Psychedelics in developmental stuttering to modulate brain functioning: a new therapeutic perspective?

Developmental stuttering (DS) is a neurodevelopmental speech-motor disorder characterized by symptoms such as blocks, repetitions, and prolongations. Persistent DS often has a significant negative impact on quality of life, and interventions for it have limited efficacy. Herein, we briefly review existing research on the neurophysiological underpinnings of DS -specifically, brain metabolic and default mode/social-cognitive networks (DMN/SCN) anomalies- arguing that psychedelic compounds might be considered and investigated (e.g., in randomized clinical trials) for treatment of DS. The neural background of DS is likely to be heterogeneous, and some contribution from genetically determinants of metabolic deficiencies in the basal ganglia and speech-motor cortical regions are thought to play a role in appearance of DS symptoms, which possibly results in a cascade of events contributing to impairments in speech-motor execution. In persistent DS, the difficulties of speech are often linked to a series of associated aspects such as social anxiety and social avoidance. In this context, the SCN and DMN (also influencing a series of fronto-parietal, somato-motor, and attentional networks) may have a role in worsening dysfluencies. Interestingly, brain metabolism and SCN/DMN connectivity can be modified by psychedelics, which have been shown to improve clinical evidence of some psychiatric conditions (e.g., depression, post-traumatic stress disorder, etc.) associated with psychological constructs such as rumination and social anxiety, which also tend to be present in persistent DS. To date, while there have been no controlled trials on the effects of psychedelics in DS, anecdotal evidence suggests that these agents may have beneficial effects on stuttering and its associated characteristics. We suggest that psychedelics warrant investigation in DS.

Optimal dose for the efficacy of asenapine in patients with schizophrenia: Real-world data.

AIMS: A meta-analysis of short-term studies revealed no significant differences between the doses of asenapine, 10 and 20 mg/day, in the acute treatment of schizophrenia. However, it should be noted that many patients from clinical practice were excluded, and the dose-response to asenapine in a real-world setting is still unclear. Additionally, the dose-response in the maintenance phase is not clear. This study aimed to evaluate the differences in the efficacy of different asenapine doses in patients with maintenance phase of schizophrenia in a real-world setting. METHODS: This study conducted post-marketing surveillance of asenapine in clinical settings in Japan. It followed patients diagnosed with schizophrenia who received asenapine for the first time for a maximum of 52 weeks. These patients were divided into two categories based on their average daily asenapine dosage: ≤10 mg/day and >10 mg/day. Asenapine efficacy was assessed by adjusting for patient demographics using multivariate logistic regression analysis, employing the Clinical Global Impression-Global Improvement (CGI-I) scale, which has seven categories. RESULTS: A total of 2774 patients were included in the analysis. Of these, 1689 and 1085 patients were treated with asenapine ≤10 mg/day and >10 mg/day, respectively. The CGI-I improvement rate was significantly higher in the asenapine >10 group (p = 0.012) after adjusting for patient background factors. CONCLUSION: These results suggest that asenapine doses >10 mg/day may be more effective than 10 mg/day in the treatment of schizophrenia; however, further studies are needed to confirm these findings.

Recent applications of positron emission tomographic (PET) imaging in psychiatric drug discovery.

INTRODUCTION: Psychiatry is one of the medical disciplines that suffers most from a lack of innovation in its therapeutic arsenal. Many failures in drug candidate trials can be explained by pharmacological properties that have been poorly assessed upstream, in terms of brain passage, brain target binding and clinical outcomes. Positron emission tomography can provide pharmacokinetic and pharmacodynamic data to help select candidate-molecules for further clinical trials. AREAS COVERED: This review aims to explain and discuss the various methods using positron-emitting radiolabeled molecules to trace the cerebral distribution of the drug-candidate or indirectly measure binding to its therapeutic target. More than an exhaustive review of PET studies in psychopharmacology, this article highlights the contributions this technology can make in drug discovery applied to psychiatry. EXPERT OPINION: PET neuroimaging is the only technological approach that can, in vivo in humans, measure cerebral delivery of a drug candidate, percentage and duration of target binding, and even the pharmacological effects. PET studies in a small number of subjects in the early stages of the development of a psychotropic drug can therefore provide the pharmacokinetic/pharmacodynamic data required for subsequent clinical evaluation. While PET technology is demanding in terms of radiochemical, radiopharmacological and nuclear medicine expertise, its integration into the development process of new drugs for psychiatry has great added value.

