Use of antidepressants with pharmacogenetic prescribing guidelines in a 10-year depression cohort of adult primary care patients.

OBJECTIVE: To describe the usage patterns of antidepressants with published CYP2D6- and CYP2C19-based prescribing guidelines among depressed primary care patients and estimate the proportion of patients taking antidepressants not recommended for them based on their CYP2C19 and CYP2D6 genotype-predicted metabolizer status. METHODS: Medication use and pharmacogenetic testing results were collected on 128 primary care patients enrolled in a 10-year depression cohort study. At each 12-month interval, we calculated the proportion of patients that: (1) reported use of one or more of the 13 antidepressant medications (i.e. amitriptyline, citalopram, escitalopram, clomipramine, desipramine, doxepin, fluvoxamine, imipramine, nortriptyline, paroxetine, sertraline, trimipramine, venlafaxine) with published CYP2D6- and CYP2C19-based prescribing guidelines, (2) were taking an antidepressant that was not recommended for them based on their CYP2C19 and CYP2D6 genotype-predicted metabolizer phenotype, and (3) switched medications from the previous 12-month interval. RESULTS: The annual proportion of individuals taking an antidepressant with a CYP2D6- and CYP2C19-based prescribing guidelines ranged from 45 to 84%. The proportion of participants that used an antidepressant that was not recommended for them, based on available CYP2D6 and CYP2C19 metabolizer phenotype, ranged from 18 to 29% and these individuals tended to switch medications more frequently (10%) compared to their counterparts taking medication aligned with their metabolizer phenotype (6%). CONCLUSION: One-quarter of primary care patients used an antidepressant that was not recommended for them based on CYP2D6- and CYP2C19-based prescribing guidelines and switching medications tended to be more common in this group. Studies to determine the impact of CYP2D6 and CYP2C19 genotyping on reducing gene-antidepressant mismatches are warranted.

Written plans: an overlooked mechanism to develop recovery-oriented primary care for depression?

There is a global shift to foster patient-centred and recovery-oriented mental health services. This has resulted from the expansion of how the concept of recovery is understood in mental health literature and practice. Recovery is now more than a return to function or reduction in symptoms; it is a subjective, individualised and multi-faceted experience. To date there has not been investigation of how recovery-oriented services can be translated and implemented into the primary mental health care system. This paper presents the results of a survey from a prospective cohort of primary care patients with probable depression about the importance of written plans to recover. The benefits of having a written plan to recover from depression, as outlined by the participants, were analysed using Leximancer software. The findings provide insights into how written plans may be an important mechanism for implementing a recovery-oriented primary mental health care system. We conclude that the benefits of a written plan provide insight into how patients conceptualise recovery.

Methylenetetrahydrofolate reductase (MTHFR) genetic variation and major depressive disorder prognosis: A five-year prospective cohort study of primary care attendees.

Methylenetetrahydrofolate reductase (MTHFR) genetic variation has been associated with the diagnosis of major depressive disorder (MDD) but no study to date has examined the effect MTHFR variation has on MDD prognosis. We sought to examine the prospective effects of two common MTHFR variants (C677T and A1298C) as well as seven haplotype-tagging single nucleotide polymorphisms (htSNPs) on MDD prognosis over a 5-year (60-month) period. Participants were 147 depressed primary care attendees enrolled in the Diagnosis, Management and Outcomes of Depression in Primary Care (diamond) prospective cohort study. Prognosis of MDD was measured using three methods: (1) DSM-IV criteria, (2) Primary Care Evaluation of Mental Disorders Patient Health Questionnaire-9 (PHQ-9), and (3) Center for Epidemiologic Studies Depression Scale (CESD). DSM-IV criteria for MDD was assessed using the Composite International Diagnostic Interview at baseline and 24, 36, 48, and 60 months post-baseline; whereas, PHQ-9 and CESD measures were employed at baseline and 12, 24, 36, 48, and 60 months post-baseline. Repeated measures analysis of variance showed that PHQ-9 symptom severity trajectories differed by C677T genotype (F = 3.34, df = 2,144, P = 0.038), with 677CC genotype showing the most severe symptom severity course over the 60 months of observation. Neither the A1298C polymorphism nor any of the htSNPs were associated with MDD prognosis regardless of measure used. Our results suggest that the MTHFR C677T polymorphism may serve as a marker for MDD prognosis pending independent replication.

