S-adenosyl methionine (SAMe) for depression in adults.

BACKGROUND: Depression is a recurrent illness with high rates of chronicity, treatment-resistance and significant economic impact. There is evidence in the literature that S-adenosyl methionine (SAMe), a naturally occurring compound in the human body, has antidepressant efficacy. This product may be an important addition to the armamentarium of antidepressant agents. OBJECTIVES: To assess the effects of SAMe in comparison with placebo or antidepressants for the treatment of depression in adults. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Group's Specialised Register (CCMDCTR Studies and Reference Register), MEDLINE, EMBASE, PsycINFO, international trial registers ClinicalTrials.gov and the World Health Organization trials portal (ICTRP). We checked reference lists, performed handsearching and contacted experts in the field. The CCMDCTR literature search was last updated on 5 February 2016. SELECTION CRITERIA: Randomised controlled trials comparing SAMe with placebo or antidepressants in adults with a diagnosis of major depression. DATA COLLECTION AND ANALYSIS: Two authors independently performed extraction of data and assessment of risk of bias. We contacted trialists of included studies for additional information. MAIN RESULTS: This systematic review included eight trials comparing SAMe with either placebo, imipramine, desipramine or escitalopram. We accepted trials that used SAMe as monotherapy or as add-on therapy to selective serotonin reuptake inhibitors (SSRIs), and we accepted both oral and parenteral administration. The review involved 934 adults, of both sexes, from inpatient and outpatient settings.The trials were at low risk of reporting bias. We judged the risk of selection, performance, detection and attrition bias as unclear or low, and one study was at high risk of attrition bias.There was no strong evidence of a difference in terms of change in depressive symptoms from baseline to end of treatment between SAMe and placebo as monotherapy (standardised mean difference (SMD) -0.54, 95% confidence interval (CI) -1.54 to 0.46; P = 0.29; 142 participants; 2 studies; very low quality evidence). There was also no strong evidence of a difference in terms of drop-out rates due to any reason between SAMe and placebo, when used as monotherapy (risk ratio (RR) 0.88, 95% CI 0.61 to 1.29; P = 0.52; 142 participants; 2 studies; low quality evidence).Low quality evidence showed that the change in depressive symptoms from baseline to end of treatment was similar between SAMe and imipramine, both as monotherapy (SMD -0.04, 95% CI -0.34 to 0.27; P = 0.82; 619 participants; 4 studies). There was also no strong evidence of a difference between SAMe and a tricyclic antidepressant in terms of drop-outs due to any reason (RR 0.61, 95% CI 0.28 to 1.31; P = 0.2; 78 participants; 3 studies; very low quality evidence).There was little evidence of a difference in terms of change in depressive symptoms from baseline to end of treatment between SAMe and escitalopram, both as monotherapy (MD 0.12, 95% CI -2.75 to 2.99; P = 0.93; 129 participants; 1 study; low quality evidence). There was no strong evidence of a difference between SAMe and escitalopram in terms of drop-outs due to any reason (RR 0.81, 95% CI 0.57 to 1.16; P = 0.26; 129 participants; 1 study; low quality evidence).There was low quality evidence that SAMe is superior to placebo as add-on to SSRIs in terms of change in depressive symptoms from baseline to end of treatment (MD -3.90, 95% CI -6.93 to -0.87; P = 0.01; 73 participants; 1 study). There was no strong evidence of a difference between SAMe and placebo as adjunctive therapy to an SSRI in terms of drop-outs due to any reason (RR 0.70, 95% CI 0.31 to 1.56; P = 0.38; 73 participants; 1 study; very low quality evidence).For all comparisons, secondary outcome measures of response and remission rates were consistent with these primary outcome measures.With regard to all extractable measures of the acceptability of SAMe, the quality of the evidence was low to very low. SAMe was not different from placebo and established antidepressants. The exception was that compared to imipramine, fewer participants experienced troublesome adverse effects when treated with parenteral SAMe.The specific adverse effects were not detailed in most of the included studies. There were two reports of mania/hypomania recorded for 441 participants in the SAMe arm. AUTHORS' CONCLUSIONS: Given the absence of high quality evidence and the inability to draw firm conclusions based on that evidence, the use of SAMe for the treatment of depression in adults should be investigated further. Future trials should be in the form of large randomised controlled clinical trials of high methodological quality, with particular attention given to randomisation, allocation concealment, blinding and the handling of missing data. Comparator antidepressants from all classes should be used. Adverse events should be detailed for each participant, bearing in mind that induction of mania is of particular interest.