Psychedelic therapy in the treatment of addiction: the past, present and future.

Psychedelic therapy has witnessed a resurgence in interest in the last decade from the scientific and medical communities with evidence now building for its safety and efficacy in treating a range of psychiatric disorders including addiction. In this review we will chart the research investigating the role of these interventions in individuals with addiction beginning with an overview of the current socioeconomic impact of addiction, treatment options, and outcomes. We will start by examining historical studies from the first psychedelic research era of the mid-late 1900s, followed by an overview of the available real-world evidence gathered from naturalistic, observational, and survey-based studies. We will then cover modern-day clinical trials of psychedelic therapies in addiction from first-in-human to phase II clinical trials. Finally, we will provide an overview of the different translational human neuropsychopharmacology techniques, including functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), that can be applied to foster a mechanistic understanding of therapeutic mechanisms. A more granular understanding of the treatment effects of psychedelics will facilitate the optimisation of the psychedelic therapy drug development landscape, and ultimately improve patient outcomes.

A Longitudinal Investigation of Blood Neurofilament Light Chain Levels in Chronic Cocaine Users.

The identification of a blood marker of brain pathology that is sensitive to substance-induced neurotoxicity and dynamically responds to longitudinal changes in substance intake would substantially improve clinical monitoring in the field of substance use and addiction. Here, we explored the hypothesis that plasma levels of neurofilament light chain (NfL), a promising marker of neuroaxonal pathology, are elevated in chronic cocaine users and longitudinally associated with changes in cocaine use. Plasma NfL levels were determined using single molecule array (SIMOA) technology at baseline and at a 4-month follow-up. Substance use was subjectively assessed with an extensive interview and objectively measured via toxicological analysis of urine and 4-month hair samples. In a generalized linear model corrected for sex, age, and body mass index, NfL plasma levels were elevated in cocaine users (n=35) compared to stimulant-naïve healthy controls (n=35). A positive correlation between cocaine hair concentration and NfL levels was also found. Changes in cocaine hair concentration (group analysis of increasers vs. decreasers) over the 4-month interval predicted NfL levels at follow-up, indicating a rise in NfL with increased cocaine use and a reduction with decreased use. No associations between use or change of use of other substances (including the neurotoxic cocaine adulterant levamisole) and NfL levels were found. Our findings demonstrate that NfL is a sensitive marker for assessing cocaine-related neuroaxonal pathology, supporting the utility of blood NfL analysis in addiction research but also suggesting the detailed assessment of substance use in neurological studies and diagnostics.

The Relationships Among Metal Homeostasis, Mitochondria, and Locus Coeruleus in Psychiatric and Neurodegenerative Disorders: Potential Pathogenetic Mechanism and Therapeutic Implications.

While alterations in the locus coeruleus-noradrenergic system are present during early stages of neuropsychiatric disorders, it is unclear what causes these changes and how they contribute to other pathologies in these conditions. Data suggest that the onset of major depressive disorder and schizophrenia is associated with metal dyshomeostasis that causes glial cell mitochondrial dysfunction and hyperactivation in the locus coeruleus. The effect of the overactive locus coeruleus on the hippocampus, amygdala, thalamus, and prefrontal cortex can be responsible for some of the psychiatric symptoms. Although locus coeruleus overactivation may diminish over time, neuroinflammation-induced alterations are presumably ongoing due to continued metal dyshomeostasis and mitochondrial dysfunction. In early Alzheimer's and Parkinson's diseases, metal dyshomeostasis and mitochondrial dysfunction likely induce locus coeruleus hyperactivation, pathological tau or α-synuclein formation, and neurodegeneration, while reduction of glymphatic and cerebrospinal fluid flow might be responsible for ß-amyloid aggregation in the olfactory regions before the onset of dementia. It is possible that the overactive noradrenergic system stimulates the apoptosis signaling pathway and pathogenic protein formation, leading to further pathological changes which can occur in the presence or absence of locus coeruleus hypoactivation. Data are presented in this review indicating that although locus coeruleus hyperactivation is involved in pathological changes at prodromal and early stages of these neuropsychiatric disorders, metal dyshomeostasis and mitochondrial dysfunction are critical factors in maintaining ongoing neuropathology throughout the course of these conditions. The proposed mechanistic model includes multiple pharmacological sites that may be targeted for the treatment of neuropsychiatric disorders commonly.

