A significant proportion of people with clozapine-treated schizophrenia develop ‘checking’ compulsions, a phenomenon yet to be understood.

To use habit formation models developed in cognitive neuroscience to investigate the dynamic interplay between psychosis, clozapine dose and obsessive–compulsive symptoms (OCS).

Using the anonymised electronic records of a cohort of clozapine-treated patients, including longitudinal assessments of OCS and psychosis, we performed longitudinal multi-level mediation and multi-level moderation analyses to explore associations of psychosis with obsessiveness and excessive checking. Classic bivariate correlation tests were used to assess clozapine load and checking compulsions. The influence of specific genetic variants was tested in a subsample.

A total of 196 clozapine-treated individuals and 459 face-to-face assessments were included. We found significant OCS to be common (37.9%), with checking being the most prevalent symptom. In mediation models, psychosis severity mediated checking behaviour indirectly by inducing obsessions (r = 0.07, 95% CI 0.04–0.09; P < 0.001). No direct effect of psychosis on checking was identified (r = −0.28, 95% CI −0.09 to 0.03; P = 0.340). After psychosis remission (n = 65), checking compulsions correlated with both clozapine plasma levels (r = 0.35; P = 0.004) and dose (r = 0.38; P = 0.002). None of the glutamatergic and serotonergic genetic variants were found to moderate the effect of psychosis on obsession and compulsion (SLC6A4, SLC1A1 and HTR2C) survived the multiple comparisons correction.

We elucidated different phases of the complex interplay of psychosis and compulsions, which may inform clinicians’ therapeutic decisions.

The non-selective serotonin 2A (5-HT2A) receptor agonist lysergic acid diethylamide (LSD) holds promise as a treatment for some psychiatric disorders. Psychedelic drugs such as LSD have been suggested to have therapeutic actions through their effects on learning. The behavioural effects of LSD in humans, however, remain incompletely understood. Here we examined how LSD affects probabilistic reversal learning (PRL) in healthy humans.

Healthy volunteers received intravenous LSD (75 μg in 10 mL saline) or placebo (10 mL saline) in a within-subjects design and completed a PRL task. Participants had to learn through trial and error which of three stimuli was rewarded most of the time, and these contingencies switched in a reversal phase. Computational models of reinforcement learning (RL) were fitted to the behavioural data to assess how LSD affected the updating (‘learning rates’) and deployment of value representations (‘reinforcement sensitivity’) during choice, as well as ‘stimulus stickiness’ (choice repetition irrespective of reinforcement history).

Raw data measures assessing sensitivity to immediate feedback (‘win-stay’ and ‘lose-shift’ probabilities) were unaffected, whereas LSD increased the impact of the strength of initial learning on perseveration. Computational modelling revealed that the most pronounced effect of LSD was the enhancement of the reward learning rate. The punishment learning rate was also elevated. Stimulus stickiness was decreased by LSD, reflecting heightened exploration. Reinforcement sensitivity differed by phase.

Increased RL rates suggest LSD induced a state of heightened plasticity. These results indicate a potential mechanism through which revision of maladaptive associations could occur in the clinical application of LSD.

The serotonin (5-HT) hypothesis of anorexia nervosa (AN) posits that individuals predisposed toward or recovered from AN (recAN) have a central nervous hyperserotonergic state and therefore restrict food intake as a means to reduce 5-HT availability (via diminished tryptophan-derived precursor supply) and alleviate associated negative mood states. Importantly, the 5-HT system has also been generally implicated in reward processing, which has also been shown to be altered in AN.

In this double-blind crossover study, 22 individuals recAN and 25 healthy control participants (HC) underwent functional magnetic resonance imaging (fMRI) while performing an established instrumental reward learning paradigm during acute tryptophan depletion (ATD; a dietary intervention that lowers central nervous 5-HT availability) as well as a sham depletion.

On a behavioral level, the main effects of reward and ATD were evident, but no group differences were found. fMRI analyses revealed a group × ATD × reward level interaction in the ventral anterior insula during reward anticipation as well as in the medial orbitofrontal cortex during reward consumption.

The precise pattern of results is suggestive of a ‘normalization’ of reward-related neural responses during ATD in recAN compared to HC. Our results lend further evidence to the 5-HT hypothesis of AN. Decreasing central nervous 5-HT synthesis and availability during ATD and possibly also by dieting may be a means to normalize 5-HT availability and associated brain processes.

Major depressive disorder (MDD) is closely related to obesity, inflammation, and insulin resistance, all together being etiologically linked to metabolic syndrome (MetS) development. The depressive disorder has a neuroendocrinological component, co-influencing the MetS, while MetS is characterised by increased cytokine levels, which are known to cause a depressed mood. This study aimed to establish biological subtypes of the depressive disorder based on researched clinical, laboratory, and anthropometric variables.

We performed a cross-sectional study on a sample of 293 subjects (145 suffering from a depressive disorder and 148 healthy controls). Results were analysed with multivariate statistical methods as well as with cluster and discriminant analysis. In order to classify depressive disorder on the grounds of laboratory, anthropometric, and clinical parameters, we performed cluster analysis, which resulted in three clusters.

The first cluster is characterised by low platelet serotonin, high cortisol levels, high blood glucose levels, high triglycerides levels, high Hamilton Depression Rating Scale score, high waist circumference, high C-Reactive Protein values, and a high number of previous depressive episodes, was named Combined (Metabolic) depression. The inflammatory depression cluster is defined with average platelet serotonin values, normal cortisol, and all other parameter levels, except for increased IL-6 levels. The serotoninergic depression cluster is characterised by markedly low platelet serotonin, and all other parameters are within the normal range.

