BACKGROUND:Weight gain and metabolic disturbances are common adverse effects of antipsychotic medications such as clozapine and olanzapine. Beyond their primary role in glycemic control, sodium-glucose cotransporter 2 (SGLT2) inhibitors have been associated with weight loss and improvements in various metabolic parameters. This study compared the efficacy and safety of empagliflozin and metformin in patients with antipsychotic-induced weight gain (AIWG). METHODS:In this 12-week, double-blind, randomized controlled trial, 84 adults with schizophrenia or bipolar disorder and established weight gain from clozapine or olanzapine were assigned to receive either empagliflozin (10 mg daily) or metformin (1000 mg daily). The primary outcome was the percentage change in body weight from baseline to week 12. Secondary outcomes included changes in absolute body weight, body mass index (BMI), waist circumference, waist-hip ratio, and the proportion of patients achieving ≥ 5% weight loss. Exploratory outcomes assessed changes in glycemic and lipid parameters, fasting insulin, and insulin resistance (HOMA-IR). Safety was evaluated by monitoring adverse events, treatment discontinuations, and serious adverse events. RESULTS:Of the 84 randomized participants, 38 (90.5%) in the empagliflozin group and 39 (92.9%) in the metformin group completed the 12-week study. Both treatments produced significant within-group reductions in anthropometric measures (all p < 0.001) and there were no statistically significant differences between groups in the magnitude of change for body weight, BMI, waist circumference, hip circumference, or waist-hip ratio (all p > 0.05). Both groups showed improvements in glycemic and lipid parameters, but empagliflozin resulted in significantly greater reductions in TG (p = 0.004), fasting insulin (p = 0.005), and HOMA-IR (p = 0.012), as well as a greater increase in HDL-C (p < 0.001) compared to metformin. The overall incidence of adverse effects was comparable (33.3% vs. 38.1%; p = 0.650), with no serious adverse events reported. CONCLUSIONS:These findings suggest that empagliflozin is a promising alternative to metformin for managing metabolic complications in patients treated with clozapine or olanzapine. These findings warrant confirmation and further investigation in larger, long-term studies. TRIAL REGISTRATION:The trial was registered prospectively at the Iranian Registry of Clinical Trials (IRCT) with the ID code IRCT20120215009014N538 on November 12, 2024.
Double blind randomized placebo controlled trials (RCTs) have been regarded as the gold standard for evaluation of potential treatments. Nevertheless RCTs for psychiatric illnesses, almost all of which sorely need better medications, have been plagued with high placebo response, practically diluting true drug effects (if any) and potentially discouraging novel drug developments. Various strategies have been considered to tackle this significant issue but none has been particularly successful to date. The author proposes to examine the belief of treatment allocation by the study participants, (at least) twice, during the study period. The results will be interpreted in terms of correctness and consistency, regardless of the actual treatment allocation. Whether response trajectory differs based on these parameters (e.g., robust placebo response stems from those who consistently guessed placebo as active drug) should be tested and analyzed. The concept could be useful regarding functional unblinding, another serious issue in psychiatric RCTs, for drugs with strong clinical effects.
OBJECTIVE:'Ego dissolution' refers to a temporary state characterized by diminished self-referential processing, which leads to a breakdown of personal boundaries and an enhanced sense of unity with the environment. Both psychedelics, such as ayahuasca, and contemplative practices, like meditation, have been proposed as mechanisms for modulating the ego. While ayahuasca induces transient self-perception alterations, meditation promotes more sustained changes through cognitive and emotional regulation. This study examines whether ayahuasca consumption modulates the ego and compares its effects with those of meditation. METHODS:A total of 37 ayahuasca users and 137 meditators participated. We used the "Delusion of Me" (DoM) index, a unidimensional self-report measure comprising three domains: acceptance, decentering, and non-attachment. It could be considered closely related to the concept of self 'as a content' and may potentially serve as a measure of ego. RESULTS:Meditators exhibited significantly higher DoM scores than ayahuasca users. The quadratic regression did not show a cumulative effect, with no significant relationship found between the number of ayahuasca sessions and DoM scores. CONCLUSIONS:Meditation practice correlated with higher DoM scores and cumulative practice showed a significant non-linear association with DoM. Conversely, repeated ayahuasca exposure demonstrated no evidence of a cumulative association in this sample.
