bleeding risk and monitor closely
Educate at risk patients regarding signs of bleeding
Antiplatelet agents
Consider histamine­2 (H2) antagonist in high­risk patients

Triptans MAOIs, SSRIs, and SNRIs FDA warning in labeling

Very low risk
Monitor for signs of serotonin syndrome when frequent high doses are used
Triptan toxicity possible when almotriptan, rizatriptan, sumatriptan, or
zolmitriptan are combined with MAO inhibitors

Linezolid All serotonergic Linezolid is weak, reversible, nonselective, MAOI

antidepressants FDA labeling recommends against use with other MAOIs and recommends
discontinuing antidepressants if linezolid is started
Actual rate of serotonin syndrome with combination reported at <1%
Abrupt discontinuation of antidepressants can have negative consequences
If linezolid is indicated and patient is already on an antidepressant, monitor for
signs of serotonin syndrome upon initiating combination
If patient is on short course of linezolid and in need of treatment for
depression, consider postponing antidepressant initiation until course is
complete

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Tramadol Bupropion, duloxetine, Decreased metabolism results in increased SNRI activity of tramadol
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• Notice high dose tramadol combined with CYP2D6 inhibitors resulting in
serotonin syndrome have been reported
Monitor for increased signs of serotonin syndrome and decreased analgesic
inhibitors, the decrease in metabolism may result in higher levels of tramadol, which also exhibits SNRI effects. Therefore, high doses of the
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See Table 88­10 for key examples of PD interactions.60,86,93­96

TABLE 88­10
Select Pharmacodynamic Medication Interactions of Antidepressants

Medication/Medication Antidepressants/Antidepressant Effect and Management

Class Class

NSAIDs SSRIs, SNRIs, TCAs, trazodone, FDA warning for increased risk of bleeding
Aspirin vilazodone, vortioxetine Number needed to harm with NSAIDs = 82 vs >700 with SSRI alone
Anticoagulants Assess for baseline bleeding risk and monitor closely
Educate at risk patients regarding signs of bleeding
Antiplatelet agents
Consider histamine­2 (H2) antagonist in high­risk patients

Triptans MAOIs, SSRIs, and SNRIs FDA warning in labeling

Very low risk
Monitor for signs of serotonin syndrome when frequent high doses are used
Triptan toxicity possible when almotriptan, rizatriptan, sumatriptan, or
zolmitriptan are combined with MAO inhibitors

Linezolid All serotonergic Linezolid is weak, reversible, nonselective, MAOI

antidepressants FDA labeling recommends against use with other MAOIs and recommends
discontinuing antidepressants if linezolid is started
Actual rate of serotonin syndrome with combination reported at <1%
Abrupt discontinuation of antidepressants can have negative consequences
If linezolid is indicated and patient is already on an antidepressant, monitor for
signs of serotonin syndrome upon initiating combination
If patient is on short course of linezolid and in need of treatment for
depression, consider postponing antidepressant initiation until course is
complete

Tramadol Bupropion, duloxetine, Decreased metabolism results in increased SNRI activity of tramadol
fluoxetine, paroxetine Rare cases of high dose tramadol combined with CYP2D6 inhibitors resulting in
serotonin syndrome have been reported
Monitor for increased signs of serotonin syndrome and decreased analgesic
response when combination is used

Data from References 60, 86, and 93­96.

There are two types of PD medication interactions that may occur between antidepressant medications and NSAIDs. An increased risk for abnormal
bleeding (eg, upper GI and intracranial hemorrhage) associated with combined antidepressants and NSAID use is a potentially very serious
pharmacodynamic interaction.94 This interaction is likely mediated by serotonergic mechanisms that occur at the platelet level. Additionally, NSAIDs
may lessen the efficacy of SSRIs; however, the evidence is insufficient to draw firm conclusions.95 However, given the volume of prescriptions for both
NSAIDs and SSRIs, this is an area of pharmacotherapy that certainly deserves further research and thoughtful prescribing practices.

Lastly, refer to the section “Monoamine Oxidase Inhibitors” above and Table 88­5 regarding the hypertensive crisis that may result following
coadministration of MAOIs and other medications that increase vasopressor response (eg, amphetamines). Notably, MAOIs and TCAs have been
coadministered safely in TRD patients with apparent increased efficacy compared with monotherapy; however, severe reactions (eg, hypertensive
crisis) and fatalities have occurred.2,89 Therefore, this combination should be used sparingly by experienced clinicians and monitored extremely
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Alternative Pharmacotherapy
NSAIDs and SSRIs, this is an area of pharmacotherapy that certainly deserves further research and thoughtful prescribing practices.
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Lastly, refer to the section “Monoamine Oxidase Inhibitors” above and Table 88­5 regarding the hypertensive crisis that may result
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coadministration of MAOIs and other medications that increase vasopressor response (eg, amphetamines). Notably, MAOIs and TCAs have been
coadministered safely in TRD patients with apparent increased efficacy compared with monotherapy; however, severe reactions (eg, hypertensive
crisis) and fatalities have occurred.2,89 Therefore, this combination should be used sparingly by experienced clinicians and monitored extremely
carefully.

Alternative Pharmacotherapy

The APA Task Force on Complementary and Alternative Medicine (CAM) as well as CANMAT guidelines include evidence­based and consensus­based
recommendations on the use of CAM for the treatment of MDD.59,97 While these recommendations are not the focus of this chapter, clinicians treating
patients with MDD should be cognizant of them.

