Lucan · Conditions

Major depressive disorder

Australian guidance: eTG Psychotropic — Depression + RANZCP Mood Disorders CPG

1. Definition and epidemiology

Major depressive disorder (MDD) is a mood disorder characterised by one or more major depressive episodes featuring persistent low mood and/or anhedonia with associated cognitive, somatic, and neurovegetative symptoms causing clinically significant functional impairment. In Australia, the 12-month prevalence of MDD is approximately 6%, with a lifetime risk of 11 to 15%. Primary care bears the majority of the diagnostic burden, with one in ten patients presenting with depressive symptoms, and the average age of onset is the mid-20s with a female-to-male ratio of 2:1.

2. Pathophysiology

The pathophysiology of MDD is multifactorial, involving gene-environment interactions across biological and psychosocial domains. The monoamine hypothesis underpins most pharmacological treatment: deficiency or dysregulation of serotonin, noradrenaline, and dopamine within the synaptic cleft reduces downstream neurotransmission. Antidepressants act principally at presynaptic and postsynaptic membrane receptors and reuptake transporters to increase monoamine concentration within the synapse, ultimately facilitating secondary messenger cascades including cyclic AMP, PKA, and CREB-mediated transcription. These downstream effects stimulate neurogenesis, particularly in the hippocampus, which is thought to underlie the antidepressant effect. Neuroinflammatory, hypothalamic-pituitary-adrenal axis dysregulation, and circadian rhythm disruption are also implicated. The RANZCP MDcpg2020 additionally frames MDD through the ACE model, decomposing symptom expression across three domains: activity, cognition, and emotion, which vary independently and help explain treatment response heterogeneity.

3. Clinical presentation and diagnostic criteria

MDD diagnosis requires DSM-5 or ICD-11 criteria: five or more symptoms present for at least two weeks, including at least one of depressed mood or anhedonia. Remaining criteria include sleep disturbance (insomnia or hypersomnia), change in appetite or weight, psychomotor retardation or agitation, fatigue or loss of energy, feelings of worthlessness or excessive guilt, impaired concentration or indecisiveness, and recurrent thoughts of death or suicidal ideation. Symptoms must cause significant functional impairment and not be attributable to a substance or medical condition. Clinically important subtypes include melancholia (psychomotor slowing, diurnal variation, anhedonia), anxious distress, and psychotic depression. Severity is classified as mild, moderate, or severe based on symptom burden and functional impairment. Early morning wakening is characteristic. Symptom onset may be insidious and patients often do not volunteer suicidal ideation unless specifically asked.

4. Investigations and AU-specific cutoffs

MDD is a clinical diagnosis; investigations serve primarily to exclude organic causes and screen for comorbidities:

• Full blood count: exclude anaemia contributing to fatigue
• Thyroid stimulating hormone (TSH): hypothyroidism mimics depression; AU laboratory reference range approximately 0.4 to 4.0 mIU/L
• Fasting glucose and HbA1c: exclude diabetes mellitus, which has a bidirectional relationship with depression
• Electrolytes, urea, and creatinine: exclude metabolic contributions
• Liver function tests: relevant before initiating hepatically metabolised antidepressants
• Serum B12 and folate: deficiency associated with depressive symptoms; MTHFR polymorphisms may reduce conversion of folate to its active metabolite methylfolate, and genetic analysis can now be considered where methylfolate supplementation may have utility
• Urine drug screen: exclude substance misuse contribution
• ECG: required before initiating tricyclic antidepressants (TCAs) and for QTc monitoring with certain SSRIs (particularly citalopram and escitalopram at higher doses)
• Validated rating scales such as the PHQ-9 are widely used in Australian primary care for severity assessment and monitoring treatment response

5. Management

Management of MDD in Australia follows a stepped-care model anchored to the RANZCP MDcpg2020 and eTG Psychotropic guidelines. The framework distinguishes Actions (foundational, applied universally), Choices (evidence-based pharmacotherapy and psychological treatments), and Alternatives (reserved for treatment resistance).

Actions form the essential foundation and include restoring a normal sleep pattern, physical activity, addressing psychosocial stressors, psychoeducation, and building a strong therapeutic alliance. These should be implemented comprehensively from the outset and contribute to long-term resilience.

For mild to moderate MDD, psychological interventions are first-line. Cognitive-behavioural therapy (CBT) delivered face-to-face or via the internet (iCBT) is as effective as face-to-face treatment, including for severe and complex presentations when delivered in therapist-guided format. Australian digital platforms including MindSpot and This Way Up provide free or low-cost iCBT with therapist assistance.

