Depression

Clinical Snapshot

Major depressive disorder (MDD) is diagnosed when 5 or more defined symptoms are present during the same 2-week period, representing a change from usual functioning, with at least 1 symptom being either persistent depressed mood or a marked loss of interest or pleasure (see Recognize the Condition for the full criteria table).^[1] In the DSM-5-TR, MDD sits within a broader family of depressive disorders — persistent depressive disorder, disruptive mood dysregulation disorder, premenstrual dysphoric disorder, substance-induced mood disorder, mood disorder due to a general medical condition, and other/unspecified depressive disorder — but this chapter focuses on MDD and persistent depressive disorder (dysthymia), since CANMAT's antidepressant recommendations apply identically to both despite their differing diagnostic criteria.^[2]

Recognize the Condition

DSM-5-TR diagnostic criteria for a major depressive episode

5 or more of the following symptoms during the same 2-week period, representing a change from the patient's usual functioning, with at least 1 symptom being either persistent depressed mood or marked loss of interest/pleasure. Symptoms must be severe enough to interfere with daily life (social relationships, work, school, or other important activities); must not be substance-induced, caused by a medical condition, or related to schizophrenia or another psychotic disorder; and there must be no history of a manic or hypomanic episode (unless substance-induced or due to another medical condition). When symptoms arise in the context of a significant life stressor, clinical judgment is required to determine whether the criteria are met.^[1]

Symptom	Description
Depressed mood	Persistent low or depressed mood for most of the day, almost daily; in children and adolescents may present primarily as irritability.
Loss of interest or pleasure	Significant reduction of interest or pleasure in usual daily activities (anhedonia).
Fatigue or low energy	Ongoing fatigue or low energy almost daily.
Sleep disturbance	Difficulty initiating or maintaining sleep, early morning awakening, or excessive sleep almost daily.
Appetite or weight change	Clinically meaningful change in appetite or body weight not due to intentional dieting; in children, failure to achieve expected weight gain.
Psychomotor slowing or agitation	Observable slowing of movement or speech, or increased restlessness or agitation, almost daily.
Impaired concentration or indecisiveness	Impaired concentration, thinking, or indecisiveness almost daily.
Feelings of low self-worth or guilt	Disproportionate feelings of worthlessness or guilt almost daily.
Thoughts of death or self-harm	Repeated thoughts about death; suicidal ideation with or without a plan, or suicidal behaviour.

Persistent depressive disorder (dysthymia)

A consolidation of the older "dysthymic disorder" and "chronic major depressive disorder" categories. Diagnostic criteria differ from MDD — depressed mood for most of the day, more days than not, for at least 2 years, plus at least 2 of: increased or decreased appetite, insomnia or hypersomnia, reduced energy or fatigue, reduced self-esteem, reduced concentration or difficulty making decisions, and hopelessness. Symptoms are typically fewer and less severe than in MDD, but antidepressant treatment recommendations are the same for both conditions.^[1]

Screening for medication-induced depressive symptoms

As part of every diagnostic assessment, screen for current prescription medicines associated with depressive symptoms, including oral contraceptives, analgesics, proton pump inhibitors, and antihypertensives — an identified drug cause changes management away from starting an antidepressant.^[2]

Risk Factors

Personal history of a prior depressive episode — the single strongest predictor of a future episode.
Family history of depression or other mood disorder.
Comorbid anxiety disorder or substance use disorder.
Chronic medical illness or chronic pain.
Prior suicide attempt or self-harm.
Significant psychosocial stressors — bereavement, relationship breakdown, financial or occupational stress, social isolation.
Perinatal and postpartum period.
Perimenopausal and postmenopausal transition.
Sex — depression is generally more prevalent in women than men.
Lack of social support.

Red Flags & Refer

Escalate to urgent psychiatric assessment (same-day/emergency) for any of the following:

Suicidal ideation with a plan, intent, or access to means — this requires an immediate safety assessment and, depending on acuity, emergency department referral; do not simply start or adjust an antidepressant and arrange routine follow-up.
Psychotic features (delusions or hallucinations) accompanying the depressive episode — needs combined antidepressant plus antipsychotic therapy or electroconvulsive therapy, not antidepressant monotherapy.
Catatonia.
Severe functional impairment — inability to care for basic needs, work, or maintain safety.
Postpartum onset with rapid, severe symptoms, confusion, or perceptual disturbances — possible postpartum psychosis, a psychiatric emergency with a serious risk of suicide and infanticide requiring immediate referral.
A previously unrecognized history of a manic or hypomanic episode uncovered during assessment — this changes the diagnosis to bipolar depression, which requires a different treatment strategy (see Bipolar Disorder) and must not be treated with unopposed antidepressant monotherapy.
Signs of serotonin syndrome in a patient on serotonergic therapy — agitation, diaphoresis, fever, tremor, hyperreflexia, clonus, nystagmus, dilated pupils, or delirium. Stop the causative drug(s) immediately and refer to hospital; this is rare but potentially fatal, and risk is highest with monoamine oxidase inhibitors (MAOIs).^[3]
Emergent or worsening suicidal ideation after starting or adjusting an antidepressant, particularly in children, adolescents, and young adults, and particularly in the first weeks of treatment.

Assessment & Diagnosis

Differentiating MDD from commonly confused presentations

Feature	Major depressive disorder	Persistent depressive disorder	Bipolar depression	Grief / bereavement
Course	Discrete episode, most of the day nearly every day, ≥2 weeks	Chronic — depressed mood most days for ≥2 years, with fewer/milder symptoms	A depressive episode indistinguishable from MDD on its own	Fluctuating waves of sadness tied to reminders of the loss, with preserved capacity for positive emotion between waves
Diagnostic threshold	≥5 of 9 DSM-5-TR symptoms including depressed mood or anhedonia	Depressed mood plus ≥2 of 6 associated symptoms for ≥2 years	Same depressive-episode criteria as MDD, but a lifetime manic/hypomanic episode is also present	Does not meet the pervasive, functionally-impairing MDD threshold, though grief can evolve into a true major depressive episode
Screen for mania/hypomania	Negative	Negative	Positive — screen every new depression presentation with the MDQ or direct history	Negative
Key management implication	Standard antidepressant/psychotherapy algorithm applies	Same antidepressant recommendations as MDD despite the different diagnostic criteria	Do not start unopposed antidepressant monotherapy — requires a different treatment strategy (see Bipolar Disorder)	Primarily supportive; treat as MDD only if full criteria and functional impairment are met

History

Conduct a full diagnostic work-up including differential diagnosis, suicidality, and organic causes of depression.
Assess personal and family psychiatric history, including previous antidepressant use and response, and alcohol, tobacco, and substance use/dependence.
Screen every new presentation for a history of manic or hypomanic episodes — patients with bipolar disorder often first present during a depressive episode, and unopposed antidepressant monotherapy is inappropriate if bipolar disorder is present.
Screen for medications associated with depressive symptoms: oral contraceptives, analgesics, proton pump inhibitors, antihypertensives.
Assess suicide risk directly and explicitly at every assessment — ideation, plan, intent, access to means, prior attempts, and protective factors — this is never optional and never inferred from mood alone.

