Treatment of Adult Major Depressive Disorder (MDD)

Last Updated: December 16, 2019

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This tool is designed to support primary care providers in the treatment of adult patients (≥ 18 years) who have major depressive disorder (MDD). MDD is the most prevalent depressive disorder, and approximately 7% of Canadians meet the diagnostic criteria every year.1,2 The treatment of MDD involves psychotherapy and/or pharmacotherapy. Providers should work with patients to create a treatment plan together using providers’ clinical expertise and keeping in mind the patient’s preferences, as well as the practicality, feasibility, availability and affordability of treatment.

In case of an emergency: Advise your patient, their family, caregivers and friends to call 911 or go to the Emergency Department.

Consult the CEP’s Keeping Your Patients Safe on how to complete a Form 1, if you believe that your patient is at immediate risk of harming themselves or others.

Click on the sections below to get started:

Screen patient for MDD

Talking points

It is important to provide your patient with non-judgmental care (e.g. “Being diagnosed with depression is nothing to be ashamed of, it is very common and many adults are diagnosed with it every year”).

  • Don’t use clinical/psychiatric language (e.g. “mental health,” “psychiatric,” and/or “maladaptive”) unless the patient uses these terms first.
  • Use understandable language for cognitive distortions (e.g. “assumption” which covers many cognitive distortions, “thought trap” instead of rumination).
  • Use positive language, and maintain a focus on your patient’s strengths.
  • Avoid stigmatizing labels (e.g. “abnormal”, “unusual”).
  • Talk about symptoms instead of disorders/diagnoses.
Screen

If patient has suspected depression, screen the patient using the PHQ-9.3

Quick Reference: Interpreting PHQ-9 results

PHQ-9 score <4: Patient’s PHQ-9 score does not meet criteria for MDD

  • Set EMR reminders to follow-up at the patient’s next appointment to see if their PHQ-9 score changes.

PHQ-9 score 5-9: Mild MDD indicated
PHQ-9 score 10-14: Moderate MDD indicated
PHQ-9 score >14: Severe MDD indicated

Conduct risk assessment

Confirm MDD diagnosis

Conduct Diagnostic Work-up

  • Rule out causes of secondary MDD by considering testing for B-12 deficiency, CBC, folic acid deficiency, corticosteroid medication, hypothyroidism and syphilis. If necessary, treat the cause of secondary MDD and other disorders.
  • Rule out comorbid alcohol5 and substance use disorder6
  • Rule out bipolar disorder7
  • Assess if patient has a sleeping disorder8
  • Rule out other chronic diseases
Confirm the diagnosis of MDD using the DSM-V criteria

A DSM-V score of > 5 with symptoms during the same two week period that are a change from the previous functioning. Depressed Mood (Q1) and/or loss of interest/pleasure (Q2) must be present.9

Assess suicidality

Suicidal thoughts, plans, and attempts are very common among people with MDD.10 Every clinical encounter with a patient that has MDD should include an assessment of suicide risk.10

In case of an emergency: Advise your patient, their family, caregivers and friends to call 911 or go to the Emergency Department.

Consult the CEP’s Keeping Your Patients Safe on how to complete a Form 1, if you believe that your patient is at immediate risk of harming themselves or others.

Assess if a patient is at risk of suicide or developing suicidal thoughts by using the Columbia-Suicide Severity Rating Scale (C-SSRS).

Use active listening: involves receiving a message, processing it, and sending it back. Remember that your patient is the expert on their own experience.

Manage suicide-related behaviour

  • Schedule periodic follow-up appointments to track your patient’s progress and assess their well-being.
  • Monitor the presence and strength of the patients’ protective factors.4
  • Help your patient identify the nearest distress centre.11

Create a management plan

Create a safety plan with lower-risk patients

Having a safety plan in place is important for both patients and providers as it:

  1. facilitates honest communication between patient and provider;
  2. establishes a collaborative relationship between patient and provider;
  3. facilitate the patient’s active involvement; and
  4. enhances patient’s commitment to treatment.

Basic components of a safety plan:

  1. Work with your patient to develop a safety plan that they can use when in crisis.
  2. Recognize warning signs that are proximal to an impending suicidal crisis.
  3. Identify and employ internal coping strategies without needing to contact another person.
  4. Use contacts with people as a means of distraction from suicidal thoughts and urges (e.g. going to healthy social settings without discussing suicidal thoughts).
  5. Contact family members or friends who may help to resolve a crisis and with whom suicidality can be discussed.
  6. Contact mental health professionals or agencies.
  7. Reduce the potential use of lethal means.
  • See Keeping Your Patients Safe and Portico for more information.
  • Click here to access a safety plan template.
Establish treatment plan

Depending on the severity of your patient’s MDD, non-pharmacological, pharmacological therapies and/or complementary and alternative medicines are available. Providers should work with patients to create a treatment plan together using providers’ clinical expertise and keeping in mind the patient’s preferences, as well as the practicality, feasibility, availability and affordability of treatment.

It is suggested to offer a combination of psychotherapy and pharmacotherapy for patients with:

  • Severe (i.e. PHQ-9 >20) MDD
  • Chronic (duration greater than two years) MDD
  • Recurrent (with three or more episodes) MDD

For additional help, consult specialists across the province to provide the best care possible for patients with complex MDD at OTN eConsult15 and the Collaborative Mental Health Network (CMHN).16

Click below to review the psychotherapy, pharmacotherapy, complementary and alternative medicine treatments available to the patient.

