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Pharmacogenomics and Precision Medicine in Psychiatry: From Basic Research to Clinical Practice

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A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Pharmacogenetics".

Deadline for manuscript submissions: closed (10 May 2023) | Viewed by 26613

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Prof. Dr. Angelos Halaris

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Department of Psychiatry, Loyola University Stritch School of Medicine, Maywood, IL 60153, USA
Interests: affective disorders; anxiety; major depressive disorder; bipolar disorders; treatment resistance; pharmacogenomics; general psychiatry
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Special Issue Information

Dear Colleagues,

Over the past decade, the prevalence of mental illnesses has been steadily increasing worldwide. There are many reasons for the continuously increasing prevalence rates, but the precise diagnosis, treatment selection, and prevention of mental illnesses lag woefully behind. The disease model that is still being utilized is based largely, if not exclusively, on phenomenology, unlike other medical conditions, where precision medicine has accomplished significant advances utilizing specific laboratory measures, sophisticated imaging techniques and genomics. The concept of precision medicine has ushered in a new era in medicine, in general, and psychiatry in particular, where it is sorely needed. The etiopathology, diagnostic precision, and targeted pharmacotherapies will undoubtedly benefit mentally ill individuals while also enhancing our ability to detect predisposition and vulnerabilities toward mental illness, thereby enabling effective preventive measures. Recent impressive advancements in psychoneuroimmunology, genomics, epigenetics, polygenic risk factors, and pharmacogenomics hold great promise. Innovative therapeutic agents based on new scientific discoveries will lessen the personal and societal burden of mental illness. Therefore, worldwide dissemination of this information and rapid translation and introduction into medical practices must receive the highest priority. This Special Issue in the Journal of Personalized Medicine aims to highlight the current state of science in the above-identified fields. Basic research studies, clinical and translational studies, as well as new drug developments are all relevant topics to be included in this Special Issue.

Original research papers, brief scientific reports, as well as review papers, regarding the relevant topic, will be considered for publication in this Special Issue, titled “Pharmacogenomics and Precision Medicine in Psychiatry: From Basic Research to Clinical Practice”.

It will cover issues concerning any psychiatric and neuropsychiatric disorder, genomics, epigenetics, pharmacogenomics, genomic testing, psychoneuroimmunology, translational, and precision psychiatry.

We will be accepting both reviews and original publications.

Prof. Dr. Angelos Halaris
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

precision medicine
genomics
epigenetics
pharmacogenomics
psychoneuroimmunology
inflammation
single nucleotide polymorphisms
biomarkers

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Published Papers (11 papers)

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Research

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15 pages, 553 KiB

Open AccessArticle

Systemic Inflammatory Response Index (SIRI) at Baseline Predicts Clinical Response for a Subset of Treatment-Resistant Bipolar Depressed Patients

by Stephen Murata, Nausheen Baig, Kyle Decker and Angelos Halaris

J. Pers. Med. 2023, 13(9), 1408; https://doi.org/10.3390/jpm13091408 - 20 Sep 2023

Cited by 3 | Viewed by 1595

Abstract

Background: in a recent double-blind, placebo controlled RCT we demonstrated that selective inhibition of cyclo-oxygenase 2 (COX2) is an effective adjunctive strategy in treatment-resistant bipolar depression (TRBDD). To better clarify the mechanisms underlying TRBDD and treatment response, we conducted a retrospective exploratory analysis of the systemic inflammatory response index (SIRI = absolute neutrophils × absolute monocytes/absolute lymphocytes) in relation to other biomarkers and clinical outcomes after escitalopram (ESC), combined with the COX-2 inhibitor, celecoxib (CBX), versus placebo. Methods: Baseline measures of SIRI were compared between TRBDD and healthy controls (HC), and correlated with blood-based inflammatory cytokines, kynurenines, and growth factors. Post-treatment Hamilton Depression Rating Scale 17 (HAMD-17) total scores (clinical outcome) were modelled according to SIRI adjusting for demographics (including relevant interactions with SIRI), baseline depression, treatment arm, and treatment timepoint using multiple linear regression and robust linear mixed effects models. Results: Baseline SIRI did not distinguish TRBDD from HC groups. Baseline SIRI was significantly correlated with lower baseline MCP-1. The relationship between SIRI and HAMD-17 was significant at treatment week 8, in contrast to baseline. Finally, baseline SIRI predicted elevated post-treatment HAMD-17 scores, amongst patients with elevated depression scores at baseline. Significance: High pre-treatment SIRI may predict poorer depressive outcomes amongst TRBDD patients with baseline elevated depression. Full article