Screening and severity-assessment tools

Tool	Purpose / population	Format
PHQ-9	Patient-rated screening and severity tracking; corresponds directly to DSM-5 major depressive episode criteria. The first 2 items alone are a useful rapid screen.^[4]	9 items, patient-rated
QIDS-SR16	Widely used alternative to the PHQ-9, available in multiple languages.	16 items, patient-rated, under 10 minutes
HAMD-7	Validated brief severity and remission rating for use by health-care professionals.	7 items, clinician-rated
MDQ	Screens for manic or hypomanic symptoms — use in every new depression presentation to rule out bipolar disorder.	Patient-rated screening instrument
EPDS	The most widely used and validated tool for depressive symptoms during pregnancy and the postpartum period.	10 items, patient-rated

PHQ-9 scoring

Each of the 9 items is rated by the patient for how often it has bothered them over the past 2 weeks: 0 = not at all, 1 = several days, 2 = more than half the days, 3 = nearly every day. Items correspond directly to the DSM-5-TR criteria above (interest/pleasure; mood; sleep; energy; appetite; self-worth/guilt; concentration; psychomotor change; thoughts of death or self-harm).^[4]

Total score	Severity
0–4	Minimal / none
5–9	Mild
10–14	Moderate
15–19	Moderately severe
20–27	Severe

Any response above "not at all" on the thoughts-of-death/self-harm item requires direct, explicit suicide risk follow-up regardless of the total score — a low total score does not rule out significant suicide risk.

Baseline investigations

Review physical health, including body mass index and, where appropriate, waist circumference; screen for metabolic syndrome, sexual health/dysfunction, hypertension, and alcohol/tobacco/substance use.
Consider: pregnancy test, hemoglobin (anemia), thyroid-stimulating hormone, liver function tests.
Where indicated: ECG for pre-existing cardiovascular disease or QTc-prolongation risk; bone density scan when osteoporosis risk factors are present; electrolytes, especially in older patients.
Routine neuroimaging or EEG is not indicated in the absence of focal neurologic findings or an atypical presentation suggesting a structural or organic cause.

^[2]

Treatment Targets

Achieve full remission of depressive symptoms, not merely a reduction in severity.
Treat concomitant symptoms and comorbid disorders (anxiety, insomnia, pain).
Eliminate suicide risk.
Restore occupational, social, and functional capacity to baseline.
Prevent relapse and recurrence through an adequate continuation/maintenance course.

Choose Initial Treatment

Direct treatment rule

Mild depression psychotherapy (CBT, interpersonal therapy, or behavioural activation) or supervised exercise is appropriate as first-line monotherapy — an antidepressant is not required as the initial step.

Moderate-to-severe depression, or any severity with a past history of depression antidepressant medication is first-line; combining an antidepressant with psychotherapy (interpersonal therapy or CBT) is preferred over either modality alone when both are accessible, since combination therapy provides added protection against early relapse even though it adds little extra benefit for symptom relief alone in mild-moderate cases.

Choice of first-line antidepressant select from the CANMAT first-line agents — an SSRI (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), an SNRI (desvenlafaxine, duloxetine, levomilnacipran, venlafaxine), or another first-line agent (bupropion, mirtazapine, vilazodone, vortioxetine) — individualized to side-effect profile, patient preference, comorbidities, and prior response; no single first-line agent is mandated over another.^[2]

Psychotic features present combine an antidepressant with an antipsychotic, or refer for electroconvulsive therapy — antidepressant monotherapy is not appropriate.

Severe depression, active suicidality, or need for rapid symptom relief start an antidepressant (± psychotherapy) and refer for electroconvulsive therapy consideration in parallel rather than waiting for a full medication trial to fail first.

Seasonal pattern light therapy is first-line; for nonseasonal mild-to-moderate depression, light therapy is a reasonable second-line or adjunctive option rather than first-line monotherapy.

History of a manic or hypomanic episode identified do not start unopposed antidepressant monotherapy — manage as bipolar depression (see Bipolar Disorder), which requires a different treatment strategy.

Non-Pharmacologic Treatment

Psychotherapy

Cognitive behavioural therapy (CBT), behavioural activation (BA), and interpersonal therapy (IPT) are first-line psychological treatments, as effective as medication for mild-to-moderate depression. Interpersonal therapy may be preferable when major interpersonal issues are prominent. Mindfulness-based CBT is particularly useful for preventing relapse; acceptance and commitment therapy has some efficacy in acute depression. Consider the significance of therapist cultural competence when treating racialized groups.

Technology-based psychotherapy

Internet- and app-based CBT is available (e.g., MindBeacon, BounceBack, moodgym, Headspace), with efficacy supported by multiple meta-analyses. Guided programs (with clinician support) are preferred over unguided self-help; unguided programs are appropriate only when clinician-guided support or no other intervention is available, particularly for moderate-to-severe depression. Encourage patients to complete program modules and homework exercises alongside, not instead of, routine clinical follow-up.

Motivational interviewing

Effective specifically for co-occurring substance use, with its effect primarily on the substance use rather than on depressive symptoms directly.

Psychoeducation

Provide these 5 adherence-focused messages with every new antidepressant prescription, and reinforce them at follow-up:

Take the medication daily.
Call your prescriber or pharmacist with questions about side effects or other issues.
It may take 2–4 weeks to see a noticeable effect.
Continue taking the medication even after you start feeling better.
Do not stop the antidepressant without checking with your prescriber.

Exercise

Regular supervised physical exercise — low-to-moderate intensity, 30–40 minutes per session, 3–4 times weekly, for a minimum of 9 weeks — is a first-line monotherapy option for mild depression, and a reasonable adjunct to pharmacotherapy and/or psychotherapy for moderate depression.

Diet

Adjunctive healthy or Mediterranean-style diet (increasing fruits, vegetables, lean protein, nuts/seeds, olive oil; reducing refined and processed foods) is recommended as a third-line lifestyle intervention.

Light therapy

First-line option for MDD with a seasonal pattern; a reasonable second-line or adjunct measure for nonseasonal mild-to-moderate MDD. Use a light box with 10,000-lux intensity and a UV filter, angled toward the face, for 30 minutes daily, preferably in the morning. Start at 10–15 minutes daily and increase gradually to the full 30 minutes to minimize side effects (headache, eye strain, irritability, insomnia), which are usually mild and rarely require discontinuation. Patients with a pre-existing eye condition that increases light sensitivity should check with their eye-care practitioner before starting.

Neurostimulation

Repetitive transcranial magnetic stimulation, magnetic seizure therapy, and transcranial direct current stimulation are increasingly used adjunctive strategies, particularly for treatment-resistant depression, though availability is limited outside specialized centres.

Pharmacologic Treatment Options

CANMAT antidepressant classification

First-line agents

Bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, mirtazapine, paroxetine, sertraline, venlafaxine, vilazodone, vortioxetine (listed alphabetically, not in order of preference).

Second-line agents

Moclobemide, extended-release quetiapine, trazodone, and the tricyclic antidepressants (amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, trimipramine).

Third-line agents

Phenelzine and tranylcypromine (irreversible monoamine oxidase inhibitors).

^[2]