Psychotherapy options

When selecting a specific type of psychotherapy consider the patient’s treatment goals and preferences (e.g. group or individual therapy), whether the patient has had a prior positive response to psychotherapy treatment and if providers skilled in the preferred psychotherapy approach are available. 

Stepped care approach

Start with the least intrusive form of care and progress to more intensive care if needed.

Talking points

Set realistic expectations when initiating treatment:

  • “If you stick to your treatment, you should feel better than you do now. It’s also okay if you don’t feel better right away. We can help to eventually make your life feel easier.”
  • “Recovery will have its ups and downs.”
  • “People who stick to their treatment plan are the ones who see the most improvement over time. So, we are going to work together to make sure that happens.”

Provide your patient with adequate support:

  • “Depression is a common experience, you’re not alone in this. It takes a lot of strength to seek support.”
First line pyschotherapy options
Scroll (left-right) for details
  • Cognitive-behavioral therapy (CBT)

    Description

    • CBT treats MDD by teaching patients to modify both thinking and behavior.13, 29

    Relative efficacy

    • CBT remains the most established evidence-based, first-line treatment for depression.30
  • Interpersonal psychotherapy (IPT)

    Description

    • IPT focuses on patients’ relational stressors involving losses, changes, disagreements, or interpersonal sensitivity, which are associated with the onset or perpetuation of present symptoms.30
  • Behavioral Activation (BA)

    Description

    • BA is a particular version of BT that targets the link between avoidant behavior and depression and expands the treatment component of BT.13
  • Behavior Therapy (BT)
    • Description

    BT for major depression refers to a class of psychotherapy interventions that treat MDD by teaching patients to increase rewarding activities.13

  • Acceptance and Commitment Therapy (ACT)

    Description

    • ACT is a manualized psychotherapy intervention derived from relational frame theory that emphasizes acceptance of emotional distress and engagement in goal directed behaviors.13
  • Mindfulness-based Cognitive Therapy (MBCT)
    • Description
      MBCT integrates traditional CBT interventions with mindfulness-based skills, including mindfulness meditation, imagery, experiential exercises, and other techniques that aid patients in experiencing affect without necessarily attempting to change it.13
  • Problem-solving Therapy (PST)

    Description

    • PST is defined as a discrete, time-limited, structured psychological intervention that focuses on learning to cope with specific problem areas and where therapist and patient work collaboratively to identify and prioritize key problem areas.13
  • Short-Term Psychodynamic Psychotherapy (STPP)

    Description

    • STPP is defined as psychodynamic psychotherapy of approximately 10 to 20 weeks duration.13

    Relative efficacy

    • STPP is considered not as effective as other first line psychotherapies.30

Pharmacotherapy options

The selection of a first-line antidepressant is dependent on the following considerations:

Patient

  • Clinical features and dimensions (see below)
  • Comorbid conditions
  • Response and side effects of previous use of antidepressants
  • Patient preference

Medication

  • Comparative efficacy
  • Comparative tolerability warnings, contraindications and precautions
  • Potential interactions with other medications.
  • Simplicity of use
  • Cost and availability
Treatment recommendations based on clinical specifiers/dimensions

The following are treatment options available to treat the clinical specifier and dimension of a patients MDD. 

For depression with melancholic features, atypical features, with seasonal pattern, no specific antidepressants have demonstrated superiority.

Specifiers/Dimensions
  • Use an antidepressant with efficacy in generalized anxiety disorder (level of evidence: •)
  • Benzodiazepines (level of evidence: • •)
  • Use antipsychotic and antidepressant co-treatment (level of evidence: • • • •)
  • Lurasidone (level of evidence: • • •)
  • Ziprasidone (level of evidence: • •)
  • Vortioxetine (level of evidence: • • • •)
  • Bupropion (level of evidence: • • •)
  • Duloxetine (level of evidence: • • •)
  • SSRIs (level of evidence: • • •)
  • Moclobemide (level of evidence: • •)
  • Agomelatine (level of evidence: • • • •)
  • Mirtazapine (level of evidence: • • •)
  • Quetiapine (level of evidence: • • •)
  • Trazodone (level of evidence: • • •)

For pain

  • Duloxetine (level of evidence: • • • •)
  • Other SNRIs (level of evidence: • • •)

For fatigue

  • Bupropion (level of evidence: • • • •)
  • SSRIs (level of evidence: • • •)

For energy

  • Duloxetine (level of evidence: • • •)

Adapted from the Canadian Network for Mood and Anxiety Treatments (CANMAT). 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments. 2016.

