Study of the different sleep disturbances during the prodromal phase of depression and mania in bipolar disorders.

BACKGROUND: One of the challenges in bipolar disorder (BD) lies in early detection of the illness and its recurrences, to improve prognosis. Sleep disturbances (SD) have been proposed as reliable predictive markers of conversion. While preliminary studies have explored the relationship between SD and the onset of mood episodes, the results remain heterogeneous and a few have specifically examined patients' perception of prodromal symptoms and their progression until the episode occurs. Identifying prodromes represents a crucial clinical challenge, as it enables early intervention, thereby reducing the severity of BD. Therefore, the objective of this study is to better characterize and evaluate the progressive nature of SD as prodromal symptoms of mood episodes, and patients' perception of it. METHODS: Patients diagnosed with BD, either hospitalized or seeking treatment for a (hypo)manic or depressive episode benefited from standardized questionnaires, structured interviews, and self-report questionnaires to evaluate SD prior to the current episode, as well as sociodemographic and clinical information. RESULTS: Out of the 41 patients included, 59% spontaneously reported SD prior to the episode, appearing 90 days before depression and 35 days before mania (pre-indexed/spontaneous reports: 51.22% insomnia complaints, 4.88% hypersomnolence complaints, 7.32% parasomnias, 2.44% sleep movements). After inquiry about specific SD, the percentage of patients reporting prodromal SD increased significantly to 83%, appearing 210 days before depression and 112.5 days before mania (post-indexed reports: 75.61% presented with insomnia complaints appearing 150 days before depression and 20 days before mania, 46.34% had hypersomnolence complaints appearing 60 days before depression, 43.9% had parasomnias appearing 210 days before depression and 22.5 days before mania, 36.59% had sleep movements appearing 120 days before depression and 150 days before mania). Of note, bruxism appeared in 35% of patients before mania, and restless legs syndrome in 20% of patients before depression. CONCLUSION: This study highlights the very high prevalence of SD prior to a mood episode in patients with BD with differences between depressive and manic episodes. The more systematic screening of sleep alterations of the prodromal phase improved the recognition and characterization of different symptoms onset by patients. This underscores the need for precise questioning regarding sleep patterns in patients, to better identify the moment of transition toward a mood episode, referred to as "Chronos syndrome". The study emphasizes the importance of educating patients about the disorder and its sleep prodromal symptoms to facilitate early intervention and prevent recurrences.

[Insomnia and psychiatric disorders]. / Insomnie et troubles psychiatriques.

INSOMNIA AND PSYCHIATRIC DISORDERS. Insomnia is frequent in psychiatric disorders. In particular, insomnia can be a risk factor, as well as a comorbid condition, or a symptom and an early sign of psychiatric disorders. Insomnia may emerge during any stage of illness. It includes prodromal, first episode, acute, recurrence, and even remission stages, thereby being associated with a worse course of illness. Insomnia increased symptom severity, relapses or recurrences, and increased suicidal risk. Thus, insomnia is an important modifiable risk factor to prevent psychiatric disorders and/or achieve and maintain remission. Thereby insomnia evaluation and management should be a priority in psychiatric cares. Indeed, it has been demonstrated that targeting insomnia can not only improve insomnia itself but also have a positive impact on the trajectory of psychiatric disorders.

INSOMNIE ET TROUBLES PSYCHIATRIQUES. L'insomnie est un trouble fréquent au cours des pathologies psychiatriques. En particulier, elle peut constituer un facteur de risque, ainsi qu'une condition comorbide, ou un symptôme et un signe précoce de troubles psychiatriques. Elle correspond au trouble du sommeil le plus courant associé aux pathologies psychiatriques et peut apparaître à n'importe quel stade de la maladie (prodromes, premier épisode, phase aiguë, récidive et même rémission). Elle est associée à une évolution plus défavorable de la maladie, à une sévérité accrue des symptômes, à des rechutes ou des récidives et à un risque suicidaire plus élevé. Ainsi, l'insomnie est un facteur de risque modifiable important pour prévenir les troubles psychiatriques et/ou atteindre et maintenir la rémission. L'évaluation et la prise en charge de l'insomnie devraient donc être une priorité dans les soins psychiatriques. En effet, il a été démontré que le fait de cibler l'insomnie peut non seulement améliorer l'insomnie en elle-même mais également avoir un impact favorable sur la trajectoire des troubles psychiatriques.

Comparative study of sleep and circadian rhythms in patients presenting unipolar or bipolar major depressive episodes.

