Who sleeps well in Canada? The social determinants of sleep health among middle-aged and older adults in the Canadian Longitudinal Study on Aging.

OBJECTIVES: Sleep health inequities likely contribute to disparities in health outcomes. Our objective was to identify social determinants of sleep health among middle-aged/older adults in Canada, where prior evidence is limited. METHODS: We analyzed cross-sectional data from the Canadian Longitudinal Study on Aging, a survey of over 30,000 community-dwelling adults aged 45-85years. Self-reported measures included sleep duration, sleep satisfaction, and sleep efficiency. We explored associations between sleep measures and social determinants of health. We used modified Poisson regression to estimate prevalence ratios for sleep satisfaction and sleep efficiency, and linear regression for sleep duration. Estimates were adjusted for all social, lifestyle, and clinical covariates. We explored effect modification by sex. RESULTS: Of the 11 social determinants explored, all were significantly associated with at least one domain of sleep health. These associations were reduced to 9 variables with adjustment for all social variables, and 7 with further adjustment for lifestyle and clinical covariates, including differences by sex, age, education, marital status, employment, race/ethnicity, and sexual orientation. Better sleep health in >1 domain was observed among males, older age groups (65 and older), higher income groups, the retired group, and homeowners with adjustment for social variables, and only in males and older age groups with additional adjustment for lifestyle and clinical variables. Only sleep duration associations were modified by sex. CONCLUSIONS: Sleep health disparities among Canadian adults exist across socioeconomic gradients and racial/ethnic minority groups. Poor sleep health among disadvantaged groups warrants increased attention as a public health problem in Canada.

Pharmacological treatments in panic disorder in adults: a network meta-analysis.

BACKGROUND: A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines. OBJECTIVES: To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses. MAIN RESULTS: Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low. AUTHORS' CONCLUSIONS: In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.

A Systematic Review of the Effect of Short Term Transcranial Direct Current Stimulation Therapy in Methamphetamine Use Disorder.

Background: Methamphetamine use disorder (MUD) has become more and more common. Some studies have shown that Transcranial Direct Current stimulation (tDCS) may reduce craving when stimulating the dorsal lateral prefrontal cortex. Objectives: The aim of this systematic review was to evaluate the effect of transcranial direct current stimulation (tDCS) on MUD. Databases were searched through May 2022. Randomized Controlled Trials (RCT) and pre-post studies investigating the efficacy of tDCS in MUD were included. The Cochrane Manual of Systematic Evaluation 6.3 bias risk assessment tool was used to assess the risk of bias. For each article, where possible, we extracted the population(s), standardized mean differences (SMD), standard deviations, and other study metrics (design, year, randomization, and details) on efficacy and tolerability outcomes. We assessed each article's quality via the GRADE assessment protocol. Results: Six studies involving 220 patients were included. All six studies included reported continuous data on craving. Results from craving favored active tDCS over sham tDCS at the end of treatment (SMD -0.58, 95% CI -0.85 to -0.30; studies = 6, participants = 220; I2 = 60%). Tolerability data showed that tDCS does not cause more tingling or itching sensation compared to sham tDCS. Conclusions: Further trials with larger sample sizes and longer durations are needed to determine whether tDCS is a valuable tool in treating MUD.

Sleep Problems and Psychological Well-Being: Baseline Findings from the Canadian Longitudinal Study on Aging.

International studies have demonstrated associations between sleep problems and poor psychological well-being; however, Canadian data are limited. This study investigated this association using cross-sectional baseline data from the Canadian Longitudinal Study on Aging, a national survey of 30,097 community-dwelling adults, 45-85 years of age. Short sleep duration, sleep dissatisfaction, insomnia symptoms, and daytime impairment were consistently associated with a higher prevalence of dissatisfaction with life, psychological distress, and poor self-reported mental health. Long sleep duration was associated with a higher prevalence of psychological distress and poor self-reported mental health, but not with dissatisfaction with life. Associations between sleep problems and psychological distress were 11-18 per cent stronger in males. With each 10-year increase in age, the association between daytime impairment and life dissatisfaction increased by 11 per cent, and insomnia symptoms and poor mental health decreased by 11 per cent. Sleep problems in middle-aged and older adults warrant increased attention as a public health problem in Canada.

Cognitive behavioural therapy (group) for schizophrenia.

