Clozapine is the gold standard for treatment-resistant schizophrenia; however, its superior efficacy is accompanied by potentially serious adverse events (neutropenia, seizures, constipations, pneumonia), many of which are also concentration-dependent. As such, clozapine dose titration should be guided by therapeutic drug monitoring (TDM). However, access to TDM is often limited. The present study describes a new deep neural network that can predict the concentrations, toxicity and therapeutic dose range for clozapine and norclozapine. The model was trained on basic clinical data (biological sex, age, clozapine daily dose, BMI, CRP and number of CYP 1A2 and 3A4 substrates, inhibitors and inducers) from 69 patients with treatment-refractory patients treated with different clozapine doses. Our findings provide the training efficacy data for the model, as well as an analysis of clozapine and norclozapine blood concentrations in a test group of three additional patients, to demonstrate its practical capabilities. The model is licensed on a free and permissive 2-Clause BSD license and is available to all clinicians; it can be accessed as a web application, available at https://csk.umed.pl/clotop.

The predictors of clinical evolution after nonaffective first-episode psychosis (NAFEP) have yet to be fully elucidated. It is important to weigh the long-term benefits of maintained antipsychotic (AP) treatment against the risks of relapse upon discontinuation. Between January 2017 and December 2022, we recruited 211 NAFEP patients from the Programa de Primeros Episodios Psicóticos de Navarra (PEPsNa) who achieved clinical remission within two years and continued follow-up. Clinicians recommended discontinuation of antipsychotics for 47 participants, resulting in significantly fewer relapses (10.6%, p ≤ 0.05) and a longer relapse-free survival time (95% confidence interval= 16.9 to 18.2 months). For every four individuals out of 72 who voluntarily discontinued APs (in contrast to those who were advised to discontinue APs), there was one more relapse (number needed to harm= 4; p ≤ 0.01). Moreover, one additional relapse was prevented for every seven individuals who continued APs instead of voluntarily discontinuing APs (number needed to treat= 7; p ≤ 0.05). Lower premorbid risk factors and better clinical profiles, such as shorter DUP, shorter time to remission, good real-world performance, better neurocognitive functioning, lack of a schizophrenia spectrum diagnosis, and a lower average dose of APs led clinicians to recommend AP discontinuation after achieving remission from NAFEP. This guided discontinuation of APs did not lead to a higher risk of relapse, but participants who voluntarily withdrew from treatment had a higher risk of relapse.

Adverse posttraumatic neuropsychiatric sequelae (APNS) are common after traumatic events. We examined whether wrist-wearable devices could provide heart rate variability (HRV) biomarkers for recovery after traumatic stress exposure in a large socioeconomically disadvantaged cohort. Participants were enrolled in the emergency department within 72 hours after a traumatic event as part of the AURORA (Advancing Understanding of RecOvery afteR traumA) multicenter prospective observational cohort study and followed over 6 months. HRV biomarkers were derived and validated for associations with specific APNS symptoms at a point in time and changes in symptom severity over time. Sixty-four HRV characteristics were derived and validated as cross-sectional biomarkers of APNS symptoms, including pain (26), re-experiencing (8), somatic (7), avoidance (7), concentration difficulty (6), hyperarousal (5), nightmares (1), anxiety (1), and sleep disturbance (3). Changes in 22 HRV characteristics were derived and validated as biomarkers identifying changes in APNS symptoms, including reexperiencing (11), somatic (3), avoidance (2), concentration difficulty (1), hyperarousal (1), and sleep disturbance (4). Changes in HRV variables over time predicted symptom improvement (PPV 0.68-0.87) and symptom worsening (NPV 0.71-0.90). HRV biomarkers collected from wrist-wearable devices may have utility as screening tools for APNS symptoms that occur after traumatic stress exposure in high-risk populations.

