On the third day of the congress, the program featured several highly relevant sessions that focused on the impact of sex and gender differences in precision psychiatry, neurocircuits in depression and topics like ethical challenges of precision psychiatry.
Here are the highlights from the third day in detail:
Implementing precision psychiatry in clinical practice: what are we waiting for?
Advancements in the application of precision psychiatry in early psychosis
Speaker: Paolo Fusar-Poli
In his presentation, Dr. Paolo discussed advances in precision psychiatry, specifically focusing on early psychosis. As a clinician working with prodromal psychosis, the speaker emphasized the importance of preventing psychosis in individuals at clinical high risk. These individuals, typically aged 14 to 35, show functional impairments and mild symptoms that do not yet meet the criteria for a major psychosis episode. Detecting and predicting outcomes for these attenuated symptoms is crucial.
Traditional methods, such as leaflets and outreach campaigns, have proven insufficient in reaching many young people. To address this, a digital screening system was developed, funded by the Wellcome Trust and implemented in several institutions including King’s College London and the University of Glasgow. This system uses a mobile app for initial assessments, analyzing speech and cognition, and applying algorithms to estimate the risk of developing psychosis. If a risk is detected, further assessments are conducted.
Additionally, Dr. Paolo discussed the use of electronic health records (EHR) in secondary mental health care. They developed a risk calculator using sociodemographic factors and initial diagnoses to predict psychosis onset. This method was enhanced with natural language processing (NLP) to extract specific symptoms from clinician notes, improving prediction accuracy.
Replication of the tool in various regions, including the US, showed varying degrees of accuracy. The refined version, incorporating NLP, achieved higher accuracy. They also developed a dynamic risk calculator that updates predictions over time, demonstrating improved prognostic accuracy.To expand precision psychiatry into primary healthcare, a partnership with the industry led to the development of another screening method tested in the US. This tool, using neural network models, showed good accuracy and potential clinical benefits.
Despite many risk calculators being developed, few are implemented in clinical practice. Dr. Paolo’s team collaborated with clinicians and patients to create a digital interface for their algorithms, piloting it in the NHS. The implementation study showed high clinician and patient adherence to the recommendations made by the calculator.
Looking ahead, the team is refining algorithms to predict not only psychosis but also bipolar disorder. They are involved in a large international study, ProNet, aiming to enhance prediction through deep phenotyping. This ongoing research is part of a broader effort to advance precision psychiatry and implement these tools effectively in clinical settings.
Ethical challenges of precision psychiatry: are there solutions?
Speaker: Mirko Manchia
The lecture began with an introduction to the ethical implications of precision psychiatry, highlighting the collaborative efforts of two European Colleges of Neuropsychopharmacology networks. These networks focus on bipolar disorder and the prevention of mental health issues, spearheaded by professors Ale Andreas and Paul Fu. They formed a cluster to address severe mental disorders, emphasizing the ethical challenges and implementation of precision psychiatry by involving various stakeholders.
During the COVID-19 pandemic, a virtual workshop was conducted in February 2021, involving bioethicists, philosophers, oncologists, psychiatrists, and individuals with lived experiences of mental illness. This workshop resulted in a white paper outlining ethical considerations for implementing precision psychiatry. Precision psychiatry aims to move beyond the traditional “one size fits all” approach to a more personalized method, referred to as stratified precision psychiatry. It uses individualized prediction models for diagnosis, prognosis, screening, and treatment, based on integrating diverse data sets.
Francis Collins, former head of the NIH, emphasized that this approach requires large longitudinal studies with multiple time points to ensure statistical robustness. This data integration includes genomics, clinical data, omics, and environmental predictors, which can create new taxonomies of conditions identifiable by specific risk signatures. Precision psychiatry involves digital monitoring, cognitive assessments, brain imaging, and multi-omics data, processed through machine learning and deep learning models.
Dr. Mirko highlighted that one major barrier to precision psychiatry is stigmatization, which can prevent individuals from accessing these approaches. Even with its potential to improve treatment effectiveness and quality of life, stigmatization remains a significant challenge. Economic disparities also pose a problem, as precision psychiatry can be costly and may widen the gap in access to care. Algorithms must be developed using non-discriminatory data to avoid biased predictions and ineffective models.
