JAMA Psychiatry Current Issue

APOE ϵ 4 , Aging, and Effects on White Matter Across the Adult Life Span

Felsky D, Voineskos AN. — Sat, 01 Jun 2013 00:00:00 GMT

The article by Nichols et al is an important and useful addition to the literature. To our knowledge, it was the first to examine the effects of apolipoprotein E (APOE) genetic variation using an episodic memory task during functional magnetic resonance imaging across the adult life span. During task performance, they found an age × genotype interaction: in younger subjects, ϵ4 carriers showed less hippocampal activation than ϵ4 noncarriers, whereas the opposite was true for older subjects. A recent review, however, highlighted the almost equal distribution of either “underactivation” or “overactivation” in ϵ4 carriers compared with noncarriers during episodic memory functional magnetic resonance imaging studies in both younger and older participants. Therefore, despite the results of Nichols et al, an explanation for the discrepant results in the literature remains elusive. One important consideration of ϵ4 activity on the blood oxygen level–dependent signal is its well-documented effect on resting cerebral blood flow. Indeed, patients with Alzheimer disease (AD) early in the disease process show decreased blood flow at rest in the hippocampal complex and posterior cingulate cortex. Furthermore, the ϵ4 allele has been shown to influence functional connectivity at rest among regions that compose episodic memory circuitry.

A Comprehensive Family-Based Replication Study of Schizophrenia Genes A Replication Study of Schizophrenia Genes

Aberg KA, Liu Y, Bukszár J, et al. — Sat, 01 Jun 2013 00:00:00 GMT

Importance

Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets.

Objective

To identify SCZ susceptibility genes.

Design

We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1 085 772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs.

Setting

Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases.

Patients

We included 11 185 cases and 10 768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families.

Main Outcomes and Measures

Case-control status for SCZ.

Results

Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P <. 01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P < 2.20 × 10⁻¹⁶) and 93% in subjects of European ancestry only (P < 2.20 × 10⁻¹⁶). Our results supported the major histocompatibility complex region showing a 3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 × 10⁻¹⁰) and NOTCH4 (P = 3.16 × 10⁻⁷) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 × 10⁻⁷), AS3MT (P = 9.01 × 10⁻⁷), CNNM2 (P = 6.07 × 10⁻⁷), and NT5C2 (P = 4.09 × 10⁻⁷). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction) and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse).

Conclusions and Relevance

We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.

A Multisite, Double-blind, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of Vigabatrin for Treating Cocaine Dependence Vigabatrin for Treating Cocaine Dependence

Somoza EC, Winship D, Gorodetzky CW, et al. — Sat, 01 Jun 2013 00:00:00 GMT

Importance

Cocaine dependence is a significant public health problem, yet no validated pharmacological treatment exists. The potent γ-aminobutyric acid (GABA)ergic medication vigabatrin has previously been shown to be effective in a double-blind single-site study conducted in Mexico.

Objective

To evaluate the safety and efficacy of vigabatrin for the treatment of cocaine dependence in a US sample.

Design and Setting

Multisite, randomized, double-blind, placebo-controlled, 12-week clinical trial with follow-up visits at weeks 13, 16, 20, and 24 in 11 US sites.

Participants

In total, 186 treatment-seeking participants with cocaine dependence (mean age, 45 years). Approximately 67% were male, and about 60% were of African American race/ethnicity.

Interventions

Participants received twice-daily doses of vigabatrin (total dosage, 3.0 g/d) or matched placebo, plus weekly computerized cognitive behavioral therapy and biweekly individual counseling for 13 weeks. Contingency management encouraged the provision of urine samples.

Main Outcomes and Measures

The primary outcome measure was the proportion of participants with cocaine abstinence during the last 2 weeks of the 12-week treatment phase as assessed by self-reports and quantitative urine drug screens. The weekly fraction of cocaine use days and the number of drug-free urine samples during weeks 1 through 13 were key secondary measures.

