Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis.

BACKGROUND: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment. METHODS: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005. FINDINGS: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory). INTERPRETATION: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme.

Adverse cardiovascular events and mortality in men during testosterone treatment: an individual patient and aggregate data meta-analysis.

Background: Testosterone is the standard treatment for male hypogonadism, but there is uncertainty about its cardiovascular safety due to inconsistent findings. We aimed to provide the most extensive individual participant dataset (IPD) of testosterone trials available, to analyse subtypes of all cardiovascular events observed during treatment, and to investigate the effect of incorporating data from trials that did not provide IPD. Methods: We did a systematic review and meta-analysis of randomised controlled trials including IPD. We searched MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Epub Ahead of Print, Embase, Science Citation Index, the Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effects for literature from 1992 onwards (date of search, Aug 27, 2018). The following inclusion criteria were applied: (1) men aged 18 years and older with a screening testosterone concentration of 12 nmol/L (350 ng/dL) or less; (2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; (3) a comparator of placebo treatment; and (4) studies assessing the pre-specified primary or secondary outcomes of interest. Details of study design, interventions, participants, and outcome measures were extracted from published articles and anonymised IPD was requested from investigators of all identified trials. Primary outcomes were mortality, cardiovascular, and cerebrovascular events at any time during follow-up. The risk of bias was assessed using the Cochrane Risk of Bias tool. We did a one-stage meta-analysis using IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD. The study is registered with PROSPERO, CRD42018111005. Findings: 9871 citations were identified through database searches and after exclusion of duplicates and of irrelevant citations, 225 study reports were retrieved for full-text screening. 116 studies were subsequently excluded for not meeting the inclusion criteria in terms of study design and characteristics of intervention, and 35 primary studies (5601 participants, mean age 65 years, [SD 11]) reported in 109 peer-reviewed publications were deemed suitable for inclusion. Of these, 17 studies (49%) provided IPD (3431 participants, mean duration 9·5 months) from nine different countries while 18 did not provide IPD data. Risk of bias was judged to be low in most IPD studies (71%). Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17-1·24]; p=0·13). Cardiovascular risk was similar during testosterone treatment (120 [7·5%] of 1601 events) and placebo treatment (110 [7·2%] of 1519 events; OR 1·07 [95% CI 0·81-1·42]; p=0·62). Frequently occurring cardiovascular events included arrhythmia (52 of 166 vs 47 of 176), coronary heart disease (33 of 166 vs 33 of 176), heart failure (22 of 166 vs 28 of 176), and myocardial infarction (10 of 166 vs 16 of 176). Overall, patient age (interaction 0·97 [99% CI 0·92-1·03]; p=0·17), baseline testosterone (interaction 0·97 [0·82-1·15]; p=0·69), smoking status (interaction 1·68 [0·41-6·88]; p=0.35), or diabetes status (interaction 2·08 [0·89-4·82; p=0·025) were not associated with cardiovascular risk. Interpretation: We found no evidence that testosterone increased short-term to medium-term cardiovascular risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone. Funding: National Institute for Health Research Health Technology Assessment Programme.

The incidence and economic impact of aggression in closed long-stay psychiatric wards.

OBJECTIVE: Aggressive behaviour is highly prevalent in long-term psychiatric inpatient care. We aimed to estimate the overall incidence of aggression, the time staff took to handle aggression incidents, and the weighted average financial costs thereof. METHODS: A random sampling procedure was conducted at long-term psychiatric inpatient care facilities. Nurses were asked to recall all incidents (i.e., verbal, physical towards objects, self, or others) of their shift. For the time spent on each type of incident, staff were monitored in real-time. Estimated costs were calculated by the time spent multiplied by hourly wages in addition to material-related costs. RESULTS: Incidence rates were 90 incidents per patient year. The average time spent per incident was 125 min but differed for each type of incident. Almost 80% of this time was consumed by nursing staff. The average cost per aggression incident was €78; extrapolated per patient year, the total costs were approximately €7000. CONCLUSIONS: The current study found a high rate of aggression incidents in closed long-stay psychiatric wards. Reports of aggression on these types of wards are scarce. Nevertheless, aggression seems to have a severe impact on invested time and related costs, which suggests a need for aggression-prevention and de-escalating programs.Key pointsAggression incidents are highly prevalent and are accompanied by high costs.The effect of aggression incidents on the workload for staff members is high, especially for nursing staff.Studies across countries on the incidence and the costs of aggression among psychiatric inpatients are needed to help model the effects of (new) strategies for aggression reduction.

