Exploring the association between suicidal thoughts, self-injury, and GLP-1 receptor agonists in weight loss treatments: Insights from pharmacovigilance measures and unmasking analysis.

INTRODUCTION: The study addresses concerns about potential psychiatric side effects of Glucagon-like peptide-1 receptor agonists (GLP-1 RA). AIM: The aim of this work was to analyse adverse drug reports (ADRs) from the Food and Drug Administration Adverse Events Reporting System (FAERS) using metformin and orlistat as comparators. METHODS: Descriptive and pharmacovigilance disproportionality analyses was performed. RESULTS: A total of 209,354 ADRs were reported, including 59,300 serious cases. Of those, a total of 5378 psychiatric disorder cases, including 383 'serious' cases related to selected ADRs were registered during 2005-2023. After unmasking, 271 cases where individual GLP-1 RA were implicated showing liraglutide (n = 90; Reported Odds Ratio (ROR) = 1.64), exenatide (n = 67; ROR = 0.80), semaglutide (n = 61; ROR = 2.03), dulaglutide (n = 45; ROR = 0.84), tirzepatide (n = 5; ROR = 1.76) and albiglutide (n = 2; ROR = 0.04). A greater association between these ADRs with metformin was observed, but not orlistat. With regards to selected preferred terms (PTs), 42 deaths including 13 completed suicides were recorded. Suicidal ideation was recorded in n = 236 cases for 6/7 GLP-1 RA (excluding lixisenatide). DISCUSSION: Suicide/self-injury reports pertaining to semaglutide; tirzepatide; and liraglutide were characterised, although lower than metformin. It is postulated that rapid weight loss achieved with GLP-1 RA can trigger significant emotional, biological, and psychological responses, hence possibly impacting on suicidal and self-injurious ideations. CONCLUSIONS: With the current pharmacovigilance approach, no causality link between suicidal ideation and use of any GLP-1 RA can be inferred. There is a need for further research and vigilance in GLP-1 RA prescribing, particularly in patients with co-existing psychiatric disorders.

To bridge or not to bridge: Moral Judgement in Cocaine Use Disorders, a case-control study on human morality.

BACKGROUND: In the "Dual-Process theory", morality is characterized by the interaction between an automatic-emotional process, mediated by the Anterior Cingulate Cortex (ACC) and linked to personal-deontological decisions, and a rational-conscious one, mediated by the Dorso-Lateral Prefrontal Cortex (DLPFC) and linked to impersonal-utilitarian decisions. These areas are altered by chronic use of cocaine, with a possible impact on moral decision-making. OBJECTIVE: To evaluate the difference between a group of Cocaine Use Disorder (CUD) patients and a control group in moral decision-making. METHODS: Subjects with CUD were compared to an equal-sized healthy group regarding their moral decision-making. Trolley and Footbridge Moral Dilemmas were administered to each group. The quality of the answer (yes or no) and the time needed to answer were recorded. RESULTS: The recruited group includes 72 subjects, 36 with CUD and 36 healthy subjects (average age of 39.51 ± 9.89). In the Trolley dilemma, almost all the subjects (97.3%) answered "yes", while in the Footbridge dilemma CUD subjects answered "yes" more often (52.7%) than the healthy group (19.4%). CONCLUSION: For strong emotional dilemmas (Footbridge), cocaine users answered "yes" with a higher frequency compared to healthy subjects, highlighting a wider utilitarian tendency in decision-making and a poor emotional participation.

New/emerging psychoactive substances and associated psychopathological consequences.

BACKGROUND: The present paper provides an updated review of both the large number of new/novel/emerging psychoactive substances (NPS) and their associated psychopathological consequences. Focus was here given on identification of those NPS being commented in specialised online sources and the related short-/long-term psychopathological and medical ill-health effects. METHODS: NPS have been identified through an innovative crawling/navigating software, called the 'NPS.Finder®', created in order to facilitate the process of early recognition of NPS online. A range of information regarding NPS, including chemical and street names; chemical formula; three-dimensional image and anecdotally reported clinical/psychoactive effects, were here made available. RESULTS: Using the 'NPS.Finder®' approach, a few thousand NPS were here preliminarily identified, a number which is about 4-fold higher than those figures suggested by European and international drug agencies. NPS most commonly associated with the onset of psychopathological consequences included here synthetic cannabinoids/cannabimimetics; new synthetic opioids; ketamine-like dissociatives; novel stimulants; novel psychedelics and several prescription and over-the-counter medicines. CONCLUSIONS: The ever-increasing changes in terms of recreational psychotropics' availability represent a relatively new challenge for psychiatry, as the pharmacodynamics and pharmacokinetics of many NPS have not been thoroughly understood. Health/mental health professionals should be informed about the range of NPS; their intake modalities; their psychoactive sought-after effects; the idiosyncratic psychotropics' combinations and finally, their medical and psychopathological risks.

