PURPOSE/BACKGROUND:Previous studies among psychiatric patients have shown differences between men and women in psychotropic medication prescription patterns. The factors underlying these differences are still poorly understood. This exploratory study aimed to investigate a range of clinical and demographic factors in their contributions to explaining these gender differences. METHODS/PROCEDURES:In 2476 outpatients with a mental disorder (mean age 46.1 year, 58.2% women) enrolled in pharmacotherapy monitoring program, regression analyses were used to investigate the associations of gender with use of any psychotropic (yes/no), use of each separate psychotropic type (yes/no), number (0 to 4) and dosage of each used psychotropic. Next, clinical and demographic effect modifiers and explanatory/confounding factors of these associations were identified. FINDINGS/RESULTS:Frequencies of general psychotropic use, antidepressant use, anxiolytic use, as well as polypharmacy were significantly higher in women than in men across all ages (premenopausal, perimenopausal, and postmenopausal), with equal dosing of psychotropics, except for higher doses of mood stabilizers in men. Longer illness duration and having a partner were effect modifiers of the gender effect, while higher frequencies of an affective/anxiety diagnosis, higher somatic complaints and symptomatic distress, more previous mental health service (MHS) visits and no current occupation were explanatory factors. IMPLICATIONS/CONCLUSIONS:Psychotropic use and psychotropic polypharmacy were more common in women than in men. Women on psychotropic medications were more often diagnosed with affective/anxiety diagnoses, experienced more symptomatic distress and somatic complaints, and visited more healthcare services than men, reaffirming findings from previous studies. Future longitudinal studies should investigate in further detail whether these outcomes are cause or consequence of gender differences in psychotropic medication use.

Objectives To analyze sex differences in outcomes in Tourette syndrome (TS) and Persistent Motor or Vocal tic disorders (PMVT) in the Tourette Association of America International Consortium for Genetics (TAAICG) dataset. Methods The relationship between sex and clinical measures was explored in 2,403 participants (N = 2,109 with TS; N = 294 with PMVT) from the TAAICG dataset using generalized estimating equation regression models, and adjusted for age and family relationships. Results Female (vs male) participants with TS (25.5% of the sample) had 0.46 times lower odds of being formally diagnosed clinically with TS before the research study (p < 0.00001), later age at symptom onset (6.5 +/- 2.8 vs 6.0 +/- 2.7; p = 0.001), later age at diagnosis (13.3 +/- 11.2 vs 10.7 +/- 8.1; p = 0.0001), a longer time-to-diagnosis (3 [1, 7] vs 2 [1, 5], p = 0.01), and lower tic severity (28.4 +/- 9.1 vs 30.7 +/- 8.7); p < 0.0001). Female (vs male) participants with PMVT (42.9% of the sample) had an earlier age at symptom onset (7.9 +/- 3.3 vs 8.9 +/- 3.7; p = 0.05). Discussion Female (vs male) participants with TS are less likely to be formally diagnosed, have later age at symptom onset, later age at diagnosis, and longer time-to-diagnosis. Female (vs male) participants with PMVT have an earlier age at symptom onset. Future research is needed to understand differences longitudinally in TS and PMVT.

ObjectiveObsessive compulsive disorder (OCD) and anorexia nervosa (AN) are conditions associated with poor cognitive flexibility, a factor considered to interfere with treatment, but research into the relationship between cognitive flexibility and treatment outcome is limited. This study explores whether baseline measures of cognitive flexibility predict outcomes in OCD and AN, evaluates whether changes in these measures contribute to treatment outcome, and evaluates the effectiveness of adjunctive cognitive remediation therapy (CRT) in improving cognitive flexibility.MethodsThis secondary analysis utilized linear mixed model analysis on data from a randomized controlled multicenter clinical trial involving adult participants with OCD (n=71) AND AN (n=61). Participants underwent 10 twice-weekly sessions of either CRT or a non-specific active control intervention (specialized attention therapy; SAT), followed by treatment as usual. Assessments using Yale-Brown Obsessive Compulsive Scale and the Eating Disorder Examination Questionnaire were conducted at baseline, post-CRT/SAT and at 6 and 12 months. Cognitive flexibility was evaluated through the Trail Making Test (TMT), the Color-Word Interference Test (CWIT) and the Detail and Flexibility Questionnaire (DFlex).ResultsLevels of cognitive flexibility at baseline did not predict or moderate treatment outcome, nor did change in cognitive flexibility (baseline post-CRT/SAT) mediate treatment outcome, with CRT providing no greater improvement in measures of cognitive flexibility than SAT.ConclusionsThis study failed to find any relationship between measures of cognitive flexibility and treatment outcome in OCD and AN, and thus questions hypothetical associations between measures of cognitive flexibility and mechanisms of change in patients with OCD and AN.

