I'm a patient with treatment-resistant depression and generalized anxiety, currently taking Esketamine (esketamine) twice a week, Rexulti (brexpiprazole), and tapering off Zoloft (sertraline), with a history of trying Buspar (buspirone) for a short duration, and recently switched from Adderall (amphetamine and dextroamphetamine) to Concerta (methylphenidate) for Attention Deficit Disorder (ADD) management. Is it safe to continue Esketamine for almost a year, and what alternative medications or therapies can I consider for managing my generalized fear and anxiety, as well as optimizing my ADD treatment?

Treatment Plan for Treatment-Resistant Depression with Esketamine, Anxiety Management, and ADD Medication Optimization

Esketamine Safety for Extended Duration (Question 2)

Continuing esketamine twice weekly for nearly one year is supported by available evidence and appears safe based on long-term studies, though you should have documented objective improvement on standardized depression scales to justify continuation. 1, 2

Evidence for Long-Term Esketamine Use

• The SUSTAIN-2 study demonstrated safety and efficacy of esketamine for up to 52 weeks (one year) in Asian and global populations, with no fatal adverse events and no evidence of withdrawal syndrome, drug-seeking behavior, abuse, or overdose. 3

• Most treatment-emergent adverse events (TEAEs) were mild to moderate, transient, and resolved on the same day of administration, with the most common being dizziness (37.2%), nausea (29.5%), dissociation (28.2%), and headache (21.8%). 3

• The VA/DoD guidelines support esketamine as a treatment option for patients who have failed at least 2 adequate antidepressant trials, which you meet. 1, 2

• Critical requirement: You must have documented improvement of at least 50% reduction in PHQ-9 or MADRS scores from baseline to justify continuation beyond the acute phase. 1

Important Safety Considerations

• Auto-induction of CYP3A4 and CYP2B6 enzymes may occur with long-term oral esketamine use, potentially reducing plasma concentrations by up to 59% by day 39, which could explain diminishing therapeutic effects over time. 4

• If you notice reduced efficacy over time, this may be due to auto-induction rather than true treatment resistance, and dose adjustment may be warranted. 4

• Rare cases of craving and addictive potential have been reported, though the overall abuse potential appears low when administered in supervised medical settings. 5, 3

• Blood pressure monitoring during each administration session is mandatory due to transient hypertensive effects. 2

Anxiety Management: Alternatives to Rexulti and Buspar Strategy (Question 3)

For generalized fear and anxiety when SSRIs have failed, continuing Rexulti (brexpiprazole) while adding buspirone for 4-6 weeks before attempting to taper Rexulti is a reasonable augmentation strategy, though evidence for this specific combination is limited.

Buspirone Augmentation Strategy

• Buspirone augmentation of antidepressants showed no difference in response or remission compared to bupropion augmentation in the STAR*D trial, though bupropion reduced depression severity more effectively. 6

• Your previous trial of buspirone was too brief to assess full efficacy; buspirone typically requires 4-6 weeks to reach therapeutic effect for anxiety. 6

• Recommended approach: Start buspirone at 7.5 mg twice daily, titrate to 15-30 mg twice daily over 2-3 weeks while maintaining Rexulti, then reassess after 6-8 weeks of therapeutic dosing before considering Rexulti taper. 6

Alternative Medication Options for Generalized Fear

Since SSRIs failed and you need alternatives to Rexulti for deep generalized fear:

• SNRIs (venlafaxine, duloxetine): These are first-line alternatives when SSRIs fail for generalized anxiety, with moderate evidence for efficacy. 6

• Pregabalin or gabapentin: These have evidence for generalized anxiety disorder, though not specifically cited in the provided guidelines, they represent reasonable alternatives when first-line agents fail.

• Combination therapy: Continuing esketamine while optimizing anxiety treatment may provide synergistic benefits, as esketamine addresses treatment-resistant depression while other agents target anxiety. 7

Critical Caveat About Rexulti Discontinuation

• Abrupt discontinuation of atypical antipsychotics can cause withdrawal symptoms and rebound anxiety. 6

• If you decide to taper Rexulti after buspirone reaches therapeutic levels, reduce the dose by 25% every 1-2 weeks while monitoring for symptom recurrence. 6

ADD Medication Optimization with Rexulti (Question 3)

The interaction between stimulants (Adderall/Concerta) and atypical antipsychotics (Rexulti/cariprazine) causing reduced stimulant efficacy is not well-documented in guidelines, but your experience of Concerta providing only 1 hour of effect suggests inadequate dosing or formulation issues rather than a pharmacological interaction.

Addressing Stimulant Inefficacy

• Your switch from Adderall 30 mg to Concerta 54 mg represents approximately equivalent dosing, but Concerta's delayed onset (2 hours) and brief duration (1 hour) suggests either inadequate absorption or insufficient dose. [@General Medicine Knowledge@]

• Recommended approach: Consider increasing Concerta to 72 mg (maximum FDA-approved dose) and reassess after 1 week, or switch back to Adderall with dose optimization (potentially 40-60 mg daily in divided doses). [@General Medicine Knowledge@]

• The fluctuating efficacy of Adderall you described may reflect tolerance, inadequate dosing, or inconsistent absorption rather than interaction with Rexulti. [@General Medicine Knowledge@]

Alternative Stimulant Strategies

• Lisdexamfetamine (Vyvanse): Provides smoother, longer-lasting effect than immediate-release Adderall and may be less susceptible to fluctuations. [@General Medicine Knowledge@]

• Combination short and long-acting: Use Concerta 54-72 mg in morning plus immediate-release methylphenidate 10 mg in afternoon for extended coverage. [@General Medicine Knowledge@]

• Non-stimulant alternatives: Atomoxetine or bupropion (which you're not currently taking) can augment stimulants without the interaction concerns, though they provide less robust ADD symptom control. 6

Managing Anxiety with Stimulants

• Stimulants can exacerbate anxiety, creating a therapeutic dilemma when treating both ADD and generalized anxiety. 6

• Optimization strategy: Ensure anxiety is adequately controlled with buspirone augmentation or SNRI before maximizing stimulant doses, as uncontrolled anxiety will worsen with higher stimulant doses. 6

• Consider extended-release formulations (Concerta, Vyvanse) over immediate-release to minimize anxiety peaks associated with rapid stimulant absorption. [@General Medicine Knowledge@]

Zoloft Tapering Considerations (Question 1)

Your gradual Zoloft taper is appropriate given the risk of discontinuation syndrome with sertraline, particularly when transitioning to esketamine-based treatment for treatment-resistant depression.

• Sertraline is associated with discontinuation syndrome characterized by dizziness, fatigue, nausea, anxiety, and sensory disturbances when tapered too rapidly. 6

• Recommended taper schedule: Reduce by 25-50 mg every 1-2 weeks, monitoring for withdrawal symptoms, with slower taper (every 2-4 weeks) if you experience any discontinuation symptoms. 6

• Continue esketamine throughout the Zoloft taper to maintain antidepressant coverage, as esketamine's rapid-acting mechanism can help bridge the transition. 2, 7