Currently, there is a major challenge in distinguishing between unipolar and bipolar major depressive episode. A significant body of research has been dedicated to identifying biomarkers that can aid in this differentiation due to its crucial implications, particularly for therapeutic and prognostic purposes. Among the biomarkers of interest, markers related to sleep and circadian rhythms show promise and could potentially aid in making this distinction. Nevertheless, no study has simultaneously examined sleep-wake disorders, circadian rhythms, and seasonal patterns using both subjective and objective measures. This study aims to characterize and compare the sleep-wake and rhythm disorders including patients with unipolar major depressive episode (n = 72) and with bipolar major depressive episode (n = 43) using both subjective markers (using self-report questionnaires and sleep complaints) and objective markers (using actigraphy). Patients with unipolar major depressive episode seem to experience significantly poorer quality of sleep, more symptoms of insomnia and lower sleep efficiency compared to patients with bipolar major depressive episode. On the other hand, patients with bipolar major depressive episode exhibit significantly more symptoms of motor retardation and hypersomnia compared to patients with unipolar disorder. These results hold significant implications for identifying individuals with unipolar major depressive episode or bipolar major depressive episode using sleep and circadian markers, and for developing recommended and personalized therapeutic strategies.

Eco-anxiety: An adaptive behavior or a mental disorder? Results of a psychometric study.

OBJECTIVE: Eco-anxiety is a complex construct that has been created to grasp the psychological impact of the consequences of global warming. The concept needs a reliably valid questionnaire to better evaluate its impact on the risk of anxiety and depressive disorders. The Eco-Anxiety Questionnaire (EAQ-22) evaluates two dimensions: 'habitual ecological anxiety' and 'distress related to eco-anxiety'. However, a version in French, one of the world's widely spoken languages, was until now lacking. We aimed to translate and validate the French EAQ-22 and to evaluate the prevalence of the level of the two dimensions of eco-anxiety and the relationship with anxiety and depressive symptoms in a representative adult sample of the French general population. METHODS: This study was performed under the auspices of the Institut national du sommeil et de la vigilance (INSV). Participants (18-65 years) were recruited by an institute specialized in conducting online surveys of representative population samples (quota sampling). Two native French speakers and two native English speakers performed a forward-backward translation of the questionnaire. The Hospital Anxiety and Depression scale (HAD) was administered to assess anxiety (HAD-A) and depressive (HAD-D) symptoms and for external validity. Internal structural validity and external validity were analysed. RESULTS: Evaluation was performed on 1004 participants: mean age 43.47 years (SD=13.41, range: [19-66]); 54.1% (n=543) women. Using the HAD, 312 (31.1%) patients had current clinically significant anxiety symptoms (HAD-A>10) and 150 (14.9%) had current clinically significant depressive symptoms (HAD-D>10). Cronbach's alpha coefficient was 0.934, indicating very good internal consistency. Correlation between EAQ-22 and HAD scores was low (r[1004]=0.209, P<0.001), 'habitual ecological anxiety' was correlated less with HAD-A and HAD-D than 'distress related to eco-anxiety', indicating good external validity. CONCLUSION: This study validates the French EAQ-22 and paves the way for using the EAQ-22 as a global tool for assessing eco-anxiety. Further prospective studies are now required to better evaluate the impact of eco-anxiety on the occurrence of anxiety and depressive disorder.

Images: "Too much heat for my non-24-hour sleep-wake disorder!" A case report.

The non-24-hour sleep-wake disorder (N24SWD) is a rare condition, sometimes associated with blindness or with suprachiasmatic nuclei lesions, resulting in a free-running rhythm or hypernycthemeral syndrome. Synchronizers, such as light, when light perception remains, melatonin, food intakes, physical activity, social interactions, and temperature, play a key role in the treatment of N24SWD. In this report, we describe a case illustrating the impact of outdoor temperature in a 34-year-old man with N24SWD effectively treated through a combination of chronotherapy interventions. During 3 consecutive heat waves, he experienced a recurrence of his natural 25.5-hour free-running rhythm, with a consistent bedtime phase delay caused by temperature, resulting in the discontinuation of chronotherapy. After these heat waves, he was able again to resynchronize his rhythms with the combination of chronotherapeutics. This case report highlights that patients with N24SWD may be particularly at risk of relapse during heat waves, with direct implications for monitoring and reinforcing chronotherapies. CITATION: Garrivet J, d'Ortho M-P, Frija-Masson J, et al. "Too much heat for my non-24-hour sleep-wake disorder!" A case report. J Clin Sleep Med. 2024;20(2):329-333.