BACKGROUND: Schizophrenia is a disabling psychotic disorder characterised by positive symptoms of delusions, hallucinations, disorganised speech and behaviour; and negative symptoms such as affective flattening and lack of motivation. Cognitive behavioural therapy (CBT) is a psychological intervention that aims to change the way in which a person interprets and evaluates their experiences, helping them to identify and link feelings and patterns of thinking that underpin distress. CBT models targeting symptoms of psychosis (CBTp) have been developed for many mental health conditions including schizophrenia. CBTp has been suggested as a useful add-on therapy to medication for people with schizophrenia. While CBT for people with schizophrenia was mainly developed as an individual treatment, it is expensive and a group approach may be more cost-effective. Group CBTp can be defined as a group intervention targeting psychotic symptoms, based on the cognitive behavioural model. In group CBTp, people work collaboratively on coping with distressing hallucinations, analysing evidence for their delusions, and developing problem-solving and social skills. However, the evidence for effectiveness is far from conclusive. OBJECTIVES: To investigate efficacy and acceptability of group CBT applied to psychosis compared with standard care or other psychosocial interventions, for people with schizophrenia or schizoaffective disorder. SEARCH METHODS: On 10 February 2021, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials, which is based on CENTRAL, MEDLINE, Embase, four other databases and two trials registries. We handsearched the reference lists of relevant papers and previous systematic reviews and contacted experts in the field for supplemental data. SELECTION CRITERIA: We selected randomised controlled trials allocating adults with schizophrenia to receive either group CBT for schizophrenia, compared with standard care, or any other psychosocial intervention (group or individual). DATA COLLECTION AND ANALYSIS: We complied with Cochrane recommended standard of conduct for data screening and collection. Where possible, we calculated risk ratio (RR) and 95% confidence interval (CI) for binary data and mean difference (MD) and 95% CI for continuous data. We used a random-effects model for analyses. We assessed risk of bias for included studies and created a summary of findings table using GRADE. MAIN RESULTS: The review includes 24 studies (1900 participants). All studies compared group CBTp with treatments that a person with schizophrenia would normally receive in a standard mental health service (standard care) or any other psychosocial intervention (group or individual). None of the studies compared group CBTp with individual CBTp. Overall risk of bias within the trials was moderate to low. We found no studies reporting data for our primary outcome of clinically important change. With regard to numbers of participants leaving the study early, group CBTp has little or no effect compared to standard care or other psychosocial interventions (RR 1.22, 95% CI 0.94 to 1.59; studies = 13, participants = 1267; I2 = 9%; low-certainty evidence). Group CBTp may have some advantage over standard care or other psychosocial interventions for overall mental state at the end of treatment for endpoint scores on the Positive and Negative Syndrome Scale (PANSS) total (MD -3.73, 95% CI -4.63 to -2.83; studies = 12, participants = 1036; I2 = 5%; low-certainty evidence). Group CBTp seems to have little or no effect on PANSS positive symptoms (MD -0.45, 95% CI -1.30 to 0.40; studies =8, participants = 539; I2 = 0%) and on PANSS negative symptoms scores at the end of treatment (MD -0.73, 95% CI -1.68 to 0.21; studies = 9, participants = 768; I2 = 65%). Group CBTp seems to have an advantage over standard care or other psychosocial interventions on global functioning measured by Global Assessment of Functioning (GAF; MD -3.61, 95% CI -6.37 to -0.84; studies = 5, participants = 254; I2 = 0%; moderate-certainty evidence), Personal and Social Performance Scale (PSP; MD 3.30, 95% CI 2.00 to 4.60; studies = 1, participants = 100), and Social Disability Screening Schedule (SDSS; MD -1.27, 95% CI -2.46 to -0.08; studies = 1, participants = 116). Service use data were equivocal with no real differences between treatment groups for number of participants hospitalised (RR 0.78, 95% CI 0.38 to 1.60; studies = 3, participants = 235; I2 = 34%). There was no clear difference between group CBTp and standard care or other psychosocial interventions endpoint scores on depression and quality of life outcomes, except for quality of life measured by World Health Organization Quality of Life Assessment Instrument (WHOQOL-BREF) Psychological domain subscale (MD -4.64, 95% CI -9.04 to -0.24; studies = 2, participants = 132; I2 = 77%). The studies did not report relapse or adverse effects. AUTHORS' CONCLUSIONS: Group CBTp appears to be no better or worse than standard care or other psychosocial interventions for people with schizophrenia in terms of leaving the study early, service use and general quality of life. Group CBTp seems to be more effective than standard care or other psychosocial interventions on overall mental state and global functioning scores. These results may not be widely applicable as each study had a low sample size. Therefore, no firm conclusions concerning the efficacy of group CBTp for people with schizophrenia can currently be made. More high-quality research, reporting useable and relevant data is needed.

The Impact of Infectious Disease-Related Public Health Emergencies on Suicide, Suicidal Behavior, and Suicidal Thoughts.

Background: Infectious disease-related public health emergencies (epidemics) may increase suicide risk, and high-quality evidence is needed to guide an international response. Aims: We investigated the potential impacts of epidemics on suicide-related outcomes. Method: We searched MEDLINE, EMBASE, PsycInfo, CINAHL, Scopus, Web of Science, PsyArXiv, medRxiv, and bioRxiv from inception to May 13-16, 2020. Inclusion criteria: primary studies, reviews, and meta-analyses; reporting the impact of epidemics; with a primary outcome of suicide, suicidal behavior, suicidal ideation, and/or self-harm. Exclusion criteria: not concerned with suicide-related outcomes; not suitable for data extraction. PROSPERO registration: #CRD42020187013. Results: Eight primary papers were included, examining the effects of five epidemics on suicide-related outcomes. There was evidence of increased suicide rates among older adults during SARS and in the year following the epidemic (possibly motivated by social disconnectedness, fears of virus infection, and concern about burdening others) and associations between SARS/Ebola exposure and increased suicide attempts. A preprint study reported associations between COVID-19 distress and past-month suicidal ideation. Limitations: Few studies have investigated the topic; these are of relatively low methodological quality. Conclusion: Findings support an association between previous epidemics and increased risk of suicide-related outcomes. Research is needed to investigate the impact of COVID-19 on suicide outcomes.

A Systematic Review of the Use of Telepsychiatry in Depression.

