Treatment-Resistant Depression: Esketamine Is Promising, but Personalized Medicine Including Pharmacogenetic Testing Should Come First.

Pleiotropic genes in psychiatry: Calcium channels and the stress-related FKBP5 gene in antidepressant resistance

The advent of intra-nasal esketamine (ESK), one of the first so called fast-acting antidepressant, promises to revolutionize the management of treatment resistant depression (TRD). This NMDA receptor antagonist has proven to be rapidly effective in the short- and medium-term course of the illness, revealing its potential in targeting response in TRD. Although many TRD ESK responders are able to achieve remission, a considerable portion of them undergo a metamorphosis of their depression into different clinical presentations, characterized by instable responses and high recurrence rates that can be considered closer to the concept of Difficult to Treat Depression (DTD) than to TRD. The management of these DTD patients usually requires a further complex multidisciplinary approach and can benefit from the valuable contribution of new personalized medicine tools such as therapeutic drug monitoring and pharmacogenetics. Despite this, these patients usually come with long and complex previous treatments history and, often, advanced and sophisticated ongoing pharmacological schemes that can make the finding of new alternative options to face the current recurrences extremely challenging. In this paper, we describe two DTD patients—already receiving intranasal ESK but showing an instable course—who were clinically stabilized by the association with minocycline, a semisynthetic second-generation tetracycline with known and promising antidepressant properties.

Major depressive disorder (MDD) is the most common psychiatric disease worldwide with a huge socio-economic impact. Pharmacotherapy represents the most common option among the first-line treatment choice; however, only about one third of patients respond to the first trial and about 30% are classified as treatment-resistant depression (TRD). TRD is associated with specific clinical features and genetic/gene expression signatures. To date, single sets of markers have shown limited power in response prediction. Here we describe the methodology of the PROMPT project that aims at the development of a precision medicine algorithm that would help early detection of non-responder patients, who might be more prone to later develop TRD. To address this, the project will be organized in 2 phases. Phase 1 will involve 300 patients with MDD already recruited, comprising 150 TRD and 150 responders, considered as extremes phenotypes of response. A deep clinical stratification will be performed for all patients; moreover, a genomic, transcriptomic and miRNomic profiling will be conducted. The data generated will be exploited to develop an innovative algorithm integrating clinical, omics and sex-related data, in order to predict treatment response and TRD development. In phase 2, a new naturalistic cohort of 300 MDD patients will be recruited to assess, under real-world conditions, the capability of the algorithm to correctly predict the treatment outcomes. Moreover, in this phase we will investigate shared decision making (SDM) in the context of pharmacogenetic testing and evaluate various needs and perspectives of different stakeholders toward the use of predictive tools for MDD treatment to foster active participation and patients’ empowerment. This project represents a proof-of-concept study. The obtained results will provide information about the feasibility and usefulness of the proposed approach, with the perspective of designing future clinical trials in which algorithms could be tested as a predictive tool to drive decision making by clinicians, enabling a better prevention and management of MDD resistance.

Pharmacotherapies for depression are often ineffective and treatment-resistant depression (TRD) is common across bipolar disorder (BD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). Patient genetic information can be used to predict treatment outcomes. Prospective studies indicate that pharmacogenetic (PGX) tests have utility in the treatment of depression. However, few studies have examined the utility of PGX in other diagnoses typified by depression, or in veterans, a cohort with high rates of medical comorbidity, social stress, and suicide. To determine the efficacy of genetically guided pharmacological treatment of TRD. We conducted an 8-week, prospective, multisite, single-blind study in 182 veterans with TRD including patients with BD, MDD, and PTSD. Subjects were randomly assigned to PGX-guided treatment in which the clinician incorporated PGX information into decision-making, or treatment as usual (TAU). Overall, the PGX group improved marginally faster compared to TAU, but the difference was not statistically significant. Secondary analyses revealed that only PTSD patients showed a potential benefit from PGX testing. Patients predicted by PGX testing to have moderate levels of genetic risk showed a significant benefit from the PGX-guided treatment, whereas other risk groups demonstrated no benefit. Clinicians generally found the PGX test was useful, particularly in more depressed patients and/or those with more warnings for significant or serious adverse outcomes. Clinicians more often used the results to select a drug, but only rarely to adjust dosing. The data reveal possible group differences in the utility of PGX testing in veterans with TRD.ClinicalTrials.gov Identifier: NCT04469322.