OBJECTIVE:To assess the prevalence and severity of vitamin D deficiency in patients with bipolar disorder and examine potential associations with their sociodemographic and clinical characteristics. METHODS:A retrospective study was conducted on 185 inpatients aged 18-65, diagnosed with bipolar disorder and hospitalized at the Clinic for Psychiatry, University Clinical Center of Serbia, between 2022 and 2024. Data were obtained by analyzing medical records using the hospital information system "Heliant". RESULTS:Vitamin D deficiency was observed in 76.8% of patients, with 14.6% having severe deficiency, 36.8% deficiency, and 25.4% insufficiency. Significant associations were found between vitamin D deficiency and the autumn/winter season, as well as lower education levels. Additionally, manic episodes were more frequently observed during spring and summer. No other significant associations were identified. CONCLUSION:A high prevalence of vitamin D deficiency was found among patients with bipolar disorder. Routine screening and early intervention should be considered, including education, supplementation, and lifestyle modifications. Integrating preventive strategies into psychiatric care may improve clinical outcomes and mood stability. Further longitudinal and interventional research is needed to clarify the potential role of vitamin D and to guide evidence-based prevention and treatment in bipolar disorder.
OBJECTIVE:The CYP2D6*10 allele, which is prevalent in the Indian population, is of particular clinical significance. This study aims to investigate the effect of the CYP2D6*10 allele on the pharmacokinetics of risperidone and its metabolites following single-dose administration in healthy South Indian volunteers. METHODS:The study was conducted with twenty healthy volunteers who were administered a single 2 mg dose of risperidone. CYP2D6 genotyping was performed using the PCR-RFLP method. Plasma levels of risperidone (RIS) and its active metabolite 9-hydroxyrisperidone (9-OHRIS) were quantified using a UPLC-DAD system. RESULTS:Significant differences in pharmacokinetic parameters were observed across the CYP2D6*10 genotypes. For intermediate metabolizers, the Cmax, AUC0-t, and T1/2 were approximately 1.2 times higher, and the metabolic ratio was double compared to normal metabolizers. Notably, the Cmax of the active moiety was significantly higher in intermediate metabolizers compared to normal metabolizers (p < 0.05). These findings indicate that CYP2D6 polymorphisms are associated with altered pharmacokinetic profiles of risperidone, with a reduced metabolic activation in individuals carrying the *10 allele. CONCLUSION:The results suggest that CYP2D6 genotyping could help inform personalized dosing strategies for risperidone, though further randomized controlled trials are required to confirm these findings.
INTRODUCTION:Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol are among the most commonly used medications worldwide. It has been suggested that the misuse of such medications is not uncommon. The objective of the present research was to explore prevalence, reported reasons and psychopathological concomitants related to NSAIDs/paracetamol misuse in a sample of users. METHODS:The sample was made of 346 NSAIDs or paracetamol users (age range: 18-64 years); assessments included the 4-item Perceived Stress Scale (PSS-4), the 10-item version of the Adverse Childhood Experiences International Questionnaire (ACE-IQ-10), the Body Image Concern Inventory (BICI), the Alcohol Use Disorders Identification Test-C (AUDIT-C), and questions related to NSAIDs/paracetamol misuse. RESULTS:Forty-eight individuals (13.9%) were categorized as NSAIDs/paracetamol misusers. A logistic regression model showed that higher scores in AUDIT-C, BICI and ACE-IQ-10, and the use of psychiatric medications, were significantly associated with the likelihood of NSAIDs/paracetamol misuse. Specific reasons related to the misuse are also reported. DISCUSSION:Our findings provide novel insights into the relationship between NSAIDs/paracetamol misuse and psychopathology, with potential clinical implications for prevention and treatment.
