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Sunday, May 7, 2017

May 2017

Association of Mental Disorders and Related Medication Use With Risk for Major Osteoporotic FracturES

JAMA Psychiatry


Osteoporotic fractures are a leading cause of disability, costs, and mortality. FRAX is a tool used to assess fracture risk in the general population. Mental disorders and medications to treat them have been reported to adversely affect bone health, but, to date, they have not been systematically studied in relation to osteoporotic fractures.

To examine the association of mental disorders and psychotropic medication use with osteoporotic fracture risk in routine clinical practice.

Design, Setting, and Participants
In this population-based cohort study, bone mineral density and risk factors were used to calculate FRAX scores using data from the Manitoba Bone Density Program database of all women and men 40 years of age or older in Manitoba, Canada, referred for a baseline dual-energy x-ray absorptiometry scan from January 1, 1996, to March 28, 2013. Population-based health services data were used to identify primary mental disorders during the 3 prior years, psychotropic medication use during the prior year, and incident fractures. Cox proportional hazards regression models estimated the risk for incident fractures based on mental disorders and use of psychotropic medications. Data analysis was conducted from November 25, 2013, to October 15, 2016.

Main Outcomes and Measures
Incident nontraumatic major osteoporotic fractures (MOFs) and hip fractures.

Of the 68 730 individuals (62 275 women and 6455 men; mean age, 64.2 [11.2] years) in the study, during 485 322 person-years (median, 6.7 years) of observation, 5750 (8.4%) sustained an incident MOF, 1579 (2.3%) sustained an incident hip fracture, and 8998 (13.1%) died. In analyses adjusted for FRAX score, depression was associated with MOF (adjusted hazard ratio [aHR], 1.39; 95% CI, 1.27-1.51; P < .05) and hip fracture (aHR, 1.43; 95% CI, 1.22-1.69; P < .05) before adjustment for medication use, but these associations were not significant after adjustment for medication use. In contrast, the use of selective serotonin reuptake inhibitors (aHR for MOF, 1.43; 95% CI, 1.27-1.60; P < .05; aHR for hip fracture, 1.48; 95% CI, 1.18-1.85; P < .05), antipsychotics (aHR for MOF, 1.43; 95% CI, 1.15-1.77; P < .05; aHR for hip fracture, 2.14; 95% CI, 1.52-3.02; P < .05), and benzodiazepines (aHR for MOF, 1.15; 95% CI, 1.04-1.26; P < .05; aHR for hip fracture, 1.24; 95% CI, 1.05-1.47; P < .05) were each independently associated with significantly increased risk for both MOF and hip fracture. FRAX significantly underestimated the 10-year risk of MOF by 29% and of hip fracture by 51% for those with depression. It also underestimated the 10-year risk of MOF by 36% for use of selective serotonin reuptake inhibitors, by 63% for use of mood stabilizers, by 60% for use of antipsychotics, and by 13% for use of benzodiazepines. FRAX underestimated the 10-year risk of hip fracture by 57% for use of selective serotonin reuptake inhibitors, by 98% for use of mood stabilizers, by 171% for use of antipsychotics, and by 31% for use of benzodiazepines. FRAX correctly estimated fracture risk in people without mental disorders and those not taking psychotropic medications.

Conclusions and Relevance
Mental disorders and medication use were associated with an increased risk for fracture, but in simultaneous analyses, only medication use was independently associated with fracture. Depression and psychotropic medication use are potential risk indicators that are independent of FRAX estimates.

The U.S. Food and Drug Administration approved valbenazine (INGREZZA) capsules to treat adults with tardive dyskinesia


The U.S. Food and Drug Administration approved Ingrezza (valbenazine) capsules to treat adults with tardive dyskinesia. This is the first drug approved by the FDA for this condition.  
Tardive dyskinesia is a neurological disorder characterized by repetitive involuntary movements, usually of the jaw, lips and tongue, such as grimacing, sticking out the tongue and smacking the lips. Some affected people also experience involuntary movement of the extremities or difficulty breathing.

"Tardive dyskinesia can be disabling and can further stigmatize patients with mental illness," said Mitchell Mathis, M.D., director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. "Approving the first drug for the treatment of tardive dyskinesia is an important advance for patients suffering with this condition."

Tardive dyskinesia is a serious side effect sometimes seen in patients who have been treated with antipsychotic medications, especially the older medications, for long periods to treat chronic conditions, such as schizophrenia and bipolar disorder. Tardive dyskinesia can also occur in patients taking antipsychotic medications for depression and certain medications for gastrointestinal disorders and other conditions. It is unclear why some people who take these medications develop tardive dyskinesia yet others do not.

