Publications by authors named "Chiara Fabbri"

101 Publications

Oral Microbiome Dysbiosis Is Associated With Symptoms Severity and Local Immune/Inflammatory Response in COVID-19 Patients: A Cross-Sectional Study.

Front Microbiol 2021 23;12:687513. Epub 2021 Jun 23.

Section of Microbiology, CIAS Research Center and LTTA, Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.

The human oral microbiome (HOM) is the second largest microbial community after the gut and can impact the onset and progression of several localized and systemic diseases, including those of viral origin, especially for viruses entering the body via the oropharynx. However, this important aspect has not been clarified for the new pandemic human coronavirus SARS-CoV-2, causing COVID-19 disease, despite it being one of the many respiratory viruses having the oropharynx as the primary site of replication. In particular, no data are available about the non-bacterial components of the HOM (fungi, viruses), which instead has been shown to be crucial for other diseases. Consistent with this, this study aimed to define the HOM in COVID-19 patients, to evidence any association between its profile and the clinical disease. Seventy-five oral rinse samples were analyzed by Whole Genome Sequencing (WGS) to simultaneously identify oral bacteria, fungi, and viruses. To correlate the HOM profile with local virus replication, the SARS-CoV-2 amount in the oral cavity was quantified by digital droplet PCR. Moreover, local inflammation and secretory immune response were also assessed, respectively by measuring the local release of pro-inflammatory cytokines (L-6, IL-17, TNFα, and GM-CSF) and the production of secretory immunoglobulins A (sIgA). The results showed the presence of oral dysbiosis in COVID-19 patients compared to matched controls, with significantly decreased alpha-diversity value and lower species richness in COVID-19 subjects. Notably, oral dysbiosis correlated with symptom severity ( = 0.006), and increased local inflammation ( < 0.01). In parallel, a decreased mucosal sIgA response was observed in more severely symptomatic patients ( = 0.02), suggesting that local immune response is important in the early control of virus infection and that its correct development is influenced by the HOM profile. In conclusion, the data presented here suggest that the HOM profile may be important in defining the individual susceptibility to SARS-CoV-2 infection, facilitating inflammation and virus replication, or rather, inducing a protective IgA response. Although it is not possible to determine whether the alteration in the microbial community is the cause or effect of the SARS-CoV-2 replication, these parameters may be considered as markers for personalized therapy and vaccine development.
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http://dx.doi.org/10.3389/fmicb.2021.687513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261071PMC
June 2021

Combining psychopharmacotherapy and psychotherapy is not associated with better treatment outcome in major depressive disorder - evidence from the European Group for the Study of Resistant Depression.

J Psychiatr Res 2021 Jun 16;141:167-175. Epub 2021 Jun 16.

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Austria; Center for Brain Research, Medical University of Vienna, Vienna, Austria. Electronic address:

Despite plenty of effective antidepressant (AD) treatments, the outcome of major depressive disorder (MDD) is often unsatisfactory, probably due to improvable exploitation of available therapies. This European, cross-sectional, naturalistic multicenter study investigated the frequency of additional psychotherapy in terms of a manual-driven psychotherapy (MDP) in 1410 adult in- and outpatients with MDD, who were primarily treated with AD psychopharmacotherapy. Socio-demographic and clinical patterns were compared between patients receiving both treatments and those lacking concomitant MDP. In a total of 1279 MDD patients (90.7%) with known status of additional MDP, those undergoing a psychopharmacotherapy-MDP combination (31.2%) were younger, higher educated, more often employed and less severely ill with lower odds for suicidality as compared to patients receiving exclusively psychopharmacotherapy (68.8%). They experienced an earlier mean age of MDD onset, melancholic features, comorbid asthma and migraine and received lower daily doses of their first-line ADs. While agomelatine was more often established in these patients, MDD patients without MDP received selective serotonin reuptake inhibitors more frequently. These two patient groups did not differ in terms of response, non-response and treatment resistant depression (TRD). Accordingly, the employment of additional MDP could not be related to better treatment outcomes in MDD. The fact that MDP was applied in a minority of patients with rather beneficial socio-demographic and clinical characteristics might reflect inferior accessibility of these psychotherapeutic techniques for socially and economically disadvantaged populations.
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http://dx.doi.org/10.1016/j.jpsychires.2021.06.028DOI Listing
June 2021

Transcriptome-wide association study of treatment-resistant depression and depression subtypes for drug repurposing.

Neuropsychopharmacology 2021 Jun 22. Epub 2021 Jun 22.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Major depressive disorder (MDD) is the single largest contributor to global disability and up to 20-30% of patients do not respond to at least two antidepressants (treatment-resistant depression, TRD). This study leveraged imputed gene expression in TRD to perform a drug repurposing analysis. Among those with MDD, we defined TRD as having at least two antidepressant switches according to primary care records in UK Biobank (UKB). We performed a transcriptome-wide association study (TWAS) of TRD (n = 2165) vs healthy controls (n = 11,188) using FUSION and gene expression levels from 21 tissues. We identified compounds with opposite gene expression signatures (ConnectivityMap data) compared to our TWAS results using the Kolmogorov-Smirnov test, Spearman and Pearson correlation. As symptom patterns are routinely assessed in clinical practice and could be used to provide targeted treatments, we identified MDD subtypes associated with TRD in UKB and analysed them using the same pipeline described for TRD. Anxious MDD (n = 14,954) and MDD with weight gain (n = 4697) were associated with TRD. In the TWAS, two genes were significantly dysregulated (TMEM106B and ATP2A1 for anxious and weight gain MDD, respectively). A muscarinic receptor antagonist was identified as top candidate for repurposing in TRD; inhibition of heat shock protein 90 was the main mechanism of action identified for anxious MDD, while modulators of metabolism such as troglitazone showed promising results for MDD with weight gain. This was the first TWAS of TRD and associated MDD subtypes. Our results shed light on possible pharmacological approaches in individuals with difficult-to-treat depression.
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http://dx.doi.org/10.1038/s41386-021-01059-6DOI Listing
June 2021

Sex-related effects in major depressive disorder: Results of the European Group for the Study of Resistant Depression.