Clinical efficacy of a Decision Support Tool (Link-me) to guide intensity of mental health care in primary practice: a pragmatic stratified randomised controlled trial.

BACKGROUND: The volume and heterogeneity of mental health problems that primary care patients present with is a substantial challenge for health systems, and both undertreatment and overtreatment are common. We developed Link-me, a patient-completed Decision Support Tool, to predict severity of depression or anxiety, identify priorities, and recommend interventions. In this study, we aimed to examine if Link-me reduces psychological distress among individuals predicted to have minimal/mild or severe symptoms of anxiety or depression. METHODS: In this pragmatic stratified randomised controlled trial, adults aged 18-75 years reporting depressive or anxiety symptoms or use of mental health medication were recruited from 23 general practices in Australia. Participants completed the Decision Support Tool and were classified into three prognostic groups (minimal/mild, moderate, severe), and those in the minimal/mild and severe groups were eligible for inclusion. Participants were individually and randomly assigned (1:1) by a computer-generated allocation sequence to receive either prognosis-matched care (intervention group) or usual care plus attention control (control group). Participants were not blinded but intervention providers were only notified of those allocated to the intervention group. Outcome assessment was blinded. The primary outcome was the difference in the change in scores between the intervention and control group, and within prognostic groups, on the 10-item Kessler Psychological Distress Scale at 6 months post randomisation. The trial was registered on the Australian and New Zealand Clinical Trials Registry, ACTRN12617001333303. OUTCOMES: Between Nov 21, 2017, and Oct 31, 2018, 24 616 patients were invited to complete the eligibility screening survey. 1671 of these patients were included and randomly assigned to either the intervention group (n=834) or the control group (n=837). Prognosis-matched care was associated with greater reductions in psychological distress than usual care plus attention control at 6 months (p=0·03), with a standardised mean difference (SMD) of -0·09 (95% CI -0·17 to -0·01). This reduction was also seen in the severe prognostic group (p=0·003), with a SMD of -0·26 (-0·43 to -0·09), but not in the minimal/mild group (p=0·73), with a SMD of 0·04 (-0·17 to 0·24). In the complier average causal effect analysis in the severe prognostic group, differences were larger among those who received some or all aspects of the intervention (SMD range -0·58 to -1·15). No serious adverse effects were recorded. INTERPRETATION: Prognosis-based matching of interventions reduces psychological distress in patients with anxiety or depressive symptoms, particularly in those with severe symptoms, and is associated with better outcomes when patients access the recommended treatment. Optimisation of the Link-me approach and implementation into routine practice could help reduce the burden of disease associated with common mental health conditions such as anxiety and depression. FUNDING: Australian Government Department of Health.

The assertive cardiac care trial: A randomised controlled trial of a coproduced assertive cardiac care intervention to reduce absolute cardiovascular disease risk in people with severe mental illness in the primary care setting.

BACKGROUND: Cardiovascular disease (CVD) accounts for 40% of the excess mortality identified in people with severe mental illness (SMI). Modifiable CVD risk factors are higher and can be exacerbated by the cardiometabolic impact of psychotropic medications. People with SMI frequently attend primary care presenting a valuable opportunity for early identification, prevention and management of cardiovascular health. The ACCT Healthy Hearts Study will test a coproduced, nurse-led intervention delivered with general practitioners to reduce absolute CVD risk (ACVDR) at 12 months compared with an active control group. METHODS/DESIGN: ACCT is a two group (intervention/active control) individually randomised (1:1) controlled trial (RCT). Assessments will be completed baseline (pre-randomisation), 6 months, and 12 months. The primary outcome is 5-year ACVDR measured at 12 months. Secondary outcomes include 6-month ACVDR; and blood pressure, lipids, HbA1c, BMI, quality of life, physical activity, motivation to change health behaviour, medication adherence, alcohol use and hospitalisation at 6 and 12 months. Linear mixed-effects regression will estimate mean difference between groups for primary and secondary continuous outcomes. Economic cost-consequences analysis will be conducted using quality of life and health resource use information and routinely collected government health service use and medication data. A parallel process evaluation will investigate implementation of the intervention, uptake and outcomes. DISCUSSION: ACCT will deliver a coproduced and person-centred, guideline level cardiovascular primary care intervention to a high need population with SMI. If successful, the intervention could lead to the reduction of the mortality gap and increase opportunities for meaningful social and economic participation. Trial registration ANZCTR Trial number: ACTRN12619001112156.

