Effect of CYP2D6 genetic variation on patient-reported symptom improvement and side effects among children and adolescents treated with amphetamines.

OBJECTIVES: Amphetamine-based medications are recommended as a first-line pharmacotherapy for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. However, the efficacy and tolerability of these medications vary across individuals, which could be related to interindividual differences in amphetamine metabolism. This study examined if genotype-predicted phenotypes of the cytochrome P450 isozyme CYP2D6 were associated with self-reported side effects and symptom improvement in youth treated with amphetamines. METHODS: Two hundred fourteen participants aged 6-24 who had a history of past or current amphetamine treatment were enrolled from Western Canada. Amphetamine dose and duration information was collected from the participants along with questions regarding adherence, concomitant medications, symptom improvement and side effects. DNA was extracted from saliva samples and genotyped for CYP2D6 . Binomial logistic regression models were used to determine the effect of CYP2D6 metabolizer phenotype with and without correction for phenoconversion on self-reported symptom improvement and side effects. RESULTS: Genotype-predicted CYP2D6 poor metabolizers had significantly higher odds of reporting symptom improvement when compared to intermediate metabolizers (OR = 3.67, 95% CI = 1.15-11.7, P  = 0.029) after correction for phenoconversion and adjusting for sex, age, dose, duration, and adherence. There was no association between CYP2D6 metabolizer phenotype and self-reported side effects. CONCLUSION: Our findings indicate that phenoconverted and genotype-predicted CYP2D6 poor metabolizer phenotype is significantly associated with higher odds of symptom improvement in children and adolescents treated with amphetamine. If replicated, these results could inform the development of future dosing guidelines for amphetamine treatment in children and adolescents.

Impact of Cytochrome P450 Genetic Variation on Patient-Reported Symptom Improvement and Side Effects Among Children and Adolescents Treated with Fluoxetine.

Background: Clinical practice guidelines recommend the use of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), as a first-line pharmacotherapy for major depressive disorder (MDD) and obsessive compulsive disorder (OCD) in children and adolescents. However, response and tolerability to fluoxetine varies from child to child, which may in part, be a result of interindividual differences in fluoxetine metabolism. In this study, we examined whether genotype-predicted activity scores of cytochrome P450 enzymes were associated with patient-reported symptom improvement and side effects in children and adolescents treated with fluoxetine. Methods: Ninety children and adolescents aged 7-18 with a MDD or OCD diagnosis and a history of fluoxetine treatment were recruited from Western Canada. For each participant, fluoxetine dose and duration information were collected, as well as questions about adherence, side effects, and symptom improvement. DNA was extracted from a saliva sample and genotyped for CYP2D6, CYP2C19, CYP2C9, CYP3A4, and CYP3A5. Logistic regression models were fitted to assess the impact of activity scores on symptom improvement and side effects. Results: Increased CYP2D6 activity score was significantly associated with reduced odds of symptom improvement (odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.23-0.91, p = 0.028) as well as a trend association with reduced side effects (OR = 0.49, 95% CI = 0.22-1.07, p = 0.072), after adjusting for age, sex, diagnosis, dose, duration, adherence, and activity scores of the other assessed CYP enzymes. No associations with symptom improvement or side effects were detected for the other CYP enzymes examined. Conclusions: Our results suggest that an increase in the genotype-predicted CYP2D6 activity score was associated with a decrease in the odds of reporting symptom improvement among children and adolescents treated with fluoxetine. These findings will contribute to future updates of pharmacogenetic-based SSRI prescribing guidelines and if replicated, could inform fluoxetine treatment in children and adolescents with MDD or OCD. Clinical Trial Registration: NCT04797364.

The genetic architecture of youth anxiety: a study protocol.

