Sunday, July 3, 2016

July 2016

Pharmacokinetic Pharmacogenetic Prescribing Guidelines for Antidepressants: A Template for Psychiatric Precision Medicine 

Mayo Clinic Proceedings


Antidepressants are commonly prescribed medications in the United States, and there is increasing interest in individualizing treatment selection for more than 20 US Food and Drug Administration–approved treatments for major depressive disorder. Providing greater precision to pharmacotherapeutic recommendations for individual patients beyond the large-scale clinical trials evidence base can potentially reduce adverse effect toxicity profiles and increase response rates and overall effectiveness. It is increasingly recognized that genetic variation may contribute to this differential risk to benefit ratio and thus provides a unique opportunity to develop pharmacogenetic guidelines for psychiatry. Key studies and concepts that review the rationale for cytochrome P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19) genetic testing can be delineated by serum levels, adverse events, and clinical outcome measures (eg, antidepressant response). In this article, we report the evidence that contributed to the implementation of pharmacokinetic pharmacogenetic guidelines for antidepressants primarily metabolized by CYP2D6 and CYP2C19.

Reversal of cognitive decline in Alzheimer's disease



Alzheimer's disease is one of the most significant healthcare problems nationally and globally. Recently, the first description of the reversal of cognitive decline in patients with early Alzheimer's disease or its precursors, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment), was published. The therapeutic approach used was programmatic and personalized rather than monotherapeutic and invariant, and was dubbed metabolic enhancement for neurodegeneration (MEND). Patients who had had to discontinue work were able to return to work, and those struggling at work were able to improve their performance. The patients, their spouses, and their co-workers all reported clear improvements. Here we report the results from quantitative MRI and neuropsychological testing in ten patients with cognitive decline, nine ApoE4+ (five homozygous and four heterozygous) and one ApoE4-, who were treated with the MEND protocol for 5-24 months. The magnitude of the improvement is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective. These results have far-reaching implications for the treatment of Alzheimer's disease, MCI, and SCI; for personalized programs that may enhance pharmaceutical efficacy; and for personal identification of ApoE genotype.

Cardiovascular safety of methylphenidate among children and
young people with attention-deficit/hyperactivity disorder
(ADHD): nationwide self controlled case series study



To determine whether treatment with methylphenidate in children and young people with attention-deficit/hyperactivity disorder (ADHD) was associated with cardiovascular events.

Self controlled case series analysis.

Nationwide health insurance database, 1 January 2008 to 31 December 2011, in South Korea.

1224 patients aged ≤ 17 who had experienced an incident cardiovascular event and had had at least one incident prescription for methylphenidate.

Main Outcome Measures
A recorded diagnosis (either a primary or secondary cause) of any of the following cardiovascular adverse events: arrhythmias (ICD-10 (international classification of diseases, 10th revision) codes I44, I45, I47, I48, I49), hypertension (codes I10-I15), myocardial infarction (code I21), ischemic stroke (code I63), or heart failure (code I50). Incidence rate ratios were calculated with conditional Poisson regression and adjusted for time varying comorbidity and comedication.

Increased risk of arrhythmia was observed in all exposed time periods—that is, periods of treatment with methylphenidate—(incidence rate ratio 1.61, 95% confidence interval 1.48 to 1.74), and the risk was highest in the children who had congenital heart disease. No significant risk of myocardial infarction was observed for all exposed time periods (1.33, 0.90 to 1.98), though risk was higher in the early risk periods between eight and 56 days after the start of treatment with methylphenidate. No significant increased risk was observed for hypertension, ischemic stroke, or heart failure.

The relative risk of myocardial infarction and arrhythmias is increased in the early period after the start of methylphenidate treatment for ADHD in children and young people. Though the absolute risk is likely to be low, the risk-benefit balance of methylphenidate should be carefully considered, particularly in children with mild ADHD.

Cortisol awakening response in patients with psychosis: Systematic review and meta-analysis

Neuroscience & Biobehavioral Reviews
The cortisol awakening response (CAR), defined as the increase in cortisol release in response to waking up, shows associations with social and environmental risk factors of schizophrenia and has been studied as a potential biomarker in schizophrenia. We report a systematic review and meta-analysis of 11 studies and 879 participants focusing on the CAR of patients with schizophrenia, first-episode psychosis, and at-risk mental states. Random-effects meta-analysis showed that CAR is attenuated in patients with psychosis compared to healthy controls (g = −0.426, 95% CI −0.585 to −0.267, p < 0.001, 11 between-group comparisons, n = 879). Subgroup analysis showed flattened CAR in patients with schizophrenia (g = −0.556, 95% CI −1.069 to −0.044, p < 0.05, 2 between-group comparisons, n = 114) and first-episode psychosis (g = −0.544, 95% CI −0.731 to −0.358, p < 0.001, 6 between-group comparisons, n = 505), but not in individuals with at-risk mental states. These distinctive alterations of hypothalamic-pituitary-adrenal axis function may have important implications for CAR as a marker for transition risk. However, the lack of objective verification of sampling adherence in these studies may limit the interpretation of the results.

