Therapygenetic effects of 5-HTTLPR on cognitive-behavioral therapy in anxiety disorders: a meta-analysis

There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety disorders. We investigated both categorical (symptom reduction of at least 50%) and dimensional outcomes from baseline to post-treatment and follow-up. Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder. No significant effects of 5-HTTLPR genotype on categorical or dimensional outcomes at post and follow-up were detected. We conclude that current evidence does not support the hypothesis of 5-HTTLPR as a moderator of treatment outcome for CBT in anxiety disorders. Future research should address whether other factors such as long-term changes or epigenetic processes may explain further variance in these complex gene-environment interactions and molecular-genetic pathways that may confer behavioral change following psychotherapy

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

From DNA to CBT : an investigation psychological therapy response and genetics

Background: Social anxiety disorder, panic disorder, and major depressive disorder are common, disabling, and heritable disorders. The first line of treatment for all anxiety disorders and mild to moderate depression is cognitive behavior therapy (CBT). However, 40–60% of patients fail to respond adequately to treatment and the ability to a priori predict who will respond to treatment is essential for being able to choose alternative treatments to those who will fail the treatment. As clinical and demographic variables so far have shown limited predictive value of in guiding therapeutic decisions, is has been suggested to incorporate genetic variation in the set of predictors to increase precision. Aims: The general aim of this thesis was to investigate the genetic underpinnings of psychological treatment outcomes for social anxiety disorder, panic disorder, and major depressive disorder. Specifically, we aimed to identify the clinical and genetic predictors of patients with social anxiety, and to evaluate participant responses to CBT (Study I); next we increased the sample size from Study I and collaborated with another site and investigated three polymorphisms and their predictive value in CBT response for social anxiety (Study II). Subsequently, we aimed to calculate polygenic risk scores by performing a genomewide association analysis to study genetic variation and CBT responses to major depression (Study III); finally, we further extended the sample size by performing a meta-analysis, and by calculating polygenic risk scores to study potential genetic overlap with other cognitive and psychiatric traits, and the link between genetic variations and CBT responses in patients with anxiety disorders. Methods: In Study I and II, we recruited participants from randomized controlled trials to investigate clinical variables (Study I) and candidate gene polymorphisms (Study I and II); as potential predictors of CBT response for social anxiety disorder. Study III and IV we recruited larger samples and performed genome-wide association analyses to estimate genetic variance in CBT response and to calculate polygenic risk for CBT outcome for major depression and anxiety disorders. Results: In Study I, several clinical, but neither of the genetic variables predicted CBT outcome for social anxiety. In Study II, neither of the genetic polymorphisms predicted response to CBT for SAD. In Study III, an association of higher load of autism spectrum polygenic risk scores and less decrease in depressive symptoms after CBT was shown. In Study IV, no genome-wide significant loci or genetic overlap with psychiatric or cognitive traits were present. Conclusions: The results in this thesis presents the first findings of an association of aggregated genetic risk scores and CBT outcome in depression. Our results indicate that the use of polygenic risk scores may be a fruitful approach in genetic studies of CBT outcomes. In addition, the results provide support for the continued efforts of collecting larger and more homogenous samples in studies of complex traits such as psychological treatment response

