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1.  [No title available] 
PMCID: PMC3918432  PMID: 24308926
2.  [No title available] 
PMCID: PMC3921964  PMID: 24290367
3.  The effects of early and sustained intervention on the long-term morbidity of schizophrenia 
Journal of psychiatric research  1998;32(0):169-177.
By examining the literature concerning early intervention with antipsychotic medications, and how it affects long-term morbidity, this article will review the concept that early intervention with antipsychotic medications improves the long-term course of schizophrenia. It also looks at the potential long-term effects of discontinuing antipsychotic medications early in the course of schizophrenia. It appears that early intervention with antipsychotic medications decreases some of the long-term morbidity associated with schizophrenia. Some of the implications of this finding are discussed in the context of both clinical practice and clinical research. “For simple weak-mindedness, which signifies a kind of recovery with defect, it is distinctly enlightening and often confirmed by experience that, sooner or later, a fresh exacerbation of the disease may follow and bring about a higher degree and another form of dementia.”(Kraepelin, 1971, p. 205)
PMCID: PMC4308051  PMID: 9793870
4.  Riluzole likely lacks antidepressant efficacy in ketamine non-responders 
PMCID: PMC4300112  PMID: 25139008
Major depressive disorder; Treatment-resistant depression; Ketamine; Riluzole; Glutamate
5.  Genome-wide Association Studies of Maximum Number of Drinks 
Journal of psychiatric research  2013;47(11):1717-1724.
Maximum number of drinks (MaxDrinks) defined as “Maximum number of alcoholic drinks consumed in a 24-hour period” is an intermediate phenotype that is closely related to alcohol dependence (AD). Family, twin and adoption studies have shown that the heritability of MaxDrinks is approximately 0.5. We conducted the first genome-wide association (GWA) study and meta-analysis of MaxDrinks as a continuous phenotype. 1059 individuals were from the Collaborative Study on the Genetics of Alcoholism (COGA) sample and 1628 individuals were from the Study of Addiction – Genetics and Environment (SAGE) sample. Family sample with 3137 individuals was from the Australian twin-family study of alcohol use disorder (OZALC). Two population-based Caucasian samples (COGA and SAGE) with 1 million single-nucleotide polymorphisms (SNPs) were used for gene discovery and one family-based Caucasian sample was used for replication. Through meta-analysis we identified 162 SNPs associated with MaxDirnks (p < 10−4). The most significant association with MaxDrinks was observed with SNP rs11128951 (p = 4.27×10−8) near SGOL1 gene at 3p24.3. Furthermore, several SNPs (rs17144687 near DTWD2, rs12108602 near NDST4, and rs2128158 in KCNB2) showed significant associations with MaxDrinks (p < 5×10−7) in the meta-analysis. Especially, 8 SNPs in DDC gene showed significant associations with MaxDrinks (p< 5×10−7) in the SAGE sample. Several flanking SNPs in above genes/regions were confirmed in the OZALC family sample. In conclusions, we identified several genes/regions associated with MaxDrinks. These findings can improve the understanding about the pathogenesis of alcohol consumption phenotypes and alcohol-related disorders.
PMCID: PMC4286179  PMID: 23953852
Maximum number of drinks; Genome-wide association; Meta-analysis; SGOL1; DTWD2; NDST4; KCNB2; DDC
6.  Depression is associated with increased sensitivity to signals of disgust: A functional magnetic resonance imaging study 
Journal of psychiatric research  2010;44(14):894-902.
Emotions of fear and disgust are related to core symptoms of depression. The neurobiological mechanisms of these associations are poorly understood. This functional magnetic resonance imaging study aimed at examining the Blood oxygenation level dependent (BOLD) response to facial expressions of fear and disgust in patients with major depressive disorder.
Nine patients in an episode of major depression and nine healthy controls underwent two functional magnetic resonance imaging experiments where they judged the gender of facial identities displaying different degrees (mild, strong) of fear or disgust, intermixed with non-emotional faces.