Omega­3 Fatty Acids

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) omega­3 fatty acids are generally low­risk and demonstrate variable benefit as
augmentation in the treatment of MDD. Use of EPA alone or the combination of EPA/DHA is likely more effective than DHA alone. As these agents may
increase bleeding risk, their use should be carefully considered in patients taking SSRIs and other concomitant medications associated with bleeding
risk (eg, NSAIDs, anticoagulants).

St. John’s Wort

There is a lack of consensus regarding St. John’s wort for the treatment of MDD. Furthermore, St. John’s wort induces hepatic metabolic enzymes and
is associated with significant interactions. The APA Task Force conservatively states that St. John’s wort may be reasonable for some individuals with
mild­to­moderate MDD while CANMAT considers it to have level 1 evidence as first­line therapy for mild­to­moderate MDD.2,4 Further, the BAP
guidelines state a “standardized” preparation of St. John’s wort “could be considered” in patients with mild­to­moderate MDD, if other first­line
medications are not an option.3

S ­Adenosyl­L­Methionine (SAMe)

The use of SAMe received a favorable review by the APA Task Force. However, the final consensus was that more rigorous studies need to confirm the
efficacy of SAMe for treating MDD. The CANMAT guidelines consider SAMe as a second­line augmentation strategy while the BAP guidelines state that
evidence is developing for use of SAMe as an augmentation strategy in the treatment of MDD.3

Folate

The three compounds in this category are (a) folic acid, (b) folinic acid, and (c) 5­methyltetrahydrofolate (5­MTHF) as these compounds are involved in
the synthesis of key neurotransmitters such as 5­HT. The APA Task Force states that augmentation with these compounds is reasonable, but more
work is needed to clarify which subgroup of patients may achieve the greatest response.59 For example, in one study, only females responded to folic
acid augmentation of fluoxetine treatment. Regardless, CANMAT guidelines consider folate supplementation a third­line augmentation strategy.4

Special Populations

Older Adult Patients

Depression in older adults is a major public health problem as many older adult patients with depression are inadequately treated, or have their
depression missed or mistaken for another disorder, such as dementia. In these patients, depressed mood, the typical signature symptom of
depression, may be less prominent than other depressive symptoms such as loss of appetite, cognitive impairment, sleeplessness, anergia, and
anhedonia. Previous research supports that somatic (physical) complaints (eg, pain, fatigue, gastrointestinal symptoms) present more frequently in
older adults with depression. However, there are many confounders that may account for this (eg, higher rates of physical illness).34 Appropriate
recognition and treatment of depression in older adults is extremely important as individuals 65 years of age and older have a high rate of suicidality.
Increased suicide attempts in older adults with depression have been associated with access to firearms, diminished cognitive functioning, sleep
disruptions, poor social interactions, and inattention among primary caregivers.98

Before initiating antidepressant treatment, a complete physical examination should be performed. When prescribed antidepressants, older adults may
be either overtreated or under­treated. Overtreatment occurs when age­related PK and PD factors are overlooked and under­treatment results from
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an overly88:
Chapter conservative
Depressiveapproach as aAmy
Disorders, [Link]
the patient’s advanced age or concurrent medical problems. In older adults, SSRIs are usually
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as first­line
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• Accessibility
anticholinergic, and cardiovascular adverse reactions). Furthermore, there is evidence to suggest that the long­term use of antidepressants such as
SSRIs in older adults, administered with either psychotherapy or clinical management, may prevent a depressive relapse.34,35 Hyponatremia is more
recognition and treatment of depression in older adults is extremely important as individuals 65 years of age and older have a high rate of suicidality.
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Increased suicide attempts in older adults with depression have been associated with access to firearms, diminished cognitive functioning, sleep
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disruptions, poor social interactions, and inattention among primary caregivers.98

Before initiating antidepressant treatment, a complete physical examination should be performed. When prescribed antidepressants, older adults may
be either overtreated or under­treated. Overtreatment occurs when age­related PK and PD factors are overlooked and under­treatment results from
an overly conservative approach as a result of the patient’s advanced age or concurrent medical problems. In older adults, SSRIs are usually selected
as first­line treatment, and this may enable the clinician to avoid some of the problematic intolerances commonly associated with TCAs (eg, sedative,
anticholinergic, and cardiovascular adverse reactions). Furthermore, there is evidence to suggest that the long­term use of antidepressants such as
SSRIs in older adults, administered with either psychotherapy or clinical management, may prevent a depressive relapse.34,35 Hyponatremia is more
common in elderly females, especially in those taking concomitant diuretics. Mirtazapine has been shown to be an effective antidepressant in adults
older than 65 years of age and better tolerated than the SSRI paroxetine. Furthermore, secondary measures of anxiety and sleep were improved
following mirtazapine administration.99 In addition to sleep benefits, mirtazapine can be helpful in improving appetite which is commonly diminished
in older adults with depression. For those patients whose depressive symptoms include lack of overall energy, use of bupropion may capitalize on the
stimulant effect of this medication. Regardless of the specific antidepressant chosen, the effect sizes for antidepressants as a pharmacological class,
compared to placebo, may be smaller in older adult patients than in younger adult populations.3

Pediatric Patients

Accumulating evidence indicates that childhood depression occurs quite commonly and symptoms of depression in the young may vary from accepted
diagnostic criteria to include several nonspecific symptoms such as boredom, anxiety, somatic complaints (eg, stomach ache), and impulsivity.100

