Translational Psychiatry最新文献

Importance: Comparing treatments for severe and medication-resistant depression is essential for guiding clinical decision-making.

Objective: In this meta-analysis, we investigate the efficacy of electroconvulsive therapy (ECT) compared to ketamine for the treatment of major depressive disorder (MDD) and address the discrepant results of prior meta-analyses.

Data sources: We systematically searched PubMED (MEDLINE), Embase, and Cochrane Library databases for studies published up to 31 November 2024.

Study selection: Eligible studies met the following criteria: (1) participants diagnosed with major depression, (2) ECT and ketamine (administered via parenteral routes) treatment arms with comparable treatment durations and assessment periods, and (3) efficacy measured by standardized depression scales at a minimum of two time points.

Data extraction and synthesis: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two independent reviewers assessed study eligibility, evaluated risk of bias (Cochrane Risk of Bias 2 tool), and extracted data from all available time points. A mixed-effects meta-regression analysis incorporated time as a fixed effect - minimising issues arising from temporal discrepancies between studies - and study as a random effect.

Main outcomes and measures: Efficacy was assessed by change in depression symptoms from baseline on a standardised measurement tool.

Results: Seven studies (731 participants) out of 1220 identified articles were eligible for analysis. Depression scores were significantly lower at baseline in the ketamine group compared to ECT (SMD = -0·28; p = 0·018; 95% CI -0·51-·05). Meta-regression analysis, adjusted for baseline scores, revealed a significant effect of time for standardised mean differences (β = 0·018; p < 0·0001; 95% CI 0·009-0·026), indicating that ECT led to a faster rate of improvement of approximately 0·02 SMD per day, amounting to a predicted SMD = 0·59 (95% CI -0·26-1·43) over four weeks.

Conclusions and relevance: ECT resulted in a more rapid reduction of depressive symptoms, with a projected moderate efficacy advantage over ketamine by the end of a four-week course, within the established range for a clinically meaningful benefit.

Repetitive transcranial magnetic stimulation (rTMS) targeting the orbitofrontal cortex (OFC) has shown promise in treating schizophrenia, yet its immediate and long-term effects on brain dynamics remain unclear. This study investigated the electrophysiological impact of OFC-rTMS by analyzing EEG microstates in patients with schizophrenia and healthy controls. A total of 87 patients were randomized to receive either 20 sessions of 1 Hz OFC-rTMS or sham stimulation, while 51 healthy controls received a single active rTMS session. Resting-state EEG recordings were obtained at baseline, immediately after the first session, and following the full course of treatment. Microstate analysis was performed by clustering EEG topographies into four canonical classes and extracting temporal features. At baseline, patients exhibited elevated microstate C and reduced microstate D compared to controls. A single active session reduced microstate C occurrence in both groups, with no changes observed in the sham group. After 20 sessions, the active rTMS group showed a sustained decrease in microstate C and increased microstate D across multiple metrics. Notably, exploratory subgroup analysis revealed that clinical responders to OFC-rTMS exhibited greater immediate reductions in microstate C following the first session compared to non-responders. These findings suggest that OFC-rTMS induces both immediate and long-term modulation of EEG microstates in schizophrenia, particularly normalizing abnormalities in microstate C. Early EEG responses may serve as potential biomarkers for long-term therapeutic response.

Major depressive disorder (MDD) remains a leading cause of disability worldwide, and innovative adjunctive strategies are needed to enhance treatment outcomes. This critical appraisal examines a recent pilot study by Decker et al., which evaluated a 10-12 week well-formulated ketogenic diet (WFKD) as an adjunct therapy for college students with MDD. In this uncontrolled cohort (n = 16 completers), mean PHQ-9 and HRSD scores decreased by approximately 69-71% (p < 0.001), accompanied by notable improvements in self-reported wellbeing, cognitive performance, body composition, and metabolic biomarkers (e.g., leptin reduction, BDNF increase). These findings suggest that metabolic interventions may exert clinically meaningful antidepressant effects comparable to conventional therapies. However, as a single-arm study with a small, self-selected sample, causality cannot be established, and placebo effects or concurrent counseling may have contributed to outcomes. The authors appropriately call for larger, randomized controlled trials with longer follow-up and diverse populations to confirm efficacy, explore underlying mechanisms (e.g., neuroinflammation, gut-brain axis modulation), and optimize implementation. If validated, integrating dietary strategies into psychiatric and college counseling programs could offer a low-risk, holistic approach to improving mental health outcomes.

