What are the Australian guidelines for treating major depressive disorder, including recommendations for severity‑based therapy, first‑line pharmacologic agents and dosing, monitoring schedule, and management of treatment‑resistant cases?

Australian Guidelines for Treating Major Depressive Disorder

First-Line Treatment Selection

For moderate to severe major depressive disorder, initiate either cognitive behavioral therapy (CBT) or a second-generation antidepressant (SSRI or SNRI), with the choice determined by severity, adverse effect profiles, cost, accessibility, and patient preference. 1, 2, 3

The 2020 Royal Australian and New Zealand College of Psychiatrists (RANZCP) clinical practice guidelines emphasize that treatment choice should be guided by clinician skills, patient circumstances, and preferences, while recognizing that all recognized antidepressants, CBT, and interpersonal psychotherapy (IPT) demonstrate equal effectiveness in moderately severe depression. 4, 5

Severity-Based Treatment Algorithm

Mild Depression (5-6 symptoms, minimal functional impairment):

• Start with CBT alone as monotherapy; antidepressants should not be used initially because drug-placebo differences are virtually nonexistent in this population. 2, 6, 3
• Reserve pharmacotherapy only for patients who prefer medication or lack access to psychological therapy. 2

Moderate Depression (7-8 symptoms, moderate functional impairment):

• Either CBT or a second-generation antidepressant as monotherapy; both demonstrate comparable remission rates with a number needed to treat (NNT) of 7-8. 2, 3
• The RANZCP guidelines confirm that in moderately severe depression, all recognized antidepressants, CBT, and IPT are equally effective. 4, 5

Severe Depression (≥9 symptoms, severe functional impairment, or high-risk features):

• Initiate combination therapy with both an antidepressant (SSRI or SNRI) and CBT concurrently; this strategy nearly doubles remission rates (57.5% vs 31.0%) compared with antidepressant monotherapy. 2, 3
• For depression with psychotic features, electroconvulsive therapy (ECT) or a tricyclic combined with an antipsychotic are equally effective according to RANZCP guidelines. 4
• Antidepressant treatment should precede psychological therapy in severe depression without psychosis. 4

First-Line Pharmacologic Agents and Dosing

The RANZCP guidelines recommend seven first-line antidepressants as "Choices" before moving to alternative strategies: 5

Selective Serotonin Reuptake Inhibitors (SSRIs):

• Escitalopram: Start at 10 mg once daily 2
• Sertraline, fluoxetine, paroxetine, citalopram: Start at 20 mg once daily 2

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs):

• Venlafaxine or duloxetine: Preferred in patients with comorbid chronic pain (remission rates ≈49% vs 42% with SSRIs) 2

Other Second-Generation Antidepressants:

• Bupropion: Associated with the lowest incidence of sexual adverse effects compared with SSRIs 2

Critical prescribing note: Tricyclic antidepressants (TCAs) should not be used as first-line agents due to higher adverse-effect profiles, greater overdose risk, and no superiority over second-generation agents, despite Australian real-world data showing 25% of initial prescriptions are TCAs (particularly by general practitioners). 2, 7

No SSRI or SNRI demonstrates superior efficacy over another; selection should be based on side-effect profile (paroxetine has highest sexual dysfunction rates), cost (generic SSRIs are most affordable), patient preference, prior response, and comorbidities. 2

Monitoring Schedule

Week 1-2 Assessment (Mandatory):

• Conduct assessment within 1-2 weeks of treatment initiation to evaluate suicidality (risk peaks during first 1-2 months), emergence of agitation/irritability or behavioral changes, early adverse effects, and adherence. 2, 6
• SSRIs increase suicide-attempt risk in young adults (age 18-24) with an odds ratio of 2.30 compared with placebo. 2

Week 4 Assessment:

• For patients receiving psychological treatment, mental health professionals should assess treatment response at 4 weeks using standardized validated instruments. 1

Week 6-8 Assessment:

• If symptom reduction is <50% on standard rating scales (PHQ-9, HAM-D, MADRS, or QIDS-SR), modify the treatment plan through dose escalation, class switch, augmentation, or addition of CBT. 1, 2, 6
• The RANZCP guidelines recommend using the MADRS10 as the preferred outcome instrument to assess treatment response, together with patient-reported QIDS-SR. 1, 5

