2/26/24, 10:54 PM Depression

Depression
Sidney H. Kennedy, MD, FRCPC
Sagar V. Parikh, MD, FRCPC
Sophie Grigoriadis, MD, PhD, FRCPC
Date of Revision: March 27, 2023
Peer Review Date: October 5, 2022

Introduction
In the Diagnostic and Statistical Manual of Mental Disorders 5th edition, Text Revision (DSM-5-TR), depressive
disorders include​[1]:
Major depressive disorder (MDD)
Persistent depressive disorder
Disruptive mood dysregulation disorder
Premenstrual dysphoric disorder
Substance-induced mood disorder (caused by substances such as alcohol or medications)
Mood disorder due to a general medical condition (when the depression is thought to be a direct physiological
consequence of the medical disorder)
Other specified depressive disorder (depressive episodes deviating from the precise criteria for MDD)
Unspecified depressive disorder

This chapter primarily focuses on major depressive disorder and persistent depression disorder.

Major depressive episodes may be single or, more often, recurrent; see Table 1 for diagnostic criteria. Persistent
depressive disorder, or dysthymia, is a consolidation of dysthymic disorder and chronic major depressive disorder. In
contrast to MDD, the symptoms of persistent depressive disorder are typically fewer and less severe. The diagnostic
criteria of persistent depressive disorder include depressed mood for at least 2 years and at least 2 of the following:
increased or decreased appetite, insomnia or hypersomnia, reduced energy or fatigue, reduced self-esteem, reduced
concentration or ability to make decisions, and hopelessness.​[1]

The lifetime prevalence of MDD in Canada is approximately 10% and the annual prevalence of a major depressive
episode is just under 5%. Depression has a negative impact on work productivity and accounts for over 5% of illness-
related productivity loss. Not surprisingly, MDD is also associated with serious impairment in quality of life and a high
economic burden.​[2]

Goals of Therapy
Achieve remission of depressive symptoms
Treat concomitant symptoms/disorders
Prevent suicide
Restore optimal functioning
Prevent recurrence

Investigations
The following screening questions/assessment tools are recommended for use by primary health-care professionals:

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[3]
The Patient Health Questionnaire (PHQ-9)​ is a patient-rated assessment tool that consists of 9 questions that
correspond to the DSM-5 criteria for a major depressive episode.​[4] The first 2 questions from the PHQ-9 serve as
a useful and rapid screening tool:​[5]
During the past 2 weeks, how often have you been bothered by little interest or pleasure in doing things?
During the past 2 weeks, how often have you been bothered by feeling down, depressed or hopeless?
The Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16) is a widely used alternative to the
PHQ-9. It is available in multiple languages, takes less than 10 minutes to complete and consists of 16 multiple
choice questions that cover DSM-5 criteria.
The 7-item Hamilton Depression Rating Scale (HAMD-7)​[6] is a validated, brief, health-care professional
assessment designed to rate severity and remission.
The Mood Disorder Questionnaire (MDQ)​[7] is a useful screening instrument for manic or hypomanic symptoms.
The Edinburgh Postnatal Depression Scale (EPDS)​[8] is the most widely used and well-validated tool to screen for
depressive symptoms during pregnancy and the postpartum period.
MoodFx is a free website that offers tools for patients to use in measurement-based care—the use of
measurement tools to assess disease progress and aid in therapeutic decisions.

As part of a standard diagnostic interview, it is important to screen for current prescription medicines that may be
associated with depressive symptoms (e.g., oral contraceptives, analgesics, proton pump inhibitors, antihypertensives).​
[9] It is also important to recognize that patients with bipolar disorder often present to health-care providers for the first
time during a major depressive episode. As such, primary care physicians should assess those presenting with
depression for a history of manic or hypomanic episodes. The treatment of bipolar depression requires different
strategies than that of MDD; see Bipolar Disorder for more information.

Once a diagnosis of depression is confirmed, baseline and ongoing monitoring parameters are recommended; see
Table 2 for more information.

[1]
Table 1: Diagnostic Criteria of Major Depressive Disorder​
A. Five (or more) of the following symptoms have been present during the same 2-week period and
represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood
or (2) loss of interest or pleasure. Note: do not include symptoms that are clearly attributable to another
medical condition.​[a]
1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g.,
feels sad, empty, hopeless) or observation made by others (e.g., appears tearful). Note: in children
and adolescents, can be irritable mood
2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every
day (as indicated by either subjective account or observation)
3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body
weight in a month), or decrease or increase in appetite nearly every day. Note: in children, consider
failure to make expected weight gain
4. Insomnia or hypersomnia nearly every day
5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective
feelings of restlessness or being slowed down)
6. Fatigue or loss of energy nearly every day
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every
day (not merely self-reproach or guilt about being sick)
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either subjective
account or as observed by others)
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific
plan, or a suicide attempt or a specific plan for committing suicide.

B. The symptoms cause clinically significant distress or impairment in social, occupational or other important
areas of functioning.​[a]

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C. The episode is not attributable to the physiological effects of a substance or to another medical condition.​
[a][b]
​

D. At least one major depressive episode is not better explained by schizoaffective disorder and is not
superimposed on schizophrenia, schizophreniform disorder, delusional disorder, or other specified and
unspecified schizophrenia spectrum and other psychotic disorders.

E. There has never been a manic or hypomanic episode. Note: this exclusion does not apply if all of the
manic-like or hypomanic-like episodes are substance-induced or are attributable to the physiological
effect of another medical condition.

[a] Criteria A–C represent a major depressive episode.

[b] Responses to a significant loss (e.g., bereavement, financial ruin, losses from a natural disaster, a serious medical
illness or disability) may include the feelings of intense sadness, rumination about the loss, insomnia, poor appetite and
weight loss noted in Criterion A, which may resemble a depressive episode. Although such symptoms may be
understandable or considered appropriate to the loss, the presence of a major depressive episode in addition to the
normal response to a significant loss should also be carefully considered. This decision inevitably requires the exercise of
clinical judgment based on the individual’s history and the cultural norms for the expression of distress in the context of
loss.
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders: DSM-5–TR. 5th ed. Copyright 2022 American Psychiatric
Association.

[10]
Table 2: Monitoring Parameters for Depression​
Assessment Monitoring Parameter
Type
Baseline Highly recommended
assessments Conduct diagnostic work up/differential diagnosis including considering organic
causes of depression
Assess personal and family history including previous antidepressant use and alcohol,
tobacco and substance use and dependence
Review physical health, including body mass index and (whenever deemed
appropriate) waist circumference; metabolic syndrome; sexual health/dysfunction;
hypertension; alcohol, tobacco and substance use and dependence

Consider
Pregnancy test
Liver function test

Where indicated
Electrocardiogram for pre-existing cardiovascular disease
Bone density scan, especially when risk factors for osteoporosis are present
Electrolytes, especially in older patients

Ongoing Change compared to baseline

assessment Symptom changes, utilizing one of the assessment scales mentioned in Investigations
Weight and (where appropriate) waist circumference
Sexual dysfunction

Treatment-emergent adverse effects

Suicidal thinking, especially in transitional youth
Elevated serum transaminases
Hyponatraemia, especially in elderly

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Assessment Monitoring Parameter

Type
Hypertension; orthostatic hypotension

Special Special considerations are required for children, the elderly, patients during reproductive
populations events, and those with concurrent mental or physical disorders

Modified with permission from Dodd S, Mitchell PB, Bauer M et al. Monitoring for antidepressant-associated adverse events in the treatment of
patients with major depressive disorder: an international consensus statement. World J Biol Psychiatry 2018;19(5):330-48.

Therapeutic Choices
The main evidence for guideline-based treatment recommendations comes from studies of middle-aged patients;
however, MDD occurs across the lifespan and presents specific challenges that need to be addressed in children and
youth, people later in life, and patients in the perinatal and menopausal stages of life. The CANMAT 2016 clinical
guidelines for MDD summarize the treatment protocol for each of these stages.​[11]

The most impressive evidence for the success of pharmacologic and depression-specific psychological therapies, in
terms of both clinical efficacy and restoration of occupational functioning, comes from controlled trials involving
multifaceted health-system interventions.​[12][13]
​ These interventions, tested mostly in primary care settings, involve
primary care physicians working in conjunction with another health-care provider (e.g., pharmacist, nurse, psychologist,
psychiatrist); the prescriber initiates the antidepressants while the other practitioner educates the patient about
depression and monitors the progress during treatment.​[14][15]
​ Multifaceted interventions (nonpharmacologic and
pharmacologic) can substantially reduce long-term expense and increase the likelihood of the patient returning to work.​
[16][17][18][19][20]
​ ​ ​ ​ Unfortunately not all clinicians and patients have access to these resources.

Nonpharmacologic Choices

Psychotherapy
While pharmacotherapy is preferable in severe depression and also when comorbid personality disorders are
present, psychotherapies are as effective as medication for depression of mild to moderate severity.​[21]
Cognitive behavioural therapy (CBT), behavioural activation (BA) and interpersonal therapy (IPT) are
considered first-line recommendations for treating depression.​[21]

Each type of intervention has subtle advantages in specific circumstances, and patient preferences are
important to consider. Interpersonal therapy may be preferable when major interpersonal issues are present.
Newer versions of CBT and IPT have evolved and show particular promise: mindfulness-based CBT (mCBT) is
particularly effective in preventing relapse into depression​[22] and acceptance and commitment therapy (ACT)
has some efficacy in acute depression.​[23] It is also important to consider the significance of therapist cultural
competence in delivering care to racialized groups.​[24]

Technology-Based Psychotherapy

Cognitive behavioural therapy is also available on the internet and through mobile applications, in some
cases for a modest fee (e.g., BEACON, Beating the Blues, Moodgym and Living Life).​[25] Multiple meta-
analyses have demonstrated the efficacy of web-based CBT;​[26] unguided self-help may be less effective
than guided self-help, particularly in individuals with moderate-to-severe depression.​[27][28]
​ Patients should
be encouraged to complete the modules and simple homework exercises on these sites in tandem with
attending routine clinical care visits.