Depress Anxiety 2021 Jun 10. Epub 2021 Jun 10.

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.

Background: Sex-related effects on the evolution and phenotype of major depressive disorder (MDD) were reported previously.

Methods: This European multicenter cross-sectional study compared sociodemographic, clinical, and treatment patterns between males and females in a real-world sample of 1410 in- and outpatients with current MDD.

Results: Male MDD patients (33.1%) were rather inpatients, suffered from moderate to high suicidality levels, received noradrenergic and specific serotonergic antidepressants (ADs) as first-line AD treatment, generally higher mean AD daily doses, and showed a trend towards a more frequent administration of add-on treatments. Female MDD patients (66.9%) were rather outpatients, experienced lower suicidality levels, comorbid thyroid dysfunction, migraine, asthma, and a trend towards earlier disease onset.

Conclusions: The identified divergencies may contribute to the concept of male and female depressive syndromes and serve as predictors of disease severity and course, as they reflect phenomena that were repeatedly related to treatment-resistant depression (TRD). Especially the greater necessity of inpatient treatment and more complex psychopharmacotherapy in men may reflect increased therapeutic efforts undertaken to treat suicidality and to avoid TRD. Hence, considering sex may guide the diagnostic and treatment processes towards targeting challenging clinical manifestations including comorbidities and suicidality, and prevention of TRD and chronicity.
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http://dx.doi.org/10.1002/da.23165DOI Listing
June 2021

Genetic underpinnings of sociability in the general population.

Neuropsychopharmacology 2021 Aug 30;46(9):1627-1634. Epub 2021 May 30.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Levels of sociability are continuously distributed in the general population, and decreased sociability represents an early manifestation of several brain disorders. Here, we investigated the genetic underpinnings of sociability in the population. We performed a genome-wide association study (GWAS) of a sociability score based on four social functioning-related self-report questions from 342,461 adults in the UK Biobank. Subsequently we performed gene-wide and functional follow-up analyses. Robustness analyses were performed in the form of GWAS split-half validation analyses, as well as analyses excluding neuropsychiatric cases. Using genetic correlation analyses as well as polygenic risk score analyses we investigated genetic links of our sociability score to brain disorders and social behavior outcomes. Individuals with autism spectrum disorders, bipolar disorder, depression, and schizophrenia had a lower sociability score. The score was significantly heritable (SNP h of 6%). We identified 18 independent loci and 56 gene-wide significant genes, including genes like ARNTL, DRD2, and ELAVL2. Many associated variants are thought to have deleterious effects on gene products and our results were robust. The sociability score showed negative genetic correlations with autism spectrum, disorders, depression, schizophrenia, and two sociability-related traits-loneliness and social anxiety-but not with bipolar disorder or Alzheimer's disease. Polygenic risk scores of our sociability GWAS were associated with social behavior outcomes within individuals with bipolar disorder and with major depressive disorder. Variation in population sociability scores has a genetic component, which is relevant to several psychiatric disorders. Our findings provide clues towards biological pathways underlying sociability.
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http://dx.doi.org/10.1038/s41386-021-01044-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280100PMC
August 2021

Pharmacogenetic-Guided Treatment of Depression: Real-World Clinical Applications, Challenges, and Perspectives.

Clin Pharmacol Ther 2021 May 28. Epub 2021 May 28.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Depression is a leading cause of disability worldwide and, despite the availability of numerous antidepressants, the lack of standardized criteria to apply personalized prescription is still a major issue. Pharmacogenetic (PGx) markers in cytochrome P450 (CYP450) genes are already usable to guide antidepressant choice/titration according to clinical guidelines; they are an important step toward personalized psychiatry as they can reduce the time to identify an effective and tolerated treatment. Clinical application is still limited due to the financial and organizational challenges, but the number of services providing genotyping of pharmacogenes is increasing, with encouraging projections of cost-effectiveness. Critical aspects that emerged from the available studies are the importance of integration of genotyping results in electronic medical records, standardization, and regular updates of decision support systems, training and collaboration of different professionals, need of longer follow-ups to estimate cost-effectiveness, and importance of avoiding inequalities in access to genotyping. Diversities exist among the groups of patients to whom genotyping is offered (pre-emptive or reactive testing) and the type of clinical services (e.g., hospitals and primary care), currently without a consensus on which is the best approach. Future studies should aim to clarify these issues, as well as consider and compare PGx applications among different countries and healthcare systems. Finally, the extension of genotyping outside pharmacokinetic genes should be considered as a key step to improve the clinical impact of PGx, as this could significantly increase the variance explained in treatment outcomes.
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http://dx.doi.org/10.1002/cpt.2315DOI Listing
May 2021

No benefit of an adjunctive phototherapy protocol in treatment of periodontitis: A split-mouth randomized controlled trial.

J Clin Periodontol 2021 Aug 17;48(8):1093-1102. Epub 2021 May 17.

Research Centre for the Study of Periodontal and Peri-implant Diseases, University of Ferrara, Ferrara, Italy.

Aim: To assess the efficacy of a commercially available adjunctive phototherapy protocol ("Perio-1") in treatment of periodontitis.

Materials And Methods: In an examiner-blind, randomized, controlled, split-mouth, multicentre study, 60 periodontitis patients received root surface debridement (RSD) in sextants either alone (control sextants) or with the adjunctive phototherapy protocol (test sextants). Re-evaluation was performed at 6, 12 and 24 weeks.

Results: No statistically significant differences in mean (± standard deviation) clinical attachment level (CAL) change from baseline to week 24 were observed between test (-1.00 ± 1.16 mm) and control sextants (-0.87 ± 0.79 mm) at sites with probing pocket depths (PPDs) ≥5 mm ("deep sites") at baseline (p = .212). Comparisons between test and control sextants for all other parameters (CAL change at all sites, PPD change at deep sites/all sites, bleeding on probing, plaque scores), and for all change intervals, failed to identify any statistically significant differences.

