Subanalysis of the CYP-GUIDES Trial: CYP2D6 Functional Stratification and Operational Timeline Selection.

CYP-GUIDES (Cytochrome Psychotropic Genotyping Under Investigation for Decision Support) was a Randomized Controlled Trial comparing 2 outcomes in hospitalized patients with major depressive disorder treated according to the patient's CYP2D6 genotype and functional status versus standard psychotropic therapy. The primary outcome was hospital Length of Stay (LOS) and the secondary was Re-Admission Rate (RAR) 30 days after discharge. Methodology, total results and database of the trial have been published. Here we present a subanalysis that isolated 3 confounders to assess the impact of CYP2D6 therapeutic guidance on LOS: a single Electronic Medical Record, a minimum 3-day LOS, and CYP2D6 functional stratification of patients. CYP2D6 functional stratification enabled subgrouping patients and comparing outcomes according to CYP2D6 functionality within Group G and Group S. Subfunctional patients evidenced a 2-day shorter LOS in Group G compared to Group S. Drug administration for subfunctional patients in Group S evidenced a higher percentage of CYP2D6 substrate psychotropics being prescribed as well as a greater number of prescriptions than in functional patients. We conclude that there was an effect of pharmacogenetic clinical decision support that reduced LOS in patients with CYP2D6 subfunctional status and reduced prescribing of CYP2D6 substrate dependent drugs.

Results of the CYP-GUIDES randomized controlled trial: Total cohort and primary endpoints.

CYP-GUIDES (Cytochrome Psychotropic Genotyping Under Investigation for Decision Support) is a randomized controlled trial (RCT) comparing 2 outcomes in hospitalized patients with major depressive disorder (MDD) treated according to the patient's CYP2D6 genotype and functional status versus standard psychotropic therapy. The primary outcome was hospital Length of Stay (LOS) and the secondary outcome was the Re-Admission Rate (RAR) 30 days after discharge. The trial setting was the Institute of Living at Hartford Hospital. CYP2D6 genotyping was implemented to detect common polymorphisms resulting in an enzyme with sub-normal, normal or supra-normal function. The electronic medical record (EMR) was utilized to transmit clinically actionable drug prescribing guidance based on the patient's CYP2D6 genotype to the physician. The RCT recruited 1500 patients, genotyped CYP2D6 in 1459, and randomized 477 to standard therapy (Group S), for whom treatment-as-usual guidance was delivered without consideration of patient CYP2D6 genotype, and 982 to genetically-guided therapy (Group G) where CYP2D6-based treatment recommendations were provided via EMR to physicians. For inpatients in Group G whose CYP2D6 function was sub- or supra-normal, medications primarily metabolized by the CYP2D6 enzyme were proscribed. The RCT developed a database of potential benefit to the field. The genetic, pharmacologic and clinical information is being simultaneously published. Results did not reveal differences in LOS or RAR between Group G and Group S, but confounders may have obscured the effects of pharmacogenetic guidance. We present strategies to assess effects of pharmacogenetic guidance on the most vulnerable patients at either extreme of CYP2D6 function treated with multiple psychotropics.

Predictors of response to synchronized transcranial magnetic stimulation for major depressive disorder.

BACKGROUND: Synchronized transcranial magnetic stimulation (sTMS) is a new modality to reduce symptoms of major depressive disorder (MDD). sTMS uses rotating neodymium magnets to deliver low-field stimulation matched to the individual alpha frequency (IAF). A previous multisite study showed that sTMS significantly reduced MDD symptoms in the per-protocol sample. To this end, we evaluated clinical features associated with optimal sTMS outcomes. METHODS: Using the per-protocol sample (n = 120) from the parent sham-controlled trial, we performed univariate and stepwise linear regression to identify predictors of response after 6 weeks of sTMS. A subsample (n = 83) that entered a 4-week open/active continuation phase also was examined. Candidate variables included age, sex, comorbid anxiety, number of failed antidepressants in the current depressive episode, MDD severity (17-item Hamilton Depression Rating Scale; HAMD17), anxiety symptom severity (HAMD17 anxiety/somatization factor), and IAF. RESULTS: We found that greater baseline depressive (p < 0.001) and anxiety (p < 0.001) symptom severity were associated with better response to active sTMS, whereas fewer failed antidepressant trials predicted superior response to sham (p < 0.001). MDD severity and antidepressant resistance predicted outcomes in open/active phase sTMS; lower IAF predicted poorer response in participants who received 10 weeks of active sTMS (p = 0.001). CONCLUSIONS: Participants with greater severity of depression and higher anxiety had superior responses to active sTMS, whereas treatment naïve individuals exhibited a greater response to sham. These results lend support to the primary efficacy findings, and support further investigation of sTMS as a therapeutic noninvasive brain stimulation modality.

