Clinical Utility of Fluid Biomarker in Depressive Disorder

Alessandro Serretti(Alessandro Serretti ) 대한정신약물학회 2022 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.20 No.4

Major depressive disorders are ranked as the single largest contributor to non-fatal health loss and biomarkers could largely improve our routine clinical activity by predicting disease course and guiding treatment. However there is still a dearth of valid biomarkers in the field of psychiatry. The initial assumption that a single biomarker can capture the myriad of complex processes proved to be naive. The purpose of this paper is to critically review the field and to illustrate the possible practical application for routine clinical care. Biomarkers derived from DNA analysis are the ones that have received the most attention. Other potential candidates include circulating transcription products, proteins, and inflammatory markers. DNA polygenic risk scores proved to be useful in other fields of medicine and preliminary results suggest that they could be useful both as risk and diagnostic biomarkers also in depression and for the choice of treatment. A number of other possible fluid biomarkers are currently under investigation for diagnosis, outcome prediction, staging, and stratification of interventions, however research is still needed before they can be used for routine clinical care. When available, clinicians may be able to receive a lab report with detailed information about disease risk, outcome prediction, and specific indications about preferred treatments.

Anhedonia and Depressive Disorders

Alessandro Serretti 대한정신약물학회 2023 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.21 No.3

Anhedonia is a core symptom of depression and of several psychiatric disorders. Anhedonia has however expanded from its original definition to encompass a spectrum of reward processing deficits that received much interest in the last decades. It is a relevant risk factor for possible suicidal behaviors, and that it may operate as an independent risk factor for suicidality apart from the episode severity. Anhedonia has also been linked to inflammation with a possible reciprocal deleterious effect on depression. Its neurophysiological bases mainly include alterations in striatal and prefrontal areas, with dopamine being the most involved neurotransmitter. Anhedonia is thought to have a significant genetic component and polygenic risk scores are a possible tool for predicting an individual’s risk for developing anhedonia. Traditional antidepressants, such as selective serotonin reuptake inhibitors, showed a limited benefit on anhedonia, also considering their potential pro-anhedonic effect in some subjects. Other treatments may be more effective in treating anhedonia, such as agomelatine, vortioxetine, ketamine and transcranial magnetic stimulation. Psychotherapy is also widely supported, with cognitive-behavioral therapy and behavioral activation both showing benefit. In conclusion, a large body of evidence suggests that anhedonia is, at least partially, independent from depression, therefore it needs careful assessment and targeted treatment.

The Present and Future of Precision Medicine in Psychiatry: Focus on Clinical Psychopharmacology of Antidepressants

Alessandro Serretti 대한정신약물학회 2018 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.16 No.1

Precision medicine is a concept which is recently gaining momentum in all branches of medicine. In particular in psychiatry it is greatly needed given the huge societal costs of psychiatric disorders and given the long time needed to observe benefit from treatments and the response variability. The future will be based on biological determinants, however until such an interesting but still futuristic aim will be reached, at present we may only rely on clinical features to guide our individualized prescription which is currently still frequently based on personal opinion and subjective previous experiences. The aim of this review is to offer an overview of the main aspects to take into consideration when prescribing an antidepressant treatment to reach the best precision medicine using clinical information. More than 40 compounds are available for treating depression and a similar amount of compounds for other psychiatric disorders. The process of matching the profile of the patient with all different profiles of available compounds is therefore quite complex. Our everyday prescribing procedure should take into consideration a number of factors such as the knowledge of the profile of available compounds versus the symptomatology profile of the subject, previous efficacy, medical comorbidities, tolerability profile, individual preferences, and family history. While we are waiting more complex algorithms including biological or genetic measures, it is possible to optimize our current prescription practice by using all available information in order to obtain as much as possible an evidence based precision medicine prescription.

No Effect of Serotoninergic Gene Variants on Response to Interpersonal Counseling and Antidepressants in Major Depression

Alessandro Serretti,Chiara Fabbri,Silvia Pellegrini,Stefano Porcelli,Pierluigi Politi,Silvio Bellino,Marco Menchetti,Veronica Mariotti,Cristina Demi,Valentina Martinelli,Marco Cappucciati,Paola Bozzat 대한신경정신의학회 2013 PSYCHIATRY INVESTIGATION Vol.10 No.2

Objective-Gene variants within the serotonin pathway have been associated with major depressive disorder (MDD) treatment outcomes, however a possible different modulation on pharmacological or psychological treatments has never been investigated. Methods-One hundred sixty MDD patients were partially randomized to either inter-personal counseling (IPC) or antidepressants. The primary outcome was remission at week 8. Five serotonergic polymorphisms were investigated (COMT rs4680, HTR1A rs6295, HTR2A rs2224721, HTR2A rs7997012 and SLC6A4 rs421417). Results-IPC (n=43) and antidepressant (n=117) treated patients did not show any difference in remission rates at week 8 (corrected for baseline severity, age and center). None of the studied gene variants impacted on response and remission rates at week 8 neither in the IPC nor in the antidepressant group. An analysis of the whole sample showed a trend of association between rs7997012 AA genotype and a better treatment outcome. Conclusion-Our study confirms that IPC is an effective psychological intervention comparable to antidepressants in mild-moderate MDD. Polymorphisms related to the serotonin system did not exert a major effect on clinical outcomes in none of the treatment groups.