Major depressive disorder with hypersomnolence complaint: A comparison study with non-depressed individuals examining objective biomarkers.

BACKGROUND: Hypersomnolence is common in major depressive disorder (MDD), associated with more severe episodes, suicide and antidepressant resistance. Nevertheless, few studies used polysomnography (PSG) and multiple sleep latency test (MSLT) to characterize these patients. In this context, we compared patients visiting a sleep center for hypersomnolence complaint with MDD (HSC/MDD+) and without MDD (HSC/MDD-). METHODS: HSC/MDD+ and HSC/MDD- groups were defined according to DSM-5 criteria and CES-D scale, and had a 30 h-PSG with ad libitum-sleep and PSG followed by MLST. RESULTS: HSC/MDD+ had an increased self-declared total sleep time (sTST) of about 10 h30 similar to HSC/MDD- (630.8 ± 17.3 min-vs-616.5 ± 18.1 min, respectively, p = 0.39). Nevertheless, their objective TST (oTST) on ad libitum PSG was significantly longer and about 10 h50 (648.6 ± 23.9 min-vs-587.4 ± 19.0 min, respectively, p = 0.038). HSC/MDD+ also significantly better estimated their sleep duration, with a lower difference between their sTST and oTST compared to HSC/MDD- (10.0 ± 1.7 %-vs-17.4 ± 2.1 %, respectively, p = 0.009) and confirmed significantly more frequently the hypersomnia diagnosis -i.e. oTST>10H- (82.6 ± 8.1 %-vs-54.6 ± 10.9 %, respectively, p = 0.046). Using the Kupfer index (KI), we confirmed a reduced REM sleep latency in patients MDD/HSC+ (15.2 ± 10.0 %-vs-2.3 ± 2.3 %, respectively, p = 0.039). Both groups had comparable increased diurnal sleepiness assessed with the Epworth scale (14.1 ± 1.1-vs-14.8 ± 1.1, respectively, p = 0.65). HSC/MDD+ had less MSLT sleep latency <8 min (9.1 ± 5.1 %-vs-27.3 ± 6.8 %, respectively, p = 0.048). LIMITATIONS: Retrospective cross-sectional study. CONCLUSIONS: HSC/MDD+ accurately estimated their sleep duration, objectively confirmed hypersomnia and may specifically had a decreased Kupfer index.

Lower risk of hospitalisation for depression following hospitalisation for COVID-19 versus for another reason.

INTRODUCTION: Although hospitalisation for COVID-19 is associated with a higher post-discharge risk of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), this risk has not been compared to that following hospitalisation for a reason other than COVID-19. METHODS: Using data from France's National Health Data System (SNDS) database, we compared patients hospitalised for mood disorders in the 12 months following COVID-19/another reason hospitalisation. RESULTS: 96,313 adult individuals were hospitalised for COVID-19, and 2,979,775 were hospitalised for another reason. In the 12 months post-discharge, 110,976 (3.83 %) patients were hospitalised for mood disorders. In unadjusted analyses, patients initially hospitalised for COVID-19 (versus another reason) were more likely to be subsequently hospitalised for a mood disorder (4.27 % versus 3.82 % versus, respectively, p < 0.0001). These patients were also more likely to have a history of mood disorders, especially depressive disorders (6.45 % versus 5.77 %, respectively, p < 0.0001). Women, older age, lower social deprivation, a history of mood disorders, longer initial hospitalisation (COVID-19 or other), and a higher level of clinical care during initial hospitalisation were all significantly associated with the risk of subsequent hospitalisation for MDD and BD. In contrast, after adjusting for all these factors, persons initially hospitalised for COVID-19 were less likely to be subsequently hospitalised for MDD (OR = 0.902 [0.870-0.935]; p < 0.0001). No difference between both groups was observed for BD. LIMITATIONS: Other reasons were not separately studied. CONCLUSIONS: After adjusting for confounding factors, initial hospitalisation for COVID-19 versus for another reason was associated with a lower risk of hospitalisation for a mood disorder.

Circadian-like patterns in electrochemical skin conductance measured from home-based devices: a retrospective study.

