Examining Individual and Synergistic Contributions of PTSD and Genetics to Blood Pressure: A Trans-Ethnic Meta-Analysis.

Growing research suggests that posttraumatic stress disorder (PTSD) may be a risk factor for poor cardiovascular health, and yet our understanding of who might be at greatest risk of adverse cardiovascular outcomes after trauma is limited. In this study, we conducted the first examination of the individual and synergistic contributions of PTSD symptoms and blood pressure genetics to continuous blood pressure levels. We harnessed the power of the Psychiatric Genomics Consortium-PTSD Physical Health Working Group and investigated these associations across 11 studies of 72,224 trauma-exposed individuals of European (n = 70,870) and African (n = 1,354) ancestry. Genetic contributions to blood pressure were modeled via polygenic scores (PGS) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that were derived from a prior trans-ethnic blood pressure genome-wide association study (GWAS). Results of trans-ethnic meta-analyses revealed significant main effects of the PGS on blood pressure levels [SBP: ß = 2.83, standard error (SE) = 0.06, p < 1E-20; DBP: ß = 1.32, SE = 0.04, p < 1E-20]. Significant main effects of PTSD symptoms were also detected for SBP and DBP in trans-ethnic meta-analyses, though there was significant heterogeneity in these results. When including data from the largest contributing study - United Kingdom Biobank - PTSD symptoms were negatively associated with SBP levels (ß = -1.46, SE = 0.44, p = 9.8E-4) and positively associated with DBP levels (ß = 0.70, SE = 0.26, p = 8.1E-3). However, when excluding the United Kingdom Biobank cohort in trans-ethnic meta-analyses, there was a nominally significant positive association between PTSD symptoms and SBP levels (ß = 2.81, SE = 1.13, p = 0.01); no significant association was observed for DBP (ß = 0.43, SE = 0.78, p = 0.58). Blood pressure PGS did not significantly moderate the associations between PTSD symptoms and blood pressure levels in meta-analyses. Additional research is needed to better understand the extent to which PTSD is associated with high blood pressure and how genetic as well as contextual factors may play a role in influencing cardiovascular risk.

Genomic influences on self-reported childhood maltreatment.

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h2snp), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n = 124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder group (PGC-PTSD) (n = 26,290). h2snp for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10-8, FOXP1; rs10262462, p = 3.24 × 10-8, FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h2snp for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r2 = 0.0025; p = 1.8 × 10-15). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (rg = 0.70, p = 4.65 × 10-40), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.

High expectancy and early response produce optimal effects in sertraline treatment for post-traumatic stress disorder.

BACKGROUND: Better indicators of prognosis are needed to personalise post-traumatic stress disorder (PTSD) treatments.AimsWe aimed to evaluate early symptom reduction as a predictor of better outcome and examine predictors of early response. METHOD: Patients with PTSD (N = 134) received sertraline or prolonged exposure in a randomised trial. Early response was defined as 20% PTSD symptom reduction by session two and good end-state functioning defined as non-clinical levels of PTSD, depression and anxiety. RESULTS: Early response rates were similar in prolonged exposure and sertraline (40 and 42%), but in sertraline only, early responders were four times more likely to achieve good end-state functioning at post-treatment (Number Needed to Treat = 1.8, 95% CI 1.28-3.00) and final follow-up (Number Needed to Treat = 3.1, 95% CI 1.68-16.71). Better outcome expectations of sertraline also predicted higher likelihood of early response. CONCLUSIONS: Higher expectancy of sertraline coupled with early response may produce a cascade-like effect for optimal conditions for long-term symptom reduction. Therefore, assessing expectations and providing clear treatment rationales may optimise sertraline effects. DECLARATION OF INTEREST: None.

Do changes in trauma-related beliefs predict PTSD symptom improvement in prolonged exposure and sertraline?