Level of evidence:
• • • • = Meta-analysis with narrow confidence intervals and/or 2 or more RCTs with adequate sample size, preferably placebo-controlled,
• • • = Meta-analysis with wide confidence intervals and/or 1 or more RCTs with adequate sample size,
• • = Small-sample RCTs or nonrandomized, controlled prospective studies or case series or high-quality retrospective studies,
• = Expert opinion/consensus

First-line antidepressant options17,19

The medications listed below (organized by drug class), are all equal in efficacy and in evidence.17,18 

Scroll (left-right) for details
  • Dual Action Antidepressant
    Bupropion

    Covered by Ontario Drug Benefit18

    Product monograph for SR
    Product monograph for XL

    Formulations

    • 100 mg and 150 mg tablet

    Dosage

    • SR formulation (doses >150 mg/day PO should be given in divided doses)
      • Initial: 150 mg/day PO
      • Usual: 150–300 mg/day PO
      • High: 375–450 mg/day PO
    • XL formulation (given once daily)
      • Initial: 150 mg/day PO
      • Usual: 150–300 mg/day PO
      • High: 450 mg/day PO

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Serotonin Modulator
    Vortioxetine

    Not covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 5 mg, 10 mg, 15 mg, 20 mg tablet

    Dosage

    • Initial: 5–10 mg daily PO
    • Usual: 10–20 mg daily PO

    For details on drug interactions, see Appendix E.

    View Side Effects
  • Serotonin-Norepinephrine Reuptake Inhibitor
    Desvenlafaxine

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 50 and 100 mg extended-release tablet

    Dosage

    • Initial: 50 mg daily PO
    • Usual: 50 mg daily PO
    • High: 100 mg daily PO

    For details on drug interactions, see Appendix E.

    View Side Effects
  • Serotonin-Norepinephrine Reuptake Inhibitor
    Duloxetine

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 30 mg and 60 mg delayed release capsule

    Dosage

    • Initial: 60 mg daily PO
    • Usual: 60 mg daily PO
    • High: 120 mg/day PO
    • If necessary, for tolerability, may start with 30 mg/day and increase to 60 mg in 1–2 wk

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Serotonin-Norepinephrine Reuptake Inhibitor
    Venlafaxine

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 37.5 mg, 75 mg, 150 mg capsule

    Dosage

    • Initial: 37.5–75 mg/day PO
    • Usual: 112.5–225 mg/day PO
    • High: 300–375 mg/day PO

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Citalopram

    * Avoid combined use with drugs associated with prolonged QTc interval19

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg, 20 mg, 40 mg tablet

    Dosage

    • Initial: 10–20 mg/day PO
    • Usual: 20–40 mg/day PO
    • High: 40 mg/day PO19
    • Titration guidance: increase as needed by 20 mg daily, at intervals of ≥1 wk39

     
    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Escitalopram

    * Avoid combined use with drugs associated with prolonged QTc interval19

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg and 20 mg tablet

    Dosage

    • Initial: 10 mg/day PO
    • Usual: 10–20 mg/day PO
    • High: 20 mg/day PO
    • Titration guidance: increase as needed by 5–10 mg daily at intervals of ≥1 wk39

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Fluoxetine

    * Avoid combined use with drugs associated with prolonged QTc interval19

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg and 20 mg capsule

    Dosage

    • Initial: 10–20 mg/day PO
    • Usual: 20–40 mg/day PO
    • High: 60–80 mg/day PO

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Fluvoxamine

    * Avoid combined use with drugs associated with prolonged QTc interval19

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 50 mg and 100 mg tablet

    Dosage

    • Initial: 50–100 mg/day PO
    • Usual: 150–200 mg/day PO
    • High: 300 mg/day PO
    • Titration guidance: Increase as needed by 50 mg daily every 3–4 days39

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Paroxetine, Controlled-Release

    * Avoid combined use with drugs associated with prolonged QTc interval19

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 12.5 mg, 25 mg controlled-release tablet

    Dosage

    • Initial: 12.5–25 mg/day PO
    • Usual: 25–50 mg/day PO
    • High: 75 mg/day PO
    • Titration guidance: increase as needed by 12.5 mg daily at intervals of ≥1 wk39

     
    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Paroxetine, Immediate-Release

    * Avoid combined use with drugs associated with prolonged QTc interval19

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg, 20 mg, 30 mg, 40 mg immediate-release tablet

    Dosage

    • Initial: 10–20 mg/day PO
    • Usual: 20–40 mg/day PO;
    • High: 60 mg/day PO

    Titration guidance: increase as needed by 10 mg daily at intervals of 1–2 wk39

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Sertraline

    * Avoid combined use with drugs associated with prolonged QTc interval19

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg, 20 mg, 30 mg, 40 mg immediate-release tablet

    Dosage

    • Initial: 10–20 mg/day PO;
    • Usual: 20–40 mg/day PO;
    • High: 60 mg/day PO
    • Titration guidance: increase as needed by 10 mg daily at intervals of 1–2 wk39

     
    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Tetracyclic antidepressant
    Mirtazapine

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 15 mg, 30 mg, 45 mg tablet

    Dosage

    • Initial: 15–30 mg/day PO
    • Usual: 30–45 mg/day PO
    • High: 60 mg/day PO

     
    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions

Complementary and alternative medicine options

Complementary and alternative medicine (CAM) treatments are a group of diverse medical and health care systems, practices and products that are not generally considered part of conventional medicine.20

Patients may prefer CAM treatments due to fewer side effects, lower costs, perceived efficacy and empowerment. CAM treatments may be appropriate for patients with mild MDD while pharmacological and psychological treatments remain the first-line interventions for moderate to severe MDD.