Results

No significant differences were observed between the vigabatrin group and the placebo group on the primary outcome measure (P = .67), key secondary measures (P > .99), or other outcome measures. However, while pill counts and self-reports indicated that more than 66% of all participants (and >63% of the vigabatrin group) took more than 70% of their medication, post hoc vigabatrin urine concentration levels suggested that approximately 40% to 60% of patients taking vigabatrin may not have been adherent. This lack of adherence may have obscured any evidence of vigabatrin efficacy. No visual acuity or visual field deterioration occurred in any of the participants.

Conclusions and Relevance

No protocol-defined differences in efficacy between vigabatrin treatment and placebo were detected for any outcome variable. This may have been due to medication nonadherence or, alternatively, due to the weak efficacy of vigabatrin.

Trial Registration

clinicaltrials.gov Identifier: NCT00611130

Abnormally High Degree Connectivity of the Orbitofrontal Cortex in Obsessive-Compulsive Disorder Connectivity of the Orbitofrontal Cortex in OCD

Beucke JC, Sepulcre J, Talukdar T, et al. — Sat, 01 Jun 2013 00:00:00 GMT

Importance

Neurobiological models of obsessive-compulsive disorder (OCD) predict hyperactivity in brain circuits involving the orbitofrontal cortex and the basal ganglia, but it is unclear whether these areas are also characterized by altered brain network properties.

Objectives

To determine regions of abnormal degree connectivity in patients with OCD and to investigate whether connectivity measures are affected by antidepressant medication in OCD.

Design

Case-control cross-sectional study using resting-state functional magnetic resonance imaging and a data-driven, model-free method to test for alterations in the degree of whole-brain, distant, and local connectivity in unmedicated patients with OCD compared with healthy controls.

Setting

Outpatient clinic for OCD.

Participants

Twenty-three patients with OCD (12 women, 11 men) receiving no medication, 23 patients with OCD (14 women, 9 men) treated with antidepressant medication, and 2 equally sized control samples matched for age, sex, handedness, educational level, and IQ.

Main Outcome Measures

Statistical parametric maps testing the degree of distant and local functional connectivity of each voxel (hub analysis at voxel level) and OCD symptom severity.

Results

Unmedicated patients with OCD showed greater distant connectivity in the orbitofrontal cortex and subthalamic nucleus and greater local connectivity in the orbitofrontal cortex and the putamen. Furthermore, distant connectivity of the orbitofrontal cortex and the putamen positively correlated with global OCD symptom severity. Medicated patients with OCD showed reduced local connectivity of the ventral striatum compared with the unmedicated patients.

Conclusions and Relevance

Consistent with neurobiological models of OCD, the orbitofrontal cortex and the basal ganglia are hyperconnected in unmedicated patients. The finding of distant connectivity alterations of the orbitofrontal cortex and the basal ganglia represents initial evidence of greater connections with distant cortical areas outside of corticostriatal circuitry. Furthermore, these data suggest that antidepressant medication may reduce connectivity within corticobasal ganglia-thalamo-cortical circuits in OCD.

About This Journal

Sat, 01 Jun 2013 00:00:00 GMT

Brain Response to Empathy-Eliciting Scenarios Involving Pain in Incarcerated Individuals With Psychopathy Brain Response to Empathy-Eliciting Scenarios

Decety J, Skelly LR, Kiehl KA. — Sat, 01 Jun 2013 00:00:00 GMT

Importance

A marked lack of empathy is a hallmark characteristic of individuals with psychopathy. However, neural processes associated with empathic processing have not yet been directly examined in psychopathy, especially in response to the perception of other people in pain and distress.

Objective

To identify potential differences in patterns of neural activity in incarcerated individuals with psychopathy and incarcerated persons serving as controls during the perception of empathy-eliciting stimuli depicting other people experiencing pain.

Design

In a case-control study, brain activation patterns elicited by dynamic stimuli depicting individuals being harmed and facial expressions of pain were compared between incarcerated individuals with psychopathy and incarcerated controls.

Setting

Participants were scanned on the grounds of a correctional facility using the Mind Research Network's mobile 1.5-T magnetic resonance imaging system.

Participants

Eighty incarcerated men were classified according to scores on the Hare Psychopathy Checklist–Revised (PCL-R) as high (27 men; PCL-R, ≥30), intermediate (28 men; PCL-R, 21-29), or low (25 men; PCL-R, ≤20) levels of psychopathy.