Hyperactivity is frequently observed in individuals with autism spectrum disorder (ASD) and significantly affects various aspects of life. This underscores the critical need for effective intervention methods tailored to the needs of individuals with ASD. Non-human primate models offer a promising avenue for elucidating the intricate interplay between ASD characteristics and developing individualized therapeutic strategies. This study examined the activity levels and behavioral dynamics in a prenatal valproic acid-induced (VPA) common marmoset model of ASD using ultraminiature data loggers, employing a more detailed approach to behavioral pattern analysis than is traditionally utilized. Although the overall activity levels showed no significant differences, the VPA group exhibited increased activity during specific hours, which is consistent with human ASD studies. Sample Entropy, a statistical measure used to quantify the regularity and unpredictability of time-series data, was higher during daytime in the VPA group, indicating reduced regularity in activity patterns akin to impulsive behavior in ASD. Subtle patterns that were not discernible through simple group comparisons were identified, highlighting the potential of this method as a valuable tool for the behavioral analysis of human ASD. Associations between erratic activity patterns, brief resting intervals, and elevated cortisol levels were observed, all of which correspond to stress phenotypes in individuals with ASD. The findings revealed variations in activity among the adult VPA groups, potentially linked to stress responses. Additionally, VPA juvenile marmosets showed increased locomotor activity in the social interaction test, complementing the adult behavioral findings and suggesting age-dependent manifestations of hyperactivity in this model. This non-human primate model effectively replicates real-world scenarios encountered by individuals with ASD exhibiting hyperactivity, thus holding significant implications for the advancement of personalized therapeutic strategies.

Perceived control is a key mechanism implicated in stress resilience. A tendency to perceive control over stressors may protect individuals against negative outcomes across various situations by increasing active coping and preventing exacerbated stress reactions. Assuming that individual differences in perceived control during an uncontrollable stress task may represent an underlying resilience factor, we investigated associations of perceived control with neural, endocrine, and affective responses to a different, psychosocial stressor, and with overall mental health. 116 male participants aged 18-30 completed a psychosocial stress task, and we assessed stress responses via functional magnetic resonance imaging, cortisol levels, and affective state questionnaires. General mental health was assessed via self-report. Perceived control was measured during a second, uncontrollable stress task and growth mixture modeling revealed a high- and a low-control class. Comparison of these classes showed that the high-control class experienced less helplessness during the uncontrollability task and demonstrated more flexible responses to psychosocial stress as reflected in cortisol secretion and activation of the bilateral posterior insula. Further, the high-control class reported fewer psychosomatic symptoms and a less external locus of control. These findings suggest that perceived control might act as a resilience factor, influencing stress processing across multiple domains. The study highlights the potential for perceived control to be harnessed in resilience-building interventions and underscores the need for further experimental and longitudinal research to confirm its role in modulating stress responses.

Guideline-conform treatment of mental disorders is compromised in immigrant populations, but longitudinal pharmacoepidemiologic patterns in bipolar disorder (BD) remain unknown. We aimed to close this knowledge gap by applying state sequence analysis (SSA) to comprehensively assess individual-level medication use. Psychopharmacological medication use was assessed among Swedish-born, second-generation, non-refugee and refugee first-generation immigrants with incident BD diagnosed in Sweden 2006-2015 (n = 24,578, 16-65 years). Three years of medication-use were conceptualized with SSA as consecutive sequences of three-month periods. Anticonvulsant mood-stabilizer, lithium and antipsychotic use was considered adequate treatment. Typologies were identified by clustering and associated with population groups and covariates applying multinomial logistic regression, yielding odds ratios (OR) for comparison to the majority typology as well as estimated probabilities for each typology. Immigrant populations discontinued medication within 6 months more frequently than Swedish-born (42.1-45.7% vs 36.8%). Transitions from periods lacking medication to adequate treatment showed low likelihood across population groups (8.9-10.1%). Treatment failure (48.3% of refugees, 32.3% of Swedish-born), representing lack of adequate and antidepressant medication, predominated among seven identified typologies. Compared to Swedish-born and treatment failure, adjusted OR for other typologies were lower for refugees (0.3-0.5) and other immigrant groups (0.5-0.8). Adjusting for covariates, highest probabilities for treatment failure were computed for non-refugee (44%) and refugee first-generation immigrants (51%), followed by individuals with low education level (42%) and psychiatric comorbidities (attention-deficit/hyperactivity disorder 38%, substance-use disorder 37%). In conclusion, immigrant groups, particularly refugees, with incident BD are less likely to receive adequate treatment, requiring special emphasis on guideline-conformance.