IntroductionThe aim of this study was to directly compare behavior therapy (exposure & response prevention; ERP) with pharmacotherapy (risperidone) with respect to tic severity and quality of life in patients with Tourette's disorder or tic disorders.MethodA total of 30 participants were randomly assigned to either ERP (12 weekly 1-hour sessions) or risperidone (flexible dosage of 1-6 mg) with follow-up at 3 and 9 months after end of treatment. Outcome measures included tic severity as measured by the Yale Global Tic Severity Scale, quality of life and side effects. Predefined informative hypotheses were evaluated using Bayes factors (BF), a Bayesian alternative for null hypothesis testing with p-values, that provides a more reliable and powerful method in the case of small samples. A BF larger than one indicates support for the informative hypothesis and the larger the BF, the stronger the support, with a BF between 3 and 10 being considered to provide moderate evidence.ResultsBoth ERP and Risperidone were found to be effective with respect to tic severity at end of treatment (BF 5.35). At 9 months follow-up, results remained stable (BF 4.59), with an advantage of ERP over Risperidone at 3 months follow-up (BF 3.92). With respect to quality of life, an effect was found for ERP (BF 3.70 at 3 months follow up; BF 3.08 at 9 months follow-up). Dropout rates were higher in the medication condition, mainly due to significantly more side effects halfway during treatment, fading out towards end of treatment.DiscussionBehavior therapy and medication are equally viable options in the treatment of tic disorders, with a slight preference for ERP based on follow-up results on tic severity and quality of life, and side effects.Clinical trial registrationhttps://onderzoekmetmensen.nl/nl/node/23410/pdf, identifier NL-OMON23410.

Obsessive-compulsive disorder (OCD) affects ~1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3 and CTNND1 and multiple genes in the major histocompatibility complex (MHC) region. We estimated that ~11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and the cortex, along with D1 and D2 type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa and Tourette syndrome and was negatively associated with inflammatory bowel diseases, educational attainment and body mass index.

To enable patient-centred treatment choices, shared decision-making (SDM) is essential. To date, instruments facilitating SDM in depression treatment are scarce, especially those that add personalized information, next to more general patient information. Co-creation is essential and seldom used in the development of such tools. We describe the development of an instrument that provides patients with depression and their clinicians with: (1) systematic information regarding symptoms, medical history, situational factors and potentially successful treatment strategies in a digital report and (2) objective treatment information guiding treatment decisions. The study was co-led by researchers and patient representatives, indicating all decisions regarding the development of the instrument were taken together. Data collection, analyses and tool development took place between 2017 – 2021. A mixed-methods approach was applied. Qualitative research provided insight into the end-users’ needs and preferences. A scoping review provided a summary of the available literature on identified predictors of treatment response. K-means cluster analysis was applied to suggest potentially successful treatment options based on similar patients and their outcomes in the past. These data were combined in a digital report. Treatment option grids were developed by patient advocacy groups to provide objective information on evidence-based treatment options. The ‘Instrument for SDM in Depression’ (I-SHARED) was developed, incorporating individual characteristics and preferences. Qualitative analysis and the scoping review resulted in the identification of four categories of predictors of treatment response. The cluster analysis identified five distinct clusters based on symptoms, functioning and age. The co-created I-SHARED report combined all findings and was integrated into an existing electronic health record system ready for piloting, together with the treatment option grids. The collaboratively developed decision aid for depression, including a clustering algorithm to predict potentially successful treatment options, has the potential to support SDM between patients and clinicians.