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Motivational Interviewing

Motivational interviewing is a type of psychotherapy intended to improve the patient’s motivation to change
problematic behaviour. It is strikingly effective for treatment of substance abuse when depression is also
present.​[21] Its effects are primarily on the substance abuse, not on the depressive symptoms.

Psychoeducation

In addition to psychotherapy, measures to enhance adherence to antidepressant therapy are useful.

Psychoeducation with the following 5 simple messages is effective:​[29]

Take medication daily.

Call your prescriber or pharmacist for questions about side effects or other issues.
Remember that it may take 2–4 weeks to see a noticeable effect from antidepressants.
Continue to take medication even if you are feeling better.
Do not stop taking your antidepressant without checking with your prescriber.

Other Nonpharmacologic Therapy

There is evidence for the benefit of regular physical exercise and yoga as monotherapy in mild to moderate
depression and as an adjunct to pharmacotherapy and/or psychotherapy in moderate to severe depression.​[30]​
[31] Although there are few well-controlled studies of diet modification in the treatment of depression, a proof-of-
concept RCT demonstrated feasibility of and positive outcomes for a dietary intervention that mainly reduced
refined and processed foods while increasing healthier options (e.g., fruits, vegetables, lean proteins,
nuts/seeds, olive oil).​[32]

Light therapy is considered a first-line option for MDD with a seasonal pattern or as an adjunct measure for
nonseasonal MDD of mild to moderate severity.​[30]​[33]​[34] In a randomized controlled trial, a combination of
fluoxetine and light therapy demonstrated higher remission rates than either modality alone in patients with
nonseasonal MDD.​[35] Light therapy involves exposure to a light box with 10 000-lux intensity slanted toward the
face for 30 minutes per day, preferably in the morning. Improvement in depressive symptoms usually occurs
within 1–3 weeks. Side effects of light therapy (e.g., headache, eye strain, irritability, insomnia) are usually mild
and do not lead to treatment discontinuation. These can be minimized by having patients start with 10–15
minutes of exposure per day and gradually increase to 30 minutes per day. Patients with eye conditions that
make them more vulnerable to light should check with their eye-care practitioner before starting light therapy.
Light boxes with UV filters are recommended.

Novel neurostimulation therapies are proliferating as adjunctive strategies to treat depression. These include
repetitive transcranial magnetic stimulation, magnetic seizure therapy and transcranial direct current stimulation,
which have increasingly been evaluated but are not routinely available.​[36][37]
​

Pharmacologic Choices
Figure 1 illustrates an algorithm for the pharmacologic management of depression with or without a remission of
symptoms.

Although diagnostic criteria for MDD and persistent depressive disorder (see Table 1) differ, recommendations for
the use of antidepressants are the same in both conditions. Table 3 lists first-, second- and third-line
antidepressants according to the 2016 CANMAT guidelines.​[38] Table 6 provides more details about the drugs used
to treat depression. A minimum therapeutic dose should be achieved in the first 2 weeks of treatment and increased
if necessary over the next 4–6 weeks. Patients need to be informed of common side effects and that some of these
unwanted effects usually subside within 2 weeks (see Table 4). Consider switching within the same class during

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weeks 3–8 if a favourable response is overshadowed by persistent and troublesome side effects that do not
respond to measures such as adjusting the dose or time of administration.

A network meta-analysis of 21 antidepressants involving over 100 000 patients confirmed superiority over placebo
for all included agents and identified the following agents as more effective than other antidepressants:
agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine and vortioxetine.​[39] When
acceptability (based on drop-out rates) was considered, the leading agents were agomelatine, citalopram,
escitalopram, fluoxetine, sertraline and vortioxetine. Based on this systematic review, agomelatine, escitalopram
and vortioxetine appear to be 3 of the most effective and well-tolerated options.​[40] Agomelatine is not available in
Canada.

A systematic review of observational studies involving more than 200 000 adults in mid- and late-life with moderate
to severe depression found that exposure to SSRIs reduced the risk of suicide by more than 40% and 50%, in the
respective age groups.​[41]

In contrast, regulatory authorities have issued cautions that highlight the potential of antidepressants to increase
suicidal ideation, particularly in children and young adults. Clinicians are faced with complex decisions about when
to use CBT and/or pharmacotherapy to treat depression in younger age groups and are advised to monitor patients
carefully for any emergent suicidal ideation or acts, particularly during the early phase of treatment.​[42] The risk of
emergent or worsening suicidal ideation must be weighed against the risks associated with untreated depression
(suicide, increased duration and severity of illness, higher incidence of relapse).

[38]
Table 3: CANMAT Classification of Antidepressants​
First-Line Agents​[a] bupropion Second-Line levomilnacipran
citalopram Agents​[a] moclobemide
desvenlafaxine quetiapine
duloxetine trazodone
escitalopram tricyclic antidepressants
fluoxetine (amitriptyline,
clomipramine,
fluvoxamine desipramine, doxepin,
mirtazapine imipramine, nortriptyline,
trimipramine)
paroxetine
vilazodone
sertraline
venlafaxine
Third-Line Agents​ phenelzine
vortioxetine [a]
tranylcypromine

[a] Within each category, antidepressants are listed in alphabetical order rather than in order of preference.

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs are first-choice antidepressants due to greater tolerability, ease of dosing and relatively low cost. Both
time to onset (2–4 weeks) and rate of response (60–70%) are comparable to tricyclic antidepressants (TCAs);
side effects mainly affect the GI tract, the CNS and sexual function.​[38] SSRIs can increase the risk of GI
bleeding, particularly in patients with additional risk factors such as concomitant NSAID therapy or a history of
GI bleeding. They should be used with caution in patients already at higher risk of GI bleeding.​[43] Unlike GI or
CNS side effects, sexual dysfunction is more likely to persist during SSRI therapy and can involve impairment of
desire, arousal and/or orgasm/ejaculation; there are also unsubstantiated reports of persisting sexual
dysfunction following discontinuation of SSRIs/SNRIs.​[44] Consider the importance of sexual function to the
patient when prescribing an antidepressant. Non-SSRI antidepressants that cause less sexual dysfunction (e.g.,
bupropion, mirtazapine, moclobemide) may be more acceptable for some patients.​[38]

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Six SSRIs are currently available in Canada (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine
and sertraline). Escitalopram, the stereoisomer of citalopram, has a similar side effect profile but superior
efficacy to citalopram​[45] and is at least as effective as venlafaxine.​[46] With the exception of fluoxetine, all
SSRIs are commonly associated with discontinuation effects when stopping therapy. See Antidepressant
Discontinuation Syndrome for more information. These effects can be severe and protracted in a small
proportion of patients. Patients should be assessed regularly during and after treatment discontinuation for
withdrawal symptoms and relapse.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Venlafaxine has inhibitory effects on serotonin reuptake at any therapeutic dose. At doses of >150 mg daily, it
also inhibits norepinephrine reuptake. Compared with SSRIs, rates of remission have been reported to be 6–
10% higher with venlafaxine, although these results are mainly based on comparisons with fluoxetine.​[47][48]
​
Dose-related hypertension occurs rarely and is more likely to be seen at doses ≥225 mg. Monitor BP and avoid
use in patients with uncontrolled hypertension.

Desvenlafaxine is the active metabolite of venlafaxine and may have a decreased risk of serious drug
interactions. In the treatment of depression, the response and remission rates are comparable to venlafaxine.
Desvenlafaxine is one of the few antidepressants to have been systematically evaluated and found to be
efficacious in peri- and postmenopausal patients.​[49] Common adverse effects include insomnia, somnolence,
dizziness and nausea.​[50][51]
​

Duloxetine appears to exert effects on both serotonin and norepinephrine systems at the starting dose of 60
mg daily and has comparable efficacy to venlafaxine.​[52] In addition to depression, duloxetine is indicated for
neuropathic pain and for pain associated with fibromyalgia. Isolated cases of hepatic injury have been reported
but there is no requirement for routine monitoring of liver enzymes. It is primarily metabolized by CYP1A2, of
which tobacco smoke is a potent inducer; therefore, cigarette smokers are likely to have lower plasma levels
and may require higher dosing of duloxetine.​[53]

Levomilnacipran has higher potency for norepinephrine than serotonin reuptake inhibition (2:1). In the
treatment of depression, the response and remission rates were 45% and 28%, respectively. Common adverse
effects include nausea, headache, dry mouth, hyperhidrosis, constipation and dizziness. Blood pressure and
heart rate may increase and should be carefully monitored.​[54]

Dual Action Antidepressants

Bupropion is thought to exert antidepressant effects through norepinephrine and dopamine reuptake inhibition.​
[55] It is a first-line agent for MDD and is also indicated for smoking cessation under a different brand name.​[56]
Bupropion lowers the seizure threshold in a dose-dependent manner. It is contraindicated in patients with a
seizure disorder or recent history of anorexia or bulimia nervosa, and should be used with extreme caution
where there is a history of head trauma or seizure. Patients should be aware that the use of the medication with
alcohol may lower seizure threshold. Treatment-emergent GI disturbance and sexual dysfunction occurs less
frequently with bupropion compared with SSRIs.​[57]

Mirtazapine acts on both the noradrenergic and serotonergic systems. It has a lower rate of GI and sexual side
effects but is associated with sedation and weight gain.​[58]

Other Serotonin Modulators

Trazodone is a potent postsynaptic serotonin (5-HT2) receptor antagonist with weak serotonin reuptake
inhibitory effects.​[59] Because of severe daytime sedation, trazodone is rarely prescribed at therapeutic
antidepressant doses (300–400 mg daily) but is often prescribed at lower doses (50–100 mg) as a hypnotic in
combination with other antidepressants.​[60] Tolerance, as seen with benzodiazepines, does not develop with
trazodone and there is the potential for trazodone to enhance antidepressant effects.