Telepsychiatry, the use of televideo in psychiatric assessment and treatment, is utilized throughout Canada. Major depressive disorder (MDD) is common, with significant burdens of suffering and cost. This systematic review explores the literature on the use of televideo to diagnose and treat MDD, particularly acceptability and patient satisfaction, efficacy, and cost-effectiveness. A literature search was conducted for years 1946 to 2019. Study eligibility criteria included: MDD as the condition of interest, use of televideo technology, randomized controlled trials (RCTs), Adult (18 years or older) population, any clinical setting, and any healthcare professional providing care. The study must have included at least one of the following measures, satisfaction, efficacy, and cost-effectiveness. Fourteen studies were included. Satisfaction is equivalent to or significantly higher than face-to-face intervention. Both televideo and control groups found relief from depressive symptoms, with differences either statistically insignificant or in favour of televideo. Despite increased cost upfront for televideo due to the technology required, televideo would eventually be more cost-effective due to reducing travel expenses. Limitations include that there is little RCT data, and what exists often uses a collaborative treatment model. Many studies consisted solely of U.S. Veterans, and have limited generalizability. Further research needed to directly compare psychiatrist assessment over televideo versus in-person, and determine if particular patient subgroups benefit more from televideo or in-person intervention.Systematic review registration number: CRD42016048224.

Sleep behaviours and multimorbidity occurrence in middle-aged and older adults: findings from the Canadian Longitudinal Study on Aging (CLSA).

OBJECTIVE: Poor sleep quality and reduced sleep duration impact over half of older adults and are associated with adverse health outcomes, such as multiple chronic conditions (multimorbidity) and reduced longevity. Our objective was to examine the relationship between sleep behaviours and multimorbidity in Canada. METHODS: We analysed data from the Canadian Longitudinal Study on Aging (CLSA), a cross-sectional national health survey of community-dwelling adults over the age of 45 years. A total of 30,011 participants had physiological and psychosocial data collected at baseline. Sleep measures included self-reported sleep duration (short: <6 h; normal: 6-8 h; long: >8 h) and sleep quality (dissatisfied/very dissatisfied; neutral; satisfied/very satisfied). Multimorbidity was defined using two definitions (public health and primary care) and two cut-points (2 or more and 3 or more chronic conditions). RESULTS: Approximately 70% were living with multimorbidity using the primary care definition (females: 67.9%; males 57.9%), whereas approximately 30% were living with multimorbidity using the public health definition (females: 30.9%; males: 24.0%). Adjusted analyses indicated that the odds of multimorbidity were higher for participants who selfreported either short or long sleep duration, as well as dissatisfaction with sleep quality. Associations were stronger among younger age groups (45-54 years and 55-64 years). CONCLUSIONS: Disrupted sleep may be a risk factor for multimorbidity across sexes and age groups. It is necessary to understand the potential impact of sleep on the risk of multimorbidity to inform both clinical and public health guidelines for the prevention and management of this major health issue.

Italian Validation of the Screen for Cognitive Impairment in Psychiatry.

Cognitive impairments have profound implications for the management of severe mental disorders; however, they are rarely assessed in everyday clinical practice due to constraints in time, resource and expertise. Novel and short instruments, such as the Screen for Cognitive Impairment in Psychiatry (SCIP), which overcome such limitations are greatly needed. The study aims to assess the validity and reliability, among healthy subjects, of the Italian translation of the SCIP, a brief, accessible tool to detect cognitive impairments among individuals suffering from mental disorders, as the first step to validate the instrument in clinical settings. One-hundred and twenty healthy subjects completed two of the three alternative forms of the SCIP. Cronbach Alpha (0.70) supported the reliability of the SCIP scores. Correlation coefficients supported the test-retest reliability of the tool. Learning effects were observed despite the use of alternative forms. Factor analysis indicated a two-factor solution explaining 55.4% of the total variance: the first factor ("memory") loading for VLT-I and VLT-D and less for WMT; the second factor ("executive function") loading for VFT and PST and less for WMT. The study proved the validity and reliability of the Italian version of the SCIP as a reliable and simple instrument to screen for cognitive impairment in the general population.

Benzodiazepines versus placebo for panic disorder in adults.

BACKGROUND: Panic disorder is characterised by recurrent unexpected panic attacks consisting of a wave of intense fear that reaches a peak within a few minutes. Panic disorder is a common disorder, with an estimated lifetime prevalence of 1% to 5% in the general population and a 7% to 10% prevalence in primary care settings. Its aetiology is not fully understood and is probably heterogeneous.Panic disorder is treated with psychological and pharmacological interventions, often used in combination. Although benzodiazepines are frequently used in the treatment of panic disorder, guidelines recommend antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as first-line treatment for panic disorder, particularly due to their lower incidence of dependence and withdrawal reaction when compared to benzodiazepines. Despite these recommendations, benzodiazepines are widely used in the treatment of panic disorder, probably because of their rapid onset of action. OBJECTIVES: To assess the efficacy and acceptability of benzodiazepines versus placebo in the treatment of panic disorder with or without agoraphobia in adults. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR Studies and References), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950-), Embase (1974-), and PsycINFO (1967-) up to 29 May 2018. We handsearched reference lists of relevant papers and previous systematic reviews. We contacted experts in the field for supplemental data. SELECTION CRITERIA: All double-blind (blinding of patients and personnel) controlled trials randomising adults with panic disorder with or without agoraphobia to benzodiazepine or placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently checked the eligibility of studies and extracted data using a standardised form. Data were then entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details, settings, and outcome measures in terms of efficacy, acceptability, and tolerability. MAIN RESULTS: We included 24 studies in the review with a total of 4233 participants, of which 2124 were randomised to benzodiazepines and 1475 to placebo. The remaining 634 participants were randomised to other active treatments in three-arm trials. We assessed the overall methodological quality of the included studies as poor. We rated all studies as at unclear risk of bias in at least three domains. In addition, we judged 20 of the 24 included studies as having a high risk of bias in at least one domain.Two primary outcomes of efficacy and acceptability showed a possible advantage of benzodiazepines over placebo. The estimated risk ratio (RR) for a response to treatment was 1.65 (95% confidence interval (CI) 1.39 to 1.96) in favour of benzodiazepines, which corresponds to an estimated number needed to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 7). The dropout rate was lower among participants treated with benzodiazepines (RR 0.50, 95% CI 0.39 to 0.64); the estimated NNTB was 6 (95% CI 5 to 9). We rated the quality of the evidence as low for both primary outcomes. The possible advantage of benzodiazepine was also seen for remission (RR 1.61, 95% CI 1.38 to 1.88) and the endpoint data for social functioning (standardised mean difference (SMD) -0.53, 95% CI -0.65 to -0.42), both with low-quality evidence. We assessed the evidence for the other secondary outcomes as of very low quality. With the exception of the analyses of the change score data for depression (SMD -0.22, 95% CI -0.48 to 0.04) and social functioning (SMD -0.32, 95% CI -0.88 to 0.24), all secondary outcome analyses showed an effect in favour of benzodiazepines compared to placebo. However, the number of dropouts due to adverse effects was higher with benzodiazepines than with placebo (RR 1.58, 95% CI 1.16 to 2.15; low-quality evidence). Furthermore, our analyses of adverse events showed that a higher proportion of participants experienced at least one adverse effect when treated with benzodiazepines (RR 1.18, 95% CI 1.02 to 1.37; low-quality evidence). AUTHORS' CONCLUSIONS: Low-quality evidence shows a possible superiority of benzodiazepine over placebo in the short-term treatment of panic disorders. The validity of the included studies is questionable due to possible unmasking of allocated treatments, high dropout rates, and probable publication bias. Moreover, the included studies were only short-term studies and did not examine the long-term efficacy nor the risks of dependency and withdrawal symptoms. Due to these limitations, our results regarding the efficacy of benzodiazepines versus placebo provide only limited guidance for clinical practice. Furthermore, the clinician's choice is not between benzodiazepines and placebo, but between benzodiazepines and other agents, notably SSRIs, both in terms of efficacy and adverse effects. The choice of treatment should therefore be guided by the patient's preference and should balance benefits and harms from treatment in a long-term perspective.

