What is the next best step in managing a patient with persistent and overwhelming anxiety, paresthesias (Electrostatic Sensory Reactions) in the lower legs, arms, and back, and cognitive impairment, who has been off multiple medications (polypharmacy) for a certain period, has a history of impaired fasting glucose, and has undergone extensive negative workup, including thyroid studies, B12 (Vitamin B12) level of 385 pg/mL, pheochromocytoma (Adrenal Gland Tumor) and celiac (Celiac Disease) screens, Complete Blood Count (CBC)/metabolic panel/Antinuclear Antibody (ANA), and Computed Tomography (CT) abdomen/pelvis, with mild inflammatory markers, including Elevated Sedimentation Rate (ESR) and C-Reactive Protein (CRP), and normal Hemoglobin A1c (HbA1c) and fasting glucose?

Management of Persistent Anxiety, Paresthesias, and Cognitive Impairment Following Polypharmacy Discontinuation

The next best step is to restart an SSRI, preferably escitalopram, at the previously effective dose, followed by a very slow taper over months, as this constellation of symptoms is classic for SSRI discontinuation syndrome. 1

Primary Diagnosis: SSRI Discontinuation Syndrome

The clinical presentation strongly suggests SSRI withdrawal rather than a primary medical condition:

• The triad of persistent anxiety (despite prior SSRI treatment), paresthesias ("electrostatic sensory reactions" in lower legs, arms, and back), and cognitive impairment following medication discontinuation is pathognomonic for SSRI discontinuation syndrome. 1

• The characteristic "electric shock sensations" in the distribution described match the sensory disturbances classically seen with SSRI withdrawal. 1

• The extensive negative workup (thyroid, pheochromocytoma, celiac, CBC, metabolic panel, ANA, CT imaging) effectively rules out primary medical causes of these symptoms. 1

Immediate Management Algorithm

Step 1: Restart SSRI Therapy

• Reinitiate escitalopram at the previously effective dose (typically 10-20 mg daily). 1

• Escitalopram is preferred because it has the least effect on CYP450 enzymes and lower propensity for drug interactions compared to other SSRIs. 1

• Symptoms should begin improving within 1-2 weeks of restarting the medication. 1, 2

Step 2: Concurrent Diagnostic Workup

While restarting the SSRI, obtain additional testing to rule out contributing factors:

• Check methylmalonic acid (MMA) and homocysteine levels to definitively exclude functional B12 deficiency, as the B12 level of 385 pg/mL is in the low-normal range and may not exclude tissue deficiency. 1, 3, 4

• Arrange skin biopsy for small fiber neuropathy evaluation, given the impaired fasting glucose (116 mg/dL) and mild inflammatory markers (ESR 29, CRP 15), as small fiber neuropathy can cause paresthesias and is associated with prediabetes even before overt diabetes develops. 1

Step 3: Implement Proper Tapering Protocol

Once symptoms resolve on the restarted SSRI:

• Taper at 1-2 week intervals, reducing the dose by 25% every 2-4 weeks rather than attempting abrupt cessation. 1

• This gradual approach over months (not weeks) is essential for shorter half-life SSRIs like escitalopram to prevent recurrence of withdrawal symptoms. 1

• Monitor closely for re-emergence of anxiety, paresthesias, or cognitive symptoms during the taper. 1

Secondary Considerations

Address Prediabetes

• The fasting glucose of 116 mg/dL indicates impaired fasting glucose, which requires intervention. 5

• Implement lifestyle modification including structured physical activity and dietary changes. 5

• Repeat metabolic testing (HbA1c, fasting glucose) in 3 months to monitor progression. 5

• The mild inflammatory markers may be related to prediabetes and metabolic syndrome rather than representing a primary inflammatory condition. 5

Psychiatric Management

• Consider combining SSRI therapy with cognitive behavioral therapy (CBT) targeting anxiety patterns, as combination treatment provides superior outcomes compared to medication alone. 2

• Screen for comorbid depression using validated tools, as approximately one-third of anxiety patients have comorbid conditions. 5, 2

• If anxiety remains overwhelming despite SSRI reinitiation, consider adding structured CBT with specific elements including cognitive restructuring, relaxation techniques, and gradual exposure. 2

Monitor for Serotonin Syndrome

• When restarting SSRIs, especially if combining with other serotonergic agents, monitor for signs of serotonin syndrome (agitation, confusion, tremor, hyperthermia, hyperreflexia). 1

Common Pitfalls to Avoid

• Do not pursue extensive additional medical workup before addressing the obvious SSRI discontinuation syndrome. The negative workup already obtained is comprehensive. 1

• Do not attempt to manage anxiety with benzodiazepines as first-line treatment due to risks of dependence, tolerance, and withdrawal. 2

• Do not dismiss the B12 level as "normal" without checking MMA and homocysteine, as functional B12 deficiency can occur with low-normal serum levels and cause paresthesias, anxiety, depression, and cognitive impairment. 3, 4

• Do not ignore the prediabetes, as it increases risk for small fiber neuropathy and can contribute to paresthesias independent of SSRI withdrawal. 1

Expected Timeline

• Statistically significant improvement in anxiety should begin within 2 weeks of restarting escitalopram, with clinically significant improvement by week 6, and maximal benefit by week 12. 2

• Paresthesias typically resolve more rapidly (within days to 2 weeks) once the SSRI is restarted. 1

• Cognitive symptoms may take longer to fully resolve (4-12 weeks). 5, 1