Incident infection during the first year of treatment – A comparison of clozapine and paliperidone palmitate long-acting injection

Background: To examine the risk of infection in patients prescribed clozapine compared with patients prescribed paliperidone palmitate long-acting injection (PPLAI). Method: A retrospective, 1-year, cohort study conducted on events occurring in eligible patients beginning treatment for the first time with clozapine or PPLAI between June 2017 and June 2019 in a UK mental health trust providing in-patient and out-patient services. Results: The study included 64 patients starting clozapine and 120 patients starting PPLAI. Incidence of infection was greater in clozapine starters than in PPLAI starters (28% vs 6%; p = 0.001; adjusted odds ratio 5.82 (95% confidence interval (CI) = 2.15–15.76, p = 0.001). Infectious episodes in clozapine patients were not related to changes in neutrophil counts. Incident infection in the clozapine group was highest in the first 3 months of treatment. The most commonly reported infection in the clozapine group was chest infection; however, the majority of infections were non-chest-related. Conclusion: Patients starting clozapine showed a substantially increased likelihood of infection compared with patients starting PPLAI.

A phase 1 study to assess potential interaction between ASP8062 and alcohol in healthy adult subjects

Background: ASP8062 is a novel orally active GABAB receptor positive allosteric modulator in clinical development for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD). Aims: This study assessed the potential pharmacokinetic/pharmacodynamic interaction between ASP8062 and alcohol under single-dose conditions in healthy adults. Methods: A double-blind, placebo-controlled, crossover phase 1 study was conducted in which 20 subjects were randomly assigned to four treatment sequences (ASP8062 + alcohol; ASP8062 + placebo alcohol; placebo + alcohol; placebo + placebo alcohol) each consisting of four treatment periods, separated by washout periods of at least 14 days. An analysis of variance was used to assess pharmacokinetic interaction and a mixed-effects analysis of covariance was used to assess pharmacodynamic interaction. Results/outcomes: After administration of alcohol, a mild to minimal increase in plasma exposure (AUCinf and Cmax) of ASP8062 was observed, but tmax and t½ for ASP8062 remained unchanged after administration of alcohol. In contrast, ASP8062 did not affect the AUClast and Cmax of ethanol. No clinically relevant differences in cognition measurements were observed with ASP8062 compared with placebo, but there were expected impairments in psychomotor and executive function with alcohol alone. ASP8062 in combination with alcohol resulted in worse scores in cognition measurements than alcohol alone, but this potentiation was not consistent. ASP8062 administered alone was safe and well-tolerated and safety findings in subjects administered alcohol alone were not augmented when ASP8062 was administered in combination with alcohol. Conclusion/interpretation: The data support further clinical studies investigating ASP8062 in patients with AUD.

Lifetime use of MDMA/ecstasy and psilocybin is associated with reduced odds of major depressive episodes

Background: Depression is a major mental health issue worldwide, with high rates of chronicity and non-recovery associated with the condition. Existing treatments such as antidepressant medication and psychological treatments have modest effectiveness, suggesting the need for alternative interventions. Aim: The aim of this study was to examine the relationships between MDMA (3,4-methylenedioxymethamphetamine)/ecstasy and psilocybin use and major depressive episodes (MDEs). Methods: This observational study used data from a large ( N = 213,437) nationally representative sample of US adults to test the association of lifetime use of MDMA/ecstasy, psilocybin and other classic psychedelics (lysergic acid diethylamide (LSD), peyote, mescaline), other illegal substances (e.g. cocaine, phencyclidine (PCP)), and legal/medicinal substances of misuse (e.g. pain relievers, tranquilizers) with lifetime, past year, and past year severe MDEs. Results: Results revealed that lifetime MDMA/ecstasy use was associated with significantly lowered odds of a lifetime MDE (adjusted odds ratio (aOR) = 0.84; p < 0.001), past year MDE (aOR = 0.84; p < 0.001), and past year severe MDE (aOR = 0.82; p < 0.001). Psilocybin was associated with significantly lowered odds of a past year MDE (aOR = 0.90; p < 0.05) and past year severe MDE (aOR = 0.87; p < 0.05). All other substances either shared no relationship with a MDE or conferred increased odds of an MDE. Conclusions: These results suggest that MDMA/ecstasy and psilocybin use is associated with lower risk of depression. Experimental studies are needed to test whether there is a causal association between use of these compounds and the alleviation of depressive symptoms.