Influence of covariates on heterogeneity in Hamilton Anxiety Scale ratings in placebo-controlled trials of benzodiazepines in generalized anxiety disorder: Systematic review and meta-analysis.

BACKGROUND: Generalized anxiety disorder is a common psychiatric condition that is associated with decreased quality of life and significant disability. Benzodiazepines are anti-anxiety drugs used widely in the treatment of generalized anxiety disorder. This study examines the influence of several variables on benzodiazepine efficacy in generalized anxiety disorder. METHOD: We performed a systematic review of placebo-controlled randomized controlled trials with benzodiazepines in generalized anxiety disorder. Fifty-eight studies were deemed eligible to include in the meta-analysis. The studies dated from 1977 to 2013 and included over 5400 participants. From each paper, we extracted: benzodiazepine name and dose, dosing regimen, baseline Hamilton Anxiety Scale (HAM-A) score, change in HAM-A score at study endpoint, drop-out rate, year of study publication, diagnostic criteria used, study size, study duration, location, any conflicts of interest and side-effect profile. We then assessed the influence, direct and indirect, of individual variables on the primary outcome (mean difference at endpoint, HAM-A score). RESULTS: Three factors were shown to be associated statistically with change in HAM-A; baseline HAM-A for benzodiazepine arm, baseline HAM-A for the placebo arm, and duration of the study. A higher baseline HAM-A in both arms was associated with a greater mean difference in HAM-A. A shorter study length was also associated with a greater mean difference. DISCUSSION: The major factors determining benzodiazepine response was baseline anxiety level for the benzodiazepine arm and study duration. In any design of further meta-analyses and clinical trials for generalized anxiety disorder we suggest that these should be considered these as confounding factors.

A Comparison of Inpatient Adult Psychiatric Services in Italy and Canada.

We examine the possibility the Organisation for Economic Co-operation and Development (OECD) bed count for Italy may be an underestimation of the actual beds available. We compared bedded services for mental disorders in two regions in Italy and Canada respectively. We found out that if we consider acute psychiatric beds only, the district of Ferrara has 30 beds (8.5 per 100,000) and the Middlesex and Elgin Counties have 89 beds (16.3 beds for 100,000). However, if we include the rehabilitation beds (that are located within a hospital setting in Ontario and in a residential community setting in Ferrara), we find that the district of Ferrara has 95 beds (27.0 per 100,000) and the Middlesex and Elgin Counties have 176 beds (32.3 per 100,000). As a result, the 10/100,000 beds rate for Italy reported by the OECD is an underestimate compared to figures reported for most other countries, as the beds included are hospital beds only.

Antidepressants versus placebo for panic disorder in adults.

