Alternative Sleep Medications for Treatment-Resistant Insomnia
For a patient on Rexulti and Trintellix who has failed melatonin, mirtazapine, clonidine, and trazodone, the next recommended options are suvorexant (10-20 mg), eszopiclone (2-3 mg), or low-dose doxepin (3-6 mg), with suvorexant being the preferred choice given its unique mechanism and favorable side effect profile in patients already on psychiatric medications. 1, 2
Recommended Next-Line Agents
Orexin Receptor Antagonists (Preferred Option)
Suvorexant (Belsomra) 10-20 mg is the strongest recommendation for this clinical scenario, as it works through a completely different mechanism (blocking wakefulness-promoting orexin neuropeptides) rather than targeting GABA or histamine receptors like previously failed agents 3, 1, 2
Suvorexant is specifically recommended by the American Academy of Sleep Medicine for sleep maintenance insomnia and has demonstrated efficacy over 12 months of continuous use without significant withdrawal effects 3, 4, 5
The drug must be taken within 30 minutes of bedtime with at least 7 hours available for sleep, and should not be combined with alcohol 2
Common side effects include next-day drowsiness, abnormal dreams, and temporary sleep paralysis, but it lacks the cognitive impairment, dependence, and rebound insomnia seen with benzodiazepines 2, 6
Critical caveat: Suvorexant may have enhanced effects in females, obese patients, and those with respiratory disease, requiring dose adjustments 4
Z-Drugs (Strong Alternative)
Eszopiclone 2-3 mg is recommended by the American Academy of Sleep Medicine for both sleep onset and sleep maintenance insomnia 3, 1
Zolpidem 10 mg is another option for both sleep onset and maintenance, though it carries higher risk of complex sleep behaviors (sleep-walking, sleep-driving) 1
Zaleplon 10 mg specifically targets sleep onset insomnia if that is the primary complaint 3, 1
Low-Dose Tricyclic Antidepressant
Doxepin 3-6 mg is recommended specifically for sleep maintenance insomnia through selective H1 receptor antagonism at low doses 3, 1, 7
This is distinct from higher-dose doxepin used for depression and has a more favorable side effect profile at these low doses 7
Agents to Consider with Caution
Benzodiazepines (Use Only If Above Options Fail)
Temazepam 15 mg is recommended for both sleep onset and maintenance insomnia, though benzodiazepines carry risks of cognitive impairment, tolerance, dependence, and falls 3, 1
Triazolam 0.25 mg is an option specifically for sleep onset insomnia 3, 1
These should be reserved for situations where orexin antagonists and Z-drugs have failed, given their side effect profile 7
Melatonin Receptor Agonist
Ramelteon 8 mg is recommended for sleep onset insomnia specifically, though the patient has already failed melatonin supplementation 3, 1, 8
Ramelteon works through MT1 and MT2 melatonin receptors and has demonstrated efficacy in reducing latency to persistent sleep in both younger and older adults 8, 7
It may still be worth trying despite melatonin failure, as ramelteon is a selective receptor agonist with different pharmacokinetics than over-the-counter melatonin 8
Important Clinical Considerations
Drug Interactions with Current Medications
Rexulti (brexpiprazole) and Trintellix (vortioxetine) are both metabolized through CYP pathways, so careful attention to potential interactions is needed when adding sleep medications 2
Suvorexant specifically should not be combined with strong CYP3A inhibitors, and patients should be asked about all medications including over-the-counter products 2
Monitoring Strategy
The American Academy of Sleep Medicine recommends following patients every few weeks initially to assess effectiveness, side effects, and need for ongoing medication 1
If insomnia does not improve within 7-10 days, this suggests another underlying condition may be causing the sleep problem and requires further evaluation 2
Pharmacological treatment should be supplemented with cognitive behavioral therapy for insomnia (CBT-I) when possible, as this is the first-line treatment recommended by guidelines 1
Common Pitfalls to Avoid
Do not use diphenhydramine or other over-the-counter antihistamines, as these are explicitly not recommended by the American Academy of Sleep Medicine for chronic insomnia 3, 1
Avoid combining multiple sedating agents without careful consideration, as this increases fall risk and cognitive impairment 1
Do not prescribe higher doses thinking more is better - the 16 mg dose of ramelteon and 20 mg dose of suvorexant showed no additional benefit over lower doses but increased side effects 8, 4