Silent Infections are not So Silent: The Emerging Role of Combined Infections, Inflammation, and Vitamin Levels in OCD.

Objective: Recent evidence highlights that different agents may trigger immune-mediated processes involved in the pathophysiology of different neuropsychiatric conditions. Given the limited information on obsessive-compulsive disorder (OCD), the present study aimed at assessing current/past infections and plasma levels of vitamin D, vitamin B12, folic acid, homocysteine and common peripheral inflammatory markers in a group of OCD outpatients. Method: The sample included 217 adult outpatients with an OCD diagnosis according to the DSM-5 criteria. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) was used to assess the clinical phenotype and symptom severity. Laboratory blood tests measured levels of vitamin D, vitamin B12, folic acid, homocysteine, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), blood count and antibodies titers for cytomegalovirus (CMV), Epstein Barr virus (EBV), Toxoplasma gondii and antistreptolysin titer. Results: Sixty-one patients had a previous EBV infection, 46 were seropositive for CMV IgG, 24 showed positive antistreptolysin titer, 14 were seropositive for Toxoplasma gondii IgG, and four for CMV IgM. More than a half of patients showed vitamin D insufficiency. Compared to seronegative patients, patients with a past EBV infection displayed significantly higher scores on the Y-BOCS total score and compulsion subscale, and other symptoms. Vitamin D was negatively correlated with both the Y-BOCS total score and the subscales scores. Folic acid was negatively correlated with the Y-BOCS total and obsessions subscale score. Conclusions: The findings of our study show an association between Epstein-Barr infection and hypovitaminosis D and the overall severity and specific symptom patterns of OCD. The laboratory measures used in this study are useful, cheap and easy parameters that should be routinely assessed in patients with OCD. Further studies are needed to clarify their role in OCD pathophysiology and outcomes, as well as the potential therapeutic impact of vitamins and antibiotics/immunomodulatory agents in OCD and other psychiatric conditions.

Early experience with the new DORA daridorexant in patients with insomnia disorder and comorbid mental disturbances: Results of a naturalistic study with 3 months follow-up.

Insomnia disorder may affect mental health, increasing suicidal risk. Targeting insomnia is crucial in the clinical practice. Sixty-six consecutive patients with insomnia disorder according with the DSM-5-TR criteria were treated with the dual orexin receptor antagonist, daridorexant 50 mg. Baseline (T0), 1 month (T1) and 3 month (T2) evaluations were performed. Insomnia severity (Insomnia Severity Index), mood, anxiety symptoms and suicidal risk (Beck Depression Inventory-II, Young Mania Rating Scale, Self-Reported Anxiety Scale, Suicidal Ideation Scale), dysfunctional insomnia-cognitive factors and pre-sleep arousal (Dysfunctional Beliefs About Sleep, Pre-Sleep Arousal Scale) were evaluated. The final sample included 66 patients (n = 36, 54% females, mean age 60 ± 13.6 years). Most of them, 64%, suffered from insomnia disorder comorbid with unipolar/bipolar depression, anxiety disorders and substance use disorders. Repeated ANOVA analyses showed that Insomnia Severity Index, Dysfunctional Beliefs About Sleep and Pre-Sleep Arousal Scale total score decreased across time (F = 68.818, p < 0.001; F = 47.561, p < 0.001; F = 28.142, p < 0.001, respectively). Similarly, Beck Depression Inventory-II, Self-Reported Anxiety Scale, Young Mania Rating Scale, and Suicidal Ideation Scale significantly decreased over time (p < 0.001). Predictors of insomnia remission (Insomnia Severity Index < 8) at T1 were improvement of Insomnia Severity Index at T1 (F = 60.205, p < 0.001), and improvement of Dysfunctional Beliefs About Sleep at T1 (F = 4.432, p = 0.041). Insomnia remission at T2 was best predicted by improvement of Dysfunctional Beliefs About Sleep at T2 (F = 3.993, p = 0.023). Multiple-regression models showed that clinical improvement of Beck Depression Inventory-II was best predicted by improvement in Dysfunctional Beliefs About Sleep at T1 and T2, manic symptoms by Insomnia Severity Index at T2, anxiety symptoms by Dysfunctional Beliefs About Sleep, Insomnia Severity Index and somatic Pre-Sleep Arousal Scale at T1 and T2. With the caution of a naturalistic design, early experience with daridorexant showed that by targeting insomnia it may be possible to improve not only insomnia symptoms but also comorbid symptoms.