Assessment of Factors Associated With Long-term Posttraumatic Stress Symptoms Among 56 388 First Responders After the 2011 Great East Japan Earthquake.

Importance: First responders are at risk for developing symptoms of posttraumatic stress disorder (PTSD). Little is known about the risk factors for developing PTSD during a years-long period after complex mass disasters. Objective: To explore the long-term course of PTSD symptoms and to identify risk factors and their relative association with PTSD among first responders dispatched to the 2011 Japanese earthquake, tsunami, and nuclear disaster. Design, Setting, and Participants: This 6-year, large, prospective cohort study was part of a continuous longitudinal study of Japan Ground Self-Defense Force first responders. The data were collected at 1, 6, 12, 24, 36, 48, 60, and 72 months after mission completion from 2011 to 2017. Of approximately 70 000 eligible participants, 56 388 were enrolled in this study. Data were analyzed from 2017 to 2020. Exposures: Stress exposures owing to personal or professional disaster experience (eg, duties with body recovery or radiation exposure risk) and working conditions (eg, deployment length, postdeployment overtime work). Main Outcomes and Measures: The Impact of Event Scale-Revised score assessed PTSD symptoms; scores of at least 25 were defined as probable PTSD. Cox proportional hazards regression models assessed the risk factors for incidence of probable PTSD. Results: Among the 56 388 participants, 97.1% were men, and the median age at enrollment was 34 (range, 18-63) years. A probable PTSD rate was 2.7% at 1 month and showed a downward trend in the first year and a subsequent plateau. The cumulative incidence of probable PTSD was 6.75%. The severity of PTSD symptoms demonstrated a high degree of rank-order stability over time. Rather than professional disaster experience, sociodemographic factors and working conditions were independently associated with the incidence of probable PTSD: personal experience of the disaster (hazard ratio [HR], 1.96; 95% CI, 1.72-2.24), deployment length of at least 3 months (HR vs <1 month, 1.75; 95% CI, 1.52-2.02), increased age (HR for ≥46 vs ≤25 years, 2.28; 95% CI, 1.79-2.92), and postdeployment overtime work of at least 3 months (HR vs little to none, 1.61; 95% CI, 1.39-1.87). Conclusions and Relevance: Given these findings, in the future, first responders' PTSD symptoms might be mitigated by shortening deployment length, avoiding postdeployment overtime work, and paying special attention to the needs of personnel with personal experience of the disaster or older age. Efforts to alleviate responders' initial symptoms will be required.

Association of Use of Oral Contraceptives With Depressive Symptoms Among Adolescents and Young Women.