(This article belongs to the Special Issue Pharmacogenomics and Precision Medicine in Psychiatry: From Basic Research to Clinical Practice)

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14 pages, 1174 KiB

Open AccessFeature PaperArticle

Pharmacogenetics of Long-Term Outcomes of Schizophrenia Spectrum Disorders: The Functional Role of CYP2D6 and CYP2C19

by Amrit K. Sandhu, Elnaz Naderi, Morenika J. Wijninga, Edith J. Liemburg, GROUP Investigators, Danielle Cath, Richard Bruggeman and Behrooz Z. Alizadeh

J. Pers. Med. 2023, 13(9), 1354; https://doi.org/10.3390/jpm13091354 - 4 Sep 2023

Cited by 2 | Viewed by 1489

Abstract

Schizophrenia spectrum disorders (SSD) are complex mental disorders, and while treatment with antipsychotics is important, many patients do not respond or develop serious side effects. Genetic variation has been shown to play a considerable role in determining an individual’s response to antipsychotic medication. However, previous pharmacogenetic (PGx) studies have been limited by small sample sizes, lack of consensus regarding relevant genetic variants, and cross-sectional designs. The current study aimed to investigate the association between PGx variants and long-term clinical outcomes in 691 patients of European ancestry with SSD. Using evidence from the literature on candidate genes involved in antipsychotic pharmacodynamics, we created a polygenic risk score (PRS) to investigate its association with clinical outcomes. We also created PRS using core variants of psychotropic drug metabolism enzymes CYP2D6 and CYP2C19. Furthermore, the CYP2D6 and CYP2C19 functional activity scores were calculated to determine the relationship between metabolism and clinical outcomes. We found no association for PGx PRSs and clinical outcomes; however, an association was found with CYP2D6 activity scores by the traditional method. Higher CYP2D6 metabolism was associated with high positive and high cognitive impairment groups relative to low symptom severity groups. These findings highlight the need to test PGx efficacy with different symptom domains. More evidence is needed before pharmacogenetic variation can contribute to personalized treatment plans. Full article

(This article belongs to the Special Issue Pharmacogenomics and Precision Medicine in Psychiatry: From Basic Research to Clinical Practice)

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23 pages, 680 KiB

Open AccessArticle

Utilizing the Systemic Immune-Inflammation Index and Blood-Based Biomarkers in Association with Treatment Responsiveness amongst Patients with Treatment-Resistant Bipolar Depression

