Is it safe to discontinue Sertraline (Selective Serotonin Reuptake Inhibitor) in a patient with a history of treatment-resistant depression, post-traumatic stress disorder (PTSD), and attention deficit hyperactivity disorder (ADHD), who is currently stable on Esketamine (S-ketamine) 84 mg twice weekly and Rexulti (Brexpiprazole) 1-1.5 mg, with a recent history of severe emotional trauma and relapse?

Discontinuing Sertraline While Continuing Esketamine and Rexulti

Direct Answer to Safety of Discontinuation

Yes, it is safe and appropriate to discontinue sertraline while continuing esketamine 84 mg twice weekly and stable Rexulti 1-1.5 mg, provided you follow a gradual taper protocol and maintain close monitoring for withdrawal symptoms and mood destabilization. 1

Your proposed taper schedule (200→175→125→75→50→25 mg→every other day→every two days→stop) represents a cautious approach that aligns with FDA guidance recommending gradual dose reduction rather than abrupt cessation to minimize discontinuation symptoms 1.

Relapse Risk Assessment

The realistic relapse risk after stopping sertraline is substantial but mitigated by your concurrent esketamine therapy:

• Without antidepressant continuation, relapse rates reach 56% within 52 weeks compared to 39% with maintenance therapy in primary care patients who felt well enough to discontinue 2
• However, your situation differs critically: you have active esketamine treatment providing robust antidepressant coverage, which was not present in the discontinuation studies 2
• Recent high-quality evidence demonstrates esketamine monotherapy (84 mg twice weekly) produces significant antidepressant effects with effect size 0.63 and mean MADRS improvement of -6.8 points versus placebo at 4 weeks 3
• For PTSD specifically, relapse rates after SSRI discontinuation range from 26-52% depending on criteria used, with 5-16% relapse in those maintained on medication 4

Your concurrent esketamine therapy substantially reduces this relapse risk, as you are not truly discontinuing all antidepressant treatment—you are eliminating an ineffective agent (sertraline caused significant side effects with no benefit after 6 months) while maintaining a highly effective treatment 3.

Withdrawal Syndrome Management

Sertraline discontinuation syndrome is well-documented and requires careful monitoring:

• Common withdrawal symptoms include: dizziness, sensory disturbances (electric shock sensations/paresthesias), anxiety, irritability, agitation, confusion, headache, lethargy, emotional lability, insomnia, and in rare cases orthostatic hypotension 1, 5, 6
• Symptoms typically emerge within days of dose reduction and last several weeks, though late onset and prolonged persistence can occur 6
• Critical pitfall: Withdrawal symptoms are easily misidentified as depression relapse—distinguish by timing (withdrawal occurs within days of dose change) and symptom quality (sensory disturbances, dizziness suggest withdrawal rather than relapse) 6
• Your gradual taper schedule significantly reduces but does not eliminate withdrawal risk 1

If intolerable symptoms emerge during taper: Resume the previous dose, stabilize, then decrease more gradually 1.

Buspirone as Alternative to Rexulti

Buspirone is a reasonable option for deep, fear-based anxiety, but with important caveats:

• Buspirone lacks the robust evidence base that Rexulti has for augmentation in treatment-resistant depression 4
• For PTSD-related anxiety, SSRIs (which you're discontinuing) have stronger evidence than buspirone 4
• However, given your concern about Rexulti-stimulant antagonism affecting ADD treatment, buspirone offers a non-dopaminergic anxiolytic alternative 4

Your proposed 2-month overlap strategy (buspirone + Rexulti, then taper Rexulti) is clinically sound:

• This allows assessment of buspirone efficacy before removing Rexulti's proven benefit
• Monitor closely for anxiety breakthrough during Rexulti taper—if anxiety worsens significantly, this indicates buspirone alone is insufficient 4
• The overlap avoids creating an anxiolytic gap that could destabilize your recovery

Long-term Esketamine Safety

Long-term esketamine twice weekly followed by maintenance dosing is supported by available evidence:

• The recent 2025 monotherapy trial demonstrates efficacy and acceptable tolerability at 84 mg twice weekly for 4 weeks 3
• Most common adverse events were nausea (24.8%), dissociation (24.3%), dizziness (21.7%), and headache (19.0%)—all manageable and typically transient 3
• Your plan to continue twice weekly during sertraline taper plus one month, then transition to maintenance dosing, represents conservative practice
• No evidence suggests safety concerns with your proposed duration (approximately 1 year twice weekly total) 3

Monitor for: Dissociative symptoms, blood pressure changes during administration, and any cognitive effects, though these are typically acute and resolve between doses 3.

Serotonin Syndrome Risk During Transition

The risk of serotonin syndrome during your sertraline taper while on esketamine is low but requires monitoring:

• Esketamine combined with serotonergic agents can theoretically increase serotonin syndrome risk 1
• Monitor for: Mental status changes, autonomic instability (tachycardia, labile blood pressure, diaphoresis, hyperthermia), neuromuscular symptoms (tremor, rigidity, hyperreflexia), and GI symptoms 1
• Risk is highest during the first 24-48 hours after dose changes 7
• As you taper sertraline downward, serotonin syndrome risk decreases progressively 1

Practical Algorithm for Your Transition

Week-by-week approach:

1. Continue current regimen (sertraline taper as planned, esketamine 84 mg BIW, Rexulti 1-1.5 mg, Seroquel 50 mg HS) 1, 3
2. Monitor withdrawal symptoms at each sertraline dose reduction: If severe dizziness, paresthesias, or emotional lability emerge, hold at current dose for additional week 1, 6
3. Consider starting buspirone (typical starting dose 7.5 mg BID, titrate to 15-30 mg BID) once sertraline is at 50 mg or below to establish therapeutic levels before Rexulti taper 4
4. After sertraline fully discontinued and stable for 2-4 weeks, begin buspirone-Rexulti overlap if pursuing that strategy 4
5. Maintain esketamine 84 mg BIW throughout transition and for one month post-sertraline discontinuation as planned 3
6. If anxiety or depression worsen significantly during transition, this indicates need to maintain current regimen or adjust strategy 2

Critical Safety Monitoring Points

• Weekly mood and anxiety assessment during sertraline taper using standardized measures (PHQ-9, GAD-7) 2
• Daily symptom diary to distinguish withdrawal from relapse 6
• Blood pressure monitoring if dizziness or orthostatic symptoms emerge 5
• Immediate contact with prescriber if suicidal ideation emerges (though risk is lower in adults >24 years, monitoring remains essential) 1