Context  Family interventions have been found to hasten episode recovery and delay recurrences among adults with bipolar disorder.

Objective  To examine the benefits of family-focused treatment for adolescents (FFT-A) and pharmacotherapy in the 2-year course of adolescent bipolar disorder.

Design  Two-site outpatient randomized controlled trial with 2-year follow-up.

Patients  A referred sample of 58 adolescents (mean [SD] age, 14.5 [1.6] years) with bipolar I (n = 38), II (n = 6), or not otherwise specified disorder (n = 14) with a mood episode in the prior 3 months.

Interventions  Patients were randomly assigned to FFT-A and protocol pharmacotherapy (n = 30) or enhanced care (EC) and protocol pharmacotherapy (n = 28). The FFT-A consisted of 21 sessions in 9 months of psychoeducation, communication training, and problem-solving skills training. The EC consisted of 3 family sessions focused on relapse prevention.

Main Outcome Measures  Independent "blind" evaluators assessed patients every 3 to 6 months for 2 years. Outcomes included time to recovery from the index episode, time to recurrence, weeks in episode or remission, and mood symptom severity scores.

Results  Analyses were by intent to treat. Rates of 2-year study completion did not differ across the FFT-A (60.0%) and EC conditions (64.3%). Although there were no group differences in rates of recovery from the index episode, patients in FFT-A recovered from their baseline depressive symptoms faster than patients in EC (hazard ratio, 1.85; 95% confidence interval, 1.04-3.29; P = .04). The groups did not differ in time to recurrence of depression or mania, but patients in FFT-A spent fewer weeks in depressive episodes and had a more favorable trajectory of depression symptoms for 2 years.

Conclusions  Family-focused therapy is effective in combination with pharmacotherapy in stabilizing bipolar depressive symptoms among adolescents. To establish full recovery, FFT-A may need to be supplemented with systematic care interventions effective for mania symptoms.

Trial Registration  clinicaltrials.gov Identifier NCT00571402.

Context  Neuroticism is a trait that reflects a tendency toward negative mood states. It has long been linked to internalizing psychiatric conditions, such as anxiety and depression, and it accounts for much of the substantial comorbidity seen between these disorders.

Objective  To identify common genetic variants that affect neuroticism to better understand (the comorbidity between) a broad range of psychiatric disorders and to develop effective treatments.

Design, Setting, and Participants  More than 420 000 genetic markers were tested for their association with neuroticism in a genomewide association study (GWAS). The GWAS sample consisted of 1227 healthy individuals ascertained from a US national sampling frame and available from the National Institute of Mental Health genetics repository. The most promising markers were subsequently tested in a German replication sample comprising 1880 healthy individuals.

Main Outcome Measures  A strict definition of replication (same marker, same direction of effects, and same measure) combined with a threshold we proposed previously for declaring significance in genetic studies that ensures a mean probability of producing false-positive findings of less than 10%.

Results  The most promising results in the GWAS and replication samples were single-nucleotide polymorphisms (SNPs) in the gene MAMDC1. These SNPs all tagged the same 2 haplotypes and had P values of 10^–5 to 10^–6 in the GWAS sample and of .006 to .02 in the replication sample. Furthermore, the replication involved the same SNPs and the same direction of effects. In a combined analysis of all data, several SNPs were significant according to the threshold that allows for 10% false-positive findings.

Conclusions  The small effect sizes may limit the prognostic, diagnostic, and therapeutic use of SNP markers such as those in MAMDC1. However, the present study demonstrates the potential of a GWAS to discover potentially important pathogenic pathways for which clinically more powerful (bio)markers may eventually be developed.

Context  It is a common experience in temperate zones that individuals feel happier and more energetic on bright and sunny days and many experience a decline in mood and energy during the dark winter season. Brain serotonin is involved in the regulation of physiologic functions, such as mating, feeding, energy balance, and sleep. Although these behaviors and serotonin-related conditions show a clear seasonal pattern in humans, the molecular background of seasonal changes in serotonin function is entirely unknown. The serotonin transporter is a key element in regulating intensity and spread of the serotonin signal.

Objectives  To detect seasonal variations in serotonin transporter binding in the living human brain and to detect correlations between serotonin transporter binding and duration of daily sunshine.

Design  Regional serotonin transporter binding potential values, an index of serotonin transporter density, were assessed from December 1, 1999, to December 9, 2003, in a consecutive sample of healthy volunteers. Binding potential values were related to meteorologic data.

Setting  Tertiary care psychiatric hospital.

Participants  Volunteer sample of 88 drug-naïve healthy individuals.