Conclusions: The phototherapy protocol did not provide any additional clinical benefits over those achieved by RSD alone. (German Clinical Trials Register DRKS00011229).
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http://dx.doi.org/10.1111/jcpe.13465DOI Listing
August 2021

No benefit of an adjunctive phototherapy protocol in treatment of periodontitis: A split-mouth randomized controlled trial.

J Clin Periodontol 2021 Aug 17;48(8):1093-1102. Epub 2021 May 17.

Research Centre for the Study of Periodontal and Peri-implant Diseases, University of Ferrara, Ferrara, Italy.

Aim: To assess the efficacy of a commercially available adjunctive phototherapy protocol ("Perio-1") in treatment of periodontitis.

Materials And Methods: In an examiner-blind, randomized, controlled, split-mouth, multicentre study, 60 periodontitis patients received root surface debridement (RSD) in sextants either alone (control sextants) or with the adjunctive phototherapy protocol (test sextants). Re-evaluation was performed at 6, 12 and 24 weeks.

Results: No statistically significant differences in mean (± standard deviation) clinical attachment level (CAL) change from baseline to week 24 were observed between test (-1.00 ± 1.16 mm) and control sextants (-0.87 ± 0.79 mm) at sites with probing pocket depths (PPDs) ≥5 mm ("deep sites") at baseline (p = .212). Comparisons between test and control sextants for all other parameters (CAL change at all sites, PPD change at deep sites/all sites, bleeding on probing, plaque scores), and for all change intervals, failed to identify any statistically significant differences.

Conclusions: The phototherapy protocol did not provide any additional clinical benefits over those achieved by RSD alone. (German Clinical Trials Register DRKS00011229).
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http://dx.doi.org/10.1111/jcpe.13465DOI Listing
August 2021

Genetic and clinical characteristics of treatment-resistant depression using primary care records in two UK cohorts.

Mol Psychiatry 2021 Mar 22. Epub 2021 Mar 22.

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Treatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Primary care electronic health records provide an easily accessible approach to investigate TRD clinical and genetic characteristics. MDD defined from primary care records in UK Biobank (UKB) and EXCEED studies was compared with other measures of depression and tested for association with MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least 6 weeks. Clinical-demographic characteristics, SNP-based heritability (h) and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD, respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 71-88% with other MDD definitions. In UKB, TRD vs healthy controls and non-TRD vs healthy controls h was comparable (0.25 [SE = 0.04] and 0.19 [SE = 0.02], respectively). TRD vs non-TRD was positively associated with the PRS of attention deficit hyperactivity disorder, with lower socio-economic status, obesity, higher neuroticism and other unfavourable clinical characteristics. This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.
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http://dx.doi.org/10.1038/s41380-021-01062-9DOI Listing
March 2021

The Role of Relationship Status in Major Depressive Disorder - Results of the European Group for the Study of Resistant Depression.

J Affect Disord 2021 05 5;286:149-157. Epub 2021 Mar 5.

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria; Center for Brain Research, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: While the association between relationship status and the development of depressive symptoms in the general population were reported previously, its relation to the severity and the course of major depressive disorder (MDD) as well as the treatment patterns and response rates needs to be elucidated.

Methods: The present international multicenter cross-sectional study performed by the European Group for the Study of Resistant Depression (GSRD) investigated socio-demographic and clinical patterns of relationship status in a real-world sample of 1410 adult in- and outpatients with MDD as primary diagnosis.

Results: While 49.9% of all MDD patients were partnered, 25.4% were separated, and 24.8% were single. Single relationship status was linked to younger mean age, earlier mean age of onset, and current suicidal risk. Being separated was related to older mean age, unemployment, greater symptom severity, current suicidal risk, and add-on treatment strategies. Partnered relationship status was associated with less frequent current suicidal risk.

Limitations: The retrospective assessment of treatment response that was exclusively based on psychopharmacotherapeutic strategies should be critically considered and weighed while interpreting the present results providing novel insights into the complex interaction of relationship status with the clinical phenotype of MDD.

Conclusions: Although MDD patients living in relationships do not seem to be omitted from the evolution of MDD, they may be spared from chronicity and suicidality. Hence, being aware of the current relationship status might support clinicians in the diagnostic and therapeutic process towards optimized management of such challenging clinical phenomena and their negative consequences.
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http://dx.doi.org/10.1016/j.jad.2021.02.070DOI Listing
May 2021

Melancholic features in major depression - a European multicenter study.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Aug 18;110:110285. Epub 2021 Feb 18.

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria; Center for Brain Research, Medical University of Vienna, Vienna, Austria. Electronic address:

There is still a debate, if melancholic symptoms can be seen rather as a more severe subtype of major depressive disorder (MDD) or as a separate diagnostic entity. The present European multicenter study comprising altogether 1410 MDD in- and outpatients sought to investigate the influence of the presence of melancholic features in MDD patients. Analyses of covariance, chi-squared tests, and binary logistic regression analyses were accomplished to determine differences in socio-demographic and clinical variables between MDD patients with and without melancholia. We found a prevalence rate of 60.71% for melancholic features in MDD. Compared to non-melancholic MDD patients, they were characterized by a significantly higher likelihood for higher weight, unemployment, psychotic features, suicide risk, inpatient treatment, severe depressive symptoms, receiving add-on medication strategies in general, and adjunctive treatment with antidepressants, antipsychotics, benzodiazepine (BZD)/BZD-like drugs, low-potency antipsychotics, and pregabalin in particular. With regard to the antidepressant pharmacotherapy, we found a less frequent prescription of selective serotonin reuptake inhibitors (SSRIs) in melancholic MDD. No significant between-group differences were found for treatment response, non-response, and resistance. In summary, we explored primarily variables to be associated with melancholia which can be regarded as parameters for the presence of severe/difficult-to treat MDD conditions. Even if there is no evidence to realize any specific treatment strategy in melancholic MDD patients, their prescribed medication strategies were different from those for patients without melancholia.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110285DOI Listing
August 2021

Efficacy of the additional use of subgingival air polishing with erythritol powder in the treatment of periodontitis patients: a randomized controlled clinical trial.