1792 – Inpatient suicide risk association with depression, anxiety disorders and pharmacogenetic testing

Chapter 7 - Tools to aid precision treatments to prevent or manage treatment-resistant depression (TRD): Pharmacogenomics, machine learning, and artificial intelligence

BackgroundIn the shadow of global pandemics of COVID-19, a new silent one concerning mental health is emerging. The complete understanding of the pathophysiology of mental diseases remains elusive, resulting in insufficient remission, frequent incidence of adverse drug reactions as well as resistance to treatment. While a vast number of affected individuals worldwide do not have access to effective mental disorder care, treatment resistance affects 20-60% patients.1 A personalized approach has been recently incorporated to the therapy also in psychiatry and one of the strategies is pharmacogenetic (PGx) testing, which has the potential to guide effective drug therapy and minimize side effects.Aims & ObjectivesThe objective of this study was to assess the viewpoints of Slovak psychiatrists regarding the integration of PGx testing in psychiatric clinical practice.MethodQuestionnaires were distributed directly to attendees at two psychiatric conferences held in Slovakia in 2023. The questionnaires were designed to be anonymous and were structured based on research conducted by a collaborative team in Italy. They covered various aspects, including basic demographic information, prior experience with PGx testing, self-perceived competence in PGx, perceived utility, potential risks, and challenges, as well as the participants' willingness to expand their knowledge about the application of PGx in psychiatry. The questionnaire is currently available online and was shared within the Slovak psychiatric community.ResultsOut of 60 directly approached conference participants we received 53 responses as 5 individuals declined to participate because of the questionnaire topic and 2 reported time constraints. Our respondents were from various age groups, the majority were females (66%) and had different backgrounds such as psychiatrists for adults (45.3%), pedopsychiatrists (15.1%), clinicians with expertise in both areas (3.8%), residents in a psychiatry program (20.7%) or pharmacists and researchers working in the field of psychiatry (15.1%). Only 4 participants (7.5%) had previous experience with PGx testing in psychiatric clinical practice and only 3 claimed its clinical benefit. The data indicated that 88.7% of participants believed it was their responsibility to provide PGx testing to their patients, but only 41.5% felt confident in their ability to do so. Based on the responses, 64.2% of attendees thought that PGx would be very or extremely useful in selection of medication, 62.3% in drug intolerance and adverse reactions, 56.6% in dosing adjustment, 66.0% in treatment resistant depression, 62.3% in treatment resistant schizophrenia, and 60.4% in resistant obsessive-compulsory disorder. The most significant concerns expressed were the absence of standards or guidelines (77.4%) and the cost of the tests (64.2%). Notably, 84.9% of the participants indicated their eagerness to acquire further knowledge about the integration of PGx in psychiatric clinical practice.Discussion & ConclusionThe results of this questionnaire found that most clinicians felt that they should possess the skills to apply PGx testing in psychiatric clinical practice and were enthusiastic about increasing their expertise. The primary concerns centered around the lack of well-defined guidelines and the financial considerations linked to the testing.The study was supported by grants VEGA-1/0145/22 and APVV-22-0342.

The pathophysiology of mental illnesses is not fully understood, leading to insufficient remission, frequent adverse drug reactions, and treatment resistance. Pharmacogenetic (PGx) testing, apersonalized approach recently adopted also in psychiatry, can guide effective drug therapy and minimize side effects. The objective of this study was to determine the perspective of Slovak clinicians regarding the integration of PGx testing in psychiatric clinical practice. Questionnaires covering various aspects such as prior experience with PGx testing, self-perceived competence, perceived utility, potential risks and challenges were distributed directly to attendees at two psychiatric conferences held in Slovakia in 2023 and their responses were statistically analysed. Out of 54 respondents, only 7.4% had previous experience with PGx in clinical practice. The most clinicians felt that they should possess the skills to apply PGx testing in psychiatric clinical practice and were enthusiastic about increasing their expertise. They found PGx useful in medication selection, adverse effect management, and treatment-resistant depression. The primary concerns centered around the lack of well-defined guidelines and the financial considerations linked to the testing. Considering the participants' interest in PGx and its integration into clinical practice, educational programmes based on recommendations, guidelines, and convincing evidence could be organized (Tab. 4, Ref. 30). Text in PDF www.elis.sk Keywords: pharmacogenetics, pharmacogenomics, psychiatry, personalized treatment, Slovakia, perspective.

P.3.003 - Pleiotropic genes in psychiatry: calcium channels and the stress-related FKBP5 gene in antidepressant resistance

This chapter reviews the evidence for first-line treatment of major depressive disorder (MDD), and strategies for patients with treatment-resistant depression. Many trials have investigated the efficacy of selective serotonin reuptake inhibitors (SSRIs) compared with other antidepressants. Patients with MDD are at higher risk of suicide, and guidelines indicate that patients should be assessed for suicide at the start of treatment and regularly over the course of treatment. As augmenting agents, atypical antipsychotics, lithium, and triiodothyronine (T3) have been studied the most extensively, and shown to have benefit. However, their risks and side-effect profiles may make them less attractive to patients, and patient preference and safety should determine treatment decisions for refractory or chronic MDD. The use of biomarkers, including pharmacogenetic testing, may one day provide more accurate predictors of response or adverse outcomes, allowing targeted treatments and the promise of personalized medicine.