The following is presented as guidance for clinicians when considering CAM treatments in the context of individual patients and not as standards of care.20

Scroll (left-right) for details
  • Monotherapy
    Exercise

    Treatment category

    • First-line for Mild and Moderate MDD
    • Second-line for Severe MDD

    Administration

    • 30 minutes of moderate-intensity exercise at least 3 times weekly for a minimum of 9 weeks is considered effective.
  • Monotherapy
    St. John’s wort

    Treatment category

    • First-line for Mild and Moderate MDD
      Second-line for Severe MDD

    Administration

    • Formulations of St John’s wort have varied widely, as has the dose range (500 to 1800 mg/day), while treatment duration has spanned 4 to 12 weeks.

    Caution

    • St John’s wort can cause many side effects, including gastrointestinal issues, headaches, skin irritation, photosensitivity and dry mouth. There is a concern that higher potency extracts may interfere with the metabolism of various medications, including antidepressants.20
  • Monotherapy or adjunctive
    Light therapy

    Treatment category

    • Second-line for Mild, Moderate and Severe MDD

    Administration

    • The standard protocol is 10,000 lux (light intensity) for 30 minutes per day during the early morning for up to 6 weeks.
  • Monotherapy or adjunctive
    Omega-3

    Treatment category

    • Second-line for Mild, Moderate and Severe MDD

    Administration

    • The typical dose range is 3 to 9 g/day of 0-3 or 1 to 2 g of EPA plus 1 to 2 g of DHA per day. Duration of treatment ranges from 4 to 16 weeks.
  • Adjunctive
    SAM-e

    Treatment category

    • Second-line for Mild, Moderate and Severe MDD

    Administration

    • Oral (over-the-counter): 800 – 1600 mg/day given in divided doses with meals over 4-12 weeks.
    • Intravenous and intramuscular formulations: SAM-e, at doses of 200 to 400 mg/day across 2 to 8 weeks, which may be more effective than oral supplements.

  • Adjunctive
    Yoga

    Treatment category

    • Second-line for Mild, Moderate and Severe MDD

    Administration

    • Duration varies, averaging 2-4 sessions a week over a course of 2-3 months.

Content within this section has been adapted from the Canadian Network for Mood and Anxiety Treatments (CANMAT). 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 5. Complementary and Alternative Medicine Treatments. 2016.20

Follow-up and monitoring

Functional outcomes of treatment

Recovery from depression includes both symptom relief and improved functioning.17 After achieving symptom remission, treatment is recommended to be maintained for 6-9 months. Use clinical expertise and consider patient’s life events before determining tapering and/or stopping treatments. Unless there are clinical reasons otherwise, it is recommended to slowly taper patients off antidepressants over several weeks to avoid discontinuation syndrome. It is helpful to explain to patients what to watch out for once they have discontinued antidepressants (e.g. flu-like symptoms, insomnia, nausea and imbalance). If symptoms persist or are worrisome the patient should contact their providers.

Inadequate treatment response pathway

In patients who have not achieved remission on the highest tolerated dose after two weeks of confirmed adherence, it is recommended to switch to another monotherapy (medication or psychotherapy) or augment with a second medication or psychotherapy. For early treatment-resistant patients, consider switching to an antidepressant with superior efficacy or use other medications adjunctively.17

Use the pathway below to determine next steps:

*For chronic (characterized as MDD with duration greater than two years)13 and resistant (treated with, but failed to respond to, at least four adequate medication and/or ECT treatment regimens)13 depressions, consider:
1) a chronic disease approach, with less emphasis on symptom remission and more emphasis on improvement in functioning and quality of life; and,
2) larger evaluation periods for improvement.

Switching antidepressants

Considering switching to another antidepressants when:

  • It is the first antidepressant trial (in subsequent trials lack of response may not be a factor for choosing between switching and adding adjunctive medications).
  • There is failure of one or more antidepressants (in this case, consider switching to a second- or third-line antidepressant).
  • There are poorly tolerated side effects to the initial antidepressant. Work with your patient to see if they can try to tolerate the side effects for one to two weeks to see if they disappear or are no longer problematic before switching.
  • There is more time to wait for a response (less severe, less functional impairment).
  • Patient prefers to switch to another antidepressant.
Options

When considering switching to another antidepressant, there is not enough of a difference in efficacy between antidepressants to make a decision on this factor alone. When initially selecting an antidepressant base it on tolerability first but if there is no improvement, consider switching to a different antidepressant. There has been some Meta-analysis on a few antidepressants that suggest there may be a very slight difference in efficacy. When switching, you may want to consider these medications with a slightly better efficacy.

Antidepressants with superior efficacy
Scroll (left-right) for details
  • Serotonin-Norepinephrine Reuptake Inhibitor
    Venlafaxine

    Level of evidence
    • • • •
     

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 37.5 mg, 75 mg, 150 mg capsule

    Dosage

    • Initial: 37.5–75 mg/day PO
    • Usual: 112.5–225 mg/day PO
    • High: 300–375 mg/day PO

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Citalopram

    Level of evidence
    • • • •
     

    * Avoid combined use with drugs associated with prolonged QTc interval19

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg, 20 mg, 40 mg tablet

    Dosage

    • Initial: 10–20 mg/day PO
    • Usual: 20–40 mg/day PO
    • High: 40 mg/day PO19
    • Titration guidance: increase as needed by 20 mg daily, at intervals of ≥1 wk39