The lecture also touched on the importance of ethical frameworks in precision psychiatry. Communication of mental health risks is particularly challenging, especially when predicting disorders in young individuals, which can impact their life and career trajectories. A multidisciplinary governance framework is essential to facilitate transparent risk prediction and effective communication between healthcare providers and patients.
Practical examples illustrated the ethical challenges in communicating risk estimates. For instance, neuroimaging data can predict recovery outcomes for schizophrenic patients, highlighting the need for intensive follow-up and tailored treatments. Another study on precision mapping of the brain’s salience network demonstrated its enlargement in individuals at risk for depression, emphasizing the importance of early prevention and cognitive behavioral therapies.
In conclusion, Dr. Mirko presentation underscored the critical role of multimodal data integration and personalized approaches in precision psychiatry, while addressing ethical concerns, stigmatization, and the need for equitable access to care.
New approaches for multimodal prediction in precision psychiatry
Speaker: Ole A. Andreassen
Dr. Ole presentation discussed the importance and progress of integrating multimodal data in precision medicine, particularly in psychiatry. Emphasizing the need to harness big data, the speaker highlighted the development of predictive tools to adapt treatments for individuals with severe mental illnesses. By using large Nordic samples and prioritizing privacy, the approach aims to combine registry data, biobanks, and eHealth records. The challenge of overlapping diagnoses and comorbidities in mental health was noted, contrasting with more straightforward conditions like cancer.
The speaker illustrated the potential of polygenic risk scores despite current limitations, explaining that multiple small genetic effects contribute to disorders like schizophrenia, bipolar disorder, and Alzheimer’s. The use of federated learning allows for the analysis of distributed data without compromising individual privacy. Dr. Ole also discussed the challenges of using genetics alone for predictions, particularly in Alzheimer’s, where combining genetics with imaging and clinical data improves predictive accuracy.
The concept of precision psychiatry involves utilizing technologies like supervised machine learning to analyze large-scale genetic and clinical data, aiming to improve treatment outcomes. Dr. Ole mentioned specific projects and consortia working on these advancements and highlighted the need for careful use of polygenic risk scores to avoid misinforming patients. The discussion included examples of integrating clinical assessments and genetic data to predict Alzheimer’s onset and the potential to use these methods in clinical trials to reduce costs.
Overall, the lecture emphasizes the potential and ongoing efforts to integrate various data types to enhance precision medicine in psychiatry, aiming for better prediction, diagnosis, and treatment of mental health disorders.
The impact of sex and gender differences in precision psychiatry
Speaker: Claudia Pisanu
In this presentation, Dr. Claudia discussed the impact of sex and gender on health, particularly within the context of precision psychiatry. The session underscored the importance of gender medicine, which examines biological differences between men and women and how these differences affect health outcomes. Historically, medical research, including drug testing, has predominantly focused on males, leading to a significant male bias. Notably, a 2009 study revealed that male animals were used five to six times more than females in preclinical research in fields like neuroscience and pharmacology. Though there have been improvements, a 2019 follow-up study showed that only pharmacology saw substantial increases in studies including both sexes and considering sex as an experimental variable.
Women often receive less evidence-based care, partly due to myths like female data being more variable than male data. Additionally, from 1977 to 1993, the FDA excluded women of childbearing age from most clinical trials. Recent regulations, such as a 2022 European law, now require justifications for excluding certain groups from clinical trials.
Sex and gender differences are evident in the incidence of psychiatric disorders, with major depression more common in women, and schizophrenia and ADHD more common in men. These differences also extend to clinical presentation and treatment response, but the biological factors underlying these differences remain understudied. For example, socioeconomic factors significantly impact women with anxiety disorders, leading to lower socioeconomic status and substantial debt.
Research also shows sex-based differences in brain structure and function. Precise analyses have found regional differences in gray matter volume between men and women, consistent across species and linked to gene expression. Studies using machine learning on brain imaging data have identified the “brain age gap,” indicating that biological brain age can differ from chronological age, with women often showing younger biological ages in some clusters.
