Therapeutic Potentials of Ketamine and Esketamine in Obsessive–Compulsive Disorder (OCD), Substance Use Disorders (SUD) and Eating Disorders (ED): A Review of the Current Literature

The obsessive–compulsive spectrum refers to disorders drawn from several diagnostic categories that share core features related to obsessive–compulsive disorder (OCD), such as obsessive thoughts, compulsive behaviors and anxiety. Disorders that include these features can be grouped according to the focus of the symptoms, e.g., bodily preoccupation (i.e., eating disorders, ED) or impulse control (i.e., substance use disorders, SUD), and they exhibit intriguing similarities in phenomenology, etiology, pathophysiology, patient characteristics and clinical outcomes. The non-competitive N-methyl-D-aspartate receptor (NMDAr) antagonist ketamine has been indicated to produce remarkable results in patients with treatment-resistant depression, post-traumatic stress disorder and OCD in dozens of small studies accrued over the past decade, and it appears to be promising in the treatment of SUD and ED. However, despite many small studies, solid evidence for the benefits of its use in the treatment of OCD spectrum and addiction is still lacking. Thus, the aim of this perspective article is to examine the potential for ketamine and esketamine in treating OCD, ED and SUD, which all involve recurring and intrusive thoughts and generate associated compulsive behavior. A comprehensive and updated overview of the literature regarding the pharmacological mechanisms of action of both ketamine and esketamine, as well as their therapeutic advantages over current treatments, are provided in this paper. An electronic search was performed, including all papers published up to April 2021, using the following keywords (“ketamine” or “esketamine”) AND (“obsessive” OR “compulsive” OR “OCD” OR “SUD” OR “substance use disorder” OR “addiction” OR “craving” OR “eating” OR “anorexia”) NOT review NOT animal NOT “in vitro”, on the PubMed, Cochrane Library and Web of Science online databases. The review was conducted in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The use and efficacy of ketamine in SUD, ED and OCD is supported by glutamatergic neurotransmission dysregulation, which plays an important role in these conditions. Ketamine’s use is increasing, and preliminary data are optimistic. Further studies are needed in order to better clarify the many unknowns related to the use of both ketamine and esketamine in SUD, ED and OCD, and to understand their long-term effectiveness.Peer reviewedFinal Published versio

Aberrant salience in cannabis-induced psychosis: a comparative study

© 2024 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Background: Natural Cannabis (NC) and Synthetic Cannabinoids (SCs) use can increase the risk and exacerbate the course of psychotic disorders. These could be influenced by the Aberrant Salience (AS) construct. It refers to an excess of attribution of meaning to stimuli that are otherwise regarded as neutral, thereby transform them into adverse, dangerous, or mysterious entities. This leads the patient to engage in aberrant and consequently incorrect interpretative efforts concerning the normal perception of reality and its relationship with our analytical abilities. AS appears to play a significant role in the onset and perpetuation of psychotic disorders. The internal conflict arising from aberrant attributions of significance leads to delusional thoughts, ultimately culminating in the establishment of a self-sustaining psychosis. Aims: To examine the differences between psychoses course not associated with cannabis use and those associated with NC-use and SCs-use, in terms of psychotic and dissociative symptoms, AS, global functioning and suicidal ideation. Methods: A sample of 62 patients with First Episode Psychosis (FEP) was divided into 3 groups: non cannabis users (non-users, N = 20); NC-users or rather Delta-9-tetrahydrocannabinol (THC) users (THC-users, N = 21); SCs-users, commonly referred to as SPICE-users (SPICE-users, N = 20). Each group underwent assessments at the onset of psychotic symptoms, as well as at the 3 months and 6 months marks, utilizing a range of psychopathological scales. These included the Positive and Negative Syndrome Scale (PANSS) for investigating psychotic symptoms, the Global Assessment of Functioning (GAF) scale for assessing overall functioning, the Dissociative Experiences Scale (DES-II) for measuring dissociative symptoms, the Scale for Suicide Ideation (SSI) for evaluating suicidal ideation and the Aberrant Salience Inventory (ASI) scale for gauging AS. Results: SPICE-users showed more severe and persistent positive symptoms, while negative symptoms were mostly represented among non-users. Non-users showed better recovery than SPICE-users in global functioning. All groups showed a decrease in both ASI scores and subscale scores. SPICE-users exhibited higher global AS scores and less improvement in this aspect compared to other groups. Conclusion: This study may help understanding the role of AS in both non-substance-related and substance-induced psychosis. This knowledge may lead clinician to a better diagnosis and identify patient-tailored psychopharmacological treatment.Peer reviewe