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Escitalopram

    Level of evidence
    • • • •
     

    * Avoid combined use with drugs associated with prolonged QTc interval19

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg and 20 mg tablet

    Dosage

    • Initial: 10 mg/day PO
    • Usual: 10–20 mg/day PO
    • High: 20 mg/day PO
    • Titration guidance: increase as needed by 5–10 mg daily at intervals of ≥1 wk39

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Sertraline

    Level of evidence
    • • • •
     

    * Avoid combined use with drugs associated with prolonged QTc interval19

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg, 20 mg, 30 mg, 40 mg immediate-release tablet

    Dosage

    • Initial: 10–20 mg/day PO;
    • Usual: 20–40 mg/day PO;
    • High: 60 mg/day PO
    • Titration guidance: increase as needed by 10 mg daily at intervals of 1–2 wk39

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Tetracyclic antidepressant
    Mirtazapine

    Level of evidence
    • • • •
     

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 15 mg, 30 mg, 45 mg tablet

    Dosage

    • Initial: 15–30 mg/day PO
    • Usual: 30–45 mg/day PO
    • High: 60 mg/day PO

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions

* Avoid combined use with drugs associated with prolonged QTc interval19

Level of evidence:
• • • • = Meta-analysis with narrow confidence intervals and/or 2 or more RCTs with adequate sample size, preferably placebo-controlled,
• • • = Meta-analysis with wide confidence intervals and/or 1 or more RCTs with adequate sample size,
• • = Small-sample RCTs or nonrandomized, controlled prospective studies or case series or high-quality retrospective studies,
• = Expert opinion/consensus

Adjunctive medications17

Consider adding an adjunctive medication to your patient’s treatment when:

  • There have been two or more antidepressant trials
  • The initial antidepressant is well-tolerated
  • There are specific residual symptoms or side effects to the initial antidepressant that can be targeted
  • There is less time to wait for a response (more severe, more functional impairment)
  • Patient prefers to add on another medication

Consult with a pharmacist before initiating adjunctive medication.

Options
Scroll (left-right) for details
  • First line adjunctive therapy
    Aripiprazole

    Level of evidence
    • • • •
     

    Dosing
    2-15 mg

    Adverse effects19

    • EPS (akathisia, parkinsonism)
    • Dizziness
    • Orthostatic hypotension
    • Headache
    • GI complaints
    • Nasopharyngitis
    • Tremor
    • Sedation
    • Insomnia
  • First line adjunctive therapy
    Quetiapine

    Level of evidence
    • • • •

    Dosing
    150-300 mg

    Adverse effects19

    • Sedation
    • Dizziness
    • Weight gain
    • Orthostatic hypotension
    • Hepatic transaminase elevation
    • Headache
    • Anticholinergic effects
    • Increased risk of diabetes and dyslipidemia
    • Possible increased risk of cataracts
    • May reduce thyroid hormone levels
  • First line adjunctive therapy
    Risperidone

    Level of evidence
    • • • •

    Dosing
    1-3 mg

    Adverse effects19

    • Sedation
    • Headaches
    • Weight gain
    • Orthostatic hypotension
    • Rhinitis
    • Anxiety
    • Dose-related hyperprolactinemia
    • EPS
    • Risk of intraoperative floppy iris syndrome in patients undergoing cataract surgery who have been exposed to risperidone
  • Second line adjunctive therapy
    Brexpiprazole*

    Level of evidence
    • • • •

    Dosing
    1-3 mg

    Adverse effects19

    • Weight gain
    • Hyperglycemia
    • Elevated triglycerides
    • EPS (appears to be less common than with aripiprazole)
    • Headache
    • Orthostatic hypotension (rare)
  • Second line adjunctive therapy
    Bupropion

    Level of evidence
    • • •

    Dosing
    150-300 mg

    Adverse effects19

    • Agitation
    • Insomnia
    • Anorexia
    • Contraindicated in anorexia or bulimia nervosa and seizure disorders
  • Second line adjunctive therapy
    Lithium

    Level of evidence
    • • •

    Dosing
    600-1200 mg (therapeutic serum levels)

    Adverse effects32

    • Gastrointestinal discomfort
    • Nausea
    • Vertigo
    • Muscle weakness
    • Dazed feeling that frequently disappear after stabilization of therapy
  • Second line adjunctive therapy
    Mirtazapine/mianserin

    Level of evidence
    • • •

    Dosing
    600-1200 mg (therapeutic serum levels)

    Adverse effects32

    • Gastrointestinal discomfort
    • Nausea
    • Vertigo
    • Muscle weakness
    • Dazed feeling that frequently disappear after stabilization of therapy
  • Second line adjunctive therapy
    Modafinil

    Level of evidence
    • • • 

    Dosing
    100-400 mg

    Adverse effects33

    • Headache
    • Nausea
    • Rhinitis
    • Nervousness
    • Diarrhea
    • Back pain
    • Anxiety
    • Dizziness
    • Dyspepsia
    • Insomnia
  • Second line adjunctive therapy
    Olanzapine

    Level of evidence
    • • • • 

    Dosing
    2.5-10 mg

    Adverse effects19

    • Weight gain
    • Dizziness
    • Sedation
    • Anticholinergic effects
    • Hepatic aminotransferase elevation
    • Orthostatic hypotension
    • Increased risk of diabetes and dyslipidemia
    • EPS (especially akathisia)
  • Second line adjunctive therapy
    Triiodothyronine

    Level of evidence
    • • • 

    Dosing
    25-50 mcg

Level of evidence:
• • • • = Meta-analysis with narrow confidence intervals and/or 2 or more RCTs with adequate sample size, preferably placebo-controlled,
• • • = Meta-analysis with wide confidence intervals and/or 1 or more RCTs with adequate sample size,
• • = Small-sample RCTs or nonrandomized, controlled prospective studies or case series or high-quality retrospective studies,
• = Expert opinion/consensus

Special patient populations

Pregnant and postpartum patients

For pregnant and postpartum patients use the Edinburgh Postnatal Depression Scale (EPDS)35 to screen for depression.

