Major Depressive Disorder (MDD) is a common mood disorder characterized by persistent depressed mood and/or marked loss of interest or pleasure in activities for at least two weeks. It results in significant impairment in social, occupational, educational, and interpersonal functioning.

MDD is associated with substantial morbidity, reduced quality of life, increased risk of suicide, and increased burden from comorbid psychiatric and medical conditions. It may occur as a single episode or as a recurrent disorder.

Epidemiology

• Lifetime prevalence is approximately 10–20%.

• It is more common in females, with an approximate female-to-male ratio of 2:1.

• Common age of onset is late adolescence and early adulthood.

• Recurrence is common, with more than 50% of patients experiencing further depressive episodes after the first episode.

• MDD frequently occurs alongside anxiety disorders, substance use disorders, and chronic medical illnesses.

Risk Factors

Biological Factors

• Family history of depression.

• Genetic predisposition.

• Neurotransmitter dysfunction involving serotonin, norepinephrine, and dopamine pathways.

• Chronic medical illnesses including:

  • Diabetes mellitus.

  • Cardiovascular disease.

  • Cancer.

  • Hypothyroidism.

• Hormonal changes including postpartum and menopausal changes.

Psychological Factors

• Low self-esteem.

• Negative cognitive patterns.

• Childhood trauma or abuse.

• Personality vulnerabilities.

• Poor coping mechanisms.

Social and Environmental Factors

• Bereavement.

• Financial stress.

• Social isolation.

• Relationship conflicts.

• Substance misuse.

• Major life stressors.

Pathophysiology

Major Depressive Disorder results from complex interactions between genetic, neurobiological, psychological, and environmental factors.

Major mechanisms include:

• Reduced monoamine neurotransmission involving serotonin, norepinephrine, and dopamine.

• Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis.

• Neuroinflammatory processes.

• Reduced neuroplasticity.

• Altered hippocampal function.

• Abnormal connectivity within brain circuits involved in mood regulation.

These abnormalities contribute to disturbances in mood, cognition, motivation, sleep, and emotional regulation.

Clinical Presentation

Patients present with emotional, cognitive, behavioural, and physical symptoms causing impairment in daily functioning.

Severity may range from mild to severe depression, with or without psychotic features.

Symptoms

Symptoms usually persist for at least two weeks and represent a change from previous functioning.

Psychological Symptoms

• Persistent depressed mood.

• Loss of interest or pleasure (anhedonia).

• Feelings of worthlessness.

• Excessive guilt.

• Hopelessness.

• Reduced concentration.

• Indecisiveness.

• Recurrent thoughts of death or suicide.

Somatic Symptoms

• Change in appetite.

• Sleep disturbances (insomnia or hypersomnia).

• Agitation.

• Psychomotor retardation.

• Loss of energy.

• Fatigue.

• Reduced activity.

Clinical Signs

Clinical examination may reveal:

• Depressed or low mood.

• Reduced emotional expression.

• Poor eye contact.

• Psychomotor agitation or retardation.

• Reduced speech or slowed responses.

• Poor concentration during interview.

• Social withdrawal.

• Neglect of personal care.

• Reduced motivation.

• Suicidal thoughts or behaviour.

• Psychotic features in severe cases:

  • Delusions.

  • Hallucinations.

Differential Diagnosis

Consider:

• Bipolar disorder.

• Schizoaffective disorder.

• Persistent depressive disorder (dysthymia).

• Adjustment disorder.

• Anxiety disorders.

• Substance-induced mood disorder.

• Hypothyroidism.

• Dementia, especially in elderly patients.

• Medical illnesses causing depressive symptoms.

Diagnostic Criteria

Diagnosis is based on clinical assessment using DSM-5 criteria.

The diagnosis requires:

• At least five symptoms present during the same two-week period.

• Symptoms occurring most of the day, nearly every day.

• At least one of the symptoms must be:

  • Depressed mood.

  • Loss of interest or pleasure.

Additional symptoms include:

• Appetite or weight change.

• Sleep disturbance.

• Psychomotor agitation or retardation.

• Fatigue or loss of energy.

• Feelings of worthlessness or excessive guilt.

• Reduced concentration.

• Recurrent thoughts of death or suicide.

The symptoms must:

• Cause clinically significant distress or impairment.

• Not be attributable to substances or another medical condition.

• Not occur exclusively during psychotic disorders.

• Not be better explained by bipolar disorder.

Severity classification:

• Mild depression.

• Moderate depression.

• Severe depression.