The influence of stimulus onset asynchrony, task order, sex and hormonal contraception on prepulse inhibition and prepulse facilitation: Methodological considerations for drug and imaging research.

BACKGROUND: Prepulse-induced startle modulation occurs when a weak sensory stimulus ('prepulse') is presented before a startling sensory stimulus ('pulse'), producing an inhibited (Prepulse Inhibition, PPI) or facilitated (Prepulse Facilitation, PPF) startle response. We recently identified several gaps and outlined future lines of enquiry to enable a fuller understanding of the neurobiology of PPI and PPF in healthy and clinical populations. However, before embarking on these studies, it is important to consider how task and population characteristics affect these phenomena in healthy humans. METHODS: We examined PPI and PPF in separate tasks, with counterbalanced task order across participants in one session, using a range of stimulus onset asynchronies (SOAs), in 48 healthy adults (23 men, 25 women; 10 hormonal contraceptive users) to determine which SOAs produce the strongest PPI and PPF and also explored how sex and hormonal contraception might influence PPI and PPF under these experimental conditions. RESULTS: Both PPI and PPF were affected by SOA, with greatest PPI observed at 60 and 120 ms, and greatest PPF at 4500 and 6000 ms. PPI was influenced by sex (more PPI in men than women) and hormonal contraception, whereas PPF was affected by task order (greater PPF when the PPF task followed, rather than preceded, the PPI task). CONCLUSIONS: Our findings indicate that studies of PPI and PPF need to consider, not only sex and hormonal status of study participants, but also task characteristics and presentation order to reduce variance and increase replicability across studies.

Recreational drug use and prospective memory.

Prospective memory (PM) impairment in recreational drug users has been documented in recent years. However, most studies on the effects of drugs on PM contain several methodological challenges, such as small sample size (< 100 participants), unrepresentative sample type (e.g., student or patient), short abstinence period (< 7 days), and lack of control of potential confounds (e.g., sleep and IQ). The present study investigated the possible consequences of recreational drug use on prospective memory, using self-report and lab-based prospective memory measures while overcoming the methodological challenges. The sample was composed of 47 non-users (27 females, age range from 18 to 50 +) and 53 drug users (21 females, age range from 18 to 50 +). Recreational drug users reported significantly more deficits in the long-term episodic, short-term habitual, and internally cued PM failures subscales of the Prospective Memory Questionnaire. However, these deficits were eliminated after controlling for covariates (e.g., age, sleep quality, general health, alcohol usage). Recreational drug users also performed worse than non-users in the short-term, long-term, event-based, and time-based PM subscales of the Royal Prince Alfred Prospective Memory Test. These results remained significant after controlling for the covariates. Drug users demonstrated greater impairments on time-based and long-term PM tasks thought to be linked with executive functioning. Taken together, the present study provides further support for recreational drug-related deficits in PM and highlights a dissociation between self-report and lab-based PM measures.

Assessment of Antipsychotic Medications on Social Media: Machine Learning Study.

Background: Antipsychotic medications are the first-line treatment for schizophrenia. However, non-adherence is frequent despite its negative impact on the course of the illness. In response, we aimed to investigate social media posts about antipsychotics to better understand the online environment in this regard. Methods: We collected tweets containing mentions of antipsychotic medications posted between January 1st 2019 and October 31st 2020. The content of each tweet and the characteristics of the users were analyzed as well as the number of retweets and likes generated. Results: Twitter users, especially those identified as patients, showed an interest in antipsychotic medications, mainly focusing on the topics of sexual dysfunction and sedation. Interestingly, paliperidone, despite being among one of the newest antipsychotics, accounted for a low number of tweets and did not generate much interest. Conversely, retweet and like ratios were higher in those tweets asking for or offering help, in those posted by institutions and in those mentioning cognitive complaints. Moreover, health professionals did not have a strong presence in tweet postings, nor did medical institutions. Finally, trivialization was frequently observed. Conclusion: This analysis of tweets about antipsychotic medications provides insights into experiences and opinions related to this treatment. Twitter user perspectives therefore constitute a valuable input that may help to improve clinicians' knowledge of antipsychotic medications and their communication with patients regarding this treatment.