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[61]
Vortioxetine is a novel serotonergic antidepressant;​ its mechanism of action is thought to involve a
combination of direct 5-HT receptor modulation and serotonin transporter (SERT) inhibition. In patients with
MDD, vortioxetine has also shown positive effects on neuropsychological performance in multiple cognitive
domains.​[62] In clinical trials, the most common side effects were GI-related. Mild to moderate nausea, typically
in the first week of treatment, is usually self-resolving. The incidence of treatment-emergent sexual dysfunction
and disrupted sleep may be lower with vortioxetine compared with SSRIs.​[63] However, patients should still be
monitored for these adverse effects.

Vilazodone is a multimodal antidepressant that acts as a serotonin reuptake inhibitor and a partial agonist at 5-
HT1A. Vilazodone should be taken with food to ensure adequate absorption and a titration schedule is
recommended to avoid GI effects. Nausea, diarrhea and headache are the most prominent adverse effects.
Sexual side effects occur less frequently with vilazodone compared to SSRIs.

Tricyclic Antidepressants
Tricyclic antidepressants (TCAs) are generally reserved as second-line medications; their mechanism involves
inhibition of the reuptake of norepinephrine and/or serotonin to varying degrees. Amitriptyline is the most
frequently prescribed TCA, often at considerably lower doses of 25–50 mg per day for nighttime sedation or
analgesia. Nortriptyline, a metabolite of amitriptyline and a secondary amine, has been used to treat
depression in older populations for many years. Clomipramine, the most serotonergic TCA, is still favoured in
the treatment of obsessive compulsive disorder. In all cases, TCA use is limited by tolerability and safety
concerns, especially cardiotoxicity following overdose.

Monoamine Oxidase Inhibitors

Prescribing irreversible MAOIs phenelzine and tranylcypromine is generally reserved for specialized mood
disorder clinics because these agents are associated with potentially fatal food and drug interactions
(hypertensive crisis, serotonin syndrome). Nevertheless, all prescribers and pharmacists should be aware of
these risks and how they can be avoided when faced with a patient taking an irreversible MAOI. Despite the
potential risks, under careful conditions, MAOIs may prove effective where other antidepressants have failed.

Moclobemide, a reversible and selective MAO-A inhibitor, does not require dietary restrictions when prescribed
within the recommended dose range. Moclobemide is a well-tolerated alternative to SSRI or SNRI agents,
particularly in patients with a significant anxiety component to their depressive episode. Although moclobemide
is often perceived as being less effective than irreversible MAOIs, this has not been substantiated in clinical
trials.

Antidepressant Adverse Effects

[38][64][65][66][67][68][69]
Table 4: Management of Treatment Emergent Adverse Effects of Antidepressant Therapy​
[70]

The adverse effects listed in this table may occur with all antidepressants unless otherwise stated. The
individual agents identified below are among the more commonly used antidepressants that have the
highest prevalence of the listed adverse effect. Incidence rates are included when available.
General management: If adverse effects are severe, persist for longer than 2 weeks or are
intolerable to the patient, consider (1) lowering dose or (2) switching agent.

Adverse Effect Management Prevalence

GI upset (nausea, Usually diminishes after 1–2 wk Nausea: fluvoxamine (37%),

constipation, diarrhea) of therapy venlafaxine (37%), paroxetine (26%),
Nausea: once-daily dosing; take sertraline (26%), vilazodone (24%),
with food; have small, frequent vortioxetine (23%), citalopram (21%),
meals; avoid strong smells desvenlafaxine (22%), fluoxetine (21%),
duloxetine (20%)
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Constipation: increase fibre Constipation: fluvoxamine (18%),
intake, fluids, laxatives, exercise venlafaxine (15%), paroxetine (14%),
Diarrhea: have small, frequent duloxetine (11%)
meals; take probiotics; limit Diarrhea: vilazodone (29%),
caffeine, alcohol, spicy food; sertraline (18%), paroxetine (11%)
fluid replacement

Activation (anxiety, Usually diminishes after 1–2 wk Nervousness: fluoxetine (14%),

nervousness, agitation) of therapy venlafaxine (10%)
Consider short-term use of Anxiety: fluoxetine (12%)
benzodiazepines only for Agitation: fluvoxamine (16%)
extreme anxiety; avoid use
whenever possible.
Severe agitation could be
indicative of intolerance to SSRI
therapy; switch to a different
drug class

Somnolence Usually diminishes after 1–2 wk Mirtazapine (54%), fluvoxamine (26%),

of therapy paroxetine (23%), venlafaxine (17%),
Bedtime dosing fluoxetine (13%), sertraline (13%)

Insomnia Usually diminishes after 1–2 wk Venlafaxine (17%), bupropion (16%),

of therapy fluoxetine (16%), sertraline (16%),
Daytime dosing fluvoxamine (14%), paroxetine (13%),
duloxetine (11%)
Consider short-term use of
hypnotic (e.g., benzodiazepines
and Z-drugs) only for severe
cases; avoid use whenever
possible. Lemborexant may be
considered.
Counsel on sleep hygiene

Weight gain Antidepressants are associated Amitriptyline (>30%), citalopram (>2%),

with >5% weight gain, sustained duloxetine (>2%), fluoxetine (>2%),
over >5 y mirtazapine (>30%), paroxetine (>10%),
Counsel on healthy diet and sertraline (>2%), trazodone (>2%),
exercise routine, monitor weight venlafaxine (>2%)
and metabolic parameters (BP,
lipid, glucose)
Consider switching to
bupropion, which is usually
associated with weight loss

Sexual dysfunction Improvement in sexual function All SSRIs and SNRIs are associated with
usually occurs in patients who a high risk of sexual dysfunction
achieve remission of depression Limited evidence suggests paroxetine
Consider starting PDE5 inhibitor may have the highest prevalence
in male patients Risk of erectile dysfunction may be
Consider switching to higher with SNRIs vs. SSRIs​[71]
antidepressants least
associated with sexual
dysfunction: bupropion,

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mirtazapine, vilazodone,
vortioxetine

Serotonin syndrome Stop the drug(s) and refer Rare, and may occur when multiple
(dilated pupils, patient to the hospital serotonergic agents are used
hyperreflexia, MAOIs have the highest risk and require
sweating, fever, a minimum 2-wk washout period before
agitation, nystagmus, another serotonergic agent is initiated
clonus, delirium)
Amitriptyline, mirtazapine and trazodone
are unlikely to cause serotonin syndrome

Abbreviations:
MAOI = monoamine oxidase inhibitor; PDE5 = phosphodiesterase 5; SNRI = serotonin norepinephrine reuptake
inhibitor; SSRI = selective serotonin reuptake inhibitor

Antidepressant Discontinuation Syndrome

Rapid discontinuation or dose reduction of most antidepressants may be associated with discontinuation
syndrome.​[72] This syndrome is often reported with SSRIs, likely because these drugs are the most frequently
prescribed, but any antidepressant taken for 6 weeks or more may be associated with discontinuation-related
symptoms. Patients taking agents with a shorter half-life (e.g., paroxetine, venlafaxine) are at greatest risk of
discontinuation-emergent symptoms, which include anxiety, crying, headache, increased dreaming, insomnia,
irritability, myoclonus, nausea, electric shocks, tremor, flulike symptoms, imbalance and sensory disturbance.

Patients experience somatic, neurologic and psychological symptoms attributed to a rapid decrease in the
availability of 5-HT​[73] within 1–7 days of stopping the drug. If untreated, symptoms typically last between 3 days
and 3 weeks, but may occasionally persist for several months.​[74]

Inform patients that discontinuation syndrome may occur if they abruptly stop or reduce the dose of their
medication. Taper antidepressant doses gradually by approximately 25% per week and monitor for a re-
emergence of depressive symptoms.​[72] Fluoxetine has a long half-life and can be tapered more rapidly than
other SSRIs.

Reassure patients who experience discontinuation syndrome that the condition is not serious or life-threatening
and severe symptoms will usually resolve in 3 days or less. The syndrome can be reversed by restarting the
antidepressant and tapering the dose more slowly. Alternatively, if a slow taper is poorly tolerated, substitute
with 1 dose of fluoxetine 10–20 mg PO. If discontinuation-emergent symptoms have not resolved after several
days, additional doses of fluoxetine 20 mg may be taken if necessary; a total of 3 doses spread over 7–10 days
is considered acceptable. Consider a herbal product containing ginger if drug interactions or adverse effects
limit use of other possible antinausea medications (see Nausea and Vomiting).​[75]

There is some evidence that cognitive or mindfulness-based therapies combined with tapering may lessen the
discontinuation-emergent effects.​[76][77]
​ Another novel approach used in the Netherlands involves the use of
extemporaneously packaged pills in dose decrements as small as 0.5 mg to be used over several weeks.​[78]

Atypical Antipsychotics
Extended-release quetiapine, a second-generation or “atypical” antipsychotic agent, has been approved in
Canada for the treatment of depression and is considered to be a second-line option.​[38][79] ​ Immediate-release
quetiapine is also used (off-label) for this indication but is associated with greater sedation.​[80]

Aripiprazole and brexpiprazole are approved as adjuncts to antidepressants in adults with MDD who have not
had an adequate response to an antidepressant alone during the current episode. Olanzapine and risperidone
are also used (off-label) for treatment-resistant depression.
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Response to antipsychotics should generally be observed within 2 weeks of initiation. See Treatment-Resistant
Depression for information regarding the role of antipsychotics in the treatment of depression.