In this study, we investigated the potential of electrochemical skin conductance (ESC) measurements gathered from home-based devices to detect circadian-like patterns. We analyzed data from 43,284 individuals using the Withings Body Comp or Body Scan scales, which provide ESC measurements. Our results highlighted a circadian pattern of ESC values across different age groups and countries. Our findings suggest that home-based ESC measurements could be used to evaluate circadian rhythm disorders associated with neuropathies and contribute to a better understanding of their pathophysiology. However, further controlled studies are needed to confirm these results. This study highlights the potential of digital health devices to generate new scientific and medical knowledge.

Major depressive episode with insomnia and excessive daytime sleepiness: A more homogeneous and severe subtype of depression.

Previous studies have noted the crucial role of excessive daytime sleepiness (EDS) in the course of depressive illness, and more recently, a few studies documented its strong associations with an increased risk of suicide. While insomnia is associated with heightened emotional reactivity, suicidal behaviors, and increased relapses and recurrence. Our main hypothesis is that major depressive episodes (MDE) with insomnia and EDS are associated with more severe manifestations of depression. However, to date, no study has directly compared MDE with insomnia without EDS (Ins), and MDE with insomnia with EDS (InsEDS) using both subjective biomarkers (administration of self-assessment questionnaires for psychiatric evaluation and sleep complaints) and objective biomarkers (of sleep and circadian rhythms (using actigraphy). The InsEDS group, compared to the Ins group, exhibited significantly increased suicidal ideation, larger seasonal impacts on mood, alterations in sleep duration, weight, appetite, energy levels, and social activities throughout the year. Furthermore, they had significant delayed onset of daily activity measured with actigraphy. These findings provided new insights into the link between suicide, sleep, alertness, and biological clock. They also hold significant implications for identifying individuals with more severe depressive manifestations and for developing tailored and personalized therapeutic strategies.

The European Insomnia Guideline: An update on the diagnosis and treatment of insomnia 2023.

Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and its comorbidities are: clinical interview (encompassing sleep and medical history); the use of sleep questionnaires and diaries (and physical examination and additional measures where indicated) (A). Actigraphy is not recommended for the routine evaluation of insomnia (C), but may be useful for differential-diagnostic purposes (A). Polysomnography should be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders, etc.), treatment-resistant insomnia (A) and for other indications (B). Cognitive-behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (including patients with comorbidities), either applied in-person or digitally (A). When cognitive-behavioural therapy for insomnia is not sufficiently effective, a pharmacological intervention can be offered (A). Benzodiazepines (A), benzodiazepine receptor agonists (A), daridorexant (A) and low-dose sedating antidepressants (B) can be used for the short-term treatment of insomnia (≤ 4 weeks). Longer-term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B). Orexin receptor antagonists can be used for periods of up to 3 months or longer in some cases (A). Prolonged-release melatonin can be used for up to 3 months in patients ≥ 55 years (B). Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon and phytotherapeutics are not recommended for insomnia treatment (A). Light therapy and exercise interventions may be useful as adjunct therapies to cognitive-behavioural therapy for insomnia (B).

The nightmare severity index (NSI): A short new multidimensional tool for assessing nightmares.

This psychometric pilot study aims to evaluate a new multidimensional simple scale, named the nightmare severity index (NSI) - close to the existing insomnia (ISI) and hypersomnia (HSI) severity indexes. The NSI encompasses all main dimensions of nightmare disorder, evaluating four subdimensions: frequency, emotional impact, diurnal impact, and nocturnal impact of nightmares. The NSI was completed by a total of 102 patients. The majority of the population consisted of women (64%) and outpatient individuals (76%) diagnosed with mood disorders such as depression (31%) and bipolar disorder (41%). Comorbidity with post-traumatic stress disorder (PTSD) was prevalent (44%), and psychotropic medications were commonly used (47%). Internal validity analyses indicated that the NSI was well suited for exploratory factor analysis. All items demonstrated satisfactory correlations with the factors, and the questionnaire exhibited good internal consistency (Cronbach's alpha >0.7). Higher NSI scores were observed among individuals experiencing nightmare symptoms considering the DSM-5/ICSD-3 criteria. In summary, the NSI proves to be a promising and valuable tool for clinical practice, demonstrating good acceptability, internal validity, and the ability to assess nightmare severity.

Poor Sleep Quality May Independently Predict Suicidal Risk in Covid-19 Survivors: A 2-Year Longitudinal Study.