Compared with healthy controls, patients with depression demonstrated greater activation in left insula, left orbito-frontal gyrus, left middle/inferior temporal gyrus, and right middle/inferior temporal gyrus to expressions of strong disgust. Depressed patients also demonstrated reduced activation in left inferior parietal lobe to mildly fearful faces.
Enhanced activation to facial expressions of disgust may reflect an emotion processing bias that suggests high relevance of emotion of disgust to depression.
PMCID: PMC4282743  PMID: 20307892
Depression; fMRI; Fear; Disgust
7.  DTI-measured white matter abnormalities in adolescents with Conduct Disorder 
Journal of psychiatric research  2013;48(1):10.1016/j.jpsychires.2013.09.015.
Emerging research suggests that antisocial behavior in youth is linked to abnormal brain white matter microstructure, but the extent of such anatomical connectivity abnormalities remain largely untested because previous Conduct Disorder (CD) studies typically have selectively focused on specific frontotemporal tracts. This study aimed to replicate and extend previous frontotemporal diffusion tensor imaging (DTI) findings to determine whether noncomorbid CD adolescents have white matter microstructural abnormalities in major white matter tracts across the whole brain. Seventeen CD-diagnosed adolescents recruited from the community were compared to a group of 24 non-CD youth which did not differ in average age (12–18) or gender proportion. Tract-based spatial statistics (TBSS) fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) measurements were compared between groups using FSL nonparametric two-sample t test, clusterwise whole-brain corrected, p<.05. CD FA and AD deficits were widespread, but unrelated to gender, verbal ability, or CD age of onset. CD adolescents had significantly lower FA and AD values in frontal lobe and temporal lobe regions, including frontal lobe anterior/superior corona radiata, and inferior longitudinal and fronto-occpital fasciculi passing through the temporal lobe. The magnitude of several CD FA deficits was associated with number of CD symptoms. Because AD, but not RD, differed between study groups, abnormalities of axonal microstructure in CD rather than myelination are suggested. This study provides evidence that adolescent antisocial disorder is linked to abnormal white matter microstructure in more than just the uncinate fasciulcus as identified in previous DTI studies, or frontotemporal brain structures as suggested by functional neuroimaging studies. Instead, neurobiological risk specific to antisociality in adolescence is linked to microstructural abnormality in numerous long-range white matter connections among many diverse different brain regions.
PMCID: PMC3863548  PMID: 24139595
8.  Functional Reorganization of Neural Networks during Repeated Exposure to the Traumatic Memory in Posttraumatic Stress Disorder: an Exploratory fMRI Study 
Repeated exposure to the traumatic memory (RETM) is a common component of treatments for posttraumatic stress disorder (PTSD). This treatment is based on a fear extinction model; however, the degree to which this treatment actually engages and modifies neural networks mediating fear extinction is unknown. Therefore, the purpose of the current exploratory study was to define the dynamic changes in neural processing networks while participants completed a novel adaptation of RETM.
Participants were adult women (N=16) with PTSD related to physical or sexual assault. Prior to scanning, participants provided written narratives of a traumatic event related to their PTSD as well as a neutral control event. RETM during fMRI consisted of 5 sequential presentations of the blocked narrative types, lasting three minutes each. Self-reported anxiety was assessed after each presentation.
Relative to changes in functional connectivity during the neutral control script, RETM was associated with strengthened functional connectivity of the right amygdala with the right hippocampus and right anterior insular cortex, left amygdala with the right insular cortex, medial PFC with right anterior insula, left hippocampus with striatum and dorsal cingulate cortex, and right hippocampus with striatum and orbitofrontal cortex. Greater PTSD severity generally led to less changes in functional connectivity with the right insular cortex.
These results provide evidence that RETM engages and modifies functional connectivity pathways with neural regions implicated in fear extinction. The results also implicate the engagement of the right insular cortex and striatum during RETM and suggest their importance in human fear extinction to trauma memories. However, comorbidity in the sample and the lack of a control group limit inferences regarding RETM with PTSD populations specifically.