The efficacy of Ingrezza was shown in a clinical trial of 234 participants that compared Ingrezza to placebo. After six weeks, participants who received Ingrezza had improvement in the severity of abnormal involuntary movements compared to those who received placebo.

Ingrezza may cause serious side effects including sleepiness and heart rhythm problems (QT prolongation). Its use should be avoided in patients with congenital long QT syndrome or with abnormal heartbeats associated with a prolonged QT interval. Those taking Ingrezza should not drive or operate heavy machinery or do other dangerous activities until it is known how the drug affects them.  

Association of Suicidality and Depression With 5α-Reductase Inhibitors

JAMA Internal Medicine


There have been concerns raised by patients and regulatory agencies regarding serious psychiatric adverse effects associated with 5α-reductase inhibitors.

To determine if there is an increased risk of suicide, self-harm, or depression among older men starting a 5α-reductase inhibitor for prostatic enlargement.

Design, Setting, and Participants
A population-based, retrospective, matched cohort study using linked administrative data for 93 197 men ages 66 years or older (median [IQR] age, 75 [70-80] years) in Ontario, Canada, who initiated a new prescription for a 5α-reductase inhibitor during the study period (2003 through 2013). Participants were matched (using a propensity score that included 44 of our 96 covariates that included medical comorbidities, medication usage, and health care system utilization) to an equal number of men not prescribed a 5α-reductase inhibitor.

Duration of finasteride or dutasteride usage.

Main Outcomes and Measures
Suicide. Secondary outcomes were self-harm and depression.

Men who used 5α-reductase inhibitors were not at a significantly increased risk of suicide (HR, 0.88; 95% CI, 0.53-1.45). Risk of self-harm was significantly increased during the initial 18 months after 5α-reductase inhibitor initiation (HR, 1.88; 95% CI, 1.34-2.64), but not thereafter. Incident depression risk was elevated during the initial 18 months after 5α-reductase inhibitor initiation (HR, 1.94; 95% CI, 1.73-2.16), and continued to be elevated, but to a lesser degree, for the remainder of the follow-up period (HR, 1.22; 95% CI, 1.08-1.37). The absolute increases in the event rates for these 2 outcomes were 17 per 100 000 patient-years and 237 per 100 000 patient-years, respectively. The type of 5α-reductase inhibitor (finasteride or dutasteride) did not significantly modify the observed associations with suicide, self-harm, and depression.

Conclusions and Relevance
In a large cohort of men ages 66 years or older, we did not demonstrate an increased risk of suicide associated with 5α-reductase inhibitor use. However, the risk of self-harm and depression were increased compared with unexposed men. This is in keeping with postmarketing experience and patient concerns, and discontinuation of the medication in these circumstances may be appropriate.

Self-Reported Mental Health Problems Among Adults Born Preterm: A Meta-Analysis


Preterm birth increases the risk for mental disorders in adulthood, yet findings on self-reported or subclinical mental health problems are mixed.

To study self-reported mental health problems among adults born preterm at very low birth weight (VLBW; ≤1500 g) compared with term controls in an individual participant data meta-analysis.

Data Sources
Adults Born Preterm International Collaboration.

Study Selection
Studies that compared self-reported mental health problems using the Achenbach Young Adult Self Report or Adult Self Report between adults born preterm at VLBW (n = 747) and at term (n = 1512).

Data Extraction
We obtained individual participant data from 6 study cohorts and compared preterm and control groups by mixed random coefficient linear and Tobit regression.

Adults born preterm reported more internalizing (pooled β = .06; 95% confidence interval .01 to .11) and avoidant personality problems (.11; .05 to .17), and less externalizing (–.10; –.15 to –.06), rule breaking (–.10; –.15 to –.05), intrusive behavior (–.14; –.19 to –.09), and antisocial personality problems (–.09; –.14 to –.04) than controls. Group differences did not systematically vary by sex, intrauterine growth pattern, neurosensory impairments, or study cohort.

Exclusively self-reported data are not confirmed by alternative data sources.

Self-reports of adults born preterm at VLBW reveal a heightened risk for internalizing problems and socially avoidant personality traits together with a lowered risk for externalizing problem types. Our findings support the view that preterm birth constitutes an early vulnerability factor with long-term consequences on the individual into adulthood.