Data collected under controlled conditions that support the efficacy of antidepressants in children and adolescents are sparse, and only fluoxetine and
escitalopram are FDA­approved for depression in patients younger than 18 years of age, although other antidepressants (eg, sertraline) have been
studied in this population.100 The Treatment of Adolescent Depression Study (TADS) found that the combination of fluoxetine and CBT was superior to
fluoxetine monotherapy or CBT alone in adolescents 12 to 17 years of age.101 The Treatment of Resistant Depression in Adolescents (TORDIA) study
switched adolescents 12 to 18 years of age with SSRI­resistant depression to venlafaxine or sertraline with or without CBT after nonresponse to
antidepressant. Overall this study found no difference in outcomes between the two medications and also found no difference in outcomes when CBT
was added to medication.102 Additionally, the Adolescent Depression Antidepressant and Psychotherapy Trial (ADAPT) did not find a benefit of adding
CBT to SSRI therapy in adolescents 11 to 17 years of age.103

The use of antidepressants in children and adolescents was complicated when the FDA issued a boxed warning in the product labeling for
antidepressant medications warning clinicians and patients of the increased risk for suicidal ideation and behavior when antidepressants are used in
this population. Results of subsequent studies attempting to elucidate the risk of antidepressants in young patients have varied. A meta­analysis of
published and unpublished clinical trials supported an increased risk; however, the study was impeded by limited data access. In contrast, several
retrospective longitudinal reviews of antidepressant use in children refute the increased risk of suicide attempts or deaths.104 Furthermore, studies
demonstrated a decreased rate of prescribing antidepressants and an increase in deaths by suicide after the warning appeared in labeling.105

The treatment of depression in children remains challenging, as depression can be difficult to diagnose and, once identified, treat. Furthermore,
differences in efficacy between medication and placebo may be small and not significant in children below the age of 13 years.3 However,
antidepressants (in particular, the SSRIs) remain viable treatment options when prescribed and monitored appropriately.

Pregnant and Lactating Patients

The crucial decision as to whether to use antidepressants during pregnancy continues to be debated and must always include a risk­benefit analysis
based upon the available evidence at the time of treatment. Approximately 14% of pregnant individuals develop clinically significant depression during
pregnancy.106 Furthermore, it has been documented that those who discontinued antidepressant therapy before or during pregnancy were five times
more likely to have a relapse than those who continued treatment.107 While numerous studies, reviews, and meta­analyses have been published over
the last decade, the absolute risk of antidepressants in pregnancy is still not clear due to methodological issues and confounding factors (eg, prenatal
care, continued depressive symptoms during treatment, medical and psychiatric comorbidities, and substance use).108 An approximate 25% relative
increase in congenital heart defects associated with SSRIs is the most consistent finding; however, the increase in risk ranges from 10% to a twofold
increase across studies.108 Other findings have included increased risk of low birth weight and newborn respiratory distress.106 An oft­cited study
reported a sixfold greater likelihood of persistent pulmonary hypertension of newborn infants exposed to an SSRI after the 20th week of gestation;
however, the degree of this risk has been debated.109 These are selected examples of studies assessing both risks and benefits of antidepressants in
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in treating • Accessibility
pregnant individuals or individuals who desire pregnancy: (a)
Pregnancy does not protect against the occurrence of depression, and the likelihood of relapse is very high in untreated individuals with recurrent
illness. (b) Depression during pregnancy adversely affects child development, and prenatal depression may adversely affect the offspring. (c) When
the last decade, the absolute risk of antidepressants in pregnancy is still not clear due to methodological issues and confounding factors (eg, prenatal
care, continued depressive symptoms during treatment, medical and psychiatric comorbidities, and substance use).108 AnUniversity
approximate 25%West
of the relative
Indies
increase in congenital heart defects associated with SSRIs is the most consistent finding; however, the increase in risk ranges from
Access 10%by:to a twofold
Provided

increase across studies.108 Other findings have included increased risk of low birth weight and newborn respiratory distress.106 An oft­cited study
reported a sixfold greater likelihood of persistent pulmonary hypertension of newborn infants exposed to an SSRI after the 20th week of gestation;
however, the degree of this risk has been debated.109 These are selected examples of studies assessing both risks and benefits of antidepressants in
pregnancy. A full exploration of the conflicting literature on this topic is beyond the scope of this chapter.

Four therapeutic principles have been proposed to guide the clinician in treating pregnant individuals or individuals who desire pregnancy: (a)
Pregnancy does not protect against the occurrence of depression, and the likelihood of relapse is very high in untreated individuals with recurrent
illness. (b) Depression during pregnancy adversely affects child development, and prenatal depression may adversely affect the offspring. (c) When
attempting to balance benefit and risk, transient postnatal behavioral abnormalities in the offspring of pregnant individuals receiving
pharmacotherapy must not be assumed to portend long­term compromise. (d) SSRIs, the most commonly used and best­tolerated treatment for
depression, carry a small but significant risk for a serious medical consequence.110

The APA and the American College of Obstetricians and Gynecologists have a report discussing the treatment of depression during pregnancy. One of
the prominent conclusions of this report was that both antidepressant treatment and untreated depression have been associated with potential
problems during pregnancy. However, studies to date have not been able to adequately control for all the necessary variables involved in birth
outcomes (eg, maternal depressive disorder) and more work needs to be done.111