PMCID: PMC4019667  PMID: 24139810
PTSD; fear extinction; neuroimaging; exposure therapy
9.  Dialectical behavior therapy alters emotion regulation and amygdala activity in patients with borderline personality disorder 
Siever and Davis’ (1991) psychobiological framework of borderline personality disorder (BPD) identifies affective instability (AI) as a core dimension characterized by prolonged and intense emotional reactivity. Recently, deficient amygdala habituation, defined as a change in response to repeated relative to novel unpleasant pictures within a session, has emerged as a biological correlate of AI in BPD. Dialectical behavior therapy (DBT), an evidence-based treatment, targets AI by teaching emotion-regulation skills. This study tested the hypothesis that BPD patients would exhibit decreased amygdala activation and improved habituation, as well as improved emotion regulation with standard 12-month DBT.
Event-related fMRI was obtained pre- and post-12-months of standard-DBT in unmedicated BPD patients. Healthy controls (HCs) were studied as a benchmark for normal amygdala activity and change over time (n = 11 per diagnostic-group). During each scan, participants viewed an intermixed series of unpleasant, neutral and pleasant pictures presented twice (novel, repeat). Change in emotion regulation was measured with the Difficulty in Emotion Regulation (DERS) scale.
fMRI results showed the predicted Group × Time interaction: compared with HCs, BPD patients exhibited decreased amygdala activation with treatment. This post-treatment amygdala reduction in BPD was observed for all three pictures types, but particularly marked in the left hemisphere and during repeated-emotional pictures. Emotion regulation measured with the DERS significantly improved with DBT in BPD patients. Improved amygdala habituation to repeated-unpleasant pictures in patients was associated with improved overall emotional regulation measured by the DERS (total score and emotion regulation strategy use subscale).
These findings have promising treatment implications and support the notion that DBT targets amygdala hyperactivity—part of the disturbed neural circuitry underlying emotional dysregulation in BPD. Future work includes examining how DBT-induced amygdala changes interact with frontal-lobe regions implicated in emotion regulation.
PMCID: PMC4263347  PMID: 25038629
Borderline personality disorder; Emotion regulation; Amygdala; Habituation; fMRI
10.  The Latent Structure of Oppositional Defiant Disorder in Children and Adults 
Journal of psychiatric research  2013;47(12):10.1016/j.jpsychires.2013.08.016.
An understanding of the latent structure of oppositional defiant disorder (ODD) is essential for better developing causal models, improving diagnostic and assessment procedures, and enhancing treatments for the disorder. Although much research has focused on ODD—including recent studies informing the diagnostic criteria for DSM-5—research examining the latent structure of ODD is sparse, and no known study has specifically undertaken a taxometric analysis to address the issue of whether ODD is a categorical or dimensional construct. To address this gap, the authors conducted two separate studies using a set of taxometric analyses with data from the NICHD Study of Early Child Care and Youth Development (child study; N = 969) and with data from a large mixed sample of adults, which included participants reporting psychiatric difficulties as well as healthy controls (adult study; N = 600). The results of a variety of non-redundant analyses across both studies revealed a dimensional latent structure for ODD symptoms among both children and adults. These findings are consistent with previous studies that have examined latent structure of related constructs (e.g., aggression, antisocial behavior) as well as studies that have examined the dimensional versus categorical structure of ODD using methods other than taxometric analysis.
PMCID: PMC3825265  PMID: 24075326
oppositional defiant disorder; taxometric analysis; latent structure
11.  Cognitive decline in short and long sleepers: A prospective population-based study (NEDICES) 
Journal of psychiatric research  2013;47(12):10.1016/j.jpsychires.2013.09.007.
It is not clear whether cognitive decline progresses more quickly in long sleepers than in short sleepers or than in participants with usual sleep duration. We assessed cognitive decline as a function of self-reported sleep duration in a prospective population-based cohort (NEDICES).