by Kyle Decker, Stephen Murata, Nausheen Baig, Sakibur Hasan and Angelos Halaris

J. Pers. Med. 2023, 13(8), 1245; https://doi.org/10.3390/jpm13081245 - 10 Aug 2023

Cited by 1 | Viewed by 1674

Abstract

(1) Background: Inflammation is associated with depressive illness and treatment resistance. This study assessed a novel inflammatory index, the Systemic Immune-Inflammation Index (SII), in patients diagnosed with treatment-resistant bipolar depression (TRBDD) before and after treatment with escitalopram (ESC) and celecoxib (CBX) add-on or ESC and placebo (PBO), and compared them to healthy control (HC) subjects. (2) Methods: This is a secondary biological analysis from a double-blind randomized placebo-controlled trial of CBX augmentation in TRBDD. Our subsample with available complete blood count (CBC) data included 52 TRBDD subjects, randomized into an ESC + CBX, (n = 29), an ESC + PBO arm (n = 23), and an HC group (n = 32). SII was calculated from the CBC with differential (SII = platelets x neutrophils/lymphocytes) at baseline and end of treatment (8 weeks). Blood inflammation biomarkers, growth factors, and kynurenine metabolites were determined at both timepoints. Depressive symptom severity was the primary outcome, using the HAMD-17 rating scale score to quantitate treatment response and remission rates. (3) Results: Baseline SII did not discriminate TRBDD from HC, nor was it associated with HAMD-17 score at any timepoint, although it was significantly associated with lower baseline VEGF (p = 0.011) and higher week 8 levels of IL1-β (p = 0.03) and CRP (p = 0.048). Post-treatment HAMD-17 was not independently predicted using baseline SII unless an interaction with age was present (p = 0.003 was included), even after relevant adjustments. A similar effect was seen with baseline neutrophils. (4) Conclusions: While SII was not an independent predictor of treatment outcome, elevated baseline SII was a predictor of poor treatment response amongst older patients with TRBDD. Full article

(This article belongs to the Special Issue Pharmacogenomics and Precision Medicine in Psychiatry: From Basic Research to Clinical Practice)

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11 pages, 526 KiB

Open AccessArticle

Towards the First Biomarker Test for Bipolar Spectrum Disorder: An Evaluation of 199 Patients in an Outpatient Setting

by Andy Zamar, Ashma Mohamed, Abbi Lulsegged, Daniel Stahl and Christos Kouimtsidis

J. Pers. Med. 2023, 13(7), 1108; https://doi.org/10.3390/jpm13071108 - 7 Jul 2023

Cited by 1 | Viewed by 3128

Abstract

Bipolar spectrum disorder seems to be challenging to diagnose, particularly unspecified or subthreshold types. The delay in diagnosis in the UK for bipolar I and II types is a staggering 10–13 years, with only 15% correctly diagnosed without delay. In the USA, the delay is 6–8 years, and there is a 60% incorrect diagnosis rate. The HCL-32 questionnaire is adequate, but not sufficient by itself, and patients may find it difficult to complete, particularly if they are unwell. We have investigated a biomarker test which can be used in day-to-day clinical practice to assist diagnosis. We evaluated 199 patients diagnosed with ICD-10 bipolar I, II, and unspecified disorders, using the HCL-32 questionnaire with a cut-off point of 14 and above, supplemented by history taking and examination using the principles of the CIDI 3, interviews of relatives, and longitudinal mood charts where available. The results were compared to the general population and a sample of patients diagnosed with recurrent depression for assessment of sensitivity and specificity. We evaluated four mutations of SLCO1C1, DiO1, and two DiO2alleles as potential biomarkers for bipolar spectrum disorder, and identified three mutations that exhibited high sensitivity, with rates of up to 87% and specificity of up to 46% in distinguishing bipolar spectrum disorders from recurrent depressive disorder. Additionally, mutations in SLCO1C1 and DiO1 exhibited a sensitivity of up to 86% and a specificity of up to 60% in detecting bipolar spectrum disorder compared to the general population within a clinical setting. These biomarkers have the potential to be used as a diagnostic test that is not open to subjective interpretation and can be administered even if patients are very unwell, requiring, though, the patient’s consent. Further studies confirming these results are needed to compare the validity of using individual or a best combination of single nucleotide polymorphisms to identify bipolar spectrum disorders, particularly subthreshold presentations, and to differentiate them from other mood disorders such as major depression and recurrent depressive disorder. Full article

(This article belongs to the Special Issue Pharmacogenomics and Precision Medicine in Psychiatry: From Basic Research to Clinical Practice)

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20 pages, 1413 KiB

Open AccessArticle

Pharmacogenetics of Lethal Opioid Overdose: Review of Current Evidence and Preliminary Results from a Pilot Study

by Leen Magarbeh, Ilona Gorbovskaya, Richard Wells, Reuven Jhirad, Bernard Le Foll and Daniel J. Müller