OBJECTIVE: Negative trauma-related belief change has been found to predict subsequent improvement in symptoms of posttraumatic stress disorder (PTSD) in prolonged exposure (PE) and other therapies, consistent with several psychological theories of treatment change (e.g., Foa & Kozak, 1986). However, belief change has not been examined in selective serotonin reuptake inhibitors such as sertraline. We examined processes associated with symptom improvement in 2 treatments for PTSD, hypothesizing that belief change would robustly predict PTSD improvement in patients treated with PE but not those treated with sertraline, reflecting moderation by treatment. METHOD: Patients with chronic PTSD (N = 134; 78% women, 71.6% Caucasian, M = 38.1 years, SD = 11.8) received 10 weeks of PE or sertraline in a randomized, controlled trial. Patients reported PTSD and depression symptoms, and trauma-related beliefs (Post-Traumatic Cognitions Inventory; Foa, Ehlers, Clark, D Tolin, & Orsillo, 1999) at pretreatment, every treatment session, and posttreatment. RESULTS: Using time-lagged mixed regression models, change in trauma-related beliefs predicted subsequent PTSD symptom improvement, an effect moderated by treatment and particularly strong in PE (d = 0.93) compared with sertraline (d = 0.35). Belief change also predicted depressive symptom improvement but more modestly and bidirectionally, with no difference by treatment modality. CONCLUSIONS: Trauma-related belief change precedes PTSD improvement more robustly in PE than in sertraline and with greater specificity compared with depressive symptoms. These findings highlight potentially divergent processes contributing to symptom change in these PTSD treatments, with belief change as a key mechanism of PE. (PsycINFO Database Record

What would you choose? Sertraline or prolonged exposure in community and PTSD treatment seeking women.

BACKGROUND: Both sertraline (SER) and prolonged exposure (PE) are empirically supported treatments for chronic posttraumatic stress disorder (PTSD). While efficacious, these treatments are quite different in approach, and such differences may influence both treatment choice and treatment outcome. To date, we know very little about the relative efficacy of pharmacological and psychological treatments for chronic PTSD. METHOD: In Study 1, we compared rates of treatment choice (SER or PE) in 74 trauma-exposed women. In Study 2, we extended this work to an open-choice treatment trial, in which 31 female assault survivors with chronic PTSD received their choice of SER or PE for ten weeks and were followed over time. RESULTS: In Study 1 (82%) and Study 2 (74.2%), the majority of women chose PE. In Study 2, both SER and PE evidenced moderate to large unadjusted effect sizes, with evidence of an advantage for PE in propensity adjusted analyses at posttreatment. Women with co-occurring major depressive disorder (MDD) were more likely to choose SER than those without MDD. However, among those with MDD, the advantage of PE was particularly evident. CONCLUSIONS: Our results highlight the presence of clear treatment preferences for PTSD and their potential impact on outcome. This study underscores the importance of systematic study of patient preferences and encourages a rethinking of one-size fits all approaches to treatment for mental disorders.

Switching from imipramine to sertraline in panic disorder.

BACKGROUND: There are no systematic switching studies of antidepressants in the treatment of panic disorder. The present pilot study examined the usefulness of switching from imipramine to sertraline in 18 patients diagnosed with panic disorder with agoraphobia. METHOD: 15 patients who had had an unsatisfactory outcome in a 24-week, open, weight-adjusted fixed-dose imipramine treatment study and 3 patients who had had a very satisfactory outcome but had subsequently relapsed following imipramine discontinuation were systematically switched to protocolized, 24-week open treatment with sertraline, 50-100 mg/day. Uniform measures of efficacy and side effects were used throughout the study. The net benefit obtained from the switch was assessed using an operationalized outcome grade ranging from 0-2, where 0 = inadequate duration of trial (dropouts) or non-response, 1 = partial response or full responders with side effects necessitating a change in treatment, and 2 = full response without complications. RESULTS: Based on paired t-tests, following the switch from imipramine to sertraline, a significant improvement was seen on phobic and panic symptomatologies, side effects, and overall outcome grade (from 0.67 [+/- 0.77] to 1.17 [+/- 0.92], p < or = 0.05]. Of the 18 patients who were switched to sertraline treatment, 9 (50%) clearly gained from the switch, 6 (33.3%) had an outcome similar to that achieved with imipramine, and 3 (16.7%) had a worse outcome following the switch. Of the 9 patients who failed to respond to or were unable to tolerate treatment with imipraminel (rating of 0), 3 patients (33.3%) achieved full and 2 patients (22.2%) achieved partial response after switching to sertraline. CONCLUSION: The findings in this study suggest that switching between antidepressants with established antipanic efficacy may be an effective strategy in the management of patients with panic disorder who have had an unsatisfactory outcome with the first antidepressant tried.

Sertraline in panic disorder: initial treatment versus switch strategy.

The study explored whether there is differential efficacy for patients with panic disorder treated with sertraline initially (primary group) versus those switched (transfer group) after intolerance or nonresponse to imipramine in the context of the open 24-week treatment phase of a long-term maintenance/discontinuation study. Similar assessment and treatment procedures were used in the 2 groups and there were no concurrent cognitive behavioral interventions. A consistent pattern suggesting decreased efficacy for the transfer treatment group (n = 11, 68 +/- 25 mg/d) compared with the primary treatment group (n = 11, 70 +/- 25 mg/d) was found on response rates, univariate repeated measures analysis of variance and within group effect sizes in intent to treat, and completer samples. These preliminary findings concord well with clinical intuition but are contrary to findings in the treatment of depression. Replication studies seem warranted.

