Comparisons Between Successful Versus Unsuccessful Switches From Benzodiazepines or Zolpidem (Z-Drug) to Controlled-Release Melatonin in Patients With Major Depressive Disorder and Insomnia
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OBJECTIVES: Chronic use of benzodiazepines and zolpidem (BDZ/Z-drugs) leads to dependency, cognitive impairment, and falls. Although controlled-release melatonin (Melatonin CR) may be an alternative, a switch in clinical settings has proven difficult. We investigated the factors associated with successful switch to Melatonin CR in patients with major depressive disorder (MDD) and insomnia. METHODS: This retrospective observational study involved 170 patients diagnosed with MDD and insomnia, and aged older than 55 years, who were treated with BDZ/Z-drug for at least the past 90 days and never before exposed to Melatonin CR. All patients were treated with a standard antidepressant therapy and Melatonin CR for their insomnia. A successful switch was defined as three or more consecutive prescriptions of Melatonin CR separated by at least one-month interval, after discontinuation of the BDZ/Z-drug. RESULTS: Seventy-nine patients (46.5%) who switched successfully showed no significant differences in sex, age, education, and occupational status compared with the unsuccessful group. The types of antidepressants used or BDZ/Z-drug treatment did not differ significantly between the two groups. Fewer somatic symptoms were observed in the successful group. In the multivariate analysis, the successful group showed significantly less somatic anxiety, shorter duration from first BDZ/Z-drug use to the first antidepressant use, and shorter total duration of BDZ/Z-drug therapy. CONCLUSIONS: A successful switch from BDZ/Z-drug to Melatonin CR was associated with less baseline somatic anxiety, earlier use of antidepressants, and shorter total duration of BDZ/Z-drug use, but was less strongly associated with the type of antidepressants in MDD patients with insomnia.
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Predictors of greater success with melatonin-assisted withdrawal included fewer anxiety symptoms, a shorter interval before initiation of antidepressants during tapering, and a shorter overall duration of BZD/Z-drug use.
“The predictors of greater success with melatonin-assisted withdrawal included fewer anxiety symptoms, a shorter interval before the initiation of antidepressants during tapering (regardless of the specific agent), and a shorter overall duration of BZD/Z-drug use. 84”
From Z-drug abuse and dependence: Clinical guideline of the Brazilian Academy of Neurology for diagnosis and management (2025) · cites this paper as [84]
The Results section, “Predictors of BDZ/Z-Drug Discontinuation,” associates successful switching with lower anxiety scores, shorter BZD/Z-drug use, and a shorter interval from first BZD/Z-drug use to first antidepressant use. The paper does not establish that antidepressants were initiated during tapering; that timing is an unsupported addition. It reports no significant difference by antidepressant type, but this does not establish success regardless of the specific agent. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe effectiveness of extended-release melatonin as an adjunctive agent for deprescribing BZDs and Z-drugs remains controversial; some studies reported beneficial effects, others found no advantage compared to placebo.
“Its effectiveness remains controversial: while some studies 84 85 have reported beneficial effects, others 86 have found no advantage compared to placebo.”
From Z-drug abuse and dependence: Clinical guideline of the Brazilian Academy of Neurology for diagnosis and management (2025) · cites this paper as [84]
The Introduction describes controlled-release melatonin as an alternative to BZD/Z-drugs, and the Discussion reports successful switches among older patients with major depressive disorder and insomnia (page numbers unavailable). The paper does not report a placebo comparison or say that studies found no advantage over placebo, so it supports the beneficial-effects side but not the claimed controversy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThere is limited clinical evidence to confirm the efficacy of add-on pharmacological approaches for Z-drug deprescription, but expert opinion supports their use.
“Although there is limited clinical evidence 84 85 86 90 91 97 to confirm the efficacy of these approaches, expert opinion supports their use (particularly when guided by a comprehensive evaluation of patient comorbidities) as a means to facilitate Z-drug withdrawal.”
From Z-drug abuse and dependence: Clinical guideline of the Brazilian Academy of Neurology for diagnosis and management (2025) · cites this paper as [84]
The Introduction says evidence for controlled-release melatonin in patients with major depressive disorder and insomnia is limited. The Discussion suggests that adjunctive antidepressants may facilitate BDZ/Z-drug discontinuation and recommends earlier evaluation of depressive symptoms, but it does not establish a broader expert opinion supporting add-on drugs for Z-drug withdrawal generally. (LLM, conf=0.83)
Experimental — accuracy not yet measuredReported rates of successful discontinuation using 2 mg of prolonged-release melatonin ranged from 31 to 46.5%.
“The reported rates of successful discontinuation using 2 mg of prolonged-release melatonin ranged from 31 to 46.5%. 84 85 86”
From Z-drug abuse and dependence: Clinical guideline of the Brazilian Academy of Neurology for diagnosis and management (2025) · cites this paper as [84]
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References 39 · Cited by 7
- Authors
- An, J. H., Park, M. J., Fava, M., Mischoulon, D., Kim, H., Jang, J., Hong, J. P., Park, J. S., & Jeon, H. J.
- Affiliations
- Samsung Medical Center (KR)
- Harvard University (US)
- Ajou University (KR)
- Corresponding author
- Jeon, Hong Jin
- Venue
- Frontiers in Psychiatry
- Publisher
- Frontiers Media SA
- Published
- 2020-05-19
- Volume
- 11
- Pages
- 444-444
- ISSN
- 1664-0640 (ISSN-L)
- PMC
- PMC7248372
- OpenAlex
- W3027356159
- Cited by
- 7
- References
- 39
- Citations by year
- 2026: 2 · 2025: 4 · 2023: 1
- FWCI
- 0.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Research Foundation of Korea (NRF- 2016M3C7A1947307; PI HJJ)
- Topics
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
- Keywords
- benzodiazepine withdrawal, zolpidem, major depressive disorder, insomnia, drug switching, somatic anxiety, older adults
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