The objective of this study was to reveal the effectiveness of repetitive transcranial magnetic stimulation (rTMS) for Japanese patients with treatment-resistant depression (TRD) in clinical practice, based on real-world data from a nationwide multicenter observational study in Japan. Clinical data of patients with TRD treated with rTMS (NeuroStar TMS treatment system) under public insurance coverage were retrospectively collected from 21 institutes nationwide between June 2019 and December 2023. Depression severity was assessed by the 17-item Hamilton Depression Rating Scale (HAMD-17). Response and remission were defined as ≥50 % reduction from baseline and ≤7 points on the HAMD-17, respectively. The primary outcome was the changes in the HAMD-17 score from baseline to the endpoint following rTMS. Data from 497 patients with TRD were candidates for this study. The HAMD-17 scores (mean (SD)) improved significantly from 18.9 (5.3) to 9.7 (6.6), respectively. The response and remission rates at the end of rTMS therapy as assessed by the HAMD-17 were 53.5 % and 42.8 %, respectively. The dropout rate due to adverse effects was 4.2 %, and the treatment was generally well tolerated. No convulsive seizures or manic changes were observed. These results indicate that conventional rTMS is effective and safe in Japanese patients with TRD.

The burden of self-stigma in psychosis has been widely studied, leading to the development and implementation of self-stigma reduction programmes to ameliorate its impact. In order to successfully improve self-stigma in psychosis, we must evaluate the effect of available interventions to help clinicians select the most appropriate approach for their patients. This systematic review and meta-analysis aimed to evaluate the effect of self-stigma reduction interventions in people with psychosis while considering the interventions' characteristics as an important moderator of their effect. The results from this systematic review suggest that interventions involving more than one component, particularly those combining psychoeducation, social skills training and cognitive approaches, were most effective at reducing self-stigma in people with psychosis. Additionally, shorter interventions were found best reduced self-stigma at post-treatment evaluation. A meta-analysis mirrored these results, finding an overall favourable effect of interventions but high heterogeneity in the sample. Subgroup analyses found larger self-stigma reductions following multi-component interventions compared to single-component interventions. An analysis of risk of bias revealed a trend suggesting studies with lower risk of bias produced smaller effects. The results of this review can inform practitioners select and develop interventions to reduce self-stigma in psychosis.

Mental illness increases risk for obesity which is often attributed to medications. We assessed the impact of childhood maltreatment on body-mass-index (BMI) and obesity in N = 261 adult psychiatric inpatients and N = 81 controls. There was an increased risk for obesity in psychiatric inpatients compared to controls. Conditioned random forest regression revealed parental abuse at ages 4-5 and peer-related violence at 7-13 as crucial factors in BMI elevation among individuals with mental illness, while type of psychiatric diagnoses, and use of psychotropics were not. Recognizing this link may aid in understanding the mechanisms and the development of strategies to mitigate the risk.

Therapeutic latency, lack of response, and adverse drug reactions are major challenges in current treatment approaches for major depressive disorder (MDD). Following the success of ketamine, more clinical research on NMDA antagonists is needed for a safe and long-term therapy in MDD. Hence, this study was conducted to evaluate the efficacy and safety of adjunct dextromethorphan to SSRIs in MDD.

The aim of this study was to examine relationships among trauma burden, post-traumatic stress disorder, and perceived social support in a large, diverse group of trauma-exposed children and adolescents followed longitudinally. Specifically, we tested the social erosion hypothesis (i.e., mental health challenges negatively affect the quality of social relationships and contribute to reduced social support over time) using a sample of 1,829 trauma-exposed youth (aged 8-21) recruited through the multi-site Texas Childhood Trauma Research Network. Youth who reported more trauma burden (i.e., a greater number of traumas) perceived significantly lower levels of social support from family and peers, and those with more interpersonal trauma perceived significantly lower levels of social support from all sources, after controlling for multiple demographic variables and psychiatric comorbidities. Notably, the negative associations between trauma and perceived social support were most prominent among individuals without a PTSD diagnosis. Trauma burden was not associated with declines in perceived social support over a 12-month period. Additionally, in these trauma-exposed youth, being assigned female at birth was positively associated with perceived support from family members and negatively associated with perceived social support from a close friend. These findings extend our understanding of how trauma and PTSD independently predict and interact to predict perceived social support.