From DNA to CBT : an investigation psychological therapy response and genetics

Background: Social anxiety disorder, panic disorder, and major depressive disorder are common, disabling, and heritable disorders. The first line of treatment for all anxiety disorders and mild to moderate depression is cognitive behavior therapy (CBT). However, 40–60% of patients fail to respond adequately to treatment and the ability to a priori predict who will respond to treatment is essential for being able to choose alternative treatments to those who will fail the treatment. As clinical and demographic variables so far have shown limited predictive value of in guiding therapeutic decisions, is has been suggested to incorporate genetic variation in the set of predictors to increase precision. Aims: The general aim of this thesis was to investigate the genetic underpinnings of psychological treatment outcomes for social anxiety disorder, panic disorder, and major depressive disorder. Specifically, we aimed to identify the clinical and genetic predictors of patients with social anxiety, and to evaluate participant responses to CBT (Study I); next we increased the sample size from Study I and collaborated with another site and investigated three polymorphisms and their predictive value in CBT response for social anxiety (Study II). Subsequently, we aimed to calculate polygenic risk scores by performing a genomewide association analysis to study genetic variation and CBT responses to major depression (Study III); finally, we further extended the sample size by performing a meta-analysis, and by calculating polygenic risk scores to study potential genetic overlap with other cognitive and psychiatric traits, and the link between genetic variations and CBT responses in patients with anxiety disorders. Methods: In Study I and II, we recruited participants from randomized controlled trials to investigate clinical variables (Study I) and candidate gene polymorphisms (Study I and II); as potential predictors of CBT response for social anxiety disorder. Study III and IV we recruited larger samples and performed genome-wide association analyses to estimate genetic variance in CBT response and to calculate polygenic risk for CBT outcome for major depression and anxiety disorders. Results: In Study I, several clinical, but neither of the genetic variables predicted CBT outcome for social anxiety. In Study II, neither of the genetic polymorphisms predicted response to CBT for SAD. In Study III, an association of higher load of autism spectrum polygenic risk scores and less decrease in depressive symptoms after CBT was shown. In Study IV, no genome-wide significant loci or genetic overlap with psychiatric or cognitive traits were present. Conclusions: The results in this thesis presents the first findings of an association of aggregated genetic risk scores and CBT outcome in depression. Our results indicate that the use of polygenic risk scores may be a fruitful approach in genetic studies of CBT outcomes. In addition, the results provide support for the continued efforts of collecting larger and more homogenous samples in studies of complex traits such as psychological treatment response

Predictors of Symptomatic Change and Adherence in Internet-Based Cognitive Behaviour Therapy for Social Anxiety Disorder in Routine Psychiatric Care

Objective A central goal of health care is to improve patient outcomes. Although several studies have demonstrated the effectiveness of therapist guided internet-based cognitive behaviour therapy (ICBT) for social anxiety disorder (SAD), a significant proportion of patients do not respond to treatment. Consequently, the aim of this study was to identify individual characteristics and treatment program related factors that could help clinicians predict treatment outcomes and adherence for individuals with SAD. Method The sample comprised longitudinal data collected during a 4-year period of adult individuals (N = 764) treated for SAD at a public service psychiatric clinic. Weekly self-rated Liebowitz Social Anxiety Scale (LSAS-SR) scores were provided. Rates of symptomatic change during treatment and adherence levels were analysed using multilevel modelling. The following domains of prognostic variables were examined: (a) socio-demographic variables; (b) clinical characteristics; (c) family history of mental illness; and (d) treatment-related factors. Results Higher treatment credibility and adherence predicted a faster rate of improvement during treatment, whereas higher overall functioning level evidenced a slower rate of improvement. Treatment credibility was the strongest predictor of greater adherence. Having a family history of SAD-like symptoms was also associated with greater adherence, whereas Attention-Deficit/Hyperactivity Disorder (ADHD)-like symptoms, male gender, and family history of minor depression predicted lower adherence. Also, the amount of therapist time spent per treatment module was negatively associated with adherence. Conclusions Results from a large clinical sample indicate that the credibility of ICBT is the strongest prognostic factor explaining individual differences in both adherence level and symptomatic improvement. Early screening of ADHD-like symptoms may help clinicians identify patients who might need extra support or an adjusted treatment. Therapist behaviours that promote adherence may be important for treatment response, although more research is needed in order to determine what type of support would be most beneficial.Funding Agencies|Stockholm County Council</p

Genetic polymorphisms in monoamine systems and outcome of cognitive behavior therapy for social anxiety disorder