End of Treatment Assessment:

• Regular assessment should continue through end of treatment using standardized validated instruments. 1

Treatment Duration

First depressive episode:

• Continue antidepressant for 4-9 months after achieving satisfactory response to reduce relapse risk. 2, 3
• The RANZCP guidelines emphasize that depression has a high rate of recurrence and efforts to reduce this are crucial. 4

Recurrent depression (≥2 prior episodes):

• Maintain therapy for at least 1 year or longer; maintenance drug or psychological treatment strategies can avert 50-52% of disability-adjusted life years over 5 years, even with adherence rates around 60%. 2, 8
• Australian modeling data demonstrates that current episodic treatment patterns avert only 13% of disease burden, whereas maintenance treatment could avert approximately 50% of the burden. 8

Management of Treatment-Resistant Depression

Treatment-resistant depression (TRD) is defined as failure to respond (<25% symptom reduction) to at least two antidepressants at adequate dose and duration (minimum 4 weeks at maximum FDA-approved dose). 1, 2

Partial response depression (PRD) is defined as 25-50% symptom reduction to at least one antidepressant. 1

MIDAS Strategy (Medication: Increasing Dose, Augmenting, Switching):

For inadequate response after 6-8 weeks, the RANZCP guidelines recommend the following sequential approach: 5

1. Switching to a different second-generation antidepressant: Various switch strategies demonstrate similar efficacy with moderate-certainty evidence. 2, 3

2. Augmentation with buspirone or bupropion SR: Provides efficacy comparable to switching strategies. 2

3. Adding CBT to ongoing pharmacotherapy: Produces statistically superior outcomes compared with antidepressant monotherapy in treatment-resistant cases. 2, 3

4. Acupuncture as adjunct to antidepressants: In three randomized trials (≈800 participants), adjunctive acupuncture increased remission rates (35.7% vs 26.1%; risk ratio 1.45) with moderate-certainty evidence. 2

5. Consideration of ketamine or esketamine for patients who have failed ≥2 adequate antidepressant trials. 2

6. Repetitive transcranial magnetic stimulation (rTMS) or theta-burst stimulation. 2

7. Electroconvulsive therapy (ECT): Indicated for multiple treatment failures or when rapid clinical improvement is required. 2, 4

Additional Psychotherapy Options:

The RANZCP guidelines advocate for psychological interventions as "Actions" that should be implemented from the outset, including: 5

• Acceptance and Commitment Therapy 2
• Behavioral Activation 2
• Interpersonal Psychotherapy 2, 4
• Mindfulness-Based Cognitive Therapy 2
• Problem-Solving Therapy 2
• Short-Term Psychodynamic Psychotherapy 2

Bright Light Therapy:

• Recommended for mild to moderate major depressive disorder regardless of seasonal pattern; may be used as monotherapy or combined with other treatments. 2

Critical Pitfalls to Avoid

1. Inadequate adherence assessment: Up to 50% of patients demonstrate non-adherence, which can masquerade as treatment resistance; adherence assessment is essential before escalating treatment. 2

2. Premature discontinuation: Approximately 63% of patients experience at least one adverse effect, most of which are transient; continued monitoring rather than premature discontinuation is crucial. 2

3. Insufficient treatment duration: Australian real-world data shows the overall median time patients remained on treatment was only 4.5 months (5.8 months for SSRIs, 0.9 months for TCAs), well below the recommended 4-9 months minimum. 7

4. Inappropriate use of antidepressants in mild depression: Drug-placebo differences are virtually nonexistent in mild depression; this represents inappropriate treatment with no demonstrated benefit. 6

5. Failure to document adequate trials: Before diagnosing TRD, confirm that previous trials involved adequate dose (maximum FDA-approved dose), adequate duration (minimum 4 weeks), and documented adherence (consider checking plasma levels if uncertain). 1, 2

6. Overlooking comorbidities: Screen routinely for comorbid anxiety disorders, substance-use disorders, and bipolar spectrum conditions, as these markedly influence prognosis and therapeutic choices. 2

7. Inadequate safety planning: Develop a written safety plan at the initial visit that (1) limits access to lethal means, (2) identifies a responsible third party for monitoring, and (3) establishes an emergency communication protocol. 2