Importance: Oral contraceptives have been associated with an increased risk of subsequent clinical depression in adolescents. However, the association of oral contraceptive use with concurrent depressive symptoms remains unclear. Objectives: To investigate the association between oral contraceptive use and depressive symptoms and to examine whether this association is affected by age and which specific symptoms are associated with oral contraceptive use. Design, Setting, and Participants: Data from the third to sixth wave of the prospective cohort study Tracking Adolescents' Individual Lives Survey (TRAILS), conducted from September 1, 2005, to December 31, 2016, among females aged 16 to 25 years who had filled out at least 1 and up to 4 assessments of oral contraceptive use, were used. Data analysis was performed from March 1, 2017, to May 31, 2019. Exposure: Oral contraceptive use at 16, 19, 22, and 25 years of age. Main Outcomes and Measures: Depressive symptoms were assessed by the DSM-IV-oriented affective problems scale of the Youth (aged 16 years) and Adult Self-Report (aged 19, 22, and 25 years). Results: Data from a total of 1010 girls (743-903 girls, depending on the wave) were analyzed (mean [SD] age at the first assessment of oral contraceptive use, 16.3 [0.7]; (mean [SD] age at the final assessment of oral contraceptive use, 25.6 [0.6] years). Oral contraceptive users particularly differed from nonusers at age 16 years, with nonusers having a higher mean (SD) socioeconomic status (0.17 [0.78] vs -0.15 [0.71]) and more often being virgins (424 of 533 [79.5%] vs 74 of 303 [24.4%]). Although all users combined (mean [SD] ages, 16.3 [0.7] to 25.6 [0.6] years) did not show higher depressive symptom scores compared with nonusers, adolescent users (mean [SD] age, 16.5 [0.7] years) reported higher depressive symptom scores compared with their nonusing counterparts (mean [SD] age, 16.1 [0.6] years) (mean [SD] score, 0.40 [0.30] vs 0.33 [0.30]), which persisted after adjustment for age, socioeconomic status and ethnicity (ß coefficient for interaction with age, -0.021; 95% CI, -0.038 to -0.005; P = .0096). Adolescent contraceptive users particularly reported more crying (odds ratio, 1.89; 95% CI, 1.38-2.58; P < .001), hypersomnia (odds ratio, 1.68; 95% CI, 1.14-2.48; P = .006), and more eating problems (odds ratio, 1.54; 95% CI, 1.13-2.10; P = .009) than nonusers. Conclusions and Relevance: Although oral contraceptive use showed no association with depressive symptoms when all age groups were combined, 16-year-old girls reported higher depressive symptom scores when using oral contraceptives. Monitoring depressive symptoms in adolescents who are using oral contraceptives is important, as the use of oral contraceptives may affect their quality of life and put them at risk for nonadherence.

Prognostic significance of geriatric assessment in combination with laboratory parameters in elderly patients with aggressive non-Hodgkin lymphoma.

The age-adjusted International Prognostic Index (IPI) is an important prognostic factor for patients with non-Hodgkin lymphoma (NHL). We investigated whether a geriatric assessment (GA) is of additional prognostic value in NHL. In this prospective cohort study of 44 patients aged 70 years or older with NHL receiving rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), a GA was administered before the start of chemotherapy. GA was composed of the Mini Nutritional Assessment (MNA), Groningen Frailty Indicator (GFI), Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), Mini Mental State Examination (MMSE) and levels of albumin, creatinine, lactate dehydrogenase (LDH) and hemoglobin. Multivariate analyses were performed using logistic regression and the Cox regression model. After adjustment for sex, age, comorbidity and univariate laboratory values with p ≤ 0.1, abnormal MNA and GFI scores and low hemoglobin level were associated with not being able to complete the intended chemotherapy: odds ratio (OR) 8.29 (95% confidence interval [CI]: 1.24-55.6; p = 0.03), 9.17 (95% CI: 1.51-55.8; p = 0.02) and 5.41 (95% CI: 0.99-29.8; p = 0.05), respectively. Adjusted for sex, age, comorbidity, age-adjusted IPI and univariate laboratory values with p ≤ 0.1, frailty by GFI and low hemoglobin were associated with worse survival, with a hazard ratio (HR) of mortality of 2.55 (95% CI: 1.07-6.10; p = 0.04) and 4.90 (95% CI: 1.76-13.7; p = 0.002), respectively. We conclude that (risk of) malnutrition, measured with the MNA, frailty, measured with the GFI, and low hemoglobin level had additional predictive value for early treatment withdrawal, and GFI and hemoglobin were, independent of the age-adjusted IPI, predictive for an increased mortality risk.

Exploration of functional health, mental well-being and cross-sex hormone use in a sample of Thai male-to-female transgendered persons (kathoeys).