Polygenic phenotypic plasticity moderates the effects of severe childhood abuse on depressive symptom severity in adulthood: A 5-year prospective cohort study.

Objective To test the phenotypic plasticity framework using a polygenic approach in a prospective depression cohort of primary care attendees with and without histories of severe childhood abuse. Methods Depressive symptoms were assessed at baseline and annually for 5 years post-baseline using the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire-9 (PHQ-9) among 288 adult primary care attendees. Twelve polymorphisms in nine genes were genotyped and polygenic phenotypic plasticity allelic load (PAL) calculated. Linear mixed models assessed differences in depressive symptom severity over the 5-year follow-up period by PAL and history of severe childhood abuse. Results A higher PAL conferred greater depressive symptom severity among those with a history of severe childhood abuse but conferred significantly lower symptom severity among those without this history. Importantly, this interaction withstood adjustments for important covariates (e.g., antidepressant use, comorbid anxiety) and was stable over the 5 years of observation. Conclusions Aligned with the phenotypic plasticity framework, depressive symptom severity was dependent on the interaction between PAL and history of severe childhood abuse in a "for better and for worse" manner. Measures of polygenic phenotypic plasticity, such as ours, may serve as a trait marker of sensitivity to negative and potentially positive environmental influences.

The Brain-Derived Neurotrophic Factor Val66Met Polymorphism Moderates the Effects of Childhood Abuse on Severity of Depressive Symptoms in a Time-Dependent Manner.

Cross-sectional studies have demonstrated that the brain-derived neurotrophic factor (BDNF) Val66Met single-nucleotide polymorphism moderates the association between exposure to negative life events and depression outcomes. Yet, it is currently unclear whether this moderating effect is applicable to positive life events and if the moderating effect is stable over time. To address these gaps in the literature, we examined clinical and BDNF genotypic data from a 5-year prospective cohort of 310 primary care attendees. Primary care attendees were selected based on existence of depressive symptoms at screening. Depressive symptoms were assessed at baseline and annually for 5 years post-baseline using the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire-9 (PHQ-9). Linear mixed models assessed differences in depressive symptom severity over the 5-year follow-up period by BDNF Val66Met and history of life events, both negative and positive. Analysis identified a novel three-way interaction between the BDNF Val66Met polymorphism, history of severe childhood abuse, and time. Post hoc analysis stratified by time showed a two-way interaction between Val66Met and severe childhood abuse at baseline that was not detectable at any other time point. An interaction between Val66Met and positive life events was not detected. Our longitudinal results suggest that the BDNF Val66Met polymorphism moderates the depressive symptom severity experienced by those with a history of severe childhood abuse but does so in a time-dependent manner. Our results further support the notion that gene-environment-depression interactions are dynamic and highlight the importance of longitudinal assessment of these interactions. Given these novel longitudinal findings; replication is required.

Serotonin transporter polymorphism (5HTTLPR), severe childhood abuse and depressive symptom trajectories in adulthood.

BACKGROUND: Cross-sectional studies suggest that the serotonin transporter promoter region polymorphism (5-HTT gene-linked polymorphic region, 5HTTLPR) moderates the relationship between childhood abuse and major depressive disorder. AIMS: To examine whether the 5HTTLPR polymorphism moderates the effect childhood abuse has on 5-year depressive symptom severity trajectories in adulthood. METHOD: At 5-year follow-up, DNA from 333 adult primary care attendees was obtained and genotyped for the 5HTTLPR polymorphism. Linear mixed models were used to test for a genotype × childhood abuse interaction effect on 5-year depressive symptom severity trajectories. RESULTS: After covariate adjustment, homozygous s allele carriers with a history of severe childhood abuse had significantly greater depressive symptom severity at baseline compared with those without a history of severe childhood abuse and this effect persisted throughout the 5-year period of observation. CONCLUSIONS: The 5HTTLPR s/s genotype robustly moderates the effects of severe childhood abuse on depressive symptom severity trajectories in adulthood. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

The CORE study protocol: a stepped wedge cluster randomised controlled trial to test a co-design technique to optimise psychosocial recovery outcomes for people affected by mental illness in the community mental health setting.