7T Proton Magnetic Resonance Spectroscopy of Gamma-Aminobutyric Acid, Glutamate, and Glutamine Reveals Altered Concentrations in Patients With Schizophrenia and Healthy Siblings

Biological Psychiatry

The N-methyl-D-aspartate receptor hypofunction model of schizophrenia predicts dysfunction in both glutamatergic and gamma-aminobutyric acidergic (GABAergic) transmission. We addressed this hypothesis by measuring GABA, glutamate, glutamine, and the sum of glutamine plus glutamate concentrations in vivo in patients with schizophrenia using proton magnetic resonance spectroscopy at 7T, which allows separation of metabolites that would otherwise overlap at lower field strengths. In addition, we investigated whether altered levels of GABA, glutamate, glutamine, and the sum of glutamine plus glutamate reflect genetic vulnerability to schizophrenia by including healthy first-degree relatives.

Proton magnetic resonance spectroscopy at 7T was performed in 21 patients with chronic schizophrenia who were taking medication, 23 healthy first-degree relatives of patients with schizophrenia, and 24 healthy nonrelatives. Glutamate, glutamine, and GABA were measured cortically and subcortically in bilateral basal ganglia and occipital cortex.

Patients with schizophrenia had reduced cortical GABA compared with healthy relatives and the combined sample of healthy relatives and healthy nonrelatives, suggesting that altered GABAergic systems in schizophrenia are associated with either disease state or medication effects. Reduced cortical glutamine relative to healthy control subjects was observed in patients with schizophrenia and the combined sample of healthy relatives and patients with schizophrenia, suggesting that altered glutamatergic metabolite levels are associated with illness liability. No group differences were found in the basal ganglia.

Taken together, these findings are consistent with alterations in GABAergic and glutamatergic systems in patients with schizophrenia and provide novel insights into these systems in healthy relatives.

Association Between Religious Service Attendance and Lower Suicide Rates Among US Women

JAMA Psychiatry

Previous studies have linked suicide risk with religious participation, but the majority have used ecologic, cross-sectional, or case-control data.


To examine the longitudinal association between religious service attendance and suicide and the joint associations of suicide with service attendance and religious affiliation.

Design, Setting, and Participants  

We evaluated associations between religious service attendance and suicide from 1996 through June 2010 in a large, long-term prospective cohort, the Nurses’ Health Study, in an analysis that included 89 708 women. Religious service attendance was self-reported in 1992 and 1996. Data analysis was conducted from 1996 through 2010.

Main Outcomes and Measures  

Cox proportional hazards regression models were used to examine the association between religious service attendance and suicide, adjusting for demographic covariates, lifestyle factors, medical history, depressive symptoms, and social integration measures. We performed sensitivity analyses to examine the influence of unmeasured confounding.


Among 89 708 women aged 30 to 55 years who participated in the Nurses’ Health Study, attendance at religious services once per week or more was associated with an approximately 5-fold lower rate of suicide compared with never attending religious services (hazard ratio, 0.16; 95% CI, 0.06-0.46). Service attendance once or more per week vs less frequent attendance was associated with a hazard ratio of 0.05 (95% CI, 0.006-0.48) for Catholics but only 0.34 (95% CI, 0.10-1.10) for Protestants (P = .05 for heterogeneity). Results were robust in sensitivity analysis and to exclusions of persons who were previously depressed or had a history of cancer or cardiovascular disease. There was evidence that social integration, depressive symptoms, and alcohol consumption partially mediated the association among those occasionally attending services, but not for those attending frequently.

Conclusions and Relevance  

In this cohort of US women, frequent religious service attendance was associated with a significantly lower rate of suicide.

Transcutaneous electrical acupoint stimulation as an adjunct therapy for obsessive-compulsive disorder: A randomized controlled study

Journal of Psychiatric Research


Transcutaneous electrical acupoint stimulation (TEAS) is thought to have potential to treat obsessive-compulsive disorder (OCD).

The purpose of this study was to determine whether adding TEAS to cognitive behavioral therapy (CBT) and clomipramine would improve the efficacy of these conventional treatments in OCD.

In this randomized controlled trial, 360 OCD patients were assigned to receive TEAS combined with CBT plus clomipramine (Group A, n = 120), TEAS combined with CBT plus placebo (Group B, n = 120), and simulated (placebo) TEAS combined with CBT plus clomipramine (Group C, n = 120) for 12 weeks. The primary outcome was measured using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS).