Tics can have a serious impact on the quality of life of children and their families. Behavioural therapy is an evidence-based first line treatment for tic disorders. This randomised controlled trial studied the efficacy of a brief, condensed group-based programme for children with tics (Dutch Trial Registry NL8052, 27 September 2019). Tackle your Tics is a four-day group treatment, including exposure and response prevention and supporting components, delivered by therapists and ‘experts by experience’. We collected outcome measures at baseline (T1), directly post-treatment (T2), and at three- and 6-months follow-up (T3, T4) including tic severity (primary outcome measure), tic-related impairment, quality of life, tic-related cognitions, emotional/behavioural functioning, family functioning, treatment satisfaction and adherence. Outcomes directly post-treatment improved in both the treatment group (n = 52) and waiting list (n = 54), but showed no statistically significant differences between the conditions (differential change over time T1-T2) on tic severity (Yale Global Tic Severity Scale), quality of life (Gilles de la Tourette Syndrome Quality of Life Scale), tic-related cognitions and family functioning. At longer term (T3), again no between-group difference was found on tic severity, but tic-related impairment, quality of life and emotional/behavioural functioning significantly improved in the treatment group compared to the waiting list. Mean treatment satisfaction scores were favourable for both children and parents. Directly posttreatment, Tackle your Tics showed no superior effect compared to waiting list. However, on longer term this brief four-day group treatment was effective in improving tic-related impairment, quality of life and emotional/behavioural functioning.

BACKGROUND:Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. METHODS:We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. RESULTS:We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. CONCLUSIONS:Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

While 1–2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13–38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations at the single-nucleotide polymorphism (SNP) or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (Pfixed = 3.06 × 10−5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (Ngenes = 28, Beta = 0.79, SE = 0.16, Pbon = 0.008). Expression of genes in this set is high at sites of insulin mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33–43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (rG = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.

Background To examine the association between race, ethnicity, and parental educational attainment on tic-related outcomes among Tourette Syndrome (TS) participants in the Tourette Association of America International Consortium for Genetics database.Methods 723 participants in the TAAICG dataset aged ≤ 21 years were included. The relationships between tic-related outcomes and race and ethnicity were examined using linear and logistic regressions. Parametric and non-parametric tests were performed to examine the association between parental educational attainment and tic-related outcomes.Results Race and ethnicity were collapsed as Non-Hispanic white (N=566, 88.0%) versus Other (N=77, 12.0%). Tic symptom onset was earlier by 1.1 years (p<0.0001) and TS diagnosis age was earlier by 0.9 years (p=0.0045) in the Other group (vs. Non-Hispanic white). Sex and parental education as covariates did not contribute to the differences observed in TS diagnosis age. There were no significant group differences observed across the tic-related outcomes in parental education variable.Discussion Our study was limited by the low number of non-white or Hispanic individuals in the cohort. Racial and ethnic minority groups experienced an earlier age of TS diagnosis than Non-Hispanic white individuals. Tic severity did not differ between the two groups, and parental educational attainment did not affect tic-related outcomes. There remain significant disparities and gaps in knowledge regarding TS and associated comorbid conditions. Our study suggests the need for more proactive steps to engage individuals with tic disorders from all racial and ethnic minority groups to participate in research studies.

AbstractObjectivesAlthough common, sleep disorders often remain undiagnosed in psychiatric patients. A screening instrument, like the Holland Sleep Disorders Questionnaire (HSDQ) could improve this. Previous work indicated a 6‐factor structure for the HSDQ, but this hasn't been investigated in psychiatric patients.MethodsHSDQ data was collected in a psychiatric‐outpatient sample (n = 1082) and general‐population sample (n = 2089). Internal reliability of the HSDQ was investigated and Confirmatory Factor Analyses (CFA) were used to compare 1‐, 6‐, and second‐order 6‐factor models in both samples. Next, multigroup‐CFA was used to investigate measurement invariance.ResultsExcept for one subscale, internal reliability was acceptable in both samples. The 6‐factor structure model fitted best in both samples and investigation of measurement invariance showed evidence for equality of the overall factor structure (configural invariance). Addition of equality constraints on factor loadings (metric invariance) and item thresholds (scalar invariance) showed good fit for all fit statistics, except for one. Exploratory analyses identified three items for metric and three different items for scalar invariance explaining this non‐invariance.ConclusionThe HSDQ has a 6‐factor structure in psychiatric patients, which is comparable to the general population. However, due to the observed non‐invariance, users should be cautious with comparing HSDQ scores between psychiatric and general populations.