Participants were evaluated at baseline and 3 years later. Baseline demographic variables were recorded and participants indicated their daily sleep usual duration as the sum of nighttime sleep and daytime napping. The average daily total usual sleep duration was grouped into three categories: ≤5 hours (short sleepers), 6 to 8 hours (reference category), and ≥9 hours (long sleepers). At baseline and at follow-up, a 37-item version of the Mini-Mental State Examination (37-MMSE) was administered.
The final sample, 2,715 participants (72.9±6.1 years), comprised 298 (11%) short sleepers, 1,086 (40%) long sleepers, and 1,331 (49%) in the reference group (6 to 8 hours). During the three year follow-up period, the 37-MMSE declined by 0.5±4.0 points in short sleepers, 0.6±4.3 points in long sleepers, and 0.2±3.8 points in the reference group (p=0.08). The difference between short sleepers and the reference group was not significant (p=0.142); however, the difference between long sleepers and the reference group was significant (p=0.040). In analyses adjusted for baseline age and other potential confounders, this difference remained robust.
In this study, cognitive test scores among long sleepers declined more rapidly than observed in a reference group. Additional studies are needed to confirm these results.
PMCID: PMC3839098  PMID: 24094933
Cognitive function; elderly; epidemiology; sleep duration; population-based study
12.  Comorbid substance use disorders with other Axis I and II mental disorders among treatment-seeking Asian Americans, Native Hawaiians/Pacific Islanders, and mixed-race people 
Journal of psychiatric research  2013;47(12):10.1016/j.jpsychires.2013.08.022.
Little is known about behavioral healthcare needs of Asian Americans (AAs), Native Hawaiians/Pacific Islanders (NHs/PIs), and mixed-race people (MRs)—the fastest growing segments of the U.S. population. We examined substance use disorder (SUD) prevalences and comorbidities among AAs, NHs/PIs, and MRs (N=4572) in a behavioral health electronic health record database. DSM-IV diagnoses among patients aged 1–90 years who accessed behavioral healthcare from 11 sites were systematically captured: SUD, anxiety, mood, personality, adjustment, childhood-onset, cognitive/dementia, dissociative, eating, factitious, impulse-control, psychotic/schizophrenic, sleep, and somatoform diagnoses. Of all patients, 15.0% had a SUD. Mood (60%), anxiety (31.2%), adjustment (30.9%), and disruptive (attention deficit-hyperactivity, conduct, oppositional defiant, disruptive behavior diagnosis, 22.7%) diagnoses were more common than others (psychotic 14.2%, personality 13.3%, other childhood-onset 11.4%, impulse-control 6.6%, cognitive 2.8%, eating 2.2%, somatoform 2.1%). Less than 1% of children aged <12 years had SUD. Cannabis diagnosis was the primary SUD affecting adolescents aged 12–17. MRs aged 35–49 years had the highest prevalence of cocaine diagnosis. Controlling for age at first visit, sex, treatment setting, length of treatment, and number of comorbid diagnoses, NHs/PIs and MRs were about two times more likely than AAs to have ≥2 SUDs. Regardless of race/ethnicity, personality diagnosis was comorbid with SUD. NHs/PIs with a mood diagnosis had elevated odds of having SUD. Findings present the most comprehensive patterns of mental diagnoses available for treatment-seeking AAs, NHs/PIs, and MRs in the real-world medical setting. In-depth research is needed to elucidate intraracial and interracial differences in treatment needs.
PMCID: PMC3846388  PMID: 24060266
Asian Americans; comorbidity; mixed race; Native Hawaiians; Pacific Islanders; substance use disorder
13.  Altered neural activity of magnitude estimation processing in adults with the fragile X premutation 
Journal of psychiatric research  2013;47(12):10.1016/j.jpsychires.2013.08.014.