OBJECTIVE:Impulsivity is a transdiagnostic risk factor for numerous health morbidities and is strongly associated with early relapse and poor treatment outcomes in addictions and mood-disorders. Lithium carbonate can be helpful in moderating the impulsive behaviors associated with mania, possibly mediated by reduced myo-inositol activity following inhibition of the enzyme inositol monophosphatase (IMPase). We tested the hypothesis that impulsivity-as motor disinhibition, decisions without adequate information, and stronger preferences for small immediate rewards over larger later rewards-can be moderated by the IMPase inhibitor ebselen in healthy adult volunteers. METHODS:One hundred and thirty healthy adults completed a between-subjects, double-blind, placebo-controlled protocol. Over 2 days, participants received a previously validated dose of 1800 mg of ebselen or placebo before completing tests of impulsivity and decision-making. RESULTS:There were no substantive changes in any measure of impulsivity following treatment with ebselen compared with placebo. Neither was there any convincing evidence of stronger treatment effects in high-trait impulsive participants compared with low-trait participants. CONCLUSION:These results fail to replicate findings that ebselen administration moderates validated measures of impulsivity in healthy adults, at least at doses shown to reduce myo-inositol within the medial prefrontal cortex and produce changes in emotional processing and reward-based learning.
INTRODUCTION:Atypical antipsychotics are widely prescribed in child and adolescent psychiatry and are known to affect cardiac repolarization, most commonly reflected by QTc prolongation. However, QTc alone may not fully capture repolarization heterogeneity. The frontal QRS-T angle f(QRS-T) is an electrocardiographic marker reflecting ventricular depolarization-repolarization mismatch. This study aimed to evaluate and compare f(QRS-T) alongside other repolarization parameters in children and adolescents receiving atypical antipsychotics versus healthy controls. METHODS:This retrospective observational study included 45 children and adolescents (6-17 years) receiving atypical antipsychotics for at least six months and 45 age- and sex-matched healthy controls. Standard 12-lead ECG recordings were obtained to measure f(QRS-T), QTc, Tp-e interval, and Tp-e-based ratios. Correlation analyses assessed associations between f(QRS-T), QTc, and duration of antipsychotic use. Hierarchical multiple linear regression was performed to identify independent predictors of f(QRS-T) in the patient group. Receiver operating characteristic (ROC) analysis evaluated the discriminative ability of f(QRS-T) for QTc prolongation (QTc ≥ 440 ms). RESULTS:Children receiving atypical antipsychotics exhibited significantly higher f(QRS-T), QTc interval, Tp-e interval, Tp-e(c), Tp-e(c)/QT, and iCEBc ratios compared with healthy controls (p < 0.05). Frontal QRS-T angle was positively correlated with QTc (r = 0.406, p < 0.001) but not with the duration of antipsychotic treatment. In hierarchical regression analysis, age, sex, QTc and duration of antipsychotic use were not independent predictors of f(QRS-T). ROC analysis demonstrated that f(QRS-T) moderately discriminated patients with QTc prolongation (AUC = 0.735); a cut-off value of 26.5° yielded a sensitivity of 72% and a specificity of 60%. CONCLUSION:f(QRS-T) is significantly increased in children and adolescents receiving atypical antipsychotics and is associated with QTc prolongation, although it is not independently predicted by treatment duration or conventional QT-based indices. These findings suggest that f(QRS-T) may serve as a complementary electrocardiographic marker of repolarization heterogeneity alongside QTc in the cardiac safety monitoring of pediatric patients treated with atypical antipsychotics.