Assessment of health-related quality of life in patients with adult onset Still disease: Results from a multicentre cross-sectional study

We aimed to investigate the health-related quality of life (HRQoL) in Adult onset Still disease (AOSD) patients, a rare systemic auto-inflammatory disorder of unknown etiology usually affecting young adults. In this multicentre cross-sectional study, AOSD patients and age and gender matched healthy controls (HCs) were included. All patients had a low or absent clinical expressiveness, they were categorized as having a monocyclic pattern or a chronic disease course. The Health Assessment Questionnaire (HAQ), European Quality of Life Questionnaire (EUROQoL), 36-Items Short-Form Healthy Survey (SF-36), Functional Assessment of Chronic Illness Therapy Fatigue subscale (FACIT-F), 100 mm-visual analogue scale (VAS) of pain, fatigue, and global health assessment, were used to evaluate HRQoL. The results were compared between patients and HCs, analyzed according to clinical course, and correlated with clinical features at the time of diagnosis. HRQoL resulted to be altered in 53 AOSD patients compared to 53 age and gender matched HCs. Many SF-36 domains differed between the 2 groups, mainly those of physical functioning which were reduced in AOSD respect to HCs. Furthermore, HAQ, FACIT-F, EuroQoL, VAS state of health, VAS pain, and VAS fatigue significantly differed between AOSD and HCs. No substantial differences were found comparing monocyclic pattern with chronic disease course. AOSD patients showed an impairment of many SF-36 domains, HAQ, FACIT-F, EuroQoL, VAS state of health, VAS pain, and VAS fatigue when compared to matched HCs, despite a low or absent clinical expressiveness; these findings were similarly retrieved in both monocyclic pattern and chronic disease course

Suicide and Genetic Biomarkers. Toward Personalized Tailored-treatment with Lithium and Clozapine

Background: Suicide is a major public health problem on a global scale, with about 800.000 deaths every year. In particular, it represents one of the main causes of death among adolescents and young adults aged between 15 and 29 years. The World Health Organization (WHO) describes suicide as "an act of deliberate killing" and that is placed at the extreme end of the continuous spectrum of suicidal behaviors (SBs). These include suicidal ideation, attempted suicide and suicide itself. Objective: The aim of the present review was to better clarify the suicide vulnerability genetic biomarkers and genetic variants correlated with the response to lithium and clozapine and to evaluate some correspondences. Methods: We reviewed the current literature, focusing our attention on genetic molecular studies about neurobiological systems involved in SBs and pharmacogenetic studies about antisuicidal drugs (lithium and clozapine). Results: The studies that we have reviewed have shown mixed results. Interestingly, rs1800532 polymorphism of the SLC6A4 gene, encoding for the serotonin transporter, is potentially correlated with both suicide vulnerability and a poor response to lithium and clozapine. Conclusion: Due to the impact of suicide on public health, more studies are needed to open a promising route to prevent suicide in personalized and precise psychiatry

Gut Microbiota and Bipolar Disorder: An Overview on a Novel Biomarker for Diagnosis and Treatment