Objective: Multiple symptoms of psychiatric, neurological, and physical illnesses may be part of Post-COVID conditions and may pose COVID-19 survivors a high suicidal risk. Accordingly, we aimed to study factors contributing to suicidal risk in Post COVID-19 patients. Method: Consecutive patients with post COVID-19 conditions were followed for 2 years at the University Hospital of Ferrara at baseline (T0), 6 (T1), 12 (T2), and 24 (T3) months. Demographics, and clinical data for all patients included: disease severity, hospital length of stay, comorbidity, clinical complications, sleep quality, cognitive complaints, anxiety and stress-related symptoms, depressive symptoms, and suicidal ideation. Results: The final sample included 81 patients with post COVID survivors. The mean age was 64 + 10,6 years, 35,8% were females, 65,4% had medical comorbidities, and 69,1% had WHO severe form of COVID forms. At T0 more than 90% of patients showed poor sleep quality, 59.3% reported moderate/severe depressive symptoms, and 51.% experienced anxiety, 25.9% experienced post-traumatic stress symptoms. At T0 suicidal ideation, interested 6.1% and at T3 it increased to 7.4%. In the regression analysis, suicidal ideation at baseline was best predicted by poor sleep quality (O.R. 1.71, p=0.044) and, after 2 years, suicidal ideation was best predicted by poor sleep quality experienced at baseline (OR 67.3, p=0.001). Conclusions: Poor sleep quality may play as an independent predictor of suicidal risk in post-COVID survivors. Evaluating and targeting sleep disturbances in COVID survivors is important to prevent the consequences of disrupted sleep in mental health.

Predictors of cognitive behavioral therapy for insomnia (CBT-I) effects in insomnia with major depressive episode.

Insomnia plays a critical role in the onset and maintenance of Major Depressive Episode (MDE). Cognitive behavioral therapy for insomnia (CBT-I) can successfully improve the sleep of patients with insomnia and MDE. Nonetheless, the factors influencing CBT-I's effects in MDE remain uncertain. This study aimed to identify predictors of insomnia improvement following CBT-I, as well as predictors of insomnia response, remission in patients with MDE and specific insomnia subtypes. Initially, we compared a 4-session weekly CBT-I treatment to baseline sleep education (SE) in a control group. This confirmed CBT-I's positive effects and the need to explore predictive factors. Notably, treatment-resistant depression (TRD) predicted reduced insomnia severity with CBT-I. Patients exhibiting seasonal fluctuations in depressive symptoms and sleep patterns throughout the year, or having daytime dysfunction, experienced enhanced CBT-I efficacy, especially for early awakenings insomnia. Conversely, shorter sleep duration predicted a less favorable response to CBT-I, less improvement in daytime dysfunction and sleep disturbance worries. Additionally, MDE with suicide attempts predicted a poorer improvement of daytime dysfunction. Further research is essential to comprehensively grasp the mechanisms behind CBT-I's heightened effectiveness in MDE patients with TRD and seasonal fluctuations.

Effects of smoking on sleep architecture and ventilatory parameters including apneas: Results of the Tab-OSA study.

Background: The interaction between smoking and sleep seems appears to be bidirectional, but few studies evaluated the impact of smoking and its cessation on objective sleep parameters. In this context, this new study aimed to assess the impact of smoking and its cessation on sleep architecture and on ventilatory sleep parameters, particularly the presence of sleep apnea syndrome (apnea-hypopnea index (AHI)≥15). Methods: Patients hospitalized for polysomnographic sleep exploration were compared according to their smoking status: active smokers (AS), former smokers (FS), non-smokers (NoNi). Psychiatric and non-psychiatric co-morbidities and treatment or substance use were taken into account in the analyses. Results: A total of 170 participants were included (N = 37 FS, 39 AS, 86 NoNi). A significant decrease in the mean nocturnal O2 saturation was observed for FS and AS compared to NoNi. No differences were found regarding AHI. Regarding sleep architecture, we observed a significant decrease in the slow wave sleep duration for AS compared to NoNi, and interestingly not between FS and NoNi. Conclusion: This study suggests that current smokers suffer from alterations in both sleep architecture and ventilatory parameters, the later appears to persist even after smoking cessation.

The risk of hospitalization for psychotic disorders following hospitalization for COVID-19: a French nationwide longitudinal study.