BACKGROUND:Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for metabolic disorders. Howeve, their effects on depressive symptoms and psychological well-being remain uncertain. METHODS:We conducted a systematic review and meta-analysis of randomized controlled trials evaluating the effects of GLP-1RAs on depressive symptoms and psychological well-being. Random-effects models were used to calculate standardized mean differences (SMDs). Subgroup and meta-regression analyses were performed to explore heterogeneity. The protocol was registered with PROSPERO (CRD42024566217). RESULTS:In total, 25 trials (17,751 participants) evaluated psychological well-being and 11 trials (1961 participants) evaluated depressive symptoms. GLP-1RA treatment was associated with a small but significant improvement in psychological well-being compared with control conditions (SMD = 0.374, 95% CI 0.093-0.656), whereas no significant effect was observed for depressive symptoms (SMD = 0.079, 95% CI -0.024-0.182). Improvements in psychological well-being were consistently observed in studies using semaglutide, tirzepatide or liraglutide, subcutaneous administration, and in populations with type 2 diabetes mellitus or obesity. CONCLUSIONS:GLP-1RA treatment was associated with modest improvements in psychological well-being but not depressive symptoms. These findings should be interpreted cautiously and suggest that any observed psychological benefits are likely indirect, potentially reflecting improvements in metabolic status or general health, rather than direct mood-improving effects.
OBJECTIVE:Zolpidem and zopiclone are widely prescribed hypnotics for older adults, yet their comparative safety regarding hip fracture risk remains unclear. This study aimed to compare the risk of hip fracture between zolpidem and zopiclone among adults aged 65-84 years. METHODS:Electronic health records from 166 global healthcare organizations in the TriNetX platform were analyzed. Adults aged 65-84 years who were newly prescribed zolpidem or zopiclone were identified. Propensity score matching was used to balance baseline characteristics. The TriNetX "Compare Outcomes" tool was used to estimate the cumulative incidence of hip fracture, hazard ratio, and 95% confidence interval between zolpidem users and zopiclone users. RESULTS:After propensity score matching, 41,500 adults were included in each group. During the 1-year follow-up period, 100 adults in the zolpidem group and 174 adults in the zopiclone group experienced a hip fracture, corresponding to cumulative incidences of 0.24% and 0.42%, respectively. In the Cox proportional hazards regression model, zolpidem use was associated with a reduced risk of hip fracture (hazard ratio 0.51; 95% confidence interval, 0.40-0.66). CONCLUSION:Zolpidem was associated with a lower risk of hip fracture compared with zopiclone among adults aged 65-84 years. These findings highlight the need for further research to confirm these differences and explore underlying mechanisms.
BACKGROUND AND OBJECTIVE:Isotretinoin is a systemic agent widely used in the treatment of severe acne vulgaris. Previous studies have reported that isotretinoin use may be associated with depression, anxiety, and sleep disorders. The aim of this study was to evaluate changes in sleep quality, anxiety, and depression in patients with acne vulgaris during isotretinoin treatment. MATERIALS AND METHODS:This retrospective analysis of prospectively collected data included 155 patients receiving isotretinoin treatment at a tertiary dermatology outpatient clinic in Turkey between January 2023 and December 2024. The Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Global Acne Grading System (GAGS) were administered to patients before treatment, at the end of the first month, and at the end of the third month of treatment. Patients with a history of psychiatric disorders, use of psychotropic medications, or systemic diseases affecting sleep or mood were excluded from the study. RESULTS:Isotretinoin treatment was associated with a significant reduction in acne severity over the 3-month follow-up period. A transient increase in depressive and anxiety symptoms was observed during the first month of treatment, followed by a significant improvement by the third month. Overall, isotretinoin treatment was not associated with a significant deterioration in sleep quality throughout the study period. CONCLUSION:Isotretinoin treatment was associated with a significant reduction in acne severity, depression, and anxiety, while no significant overall change in sleep quality was observed. The temporary increase in depression and anxiety observed at the end of the first month may be related to the cutaneous side effects of isotretinoin. Further prospective studies are needed to better clarify the neuropsychiatric effects of isotretinoin.