Drug / intervention	Role	Dose / use	Important adverse effects	Teaching points
Escitalopram Preferred	1st-line SSRI	Initial 10 mg PO daily; usual 10-20 mg/day	GI upset, headache, sexual dysfunction, hyponatremia (SIADH), dose-related QTc prolongation	Early GI/anxiety side effects usually ease within 2 weeks; do not stop abruptly.
Sertraline Preferred	1st-line SSRI; preferred in pregnancy, breastfeeding, and cardiac disease	Initial 25-50 mg PO daily; usual 50-100 mg/day, up to 150-200 mg/day	GI upset (diarrhea), sexual dysfunction, insomnia	Take with food to reduce GI upset.
Venlafaxine XR Preferred	1st-line SNRI	Initial 37.5-75 mg PO daily; usual 112.5-225 mg/day	Nausea, dose-related hypertension (≥225 mg/day), pronounced discontinuation symptoms	Monitor blood pressure at higher doses; taper slowly on discontinuation — short half-life gives high discontinuation-symptom risk.
Duloxetine Preferred	1st-line SNRI; dual indication for neuropathic pain and fibromyalgia	Initial 60 mg PO daily (or 30 mg/day if tolerability is a concern, increase after 1-2 weeks); usual 60 mg/day, up to 120 mg/day	Nausea, dry mouth, insomnia; isolated hepatic injury reported	Cigarette smoking induces CYP1A2 and lowers levels — smokers may need higher doses. Avoid combining with potent CYP1A2 inhibitors (ciprofloxacin, fluvoxamine).
Bupropion SR/XL Preferred	1st-line, dual-action; low rate of sexual dysfunction; also indicated for smoking cessation	SR: initial 150 mg PO daily, usual 150-300 mg/day divided BID, up to 375-450 mg/day. XL: initial 150 mg PO daily, usual 150-300 mg/day once daily, up to 450 mg/day	Insomnia, agitation, anorexia, dose-dependent seizure risk	Contraindicated in seizure disorder and current or recent anorexia/bulimia nervosa. Never combine with MAOIs, linezolid, or methylene blue.
Mirtazapine Preferred	1st-line; useful with prominent insomnia or appetite loss; low sexual dysfunction risk	Initial 15-30 mg PO at bedtime; usual 30-45 mg/day, up to 60 mg/day	Sedation, weight gain, rare agranulocytosis	Sedation and appetite stimulation are often more prominent at lower doses.
Vortioxetine Preferred	1st-line; favourable cognitive and sexual side-effect profile	Initial 5-10 mg PO daily; usual 10-20 mg/day	Nausea (usually early and self-resolving), constipation	Transient discontinuation symptoms (headache, dizziness, mood swings) can occur with abrupt stop despite generally good tolerability.
Quetiapine XR Alternative	2nd-line; low-dose augmentation or higher-dose monotherapy	Augmentation: 25-100 mg PO daily. Monotherapy: initial 50 mg daily x2 days, then 150 mg daily, may increase to 300 mg on or after day 4	Sedation, weight gain, orthostatic hypotension, metabolic effects, possible increased cataract risk	Counsel on antipsychotic-associated body-temperature dysregulation — hydration and sun protection.
Moclobemide Alternative	2nd-line reversible MAO-A inhibitor; no dietary restriction at recommended doses; useful with prominent anxiety	Initial 200-300 mg/day PO; usual 450-600 mg/day, up to 900 mg/day	Nausea, insomnia, dizziness	Still requires the same serotonin syndrome precautions and washout rules as other MAOIs when combined with other serotonergic drugs.
Nortriptyline Alternative	2nd-line TCA; better tolerated than other TCAs	Initial 25-50 mg PO daily; usual 75-150 mg/day, up to 200 mg/day	Anticholinergic effects, orthostatic hypotension, cardiotoxicity in overdose	Dangerous in overdose — use particular caution, or avoid as a first agent, in patients with active suicidal ideation.
Aripiprazole Special situation	1st-line adjunct for partial response to an antidepressant	2-15 mg PO daily added to the existing antidepressant	Akathisia, extrapyramidal symptoms, insomnia	Assess response within 2 weeks; not intended for indefinite long-term use — reassess ongoing need regularly.
Brexpiprazole Special situation	1st-line adjunct for partial response to an antidepressant	1-2 mg PO daily added to the existing antidepressant	Weight gain, akathisia (less common than with aripiprazole)	Same 2-week response-assessment and long-term reassessment principle as aripiprazole.
Esketamine (intranasal) Special situation	Treatment-resistant depression, combined with an SSRI/SNRI	28-56 mg intranasally twice weekly initially; increase by 28 mg increments as needed; taper to weekly then Q1-2 weekly by week 9	Dissociation, sedation, dizziness, increased blood pressure	Only available through a controlled distribution program with supervised administration and 2 hours of post-dose monitoring. Avoid alcohol within 24 hours of dosing.

Never combine two serotonergic agents without a deliberate, specialist-reviewed plan and appropriate washout — an SSRI/SNRI plus an MAOI, St. John's Wort, tramadol, or a triptan carries a real serotonin syndrome risk.^[3]

Special Populations

Pregnancy

Decide whether to start or continue antidepressant treatment using a risk-benefit analysis that weighs both fetal/neonatal and maternal risk — untreated depression itself carries real risk to both. For mild depression, psychotherapy (IPT or CBT) is first-line; for moderate-to-severe depression, especially with a past history of depression, antidepressant medication is first-line. If prescribed, start at the lowest effective dose.^[5]

1st line in pregnancy citalopram, escitalopram, sertraline.

2nd line in pregnancy bupropion, desvenlafaxine, duloxetine, fluoxetine, fluvoxamine, mirtazapine, venlafaxine.

Not recommended in pregnancy unless the patient was already stable on it before conception paroxetine (associated with a possible increase in major-malformation risk) and clomipramine.

Avoid in pregnancy MAOIs and doxepin.

SSRIs are not major teratogens; a possible statistical association with cardiovascular malformations has not held up in studies that control for confounding factors.^[6] Late-pregnancy SSRI exposure is associated with an increased risk of persistent pulmonary hypertension of the newborn.^[7] Poor neonatal adaptation syndrome — transient tremulousness, irritability, increased muscle tone, sleep disturbance, and respiratory distress — can follow in-utero antidepressant exposure and is usually self-limiting. Overall, the Canadian Paediatric Society concludes that the risk of serious adverse effects from in-utero SSRI/SNRI exposure is low.^[8] Discontinuing antidepressants during pregnancy carries its own risk of relapse and psychiatric emergency, particularly in patients with a history of severe or recurrent depression — this is a shared decision, never an automatic stop.

Postpartum mood disturbances

Postpartum "blues"

Common and self-limiting; not a disorder itself, but requires monitoring and supportive care since it can precede a true depressive episode.

Postpartum major depression

Managed as MDD, with the treatment approach below.

Postpartum psychosis

A psychiatric emergency — see Red Flags & Refer — with a serious risk of suicide and infanticide requiring immediate referral.

Breastfeeding

Psychotherapy (IPT or CBT) is first-line for postpartum depression, particularly while breastfeeding. When antidepressant treatment is needed:

1st line while breastfeeding sertraline, escitalopram, citalopram.

2nd line while breastfeeding bupropion, duloxetine, desvenlafaxine, venlafaxine, fluoxetine, fluvoxamine, mirtazapine.

3rd line while breastfeeding paroxetine, trazodone, and TCAs other than doxepin.

Not recommended while breastfeeding doxepin, due to documented adverse effects in the breastfed infant. Other antidepressants lack sufficient breastfeeding safety data to make a recommendation.^[5]

Older adults

Use lower starting doses and slower titration. Nortriptyline is a reasonable option in this population given its more favourable tolerability among the TCAs. Monitor electrolytes given a higher risk of SSRI/SNRI-associated hyponatremia (SIADH), and monitor for orthostatic hypotension and falls risk with sedating agents. Actively look for a medical cause or polypharmacy contribution to the depressive presentation.

Children and adolescents

Updated pediatric-specific CANMAT guidance is in development; obtain specialist input for pediatric dosing and agent selection. Regulatory authorities have cautioned that antidepressants can increase suicidal ideation in children and young adults — monitor closely for emergent or worsening suicidal ideation, especially early in treatment, and weigh this risk against the risks of untreated depression (suicide, prolonged illness, higher relapse rate).

Renal and hepatic impairment

Dose adjustment may be required in renal impairment for renally cleared agents — consult the specific product monograph. Hepatically cleared agents may need dose reduction in hepatic impairment; use caution and lower starting doses.

Monitoring & Follow-Up

Phases of antidepressant therapy

Acute phase

Achieve a minimum therapeutic dose within the first 2 weeks of treatment, increasing further over the next 4-6 weeks as needed, aiming for full remission rather than partial response.