COVID-19, like other infectious diseases, may be a risk factor for psychotic disorders. We aimed to compare the proportions of hospitalizations for psychotic disorders in the 12 months following discharge from hospital for either COVID-19 or for another reason in the adult general population in France during the first wave of the pandemic. We conducted a retrospective longitudinal nationwide study using the national French administrative healthcare database. Psychotic disorders were first studied as a whole, and then chronic and acute disorders separately. The role of several adjustment factors, including sociodemographics, a history of psychotic disorder, the duration of the initial hospitalization, and the level of care received during that hospitalization, were also analyzed. Between 1 January 2020 and 30 June 2020, a total of 14,622 patients were hospitalized for psychotic disorders in the 12 months following discharge from hospital for either COVID-19 or another reason. Initial hospitalization for COVID-19 (vs. another reason) was associated with a lower rate of subsequent hospitalization for psychotic disorders (0.31% vs. 0.51%, odds ratio (OR) = 0.60, 95% confidence interval (CI) [0.53-0.67]). This was true for both chronic and acute disorders, even after adjusting for the various study variables. Importantly, a history of psychotic disorder was a major determinant of hospitalization for psychotic disorders (adjusted OR = 126.56, 95% CI [121.85-131.46]). Our results suggest that, in comparison to individuals initially hospitalized for another reason, individuals initially hospitalized for COVID-19 present a lower risk of hospitalization for first episodes of psychotic symptoms/disorders or for psychotic relapse in the 12 months following discharge. This finding contradicts the hypothesis that there is a higher risk of psychotic disorders after a severe COVID-19.

Insomnia, poor sleep quality and perinatal suicidal risk: A systematic review and meta-analysis.

Suicidal risk in mothers is a public health priority. Risk factors include biological, psychological and psychosocial factors. Among the biological factors, the role of sleep disturbances as potential contributors to increased suicidal risk during the peripartum period is becoming apparent. To explore this further, we conducted a systematic review following the PRISMA criteria. Currently, 10 studies have examined the role of insomnia and poor sleep quality in suicidal risk during the peripartum period and have involved 807,760 women. The data showed that disturbed sleep and poor sleep quality increase the risk of suicidal ideation in both pregnant women with and without perinatal depression. The results of the meta-analysis indicated that insomnia and poor sleep quality increase the odds of suicidal risk in pregnant women by more than threefold (OR = 3.47; 95% CI: 2.63-4.57). Specifically, the odds ratio (OR) for poor sleep quality was 3.72 (95% CI: 2.58-5.34; p < 0.001), and for insomnia symptoms, after taking into account perinatal depression, was 4.76 (95% CI: 1.83-12.34; p < 0.001). These findings emphasise the importance of assessing and addressing sleep disturbances during the peripartum period to mitigate their adverse effects on peripartum psychopathology and suicidal risk.

Efficacy of melatonin and ramelteon for the acute and long-term management of insomnia disorder in adults: A systematic review and meta-analysis.

Melatonin has gained growing interest as a treatment of insomnia, despite contradictory findings, and a low level of evidence. A systematic review and meta-analysis was conducted following PRISMA criteria, to assess the efficacy of melatonin and ramelteon compared with placebo on sleep quantity and quality in insomnia disorder, while also considering factors that may impact their efficacy. This review included 22 studies, with 4875 participants, including 925 patients treated with melatonin, 1804 treated with ramelteon and 2297 receiving a placebo. Most studies evaluated the acute efficacy of prolonged release (PR) melatonin in insomnia disorder. Compared with placebo, PR melatonin appears efficacious with a small to medium effect size on subjective sleep onset latency (sSOL) (p = 0.031; weighted difference = -6.30 min), objective sleep onset latency (oSOL) (p < 0.001; weighted difference = -5.05 min), and objective sleep efficiency (oSE) (p = 0.043; weighted difference = 1.91%). For the subgroup mean age of patients ≥55, PR melatonin was efficacious on oSE with a large effect size (p < 0.001; weighted difference = 2.95%). Ramelteon was efficacious with a large effect size at 4 weeks on objective total sleep time (oTST) (p = 0.010; weighted difference = 17.9 min), subjective total sleep time (sTST) (p = 0.006; weighted difference = 11.7 min), sSOL (p = 0.009; weighted difference = -8.74 min), and oSOL (p = 0.017; weighted difference = -14 min). Regarding long-term effects, ramelteon has a large effect size on oTST (p < 0.001; weighted difference = 2.02 min) and sTST (p < 0.001; weighted difference = 14.5 min). PR melatonin and ramelteon appear efficacious compared with placebo for insomnia symptoms with PR melatonin showing mostly small to medium effect sizes. PR melatonin for individuals with a mean age ≥ 55 and ramelteon show larger effect sizes.