Clin Oral Investig 2021 Feb 6;25(2):729-736. Epub 2021 Jan 6.

Research Centre for the Study of Periodontal and Peri-Implant Diseases, University of Ferrara, Ferrara, Italy.

Objectives: To date, scarce evidence exists around the application of subgingival air polishing during treatment of severe periodontitis. The aim of this study was to evaluate the benefits of subgingival air polishing during non-surgical treatment of deep bleeding pockets in stages III-IV periodontitis patients MATERIALS AND METHODS: Forty patients with stages III-IV periodontitis were selected, and pockets with probing depth (PD) 5-9 mm and bleeding on probing (BoP) were selected as experimental sites. All patients underwent a full-mouth session of erythritol powder supragingival air polishing and ultrasonic instrumentation. Test group received additional subgingival air polishing at experimental sites. The proportion of experimental sites shifting to PD ≤ 4 mm and no BoP at 3 months (i.e., non-bleeding closed pockets, NBCPs) was regarded as the primary outcome variable.

Results: The proportion of NBCP was comparable between test and control group (47.9 and 44.7%, respectively). Baseline PD of 7-9 mm, multi-rooted teeth and the presence of plaque negatively influenced the probability of obtaining NBCP.

Conclusions: The additional application of subgingival air polishing does not seem to provide any significant clinical advantage in achieving closure at moderate to deep bleeding pockets in treatment of stages III-IV periodontitis patients. The study was registered on Clinical Trials.gov (NCT04264624).

Clinical Relevance: While air polishing can play a role in biofilm removal at supragingival and shallow sites, ultrasonic root surface debridement alone is still the choice for initial treatment of deep bleeding periodontal pockets.
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http://dx.doi.org/10.1007/s00784-020-03648-zDOI Listing
February 2021

Research Domain Criteria (RDoC): A Perspective to Probe the Biological Background behind Treatment Efficacy in Depression.

Curr Med Chem 2021 Jan 3. Epub 2021 Jan 3.

Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina. Italy.

Background: Major Depressive Disorder (MDD) and its frequent partial response to antidepressants are a major health concern and therefore an important focus of research. Despite the efforts, MDD pathogenesis and the mechanisms of antidepressant action are only partially understood. In the last few years, the need of rethinking the classification of depressive disorders and psychiatric disorders in general has been suggested, in order to provide a nosology that reflects more closely the biological background associated with disease pathogenesis and its role/significance in treatment. The classification proposed by the National Institute of Mental Health (NIMH), namely the research domain criteria (RDoC), may represent a key framework to guide research in this direction.

Methods: A literature search was performed on PubMed and Google Scholar databases in order to retrieve data regarding Antidepressants effects on specific RDoC constructs. Further, the targets of drugs of interest were identified through Drugbank database, and their possible function within RDoC constructs was discussed.

Discussion: In this review we summarize and discuss the significance of the results of pre-clinical and clinical studies investigating specific RDoC paradigms relevant to depressive phenotypes and antidepressant effects.
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http://dx.doi.org/10.2174/0929867328666210104104938DOI Listing
January 2021

Cost-effectiveness of genetic and clinical predictors for choosing combined psychotherapy and pharmacotherapy in major depression.

J Affect Disord 2021 01 29;279:722-729. Epub 2020 Oct 29.

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.

Background: Predictors of treatment outcome in major depressive disorder (MDD) could contribute to evidence-based therapeutic choices. Combined pharmacotherapy and psychotherapy show increased efficacy but higher cost compared with antidepressant pharmacotherapy; baseline predictors of pharmacotherapy resistance could be used to identify patients more likely to benefit from combined treatment.

Methods: We performed a proof-of-principle study of the cost-effectiveness of using previously identified pharmacogenetic and clinical risk factors (PGx-CL-R) of antidepressant resistance or clinical risk factors alone (CL-R) to guide the prescription of combined pharmacotherapy and psychotherapy vs pharmacotherapy. The cost-effectiveness of these two strategies was compared with standard care (ST, pharmacotherapy to all subjects) using a three-year Markov model. Model parameters were literature-based estimates of response to pharmacotherapy and combined treatment, costs (UK National Health System) and benefits (quality-adjusted life years [QALYs], one QALY=one year lived in perfect health).

Results: CL-R was more cost-effective than PGx-CL-R: the cost of one-QALY improvement was £2341 for CL-R and £3937 for PGx-CL-R compared to ST. PGx-CL-R had similar or better cost-effectiveness compared to CL-R when 1) the cost of genotyping was £100 per subject or less or 2) the PGx-CL-R test had sensitivity ≥ 0.90 and specificity ≥ 0.85. The cost of one-QALY improvement for CL-R was £3664 and of £4110 in two independent samples.

Limitations: lack of validation in large samples from the general population.

Conclusions: Using clinical risk factors to predict pharmacotherapy resistance and guide the prescription of pharmacotherapy combined with psychotherapy could be a cost-effective strategy.
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http://dx.doi.org/10.1016/j.jad.2020.10.049DOI Listing
January 2021