Continuation phase

After remission of a first episode, continue the same antidepressant at the same dose for 6-12 months.

Maintenance phase

Treat for at least 2 years — and consider long-term maintenance — for patients with psychiatric or other comorbidities, residual symptoms, or episodes that are frequent, recurrent, chronic, severe, or difficult to treat.

^[2]

Ongoing monitoring

Track symptom change against baseline using the same assessment scale (PHQ-9, QIDS-SR16, or HAMD-7) at each visit.
Weight and, where appropriate, waist circumference.
Sexual dysfunction.
Treatment-emergent adverse effects: suicidal thinking (especially in transitional youth), elevated serum transaminases, hyponatremia (especially in older patients), hypertension, and orthostatic hypotension.

Managing common treatment-emergent adverse effects

Adverse effect	Management
GI upset (nausea, constipation, diarrhea)	Usually diminishes after 1-2 weeks. For nausea: once-daily dosing, take with food, small frequent meals, avoid strong smells. For constipation: increase fibre/fluids, laxatives, exercise. For diarrhea: small frequent meals, probiotics, limit caffeine/alcohol/spicy food, fluid replacement. More prominent with fluvoxamine, venlafaxine, paroxetine, sertraline, and vilazodone.
Activation (anxiety, nervousness, agitation)	Usually diminishes after 1-2 weeks. Consider short-term benzodiazepine use only for extreme anxiety, avoided whenever possible. Severe agitation can indicate SSRI intolerance — switch to a different drug class.
Somnolence	Usually diminishes after 1-2 weeks. Bedtime dosing. More prominent with mirtazapine, fluvoxamine, and paroxetine.
Insomnia	Usually diminishes after 1-2 weeks. Daytime dosing; counsel on sleep hygiene. Consider a short-term hypnotic only for severe cases, avoided whenever possible; lemborexant may be considered. More prominent with venlafaxine and bupropion.
Weight gain	Counsel on healthy diet and exercise; monitor weight and metabolic parameters (blood pressure, lipids, glucose). Consider switching to bupropion, which is generally weight-neutral or associated with weight loss. Most prominent with amitriptyline and mirtazapine.
Sexual dysfunction	Often improves once remission is achieved. Consider a PDE5 inhibitor in male patients. Consider switching to an antidepressant less associated with sexual dysfunction: bupropion, mirtazapine, vilazodone, or vortioxetine. All SSRIs and SNRIs carry meaningful sexual dysfunction risk.
Serotonin syndrome (dilated pupils, hyperreflexia, sweating, fever, agitation, nystagmus, clonus, delirium)	Stop the causative drug(s) immediately and refer to hospital. Rare, and occurs mainly with multiple serotonergic agents combined. MAOIs carry the highest risk and require a minimum 2-week washout before starting another serotonergic agent. Amitriptyline, mirtazapine, and trazodone are unlikely to cause serotonin syndrome.^[3]

Discontinuation syndrome

Rapid discontinuation or dose reduction of any antidepressant taken for 6 weeks or more can cause discontinuation syndrome, most often reported with SSRIs given how commonly they're prescribed. Onset is typically within 1-7 days of stopping. Symptoms include anxiety, crying, headache, increased dreaming, insomnia, irritability, myoclonus, nausea, electric-shock sensations, tremor, flu-like symptoms, imbalance, and sensory disturbance; untreated, they typically last 3 days to 3 weeks but can occasionally persist for months. Risk is highest with short-half-life agents (paroxetine, venlafaxine).^[9]

Discontinuation directive

When discontinuing, taper gradually over at least 4-6 weeks — by approximately 25% per week as a starting point, individualized to tolerability — with particular care for paroxetine and venlafaxine. Fluoxetine's long half-life allows a more rapid taper. Reassure patients that discontinuation syndrome is not dangerous and severe symptoms usually resolve within days; if it occurs, either restart the antidepressant and taper more slowly, or bridge with a single dose of fluoxetine 10-20 mg PO (repeatable to a maximum of 3 doses over 7-10 days if symptoms persist). Combining tapering with cognitive or mindfulness-based support may lessen discontinuation-emergent symptoms. Rare, severe, or protracted cases may need hyperbolic tapering (dose reductions smaller than commercially available strengths) via a compounding pharmacy.

Treatment Failure / Next Step

Confirm an adequate trial has actually occurred — minimum therapeutic dose achieved within 2 weeks, and a full 4-6+ week trial at an adequate dose — before concluding the medication has failed.
Reassess the diagnosis: rule out an unrecognized manic/hypomanic history (bipolar disorder), ongoing substance use, nonadherence, or an undiagnosed medical/organic cause.
Partial response with tolerable side effects: optimize to the maximum tolerated/effective dose before considering a switch.
No meaningful response, or a favourable response overshadowed by persistent intolerable side effects (typically assessed during weeks 3-8): switch within the same class if the response was favourable but side effects are the limiting factor; switch out of class (different mechanism, e.g. SSRI to SNRI or another first-line agent) if there has been no meaningful response at all.

Most switches need no washout period — use a crossover technique, tapering the first agent while gradually increasing the new one. Clomipramine is generally not used in cross-tapers. Specific situations require a defined washout (see table below); for detailed cross-tapering instructions, consult a specialized switching resource such as SwitchRx.ca.^[2]

Switching from	Switching to	Recommended washout
Most antidepressants	Most antidepressants	Generally none — crossover taper (except clomipramine, and the exceptions below)
Any other antidepressant	Irreversible MAOI or moclobemide	5 half-lives of the first agent (3 weeks for clomipramine or imipramine)
Irreversible MAOI	Any other antidepressant	2 weeks (3 weeks for clomipramine or imipramine)
Moclobemide	Any other antidepressant	5 days
Fluoxetine	Irreversible MAOI or moclobemide	5-6 weeks
Fluoxetine	Any other antidepressant	Use caution given fluoxetine's long half-life; a washout is often recommended depending on the new agent

Failure of 2 or more adequate trials (adequate dose and duration) meets the definition of treatment-resistant depression.^[10] For moderate-to-severe or recurrent depression (more than 3 prior episodes), strongly consider combination therapy (starting 2 agents at once) or adjunctive augmentation rather than a further sequential switch.
Augmentation strategy tiers
1st-line augmentation
Aripiprazole, brexpiprazole.
2nd-line augmentation
Bupropion, ketamine, esketamine, olanzapine, quetiapine, risperidone, cariprazine, mirtazapine, modafinil, lithium, triiodothyronine.
3rd-line augmentation
Nortriptyline, lisdexamfetamine.
^[2]Do not continue adjunctive antipsychotic augmentation indefinitely without reassessment — monitor for movement disorders, weight gain, and cardiometabolic effects, and be aware of an observed increased mortality risk with adjunctive atypical antipsychotic use even in younger patients; reassess ongoing need at every follow-up rather than continuing by default.^[11]
Adjunctive CBT has evidence specifically in treatment-resistant depression. Neurostimulation (electroconvulsive therapy, repetitive transcranial magnetic stimulation) may be used for treatment-resistant depression under specialist direction.
Refer for psychiatric consultation whenever psychotic symptoms or acute suicidal ideation are present, or after failure of 3 treatment trials.