Genetics of Treatment Outcomes in Major Depressive Disorder: Present and Future

Chiara Fabbri,Alessandro Serretti 대한정신약물학회 2020 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.18 No.1

Pharmacogenetic testing is a useful and increasingly widespread tool to assist in antidepressant prescription. More than ten antidepressants (including tricyclics, selective serotonin reuptake inhibitors and venlafaxine) have already genetic biomarkers of response/side effects in clinical guidelines and drug labels. These are represented by functional genetic variants in genes coding for cytochrome enzymes (CYP2D6 and CYP2C19). Depending on the predicted metabolic activity, guidelines provide recommendations on drug choice and dosing. Despite not conclusive, the current evidence suggests that testing can be useful in patients who did not respond or tolerate at least one previous pharmacotherapy. However, the current recommendations are based on pharmacokinetic genes only (CYP450 enzymes), while pharmacodynamic genes (modulating antidepressant mechanisms of action in the brain) are still being studied because of their greater complexity. This may be captured by polygenic risk scores, which reflect the cumulative contribution of many genetic variants to a trait, and they may provide future clinical applications of pharmacogenetics. A more extensive use of genotyping in clinical practice may lead to improvement in treatment outcomes thanks to personalized treatments, but possible ethical issues and disparities should be taken into account and prevented.

How to Utilize Clinical and Genetic Information for Personalized Treatment of Major Depressive Disorder: Step by Step Strategic Approach

Chiara Fabbri,Alessandro Serretti 대한정신약물학회 2020 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE Vol.18 No.4

Depression is the single largest contributor to non-fatal health loss and affects 322 million people globally. The clinical heterogeneity of this disorder shows biological correlates and it makes the personalization of antidepressant prescription an important pillar of treatment. There is increasing evidence of genetic overlap between depression, other psychiatric and non-psychiatric disorders, which varies across depression subtypes. Therefore, the first step of clinical evaluation should include a careful assessment of psychopathology and physical health, not limited to previously diagnosed disorders. In part of the patients indeed the pathogenesis of depression may be strictly linked to inflammatory and metabolic abnormalities, and the treatment should target these as much as the depressive symptoms themselves. When the evaluation of the symptom and drug tolerability profile, the concomitant biochemical abnormalities and physical conditions is not enough and at least one pharmacotherapy failed, the genotyping of variants in CYP2D6/CYP2C19 (cytochromes responsible for antidepressant metabolism) should be considered. Individuals with altered metabolism through one of these enzymes may benefit from some antidepressants rather than others or need dose adjustments. Finally, if available, the polygenic predisposition towards cardio-metabolic disorders can be integrated with non-genetic risk factors to tune the identification of patients who should avoid medications associated with this type of side effects. A sufficient knowledge of the polygenic risk of complex medical and psychiatric conditions is becoming relevant as this information can be obtained through direct-to-consumer genetic tests and in the future it may provided by national health care systems.

Dysbindin associated with selective serotonin reuptake inhibitor antidepressant efficacy

Pae, Chi-Un,Serretti, Alessandro,Mandelli, Laura,De Ronchi, Diana,Patkar, Ashwin A.,Jun, Tae-Youn,Kim, Jung-Jin,Lee, Chang-Uk,Lee, Soo-Jung,Lee, Chul,Paik, In-Ho Lippincott Williams Wilkins, Inc. 2007 PHARMACOGENETICS AND GENOMICS Vol.17 No.1

OBJECTIVE: Antidepressant drug efficacy is partially under genetic control and a number of gene variants have been associated with antidepressants efficacy over the last few years. In the search for further genes influencing antidepressant response we focused on the dysbindin gene (dystrobrevin-binding-protein 1, DTNBP1). BASIC METHODS: One hundred and four Korean inpatients affected by major depressive disorder were treated with various antidepressants at standard therapeutic daily doses and rated with the 10-items Montgomery–Åsberg Depression rating scale (MADRS) at baseline and discharge. Five DTNBP1 variants (rs3213207 A/G, rs1011313 C/T, rs2005976 G/A, rs760761 C/T and rs2619522 A/C) were analysed for all patients. RESULTS: Rs2005976 was found to be significantly associated with final MADRS scores, with the rarest A allele associated with higher final scores (P=0.00055), rs760761 also showed a significant association (P=0.0058) and rs2619522 showed a positive trend (P=0.025). Markers were not significantly associated with Clinical Global Impression Scale scores. Five marker haplotypes were mildly associated with MADRS final scores but when considering the block composed of the three single nucleotide polymorphisms individually associated with response (rs2005976, rs760761 and rs2619522), results were more marked (P=0.0096), with the more frequent G–C–A haplotype associated with a positive outcome. CONCLUSIONS: Despite limitations due to the sample size and the mild antidepressant response, we observed a significant association between DTNBP1 variants and antidepressant response.

