Depression

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]

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]

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]

• 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.

Differentiating MDD from commonly confused presentations

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

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]

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.

• 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.

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:

1. Take the medication daily.
2. Call your prescriber or pharmacist with questions about side effects or other issues.
3. It may take 2–4 weeks to see a noticeable effect.
4. Continue taking the medication even after you start feeling better.
5. 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.

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.

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.

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

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]

1. 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.
2. Reassess the diagnosis: rule out an unrecognized manic/hypomanic history (bipolar disorder), ongoing substance use, nonadherence, or an undiagnosed medical/organic cause.
3. Partial response with tolerable side effects: optimize to the maximum tolerated/effective dose before considering a switch.
4. 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.
5. 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

6. 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]
7. 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.
8. Refer for psychiatric consultation whenever psychotic symptoms or acute suicidal ideation are present, or after failure of 3 treatment trials.

• 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.

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).

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Dual-Action Antidepressants

Other Serotonin Modulators

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.

Reversible Monoamine Oxidase-A Inhibitor

Irreversible Monoamine Oxidase Inhibitors

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

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

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]

Other Augmentation Agents

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

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.

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.