Higher polygenic risk scores for schizophrenia may be suggestive of treatment non-response in major depressive disorder.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Jun 10;108:110170. Epub 2020 Nov 10.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Up to 60% of patients with major depressive disorder (MDD) do not respond to the first treatment with antidepressants. Response to antidepressants is a polygenic trait, although its underpinning genetics has not been fully clarified. This study aimed to investigate if polygenic risk scores (PRSs) for major psychiatric disorders and trait neuroticism (NEU) were associated with non-response or resistance to antidepressants in MDD. PRSs for bipolar disorder, MDD, NEU, and schizophrenia (SCZ) were computed in 1,148 patients with MDD. Summary statistics from the largest meta-analyses of genome-wide association studies were used as base data. Patients were classified as responders, non-responders to one treatment, non-responders to two or more treatments (treatment-resistant depression or TRD). Regression analyses were adjusted for population stratification and recruitment sites. PRSs did not predict either non-response vs response or TRD vs response after Bonferroni correction. However, SCZ-PRS was nominally associated with non-response (p = 0.003). Patients in the highest SCZ-PRS quintile were more likely to be non-responders than those in the lowest quintile (OR = 2.23, 95% CI = 1.21-4.10, p = 0.02). Patients in the lowest SCZ-PRS quintile showed higher response rates when they did not receive augmentation with second-generation antipsychotics (SGAs), while those in the highest SCZ-PRS quintile had a poor response independently from the treatment strategy (p = 0.009). A higher genetic liability to SCZ may reduce treatment response in MDD, and patients with low SCZ-PRSs may show higher response rates without SGA augmentation. Multivariate approaches and methodological refinements will be necessary before clinical implementations of PRSs.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110170DOI Listing
June 2021

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

Clin Psychopharmacol Neurosci 2020 Nov;18(4):484-492

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

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 (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.
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http://dx.doi.org/10.9758/cpn.2020.18.4.484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609216PMC
November 2020

Add-on benzodiazepine treatment in patients with major depressive disorder - results from a European cross-sectional multicenter study.

Eur Neuropsychopharmacol 2020 12 9;41:70-80. Epub 2020 Oct 9.

Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria; Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria. Electronic address:

Since many patients with major depressive disorder (MDD) do not satisfactorily respond to initial antidepressant monotherapy, add-on treatment strategies with other psychiatric compounds are often established. The present European multicenter cross-sectional study comprising 1410 MDD in- and outpatients investigated the prescription pattern of benzodiazepines as add-on treatment in the psychopharmacotherapy of MDD. Analyses of variance, chi-squared tests, and logistic regression analyses were conducted to examine differences in socio-demographic, clinical, and treatment characteristics between benzodiazepine users and non-users. The prescription rate for adjunctive benzodiazepine treatment amounted to 31.35%. The most often administered benzodiazepines were lorazepam (11.13%), clonazepam (6.74%), and alprazolam (6.60%). Benzodiazepine users exhibited more severe depressive symptoms expressed by a higher mean Montgomery and Åsberg Depression Rating Scale total score at study entry (26.92 ± 11.07 vs 23.55 ± 11.23, p<.0001) and at the beginning of the current major depressive episode (35.74 ± 8.08 vs 33.31 ± 7.40, p<.0001). Furthermore, they were characterized by a higher proportion of patients receiving additional augmentation/combination medications with antidepressants (40.95% vs 24.28%, p<.0001), antipsychotics (41.63% vs 18.39%, p<.0001), and low-potency antipsychotics (10.18% vs 4.75%, p<.0001). Moreover, benzodiazepine prescription was associated with older age, unemployment, inpatient treatment, suicide risk, psychotic and melancholic features, comorbid panic disorder, agoraphobia, social phobia, and obsessive-compulsive disorder. Taken together, our findings indicate that benzodiazepine augmentation in MDD is first of all established in severe/difficult-to-treat conditions and serves as predictor for the use of additional augmentation/combination treatment strategies.
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http://dx.doi.org/10.1016/j.euroneuro.2020.09.636DOI Listing
December 2020

The search for personalized antidepressant treatments: what have we learned and where are we going.

Pharmacogenomics 2020 10 5;21(15):1095-1100. Epub 2020 Oct 5.

Department of Biomedical & NeuroMotor Sciences, University of Bologna, Bologna, Italy.

Over 20 years after the initial report of gene variants within the central nervous system modulating antidepressant response, we are now facing for the first time routine clinical pharmacogenetic applications. The scientific community is divided between enthusiasm and skepticism. It seems clear that the benefit of existing tools is not huge, at least for the central nervous system gene variants, while it is generally accepted for the metabolic gene variants. Findings from large international consortia suggest for the first time in psychiatric genetic research history that cumulative scores comprising many variants across the whole genome may reliably constitute liability factors for psychiatric disorders, this approach will most likely improve also present pharmacogenetic tools. A composite genetic score complemented with clinical risk factors for each patient is the most promising approach for a more effective method of targeted treatment for patients with depression.
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http://dx.doi.org/10.2217/pgs-2019-0086DOI Listing
October 2020

Investigating an in silico approach for prioritizing antidepressant drug prescription based on drug-induced expression profiles and predicted gene expression.

Pharmacogenomics J 2021 02 17;21(1):85-93. Epub 2020 Sep 17.

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.

In clinical practice, an antidepressant prescription is a trial and error approach, which is time consuming and discomforting for patients. This study investigated an in silico approach for ranking antidepressants based on their hypothetical likelihood of efficacy. We predicted the transcriptomic profile of citalopram remitters by performing an in silico transcriptomic-wide association study on STAR*D GWAS data (N = 1163). The transcriptional profile of remitters was compared with 21 antidepressant-induced gene expression profiles in five human cell lines available in the connectivity-map database. Spearman correlation, Pearson correlation, and the Kolmogorov-Smirnov test were used to determine the similarity between antidepressant-induced profiles and remitter profiles, subsequently calculating the average rank of antidepressants across the three methods and a p value for each rank by using a permutation procedure. The drugs with the top ranks were those having a high positive correlation with the expression profiles of remitters and that may have higher chances of efficacy in the tested patients. In MCF7 (breast cancer cell line), escitalopram had the highest average rank, with an average rank higher than expected by chance (p = 0.0014). In A375 (human melanoma) and PC3 (prostate cancer) cell lines, escitalopram and citalopram emerged as the second-highest ranked antidepressants, respectively (p = 0.0310 and 0.0276, respectively). In HA1E (kidney) and HT29 (colon cancer) cell types, citalopram and escitalopram did not fall among top antidepressants. The correlation between citalopram remitters' and (es)citalopram-induced expression profiles in three cell lines suggests that our approach may be useful and with future improvements, it can be applicable at the individual level to tailor treatment prescription.
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http://dx.doi.org/10.1038/s41397-020-00186-5DOI Listing
February 2021

Clinical Correlates and Outcome of Major Depressive Disorder and Comorbid Migraine: A Report of the European Group for the Study of Resistant Depression.