Transgender people sometimes use cross-sex hormones without medical supervision. The use of cross-sex hormones, as well as the functional health and mental well-being, among male-to-female transgendered people ('kathoeys') in Chiang Mai, Thailand, was studied. Sixty kathoeys were interviewed regarding their use of cross-sex hormones and their family relationships. Individuals also completed the Life Orientation Test Revised (LOT-R) to assess dispositional optimism, the Social Functioning Questionnaire (SFQ) and the Short Form Health Survey 36 (SF-36). Three categories were established as follows: those who never cross-dress, those who sometimes cross-dress and those who always cross-dress in public. Of the 60 subjects, 44 had used hormones for prolonged periods (9.7±6.1 years). Their use was related to the permanence of cross-dressing but unrelated to functional health and mental well-being. Fifty percent of subjects had overdosed on commonly used oral contraceptives. Three people used injectable oestrogen in a higher-than-recommended dose. Self-acceptance was high or reasonably good (83%) compared to no acceptance (17%), and neither was related to the permanence of cross-dressing. Their acceptance by parents and siblings was also relatively high (85% and 89%, respectively). The permanence of cross-dressing had no effect on the scores of optimism, SF-36 scores and social functioning. Acceptance by oneself or one's parents did not seem to affect most aspects of functional health and mental well-being, but non-acceptance by siblings generated lower scores on the social functioning and general mental health subscales. Stressors tended to include physical rather than social factors. In conclusion, the unsupervised use of cross-sex hormones was common among kathoeys, and 50% of the sample had overdosed on them. Acceptance was relatively good, except by siblings. New strategies are needed for a more responsible use of cross-sex hormones.

Reference values for mental health assessment instruments: objectives and methods of the Leiden Routine Outcome Monitoring Study.

RATIONALE, AIMS AND OBJECTIVES: Routine outcome monitoring (ROM) was developed to establish the outcome of psychotherapeutic and pharmacological treatments through repeated assessments before, during and after treatment. Although standardization of psychiatric assessments and their reference values are essential for patient care, for various ROM instruments reference values are not available. The aim of the Leiden ROM Study is to generate reference values for 22 ROM instruments, covering generic and specific mood, anxiety and somatoform (MAS) disorders, for the general population. This article describes the extensive process of recruitment, as well as baseline characteristics of patient versus non-patient groups. METHOD: Cross-sectional study in randomly selected participants aged 18-65 years from the Dutch population, included through general practitioners. RESULTS: Extensive demographic, psychosocial, mental health, and biological data from 1302 participants, recruited via general practitioners, were collected during a two-hour standardized assessment including observer-rated and self-report scales. These data will be compared with corresponding data from 7840 patients with psychopathology who were referred to secondary care. On-going quality control and calibration ensured maintenance of high quality during data collection. CONCLUSIONS: This reference group study for mental health assessments is the first study of this size carried out in the Netherlands. The results of this study are expected to be of value to secondary psychiatric care because they allow the indication of progress in health, treatment effect and possible termination of treatment. Additionally, the reference values can be used by primary care physicians as decision threshold for referral to specialized mental health care and vice versa.

Vitality predicts level of guideline-concordant care in routine treatment of mood, anxiety and somatoform disorders.

OBJECTIVE: To examine the clinical and psychosocial correlates of adherence to treatment guidelines among outpatients with common mental disorders in a routine clinical setting. METHODS: In this retrospective cohort study, we analysed 192 patients who were treated for a mood, anxiety or somatoform disorder with pharmacotherapy, psychotherapy or a combination of both treatment modalities. Guideline adherence was assessed with a disorder independent set of quality indicators during up to 3 years of follow-up. At baseline, a standardized diagnostic interview, the Brief Symptom Inventory (BSI), the Short Form 36 (SF-36) and demographic variables were assessed. Using multivariable regression analysis we identified independent predictors associated with guideline adherence. RESULTS: Patients were aged 36.8 years (SD 11.6) on average. The majority of patients were treated with psychotherapy (47.4%), followed by pharmacotherapy (37.5%) and a combination of pharmacotherapy and psychotherapy (15.1%). Three adherence groups were defined: low (29.7%), intermediate (43.2%) and high (27.1%). Univariate predictors of low adherence were low scores on the subscales vitality and social functioning of the SF-36. In the multivariable model, low adherence was independently predicted by a score lower than 50 on the subscale vitality of the SF-36 (odds ratio per 10 units increase in vitality = 1.34, 95% confidence interval: 1.06-1.71). No significant differences were found within socio-demographic variables, co-morbidity and the scores on the BSI subscales between the adherence groups. CONCLUSIONS: We found that patients with low scores on the vitality subscale of the SF-36 were at the highest risk to receive low guideline-concordant care. Understanding factors that affect treatment adherence may help to prevent non-adherence and increase the quality of care as well as cost-effectiveness.