Prenatal insomnia disorder may predict concurrent and postpartum psychopathology: A longitudinal study.

While insomnia symptoms may be a risk factor for mental disturbances, few studies evaluated "Insomnia Disorder" and its relationship with perinatal psychopathology. Pregnant women were recruited during their last routine assessment before being hospitalized for delivery during the 3rd trimester at the Gynaecological Unit of the University Hospital of Ferrara and Udine, Italy, from January 2022 to January 2023. Our assessment included baseline evaluation (T0), and evaluations at 1 month (T1) and 3 months (T2) in the postpartum period, with specific questionnaires for insomnia disorder, such as Sleep Condition Indicator, mood and anxiety symptoms and psychosocial functioning, such as Edinburgh Postnatal Depression Scale, Mood Disorder Questionnaire, State-Trait Anxiety Inventory, Work and Social Adjustment Scale. At T0, 181 pregnant women were included. Insomnia disorder affected 22.3% at T0, 23.5% at T1 and 16.2% at T2. Women with insomnia disorder at baseline were significantly more affected by concurrent anxiety and depressive symptoms, had higher bipolar diathesis and poorer psychosocial functioning in the perinatal period. Prenatal insomnia disorder predicted anxiety (T0: odds ratio 4.44, p << 0.001; T1: odds ratio 4.009, p = 0.042) and depressive symptoms (T0: odds ratio 2.66, p = 0.015; T1: odds ratio 11.20, p = 0.001; T2: odds ratio 12.50 p = 0.049) in both the prenatal and postnatal period. It also predicted poor psychosocial function during the prenatal (odds ratio 3.55, p = 0.003) and postpartum periods (T1: odds ratio 2.33, p = 0.004). Insomnia disorder is emerging as an important prenatal factor that may contribute to concurrent and postpartum psychopathology.

Is Interoception Deficit Linking Alexithymia and Eating Spectrum Symptoms? Study on a Non-Clinical Sample of Young Adults.

We investigated if interoceptive deficits could be the link between alexithymic traits and eating spectrum manifestations in a non-clinical sample. One-hundred sixty-one young adults (mean age: 23.2 ± 2.4 years) were evaluated with the Toronto Alexithymia Scale-20 (TAS-20), the Interoceptive Accuracy Scale (IAS), the Interoceptive Confusion Questionnaire (ICQ), and the Eating Attitudes Test-26 (EAT-26). Questionnaires were administered with an online procedure (Microsoft Form, Office 365 A1, Pisa, Italy) (Study Protocol #0012005/2023). We compared ICQ, IAS, and TAS-20 scores in subjects who met the threshold for a potential eating spectrum disorder according to EAT-26 scores ≥ 20 (n = 27) vs. subjects who scored <20 (n = 134), with an ANCOVA corrected for 'age' and 'gender'. Subjects with EAT-26 ≥ 20, scored significantly higher at ICQ (54.4 ± 13.2 vs. 50.2 ± 6.8; p = 0.011), TAS-20 'Total Score' (60.8 ± 11.9 vs. 58.1 ± 9.2; p = 0.006), and TAS-20 'Identifying Feelings' (21.5 ± 7.6 vs. 17.3 ± 5.8; p = 0.0001). A binary logistic regression analysis, with EAT-26 scores < 20 vs. ≥20 as the dependent variable, and ICQ, IAS, TAS-20 total scores and dimensions, age, and gender (categorical) as covariates, showed that the only variable predicting eating spectrum symptomatology was 'ICQ Total Score' (OR = 1.075, 95% CI: 1.016-1.139; p = 0.013). Interoceptive confusion was the dimension linking the occurrence of alexithymic traits and eating spectrum manifestations.

Evaluation and management of insomnia in the clinical practice in Italy: a 2023 update from the Insomnia Expert Consensus Group.

BACKGROUND: Insomnia is the most reported sleep disorder in industrialized countries, affecting, in the chronic form, around 10% of the European population. In Italy, such a percentage seems to be even higher. Although insomnia can be an independent disorder, it is frequently described as comorbid condition and may precipitate, exacerbate, or prolong a broad range of physical and mental disorders. Evaluating and targeting insomnia in the Italian clinical practice should be a priority. METHODS: The present expert opinions and recommendations represent an update from 2020 and insights from Insomnia Expert Consensus Group, based on systematic reviews according to PRISMA on available options in Italy from January 2020 to March 2023. RESULTS: We evaluated 28 papers among international guidelines, expert opinions, systematic reviews, and meta-analysis produced during the last 26 months. CONCLUSIONS: Our findings suggest that symptoms of insomnia must be assessed in the Italian clinical practice by evaluating nocturnal and daytime symptoms, comorbid conditions, and lifestyle. Cognitive behavioral therapy for insomnia should be the first option according to availability. The choice of the drug should be based on different factors including type of insomnia, age, comorbidities, and potential side effects. If the choice would be a Z-drug or a short-acting benzodiazepine (in subjects < 65 years old), the use should be in the short term (≤ 4 weeks). Indeed, eszopiclone, as a new option in Italy, may present a different profile and may be used for up to 6 months, also in the elderly. If the choice is melatonin, it should be used melatonin 2 mg prolonged release in adults ≥ 55 years for up to 13 weeks. A new dual orexin antagonist, daridorexant, is available in Italy; it has been shown to be effective in adults and elderly and it can be used for at least 3 months and up to 1 year.

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.

Towards the neurobiology of insomnia: A systematic review of neuroimaging studies.

Insomnia disorder signifies a major public health concern. The development of neuroimaging techniques has permitted to investigate brain mechanisms at a structural and functional level. The present systematic review aims at shedding light on functional, structural, and metabolic substrates of insomnia disorder by integrating the available published neuroimaging data. The databases PubMed, PsycARTICLES, PsycINFO, CINAHL and Web of Science were searched for case-control studies comparing neuroimaging data from insomnia patients and healthy controls. 85 articles were judged as eligible. For every observed finding of each study, the effect size was calculated from standardised mean differences, statistic parameters and figures, showing a marked heterogeneity that precluded a comprehensive quantitative analysis. From a qualitative point of view, considering the findings of significant group differences in the reported regions across the articles, this review highlights the major involvement of the anterior cingulate cortex, thalamus, insula, precuneus and middle frontal gyrus, thus supporting some central themes in the debate on the neurobiology of and offering interesting insights into the psychophysiology of sleep in this disorder.

Clinical usefulness of dual orexin receptor antagonism beyond insomnia: Neurological and psychiatric comorbidities.

Orexin is a neurotransmitter produced by a small group of hypothalamic neurons. Besides its well-known role in the regulation of the sleep-wake cycle, the orexin system was shown to be relevant in several physiological functions including cognition, mood and emotion modulation, and energy homeostasis. Indeed, the implication of orexin neurotransmission in neurological and psychiatric diseases has been hypothesized via a direct effect exerted by the projections of orexin neurons to several brain areas, and via an indirect effect through orexin-mediated modulation of sleep and wake. Along with the growing evidence concerning the use of dual orexin receptor antagonists (DORAs) in the treatment of insomnia, studies assessing their efficacy in insomnia comorbid with psychiatric and neurological diseases have been set in order to investigate the potential impact of DORAs on both sleep-related symptoms and disease-specific manifestations. This narrative review aimed at summarizing the current evidence on the use of DORAs in neurological and psychiatric conditions comorbid with insomnia, also discussing the possible implication of modulating the orexin system for improving the burden of symptoms and the pathological mechanisms of these disorders. Target searches were performed on PubMed/MEDLINE and Scopus databases and ongoing studies registered on Clinicaltrials.gov were reviewed. Despite some contradictory findings, preclinical studies seemingly support the possible beneficial role of orexin antagonism in the management of the most common neurological and psychiatric diseases with sleep-related comorbidities. However, clinical research is still limited and further studies are needed for corroborating these promising preliminary results.