Common Errors to Avoid

Declaring treatment failure before an adequate dose and an adequate duration (typically 4-6 or more weeks at an adequate dose) has actually been reached.
Stopping an antidepressant abruptly instead of tapering, risking discontinuation syndrome — particularly with paroxetine and venlafaxine given their short half-lives.
Missing an unrecognized history of mania or hypomania and starting unopposed antidepressant monotherapy in a patient who actually has bipolar disorder.
Combining two serotonergic agents (an SSRI/SNRI with an MAOI, St. John's Wort, tramadol, or a triptan) without an appropriate washout — real serotonin syndrome risk.
Continuing adjunctive antipsychotic augmentation indefinitely without reassessing whether it's still needed.
Missing emergent or worsening suicidal ideation, especially in children, adolescents, and young adults, and especially early in treatment.
Discontinuing antidepressant therapy in pregnancy automatically, without weighing relapse risk against medication-exposure risk as a shared decision.
Relying on routine therapeutic drug-level monitoring or routine pharmacogenetic testing for cytochrome P450 polymorphisms — both have limited value for standard SSRI/SNRI dosing; reserve pharmacogenetic testing for a genuine pattern suggesting ultra-rapid or poor-metabolizer status.
Forgetting that fluoxetine's long half-life changes both its own taper (often faster than other SSRIs) and the washout required before switching to an MAOI.
Using a 7-day-or-shorter definition of "no benefit yet" — most antidepressants take 2-4 weeks to show a noticeable effect, and patients need this explained up front to avoid premature discontinuation.

Clinical Decision Algorithm

Initial treatment selection by severity

Confirm MDD diagnosis (DSM-5-TR ≥5/9 criteria) and complete baseline assessment including suicide risk

Screen for a history of mania or hypomania (MDQ or direct history)

History of mania/hypomania present

Do not start unopposed antidepressant monotherapy — manage as bipolar depression, refer/consult psychiatry

No mania/hypomania history

Assess severity (PHQ-9 or clinical judgment)

Mild depression

1st line: psychotherapy (CBT/IPT/BA) or supervised exercise as monotherapy

Reassess at 4-6 weeks; add an antidepressant if response is inadequate or the patient prefers medication

Moderate-severe depression

1st line: antidepressant (SSRI/SNRI/other 1st-line agent) ± psychotherapy (IPT/CBT preferred as combination)

Titrate to minimum therapeutic dose within 2 weeks; increase further over the next 4-6 weeks based on response

Psychotic features, active suicide risk, or severe functional impairment

Refer urgently — antidepressant plus antipsychotic combination and/or ECT referral; psychiatric consultation

Response assessment and switching

Reassess at 2-4 weeks, then again at 4-8 weeks

Full response / remission

Continue the same dose. Continuation phase 6-12 months after remission; maintenance ≥2 years (or longer) if recurrent, chronic, severe, comorbid, or residual symptoms present

Partial response, tolerable side effects

Optimize to the maximum tolerated/effective dose before considering a switch

Still inadequate after dose optimization: add 1st-line augmentation (aripiprazole or brexpiprazole), or switch

No response, or intolerable side effects

Switch within class if response was favourable but side effects are limiting; switch out of class (different mechanism) if there was no meaningful response

Crossover taper for most switches; MAOI/moclobemide transitions require a defined washout (see Treatment Failure & Next Steps)

Treatment-resistant depression

2 or more adequate antidepressant trials (adequate dose and duration) without adequate response

Confirm the diagnosis, adherence, and rule out an unrecognized bipolar disorder or substance use

Combination/augmentation appropriate — moderate-severe, recurrent, or more than 3 prior episodes

1st-line augmentation: aripiprazole or brexpiprazole added to the current antidepressant

2nd-line augmentation: bupropion, ketamine, esketamine, olanzapine, quetiapine, risperidone, cariprazine, mirtazapine, modafinil, lithium, or triiodothyronine

Antipsychotic augmentation: reassess ongoing need regularly; monitor for movement disorders, weight gain, cardiometabolic effects, and increased mortality risk — not for indefinite routine use

Specialist-level intervention indicated

Adjunctive CBT, or refer for neurostimulation (ECT/rTMS) or intranasal esketamine combined with an SSRI/SNRI (controlled distribution program)

Refer for psychiatric consultation after failure of 3 treatment trials, or at any point for psychotic symptoms or acute suicidal ideation

Drug Tables

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Selective Serotonin Reuptake Inhibitors (SSRIs)

All SSRIs share a common adverse-effect and interaction profile: GI upset, anorexia, dry mouth, diaphoresis, headache, dizziness, insomnia, somnolence, anxiety, agitation, and tremor on initiation (usually resolving after 2 weeks); sexual dysfunction and weight gain can persist; rare SIADH with hyponatremia. All are CYP-enzyme substrates and increase GI bleeding risk when combined with NSAIDs or antiplatelet agents^{^[12]} — co-prescribe gastroprotection or avoid the combination when possible. Concurrent use with MAOIs, linezolid, or methylene blue is contraindicated (serotonin syndrome risk).

Drug	Dosage	Adverse effects	Drug interactions	Comments
Citalopram	Initial: 10-20 mg PO daily Usual: 20-40 mg/day High (specialist-guided): 40 mg/day	As above; dose-related QTc prolongation	Avoid combining with other QTc-prolonging drugs, especially at higher doses	First-line SSRI.
Escitalopram	Initial: 10 mg PO daily Usual: 10-20 mg/day High (specialist-guided): 20 mg/day	As above; dose-related QTc prolongation	Avoid combining with other QTc-prolonging drugs, especially at higher doses	First-line SSRI; the active stereoisomer of citalopram.
Fluoxetine	Initial: 10-20 mg PO daily Usual: 20-40 mg/day High (specialist-guided): 60-80 mg/day	As above; anxiety on initiation is common	Potent CYP2D6 inhibitor	First-line SSRI; long half-life allows a faster taper and a bridging role in discontinuation syndrome (see Monitoring & Follow-up).
Fluvoxamine	Initial: 50-100 mg PO daily Usual: 150-200 mg/day High (specialist-guided): 400 mg/day	As above; somnolence and nausea are common	Potent CYP1A2 inhibitor	First-line SSRI.
Paroxetine, immediate-release	Initial: 10-20 mg PO daily Usual: 20-40 mg/day High (specialist-guided): 60 mg/day	As above; anticholinergic effects and somnolence are common	Potent CYP2D6 inhibitor	First-line SSRI; short half-life gives a high discontinuation-syndrome risk — taper particularly slowly.
Paroxetine, controlled-release	Initial: 12.5-25 mg PO daily Usual: 25-50 mg/day High (specialist-guided): 75 mg/day	As above; anticholinergic effects and somnolence are common	Potent CYP2D6 inhibitor	Alternative formulation; same discontinuation caution as immediate-release.
Sertraline	Initial: 25-50 mg PO daily Usual: 50-100 mg/day High (specialist-guided): 150-200 mg/day	As above; weak CYP2D6 inhibitor effect on itself	Weak CYP2D6 inhibitor	First-line SSRI; preferred in pregnancy, breastfeeding, and cardiac disease.