INTRODUCTION: User engagement in mental health service design is heralded as integral to health systems quality and performance, but does engagement improve health outcomes? This article describes the CORE study protocol, a novel stepped wedge cluster randomised controlled trial (SWCRCT) to improve psychosocial recovery outcomes for people with severe mental illness. METHODS: An SWCRCT with a nested process evaluation will be conducted over nearly 4 years in Victoria, Australia. 11 teams from four mental health service providers will be randomly allocated to one of three dates 9 months apart to start the intervention. The intervention, a modified version of Mental Health Experience Co-Design (MH ECO), will be delivered to 30 service users, 30 carers and 10 staff in each cluster. Outcome data will be collected at baseline (6 months) and at completion of each intervention wave. The primary outcome is improvement in recovery score using the 24-item Revised Recovery Assessment Scale for service users. Secondary outcomes are improvements to user and carer mental health and well-being using the shortened 8-item version of the WHOQOL Quality of Life scale (EUROHIS), changes to staff attitudes using the 19-item Staff Attitudes to Recovery Scale and recovery orientation of services using the 36-item Recovery Self Assessment Scale (provider version). Intervention and usual care periods will be compared using a linear mixed effects model for continuous outcomes and a generalised linear mixed effects model for binary outcomes. Participants will be analysed in the group that the cluster was assigned to at each time point. ETHICS AND DISSEMINATION: The University of Melbourne, Human Research Ethics Committee (1340299.3) and the Federal and State Departments of Health Committees (Project 20/2014) granted ethics approval. Baseline data results will be reported in 2015 and outcomes data in 2017. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry ACTRN12614000457640.

G-protein ß3 subunit genetic variation moderates five-year depressive symptom trajectories of primary care attendees.

BACKGROUND: Genetic variation in the G-protein ß3 subunit (GNB3) has previously been associated with gene splicing that has been further linked to increased signal transduction and major depressive disorder. However, the effect of GNB3 genetic variation on depressive symptom trajectories is currently unknown. The aim of the present study is to examine whether genetic variation in GNB3 moderates depressive symptom trajectories among 301 primary care attendees enrolled in the Diagnosis, Management and Outcomes of Depression in Primary Care (diamond) prospective cohort study. METHODS: Depressive symptoms were assessed using three measures: (1) DSM-IV criteria, (2) Primary Care Evaluation of Mental Disorders Patient Health Questionnaire-9 (PHQ-9), and (3) Center for Epidemiologic Studies Depression Scale (CESD). DSM-IV criteria were measured at baseline, 24, 36, 48, and 60 months post-baseline, whereas, PHQ-9 and CESD measurements were taken at baseline, 12, 24, 36, 48, and 60 months post-baseline. Two haplotype-tagging single nucleotide polymorphisms [rs5443 (C825T) and rs5440] spanning the GNB3 gene including ~1Kb upstream and downstream of the gene boundaries were genotyped. RESULTS: Five-year PHQ-9 and CESD depressive symptom trajectories were moderated by rs5440. Carriers of the rs5440 GG genotype had more favourable depressive symptom trajectories compared to AG or AA genotype carriers. The rs5443 polymorphism did not moderate depressive symptom trajectories, regardless of the measure used. LIMITATIONS: Generalizability to depressed populations outside of the primary care setting may be limited. CONCLUSIONS: These results provide novel evidence suggesting genetic variation in the 5-prime region of GNB3 moderates depressive symptom trajectories among primary care attendees.

Resilience as a response to the stigma of depression: a mixed methods analysis.