BACKGROUND: Anxiety disorders are the most common psychiatric problems among Canadian youth and typically have an onset in childhood or adolescence. They are characterized by high rates of relapse and chronicity, often resulting in substantial impairment across the lifespan. Genetic factors play an important role in the vulnerability toward anxiety disorders. However, genetic contribution to anxiety in youth is not well understood and can change across developmental stages. Large-scale genetic studies of youth are needed with detailed assessments of symptoms of anxiety disorders and their major comorbidities to inform early intervention or preventative strategies and suggest novel targets for therapeutics and personalization of care. METHODS: The Genetic Architecture of Youth Anxiety (GAYA) study is a Pan-Canadian effort of clinical and genetic experts with specific recruitment sites in Calgary, Halifax, Hamilton, Toronto, and Vancouver. Youth aged 10-19 (n = 13,000) will be recruited from both clinical and community settings and will provide saliva samples, complete online questionnaires on demographics, symptoms of mental health concerns, and behavioural inhibition, and complete neurocognitive tasks. A subset of youth will be offered access to a self-managed Internet-based cognitive behavioral therapy resource. Analyses will focus on the identification of novel genetic risk loci for anxiety disorders in youth and assess how much of the genetic risk for anxiety disorders is unique or shared across the life span. DISCUSSION: Results will substantially inform early intervention or preventative strategies and suggest novel targets for therapeutics and personalization of care. Given that the GAYA study will be the biggest genomic study of anxiety disorders in youth in Canada, this project will further foster collaborations nationally and across the world.

Accelerated sequential bilateral theta-burst stimulation in major depression: an open trial.

Theta burst stimulation (TBS) is approved and widely used in the treatment of treatment resistant-major depression. More recently, accelerated protocols delivering multiple treatments per day have been shown to be efficacious and potentially enhance outcomes compared to once daily protocols. Meanwhile, bilateral treatment protocols have also been increasingly tested to enhance outcomes. Here, we examined the efficacy and safety of accelerated bilateral TBS in major depressive disorder (MDD). In this open label pilot study, 25 patients with MDD (60%: women; mean age (SD): 45.24 (12.22)) resistant to at least one antidepressant, received bilateral TBS, consisting of 5 sequential bilateral intermittent TBS (iTBS) (600 pulses) and continuous TBS (cTBS) (600 pulses) treatments delivered to the left and right dorsolateral prefrontal cortex (DLPFC), respectively, daily for 5 days at 120% resting motor threshold. Outcome measures were post-treat treatment changes at day 5 and 2-weeks in Hamilton Depression Rating Scale (HDRS-17) scores and response (≥ 50% reduction from the baseline scores) and remission (≤ 7) rates. There was a significant reduction in HDRS scores at day 5 (p < 0.001) and 2-weeks post treatment (p < 0.001). The response rates increased from 20% at day 5 to 32% at 2-weeks post treatment suggesting delayed clinical effects. However, reduction in symptom scores between two post treatment endpoints was non-significant. 60% of patients could not tolerate the high intensity stimulation. No major adverse events occurred. Open label uncontrolled study with small sample size. These preliminary findings suggest that accelerated bilateral TBS may be clinically effective and safe for treatment resistant depression. Randomized sham-controlled trials are needed to establish the therapeutic role of accelerated bilateral TBS in depression.Trial registration: ClinicalTrials.gov, NCT10001858.

Personal recovery associated with deep brain stimulation for treatment-resistant depression: A constructivist grounded theory study.

