03. Melatonin, Trazodone, or Doxepin for Sleep Disorders

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Comparing Non-Benzo Sleep Aids

There are many reasons to avoid benzodiazepine receptor agonists in our patients with insomnia. These include:

• Co-prescription of opioids
• Untreated sleep apnea
• Co-occurring substance use disorder
• History of sleepwalking
• Increased risk of falls or confusion (especially in elderly patients)

So, what can we offer patients when benzodiazepine receptor agonists (benzodiazepines and Z-drugs) are not an option? Common alternatives include trazodone, low-dose doxepin, and melatonin.

A recent study aimed to answer this question by comparing these three medications in a real-world setting over six months. This type of comparative study for off-patent medications is rare, making the findings particularly valuable.

Study Design and Patient Eligibility

The researchers recruited 175 patients with clinically severe sleep problems between ages 18-65 from inpatient and outpatient psychiatry units. Patients had major depressive disorder, generalized anxiety disorder, or bipolar disorder. Exclusion criteria included:

• History of substance misuse
• Use of other sedative or hypnotic medications
• Serious medical conditions

Subjects were randomized to receive one of three medications open-label:

• Trazodone 50 mg qhs
• Doxepin 10 mg qhs
• Melatonin 3 mg qhs

Physicians reviewed, and confirmed group assignments based on clinical factors, though the article doesn’t specify how often subjects were excluded or medications changed.

Sleep Quality Improvements

The primary outcome measure was the Pittsburgh Sleep Quality Index (PSQI). The PSQI assesses seven factors:

• Perceived sleep quality
• Sleep latency
• Sleep duration
• Sleep efficiency
• Use of sleep medication
• Daytime dysfunction

Scores range from 0 to 21, with 5 as the usual cutoff for insomnia. At baseline, the average PSQI in each group was between 14.1 and 14.4. All three medications significantly improved sleep quality. At six months, average PSQI scores were:

• Trazodone: 7.1
• Doxepin: 7.5
• Melatonin: 8.3

It’s unclear if all subjects received an automatic 3-point improvement on the PSQI simply for taking one of the study medications each night.

Daytime Sleepiness Reduction

A secondary outcome measure was the Epworth Sleepiness Scale, which measures the likelihood of dozing off during various daytime activities (e.g., reading, watching TV, sitting quietly after a meal, waiting at a stoplight). Scores range from 0 to 24. All groups showed improvement on this scale. The average reduction in score was:

• Trazodone: 4.8
• Doxepin: 4.2
• Melatonin: 3.9

Side Effect Profiles

The authors compared reported side effect frequencies:

• Morning grogginess: Reported by 15% of subjects taking trazodone (significantly more than with doxepin at 9% or melatonin at 5%).
• Dizziness: Reported by 10% of subjects taking melatonin (not significantly more than with doxepin at 7% or trazodone at 5%).
• Weight gain: Reported by 9% of subjects taking doxepin and 3% taking trazodone; none reported with melatonin.
• Dry mouth: Reported by 13% of subjects taking doxepin, 5% taking trazodone, and 2% taking melatonin.
• Orthostatic hypotension: Reported by 10% of subjects taking trazodone and 2% taking doxepin; none reported with melatonin.

The side effect profiles align with each medication’s primary receptor activities. Doxepin’s weight gain and dry mouth reflect its antihistaminergic effects. Trazodone’s orthostatic hypotension aligns with its alpha-1 blocking activity.

Study Limitations and Considerations

A key strength (and limitation) of this study is its real-world design. Subjects were drawn from both inpatient and outpatient settings. This raises the question of how much sleep improvement was due to the study medication versus the resolution of the underlying mood or anxiety disorder. A placebo arm would have helped to clarify this.

Clinical Implications

Despite this limitation, I find the study useful for comparing common alternatives to benzodiazepine receptor agonists. While trazodone, doxepin, and melatonin all reduced PSQI scores by nearly 50%, none of the medications, on average, brought patients below the cutoff score of 5 for insomnia. This raises the question of whether dose adjustments would have been beneficial.