Main Outcome Measure

Neurohemodynamic response to empathy-eliciting dynamic scenarios revealed by functional magnetic resonance imaging.

Results

Participants in the psychopathy group exhibited significantly less activation in the ventromedial prefrontal cortex, lateral orbitofrontal cortex, and periaqueductal gray relative to controls but showed greater activation in the insula, which was positively correlated with scores on both PCL-R factors 1 and 2.

Conclusions and Relevance

In response to pain and distress cues expressed by others, individuals with psychopathy exhibit deficits in the ventromedial prefrontal cortex and orbitofrontal cortex regardless of stimulus type and display selective impairment in processing facial cues of distress in regions associated with cognitive mentalizing. A better understanding of the neural responses to empathy-eliciting stimuli in psychopathy is necessary to inform intervention programs.

Deficits in Conditioned Fear Extinction in Obsessive-Compulsive Disorder and Neurobiological Changes in the Fear Circuit Fear Extinction in OCD and Neurobiological Changes

Milad MR, Furtak SC, Greenberg JL, et al. — Sat, 01 Jun 2013 00:00:00 GMT

Importance

Obsessive-compulsive disorder (OCD) may be characterized by impaired self-regulation and behavioral inhibition. Elevated fear and anxiety are common characteristics of this disorder. The neurobiology of fear regulation and consolidation of safety memories have not been examined in this patient population.

Objective

To examine the psychophysiological and neurobiological correlates of conditioned fear extinction in patients with OCD.

Design

Cross-sectional, case-control, functional magnetic resonance imaging study.

Setting

Academic medical center.

Participants

Twenty-one patients with OCD and 21 healthy participants.

Main Outcomes and Measures

Skin conductance responses and blood oxygenation level–dependent responses.

Results

The between-group difference noted in our psychophysiological measure (skin conductance responses) was during extinction recall: patients with OCD showed impaired extinction recall relative to control subjects. Regarding the functional magnetic resonance imaging data, patients with OCD showed significantly reduced activation in the ventromedial prefrontal cortex across training phases. Moreover, reduced activation in the patients with OCD was noted in the caudate and hippocampus during fear conditioning, as well as in the cerebellum, posterior cingulate cortex, and putamen during extinction recall. Contrary to our prediction, OCD symptom severity was positively correlated with the magnitude of extinction memory recall. Also contrary to our prediction, functional responses of the ventromedial prefrontal cortex were positively correlated with symptom severity, and functional responses of the dorsal anterior cingulate cortex were inversely correlated with symptom severity.

Conclusions and Relevance

As expected, our study showed that fear extinction and its neural substrates are impaired in patients with OCD. However, this study also yielded some surprising and unexpected results regarding the correlates between extinction capacity and its neural substrates and the severity of symptoms expressed in this disorder. Thus, our data report neural correlates of deficient fear extinction in patients with OCD. The negative correlations between fear extinction deficits and Yale-Brown Obsessive-Compulsive Scale symptoms in OCD suggest that there may be other factors, in addition to fear extinction deficiency, that contribute to the psychopathology of OCD.

Evidence for Multiple Genetic Factors Underlying DSM-IV Criteria for Major Depression Risk Factors for DSM-IV Major Depression Criteria

Kendler KS, Aggen SH, Neale MC. — Sat, 01 Jun 2013 00:00:00 GMT

Importance

We do not know whether the clinical criteria for major depression (MD) reflect a single or multiple dimensions of genetic risk.

Objective

To determine the structure of genetic and environmental risk factors for the 9 DSM-IV symptomatic MD criteria.

Design

Population-based twin registry.

Setting

Virginia.

Participants

Seven thousand five hundred members of adult twin pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders.

Main Outcome Measure

Symptoms of lifetime MD as assessed at personal interview.

Results

The best-fit twin model was multidimensional, requiring 3 genetic, 1 common environmental and 3 unique environmental common factors, and criterion-specific unique environmental factors. The first genetic factor was characterized by high loadings on cognitive and psychomotor depressive symptoms. The second and third genetic factors had strong loadings for mood and neurovegetative depressive symptoms, respectively. Genetic factor scores derived from these 3 factors differentially predicted patterns of comorbidity, other historical/clinical features of MD, and demographic variables. These results suggested that the first genetic factor reflected a general liability to internalizing disorders, while the third genetic factor was more specific for melancholic MD. The 3 unique environmental common factors reflected, respectively, global depressive, core mood, and cognitive depressive symptoms.

