What alternative sleep aids can be prescribed for a patient with insomnia who is taking lithium, Latuda (lurasidone), and olanzapine at bedtime, and has not responded to Ativan (lorazepam) and mirtazapine?

Refractory Insomnia in a Patient on Lithium, Latuda, and Olanzapine

For this patient with treatment-refractory insomnia on multiple psychotropic medications including lithium, Latuda, and olanzapine, I recommend adding low-dose doxepin 3-6 mg at bedtime as the next-line agent, or alternatively suvorexant 10-20 mg if sleep maintenance is the primary issue. 1, 2

Rationale for This Recommendation

Your patient has already failed two common approaches—benzodiazepines (Ativan/lorazepam) and sedating antidepressants (mirtazapine)—making this a refractory case requiring escalation beyond typical first-line options. 1

Why Low-Dose Doxepin is the Preferred Choice

• Low-dose doxepin (3-6 mg) is specifically recommended by the American Academy of Sleep Medicine as a second-line agent for sleep maintenance insomnia and works through a different mechanism (histamine H1 receptor antagonism at low doses) than the previously failed mirtazapine. 1, 2

• This dose range is dramatically lower than antidepressant dosing, minimizing anticholinergic side effects and drug interactions with the patient's existing psychotropic regimen. 3

• Doxepin at this low dose has less anticholinergic activity than other tricyclics like amitriptyline, making it safer in combination with olanzapine (which already has anticholinergic properties). 3

Alternative: Suvorexant for Sleep Maintenance

• Suvorexant (orexin receptor antagonist) at 10-20 mg is recommended by the American Academy of Sleep Medicine specifically for sleep maintenance insomnia and reduces wake time after sleep onset by 16-28 minutes compared to placebo. 1, 2

• Suvorexant improves subjective total sleep time by 22.3-49.9 minutes and works through a completely novel mechanism (orexin receptor antagonism) that doesn't overlap with any previously tried agents. 2

• This agent should be reevaluated after 7-10 days to assess response and rule out comorbid sleep disorders if insomnia persists. 2

Why Not Other Options?

Trazodone is NOT Recommended

• The American Academy of Sleep Medicine explicitly does not recommend trazodone for sleep onset or maintenance insomnia despite its widespread off-label use. 1, 2

• While trazodone may be considered in bipolar patients due to low mania risk 4, your patient has already failed mirtazapine (another sedating antidepressant), making another agent in this class less likely to succeed.

• Trazodone is less effective than hypnotics for sleep onset and needs to be administered at least 1 hour before bedtime. 5

Additional Z-Drugs May Be Considered

• Eszopiclone 2-3 mg is suggested for both sleep onset and sleep maintenance insomnia and represents a different benzodiazepine receptor agonist than the failed lorazepam. 1

• Zolpidem 10 mg (or 5 mg in elderly) or temazepam 15 mg could be tried as they are intermediate-acting and may work where lorazepam failed, though they share similar mechanisms. 3, 1

• These agents are short-to-intermediate acting BzRAs that may have better efficacy profiles than lorazepam for primary insomnia. 3

Critical Considerations in This Complex Case

Drug Interaction Concerns

• Monitor carefully for excessive sedation given the combination of lithium, Latuda (lurasidone), olanzapine, and now adding another sedating agent. 2

• Olanzapine already has significant sedating properties—if the patient is taking it at bedtime and still can't sleep, this suggests either inadequate dosing of olanzapine for sedation or a primary sleep disorder requiring different mechanisms. 2

Rule Out Comorbid Sleep Disorders

• If insomnia persists after 7-10 days of appropriate treatment, reevaluate for comorbid sleep disorders such as restless legs syndrome (which can be worsened by antipsychotics like olanzapine) or obstructive sleep apnea. 2

• Lithium can cause polyuria/nocturia, which may be contributing to sleep maintenance problems—assess for this and consider timing of lithium dosing. 2

Implement Cognitive Behavioral Therapy for Insomnia (CBT-I)

• CBT-I should be implemented alongside any pharmacotherapy as it has superior long-term efficacy compared to medications alone and may help stabilize mood in patients on mood stabilizers. 4, 2

• Specific behavioral interventions include stimulus control therapy, sleep restriction therapy, and relaxation techniques—not just generic "sleep hygiene." 3, 1

Practical Dosing Algorithm

First Choice: Low-Dose Doxepin

• Start doxepin 3 mg at bedtime, can increase to 6 mg after 3-7 days if inadequate response. 1, 2
• Administer 30 minutes before bedtime to allow for absorption. 3
• Follow up in 2-4 weeks to assess effectiveness and monitor for daytime sedation or anticholinergic effects. 4

Second Choice: Suvorexant

• Start suvorexant 10 mg at bedtime, can increase to 20 mg if needed. 2
• Take within 30 minutes of going to bed with at least 7 hours remaining before planned awakening. 2
• Reassess after 7-10 days for effectiveness. 2

Third Choice: Alternative BzRA

• Try eszopiclone 2-3 mg or zolpidem 10 mg (different BzRA than failed lorazepam). 1
• Use lowest effective dose for shortest duration possible. 1

Common Pitfalls to Avoid

• Do not use over-the-counter antihistamines (diphenhydramine) as they lack efficacy data and cause problematic anticholinergic effects, especially dangerous when combined with olanzapine. 1, 2

• Avoid increasing olanzapine dose solely for sedation as this increases metabolic and neurological side effect risks without addressing the underlying sleep disorder. 2

• Do not continue pharmacotherapy long-term without periodic reassessment and attempts to taper when conditions allow. 1, 2

• Failing to consider that persistent insomnia despite multiple medications may indicate a primary sleep disorder requiring polysomnography. 2