Pharmacogenomic Testing for Major Depression: A Qualitative Study of the Perceptions of People with Lived Experience and Professional Stakeholders.

OBJECTIVES: With increasing evidence for the clinical utility of pharmacogenomic (PGx) testing for depression, there is a growing need to consider issues related to the clinical implementation of this testing. The perspectives of key stakeholders (both people with lived experience [PWLE] and providers) are critical, but not frequently explored. The purpose of this study was to understand how PWLE and healthcare providers/policy experts (P/HCPs) perceive PGx testing for depression, to inform the consideration of clinical implementation within the healthcare system in British Columbia (BC), Canada. METHODS: We recruited two cohorts of participants to complete individual 1-h, semi-structured interviews: (a) PWLE, recruited from patient and research engagement networks and organizations and (b) P/HCPs, recruited via targeted invitation. Interviews were audiotaped, transcribed verbatim, de-identified, and analysed using interpretive description. RESULTS: Seventeen interviews were completed with PWLE (7 with experience of PGx testing for depression; 10 without); 15 interviews were completed with P/HCPs (family physicians, psychiatrists, nurses, pharmacists, genetic counsellors, medical geneticists, lab technologists, program directors, and insurers). Visual models of PWLE's and P/HCP's perceptions of and attitudes towards PGx testing were developed separately, but both were heavily influenced by participants' prior professional and/or personal experiences with depression and/or PGx testing. Both groups expressed a need for evidence and numerous considerations for the implementation of PGx testing in BC, including the requirement for conclusive economic analyses, patient and provider education, technological and clinical support, local testing facilities, and measures to ensure equitable access to testing. CONCLUSIONS: While hopeful about the potential for therapeutic benefit from PGx testing, PWLE and P/HCPs see the need for robust evidence of utility, and BC-wide infrastructure and policies to ensure equitable and effective access to PGx testing. Further research into the accessibility, effectiveness, and cost-effectiveness of various implementation strategies is needed to inform PGx testing use in BC.

Public values and guiding principles for implementing epitope compatibility in kidney transplantation allocation criteria: results from a Canadian online public deliberation.

BACKGROUND: Epitope compatibility in deceased donor kidney allocation is an emerging area of precision medicine (PM), seeking to improve compatibility between donor kidneys to transplant candidates in the hope of avoiding kidney rejection. Though the potential benefits of using epitope compatibility are promising, the implied modification of deceased organ allocation criteria requires consideration of significant clinical and ethical trade-offs. As a matter of public policy, these trade-offs should consider public values and preferences. We invited members of the Canadian public to participate in a deliberation about epitope compatibility in deceased donor kidney transplantation; to identify what is important to them and to provide recommendations to policymakers. METHODS: An online public deliberation was conducted with members of the Canadian public, in which participants were asked to construct recommendations for policymakers regarding the introduction of epitope compatibility to kidney allocation criteria. In the present paper, a qualitative analysis was conducted to identify the values reflected in participants' recommendations. All virtual sessions were recorded, transcribed, and analyzed using NVivo 12 software. RESULTS: Thirty-two participants constructed nine recommendations regarding the adoption of epitope compatibility into deceased donor kidney allocation. Five values were identified that drove participants' recommendations: Health Maximization, Protection/Mitigation of Negative Impacts, Fairness, Science/Evidence-based Healthcare, and Responsibility to Maintain Trust. Conflicts between these values were discussed in terms of operational principles that were required for epitope compatibility to be implemented in an acceptable manner: the needs for Flexibility, Accountability, Transparent Communication and a Transition Plan. All nine recommendations were informed by these four principles. Participant deliberations were often dominated by the conflict between Health Maximization and Fairness or Protection/Mitigation of Negative Impacts, which was discussed as the need for Flexibility. Two additional values (Efficient Use of Resources and Logic/Rationality) were also discussed and were reasons for some participants voting against some recommendations. CONCLUSIONS: Public recommendations indicate support for using epitope compatibility in deceased donor kidney allocation. A flexible approach to organ allocation decision-making may allow for the balancing of Health Maximization against maintaining Fairness and Mitigating Negative Impacts. Flexibility is particularly important in the context of epitope compatibility and other PM initiatives where evidence is still emerging.

Development and evaluation of an educational resource for parents of children with 22q11.2 deletion syndrome about the psychiatric manifestations of the condition.