Int J Neuropsychopharmacol 2020 12;23(9):571-577

Center for Brain Research, Medical University of Vienna, Vienna, Austria.

Background: The present multicenter study aimed at defining the clinical profile of patients with major depressive disorder (MDD) and comorbid migraine.

Methods: Demographic and clinical information for 1410 MDD patients with vs without concurrent migraine were compared by descriptive statistics, analyses of covariance, and binary logistic regression analyses.

Results: The point prevalence rate for comorbid migraine was 13.5% for female and 6.2% for male patients. MDD + migraine patients were significantly younger, heavier, more likely female, of non-Caucasian origin, outpatient, and suffering from asthma. The presence of MDD + migraine resulted in a significantly higher functional disability. First-line antidepressant treatment strategy revealed a trend towards agomelatine. Second-generation antipsychotics were significantly less often administered for augmentation treatment in migraineurs. Overall, MDD + migraine patients tended to respond worse to their pharmacotherapy.

Conclusion: Treatment guidelines for comorbid depression and migraine are warranted to ensure optimal efficacy and avoid possible pitfalls in psychopharmacotherapy, including serotonin syndrome.
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http://dx.doi.org/10.1093/ijnp/pyaa035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710912PMC
December 2020

Precision psychiatry in clinical practice.

Int J Psychiatry Clin Pract 2021 Mar 27;25(1):19-27. Epub 2020 Aug 27.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

The treatment of depression represents a major challenge for healthcare systems and choosing among the many available drugs without objective guidance criteria is an error-prone process. Recently, pharmacogenetic biomarkers entered in prescribing guidelines, giving clinicians the possibility to use this additional tool to guide prescription and improve therapeutic outcomes. This marked an important step towards precision psychiatry, which aim is to integrate biological and environmental information to personalise treatments. Only genetic variants in cytochrome enzymes are endorsed by prescribing guidelines, but in the future polygenic predictors of treatment outcomes may be translated into the clinic. The integration of genetics with other relevant information (e.g., concomitant diseases and treatments, drug plasma levels) could be managed in a standardised way through ad hoc software. The overcoming of the current obstacles (e.g., staff training, genotyping and informatics facilities) can lead to a broad implementation of precision psychiatry and represent a revolution for psychiatric care.Key pointsPrecision psychiatry aims to integrate biological and environmental information to personalise treatments and complement clinical judgementPharmacogenetic biomarkers in cytochrome genes were included in prescribing guidelines and represented an important step towards precision psychiatryTherapeutic drug monitoring is an important and cost-effective tool which should be integrated with genetic testing and clinical evaluation in order to optimise pharmacotherapyOther individual factors relevant to pharmacotherapy response (e.g., individual's symptom profile, concomitant diseases) can be integrated with genetic information through artificial intelligence to provide treatment recommendationsThe creation of pharmacogenetic services within healthcare systems is a challenging and multi-step process, education of health professionals, promotion by institutions and regulatory bodies, economic and ethical barriers are the main issues.
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http://dx.doi.org/10.1080/13651501.2020.1809680DOI Listing
March 2021

The Role of Genetics in Bipolar Disorder.

Authors:
Chiara Fabbri

Curr Top Behav Neurosci 2021 ;48:41-60

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Bipolar disorder (BP) is a highly heritable disease, with heritability estimated between 60 and 85% by twin studies. The underlying genetic architecture was poorly understood for years since the available technology was limited to the candidate gene approach that did not allow to explore the contribution of multiple loci throughout the genome. BP is a complex disorder, which pathogenesis is influenced by a number of genetic variants, each with small effect size, and environmental exposures. Genome-wide association studies (GWAS) provided meaningful insights into the genetics of BP, including replicated genetic variants, and allowed the development of novel multi-marker methods for gene/pathway analysis and for estimating the genetic overlap between BP and other traits. However, the existing GWAS had also relevant limitations. Notably insufficient statistical power and lack of consideration of rare variants, which may be responsible for the relatively low heritability explained (~20% in the largest GWAS) compared to twin studies. The availability of data from large biobanks and automated phenotyping from electronic health records or digital phenotyping represent key steps for providing samples with adequate power for genetic analysis. Next-generation sequencing is becoming more and more feasible in terms of costs, leading to the rapid growth in the number of samples with whole-genome or whole-exome sequence data. These recent and unprecedented resources are of key importance for a more comprehensive understanding of the specific genetic factors involved in BP and their mechanistic action in determining disease onset and prognosis.
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http://dx.doi.org/10.1007/7854_2020_153DOI Listing
March 2021

Drug repositioning for treatment-resistant depression: Hypotheses from a pharmacogenomic study.

Prog Neuropsychopharmacol Biol Psychiatry 2021 01 30;104:110050. Epub 2020 Jul 30.

Department of Biomedical and NeuroMotor Sciences, University of Bologna, Italy.