J. Pers. Med. 2023, 13(6), 918; https://doi.org/10.3390/jpm13060918 - 30 May 2023

Cited by 1 | Viewed by 2700

Abstract

There has been a worldwide substantial increase in accidental opioid-overdose deaths. The aim of this review, along with preliminary results from our pilot study, is to highlight the use of pharmacogenetics as a tool to predict causes of accidental opioid-overdose death. For this review, a systematic literature search of PubMed^® between the time period of January 2000 to March 2023 was carried out. We included study cohorts, case–controls, or case reports that investigated the frequency of genetic variants in opioid-related post-mortem samples and the association between these variants and opioid plasma concentrations. A total of 18 studies were included in our systematic review. The systematic review provides evidence of the use of CYP2D6, and to a lower extent, CYP2B6 and CYP3A4/5 genotyping in identifying unexpectedly high or low opioid and metabolite blood concentrations from post-mortem samples. Our own pilot study provides support for an enrichment of the CYP2B6*4-allele in our methadone-overdose sample (n = 41) compared to the anticipated frequency in the general population. The results from our systematic review and the pilot study highlight the potential of pharmacogenetics in determining vulnerability to overdose of opioids. Full article

(This article belongs to the Special Issue Pharmacogenomics and Precision Medicine in Psychiatry: From Basic Research to Clinical Practice)

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15 pages, 3394 KiB

Open AccessArticle

Determination of the Duplicated CYP2D6 Allele Using Real-Time PCR Signal: An Alternative Approach

by Mazen A. Atiq, Sandra E. Peterson, Loralie J. Langman, Linnea M. Baudhuin, John L. Black and Ann M. Moyer

J. Pers. Med. 2023, 13(6), 883; https://doi.org/10.3390/jpm13060883 - 24 May 2023

Cited by 2 | Viewed by 1776

Abstract

CYP2D6 duplication has important pharmacogenomic implications. Reflex testing with long-range PCR (LR-PCR) can resolve the genotype when a duplication and alleles with differing activity scores are detected. We evaluated whether visual inspection of plots from real-time-PCR-based targeted genotyping with copy number variation (CNV) detection could reliably determine the duplicated CYP2D6 allele. Six reviewers evaluated QuantStudio OpenArray CYP2D6 genotyping results and the TaqMan Genotyper plots for seventy-three well-characterized cases with three copies of CYP2D6 and two different alleles. Reviewers blinded to the final genotype visually assessed the plots to determine the duplicated allele or opt for reflex sequencing. Reviewers achieved 100% accuracy for cases with three CYP2D6 copies that they opted to report. Reviewers did not request reflex sequencing in 49–67 (67–92%) cases (and correctly identified the duplicated allele in each case); all remaining cases (6–24) were marked by at least one reviewer for reflex sequencing. In most cases with three copies of CYP2D6, the duplicated allele can be determined using a combination of targeted genotyping using real-time PCR with CNV detection without need for reflex sequencing. In ambiguous cases and those with >3 copies, LR-PCR and Sanger sequencing may still be necessary for determination of the duplicated allele. Full article

(This article belongs to the Special Issue Pharmacogenomics and Precision Medicine in Psychiatry: From Basic Research to Clinical Practice)

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Review

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19 pages, 345 KiB

Open AccessReview

Immunological Biomarkers as Predictors of Treatment Response in Psychotic Disorders