Pharmacotherapy for chronic cognitive impairment in traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of chronic disability. Worldwide, it is the leading cause of disability in the under 40s, resulting in severe disability in some 150 to 200 million people per annum. In addition to mood and behavioural problems, cognition-particularly memory, attention and executive function-are commonly impaired by TBI. Cognitive problems following TBI are one of the most important factors in determining people's subjective well-being and their quality of life. Drugs are widely used in an attempt to improve cognitive functions. Whilst cholinergic agents in TBI have been reviewed, there has not yet been a systematic review or meta-analysis of the effect on chronic cognitive problems of all centrally acting pharmacological agents. OBJECTIVES: To assess the effects of centrally acting pharmacological agents for treatment of chronic cognitive impairment subsequent to traumatic brain injury in adults. SEARCH METHODS: We searched ALOIS-the Cochrane Dementia and Cognitive Improvement Group's Specialised Register-on 16 November 2013, 23 February 2013, 20 January 2014, and 30 December 2014 using the terms: traumatic OR TBI OR "brain injury" OR "brain injuries" OR TBIs OR "axonal injury" OR "axonal injuries". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. Supplementary searches were also performed in MEDLINE, EMBASE, PsycINFO, The Cochrane Library, CINAHL, LILACs, ClinicalTrials.gov, the World Health Organization (WHO) Portal (ICTRP) and Web of Science with conference proceedings. SELECTION CRITERIA: We included randomised controlled trials (RCTs) assessing the effectiveness of any one centrally acting pharmacological agent that affects one or more of the main neurotransmitter systems in people with chronic traumatic brain injury; and there had to be a minimum of 12 months between the injury and entry into the trial. DATA COLLECTION AND ANALYSIS: Two review authors examined titles and abstracts of citations obtained from the search. Relevant articles were retrieved for further assessment. A bibliographic search of relevant papers was conducted. We extracted data using a standardised tool, which included data on the incidence of adverse effects. Where necessary we requested additional unpublished data from study authors. Risk of bias was assessed by a single author. MAIN RESULTS: Only four studies met the criteria for inclusion, with a total of 274 participants. Four pharmacological agents were investigated: modafinil (51 participants); (-)-OSU6162, a monoamine stabiliser (12 participants of which six had a TBI); atomoxetine (60 participants); and rivastigmine (157 participants). A meta-analysis could not be performed due to the small number and heterogeneity of the studies.All studies examined cognitive performance, with the majority of the psychometric sub-tests showing no difference between treatment and placebo (n = 274, very low quality evidence). For (-)-OSU6162 modest superiority over placebo was demonstrated on three measures, but markedly inferior performance on another. Rivastigmine was better than placebo on one primary measure, and a single cognitive outcome in a secondary analysis of a subgroup with more severe memory impairment at baseline. The study of modafinil assessed clinical global improvement (n = 51, low quality evidence), and did not find any difference between treatment and placebo. Safety, as measured by adverse events, was reported by all studies (n = 274, very low quality evidence), with significantly more nausea reported by participants who received rivastigmine compared to placebo. There were no other differences in safety between treatment and placebo. No studies reported any deaths. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether pharmacological treatment is effective in chronic cognitive impairment in TBI. Whilst there is a positive finding for rivastigmine on one primary measure, all other primary measures were not better than placebo. The positive findings for (-)-OSU6162 are interpreted cautiously as the study was small (n = 6). For modafinil and atomoxetine no positive effects were found. All four drugs appear to be relatively well tolerated, although evidence is sparse.

Childhood trauma in bipolar disorder.

OBJECTIVE: There has been little investigation of early trauma in bipolar disorder despite evidence that stress impacts on the course of this illness. We aimed to compare the rates of childhood trauma in adults with bipolar disorder to a healthy control group, and to investigate the impact of childhood trauma on the clinical course of bipolar disorder. METHODS: Retrospective assessment of childhood trauma was conducted using the Childhood Trauma Questionnaire (CTQ) in 60 outpatients with bipolar disorder being treated for a depressive episode and 55 control participants across two centres in north-east England and New Zealand. RESULTS: Significantly higher rates of childhood trauma were observed in patients with bipolar I and bipolar II disorder compared to controls. Logistic regression, controlling for age and sex, identified emotional neglect to be the only significant CTQ subscale associated with a diagnosis of bipolar disorder. Childhood history of sexual abuse was not a significant predictor. Associations with clinical severity or course were less clear. CONCLUSIONS: Childhood emotional neglect appears to be significantly associated with bipolar disorder. Limitations include the relatively small sample size, which potentially increases the risk of type II errors. Replication of this study is required, with further investigation into the neurobiological consequences of childhood trauma, particularly emotional neglect.

Mental health law in Peru: work in progress.

Mental health law in Peru is developing. The Peruvian Constitution enshrines important human rights principles in relation to people with mental health problems but the enactment of such principles into national legislation is very patchy. This means that people with mental health problems, especially those admitted to hospital, may not receive optimum care and may be at risk of having their human rights breached. In this article we consider how far the current national legislation meets these constitutional rights and what the legislation that is in development may ultimately achieve.

Adverse events and deterioration reported by participants in the PACE trial of therapies for chronic fatigue syndrome.

OBJECTIVE: Adverse events (AEs) are health related events, reported by participants in clinical trials. We describe AEs in the PACE trial of treatments for chronic fatigue syndrome (CFS) and baseline characteristics associated with them. METHODS: AEs were recorded on three occasions over one year in 641 participants. We compared the numbers and nature of AEs between treatment arms of specialist medical care (SMC) alone, or SMC supplemented by adaptive pacing therapy (APT), cognitive behaviour therapy (CBT) or graded exercise therapy (GET). We examined associations with baseline measures by binary logistic regression analyses, and compared the proportions of participants who deteriorated by clinically important amounts. RESULTS: Serious adverse events and reactions were infrequent. Non-serious adverse events were common; the median (quartiles) number was 4 (2, 8) per participant, with no significant differences between treatments (P=.47). A greater number of NSAEs were associated with recruitment centre, and baseline physical symptom count, body mass index, and depressive disorder. Physical function deteriorated in 39 (25%) participants after APT, 15 (9%) after CBT, 18 (11%) after GET, and 28 (18%) after SMC (P<.001), with no significant differences in worsening fatigue. CONCLUSIONS: The numbers of adverse events did not differ significantly between trial treatments, but physical deterioration occurred most often after APT. The reporting of non-serious adverse events may reflect the nature of the illness rather than the effect of treatments. Differences between centres suggest that both standardisation of ascertainment methods and training are important when collecting adverse event data.