Pharmacogenetics and Depression: A Critical Perspective

Filippo Corponi,Chiara Fabbri,Alessandro Serretti 대한신경정신의학회 2019 PSYCHIATRY INVESTIGATION Vol.16 No.9

Depression leads the higher personal and socio-economical burden within psychiatric disorders. Despite the fact that over 40 antidepressants (ADs) are available, suboptimal response still poses a major challenge and is thought to be partially a result of genetic variation. Pharmacogenetics studies the effects of genetic variants on treatment outcomes with the aim of providing tailored treatments, thereby maximizing efficacy and tolerability. After two decades of pharmacogenetic research, variants in genes coding for the cytochromes involved in ADs metabolism (CYP2D6 and CYP2C19) are now considered biomarkers with sufficient scientific support for clinical application, despite the lack of conclusive cost/effectiveness evidence. The effect of variants in genes modulating ADs mechanisms of action (pharmacodynamics) is still controversial, because of the much higher complexity of ADs pharmacodynamics compared to ADs metabolism. Considerable progress has been made since the era of candidate gene studies: the genomic revolution has made possible to assess genetic variance on an unprecedented scale, throughout the whole genome, and to analyze the cumulative effect of different variants. The results have revealed key information on the biological mechanisms mediating ADs effect and identified hypothetical new pharmacological targets. They also paved the way for future availability of polygenic pharmacogenetic panels to predict treatment outcome, which are expected to explain much higher variance in ADs response compared to CYP2D6 and CYP2C19 only. As the demand and availability of AD pharmacogenetic testing is projected to increase, it is important for clinicians to keep abreast of this evolving area to facilitate informed discussions with their patients.

CACNA1C gene and schizophrenia: a case–control and pharmacogenetic study

Porcelli, Stefano,Lee, Soo-Jung,Han, Changsu,Patkar, Ashwin A.,Serretti, Alessandro,Pae, Chi-Un Wolters Kluwer Health, Inc. All rights reserved. 2015 PSYCHIATRIC GENETICS Vol.25 No.4

AIM: The present study aimed to explore whether 24 single nucleotide polymorphisms (SNPs) within the CACNA1C gene were associated with schizophrenia (SCZ) and antipsychotic response. METHODS: A sample of 176 SCZ inpatients and 326 healthy controls of Korean ethnicity was collected for this purpose. Psychopathological status was evaluated at baseline and at discharge using the Positive and Negative Syndrome Scale (PANSS). RESULTS: In the case–control study, rs1006737 (P=0.05) and rs2239104 (P=0.03) were associated with SCZ. Further, the rs10848635–rs1016388–rs1006737 haplotype was also associated with SCZ (P=0.03, simulate P=0.02). In the pharmacogenetic analyses, we did not find any association among the investigated SNPs and improvement in the PANSS total score. However, rs723672 and rs1034936 were associated with improvement in the PANSS positive subscale (respectively, P=0.02 and 0.05), rs2283271 in the negative subscale (P=0.01), rs10848635 and rs1016388 in the general subscale (respectively, P=0.03 and 0.04), and the rs3819536–rs2238062 haplotype (global statistics, P=0.1; simulate P=0.04). CONCLUSIONS: Our findings further support a role for the CACNA1C gene, particularly for the rs1006737, in SCZ. Further, five SNPs were associated with improvement in PANSS subscales, suggesting a role for this gene in antipsychotic response as well. However, taking into account the limitations of the present study, further research is needed to confirm our findings.

Investigation of an epistastic effect between a set of TAAR6 and HSP‐70 genes variations and major mood disorders

Pae, Chi‐,Un,Drago, Antonio,Forlani, Martina,Patkar, Ashwin A.,Serretti, Alessandro Wiley Subscription Services, Inc., A Wiley Company 2010 American Journal of Medical Genetics Part B: Neuro Vol. No.

<P><B>Abstract</B></P><P>Epistasis, the interaction between genes, is a topic of current interest in molecular and quantitative genetics. We have further studied a previously investigated sample of 187 major depressive disorder (MDD) patients, 171 bipolar disorder (BD) patients, and 288 controls, and tried to analyze the interaction between a set of variations of independent genes: the trace amine receptor 6 (rs4305745, rs8192625, rs7452939, rs6903874, and rs6937506) and the heat shock protein 70 (rs562047, rs1061581, rs2227956). The multifactor dimensionality reduction (MDR) method was applied and the covariates associated with diagnosis were also controlled. A significant predictive value of specific interactions between genotypes located in the investigated genes was found. We then report preliminary evidence that the epistasis between trace amine receptor 6 and heat shock protein 70 variations may compose a risk profile for major mood disorders. The level of statistical significance (<I>P</I> < 0.001) and the testing balancing accuracy over 0.62 suggest a cautious optimism toward this result, although the possibility of false positivity warrants further analyses in independent samples. © 2009 Wiley‐Liss, Inc.</P>