by Elif Bayram Orbe and Michael Eriksen Benros

J. Pers. Med. 2023, 13(9), 1382; https://doi.org/10.3390/jpm13091382 - 15 Sep 2023

Cited by 6 | Viewed by 1693

Abstract

Psychotic disorders, notably schizophrenia, impose a detrimental burden on both an individual and a societal level. The mechanisms leading to psychotic disorders are multifaceted, with genetics and environmental factors playing major roles. Increasing evidence additionally implicates neuro-inflammatory processes within at least a subgroup of patients with psychosis. While numerous studies have investigated anti-inflammatory add-on treatments to current antipsychotics, the exploration of immunological biomarkers as a predictor of treatment response remains limited. This review outlines the current evidence from trials exploring the potential of baseline inflammatory biomarkers as predictors of the treatment effect of anti-inflammatory drugs as add-ons to antipsychotics and of antipsychotics alone. Several of the studies have found correlations between baseline immunological biomarkers and treatment response; however, only a few studies incorporated baseline biomarkers as a primary endpoint, and the findings thus need to be interpreted with caution. Our review emphasizes the need for additional research on the potential of repurposing anti-inflammatory drugs while utilizing baseline inflammatory biomarkers as a predictor of treatment response and to identify subgroups of individuals with psychotic disorders where add-on treatment with immunomodulating agents would be warranted. Future studies investigating the correlation between baseline inflammatory markers and treatment responses can pave the way for personalized medicine approaches in psychiatry centred around biomarkers such as specific baseline inflammatory biomarkers in psychotic disorders. Full article

(This article belongs to the Special Issue Pharmacogenomics and Precision Medicine in Psychiatry: From Basic Research to Clinical Practice)

14 pages, 251 KiB

Open AccessFeature PaperReview

Pharmacogenomics and the Management of Mood Disorders—A Review

by Kristian Kleine Schaars and Roos van Westrhenen

J. Pers. Med. 2023, 13(7), 1183; https://doi.org/10.3390/jpm13071183 - 24 Jul 2023

Cited by 2 | Viewed by 2351

Abstract

Due to the chronic relapsing nature of mental disorders and increased life expectancy, the societal burden of these non-communicable diseases will increase even further. Treatments for mental disorders, such as depression, are available, but their effect is limited due to patients’ (genetic) heterogeneity, low treatment compliance and frequent side effects. In general, only one-third of the patients respond to treatment. Today, medication selection in psychiatry relies on a trial-and-error approach based mainly on physicians’ experience. Pharmacogenetic (PGx) testing can help in this process by determining the person-specific genetic factors that may predict clinical response and side effects associated with genetic variants that impact drug-metabolizing enzymes, drug transporters or drug targets. PGxis a discipline that investigates genetic factors that affect the absorption, metabolism, and transport of drugs, thereby affecting therapy outcome. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Studies in depressed patients show that genotyping of drug-metabolizing enzymes can increase the effectiveness of treatment, which could benefit millions of patients worldwide. This review highlights these studies, gives recommendations and provides future perspectives on how to proceed with PGx testing. Finally, it is recommended to consider genotyping for CYP2D6 and CYP2C19, when there is an indication (side effects or inefficacy). Full article

(This article belongs to the Special Issue Pharmacogenomics and Precision Medicine in Psychiatry: From Basic Research to Clinical Practice)

18 pages, 371 KiB

Open AccessReview

Fight the Fire: Association of Cytokine Genomic Markers and Suicidal Behavior May Pave the Way for Future Therapies

by Xenia Gonda, Gianluca Serafini and Peter Dome

J. Pers. Med. 2023, 13(7), 1078; https://doi.org/10.3390/jpm13071078 - 29 Jun 2023

Cited by 5 | Viewed by 1875

Abstract

The fight against suicide is highly challenging as it may be one of the most complex and, at the same time, most threatening among all psychiatric phenomena. In spite of its huge impact, and despite advances in neurobiology research, understanding and predicting suicide remains a major challenge for both researchers and clinicians. To be able to identify those patients who are likely to engage in suicidal behaviors and identify suicide risk in a reliable and timely manner, we need more specific, novel biological and genetic markers/indicators to develop better screening and diagnostic methods, and in the next step to utilize these molecules as intervention targets. One such potential novel approach is offered by our increasing understanding of the involvement of neuroinflammation based on multiple observations of increased proinflammatory states underlying various psychiatric disorders, including suicidal behavior. The present paper overviews our existing understanding of the association between suicide and inflammation, including peripheral and central biomarkers, genetic and genomic markers, and our current knowledge of intervention in suicide risk using treatments influencing inflammation; also overviewing the next steps to be taken and obstacles to be overcome before we can utilize cytokines in the treatment of suicidal behavior. Full article

