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.

Blood platelets, due to shared biochemical and functional properties with presynaptic serotonergic neurons, constituted, over the years, an attractive peripheral biomarker of neuronal activity. Therefore, the literature strongly focused on the investigation of eventual structural and functional platelet abnormalities in neuropsychiatric disorders, particularly in depressive disorder. Given their impact in biological psychiatry, the goal of the present paper was to review and critically analyze studies exploring platelet activity, functionality, and morpho-structure in subjects with depressive disorder.

According to the PRISMA guidelines, we performed a systematic review through the PubMed database up to March 2020 with the search terms: (1) platelets in depression [Title/Abstract]”; (2) “(platelets[Title]) AND depressive disorder[Title/Abstract]”; (3) “(Platelet[Title]) AND major depressive disorder[Title]”; (4) (platelets[Title]) AND depressed[Title]”; (5) (platelets[Title]) AND depressive episode[Title]”; (6) (platelets[Title]) AND major depression[Title]”; (7) platelet activation in depression[All fields]”; and (8) platelet reactivity in depression[All fields].”

After a detailed screening analysis and the application of specific selection criteria, we included in our review a total of 106 for qualitative synthesis. The studies were classified into various subparagraphs according to platelet characteristics analyzed: serotonergic system (5-HT2A receptors, SERT activity, and 5-HT content), adrenergic system, MAO activity, biomarkers of activation, responsivity, morphological changes, and other molecular pathways.

Despite the large amount of the literature examined, nonunivocal and, occasionally, conflicting results emerged. However, the findings on structural and metabolic alterations, modifications in the expression of specific proteins, changes in the aggregability, or in the responsivity to different pro-activating stimuli, may be suggestive of potential platelet dysfunctions in depressed subjects, which would result in a kind of hyperreactive state. This condition could potentially lead to an increased cardiovascular risk. In line with this hypothesis, we speculated that antidepressant treatments would seem to reduce this hyperreactivity while representing a potential tool for reducing cardiovascular risk in depressed patients and, maybe, in other neuropsychiatric conditions. However, the problem of the specificity of platelet biomarkers is still at issue and would deserve to be deepened in future studies.

Early life stress has been associated with emotional dysregulations and altered architecture of limbic-prefrontal brain systems engaged in emotional processing. Serotonin regulates both, developmental and experience-dependent neuroplasticity in these circuits. Central serotonergic biosynthesis rates are regulated by Tryptophan hydroxylase 2 (TPH2) and transgenic animal models suggest that TPH2-gene associated differences in serotonergic signaling mediate the impact of aversive early life experiences on a phenotype characterized by anxious avoidance.

The present study employed an imaging genetics approach that capitalized on individual differences in a TPH2 polymorphism (703G/T; rs4570625) to determine whether differences in serotonergic signaling modulate the effects of early life stress on brain structure and function and punishment sensitivity in humans (n = 252).

Higher maltreatment exposure before the age of 16 was associated with increased gray matter volumes in a circuitry spanning thalamic-limbic-prefrontal regions and decreased intrinsic communication in limbic-prefrontal circuits selectively in TT carriers. In an independent replication sample, associations between higher early life stress and increased frontal volumes in TT carriers were confirmed. On the phenotype level, the genotype moderated the association between higher early life stress exposure and higher punishment sensitivity. In TT carriers, the association between higher early life stress exposure and punishment sensitivity was critically mediated by increased thalamic-limbic-prefrontal volumes.

The present findings suggest that early life stress shapes the neural organization of the limbic-prefrontal circuits in interaction with individual variations in the TPH2 gene to promote a phenotype characterized by facilitated threat avoidance, thus promoting early adaptation to an adverse environment.

To provide evidence to the link between serotonin (5-HT), energy metabolism, and the human obese phenotype, the present study investigated the binding and function of the platelet 5-HT transporter (SERT), in relation to circulating insulin, leptin, and glycolipid metabolic parameters.

Seventy-four drug-free subjects were recruited on the basis of divergent body mass index (BMIs) (16.5-54.8 Kg/m2). All subjects were tested for their blood glycolipid profile together with platelet [3H]-paroxetine ([3H]-Par) binding and [3H]-5-HT reuptake measurements from April 1st to June 30th, 2019.

The [3H]-Par Bmax (fmol/mg proteins) was progressively reduced with increasing BMIs (P < .001), without changes in affinity. Moreover, Bmax was negatively correlated with BMI, waist/hip circumferences (W/HC), triglycerides (TD), glucose, insulin, and leptin, while positively with high-density lipoprotein (HDL) cholesterol (P < .01). The reduction of 5-HT uptake rate (Vmax, pmol/min/109 platelets) among BMI groups was not statistically significant, but Vmax negatively correlated with leptin and uptake affinity values (P < .05). Besides, [3H]-Par affinity values positively correlated with glycemia and TD, while [3H]-5-HT reuptake affinity with glycemia only (P < .05). Finally, these correlations were specific of obese subjects, while, from multiple linear-regression analysis conducted on all subjects, insulin (P = .006) resulting negatively related to Bmax independently from BMI.

Present findings suggest the presence of a possible alteration of insulin/5-HT/leptin axis in obesity, differentially impinging the density, function, and/or affinity of the platelet SERT, as a result of complex appetite/reward-related interactions between the brain, gut, pancreatic islets, and adipose tissue. Furthermore, they support the foremost cooperation of peptides and 5-HT in maintaining energy homeostasis.