Genetic studies, like those using data from the Psychiatric Genomics Consortium, have found sex-specific effects in genetic predispositions to psychiatric disorders. For instance, there are sex differences in the genetic variants associated with schizophrenia and metabolic traits.
Sex differences also affect interactions with the healthcare system and drug prescriptions. For ADHD, diagnostic criteria based on male patients lead to delayed diagnoses and less frequent medication prescriptions for women. Similarly, women are less likely to be prescribed opioids for pain control, especially if they have psychiatric comorbidities.
There are known sex differences in responses to psychotropic drugs due to factors like body composition and drug metabolism. However, data on clinical responses or adverse effects remain limited. For example, studies on antipsychotics suggest some adverse effects are more common in women, but the data are underpowered to identify significant differences. Similarly, for mood stabilizers and antidepressants, existing studies lack consensus on gender differences in response and underlying mechanisms.
A notable initiative, the Precision Medicine Depression Treatment (PROMPT) project, aims to integrate clinical omics and sex-related data to develop an algorithm for predicting treatment-resistant depression, highlighting the need to incorporate sex differences into precision psychiatry research. Dr. Claudia concluded by emphasizing the necessity of understanding these differences to achieve a personalized approach in psychiatry.
Inflammation in depression: a bird’s eye view across the body and across the lifespan
The placenta-brain axis: transmission of maternal inflammatory and stress response
Speaker: Cristiana Cruceanu
Dr. Cristiana began her presentation with an emphasis on the significance of the topic of inflammation and depression, highlighting the importance of understanding the relationship between maternal mental health and the development of the fetus. The speaker introduced the concept of the placenta-brain axis and its role in transmitting maternal depression and stress-related phenotypes to the fetus. Chronic stress and neuroinflammation were discussed as key factors in depression, particularly in women of reproductive age, exacerbated by situations such as the COVID-19 pandemic.
The developmental origins of health and disease hypothesis was explained, proposing that environmental exposures during early development, including the prenatal period, have lasting effects on health and susceptibility to illness. Genetic and environmental interactions were underscored as critical to understanding these effects. Dr. Cristiana’s group has conducted studies using in vitro systems, like cerebral organoids, to model early brain development and examine the impact of glucocorticoid exposure on neuronal development. These organoids, despite their limitations, offer valuable insights into the transcriptional responses to glucocorticoids and their potential long-term effects on mental health.
The research included both acute and chronic glucocorticoid exposure studies, revealing significant impacts on gene expression and neurodevelopment, particularly in inhibitory neurons. Chronic exposure studies showed even more profound effects on gene expression and chromatin architecture, indicating a strong influence on developmental processes and potential risk for mental illness.
The presentation also covered the use of in vitro models to study the placenta, emphasizing its crucial role in mediating maternal stress and its effects on fetal development. The speaker presented findings from a cohort study that showed significant transcriptional differences in the placenta of mothers who experienced early life stress compared to those who did not. These differences were linked to stress response genes and placental disorders, highlighting the placenta as a critical mediator of maternal-fetal health.
In conclusion, Dr. Cristiana emphasizes the importance of understanding critical periods in both brain and placental development and the need for precise experimental designs to capture cell-type specific responses.
Reconstruction of immune-related depression from transcriptomics and cytokine signatures to symptoms
Speaker: Janine Knauer-Arloth
In this presentation, Dr. Janine discussed the reconstruction of immune-related depression by analyzing transcriptome and cytokine signatures. She emphasized the high prevalence and burden of psychiatric disorders and the necessity for a better understanding of their underlying mechanisms due to high non-response rates to treatments. The talk highlighted various factors contributing to depression, including genetics, the HPA axis, inflammation, and brain remodeling, all of which interact in complex ways.
Dr. Janine presented data suggesting a strong link between depression and inflammation, noting that patients often exhibit increased inflammatory cytokines. Her research aimed to stratify patients based on immune markers by analyzing a large transdiagnostic sample from the Max Planck Institute, incorporating phenotype data, blood samples, RNA measurements, and immune markers. She employed a two-step approach: clustering based on biological features and then annotating clusters using symptom-related variables. This led to the identification of four distinct clusters of depression, each characterized by different immune and gene expression profiles.
