JAMA Psychiatry

2014 JAMA Psychiatry

doi: 10.1001/jamapsychiatry.2013.2733

Research Callous-Unemotional Traits and Proactive Aggression Lozier and colleagues used an implicit face-emotion processing paradigm to measure amygdala activity associated with callous-unemotional (CU) traits and externalizing behaviors in youths with conduct problems. They found amygdala responses to fearful expression were negatively associated with CU traits and positively associated with externalizing behaviors, and that reduced amygdala activity mediated the relationship between CU traits and proactive aggression. Identification of Pathways for Bipolar Disorder Nurnberger and colleagues examined genome wide association data in the Psychiatric Genomics Consortium Bipolar Group for information regarding specific genes and neurobiologic pathways associated with bipolar disorder. A set of 226 empirically significant genes was identified, targeting hormonal regulation, calcium channels, second messenger systems, and glutamate signaling. Comparison with a brain gene expression data set implicated neuronal development pathways as well. These results reinforce specific neurobiologic hypotheses regarding bipolar disorder and may suggest new strategies for prevention and treatment. Mitochondrial Dysfunction as a Subtype of ASD Using high-resolution magnetic resonance spectroscopic imaging, Goh and colleagues detected significantly elevated brain lactate in individuals with autism spectrum disorder (ASD) (13%), with higher rates in adults (20%) than children (6%). In addition, by mapping lactate in small, contiguous voxels throughout the brain, they identified regions of the brain affected by mitochondrial dysfunction in ASD. Intravenous Ketamine for Treatment of Chronic PTSD Feder and colleagues reported significant improvement in posttraumatic stress disorder (PTSD) symptom severity 24 hours after a single intravenous infusion of ketamine in patients with chronic PTSD compared with midazolam. Ketamine was also associated with improvement in comorbid depressive symptom severity and overall clinical presentation, with only transient dissociative symptoms. Continuing Medical Education Nonsuicidal Self-injury and Suicidal Ideation By applying the classic twin design to a sample of 10 678 Australian twins, Maciejewski and colleagues found that individual differences in nonsuicidal self-injury and suicidal ideation are both substantially influenced by genetic and residual (including nonshared environmental) factors, while shared environment does not play a role. Furthermore, the substantial phenotypic correlation between both behaviors was largely driven by overlapping genetic influences, whereas overlapping residual influences accounted for the remainder.

Nurnberger, John I.; Koller, Daniel L.; Jung, Jeesun; Edenberg, Howard J.; Foroud, Tatiana; Guella, Ilaria; Vawter, Marquis P.; Kelsoe, John R.

2014 JAMA Psychiatry

doi: 10.1001/jamapsychiatry.2014.176pmid: 24718920

ImportanceGenome-wide investigations provide systematic information regarding the neurobiology of psychiatric disorders. ObjectiveTo identify biological pathways that contribute to risk for bipolar disorder (BP) using genes with consistent evidence for association in multiple genome-wide association studies (GWAS). Data SourcesFour independent data sets with individual genome-wide data available in July 2011 along with all data sets contributed to the Psychiatric Genomics Consortium Bipolar Group by May 2012. A prior meta-analysis was used as a source for brain gene expression data. Study SelectionThe 4 published GWAS were included in the initial sample. All independent BP data sets providing genome-wide data in the Psychiatric Genomics Consortium were included as a replication sample. Data Extraction and SynthesisWe identified 966 genes that contained 2 or more variants associated with BP at P < .05 in 3 of 4 GWAS data sets (n = 12 127 [5253 cases, 6874 controls]). Simulations using 10 000 replicates of these data sets corrected for gene size and allowed the calculation of an empirical P value for each gene; empirically significant genes were entered into a pathway analysis. Each of these pathways was then tested in the replication sample (n = 8396 [3507 cases, 4889 controls]) using gene set enrichment analysis for single-nucleotide polymorphisms. The 226 genes were also compared with results from a meta-analysis of gene expression in the dorsolateral prefrontal cortex. Main Outcomes and MeasuresEmpirically significant genes and biological pathways. ResultsAmong 966 genes, 226 were empirically significant (P < .05). Seventeen pathways were overrepresented in analyses of the initial data set. Six of the 17 pathways were associated with BP in both the initial and replication samples: corticotropin-releasing hormone signaling, cardiac β-adrenergic signaling, phospholipase C signaling, glutamate receptor signaling, endothelin 1 signaling, and cardiac hypertrophy signaling. Among the 226 genes, 9 differed in expression in the dorsolateral prefrontal cortex in patients with BP: CACNA1C, DTNA, FOXP1, GNG2, ITPR2, LSAMP, NPAS3, NCOA2, and NTRK3. Conclusions and RelevancePathways involved in the genetic predisposition to BP include hormonal regulation, calcium channels, second messenger systems, and glutamate signaling. Gene expression studies implicate neuronal development pathways as well. These results tend to reinforce specific hypotheses regarding BP neurobiology and may provide clues for new approaches to treatment and prevention.