Intervention  Carbon 11–labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile positron emission tomography.

Main Outcome Measure  Regional serotonin transporter binding potential values.

Results  Serotonin transporter binding potential values were significantly higher in all investigated brain regions in individuals investigated in the fall and winter compared with those investigated in the spring and summer (P = .01 to .001). Moreover, binding potential values showed negative correlations with average duration of daily sunshine in all brain regions ( = –0.21 to –0.39; P = .05 to <.001), such that higher values occurred at times of lesser light.

Conclusions  Serotonin transporter binding potential values vary throughout the year with the seasons. Since higher serotonin transporter density is associated with lower synaptic serotonin levels, regulation of serotonin transporter density by season is a previously undescribed physiologic mechanism that has the potential to explain seasonal changes in normal and pathologic behaviors.

Context  Brain maturation starts well before birth and occurs as a unified process with developmental interaction among different brain regions. Gene and environment play large roles in such a process. Studies of individuals with genetic disorders such as fragile X syndrome (FXS), which is a disorder caused by a single gene mutation resulting in abnormal dendritic and synaptic pruning, together with healthy individuals may provide valuable information.

Objective  To examine morphometric spatial patterns that differentiate between FXS and controls in early childhood.

Design  A cross-sectional in vivo neuroimaging study.

Setting  Academic medical centers.

Participants  A total of 101 children aged 1 to 3 years, comprising 51 boys with FXS, 32 typically developing boys, and 18 boys with idiopathic developmental delay.

Main Outcome Measures  Regional gray matter volume as measured by voxel-based morphometry and manual tracing, supplemented by permutation analyses; regression analyses between gray and white matter volumes, IQ, and fragile X mental retardation protein level; and linear support vector machine analyses to classify group membership.

Results  In addition to aberrant brain structures reported previously in older individuals with FXS, we found reduced gray matter volumes in regions such as the hypothalamus, insula, and medial and lateral prefrontal cortices. These findings are consistent with the cognitive and behavioral phenotypes of FXS. Further, multivariate pattern classification analyses discriminated FXS from typical development and developmental delay with more than 90% prediction accuracy. The spatial patterns that classified FXS from typical development and developmental delay included those that may have been difficult to identify previously using other methods. These included a medial to lateral gradient of increased and decreased regional brain volumes in the posterior vermis, amygdala, and hippocampus.

Conclusions  These findings are critical in understanding interplay among genes, environment, brain, and behavior. They signify the importance of examining detailed spatial patterns of healthy and perturbed brain development.

Context  Research on psychiatric disturbances in low-birth-weight (LBW) children (≤2500 g), which has focused primarily on the extreme low end of the LBW distribution, has suggested an increased risk of attention, externalizing, and internalizing problems.

Objective  To examine the long-term effects of LBW on psychiatric problems in socially disadvantaged children and in middle-class children.

Design  A stratified random sample assessed at ages 6, 11, and 17 years.

Setting  Random samples of LBW and normal-birth-weight children from newborn discharge lists (1983 through 1985) of 2 major hospitals in southeast Michigan, one serving an inner city and the other serving middle-class suburbs.

Participants  Cohort members with 1 or more assessments (n = 823).

Main Outcome Measures  Attention, internalizing, and externalizing problems rated by mothers and teachers (Child Behavior Checklist and Teacher's Report Form, respectively) at ages 6, 11, and 17 years, using standard cutoffs that identify children with disturbances above the normal range.

Results  Low-birth-weight children had modest excesses of externalizing and internalizing disturbances (adjusted odds ratios = 1.53 and 1.28, respectively) (P = .001 and .02, respectively). An increased risk of attention problems was associated with LBW only in the urban community (adjusted odds ratio = 2.78) (P = .001) and was greater among very LBW children (≤1500 g) than heavier LBW children (1501-2500 g). In the suburban community, there was no increased risk for attention problems associated with LBW. Psychiatric outcomes of LBW did not vary across ages of assessments.

Conclusions  Effects of LBW on psychiatric disturbance appear to be stable through the period of school attendance. The differential effect of LBW on attention problems between the 2 communities suggests the possibility of interplay between prenatal adversity and social environment.

Context  Diffusion tensor imaging (DTI) studies in adults with bipolar disorder (BD) indicate altered white matter (WM) in the orbitomedial prefrontal cortex (OMPFC), potentially underlying abnormal prefrontal corticolimbic connectivity and mood dysregulation in BD.

Objective  To use tract-based spatial statistics (TBSS) to examine WM skeleton (ie, the most compact whole-brain WM) in subjects with BD vs healthy control subjects.

