Aerobic Exercise: Randomized Controlled Trial Data Suggest Qualified Benefits for Erectile Dysfunction.

Erectile dysfunction (ED) refers to the difficulty in achieving and maintaining a degree of penile erection that suffices for satisfactory sexual activity. ED is multifactorial in origin; its prevalence therefore varies with the population studied. In the general population, ED is present in 18-52% of men in younger to older age groups and in 43-76% of men with different medical conditions. Phosphodiesterase-5 inhibitor drugs are gold standard treatments for ED. However, because many lifestyle disorders predispose to ED and because aerobic exercise is beneficial for these lifestyle disorders, aerobic exercise may be a possible intervention for ED. In this context, a recent systematic review and meta-analysis identified 11 randomized controlled trials (RCTs; pooled N = 1,147) of aerobic exercise vs nonexercising control conditions for the treatment of ED. These RCTs had been conducted in men with different medical and surgical conditions, commonly obesity, metabolic syndrome, diabetes mellitus, and cardiovascular disease. The exercise interventions were varied but mostly involved 30-60 minutes sessions of activity, 3-5 times a week, for a median duration of 6 months. Advice for diet and weight loss was also commonly provided. The meta analysis found that aerobic exercise was significantly superior to nonexercising control conditions, with greater improvement in erectile functioning observed in subjects with greater baseline impairment. Limitations of the findings were that subjects could not be blinded to the nature of the intervention and that the magnitude of benefit with exercise, although statistically significant, fell below thresholds suggested for clinical significance. Aerobic exercise might therefore be more useful for the primary prevention of ED, for which preliminary evidence already exists. Exercise can also be recommended, along with other lifestyle guidance, to improve sexual functioning in both men and women and to improve health across a range of domains.

Epilepsy, Antiepileptic Drugs, and Adverse Pregnancy Outcomes, 2: Major Congenital Malformations With Antiepileptic Drug Monotherapy.

Women with epilepsy (WWE) are usually advised antiepileptic drug (AED) treatment even during pregnancy. It is therefore important to know what the major congenital malformation (MCM) risks might be with untreated epilepsy, and with first-trimester exposure to different AEDs in monotherapy. This article reviews recent findings from a large multinational registry, a large multinational population based study, and a large meta-analysis. In summary, data from the meta-analysis suggest that the MCM rate is 2%-3% in women without epilepsy and about 3% in WWE who were unexposed to AEDs during pregnancy. Data from the meta analysis also suggest that the MCM rate is approximately population level at 2.6%-3.5% with levetiracetam and lamotrigine and that it is about 4%-5% with carbamazepine, 2.8%-4.8% with oxcarbazepine, about 4% with topiramate, about 5%-7% with phenytoin, about 6%-9% with phenobarbital, and nearly 10% with valproate. The MCM risk with valproate is significantly higher than that with other AEDs (including topiramate and phenobarbital) that significantly increase the risk. Data from the registry suggest that risks are dose-dependent with valproate, phenobarbital, and carbamazepine and that the risk with valproate may be as high as 25% at doses >1,450 mg/d. Valproate is also associated with a wide range of MCMs. Data from the population-based study were generally confirmatory. Strengths and limitations of the studies are considered. The findings of these studies encourage the consideration of levetiracetam or lamotrigine monotherapy for WWE who are pregnant and strongly discourage the consideration of the older AEDs, especially phenytoin and phenobarbitone, and most especially valproate. These considerations also apply to all WWE of childbearing age because it may not be easy to change AEDs when pregnancy is planned and because pregnancy is often unplanned.

A randomised, open-label, pragmatic pilot comparison of oral and intravenous ketamine in treatment-resistant depression.

BACKGROUND: For depression, ketamine is more conveniently administered by oral than by intravenous (iv) routes. The relative antidepressant efficacy of oral vs iv ketamine is unknown. OBJECTIVES: To assess the acute efficacy and the persistence of improvement with open-label oral versus iv ketamine in outpatients with treatment-resistant depression (TRD). METHODS: Adults with TRD were randomized to oral (N=30) or IV (N=31) ketamine. Oral ketamine was dosed at 150 mg in 50 mL of water, sipped across 15 min. IV ketamine was dosed at 0.5 mg/kg, infused across 40 min. Ketamine sessions (total, 7) were administered on alternate days for 2 weeks. Ongoing antidepressant drugs were continued unchanged. Patients were assessed at baseline, day 14, and day 30. The primary outcome was the endpoint Hamilton Rating Scale for Depression score on day 14. Secondary outcomes were endpoint scores on the Montgomery-Asberg Depression Rating Scale, Beck Depression Inventory, and Clinical Global Impression-Severity of Illness and Improvement. RESULTS: Overall dropout was lower with oral than with iv ketamine (26.7 % vs 54.8 %; P=0.03). The 2 groups did not differ in depression ratings and in response and remission rates on all instruments on both days 14 and 30. Adverse events such as headache (56.7 % vs 74.2 %) and drowsiness (0.0 % vs 22.6 %) were less common with oral ketamine. CONCLUSION: In TRD outpatients treated in general hospitals, oral ketamine maybe better accepted and tolerated than iv ketamine. Conclusions about relative efficacy cannot be drawn because of the high dropout rate with iv ketamine.