Cognitive performance has been found to be associated with the complex structure of human cerebral cortex. However, due to the limitations of previous cortical parcellation atlases, the cortical genetic patterns determining cognitive performance remain unknown. Here, we utilized the latest Human Connectome Project Multi-Modal Parcellation (HCP-MMP) atlas to divide the cerebral cortex into 180 regions per hemisphere. We investigated the shared genetic architecture between four types of magnetic resonance imaging (MRI)-derived cortical phenotypes and cognitive performance using large-scale genome-wide association studies (N for cortical phenotypes = 36,843; N for cognitive performance = 257,828). We observed extensive genetic overlap between cortical surface area, volume, and local gyrification index (LGI) with cognitive performance, particularly the subregions in the insula, cingulate cortex, and ventromedial prefrontal cortex, many of which were novel findings. However, the thickness of some prefrontal regions was negatively correlated with cognitive performance. We identified 18 and 312 shared genetic loci for global and regional cortical phenotypes with cognitive performance, respectively. These genetic loci were involved in a substantial number of biological processes related to neuronal development, cell growth, and neuronal death or apoptosis. The cortical patterns defined by these shared loci were established entirely along the sensorimotor-association (S-A) axis. These findings provide new insights into the genetic relationship between cognitive performance and the human cerebral cortex under a more refined multimodal cortical parcellation scheme.

Alcohol use disorder (AUD) is a serious mental health condition and a risk factor for morbidity and preterm death. The drug acamprosate (Campral® - calcium-bis[N-acetylhomotaurinate]) is one of few pharmacological treatments available for AUD. Recent research suggests that the properties of acamprosate may be attributed to calcium, but the acute and long-term effects by calcium supplementation on ethanol-induced dopamine release and relapse-like drinking is not fully known. We used in vivo microdialysis and the alcohol deprivation model, to further define the interaction of local or systemic calcium and ethanol on accumbal dopamine and taurine levels, and to outline the impact of acute and repeated calcium treatment on dopamine and the alcohol deprivation effect (ADE) in male Wistar rats. The role of calcium was further studied by local administration of an L-type Ca²⁺ channel (LTCC) blocker. The results demonstrate that acute local administration of calcium in naïve rats increased nucleus accumbens extracellular dopamine levels, and prevented ethanol from further increasing dopamine. In addition, the ethanol-induced elevation of taurine was delayed in animals receiving calcium. Following sub-chronic systemic calcium administration, the dopamine-elevating property of calcium was lost. The LTCC inhibitor nicardipine decreased accumbal dopamine levels and prevented both calcium and ethanol from altering dopamine output. Acute systemic calcium administration abolished the ADE in treatment-naïve rats, but not in rats pretreated with sub-chronic calcium. Taken together, the results suggest that acute properties of calcium abolish ethanol-induced effects within the mesolimbic dopamine system, while there is an indication of tolerance development to both the dopaminergic and behavioral ethanol-related effects of calcium, thus mimicking the outcomes previously observed with acamprosate.

Psychopharmacotherapy is often used to treat anxiety- and stress-associated psychiatric disorders, including post-traumatic stress disorder (PTSD). Adjunctive therapy is most typically used with medications that influence serotonin balance, such as selective serotonin reuptake inhibitors (SSRIs). Contrary to expectations, SSRIs show an anxiety-increasing effect during the initial treatment phase. Among the 14 different serotonin receptor subtypes, pharmacological studies have demonstrated that 5-HT2C receptors (5-HT2CRs) in the bed nucleus of the stria terminalis (BNST) play a significant role in the anxiogenic effect of acute SSRI treatment. Although numerous studies have confirmed the role of the 5-HT2CR in anxiety behavior, little is known about its involvement in learned fear and fear extinction. In particular, fear extinction is considered a central neural mechanism in the treatment of PTSD patients. Recent results from 5-HT2CR knockout mice (2CKO) revealed that global loss of 5-HT2CRs enhances fear extinction, without affecting fear acquisition. Here, we implemented a chemogenetic approach to examine the neuronal substrate which underlies this extinction-enhancing effect in 2CKO mice. DREADD-activation of BNST^CRF neurons promotes fear extinction in 5-HT2CR WT mice, whereas DREADD-inactivation of BNST^CRF neurons impairs fear extinction in 2CKO mice. Thus, using activating and inactivating DREADDs, we were able to bidirectionally modulate fear extinction. These findings provide a possible explanation for the fear extinction-enhancing effect in 2CKO mice with relevance for the treatment of PTSD patients.