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

ABSTRACT: 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.

SUBMITTER: Fabbri C

PROVIDER: S-EPMC7006978 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Fabbri Chiara C Serretti Alessandro A

Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology 20200201 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 re ...[more]

PMID: 31958900

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Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Project description:ContextIt has been suggested that patients with major depressive disorder (MDD) who display pretreatment features suggestive of bipolar disorder or bipolar spectrum features might have poorer treatment outcomes.ObjectiveTo assess the association between bipolar spectrum features and antidepressant treatment outcome in MDD.DesignOpen treatment followed by sequential randomized controlled trials.SettingPrimary and specialty psychiatric outpatient centers in the United States.ParticipantsMale and female outpatients aged 18 to 75 years with a DSM-IV diagnosis of nonpsychotic MDD who participated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.InterventionsOpen treatment with citalopram followed by up to 3 sequential next-step treatments.Main outcome measuresNumber of treatment levels required to reach protocol-defined remission, as well as failure to return for the postbaseline visit, loss to follow-up, and psychiatric adverse events. For this secondary analysis, putative bipolar spectrum features, including items on the mania and psychosis subscales of the Psychiatric Diagnosis Screening Questionnaire, were examined for association with treatment outcomes.ResultsOf the 4041 subjects who entered the study, 1198 (30.0%) endorsed at least 1 item on the psychosis scale and 1524 (38.1%) described at least 1 recent maniclike/hypomaniclike symptom. Irritability and psychoticlike symptoms at entry were significantly associated with poorer outcomes across up to 4 treatment levels, as were shorter episodes and some neurovegetative symptoms of depression. However, other indicators of bipolar diathesis including recent maniclike symptoms and family history of bipolar disorder as well as summary measures of bipolar spectrum features were not associated with treatment resistance.ConclusionSelf-reported psychoticlike symptoms were common in a community sample of outpatients with MDD and strongly associated with poorer outcomes. Overall, the data do not support the hypothesis that unrecognized bipolar spectrum illness contributes substantially to antidepressant treatment resistance.

Project description:Trazodone is a triazolopyridine derivative that belongs to the class of serotonin receptor antagonists and reuptake inhibitors (SARIs). The drug is approved and marketed in several countries worldwide for the treatment of major depressive disorder (MDD) in adult patients. In clinical studies, trazodone has demonstrated comparable antidepressant activity to other drug classes, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline (norepinephrine) reuptake inhibitors (SNRIs). Moreover, the SARI action of trazodone may overcome the tolerability issues that are often associated with second-generation antidepressants such as SSRIs (i.e. insomnia, anxiety and sexual dysfunction). Recent focus has been placed on the development of a new prolonged-release once-a-day formulation of trazodone (TzCOAD), which may provide improved tolerability over the conventional immediate-release formulation of trazodone. Clinical studies have led to the recent approval in the USA of TzCOAD (as Oleptro™; Angelini Labopharm LLC, Princeton, NJ, USA), which may see resurgence of interest in the drug for the management of patients with MDD. Although trazodone is approved for the treatment of depression, evidence supports the use of low-dose trazodone as an off-label hypnotic for the treatment of sleep disorders in patients with MDD. The most common adverse effects reported with trazodone are drowsiness (somnolence/sedation), headache, dizziness and dry mouth. Other events reported, albeit with low incidence, include orthostatic hypotension (particularly in elderly patients or those with heart disease), minimal anticholinergic activity, corrected QT interval prolongation and torsade de pointes, cardiac arrhythmias, and rare occurrences of priapism and suicidal ideation. Overall, trazodone is an effective and well tolerated antidepressant (SARI) with an important role in the current treatment of MDD both as monotherapy and as part of a combination strategy. Trazodone is effective in controlling a wide range of symptoms of depression, while avoiding the negative effects on sleep seen with SSRI antidepressants. The recently approved prolonged-release formulation should provide further optimization of this antidepressant and may be useful for enabling an appropriate therapeutic dose to be administered with improved patient compliance.

Dataset Information

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

Publications

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

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