Curiosities in a Table: Learning Points for Responsible Clinical Rating.

This article presents a table containing redacted data from a real study. The table contains three curiosities: statistical significance in the absence of clinical significance, narrow standard deviations, and the absence of a placebo effect. The data in the table had been obtained by an inexperienced rater; how the inexperience compromised the data is explained. Action points for rater experience, rater training, and rating procedures are suggested.

Epilepsy, Antiepileptic Drugs, and Adverse Pregnancy Outcomes, 1: Examination and Interpretation of Recent Research.

The age-standardized global prevalence of epilepsy is about 0.3% in women. Seizures are associated with morbidity and mortality risks; so, women with epilepsy (WWE) are usually advised antiepileptic drug (AED) treatment even during pregnancy. Women may also knowingly or unknowingly be exposed during pregnancy to AEDs advised for other on- or off-label indications. In this context, a meta-analysis of 35 adverse gestational outcomes examined in 76 observational studies found that WWE were at increased risk of most of the adverse outcomes, regardless of gestational exposure to AEDs. AEDs, especially in polytherapy, further increased at least a few of the gestational risks, including risks of congenital conditions, neonatal intensive care unit admission, small for gestational age, low birth weight, and neonatal/infant death (it is unclear whether the lack of statistical significance for the remaining risks was because AED exposure was truly limited to these risks or whether the nonsignificant analyses were underpowered). Reassuringly, the increases in risk were mostly in the small to modest range. This meta-analysis pooled unadjusted risks (which would probably be larger than adjusted risks), so readers are informed about expected findings in the population but not about cause-effect relationships that may be cautiously hypothesized from adjusted analyses. A take-home message is that, because of the wide range of outcomes for which risk is increased, WWE should be closely monitored and followed all through pregnancy, regardless of treatment with AEDs. This article also provides readers with suggestions on how to critically interpret literature with regard to 8 matters: confounding by indication and confounding by severity of indication, as specific to the indication for AED prescription; unadjusted and adjusted analyses; the base rate of an outcome in the population; the examination of multiple outcomes; the uniform direction of findings; the sample numbers; the timing of AED exposure; and self-fulfilling prophecies.

Primary outcomes, secondary outcomes, and their relevance to how many papers are published from a study: A primer for authors, reviewers, and editors.

In research, outcomes are often categorized as primary and secondary. The primary outcome is the most important one; it determines whether the study is considered 'successful' or not. Secondary outcomes are chosen because they provide supporting evidence for the results of the primary outcome or additional information about the subject being studied. For reasons that are explained in this paper, secondary outcomes should be cautiously interpreted. There are varying practices regarding publishing secondary outcomes. Some authors publish these separately, while others include them in the main publication. In some contexts, the former can lead to concerns about the quality and relevance of the data being published. In this article, we discuss primary and secondary outcomes, the importance and interpretation of secondary outcomes, and considerations for publishing multiple outcomes in separate papers. We also discuss the special case of secondary analyses and post hoc analyses and provide guidance on good publishing practices. Throughout the article, we use relevant examples to make these concepts easier to understand. While the article is primarily aimed at early career researchers, it offers insights that may be helpful to researchers, reviewers, and editors across all levels of expertise.

Understanding Factorial Designs, Main Effects, and Interaction Effects: Simply Explained with a Worked Example.

A factorial design examines the effects of two independent variables on a single, continuous dependent variable. The statistical test employed to analyze the data is a two-way analysis of variance (ANOVA). This test yields three results: a main effect for each of the independent variables and an interaction effect between the two independent variables. This article explains factorial designs and two-way ANOVA with the help of a worked example using hypothetical data in a spreadsheet provided as a supplementary file. The main effects and interaction effects are explained and illustrated using tables and figures. A short discussion provides general notes about the concepts explained in this article, along with brief notes on repeated measures ANOVA and higher order ANOVAs. Many additional examples, with figures and explanations, are provided in the supplementary materials, which the reader is strongly encouraged to view.