BACKGROUND: Panic disorder is characterised by repeated, unexpected panic attacks, which represent a discrete period of fear or anxiety that has a rapid onset, reaches a peak within 10 minutes, and in which at least four of 13 characteristic symptoms are experienced, including racing heart, chest pain, sweating, shaking, dizziness, flushing, stomach churning, faintness and breathlessness. It is common in the general population with a lifetime prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions. Amongst pharmacological agents, the National Institute for Health and Care Excellence (NICE) and the British Association for Psychopharmacology consider antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as the first-line treatment for panic disorder, due to their more favourable adverse effect profile over monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). Several classes of antidepressants have been studied and compared, but it is still unclear which antidepressants have a more or less favourable profile in terms of effectiveness and acceptability in the treatment of this condition. OBJECTIVES: To assess the effects of antidepressants for panic disorder in adults, specifically:1. to determine the efficacy of antidepressants in alleviating symptoms of panic disorder, with or without agoraphobia, in comparison to placebo;2. to review the acceptability of antidepressants in panic disorder, with or without agoraphobia, in comparison with placebo; and3. to investigate the adverse effects of antidepressants in panic disorder, with or without agoraphobia, including the general prevalence of adverse effects, compared to placebo. SEARCH METHODS: We searched the Cochrane Common Mental Disorders' (CCMD) Specialised Register, and CENTRAL, MEDLINE, EMBASE and PsycINFO up to May 2017. We handsearched reference lists of relevant papers and previous systematic reviews. SELECTION CRITERIA: All double-blind, randomised, controlled trials (RCTs) allocating adults with panic disorder to antidepressants or placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently checked eligibility and extracted data using a standard form. We entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details and settings. Primary outcomes included failure to respond, measured by a range of response scales, and treatment acceptability, measured by total number of dropouts for any reason. Secondary outcomes included failure to remit, panic symptom scales, frequency of panic attacks, agoraphobia, general anxiety, depression, social functioning, quality of life and patient satisfaction, measured by various scales as defined in individual studies. We used GRADE to assess the quality of the evidence for each outcome MAIN RESULTS: Forty-one unique RCTs including 9377 participants overall, of whom we included 8252 in the 49 placebo-controlled arms of interest (antidepressant as monotherapy and placebo alone) in this review. The majority of studies were of moderate to low quality due to inconsistency, imprecision and unclear risk of selection and performance bias.We found low-quality evidence that revealed a benefit for antidepressants as a group in comparison with placebo in terms of efficacy measured as failure to respond (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.66 to 0.79; participants = 6500; studies = 30). The magnitude of effect corresponds to a number needed to treat for an additional beneficial outcome (NNTB) of 7 (95% CI 6 to 9): that means seven people would need to be treated with antidepressants in order for one to benefit. We observed the same finding when classes of antidepressants were compared with placebo.Moderate-quality evidence suggested a benefit for antidepressants compared to placebo when looking at number of dropouts due to any cause (RR 0.88, 95% CI 0.81 to 0.97; participants = 7850; studies = 30). The magnitude of effect corresponds to a NNTB of 27 (95% CI 17 to 105); treating 27 people will result in one person fewer dropping out. Considering antidepressant classes, TCAs showed a benefit over placebo, while for SSRIs and serotonin-norepinephrine reuptake inhibitor (SNRIs) we observed no difference.When looking at dropouts due to adverse effects, which can be considered as a measure of tolerability, we found moderate-quality evidence showing that antidepressants as a whole are less well tolerated than placebo. In particular, TCAs and SSRIs produced more dropouts due to adverse effects in comparison with placebo, while the confidence interval for SNRI, noradrenergic reuptake inhibitors (NRI) and other antidepressants were wide and included the possibility of no difference. AUTHORS' CONCLUSIONS: The identified studies comprehensively address the objectives of the present review.Based on these results, antidepressants may be more effective than placebo in treating panic disorder. Efficacy can be quantified as a NNTB of 7, implying that seven people need to be treated with antidepressants in order for one to benefit. Antidepressants may also have benefit in comparison with placebo in terms of number of dropouts, but a less favourable profile in terms of dropout due to adverse effects. However, the tolerability profile varied between different classes of antidepressants.The choice of whether antidepressants should be prescribed in clinical practice cannot be made on the basis of this review.Limitations in results include funding of some studies by pharmaceutical companies, and only assessing short-term outcomes.Data from the present review will be included in a network meta-analysis of psychopharmacological treatment in panic disorder, which will hopefully provide further useful information on this issue.

Vortioxetine for depression in adults.