In summary, the risks and benefits of medication therapy during pregnancy must always be weighed, and concerns about the risks of untreated
depression during pregnancy should be considered. These include the possibility of low birth weight secondary to poor pregnancy weight gain,
suicidality, potential for hospitalization, potential for relationship discord, inability to engage in appropriate obstetric care, and difficulty caring for
other children. Several different approaches exist for dealing with pregnancy and antidepressant use. First, discontinuation of an antidepressant
before conception is an option for individuals who are stable and appear likely to remain well while not taking antidepressant medication (eg, no
history of recurrence upon discontinuation, no history of severe symptoms or suicidality, stable psychosocial supports). Second, continuation of the
antidepressant until conception may be reasonable and one with the lowest risk for the fetus should be chosen in individuals of child bearing potential
or those trying to conceive. For those who have a history of depressive relapse after medication discontinuation, the antidepressant should be
continued throughout pregnancy. There is a great deal of uncertainty regarding long­term antidepressant exposure in infants exposed through human
milk due to the lack of data. However, sertraline is recommended and appears in relatively low concentrations in human milk and in samples taken
from infants.112 The risks of not treating depression in a patient who is pregnant or providing milk to an infant should not be underestimated or
minimized. Additional information can be found in Chapter 99, “Pregnancy and Lactation.”

Relative Resistance and Treatment­Resistant Depression

The majority of patients with TRD likely have had inadequate (low dose, short duration) therapy (relative resistance). This theory is supported by data
from the National Institute of Mental Health (NIMH) Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which is generally
considered to be one of the premier antidepressant trials among patients with depressive disorders.56,113 According to this study, one in three patients
with depression who previously did not achieve remission with an antidepressant (citalopram) became symptom free with an additional medication
(bupropion SR or buspirone) and one in four achieved remission after switching to a different antidepressant (bupropion SR, sertraline, or venlafaxine
XR). Furthermore, patients can be switched to another medication within the same class.114 For example, patients in the STAR*D study not responding
to an initial SSRI were shown to be as likely to respond to another SSRI as they were to a medication from a different class.115 Other key findings of
STAR*D include the importance of maximizing dose (higher doses associated with higher remission rates) and adequate trial duration of at least 8 to
12 weeks before deeming a medication ineffective.56 The BAP guidelines place a higher level of confidence in both augmentation and switching
strategies, compared to dosage increase approaches.3

Although several different definitions for TRD have been proposed, the most widely accepted is depression that has not achieved remission after two
optimal antidepressant trials, which represents more than 40% of patients with MDD treated with antidepressants.115 Three pharmacologic
approaches that have been used with success for TRD include the following:

1. The current antidepressant may be stopped and another agent initiated (ie, switching). For example, the STAR*D trial compared switching to
mirtazapine (up to 60 mg/day) versus nortriptyline (up to 200 mg/day) after two consecutive ineffective medication treatments.115 In the
mirtazapine group, 12.3% of patients met the remission criterion of a score of 7 or less on the Hamilton Rating Scale for Depression (HAM­D), while
19.8% of nortriptyline patients met this criterion at the end of 14 weeks.

2. The current
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is by the addition of another agent such as lithium, or another antidepressant (ie, combination
antidepressant
Chapter treatment).
88: Depressive For example,
Disorders, Amy M. the STAR*D trial evaluated the addition of lithium or triiodothyronine (T3) to current antidepressant
VandenBerg Page 37 / 53
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treatment. After approximately 10 weeks, T3 augmentation resulted in higher remission rates (24.7%) compared with lithium (15.9%). However, the

differences between these two augmentation strategies were modest and not statistically significant.116 Although T3 and lithium demonstrated
1. The current antidepressant may be stopped and another agent initiated (ie, switching). For example, the STAR*D trial compared switching to
University of the West Indies
mirtazapine (up to 60 mg/day) versus nortriptyline (up to 200 mg/day) after two consecutive ineffective medication treatments.115 In the
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mirtazapine group, 12.3% of patients met the remission criterion of a score of 7 or less on the Hamilton Rating Scale for Depression (HAM­D), while
19.8% of nortriptyline patients met this criterion at the end of 14 weeks.

2. The current antidepressant can be augmented by the addition of another agent such as lithium, or another antidepressant (ie, combination
antidepressant treatment). For example, the STAR*D trial evaluated the addition of lithium or triiodothyronine (T3) to current antidepressant
treatment. After approximately 10 weeks, T3 augmentation resulted in higher remission rates (24.7%) compared with lithium (15.9%). However, the

differences between these two augmentation strategies were modest and not statistically significant.116 Although T3 and lithium demonstrated
similar remission rates in this seminal trial, the BAP guidelines provide a stronger recommendation rating for lithium (ie, “A”) compared to T3­
based approaches (ie, “B”).116 In contrast, the CANMAT guidelines consider both agents second­line for augmentation with level 2 evidence.4

3. The use of SGAs to augment the antidepressant response is increasing. Aripiprazole, brexpiprazole, and quetiapine are FDA­approved for
adjunctive treatment for MDD. Aripiprazole and quetiapine have been recommended as first­line agents to augment an antidepressant
medication.4 In a predominantly male population in the Veterans Health Administration, augmentation with aripiprazole was found to be more
effective than switching to bupropion but no different from bupropion augmentation.117

The APA practice guideline for the treatment of patients with MDD offers direction for managing patients whose symptoms are refractory to
medications. These guidelines advise that if patients are still symptomatic after 6 to 8 weeks of medication, a reappraisal of the treatment regimen
should be considered.2 Those with partial response should consider changing the dose, augmenting the antidepressant, or adding psychotherapy or
ECT. For those with no response, options include changing to a different antidepressant or adding psychotherapy or ECT. Again, the BAP guidelines
suggest that stronger evidence exists for switching or augmentation strategies compared to dose increases in patients with inadequate antidepressant
response.3 Comorbid medical or psychiatric conditions should be identified and treated because they may complicate treatment.