The gut microbiota is the set of microorganisms that colonize the gastrointestinal tract of living creatures, establishing a bidirectional symbiotic relationship that is essential for maintaining homeostasis, for their growth and digestive processes. Growing evidence supports its involvement in the intercommunication system between the gut and the brain, so that it is called the gut–brain–microbiota axis. It is involved in the regulation of the functions of the Central Nervous System (CNS), behavior, mood and anxiety and, therefore, its implication in the pathogenesis of neuropsychiatric disorders. In this paper, we focused on the possible correlations between the gut microbiota and Bipolar Disorder (BD), in order to determine its role in the pathogenesis and in the clinical management of BD. Current literature supports a possible relationship between the compositional alterations of the intestinal microbiota and BD. Moreover, due to its impact on psychopharmacological treatment absorption, by acting on the composition of the microbiota beneficial effects can be obtained on BD symptoms. Finally, we discussed the potential of correcting gut microbiota alteration as a novel augmentation strategy in BD. Future studies are necessary to better clarify the relevance of gut microbiota alterations as state and disease biomarkers of BD

Adult-onset Still's disease with elderly onset: results from a multicentre study

Objective In this study, we aimed to describe the clinical characteristics, life-threatening complications occurrence, and mortality of adult-onset Still's disease (AOSD) patients with elderly onset. Methods A multicentre retrospective study of prospectively followed-up AOSD patients included in Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort was performed. Results Out of 221 assessed patients, 37 (16.7%) had an onset of the disease aged over 60 years. When compared with younger patients, these were characterised by a higher prevalence of pericarditis (p=0.008), comorbidities (p < 0.0001), and mortality (p=0.023). Age predicted the presence of serositis in both univariate (HR: 1.02, 95%CI: 1.01-1.03, p=0.007) and multivariate analyses (HR: 1.02, 95%CI: 1.01-1.04, p=0.007). Age was also a significant predictor of parenchymal lung disease in both univariate (HR: 1.03, 95%CI: 1.01-1.05, p=0.017) and multivariate analyses (HR: 1.03, 95%CI: 1.00-1.05, p=0.048). Furthermore, age resulted to be a negative predictor of polycyclic pattern only in univariate analysis (HR: 0.99, 95%CI: 0.97-1.00, p=0.048). Finally, age significantly predicted the mortality in both univariate (HR: 1.03, 95%CI: 1.00-1.06, p=0.034) and multivariate analyses (HR: 1.05, 95%CI: 1.01-1.08, p=0.012). Conclusion Clinical features of AOSD patients in the elderly were described in our cohort. Although the main clinical characteristics were similar comparing older and younger patients, patients aged over 60 years at disease onset were characterised by an increased prevalence of serositis, comorbidities, mostly cardiometabolic, and a higher mortality rate. Age predicted the presence of parenchymal lung disease and mortality, and it could be considered a negative prognostic factor in AOSD

Cytokine profile, ferritin, and multi-visceral involvement characterise macrophage activation syndrome during adult-onset Still's disease

Objectives: To multidimensionally characterise macrophage activation syndrome (MAS) complicating adult-onset Still's disease (AOSD) considering cytokine profile, inflammatory markers, and multi-visceral involvement of the disease. To perform a high-dimensional phenotypic analysis of circulating immune cells in AOSD patients with and without MAS. To assess interferon (IFN) related pathways in AOSD synovial tissues by a bulky RNA sequencing. Methods: Clinical and biologic data were collected and compared in AOSD patients with and without MAS. Sera biomolecules were analysed by Luminex multiplexing technology. Mass cytometry (CyTOF) was used to characterise circulating immune cells. A bulky RNA sequencing was performed in AOSD synovial tissues. Results: 40 consecutive AOSD patients were assessed, 14 complicated with MAS. Paralleling with increases of systemic score and ferritin, MAS patients showed higher levels of IL-1α, IL-1β, IL-1Ra, IL-2Ra, IL-6, IL-10, IL-17A, IFN-γ, G-CSF, MCP-1, MIP-1α, SCF. Combining the discriminatory ability of these data in identifying MAS, the best model was composed by systemic score, ferritin, IFN-γ, and IL-10. By CyTOF analysis, MAS patients showed an increase of circulating "classical monocytes" and a reduction of total NK cells. Our assessment showed 3477 IFN related genes (IRGs) were differently expressed in AOSD synovial tissues. Conclusions: A multidimensional characterisation of AOSD patients suggested that IFN-γ, IL-10, ferritin, and systemic score discriminated the occurrence of cytokine storm syndrome associated with MAS. The inflammatory milieu of AOSD and MAS may be related to a signature of circulating immune cells. Finally, our results about IRGs reinforced the role of IFN-γ in these patients