Complex psychotropic polypharmacy in bipolar disorder across varying mood polarities: A prospective cohort study of 2712 inpatients.

BACKGROUND: It is common for patients with bipolar disorder (BP) to receive multiple psychotropics, but few studies have assessed demographic and clinical features associated with risk for receiving complex psychotropic polypharmacy. METHODS: This longitudinal cohort study examined 2712 inpatients with a DSM-IV clinical diagnosis of BP to assess associations between complex polypharmacy (defined as ≥4 psychotropics) and demographic and clinical features; associations with risk of rehospitalization were also examined. Logistic regressions were performed with the sample as a whole and with each of four DSM-IV BP subtypes individually. RESULTS: Complex polypharmacy was present in 21.0%. BP-I depressed patients were more likely to receive complex regimens than BP-I manic, BP-I mixed or BP-II patients. In the sample as a whole, variables significantly associated with complex polypharmacy included female, white, psychotic features and a co-diagnosis of borderline personality, post-traumatic stress or another anxiety disorder. The only examined medication not significantly associated with complex polypharmacy was lithium, although only in BP-I depressed and BP-I mixed. Complex polypharmacy was associated with rehospitalization in BP-I mania within 15 and 30days post index hospitalization. LIMITATIONS: All data were from one clinical facility; results may not generalize to other settings and patient populations. CONCLUSIONS: BP-I depression may pose a greater treatment challenge than the other BP subtypes. Lithium may confer an overall advantage compared to other medications in BP-I depressed and BP-I mixed. Further research is needed to guide pharmacotherapy decisions in BP patients.

Resting-State Functional Connectivity in Generalized Anxiety Disorder and Social Anxiety Disorder: Evidence for a Dimensional Approach.

Generalized anxiety disorder (GAD) and social anxiety disorder (SAD) are currently considered distinct diagnostic categories. Accumulating data suggest the study of anxiety disorders may benefit from the use of dimensional conceptualizations. One such dimension of shared dysfunction is emotion regulation (ER). The current study evaluated dimensional (ER) and categorical (diagnosis) neurocorrelates of resting-state functional connectivity (rsFC) in participants with GAD and SAD and healthy controls (HC). Functional magnetic resonance imaging (fMRI) rsFC was estimated between all regions of the default mode network (DMN), salience network (SN), and bilateral amygdala (N = 37: HC-19; GAD-10; SAD-8). Thereafter, rsFC was predicted by both ER, (using the Difficulties in Emotion Regulation Scale [DERS]), and diagnosis (DSM-5) within a single unified analysis of covariance (ANCOVA). For the ER dimension, there was a significant association between impaired ER abilities and anticorrelated rsFC of amygdala and DMN (L.amygdala-ACC: p = 0.011, beta = -0.345), as well as amygdala and SN (L.amygdala-posterior cingulate cortex [PCC]: p = 0.032, beta = -0.409). Diagnostic status was significantly associated with rsFC differences between the SAD and HC groups, both within the DMN (PCC-MPFC: p = 0.009) and between the DMN and SN (R.LP-ACC: p = 0.010). Although preliminary, our results exemplify the potential contribution of the dimensional approach to the study of GAD and SAD and support a combined categorical and dimensional model of rsFC of anxiety disorders.

Reduction of Seclusion and Restraint in an Inpatient Psychiatric Setting: A Pilot Study.

The authors describe a quality and safety initiative designed to decrease seclusion/restraint (S/R) and present the results of a pilot study that evaluated the effectiveness of this program. The study sample consisted of consecutive admissions to a 120-bed psychiatric service after the intervention was implemented (October 2010-September 2012, n = 8029). Analyses compared S/R incidence and duration in the study sample to baseline (consecutive admissions during the year prior to introduction of the intervention, October 2008-September 2009, n = 3884). The study intervention, which used evidence-based therapeutic practices for reducing violence/aggression, included routine use of the Brøset Violence Checklist, mandated staff education in crisis intervention and trauma informed care, increased frequency of physician reassessment of need for S/R, formal administrative review of S/R events and environmental enhancements (e.g., comfort rooms to support sensory modulation). Statistically significant associations were found between the intervention and a decrease in both the number of seclusions (p < 0.01) and the duration of seclusion per admission (p < 0.001). These preliminary results support the conclusion that this intervention was effective in reducing use of seclusion. Further study is needed to determine if these prevention strategies are generalizable, the degree to which each component of the intervention contributes to improve outcome, and if continuation of the intervention will further reduce restraint use.

