What are the differential diagnoses for a patient with a single episode of unspecified major depressive disorder and an unspecified panic‑type anxiety disorder?

Differential Diagnosis for Major Depressive Disorder with Panic Disorder

The differential diagnosis must systematically exclude medical conditions, substance-induced causes, other primary psychiatric disorders, and somatic symptom presentations before confirming MDD with panic disorder as the primary diagnosis.

Medical Conditions That Mimic Depression and Panic

Before accepting a psychiatric diagnosis, rule out these organic causes:

Endocrine Disorders

• Hyperthyroidism can produce anxiety, panic symptoms, palpitations, and mood lability that mimic both depression and panic disorder 1
• Hypothyroidism must be excluded as it directly causes depressive symptoms 2
• Hypoglycemia and diabetes trigger panic-like episodes through blood sugar fluctuations, particularly autonomic symptoms 1

Cardiovascular Conditions

• Cardiac arrhythmias initiate or mimic panic attacks with palpitations, chest discomfort, and autonomic arousal 1
• These require ECG evaluation to distinguish from primary panic disorder 1

Respiratory Disorders

• Asthma overlaps significantly with panic symptoms, presenting with shortness of breath and respiratory distress 1
• The distinction hinges on objective pulmonary function testing 1

Neurological Conditions

• Migraines present with anxiety and autonomic symptoms that can be mistaken for panic 1
• Evaluate for headache patterns and neurological examination 1

Chronic Pain

• Chronic pain conditions trigger secondary anxiety and depressive symptoms 1
• Assess temporal relationship between pain onset and mood/anxiety symptoms 1

Substance-Induced Anxiety and Depression

Medical or substance-induced causes must be determined and treated before diagnosing primary psychiatric disorders 2:

Direct Substance Effects

• Caffeine excess directly provokes anxiety and panic attacks 1
• Medications (e.g., corticosteroids, interferon, stimulants) induce anxiety or depression as side effects 2, 1
• Illicit drug use (stimulants, cannabis) triggers anxiety states 1

Withdrawal States

• Alcohol and substance withdrawal creates rebound anxiety and panic 1
• Benzodiazepine withdrawal produces severe anxiety that mimics primary panic disorder 3
• Obtain detailed substance use history including prescription medications 2

Primary Psychiatric Disorders in the Differential

Generalized Anxiety Disorder (GAD)

GAD is differentiated from panic disorder by chronicity and the absence of discrete panic attacks 3:

• GAD features chronic worry focused on multiple life situations rather than episodic panic 4
• GAD manifests without identifiable emotional stressors, unlike adjustment disorder 3
• Panic disorder involves episodic, abrupt attacks with ≥4 autonomic/cardiopulmonary/neurologic symptoms, whereas GAD presents persistent, non-paroxysmal anxiety 3
• Use GAD-7 screening: scores ≥5,10, and 15 indicate mild, moderate, and severe anxiety respectively 2

Adjustment Disorder with Anxiety

• Adjustment disorder requires identifiable emotional stressors and symptoms that do not meet full criteria for other disorders 3
• Symptoms must occur within 3 months of the stressor 3

Bipolar Disorder

• Bipolar disorder can present with depressive episodes and anxiety; screen for history of manic or hypomanic episodes 1
• Mixed episodes involve near-daily mood fluctuations qualifying for both manic and major depressive criteria 2

Post-Traumatic Stress Disorder (PTSD)

• PTSD frequently manifests as anxiety symptoms including panic attacks 1
• In some cultures, panic attacks attributed to trauma recollections may not meet panic disorder criteria due to "expectedness" 2
• Screen for trauma history, particularly sexual harassment, assault, and trauma which are common underlying triggers in women 1

Obsessive-Compulsive Disorder (OCD)

• OCD can present with significant anxiety; assess for intrusive thoughts and compulsive behaviors 1

Somatic Symptom Disorder (SSD)

SSD requires ≥1 distressing somatic symptom plus excessive psychological response (high health anxiety, excessive time/energy devoted to symptoms) lasting >6 months 5:

• Patients often present with somatic symptoms having no identifiable physiologic foundation (headache, noncardiac angina, fatigue, insomnia, abdominal discomfort) 3
• Distinguish from panic disorder by the persistent preoccupation with physical symptoms rather than discrete panic episodes 5