The analysis showed that age and BMI were significant factors in differentiating these clusters, with two clusters showing higher BMI and immune activation. Further examination of immune markers and gene expression revealed distinct patterns, with certain immune markers like CRP and IL-1 being prominent. Gene set enrichment analysis indicated different active pathways across the clusters, particularly brain-related pathways.
Dr. Janine also explored the role of immune cell composition, finding differences in cell types between clusters and linking these to clinical phenotypes. Single-cell sequencing data from patients revealed that higher CRP levels were associated with increased CD4 TCM cells and decreased CD8 TCM cells, while IL-6 did not show significant changes. Differential gene expression analysis highlighted several important genes involved in depression and inflammation, with some genes showing opposite regulation patterns between CRP and IL-6.
In conclusion, Dr. Janine underscored the importance of integrating multiple data domains to better understand and classify depression subtypes, noting the potential for these findings to advise treatment responses. Future research directions include incorporating control groups and sophisticated models to address confounding factors and further explore the opposite effects observed in cytokine regulation.
A post-mortem investigation of cerebral neuroinflammation in depressed individuals with and without a history of child abuse
Speaker: Naguib Mechawar
In this session, Dr. Naguib presented on the neurobiological basis of depression and suicide, focusing on the long-term effects of early life adversity, particularly childhood abuse. His lab is part of the McGill Group for Suicide Studies, which collaborates with the Douglas Bell Canada Brain Bank, the oldest brain bank in Canada. They work with well-characterized human brain samples to investigate neuroplasticity and neuroinflammation associated with early life adversity.
The presentation highlighted the significant prevalence of childhood abuse, estimating that as many as one in three individuals experience some form of maltreatment, which correlates with poor health outcomes and increased rates of depression and suicide. He shared findings from studies showing a cumulative effect of various types of maltreatment on depression and suicidal ideation in young adults.
The discussion then shifted to neuroinflammation, where Dr. Naguib cited research indicating that a subset of depressed patients exhibits a neuroinflammatory component. He presented data from his lab showing that while there were few significant changes in cytokines in individuals with a history of childhood abuse, certain pro-inflammatory markers were elevated in depressed suicides compared to controls. The analysis of microglial morphology also suggested no impact from early life adversity.
Overall, the findings suggest that early life adversity significantly impacts neurovascular health, particularly in females, with ongoing research aimed at disentangling the effects of depression from those of early life experiences. Dr. Naguib concluded by thanking the funding sources and collaborators involved in this vital research.
Immunometabolic causal mechanisms, potential drug targets and blood biomarkers for depression: insights from multi-omics
Speaker: Golam Khandaker
Dr. Golam discussed the intricate relationship between immune mechanisms and depressive disorders. He emphasized the significant role that inflammation and immune dysfunction play not only in depression but also in other neuropsychiatric conditions such as schizophrenia and bipolar disorder, as well as neurodegenerative diseases like Alzheimer’s. The speaker highlighted compelling evidence showing that immune activation can lead to depressive symptoms, citing studies where patients treated with interferon, a potent immune activator, developed depression. He referenced research indicating that even mild immune activation could induce cognitive impairment and depressive symptoms.
The speaker outlined the findings of a systematic review that identified alterations in blood cell types associated with depression, pointing to dysregulation in both innate and adaptive immune responses. Key observations included elevated levels of pro-inflammatory cytokines during acute depressive episodes. However, he raised critical questions about causality: which immune proteins genuinely contribute to depression, and which are merely coincidental or a result of reverse causation. He also discussed the potential for targeting specific immune pathways in future clinical trials and the importance of personalizing treatment to identify patients likely to benefit from immunotherapy.
The professor presented results from a comprehensive study on immunological proteins and psychiatric conditions, employing advanced genomic techniques such as Mendelian randomization and genetic colocalization. This study examined 735 immune response-related proteins in relation to various psychiatric outcomes, ultimately identifying 21 biomarkers with strong causal evidence linked to conditions like depression, schizophrenia, and bipolar disorder, with 18 of these being potential druggable targets.