Introduction Genetic factors are thought to play an important role in antipsychotic-induced weight gain (AIWG). Polygenic risk scores (PRS) could provide a measure of genetic predisposition to antipsychotic drug induced weight gain (AIWG).We conducted a study to examine how a PRS, generated using SNPs, identified from a recent meta-analysis, related to weight-change over time in people with first episode-psychosis. Methods The PRS included SNPs in six different genes, identified as having significant associations (p < 0.05) with AIWG. These were HTR2C rs3813929; MTHFR rs1801133; ADRA2A rs1800544; MC4R rs489693; LEPR rs1137101 and CNR1 rs1049353. An additive PRS and a risk allele based weighted PRS were created based on risk allele counts and presence or absence of risk alleles respectively. The additive PRS was also used to create low/high genetic risk groups for analysis. The association between PRS and weight gain per day (WGPD) in grams/day as well as BMI percentage change (=> 7%) was investigated using regression models. Results In multiple regression analysis, the additive PRS significantly predicted AIWG in females (adjusted r2 = 0.59, B: unstandardised regression coefficient = 24.4 g/day p < 0.05), but not in males. ANCOVA showed that high genetic risk groups had greater WGPD (p = 0.018), with significant PRS gender interactions driven by markedly higher WGPD in high-risk females (p = 0.039). None of the models tested were associated with BMI percentage change. Conclusion We report a PRS that is predictive of weight gain in women treated for first episode psychosis, accounting for 59% of the variance daily weight-gain over time. Validation in an independent cohort is required, as is determining whether it is feasible to apply the PRS prospectively.
BACKGROUND:The paliperidone palmitate 3-month (PP3M) formulation offers an extended dosing interval compared to the 1-month (PP1M) formulation. However, data on the comparative side effect profiles of PP1M versus PP3M in real-world settings remain limited. This study aimed to compare the side effect profiles in patients with schizophrenia receiving PP1M and those who switched from PP1M to PP3M. MATERIAL AND METHODS:Of 473 patients with schizophrenia screened, 132 received long-acting injectable antipsychotics; 67 initiated PP1M, of whom 43 subsequently converted to PP3M and had evaluable data at both time points. The primary analysis used a within-patient mirror-image design (PP1M month-4 vs PP3M month-4). Side effects were assessed using the UKU Side Effect Rating Scale, and symptom severity was evaluated with the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms, at 4 months after PP1M initiation and 4 months after PP3M switch. RESULTS:UKU side-effect profiles were broadly similar after conversion to PP3M, with no increase in the UKU total score. The most frequent side effects for both formulations were increased fatigability, hypokinesia, weight gain, and diminished sexual desire. The frequency of side effects remained mostly stable, with constipation showing a significant decrease after switching. Side effects were more prevalent in patients with schizophrenia using multiple antipsychotics compared to monotherapy. CONCLUSION:In this within-patient cohort stabilized on PP1M, conversion to PP3M was not associated with an increase in overall UKU side-effect burden. Selecting the appropriate dose before switching and preferring monotherapy may enhance treatment comfort. These results may help guide clinicians in selecting long-acting injectable antipsychotics in practice.
BACKGROUND:Anxiolytic medications, particularly benzodiazepines, are widely prescribed, giving impetus to long-standing debates about how often these agents should be employed in clinical practice. There are, however, few cross-country studies of the pharmacoepidemiology of these agents. We report on the frequency of anxiolytic medication use, reasons for use, and perceived effectiveness of use in general population surveys across 20 countries. METHODS:Face-to-face interviews with community samples totaling n = 49,919 respondents in the World Health Organization World Mental Health (WMH) Surveys asked about anxiolytic medication use anytime in the prior 12 months in conjunction with validated fully structured diagnostic interviews. Treatment questions were administered independently of diagnoses to all respondents. RESULTS:A weighted 5.6% (n = 4079) of respondents reported anxiolytic medication use within the past 12 months; the vast majority comprised benzodiazepine use, and use was highest amongst respondents with a subthreshold major depressive episode (MDE) (25.2%) and a 12-month MDE (19.8%). Rates were significantly higher in high-income countries (HICs) than low- and middle-income countries (LMICs) (8.5% vs. 2.2%, χ2 1 = 559.6, p < 0.001). Short-acting benzodiazepines and z-drugs were most commonly used for sleep (66.5% and 85.5%), while intermediate-acting benzodiazepines and long-acting benzodiazepines were most commonly used either for sleep (37.9% and 30.1%) or anxiety (33.3% and 32.0%). Across all conditions, anxiolytic medications were reported as very effective by 55.7% of users and somewhat effective by an additional 32.2% of users, with similar proportions in HICs and LMICs. Negative predictors of high perceived effectiveness were a 12-month MDE and taking anxiolytic medication for comorbid anxiety and depression. CONCLUSION:These data do not definitely answer the question of how often benzodiazepines should be prescribed in clinical practice, but they usefully inform discussions of how to optimize their use. It is noteworthy that anxiolytic medications, particularly benzodiazepines, are largely prescribed for anxiety and sleep, and that they are widely perceived to be either very or somewhat effective by users. However, more targeted prescription of these agents may be necessary; in particular antidepressant intervention should be prioritized in the pharmacotherapy of major depressive disorder.