Mutations of the fragile X mental retardation 1 (FMR1) gene are the genetic cause of fragile X syndrome (FXS). Expanded CGG trinucleotide repeat (> 200 repeats) result in transcriptional silencing of the FMR1 gene and deficiency/absence of the FMR1 protein (FMRP). Carriers with a premutation allele (55–200 CGG repeats) are often associated with mildly reduced levels of FMRP and/or elevated levels of FMR1 mRNA, and are associated with the risk of developing a neurodegenerative disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). While impairments in numerical processing have been well documented in FXS, recent behavioral research suggests that premutation carriers also present with subtle but significant impairments in numerical processing. Using fMRI, the current study examined whether asymptomatic adults with the premutation would show aberrant neural correlates of magnitude estimation processing in the fronto-parietal area. Using a magnitude estimation task, we demonstrated that activity in the intraparietal sulcus and inferior frontal gyrus, associated with magnitude estimation processing, was significantly attenuated in premutation carriers compared to their neurotypical counterparts despite their comparable behavioral performance. Further, multiple regression analysis using CGG repeat size and FMR1 mRNA indicated that increased CGG repeat size is a primary factor for the decreased fronto-parietal activity, suggesting that reduced FMRP, rather than a toxic gain-of-function effect from elevated mRNA, contributes to altered neural activity of magnitude estimation processing in premutation carriers. In conclusion, we provide the first evidence on the aberrant neural correlates of magnitude estimation processing in premutation carriers accounted for by their FMR1 gene expression.
PMCID: PMC3880247  PMID: 24045061
14.  Blunted Reward Responsiveness in Remitted Depression 
Journal of psychiatric research  2013;47(12):1864-1869.
Major Depressive Disorder has been associated with blunted responsiveness to rewards, but inconsistencies exist whether such abnormalities persist after complete remission. To address this issue, across two independent studies, 47 adults with remitted Major Depressive Disorder (rMDD) and 37 healthy controls completed a Probabilistic Reward Task, which used a differential reinforcement schedule of social or monetary feedback to examine reward responsiveness (i.e., ability to modulate behavior as a function of reinforcement history). Relative to controls, adults with rMDD showed blunted reward responsiveness. Importantly, a history of depression predicted reduced reward learning above and beyond residual depressive (including anhedonic) symptoms and perceived stress. Findings indicate that blunted reward responsiveness endures even when adults are in remission and might be a trait-related abnormality in MDD. More research is warranted to investigate if blunted reward responsiveness may predict future depressive episodes and whether targeting reward-related deficits may prevent the re-occurrence of the disorder.
PMCID: PMC3978009  PMID: 24064208
Reward; Positive Reinforcement; Major Depressive Disorder
15.  Glucocorticoid and Mineralocorticoid Receptor Expression in the Human Hippocampus in Major Depressive Disorder 
Journal of psychiatric research  2012;47(3):307-314.
Approximately 50% of mood disorder patients exhibit hypercortisolism. Cortisol normally exerts its functions in the CNS via binding to mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Both MR and GR are highly expressed in human hippocampus and several studies have suggested that alterations in the levels of MR or GR within this region may contribute to the dysregulation in major depressive disorder (MDD). Studies have also shown functional heterogeneity across the hippocampus, with posterior hippocampus preferentially involved in cognitive processes and anterior hippocampus involved in stress, emotion and affect. We therefore hypothesize that GR and MR expression in hippocampus of control and MDD patients may vary not only with disease, but also with regional specificity along the anterior/posterior axis. Student’s t-test analysis showed decreased expression of MR in the MDD group compared to controls in the anterior, but not the posterior hippocampus, with no significant changes in GR. Linear regression analysis showed a marked difference in MR:GR correlation between suicide and non-suicide patients in the posterior hippocampus. Our findings are consistent with previous reports of hippocampal corticosteroid receptor dysregulation in mood disorders, but extend those findings by analysis across the anterior/posterior axis of the hippocampus. A decrease in MR in the anterior but not posterior hippocampus of MDD patients emphasizes the important functional role of the anterior hippocampus in neuroendocrine regulation in humans.