Akdeniz, Ceren; Tost, Heike; Streit, Fabian; Haddad, Leila; Wüst, Stefan; Schäfer, Axel; Schneider, Michael; Rietschel, Marcella; Kirsch, Peter; Meyer-Lindenberg, Andreas

2014 JAMA Psychiatry

doi: 10.1001/jamapsychiatry.2014.35pmid: 24740491

ImportanceRelative risk for the brain disorder schizophrenia is more than doubled in ethnic minorities, an effect that is evident across countries and linked to socially relevant cues such as skin color, making ethnic minority status a well-established social environmental risk factor. Pathoepidemiological models propose a role for chronic social stress and perceived discrimination for mental health risk in ethnic minorities, but the neurobiology is unexplored. ObjectiveTo study neural social stress processing, using functional magnetic resonance imaging, and associations with perceived discrimination in ethnic minority individuals. Design, Setting, and ParticipantsCross-sectional design in a university setting using 3 validated paradigms to challenge neural social stress processing and, to probe for specificity, emotional and cognitive brain functions. Healthy participants included those with German lineage (n = 40) and those of ethnic minority (n = 40) from different ethnic backgrounds matched for sociodemographic, psychological, and task performance characteristics. Control comparisons examined stress processing with matched ethnic background of investigators (23 Turkish vs 23 German participants) and basic emotional and cognitive tasks (24 Turkish vs 24 German participants). Main Outcomes and MeasuresBlood oxygenation level–dependent response, functional connectivity, and psychological and physiological measures. ResultsThere were significant increases in heart rate (P < .001), subjective emotional response (self-related emotions, P < .001; subjective anxiety, P = .006), and salivary cortisol level (P = .004) during functional magnetic resonance imaging stress induction. Ethnic minority individuals had significantly higher perceived chronic stress levels (P = .02) as well as increased activation (family-wise error–corrected [FWE] P = .005, region of interest corrected) and increased functional connectivity (PFWE = .01, region of interest corrected) of perigenual anterior cingulate cortex (ACC). The effects were specific to stress and not explained by a social distance effect. Ethnic minority individuals had significant correlations between perceived group discrimination and activation in perigenual ACC (PFWE = .001, region of interest corrected) and ventral striatum (PFWE = .02, whole brain corrected) and mediation of the relationship between perceived discrimination and perigenual ACC–dorsal ACC connectivity by chronic stress (P < .05). Conclusions and RelevanceEpidemiologists proposed a causal role of social-evaluative stress, but the neural processes that could mediate this susceptibility effect were unknown. Our data demonstrate the potential of investigating associations from epidemiology with neuroimaging, suggest brain effects of social marginalization, and highlight a neural system in which environmental and genetic risk factors for mental illness may converge.

Freeman, Jennifer; Sapyta, Jeffrey; Garcia, Abbe; Compton, Scott; Khanna, Muniya; Flessner, Chris; FitzGerald, David; Mauro, Christian; Dingfelder, Rebecca; Benito, Kristen; Harrison, Julie; Curry, John; Foa, Edna; March, John; Moore, Phoebe; Franklin, Martin

2014 JAMA Psychiatry

doi: 10.1001/jamapsychiatry.2014.170pmid: 24759852

ImportanceCognitive behavior therapy (CBT) has been established as efficacious for obsessive-compulsive disorder (OCD) among older children and adolescents, yet its effect on young children has not been evaluated sufficiently. ObjectiveTo examine the relative efficacy of family-based CBT (FB-CBT) involving exposure plus response prevention vs an FB relaxation treatment (FB-RT) control condition for children 5 to 8 years of age. Design, Setting, and ParticipantsA 14-week randomized clinical trial (Pediatric Obsessive-Compulsive Disorder Treatment Study for Young Children [POTS Jr]) conducted at 3 academic medical centers between 2006 and 2011, involving 127 pediatric outpatients 5 to 8 years of age who received a primary diagnosis of OCD and a Children’s Yale-Brown Obsessive Compulsive Scale total score of 16 or higher. InterventionsParticipants were randomly assigned to 14 weeks of (1) FB-CBT, including exposure plus response prevention, or (2) FB-RT. Main Outcomes and MeasuresResponder status defined as an independent evaluator–rated Clinical Global Impression–Improvement scale score of 1 (very much improved) or 2 (much improved) and change in independent evaluator–rated continuous Children’s Yale-Brown Obsessive Compulsive Scale total score. ResultsFamily-based CBT was superior to FB-RT on both primary outcome measures. The percentages of children who were rated as 1 (very much improved) or 2 (much improved) on the Clinical Global Impression–Improvement scale at 14 weeks were 72% for FB-CBT and 41% for FB-RT. The effect size difference between FB-CBT and FB-RT on the Clinical Global Impression–Improvement scale was 0.31 (95% CI, 0.17-0.45). The number needed to treat (NNT) with FB-CBT vs FB-RT was estimated as 3.2 (95% CI, 2.2-5.8). The effect size difference between FB-CBT and FB-RT on the Children’s Yale-Brown Obsessive Compulsive Scale at week 14 was 0.84 (95% CI, 0.62-1.06). Conclusions and RelevanceA comprehensive FB-CBT program was superior to a relaxation program with a similar format in reducing OCD symptoms and functional impairment in young children (5-8 years of age) with OCD. Trial Registrationclinicaltrials.gov Identifier: NCT00533806