A translational approach for NMDA receptor profiling as a vulnerability biomarker for depression and schizophrenia

Experimental Physiology

Altered NMDA receptor activity and glutamate signalling might underlie the pathogenesis of both schizophrenia and depression in subgroups of patients. In schizophrenia, pharmacological modelling, post-mortem and imaging data suggest reduced NMDA signalling. In contrast, recent clinical trials demonstrating the efficacy of the NMDA antagonist ketamine in severely depressed patients suggest increased NMDA receptor signalling. We conducted a proof-of-concept study to assess whether there is any in vivo evidence for an inverse association in depression and schizophrenia with respect to the NMDA receptor function. For this purpose, we used a translational approach, based on findings from animal studies that NMDA receptor is a key mediator of arginine vasopressin (AVP) release into the bloodstream. Using hypertonic saline to increase plasma osmolality (POsm) and thereby induce AVP release, as done in animal studies, we found that in depressed patients the NMDA receptor-mediated AVP release induced by hypertonic saline infusion was significantly increased [0.24 (0.15) pg ml−1 mosmol−1, P < 0.05] compared with schizophrenia patients [0.07 (0.07) pg ml−1 mosmol−1]. Slopes for healthy control subjects were 0.11 (0.09) pg ml−1 mosmol−1 which was less than the depressed group. These findings are consistent with implicated NMDA receptor-related abnormalities in depression and schizophrenia in subgroups of patients and provide the first in vivo evidence of this dichotomy.

Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia



Background and Purpose
Sugar and artificially-sweetened beverage intake have been linked to cardiometabolic risk factors, which increase the risk of cerebrovascular disease and dementia. We examined whether sugar- or artificially sweetened beverage consumption was associated with the prospective risks of incident stroke or dementia in the community-based Framingham Heart Study Offspring cohort.

We studied 2888 participants aged >45 years for incident stroke (mean age 62 [SD, 9] years; 45% men) and 1484 participants aged >60 years for incident dementia (mean age 69 [SD, 6] years; 46% men). Beverage intake was quantified using a food-frequency questionnaire at cohort examinations 5 (1991–1995), 6 (1995–1998), and 7 (1998–2001). We quantified recent consumption at examination 7 and cumulative consumption by averaging across examinations. Surveillance for incident events commenced at examination 7 and continued for 10 years. We observed 97 cases of incident stroke (82 ischemic) and 81 cases of incident dementia (63 consistent with Alzheimer’s disease).

After adjustments for age, sex, education (for analysis of dementia), caloric intake, diet quality, physical activity, and smoking, higher recent and higher cumulative intake of artificially sweetened soft drinks were associated with an increased risk of ischemic stroke, all-cause dementia, and Alzheimer’s disease dementia. When comparing daily cumulative intake to 0 per week (reference), the hazard ratios were 2.96 (95% confidence interval, 1.26–6.97) for ischemic stroke and 2.89 (95% confidence interval, 1.18–7.07) for Alzheimer’s disease. Sugar-sweetened beverages were not associated with stroke or dementia.

Artificially sweetened soft drink consumption was associated with a higher risk of stroke and dementia.

Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition



Midlife vascular risk factors have been associated with late-life dementia. Whether these risk factors directly contribute to brain amyloid deposition is less well understood.

To determine if midlife vascular risk factors are associated with late-life brain amyloid deposition, measured using florbetapir positron emission tomography (PET).

Design, Setting, and Participants
The Atherosclerosis Risk in Communities (ARIC)–PET Amyloid Imaging Study, a prospective cohort study among 346 participants without dementia in 3 US communities (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi) who have been evaluated for vascular risk factors and markers since 1987-1989 with florbetapir PET scans in 2011-2013. Positron emission tomography image analysis was completed in 2015.

Vascular risk factors at ARIC baseline (age 45-64 years; risk factors included body mass index ≥30, current smoking, hypertension, diabetes, and total cholesterol ≥200 mg/dL) were evaluated in multivariable models including age, sex, race, APOE genotype, and educational level.

Main Outcomes and Measures
Standardized uptake value ratios (SUVRs) were calculated from PET scans and a mean global cortical SUVR was calculated. Elevated florbetapir (defined as a SUVR >1.2) was the dependent variable.

Among 322 participants without dementia and with nonmissing midlife vascular risk factors at baseline (mean age, 52 years; 58% female; 43% black), the SUVR (elevated in 164 [50.9%] participants) was measured more than 20 years later (median follow-up, 23.5 years; interquartile range, 23.0-24.3 years) when participants were between 67 and 88 (mean, 76) years old. Elevated body mass index in midlife was associated with elevated SUVR (odds ratio [OR], 2.06; 95% CI, 1.16-3.65). At baseline, 65 participants had no vascular risk factors, 123 had 1, and 134 had 2 or more; a higher number of midlife risk factors was associated with elevated amyloid SUVR at follow-up (30.8% [n = 20], 50.4% [n = 62], and 61.2% [n = 82], respectively). In adjusted models, compared with 0 midlife vascular risk factors, the OR for elevated SUVR associated with 1 vascular risk factor was 1.88 (95% CI, 0.95-3.72) and for 2 or more vascular risk factors was 2.88 (95% CI, 1.46-5.69). No significant race × risk factor interactions were found. Late-life vascular risk factors were not associated with late-life brain amyloid deposition (for ≥2 late-life vascular risk factors vs 0: OR, 1.66; 95% CI, 0.75-3.69).