Before changing a patient’s treatment, the clinician is advised to evaluate the adequacy of the medication dosage and adherence with the
prescribed regimen. Issues to be addressed in assessing the patient who has not responded to treatment include the following:

1. Is the diagnosis correct?

2. Does the patient have a psychotic depression?

3. Has the patient received an adequate dose and adequate duration of treatment?

4. Do adverse medication reactions preclude adequate dosing?

5. Is patient adherence to the prescribed regimen appropriate?

6. Was a stepwise approach to treatment used?

7. Was treatment outcome adequately measured?

8. Is there a coexisting or preexisting medical or psychiatric disorder?

9. Are there other factors that interfere with treatment?

Personalized Pharmacotherapy

Pharmacogenetic (PGx) applications in psychiatry have been explored for some time. Multiple commercially available PGx tests are now available
and in patients who present with the testing already completed or for whom a test is ordered, evidence­based guidelines produced by the Clinical
Pharmacogenomics Implementation Consortium (CPIC) can help determine test interpretation ([Link]). CPIC does not specifically recommend
testing in patients, but rather serves as a resource for clinicians who are presented with PGx testing results and are looking for assistance in their
interpretation. Therefore, while this testing may, one day, be routinely used to guide pharmacotherapy, it is not utilized routinely in practice for several
reasons.118 Included on several of the commercially available test are genes associated with PK parameters that have long been one of the primary
considerations when choosing among the antidepressants, particularly within a medication class.2 For example, PK parameters help the clinician
choose a particular SSRI (eg, longer fluoxetine half­life for partial nonadherence). The data regarding the interpretation of PGx testing results for the
PK genes is more concrete than that associated with PD genes.

A clinician can2025­5­6
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aspects of a medication’s
P Your IP is pharmacological profile to tailor the treatment to a particular patient. For example, antidepressants
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can generally be classifiedDisorders, Amy M. VandenBerg
as either activating or sedating based upon their mechanism of action, and this is often a major consideration in Page 38 / 53
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antidepressant choice. Medications that promote noradrenergic activity (eg, bupropion, venlafaxine) or serotonin (eg, SSRIs) may be activating upon
initiation and therefore poor choices for a patient suffering from significant insomnia. In contrast, mirtazapine and trazodone have been shown to
67
reasons.118 Included on several of the commercially available test are genes associated with PK parameters that have long been one of the primary
University of the West Indies
considerations when choosing among the antidepressants, particularly within a medication class.2 For example, PK parameters help the clinician
Access Provided by:
choose a particular SSRI (eg, longer fluoxetine half­life for partial nonadherence). The data regarding the interpretation of PGx testing results for the
PK genes is more concrete than that associated with PD genes.

A clinician can use other aspects of a medication’s pharmacological profile to tailor the treatment to a particular patient. For example, antidepressants
can generally be classified as either activating or sedating based upon their mechanism of action, and this is often a major consideration in
antidepressant choice. Medications that promote noradrenergic activity (eg, bupropion, venlafaxine) or serotonin (eg, SSRIs) may be activating upon
initiation and therefore poor choices for a patient suffering from significant insomnia. In contrast, mirtazapine and trazodone have been shown to
improve sleep, likely due to antagonism of H1 and 5­HT2A receptors.67 Furthermore, doxepin is FDA­approved (in lower doses compared to those used

for depression) as pharmacotherapy for primary insomnia.60

EVALUATION OF THERAPEUTIC OUTCOMES

Several monitoring parameters, in addition to plasma or serum concentrations, are useful in managing patients (Tables 88­3 and 88­11).2,60
Patients must be monitored for adverse medication reactions, such as sedation and anticholinergic effects, and for remission of previously
documented target symptoms. The presence of adverse medication reactions does not necessarily indicate adequate or excessive dosage. In addition,
changes in social and occupational functioning should be assessed. Patients receiving SNRIs should have their blood pressure monitored at regular
intervals. Patients older than 40 years of age should receive a pretreatment ECG before starting TCA therapy, and follow­up ECGs should be performed
periodically to assess for arrhythmias. Patients should be monitored for the emergence of suicidal ideation after initiation or discontinuation of any
antidepressant, especially if other risk factors for death by suicide (eg, sleep disturbances) are present. If significant activation or insomnia occurs
upon antidepressant initiation, a short­term anxiolytic or hypnotic may be appropriate.67 Weight gain and sexual dysfunction, common adverse
reactions associated with most antidepressants, may increase nonadherence and should be monitored and discussed with the patient (Table 88­11).

TABLE 88­11
Adverse Medication Reactions and Monitoring Parameters Associated with Select Antidepressants

Medication Adverse Monitoring Comments

Medication
Reaction

Antidepressants from Each Pharmacologic Class

Common to all antidepressants

Suicidality Behavioral changes (US boxed warning) for all antidepressants; caregivers should be alerted
to monitor for acute changes in behavior (especially early in treatment)
Mental status

Selective Serotonin Reuptake Inhibitors (SSRIs)

Common to
all

Anxiety or Assess severity and impact on Most prominent on initial treatment; lower initial doses recommended in
nervousness patient functioning and quality of patients with prominent anxiety
life

Hyponatremia Serum sodium More likely in older adult females; sodium may decrease within 72 hours
of initiating antidepressant

Nausea Frequency and severity May improve with slower dose titration

Sleep changes Sleep patterns Among SSRI class: fluoxetine may be more activating; paroxetine may be
(insomnia and more sedating
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Sexual dysfunction Assess severity and impact on Spontaneous self­reporting may be low; clinician should assess
patient functioning and quality of symptoms; reversible on medication discontinuation
 of initiating antidepressant
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Nausea Frequency and severity May improve with slower dose titration