Improvements in emotion regulation following repetitive transcranial magnetic stimulation for generalized anxiety disorder.

Generalized anxiety disorder (GAD) is characterized by emotion regulation difficulties, which are associated with abnormalities in neural circuits encompassing fronto-limbic regions including the dorsolateral prefrontal cortex (DLPFC). The aim of this study was to determine whether DLPFC neuromodulation improves emotion regulation in patients with GAD. This is a secondary analysis from a randomized-controlled trial comparing 30 sessions of low-frequency right-sided active (n=13) versus sham (n=12, sham coil) repetitive transcranial magnetic stimulation (rTMS) at the right DLPFC in patients with GAD. Results indicated statistically significant improvements in self-reported emotion regulation difficulties at posttreatment and 3-month follow-up in the active group only. Improvements were found primarily in the domains of goal-directed behaviors and impulse control and were significantly associated with a global clinician rating of improvement. These preliminary results support rTMS as a treatment for GAD and suggest improved emotion regulation as a possible mechanism of change.

Repetitive transcranial magnetic stimulation for generalised anxiety disorder: a pilot randomised, double-blind, sham-controlled trial.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) holds promise for treating generalised anxiety disorder (GAD) but has only been studied in uncontrolled research. AIMS: This is the first randomised controlled trial (clinicaltrials.gov: NCT01659736) to investigate the efficacy and neural correlates of rTMS in GAD. METHOD: Twenty five participants (active n = 13; sham, n = 12) enrolled. rTMS was targeted at the right dorsolateral prefrontal cortex (DLPFC, 1 Hz, 90% resting motor threshold). RESULTS: Response and remission rates were higher in the active v. sham groups and there were significant group × time interactions for anxiety, worry and depressive symptoms, favouring active v. sham. In addition, right DLPFC activation during a decision-making gambling task increased at post-treatment for active rTMS only, and changes in neuroactivation correlated significantly with changes in worry symptoms. CONCLUSIONS: Findings provide preliminary evidence that rTMS may improve GAD symptoms in association with modifying neural activity in the stimulation site.

Practical interpretation of CYP2D6 haplotypes: Comparison and integration of automated and expert calling.

We describe a population genetic approach to compare samples interpreted with expert calling (EC) versus automated calling (AC) for CYP2D6 haplotyping. The analysis represents 4812 haplotype calls based on signal data generated by the Luminex xMap analyzers from 2406 patients referred to a high-complexity molecular diagnostics laboratory for CYP450 testing. DNA was extracted from buccal swabs. We compared the results of expert calls (EC) and automated calls (AC) with regard to haplotype number and frequency. The ratio of EC to AC was 1:3. Haplotype frequencies from EC and AC samples were convergent across haplotypes, and their distribution was not statistically different between the groups. Most duplications required EC, as only expansions with homozygous or hemizygous haplotypes could be automatedly called. High-complexity laboratories can offer equivalent interpretation to automated calling for non-expanded CYP2D6 loci, and superior interpretation for duplications. We have validated scientific expert calling specified by scoring rules as standard operating procedure integrated with an automated calling algorithm. The integration of EC with AC is a practical strategy for CYP2D6 clinical haplotyping.

Efficacy and Safety of Low-field Synchronized Transcranial Magnetic Stimulation (sTMS) for Treatment of Major Depression.

