What medications are indicated for an adult patient with insomnia, particularly those with a history of depression or anxiety?

Medications Indicated for Adult Insomnia

First-Line Treatment: Cognitive Behavioral Therapy for Insomnia (CBT-I)

Before prescribing any medication, initiate Cognitive Behavioral Therapy for Insomnia (CBT-I) as the standard of care for all adults with chronic insomnia. 1

• CBT-I demonstrates superior long-term efficacy compared to pharmacotherapy, with sustained benefits after treatment discontinuation and minimal adverse effects 1, 2
• CBT-I reduces sleep onset latency by 19 minutes, wake after sleep onset by 26 minutes, and improves sleep efficiency by 9.91% 2
• CBT-I is particularly effective in patients with comorbid depression (effect size 0.5) and PTSD (effect size 1.5), simultaneously improving both insomnia and psychiatric symptoms 3
• Delivery methods include individual therapy, group sessions, telephone-based programs, web-based modules, or self-help books—all showing effectiveness 1
• CBT-I components include stimulus control therapy, sleep restriction therapy, cognitive restructuring, relaxation training, and sleep hygiene education 1

First-Line Pharmacotherapy (When CBT-I Alone Is Insufficient)

If CBT-I is insufficient or unavailable after 4-8 weeks, add pharmacotherapy using shared decision-making, with short/intermediate-acting benzodiazepine receptor agonists (BzRAs) or ramelteon as first-line options. 1, 4

For Sleep Onset and Maintenance Insomnia:

• Eszopiclone 2-3 mg: Moderate-quality evidence showing improvement in both sleep onset latency and total sleep time 1, 4, 5

  • Most common side effects: unpleasant taste (metallic), dry mouth, drowsiness, dizziness 5
  • FDA warning: Complex sleep behaviors (sleep-driving, sleep-walking) may occur 5
  • Dose adjustment: Maximum 2 mg in hepatic impairment 4

• Zolpidem 10 mg (5 mg in elderly): Low to moderate-quality evidence for both sleep onset and maintenance 1, 4

  • FDA mandates lower dosing in elderly (5 mg maximum) due to increased sensitivity and fall risk 4
  • Morning driving impairment documented; daytime somnolence occurs in 7% of users 4

• Temazepam 15 mg: Effective for both sleep onset and maintenance, though carries higher dependence risk than non-benzodiazepines 4

For Sleep Onset Insomnia Only:

• Zaleplon 10 mg (5 mg in elderly): Very short half-life with minimal residual sedation 4, 6

  • Memory impairment present only at 1 hour post-dosing, resolved by 2-3 hours 6
  • Dose reduction to 5 mg required in hepatic impairment (clearance reduced by 70% in compensated cirrhosis, 87% in decompensated cirrhosis) 6

• Ramelteon 8 mg: Melatonin receptor agonist with zero addiction potential, non-DEA scheduled 4

  • Preferred for patients with substance abuse history 4
  • No dependence, tolerance, or withdrawal symptoms 4

• Triazolam 0.25 mg: Not considered first-line due to association with rebound anxiety 4

For Sleep Maintenance Insomnia Only:

• Low-dose doxepin 3-6 mg: Reduces wake after sleep onset by 22-23 minutes with minimal anticholinergic effects at this dose 1, 4

  • Preferred option for sleep maintenance with minimal next-day sedation 4

• Suvorexant (orexin receptor antagonist): Moderate-quality evidence showing 16-28 minute reduction in wake after sleep onset 1, 4

  • Lower risk of cognitive and psychomotor effects compared to benzodiazepines 4
  • Primary adverse effect: daytime somnolence (7% vs 3% placebo) 4

Second-Line Options for Patients with Comorbid Depression/Anxiety

For patients with comorbid depression or anxiety, sedating antidepressants are the preferred initial pharmacologic choice, as they simultaneously address both the mood disorder and sleep disturbance. 4, 7

• Mirtazapine: Must be taken nightly on scheduled basis (not PRN) due to 20-40 hour half-life requiring several days to reach steady-state 4
• Low-dose doxepin 3-6 mg: Effective for sleep maintenance with antidepressant properties at higher doses 4
• Amitriptyline: Sedating tricyclic antidepressant option when depression is present 4

Medications NOT Recommended

The following agents should be avoided due to lack of efficacy data, safety concerns, or problematic side effects: 1, 4, 7

• Trazodone: Explicitly not recommended by the American Academy of Sleep Medicine due to cardiac risks, lack of efficacy data, and morning grogginess 4, 7
• Over-the-counter antihistamines (diphenhydramine, doxylamine): Lack of efficacy data, daytime sedation, confusion, urinary retention, tolerance development after 3-4 days 4, 7
• Atypical antipsychotics (quetiapine, olanzapine): Insufficient evidence for insomnia treatment with significant metabolic side effects including weight gain and metabolic syndrome 4, 7
• Herbal supplements (valerian, melatonin supplements, L-tryptophan): Insufficient evidence of efficacy 1, 4
• Barbiturates and chloral hydrate: Not recommended for insomnia treatment 1, 4
• Tiagabine (anticonvulsant): Not recommended for sleep onset or maintenance insomnia 4

