Thorsten Mikoteit

Purpose: Trazodone is metabolized by CYP3A4 to the active metabolite meta-chlorophenylpiperazine (mCPP), which is associated with various adverse drug reactions (ADRs). mCPP is further inactivated by CYP2D6. Despite the knowledge of trazodone metabolism, the evidence regarding the impact of pharmacogenetics remains limited. This study aimed to examine the association between pharmacogenetic variants in genes involved in the metabolism of trazodone and the occurrence of ADRs during trazodone treatment. Methods: We performed an explorative observational study using available data and serum samples from 2 ongoing pharmacogenetic studies. For patients treated with trazodone, we analyzed information on trazodone tolerability, genetic variants in CYP2D6, CYP3A5, and ABCB1 , as well as co-medications to assess potential drug-drug-gene interactions (phenoconversion). Serum levels of mCPP and trazodone were measured in a subset of patients. Results: Data from 98 patients were analyzed. Reduced CYP2D6 activity was associated with an increased risk of ADRs during trazodone therapy. After accounting for phenoconversion and adjusting for sex, trazodone dose, and CYP3A5 phenotype, CYP2D6 poor metabolizers were found to be more likely to develop ADRs compared with normal metabolizers (OR: 8.96; 95% CI=1.67-48.08). No association with ADRs was found for genetic variants in CYP3A5 and ABCB1 . Subgroup analysis revealed that reduced CYP2D6 activity was associated with a higher mCPP-to-trazodone ratio and a greater tendency for ADRs. Conclusions: Our findings suggest that mCPP could contribute to trazodone-related ADRs, especially in individuals with reduced CYP2D6 metabolism. Larger clinical studies are needed to confirm that CYP2D6 genotyping could contribute to preventing ADRs in clinical practice.

Background: Longitudinal studies on cognitive disengagement syndrome (CDS) are scarce, and only one study has investigated the trajectory of CDS from childhood to early adulthood. Given this, the aims of the present study were to explore, with a quasi-longitudinal design, (1) whether scores for childhood CDS were associated with scores for CDS during early adulthood; (2) whether childhood CDS scores were associated with childhood and adult scores for depression, anxiety, stress, and insomnia; (3) whether childhood CDS, depression, anxiety, stress, and insomnia and adult depression, anxiety, stress, and insomnia were independently associated with adult scores for CDS, and (4) whether childhood CDS scores were directly and indirectly associated with adult CDS scores via adult depression and stress in two conditional effect models. Methods: A total of 246 young adult students (mean age = 22.62; 56.3% females) participated in a cross-sectional and quasi-longitudinal study. The participants completed questionnaires assessing CDS (Adult Concentration Inventory; ACI), depression, anxiety, stress, and insomnia for the following two developmental periods: for the present time point as young adults and for a past time point, when they were about eight years old. To enable retrospective past recall, the participants undertook a standardized imagination exercise. Results: Childhood scores for CDS, depression, anxiety, stress, and insomnia were highly associated with adult scores for CDS, depression, anxiety, stress, and insomnia. In the regression model, higher childhood scores for CDS, depression, and anxiety and higher adult scores for depression, stress, and insomnia, but not adult anxiety, were strongly and independently associated with adult scores for CDS. In the two conditional effects models, childhood CDS was associated with adult CDS directly and indirectly via adult depression and adult stress. Conclusions: In this quasi-longitudinal study, childhood scores for CDS were associated with adult scores for CDS, suggesting a potentially stable trajectory of CDS from childhood to early adulthood. Further, the two conditional effects models suggested that childhood and adult CDS were both directly and indirectly associated via adult depression and stress. As such, symptoms of depression, anxiety, stress, and insomnia should be considered in conceptualizations of adult CDS. Next, given that standardized psychotherapeutic interventions for depression, stress, and insomnia are available, such interventions might also favorably impact CDS symptoms. These findings further underscore the importance of prospective longitudinal and intervention studies on adult CDS.

Background: Young adulthood is a demanding developmental stage, in that individuals are often faced with making major and long-lasting decisions related to career and family. This is also a heightened time of mental health difficulties. There is recent evidence that cognitive disengagement syndrome (CDS; previously sluggish cognitive tempo) may also be more prevalent in young adults and associated with poorer functioning. However, the relation between CDS symptoms and anxiety, depression, stress, and insomnia remains insufficiently investigated among young adults. Given this, the aims of the present study were as follows: (1) to investigate the associations between CDS and symptoms of depression, anxiety, stress, and insomnia; (2) to investigate if and which dimensions of ill-being were more robustly related to higher CDS scores; (3) to explore if stress scores moderated the associations between CDS symptoms and insomnia; and (4) to explore if higher insomnia categories were associated with higher CDS scores. Methods: A total of 246 young adult students in Switzerland (mean age = 22.62; 56.3% females) completed a booklet of questionnaires covering socio-demographic information, cognitive disengagement syndrome (Adult Concentration Inventory; ACI), and symptoms of depression, anxiety, stress, and insomnia as part of this cross-sectional study. Results: Higher CDS scores on the ACI were associated with higher scores for depression, anxiety, stress, and insomnia. Depression, anxiety, stress, and insomnia were independently associated with higher scores for CDS. Higher categories of stress moderated the associations between higher CDS scores and higher insomnia. Higher insomnia categories were related to higher CDS scores. Conclusions: The present data showed that among a small sample of young adult students, higher CDS scores were associated with higher psychological ill-being (depression, anxiety, stress, and insomnia). If we consider CDS as a trait, specific performance-enhancing medication or psychotherapeutic interventions might favorably influence dimensions of psychological ill-being such as depression, anxiety, stress, and insomnia.