Although postpartum psychosis is rare, women with this disorder may have homicidal impulses toward the newborn. Careful assessment of homicidal and suicidal ideation, as well as intention and plans are important. Postpartum psychosis must always be treated as a psychiatric emergency, with hospitalization considered for the safety of the mother and baby.14

Keep in mind: Specialists are available across the province to provide the best care possible for your patients at OTN eConsult15 and the Collaborative Mental Health Network (CMHN)16

First-line treatment recommendations
  • For women who wish to become pregnant, are pregnant, or are breastfeeding, depression-focused psychotherapy alone is recommended.
  • Depending on the severity of symptoms, depression-focused psychotherapy should be considered as the first option.14
  • Most medications can be safely used by breastfeeding mothers. Consider all risks and benefits of pharmacotherapy for both mother and baby before prescribing medication.

Mild to moderate MDD21

  • Antenatal patients: psychotherapy (individual or group)
  • Postpartum patients: psychotherapy (individual or group)

Severe MDD

  • Antenatal patients: pharmacotherapy is the first-line treatment, either alone or in combination with psychotherapy.
  • Postpartum patients: Pharmacotherapy should be used first-line, with or without psychotherapy.21 

*Electroconvulsive therapy (ECT) can be an effective treatment for severe MDD in pregnant and postpartum patients who:
1) have psychotic features;
2) treatment-resistant patients; and
3) who elect to use this modality as a matter of preference.14,21
Weigh the risks and benefits of ECT with pregnant patients before recommending treatment.

Pyschotherapy options
Scroll (left-right) for details
  • Cognitive-behavioral therapy (CBT)

    Description

    • CBT treats MDD by teaching patients to modify both thinking and behavior.13, 29

    Relative efficacy

    • CBT remains the most established evidence-based, first-line treatment for depression.30
  • Interpersonal psychotherapy (IPT)

    Description

    • IPT focuses on patients’ relational stressors involving losses, changes, disagreements, or interpersonal sensitivity, which are associated with the onset or perpetuation of present symptoms.30
Pharmacotherapy options

• Valproate and paroxetine must not be used in pregnant women13,22
• St John’s Wort must not be used in pregnant or breastfeeding women13

Scroll (left-right) for details
  • Selective Serotonin Reuptake Inhibitor*
    Citalopram

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg, 20 mg, 40 mg tablet

    Dosage

    • Initial: 10–20 mg/day PO
    • Usual: 20–40 mg/day PO
    • High: 40 mg/day PO19
    • Titration guidance: increase as needed by 20 mg daily, at intervals of ≥1 wk39

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Escitalopram

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg and 20 mg tablet

    Dosage

    • Initial: 10 mg/day PO
    • Usual: 10–20 mg/day PO
    • High: 20 mg/day PO
    • Titration guidance: increase as needed by 5–10 mg daily at intervals of ≥1 wk39

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Sertraline

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg, 20 mg, 30 mg, 40 mg immediate-release tablet

    Dosage

    • Initial: 10–20 mg/day PO;
    • Usual: 20–40 mg/day PO;
    • High: 60 mg/day PO
    • Titration guidance: increase as needed by 10 mg daily at intervals of 1–2 wk39

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions

* Avoid combined use with drugs associated with prolonged QTc interval19

For second-line treatment options for antenatal and for postpartum MDD please see Appendix D.

Older adult patients

Late-life depression (LLD) can be defined as MDD occuring in adults 60 years and older. It is important to differentiate early adult-onset (MDD) depression recurring in late life from late-onset depression.21

For older adults use the Geriatric Depression Scale (GDS) to screen for depression.

According to the 2019 American Geriatric’s Society Beers Criteria: antipsychotics, mirtazapine, SNRIs, SSRIs and TCA are to be used with caution in the older adult population because it may exacerbate or cause SIADH or hyponatremia.25

Keep in mind: Specialists are available across the province to provide the best care possible for your patients at OTN eConsult15 and the Collaborative Mental Health Network (CMHN).16

First line treatment recommendations
  • Check the patient’s family history, consult patient’s family or caregiver to provide input on their cognition and conduct assessments to rule out dementia.
  • Use the Montreal Cognitive Assessment (MoCA) or Mini-Mental State Exam (MMSE) to asses the patient. The MoCA Clinic and Institute recommends to complete the MoCA Training & Certification Program46 before providers administer, interpret and score test results to avoid misdiagnosis and liability.25
  • Start at the lowest possible dose of an antidepressant and increase dose as needed.
  • Monitor sodium level closely when starting or changing dosages in older adults.25

Mild to moderate MDD13, 21

  • Pharmacotherapy is the first-line treatment, either alone or in combination with psychotherapy.