Parents of children with 22q11.2 deletion syndrome (22q11DS) report concern about the psychiatric manifestations of the condition, but typically receive little information about this in clinical encounters and instead find information about it elsewhere. We developed an educational booklet about the psychiatric manifestations of 22q11DS and assessed its utility among parents of children with the condition. First, six parents of individuals with 22q11DS completed cognitive interviews to review an established generic booklet about the genetics of psychiatric conditions-and to suggest 22q11DS-specific adaptations. We used these suggestions to develop a novel booklet specific to psychiatric conditions and 22q1DS. Then, before and 1-month after reading the novel 22q11DS-specific online booklet, 73 parents of children with 22q11DS (with/without psychiatric conditions) completed validated scales (measuring empowerment, stigma, intolerance of uncertainty), an adapted version of a scale measuring worry about their child developing psychiatric illness, and purpose-designed items assessing perceptions of understanding of 22q11DS and mental illness, confidence in recognizing early signs, etc. After reading the 22q11DS online booklet, participants' feelings of empowerment increased (p = 0.002), while feelings of worry about their child developing psychiatric illness decreased (p = 0.05), and they reported better understanding 22q11DS and mental illness, and increased confidence in recognizing early warning signs. There is potential benefit in broadly distributing this educational booklet to parents of children with 22q11DS.

A cross-sectional study of the relationship between CYP2D6 and CYP2C19 variations and depression symptoms, for women taking SSRIs during pregnancy.

Depression during pregnancy affects 10-15% of women, and 5% of women take antidepressants during pregnancy. Clinical guidelines provide recommendations for selective serotonin reuptake inhibitor (SSRI) drug choice and dose based on CYP2D6 and CYP2C19 genotype; however, they are based on evidence from non-pregnant cohorts. This study aimed to test the hypothesis that women with function-altering variants (increased, decreased, or no function) in these pharmacogenes, taking SSRIs prenatally, would have more depression symptoms than women whose pharmacogenetic variants are associated with normal SSRI metabolism. Comprehensive CYP2D6 and CYP2C19 genotyping using a range of methods, including gene copy number analysis, was performed as secondary analyses on two longitudinal cohorts of pregnant women (N = 83) taking the SSRIs paroxetine, citalopram, escitalopram, or sertraline. The Kruskal-Wallis test compared mean depression scores across four predicted metabolizer groups: poor (n = 5), intermediate (n = 10), normal (n = 53), and ultrarapid (n = 15). There were no significant differences between mean depression scores across the four metabolizer groups (H(3) = .73, p = .87, eta-squared = .029, epsilon-squared = .0089). This is the first study of the relationship in pregnancy between CYP2C19 pharmacogenetic variations and depression symptoms in the context of SSRI use. Findings from this initial study do not support the clinical use of pharmacogenetic testing for SSRI use during the second or third trimesters of pregnancy, but these findings should be confirmed in larger cohorts. There is an urgent need for further research to clarify the utility of pharmacogenetic testing for pregnant women, especially as companies offering direct-to-consumer genetic testing expand their marketing efforts.

Reflections of parents of children with 22q11.2 Deletion Syndrome on the experience of receiving psychiatric genetic counseling: 'Awareness to Act'.

Individuals with 22q11.2 deletion syndrome (22qDS) have a 25%-41% risk for a psychotic disorder. Although early intervention for psychiatric conditions leads to the best long-term outcomes, healthcare providers often provide inadequate information about these issues and psychiatric services are underused by this population. We conducted semi-structured interviews with parents of children with 22qDS a month after they received psychiatric genetic counseling (pGC), to evaluate outcomes and perceived value of pGC with respect to parents' needs. Using grounded theory, we generated a theoretical framework of the process of building parental awareness of psychiatric risks associated with 22qDS and protective and management strategies for mental health (MH). Parents described how after their child's diagnosis with 22qDS, a variety of barriers stalled their building awareness of psychiatric risk and protective/management strategies: dealing with the immediate symptoms of 22qDS; child's young age; parental fear and stigma; and missing MH guidance. These barriers led them to carry the burden of worrying over missing emerging psychiatric symptoms and the stress over advocating for their child's MH. Parents indicated pGC was beneficial in that led them to achieve an 'awareness to act,' feeling confident in being alert and equipped to protect and/or manage their child's MH.

A Matched Cohort Study of Postpartum Placentophagy in Women With a History of Mood Disorders: No Evidence for Impact on Mood, Energy, Vitamin B12 Levels, or Lactation.