Dr. Golam then shifted to discussing immune-based subtyping of depression, noting that inflammation is not universally relevant to all patients with depression. He cited research indicating that about 27% of individuals with depression exhibited signs of inflammation, and significant variability existed in how immune proteins correlated with depressive symptoms. Through analysis, his team identified two distinct clusters of depression: one characterized by somatic symptoms linked to elevated inflammatory markers, and another defined by anxiety symptoms associated with liver-related biomarkers.
This clustering suggested a potential for using immunological biomarkers alongside clinical assessments to improve the stratification and predictability of depression, particularly in cases with somatic and mood-related symptoms. Dr. Golam emphasized the need for further interventional studies to validate these findings and the importance of adapting treatment approaches based on individual patient profiles.
Neurocircuits in depression
Speaker: Conor Liston
During this highly interactive and engaging session, Dr. Conor Liston discussed his research on the biological foundation of depression. Dr. Conor emphasized the immense global burden of depression, noting that current treatments, though lifesaving for many, often require a lengthy trial-and-error process, leaving two-thirds of patients unsatisfied. He expressed optimism about the potential of new technologies, such as brain imaging, optogenetics, and genomics, which are allowing researchers to explore brain circuits in unprecedented detail.
Dr. Conor explained that depression is fundamentally a disorder of brain circuits rather than simply a chemical imbalance, which challenges the traditional serotonin-centered view of depression. He elaborated on how brain circuits like those involved in effort valuation and reward anticipation are disrupted in depression, and how understanding these disruptions could lead to more targeted treatments. One of the biggest challenges in treating depression, according to Dr. Conor, is its heterogeneity. Depression manifests with a wide range of symptoms, which means different patients may have very different biological issues, despite receiving the same diagnosis.
The speaker highlighted the need for a longitudinal approach to studying depression, focusing on how patients cycle in and out of depressive episodes. He shared insights from his lab, including the discovery of specific brain circuits that are critical for encoding rewards and how these circuits are affected by stress and antidepressants. His team is also working to refine the use of neuroimaging to subtype depression and predict which treatments will work best for individual patients, with particular interest in transcranial magnetic stimulation (TMS) as a non-invasive yet effective treatment option.
Throughout the discussion, Dr. Conor remained cautiously optimistic, recognizing the limitations of the current understanding of depression, but enthusiastic about the advances being made. He responded to questions about the future of precision medicine in psychiatry, emphasizing that while significant challenges remain, there is hope that new diagnostic and therapeutic tools could dramatically improve how depression is treated in the coming years.
New Medication Symposium
Topline Results: PORTICO a double-blind, randomized placebo-controlled, adaptive phase IIb trial to assess vafidemstat’s efficacy in treating borderline personality disorder
Speaker: Michael Ropacki
In this session, Dr. Michael, presented the results of the PORTICO trial, which focused on a medication aimed at treating borderline personality disorder (BPD). The discussion highlighted the multifactorial etiology of BPD, emphasizing recent research that suggests LSD1 inhibition plays a crucial role in treatment. The drug, vafidemstat, is an LSD1 inhibitor with an epigenetic mechanism of action that promotes neuroplasticity, helping to address symptoms such as agitation and aggression prevalent in BPD. The trial involved over 423 patients and demonstrated vafidemstat safety and tolerability, showing no significant side effects commonly associated with atypical antipsychotics, such as weight gain or sedation.
The PORTICO trial was a phase two, double-blind, placebo-controlled study that evaluated vafidemstat over 14 weeks, with 211 patients randomized to either the treatment or placebo. The trial design included multiple primary endpoints focused on agitation and overall disease symptoms, acknowledging the absence of a gold standard for measuring pharmacological improvement in BPD. The findings indicated that while the primary endpoint related to clinical global impressions of agitation did not reach statistical significance, there was a notable 12.2% reduction in agitation symptoms compared to placebo. Conversely, the trait anger measure showed a statistically significant reduction of 58.6%, indicating promising results for anger management in BPD patients.
The study’s comprehensive design allowed for real-world applicability, including participants with common comorbidities, which are often excluded in clinical trials. Measures indicated that the patient population was adequately agitated and aggressive, further supporting the trial’s findings. Despite the primary endpoints not meeting significance, several important secondary outcomes revealed clinically meaningful reductions in both agitation (59%) and overall BPD symptoms (31%).