INTRODUCTION:Although cognitive behavioral therapy (CBT) effectively treats obsessive-compulsive disorder (OCD), many patients refuse CBT or drop out prematurely, partly because of anxiety regarding exposure and response prevention (ERP) exercises. Inference-based cognitive behavioral therapy (I-CBT) focuses on correcting distorted inferential thinking patterns, enhancing reality-based reasoning, and addressing obsessional doubt by targeting underlying dysfunctional reasoning, without incorporating an ERP component. We hypothesized that I-CBT would be non-inferior to CBT. Additionally, we hypothesized that I-CBT would be more tolerable than CBT. METHODS:197 participants were randomly assigned to 20 sessions CBT or I-CBT and assessed at baseline, posttreatment, and 6 and 12 months' follow-up. The primary outcome was OCD symptom severity measured using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS; non-inferiority margin: 2 points). The secondary outcome, treatment tolerability, was assessed using the Treatment Acceptability/Adherence Scale (TAAS). A linear mixed-effects model was used to assess the non-inferiority of the primary outcome and superiority of secondary outcomes. RESULTS:Statistically significant within-group improvements in the primary and secondary outcomes were observed in both treatments. No statistically significant between-group differences in Y-BOCS were found at any assessment point, but the confidence intervals exceeded the non-inferiority threshold, making the results inconclusive. The estimated mean posttreatment TAAS score was significantly higher in the I-CBT group than in the CBT group. CONCLUSION:While both CBT and I-CBT are effective for OCD, whether I-CBT is non-inferior to CBT in terms of OCD symptom severity remains inconclusive. Nevertheless, I-CBT offers better tolerability and warrants consideration as an alternative treatment for OCD.

Abstract Background Tailoring antidepressant drugs (AD) to patients’ genetic drug-metabolism profile is promising. However, literature regarding associations of ADs’ treatment effect and/or side effects with drug metabolizing genes CYP2D6 and CYP2C19 has yielded inconsistent results. Therefore, our aim was to longitudinally investigate associations between CYP2D6 (poor, intermediate, and normal) and CYP2C19 (poor, intermediate, normal, and ultrarapid) metabolizer-status, and switching/discontinuing of ADs. Next, we investigated whether the number of perceived side effects differed between metabolizer statuses. Methods Data came from the multi-site naturalistic longitudinal cohort Netherlands Study of Depression and Anxiety (NESDA). We selected depression- and/or anxiety patients, who used AD at some point in the course of the 9 years follow-up period (n = 928). Medication use was followed to assess patterns of AD switching/discontinuation over time. CYP2D6 and CYP2C19 alleles were derived using genome-wide data of the NESDA samples and haplotype data from the PharmGKB database. Logistic regression analyses were conducted to investigate the association of metabolizer status with switching/discontinuing ADs. Mann–Whitney U-tests were conducted to compare the number of patient-perceived side effects between metabolizer statuses. Results No significant associations were observed of CYP metabolizer status with switching/discontinuing ADs, nor with the number of perceived side effects. Conclusions We found no evidence for associations between CYP metabolizer statuses and switching/discontinuing AD, nor with side effects of ADs, suggesting that metabolizer status only plays a limited role in switching/discontinuing ADs. Additional studies with larger numbers of PM and UM patients are needed to further determine the potential added value of pharmacogenetics to guide pharmacotherapy.