• Severe depression with psychotic features.

Investigations

Investigations are performed to exclude medical causes and establish baseline safety before treatment.

Recommended Investigations

• Full blood picture (FBP).

• Thyroid function tests.

• Blood glucose.

• Liver function tests (LFT).

• Renal function tests (RFT).

• Serum electrolytes.

• Vitamin B12 and folate where indicated.

• Substance use screening.

Additional Investigations

Depending on clinical suspicion:

• ECG before antidepressant therapy when indicated.

• Neuroimaging (CT/MRI brain) if neurological symptoms are present.

• Pregnancy test where applicable.

Management

Management involves psychological interventions, pharmacological treatment, psychosocial support, and monitoring for suicide risk.

Initial management includes:

• Assessment of severity.

• Assessment of suicide risk.

• Identification and management of contributing medical or psychosocial factors.

• Establishment of a therapeutic relationship.

• Selection of psychological and/or pharmacological treatment depending on severity.

Non-pharmacological Treatment

Psychological Interventions

Effective psychotherapies include:

• Cognitive Behavioural Therapy (CBT).

• Interpersonal psychotherapy.

• Stress management and coping skills training.

• Problem-solving therapy.

• Family or marital therapy where appropriate.

Psychosocial Measures

• Sleep hygiene advice.

• Structured daily activities.

• Enhancement of social support.

• Physical activity where appropriate.

• Substance misuse prevention.

Pharmacological Treatment

Pharmacological treatment is indicated for:

• Moderate to severe depression.

• Significant functional impairment.

• Depression with suicidal risk.

• Failure of psychological treatment alone.

Treatment response should be assessed clinically, and doses adjusted according to symptom improvement and adverse effects.

Antidepressant treatment

Amitriptyline – 12.5–75 mg – PO – 24 hourly at night; increase gradually to maximum 150 mg 24 hourly. (Elderly: initially 12.5–50 mg, maximum 75 mg).

OR

Citalopram – 10–60 mg – PO – 24 hourly.

OR

Fluoxetine – 20–60 mg – PO – 24 hourly in the morning.

Treatment monitoring

• Treatment efficacy is assessed by improvement of depressive symptoms.

• Dose should be titrated according to clinical response.

• Patients recently started on antidepressants should be monitored closely for increased agitation and suicidal behaviour, particularly young patients below 25 years.

• Sleep and appetite symptoms may improve earlier than mood symptoms.

• If there is partial or no response:

  • Increase the dose where appropriate.

  • Switch to another antidepressant.

  • First consider an alternative SSRI.

  • Second-line treatment involves an antidepressant from a different class.

Management According to Underlying Cause

Depression with Psychotic Features

• Requires specialist psychiatric assessment.

• Combination treatment with antidepressant and antipsychotic therapy may be required.

• Urgent referral is indicated.

Depression Associated with Medical Illness

• Identify and manage the underlying medical condition.

• Coordinate treatment with relevant specialists.

Depression During Pregnancy or Lactation

• Assess risks and benefits of medication.

• Refer for specialist psychiatric management where necessary.

Referral

Refer to the next level of care in the following situations:

• Suicidal ideation or high suicide risk.

• Major depression with psychotic features.

• Failure to respond to available antidepressants.

• Depression with severe functional impairment.

• Patients with significant medical illness, including:

  • Heart disease.

  • Epilepsy.

• Poor social support systems.

• Pregnancy and lactation.

• Treatment-resistant depression.

Urgent psychiatric referral is required for:

• Active suicidal thoughts or plans.

• Psychotic depression.

• Severe behavioural disturbance.

• Inability to maintain patient safety.

Complications

Possible complications include:

• Suicide.

• Substance misuse.

• Occupational impairment.

• Relationship breakdown.

• Chronic recurrent depression.

• Reduced quality of life.

• Increased cardiovascular morbidity.

• Social isolation.

Prognosis

• Most patients improve with appropriate treatment.

• Early diagnosis and treatment improve outcomes.

• Relapse is common, particularly when treatment is stopped prematurely.

• Some patients develop chronic depressive symptoms requiring long-term management.

• Continued follow-up reduces relapse risk.

Prevention

Preventive strategies include:

• Early identification of individuals at risk.

• Effective treatment of depressive episodes.

• Maintenance antidepressant therapy in recurrent depression.

• Stress reduction strategies.

• Strengthening social support systems.

• Prevention and treatment of substance misuse.

• Regular mental health follow-up.

• Patient and family education.