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Drug	Dosage	Adverse effects	Drug interactions	Comments
Desvenlafaxine	Initial: 50 mg PO daily Usual: 50 mg/day High (specialist-guided): 100 mg/day	Nausea, sleep disturbance, drowsiness, nervousness, dizziness, dry mouth	Potent CYP3A4 inhibitors may increase levels. Use with MAOIs, linezolid, or methylene blue may cause a potentially fatal reaction (tremor, agitation, hypomania, hyperthermia, hypertension). Use caution combining with other serotonergic agents.	First-line SNRI; the active metabolite of venlafaxine. One of the few antidepressants systematically evaluated as effective in peri- and postmenopausal patients.
Duloxetine	Initial: 30-60 mg PO daily Usual: 60 mg/day High (specialist-guided): 120 mg/day	Nausea, drowsiness, insomnia, dizziness, dry mouth; isolated hepatic injury reported	Do not use with potent CYP1A2 inhibitors (ciprofloxacin, fluvoxamine, ketoconazole). Use with MAOIs, linezolid, or methylene blue may cause a potentially fatal reaction (tremor, agitation, hypomania, hyperthermia, hypertension). Use caution combining with other serotonergic agents.	First-line SNRI; also indicated for neuropathic pain and fibromyalgia. Cigarette smoke induces CYP1A2 — smokers may need higher doses.
Levomilnacipran	Initial: 20 mg/day PO for 2 days, then 40 mg/day Usual: 40-120 mg/day High (specialist-guided): 120 mg/day	Nausea, dry mouth, constipation, hyperhidrosis, headache, dizziness, increased heart rate, tachycardia, erectile dysfunction	Potent CYP3A4 inhibitors may increase levels. Use with MAOIs, linezolid, or methylene blue may cause a potentially fatal reaction (tremor, agitation, hypomania, hyperthermia, hypertension). Use caution combining with other serotonergic agents.	First-line SNRI; higher norepinephrine-to-serotonin reuptake-inhibition ratio than other SNRIs. Monitor blood pressure and heart rate.
Venlafaxine XR	Initial: 37.5-75 mg PO daily Usual: 112.5-225 mg/day High (specialist-guided): 300-375 mg/day	Nausea, sleep disturbance, drowsiness, nervousness, dizziness, dry mouth; dose-related hypertension, particularly ≥225 mg/day	Strong CYP2D6/CYP3A4 inhibitors (ketoconazole, quinidine, fluoxetine, paroxetine) may increase levels. Use with MAOIs, linezolid, or methylene blue may cause a potentially fatal reaction (tremor, agitation, hypomania, hyperthermia, hypertension). Use caution combining with other serotonergic agents.	First-line SNRI; monitor blood pressure. Short half-life gives a high discontinuation-syndrome risk.

Dual-Action Antidepressants

Drug	Dosage	Adverse effects	Drug interactions	Comments
Bupropion (SR/XL)	SR initial: 150 mg/day PO, divided doses if >150 mg SR usual: 150-300 mg/day SR high (specialist-guided): 375-450 mg/day XL initial: 150 mg/day PO once daily XL usual: 150-300 mg/day XL high (specialist-guided): 450 mg/day	Agitation, insomnia, anorexia; contraindicated in seizure disorder and current/recent anorexia or bulimia nervosa	May increase levels of cyclophosphamide, ifosfamide, and orphenadrine. Use with MAOIs, linezolid, or methylene blue may cause a potentially fatal reaction (tremor, agitation, hypomania, hyperthermia, hypertension). Use caution combining with other serotonergic agents.	First-line, dual-action (norepinephrine/dopamine); low sexual dysfunction and GI-effect rates. Also indicated for smoking cessation under a different brand.
Mirtazapine	Initial: 15-30 mg/day PO Usual: 30-45 mg/day High (specialist-guided): 60 mg/day	Weight gain, sedation; QTc prolongation and torsades de pointes reported at risk or in overdose	Sedative effects potentiated by alcohol or benzodiazepines. Use with MAOIs, linezolid, or methylene blue may cause a potentially fatal reaction (tremor, agitation, hypomania, hyperthermia, hypertension). Use caution combining with other serotonergic agents.	First-line; acts on both noradrenergic and serotonergic systems. Orally disintegrating tablets can be taken without water.

Other Serotonin Modulators

Drug	Dosage	Adverse effects	Drug interactions	Comments
Trazodone	Initial: 150-200 mg/day PO Usual: 300-400 mg/day High (specialist-guided): 600 mg/day	Drowsiness, orthostatic hypotension, nausea, headache, dry mouth, priapism	Toxicity increased by CYP3A4 inhibitors (clarithromycin, erythromycin, grapefruit juice, ketoconazole); effectiveness reduced by CYP3A4 inducers (carbamazepine, phenytoin, rifampin). May potentiate other CNS depressants and antihypertensives. Avoid with MAOIs.	Second-line at full antidepressant doses given severe daytime sedation; more often used at low doses as a hypnotic alongside another antidepressant. No tolerance develops as with benzodiazepines.
Vilazodone	Initial: 10 mg/day PO with food x7 days Usual: 20 mg/day with food, may increase to 40 mg/day after 7 days if needed High (specialist-guided): 40 mg/day	Diarrhea, nausea, vomiting, insomnia	Potent CYP3A4 inhibitors may significantly increase levels — do not exceed 20 mg/day if combined with one. Use with MAOIs, linezolid, or methylene blue may cause a potentially fatal reaction (tremor, agitation, hypomania, hyperthermia, hypertension). Use caution combining with other serotonergic agents.	First-line; multimodal (serotonin reuptake inhibition plus 5-HT1A partial agonism). Take with food for adequate absorption. Lower sexual dysfunction rate than SSRIs.
Vortioxetine	Initial: 5-10 mg/day PO Usual: 10-20 mg/day High (specialist-guided): 20 mg/day	Nausea, constipation, vomiting; transient discontinuation symptoms (headache, increased dreaming, mood swings, muscle tension, vertigo, rhinorrhea)	Potential additive bleeding risk with warfarin, ASA, and other antiplatelet agents. Use with MAOIs, linezolid, or methylene blue may cause a potentially fatal reaction (tremor, agitation, hypomania, hyperthermia, hypertension). Use caution combining with other serotonergic agents.	First-line; multimodal serotonergic mechanism with a favourable cognitive and sexual side-effect profile.

Tricyclic Antidepressants (TCAs)

Second-line, reserved given tolerability and cardiotoxicity-in-overdose concerns. All share anticholinergic effects (dry mouth, blurred vision, constipation, urinary hesitancy, tachycardia, delirium), antihistaminergic effects (sedation, weight gain), orthostatic hypotension, a lowered seizure threshold, and sexual dysfunction. Inducers of CYP1A2 (barbiturates, carbamazepine, rifampin) may decrease effect; cimetidine and antipsychotics may increase effect and toxicity; caution with antiarrhythmics, and may reduce the antihypertensive effect of clonidine or augment the hypotensive effect of thiazides. Use with MAOIs, linezolid, or methylene blue may cause a potentially fatal reaction (tremor, agitation, hypomania, hyperthermia, hypertension). Use caution combining with other serotonergic agents.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Amitriptyline	Initial: 25-50 mg/day PO Usual: 75-200 mg/day High (specialist-guided): 250-300 mg/day	As above	As above	Most frequently prescribed TCA; often used at lower doses for sleep or analgesia.
Clomipramine	Initial: 25-50 mg/day PO Usual: 75-200 mg/day High (specialist-guided): 250-300 mg/day	As above	As above	The most serotonergic TCA; still favoured for obsessive-compulsive disorder. Not recommended in cross-tapers when switching antidepressants.
Desipramine	Initial: 25-50 mg/day PO Usual: 75-200 mg/day High (specialist-guided): 250-300 mg/day	As above	As above	Secondary-amine TCA.
Doxepin	Initial: 25-50 mg/day PO Usual: 75-200 mg/day High (specialist-guided): 250-300 mg/day	As above	As above	Avoid in pregnancy; not recommended while breastfeeding due to documented infant adverse effects.
Imipramine	Initial: 25-50 mg/day PO Usual: 75-200 mg/day High (specialist-guided): 250-300 mg/day	As above	As above	One of the original TCAs.
Nortriptyline	Initial: 25-50 mg/day PO Usual: 75-150 mg/day High (specialist-guided): 200 mg/day	As above	As above	A metabolite of amitriptyline; better tolerated than other TCAs and long used in older adults.
Trimipramine	Initial: 25-50 mg/day PO Usual: 75-200 mg/day High (specialist-guided): 250-300 mg/day	As above	As above

Reversible Monoamine Oxidase-A Inhibitor

Drug	Dosage	Adverse effects	Drug interactions	Comments
Moclobemide	Initial: 200-300 mg/day PO Usual: 450-600 mg/day High (specialist-guided): 900 mg/day	Nausea, insomnia, dizziness	Increased risk of potentially fatal serotonin syndrome and/or hypertensive crisis with other serotonergic agents — consult a reliable drug interaction reference before co-prescribing.	No dietary restriction required at recommended doses, unlike the irreversible MAOIs. Often well tolerated, particularly with a prominent anxiety component.