Natural Health Products

Several natural health products have been evaluated for the treatment of depression. It is important to consider
potential drug interactions with these products since many should not be used in combination with prescription
antidepressants. See Table 6 for more information.

There is some evidence to support St. John’s wort as a potential monotherapy option for patients with MDD of
mild to moderate severity.​[30][81]
​ As an inducer of CYP3A4 and P-glycoprotein, St. John’s wort can decrease the
bioavailability of many drugs. When combined with other serotonergic medications, there is an increased risk of
serotonin syndrome. Consider potential interactions before recommending this agent.

S-adenosylmethionine (SAM-e), a synthetic form of a dietary amino acid, has been evaluated as adjunctive
and monotherapy with limited evidence to support its use in MDD.​[81] SAM-e is well tolerated with few adverse
effects, but may be associated with an increased risk of serotonin syndrome when combined with other
serotonergic drugs.

Omega-3 fatty acids have been recommended as second-line therapy for the treatment of mild to moderate
depression.​[30] However, a meta-analysis suggests that the evidence to support their use is of low quality and
the benefits are not clinically significant.​[82]

Studies have looked at the efficacy of supplementation with folic acid and vitamin D for depression in adults.
Folic acid was not effective when used to augment antidepressant medications;​[83] however, adjunctive L-
methylfolate, a form of folate that crosses the blood–brain–barrier, 15 mg/day showed significantly greater
efficacy as adjunctive therapy with SSRIs compared with SSRIs alone.​[84] There is preliminary evidence that L-
carnosine, a polypeptide with antioxidant properties, may produce favourable antidepressant augmentation
effects.​[85] Despite the low quality of evidence and need for more robust studies, a systematic review
determined that vitamin D supplementation in adults with depression had no significant effect.​[86]

Rapid-Acting Therapy
Rapid-acting therapy is an emerging therapeutic class for the treatment of depression; these are treatments that
yield improvement in symptoms within days and may be given for a short duration. These agents are part of a
paradigm shift in the treatment of depression, particularly treatment-resistant depression. Examples include
NMDA-modulators​[87] (ketamine, esketamine, dextromethorphan/bupropion​[88]), GABAA-modulators
(brexanolone​[89], zuranolone​[90]) and the Stanford TMS protocol. Ketamine and esketamine are available in
Canada; brexanolone and dextromethorphan/bupropion are available in the U.S.

Duration of Treatment—Relapse Prevention

Experts recommend the use of maintenance antidepressant therapies for a minimum period of 9 months,
particularly when the intervals between depressive episodes become shorter and the disability associated with each
depressive episode worsens. After achieving remission in a first episode, treat for 9 months. Patients may be at risk
of recurrence if they have psychiatric or other comorbidities; residual symptoms; or if episodes are frequent,
recurrent, chronic, severe or difficult to treat (see Figure 1). In these cases, treat for at least 2 years. Long-term
maintenance treatment may also be considered.​[91]

In general, taper antidepressants slowly to minimize the risk of discontinuation-emergent symptoms. See
Antidepressant Discontinuation Syndrome for more information.

Cognitive behavioural therapy and IPT may also be effective in reducing the risk of relapse.​[21][92]
​

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Treatment-Resistant Depression
The current concept of treatment-resistant depression (TRD) emphasizes failure to respond after 2 or more
treatments of adequate dose and duration, assuming that medications were prescribed at optimal doses and for
adequate duration prior to diagnosis.​[93] However, the definition may vary according to the planned intervention,
e.g., the definition of TRD for an individual to receive CBT for TRD may be set at a lower threshold than for deep
brain stimulation. Furthermore, there is a proposal to change the term to difficult-to-treat depression, as TRD may
imply a resistance by the patient.​[94]

Antidepressants can be switched either within a medication class or to a different class. Most physicians switch out
of class, e.g., from SSRI to SNRI or TCA, when there has been no response to the first drug. Consider switching
within a class in the presence of a favourable clinical response hampered by persistent, unmanageable side effects.
For more information on switching between antidepressants see Table 5.

Table 5: Switching Antidepressants

Switching From Switching To Generally Recommended Washout Period​[a]

Most Most Generally there is no need for a washout period; a crossover

antidepressants antidepressants technique can be applied whereby the dose of the first agent is
tapered while the dose of the new antidepressant is gradually
increased. Clomipramine is generally not recommended in cross-
tapers; other exceptions are listed below. For specific cross-
tapering instructions, consult specialized resources such as
SwitchRx.ca.

Any other Irreversible MAOI 5 half-lives of first antidepressant (3 wk for clomipramine and
antidepressant or moclobemide imipramine)

Irreversible MAOI Any other 2 wk (3 wk for clomipramine or imipramine)

antidepressant

Moclobemide Any other 5 days

antidepressant

Fluoxetine Irreversible MAOI 5–6 wk

or moclobemide

Fluoxetine Any other Use caution after fluoxetine discontinuation due to its long half-
antidepressant life. A washout period is often recommended, depending on the
new agent.

Abbreviations:
MAOI = monoamine oxidase inhibitor

[a]
Recommendations are for general guidance only. For instructions specific to a patient scenario, consult specialized
references such as SwitchRx.ca.

Augmentation or combination therapy is recommended when a patient tolerates the first antidepressant but has
only a partial response.​[38] Furthermore, for moderate-severe depression, or refractory depression, combination
therapy should be strongly considered, particularly in individuals with a history of more than 3 previous depressive
episodes.​[95] Two meta-analyses involving 48 and 65 trials, respectively, supported augmentation for treatment-
resistant depression; options include atypical antipsychotics (specifically aripiprazole, olanzapine, quetiapine,
risperidone, brexpiprazole and cariprazine), liothyronine, nortriptyline, lithium, modafinil and
lisdexamfetamine).​[96][97]
​ Antipsychotic augmentation is not recommended for long-term use, and close
monitoring for movement disorders, weight gain and cardiometabolic effects is indicated. There is some evidence
for increased mortality risk in non-elderly patients who receive augmentation with atypical antipsychotics.​[98]
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[99][100]
The combination of bupropion with SSRIs is also an option.​ ​

There is considerable interest in using intravenous ketamine or intranasal esketamine, NMDA receptor
antagonists, as rapidly acting interventions for treatment-resistant depression.​[101] This represents a new avenue of
therapeutic exploration, highlighting the relevance of the glutamatergic system to TRD.

Intranasal esketamine is approved in Canada for the treatment of TRD in combination with an SSRI or SNRI.​[102] It
is available only through a controlled distribution program to ensure that all involved parties are trained on proper
administration and monitoring.

Most evidence supports the efficacy of ketamine as a rapid-acting intervention.​[87] To date, most reports have been
limited to short-term therapy, and the duration of therapy remains unclear. In 2021, CANMAT recommended a one-
time dose of ketamine as a third-line option for TRD.​[87] While most ketamine clinics are not covered by health
insurance, a few hospital-based centres do provide ketamine infusion treatment at no cost to the patient.

Among nonpharmacologic options, there is evidence to support adjunctive CBT in treatment-resistant depression.​
[103]
Neurostimulation therapies such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic
stimulation (rTMS) can be used in the management of treatment-resistant depression;​[37] however, a discussion
about their use is beyond the scope of this chapter.

Choices during Pregnancy and Breastfeeding

Depression during Pregnancy

During pregnancy, symptoms of depression are common and can be challenging to disentangle from symptoms
frequently reported during pregnancy (fatigue, sleeplessness, appetite changes). Perinatal depression is one of the
most common complications of pregnancy​[104] and is a risk factor for suicide and infanticide.​[105][106] Pregnant
patients with a history of depression or with current depressive symptoms should receive preventative interventions
such as counselling.​[107]

The decision to initiate or continue antidepressant treatment during pregnancy should be based on a risk-benefit
analysis that considers both the fetus and the pregnant patient. Untreated depression in pregnant patients is
associated with untoward effects for the fetus/neonate, patient and others.​[108][109]
​ [110]
​ [111]
​ [112]
​ If untreated,
symptoms of depression may continue into the postpartum period or reoccur as postpartum depression.​[113][114]
​

Patients with a history of severe or recurrent depression who discontinue antidepressants during pregnancy may be
at increased risk of relapse.​[115] Discontinuing antidepressants during pregnancy may increase risk of exacerbated
anxiety and psychiatric emergency during the perinatal period.​[116][117]

Management
If symptoms are mild or if criteria for a mild-moderate depressive episode are met, psychotherapy (such as IPT
and CBT) is the first treatment option.​[11][118]
​ For moderate-severe episodes, antidepressant medication should
be considered first line, especially in patients with a past history of depression.​[11][119]
​ Although a dose-
dependent relationship has not been elucidated, if antidepressants are prescribed during pregnancy, use the
lowest effective dose. As this area is actively evolving, clinicians are advised to consult a drug information
service for the most up-to-date information (e.g., MotherToBaby.org).

Risks of Antidepressants During Pregnancy

Evidence suggests that SSRIs are not major teratogens. Although a statistical association may exist
between cardiovascular malformations (e.g., septal defects) and fetal exposure to SSRIs, recent studies

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controlling for confounding factors do not support this association.​[120][121]

​ [122]
​ SSRI exposure late in
pregnancy may be associated with an increased risk of persistent pulmonary hypertension in the newborn.​
[123][124][125]
​ ​ Paroxetine and fluoxetine may have higher associated risks than other SSRIs; see
Pharmacologic Choices During Pregnancy.

