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.

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.

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.

Subcutaneous Immunoglobulins Are a Valuable Treatment Option in Myasthenia Gravis

Martina Garnero,Sabrina Fabbri,Chiara Gemelli,Luana Benedetti,Giovanni Luigi Mancardi,Angelo Schenone,Marina Grandis 대한신경과학회 2018 Journal of Clinical Neurology Vol.14 No.1

Feasibility and Accuracy of Transduodenal Endoscopic Ultrasound-Guided Fine-Needle Aspiration of Solid Lesions Using a 19-Gauge Flexible Needle: A Multicenter Study

Germana de Nucci,Maria Chiara Petrone,Nicola Imperatore,Edoardo Forti,Roberto Grassia,Silvia Giovanelli,Laura Ottaviani,Vincenzo Mirante,Giuseppe Sabatino,Carlo Fabbri,Mauro Manno,Paolo Giorgio Arcidi 대한소화기내시경학회 2021 Clinical Endoscopy Vol.54 No.2

Background/Aims: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the go-to method for obtaining samplesfrom gastrointestinal tract and pancreatic lesions. When the transduodenal approach is utilized, the use of a more flexible needle,such as a nitinol 19-gauge (G) needle, has been recommended. The aim of this study was to evaluate the feasibility and accuracy of19-G flexible aspiration needles in obtaining samples from solid lesions through a transduodenal approach. Methods: This was a retrospective analysis of prospectively collected data from eight Italian endoscopy centers. Consecutive patientswith solid lesions who underwent transduodenal EUS-FNA with a 19-G flexible needle were included. Results: A total of 201 patients were enrolled. According to histology, EUS, radiology and 12 months of follow-up, 151 patientshad malignant lesions and 50 patients had benign lesions. EUS-FNA was feasible in all cases. An adequate histologic sample wasobtained in all except eight cases (96.1%). The sensitivity of EUS-FNA was 92.1% (95% confidence interval [CI], 86.8%–95.7%), andthe specificity was 100% (95% CI, 90.5%–100%). The positive predictive value was 100% (95% CI, 93.4%–100%), and the negativepredictive value was 74% (95% CI, 62.8%–82.7%). The diagnostic accuracy was 93.5% (95% CI, 89.2%–96.5%). Conclusions: The transduodenal approach for obtaining samples from solid lesions using a 19-G flexible needle seems feasible andaccurate.

Age of Onset in Schizophrenia Spectrum Disorders: Complex Interactions between Genetic and Environmental Factors

Laura Mandelli,Elena Toscano,Stefano Porcelli,Chiara Fabbri,Alessandro Serretti 대한신경정신의학회 2016 PSYCHIATRY INVESTIGATION Vol.13 No.2

In this study we evaluated the role of a candidate gene for major psychosis, Sialyltransferase (ST8SIA2), in the risk to develop a schizophrenia spectrum disorders, taking into account exposure to stressful life events (SLEs). Eight polymorphisms (SNPs) were tested in 94 Schizophreniainpatients and 176 healthy controls. Schizophrenia patients were also evaluated for SLEs in different life periods. None of the SNPs showed association with schizophrenia. Nevertheless, when crossing genetic variants with childhood SLEs, we could observe trends of interaction with age of onset. Though several limitations, our results support a protective role of ST8SIA2 in individuals exposed to moderate childhood stress.

Reduced CXCL1/GRO chemokine plasma levels are a possible biomarker of elderly depression

Fanelli, Giuseppe,Benedetti, Francesco,Wang, Sheng-Min,Lee, Soo-Jung,Jun, Tae-Youn,Masand, Prakash S.,Patkar, Ashwin A.,Han, Changsu,Serretti, Alessandro,Pae, Chi-Un,Fabbri, Chiara Elsevier 2019 Journal of affective disorders Vol.249 No.-

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Depression is the single largest contributor to non-fatal health loss worldwide. A role of inflammation in major depressive disorder (MDD) was suggested, and we sought to determine if cytokine levels predict the severity of depressive symptomatology or distinguish MDD patients from healthy controls (HCs).</P> <P><B>Methods</B></P> <P>The severity of depressive symptoms and cognitive impairment were assessed by the Korean version of the Geriatric Depression Scale (GDS-K) and Mini-Mental State Examination (MMSE-KC) in 152 elderly subjects (76 with MDD). Plasma levels of 28 cytokines were measured and analysed as continuous predictors or dichotomized using the median value. The association between individual cytokines, MDD risk and depressive symptoms severity was investigated using multiple logistic and linear regressions that included the relevant covariates. A Cytokine Weighted Score (CWS) was calculated by weighting cytokines according to previously reported effect sizes on MDD risk. Sensitivity analyses were performed excluding subjects with significant cognitive impairment.</P> <P><B>Results</B></P> <P>CXCL10/IP-10 levels were higher in subjects with MDD vs. HCs while the opposite was observed for CXCL1/GRO. Only the second association survived after adjusting for possible confounders and excluding subjects with severe cognitive impairment. Using dichotomized cytokine levels, CXCL1/GRO and TNF-α were negatively associated with MDD. The CWS was also negatively associated with MDD. Cytokine levels did not predict the severity of depressive symptoms.</P> <P><B>Limitations</B></P> <P>Our cross-sectional approach was not able to longitudinally evaluate any temporal fluctuations in the considered cytokine levels.</P> <P><B>Conclusions</B></P> <P>This study found significantly lower CXCL1/GRO chemokine plasma levels in elderly subjects with MDD compared to HCs.</P> <P><B>Highlights</B></P> <P> <UL> <LI> CXCL1/GRO and TNF-α plasma levels were negatively associated with MDD in elderly subjects. </LI> <LI> A Cytokine Weighted Score (CWS) was negatively associated with MDD. </LI> <LI> Peripheral cytokine levels did not predict the severity of depressive symptoms in MDD. </LI> </UL> </P>