BACKGROUND: Stigma has been shown to have a significant influence on help-seeking, adherence to treatment and social opportunities for those experiencing depression. There is a need for studies which examine how the stigma of depression intersects with responses to depression. METHODS: 161 telephone interviews with people experiencing depressive symptoms, derived from a longitudinal cohort study, were sampled on the basis of their perceptions of stigma around depression. Interview transcripts were searched for references to stigma and analysed thematically. The frequency of the themes was calculated and cross-referenced, producing a meta-theme matrix. RESULTS: Stigma was closely linked to ideas about responsibility for causation and/or continuation of depressive symptoms. Stigmatized individuals felt compelled to take steps to develop their resilience including drawing on existing support networks and expanding on positive emotions and personal strengths in order to counteract this stigma. However, such strategies were burdensome for some. These participants gained relief from relinquishing their personal responsibility. LIMITATIONS: The data were briefer than many interview studies. This narrowed its interpretation, but allowed a large sample of participants. CONCLUSIONS: When considering how to tailor therapies for those experiencing depressive symptoms, health professionals should consider the interaction of stigma with coping strategies. Many individuals can build on existing relationships and personal strengths to develop resilience, some however need to first relinquish the expectation of having sufficient pre-existing resilience within themselves.

Embedding effective depression care: using theory for primary care organisational and systems change.

BACKGROUND: Depression and related disorders represent a significant part of general practitioners (GPs) daily work. Implementing the evidence about what works for depression care into routine practice presents a challenge for researchers and service designers. The emerging consensus is that the transfer of efficacious interventions into routine practice is strongly linked to how well the interventions are based upon theory and take into account the contextual factors of the setting into which they are to be transferred. We set out to develop a conceptual framework to guide change and the implementation of best practice depression care in the primary care setting. METHODS: We used a mixed method, observational approach to gather data about routine depression care in a range of primary care settings via: audit of electronic health records; observation of routine clinical care; and structured, facilitated whole of organisation meetings. Audit data were summarised using simple descriptive statistics. Observational data were collected using field notes. Organisational meetings were audio taped and transcribed. All the data sets were grouped, by organisation, and considered as a whole case. Normalisation Process Theory (NPT) was identified as an analytical theory to guide the conceptual framework development. RESULTS: Five privately owned primary care organisations (general practices) and one community health centre took part over the course of 18 months. We successfully developed a conceptual framework for implementing an effective model of depression care based on the four constructs of NPT: coherence, which proposes that depression work requires the conceptualisation of boundaries of who is depressed and who is not depressed and techniques for dealing with diffuseness; cognitive participation, which proposes that depression work requires engagement with a shared set of techniques that deal with depression as a health problem; collective action, which proposes that agreement is reached about how care is organised; and reflexive monitoring, which proposes that depression work requires agreement about how depression work will be monitored at the patient and practice level. We describe how these constructs can be used to guide the design and implementation of effective depression care in a way that can take account of contextual differences. CONCLUSIONS: Ideas about what is required for an effective model and system of depression care in primary care need to be accompanied by theoretically informed frameworks that consider how these can be implemented. The conceptual framework we have presented can be used to guide organisational and system change to develop common language around each construct between policy makers, service users, professionals, and researchers. This shared understanding across groups is fundamental to the effective implementation of change in primary care for depression.

How do Australian patients rate their general practitioner? A descriptive study using the General Practice Assessment Questionnaire.

OBJECTIVE: To report patient responses to the General Practice Assessment Questionnaire (GPAQ) as a measure of satisfaction with health care received from Australian general practitioners. DESIGN, SETTING AND PARTICIPANTS: A clustered cross-sectional study involving general practice patients from 30 randomly selected general practices in Victoria. Between January and December 2005, a screening survey, including a postal version of the GPAQ, was mailed to 17 780 eligible patients. MAIN OUTCOME MEASURE: Scores on the six GPAQ items. RESULTS: We analysed data from 7130 patients who completed the screening survey and fulfilled our eligibility criteria. Levels of patient satisfaction with general practice care were generally high: mean GPAQ scores ranged from 68.6 (95% CI, 66.1-71.0) for satisfaction with access to the practice to 84.0 (95% CI, 82.2-85.4) for satisfaction with communication. Intracluster correlations for the GPAQ items ranged from 0.016 for overall satisfaction with the practice to 0.163 for satisfaction with access to the practice. Compared with national benchmarks in the United Kingdom, the GPs and practices participating in our study were rated higher on all six GPAQ items. Multivariable mixed effects linear regression showed that patients who were older, rated their health more highly, visited their GP more frequently and saw the same GP each time tended to express greater satisfaction with their care. CONCLUSION: Generally patients reported high levels of satisfaction with GP care. Greater satisfaction with care was associated with older patients, good health, more frequent contact with the GP, and seeing the one GP consistently.