Irreversible Monoamine Oxidase Inhibitors

Third-line; generally reserved for specialized mood-disorder clinics given the risk of potentially fatal food and drug interactions.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Phenelzine	Initial: 15-30 mg/day PO Usual: 30-75 mg/day High (specialist-guided): 90-120 mg/day	Edema, postural hypotension, insomnia, sexual dysfunction	Many significant reactions reported; increased risk of potentially fatal serotonin syndrome and/or hypertensive crisis. Tyramine-containing foods can also precipitate hypertensive crisis — dietary counselling is mandatory.	Third-line; specialist-initiated only. Strict washout required when switching to or from other serotonergic agents (see Treatment Failure & Next Steps).
Tranylcypromine	Initial: 10-20 mg/day PO Usual: 20-60 mg/day High (specialist-guided): 60-80 mg/day	Edema, postural hypotension, insomnia, sexual dysfunction	Many significant reactions reported; increased risk of potentially fatal serotonin syndrome and/or hypertensive crisis. Tyramine-containing foods can also precipitate hypertensive crisis — dietary counselling is mandatory.	Third-line; specialist-initiated only. Strict washout required when switching to or from other serotonergic agents (see Treatment Failure & Next Steps).

NMDA Receptor Antagonists (Rapid-Acting, Treatment-Resistant Depression)

Drug	Dosage	Adverse effects	Drug interactions	Comments
Esketamine, intranasal	Weeks 1-4: 28-56 mg intranasally twice weekly, may increase by 28 mg increments up to 84 mg twice weekly Weeks 5-8: Decrease to once weekly Week 9 onward: May decrease to once every 1-2 weeks Usual maintenance: 56-84 mg intranasally every 1-2 weeks	Anxiety, dissociation, sedation, headache, dizziness, vertigo, hypoesthesia, dysgeusia, nausea, vomiting, increased blood pressure	Excess sedation with other CNS depressants — may require dose adjustment/closer monitoring. Avoid alcohol within 24 hours of a dose. Risk of hypertensive crisis with other blood-pressure-raising drugs (amphetamine salts, MAOIs, methylphenidate, triptans) — avoid combination or monitor blood pressure closely. Avoid other nasal sprays within 1 hour of dosing.	Indicated for treatment-resistant depression in combination with an SSRI or SNRI.^[13] Available only through a controlled distribution program; a trained health-care professional must supervise each dose and monitor clinical status and blood pressure for at least 2 hours afterward.
Ketamine, IV (racemic)	Typical infusion dose: 0.5 mg/kg IV infused over 40 minutes, per institutional/specialist protocol	Dissociation, sedation, elevated blood pressure and heart rate, transient perceptual disturbance	Excess sedation with other CNS depressants. Avoid combining with other agents that raise blood pressure without close monitoring.	Specialist-administered for treatment-resistant depression; the CANMAT-recommended protocol dose is given below.^[14] No standardized outpatient/primary-care regimen exists — this is a specialist- and institution-administered therapy, not a community-pharmacy dispensed product.

Second-Generation Antipsychotics (Adjunctive Augmentation)

Response to antipsychotic augmentation should generally be assessed within 2 weeks. All carry a class caution about antipsychotic-associated body-temperature dysregulation — counsel on hydration and sun protection — and are not intended for indefinite long-term use; reassess ongoing need regularly given the observed increased mortality risk with adjunctive atypical antipsychotic use.^[11]

Drug	Dosage	Adverse effects	Drug interactions	Comments
Aripiprazole	Adjunctive dose: 2-15 mg/day PO	Extrapyramidal symptoms, dizziness, orthostatic hypotension, headache, GI complaints, nasopharyngitis, tremor, sedation, insomnia	Strong CYP2D6/CYP3A4 inducers (carbamazepine, phenytoin, rifampin) substantially decrease levels; strong CYP2D6/CYP3A4 inhibitors (ketoconazole, quinidine, fluoxetine, paroxetine) substantially increase levels.	1st-line adjunctive augmentation agent.
Brexpiprazole	Adjunctive dose: 1-2 mg/day PO	Weight gain, hyperglycemia, elevated triglycerides, extrapyramidal symptoms (less common than with aripiprazole), headache, rare orthostatic hypotension	Strong CYP2D6/CYP3A4 inducers substantially decrease levels; strong CYP2D6/CYP3A4 inhibitors substantially increase levels.	1st-line adjunctive augmentation agent.
Quetiapine, extended-release	Augmentation: 25-100 mg/day PO Monotherapy initial: 50 mg/day PO x2 days, then 150 mg/day Monotherapy usual: 150 mg/day, may increase to 300 mg/day on or after day 4	Sedation, dizziness, weight gain, orthostatic hypotension, elevated transaminases, headache, anticholinergic effects, increased diabetes/dyslipidemia risk, possible increased cataract risk; may reduce thyroid hormone levels	Sedation potentiated by other CNS depressants; may potentiate antihypertensives. CYP1A2/CYP2D6 inhibitors (diltiazem, fluvoxamine, paroxetine) may increase levels; CYP1A2/CYP2D6 inducers (barbiturates, carbamazepine, phenytoin, rifampin, cigarette smoking) may decrease levels.	2nd-line; low doses augment standard antidepressants, higher doses can be used as monotherapy based on tolerability.
Olanzapine	Adjunctive dose: 2.5-10 mg/day PO	Weight gain, dizziness, sedation, anticholinergic effects, elevated transaminases, orthostatic hypotension, increased diabetes/dyslipidemia risk, extrapyramidal symptoms (especially akathisia)	Sedation potentiated by other CNS depressants; may potentiate antihypertensives. CYP1A2/CYP2D6 inhibitors (diltiazem, fluvoxamine, paroxetine) may increase levels; CYP1A2/CYP2D6 inducers (barbiturates, carbamazepine, phenytoin, rifampin, cigarette smoking) may decrease levels.	2nd-line adjunctive augmentation agent.
Risperidone	Adjunctive dose: 0.25-2 mg/day PO	Sedation, headache, weight gain, orthostatic hypotension, rhinitis, anxiety, dose-related hyperprolactinemia, extrapyramidal symptoms; risk of intraoperative floppy iris syndrome in prior users undergoing cataract surgery	Additive sedation with other CNS depressants; may potentiate antihypertensives. CYP3A4 inhibitors (clarithromycin, erythromycin, grapefruit juice, ketoconazole, prednisone) may increase levels; CYP3A4 inducers (carbamazepine, phenytoin, rifampin) may decrease levels.	2nd-line adjunctive augmentation agent.
Cariprazine	Adjunctive dose: 1.5-3 mg/day PO	Akathisia, extrapyramidal symptoms, nausea, insomnia	CYP3A4 inhibitors/inducers significantly affect levels given a long half-life active metabolite — consult a current interaction reference before co-prescribing.	2nd-line adjunctive augmentation agent per the published adjunctive-MDD trial dosing.