Conclusions and Relevance

The DSM-IV syndrome of MD does not reflect a single dimension of genetic liability. Rather, these criteria reflect 3 underlying dimensions that index genetic risk for cognitive/psychomotor, mood, and neurovegetative symptoms. While in need of replication, these results, validated by predictions using estimated genetic factor scores, have implications for gene-finding efforts for MD.

Genetic Association, Mutation Screening, and Functional Analysis of a Kozak Sequence Variant in the Metabotropic Glutamate Receptor 3 Gene in Bipolar Disorder Glutamate Receptor 3 Gene in Bipolar Disorder

Kandaswamy R, McQuillin A, Sharp SI, et al. — Sat, 01 Jun 2013 00:00:00 GMT

Importance

Genetic markers at the gene encoding the metabotropic glutamate receptor 3 (GRM3) showed allelic association with bipolar disorder.

Objective

To screen the GRM3 gene and adjacent control regions of genomic DNA in volunteers with bipolar affective disorder for mutations increasing susceptibility to bipolar disorder.

Design

Sequencing and high-resolution melting curve analysis of DNA followed by genotyping was carried out in 1099 patients with bipolar affective disorder and 1152 healthy comparator individuals.

Setting

Participants with bipolar disorder were recruited from National Health Service psychiatric services and from patient organizations.

Participants

Individuals were included if they had Research Diagnostic Criteria diagnoses of bipolar I and bipolar II disorder and were of British or Irish ancestry.

Main Outcomes and Measures

Identification of base pair changes in the GRM3 gene that affected expression or function of the GRM3 receptor that also showed an allelic association with bipolar disorder.

Results

A base pair variant (rs148754219) was found in the Kozak sequence of exon 1 of the GRM3 gene, 2 bases before the translation start codon of one of the receptor isoforms, in 23 of 2251 people who were screened and genotyped. Nineteen of the 1099 bipolar cases (1.7%) were mutation carriers compared with 4 of 1152 healthy comparators (0.3%). The variant was associated with bipolar disorder (P = .005; odds ratio, 4.20). Bioinformatic, electrophoretic mobility shift assay, and gene expression analysis found that the variant created a new transcription factor protein binding site and had a strong effect on gene transcription and translation.

Conclusions and Relevance

Confirmation of these findings is needed before the Kozak sequence variant can be accepted as a potential marker for personalized treatment of affective disorders with drugs targeting the metabotropic glutamate receptor 3.

In This Issue of JAMA Psychiatry

Sat, 01 Jun 2013 00:00:00 GMT

Leonardo da Vinci's Mona Lisa Leonardo da Vinci's Mona Lisa

Harris JC. — Sat, 01 Jun 2013 00:00:00 GMT

Psychiatric Genetics Are We There Yet? Psychiatric Genetics

Hardy J. — Sat, 01 Jun 2013 00:00:00 GMT

The familiality of the major psychiatric disorders, bipolar disease and schizophrenia, has been long recognized and yet, uniquely, the identification of accepted genetic loci has been very difficult. Positional localization of loci in kindreds with apparently mendelian forms of the disease was not confirmed, candidate gene studies did not generally yield reproducible results, and the early, moderately sized, genome-wide association studies did not yield convincing results. This lack of convincing success was in contrast, for example, to the success in neurologic diseases, where not only have many loci been found, but for each disease, they map onto biochemical pathways and obey rather simple rules as to the predisposing variants found (Table). This has led some, including me, to be skeptical of the approaches that have been taken and suggest that the absence of evidence for genetic lesions was gradually becoming the evidence for absence and that to a large extent, familiality must reflect shared environments or experiences.