Regarding safety, the treatment showed similar rates of treatment-emergent adverse events between the groups, with no deaths reported and a slight decrease in incidents of intentional self-injury among those receiving vafidemstat. Overall, while the primary efficacy endpoint was not achieved, the data indicated that vafidemstat was safe, well-tolerated, and showed potential for significant clinical improvements, warranting further exploration in phase three trials.
Evenamide as an add-on to antipsychotics demonstrates significant efficacy in patients with schizophrenia in a pivotal randomized placebo-controlled trial
Speaker: Ravi Anand
The presentation focused on the results of a unique study involving a new drug, a glutamate release inhibitor, which was added to existing antipsychotics for patients with inadequate response to treatment. The presenter highlighted that this trial was the first of its kind, aimed at improving efficacy by combining antipsychotics, particularly targeting patients who are notoriously difficult to treat. The key feature of the drug is its selective inhibition of voltage-gated sodium channels, activated only during excessive glutamate release, common in schizophrenia. It does not interact with other CNS targets, making it a novel addition to treatment regimens.
The drug has shown effectiveness in various animal models of psychosis, both as monotherapy and as an add-on, indicating potential therapeutic benefits even when traditional antipsychotics fail. The presented study, a phase three pivotal trial, involved patients from Latin America, Europe, and India, who had inadequate responses to second-generation antipsychotics. The study design included a rigorous screening process to ensure compliance and proper medication use, which revealed significant non-compliance and polypharmacy issues.
The patient population was typical for such studies, with a mean age of around 40, predominantly male, and having an illness duration of about 12 years. The trial showed high retention rates, with 95% of patients completing the study. The drug demonstrated significant improvements in the PANSS total score and CGI severity, despite the challenges of treating an inadequately responsive population. No significant side effects were reported, making the drug a promising candidate for further research.
The study’s results justified moving to a more extensive phase three trial, planned to last one year, with primary and secondary endpoints at 12 and 26 weeks, respectively. The aim is to confirm the drug’s efficacy and safety in a broader patient population, potentially offering a new effective treatment for those struggling with inadequate responses to current antipsychotic therapies.
Esketamine nasal spray as a monotherapy for treatment-resistant depression
Speaker: Carla Canuso
Dr. Carla presented on esketamine monotherapy for treatment-resistant depression, which is a severe condition associated with chronicity, comorbidity, and increased mortality, including suicide. Esketamine, a rapidly acting antidepressant and NMDA glutamate receptor antagonist, is approved in over 75 countries for treatment-resistant depression, typically in combination with oral antidepressants. However, its efficacy as a monotherapy is of significant interest, particularly for patients experiencing side effects from oral antidepressants.
The speaker discussed a large study designed to evaluate esketamine as a monotherapy. The study included adults 18 years and older, including some elderly patients, who met the criteria for treatment-resistant depression. Participants had failed at least two adequate doses and durations of therapy in their current depressive episode and had moderate to severe depression at study entry. Exclusion criteria included prior exposure to esketamine or ketamine, recent suicidal or homicidal behavior, and moderate to severe substance or alcohol use disorders.
The study design involved a screening phase of up to seven weeks, followed by a randomization to either placebo, 56 mg, or 84 mg of esketamine monotherapy. Patients were assessed during the screening phase, and those showing improvement in their MADRS scores were excluded from the primary efficacy analysis but included in the safety analysis. The double-blind phase lasted four weeks, after which patients could enter an open-label period for up to three months, with the option to add an oral antidepressant if necessary.
The primary efficacy analysis focused on patients who did not improve during the screening period, totaling 379 subjects. The study found high overall completion rates around 94%, with similar reasons for discontinuation across treatment groups, though higher dropout rates due to adverse events were observed in the 84 mg group. The patient demographics indicated they were in their mid-forties, mostly women, predominantly white, and severely ill with a mean duration of illness of about three years.
