Tomas Novak

Music is a central component of psychedelic settings, yet little experimental work has examined how psilocybin and musical composition influence music-evoked emotional responses in healthy volunteers. This exploratory, double-blind, placebo-controlled study assessed these effects during the plateau phase of psilocybin and the corresponding time window in placebo sessions following oral administration of psilocybin (0.26 mg/kg) or placebo. The study consisted of two parts. In Part 1 (n = 19), a pilot stage, the first half of participants rated music-induced affective valence for eight compositions representing different genres/subgenres (Rock/Punk, Metal/Industrial Metal, Metal/Industrial Metal, Classical/Baroque, Electronic/Dub, Folk/Nordic Folk, Electronic/Techno, Electronic/Trance, Electronic/Psytrance) using a visual analogue scale (VAS). Based on Part 1, the classical composition with the highest overall affective valence and the psytrance composition with the largest psilocybin–placebo contrast (i.e., the composition most responsive to psilocybin) were selected for Part 2 (n = 17), in which the second half of participants assessed emotional responses to music using the Geneva Emotional Music Scale (GEMS-9). Psilocybin increased wonder, transcendence, and joyful activation across both contrasting compositions. Relative to each other, the classical composition elicited greater peacefulness, tenderness, and nostalgia, whereas the psytrance composition elicited greater tension across both psilocybin and placebo conditions. A composition × condition interaction was observed for sadness: under psilocybin, sadness increased during the classical composition and decreased during the psytrance composition. These findings suggest that psilocybin and contrasting musical compositions independently influence different aspects of music-evoked emotional responses, with limited interaction effects, and point to potential implications for protocol design and music selection in psychedelic settings.

Background: Ketamine is a rapid-acting antidepressant with robust evidence, but unclear predictors of therapeutic response. Objectives: Based on previous knowledge, hemodynamic parameters and acute altered state of consciousness have been hypothesized as potential correlates of subsequent antidepressant outcome. Design: A post hoc analysis was performed using the data from an open-label study, in which 39 patients with depression received a single intravenous infusion of ketamine (0.54 mg/kg). Antidepressant response was defined as ⩾50% reduction in the Montgomery–Åsberg Depression Rating Scale (MADRS) at day 7. Methods: Systolic and diastolic blood pressure (SBP and DBP), heart rate, Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS) were assessed during the infusion, alongside plasma levels of ketamine and norketamine. Data were analyzed using mixed-effects models and correlation and regression techniques. Results: Responders exhibited significantly higher SBP and DBP during ketamine infusion compared with nonresponders. The degree of dissociation or psychotomimetic symptoms during the infusion did not differ significantly between responders and nonresponders. Antipsychotic (AP) augmentation was associated with worse antidepressant outcome as well as with lower infusion-related blood pressure values. CADSS and BPRS did not differ between AP users and nonusers. None of the parameters correlated with plasma levels of ketamine or norketamine. Conclusion: Higher blood pressure during ketamine administration was associated with better antidepressant outcome, supporting the hypothesis concerning sympathetic activation in treatment responders. Psychological parameters (as measured by CADSS and BPRS) were not linked to subsequent outcomes and did not resolve inconsistencies in previous studies. Concomitant antipsychotic medication attenuated ketamine’s antidepressant effects. Trial registration: EudraCT 2018-001539-39.

Despite the clinical importance of bipolar depression (BDE), effective treatment options are still limited. Transcranial magnetic stimulation (rTMS) has proven of moderate efficacy in major depression, but the evidence remains inconclusive for BDE. A four-week, double-blind, randomized, parallel-group, sham-controlled study (trial ID ISRCTN77188420) explored the benefits of 10Hz MRI-guided right ventrolateral (RVL) rTMS and left dorsolateral (LDL) rTMS as add-on treatments for BDE. Outcome measures included changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) score, self-assessment, response and remission rates, and side effects. Sixty patients were randomly assigned to study groups, and forty-six completed the double-blind phase. The mean change from baseline to Week 4 in MADRS was greater in both active groups compared to the sham, yet differences did not achieve significance (RVL vs sham: -4.50, 95%CI -10.63 to 1.64, p = 0.3; LDL vs sham: -4.07, 95%CI -10.24 to 2.10, p = 0.4). None of the other outcome measures yielded significant results. While not demonstrating the superiority of either 10Hz rTMS over sham, with the limited sample size, we can not rule out a moderate yet clinically meaningful effect. Further well-powered studies are essential to elucidate the role of rTMS in managing BDE.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li⁺_PGS) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li⁺_PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi⁺Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li⁺_PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li⁺_PGS was positively associated with lithium treatment response in the ConLi⁺Gen cohort, in both the categorical (P = 9.8 × 10⁻¹², R² = 1.9%) and continuous (P = 6.4 × 10⁻⁹, R² = 2.6%) outcomes. Compared to bipolar patients in the 1^st decile of the risk distribution, individuals in the 10^th decile had 3.47-fold (95%CI: 2.22–5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10⁻⁴, R² = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li⁺_PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi⁺Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1x10^− 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3β. We also found various genes associated with BP’s age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide...