What are the differential diagnoses for Major Depressive Disorder (MDD)?

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Differential Diagnoses for Major Depressive Disorder

When evaluating a patient with suspected MDD, clinicians must systematically rule out other psychiatric disorders, medical conditions, substance-induced causes, and medication effects that can mimic depressive symptoms. 1, 2

Psychiatric Differential Diagnoses

Primary Mood and Anxiety Disorders

  • Persistent Depressive Disorder (Dysthymia): Chronic depressive symptoms lasting at least 2 years but not meeting full MDD criteria; requires assessment for duration and severity patterns 1
  • Bipolar Disorder: Critical to screen for history of manic or hypomanic episodes, as treatment differs fundamentally; misdiagnosis leads to inappropriate antidepressant monotherapy 2
  • Adjustment Disorder with Depressed Mood: Depressive symptoms occurring within 3 months of an identifiable stressor but not meeting full MDD criteria 1
  • Anxiety Disorders: High comorbidity rates require assessment for generalized anxiety disorder, panic disorder, and social anxiety disorder, which can present with overlapping symptoms like insomnia, fatigue, and concentration difficulties 1, 2

Other Psychiatric Conditions

  • Substance Use Disorders: Must evaluate for alcohol and drug use, as intoxication and withdrawal can produce depressive symptoms; substance-induced mood disorder is a distinct diagnosis 2, 3
  • Psychotic Disorders: Schizophrenia and schizoaffective disorder can present with negative symptoms mimicking depression 2
  • Eating Disorders: Anorexia and bulimia nervosa frequently co-occur with depressive symptoms 1
  • Post-Traumatic Stress Disorder: Assess for trauma history, as PTSD shares symptoms of anhedonia, sleep disturbance, and concentration problems 1

Medical Conditions Mimicking MDD

Endocrine Disorders

  • Hypothyroidism: Fatigue, weight gain, psychomotor retardation, and cognitive slowing closely mimic MDD; thyroid function testing is essential 3
  • Cushing's Syndrome: Hypercortisolism produces depressive symptoms along with physical stigmata 3
  • Diabetes Mellitus: Both poorly controlled diabetes and its complications can present with fatigue, concentration problems, and mood changes 3

Neurological Conditions

  • Dementia and Mild Cognitive Impairment: Particularly in older adults, cognitive decline can present with apathy, withdrawal, and mood changes; requires cognitive assessment 2, 3
  • Parkinson's Disease: Depression occurs in up to 50% of patients and may precede motor symptoms 3
  • Multiple Sclerosis: Neuroinflammatory processes can directly cause depressive symptoms independent of psychological reaction to illness 3
  • Stroke: Post-stroke depression is common, particularly with left frontal lesions 3
  • Brain Tumors: Especially frontal lobe lesions can present with personality changes and depressive symptoms 3

Systemic Medical Illnesses

  • Chronic Pain Syndromes: Degenerative joint disease and fibromyalgia share symptoms of fatigue, sleep disturbance, and functional impairment with MDD 3
  • Chronic Obstructive Pulmonary Disease and Hypersensitivity Pneumonitis: Chronic hypoxia and systemic inflammation can produce depressive symptoms 3
  • Cardiovascular Disease: Myocardial infarction and heart failure are associated with high rates of depression 3
  • Chronic Kidney Disease: Uremia and metabolic disturbances can cause depressive symptoms 3
  • Cancer: Both the disease itself and treatment side effects can produce depressive symptoms 3
  • Infectious Diseases: HIV, hepatitis C, and other chronic infections are associated with depression 3

Nutritional and Metabolic Deficiencies

  • Vitamin B12 Deficiency: Can cause fatigue, cognitive impairment, and mood changes 3
  • Folate Deficiency: Associated with depressive symptoms 3
  • Vitamin D Deficiency: Increasingly recognized as contributing to mood symptoms 3
  • Anemia: Fatigue and cognitive slowing can mimic depression 3

Medication-Induced and Substance-Induced Depression

Medications That Can Cause Depressive Symptoms

  • Corticosteroids: High doses or chronic use can induce mood changes 3
  • Beta-blockers: Particularly lipophilic agents can cause depressive symptoms 3
  • Interferon: Used in hepatitis C treatment, commonly causes depression 3
  • Isotretinoin: Associated with mood changes in acne treatment 3
  • Hormonal Contraceptives: Can contribute to mood symptoms in susceptible individuals 3

Substance-Induced Mood Disorders

  • Alcohol: Both acute intoxication and withdrawal can mimic MDD 2
  • Stimulant Withdrawal: Cocaine and amphetamine withdrawal produce depressive symptoms 2
  • Cannabis: Chronic use associated with amotivation and depressive symptoms 2

Delirium

  • Hypoactive Delirium: Particularly in hospitalized or elderly patients, can present with psychomotor retardation, apathy, and cognitive impairment that mimics depression; distinguished by acute onset, fluctuating course, and inattention 3

Critical Assessment Approach

Essential Evaluation Components

  • Direct patient and family interviews to assess symptom onset, duration, and functional impairment across school, home, and peer settings 1
  • Collateral information from teachers or other observers when available, as patients may not clearly identify depressed mood as their chief complaint 1
  • Systematic assessment for comorbid psychiatric conditions using standardized instruments, as high comorbidity rates affect diagnosis and treatment 1, 2
  • Laboratory evaluation to rule out medical causes: thyroid function, complete blood count, comprehensive metabolic panel, vitamin B12, vitamin D, and other tests based on clinical suspicion 4, 3
  • Medication and substance use review to identify potential iatrogenic or substance-induced causes 2, 3

Common Diagnostic Pitfalls

  • Overlooking bipolar disorder by failing to screen for manic/hypomanic episodes leads to inappropriate treatment 2
  • Attributing all symptoms to medical illness when comorbid MDD is actually present and treatable 3
  • Dismissing depressive symptoms as "normal reaction" to medical illness, missing treatable MDD 3
  • Confusing neurovegetative symptoms (fatigue, sleep changes, appetite changes) that overlap between depression and medical illness 3
  • Missing substance-induced depression by inadequate substance use history 2

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Research

Diagnostic assessment of major depressive disorder.

The Journal of clinical psychiatry, 2009

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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