(This article belongs to the Special Issue Pharmacogenomics and Precision Medicine in Psychiatry: From Basic Research to Clinical Practice)

18 pages, 764 KiB

Open AccessReview

Personalized Medicine of Omega-3 Fatty Acids in Depression Treatment in Obese and Metabolically Dysregulated Patients

by Suet-Kei Wu, Wei-Jen Chen, Jane Pei-Chen Chang, Ta-Wei Guu, Ming-Che Hsin, Chih-Kun Huang, David Mischoulon, Lucile Capuron and Kuan-Pin Su

J. Pers. Med. 2023, 13(6), 1003; https://doi.org/10.3390/jpm13061003 - 15 Jun 2023

Cited by 5 | Viewed by 4154

Abstract

The co-occurrence of depression and obesity has become a significant public health concern worldwide. Recent studies have shown that metabolic dysfunction, which is commonly observed in obese individuals and is characterized by inflammation, insulin resistance, leptin resistance, and hypertension, is a critical risk factor for depression. This dysfunction may induce structural and functional changes in the brain, ultimately contributing to depression’s development. Given that obesity and depression mutually increase each other’s risk of development by 50–60%, there is a need for effective interventions that address both conditions. The comorbidity of depression with obesity and metabolic dysregulation is thought to be related to chronic low-grade inflammation, characterized by increased circulating levels of pro-inflammatory cytokines and C-reactive protein (CRP). As pharmacotherapy fails in at least 30–40% of cases to adequately treat major depressive disorder, a nutritional approach is emerging as a promising alternative. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are a promising dietary intervention that can reduce inflammatory biomarkers, particularly in patients with high levels of inflammation, including pregnant women with gestational diabetes, patients with type 2 diabetes mellitus, and overweight individuals with major depressive disorder. Further efforts directed at implementing these strategies in clinical practice could contribute to improved outcomes in patients with depression, comorbid obesity, and/or metabolic dysregulation. Full article

(This article belongs to the Special Issue Pharmacogenomics and Precision Medicine in Psychiatry: From Basic Research to Clinical Practice)

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Other

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19 pages, 672 KiB

Open AccessSystematic Review

Pharmacomicrobiomics of Antidepressants in Depression: A Systematic Review

by Lisa C. Brown, William V. Bobo, Cory A. Gall, Daniel J. Müller and Chad A. Bousman

J. Pers. Med. 2023, 13(7), 1086; https://doi.org/10.3390/jpm13071086 - 30 Jun 2023

Cited by 7 | Viewed by 3400

Abstract

This systematic review evaluated the animal and human evidence for pharmacomicrobiomics (PMx) interactions of antidepressant medications. Studies of gut microbiota effects on functional and behavioral effects of antidepressants in human and animal models were identified from PubMed up to December 2022. Risk of bias was assessed, and results are presented as a systematic review following PRISMA guidelines. A total of 28 (21 animal, 7 human) studies were included in the review. The reviewed papers converged on three themes: (1) Antidepressants can alter the composition and metabolites of gut microbiota, (2) gut microbiota can alter the bioavailability of certain antidepressants, and (3) gut microbiota may modulate the clinical or modeled mood modifying effects of antidepressants. The majority (n = 22) of studies had at least moderate levels of bias present. While strong evidence is still lacking to understand the clinical role of antidepressant PMx in human health, there is evidence for interactions among antidepressants, microbiota changes, microbiota metabolite changes, and behavior. Well-controlled studies of the mediating and moderating effects of baseline and treatment-emergent changes in microbiota on therapeutic and adverse responses to antidepressants are needed to better establish a potential role of PMx in personalizing antidepressant treatment selection and response prediction. Full article

(This article belongs to the Special Issue Pharmacogenomics and Precision Medicine in Psychiatry: From Basic Research to Clinical Practice)

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