Design  Cross-sectional, case-control, whole-brain DTI using TBSS.

Setting  University research institute.

Participants  Fifty-six individuals, 31 having a DSM-IV diagnosis of BD type I (mean age, 35.9 years [age range, 24-52 years]) and 25 controls (mean age, 29.5 years [age range, 19-52 years]).

Main Outcome Measures  Fractional anisotropy (FA) longitudinal and radial diffusivities in subjects with BD vs controls (covarying for age) and their relationships with clinical and demographic variables.

Results  Subjects with BD vs controls had significantly greater FA (t > 3.0, P ≤ .05 corrected) in the left uncinate fasciculus (reduced radial diffusivity distally and increased longitudinal diffusivity centrally), left optic radiation (increased longitudinal diffusivity), and right anterothalamic radiation (no significant diffusivity change). Subjects with BD vs controls had significantly reduced FA (t > 3.0, P ≤ .05 corrected) in the right uncinate fasciculus (greater radial diffusivity). Among subjects with BD, significant negative correlations (P < .01) were found between age and FA in bilateral uncinate fasciculi and in the right anterothalamic radiation, as well as between medication load and FA in the left optic radiation. Decreased FA (P < .01) was observed in the left optic radiation and in the right anterothalamic radiation among subjects with BD taking vs those not taking mood stabilizers, as well as in the left optic radiation among depressed vs remitted subjects with BD. Subjects having BD with vs without lifetime alcohol or other drug abuse had significantly decreased FA in the left uncinate fasciculus.

Conclusions  To our knowledge, this is the first study to use TBSS to examine WM in subjects with BD. Subjects with BD vs controls showed greater WM FA in the left OMPFC that diminished with age and with alcohol or other drug abuse, as well as reduced WM FA in the right OMPFC. Mood stabilizers and depressed episode reduced WM FA in left-sided sensory visual processing regions among subjects with BD. Abnormal right vs left asymmetry in FA in OMPFC WM among subjects with BD, likely reflecting increased proportions of left-sided longitudinally aligned and right-sided obliquely aligned myelinated fibers, may represent a biologic mechanism for mood dysregulation in BD.

Context  Advancing paternal age has been reported as a risk factor for neurodevelopmental disorders.

Objectives  To determine whether advanced paternal age is associated with an increased risk of BPD in the offspring and to assess if there was any difference in risk when analyzing patients with early-onset BPD separately.

Design  A nationwide nested case-control study based on Swedish registers was performed. Risk for BPD in the offspring of older fathers was estimated using conditional logistic regression analysis controlling for potential confounding of parity, maternal age, socioeconomic status, and parental family history of psychotic disorders.

Setting  Identification of 7 328 100 individuals and their biological parents by linking the nationwide Multigeneration Register and the Hospital Discharge Register.

Participants  A total of 13 428 patients with a BPD diagnosis on at least 2 separate hospital admissions was identified. Five healthy control subjects matched for sex and year of birth were randomized to each case.

Main Outcome Measure  Bipolar disorder based on ICD codes at discharge from hospital treatment.

Results  An association between paternal age and risk for BPD in the offspring of older men was noted. The risk increased with advancing paternal age. After controlling for parity, maternal age, socioeconomic status, and family history of psychotic disorders, the offspring of men 55 years and older were 1.37 (95% confidence interval [CI], 1.02-1.84) times more likely to be diagnosed as having BPD than the offspring of men aged 20 to 24 years. The maternal age effect was less pronounced. For early-onset (<20 years) cases, the effect of paternal age was much stronger (odds ratio, 2.63; 95% CI, 1.19-5.81), whereas no statistically significant maternal age effect was found.

Conclusions  Advanced paternal age is a risk factor for BPD in the offspring. The results are consistent with the hypothesis that advancing paternal age increases the risk for de novo mutations in susceptibility genes for neurodevelopmental disorders.

Context  A role for the centrosome has been suggested in the pathology of major mental illnesses, especially schizophrenia (SZ).

Objectives  To show that pericentriolar material 1 protein (PCM1) forms a complex at the centrosome with disrupted-in-schizophrenia 1 (DISC1) and Bardet-Biedl syndrome 4 protein (BBS4), which provides a crucial pathway for cortical development associated with the pathology of SZ. To identify mutations in the PCM1 gene in an SZ population.

Design  Interaction of DISC1, PCM1, and BBS proteins was assessed by immunofluorescent staining and coimmunoprecipitation. Effects of PCM1, DISC1, and BBS on centrosomal functions and corticogenesis in vivo were tested by RNA interference. The PCM1 gene was examined by sequencing 39 exons and flanking splice sites.