The primary endpoint was the change in MADRS scores after four weeks, showing significant improvements in both the 56 mg and 84 mg groups compared to placebo. Early and clinically meaningful reductions in depressive symptoms were noted as early as day two. The safety profile of esketamine monotherapy was consistent with known side effects, including nausea, dissociation, dizziness, and headache.
In conclusion, esketamine monotherapy at both 56 mg and 84 mg doses demonstrated significant and clinically meaningful improvements in depressive symptoms for patients with treatment-resistant depression, with a consistent safety profile. These results provide valuable information for patients who have not benefited from or have given up on oral therapies.
Simultaneous noradrenergic and serotonergic regulation in alcohol use disorder: an RCT of prazosin and cyproheptadine combination for a new paradigma
Speaker: Henri-Jean Aubin
In this presentation, the results of a proof-of-concept trial evaluating the combination of prazosin and cyproheptadine for treating alcohol use disorder were discussed. The rationale behind this combination is the simultaneous blockade of 5-HT2A and alpha-1B receptors, which is believed to restore the disrupted coupling of neurogenic and serotonergic neurons on the dopaminergic system, a disruption common in individuals with a history of heavy drinking. Preclinical studies with mice showed that while each drug alone did not affect alcohol preference, their combination significantly reduced alcohol preference, more effectively than reference drugs like naltrexone, ethanol, or baclofen.
In the clinical trial, subjects with severe alcohol use disorder, as defined by DSM-5 criteria and high-risk drinking levels per WHO standards, were randomized to receive either a placebo or a low or high dose combination of the drugs for 12 weeks. Despite the trial being conducted during COVID-19 restrictions and achieving fewer participants than planned (154 instead of 180), significant results were observed.
At baseline, more than half of the participants had very high drinking risk levels, averaging over 100 grams of alcohol per day for men and over 60 grams per day for women. The primary outcome showed significant treatment effects across all three arms, with the high dose combination proving superior to placebo at two and three months, achieving an effect size of 0.4 at month three. In the subgroup with very high baseline drinking levels, the high dose was even more effective, showing significant results at all time points and an effect size of 0.51 at month three.
Secondary outcomes, such as the number of heavy drinking days, did not reach statistical significance in the overall analysis. However, in the high-risk subgroup, significant reductions were noted at months one and two, but not at month three. Other secondary outcomes showed that both low and high doses were more effective than placebo, though often not significantly so.
The safety profile indicated no serious adverse events, with mild to moderate increases in vertigo, fatigue, and dry mouth, particularly at the high dose. There were no significant increases in sedation or orthostatic hypotension, but there was a notable increase in body weight (2.5 kg over 12 weeks) with both low and high doses.
The study concluded that the combination of prazosin and cyproheptadine, particularly at high doses, shows promise in treating alcohol use disorder, with stronger effects observed in total alcohol consumption compared to heavy drinking days and enhanced efficacy in patients with higher baseline drinking risks. These findings suggest a potential new therapeutic option comparable to existing reference drugs for reducing alcohol consumption.
Adjunctive lumateperone significantly improves symptoms of major depressive disorder: topline results from a randomized, double-blind, placebo-controlled phase 3 trial
Speaker: Willie Earley
Dr. Willie presented on the OPERON for major depressive disorder (MDD) randomized trial, focusing on a phase three study of lumateperone as an adjunctive treatment for MDD in patients who did not respond adequately to antidepressants. This study addresses the high disability and mortality associated with depression. Despite available treatments, many patients don’t respond well to antidepressants alone, prompting the use of adjunctive treatments like atypical antipsychotics.
Lumateperone, approved in the U.S. for schizophrenia and bipolar depression, acts on multiple receptors, including serotonin and dopamine, and inhibits serotonin reuptake. This trial aimed to evaluate its efficacy for MDD patients unresponsive to antidepressants. Participants, aged 18-65 with MDD and insufficient response to antidepressants, needed a MADRS score of 24+, CGIS score of 4+, and a QIDS-SR score of 14+. The nine-week study included a double-blind treatment period where patients received either lumateperone or a placebo alongside their antidepressant.
The primary efficacy measure was the change in MADRS score from baseline to day 43, with secondary measures including the CGIS score and QIDS-SR. The study enrolled about 240 patients per arm, conducted globally, predominantly female, around age 45. Most were on SSRIs, SNRIs, or bupropion. Baseline MADRS scores were around 30, and CGIS scores were about 4.7.