Poor neonatal adaptation syndrome is typically transient neonatal withdrawal and/or toxicity after exposure
to antidepressants in utero. Signs and symptoms include tremors, shaking, irritability, increased muscle tone,
sleeping disturbances and respiratory distress; more severe symptoms have also been reported.​[126][127]
​
Although reports of incidence vary from 5–85%, likely due to lack of a standardized definition, up to about
30% is typical.​[128]

Adverse delivery outcomes (e.g., preterm birth, low birth weight) have also been statistically associated with
antenatal antidepressant use, although the clinical relevance is not certain.​[129][130]
​ [131]
​

The relationships between perinatal exposure to antidepressants and incidence of autism and attention
deficit hyperactivity disorder have been the topic of great debate; however, the evidence is not strong
enough to draw clear conclusions. Studies examining the effect of antidepressant exposure on growth and
development of brain, language, and cognition also have inconsistent findings that are confounded by
maternal psychopathology.​[132] The Canadian Paediatric Society 2021 position statement summarizes the
evidence and concludes that overall “...the risk of serious adverse effects from exposure to SSRIs or SNRIs
in utero is low.”​[133]

With regards to risks to the pregnant patient, antidepressants have been associated with maternal
hypertension/pre-eclampsia, postpartum hemorrhage, and caesarean section.​[134][135]
​ Studies, however,
have not been consistent in their findings.​[136]

Pharmacologic Choices During Pregnancy

If pharmacologic therapy is indicated, citalopram, escitalopram and sertraline are first-line options.​[11]
Fluoxetine is a second-line option since its association with major malformations is more controversial.​[11]​
[120]
Paroxetine has been associated with risk for major malformations, and although the clinical magnitude
is questionable, it is still not recommended for perinatal depression, unless the patient was stable on it prior
to conception.​[11][137]
​ [138]
​

Second-line options in the treatment of perinatal depression include bupropion, desvenlafaxine, duloxetine,
fluoxetine, fluvoxamine, mirtazapine, TCAs (e.g., amitriptyline, imipramine and nortriptyline) and venlafaxine.​
[11]
MAOIs and doxepin should be avoided during pregnancy. Clomipramine should be considered only if the
patient was stabilized on it prior to conception. Other antidepressants have not been studied sufficiently in
pregnancy to make recommendations on their use (e.g., trazodone, vilazodone, vortioxetine,
levomilnacipran).

Postpartum Mood Disturbances

Postpartum mood disturbances is a term that encompasses the following 3 presentations: postpartum “blues,”
which affect up to 80% of patients after a pregnancy,​[139] postpartum major depression, which occurs in up to 16%
of patients in Canada after a pregnancy and postpartum psychosis, which occurs in ≤0.1%.​[140][141]
​ [142]
​

The blues are not a disorder per se, given that they are so common and symptoms are self-limiting, requiring only
monitoring and supportive care. However, patients with postpartum blues are at risk of developing a depressive
episode.

Management
Psychotherapy, preferably IPT or CBT, should be considered first for the treatment of postpartum depression,
particularly if the patient is breastfeeding. When the illness is more severe, psychotherapy may be inadequate
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or inappropriate, in which case antidepressant treatment should be initiated. For breastfeeding patients, the
2016 CANMAT guidelines on MDD recommend consideration of sertraline, escitalopram or citalopram as
first-line pharmacologic options;​[11] this recommendation remains current. Second-line options include
fluoxetine, paroxetine and nortriptyline. Other antidepressants lack sufficient data in breastfeeding patients.
Doxepin is not recommended due to documented significant adverse effects in the breastfed infant.
Brexanolone, a novel agent requiring an extended infusion, has been approved by the FDA for the
management of postpartum depression; it is not available in Canada.​[143]

A discussion of general principles on the use of medications in these special populations can be found in Drugs
Use during Pregnancy and Drug Use during Breastfeeding. Other specialized reference sources are also
provided in these appendices.

Therapeutic Tips
Prescribers should choose 1 or 2 agents from several antidepressant classes and use them consistently to
acquire expertise in the use of those medications.
Individualize therapy by considering patient comorbidities and most significant symptoms of depression (e.g.,
sleep disturbances, cognitive dysfunction, anxiety, somatic symptoms); see the Antidepressant Decision Support
Tool developed in 2022 to help guide selection.
Before prescribing an antidepressant, discuss side effect profiles, drug-drug interactions and discontinuation-
emergent side effects with the patient.
Provide key psychoeducational messages (as noted in Nonpharmacologic Choices) with the initial prescription.
Reinforce and add to this during regular follow-up visits.
A combination of pharmacotherapy and psychotherapy (specifically IPT or CBT) is superior to either modality
alone. In mild to moderate cases, combination therapy provides little synergy compared to either treatment alone,
but does provide protection against early relapse compared to either treatment alone. Pharmacotherapy typically
facilitates more rapid relief of symptoms, but does not prevent relapse if the medication is stopped; both IPT and
CBT reduce relapse for up to 3 years after completion of a course of psychotherapy.
Reinforce the importance of maintenance therapy beyond the acute phase.
There is a limited role for therapeutic drug-level monitoring as there is a poor correlation between serum levels of
SSRI or SNRI antidepressants and clinical response or side effects. Similarly, there is only a limited benefit in
performing pharmacogenetic testing for cytochrome P450 enzyme polymorphisms. Pharmacogenetic testing is,
however, warranted in cases such as a failure to respond to high doses of several antidepressants (which may
suggest that the patient is an ultra-rapid metabolizer) or repeated inability to tolerate low doses of several agents
(which may suggest a poor metabolizer status).
In nonresponders, review alcohol and drug abuse history, assess medication adherence and confirm diagnosis.
Refer for psychiatric consultation if the patient has psychotic symptoms or acute suicidal ideation, or after failure
of 3 treatment trials.
When discontinuing antidepressants, taper slowly over 4–6 weeks. This is particularly important for paroxetine
and venlafaxine.

Resources
General patient education: CANMAT or Moodgym or self-help books such as Mind Over Mood​[144] or Feeling Good.​
[145] Patients may also consult The Choice-D Patient and Family Guide to Depression Treatment, which translates the
CANMAT MDD guidelines into patient-friendly advice.

Patient information on drug interactions and dietary restrictions: Medication InfoShare links to pamphlets about
serotonin syndrome and food and drug interaction information for patients taking irreversible MAOI therapy.

Patient information pamphlet on stopping antidepressants: Medication InfoShare.

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Algorithms
[38]
Figure 1: Pharmacologic Treatment of Depression​

Abbreviations: CBT = cognitive behavioural therapy; ECT = electroconvulsive therapy; IPT = interpersonal
psychotherapy; rTMS = repetitive transcranial magnetic stimulation

Drug Table
Table 6: Drug Therapy for Depression
Drug/​Cost[a] Dosage Adverse Effects[b] Drug Interactions

Drug Class: Antipsychotics, second-generation

aripiprazole 2–15 mg daily PO All antipsychotics: Advise Strong inducers of CYP2D6

Abilify, generics Indication: patients about or CYP3A4 (e.g.,
augmentation of antipsychotic-associated carbamazepine, phenytoin,
< $30 body temperature rifampin) can decrease
standard
antidepressants dysregulation and aripiprazole levels
prevention of heat stroke, substantially.
e.g., hydration, sun Strong inhibitors of CYP2D6
protection. or CYP3A4 (e.g.,
Aripiprazole: EPS, ketoconazole, quinidine,
dizziness, orthostatic fluoxetine, paroxetine) can
hypotension, headache, increase aripiprazole levels
GI complaints, substantially.
nasopharyngitis, tremor,
sedation, insomnia.

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Drug/​Cost[a] Dosage Adverse Effects[b] Drug Interactions

brexpiprazole 1–3 mg daily PO All antipsychotics: Advise Strong inducers of CYP2D6

Rexulti Indication: second-line patients about or CYP3A4 (e.g.,
option for antipsychotic-associated carbamazepine, phenytoin,
$90–120 augmentation of body temperature rifampin) can decrease
standard dysregulation and aripiprazole levels
antidepressants prevention of heat stroke, substantially.
e.g., hydration, sun Strong inhibitors of CYP2D6
protection. or CYP3A4 (e.g.,
Brexpiprazole: weight ketoconazole, quinidine,
gain, hyperglycemia, fluoxetine, paroxetine) can
elevated triglycerides, increase aripiprazole levels
EPS (appears to be less substantially.
common than with
aripiprazole), headache,
orthostatic hypotension
(rare).

olanzapine 2.5–10 mg daily PO All antipsychotics: Advise Sedation with CNS

Zyprexa, Zyprexa Indication: patients about depressants; may potentiate
Zydis, Olanzapine, augmentation of antipsychotic-associated antihypertensive drug effects;
Olanzapine ODT, standard body temperature inhibitors of CYP1A2 or
other generics antidepressants dysregulation and CYP2D6 (e.g., diltiazem,
prevention of heat stroke, fluvoxamine, paroxetine) may
< $30 e.g., hydration, sun increase olanzapine levels;
protection. inducers of CYP1A2 or
Olanzapine: weight gain, CYP2D6 (e.g., barbiturates,
dizziness, sedation, carbamazepine, phenytoin,
anticholinergic effects, rifampin or cigarette smoking)
hepatic aminotransferase may decrease olanzapine
elevation, orthostatic levels.
hypotension, increased
risk of diabetes and
dyslipidemia, EPS
(especially akathisia).