From a biological point of view, depressive disorder is not uniform, and as such, these findings suggest potential clinically useful and generalisable biological subtypes of depressive disorder.

SSRI-treated psychiatric disorders (STPD), such as general anxiety disorder and major depression disorder, are common psychiatric diagnoses. Serotonin-mediated effects of solar insolation are an active topic of research. Artificial intelligence (AI) could help to better examine that complex relation.

To investigate whether AI could predict the STPD relying primarily on average ambient temperature and annual solar insolation.

Data of age, average ambient temperature and annual solar insolation were employed to predict STPD status in 7,587 subjects using an AI. To simplify the data analysis, only individuals with white ethnicity were assessed. SPTD prevalence was 17.1%. The AI was conservatively tuned to maximize the positive likelihood ratio considering predicted and real STPD statuses. The free and open source programming language R was used for all the analyses. Dataset source: Wortzel, Joshua; Kent, Shia; Avery, David; Al-Hamdan, Mohammad; Turner, Brandon; Norden, Justin; Norden, Michael; Haynor, David (2018), “Data for: Ambient temperature and solar insolation are associated with decreased prevalence of SSRI-treated psychiatric disorders”, Mendeley Data, V1, doi: 10.17632/trs43ybh92.1

Predictions obtained a positive likelihood ratio of 4.850. The results were indicative of fair performance.

AI might be useful to predict STPD. Furthermore, the results of this study might indicate a moderate effect of age, average ambient temperature and annual solar insolation on the probability of STPD occurrence. Finally, the AI used in this study is freely available, allowing anyone to experiment.

Real-life decisions are often complex because they involve making sequential choices that constrain future options. We have previously shown that to render such multi-step decisions manageable, people ‘prune’ (i.e. selectively disregard) branches of decision trees that contain negative outcomes. We have theorized that sub-optimal pruning contributes to depression by promoting an oversampling of branches that result in unsavoury outcomes, which results in a negatively-biased valuation of the world. However, no study has tested this theory in depressed individuals.

Thirty unmedicated depressed and 31 healthy participants were administered a sequential reinforcement-based decision-making task to determine pruning behaviours, and completed measures of depression and anxiety. Computational, Bayesian and frequentist analyses examined group differences in task performance and relationships between pruning and depressive symptoms.

Consistent with prior findings, participants robustly pruned branches of decision trees that began with large losses, regardless of the potential utility of those branches. However, there was no group difference in pruning behaviours. Further, there was no relationship between pruning and levels of depression/anxiety.

We found no evidence that sub-optimal pruning is evident in depression. Future research could determine whether maladaptive pruning behaviours are observable in specific sub-groups of depressed patients (e.g. in treatment-resistant individuals), or whether misuse of other heuristics may contribute to depression.

Whereas numerous experimental and clinical studies suggest a complex involvement of serotonin in the regulation of anxiety, it remains to be clarified if the dominating impact of this transmitter is best described as anxiety-reducing or anxiety-promoting. The aim of this study was to assess the impact of serotonin depletion on acquisition, consolidation, and expression of conditioned fear.

Male Sprague–Dawley rats were exposed to foot shocks as unconditioned stimulus and assessed with respect to freezing behaviour when re-subjected to context. Serotonin depletion was achieved by administration of a serotonin synthesis inhibitor, para-chlorophenylalanine (PCPA) (300 mg/kg daily × 3), (i) throughout the period from (and including) acquisition to (and including) expression, (ii) during acquisition but not expression, (iii) after acquisition only, and (iv) during expression only.

The time spent freezing was significantly reduced in animals that were serotonin-depleted during the entire period from (and including) acquisition to (and including) expression, as well as in those being serotonin-depleted during either acquisition only or expression only. In contrast, PCPA administrated immediately after acquisition, that is during memory consolidation, did not impact the expression of conditioned fear.

Intact serotonergic neurotransmission is important for both acquisition and expression of context-conditioned fear.

Risk is an essential trait of most daily decisions. Our behaviour when faced with risks involves evaluation of many factors including the outcome probabilities, the valence (gains or losses) and past experiences. Several psychiatric disorders belonging to distinct diagnostic categories, including pathological gambling and addiction, show pathological risk-taking and implicate abnormal dopaminergic, opioidergic and serotonergic neurotransmission. In this study, we adopted a transdiagnostic approach to delineate the neurochemical substrates of decision making under risk.

We recruited 39 participants, including 17 healthy controls, 15 patients with pathological gambling and seven binge eating disorder patients, who completed an anticipatory risk-taking task. Separately, participants underwent positron emission tomography (PET) imaging with three ligands, [18F]fluorodopa (FDOPA), [11C]MADAM and [11C]carfentanil to assess presynaptic dopamine synthesis capacity and serotonin transporter and mu-opioid receptor binding respectively.

Risk-taking behaviour when faced with gains positively correlated with dorsal cingulate [11C]carfentanil binding and risk-taking to losses positively correlated with [11C]MADAM binding in the caudate and putamen across all subjects.

We show distinct neurochemical substrates underlying risk-taking with the dorsal cingulate cortex mu-opioid receptor binding associated with rewards and dorsal striatal serotonin transporter binding associated with losses. Risk-taking and goal-directed control appear to dissociate between dorsal and ventral fronto-striatal systems. Our findings thus highlight the potential role of pharmacological agents or neuromodulation on modifying valence-specific risk-taking biases.