BACKGROUND: Major depressive disorder is a common mental disorder affecting a person's mind, behaviour and body. It is expressed as a variety of symptoms and is associated with substantial impairment. Despite a range of pharmacological and non-pharmacological treatment options, there is still room for improvement of the pharmacological treatment of depression in terms of efficacy and tolerability. The latest available antidepressant is vortioxetine. It is assumed that vortioxetine's antidepressant action is related to a direct modulation of serotonergic receptor activity and inhibition of the serotonin transporter. The mechanism of action is not fully understood, but it is claimed to be novel. Vortioxetine was placed in the category of "Other" antidepressants and may therefore provide an alternative to existing antidepressant drugs. OBJECTIVES: To assess the efficacy and acceptability of vortioxetine compared with placebo and other antidepressant drugs in the treatment of acute depression in adults. SEARCH METHODS: We searched Cochrane's Depression, Anxiety and Neurosis Review Group's Specialised Register to May 2016 without applying any restrictions to date, language or publication status. We checked reference lists of relevant studies and reviews, regulatory agency reports and trial databases. SELECTION CRITERIA: We included randomised controlled trials comparing the efficacy, tolerability, or both of vortioxetine versus placebo or any other antidepressant agent in the treatment of acute depression in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the studies and extracted data. We extracted data on study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy, acceptability and tolerability. We analysed intention-to-treat (ITT) data only and used risk ratios (RR) as effect sizes for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI). Meta-analyses used random-effects models. MAIN RESULTS: We included 15 studies (7746 participants) in this review. Seven studies were placebo controlled; eight studies compared vortioxetine to serotonin-norepinephrine reuptake inhibitors (SNRIs). We were unable to identify any study that compared vortioxetine to antidepressant drugs from other classes, such as selective serotonin reuptake inhibitors (SSRIs).Vortioxetine may be more effective than placebo across the three efficacy outcomes: response (Mantel-Haenszel RR 1.35, 95% CI 1.22 to 1.49; 14 studies, 6220 participants), remission (RR 1.32, 95% CI 1.15 to 1.53; 14 studies, 6220 participants) and depressive symptoms measured using the Montgomery-Åsberg Depression Scale (MADRS) (score range: 0 to 34; higher score means worse outcome: MD -2.94, 95% CI -4.07 to -1.80; 14 studies, 5566 participants). The quality of the evidence was low for response and remission and very low for depressive symptoms. We found no evidence of a difference in total dropout rates (RR 1.05, 95% CI 0.93 to 1.19; 14 studies, 6220 participants). More participants discontinued vortioxetine than placebo because of adverse effects (RR 1.41, 95% CI 1.09 to 1.81; 14 studies, 6220 participants) but fewer discontinued due to inefficacy (RR 0.56, 95% CI 0.34 to 0.90, P = 0.02; 14 studies, 6220 participants). The quality of the evidence for dropouts was moderate.The subgroup and sensitivity analyses did not reveal factors that significantly influenced the results.In comparison with other antidepressants, very low-quality evidence from eight studies showed no clinically significant difference between vortioxetine and SNRIs as a class for response (RR 0.91, 95% CI 0.82 to 1.00; 3159 participants) or remission (RR 0.89, 95% CI 0.77 to 1.03; 3155 participants). There was a small difference favouring SNRIs for depressive symptom scores on the MADRS (MD 1.52, 95% CI 0.50 to 2.53; 8 studies, 2807 participants). Very low quality evidence from eight studies (3159 participants) showed no significant differences between vortioxetine and the SNRIs as a class for total dropout rates (RR 0.89, 95% CI 0.73 to 1.08), dropouts due to adverse events (RR 0.74, 95% CI 0.51 to 1.08) and dropouts due to inefficacy (RR 1.52, 95% CI 0.70 to 3.30).Against individual antidepressants, analyses suggested that vortioxetine may be less effective than duloxetine in terms of response rates (RR 0.86, 95% CI 0.79 to 0.94; 6 studies, 2392 participants) and depressive symptoms scores on the MADRS scale (MD 1.99, 95% CI 1.15 to 2.83; 6 studies; 2106 participants). Against venlafaxine, meta-analysis of two studies found no statistically significant differences (response: RR 1.03, 95% CI 0.85 to 1.25; 767 participants; depressive symptom scores: MD 0.02, 95% CI -2.49 to 2.54; 701 participants). In terms of number of participants reporting at least one adverse effect (tolerability), vortioxetine was better than the SNRIs as a class (RR 0.90, 95% CI 0.86 to 0.94; 8 studies, 3134 participants) and duloxetine (RR 0.89, 95% CI 0.84 to 0.95; 6 studies; 2376 participants). However, the sensitivity analysis casts some doubts on this result, as only two studies used comparable dosing.We judged none of the studies to have a high risk of bias for any domain, but we rated all studies to have an unclear risk of bias of selective reporting and other biases. AUTHORS' CONCLUSIONS: The place of vortioxetine in the treatment of acute depression is unclear. Our analyses showed vortioxetine may be more effective than placebo in terms of response, remission and depressive symptoms, but the clinical relevance of these effects is uncertain. Furthermore, the quality of evidence to support these findings was generally low. In comparison to SNRIs, we found no advantage for vortioxetine. Vortioxetine was less effective than duloxetine, but fewer people reported adverse effects when treated with vortioxetine compared to duloxetine. However, these findings are uncertain and not well supported by evidence. A major limitation of the current evidence is the lack of comparisons with the SSRIs, which are usually recommended as first-line treatments for acute depression. Studies with direct comparisons to SSRIs are needed to address this gap and may be supplemented by network meta-analyses to define the role of vortioxetine in the treatment of depression.

Antidepressants and benzodiazepines for panic disorder in adults.

BACKGROUND: A panic attack is a discrete period of fear or anxiety that has a rapid onset, reaches a peak within 10 minutes and in which at least four of 13 characteristic symptoms are experienced, including racing heart, chest pain, sweating, shaking, dizziness, flushing, stomach churning, faintness and breathlessness. Panic disorder is common in the general population with a lifetime prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions. Amongst pharmacological agents, antidepressants and benzodiazepines are the mainstay of treatment for panic disorder. Different classes of antidepressants have been compared; and the British Association for Psychopharmacology, and National Institute for Health and Care Excellence (NICE) consider antidepressants (mainly selective serotonin reuptake inhibitors (SSRIs)) as the first-line treatment for panic disorder, due to their more favourable adverse effect profile over monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). In addition to antidepressants, benzodiazepines are widely prescribed for the treatment of panic disorder. OBJECTIVES: To assess the evidence for the effects of antidepressants and benzodiazepines for panic disorder in adults. SEARCH METHODS: The Specialised Register of the Cochrane Common Mental Disorders Group (CCMDCTR) to 11 September 2015. This register includes relevant randomised controlled trials from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950-), Embase (1974-) and PsycINFO (1967-). Reference lists of relevant papers and previous systematic reviews were handsearched. We contacted experts in this field for supplemental data. SELECTION CRITERIA: All double-blind randomised controlled trials allocating adult patients with panic disorder to antidepressants or benzodiazepines versus any other active treatment with antidepressants or benzodiazepines. DATA COLLECTION AND ANALYSIS: Two review authors independently checked eligibility and extracted data using a standard form. Data were entered in RevMan 5.3 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details, settings and outcome measures in terms of efficacy, acceptability and tolerability. MAIN RESULTS: Thirty-five studies, including 6785 participants overall (of which 5365 in the arms of interest (antidepressant and benzodiazepines as monotherapy)) were included in this review; however, since studies addressed many different comparisons, only a few trials provided data for primary outcomes. We found low-quality evidence suggesting no difference between antidepressants and benzodiazepines in terms of response rate (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.67 to 1.47; participants = 215; studies = 2). Very low-quality evidence suggested a benefit for benzodiazepines compared to antidepressants in terms of dropouts due to any cause, even if confidence interval (CI) ranges from almost no difference to benefit with benzodiazepines (RR 1.64, 95% CI 1.03 to 2.63; participants = 1449; studies = 7). We found some evidence suggesting that serotonin reuptake inhibitors (SSRIs) are better tolerated than TCAs (when looking at the number of patients experiencing adverse effects). We failed to find clinically significant differences between individual benzodiazepines. The majority of studies did not report details on random sequence generation and allocation concealment; similarly, no details were provided about strategies to ensure blinding. The study protocol was not available for almost all studies so it is difficult to make a judgment on the possibility of outcome reporting bias. Information on adverse effects was very limited. AUTHORS' CONCLUSIONS: The identified studies are not sufficient to comprehensively address the objectives of the present review. The majority of studies enrolled a small number of participants and did not provide data for all the outcomes specified in the protocol. For these reasons most of the analyses were underpowered and this limits the overall completeness of evidence. In general, based on the results of the current review, the possible role of antidepressants and benzodiazepines should be assessed by the clinician on an individual basis. The choice of which antidepressant and/or benzodiazepine is prescribed can not be made on the basis of this review only, and should be based on evidence of antidepressants and benzodiazepines efficacy and tolerability, including data from placebo-controlled studies, as a whole. Data on long-term tolerability issues associated with antidepressants and benzodiazepines exposure should also be carefully considered.The present review highlights the need for further higher-quality studies comparing antidepressants with benzodiazepines, which should be conducted with high-methodological standards and including pragmatic outcome measures to provide clinicians with useful and practical data. Data from the present review will be included in a network meta-analysis of psychopharmacological treatment in panic disorder, which will hopefully provide further useful information on this issue.