SA84 - PLEIOTROPIC GENES IN PSYCHIATRY: EFFECTS OF CALCIUM CHANNELS AND THE STRESS-RELATED FKBP5 GENE ON ANTIDEPRESSANT RESPONSE AND TREATMENT RESISTANCE

Solving pain problems with genetic clues

Depression and anxiety are among the most prevalent mental health disorders, posing significant challenges to individuals and society. Despite the widespread use of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), many patients fail to achieve full remission or encounter debilitating side effects. This underscores an urgent need for innovative therapeutic approaches that go beyond traditional monoaminergic systems, targeting new pathways and mechanisms involved in these complex disorders. Recent advances have highlighted promising therapeutic targets, including the glutamatergic system. Ketamine, an NMDA receptor antagonist, has demonstrated rapid and sustained improvements in mood, inspiring the development of drugs that modulate glutamate transmission. Other systems, such as neuropeptides like oxytocin and vasopressin, are gaining attention for their roles in emotional regulation, while the endocannabinoid system offers potential for regulating mood and stress response [1]. Another recent study have shown that ketamine may offer significant benefits for individuals with psychiatric conditions such as treatment-resistant bipolar depression. Evidence suggests that even a single dose of intranasal ketamine can produce swift antidepressant effects, offering an alternative option for patients unresponsive to standard treatments [2] These novel approaches bring significant challenges with them. The safety profile of new agents must be rigorously evaluated to avoid unintended consequences, and regulatory barriers can delay the availability of innovative therapies. Moreover, the heterogeneity of depression and anxiety, influenced by genetic, environmental, and social factors, highlights the need for personalised medicine. Future research must prioritise understanding these differences to optimise treatment outcomes for diverse populations. The exploration of novel targets and drugs signals a paradigm shift in the treatment of depression and anxiety, moving away from a one-size-fits-all approach toward tailored interventions. These advancements bring renewed hope to millions of patients worldwide, promising more effective, rapid, and sustainable relief. With ongoing research and careful clinical translation, these innovative therapies have the potential to transform mental health care in the coming decades.

There is a rapidly expanding evidentiary gap between new molecular markers predictive of drug response and data that supports using such molecular markers (e.g., DNA, RNA or smallmolecule-based tests) in clinical practice. This evidence gap is a barrier to realizing the promise of personalized medicine where treatments are tailored to a patient’s individual characteristics. Randomized controlled trials (RCTs) are the ‘gold-standard’ metric for establishing the evidence that a particular intervention is superior to the current standard of care. However, the RCT is not without limitations and may not be the appropriate level of evidence required to support the clinical use of pharmacogenomic testing. We live in an environment where it is impractical to expect a RCT for each new marker. We should not abandon evidence-based practices when deciding to use a new pharmaco genomic marker; instead, clinicians and researchers must decide the appropriate level of evidence, short of the RCT, that supports the use of a novel pharmacogenomic marker in clinical care.

Pharmacogenetic testing for polymorphisms affecting drug response and metabolism is now clinically available, and its use in psychiatry is expected to become more widespread. Currently, few clinical and ethical standards exist for the use of these new tests. As a step toward building consensus about testing, we assessed the attitudes and practices of psychiatrists at 3 academic departments of psychiatry where pharmacogenetic testing is clinically available. We hypothesized that testing would be used primarily in treatment-resistant illness and that clinicians would believe such tests carried little risk. Residents and faculty at 3 departments of psychiatry considered to be "early adopters" of pharmacogenetic testing were invited during the academic year 2006-2007 to complete an Internet-based survey, including questions regarding clinical practices and opinions about testing utility, risks, and necessary safeguards. The 75 respondents had ordered pharmacogenetic testing a mean of 20.86 times in the previous 12 months. Testing was judged most useful in cases of treatment-resistant depression and medication intolerance. There was a lack of consensus about the risks of testing, particularly the risk of secondary information about disease susceptibility. Respondents endorsed the use of several safeguards, including confidentiality, pretest and posttest counseling, and informed consent, but consensus about other safeguards was lacking. Women and those who had not ordered testing in the prior year were more concerned about risks and need for safeguards than were men and those who had recently ordered testing. Physicians at early adopting departments of psychiatry endorsed the clinical utility of pharmacogenetic testing and the use of some patient safeguards, but showed a lack of consensus about other safeguards and risks.