This double-blind positive-controlled study investigated the potential for the aroma of a novel blend of essential oils, Genius to enhance cognitive performance and mood in healthy adults, and whether any such benefits might be related to changes in cerebrovascular oxygenation measured using Near Infra-Red Spectroscopy. Ninety participants (61 female) were pseudo-randomly allocated to achieve a gender balance across three experimental groups: Genius aroma, Sage aroma (positive control) or no aroma (control). All participants completed mood questionnaires after completing a range of cognitive tasks whilst wearing a Near Infra-Red Spectroscopy headband. Multivariate and subsequent univariate data analysis revealed significant enhancements to memory and executive function tasks in the Genius and sage aroma conditions compared to no aroma with larger effects noted for the Genius blend. Furthermore, the novel blend outperformed the aroma of pure sage and also left participants feeling significantly more alert and less fatigued at the end of the testing session. Near Infra-Red Spectroscopy data indicated that both sage and Genius blend enhanced metabolism during task performance with a greater impact from the Genius aroma. Although suggestive of a mechanism underpinning the enhancements observed no correlations were found between the Near Infra-Red Spectroscopy signals and cognitive performance. This study strengthens the evidence base for the beneficial effects of essential oil aroma inhalation for cognitive performance, however the underlying mechanisms remain elusive.
OBJECTIVE:C-C motif chemokine ligand 5 (CCL5) and fibroblast growth factor 2 (FGF2) have been increasingly linked to neuroinflammation. This study evaluated the impact of escitalopram on serum CCL5 and FGF2 levels in patients with generalised anxiety disorder (GAD). METHODS:Thirty patients (18-50 years) with GAD diagnosed by DSM-5 criteria, and 30 healthy controls were included. All GAD patients received escitalopram and were followed up for 12 weeks. Serum CCL5 and FGF2 levels were measured before and after escitalopram treatment in GAD patients, with a baseline measurement in healthy controls using ELISA. RESULTS:We found that serum CCL5 levels were significantly increased (p = 0.001) in GAD patients compared to healthy controls and remained higher after treatment without any significant change. However, serum FGF2 levels were comparable and did not differ significantly between healthy controls and GAD patients before treatment, and increased significantly (p = 0.011) after escitalopram treatment in GAD patients. CONCLUSION:In GAD patients, serum levels of CCL5 remained elevated and FGF2 increased significantly post-treatment with escitalopram. This suggests that escitalopram could exert a partial immunomodulatory effect on CCL5 and FGF2, thus modulating inflammation-driven mechanisms of GAD. Future research in larger populations and longer follow-ups is needed to further examine these findings.