quetiapine, extended- Initial: 50 mg daily PO All antipsychotics: Advise Sedation with CNS
release for 2 days, then patients about depressants; may potentiate
Seroquel XR, 150 mg daily; if antipsychotic-associated antihypertensive drug effects;
generics necessary, can body temperature inhibitors of CYP1A2 or
increase to 300 mg on dysregulation and CYP2D6 (e.g., diltiazem,
< $30 or after day 4 prevention of heat stroke, fluvoxamine, paroxetine) may
Usual: 150 mg/day PO e.g., hydration, sun increase olanzapine levels;
protection. inducers of CYP1A2 or
High: 300 mg/day PO Quetiapine: sedation, CYP2D6 (e.g., barbiturates,
Indication: low doses dizziness, weight gain, carbamazepine, phenytoin,
(25–100 mg) can be orthostatic hypotension, rifampin or cigarette smoking)
used to augment hepatic transaminase may decrease olanzapine
standard elevation, headache, levels.
antidepressants. anticholinergic effects,
Higher doses increased risk of diabetes
(150–600 mg) may be and dyslipidemia,
prescribed as possible increased risk of
monotherapy or in cataracts; may reduce
combination based on thyroid hormone levels.
tolerability

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Drug/​Cost[a] Dosage Adverse Effects[b] Drug Interactions

risperidone 0.25–2 mg daily PO All antipsychotics: Advise Additive sedation with CNS
Risperdal, Apo- Indication: patients about depressants; may potentiate
Risperidone, augmentation of antipsychotic-associated antihypertensive drug effects;
Risperidone, other standard body temperature inhibitors of CYP3A4 (e.g.,
generics antidepressants dysregulation and clarithromycin, erythromycin,
prevention of heat stroke, grapefruit juice, ketoconazole,
< $30 e.g., hydration, sun prednisone) may increase
protection. risperidone levels; inducers of
Risperidone: sedation, CYP3A4 (e.g.,
headache, weight gain, carbamazepine, phenytoin,
orthostatic hypotension, rifampin) may decrease
rhinitis, anxiety, dose- risperidone levels.
related
hyperprolactinemia, EPS.
Risk of intraoperative
floppy iris syndrome in
patients undergoing
cataract surgery who
have been exposed to
risperidone.

Drug Class: Dual Action Antidepressants

bupropion SR formulation (doses Agitation, insomnia, Use with MAOIs, linezolid or

Wellbutrin SR, >150 mg/day PO anorexia; contraindicated methylene blue may lead to
Wellbutrin XL, should be given in in anorexia or bulimia potentially fatal reaction
Bupropion SR, Odan divided doses): nervosa and seizure initially presenting with tremor,
Bupropion SR, other disorders. agitation, hypomania,
Initial:​[c] 150 mg/day
generics hyperthermia and/or
PO
hypertension.
< $30 Usual: May increase levels of
150–300 mg/day PO cyclophosphamide, ifosfamide
and orphenadrine.
High:​[d]
375–450 mg/day PO
XL formulation (given
once daily):
Initial:​[c] 150 mg/day
PO
Usual:
150–300 mg/day PO
High:​[d] 450 mg/day
PO

mirtazapine Initial:​[c] 15–30 mg/day Weight gain, sedation. Use with MAOIs, linezolid or
Remeron, Remeron PO methylene blue may lead to
RD, Auro- potentially fatal reaction
Usual: 30–45 mg/day
Mirtazapine, Auro- initially presenting with tremor,
PO
Mirtazapine OD, agitation, hypomania,
Mirtazapine, other High:​[d] 60 mg/day PO hyperthermia and/or
generics hypertension.
Sedative effects may be
< $30 potentiated by alcohol or
benzodiazepines.

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Drug/​Cost[a] Dosage Adverse Effects[b] Drug Interactions

QTc prolongation and
torsades de pointes have
occurred in patients at risk of
QTc prolongation, in patients
taking concomitant
medications that prolong QTc
and in cases of drug
overdose.
Orally disintegrating tablets
can be taken without water.

Drug Class: Irreversible Monoamine Oxidase Inhibitors

phenelzine Initial:​[c] 15–30 mg/day Edema, postural Many significant reactions

Nardil PO hypotension, insomnia, reported. Increased risk of
sexual dysfunction. potentially fatal serotonin
$30–60 Usual: 30–75 mg/day
syndrome and/or
PO
hypertensive crisis. Consult
High:​[d] reliable drug information
90–120 mg/day PO reference; tyramine-
containing food may also
cause hypertensive crisis (see
Resources).

tranylcypromine Initial:​[c] 10–20 mg/day Edema, postural Many significant reactions

Parnate PO hypotension, insomnia, reported. Increased risk of
sexual dysfunction. potentially fatal serotonin
Usual: 20–60 mg/day
$30–60 syndrome and/or
PO hypertensive crisis. Consult
High:​[d] 60–80 mg/day reliable drug information
PO reference; tyramine-
containing food may also
cause hypertensive crisis (see
Resources).

Drug Class: NMDA Receptor Antagonists

esketamine [e]
​ Initial: 28–56 mg Anxiety, dissociation, Excess sedation with CNS
Spravato intranasally twice sedation, headache, depressants; may require
weekly. Wk 1–4: may dizziness, vertigo, dosage adjustments and/or
$275/28 mg unit increase by 28 mg hypoesthesia, dysgeusia, closer monitoring. Alcohol
increments up to nausea, vomiting, consumption is not
84 mg twice weekly. increased BP. recommended within 24 h of
Wk 5–8: decrease to administration. Risk of
once weekly. From wk hypertensive crisis with other
9: may decrease to drugs that increase BP (e.g.,
Q2 wk amphetamine salts, MAOIs,
Usual: 56–84 mg methylphenidate, triptans);
intranasally Q1–2 wk avoid combination or monitor
BP closely. Avoid using other
nasal sprays within 1 hr of
administration.

Drug Class: Reversible Monoamine Oxidase-A Inhibitors

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Drug/​Cost[a] Dosage Adverse Effects[b] Drug Interactions

moclobemide Initial:​[c] Nausea, insomnia, Many significant reactions

Manerix, generics 200–300 mg/day PO dizziness. reported. Increased risk of
potentially fatal serotonin
$30–60 Usual:
syndrome and/or
450–600 mg/day PO
hypertensive crisis. Consult
High:​[d] 900 mg/day reliable drug information
PO reference.

Drug Class: Selective Serotonin Reuptake Inhibitors

citalopram Initial:​[c] 10–20 mg/day All SSRIs: SSRIs are all substrates of
Celexa, Auro- PO Upon initiation: GI upset, various CYP enzymes and
Citalopram, anorexia, dry mouth, subject to drug interactions.
Citalopram, CTP 30, Usual:​[f] 20–40 mg/day diaphoresis, headache, Concurrent use with MAOIs,
other generics PO dizziness, insomnia, linezolid and methylene blue
High:​[d] 40 mg/day PO somnolence, anxiety, is contraindicated due to
< $30 agitation, tremor. Usually increased risk of serotonin
resolve after 2 wk of syndrome. Use caution if
therapy. Others: sexual combining with other
dysfunction, weight gain, serotonergic agents.
SIADH with Increased risk of GI bleeding
hyponatremia. with NSAIDs, antiplatelet
Citalopram: dose-related agents. Avoid concurrent use
QTc prolongation. with drugs associated with
prolonged QTc
interval/torsades de pointes.
Citalopram: higher risk of QTc
prolongation, especially at
high doses and in
combination with other QTc-
prolonging agents.

escitalopram Initial:​[c] 10 mg/day PO All SSRIs: SSRIs are all substrates of

Cipralex, Auro- Upon initiation: GI upset, various CYP enzymes and
Escitalopram, Usual:​[f] 10–20 mg/day anorexia, dry mouth, subject to drug interactions.
Escitalopram, KYE- PO diaphoresis, headache, Concurrent use with MAOIs,
Escitalopram, other High:​[d] 20 mg/day PO dizziness, insomnia, linezolid and methylene blue
generics somnolence, anxiety, is contraindicated due to
agitation, tremor. Usually increased risk of serotonin
< $30 resolve after 2 wk of syndrome. Use caution if
therapy. Others: sexual combining with other
dysfunction, weight gain, serotonergic agents.
SIADH with Increased risk of GI bleeding
hyponatremia. with NSAIDs, antiplatelet
Escitalopram: dose- agents. Avoid concurrent use
related QTc prolongation. with drugs associated with
prolonged QTc
interval/torsades de pointes.
Escitalopram: higher risk of
QTc prolongation, especially
at high doses and in
combination with other QTc-
prolonging agents.

fluoxetine Initial:​[c] 10–20 mg/day All SSRIs: SSRIs are all substrates of
Prozac, Auro- PO Upon initiation: GI upset, various CYP enzymes and
Fluoxetine, anorexia, dry mouth, subject to drug interactions.