Patients with Chronic Pain: Are Mindfulness Traits Protective Against Distress, Anxiety and Depression?

Objective: To investigate mindfulness traits/attitudes as protective factors against chronic pain related distress, depression and anxiety. Method: Fifty patients (25 with chronic non-oncologic pain-NOP; 25 with chronic oncologic pain-COP) were administered with the following scales: Visual Analogue Scale (VAS), Pain Disability Index (PDI), Italian Questionnaire for Pain (QUID), Perceived Stress Scale (PSS), State and Trait Anxiety Scale (STAY-y1 module), Beck Depression Inventory II (BDI-II), Pittsburgh Sleep Quality Index (PSQI), Psychological General Well Being Index (PGWBI), Mindful Attention Awareness Scale (MAAS). Results: MAAS value ≥ 4.38 was adopted as cut-off to compare 'high level of mindfulness' (HM) vs. 'normal level of mindfulness' (NM) attitudes. Twenty-six patients (52%) scored ≥4.38, with no different distribution between NOP and COP. HM patients scored significantly lower than NM patients on PDI 'family/home responsibilities' domain (4.5±3.2 vs. 6.4±2.8; p<.037), and on PSS (17.8±2.6 vs. 20.9±2.5; p<.0001), STAY-y1 (9.4±1.8 vs. 10.3±2.1; p<.0001), BDI-II (7.8±5.0 vs. 17.6±8.6; p<.0001) total scores. HM scored significantly higher than NM patients in all PGWBI domains. A multiple regression analysis was carried out to analyze the predictor variables of PGWB. The most complete model considered the variables MAAS, STAIy and VAS (F=42.21; p<.0001), that accounted for the 71.6% of PGWB variance. MAAS score was the only variable positively predicting for PGWB; STAIy and VAS scores predicted negatively. Conclusions: Chronic pain patients with high levels of mindfulness attitudes experienced less distress, anxiety, depressive symptoms, and more physical and general wellbeing than patients with low levels of mindfulness attitudes.

Content analysis of insomnia questionnaires: A step to better evaluate the complex and multifaceted construct of insomnia disorder.

Insomnia disorder is a mental disorder that includes various types of symptoms (e.g., insomnia initiating, worries, mood disturbances) and impairments (e.g., distress related to sleep alterations). Self-report questionnaires are the most common method for assessing insomnia but no systematic quantified analysis of their content and overlap has been carried out. We used content analysis and a visualization method to better identify the different types of clinical manifestations that are investigated by nine commonly used insomnia questionnaires for adults and the Jaccard index to quantify the degree to which they overlap. Content analysis found and visualized 16 different clinical manifestations classified into five dimensions ("Insomnia symptoms", "Insomnia-related symptoms", "Daytime symptoms", "Insomnia-related impairments", "Sleep behaviors"). The average Jaccard Index was 0.409 (moderate overlap in content). There is a lack of distinction between symptoms and impairments, and the assessment of sleep duration and hyperarousal symptoms remains overlooked. This preliminary analysis makes it possible to visualize the content of each of the nine questionnaires and to select the most appropriate questionnaire based on the issue to be addressed. Suggestions are made regarding the development of future questionnaires to better distinguish symptoms and impairments, and the different phenotypes of insomnia disorder.

["Insomnia disorder": an overview of current models and of the complex link with psychopathology.] / Il "disturbo da insonnia": una overview sui modelli attuali e sul complesso link con i quadri psicopatologici.

Insomnia disorder is the most common sleep disorder. The new models frame insomnia as a stress-related disorder and a "24-hour" syndrome with night and day symptoms. The hyperarousal has been identified as the neurobiological mechanism underlying chronic insomnia. Since chronic insomnia is considered a risk factor for psychopathology it is possible that hyperarousal may act as a link with psychopathological conditions. Assessing and treating insomnia could therefore also have a preventive value in psychopathology.

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).

Alexithymia and Interoceptive Confusion in Covid-19 Pandemic Distress.