About 20-30% of patients with major depressive disorder (MDD) develop treatment-resistant depression (TRD) and finding new effective treatments for TRD has been a challenge. This study aimed to identify new possible pharmacological options for TRD. Genes in pathways included in predictive models of TRD in a previous whole exome sequence study were compared with those coding for targets of drugs in any phase of development, nutraceuticals, proteins and peptides from Drug repurposing Hub, Drug-Gene Interaction database and DrugBank database. We tested if known gene targets were enriched in TRD-associated genes by a hypergeometric test. Compounds enriched in TRD-associated genes after false-discovery rate (FDR) correction were annotated and compared with those showing enrichment in genes associated with MDD in the last Psychiatric Genomics Consortium genome-wide association study. Among a total of 15,475 compounds, 542 were enriched in TRD-associated genes (FDR p < .05). Significant results included drugs which are currently used in TRD (e.g. lithium and ketamine), confirming the rationale of this approach. Interesting molecules included modulators of inflammation, renin-angiotensin system, proliferator-activated receptor agonists, glycogen synthase kinase 3 beta inhibitors and the rho associated kinase inhibitor fasudil. Nutraceuticals, mostly antioxidant polyphenols, were also identified. Drugs showing enrichment for TRD-associated genes had a higher probability of enrichment for MDD-associated genes compared to those having no TRD-genes enrichment (p = 6.21e-55). This study suggested new potential treatments for TRD using a in silico approach. These analyses are exploratory only but can contribute to the identification of drugs to study in future clinical trials.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110050DOI Listing
January 2021

Depression with atypical neurovegetative symptoms shares genetic predisposition with immuno-metabolic traits and alcohol consumption.

Psychol Med 2020 Jul 6:1-11. Epub 2020 Jul 6.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: Depression is a highly prevalent and heterogeneous disorder. This study aims to determine whether depression with atypical features shows different heritability and different degree of overlap with polygenic risk for psychiatric and immuno-metabolic traits than other depression subgroups.

Methods: Data included 30 069 European ancestry individuals from the UK Biobank who met criteria for lifetime major depression. Participants reporting both weight gain and hypersomnia were classified as ↑WS depression (N = 1854) and the others as non-↑WS depression (N = 28 215). Cases with non-↑WS depression were further classified as ↓WS depression (i.e. weight loss and insomnia; N = 10 142). Polygenic risk scores (PRS) for 22 traits were generated using genome-wide summary statistics (Bonferroni corrected p = 2.1 × 10-4). Single-nucleotide polymorphism (SNP)-based heritability of depression subgroups was estimated.

Results: ↑WS depression had a higher polygenic risk for BMI [OR = 1.20 (1.15-1.26), p = 2.37 × 10-14] and C-reactive protein [OR = 1.11 (1.06-1.17), p = 8.86 × 10-06] v. non-↑WS depression and ↓WS depression. Leptin PRS was close to the significance threshold (p = 2.99 × 10-04), but the effect disappeared when considering GWAS summary statistics of leptin adjusted for BMI. PRS for daily alcohol use was inversely associated with ↑WS depression [OR = 0.88 (0.83-0.93), p = 1.04 × 10-05] v. non-↑WS depression. SNP-based heritability was not significantly different between ↑WS depression and ↓WS depression (14.3% and 12.2%, respectively).

Conclusions: ↑WS depression shows evidence of distinct genetic predisposition to immune-metabolic traits and alcohol consumption. These genetic signals suggest that biological targets including immune-cardio-metabolic pathways may be relevant to therapies in individuals with ↑WS depression.
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http://dx.doi.org/10.1017/S0033291720002342DOI Listing
July 2020

Defining the oral microbiome by whole-genome sequencing and resistome analysis: the complexity of the healthy picture.

BMC Microbiol 2020 05 18;20(1):120. Epub 2020 May 18.

Section of Dentistry, Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy.

Background: The microbiome of the oral cavity is the second-largest and diverse microbiota after the gut, harboring over 700 species of bacteria and including also fungi, viruses, and protozoa. With its diverse niches, the oral cavity is a very complex environment, where different microbes preferentially colonize different habitats. Recent data indicate that the oral microbiome has essential functions in maintaining oral and systemic health, and the emergence of 16S rRNA gene next-generation sequencing (NGS) has greatly contributed to revealing the complexity of its bacterial component. However, a detailed site-specific map of oral microorganisms (including also eukaryotes and viruses) and their relative abundance is still missing. Here, we aimed to obtain a comprehensive view of the healthy oral microbiome (HOM), including its drug-resistance features.

Results: The oral microbiome of twenty healthy subjects was analyzed by whole-genome sequencing (WGS) and real-time quantitative PCR microarray. Sampled oral micro-habitat included tongue dorsum, hard palate, buccal mucosa, keratinized gingiva, supragingival and subgingival plaque, and saliva with or without rinsing. Each sampled oral niche evidenced a different microbial community, including bacteria, fungi, and viruses. Alpha-diversity evidenced significant differences among the different sampled sites (p < 0.0001) but not among the enrolled subjects (p = 0.876), strengthening the notion of a recognizable HOM. Of note, oral rinse microbiome was more representative of the whole site-specific microbiomes, compared with that of saliva. Interestingly, HOM resistome included highly prevalent genes conferring resistance to macrolide, lincosamides, streptogramin, and tetracycline.

Conclusions: The data obtained in 20 subjects by WGS and microarray analysis provide for the first time a comprehensive view of HOM and its resistome, contributing to a deeper understanding of the composition of oral microbiome in the healthy subject, and providing an important reference for future studies, allowing to identify microbial signatures related to functional and metabolic alterations associated with diseases, potentially useful for targeted therapies and precision medicine.
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http://dx.doi.org/10.1186/s12866-020-01801-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236360PMC
May 2020

Genetics and major depressive disorder: clinical implications for disease risk, prognosis and treatment.

Int Clin Psychopharmacol 2020 09;35(5):233-242

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

In the post-genomic era, genetics has led to limited clinical applications in the diagnosis and treatment of major depressive disorder (MDD). Variants in genes coding for cytochrome enzymes are included in guidelines for assisting in antidepressant choice and dosing, but there are no recommendations involving genes responsible for antidepressant pharmacodynamics and no consensus applications for guiding diagnosis or prognosis. However, genetics has contributed to a better understanding of MDD pathogenesis and the mechanisms of antidepressant action, also thanks to recent methodological innovations that overcome the challenges posed by the polygenic architecture of these traits. Polygenic risk scores can be used to estimate the risk of disease at the individual level, which may have clinical relevance in cases with extremely high scores (e.g. top 1%). Genetic studies have also shed light on a wide genetic overlap between MDD and other psychiatric disorders. The relationships between genes/pathways associated with MDD and known drug targets are a promising tool for drug repurposing and identification of new pharmacological targets. Increase in power thanks to larger samples and methods integrating genetic data with gene expression, the integration of common variants and rare variants, are expected to advance our knowledge and assist in personalized psychiatry.
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http://dx.doi.org/10.1097/YIC.0000000000000305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390499PMC
September 2020

A polygenic predictor of treatment-resistant depression using whole exome sequencing and genome-wide genotyping.