Azapirones versus placebo for panic disorder in adults.

BACKGROUND: Panic disorder is common in the general population. It is often associated with other psychiatric disorders, such as drug dependence, major depression, bipolar disorder, social phobia, specific phobia and generalised anxiety disorder. Azapirones are a class of drugs used as anxiolytics. They are associated with less drowsiness, psychomotor impairment, alcohol potentiation and potential for addiction or abuse than benzodiazepines. However, azapirones are not widely used in the treatment of panic disorder and evidence for their efficacy is unclear. It is important to find out if azapirones are effective and acceptable in the treatment of panic disorder. OBJECTIVES: To assess the effects of azapirones on panic disorder in adults, specifically:1. to determine the efficacy of azapirones in alleviating symptoms of panic disorder, with or without agoraphobia, in comparison with placebo;2. to review the acceptability of azapirones in panic disorder, with or without agoraphobia, in comparison with placebo; and3. to investigate adverse effects of azapirones in panic disorder with or without agoraphobia, including general prevalence of adverse effects, compared with placebo. SEARCH METHODS: We searched the Cochrane Depression Anxiety and Neurosis Group Trials Specialised Register (CCDANCTR, search date: 10th January 2014), which includes relevant randomised controlled trials from The Cochrane Library (all years), MEDLINE (1950-), EMBASE (1974-), and PsycINFO (1967-). SELECTION CRITERIA: Randomised controlled trials that compared azapirones with placebo for panic disorder in adults. DATA COLLECTION AND ANALYSIS: Three review authors independently identified studies, assessed trial quality and extracted data. We contacted study authors for additional information. MAIN RESULTS: Three studies involving 170 participants compared the azapirone buspirone with placebo. No study provided enough usable information on our primary efficacy outcome (response). For our primary acceptability outcome, moderate-quality evidence indicated that azapirones had lower acceptability than placebo: risk ratio (RR) for dropouts for any reason 2.13 (95% confidence interval (CI) 1.11 to 4.07; 3 studies, 170 participants. Evidence for secondary efficacy outcomes were of low quality. Results on efficacy between azapirone and placebo in terms of agoraphobia (standardised mean difference (SMD) -0.01, 95% CI -0.56 to 0.53; 1 study, 52 participants), general anxiety (mean difference (MD) -2.20, 95% CI -5.45 to 1.06; 2 studies, 115 participants) and depression (MD -1.80, 95% CI -5.60 to 2.00; 1 study, 52 participants) were uncertain. None of the studies provided information for the assessment of allocation concealment or sequence generation. Conflicts of interest were not explicitly expressed. The risk of attrition bias was rated high for all three studies. Information on adverse effects other than dropouts for any reason was insufficient to include in the analyses. AUTHORS' CONCLUSIONS: The efficacy of azapirones is uncertain due to the lack of meta-analysable data for the primary outcome and low-quality evidence for secondary efficacy outcomes. A small amount of moderate-quality evidence suggested that the acceptability of azapirones for panic disorder was lower than for placebo. However, only trials of one azapirone (namely buspirone) were included in this review; this, combined with the small sample size, limits our conclusions. If further research is to be conducted, studies with larger sample sizes, with different azapirones and with less risk of bias are necessary to draw firm conclusions regarding azapirones for panic disorder.

Agomelatine versus other antidepressive agents for major depression.