Sleep changes Sleep patterns Among SSRI class: fluoxetine may be more activating; paroxetine may be
(insomnia and more sedating
somnolence)

Sexual dysfunction Assess severity and impact on Spontaneous self­reporting may be low; clinician should assess
patient functioning and quality of symptoms; reversible on medication discontinuation
life

SSRI­Specific

Citalopram QTc interval Electrocardiogram; electrolytes Caution use in “at­risk” patients (eg, electrolyte disturbance); discontinue
(possibly prolongation (eg, potassium, magnesium) if QTc persistently >500 ms or increased >50 ms over baseline
escitalopram)

Paroxetine Anticholinergic Symptoms: dry mouth, Avoid in older adults

effects constipation, urinary retention,
mental status

Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs)

Common to
all

Cardiovascular Increases in blood pressure; heart Possibly less likely with duloxetine; may need to lower/discontinue dose
changes rate

Insomnia Sleep patterns Possibly less likely with duloxetine

Nausea Frequency and severity May improve with slower dose titration

Sexual dysfunction Assess severity and impact on Spontaneous self­reporting may be low; clinicians should assess
patient functioning and quality of symptoms; reversible on medication discontinuation
life

Sweating Frequency and severity May require change in therapy

SNRI­Specific

Desvenlafaxine Dose­related Lipid profile Elevations in total cholesterol, low­density lipoproteins, and
hyperlipidemia triglycerides

Duloxetine Liver toxicity Liver function tests May be transient upon initiation or sustained

Mixed Serotonergic Effects (Mixed 5­HT)

Nefazodone Liver toxicity Liver function tests Nefazodone boxed warning in the United States for hepatotoxicity

Trazodone Orthostatic Blood pressure, pulse May be more severe as compared with other antidepressants; rate­
hypotension limiting adverse medication reactions

Priapism Patient report of sexual Patient should seek medical attention for prolonged erection (ie, >4 hr)
dysfunction, especially painful
erection
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Serotonin and α 2 ­Adrenergic Antagonist

 Trazodone Orthostatic Blood pressure, pulse May be more severe as compared with other antidepressants; rate­
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Priapism Patient report of sexual Patient should seek medical attention for prolonged erection (ie, >4 hr)
dysfunction, especially painful
erection

Vilazodone and Nausea Frequency and severity Most common dose limiting adverse reaction
vortioxetine

Serotonin and α 2 ­Adrenergic Antagonist

Mirtazapine Weight gain Body weight Frequently occurring and significant (>7% over baseline) weight gain
among adults; diet mediated

Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)

Bupropion Seizure activity Electroencephalogram if indicated See Table 88­3 for proper dosing, which can help decrease seizure risk;
caution use in patients with eating disorders or alcohol use disorders

Data from References 2,60,62,73,74, and 80.

In addition to the clinical interview, psychometric rating instruments (such as those highlighted earlier in this chapter and in Chapter e81) allow for
rapid and reliable measurement of the nature and severity of depressive and associated symptoms. It is helpful to administer the rating scales prior to
treatment, 2 to 4 weeks and 8 to 12 weeks after initiation of therapy, and periodically thereafter. It is important to note that lack of robust response at 2
to 4 weeks does not necessarily predict lack of response at 8 to 12 weeks.56 Interviewing a family member or friend (with the patient’s permission)
regarding symptoms and daily functioning also can assist in assessment of progress, as they may notice symptom improvements before the patient.
Patients should be monitored at more frequent intervals early in treatment, particularly for suicidality. Monitoring is then continued at regular
intervals throughout the continuation and maintenance phases of treatment and assessing for reemergence of target symptoms continued for several
months after antidepressant therapy is discontinued.

Finally, one useful set of criteria that can be used with a variety of psychometric scales uses the following definitions: (a) nonresponse is less than a
25% decrease in baseline symptoms, (b) partial response is a 26% to 49% decrease in baseline symptoms, and (c) partial remission or response is
greater than a 50% decrease in baseline symptoms.53 Consistent with other recommendations, remission is a return to baseline functioning with no
symptoms present.2

CONCLUSION
Depression is a highly pervasive and complex disease state that can be impacted by comorbid medical and psychiatric conditions, psychosocial factors,
as well as medications. While the precise pathophysiology of MDD is still elusive, antidepressant medications have directly targeted monoamine
systems for the past half­century, and our understanding is evolving to include other complementary mechanisms. Additionally, research is revealing
more about the complexity of the disease and the impact of genetic polymorphisms (both on pathophysiology and impact on pharmacotherapy
outcomes). Individual patient characteristics should be considered when selecting antidepressant therapy and monitoring treatment. The goals of
treatment should include remission (complete resolution of symptoms) and improved functioning.