Background and Objective:Tourette Syndrome (TS) and Persistent Motor or Vocal Tic Disorders (PMVT) are more prevalent in males (vs. females). Females with TS may have a delay in diagnosis, and more complex tic features (vs. males). With respect to comorbidities, obsessive-compulsive disorder (OCD) is more prevalent in females; attention-deficit hyperactivity disorder (ADHD) is more prevalent in males. Less is known about sex differences in PMVT. This study analyzes sex differences in outcomes among individuals with TS and PMVT in the Tourette Association of America International Consortium for Genetics dataset (TAAICG). Design/Methods:Data from 2403 individuals (N=2109 TS; N=294 PMVT) from the TAAICG were analyzed to explore the relationship between sex and TS or PMVT outcomes: age at tic onset; age at diagnosis; time-to-diagnosis; tic severity; and comorbidity rates. Regression models were adjusted for age and family relationships to examine the impact of sex on outcomes. Results:Females with TS (25.5% of the sample) had a later age of symptom onset (6.5±2.8 vs. 6.0±2.7; p=0.001), later age at diagnosis (13.3±11.2 vs. 10.7±8.1; p=0.0001), and a longer time-to-diagnosis [3 (1,7) vs. 2 (1,5), p=0.01] than males. The total Yale-Global Tic Severity Scale (YGTSS) was lower in females with TS (28.4±9.1 vs. 30.7±8.7); p<0.0001); OCD was slightly more prevalent in females (55% vs. 48.7%; p=0.01) although OCD severity did not differ by sex; ADHD was more prevalent in males (55.7% vs 38.9%; p<0.001). Females with TS had 0.46 lower odds of being diagnosed with TS (p<0.00001). Females with PMVT (42.9% of the sample) had an earlier age of symptom onset (7.9±3.3 vs. 8.9±3.7; p=0.05). Motor or vocal tic severity (YGTSS) was not significantly different. OCD, but not ADHD, was more prevalent in females (OCD: 41.9% vs. 22.2%; p<0.001: ADHD:16.5% vs 21.0%; p=0.4). Conclusion:Females with TS are less likely to be formally diagnosed and have a later age of symptom onset, later age at diagnosis, longer time-to-diagnosis, higher prevalence of OCD, and lower prevalence of ADHD (vs. males). Females with PMVT have an earlier age of symptom onset, higher prevalence of OCD, but similar ADHD prevalence rates (vs. males). Females with TS and PMVT may be clinically different than males with TS. Future research is needed to understand differences longitudinally in TS and PMVT.

Background: Patients with affective and anxiety disorders are at risk of metabolic syndrome (MetS) and, consequently, cardiovascular disease and premature death. In this study, the course and treatment of MetS was investigated using longitudinal data from a naturalistic sample of affective- and anxiety-disordered outpatients (Monitoring Outcome of psychiatric PHARmacotherapy [MOPHAR]). Methods: Demographics, clinical characteristics, medication use, and MetS components were obtained for n = 2098 patients at baseline and, in a FU-subsample of n = 507 patients, after a median follow-up (FU) of 11 months. Furthermore, pharmacological treatment rates of MetS were investigated at baseline and FU. Finally, demographic and clinical determinants of change in MetS (component) scores were investigated. Results: At baseline, 34.6 % of n = 2098 patients had MetS, 41.4 % of whom received treatment. Of patients with persisting MetS, 46.1 % received treatment for one (or more) MetS component(s) at baseline, and 56.6 % received treatment at FU. Treatment rates of solely elevated blood pressure and reduced HDL-cholesterol did significantly, but modestly, improve. Higher age, male sex, smoking behavior, low education, diabetes, and depressive versus anxiety disorder were predictors of worse outcome at FU on at least one MetS component. Limitations: We did not have data on lifestyle interventions as a form of treatment, which might partly have explained the observed low pharmacotherapeutic treatment rates. Conclusion: MetS (components) show high persistence rates in affective- and anxiety-disordered patients, and are, despite adequate monitoring, undertreated over time. This indicates that adherence and implementation of monitoring protocols should be crucially improved in psychiatric outpatients in secondary care.