Severe MDD21

  • Pharmacotherapy should be used first-line, with or without psychotherapy.
Psychotherapy options
Scroll (left-right) for details
  • Acceptance and Commitment Therapy (ACT)

    Description

    ACT is a manualized psychotherapy intervention derived from relational frame theory that emphasizes acceptance of emotional distress and engagement in goal directed behaviors.13

  • Behavior Therapy (BT)

    Description

    BT for major depression refers to a class of psychotherapy interventions that treat MDD by teaching patients to increase rewarding activities.13

  • Behavioral Activation (BA)

    Description

    BA is a particular version of BT that targets the link between avoidant behavior and depression and expands the treatment component of BT.13

  • Cognitive-behavioral therapy (CBT)
    • CBT treats MDD by teaching patients to modify both thinking and behavior.13, 29

    Relative efficacy

    • CBT remains the most established evidence-based, first-line treatment for depression30
  • Interpersonal psychotherapy (IPT)

    Description

    • IPT focuses on patients’ relational stressors involving losses, changes, disagreements, or interpersonal sensitivity, which are associated with the onset or perpetuation of present symptoms.30
  • Mindfulness-based Cognitive Therapy (MBCT)

    Description

    MBCT integrates traditional CBT interventions with mindfulness-based skills, including mindfulness meditation, imagery, experiential exercises, and other techniques that aid patients in experiencing affect without necessarily attempting to change it.13

  • Problem-solving Therapy (PST)

    Description

    • PST is defined as a discrete, time-limited, structured psychological intervention that focuses on learning to cope with specific problem areas and where therapist and patient work collaboratively to identify and prioritize key problem areas.13
Pharmacotherapy options
Scroll (left-right) for details
  • Dual Action Antidepressant
    Bupropion

    Covered by Ontario Drug Benefit18

    Product monograph for SR
    Product monograph for XL

    Formulations

    • 100 mg and 150 mg tablet

    Dosage

    • SR formulation (doses >150 mg/day PO should be given in divided doses)
      • Initial: 150 mg/day PO
      • Usual: 150–300 mg/day PO
      • High: 375–450 mg/day PO
    • XL formulation (given once daily)
      • Initial: 150 mg/day PO
      • Usual: 150–300 mg/day PO
      • High: 450 mg/day PO

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Citalopram

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg, 20 mg, 40 mg tablet

    Dosage

    • Initial: 10–20 mg/day PO
    • Usual: 20–40 mg/day PO
    • High: 40 mg/day PO19
    • Titration guidance: increase as needed by 20 mg daily, at intervals of ≥1 wk39

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Escitalopram

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg and 20 mg tablet

    Dosage

    • Initial: 10 mg/day PO
    • Usual: 10–20 mg/day PO
    • High: 20 mg/day PO
    • Titration guidance: increase as needed by 5–10 mg daily at intervals of ≥1 wk39

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Serotonin-Norepinephrine Reuptake Inhibitor
    Desvenlafaxine

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 50 and 100 mg extended-release tablet

    Dosage

    • Initial: 50 mg daily PO
    • Usual: 50 mg daily PO
    • High: 100 mg daily PO

    For details on drug interactions, see Appendix E.

    View Side Effects
  • Tetracyclic antidepressant
    Mirtazapine

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 15 mg, 30 mg, 45 mg tablet

    Dosage

    • Initial: 15–30 mg/day PO
    • Usual: 30–45 mg/day PO
    • High: 60 mg/day PO

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Sertraline

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg, 20 mg, 30 mg, 40 mg immediate-release tablet

    Dosage

    • Initial: 10–20 mg/day PO;
    • Usual: 20–40 mg/day PO;
    • High: 60 mg/day PO
    • Titration guidance: increase as needed by 10 mg daily at intervals of 1–2 wk39

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Serotonin-Norepinephrine Reuptake Inhibitor
    Venlafaxine

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 37.5 mg, 75 mg, 150 mg capsule

    Dosage

    • Initial: 37.5–75 mg/day PO
    • Usual: 112.5–225 mg/day PO
    • High: 300–375 mg/day PO

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Serotonin Modulator
    Vortioxetine

    Not covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 5 mg, 10 mg, 15 mg, 20 mg tablet

    Dosage

    • Initial: 5–10 mg daily PO
    • Usual: 10–20 mg daily PO

    For details on drug interactions, see Appendix E.

    View Side Effects

* Avoid combined use with drugs associated with prolonged QTc interval19

For second-line treatment options see Appendix D.