Transl Psychiatry 2020 02 3;10(1):50. Epub 2020 Feb 3.

Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.

Treatment-resistant depression (TRD) occurs in ~30% of patients with major depressive disorder (MDD) but the genetics of TRD was previously poorly investigated. Whole exome sequencing and genome-wide genotyping were available in 1209 MDD patients after quality control. Antidepressant response was compared to non-response to one treatment and non-response to two or more treatments (TRD). Differences in the risk of carrying damaging variants were tested. A score expressing the burden of variants in genes and pathways was calculated weighting each variant for its functional (Eigen) score and frequency. Gene-based and pathway-based scores were used to develop predictive models of TRD and non-response using gradient boosting in 70% of the sample (training) which were tested in the remaining 30% (testing), evaluating also the addition of clinical predictors. Independent replication was tested in STAR*D and GENDEP using exome array-based data. TRD and non-responders did not show higher risk to carry damaging variants compared to responders. Genes/pathways associated with TRD included those modulating cell survival and proliferation, neurodegeneration, and immune response. Genetic models showed significant prediction of TRD vs. response and they were improved by the addition of clinical predictors, but they were not significantly better than clinical predictors alone. Replication results were driven by clinical factors, except for a model developed in subjects treated with serotonergic antidepressants, which showed a clear improvement in prediction at the extremes of the genetic score distribution in STAR*D. These results suggested relevant biological mechanisms implicated in TRD and a new methodological approach to the prediction of TRD.
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http://dx.doi.org/10.1038/s41398-020-0738-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026437PMC
February 2020

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

Clin Psychopharmacol Neurosci 2020 Feb;18(1):1-9

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

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.
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http://dx.doi.org/10.9758/cpn.2020.18.1.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006978PMC
February 2020

Genetic variants associated with psychotic symptoms across psychiatric disorders.

Neurosci Lett 2020 02 13;720:134754. Epub 2020 Jan 13.

Department of Biomedical and NeuroMotor Sciences, University of Bologna, Italy. Electronic address:

Background: Recent evidence suggests that psychiatric symptoms share a common genetic liability across diagnostic categories. The present study investigated the effects of variants within previously identified relevant genes on specific symptom clusters, independently from the diagnosis.

Methods: 1550 subjects affected by Schizophrenia (SCZ), Major Depressive Disorder or Bipolar Disorder were included. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Hamilton Depression Rating Scale (HDRS). Principal component analysis and a further clinical refinement were used to define symptom clusters. Clusters scores were tested for association with 46 genetic variants within nine genes previously linked to one or more major psychiatric disorders by large genome wide association studies (ANK3, CACNA1C, CACNB2, FKBP5, FZD3, GRM7, ITIH3, SYNE1, TCF4). Exploratory analyses were performed in each disorder separately to further elucidate the SNPs effects.

Results: five PANSS clusters (Negative; Impulsiveness; Cognitive; Psychotic; Depressive) and four HDRS clusters (Core Depressive; Somatic; Psychotic-like; Insomnia) were identified. CACNA1C rs11615998 was associated with HDRS Psychotic cluster in the whole sample. In the SCZ sample, CACNA1C rs11062296 was associated with PANSS Impulsiveness cluster and CACNA1C rs2238062 was associated with PANSS negative cluster.

Discussion: CACNA1C rs11615998 was associated with psychotic symptoms (C-allele carriers have decreased psychotic-risk) independently from the diagnosis, in line with the evidence of a cross disorder effect of many risk variants. This gene was previously associated with SCZ and cross-disorder liability to psychiatric disorders. Our findings confirmed that deep phenotyping is pivotal to clarify the role of genetic variants on symptoms patterns.
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http://dx.doi.org/10.1016/j.neulet.2020.134754DOI Listing
February 2020

Reduced plasma Fetuin-A is a promising biomarker of depression in the elderly.

Eur Arch Psychiatry Clin Neurosci 2020 Oct 20;270(7):901-910. Epub 2019 Dec 20.

Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Depression affects 7% of the elderly population, and it often remains misdiagnosed or untreated. Peripheral biomarkers might aid clinicians by allowing more accurate and well-timed recognition of the disease. We sought to determine if plasma protein levels predict the severity of depressive symptomatology or distinguish patients from healthy individuals. The severity of depressive symptoms and global cognitive functioning were assessed by the Geriatric Depression Scale (GDS) and Mini-Mental State Examination (MMSE) in 152 elderly subjects, 76 of which with major depressive disorder (MDD). Plasma levels of 24 proteins were measured by multiplexing and analyzed as continuous predictors or dichotomized using the median value. The association between individual plasma proteins and MDD risk or depressive symptoms severity was investigated using multiple logistic and linear regressions including relevant covariates. Sensitivity analyses were performed excluding cognitively impaired individuals or non-acute patients with MDD. After adjusting for possible confounders and false discovery rate (FDR) correction, we found lower Fetuin-A levels in MDD patients vs. controls (p = 1.95 × 10). This result was confirmed by the sensitivity and dichotomized analyses. Lower prolactin (PRL) levels predicted more severe depressive symptoms in acute MDD patients (p = 0.024). Fetuin-A is a promising biomarker of MDD in the elderly as this protein was negatively associated with the disorder in our sample, regardless of the global cognitive functioning. Lower PRL levels may be a peripheral signature of impaired neuroprotective processes and serotoninergic neurotransmission in more severely depressed patients.
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http://dx.doi.org/10.1007/s00406-019-01090-1DOI Listing
October 2020
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