OBJECTIVE: Although empirical studies investigating its effects are scarce, postpartum placentophagy is increasing in popularity because of purported benefits on mood, energy, lactation, and overall nutrition. Therefore, this study sought to test the hypotheses that women who consumed their placenta (placentophagy exposed [PE]) would have (1) fewer depressive symptoms, (2) more energy, (3) higher vitamin B12 levels, and (4) less pharmaceutical lactation support during the postpartum than women who did not consume their placenta (non-placentophagy exposed [NE]). METHODS: Using data from a large, longitudinal study of gene × environment effects involving perinatal women with a history of mood disorders, the study investigators identified a PE cohort and matched them 4:1 (by psychiatric diagnosis, psychotropic medication use, supplementation, income, and age) with an NE cohort from the same dataset. The study investigated differences between the PE and NE cohorts with respect to scores on the Edinburgh Postnatal Depression Scale and Sleep-Wake Activity Inventory, vitamin B12 levels, and the use of pharmaceutical lactation support (Canadian Taskforce Classification II-2). RESULTS: The sample of 138 women (28 in the PE cohort, matched to 110 in the NE cohort) provided 80% power at α = 0.0125 to detect an effect of moderate magnitude (which can be used to approximate an effect of clinically significant magnitude).There were no differences in Edinburgh Postnatal Depression Scaleor Sleep-Wake Activity Inventory scales (P = 0.28 and P = 0.39, respectively), vitamin B12 levels (P = 0.68), or domperidone use (P = 1) between the PE and NE cohorts. CONCLUSION: These data provide no support for the idea that postpartum placentophagy improves mood, energy, lactation, or plasma vitamin B12 levels in women with a history of mood disorders.

Parents' perspectives, experiences, and need for support when communicating with their children about the psychiatric manifestations of 22q11.2 deletion syndrome (22q11DS).

OBJECTIVE: To develop a theoretical model to explain how parents think about the process of communicating with their affected child about the psychiatric manifestations of 22q11DS. METHODS: Semi-structured interviews were conducted with parents of children with 22q11DS, who had all received psychiatric genetic counseling. Interviews were recorded, transcribed verbatim, and analyzed concurrently with data collection, using interpretive description. Identified themes were used to inductively develop a model of how parents think about communicating with their child about psychiatric risk in 22q11DS. RESULTS: From interviews with 10 parents, we developed a model representing the communication of psychiatric risk in 22q11DS as a process where various dynamic contextual factors (e.g., perception of risk, desire to normalize) act as either motivators or barriers to communication. Parents described challenges with the content, process, and outcome of these conversations. Parents wanted hands on, practical, personalized, and ongoing support from health professionals around communication about these issues. CONCLUSION: This model may help equip genetics professionals to support parents to communicate effectively with their children in order to improve health outcomes and family adaptation to 22q11DS. PRACTICE IMPLICATIONS: Our findings may apply not only to 22q11DS, but also to other genetic conditions where psychiatric manifestations occur.

The stepwise process of integrating a genetic counsellor into primary care.

Genetic services have historically been housed in tertiary care, requiring referral, which can present access barriers. While integrating genetics into primary care could facilitate access, many primary care physicians lack genomics expertise. Integrating genetic counsellors (GCs) into primary care could theoretically address these issues, but little is known about how to do this effectively. To understand and describe the process of integrating a GC into a multidisciplinary primary care setting, we qualitatively explored the perceptions, attitudes and reactions of existing team members prior to, and after the introduction of a GC. Semi-structured interviews were conducted immediately prior to (T1), and 9 months after (T2), the GC joining the clinic. Interviews were recorded, transcribed verbatim and analyzed concurrently with data collection using interpretive description. Twenty-four interviews were conducted with 17 participants (13 at T1, 11 at T2). Participants described several distinct, progressive stages of interaction with the GC: Disinterest or Resistance, Pre-Collaboration, Initial Collaboration, and Effective Collaboration/Integration of the GC into the team. At each stage, specific needs had to be met in order to advance to the next stage of collaboration. A variety of barriers and facilitators attended movement between different stages of the model. The Stepwise Process of Integration Model describes the process through which primary care staff and clinicians integrate a GC into their practice. The insight provided by this model could be used to facilitate more effective integration of GCs into other primary care settings.

Psychiatric genetic counseling for serious mental illness: Impact on psychopathology and psychotropic medication adherence.