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Drug/​Cost[a] Dosage Adverse Effects[b] Drug Interactions

Fluoxetine, Odan- Usual:​[f] 20–40 mg/day diaphoresis, headache, Concurrent use with MAOIs,
Fluoxetine, other PO dizziness, insomnia, linezolid and methylene blue
generics somnolence, anxiety, is contraindicated due to
High:​[d] 60–80 mg/day agitation, tremor. Usually increased risk of serotonin
< $30 PO resolve after 2 wk of syndrome. Use caution if
therapy. Others: sexual combining with other
dysfunction, weight gain, serotonergic agents.
SIADH with Increased risk of GI bleeding
hyponatremia. with NSAIDs, antiplatelet
Fluoxetine: anxiety upon agents. Avoid concurrent use
initiation is common. with drugs associated with
prolonged QTc
interval/torsades de pointes.
Fluoxetine: potent inhibitor of
CYP2D6.

fluvoxamine Initial:​[c] All SSRIs: SSRIs are all substrates of

Luvox, generics 50–100 mg/day PO Upon initiation: GI upset, various CYP enzymes and
anorexia, dry mouth, subject to drug interactions.
< $30 Usual:​[f] diaphoresis, headache, Concurrent use with MAOIs,
150–200 mg/day PO dizziness, insomnia, linezolid and methylene blue
High:​[d] 400 mg/day somnolence, anxiety, is contraindicated due to
PO agitation, tremor. Usually increased risk of serotonin
resolve after 2 wk of syndrome. Use caution if
therapy. Others: sexual combining with other
dysfunction, weight gain, serotonergic agents.
SIADH with Increased risk of GI bleeding
hyponatremia. with NSAIDs, antiplatelet
Fluvoxamine: agents. Avoid concurrent use
somnolence and nausea with drugs associated with
are common. prolonged QTc
interval/torsades de pointes.
Fluvoxamine: potent inhibitor
of CYP1A2.

paroxetine, Initial:​[c] 10–20 mg/day All SSRIs: SSRIs are all substrates of
immediate-release PO Upon initiation: GI upset, various CYP enzymes and
Paxil, Auro- anorexia, dry mouth, subject to drug interactions.
Paroxetine, Usual:​[f] 20–40 mg/day diaphoresis, headache, Concurrent use with MAOIs,
Paroxetine, other PO dizziness, insomnia, linezolid and methylene blue
generics High:​[d] 60 mg/day PO somnolence, anxiety, is contraindicated due to
agitation, tremor. Usually increased risk of serotonin
< $30 resolve after 2 wk of syndrome. Use caution if
therapy. Others: sexual combining with other
dysfunction, weight gain, serotonergic agents.
SIADH with Increased risk of GI bleeding
hyponatremia. with NSAIDs, antiplatelet
Paroxetine: agents. Avoid concurrent use
anticholinergic effects with drugs associated with
(dry mouth, constipation), prolonged QTc
somnolence are common. interval/torsades de pointes.
Paroxetine: potent CYP2D6
inhibitor.

paroxetine, Initial:​[c] All SSRIs: SSRIs are all substrates of

controlled-release 12.5–25 mg/day PO Upon initiation: GI upset, various CYP enzymes and
Paxil CR anorexia, dry mouth, subject to drug interactions.
diaphoresis, headache, Concurrent use with MAOIs,

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Drug/​Cost[a] Dosage Adverse Effects[b] Drug Interactions

Usual:​[f] 25–50 mg/day dizziness, insomnia, linezolid and methylene blue

$60–90 PO somnolence, anxiety, is contraindicated due to
agitation, tremor. Usually increased risk of serotonin
High:​[d] 75 mg/day PO resolve after 2 wk of syndrome. Use caution if
therapy. Others: sexual combining with other
dysfunction, weight gain, serotonergic agents.
SIADH with Increased risk of GI bleeding
hyponatremia. with NSAIDs, antiplatelet
Paroxetine: agents. Avoid concurrent use
anticholinergic effects with drugs associated with
(dry mouth, constipation), prolonged QTc
somnolence are common. interval/torsades de pointes.
Paroxetine: potent CYP2D6
inhibitor.

sertraline Initial:​[c] 25–50 mg/day All SSRIs: SSRIs are all substrates of
Zoloft, Auro- PO Upon initiation: GI upset, various CYP enzymes and
Sertraline, other anorexia, dry mouth, subject to drug interactions.
generics Usual:​[f] diaphoresis, headache, Concurrent use with MAOIs,
50–100 mg/day PO dizziness, insomnia, linezolid and methylene blue
< $30 somnolence, anxiety, is contraindicated due to
High:​[d]
150–200 mg/day PO agitation, tremor. Usually increased risk of serotonin
resolve after 2 wk of syndrome. Use caution if
therapy. Others: sexual combining with other
dysfunction, weight gain, serotonergic agents.
SIADH with Increased risk of GI bleeding
hyponatremia. with NSAIDs, antiplatelet
agents. Avoid concurrent use
with drugs associated with
prolonged QTc
interval/torsades de pointes.
Sertraline: weak CYP2D6
inhibitor.

Drug Class: Serotonin-Norepinephrine Reuptake Inhibitors

desvenlafaxine Initial: 50 mg daily PO Nausea, sleep Use with MAOIs, linezolid or

Pristiq, generics Usual: 50 mg daily PO disturbance, drowsiness, methylene blue may lead to
nervousness, dizziness, potentially fatal reaction
$60–90 High: 100 mg daily PO dry mouth. initially presenting with tremor,
agitation, hypomania,
hyperthermia and/or
hypertension.
Potent inhibitors of CYP3A4
may increase serum drug
concentrations.

duloxetine Initial: 60 mg daily PO Nausea, drowsiness, Use with MAOIs, linezolid or

Cymbalta, generics Usual: 60 mg daily PO insomnia, dizziness, dry methylene blue may lead to
mouth. potentially fatal reaction
$30–60 If necessary for initially presenting with tremor,
tolerability, may start agitation, hypomania,
with 30 mg/day and hyperthermia and/or
increase to 60 mg in hypertension.
1–2 wk Do not use with potent
High: 120 mg/day PO inhibitors of CYP1A2 such as

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2/26/24, 10:54 PM Depression

Drug/​Cost[a] Dosage Adverse Effects[b] Drug Interactions

ciprofloxacin, fluvoxamine and
ketoconazole.

levomilnacipran Initial: 20 mg/day PO Nausea, dry mouth, Use with MAOIs, linezolid or
Fetzima for 2 days then constipation, methylene blue may lead to
40 mg/day hyperhidrosis, headache, potentially fatal reaction
$120–150 Usual: 40–120 mg/day dizziness, increased heart initially presenting with tremor,
PO rate, tachycardia, agitation, hypomania,
insomnia, erectile hyperthermia and/or
dysfunction. hypertension.
Potent inhibitors of CYP3A4
may increase serum drug
concentrations.

venlafaxine Initial:​[c] Nausea, sleep Use with MAOIs, linezolid or

Effexor XR, 37.5–75 mg/day PO disturbance, drowsiness, methylene blue may lead to
Venlafaxine XR, other nervousness, dizziness, potentially fatal reaction
Usual:
generics dry mouth. initially presenting with tremor,
112.5–225 mg/day PO
Dose-related agitation, hypomania,
< $30 High:​[d] hypertension occurs hyperthermia and/or
300–375 mg/day PO rarely, particularly at hypertension.
doses ≥225 mg/day. Strong inhibitors of CYP2D6
or CYP3A4 (e.g.,
ketoconazole, quinidine,
fluoxetine, paroxetine) may
increase venlafaxine levels.

Drug Class: Serotonin Modulators

trazodone Initial:​[c] Drowsiness, orthostatic Toxicity may be increased by

generics 150–200 mg/day PO hypotension, nausea, inhibitors of CYP3A4 (e.g.,
headache, dry mouth, clarithromycin, erythromycin,
< $30 Usual:
priapism. grapefruit juice,
300–400 mg/day PO
ketoconazole).
High:​[d] 600 mg/day Effectiveness may be reduced
PO by inducers of CYP3A4 such
as carbamazepine, phenytoin
and rifampin.
May potentiate effects of
other CNS depressants and
augment hypotensive effects
of antihypertensives.
Avoid use with MAOIs.

vilazodone Diarrhea, nausea, Potent inhibitors of CYP 3A4

Initial:​[c] 10 mg/day PO
Viibryd vomiting, insomnia. may significantly increase
with food for 7 days
drug levels; do not use doses
$90–120 Usual: 20 mg/day PO above 20 mg/day when
with food; may coadministered with a strong
increase to 40 mg/day inhibitor.
after 7 days, if needed
Use with MAOIs, linezolid or
methylene blue may lead to
potentially fatal reaction
initially presenting with tremor,
agitation, hypomania,

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Drug/​Cost[a] Dosage Adverse Effects[b] Drug Interactions

hyperthermia and/or
hypertension.
Use caution if coadministering
with drugs that affect
serotonergic neurotransmitter
systems (e.g.,
dextromethorphan, fentanyl,
lithium, meperidine,
methadone, pentazocine,
SSRIs, St. John’s wort,
tapentadol, tramadol, triptan,
tryptophan).

vortioxetine Initial:​[c] 5–10 mg daily Nausea, constipation, Use with MAOIs, linezolid or
Trintellix PO vomiting. methylene blue may lead to
Transient symptoms potentially fatal reaction
$60–90 Usual:​[c]10–20 mg associated with abrupt initially presenting with tremor,
daily PO discontinuation include agitation, hypomania,
headache, increased hyperthermia and/or
dreaming, mood swings, hypertension.
muscle tension, vertigo, Use caution if coadministering
rhinorrhea. with drugs that affect
serotonergic neurotransmitter
systems (e.g.,
dextromethorphan, fentanyl,
lithium, meperidine,
methadone, pentazocine,
SSRIs, St. John’s wort,
tapentadol, tramadol, triptan,
tryptophan).
Potential additive bleeding
risk with drugs such as
warfarin, ASA and other
antiplatelet agents.