Imipramine vs. sertraline in panic disorder: 24-week treatment completers.

Despite the acknowledged favorable side effects profile of selective serotonin reuptake inhibitors (SSRIs), comparative studies have not found significant differences in efficacy between tricyclics (TCAs) such as imipramine and clomipramine, and SSRIs in the treatment of panic disorder. The present study focuses on treatment completers to inform patients who adhere to a recommended course of treatment on the possible differential patterns of improvement and of change in side effects between sertraline and imipramine. From an intent to treat consecutive sample of patients participating in the 24-week open phase protocolized treatment of a long-term controlled maintenance/discontinuation study, 20 imipramine completers and 16 sertraline completers with moderate to severe baseline symptomatology were compared using primarily repeated measures analysis of variance on measures of symptom severity, on 15 side effects systematically elicited using an inventory and on heart rate and weight. The results revealed greater early improvement with imipramine compared to sertraline but no enduring differences beyond week 8 of treatments. Side effects, in particular dry mouth, constipation, tremors, sweating, and cardiovascular complaints increased more in severity and were more frequent and persistent during imipramine than sertraline but, except for the 10 beats/min increase in heart rate, side effects were clinically insignificant at the end of both treatments. Change in sexual complaints and weight did not differ between the treatments. The more favorable side effect profile of SSRIs versus TCAs was demonstrated even in the best case scenario of treatment completers. The more rapid improvement with imipramine needs replication but, tentatively, it may be attributed to the greater motivational effects toward action observed with noradrenergic or dual action antidepressants compared to SSRIs.

Duration of imipramine therapy and relapse in panic disorder with agoraphobia.

It has been suggested that maintenance treatment of patients who have remitted panic disorder with agoraphobia beyond the six months of acute phase imipramine treatment may decrease the risk of relapse. This study further explores the relationship between relapse and duration of imipramine treatment in this population.Fifty-one patients, all in remission at the end of six months acute phase open trial with imipramine 2.25 mg/kg/day and randomized to double-blind maintenance or placebo substitution, discontinued imipramine treatment eventually and were followed over a 12-month risk period: 27 during first year placebo substitution, 7 after 12 months of imipramine maintenance in placebo substitution, and 17 after variable durations of imipramine maintenance in open discontinuation. There were no behaviorally oriented interventions or instructions at any time during the acute and maintenance phases of treatment or during imipramine discontinuation. Duration of imipramine treatment, the method of discontinuation (open versus placebo substitution), or any of the 9 variables from the demographic, clinical, and open treatment domains that were entered in a Cox proportional hazard model did not predict relapse. The rate of relapse after only 6 months of treatment (10 out of 27, 37%) was identical to the rate of relapse after 12 to 30 months of treatment (9 out of 24, 37.5%). The results suggest a lack of specific protective effects beyond prophylaxis and underscore the difficulty in predicting relapse in fully remitted panic disorder with agoraphobia patients. Early detection of relapse in patients who discontinue treatment may be a viable alternative to prediction.

Predictors of entering a long-term drug treatment study of panic disorder.

Three hundred thirty-three consecutive individuals with panic and agoraphobic-like symptoms were evaluated as part of the screening for entry in a long-term imipramine treatment study of panic disorder with agoraphobia. The present report compares three subgroups of potential subjects--those who entered the study (n = 139, 41.7%), those who were rejected from participation based on exclusion criteria (n = 161, 48.3%), and those who qualified to enter but refused participation (n = 33, 10.0%)-in order to characterize pretreatment attrition and address two specific questions: What variables other than inclusion and exclusion criteria predict the likelihood of entering the trial?, and What variables significantly predict the likelihood of refusal to participate? Logistic regression analysis revealed that the likelihood of entering the trial was influenced significantly and independently by a number of variables that included extroversion, anxiety, and work satisfaction and performance measures. The refused and rejected groups differed significantly on a number of variables that were not a priori exclusionary criteria, such as a history of substance abuse other than alcohol and current use of alcohol to decrease anxiety, but none of these variables emerged as independent, significant predictors of refusing behavior as a separate category of nonparticipation. Findings suggest the presence of factors common to both the rejected and the refused groups that significantly influence pretreatment attrition and caution that categorizing pretreatment attrition into refused and rejected categories may not always be clear cut. Research and clinical implications are briefly discussed.