Validation of the Psychological Insight Scale: A new scale to assess psychological insight following a psychedelic experience

Introduction: As their name suggests, ‘psychedelic’ (mind-revealing) compounds are thought to catalyse processes of psychological insight; however, few satisfactory scales exist to sample this. This study sought to develop a new scale to measure psychological insight after a psychedelic experience: the Psychological Insight Scale (PIS). Methods: The PIS is a six- to seven-item questionnaire that enquires about psychological insight after a psychedelic experience (PIS-6) and accompanied behavioural changes (PIS item 7). In total, 886 participants took part in a study in which the PIS and other questionnaires were completed in a prospective fashion in relation to a planned psychedelic experience. For validation purposes, data from 279 participants were analysed from a non-specific ‘global psychedelic survey’ study. Results: Principal components analysis of PIS scores revealed a principal component explaining 73.57% of the variance, which displayed high internal consistency at multiple timepoints throughout the study (average Cronbach’s α = 0.94). Criterion validity was confirmed using the global psychedelic survey study, and convergent validity was confirmed via the Therapeutic-Realizations Scale. Furthermore, PIS scores significantly mediated the relationship between emotional breakthrough and long-term well-being. Conclusion: The PIS is complementary to current subjective measures used in psychedelic studies, most of which are completed in relation to the acute experience. Insight – as measured by the PIS – was found to be a key mediator of long-term psychological outcomes following a psychedelic experience. Future research may investigate how insight varies throughout a psychedelic process, its underlying neurobiology and how it impacts behaviour and mental health.

MDMA/ecstasy use and psilocybin use are associated with lowered odds of psychological distress and suicidal thoughts in a sample of US adults

Background: Suicide is one of the leading causes of death worldwide and rates within the United States have risen over the past two decades. Hence, there is a critical need for novel tools to treat suicidal ideation and related mental health conditions. 3,4-Methylenedioxymethamphetamine (MDMA)/ecstasy and classic psychedelics may be two such tools. Aims: The aim of this study was to assess non-causal associations between MDMA/ecstasy and classic psychedelic use and psychological distress and suicide risk. Methods: In this study, we examined the aforementioned associations among 484,732 adult participants in the National Survey on Drug Use and Health (2008–2019). Results: Lifetime MDMA/ecstasy use was associated with reduced odds of past year suicidal thinking (10% reduced odds; odds ratio (OR) = 0.90; 95% confidence interval, CI = (0.84–0.97); p < 0.01) and past year suicidal planning (OR = 0.88; 95% CI = (0.78–0.99); p < 0.05). Furthermore, lifetime psilocybin use was associated with reduced odds of past month psychological distress (OR = 0.78; 95% CI = (0.73–0.84); p < 0.001) and past year suicidal thinking (OR = 0.90; 95% CI = (0.83–0.96); p < 0.01). Finally, lysergic acid diethylamide (LSD) was associated with increased odds of past year suicidal thinking (OR = 1.07; 95% CI = (1.00–1.15); p < 0.05). Conclusion: MDMA/ecstasy and psilocybin use are associated with reduced odds of suicidal thinking and related outcomes—though experimental studies are needed to determine whether these associations are causal. These findings call for more research into the efficacy of MDMA/ecstasy and classic psychedelics for treating psychological distress and suicidal thoughts and behaviors, and for updated drug legislation that allows for further investigation into these substances.

The effects of psilocybin on cognitive and emotional functions in healthy participants: Results from a phase 1, randomised, placebo-controlled trial involving simultaneous psilocybin administration and preparation

Background: Psilocybin, a psychoactive serotonin receptor partial agonist, has been reported to acutely reduce clinical symptoms of depressive disorders. Psilocybin’s effects on cognitive function have not been widely or systematically studied. Aim: The aim of this study was to explore the safety of simultaneous administration of psilocybin to healthy participants in the largest randomised controlled trial of psilocybin to date. Primary and secondary endpoints assessed the short- and longer-term change in cognitive functioning, as assessed by a Cambridge Neuropsychological Test Automated Battery (CANTAB) Panel, and emotional processing scales. Safety was assessed via endpoints which included cognitive function, assessed by CANTAB global composite score, and treatment-emergent adverse event (TEAE) monitoring. Methods: In this phase 1, randomised, double-blind, placebo-controlled study, healthy participants ( n = 89; mean age 36.1 years; 41 females, 48 males) were randomised to receive a single oral dose of 10 or 25 mg psilocybin, or placebo, administered simultaneously to up to six participants, with one-to-one psychological support – each participant having an assigned, dedicated therapist available throughout the session. Results: In total, 511 TEAEs were reported, with a median duration of 1.0 day; 67% of all TEAEs started and resolved on the day of administration. There were no serious TEAEs, and none led to study withdrawal. There were no clinically relevant between-group differences in CANTAB global composite score, CANTAB cognitive domain scores, or emotional processing scale scores. Conclusions: These results indicate that 10 mg and 25 mg doses of psilocybin were generally well tolerated when given to up to six participants simultaneously and did not have any detrimental short- or long-term effects on cognitive functioning or emotional processing. Clinical Trial Registration: EudraCT ( https://www.clinicaltrialsregister.eu/ ) number: 2018-000978-30.