Setting  Probands and controls were from the collection of one of us (A.E.P.).

Patients  Thirty-two probands with SZ from families that had excess allele sharing among affected individuals at 8p22 and 219 white controls.

Main Outcome Measures  Protein interaction and recruitment at the centrosome in cells; neuronal migration in the cerebral cortex; and variant discovery in PCM1 in patients with SZ.

Results  PCM1 forms a complex with DISC1 and BBS4 through discrete binding domains in each protein. DISC1 and BBS4 are required for targeting PCM1 and other cargo proteins, such as ninein, to the centrosome in a synergistic manner. In the developing cerebral cortex, suppression of PCM1 leads to neuronal migration defects, which are phenocopied by the suppression of either DISC1 or BBS4 and are exacerbated by the concomitant suppression of both. Furthermore, a nonsense mutation that segregates with SZ spectrum psychosis was found in 1 family.

Conclusions  Our data further support for the role of centrosomal proteins in cortical development and suggest that perturbation of centrosomal function contributes to the development of mental diseases, including SZ.

Context  Despite 25 years of structural imaging in bipolar disorder, brain regions affected in the disorder are ill defined.

Objectives  To use meta-analytical techniques to investigate structural brain changes in bipolar disorder and to assess the effect of medication use and demographic and clinical variables.

Data Sources  The MEDLINE, EMBASE, and PsycINFO databases were searched from 1980-2007 for studies using magnetic resonance imaging or x-ray computed tomography to compare brain structure in patients with bipolar disorder and controls.

Study Selection  We identified 1471 unique publications from which 141 studies were included in a database and 98 were selected for meta-analysis.

Data Extraction  Twenty-six demographic and clinical variables were extracted from each study where available. For the meta-analysis, mean structure size and standard deviation were extracted for continuous variables, and numbers of patients and controls with an abnormality were extracted for binary variables.

Data Synthesis  Bipolar disorder was associated with lateral ventricle enlargement (effect size = 0.39; 95% confidence interval, 0.24-0.55; P = 8x10^–7) and increased rates of deep white matter hyperintensities (odds ratio = 2.49; 95% confidence interval, 1.64-3.79; P = 2x10^–5) but not periventricular hyperintensities. Gray matter volume increased among patients when the proportion of patients using lithium increased (P = .004). Calculations from this meta-analysis show current imaging studies (which typically examine 8 regions) have a 34% chance of making a type I error. Type II errors are also appreciable (for example, 70% when measuring the lateral ventricular volume in a typical study involving 25 patients and 33 controls).

Conclusions  The meta-analyses revealed robust but regionally nonspecific changes of brain structure in bipolar disorder. Individual studies will remain underpowered unless sample size is increased or improvements in phenotypic selection and imaging methods are made to reduce within-study heterogeneity. The provision of online databases, as illustrated herein, may facilitate a more refined design and analysis of structural imaging data sets in bipolar disorder.

Context  The auditory sensory gating deficit has been considered a leading endophenotype in schizophrenia. However, the commonly used index of sensory gating, P50, has low heritability in families of people with schizophrenia, raising questions about its utility in genetic studies. We hypothesized that the sensory gating deficit may occur in a specific neuronal oscillatory frequency that reflects the underlying biological process of sensory gating. Frequency-specific sensory gating may be less complex than the P50 response, and therefore closer to the direct genetic effects, and thus a more valid endophenotype.

Objectives  To compare the gating of frequency-specific oscillatory responses with the gating of P50 and to compare their heritabilities.

Design  We explored single trial–based oscillatory gating responses in people with schizophrenia, their relatives, and control participants from the community.

Setting  Outpatient clinics.

Participants  Persons with schizophrenia (n = 102), their first-degree relatives (n = 74), and control participants from the community (n = 70).

Main Outcome Measures  Gating of frequency-specific oscillatory responses, gating of the P50 wave, and their heritability estimates.

Results  Gating of the -–band responses of the control participants were significantly different from those with schizophrenia (P < .001) and their first-degree relatives (P = .04 to .009). The heritability of -–band gating was estimated to be between 0.49 and 0.83 and was at least 4-fold higher than the P50 heritability estimate.

Conclusions  Gating of the -–frequency oscillatory signal in the paired-click paradigm is more strongly associated with schizophrenia and has significantly higher heritability compared with the traditional P50 gating. This measure may be better suited for genetic studies of the gating deficit in schizophrenia.