What are the next steps for a patient experiencing fatigue while on paroxetine (selective serotonin reuptake inhibitor) 37.5mg for anxiety, semaglutide (Wegovy) and tizanidine (muscle relaxant) without depressive symptoms?

Evaluation and Management of Fatigue in a Patient on Paroxetine, Semaglutide, and Tizanidine

The most likely culprits for this patient's tiredness are tizanidine (a known sedating muscle relaxant) and paroxetine (which commonly causes fatigue and somnolence as adverse effects), and the first step should be to assess whether tizanidine can be reduced or discontinued, followed by evaluation of paroxetine's contribution to fatigue. 1, 2

Identify the Medication-Related Causes

Tizanidine as Primary Suspect

• Tizanidine is a centrally-acting muscle relaxant with significant sedative properties that commonly causes drowsiness and fatigue as dose-dependent adverse effects 1
• Assess the current indication for tizanidine and whether it remains necessary—if muscle spasm or spasticity has improved, consider tapering or discontinuing this medication first
• If tizanidine must be continued, evaluate whether the dose can be reduced or whether timing adjustments (taking only at bedtime) might minimize daytime sedation

Paroxetine's Contribution to Fatigue

• Paroxetine commonly causes somnolence, asthenia (weakness), and fatigue as adverse effects, with incidences of 18-25% in clinical trials 1, 2, 3, 4
• The FDA label specifically lists fatigue, lethargy, and somnolence as known adverse effects of paroxetine 2
• A discontinuation syndrome from paroxetine includes fatigue and lethargy, but this patient is currently taking the medication regularly, so this represents an ongoing adverse effect rather than withdrawal 1

Semaglutide (Wegovy) Considerations

• While semaglutide can cause fatigue, particularly during initial titration or with rapid weight loss, this is less commonly the primary driver of persistent tiredness
• Assess for adequate caloric intake and nutritional status, as excessive caloric restriction combined with semaglutide may contribute to fatigue

Rule Out Other Contributing Factors

Medical Causes to Evaluate

• Check thyroid function (TSH, free T4), complete blood count for anemia, comprehensive metabolic panel for electrolyte abnormalities (particularly sodium, as SSRIs can cause hyponatremia), and glucose levels 1
• Evaluate for sleep disturbances: paroxetine disrupts normal sleep architecture by reducing REM sleep time and lengthening REM latency, which may contribute to non-restorative sleep despite adequate sleep duration 5, 6
• Screen for depression despite the patient's report of no depressive symptoms—use a standardized tool like PHQ-9, as fatigue can be an isolated manifestation of depression

Drug Interactions

• Paroxetine is both a substrate and inhibitor of CYP2D6, which can lead to drug-drug interactions 1, 6
• Review all medications (including over-the-counter products) for potential interactions that might enhance sedation

Stepwise Management Algorithm

Step 1: Address Tizanidine First

• If clinically appropriate, initiate a gradual taper of tizanidine over 2-4 weeks while monitoring for return of muscle spasm symptoms
• Reassess fatigue after 2 weeks off tizanidine—if fatigue resolves, no further medication changes needed

Step 2: Optimize Paroxetine Dosing if Fatigue Persists

• Consider switching the timing of paroxetine administration to bedtime if currently taken in the morning, as this may reduce daytime somnolence 2
• The current dose of 37.5mg is above the FDA-recommended maximum of 20mg for generalized anxiety disorder, though doses up to 60mg have been studied 2, 7, 3
• Evaluate whether anxiety control would be maintained at a lower dose (e.g., 20mg daily)—dose reduction should occur in 10mg decrements at intervals of at least 1 week to minimize discontinuation syndrome 1, 2

Step 3: Consider Alternative SSRI if Fatigue Persists

• If fatigue continues despite the above interventions and paroxetine remains necessary for anxiety control, consider switching to an SSRI with lower propensity for sedation, such as escitalopram or sertraline 1
• When switching from paroxetine, taper gradually over at least 2 weeks due to its association with discontinuation syndrome (characterized by dizziness, fatigue, lethargy, and other symptoms) 1, 2
• Citalopram/escitalopram have the least effect on CYP450 isoenzymes and may have lower propensity for drug interactions compared to paroxetine 1

Important Caveats and Pitfalls

Avoid Abrupt Discontinuation

• Never stop paroxetine abruptly—it is specifically associated with discontinuation syndrome more than other SSRIs due to its shorter half-life 1, 2
• Symptoms include dizziness, fatigue, lethargy, general malaise, myalgias, chills, headaches, nausea, vomiting, diarrhea, insomnia, sensory disturbances, and anxiety 1

Monitor for Worsening Anxiety

• When reducing or changing paroxetine, monitor closely for return of anxiety symptoms using standardized scales
• Have a plan to adjust dosing if anxiety worsens during medication changes

Do Not Use Psychostimulants for SSRI-Induced Fatigue

• Evidence shows that paroxetine does not reduce fatigue and antidepressants are not recommended for treating fatigue 1
• Psychostimulants like methylphenidate showed no superiority over placebo in most studies (15 of 19 trials), and are not recommended for general fatigue management 1

Special Monitoring in Elderly or Medically Complex Patients

• Elderly patients may have higher plasma concentrations and slower elimination of paroxetine, requiring lower initial doses (10mg daily) and slower titration 2
• Paroxetine can cause hyponatremia, particularly in elderly patients—monitor sodium levels if fatigue is accompanied by confusion, weakness, or unsteadiness 1, 2