For people with serious mental illness (SMI) (schizophrenia, bipolar disorder, schizoaffective disorder), psychiatric genetic counseling (PGC) has been shown to significantly increase empowerment and illness management self-efficacy. While these outcomes are important, they are also theoretical precursors for behavior changes (e.g. improved medication adherence), and improved mental health. Therefore, we conducted the first study (repeated-measures/within-subjects design) to test the hypothesis that PGC would reduce psychiatric symptoms due to increased medication adherence. Between 2013-2018, we recruited N = 109 individuals (age 19-72) with SMI and administered the short Positive and Negative Syndrome Scale (short-PANSS) and Brief Adherence Rating Scale (BARS) at four timepoints; twice Pre-PGC (T1: 1-month Pre-PGC and T2: immediately Pre-PGC), to assess change in adherence/symptoms without any intervention (internal control condition), and twice Post-PGC (T3: 1-month and T4: 2-months Post-PGC), to assess impact of PGC. A quantile regression model investigated the relationships between short-PANSS, timepoints, and BARS. There was a significant relationship between short-PANSS and timepoints at the 75th (T4 short-PANSS scores < T1 and T2) and 90th quantiles (T4 short-PANSS scores < T2), but these results were not explained by improved medication adherence. PGC for SMI may reduce psychiatric symptoms, but confirmatory work and studies to examine mechanism are needed.

A prospective study to explore the relationship between MTHFR C677T genotype, physiological folate levels, and postpartum psychopathology in at-risk women.

BACKGROUND: The etiology of postpartum psychopathologies are not well understood, but folate metabolism pathways are of potential interest. Demands for folate increase dramatically during pregnancy, low folate level has been associated with psychiatric disorders, and supplementation may improve symptomatology. The MTHFR C677T variant influences folate metabolism and has been implicated in depression during pregnancy. OBJECTIVE: To conduct a prospective longitudinal study to explore the relationship between MTHFR C677T genotype, folate levels, and postpartum psychopathology in at-risk women. HYPOTHESIS: In the first three months postpartum, folate will moderate a relationship between MTHFR genotype and depression, with TT homozygous women having more symptoms than CC homozygous women. METHODS: We recruited 365 pregnant women with a history of mood or psychotic disorder, and at 3 postpartum timepoints, administered the Edinburgh Postnatal Depression Scale (EPDS); Clinician-Administered Rating Scale for Mania (CARS-M) and the Positive and Negative Symptom Scale (PANSS) and drew blood for genotype/folate level analysis. We used robust linear regression to investigate interactions between genotype and folate level on the highest EPDS and CARS-M scores, and logistic regression to explore interactions with PANSS psychosis scores above/below cut-off. RESULTS: There was no significant interaction effect between MTHFR genotype and folate level on highest EPDS (p = 0.36), but there was a significant interaction between genotype, folate level and log(CARS-M) (p = 0.02); post-hoc analyses revealed differences in the effect of folate level between CC/CT, and TT genotypes, with folate level in CC and CT having an inverse relationship with symptoms of mania, while there was no relationship in participants with TT genotype. There was no significant interaction between MTHFR genotype and folate level on the likelihood of meeting positive symptom criteria for psychosis on the PANSS (p = 0.86). DISCUSSION: These data suggest that perhaps there is a relationship between MTHFR C677T, folate level and some symptoms of postpartum psychopathology.

Associations between the LEP -2548G/A Promoter and Baseline Weight and between LEPR Gln223Arg and Lys656Asn Variants and Change in BMI z Scores in Arab Children and Adolescents Treated with Risperidone.

Data on baseline (antipsychotics-naïve) age, weight, and height, and change in these at 3 subsequent follow-up time points up to 313.6 days (95% CI 303.5-323.7) were collected from 181 risperidone-treated children and adolescents (mean age 12.58 years, SD 4.99, range 2.17-17.7) attending a pediatric neurology clinic in Saudi Arabia. Owing to differences in genotypic distributions in the subsamples, results are reported for the white Arab population (n = 144). Age- and gender-normed body mass index (BMI)-standardized z scores (BMI z) were calculated (LMSgrowth program). Linear regression was performed for baseline weight and BMI z, while change in BMI z was assessed using random effects ordered logistic regression. The following single nucleotide polymorphisms (SNPs) were analyzed: rs7799039 in the LEP promoter, rs1805094 (previously rs8179183), rs1137100 and rs1137101 in the LEPR, and rs1414334 in HTR2C. We found a nominally significant association between rs7799309 and baseline weight, adjusting for height, age, gender, and diagnosis (A/G, p = 0.035, ß = -3.62 vs. G/G). The rs1137101 (G/G, p = 0.018, odds ratio [OR] = 4.13 vs. A/A) and rs1805094 C allele carriers (p = 0.019, OR = 0.51) showed nominally significant associations with change in BMI z categories. Our data support and replicate previous relevant associations for these variants (including with weight gain when on risperidone), whilst being the first report of such associations in patients of Arab ethnicity.