For many years, it has been widely accepted in the psychiatric field that clinical practice cannot be reduced to finely tuned statistical prediction systems utilizing diverse clinical data. Clinicians are recognized for their unique and irreplaceable roles. In this brief historical overview, viewed through the lens of artificial intelligence (AI), we propose that comprehending the reasoning behind AI can enhance our understanding of clinical reasoning. Our objective is to systematically identify the factors that shape clinical reasoning in medicine, based on six factors that were historically considered beyond the reach of statistical methods: open-endedness, unanalyzed stimulus-equivalences, empty cells, theory mediation, insufficient time, and highly configured functions. Nevertheless, a pertinent consideration in the age of AI is whether these once-considered insurmountable specific factors of clinicians are now subject to scrutiny or not. Through example in AI, we demonstrate that a deeper understanding of these factors not only sheds light on clinical decision-making and its heuristic processes but also underscores the significance of collaboration between AI experts and healthcare professionals. This comparison between AI and clinical reasoning contributes to a better grasp of the current challenges AI faces in the realm of clinical medicine.

Multisensory hallucinations refer to unusual perceptual events in the absence of corresponding stimuli, experienced in two or more sensory modalities. Within the schizophrenia-spectrum disorder literature, the cognitive correlates of multisensory and non-auditory hallucinations remain largely unknown. This scoping review aimed to map and synthesise research that explored relationships between cognition and non-auditory and multisensory hallucinations in schizophrenia-spectrum disorders. Published, peer-reviewed, empirical research studies were sought through three databases: Web of Science, Scopus, and PubMed. Studies that had explored visual, olfactory, tactile, and gustatory hallucinations, or multisensory hallucinations, and their relationships to any basic cognitive mechanisms were included. Of 2218 records identified, a total of 17 studies met inclusion criteria. Visual hallucinations were the most frequently explored (13 studies); followed by olfactory hallucinations (five studies), tactile hallucinations (two studies) and multisensory hallucinations (two studies). Several cognitive mechanisms were studied, yet the majority were only explored in individual studies across the sensory modalities, limiting conclusions that could be drawn. Exploring the potential mechanistic drivers for hallucinations across multiple sensory modalities would advance the field significantly and allow for development of aetiological models that better capture the full gamut of hallucinatory experiences.

The rapid rise in sports betting, especially among young adults (age 18-29), necessitates identifying health correlates of this addictive behavior. The present study examined associations between problem sports betting symptoms and mental health and well-being, which represents a timely literature gap.

Few multination-based studies have examined the longitudinal association between PA (physical activity) and persistence of supra-threshold depressive symptoms (SDS). This cohort study aimed to assess the influence of PA on persistence of SDS. Data were obtained from the Population Survey of Health, Ageing and Retirement in Europe (SHARE). The cohort was composed of individuals with SDS at baseline. Depressive symptoms were ascertained using the EURO-D scale, with a value over 4 indicatives of SDS. The study included 6,631 participants with SDS. After adjusting for nine different covariates at baseline and the changes of PA level during the follow-up period, compared to very low PA, moderately high (OR=0.82; 95 %CI: 0.69-0.98; p = 0.03), and high (OR=0.80; 95 %CI: 0.66-0.95; p = 0.01) PA levels were associated with significantly reduced persistence of depressive symptoms. In a propensity score analysis, matching low and high PA level for baseline scores of EURO-D, people with high PA levels reported a lower EURO-D of 0.53 points (p < 0.0001). In conclusion, among adults with depression, higher levels of PA were associated with a reduced persistence of depression. These real-world data complement evidence on efficacy of exercise as a treatment for depression and can inform clinical guidelines.

The economic burden of schizophrenia amounts for 1.5-3 % of healthcare expenses in developed countries, and ∼50 % derives from direct costs: 81 % of these are due to hospitalization, residential facilities and semi-residential facilities. Therefore, a better characterization of variables that influence direct costs represents a relevant issue. A total of 276 individuals with schizophrenia spectrum disorders receiving treatment from the Community Mental Health Centers of Brescia (Italy) were included in the study: for each participant socio-demographic, clinical and functional characteristics were assessed, and data related to the use of services in 2022 (then converted to costs) were collected. Regression analyses were performed to identify predictors of costs. A direct healthcare expenditure of 16477.23 (±32856.47) € per patient per year was identified. The main cost predictor was the PSP total score (p=0.005), followed by age of onset (p=0.020), and PANSS total score (p=0.033). Including PANSS sub-scales scores and PSP single items as potential predictors, the main predictor was the "socially useful activities" PSP item (p=0.002), followed by age of onset (p=0.011), and PANSS negative scale score (p=0.027). Our findings underline the need to implement rehabilitative intervention focused on the improvement of psychosocial functioning and negative symptoms, also to reduce healthcare expenses.