WHAT IS KNOWN ON THE SUBJECT?: Major depressive disorder is the most prevalent of all mental illnesses. 10%-20% of patients with depression and 1% of the population overall have treatment-resistant depression (TRD). DBS is an emerging investigational treatment for TRD with documented clinical efficacy and safety. The framework of the recovery model includes both clinical and personal recovery. Personal recovery is a self-process in which hope, empowerment and optimism are embraced to overcome the impact of mental illness on one's sense of self. Although clinical and functional outcomes of DBS for TRD have been well documented in the previous studies, personal recovery as an outcome has been explored only in a handful of studies. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This is the first qualitative study exploring personal recovery from DBS treatment specific to the target of subcallosal cingulate cortex in patients with TRD. Since the existing literature on personal recovery in DBS studies is limited, the contribution of this paper is crucial to this field. For individuals who responded to deep brain stimulation clinically, neither participants nor family believed it cured their depression, but rather there was a significant decrease in the severity of symptoms of depression. A holistic-oriented framework (that includes personal recovery) is significant for those individuals with TRD undergoing DBS. Personal and clinical recovery are two different constructs, and individuals may experience one or the other or both. The experience of participants who responded to deep brain stimulation recognized that the recovery from depression is a process of reconstructing self. This process involved a period of adjustment that evoked a deeper self-awareness, re-engagement with daily living and newfound gratitude in living. Individuals transitioned from an emotionally driven life to one where future goals were considered. Supportive relationships were instrumental in this process. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: A deep brain stimulation intervention for treatment-resistant depression offered individuals an opportunity for personal recovery where a reconstruction of self occurred. Personal recovery can be considered as an outcome in conjunction with clinical and functional outcomes in future DBS trials for TRD. The relevance of personal recovery in the prevention of relapses needs further investigation. To advocate for care and services that facilitate the process of recovery from depression, it is important to understand the personal dimensions and experience of recovery that may influence the process. To develop recovery-oriented interventions to help patients and families in recovery post-deep brain stimulation, further understanding of support and negotiating relationships during this life-altering experience is needed. ABSTRACT: Introduction Multiple trials of antidepressant treatments in patients with depression pose a major challenge to the mental health system. Deep brain stimulation (DBS) is an emerging and promising investigational treatment to reduce depressive symptoms in individuals with treatment-resistant depression (TRD). The clinical and functional outcomes of DBS for TRD have been well documented in previous studies; however, studies of personal recovery as an outcome of DBS specific to the target of subcallosal cingulate cortex in patients with TRD are limited. Aim To explore the processes of personal recovery in patients with treatment-resistant depression following subcallosal cingulate-deep brain stimulation. Method Participants were 18 patients with TRD who participated in the subcallosal cingulate (SCC)-DBS trial and 11 family members. They also participated in add-on individual cognitive behavioural therapy during the trial. A qualitative constructivist grounded theory approach was used to conceptualize the personal recovery process of patients and families. Results While every participant and their families' journey were unique following the deep brain stimulation intervention, a theoretical model of Balancing to Establish a Reconstructed Self emerged from the data. The themes underlying the model were (1) Balancing to Establish a Reconstructed Self: A Whole-Body Experience, (2) The Liminal Space in-between: Balancing with Cautious Optimism, (3) Hope: Transitioning from Emotion-Focussed Living to Goal-Oriented Planning and (4) Support: Negotiating Relationships. Discussion This is the first study examining recovery from patients' perspectives as an outcome of SCC-DBS intervention for TRD. The study shows that personal recovery is a gradual and continual process of reconstruction of the self, developing through supportive relationships. Clinical and personal recovery are two distinct constructs, and individuals may experience one or the other or both. Most patients who do respond clinically experience improvement in terms of having optimism and hope. Some patients, however, respond with significant symptom reduction but are not able to achieve personal recovery to experience joy or hope for improved quality of living. Implications for Practice Strategies for personal recovery for both patients and family need to be considered during and post deep brain stimulation intervention. Nurses working with these patients and families may benefit from education, training and support to assess and engage in conversations about their recovery process.

High-resolution virtual brain modeling personalizes deep brain stimulation for treatment-resistant depression: Spatiotemporal response characteristics following stimulation of neural fiber pathways.

Over the past 15 years, deep brain stimulation (DBS) has been actively investigated as a groundbreaking therapy for patients with treatment-resistant depression (TRD); nevertheless, outcomes have varied from patient to patient, with an average response rate of ∼50%. The engagement of specific fiber tracts at the stimulation site has been hypothesized to be an important factor in determining outcomes, however, the resulting individual network effects at the whole-brain scale remain largely unknown. Here we provide a computational framework that can explore each individual's brain response characteristics elicited by selective stimulation of fiber tracts. We use a novel personalized in-silico approach, the Virtual Big Brain, which makes use of high-resolution virtual brain models at a mm-scale and explicitly reconstructs more than 100,000 fiber tracts for each individual. Each fiber tract is active and can be selectively stimulated. Simulation results demonstrate distinct stimulus-induced event-related potentials as a function of stimulation location, parametrized by the contact positions of the electrodes implanted in each patient, even though validation against empirical patient data reveals some limitations (i.e., the need for individual parameter adjustment, and differential accuracy across stimulation locations). This study provides evidence for the capacity of personalized high-resolution virtual brain models to investigate individual network effects in DBS for patients with TRD and opens up novel avenues in the personalized optimization of brain stimulation.

Personality changes with subcallosal cingulate deep brain stimulation in patients with treatment-resistant depression.