Objective: Alexithymic traits are associated with the difficulty of perceiving 'non-affective interoceptive signals', and are related to a problematic management of stressful life events (SLEs). The main purpose of this study was to quantify the psychological response of the general population to COVID-19 pandemic stress and to evaluate potential correlations with the presence of 'alexithymic traits' and 'interoceptive confusion' (study protocol # 0077794/2022). Method: 175 subjects from general population were assessed with the Toronto-Alexithymia Scale (TAS-20), the Event-Revised Impact Scale (IES-R), the Interoceptive Accuracy Scale (IAS), and the Interoceptive Confusion Questionnaire (ICQ). Results: a significant relationship emerged between alexithymic traits (assessed with the TAS-20), the ICQ 'interoceptive confusion', and the domain of 'hyper-arousal' as assessed with IES-R. Logistic regression model showed that ICQ-Total Score and IES-R 'hyper-arousal' domain were significantly correlated with TAS-20 total score, with DR value (R2 corrected) explaining the 36.8% of the variability (standard error: 10.7). Conclusions: This study, albeit with the limitations of a cross-sectional experimental design with self-evaluation tools in a general population sample, showed a vulnerability to COVID-19 pandemic stress due to high levels of hyper-arousal in subjects with alexithymic traits and interoceptive confusion.

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.

Cancer Stem Cells and Glioblastoma: Time for Innovative Biomarkers of Radio-Resistance?

Despite countless papers in the field of radioresistance, researchers are still far from clearly understanding the mechanisms triggered in glioblastoma. Cancer stem cells (CSC) are important to the growth and spread of cancer, according to many studies. In addition, more recently, it has been suggested that CSCs have an impact on glioblastoma patients' prognosis, tumor aggressiveness, and treatment outcomes. In reviewing this new area of biology, we will provide a summary of the most recent research on CSCs and their role in the response to radio-chemotherapy in GB. In this review, we will examine the radiosensitivity of stem cells. Moreover, we summarize the current knowledge of the biomarkers of stemness and evaluate their potential function in the study of radiosensitivity.

Insomnia During the Perinatal Period and its Association with Maternal and Infant Psychopathology: A Systematic Review and Meta-Analysis.

PURPOSE OF REVIEW: While sleep serves important regulatory functions for mental health, sleep disturbances, in particular insomnia, may contribute to mental disorders. Since insomnia symptoms are frequent during the perinatal period, the aim of this work is to systematically review the potential association between perinatal insomnia and maternal and infant psychopathology. RECENT FINDINGS: A systematic search was conducted according with PRISMA guidelines, and meta-analytic calculations were conducted. Totally, 34 studies were included and involved 835,021 perinatal women. Four meta-analysis yielded four statistically significant random-effect models. All models show that women with perinatal symptoms of insomnia possess increased odds of developing clinically relevant symptoms of depression OR = 3.69, p = 0.001 and anxiety OR = 2.81; p < 0.001, as well as increased suicidal risk OR = 3.28; p < 0.001, and distress in the newborn OR = 2.80 (P = 0.007). These findings emphasize the role of assessing and addressing insomnia during the perinatal period to mitigate its negative effect on maternal and infant mental health via sleep regulation.

Preventing recurrence of postpartum depression by regulating sleep.

INTRODUCTION: Women are at a high risk of recurrence of depression in the postpartum period. Given the circumscribed duration of the risk period and knowledge of its triggers, postpartum depression should be easily preventable. However, prophylactic drug studies have reported contradictory findings partly due to the heterogeneity of the disorder. Currently, there are no studies on the efficacy of psychotherapy in the prevention of postpartum depression in women with major depressive or bipolar disorder. AREAS COVERED: This review evaluates the results of controlled medication and psychotherapeutic studies in the prevention of depression in women with major depressive disorder or bipolar disorder; it further suggests that the management of sleep loss/insomnia may be an effective strategy in the prevention of postpartum depression. EXPERT OPINION: A thorough understanding of the clinical course of the antecedent mood disorder and historical treatment response is necessary before the implementation of strategies for the prevention of postpartum depression. Targeting disturbed and/or insufficient sleep - a common and early transdiagnostic symptom of peripartum psychiatric disorders - may be a more effective intervention for the prevention of postpartum depression and psychiatric comorbidities in some individuals than the traditional approach of antidepressant use.

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.