Antipsychotic Medication Continuation vs Taper and Discontinuation in Patients With Schizophrenia and Other Nonaffective Psychotic Disorders.

Schizophrenia is a major mental illness that is managed with long-term antipsychotic medication as a standard of care. Antipsychotic medications, however, are associated with many subjective and objective adverse effects. These adverse effects have driven the study of risk-mitigation strategies such as targeted intermittent therapy and dose reduction and drug discontinuation. Randomized controlled trials (RCTs) of these strategies have been synthesized in meta-analysis; both strategies have been associated with no functional benefits and with an increased risk of relapse. The RCTs, however, have been criticized because, in many, patients were abruptly switched to the target dose or too rapidly tapered, thereby predisposing the RCT to failure of the intervention. Two important RCTs examined gradual individualized dose reduction and discontinuation. One, conducted in first-episode psychosis patients who were free from positive symptoms for 6 months, found that, at 18-month follow-up, dose reduction was associated with a higher risk of relapse (number needed to harm [NNH] = 5) and with no functional benefits. However, after return to routine clinical care, at a 7-year follow-up, the dose reduction group had better functional outcomes and similar clinical outcomes relative to the maintenance treatment group. The other RCT, conducted in patients with relapsing psychosis, found that, at a 2-year follow-up, dose reduction was associated with a higher risk of relapse (NNH = 5) and with no improvements in social, cognitive, quality of life, satisfaction, and other domains. Many large nationwide observational studies have found that antipsychotic discontinuation by patients with first-episode psychosis and schizophrenia is associated with increased relapse, rehospitalization, suicide mortality, cardiovascular mortality, and all-cause mortality. There is also the ethical matter that attempts to identify the few who may benefit from antipsychotic dose reduction and discontinuation may compromise the health and stability of the many who require long-term maintenance treatment.

A review on the pharmacology of cariprazine and its role in the treatment of negative symptoms of schizophrenia.

Management of negative symptoms is one of the most challenging and important unmet needs of schizophrenia treatment. Negative symptoms together with positive symptoms result in significant psychosocial impairment and poor quality of life. Existing studies on atypical antipsychotics reported limited treatment adherence due to higher prevalence of treatment-emergent adverse events, such as diabetes, weight gain, hyperlipidemia, hyperprolactinemia and hypertension. A compound with greater affinity for dopamine D2/D3 receptors may improve negative symptoms, mood, and cognitive impairment associated with schizophrenia. In 2015, the US FDA has approved cariprazine, a partial D2/D3 agonist for treatment of schizophrenia, mania or mixed episodes. Midlands and Lancashire Commissioning Support Unit, UK (2019) has particularly suggested cariprazine for the treatment of predominant negative symptoms of schizophrenia. India's Central Drugs Standard Control Organization (CDSCO) has approved cariprazine in 2021 for the treatment of schizophrenia, manic or mixed episodes associated with bipolar I disorder. A ten-fold greater affinity for D3 receptors and partial agonism to serotonin receptors, along with longer half-life make cariprazine distinct when compared with other atypical antipsychotics. Cariprazine is also reported to have fewer incidents of metabolic and hormonal adverse events, and has been shown to provide better relapse prevention. Recent evidence indicates promising effect of cariprazine in ameliorating negative symptoms as well as psychotic symptoms in patients with schizophrenia. In addition, improved adherence to treatment (adjunctive/monotherapy) with cariprazine in patients having inadequate response to an ongoing antipsychotic treatment has also been clinically established. This review presents the evidence-based safety and efficacy of cariprazine for treatment of predominant negative symptoms of schizophrenia.

Gestational exposure to benzodiazepines or z-hypnotics and neurodevelopmental disorders in offspring: Systematic review and meta-analysis.