Sleep problems are very common in individuals with a mental disorder. Given the abundant evidence indicating the negative impact of disturbed sleep on mental health outcome, insight into the prevalence of all types of sleep disorders in specific mental disorders and neurodevelopmental conditions is of practical importance. Therefore, we estimated the prevalence of six types of sleep disorders with the Holland Sleep Disorders Questionnaire in an overall mental health sample (n = 1082) and separately for different mental and neurodevelopmental conditions. Furthermore, associations between specific sleep disorders, psychopathology and well-being were studied. The impact of the total number of sleep disorders on these associations was examined. Overall, 46.2% of all participants scored above the cut-off for having a sleep disorder. Specifically, 26.8% scored on insomnia, 12.1% on sleep breathing disorders, 9.7% on hypersomnia, 13.7% on circadian rhythm sleep-wake disorders, 11.2% on parasomnia, and 17.9% on sleep-related movement disorders. Most sleep disorders were associated with greater severity of psychopathology and lower well-being. These associations got stronger with an increasing number of sleep disorders. Our study revealed higher suspected prevalence of most sleep disorders in a mental disorder sample compared to the general population. Moreover, the presence of sleep disorder(s) was strongly associated with symptom severity and reduced well-being. These findings extend the notion that early detection and treatment of sleep disorders in mental health populations is essential for psychiatric outcome.

Schizophrenia spectrum disorders (SSD) are complex mental disorders, and while treatment with antipsychotics is important, many patients do not respond or develop serious side effects. Genetic variation has been shown to play a considerable role in determining an individual’s response to antipsychotic medication. However, previous pharmacogenetic (PGx) studies have been limited by small sample sizes, lack of consensus regarding relevant genetic variants, and cross-sectional designs. The current study aimed to investigate the association between PGx variants and long-term clinical outcomes in 691 patients of European ancestry with SSD. Using evidence from the literature on candidate genes involved in antipsychotic pharmacodynamics, we created a polygenic risk score (PRS) to investigate its association with clinical outcomes. We also created PRS using core variants of psychotropic drug metabolism enzymes CYP2D6 and CYP2C19. Furthermore, the CYP2D6 and CYP2C19 functional activity scores were calculated to determine the relationship between metabolism and clinical outcomes. We found no association for PGx PRSs and clinical outcomes; however, an association was found with CYP2D6 activity scores by the traditional method. Higher CYP2D6 metabolism was associated with high positive and high cognitive impairment groups relative to low symptom severity groups. These findings highlight the need to test PGx efficacy with different symptom domains. More evidence is needed before pharmacogenetic variation can contribute to personalized treatment plans.

RATIONALE:Preclinical research suggests that pharmacologically elevating cannabinoid levels may attenuate fear memory expression and enhance fear extinction.OBJECTIVES:We studied the effects of cannabidiol (CBD) on fear memory expression and fear re-extinction in 69 patients with panic disorder with agoraphobia or with social anxiety disorder. Moderation by sex, diagnosis, and serotonergic antidepressant (AD) use was explored.METHODS:A cued fear conditioning paradigm was applied before the first treatment session with 300 mg CBD/placebo augmented exposure therapy. Study medication was administered orally preceding 8 weekly sessions. Fear acquisition and suboptimal extinction took place prior to the first medication ingestion (T0). After the first medication ingestion (T1), we investigated effects on fear memory expression at retention and fear re-extinction. Subjective fear, shock expectancy, skin conductance, and startle responses to conditioned (CS+) and safety stimulus (CS-) were measured.RESULTS:Across the sample, CBD reduced shock expectancy at retention under low and ambiguous threat of shock, but fear re-extinction at T1 was unaffected by CBD. However, in AD users, re-extinction of subjective fear was impaired in the CBD condition compared to placebo. In female AD users, CBD interfered with safety learning measured with fear-potentiated startle.CONCLUSIONS:The current findings provide no evidence for enhanced fear re-extinction by CBD. However, CBD acutely decreased threat expectation at retention, without affecting other indices of fear. More studies are needed to elucidate possible interactions with AD use and sex, as well as potential effects of CBD on threat expectancies.