ABBREVIATIONS

AHRQ Agency for Healthcare Research and Quality

APA American Psychiatric Association

BAP British Association of Psychopharmacology

BDI Beck Depression Inventory

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brain­derived M. VandenBerg
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CAM complementary and alternative medicine
 University of the West Indies
APA American Psychiatric Association
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BAP British Association of Psychopharmacology

BDI Beck Depression Inventory

BDNF brain­derived neurotrophic factor

CAM complementary and alternative medicine

DA dopamine

DHA docosahexaenoic acid

DSM­5 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

ECG electrocardiogram

ECT electroconvulsive therapy

EPA eicosapentaenoic acid

5­HT serotonin

GI gastrointestinal

HAM­D Hamilton Rating Scale for Depression

HPA hypothalamic–pituitary–adrenal

KKW kilocalories per kilogram per week

5­MTHF 5­methyltetrahydrofolate

MADRS Montgomery­Åsberg Depression Rating Scale

MAOI monoamine oxidase inhibitor

MDD major depressive disorder

NDRI norepinephrine and dopamine reuptake inhibitor

NE norepinephrine

NIMH National Institute of Mental Health

NT neurotransmitter

PD pharmacodynamic

PK pharmacokinetic

rTMS repetitive transcranial magnetic stimulation

SAMe S­adenosyl­L­methionine

SNRI serotonin–norepinephrine reuptake inhibitor

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SSRI selective serotonin reuptake inhibitor
 rTMS repetitive transcranial magnetic stimulation
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SAMe S­adenosyl­L­methionine

SNRI serotonin–norepinephrine reuptake inhibitor

SS serotonin syndrome

SSRI selective serotonin reuptake inhibitor

STAR*D Sequenced Treatment Alternatives to Relieve Depression

T3 triiodothyronine

TADS Treatment for Adolescents with Depression Study

TCA tricyclic antidepressant

TORDIA Treatment of Resistant Depression in Adolescents

TRD treatment resistant depression

TREAD Treatment with Exercise Augmentation for Depression

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118. Rosenblat JD, Lee Y, McIntyre RS. Does pharmacogenomics testing improve clinical outcomes for major depressive disorder. A systematic review
of clinical trials and cost­effectiveness studies. J Clin Psychiatry . 2017;78(6):720–729. [PubMed: 28068459]

SELF­ASSESSMENT QUESTIONS
1. Which of the following statements is correct when considering the addition of an SSRI to a medication regimen that includes a chronic NSAID
prescription?

A. Combination must be avoided and is contraindicated

B. Use this combination with caution and monitor patient closely

C. Combination is associated with enhanced antidepressant efficacy

D. Combination is associated with increased risk for clot formation

2. Multiple agents with novel mechanisms of action are under investigation or approved for depression. The agent FDA approved for treatment of
postpartum depression is:

A. Brexpiprazole

B. Samidorphan

C. Esketamine

D. Brexanolone

3. Which of the following antidepressants does NOT inhibit reuptake of serotonin?

A. Mirtazapine

B. Vilazodone

C. Vortioxetine

D. Trazodone

4. According to the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which of the following are associated with increased
remission rates?

A. Use of concurrent cognitive behavioral therapy

B. Achieving high dose

C. Partial response at 4 days

D. Switching to different class

5. Choose the most appropriate option for a 68­year­old patient with a history of coronary artery disease taking metoprolol and simvastatin?

A. Fluoxetine

B. Fluvoxamine

C. Sertraline
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D. Nortriptyline
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6. In a patient who has successfully achieved remission following the acute phase of treatment, which of the following is the most important factor to
 5. Choose the most appropriate option for a 68­year­old patient with a history of coronary artery disease taking metoprolol and simvastatin?
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A. Fluoxetine Access Provided by:

B. Fluvoxamine

C. Sertraline

D. Nortriptyline

6. In a patient who has successfully achieved remission following the acute phase of treatment, which of the following is the most important factor to
consider regarding the decision as to how long treatment should be continued?

A. Prescription copayment cost

B. Risk of depressive recurrence

C. Brand name product availability

D. Caregiver preference

7. For a patient with history of antidepressant induced sexual dysfunction, which agent is least likely to cause this medication adverse reaction?

A. Bupropion

B. Paroxetine

C. Amitriptyline

D. Phenelzine

8. In a patient experiencing a treatment refractory major depressive episode, which of the following steps should be confirmed prior to concluding
their symptoms are not responding to treatment?

A. Adequate dose for adequate duration

B. Adherence to prescribed regimen

C. Proper monitoring of response

D. All the above

9. To meet criteria for a major depressive episode (MDE), the patient must exhibit the following symptoms according to the DSM­5:

A. Depressed mood most of the day every day for at least 1 week

B. At least four of the symptoms as listed in the DSM­5 for MDE

C. Impairment in some area of functioning (eg, social, occupational)

D. History of “switch” into mania following antidepressant treatment

10. Which of the following scenarios is considered a pharmacokinetic medication interaction, instead of a pharmacodynamic medication interaction?

A. Fluoxetine taken with tamoxifen decreases active metabolite levels

B. Fluoxetine taken with phenelzine leads to serotonin syndrome

C. Fluoxetine taken with ibuprofen increases risk of bleeding

D. Fluoxetine taken with hydrochlorothiazide increases risk of hyponatremia

11. If serotonin syndrome is suspected in a patient being treated with antidepressants, which of the following is the most likely symptom that should
be identified?

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B. Asterixis

C. Priapism
 D. Fluoxetine taken with hydrochlorothiazide increases risk of hyponatremia University of the West Indies
Access Provided by:

11. If serotonin syndrome is suspected in a patient being treated with antidepressants, which of the following is the most likely symptom that should
be identified?

A. Clonus

B. Asterixis

C. Priapism

D. None of the above

12. When considering next­step antidepressant treatment in a patient who has not achieved full remission, which of the following approaches are
supported by the evidence, according to the British Association of Psychopharmacology (BAP) guidelines and the STAR*D trial?