Other Augmentation Agents

2nd- and 3rd-line augmentation options named in the CANMAT guideline.^[2]

Drug	Dosage	Adverse effects	Drug interactions	Comments
Lithium carbonate	Initial: 300 mg/day PO, once daily or divided Usual: 600-900 mg/day divided doses, titrated to a serum level of 0.4-0.8 mmol/L	Tremor, polyuria/polydipsia, weight gain, hypothyroidism, GI upset; narrow therapeutic index	NSAIDs, ACE inhibitors, ARBs, and thiazide diuretics can increase lithium levels; requires baseline and periodic renal and thyroid function monitoring plus serum lithium levels.	2nd-line augmentation; monitor serum level, renal function, and thyroid function.
Liothyronine (T3)	Adjunctive dose: 25-50 mcg/day PO	Palpitations, tremor, insomnia, weight loss	Additive effect with other thyroid hormone replacement; monitor for cardiac symptoms, especially in older adults or those with cardiac disease.	2nd-line augmentation, particularly when subtle thyroid dysfunction is suspected.
Modafinil	Adjunctive dose: 100-200 mg PO each morning	Headache, nausea, nervousness, insomnia	Inducer of CYP3A4 — may reduce efficacy of hormonal contraceptives; caution with other CYP3A4 substrates.	2nd-line augmentation, particularly for prominent fatigue or sedation from the primary antidepressant.
Lisdexamfetamine	Adjunctive dose: 30-70 mg PO each morning, titrated by a specialist	Insomnia, decreased appetite, increased heart rate and blood pressure, anxiety	Avoid combining with MAOIs. Additive cardiovascular stimulant effect with other stimulants or decongestants.	3rd-line augmentation; specialist-directed titration given cardiovascular stimulant effects and misuse potential.

Natural Health Products

Evidence-based natural health product options; all carry a serotonin syndrome risk when combined with prescription antidepressants — confirm the patient isn't already taking one before adding, and vice versa.

Drug	Dosage	Adverse effects	Drug interactions	Comments
St. John's Wort	Usual: 300 mg PO TID Range: 300-1800 mg/day in 2-3 divided doses	Photosensitivity (rare), GI upset, dizziness, insomnia, restlessness, agitation; case reports of mania/hypomania	Inducer of CYP3A4 and P-glycoprotein — can meaningfully reduce levels of oral contraceptives, warfarin, cyclosporine, digoxin, indinavir, and theophylline. Avoid combining with MAOIs, linezolid, methylene blue, or SSRIs given serotonin syndrome/hypertensive crisis risk.	Some evidence supports monotherapy for mild-to-moderate MDD; screen carefully for interacting medications before recommending.
SAM-e (S-adenosylmethionine)	Usual: 400-1600 mg/day PO in 2-3 divided doses	Mild insomnia, constipation, dizziness, nausea, dry mouth, sweating; case reports of increased anxiety, mania, or hypomania in bipolar disorder	Potential additive bleeding risk with warfarin, ASA, and other antiplatelet/anticoagulant agents. Avoid concurrent use with other serotonergic drugs, including antidepressants, given serotonin syndrome risk.	Evaluated as both adjunctive and monotherapy, with limited evidence supporting its use in MDD.
L-Methylfolate	Adjunctive dose: 15 mg/day PO	Generally well tolerated; occasional GI upset, insomnia, agitation	No significant CYP interactions reported; may theoretically reduce the efficacy of antifolate drugs (e.g., methotrexate).	Adjunctive therapy with an SSRI in SSRI-resistant/partial-response depression, crossing the blood-brain barrier unlike standard folic acid.^[15]

Omega-3 fatty acids, folic acid, and vitamin D have also been studied as adjunctive treatments for depression; current evidence for a clinically meaningful benefit from any of these is weak, and none is recommended as a primary strategy.

References

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) — American Psychiatric Association. Washington (DC): American Psychiatric Publishing; 2022
Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults — Canadian Journal of Psychiatry (Lam RW, Kennedy SH, Adams C, et al.). Can J Psychiatry 2024;69(9):641-687
Demystifying serotonin syndrome (or serotonin toxicity) — Canadian Family Physician (Foong AL, Grindrod KA, Patel T, Kellar J). Can Fam Physician 2018;64(10):720-727
The PHQ-9: validity of a brief depression severity measure — Journal of General Internal Medicine (Kroenke K, Spitzer RL, Williams JB). J Gen Intern Med 2001;16(9):606-613
Canadian Network for Mood and Anxiety Treatments 2024 Clinical Practice Guideline for the Management of Perinatal Mood, Anxiety, and Related Disorders — Canadian Journal of Psychiatry (Vigod SN, Frey BN, Clark CT, et al.). Can J Psychiatry 2025;70(6):429-489
Antidepressant exposure during pregnancy and congenital malformations: is there an association? A systematic review and meta-analysis of the best evidence — Journal of Clinical Psychiatry (Grigoriadis S, VonderPorten EH, Mamisashvili L, et al.). J Clin Psychiatry 2013;74(4):e293-e308
Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn — New England Journal of Medicine (Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al.). N Engl J Med 2006;354(6):579-587
Selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors in pregnancy: infant and childhood outcomes — Paediatrics & Child Health (Hendson L, Shah V, Trkulja S; Canadian Paediatric Society). Paediatr Child Health 2021;26(5):321-322
Antidepressant discontinuation syndrome — American Family Physician (Warner CH, Bobo W, Warner C, et al.). Am Fam Physician 2006;74(3):449-456
Treatment-resistant major depressive disorder: Canadian expert consensus on definition and assessment — Depression and Anxiety (Rybak YE, Lai KSP, Ramasubbu R, et al.). Depress Anxiety 2021;38(4):456-467
Mortality risk of antipsychotic augmentation for adult depression — PLoS One (Gerhard T, Stroup TS, Correll CU, et al.). PLoS One 2020;15(9):e0239206
Meta-analysis: gastrointestinal bleeding due to interaction between selective serotonin uptake inhibitors and non-steroidal anti-inflammatory drugs — Alimentary Pharmacology & Therapeutics (Loke YK, Trivedi AN, Singh S). Aliment Pharmacol Ther 2008;27(1):31-40
Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study — American Journal of Psychiatry (Popova V, Daly EJ, Trivedi M, et al.). Am J Psychiatry 2019;176(6):428-438
The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force recommendations for the use of racemic ketamine in adults with major depressive disorder — Canadian Journal of Psychiatry (Swainson J, McGirr A, Blier P, et al.). Can J Psychiatry 2021;66(2):113-125
L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials — American Journal of Psychiatry (Papakostas GI, Shelton RC, Zajecka JM, et al.). Am J Psychiatry 2012;169(12):1267-1274

Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.

Depression

DSM-5-TR diagnostic criteria for a major depressive episode

Persistent depressive disorder (dysthymia)

Screening for medication-induced depressive symptoms

Differentiating MDD from commonly confused presentations

History

Screening and severity-assessment tools

PHQ-9 scoring

Baseline investigations

Psychotherapy

Technology-based psychotherapy

Motivational interviewing

Psychoeducation

Exercise

Diet

Light therapy

Neurostimulation

CANMAT antidepressant classification

First-line agents

Second-line agents

Third-line agents

Pregnancy

Postpartum mood disturbances

Postpartum "blues"

Postpartum major depression

Postpartum psychosis

Breastfeeding

Older adults

Children and adolescents

Renal and hepatic impairment

Phases of antidepressant therapy

Acute phase

Continuation phase

Maintenance phase

Ongoing monitoring

Managing common treatment-emergent adverse effects

Discontinuation syndrome

Augmentation strategy tiers

1st-line augmentation

2nd-line augmentation

3rd-line augmentation

Selective Serotonin Reuptake Inhibitors (SSRIs)

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Dual-Action Antidepressants

Other Serotonin Modulators

Tricyclic Antidepressants (TCAs)

Reversible Monoamine Oxidase-A Inhibitor

Irreversible Monoamine Oxidase Inhibitors

NMDA Receptor Antagonists (Rapid-Acting, Treatment-Resistant Depression)

Second-Generation Antipsychotics (Adjunctive Augmentation)

Other Augmentation Agents

Natural Health Products