OBJECTIVE:Scopolamine disrupts cholinergic mechanisms via nonspecific muscarinic antagonism. Centrally, excitatory neocortical innervations are antagonised causing spectral electroencephalography (EEG) changes and cognitive impairment. Peripherally, parasympathetic control of heart rate variability (HRV) is disrupted, although acute HRV effects of scopolamine are not well-defined. METHODS:Forty adults with depression received scopolamine hydrobromide (N = 24, 4-6 μg/kg) or glycopyrronium bromide (N = 16, 4-6 μg/kg) infusions. Twelve healthy adults received scopolamine (4-6 μg/kg) infusions. EEG and electrocardiography were recorded across 4 hours post-infusion. EEG spectral, aperiodic, Lempel Ziv complexity (LZC), and microstates analyses were performed. Electrocardiographic HRV metric: proportion of high frequency power (pHF) was calculated and modelled via pharmacokinetic-pharmacodynamic models to ascertain the HRV concentration-effect relationship. RESULTS:Scopolamine increased delta power between 0.5 and 3.5 h (at 35 min: t = 3.6, p = 0.002). At 3 hours post-infusion, scopolamine increased aperiodic slope (t = -3.4, p = 0.047) and offset (t = -3.93, p = 0.003) parameters, reduced LZC (t = -4.5, p = 2 × 10-4), and microstate D mean duration (t = -3.0, p = 0.039). EEG metrics correlated with drowsiness and alcohol-like stimulant ratings. Peripherally, scopolamine reduced HRV, with two-compartment pharmacokinetic models describing a delayed pHF effect via an effect compartment. CONCLUSIONS:These effects corresponded to increased drowsiness, reduced excitation-inhibition ratio, and reduced HRV-implicating central and peripheral muscarinic mechanisms reminiscent of Alzheimer's-like cholinergic disruption. TRIAL REGISTRATION:anzctr.org.au identifier: ACTRN12619000569101 and ACTRN12622000228785.
OBJECTIVE:Stress from daily psychosocial challenges is a significant health concern with limited pharmacological treatment options. Psychosocial stress triggers distinct responses in the autonomic and central nervous systems, measurable via heart rate variability (HRV) and electroencephalogram (EEG). This post hoc analysis of clinical trial data explores the impact of the anti-stress medication Neurexan (Nx4) on HRV and EEG signals, and their correlation in a resting state following acute psychosocial stress induction. METHODS:Data from the NEURIM trial (NCT02602275), a randomized, placebo-controlled, double-blind, cross-over study, were utilized. Participants received Nx4 before exposure to ScanSTRESS, a psychosocial stress paradigm. EEG and photoplethysmogram data were collected at rest before and after stress exposure. Stress responsivity under both placebo and Nx4 conditions was evaluated through HRV and EEG signals. RESULTS:Psychosocial stress altered HRV parameters (increased LF/HF ratio, elevated Baevsky's Stress Index, reduced RMSSD) and EEG activity (decreased aperiodic offset, increased alpha power). Nx4 significantly mitigated stress-induced changes in LF/HF ratio, Baevsky's Stress Index, and aperiodic offset. A significant correlation was observed between Nx4 effects on HRV and EEG activity. CONCLUSION:Nx4 attenuates peripheral and central physiological stress responses, suggesting a comprehensive approach to mitigating stress responses in daily life.
Loss of function mutations in the WFS1 gene cause Wolfram syndrome, which is characterized by juvenile-onset diabetes mellitus, diabetes insipidus, neurodegeneration, hearing loss and optic nerve atrophy. Psychiatric symptoms, including major depression and suicidal behavior, are common in this disorder. WFS1 mutations induce this condition through altering interactions between the endoplasmic reticulum and mitochondria, resulting in diminished Ca2+ import that leads to mitochondrial dysfunction. Quite recently, it was shown that such impaired Ca2+ transport could be restored by the experimental σ1 receptor agonist PRE084. In animal models of Wolfram syndrome, this compound restored the behavioral phenotype. Based on these previous data, we propose that Wolfram syndrome may serve as a mechanistically informative model for exploring σ1 receptor modulation, mitochondrial dysfunction, and affective symptoms. This proposal is based on four arguments. Firstly, the R-enantiomer of ketamine exhibits largely selective binding to the σ1 receptor as an agonist. Secondly, R-ketamine and other σ1 agonists display antidepressant-like activity in rodent depression models. Thirdly, while both S- and R-ketamine hold potential for reducing suicidal behavior, the latter is likely to have a lower potential for abuse and fewer side effects. Fourth, Wolfram syndrome is characterized by mitochondrial dysfunction, which has also been linked to depression.