Self-rated health and physician-rated health as independent predictors of mortality in elderly men.

BACKGROUND: When assessing health status, physicians may focus on objective symptoms and diagnoses, whereas individuals may focus more on subjective symptoms, functional limitations and quality of life. METHODS: In the Zutphen Elderly Study, 710 community-living men (aged 64-84 years) were followed until death for 15 years. Self-rated health was assessed through a single-item question. Physician-rated health was estimated on a Likert scale by physicians after medical history assessment and physical examination. Both health ratings were categorised into three groups. All-cause, cardiovascular and cancer mortality rates were analysed in Cox proportional-hazards models. RESULTS: There were 352 (49.6%) men who felt healthy and 225 (31.7%) men with a good physician-rated health. During 15 years of follow-up 503 of 710 men (70.8%) died, of whom 229 (45.5%) from cardiovascular causes and 144 (28.6%) from cancer. Self-rated and physician-rated health both predicted independently all-cause mortality (hazard ratios [HR] for worst vs. best health category: 1.72; 95% confidence interval [CI]: 1.26-2.33, and 1.77; 95% CI: 1.36-2.29; respectively; P-values of <0.005). When self-rated and physician-rated health were discordant, mortality risk was highest when physicians had a less favourable view on the health status than the participant. Self-rated health predicted independently cancer mortality (HR 2.41), whereas physician-rated health cardiovascular mortality (HR 2.13). CONCLUSION: Self-rated and physician-rated health status predicted both all-cause mortality, and showed a differential pattern for cancer and cardiovascular diseases mortality.

Reliability and validity of the Global Assessment of Functioning Scale in clinical outpatients with depressive disorders.

RATIONALE, AIMS AND OBJECTIVES: The Global Assessment of Functioning Scale (GAF) is widely used to assess psychological, social and occupational functioning. The validity and reliability of the GAF in clinical practice have only scarcely been studied in naturalistic samples. METHODS: A total of 432 outpatients with a current major depressive disorder (MDD) were evaluated with routine outcome monitoring (ROM). At baseline the GAF score was assessed by the treating clinician and at ROM baseline and follow-up sessions also by a trained test nurse. Sociodemographic data, the Mini International Neuropsychiatric Interview Plus and scores on the Montgomery-Äsberg Depression Rating Scale, Beck Depression Inventory-revised, Brief Symptom Inventory and Short Form-36 were assessed. RESULTS: At baseline, the mean GAF score by the clinician was 54.8 (range 35-85), and this was systematically lower than the mean GAF score by the test nurse of 57.5 (range 31-88). GAF scores by the clinician and test nurse correlated weakly (r = 0.26). The GAF scores of the clinicians correlated strongly with disease severity, and social and physical functioning. CONCLUSION: The GAF showed rather poor inter-rater reliability as well as poor discriminant validity with disease severity and physical limitations in a large naturalistic sample of outpatients with MDD.

Potential side effects of androgen deprivation treatment in sex offenders.

Testosterone is an important hormone involved in sexual arousal, and, indeed, a profound reduction of testosterone levels may be helpful in controlling sexual impulses in sex offenders. Earlier thought of as a sex hormone only, testosterone has been increasingly shown to have manifold actions in the adult male. Normal adult levels of androgens are required for the health of bones, a large number of metabolic functions, mood, erythropoiesis, sebaceous gland activity of the skin, and several other functions. Severe androgen deficiency is associated with pathologies of these biological systems. Androgen deprivation therapy may result in osteoporosis, weight gain with an increased visceral adiposity, impaired glucose tolerance, dyslipidemia, and emotional disturbances. Some of these features combine in the metabolic syndrome that is also frequently associated with the use of psychotropic medication in general. It leads to a moderately increased risk of fractures and diabetes mellitus (by 40%-50%), and a small increased risk of cardiovascular morbidity and depression (by 10%-20%). It should be noted that small proportionate increases in risk may be of modest clinical significance when background risks are very low. Effective and safe management of sex offenders treated with testosterone-deprivation therapy should include careful monitoring of side effects and their prevention and treatment.