INTRODUCTION: Benzodiazepine (BDZP) and/or z-hypnotic dispensing during pregnancy has increased globally, as have rates of autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). This systematic review and meta-analysis aimed to estimate the association between gestational exposure to BDZP and/or z-hypnotics and diagnosis of ASD or ADHD in offspring. METHODS: We searched MEDLINE, EMBASE, and SCOPUS from inception till December 2023 for relevant English-language articles. Outcomes of interest were risk of ASD and ADHD, two independent primary outcomes, in children exposed anytime during pregnancy to BDZP and/or z-hypnotics versus those unexposed. Secondary outcomes were trimester-wise analyses. Using a random effects model, we pooled the overall and trimester-wise hazard ratios (HRs), with 95% confidence intervals (CIs), separately for risk of ASD and ADHD. RESULTS: We found six eligible retrospective cohort studies and no case-control studies. There was no increased risk of ASD associated with anytime gestational BDZP and/or z-hypnotic exposure (primary outcome, HR, 1.10; 95% CI, 0.81-1.50; 4 studies; n = 3,783,417; 80,270 exposed, 3,703,147 unexposed) nor after first trimester exposure (HR, 1.15; 95% CI, 0.83-1.58; 3 studies; n = 1,539,335; 70,737 exposed, 1,468,598 unexposed) or later trimester exposures. A very small but significantly increased risk of ADHD was noted with anytime gestational exposure to these drugs (primary outcome, HR, 1.07; 95% CI, 1.03-1.12; 4 studies; n = 2,000,777; 78,912 exposed, 1,921,865 unexposed) and also with (only) second trimester exposure (HR, 1.07; 95% CI, 1.03-1.12; 3 studies; n = 1,539,281; 33,355 exposed, 1,505,926 unexposed). Findings were consistent in sensitivity analyses. CONCLUSION: Gestational exposure to benzodiazepines or z-hypnotics was not associated with an increased risk of ASD and with only a marginally increased risk of ADHD in offspring. Given the likelihood of confounding by indication and by unmeasured variables in the original studies, our findings should reassure women who need these medications for severe anxiety or insomnia during pregnancy.

Rating Patients in Different Languages: Reliability and Validity.

Research outcomes in mental health disciplines are usually assessed using rating instruments that were developed as English language versions. However, in countries such as India, English is not the native language, and patients at even a single research center may speak in different regional tongues. It is permissible to assess such patients using rater-administered English language instruments designed to be scored after an unstructured interview conducted in the patient's preferred language. For many reasons, related to reliability and validity, it is not permissible to assess such patients in their preferred language by translating, impromptu, from English language versions of instruments that were designed to be self-administered or administered as a structured interview. In such situations, standardized, local language versions of the instruments should be used; that is, local language versions with established reliability and validity.

Confounding by Indication, Confounding Variables, Covariates, and Independent Variables: Knowing What These Terms Mean and When to Use Which Term.

The terms independent variables, covariates, confounding variables, and confounding by indication are often imprecisely used in the context of regression. Independent variables are the full set of variables whose influence on the outcome is studied. Covariates are the independent variables that are included not because they are of interest but because their influence on the outcome can be adjusted for, leaving a more precise understanding of how the single remaining independent variable influences the outcome. Confounding variables are variables that are associated with both independent variables and outcomes; so, the relationship identified between independent variables and outcomes may be due to the confounding variable rather than to the independent variable. Potential confounders should be identified, measured, and adjusted for in regression, just as other covariates are. Confounding by indication occurs when the presence of the independent variable is driven by the confounding variable. Confounding by indication is a special kind of confounding; a confounding variable is a special kind of covariate; and a covariate is a special kind of independent variable in regression analysis. These terms and concepts are explained with the help of examples.

Physical Exercise and Health, 5: Sedentary Time, Independent of Health-Related Physical Activity, as a Risk Factor for Adverse Physical Health and Mental Health Outcomes.

Medical and neuropsychiatric benefits associated with physical exercise and activity are well recognized. It is less well known that time spent in sedentary behaviors, such as television-viewing or sitting at a desk, are associated with adverse health outcomes even after taking into consideration health-related physical activity. Although sedentary behaviors have become common in daily life, people tend to substantially underestimate how sedentary they actually are. The average person spends nearly 10 hours per day in a sedentary state, during leisure activities or work; sedentariness is even greater in persons with major mental illness such as psychosis. This article explains what sedentariness is, why sedentary behaviors are common in daily life, and how sedentariness is defined and assessed. Sedentariness is an important concept in its own right; it is not merely an absence of health-related physical activity. Sedentariness is associated with adverse outcomes in children and adolescents, adults, and older adults. Examples are provided of associations between sedentariness and adverse medical outcomes such as the metabolic syndrome, cardiovascular disease, stroke, and all cause mortality. Examples are also provided of associations between sedentariness and adverse mental health outcomes such as anxiety, depression, and dementia. Importantly, the adverse associations are independent of health-related physical activity; however, higher levels of physical activity may attenuate or offset the adverse effects of sedentariness. It is hoped that this article will encourage readers to reduce sedentary behaviors with a view to improve long-term physical and mental health.