What is the best course of action for a patient experiencing mood swings and insomnia while taking sertraline 200mg, Rexulti 2mg, Wellbutrin XL 300mg, and Doxepin 20mg?

Medication Management for Mood Swings and Insomnia

Immediate Action: Address Polypharmacy and Optimize Current Regimen

This patient is experiencing breakthrough symptoms despite being on four psychotropic medications, suggesting either inadequate treatment of an underlying bipolar disorder or medication-induced mood instability—the priority is to reassess the diagnosis and systematically optimize the regimen rather than adding more medications. 1

Critical Diagnostic Consideration

Evaluate for bipolar disorder immediately. The combination of mood swings and treatment-resistant symptoms on multiple antidepressants (sertraline + bupropion) raises concern for undiagnosed bipolar disorder, where antidepressants alone can precipitate mixed/manic episodes and worsen mood instability. 2 Patients with depressive symptoms should be adequately screened with a detailed psychiatric history, including family history of suicide, bipolar disorder, and depression before continuing antidepressant therapy. 2

Medication-Specific Problems in This Regimen

Wellbutrin (bupropion) is likely contributing to insomnia and potentially mood instability. Bupropion commonly causes agitation, insomnia, and can worsen anxiety—all of which may be contributing to this patient's current symptoms. 3 The onset of action is 2 weeks with full efficacy at 4 weeks, so if the patient hasn't responded adequately by now, continuing it is unlikely to help. 3

Doxepin 20mg is above the recommended dose for insomnia. The American Academy of Sleep Medicine recommends doxepin 3-6mg specifically for sleep maintenance insomnia. 4 At 20mg, this patient is receiving a dose that carries increased anticholinergic burden without additional sleep benefit. 4

Rexulti (brexpiprazole) 2mg suggests possible bipolar disorder or treatment-resistant depression. If this was added for augmentation of antidepressants, the presence of ongoing mood swings indicates inadequate response and requires regimen reassessment. 5

Recommended Treatment Algorithm

Step 1: Optimize Insomnia Management (Immediate Priority)

Reduce doxepin from 20mg to 3-6mg at bedtime. This dose is specifically recommended by the American Academy of Sleep Medicine for sleep maintenance insomnia with moderate-quality evidence showing 22-23 minute reduction in wake after sleep onset. 4 The current 20mg dose provides no additional sleep benefit but increases anticholinergic side effects. 4

Consider discontinuing bupropion if insomnia and agitation are prominent, as these are common adverse effects that can persist throughout treatment. 3 Bupropion causes insomnia, headaches, agitation, and tremor as primary side effects. 3

Implement Cognitive Behavioral Therapy for Insomnia (CBT-I) immediately. The American Academy of Sleep Medicine recommends CBT-I as first-line treatment for all adults with chronic insomnia, to be initiated before or alongside any pharmacotherapy, with superior long-term efficacy. 4, 1 This should include stimulus control therapy, sleep restriction therapy, and cognitive restructuring. 4

Step 2: Address Mood Instability

If bipolar disorder is confirmed or strongly suspected:

• Continue Rexulti 2mg as mood stabilizer 5
• Taper and discontinue sertraline and bupropion gradually to prevent antidepressant-induced mood cycling 2
• Antidepressants used alone in bipolar disorder may increase the likelihood of precipitation of mixed/manic episodes 2

If this is treatment-resistant unipolar depression:

• Optimize sertraline to 200mg (already at maximum dose) and continue for 4-9 months minimum after achieving remission 1
• Consider switching from bupropion to mirtazapine 30mg at bedtime for combined mood and sleep benefits, with faster onset of action than SSRIs and proven efficacy when combined with SSRIs in patients with comorbid anxiety 1, 3, 6
• Mirtazapine produces significant shortening of sleep-onset latency, increases total sleep time, and leads to marked improvement in sleep efficiency in depressed patients 6

Step 3: Alternative Insomnia Pharmacotherapy (If Low-Dose Doxepin Insufficient)

If sleep remains inadequate after optimizing doxepin to 3-6mg:

First-line options for combined sleep onset and maintenance:

• Eszopiclone 2-3mg at bedtime has no short-term usage restrictions and proven efficacy when combined with escitalopram in patients with comorbid anxiety 1
• Zolpidem 10mg (5mg if elderly) is effective for both sleep onset and maintenance insomnia with short-to-intermediate action 4, 1

Dual orexin receptor antagonists (DORAs) as preferred alternative:

• Daridorexant, lemborexant, or suvorexant inhibit wakefulness rather than induce sedation, with no evidence of rebound insomnia, withdrawal, or abuse potential 7
• Daridorexant has an ideal half-life of 8 hours with demonstrated continued efficacy over 12 months 7

Step 4: Monitoring and Safety

Monitor for serotonin syndrome risk with the current combination of sertraline, Rexulti, and potential addition of mirtazapine. 2 Watch for mental status changes, autonomic instability, neuromuscular symptoms, and gastrointestinal symptoms. 2

Avoid adding trazodone. The American Academy of Sleep Medicine explicitly recommends against trazodone for sleep onset or maintenance insomnia, as trials showed modest improvements in sleep parameters but no improvement in subjective sleep quality, with harms outweighing benefits. 4

Use lowest effective dose for shortest duration necessary for any hypnotic, and consider tapering after 3-4 weeks if insomnia improves. 1

Common Pitfalls to Avoid

Do not add another medication without first optimizing or removing existing agents. This patient is already on four psychotropic medications—adding a fifth without addressing the underlying issues will worsen polypharmacy risks. 4

Do not continue bupropion if it's contributing to insomnia and agitation. The most serious side effect of bupropion is seizures, but agitation, insomnia, and tremor are common and may not resolve with continued treatment. 3

Do not use doxepin at doses above 6mg for insomnia. Higher doses provide no additional sleep benefit but significantly increase anticholinergic burden. 4

Do not fail to implement CBT-I alongside medication changes. Pharmacotherapy should supplement, not replace, behavioral interventions, which provide more sustained effects than medication alone. 4, 1

Do not ignore the possibility of bipolar disorder. Antidepressant-induced mood instability is a critical diagnostic clue that requires immediate evaluation and potential regimen change. 2