Patients on Tamoxifen

Patients with MDD that are being treated for breast cancer with Tamoxifen should not be prescribed antidepressants that inhibit CYP2D6 (buproprion, duloxetine, fluoxetine, paroxetine) because it will decrease the efficacy of the breast cancer treatment.26

For women already taking tamoxifen and other medications (e.g. aromatase inhibitors)27 with a known CYP2D6 inhibitor, any change in antidepressant treatment should be gradual to minimize the risks of SSRI withdrawal and adverse effects commonly seen on initiation of treatment.26

Moderate inhibitors that impart lesser degrees of inhibition and are reasonable alternatives:26,28
Scroll (left-right) for details
  • Selective Serotonin Reuptake Inhibitor*
    Sertraline

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg, 20 mg, 30 mg, 40 mg immediate-release tablet

    Dosage

    • Initial: 10–20 mg/day PO;
    • Usual: 20–40 mg/day PO;
    • High: 60 mg/day PO
    • Titration guidance: increase as needed by 10 mg daily at intervals of 1–2 wk39

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Citalopram

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg, 20 mg, 40 mg tablet

    Dosage

    • Initial: 10–20 mg/day PO
    • Usual: 20–40 mg/day PO
    • High: 40 mg/day PO19
    • Titration guidance: increase as needed by 20 mg daily, at intervals of ≥1 wk39

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Selective Serotonin Reuptake Inhibitor*
    Escitalopram

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 10 mg and 20 mg tablet

    Dosage

    • Initial: 10 mg/day PO
    • Usual: 10–20 mg/day PO
    • High: 20 mg/day PO
    • Titration guidance: increase as needed by 5–10 mg daily at intervals of ≥1 wk39

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Serotonin-Norepinephrine Reuptake Inhibitor
    Venlafaxine

    Covered by Ontario Drug Benefit18

    Product monograph

    Formulations

    • 37.5 mg, 75 mg, 150 mg capsule

    Dosage

    • Initial: 37.5–75 mg/day PO
    • Usual: 112.5–225 mg/day PO
    • High: 300–375 mg/day PO

    For details on drug interactions, see Appendix E.

    View Side Effects, Warnings, Contraindications and Precautions
  • Doxepin ??

* Avoid combined use with drugs associated with prolonged QTc interval19

Supporting materials and resources

For providers
Clinical resources
Clinical supports
Antenatal and postpartum MDD patients
  • e-lactancia – Is a resource to check the compatibility of medications whilst breastfeeding: http://e-lactancia.org/
  • LactMed – Is a database that contains information on drugs and other chemicals to which breastfeeding mothers may be exposed: https://toxnet.nlm.nih. gov/newtoxnet/lactmed.htm
  • Infant Risk Centre – Is a leading resource on the safety of medications during pregnancy and lactation: https://www.infantrisk.com/
  • Medications and Mother’s Milk – Online reference for evaluating medication use in breastfeeding mothers. Cost is $59.99 USD for 12 month access: https:// medsmilk.com/
  • SickKids – Is accepting referrals to the Motherisk Clinic from health-care providers. The Motherisk Clinic is a specialized referral-only service that assesses the safety of medications and/or substances consumed by pregnant or nursing women and the potential effects on their babies. Health-care providers can continue to send referrals through EpicCareLink: http://www.sickkids.ca/HealthcareProfessionalsandStudents/Referring-a-Patient/index.html
Resources for patients, their family, caregivers and friends
Information on depression
Online therapy
  • BounceBack Ontario – Guided self-help program grounded in cognitive behavioural therapy designed to help adults manage symptoms depression. Involves 6 telephone sessions with trained coaches who lead the patient through a series of workbooks. Cost is free. Patient is contacted within 5 business days of referral to schedule first appointment. Referral or patient self-referral is required: https://bouncebackontario.ca
  • Centre for Mindfulness Studies: Provides mindfulness-based cognitive therapy (MBCT), mindfulness-based stress reduction (MBSR), mindful self-compassion (MSC) and specialized mindfulness training to the general public. Available from: https://www.mindfulnessstudies.com/
  • Headspace – An online site for meditation: https://www.headspace.com/
  • Mindshift app – This app uses scientifically proven strategies based on Cognitive Behavioural Therapy (CBT) to help you learn to relax and be mindful, develop more effective ways of thinking, and use active steps to take charge of your anxiety. Available on the App Store and Google Play
  • Moodgym – A 5-module online cognitive behavioural therapy program for depression. Cost is $39 AUD for 12 month access: https://moodgym.com.au/
Support groups and wellness services
  • Canadian Mental Health Association (CMHA) – Locate your local CMHA for mental health support services and programs: https://cmha.ca/find-your-cmha
  • Mood Disorders Association of Ontario – Provides free support programs to people across Ontario, and their families, who are living with depression: https:// www.mooddisorders.ca/
  • Thought Spot app – Provides a live map for easily identifying and accessing health, mental health and wellness services in the Greater Toronto Area. Available on the App Store and Google Play
Suicide prevention
  • Canadian Association for Suicide Prevention – Tips on how to identify suicidal thoughts and tips for the patient’s loved ones or caregivers: https:// suicideprevention.ca/im-concerned-about-someone
  • Distress and Crisis Ontario (DCO) – DCO have distress centres that provide a listening ear for lonely, depressed, and/or suicidal people, usually 24 hours a day, 7 days a week. Many centres also have Suicide Survivor programs, support services for youth, telephone call out programs for seniors and vulnerable people, mental health Crisis Lines services and much more: http://www.dcontario.org/about.html
  • ReMinder Suicide Safety Plan app – Helps you to create a simple suicide safety plan, that can be accessed at any time on your phone. Available on the App Store and Google Play
  • Portico Network – This toolkit includes information, resource and tools to support clinicians in providing comprehensive care to clients and patients who demonstrate suicide-related behaviour: https://www.porticonetwork.ca/web/opop/tools/suicide-risk-assessment-toolkit

References

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