It’s also important to remember that other studies support the use of concurrent cognitive behavioral techniques, with a focus on sleep hygiene, to enhance the response to pharmacotherapy alone.

Finally, this study provides valuable information about the relative frequency of side effects. When choosing between these options, we can now better tailor our recommendations based on individual patient factors and potential side effect tolerability.

Abstract

Addressing Sleep Disorders in Psychiatry: Comparing the Use of Melatonin, Trazodone, and Doxepin

Beena Mamoon, M.D.; Amber Nawaz, M.D.; Muhammad Iftikhar Khattak, MPH., Fehmida Amir, M.D.; Amna Akbar, M.D.; Tashbiha E Batool, M.D. & Shahid Khan, M.D.

Introduction

Sleep disorders are prevalent among psychiatric patients, and pharmacological treatments such as melatonin, trazodone, and doxepin are commonly prescribed. This study aimed to assess the efficacy and acceptability of these three medications in improving sleep quality and reducing daytime drowsiness in psychiatric patients.

Methodology

A total of 175 psychiatric patients with sleep disturbances participated in this cohort study at the Abbas Institute of Medical Sciences, Muzaffarabad, Pakistan. Participants were initially randomized, with assignments subsequently reviewed and confirmed by physicians based on clinical considerations, into one of three therapy groups: doxepin, trazodone, or melatonin. They were monitored over the course of six months, from February to July 2024. The Pittsburgh Sleep Quality Index (PSQI) was used to measure sleep quality, the Epworth Drowsiness Scale (ESS) was used to measure daytime drowsiness, and the Clinical Global Impression-Improvement (CGI-I) scale was used to determine clinical improvement. Pre- and post-treatment data were analyzed in IBM SPSS Statistics for Windows, Version 26.0 (Released 2019; IBM Corp., Armonk, New York, United States) using statistical techniques such as paired t-tests, ANOVA, and chi-square tests.

Results

Trazodone, doxepin, and melatonin were evaluated for their effectiveness and tolerability in improving sleep quality and reducing daytime drowsiness among 175 psychiatric patients (n=58 for melatonin, n=59 for trazodone, n=58 for doxepin). Trazodone showed the greatest improvement in sleep quality, with significant reductions in PSQI scores at six months (mean decrease = 7.0, SD = 1.9) and the highest CGI-I improvement rates (n=59, 76%, p = 0.02), but it was associated with frequent adverse effects, including morning grogginess (n=59, 15%, p = 0.03) and orthostatic hypotension (n=59, 10%, p = 0.02). Doxepin significantly enhanced sleep continuity (PSQI reduction = 6.8, SD = 2.1) and had a better tolerability profile than trazodone but was linked to dry mouth (n=58, 13%, p = 0.04). Melatonin, while slightly less effective in improving sleep quality (PSQI reduction = 6.1, SD = 2.0), had the fewest adverse effects, including the lowest rates of morning grogginess (n=58, 5%, p = 0.03) and dizziness (n=58, 10%, p = 0.41), and significantly reduced daytime drowsiness (ESS decrease = 3.9, SD = 1.7, p = 0.04). These findings highlight trazodone and doxepin as the most effective treatments, while melatonin offers better tolerability for patients concerned about adverse effects.

Conclusion

In psychiatric patients, trazodone was the most successful medication for enhancing sleep quality; however, other groups cannot use it due to its adverse effects. For patients who were more likely to have side effects, melatonin was a safer option, but doxepin offered a good balance between effectiveness and tolerability.

Reference

Mamoon, B. M.D.; Nawaz, A. M.D.; Khattak, M. MPH., Amir, F. M.D.; Akbar, A. M.D.; Batool, T. M.D. & Khan, S. M.D. (2024). 

Addressing Sleep Disorders in Psychiatry: Comparing the Use of Melatonin, Trazodone, and Doxepin

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Cureus 16

(12): e76507.