OBJECTIVE: The role of genetics for predicting the response to cognitive behavior therapy (CBT) for social anxiety disorder (SAD) has only been studied in one previous investigation. The serotonin transporter (5-HTTLPR), the catechol-o-methyltransferase (COMT) val158met, and the tryptophan hydroxylase-2 (TPH2) G-703Tpolymorphisms are implicated in the regulation of amygdala reactivity and fear extinction and therefore might be of relevance for CBT outcome. The aim of the present study was to investigate if these three gene variants predicted response to CBT in a large sample of SAD patients. METHOD: Participants were recruited from two separate randomized controlled CBT trials (trial 1: n = 112, trial 2: n = 202). Genotyping were performed on DNA extracted from blood or saliva samples. Effects were analyzed at follow-up (6 or 12 months after treatment) for both groups and for each group separately at post-treatment. The main outcome measure was the Liebowitz Social Anxiety Scale Self-Report. RESULTS: At long-term follow-up, there was no effect of any genotype, or gene × gene interactions, on treatment response. In the subsamples, there was time by genotype interaction effects indicating an influence of the TPH2 G-703T-polymorphism on CBT short-term response, however the direction of the effect was not consistent across trials. CONCLUSIONS: None of the three gene variants, 5-HTTLPR, COMTval158met and TPH2 G-703T, was associated with long-term response to CBT for SAD

Correction: Genetic Polymorphisms in Monoamine Systems and Outcome of Cognitive Behavior Therapy for Social Anxiety Disorder.

[This corrects the article DOI: 10.1371/journal.pone.0079015.]

Genetic polymorphisms in monoamine systems and outcome of cognitive behavior therapy for social anxiety disorder

OBJECTIVE: The role of genetics for predicting the response to cognitive behavior therapy (CBT) for social anxiety disorder (SAD) has only been studied in one previous investigation. The serotonin transporter (5-HTTLPR), the catechol-o-methyltransferase (COMT) val158met, and the tryptophan hydroxylase-2 (TPH2) G-703Tpolymorphisms are implicated in the regulation of amygdala reactivity and fear extinction and therefore might be of relevance for CBT outcome. The aim of the present study was to investigate if these three gene variants predicted response to CBT in a large sample of SAD patients. METHOD: Participants were recruited from two separate randomized controlled CBT trials (trial 1: n = 112, trial 2: n = 202). Genotyping were performed on DNA extracted from blood or saliva samples. Effects were analyzed at follow-up (6 or 12 months after treatment) for both groups and for each group separately at post-treatment. The main outcome measure was the Liebowitz Social Anxiety Scale Self-Report. RESULTS: At long-term follow-up, there was no effect of any genotype, or gene × gene interactions, on treatment response. In the subsamples, there was time by genotype interaction effects indicating an influence of the TPH2 G-703T-polymorphism on CBT short-term response, however the direction of the effect was not consistent across trials. CONCLUSIONS: None of the three gene variants, 5-HTTLPR, COMTval158met and TPH2 G-703T, was associated with long-term response to CBT for SAD.

Genetic polymorphisms in monoamine systems and outcome of cognitive behavior therapy for social anxiety disorder

OBJECTIVE: The role of genetics for predicting the response to cognitive behavior therapy (CBT) for social anxiety disorder (SAD) has only been studied in one previous investigation. The serotonin transporter (5-HTTLPR), the catechol-o-methyltransferase (COMT) val158met, and the tryptophan hydroxylase-2 (TPH2) G-703Tpolymorphisms are implicated in the regulation of amygdala reactivity and fear extinction and therefore might be of relevance for CBT outcome. The aim of the present study was to investigate if these three gene variants predicted response to CBT in a large sample of SAD patients. METHOD: Participants were recruited from two separate randomized controlled CBT trials (trial 1: n = 112, trial 2: n = 202). Genotyping were performed on DNA extracted from blood or saliva samples. Effects were analyzed at follow-up (6 or 12 months after treatment) for both groups and for each group separately at post-treatment. The main outcome measure was the Liebowitz Social Anxiety Scale Self-Report. RESULTS: At long-term follow-up, there was no effect of any genotype, or gene × gene interactions, on treatment response. In the subsamples, there was time by genotype interaction effects indicating an influence of the TPH2 G-703T-polymorphism on CBT short-term response, however the direction of the effect was not consistent across trials. CONCLUSIONS: None of the three gene variants, 5-HTTLPR, COMTval158met and TPH2 G-703T, was associated with long-term response to CBT for SAD