Drug Class: Tricyclic Antidepressants

amitriptyline Initial:​[c] 25–50 mg/day Anticholinergic (dry Use with MAOIs, linezolid or
generics PO mouth, blurred vision, methylene blue may lead to
constipation, urinary potentially fatal reaction
< $30 Usual: 75–200 mg/day
hesitancy, tachycardia, initially presenting with tremor,
PO
delirium), agitation, hypomania,
High:​[d] antihistaminergic hyperthermia and/or
250–300 mg/day PO (sedation, weight gain), hypertension.
orthostatic hypotension, Inducers of CYP1A2 (e.g.,
lowered seizure barbiturates, carbamazepine
threshold; sexual and rifampin) may decrease
dysfunction. effect; cimetidine and
antipsychotics may increase
effect and toxicity; possible
interaction with
antiarrhythmics (may lead to
increased effect of either
drug); may reduce
antihypertensive effect of
clonidine; may augment

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Drug/​Cost[a] Dosage Adverse Effects[b] Drug Interactions

hypotensive effect of
thiazides.

clomipramine Initial:​[c] Anticholinergic (dry Use with MAOIs, linezolid or

Anafranil, generics 25–50 mg/day PO mouth, blurred vision, methylene blue may lead to
constipation, urinary potentially fatal reaction
$30–60 Usual: 75–200 mg/day
hesitancy, tachycardia, initially presenting with tremor,
PO
delirium), agitation, hypomania,
High:​[d] antihistaminergic hyperthermia and/or
250–300 mg/day PO (sedation, weight gain), hypertension.
orthostatic hypotension, Inducers of CYP1A2 (e.g.,
lowered seizure barbiturates, carbamazepine
threshold; sexual and rifampin) may decrease
dysfunction. effect; cimetidine and
antipsychotics may increase
effect and toxicity; possible
interaction with
antiarrhythmics (may lead to
increased effect of either
drug); may reduce
antihypertensive effect of
clonidine; may augment
hypotensive effect of
thiazides.

desipramine Initial:​[c] 25–50 mg/day Anticholinergic (dry Use with MAOIs, linezolid or
generics PO mouth, blurred vision, methylene blue may lead to
constipation, urinary potentially fatal reaction
$30–60 Usual: 75–200 mg/day
hesitancy, tachycardia, initially presenting with tremor,
PO
delirium), agitation, hypomania,
High:​[d] antihistaminergic hyperthermia and/or
250–300 mg/day PO (sedation, weight gain), hypertension.
orthostatic hypotension, Inducers of CYP1A2 (e.g.,
lowered seizure barbiturates, carbamazepine
threshold; sexual and rifampin) may decrease
dysfunction. effect; cimetidine and
antipsychotics may increase
effect and toxicity; possible
interaction with
antiarrhythmics (may lead to
increased effect of either
drug); may reduce
antihypertensive effect of
clonidine; may augment
hypotensive effect of
thiazides.

doxepin Initial:​[c] 25–50 mg/day Anticholinergic (dry Use with MAOIs, linezolid or
Sinequan PO mouth, blurred vision, methylene blue may lead to
constipation, urinary potentially fatal reaction
$60–90 Usual: 75–200 mg/day
hesitancy, tachycardia, initially presenting with tremor,
PO
delirium), agitation, hypomania,
High:​[d] antihistaminergic hyperthermia and/or
250–300 mg/day PO (sedation, weight gain), hypertension.
orthostatic hypotension, Inducers of CYP1A2 (e.g.,
lowered seizure barbiturates, carbamazepine
and rifampin) may decrease

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Drug/​Cost[a] Dosage Adverse Effects[b] Drug Interactions

threshold; sexual effect; cimetidine and
dysfunction. antipsychotics may increase
effect and toxicity; possible
interaction with
antiarrhythmics (may lead to
increased effect of either
drug); may reduce
antihypertensive effect of
clonidine; may augment
hypotensive effect of
thiazides.

imipramine Initial:​[c] 25–50 mg/day Anticholinergic (dry Use with MAOIs, linezolid or
generics PO mouth, blurred vision, methylene blue may lead to
constipation, urinary potentially fatal reaction
$30–60 Usual: 75–200 mg/day
hesitancy, tachycardia, initially presenting with tremor,
PO
delirium), agitation, hypomania,
High:​[d] antihistaminergic hyperthermia and/or
250–300 mg/day PO (sedation, weight gain), hypertension.
orthostatic hypotension, Inducers of CYP1A2 (e.g.,
lowered seizure barbiturates, carbamazepine
threshold; sexual and rifampin) may decrease
dysfunction. effect; cimetidine and
antipsychotics may increase
effect and toxicity; possible
interaction with
antiarrhythmics (may lead to
increased effect of either
drug); may reduce
antihypertensive effect of
clonidine; may augment
hypotensive effect of
thiazides.

nortriptyline Initial:​[c] 25–50 mg/day Anticholinergic (dry Use with MAOIs, linezolid or
Aventyl PO mouth, blurred vision, methylene blue may lead to
constipation, urinary potentially fatal reaction
$60–90 Usual: 75–150 mg/day
hesitancy, tachycardia, initially presenting with tremor,
PO
delirium), agitation, hypomania,
High:​[d] 200 mg/day antihistaminergic hyperthermia and/or
PO (sedation, weight gain), hypertension.
orthostatic hypotension, Inducers of CYP1A2 (e.g.,
lowered seizure barbiturates, carbamazepine
threshold; sexual and rifampin) may decrease
dysfunction. effect; cimetidine and
antipsychotics may increase
effect and toxicity; possible
interaction with
antiarrhythmics (may lead to
increased effect of either
drug); may reduce
antihypertensive effect of
clonidine; may augment
hypotensive effect of
thiazides.

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2/26/24, 10:54 PM Depression

Drug/​Cost[a] Dosage Adverse Effects[b] Drug Interactions

trimipramine Initial:​[c] 25–50 mg/day Anticholinergic (dry Use with MAOIs, linezolid or
generics PO mouth, blurred vision, methylene blue may lead to
constipation, urinary potentially fatal reaction
$30–60 Usual: 75–200 mg/day
hesitancy, tachycardia, initially presenting with tremor,
PO
delirium), agitation, hypomania,
High:​[d] antihistaminergic hyperthermia and/or
250–300 mg/day PO (sedation, weight gain), hypertension.
orthostatic hypotension, Inducers of CYP1A2 (e.g.,
lowered seizure barbiturates, carbamazepine
threshold; sexual and rifampin) may decrease
dysfunction. effect; cimetidine and
antipsychotics may increase
effect and toxicity; possible
interaction with
antiarrhythmics (may lead to
increased effect of either
drug); may reduce
antihypertensive effect of
clonidine; may augment
hypotensive effect of
thiazides.

Drug Class: Natural Health Products

S- 400–1600 mg/day PO, Mild insomnia, Potential additive bleeding

adenosylmethionine in 2–3 divided doses constipation, dizziness, risk with drugs such as
(SAM-e) nausea, dry mouth, warfarin, ASA and other
sweating; case reports of antiplatelet (including SSRIs)
$60–90 increased anxiety, mania and anticoagulant agents.
or hypomania in patients Avoid concurrent use with
with bipolar disorder. other serotonergic drugs such
as antidepressants (possible
serotonin syndrome).

St. John’s wort Usual: 300 mg TID PO Photosensitivity (rare), GI Avoid concurrent use with
(Hypericum Range: upset, dizziness, MAOIs, linezolid or methylene
perforatum) 300–1800 mg/day PO, insomnia, restlessness, blue (possible hypertensive
in 2–3 divided doses agitation; cases of mania crisis) and SSRIs (possible
< $30 or hypomania reported. serotonin syndrome).
Inducer of many cytochrome
P450 isoenzymes (1A2, 2C9,
2C19, 3A4) and
P-glycoprotein; may decrease
serum levels of many drugs
including cyclosporine,
digoxin, indinavir, oral
contraceptives, theophylline
and warfarin.

[a] Cost of 30-day supply for mean usual dose, unless otherwise specified; includes drug cost only.
[b]
See also Table 4 for relative incidence and management of adverse effects.
[c]
Lower initial doses are indicated in patients who have previously experienced side effects or who are taking multiple
medications; this often applies to elderly patients.
[d] Higher doses often exceed maximum recommended doses in manufacturers’ product monographs and are usually
associated with increased risk of adverse effects. These doses should be used with caution in appropriately selected
patients.

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2/26/24, 10:54 PM Depression
[e]
Esketamine is indicated for treatment-resistant depression, in combination with an SSRI or SNRI. It is available only
through a controlled distribution program (JANSSEN JOURNEY). A trained health-care professional is required to
supervise each dose and monitor patient clinical status and BP for at least 2 hours afterward.
[f] For SSRIs, the upper end of the “initial dose” may be the “usual dose,” e.g., fluoxetine 20 mg or sertraline 50 mg;
otherwise, increments are every 5–7 days.
Dosage adjustment may be required in renal impairment; see Dosage Adjustment in Renal Impairment.

Abbreviations: ASA = acetylsalicylic acid; BP = blood pressure; CNS = central nervous system; CYP = cytochrome
P450; EPS = extrapyramidal side effects; GI = gastrointestinal; MAOI = monoamine oxidase inhibitor; NSAID = nonsteroidal
anti-inflammatory drug; SIADH = syndrome of inappropriate antidiuretic hormone; SNRI = serotonin-norepinephrine reuptake
inhibitor; SSRI = selective serotonin reuptake inhibitor

Suggested Readings
Kennedy SH, Lam RW, McIntyre RS et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016
clinical guidelines for the management of adults with major depressive disorder in adults: Section 3. Pharmacological
treatments. Can J Psychiatry 2016;61(9):540-60.

Park LT, Zarate CA Jr. Depression in the primary care setting. N Engl J Med 2019;380(6):559-68.

Ramanuj P, Ferenchick EK, Pincus HA. Depression in primary care: part 2–management. BMJ 2019;365:I835.

Scott F, Hampsey E, Gnanapragasam S et al. Systematic review and meta-analysis of augmentation and combination
treatments for early-stage treatment-resistant depression. J Psychopharmacol 2022 Jul 21. [Epub ahead of print].

Sobieraj DM, Martinez BK, Hernandez AV et al. Adverse effects of pharmacologic treatments of major depression in
older adults. J Am Geriatr Soc 2019;67(8):1571-81.

Vaccarino SR, Kennedy SH. Treatment resistant depression. In: Vazquez GH, Zarate CA, Brietzke EM, editors.
Ketamine for Treatment-Resistant Depression: Neurobiology and Applications. Academic Press; 2021. p. 33-84.

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