BACKGROUND: Major depressive disorder (MDD), or depression, is a syndrome characterised by a number of behavioural, cognitive and emotional features. It is most commonly associated with a sad or depressed mood, a reduced capacity to feel pleasure, feelings of hopelessness, loss of energy, altered sleep patterns, weight fluctuations, difficulty in concentrating and suicidal ideation. There is a need for more effective and better tolerated antidepressants to combat this condition. Agomelatine was recently added to the list of available antidepressant drugs; it is a novel antidepressant that works on melatonergic (MT1 and MT2), 5-HT 2B and 5-HT2C receptors. Because the mechanism of action is claimed to be novel, it may provide a useful, alternative pharmacological strategy to existing antidepressant drugs. OBJECTIVES: The objective of this review was 1) to determine the efficacy of agomelatine in alleviating acute symptoms of major depressive disorder in comparison with other antidepressants, 2) to review the acceptability of agomelatine in comparison with other antidepressant drugs, and, 3) to investigate the adverse effects of agomelatine, including the general prevalence of side effects in adults. SEARCH METHODS: We searched the Cochrane Collaboration's Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) to 31 July 2013. The CCDANCTR includes relevant randomised controlled trials from the following bibliographic databases: CENTRAL (the Cochrane Central Register of Controlled Trials) (all years), EMBASE (1974 onwards), MEDLINE (1950 onwards) and PsycINFO (1967 onwards). We checked reference lists of relevant studies together with reviews and regulatory agency reports. No restrictions on date, language or publication status were applied to the search. Servier Laboratories (developers of agomelatine) and other experts in the field were contacted for supplemental data. SELECTION CRITERIA: Randomised controlled trials allocating adult participants with major depression to agomelatine versus any other antidepressive agent. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and a double-entry procedure was employed. Information extracted included study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy, acceptability and tolerability. MAIN RESULTS: A total of 13 studies (4495 participants) were included in this review. Agomelatine was compared to selective serotonin reuptake inhibitors (SSRIs), namely paroxetine, fluoxetine, sertraline, escitalopram, and to the serotonin-norepinephrine reuptake inhibitor (SNRI), venlafaxine. Participants were followed up for six to 12 weeks. Agomelatine did not show any advantage or disadvantage over the other antidepressants for our primary outcome, response to treatment (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.95 to 1.08, P value 0.75 compared to SSRIs, and RR 1.06; 95% CI 0.98 to 1.16, P value 0.16 compared to venlafaxine). Also, agomelatine showed no advantage or disadvantage over other antidepressants for remission (RR 0.83; 95% CI 0.68 to 1.01, P value 0.07 compared to SSRIs, and RR 1.08; 95% CI 0.94 to 1.24, P value 0.73 compared to venlafaxine). Overall, agomelatine appeared to be better tolerated than venlafaxine in terms of lower rates of drop outs (RR 0.40; 95% CI 0.24 to 0.67, P value 0.0005), and showed the same level of tolerability as SSRIs (RR 0.95; 95% CI 0.83 to 1.09, P value 0.44). Agomelatine induced a lower rate of dizziness than venlafaxine (RR 0.19, 95% CI 0.06 to 0.64, P value 0.007).With regard to the quality of the body of evidence, there was a moderate risk of bias for all outcomes, due to the number of included unpublished studies. There was some heterogeneity, particularly between published and unpublished studies. The included studies were conducted in inpatient and outpatient settings, thus limiting the generalisability of the results to primary care settings. With regard to precision, the efficacy outcomes were precise, but the tolerability outcomes were mostly imprecise. Publication bias was variable and depended on the outcome of the trial. Our review included unpublished studies, and we think that this reduced the impact of publication bias. The overall methodological quality of the studies was not very good. Almost all of the studies were sponsored by the pharmaceutical company that manufactures agomelatine (Servier), and some of these were unpublished. Attempts to contact the pharmaceutical company Servier for additional information on all unpublished studies were unsuccessful. AUTHORS' CONCLUSIONS: Agomelatine did not seem to provide a significant advantage in efficacy over other antidepressive agents for the acute-phase treatment of major depression. Agomelatine was better tolerated than paroxetine and venlafaxine in terms of overall side effects, and fewer participants treated with agomelatine dropped out of the trials due to side effects compared to sertraline and venlafaxine, but data were limited because the number of included studies was small. We found evidence that compared agomelatine with only a small number of other active antidepressive agents, and there were only a few trials for each comparison, which limits the generalisability of the results. Moreover, the overall methodological quality of the studies was low, and, therefore, no firm conclusions can be drawn concerning the efficacy and tolerability of agomelatine.

Agomelatine efficacy and acceptability revisited: systematic review and meta-analysis of published and unpublished randomised trials.

BACKGROUND: Agomelatine is a novel antidepressant drug with narrative, non-systematic reviews making claims of efficacy. AIMS: The present study systematically reviewed published and unpublished evidence of the acute and long-term efficacy and acceptability of agomelatine compared with placebo in the treatment of major depression. METHOD: Randomised controlled trials comparing agomelatine with placebo in the treatment of unipolar major depression were systematically reviewed. Primary outcomes were (a) Hamilton Rating Scale for Depression (HRSD) score at the end of treatment (short-term studies) and (b) number of relapses (long-term studies). RESULTS: Meta-analyses included 10 acute-phase and 3 relapse prevention studies. Seven of the included studies were unpublished. Acute treatment with agomelatine was associated with a statistically significant superiority over placebo of -1.51 HRSD points (99% CI -2.29 to -0.73, nine studies). Data extracted from three relapse prevention studies failed to show significant effects of agomelatine over placebo (relative risk 0.78, 99% CI 0.41-1.48). Secondary efficacy analyses showed a significant advantage of agomelatine over placebo in terms of response (with no effect for remission). None of the negative trials were published and conflicting results between published and unpublished studies were observed. CONCLUSIONS: We found evidence suggesting that a clinically important difference between agomelatine and placebo in patients with unipolar major depression is unlikely. There was evidence of substantial publication bias.