BACKGROUND: Deep brain stimulation (DBS) is a promising investigational approach for treatment-resistant depression. However, reports suggesting changes in personality with DBS for movement disorders have raised clinical and ethical concerns. We prospectively examined changes in personality dimensions and antidepressant response to subcallosal cingulate (SCC)-DBS for treatment-resistant depression. METHODS: Twenty-two patients with treatment-resistant depression underwent SCC-DBS. We used the NEO Five-Factor Inventory for personality assessment at baseline and every 3 months until 15 months post-DBS. We assessed depression severity monthly using the Hamilton Depression Rating Scale. RESULTS: We found a significant decrease in neuroticism (p = 0.002) and an increase in extraversion (p = 0.001) over time, showing a change toward normative data. Improvement on the Hamilton Depression Rating Scale was correlated with decreases in neuroticism at 6 months (p = 0.001) and 12 months (p < 0.001), and with an increase in extraversion at 12 months (p = 0.01). Changes on the Hamilton Depression Rating Scale over time had a significant covariate effect on neuroticism (p < 0.001) and extraversion (p = 0.001). Baseline openness and agreeableness predicted response to DBS at 6 (p = 0.006) and 12 months (p = 0.004), respectively. LIMITATIONS: Limitations included a small sample size, a lack of sham control and the use of subjective personality evaluation. CONCLUSION: We observed positive personality changes following SCC-DBS, with reduced neuroticism and increased extraversion related to clinical improvement in depression, suggesting a state effect. As well, pretreatment levels of openness and agreeableness may have predicted subsequent response to DBS. The NEO Five-Factor Inventory assessment may have a role in clinical decision-making and prognostic evaluation in patients with treatment-resistant depression who undergo SCC-DBS.

Biofeedback to treat anxiety in young people at clinical high risk for developing psychosis.

AIM: Anxiety is a common presenting concern for individuals at clinical high risk (CHR) for psychosis. Treatment for CHR is still in the early stages and has focused on transition to psychosis and positive symptom reduction, but little is known about what may be effective in reducing anxiety for these young people. One treatment that may be effective for anxiety is heart rate variability (HRV) biofeedback. The aim of this study was to test the efficacy and feasibility of using HRV biofeedback to reduce anxiety and distress in those at CHR. METHODS: Twenty participants who met minimum scores for anxiety and distress completed 4 weeks of an HRV biofeedback intervention and received pre- and post-intervention assessments. Repeated measures were used to examine changes in scores over time. RESULTS: There was a significant decrease in impaired ability to tolerate normal stressors (P ≤ 0.001) and dysphoric mood (P ≤ 0.001) over time. There was no change on self-reported measures of anxiety and distress. However, when two outliers were removed there was a trend towards improvement in self-reported anxiety (P = 0.07). These results were not impacted by including usage time as a covariate. Feedback and adherence were significant. CONCLUSIONS: HRV biofeedback may be a feasible treatment option for individuals at CHR who have concerns with impaired stress tolerance and dysphoric mood. Future studies with a randomized controlled trial design will be necessary to further determine efficacy.

Anxiety in youth at clinical high risk for psychosis.

AIM: High rates of anxiety have been observed in youth at clinical high risk (CHR) of developing psychosis. In CHR, anxiety often co-occurs with depression, and there is inconsistent evidence on anxiety in relation to transition to psychosis. The aim of this study was to examine: (i) the prevalence of anxiety disorders in individuals at CHR; (ii) clinical differences between those with and without anxiety; and (iii) the association of baseline anxiety with later transition to psychosis. METHODS: The sample consisted of 765 CHR individuals and 280 healthy controls. CHR status was determined with the Structured Interview of Prodromal Syndromes, mood and anxiety diagnoses with the Structured Clinical Interview for DSM-IV Disorders, and severity of anxiety with the Social Interaction Anxiety Scale and Self-Rating Anxiety Scale. RESULTS: In the CHR sample, 51% met criteria for an anxiety disorder. CHR participants had significantly more anxiety diagnoses and severity than healthy controls. Anxiety was correlated to attenuated psychotic and negative symptoms in CHR and those with an anxiety disorder demonstrated more suspiciousness. CHR participants with obsessive-compulsive disorder (OCD) exhibited more severe symptomatology than those without OCD. An initial presentation of anxiety did not differ between those who did or did not transition to psychosis. CONCLUSIONS: In this large sample of individuals at CHR, anxiety is common and associated with more severe attenuated psychotic symptoms. Treatment not only to prevent or delay transition to psychosis but also to address presenting concerns, such as anxiety, is warranted.