Activation of the aryl hydrocarbon receptor by clozapine induces preadipocyte differentiation and contributes to endothelial dysfunction

Background: The superior therapeutic benefit of clozapine is often associated with metabolic disruptions as obesity, insulin resistance, tachycardia, higher blood pressure, and even hypertension. Aims: These adverse vascular/ metabolic events under clozapine are similar to those caused by polycyclic aromatic hydrocarbons (PAHs), and clozapine shows structural similarity to well-known ligands of the aryl hydrocarbon receptor (AhR). Therefore, we speculated that the side effects caused by clozapine might rely on AhR signaling. Methods: We examined clozapine-induced AhR activation by luciferase reporter assays in hepatoma HepG2 cells and we proved upregulation of the prototypical AhR target gene Cyp1A1 by realtime-PCR (RT-PCR) analysis and enzyme activity. Next we studied the physiological role of AhR in clozapine’s effects on human preadipocyte differentiation and on vasodilatation by myography in wild-type and AhR-/- mice. Results: In contrast to other antipsychotic drugs (APDs), clozapine triggered AhR activation and Cyp1A1 expression in HepG2 cells and adipocytes. Clozapine induced adipogenesis via AhR signaling. After PGF2α-induced constriction of mouse aortic rings, clozapine strongly reduced the maximal vasorelaxation under acetylcholine in rings from wild-type mice, but only slightly in rings from AhR-/- mice. The reduction was also prevented by pretreatment with the AhR antagonist CH-223191. Conclusion: Identification of clozapine as a ligand for the AhR opens new perspectives to explain common clozapine therapy-associated adverse effects at the molecular level.

Impact of drug-induced Parkinsonism and tardive dyskinesia on health-related quality of life in schizophrenia

Background: Both drug-induced Parkinsonism (DIP) and tardive dyskinesia (TD) have been shown to be associated with lower health-related quality of life (HRQOL) in schizophrenia, but few studies have examined their relative impact. Aims: This study aimed to examine and compare the association of DIP and TD with HRQOL in schizophrenia. Methods: In total, 903 patients with schizophrenia were assessed on the Positive and Negative Syndrome Scale (PANSS), Simpson-Angus Scale (SAS), and Abnormal Involuntary Movement Scale (AIMS). EuroQoL five-dimensional (EQ-5D-5L) utility scores were derived from PANSS scores via a previously validated algorithm and used as a measure of HRQOL. Results: In total, 160 (17.7%) participants had only DIP, 119 (13.2%) had only TD, and 123 (13.6%) had both DIP and TD. HRQOL was lowest for participants with both DIP and TD, followed by only DIP group, only TD group, and highest in the group with neither condition. HRQOL scores differed significantly between the four groups, F(3, 892) = 13.724, p < 0.001, [Formula: see text] = 0.044). HRQOL of participants having only DIP or both DIP and TD was significantly lower than those having neither condition. There was no significant interaction between the presence of DIP and TD on the association with HRQOL. Conclusions: DIP was the main antipsychotic-induced movement disorder associated with a poorer HRQOL in patients with schizophrenia. Therefore, clinicians should focus on prevention, detection, and effective management of DIP to optimize HRQOL in patients with schizophrenia.

Sex-dependent metabolism of ketamine and (2R,6R)-hydroxynorketamine in mice and humans

Background: Ketamine is rapidly metabolized to norketamine and hydroxynorketamine (HNK) metabolites. In female mice, when compared to males, higher levels of ( 2R,6R;2S,6S)-HNK have been observed following ketamine treatment, and higher levels of ( 2R,6R)-HNK following the direct administration of ( 2R,6R)-HNK. Aim: The objective of this study was to evaluate the impact of sex in humans and mice, and gonadal hormones in mice on the metabolism of ketamine to form norketamine and HNKs and in the metabolism/elimination of ( 2R,6R)-HNK. Methods: In CD-1 mice, we utilized gonadectomy to evaluate the role of circulating gonadal hormones in mediating sex-dependent differences in ketamine and ( 2R,6R)-HNK metabolism. In humans (34 with treatment-resistant depression and 23 healthy controls) receiving an antidepressant dose of ketamine (0.5 mg/kg i.v. infusion over 40 min), we evaluated plasma levels of ketamine, norketamine, and HNKs. Results: In humans, plasma levels of ketamine and norketamine were higher in males than females, while ( 2R,6R;2S,6S)-HNK levels were not different. Following ketamine administration to mice (10 mg/kg i.p.), Cmax and total plasma concentrations of ketamine and norketamine were higher, and those of ( 2R,6R;2S,6S)-HNK were lower, in intact males compared to females. Direct ( 2R,6R)-HNK administration (10 mg/kg i.p.) resulted in higher levels of ( 2R,6R)-HNK in female mice. Ovariectomy did not alter ketamine metabolism in female mice, whereas orchidectomy recapitulated female pharmacokinetic differences in male mice, which was reversed with testosterone replacement. Conclusion: Sex is an important biological variable that influences the metabolism of ketamine and the HNKs, which may contribute to sex differences in therapeutic antidepressant efficacy or side effects.