A. Switch antidepressant

B. Augment antidepressant

C. All the above

D. None of the above

13. A patient taking tranylcypromine should completely avoid which of the following?

A. Cheese pizza from commercial chains

B. Apple juice

C. Sour cream

D. Prosciutto

14. Which of the following antidepressants have been associated with sustained elevated blood pressure that requires close monitoring during
treatment and possible dose adjustments?

A. Desvenlafaxine

B. Venlafaxine

C. Levomilnacipran

D. All the above

15. When assessing a patient with new onset symptoms of depression, which of the following medications has a clear mechanism as well as evidence to
support a high rate of treatment associated depression?

A. Varenicline

B. Tetrabenazine

C. Metoprolol

D. Sumatriptan

SELF­ASSESSMENT QUESTION­ANSWERS
1. B . Use of NSAIDs with antidepressants is not contraindicated with antidepressants. Use of chronic daily NSAIDs should be approached with caution
and monitoring due to increased risk of bleeding. NSAIDs may be associated with a higher rate of depression. NSAIDs do not increase risk of clot
formation, rather increase risk of bleeding (see Tables 88­10 and 88­11).

2. D . Brexpiprazole is a second­generation antipsychotic approved for adjunctive treatment of MDD. Samidorphan is an opioid receptor antagonist.
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Esketamine
Chapter is approved
88: Depressive for treatment
Disorders, resistant
Amy M. depression. Only brexanolone is seeking FDA approval for treatment of postpartum depression
VandenBerg Page 52 / 53
©2025
(seeMcGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility
Table 88­6).

3. A . Mirtazapine does not inhibit the serotonin transporter. Vilazodone, vortioxetine, and trazodone all inhibit the reuptake of serotonin via the
 University of the West Indies
1. B . Use of NSAIDs with antidepressants is not contraindicated with antidepressants. Use of chronic daily NSAIDs should be approached with caution
Access Provided by:
and monitoring due to increased risk of bleeding. NSAIDs may be associated with a higher rate of depression. NSAIDs do not increase risk of clot
formation, rather increase risk of bleeding (see Tables 88­10 and 88­11).

2. D . Brexpiprazole is a second­generation antipsychotic approved for adjunctive treatment of MDD. Samidorphan is an opioid receptor antagonist.
Esketamine is approved for treatment resistant depression. Only brexanolone is seeking FDA approval for treatment of postpartum depression
(see Table 88­6).

3. A . Mirtazapine does not inhibit the serotonin transporter. Vilazodone, vortioxetine, and trazodone all inhibit the reuptake of serotonin via the
transporter in addition to other mechanisms (see Table 88­4).

4. B . Patients who achieved remission in STAR*D were on higher average doses of medication. Outcomes regarding cognitive behavioral therapy were
limited due to lack of power to analyze this group. Partial response at 2 weeks (not 4 days) was predictive of remission. There were no differences
between agents in the switch arm regarding response rates.

5. C . Fluoxetine may significantly increase metoprolol levels due to inhibition of CYP2D6 resulting in bradycardia or hypotension. Fluvoxamine may
significantly increase levels of simvastatin due to inhibition of CYP3A4. Sertraline does not have significant interactions with metoprolol or
simvastatin. Nortriptyline and other TCAs are not recommended in patients over 65 years of age due to anticholinergic effects and may have
negative cardiac effects in patients post­MI (see Tables 88­9 and 88­10).

6. B . Prescription cost may negatively impact adherence, but should not be a factor in considering continuation of antidepressant treatment. Cost of
medication should be considered when initiating treatment to ensure a feasible plan for a patient. Risk of recurrence is the most important factor
when determining whether to continue treatment. Caregiver input regarding severity of illness and resolution of symptoms is important in
determining response to treatment. Brand name products are no more beneficial than generic products and should not drive treatment decisions.

7. A . Bupropion is the only agent listed that is not associated with sexual adverse effects.

8. D . All listed factors are important to assess prior to adjusting therapy due to nonresponse.

9. C . Depressed mood for most of the day must last for at least 2 weeks. At least five symptoms must be present. History of switch into mania would be
suggestive of bipolar disorder not MDE. Patients must have impairment in functioning (see Table 88­2).

10. A . Fluoxetine has a pharmacokinetic interaction with tamoxifen as it inhibits metabolism of CYP2D6 that prevents conversion of tamoxifen to its
active metabolite. When taken with phenelzine, both agents increase serotonin levels via different mechanisms. When taken with ibuprofen, both
agents increase risk of bleeding via different mechanism. When taken with hydrochlorothiazide, both agents can cause hyponatremia via different
mechanisms (see Tables 88­9 and 88­10).

11. A . Only clonus is associated with serotonin syndrome. Asterixis would be associated with liver failure. Priapism is a rare side effect of trazodone.
Trazodone does increase serotonin; however, priapism is not associated with serotonin syndrome.

12. C . There were no statistically significant differences between the switch arm and the augmentation arm in the STAR*D trial. Patients with partial
response were more likely to choose augmentation. BAP guidelines recommend switching antidepressants if there are troublesome side effects or
no improvement in symptoms and augmenting for partial/insufficient response.

13. D . Pizza from most commercial chains have low levels of tyramine along with apple juice and sour cream. Prosciutto and other dry aged meats have
high tyramine levels and should be avoided completely (see Table 88­5).

14. D . All SNRIs are associated with sustained elevated blood pressure and all agents listed are SNRIs.

15. B . Varenicline, metoprolol, and sumatriptan have been inconsistently associated with increased risk of depression. Risk is confounded by other
variables in studies and has not been clearly linked to mechanism for all agents. Tetrabenazine depletes presynaptic vesicles of monoamines and
has a black box warning for treatment associated depression.

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