Adult-onset Still's disease with elderly onset: results from a multicentre study

Objective In this study, we aimed to describe the clinical characteristics, life-threatening complications occurrence, and mortality of adult-onset Still's disease (AOSD) patients with elderly onset. Methods A multicentre retrospective study of prospectively followed-up AOSD patients included in Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort was performed. Results Out of 221 assessed patients, 37 (16.7%) had an onset of the disease aged over 60 years. When compared with younger patients, these were characterised by a higher prevalence of pericarditis (p=0.008), comorbidities (p < 0.0001), and mortality (p=0.023). Age predicted the presence of serositis in both univariate (HR: 1.02, 95%CI: 1.01-1.03, p=0.007) and multivariate analyses (HR: 1.02, 95%CI: 1.01-1.04, p=0.007). Age was also a significant predictor of parenchymal lung disease in both univariate (HR: 1.03, 95%CI: 1.01-1.05, p=0.017) and multivariate analyses (HR: 1.03, 95%CI: 1.00-1.05, p=0.048). Furthermore, age resulted to be a negative predictor of polycyclic pattern only in univariate analysis (HR: 0.99, 95%CI: 0.97-1.00, p=0.048). Finally, age significantly predicted the mortality in both univariate (HR: 1.03, 95%CI: 1.00-1.06, p=0.034) and multivariate analyses (HR: 1.05, 95%CI: 1.01-1.08, p=0.012). Conclusion Clinical features of AOSD patients in the elderly were described in our cohort. Although the main clinical characteristics were similar comparing older and younger patients, patients aged over 60 years at disease onset were characterised by an increased prevalence of serositis, comorbidities, mostly cardiometabolic, and a higher mortality rate. Age predicted the presence of parenchymal lung disease and mortality, and it could be considered a negative prognostic factor in AOSD

Adult-onset Still's disease with elderly onset, results from a multicentre study

Objectives: In this study, we aimed at describing the clinical characteristics, life-threatening complications occurrence, and mortality of adult-onset Still's disease (AOSD) patients with elderly onset. Methods: A multicentre retrospective study of prospectively followed-up AOSD patients included in Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort was performed. Results: Out of 221 assessed patients, 37 (16.7%) had an onset of the disease aged over 60 years. When compared with younger patients, these were characterised by a higher prevalence of pericarditis (p=0.008), comorbidities (p<0.0001), and mortality (p=0.023). Age predicted the presence of serositis in both univariate (HR: 1.02, 95%CI: 1.01-1.03, p=0.007) and multivariate analyses (HR: 1.02, 95%CI: 1.01-1.04, p=0.007). Age was also a significant predictor of parenchymal lung disease in both univariate (HR: 1.03, 95%CI: 1.01-1.05, p=0.017) and multivariate analyses (HR: 1.03, 95%CI: 1.00-1.05, p=0.048). Furthermore, age resulted to be a negative predictor of polycyclic pattern only in univariate analysis (HR: 0.99, 95%CI: 0.97-1.00, p=0.048). Finally, age significantly predicted the mortality in both univariate (HR: 1.03, 95%CI: 1.00-1.06, p=0.034) and multivariate analyses (HR: 1.05, 95%CI: 1.01-1.08, p=0.012). Conclusions: Clinical features of AOSD patients in elderly were described in our cohort. Although the main clinical characteristics were similar comparing older and younger patients, patients aged over 60 years at disease onset were characterised by an increased prevalence of serositis, comorbidities, mostly cardiometabolic, and a higher mortality rate. Age predicted the presence of parenchymal lung disease and mortality, and it could be considered a negative prognostic factor in AOSD