Efficacy of ketamine and its hydroxynorketamine metabolites in substance use disorders

Our laboratory is actively investigating the efficacy of ketamine and (2R,6R)-hydroxynorketamine on preventing maladaptive behavioral responses and relapse to opioid-seeking behaviors during protracted abstinence. We use rodent models for studying addictive-like behaviors and in parallel we do establish novel and translationally-valid models to understand the complex interplay between stress, exposure to drugs of abuse and the emergence of emotional disturbances. Part of this work has been published as a preprint:

https://www.biorxiv.org/content/10.1101/2023.12.07.570550v1.

Cross-species investigation of the role of Cytochromes P450 Enzymes in major depression

Depression is a pressing global public health concern with rising incidence rates. While various biological vulnerabilities contributing to depression risk have been identified, the underlying functional and molecular pathogenesis mechanisms remain under investigation. This project focuses on Cytochromes P450 (CYP) enzymes, particularly their role in depression and their influence on oxidative stress. Notably, CYP-generated bioactive metabolites 20-HETE and EET are gaining attention as key pro- and anti-inflammatory mediators with implications for cognitive function, brain cardiovascular health, and other neurological diseases. This research aims to uncover the neuroprotective and anti-depressant potential of regulating CYPs, both in vitro and in vivo, and to assess their clinical relevance in human subjects. Ultimately, this work seeks to identify novel therapeutic targets for depression, addressing its complex nature and offering hope to non-responsive patients.

Enhancing Smoking Cessation Strategies through Interdisciplinary Research

Cigarette smoking, the leading preventable risk factor for chronic diseases and premature mortality, presents a persistent challenge with the majority of individuals facing relapse post-abstinence. Our integrated research initiative combines two pivotal investigations, both centered on human subjects. The first involves a case-control study aimed at identifying genetically-supported drug targets for smoking cessation by scrutinizing participants who have successfully maintained abstinence for at least six months. This study also explores the correlation between these drug targets and motivation to quit smoking, nicotine dependence, and vulnerability to relapse. Potential targets will be identified using drug repurposing Mendelian randomization and confirmed by assessing gene methylation levels. Simultaneously, our interdisciplinary approach, the second component, examines the interaction between trait-like vulnerability factors, specifically baseline emotion regulation abilities, and biomarkers of state responses to stress, including emotion regulation and synchronized neural activation responses before smoking cessation. This work contributes to the identification of biomarkers predicting nicotine relapse vulnerability pre-cessation, revealing a critical link between emotion regulation deficits and neural activation changes that collectively predict successful smoking abstinence. By unifying these research efforts, we aim to enhance our understanding of smoking cessation and relapse dynamics, providing insights that advance smoking cessation strategies and reduce the global burden of tobacco-related health issues. For more information, please visit our clinical trials: NCT06470321 and NCT06471387.

Exploring Ketamine as a Treatment for Opioid Addiction in Humans

The currently-prescribed opioid substitution treatments exhibit limited efficacy in reversing negative affect or preventing relapse in opioid abstinent individuals, emphasizing the need for innovative therapeutics in the treatment of opioid addiction. Research has shown a high incidence (ranging from 40 to 60%) of depression and other affective disorders in opioid use disorder treatment-seeking populations. Emerging evidence suggests that ketamine may hold promise for the treatment of drug addiction, with findings indicating that ketamine administration may extend periods of abstinence, including opioid addiction. However, it remains unclear whether ketamine reverse affective behaviors emerging during protracted opioid abstinence and lead to relapse. Furthermore, the mechanisms underlying these potentially beneficial effects of ketamine have not been fully characterized. Our overarching goal is to identify biomarkers predicting vulnerability to relapse during opioid abstinence and assess whether ketamine can serve as a treatment to decrease the likelihood of relapse following extended opioid abstinence. We also aim to pinpoint neurobiophysiological markers that predict both vulnerability to relapse and the efficacy of ketamine in preventing relapse among opioid addicts. We are currently running the first ever drug-interventional clinical trial ever conducted in Cyprus to assess the efficacy of ketamine to prevent relapse: EudraCT: 2022-001997-70.

Advancing Interventions for Comorbid Opioid Addiction and Mood Disorders

Additionally, epidemiological studies reveal a pronounced comorbidity (50-60%) between opioid addiction and depression, a significant challenge in psychiatry characterized by severe symptoms, extended illness duration, poor prognosis, and heightened relapse rates. Recent research has highlighted ketamine’s antidepressant actions, mediated through a specific hydroxynorketamine (HNK) metabolite, (2S,6S;2R,6R)-HNK. Importantly, the (2R,6R)-HNK stereoisomer exhibits rapid and sustained antidepressant properties and restores sociability behavior following chronic stress. Notably, this metabolite lacks the NMDAR inhibition, mitigating the serious side effects associated with ketamine, including sensory dissociation deficits, stimulant effects, and self-administration. The overarching objective of this research is validate improved interventions for the treatment of comorbid opioid addiction and mood disorders via using rodent models. The central hypothesis posits that (2R,6R)-HNK will prevent the development of mood disorders during long-term abstinence from opioid use and also abolish stress- and priming-induced reinstatement to opioid-seeking following extinction. This research holds the promise of enhancing interventions for individuals grappling with the complex interplay of opioid addiction and mood disorders, ultimately advancing mental health care and treatment strategies.

Neuropsychiatric Disorders in the context of Neurodegenerative Diseases

Neuropsychiatric disorders, particularly depression, are a common occurrence in the context of neurodegenerative disorders (NDs). This prevalence underscores the critical need to address this issue comprehensively. One of the key reasons for this importance is that neuropsychiatric symptoms can often emerge well before the onset of overt neurological symptoms. In fact, this early appearance of mood-related symptoms can lead to misdiagnoses of primary neuropsychiatric disorders in a significant proportion of individuals, estimated at approximately one-third of cases. Accurate and timely diagnosis is pivotal, as it enables early intervention, personalized care, and the exploration of new therapeutic avenues. By better understanding and addressing these mood-related symptoms in the context of NDs, we can enhance the overall quality of life for those affected and reduce the burden on both individuals and society.

In the case of Parkinson’s Disease (PD), non-motor symptoms, including depression, can appear up to a decade prior to motor features. Therefore, the identification of diagnostic biomarkers is crucial for accurately diagnosing PD during its prodromal or early stages. To contribute to this effort, we employed an integrative bioinformatics approach that combined the analysis of single-nucleus RNA and bulk mRNA transcriptomic data. Through comparative molecular signature analysis, we identified shared and distinct molecular features that characterize PD and Major Depressive Disorder (MDD) both in the periphery and brain.

See recent related publication:

https://www.frontiersin.org/articles/10.3389/fnagi.2023.1273855/full.