Pharmacotherapy is indicated for moderate to severe MDD, or when psychological treatment alone is insufficient. SSRIs are the preferred first-line agents. Antidepressants should be optimised to therapeutic dose before switching. A substantial delay of several weeks typically occurs before clinical response, and patients should be counselled about this at commencement to prevent early cessation.

Electroconvulsive therapy (ECT) is recommended as a first-line treatment for severe melancholic or psychotic depression, imminent suicidality, catatonia, refusal of food or fluids, and previous response to ECT. ECT is a safe and effective treatment in this context (EBR I) and should not be regarded as a treatment of last resort. Repetitive transcranial magnetic stimulation (rTMS) is reserved for depression that has failed adequate pharmacotherapy and psychological treatment.

6. Pharmacology and AU PBS notes

First-line agents are SSRIs, with choice informed by symptom profile, side-effect tolerability, and safety in overdose:

• Escitalopram (Lexapro, Cipralex): preferred for anxious presentations; fewer cardiac side effects; PBS Authority required for MDD
• Sertraline (Zoloft): widely used first-line; fewer cardiac side effects; PBS unrestricted listing available
• Fluoxetine (Prozac): long half-life reduces discontinuation syndrome; PBS unrestricted
• Citalopram: note QTc prolongation risk at doses above 40 mg; not recommended above 40 mg in adults or 20 mg in elderly
• Paroxetine: more anticholinergic; significant discontinuation syndrome due to short half-life; not preferred

Second-line agents include SNRIs, NaSSAs, and others, chosen based on clinical profile:

• Venlafaxine or duloxetine (SNRIs): preferred where anxiety, cognitive difficulties, fatigue, or pain are prominent; duloxetine is also PBS-listed for generalised anxiety disorder and diabetic peripheral neuropathy
• Mirtazapine (NaSSA): preferred for prominent insomnia, poor appetite, or where sexual dysfunction is a concern; sedation is dose-dependent and greater at lower doses
• Bupropion (NDRI): indicated where fatigue is prominent; no sexual side effects; not PBS-listed for MDD in Australia as of knowledge cutoff
• Agomelatine: melatonergic agonist; advantageous side-effect profile including less sedation and less sexual dysfunction; requires monitoring of liver function tests
• Vortioxetine: serotonin receptor antagonist and reuptake inhibitor; evidence for cognitive symptom improvement in MDD; PBS Authority listing for MDD

TCAs (amitriptyline, nortriptyline, dosulepin) retain a role in melancholic depression and treatment-resistant cases; ECG monitoring and plasma level monitoring required. MAOIs (phenelzine, tranylcypromine; moclobemide is reversible) are reserved for specialist use due to dietary tyramine interaction risk.

Augmentation strategies for partial response include addition of atypical antipsychotics (quetiapine, aripiprazole, olanzapine, brexpiprazole) or lithium to existing antidepressant therapy.

7. Complications and monitoring

Suicidality: suicide risk requires active inquiry at every review. All patients should be specifically asked about suicidal ideation, plans, and access to means. The risk of suicide is highest in the early weeks of treatment when energy returns before mood fully lifts.

Treatment resistance: defined as failure to respond to two adequate antidepressant trials from different classes at therapeutic dose and duration. Reassess diagnosis, exclude bipolar disorder, address comorbidities, consider augmentation or specialist referral.

Antidepressant discontinuation syndrome: abrupt cessation or rapid dose reduction causes dizziness, nausea, flu-like symptoms, and sensory disturbances; greatest risk with paroxetine and venlafaxine due to short half-life. Taper all antidepressants gradually.

Monitoring schedule:

• Baseline: weight, blood pressure, ECG (if TCA), liver function tests (if agomelatine), and fasting metabolic panel
• At 2 and 4 weeks after initiation: symptom review and tolerability assessment
• At 6 to 8 weeks: formal response assessment using PHQ-9 or equivalent
• After remission: maintenance antidepressant therapy for at least 6 to 12 months following first episode; 2 or more years following recurrent episodes
• Ongoing: monitor for emergence of manic symptoms (which may indicate underlying bipolar disorder), metabolic side effects (weight gain with mirtazapine and TCAs), and sexual dysfunction

Post-ECT maintenance: antidepressant with or without lithium continued for at least 12 to 24 months following successful ECT course; maintenance ECT considered for recurrent severe cases.

Written for Australian practice and grounded in the guidance named above. Study material only — not medical advice. Always check against current guidelines.