Conclusions and Relevance
An increasing number of midlife vascular risk factors was significantly associated with elevated amyloid SUVR; this association was not significant for late-life risk factors. These findings are consistent with a role of vascular disease in the development of Alzheimer disease.

Functional Connectivity of the Subcallosal Cingulate Cortex And Differential Outcomes to Treatment With Cognitive-Behavioral Therapy or Antidepressant Medication for Major Depressive Disorder

The American Journal of Psychiatry


The purpose of this article was to inform the first-line treatment choice between cognitive-behavioral therapy (CBT) or an antidepressant medication for treatment-naive adults with major depressive disorder by defining a neuroimaging biomarker that differentially identifies the outcomes of remission and treatment failure to these interventions.

Functional MRI resting-state functional connectivity analyses using a bilateral subcallosal cingulate cortex (SCC) seed was applied to 122 patients from the Prediction of Remission to Individual and Combined Treatments (PReDICT) study who completed 12 weeks of randomized treatment with CBT or antidepressant medication. Of the 122 participants, 58 achieved remission (Hamilton Depression Rating Scale [HAM-D] score ≤7 at weeks 10 and 12), and 24 had treatment failure (<30% decrease from baseline in HAM-D score). A 2×2 analysis of variance using voxel-wise subsampling permutation tests compared the interaction of treatment and outcome. Receiver operating characteristic curves constructed using brain connectivity measures were used to determine possible classification rates for differential treatment outcomes.

The resting-state functional connectivity of the following three regions with the SCC was differentially associated with outcomes of remission and treatment failure to CBT and antidepressant medication and survived application of the subsample permutation tests: the left anterior ventrolateral prefrontal cortex/insula, the dorsal midbrain, and the left ventromedial prefrontal cortex. Using the summed SCC functional connectivity scores for these three regions, overall classification rates of 72%−78% for remission and 75%−89% for treatment failure was demonstrated. Positive summed functional connectivity was associated with remission with CBT and treatment failure with medication, whereas negative summed functional connectivity scores were associated with remission to medication and treatment failure with CBT.

Imaging-based depression subtypes defined using resting-state functional connectivity differentially identified an individual’s probability of remission or treatment failure with first-line treatment options for major depression. This biomarker should be explored in future research through prospective testing and as a component of multivariate treatment prediction models.

Altered Thalamo-Cortical White Matter Connectivity: Probabilistic Tractography Study in Clinical-High Risk for Psychosis and First-Episode Psychosis

Schizophrenia Bulletin


Disrupted thalamo-cortical connectivity is regarded as a core psychopathology in patients diagnosed with schizophrenia. However, whether the thalamo-cortical white matter connectivity is disrupted before the onset of psychosis is still unknown. To determine this gap in knowledge, the strength of thalamo-cortical white matter anatomical connectivity in subjects at clinical-high risk for psychosis (CHR) was compared to that of first-episode psychosis (FEP) and healthy controls. A total of 37 CHR, 21 FEP, and 37 matched healthy controls underwent diffusion-weighted magnetic resonance imaging to examine the number of probabilistic tractography “counts” representing thalamo-cortical white matter connectivity. We also investigated the relationship with psychopathology. For FEP, the connectivity between the thalamus and parietal cortex was significantly increased ( F = 5.65, P < .05) compared to that of healthy controls. However, the connectivity between thalamus and orbitofrontal cortex was significantly reduced compared to both healthy controls ( F = 11.86, P < .005) and CHR ( F = 6.63, P < .05). Interestingly, CHR exhibited a similar pattern as FEP, albeit with slightly reduced magnitude. Compared to healthy controls, there was a significant decrease ( F = 4.16, P < .05) in CHR thalamo-orbitofrontal connectivity. Also, the strength of the thalamo-orbitofrontal connectivity was correlated with the Global Assessment of Functioning score in CHR ( r = .35, P < .05). This observed pattern of white matter connectivity disruptions in FEP and in CHR suggests that this pattern of disconnectivity not only highlights the involvement of thalamus but also might be useful as an early biomarker for psychosis.

Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability

Molecular Psychiatry


The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case–control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD—for both European- and African-American individuals—and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ~10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.

Online Journals:

Biological Psychiatry - Volume 81, Issue 10, May 2017

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