Hypochondriasis (Health Anxiety Disorder)

• Persistent preoccupation with the possibility of serious physical disorders, with ordinary bodily sensations misinterpreted as abnormal 6
• ICD-11 reclassified this within obsessive-compulsive and related disorders 6

Illness Anxiety Disorder

• Similar to hypochondriasis but with minimal or no somatic symptoms; focus is on having or acquiring a serious illness 6

Comorbidity Considerations

Depression-Panic Comorbidity

Approximately 50% of patients with panic disorder ultimately experience major depression, and this comorbidity carries ominous prognostic implications 7:

• 56% of patients with major depressive disorder have comorbid anxiety, significantly increasing suicide risk 1
• The high rate of suicide attempts in panic disorder is further exacerbated by comorbid depression 7
• In >50% of cases, depression and panic disorder begin within one month of each other 8
• In one-third of cases, panic disorder precedes depression by >1 month 8
• In ~10% of cases, panic disorder appears >1 month after depression onset 8

Clinical Subtypes of Panic with Depression

Four clinical patterns exist 9:

• Type IV-1 (most common): Depressive symptoms develop secondary to panic attacks, with major depression later coexisting with panic disorder 9
• Type IV-2: Panic disorder continuously changes into major depression 9
• Type IV-3: Panic attacks and depressive symptoms occur independently 9

Screening and Assessment Tools

For Depression

• PHQ-9 should be used first for depressive symptom assessment 2
• Beck Depression Inventory (BDI): Scores ≥20 suggest clinical depression 2
• Hamilton Rating Scale for Depression (HAM-D): 7-17 = mild, 18-24 = moderate, ≥25 = severe depression 2
• CES-D: Scores ≥16 suggest moderate-to-severe depressive symptomatology; relatively unaffected by physical symptoms 2

For Anxiety

• Beck Anxiety Inventory (BAI): Score ≥10 suggests mild anxiety, ≥19 suggests moderate anxiety 2
• GAD-7: Validated for generalized anxiety disorder screening 2
• Hospital Anxiety and Depression Scale (HADS): 14-item self-report with scales for both anxiety and depression 2

Psychosocial and Environmental Triggers to Assess

Evaluate for these precipitants 1:

• Stressful or traumatic life events directly precipitating episodes
• School/work performance worries, concerns about physical appearance
• Social media comparison effects and poor self-esteem
• Peer rejection and social skills deficits triggering social anxiety
• Anxiogenic parenting behaviors (overprotective, controlling styles)
• Family history: 30-50% heritability indicates genetic vulnerability 1

Developmental and Temperamental Factors

• Behavioral inhibition in childhood (temperamental fearfulness) predicts later anxiety 1
• Autonomic hyperreactivity with exaggerated physiological stress responses 1
• Negative affectivity (tendency toward negative emotional states) increases anxiety risk 1

Critical Diagnostic Pitfalls

Cultural Considerations

• In some cultural contexts, ≈60% of anxiety-disorder cases are classified as "Not Otherwise Specified" because presentations emphasizing somatic over psychological symptoms do not fit DSM criteria 6
• Cultural syndromes (e.g., ataque de nervios, khyâl attacks, trung gió) link specific cues to panic attacks, affecting whether attacks are considered "expected" or "unexpected" 2
• 80% of Caribbean Latino patients with ataques de nervios endorse ≥1 of the 3 post-attack sequelae in panic disorder criterion A2 2

Severity and Impairment Assessment

• African Americans and Caribbean Blacks with panic disorder show higher 30-day functional impairment and objectively defined severity compared to non-Latino Whites, despite lower overall prevalence 2
• Assess for clinically significant distress or impairment in social, occupational, or other important areas of functioning 2

Referral Thresholds

• If moderate-to-severe or severe symptomatology is detected through screening, perform further diagnostic assessment to identify the nature and extent of symptoms and presence/absence of mood disorder 2
• Recognition of depression should trigger referral to a mental health care provider skilled in addressing these conditions 2
• The clinical team must decide when referral to a psychiatrist, psychologist, or equivalently trained professional is necessary 2