What are the possibilities and evaluation for an elderly male patient with a 40-year history of depression, currently on venlafaxine (Effexor) and scitalopram (Celexa), presenting with a 3-month history of difficulty walking due to imbalance, tendency to fall, decline in cognitive function, and recurrent hyponatremia, with a normal MRI brain?

Antidepressant-Induced Hyponatremia with Parkinsonism-Plus Syndrome

The most likely diagnosis is medication-induced hyponatremia causing or exacerbating a parkinsonian syndrome, and you should immediately discontinue both venlafaxine and escitalopram, as the combination of two serotonergic agents dramatically increases SIADH risk, particularly in elderly patients. 1, 2

Primary Differential Diagnosis

Most Likely: Drug-Induced Parkinsonism with SIADH

• Both venlafaxine and escitalopram cause hyponatremia through SIADH, with elderly patients at highest risk 1, 2
• The FDA explicitly warns that SSRIs and SNRIs cause hyponatremia in elderly patients, who may be at greater risk for this adverse event 1, 2
• Hyponatremia typically develops within days to weeks of starting therapy and recurs with rechallenge 3, 4
• The combination of two serotonergic agents (venlafaxine + escitalopram) is particularly problematic and increases SIADH risk 5, 6
• Chronic hyponatremia causes cognitive decline, gait instability, falls, confusion, and reduced speech—matching this patient's entire presentation 2

Secondary Consideration: Progressive Supranuclear Palsy (PSP)

• The tendency to fall backward (retropulsion), reduced speech, and cognitive decline suggest PSP 7
• However, PSP typically shows midbrain atrophy on MRI, which is absent here 7
• The temporal relationship with recurrent hyponatremia strongly implicates medication as the primary culprit

Tertiary Consideration: Normal Pressure Hydrocephalus (NPH)

• Classic triad includes gait disturbance, cognitive decline, and urinary incontinence 7
• This patient lacks incontinence, making NPH less likely
• Normal MRI argues against NPH, though early cases may not show ventricular enlargement 7

Immediate Management Algorithm

Step 1: Discontinue Offending Medications (Within 24 Hours)

• Stop both venlafaxine and escitalopram immediately 1, 2
• The FDA warns about discontinuation syndrome, so taper over 1-2 weeks if patient is stable, but given recurrent severe hyponatremia, abrupt cessation may be necessary 2
• Monitor for withdrawal symptoms including dizziness, sensory disturbances, confusion, and emotional lability 2

Step 2: Correct Hyponatremia (Immediate)

• Check serum sodium, serum osmolality, urine sodium, and urine osmolality to confirm SIADH 3, 4
• Institute fluid restriction to 800 mL/day, which normalizes sodium within 2 weeks in elderly patients with antidepressant-induced SIADH 3
• Monitor sodium every 2-3 days initially, then weekly 3
• Avoid rapid correction (>8-10 mEq/L per 24 hours) to prevent osmotic demyelination syndrome 2

Step 3: Comprehensive Evaluation (Within 1 Week)

• Screen for reversible causes of cognitive impairment: TSH, vitamin B12, complete metabolic panel 7
• Formal cognitive assessment using Montreal Cognitive Assessment (MoCA), which is more sensitive than MMSE for executive dysfunction 7
• Neuropsychological testing focusing on executive function, as vascular cognitive impairment and medication effects predominantly affect executive domains 7
• Review complete medication list for other cognitively impairing drugs 7, 8

Step 4: Gait and Fall Assessment (Within 1 Week)

• Timed gait assessment and orthostatic vital signs 7
• Evaluate for orthostatic hypotension, which is exacerbated by antidepressants and aging 7
• Assess for carotid sinus hypersensitivity, as elderly patients with falls require evaluation for multiple syncope etiologies 7

Step 5: Advanced Neuroimaging (If No Improvement in 4-6 Weeks)

• Consider MRI with volumetric sequences to evaluate for subtle midbrain atrophy (PSP) or ventricular enlargement (NPH) 7
• DaTscan if parkinsonian features persist after medication withdrawal to differentiate neurodegenerative parkinsonism from drug-induced 7

Alternative Antidepressant Strategy (After 2-4 Week Washout)

Safest Options for Elderly with Hyponatremia History

• Avoid all SSRIs and SNRIs, as cross-reactivity for SIADH is well-documented 5, 6, 4
• Consider bupropion, which has minimal hyponatremia risk, though it may worsen anxiety 8
• Mirtazapine was previously considered safer but has documented SIADH cases 9
• If antidepressant is essential, monitor sodium at baseline, day 3-5, week 2, and monthly thereafter 3, 4

Non-Pharmacologic Depression Management

• Collaborative care programs with mental health specialists are significantly more effective than typical primary care treatment for elderly depression 7
• Refer to psychiatry within 2 weeks given treatment-resistant depression and medication complications 7

Critical Monitoring Parameters

First 2 Weeks Post-Discontinuation

• Serum sodium every 2-3 days until stable above 135 mEq/L 3
• Daily assessment of gait, cognition, and fall risk 7, 8
• Monitor for antidepressant withdrawal syndrome 2

Weeks 2-6

• Weekly sodium monitoring 3
• Repeat MoCA at week 4 to assess cognitive improvement 7
• Gait reassessment at week 4 7

Long-Term (If Symptoms Persist Beyond 6 Weeks)

• Referral to movement disorders specialist for evaluation of neurodegenerative parkinsonism 7
• Consider lumbar puncture if NPH remains in differential 7
• Autonomic testing if orthostatic hypotension persists 7

Common Pitfalls to Avoid

• Never restart the same antidepressant class after documented SIADH—cross-reactivity between SSRIs and SNRIs is extremely common 5, 6, 4
• Never attribute all symptoms to depression in elderly patients with new neurological signs—medication effects and neurodegenerative disease must be excluded first 7
• Never ignore recurrent hyponatremia as "mild" or "asymptomatic"—chronic hyponatremia causes falls, cognitive impairment, and increased mortality in the elderly 2, 3
• Never combine multiple serotonergic agents in elderly patients, as this dramatically increases SIADH risk 1, 2, 5
• Never assume normal MRI excludes all pathology—early PSP, NPH, and medication effects may not show structural changes 7

Expected Clinical Course

• If medication-induced, expect gradual improvement in gait and cognition over 4-6 weeks after discontinuation and sodium normalization 3, 4
• Cognitive improvement may lag behind sodium correction by 2-4 weeks 2
• If no improvement by 6 weeks, neurodegenerative disease becomes more likely and warrants subspecialty evaluation 7