Background: Adolescence is a period of significant psychological, physical, and social changes. During this time, adolescents face increasing responsibilities, such as making educational and career decisions, managing peer relationships, and becoming more independent from their families. These changes are often accompanied by mood fluctuations and altered sleep patterns. This study aimed to explore the relationships between bright- and dark-side hypomania, insomnia, and various dimensions of health-related quality of life (HRQOL), such as self-esteem, family and peer relationships, social acceptance, and autonomy. Methods: A total of 1475 participants in mid-adolescence (mean age: 13.4 years; range: 11–16 years; 48.8% males) completed a series of self-reported questionnaires covering sociodemographic information, hypomania, including dark and bright-side hypomania, insomnia, and HRQOL. Results: Compared to participants with no or dark-side hypomania, participants with bright-side hypomania reported better HRQOL. Bright-side hypomania was significantly associated with favorable relationships with parents and home, peer relationships, and the school environment and with less insomnia. In contrast, dark-side hypomania showed significant associations with lower scores for self-esteem, moods and emotional states, peer relationships, social acceptance, the school environment, and more insomnia. Conclusions: Among a larger sample of adolescents, bright- and dark-side hypomania were associated with a broad, though specific variety of aspects of HRQOL and insomnia. Given that standardized programs are available to improve insomnia and resilience as a proxy of psychological well-being, such interventions may have the potential to improve adolescents’ psychological well-being and sleep quality concomitantly.

Major depressive disorder (MDD) is an increasingly common psychiatric illness associated with a high risk of insufficient physical activity, which in turn is associated with negative mental and physical health outcomes. Theory-based, individually tailored, in-person and remote physical activity counseling has the potential to increase physical activity levels in various populations. Given this, the present study investigated the effect of such a physical activity intervention on the physical activity behavior of in-patients with MDD. This was a multi-center, two-arm randomized controlled trial including initially insufficiently physically active adult in-patients with MDD from four study sites in Switzerland. The sample consisted of 220 participants (M_age = 41 ± 12.6 years, 52% women), 113 of whom were randomized to the intervention group and 107 to the control group. The main outcome, moderate-to-vigorous physical activity (MVPA), was assessed at three time points via hip-worn accelerometer. According to accelerometer measures, there was no significant difference in minutes spent in MVPA over a 12-month intervention period when comparing the intervention with the control group (β = −1.02, 95% CI = −10.68 to 8.64). Higher baseline physical activity significantly predicted physical activity at post and follow-up. This study showed that it is feasible to deliver an individually tailored, theory-based physical activity counseling intervention to in-patients with MDD, however yielding no significant effects on accelerometer-based MVPA levels. Further efforts are warranted to identify efficacious approaches.Trial registration: ISRCTN, ISRCTN10469580, registered on 3rd September 2018, https://www.isrctn.com/ISRCTN10469580.

Background: Patients with major depressive disorder (MDD) are characterized by neurocognitive impairments and show deficits in various cognitive performance indicators, including executive function. We examined whether sustained attention and inhibitory control differ between patients with MDD and healthy controls, and whether differences exist between patients with mild, moderate, and severe depression. Methods: Clinical in-patients (N = 212) aged 18–65 years with a current diagnosis of MDD and 128 healthy controls were recruited. Depression severity was assessed using the Beck Depression Inventory, and sustained attention and inhibitory control were assessed using the oddball and flanker tasks. The use of these tasks promises insights into executive function in depressive patients that are not biased by verbal skills. Group differences were tested via analyses of covariance. Results: Patients with MDD showed slower reaction times in both the oddball and flanker task, independent of the executive demands of the trial types. Younger participants achieved shorter reaction times in both inhibitory control tasks. After correcting for age, education, smoking, BMI, and nationality, only differences in reaction times in the oddball task were statistically significant. In contrast, reaction times were not sensitive to the symptom severity of depression. Conclusion: Our results corroborate deficits in basic information processing and specific impairments in higher-order cognitive processes in MDD patients. As difficulties in executive function underlie problems in planning, initiating, and completing goal-directed activities, they may jeopardize in-patient treatment and contribute to the recurrent nature of depression.