Results showed significant improvement in the lumateperone group compared to placebo, with an effect size of 0.61 and an LS mean difference of nearly five points on the MADRS. Efficacy was observed as early as day eight. The CGIS score also showed significant improvement, with an LS mean difference of 0.7 and an effect size of 0.67. Patient-reported outcomes on the QIDS-SR showed a 2.4-point improvement with an effect size of 0.5.
Safety analysis indicated slightly higher rates of adverse events in the lumateperone group (58% vs. 46%), with common issues being dry mouth, fatigue, and tremor, which were mild to moderate and dissipated over time. There were no significant differences in cardiometabolic profiles or clinically significant weight gain between the groups. EPS-related adverse events were low, and rates of suicidal ideations were comparable between groups.
In conclusion, lumateperone as an adjunct to antidepressants demonstrated significant improvement in depressive symptoms and had a consistent safety profile. Dr. Willie also mentioned a second, similarly designed study (study 502) that confirmed these findings.
Adjunctive Aticaprant and Anhedonia in Major Depressive disorder
Speaker: Koen Demyttenaere
In this presentation, Dr. Koen discussed the assessment of anhedonia and the effects of aticaprant, a kappa opioid receptor antagonist. Depression is a well-known but ill-defined concept, requiring either depressed mood or anhedonia (diminished interest or pleasure) for diagnosis. Notably, the DSM does not address the lack of positive mood, and research indicates that negative and positive moods are largely independent. Despite anhedonia being a core symptom of depression, widely used scales like the Hamilton and MADRS inadequately assess it. Anhedonia and decreased positive affect are significant predictors of decreased life expectancy, cognitive deficits, social dysfunction, and suicidality in depressed individuals. Patients prioritize the recovery of positive affect, and early changes in positive affect predict better treatment outcomes than changes in negative affect. However, current treatments are more effective at reducing negative effect than increasing positive effect.
Assessing anhedonia is challenging, involving a “tower of Babel” of various scales and methods. The clinical language focuses on interest and pleasure, while cognitive neuroscience uses terms like reward readiness and energy expenditure, often assessed through computer tests. A hybrid approach, like the Dimensional Anhedonia Rating Scale (DARS), attempts to bridge these languages.
Dr. Koen shifted the discussion to aticaprant, a high-affinity, selective kappa opioid receptor antagonist. Stress, substance withdrawal, and inflammation activate dynorphin, which in turn releases kappa opioid receptors, reducing dopamine release and increasing self-stimulation thresholds. Aticaprant has a high binding affinity, quick receptor occupancy, and is effective in clinical doses up to 10 mg, showing promising antidepressant-like effects in rodent studies.
The fast-fail approach in drug development, supported by the NIMH, emphasizes early imaging data to confirm target engagement in the brain. In an eight-week double-blind placebo-controlled trial, aticaprant showed positive imaging data but mixed results on neurocognitive tasks and self-rating scales, indicating a need for further research to resolve these discrepancies.
A phase 2 trial of aticaprant in patients with MDD who did not respond to SSRIs or SNRIs showed significant improvement in MADRS scores and a numerical but not statistically significant improvement in the SHAPS scale. The greatest effects were observed in patients with higher baseline anhedonia, particularly in items related to anhedonia.
The safety profile of aticaprant was favorable, with no significant changes in vital signs or lab results and common adverse events being mild. The speaker concluded that anhedonia is a multifaceted core symptom of depression, and aticaprant shows promise in addressing it, warranting further investigation in larger trials.
References
1. FOSTER, J. Implementing precision psychiatry in clinical practice: what are we waiting for?. In: 37th ECNP Congress, Milan, Italy.
2. CRUCEANU, C. Inflammation in depression: a bird’s eye view across the body and across the lifespan. In: 37th ECNP Congress, Milan, Italy.
3. LISTON, C. Neurocircuits in depression. In: 37th ECNP Congress, Milan, Italy.
4. WEISER, M. New Medication Symposium. In: 37th ECNP Congress, Milan, Italy.
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