I have complex post-traumatic stress disorder (CPTSD), anxiety, secondary depression, and attention deficit disorder (ADD), and I'm currently taking Adderall (amphetamine and dextroamphetamine) and Rexulti (brexpiprazole). Since Rexulti and Concerta (methylphenidate) blunt the effect of my ADD medication, and I've had no success with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), what alternative medications can I consider to manage my anxiety and depression without affecting my ADD treatment, and should I replace Rexulti with Buspar (buspirone)?

Managing Anxiety in CPTSD with ADD: Medication Strategy When Rexulti Blunts Stimulant Efficacy

Switch from Rexulti to an SSRI (sertraline 50-200mg daily) rather than buspirone, as SSRIs are first-line treatment for anxiety in CPTSD with superior evidence for efficacy, and they do not interfere with stimulant medications for ADD. 1, 2

Why Not Buspirone

• Buspirone is FDA-approved only for generalized anxiety disorder, not for CPTSD or treatment-resistant anxiety after SSRI/SNRI failure 3
• The evidence for buspirone in PTSD comes only from open-label studies with no controlled trials demonstrating efficacy 4, 5
• Buspirone augmentation shows higher discontinuation rates due to adverse events compared to other strategies 6
• Your statement that "all SSRI and SNRI did not work" needs reconsideration—adequate trials require therapeutic doses for 6-8 weeks, and many patients require dose optimization beyond initial attempts 1

The Core Problem: Atypical Antipsychotics Blunt Stimulants

• Rexulti (brexpiprazole) is an atypical antipsychotic that blocks dopamine D2 receptors, directly opposing the dopamine-enhancing mechanism of Adderall 6
• This pharmacological antagonism explains why both Rexulti and other antipsychotics reduce stimulant efficacy—they work against each other at the receptor level 6
• Concerta (methylphenidate) experienced the same blunting because the problem is the antipsychotic, not the specific stimulant choice 2

Recommended Treatment Algorithm

Step 1: Taper Rexulti and Start SSRI

• Begin sertraline 50mg daily (or 25mg if anxiety-prone) while tapering Rexulti over 2-4 weeks 1
• Sertraline is specifically effective for PTSD (FDA-approved), anxiety, and depression with the best tolerability profile among SSRIs 1, 4
• SSRIs have no pharmacological interaction with stimulants and will not blunt Adderall's efficacy 2
• Target dose: 100-200mg daily, titrating by 50mg every 1-2 weeks based on response 1

Step 2: Optimize Adderall Dosing

• Once Rexulti is discontinued, reassess your Adderall dose as you may need less than before (the antipsychotic was blocking its effect) 2
• Typical adult ADD doses range 10-50mg daily; many patients need 20-40mg for optimal control 2
• Monitor for return of full stimulant efficacy within days to weeks after Rexulti discontinuation 2

Step 3: Allow Adequate SSRI Trial

• Continue sertraline for minimum 6-8 weeks at therapeutic dose (100-200mg) before judging efficacy 1
• For PTSD specifically, continuation treatment for 6-12 months decreases relapse rates 4
• Monitor anxiety symptoms at 4 weeks and 8 weeks using standardized measures 1

Addressing Your Preference for "Serotonin Creators or Agonists"

• SSRIs are functional serotonin agonists—they increase synaptic serotonin concentration by blocking reuptake, making more serotonin available to activate receptors 1
• Mirtazapine is the closest to a "serotonin creator" as it enhances serotonin release and has faster onset than SSRIs, but it causes significant sedation and weight gain 6
• Buspirone is a partial 5-HT1A agonist (direct serotonin receptor agonist), but has weaker evidence in PTSD than SSRIs 3, 4, 5

If SSRIs Truly Failed Previously

Verify Adequate Trials

• Confirm previous SSRI trials reached therapeutic doses: sertraline 150-200mg, fluoxetine 40-60mg, paroxetine 40-60mg for minimum 6-8 weeks 1
• Approximately 38% of patients don't respond initially, but many respond to dose optimization or switching to a different SSRI 1

Alternative Second-Line Options

• Venlafaxine (SNRI) 75-225mg daily may have superior efficacy specifically for anxiety with depression compared to SSRIs 6, 1
• Mirtazapine 15-45mg nightly has faster onset than SSRIs and benefits comorbid anxiety/insomnia, though causes sedation 6
• Augmentation with low-dose aripiprazole (5-10mg) if you must use an antipsychotic, as it has less D2 blockade than Rexulti, though it may still blunt stimulants somewhat 6

Critical Safety Monitoring

• Monitor for treatment-emergent suicidality closely during first 1-2 months of SSRI treatment, especially with dose changes 1
• Screen for substance use given CPTSD diagnosis, as this affects treatment selection 2
• Assess for bipolar features before starting antidepressants, as CPTSD can be misdiagnosed bipolar disorder 2

Common Pitfalls to Avoid

• Don't assume one medication will treat everything—ADD requires stimulants, anxiety/CPTSD requires antidepressants, and combining them is standard practice 2
• Don't use benzodiazepines chronically for CPTSD anxiety, as they may worsen PTSD symptoms long-term and have abuse potential 4, 5
• Don't discontinue SSRIs prematurely—full response takes 6-8 weeks, and partial response at 4 weeks warrants continuation, not switching 1
• Don't combine with MAOIs—never use MAO inhibitors with stimulants or most antidepressants due to hypertensive crisis risk 2

Multimodal Treatment Approach

• Combine medication with trauma-focused cognitive behavioral therapy (CBT), which shows equivalent efficacy to antidepressants for depression and superior outcomes when combined 6, 1
• CBT plus SSRI is superior to either alone for anxiety disorders 1, 2