The relationship between reduced social connectedness and mental health outcomes is increasingly acknowledged. Yet, relatively little is known about how two crucial subjective aspects of social disconnectedness - loneliness and social relationship dissatisfaction (SRD) - are related to clinical and functional recovery. This cohort study aimed to investigate the associations of loneliness and SRD with various mental health outcomes among 15,512 outpatients from a Dutch mental health service. Demographics and data on loneliness, SRD, symptomatic distress, suicidal ideation, and role functioning, as well as treatment duration, and mortality, were collected. The study analyzed the associations between these factors overall and by diagnostic group, gender, and age, using cross-sectional and longitudinal regression, while controlling for relevant covariates. Findings revealed significant, independent, associations between loneliness, SRD, symptomatic distress, and role functioning across different diagnostic groups. Particularly strong associations were noted in bipolar and psychosis-related disorders. Gender did not significantly influence the strength of associations. In older patients, lower levels of loneliness and SRD were observed, but the impact on clinical and functional outcomes was consistent across ages. Higher loneliness and SRD were associated with longer treatment durations, regardless of age, gender or diagnosis. This study indicates the wide-reaching effects of perceived social disconnectedness on recovery and emphasizes interventions targeting loneliness and SRD to enhance outcomes.

As treatment-resistant depression (TRD) is linked to suicidal behaviors and suicidal risk is a predictor of TRD, depression with current suicidal ideation (SI) may lead to TRD. Early identification of TRD risk factors in patients with depression and current SI is crucial. The aims of our study were: i) to identify risk factors for depression non-remission and TRD in patients with depression and current SI; ii) to assess if SI at baseline mediated the relationship between depression severity at baseline and depression remission at week 6. We analyzed data from two large, prospective, naturalistic French cohorts of adult outpatients with depression (DSM-IV criteria) followed for 6 weeks after starting or changing antidepressants (LUEUR and GENESE). Sociodemographic and clinical characteristics, along with early symptom improvement, were compared between patients with and without current SI using logistic regression models (univariate and multivariate). Patients with antidepressant change or initiation were analyzed separately. Those without depression remission at week 6 after an antidepressant change were considered TRD cases. In patients with antidepressant change, the major predictor of non-remission was poorer early improvement (at week 2) of anxiety. For patients with treatment initiation, SI at baseline mediated the relation between depression severity at baseline and depression remission. Depression severity at baseline alone did not explain depression remission. Clinicians should systematically target with specific pharmacological and non-pharmacological treatments anxiety and SI and assess their changes in the short term to increase the chance of depression remission in depressed patients with current SI.

Mindfulness catalyzes health behavior change. Yet, interoception is dysregulated in depression, potentially impairing behavioral activation. We examined the mediating role of interoceptive appreciation, as measured by how much one trusts and listens to internal bodily signals, on behavior change. Primary care patients with depression, anxiety, or stress disorders related to chronic illness were randomized to Mindfulness Training for Primary Care (MTPC) using the Mindful Behavior Change curriculum or a low-dose mindfulness comparator. Participants (N = 274) completed the Multidimensional Assessment of Interoceptive Awareness (MAIA) at 0 and 8 weeks. At week 7, participants chose a health behavior action plan. During weeks 8-10, participants reported their action plan initiation (API) level. We investigated the effect of MTPC on API level (MTPC-API), the mediating role of interoceptive appreciation (Body Listening [MAIA-BL] + Trusting [MAIA-T]), and baseline depression severity as a moderator. MTPC had a significant direct effect on API. Interoceptive appreciation (MAIA-BL + MAIA-T) had a significant indirect effect on API (CI=0.15-0.56). Without depression (n = 76), MAIA-BL partially mediated MTPC-API (CI=0.02-0.87). With moderate-to-severe depression (n = 132), MAIA-T partially mediated MTPC-API (CI=0.01-0.85). Interoceptive appreciation helps people listen to motivating bodily signals. In depression, regaining body trust may be an important step on a mindful path towards change.