BACKGROUND: Transcranial Magnetic Stimulation (TMS) customarily uses high-field electromagnets to achieve therapeutic efficacy in Major Depressive Disorder (MDD). Low-field magnetic stimulation also may be useful for treatment of MDD, with fewer treatment-emergent adverse events. OBJECTIVE/HYPOTHESIS: To examine efficacy, safety, and tolerability of low-field magnetic stimulation synchronized to an individual's alpha frequency (IAF) (synchronized TMS, or sTMS) for treatment of MDD. METHODS: Six-week double-blind sham-controlled treatment trial of a novel device that used three rotating neodymium magnets to deliver sTMS treatment. IAF was determined from a single-channel EEG prior to first treatment. Subjects had baseline 17-item Hamilton Depression Rating Scale (HamD17) ≥ 17. RESULTS: 202 subjects comprised the intent-to-treat (ITT) sample, and 120 subjects completed treatment per-protocol (PP). There was no difference in efficacy between active and sham in the ITT sample. Subjects in the PP sample (N = 59), however, had significantly greater mean decrease in HamD17 than sham (N = 60) (-9.00 vs. -6.56, P = 0.033). PP subjects with a history of poor response or intolerance to medication showed greater improvement with sTMS than did treatment-naïve subjects (-8.58 vs. -4.25, P = 0.017). Efficacy in the PP sample reflects exclusion of subjects who received fewer than 80% of scheduled treatments or were inadvertently treated at the incorrect IAF; these subgroups failed to separate from sham. There was no difference in adverse events between sTMS and sham, and no serious adverse events attributable to sTMS. CONCLUSIONS: Results suggest that sTMS may be effective, safe, and well tolerated for treating MDD when administered as intended.

Treating anxious depression using repetitive transcranial magnetic stimulation.

BACKGROUND: A subset of patients given a clinical diagnosis of major depressive disorder (MDD) are described as having "anxious depression," a presentation that, in some studies, has been an indicator of poor response to pharmacotherapy. The aim of this study was to determine if anxious depression is associated with attenuated response to repetitive transcranial magnetic stimulation (rTMS), an FDA-approved treatment for MDD. METHODS: Participants were 32 adult outpatients with treatment resistant MDD who were referred for rTMS. The Hamilton Rating Scale for Depression (HAMD) was administered to assess treatment response, and anxious depression was defined as a score of seven or above on the anxiety/somatization factor of the HAMD. A quarter of the sample met the anxious depression criterion at pretreatment. RESULTS: Both depression (total score) and anxiety symptoms improved from pre- to post-treatment with moderate to large treatment effects. Patients with and without anxious depression demonstrated similar rates of improvement in depression. Patients with versus without anxious depression demonstrated larger improvements in anxiety. LIMITATIONS: The sample size was small, and assessments did not include structured diagnostic interview or independent measures of anxiety symptoms. CONCLUSIONS: For the sample as a whole, there were significant improvements in both depression and anxiety. Anxious depression was not associated with attenuated treatment response to rTMS.

Length of psychiatric hospitalization is correlated with CYP2D6 functional status in inpatients with major depressive disorder.

AIM: This study aimed to determine the effect of the CYP2D6 genotype on the length of hospitalization stay for patients treated for major depressive disorder. METHODS: A total of 149 inpatients with a diagnosis of major depressive disorder at the Institute of Living, Hartford Hospital (CT, USA), were genotyped to detect altered alleles in the CYP2D6 gene. Prospectively defined drug metabolism indices (metabolic reserve, metabolic alteration and allele alteration) were determined quantitatively and assessed for their relationship to length of hospitalization stay. RESULTS: Hospital stay was significantly longer in deficient CYP2D6 metabolizers (metabolic reserve <2) compared with functional or suprafunctional metabolizers (metabolic reserve ≥2; 7.8 vs 5.7 days, respectively; p = 0.002). CONCLUSION: CYP2D6 enzymatic functional status significantly affected length of hospital stay, perhaps due to reduced efficacy or increased side effects of the medications metabolized by the CYP2D6 isoenzyme. Functional scoring of CYP2D6 alleles may have a substantial impact on the quality of care, patient satisfaction and the economics of psychiatric treatment.

Validation of candidate genes associated with cardiovascular risk factors in psychiatric patients.

The purpose of this study was to identify genetic variants predictive of cardiovascular risk factors in a psychiatric population treated with second generation antipsychotics (SGA). 924 patients undergoing treatment for severe mental illness at four US hospitals were genotyped at 1.2 million single nucleotide polymorphisms. Patients were assessed for fasting serum lipid (low density lipoprotein cholesterol [LDLc], high density lipoprotein cholesterol [HDLc], and triglycerides) and obesity phenotypes (body mass index, BMI). Thirteen candidate genes from previous studies of the same phenotypes in non-psychiatric populations were tested for association. We confirmed 8 of the 13 candidate genes at the 95% confidence level. An increased genetic effect size was observed for triglycerides in the psychiatric population compared to that in the cardiovascular population.