OCD symptoms in all patients reduced over time, however Groups A and B had a significantly greater reduction in Y-BOCS total score and the subscale for obsession and compulsion between week 2 and week 12 compared to Group C. Groups A and B had similar scores on these measures. Both groups had significantly higher rates of clinical response than Group C (88.3% and 81.7% vs. 67.5%, respectively, p < 0.001); and higher rates of remission (30.0% and 22.5% vs. 9.2%, respectively, p < 0.001). Group B experienced fewer adverse events than the other two groups.

TEAS enhances the efficacy of conventional OCD interventions and avoids the adverse effects associated with conventional pharmacological treatment. It can be considered as an effective adjunct intervention for OCD.

Association of Cerebral Microbleeds With Cognitive Decline and Dementia

JAMA Neurology


Cerebral microbleeds are hypothesized downstream markers of brain damage caused by vascular and amyloid pathologic mechanisms. To date, whether their presence is associated with cognitive deterioration in the general population remains unclear.


To determine whether microbleeds, and more specifically microbleed count and location, are associated with an increased risk for cognitive impairment and dementia in the general population.

Design, Setting, and Participants  

The Rotterdam Study, a prospective population-based study set in the general community, assessed the presence, number, and location of microbleeds at baseline (August 2005 to December 2011) on magnetic resonance imaging studies of the brain in 4841 participants 45 years or older. Participants underwent neuropsychological testing at 2 points a mean (SD) of 5.9 (0.6) years apart and were followed up for incident dementia throughout the study period until January 1, 2013. The association of microbleeds with cognitive decline and dementia was studied using multiple linear regression, linear mixed-effects modeling, and Cox proportional hazards.


Cerebral microbleed presence, location, and number.

Main Outcomes and Measures  

Cognitive decline measured by a decrease in neuropsychological test battery scores (Mini-Mental State Examination, Letter Digit Substitution Task, Word Fluency Test, Stroop test, 15-word Verbal Learning Test, and Purdue Pegboard Test) and compound scores (eg, G factor, executive function, information processing speed, memory, motor speed) and dementia.


In total, 3257 participants (1758 women [54.7%]; mean [SD] age, 59.6 [7.8] years) underwent baseline and follow-up cognitive testing. Microbleed prevalence was 15.3% (median [interquartile range] count, 1 [1-88]). The presence of more than 4 microbleeds was associated with cognitive decline. Lobar (with or without cerebellar) microbleeds were associated with a decline in executive functions (mean difference in z score, −0.31; 95% CI, −0.51 to −0.11; P = .003), information processing (mean difference in z score, −0.44; 95% CI, −0.65 to −0.22; P < .001), and memory function (mean difference in z score, −0.34; 95% CI, −0.64 to −0.03; P = .03), whereas microbleeds in other brain regions were associated with a decline in information processing and motor speed (mean difference in z score, −0.61; 95% CI, −1.05 to −0.17; P = .007). After a mean (SD) follow-up of 4.8 (1.4) years, 72 participants developed dementia, of whom 53 had Alzheimer dementia. The presence of microbleeds was associated with an increased risk for dementia after adjustment for age, sex, and educational level (hazard ratio, 2.02; 95% CI, 1.25-3.24), including Alzheimer dementia (hazard ratio, 2.10; 95% CI, 1.21-3.64).

Conclusions and Relevance  

In the general population, a high microbleed count was associated with an increased risk for cognitive deterioration and dementia. Microbleeds thus mark the presence of diffuse vascular and neurodegenerative brain damage.

Pediatricians Urged to Routinely Screen Adolescents for Risk Factors for Suicide

Psychiatric News

The American Academy of Pediatrics (AAP) published updated guidelines to assist pediatricians and other child and adolescent health care professionals in identifying and helping adolescents at risk of suicide. The report, which replaces recommendations made in 2007, acknowledges the role bullying and the internet may play in teen suicide risk and highlights the value of antidepressant medications to treat those at risk.

According to most recent data, suicide is the second leading cause of death for adolescents aged 15 to 19. The guidelines recommend pediatricians routinely ask adolescent patients if they have thoughts of harming themselves, and screen for bullying, pathological internet use, and other risk factors including a family history of suicide, a history of physical or sexual abuse, and mood disorders.

If an adolescent is considered to be at moderate or high risk of suicide, the guidelines recommend that arrangements for immediate mental health professional evaluation should be made during the office visit. For teens considered to be at low risk of suicide, the guidelines recommend close follow-up and/or a referral for a timely mental health evaluation.

Screening for Cognitive Impairments After Traumatic Brain Injury: A Comparison of a Brief Computerized Battery With the Montreal Cognitive Assessment

The Journal of Neuropsychiatry


Detecting cognitive dysfunction in a busy traumatic brain injury (TBI) clinic is challenging given the length of conventional assessments and the need for psychometric expertise. The authors report the utility of a 10-minute, easily administered computerized battery that is more sensitive than the Montreal Cognitive Assessment in detecting cognitive impairments in people with a TBI.

Online Journals:

Biological Psychiatry - Volume 80, Issue 2, July 2016

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