Treatment Algorithm for Medication Selection

Step 1: Implement CBT-I for all patients with chronic insomnia 1

Step 2: If CBT-I insufficient after 4-8 weeks, identify primary sleep complaint 4:

• Sleep onset difficulty: Consider zaleplon 10 mg, ramelteon 8 mg, or zolpidem 10 mg 4
• Sleep maintenance difficulty: Consider eszopiclone 2-3 mg, low-dose doxepin 3-6 mg, or suvorexant 4
• Both onset and maintenance: Consider eszopiclone 2-3 mg, zolpidem 10 mg, or temazepam 15 mg 4

Step 3: If first-line BzRA unsuccessful, try alternative BzRA in same class 4

Step 4: If BzRAs unsuccessful or contraindicated, consider sedating antidepressants (particularly if comorbid depression/anxiety present) 4

Special Population Considerations

Elderly Patients (≥65 years):

• Zolpidem maximum 5 mg (not 10 mg) due to increased sensitivity, fall risk, and cognitive impairment 4, 7
• Zaleplon 5 mg (reduced from 10 mg) 4
• Ramelteon 8 mg or low-dose doxepin 3 mg: Safest choices with minimal fall risk 4
• Avoid long-acting benzodiazepines completely due to drug accumulation and prolonged daytime sedation 4

Patients with Substance Abuse History:

• Ramelteon 8 mg is the only appropriate first-line choice due to zero addiction potential and non-DEA scheduled status 4, 7
• Avoid all benzodiazepines and Z-drugs due to abuse potential 4

Patients with Hepatic Impairment:

• Zaleplon 5 mg maximum (clearance reduced by 70% in compensated cirrhosis, 87% in decompensated cirrhosis) 6
• Eszopiclone 2 mg maximum 4
• Ramelteon and low-dose doxepin remain safe options 4

Patients with Comorbid Depression or Anxiety:

• Sedating antidepressants are preferred initial pharmacologic choice (mirtazapine, low-dose doxepin, amitriptyline) 4, 7
• These simultaneously address both mood disorder and sleep disturbance 4, 7

Critical Safety Considerations

All hypnotic medications carry FDA warnings about serious adverse effects: 1, 4, 5, 6

• Complex sleep behaviors: Sleep-driving, sleep-walking, eating, talking, having sex while not fully awake 5, 6
• Daytime impairment: Morning driving impairment and decreased ability to think clearly 5, 6
• Falls and fractures: Particularly in elderly patients 1, 4
• Cognitive impairment: Memory loss, confusion, behavioral abnormalities 1, 5
• Worsening depression: Monitor for suicidal thoughts or actions 5
• Dependence and withdrawal: Particularly with benzodiazepines 4

Observational studies link hypnotic drugs to infrequent but serious adverse effects including dementia, serious injury, and fractures. 1

Essential Prescribing Principles

• Use the lowest effective dose for the shortest duration possible (typically less than 4 weeks for acute insomnia) 1, 4, 7
• Pharmacotherapy should supplement, not replace, CBT-I 1, 4, 7
• Take medication right before bed (not sooner), only when able to get 7-8 hours of sleep 5, 6
• Do not take with or after meals (delays absorption) 5
• Reassess after 1-2 weeks to evaluate efficacy on sleep latency, maintenance, daytime functioning, and adverse effects 4, 7
• If insomnia persists beyond 7-10 days of treatment, evaluate for underlying sleep disorders (sleep apnea, restless legs syndrome, circadian rhythm disorders) 4
• Taper medication when conditions allow to prevent discontinuation symptoms 4
• Educate patients about treatment goals, realistic expectations, safety concerns, potential side effects, and importance of behavioral treatments 4, 7

Common Pitfalls to Avoid

• Failing to implement CBT-I alongside medication: Behavioral interventions provide more sustained effects than medication alone 4, 7
• Using benzodiazepines as first-line treatment: Higher risk of dependence, falls, cognitive impairment, and respiratory depression compared to non-benzodiazepines 4, 7
• Prescribing trazodone for insomnia: Not recommended due to cardiac risks and lack of efficacy data 4, 7
• Using doses appropriate for younger adults in elderly patients: Requires age-adjusted dosing (e.g., zolpidem 5 mg maximum, not 10 mg) 4, 7
• Continuing pharmacotherapy long-term without periodic reassessment: Increases risk of adverse effects and unnecessary medication use 4, 7
• Using over-the-counter sleep aids or herbal supplements: Limited efficacy data and problematic side effects 4, 7
• Combining multiple sedative medications: Significantly increases risks of complex sleep behaviors, cognitive impairment, falls, and fractures 4