Ambient light modifies gonadotropin-releasing hormone pulse generator frequency in the rhesus monkey.

In the course of previous studies using continuous monitoring of the electrophysiological correlates of GnRH pulse generator activity, characterized by episodic increases in hypothalamic multiunit electrical activity (MUA volley), it was noticed that the nocturnal slowing of pulse generator frequency was an acute phenomenon observable in the first MUA volleys after the lights were turned off, as was the increase in frequency when the lights were turned on in the morning. This suggested that the reduction in pulse generator frequency at night may not be the consequence of an intrinsic diurnal rhythm, but an effect of light per se. Indeed, as reported herein, such an effect was observed when the lights were turned on or off at times other than the normal illumination period (normal light schedule, lights on from 0700-1900 h). That this was not simply a response to arousal was shown by awakening the animals with loud recorded noises in total darkness at the same unaccustomed times without a resulting change in frequency. This suggests that the effect of light is specific, perhaps mediated by the retino-hypothalamic tract. This direct action of light, however, is superimposed upon a diurnal rhythm, as shown by a reduction in pulse generator frequency during the subjective night when the monkeys were kept in constant light or constant darkness.

Glucocorticoid-prolactin interactions in Nb2 lymphoma cells: antiproliferative versus anticytolytic effects.

The interaction between the immunosuppressive effects of glucocorticoids and the mitogenic effects of prolactin (PRL) were examined in Nb2 lymphoma cells, a pre-T cell line. The synthetic glucocorticoid, dexamethasone (Dex), caused a concentration-dependent (6.25-200 nM) inhibition of basal and ovine PRL (oPRL)-stimulated Nb2 cell proliferation. Although Dex was antiproliferative, the steroid had no effect on cell viability in the presence of PRL. However, when PRL was omitted from the medium, Dex increased the proportion of dead Nb2 cells by 24 hr in a concentration (25-200 nM)-dependent fashion without affecting total cell number. The antiproliferative and cytolytic effects of Dex were mimicked by other corticosteroids (cortisol, corticosterone, aldosterone, and deoxycorticosterone) in the expected order of glucocorticoid potency, but not by other steroids (17-beta-estradiol, progesterone, testosterone, 5-alpha-dihydrotestosterone, and dehydroepiandrosterone) or triiodothyronine. In addition, the antiproliferative and cytolytic effects of glucocorticoids were antagonized by the glucocorticoid receptor antagonist RU 486. Since corticosteroid-induced cytolysis was apparent only in the absence of mitogen, the anticytolytic effects of oPRL were tested. In the presence of Dex (100 nM), oPRL (25-1600 pg/ml) caused a concentration-dependent inhibition of cytolysis without changing cell number. Other lactogenic hormones (human growth hormone, human placental lactogen, rat PRL), but not trophic nonlactogenic hormones (rat growth hormone, human chorionic gonadotropin, ACTH), also inhibited Dex (100 nM)-induced cytolysis. Agarose gel electrophoresis of DNA extracted from Nb2 cells revealed that within 12 hr, 100 nM Dex induced DNA fragmentation, indicative of programmed cell death or apoptosis. Coincubation of cells with Dex and oPRL (1 ng/ml) inhibited Dex-induced fragmentation of Nb2 cell genomic DNA. These studies reveal a complex interaction between glucocorticoids and PRL in Nb2 cells. Although a glucocorticoid receptor-mediated antiproliferative effect is evident, PRL (at concentrations that usually stimulate cell proliferation) has the capacity to protect the cell against glucocorticoid-receptor-mediated induction of apoptosis.

Hypoglycemic 'stress' and gonadotropin-releasing hormone pulse generator activity in the rhesus monkey: role of the ovary.

Observations of long standing have suggested that the 'stress' of chair restraint inhibits the GnRH pulse generator in normal female monkeys while this phenomenon is rarely observed in ovariectomized animals. The role of the ovary in the response of the GnRH pulse generator to the stress of insulin hypoglycemia was investigated in both intact and ovariectomized rhesus monkeys. Following an overnight fast the animals, previously habituated to restraint, were placed in primate chairs and GnRH pulse generator activity monitored electrophysiologically. Insulin-induced reductions in mean blood glucose concentrations of 10-40% of control values interrupted pulse generator activity in intact monkeys but were without effect in ovariectomized animals. With larger reductions in blood glucose, pulse generator activity was interrupted in both groups but the inhibition was twice as long in intact than in ovariectomized animals. The reduced responsiveness of ovariectomized animals to insulin hypoglycemia was significantly reversed by estradiol replacement. Naloxone administration did not prevent the hypoglycemia-induced inhibition of pulse generator activity in either intact or ovariectomized rhesus monkeys. It is concluded that hypoglycemic 'stress' inhibits the GnRH pulse generator by a nonopioidergic mechanism and that ovarian products, most probably estradiol, exacerbate this effect.