Auditory-based targeted cognitive training (ATCT) is an emerging adaptive neuroplasticity-based intervention. Previous studies have shown that electroencephalographic (EEG) biomarkers of auditory information processing assessed at the start of ATCT have predicted cognitive, clinical, and functional gains from a full 30-40 hour ATCT program, but participant attitudes related to coupling EEG to ATCT are not well-known. This study assessed stakeholder feedback related to EEG biomarker collection as part of ATCT to optimize future EEG-informed ATCT studies. Semi-structured interviews assessed attitudes of ATCT-naïve participants (n=50) living with a range of psychiatric disorders and cognitive function who underwent EEG assessment associated with a 1 hour ATCT exercise. A deductive approach was used to code the data and an iterative approach was employed to identify key emerging themes. Interview data yielded 62 unique themes related to EEG biomarker collection and ATCT. Qualitative analysis identified positive and negative elements of participants' experience of EEG-informed ATCT as well as ways to streamline the EEG experience. Results suggest EEG-informed ATCT studies may be optimized using actionable improvements to current protocols leveraged from themes identified.

Functional neurological symptom disorder (FNSD) is a neuropsychiatric diagnosis referring to symptoms resembling those of neurological disorders, occurring without causal neuropathology. FNSD has a complex biopsychosocial aetiology but its mechanisms are poorly understood. Remote monitoring technologies (RMT) could provide critical insights into functional neurological symptoms (FNS) in real-world contexts. We examined the feasibility and acceptability of a novel RMT protocol, to identify psychobiological correlates and antecedents of FNS in everyday life. Seventeen individuals with FNS (seizures/motor) and 17 healthy controls (HC) completed ecological momentary assessments (EMA) eight times daily for 1-week, reporting FNS severity, associated physical and psychological symptoms, and subjectively significant events. Sleep quality was reported daily. Physiological variables were measured using wearable Fitbit 5 devices. Multilevel modelling examined variables associated with FNS variability. Average EMA completion rates were good in both groups (≥80%). At week-level, the FNS group reported significantly greater subjective arousal, pain, fatigue, dissociation, negative affect, daily events, stressful events, and sleep duration, compared to HC. Objective sleep disturbance and duration, and resting heartrate, were also significantly greater in the FNS sample. FNS severity correlated significantly with daily events, affect, subjective arousal, pain, fatigue and sleep disturbance, at day- or within-day levels. Daily events and negative affect were the most prominent time-lagged predictors of within-day moment-to-moment FNS severity. RMTs are feasible and acceptable tools for investigation of FNS in real-world settings, revealing daily events and negative affect as possible triggers of FNS. Interventions targeting affective reactivity and regulation might be beneficial in this group. Larger-scale, longer-term RMT studies are needed in this population.

Psychotic symptoms are of increasing interest in mental health due to their predictive value for future psychotic disorders. While these symptoms are prevalent in the general population, their occurrence varies globally. This study aimed to explore the prevalence and factors associated with psychotic symptoms among individuals identified as substance-naïve and recent abstainers without a history of psychosis. A cross-sectional analysis was conducted on 11,686 participants who reported no lifetime substance use, no substance use in the previous three months, and did not have a diagnosis of psychosis. The study utilized the Psychosis Screening Questionnaire to estimate the one-year prevalence of psychotic symptoms and their associations with demographic and clinical attributes. Results revealed a 3.5 % overall prevalence of psychotic symptoms with 2.9 % prevalence among substance naïve and 4.3 % among recent abstainers. Factors associated with psychotic symptoms were age, being female, having chronic medical conditions, encountering traumatic life events being divorced or separated and lower education levels which positively correlated with symptom scores. There is a need for future investigations and longitudinal studies to uncover the underlying mechanisms and impacts of psychotic symptoms.