Public Safety, Mental Disorders, and Guns Public Safety, Mental Disorders, and Guns

Appelbaum PS. — Sat, 01 Jun 2013 00:00:00 GMT

In the aftermath of the shooting of 20 schoolchildren and 6 teachers in Newtown, Connecticut, on December 14, 2012, attention quickly focused on the presumed link between mental disorder and violence. With no more than rumors to rely on, the media speculated wildly on the gunman's diagnosis and drew parallels to earlier shootings involving persons with mental illness. Wayne LaPierre, executive vice president of the National Rifle Association, announced at a press conference that the problem of violence was largely due to people with mental illness, “genuine monsters . . . that are so deranged, so evil, so possessed by voices and driven by demons, that no sane person can even possibly comprehend them.”

Support for the N -Methyl- D -Aspartate Receptor Hypofunction Hypothesis of Schizophrenia From Exome Sequencing in Multiplex Families New Genes Associated With Risk for Schizophrenia

Timms AE, Dorschner MO, Wechsler J, et al. — Sat, 01 Jun 2013 00:00:00 GMT

Importance

Schizophrenia is a complex genetic disorder demonstrating considerable heritability. Genetic studies have implicated many different genes and pathways, but much of the genetic liability remains unaccounted for. Investigation of genetic forms of schizophrenia will lead to a better understanding of the underlying molecular pathways, which will then enable targeted approaches for disease prevention and treatment.

Objective

To identify new genetic factors strongly predisposing to schizophrenia in families with multiple affected individuals with schizophrenia.

Design

We performed genome-wide array comparative genomic hybridization, linkage analysis, and exome sequencing in multiplex families with schizophrenia.

Setting

Probands and their family members were recruited from academic medical centers.

Participants

We intended to identify rare disease-causing mutations in 5 large families where schizophrenia transmission appears consistent with single-gene inheritance.

Intervention

Array comparative genomic hybridization was used to identify copy number variants, while exome sequencing was used to identify variants shared in all affected individuals and linkage analysis was used to further filter shared variants of interest. Analysis of select variants was performed in cultured cells to assess their functional consequences.

Main Outcome Measures

Rare inherited disease-related genetic mutations.

Results

No segregating rare copy number variants were detected by array comparative genomic hybridization. However, in all 5 families, exome sequencing detected rare protein-altering variants in 1 of 3 genes associated with the N -methyl-D-aspartate (NMDA) receptor. One pedigree shared a missense and frameshift substitution of GRM5, encoding the metabotropic glutamate receptor subtype 5 (mGluR5), which is coupled to the NMDA receptor and potentiates its signaling; the frameshift disrupts binding to the scaffolding protein tamalin and increases mGluR5 internalization. Another pedigree transmitted a missense substitution in PPEF2, encoding a calmodulin-binding protein phosphatase, which we show influences mGluR5 levels. Three pedigrees demonstrated different missense substitutions within LRP1B, encoding a low-density lipoprotein receptor–related protein tied to both the NMDA receptor and located in a chromosome 2q22 region previously strongly linked to schizophrenia.

Conclusions and Relevance

Exome sequencing of multiplex pedigrees uncovers new genes associated with risk for developing schizophrenia and suggests potential novel therapeutic targets.

The Potential Value of a Negative Finding An Illustrative Example The Potential Value of a Negative Finding

Silverman K, DeFulio A, Leoutsakos J. — Sat, 01 Jun 2013 00:00:00 GMT

Clinical trials with positive findings are more likely to be submitted and published than those with negative findings, but negative findings can provide invaluable information, particularly when based on sound methodology. The study by Somoza and colleagues in this issue provides a powerful illustration of the potential value of a negative finding.

Two Steps Forward, One Step Back? Implications of the Supreme Court's Health Reform Ruling for Individuals With Mental Illness Implications of ACA Ruling for Mental Illness

Golberstein E, Busch SH. — Sat, 01 Jun 2013 00:00:00 GMT

A major promise of the Affordable Care Act is to improve care and financial protection for vulnerable populations such as the many lower-income Americans with mental disorders. The key features of the Affordable Care Act are the expansions of insurance coverage through federally subsidized health insurance exchanges and Medicaid eligibility for all individuals up to 138% of the federal poverty line, coupled with tax penalties for forgoing insurance. Because these insurance expansions are expected to increase coverage for lower-income populations, which have a higher prevalence of mental disorders, individuals with mental illness will see significant gains in insurance coverage and access to care.