What is the best course of action for a 30-year-old woman experiencing anxiety, somatic symptoms, and gastrointestinal issues after discontinuing sertraline (Selective Serotonin Reuptake Inhibitor), starting bupropion (Voxra) (bupropion), and switching from semaglutide (Wegovy) (semaglutide) to tirzepatide (Mounjaro) (tirzepatide)?

Management Approach for Polypharmacy-Induced Anxiety and Somatic Symptoms

The most critical immediate action is to stabilize the psychiatric medication regimen by addressing the abrupt sertraline discontinuation and rapid bupropion escalation, as these changes are the most likely drivers of her anxiety and somatic symptoms, rather than pursuing gastrointestinal investigations for transient, self-limited stool changes. 1

Primary Psychiatric Medication Management

Addressing SSRI Discontinuation Syndrome

• Sertraline withdrawal after 15 years of continuous use is highly likely causing her marked anxiety, bodily hypervigilance, and neurological symptoms (tingling sensations), as abrupt discontinuation of long-term SSRIs produces withdrawal symptoms including anxiety, agitation, and paresthesias 2, 3

• The appropriate intervention is to reinitiate sertraline at a lower dose (e.g., 25-50 mg daily) to stabilize withdrawal symptoms, then taper more gradually over weeks to months if discontinuation remains the goal 2

• SSRIs like sertraline are actually recommended as second-line gut-brain neuromodulators for functional gastrointestinal symptoms, making their discontinuation potentially counterproductive for her GI complaints 4

Managing Bupropion-Related Adverse Effects

• Bupropion carries significant risks for anxiety, agitation, panic attacks, and neuropsychiatric symptoms, particularly during dose escalation, as explicitly warned in FDA labeling 1

• The FDA specifically states: "anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania" are reported adverse effects, especially during initial therapy or dose changes 1

• Reduce bupropion to the lowest effective dose (150 mg daily) or discontinue entirely given her marked anxiety symptoms that temporally correlate with its initiation and rapid titration 1

• If continuing bupropion, the dose must be titrated gradually and should not exceed 300 mg once daily to minimize seizure risk and neuropsychiatric effects 1

Critical Drug Interaction Consideration

• The combination of bupropion and sertraline carries a documented risk of serotonin syndrome through bupropion's inhibition of cytochrome P450 2D6, which increases SSRI blood levels 5

• However, this combination has also been used successfully in treatment-refractory depression when carefully monitored 6, 7

• If both medications are continued, monitor closely for serotonin syndrome symptoms (confusion, agitation, tremor, myoclonus, autonomic instability) particularly in the first 24-48 hours after any dose adjustment 2, 3

GLP-1 Receptor Agonist Considerations

Psychiatric Effects of Tirzepatide

• Recent pharmacovigilance data shows GLP-1 agonists (semaglutide, liraglutide, tirzepatide) are associated with psychiatric adverse events including depression (50.3%), anxiety (38.7%), and suicidal ideation (19.6%) 8

• While psychiatric events comprised only 1.2% of total reports, the severity warrants monitoring, particularly given her pre-existing anxiety symptoms 8

• The switch from semaglutide to tirzepatide may be contributing to her anxiety, though this is less likely than the SSRI/bupropion changes 8

Gastrointestinal Effects

• Both semaglutide and tirzepatide significantly increase overall GI adverse events (RR 1.86), with tirzepatide showing greater risk (RR 2.94) than semaglutide (RR 1.68) 9

• Semaglutide specifically increases gallbladder-related disorders, particularly cholelithiasis, by 2.6 times, though she has already undergone cholecystectomy 9

• Her transient stool changes (variability in consistency and buoyancy over one week without persistent steatorrhea or alarm features) are consistent with common, mild GI effects of GLP-1 agonists rather than pancreatic insufficiency 9

• Neither agent significantly increases pancreatic or hepatic adverse events in controlled trials 9

Gastrointestinal Symptom Assessment

Why Pancreatic Investigation is Not Indicated

• Transient stool changes lasting approximately one week that have partially normalized, without persistent steatorrhea, difficult-to-flush stools, or ongoing malodor do not meet criteria for pancreatic insufficiency

• Her post-cholecystectomy status (without persistent postoperative GI symptoms) and the temporal relationship to medication changes point toward functional symptoms rather than structural pathology

• The single second-degree relative with pancreatic cancer at age 61, without additional family history, does not constitute a hereditary cancer syndrome requiring screening at age 30

• Available laboratory data do not suggest pancreatic, hepatic, or biliary pathology

Functional GI Symptom Management

• Her GI symptoms are most consistent with functional bowel changes exacerbated by anxiety and medication effects 4

• If GI symptoms persist after psychiatric medication stabilization, consider tricyclic antidepressants (starting amitriptyline 10 mg once daily, titrating to 30-50 mg) as gut-brain neuromodulators, which are effective for global symptoms and abdominal pain 4

• Alternatively, reinitiating an SSRI like sertraline serves dual purposes: treating anxiety and functioning as a gut-brain neuromodulator for functional GI symptoms 4

Recommended Management Algorithm

Immediate Actions (Within 24-48 Hours)

1. Reinitiate sertraline at 25-50 mg daily to address withdrawal syndrome 2

2. Reduce bupropion to 150 mg daily or discontinue given prominent anxiety symptoms 1

3. Monitor closely for serotonin syndrome if continuing both medications 2, 3, 5

4. Continue tirzepatide as GI symptoms are mild and self-limited 9

Short-Term Management (1-2 Weeks)

• Assess symptom response to medication adjustments

• If anxiety persists despite sertraline reinitiation, consider that bupropion may be contraindicated for this patient given her anxiety profile 1

• Monitor for neuropsychiatric symptoms including worsening depression, suicidal ideation, or behavioral changes as required by FDA black box warning for bupropion 1

Longer-Term Considerations

• If sertraline discontinuation remains desired, taper by no more than 10-25% every 2-4 weeks after symptom stabilization 2

• Consider adding cognitive behavioral therapy, which shows superior outcomes to medication alone for anxiety 2

• If functional GI symptoms persist after psychiatric stabilization, trial tricyclic antidepressants as gut-brain neuromodulators 4

Critical Pitfalls to Avoid

• Do not pursue extensive pancreatic workup (imaging, fecal elastase, etc.) for transient, self-limited stool changes without alarm features or persistent steatorrhea

• Do not abruptly discontinue bupropion if it has been at higher doses, as this can precipitate seizures in susceptible patients 1

• Do not misinterpret early serotonin syndrome symptoms (myoclonus, confusion, agitation) as worsening depression, which could lead to inappropriate medication escalation 5

• Do not overlook the black box warning for bupropion regarding suicidal thoughts in young adults, requiring close monitoring especially during dose changes 1

• Do not combine multiple serotonergic agents without careful monitoring for serotonin syndrome 2, 3