PMCID: PMC4248661  PMID: 23219281
16.  Pain Interference and Incident Mood, Anxiety, and Substance-Use Disorders: Findings from a Representative Sample of Men and Women in the General Population1 
Journal of psychiatric research  2013;47(11):10.1016/j.jpsychires.2013.08.004.
To examine gender differences in the longitudinal relationship between past-month pain interference and incident mood, anxiety, and substance-use disorders, chi-square tests and binomial logistic regression analyses were performed on data obtained from the National Epidemiologic Survey on Alcohol and Related Conditions from 34,465 adult respondents (47.9% men; 52.1% women) who completed waves 1 (2000–2001) and 2 (2004–2005) data collection. Models were adjusted for potentially confounding factors (i.e., age, race, marital status, educational level, employment, household income, number of stressful life events, number of general medical conditions, and wave-1 psychopathology). Respondents were categorized at wave 1 according to their past-month level of pain interference (i.e., no or low pain interference, moderate pain interference, severe pain interference). Moderate and severe pain interference (as compared to no or low pain interference) in male and female respondents was associated with the incidence of several psychiatric disorders. A stronger relationship was observed in male respondents as compared to female ones between past-month moderate pain interference and a new onset of any mood disorder (OR = 1.57, p = .03) and major depressive disorder (OR = 1.60, p = 0.03), and between past-month severe pain interference and a new onset of alcohol abuse or dependence (OR = 1.69, p = .045) and nicotine dependence (OR = 1.48, p = .04). These findings suggest that providers should consider screening patients with past-month moderate or severe pain interference for mood, anxiety, and substance-use problems and monitor the possible development of subsequent comorbid psychiatric disorders.
PMCID: PMC3835154  PMID: 23992771
pain; mental disorders; incidence; comorbidity; gender
17.  Extinction of Conditioned Fear is Better Learned and Recalled in the Morning than in the Evening 
Journal of psychiatric research  2013;47(11):1776-1784.
Sleep helps emotional memories consolidate and may promote generalization of fear extinction memory. We examined whether extinction learning and memory might differ in the morning and evening due, potentially, to circadian and/or sleep-homeostatic factors. Healthy men (N=109) in 6 groups completed a 2-session protocol. In Session 1, fear conditioning was followed by extinction learning. Partial reinforcement with mild electric shock produced conditioned skin conductance responses (SCR) to 2 differently colored lamps (CS+), but not a third color (CS−), within the computer image of a room (conditioning context). One CS+ (CS+E) but not the other (CS+U) was immediately extinguished by un-reinforced presentations in a different room (extinction context). Delay durations of 3 hr (within AM or PM), 12 hr (morning-to-evening or evening-to-morning) or 24 hr (morning-to-morning or evening-to-evening) followed. In Session 2, extinction recall and contextual fear renewal were tested. We observed no significant effects of the delay interval on extinction memory but did observe an effect of time-of-day. Fear extinction was significantly better if learned in the morning (p=.002). Collapsing across CS+ type, there was smaller morning differential SCR at both extinction recall (p=.003) and fear renewal (p=.005). Morning extinction recall showed better generalization from the CS+E to CS+U with the response to the CS+U significantly larger than to the CS+E only in the evening (p=.028). Thus, extinction is learned faster and its memory is better generalized in the morning. Cortisol and testosterone showed the expected greater salivary levels in the morning when higher testosterone/cortisol ratio also predicting better extinction learning. Circadian factors may promote morning extinction. Alternatively, evening homeostatic sleep pressure may impede extinction and favor recall of conditioned fear.
PMCID: PMC3791331  PMID: 23992769
Sleep; fear conditioning; extinction; circadian rhythm; sleep homeostasis; cortisol; testosterone
18.  Evidence for impaired sound intensity processing during prepulse inhibition of the startle response in a rodent developmental disruption model of schizophrenia 
Journal of psychiatric research  2013;47(11):1630-1635.
A number of studies have implicated disruptions in prepulse inhibition (PPI) of the startle response in both schizophrenia patients and animal models of this disorder. These disruptions are believed to reflect deficits in sensorimotor gating and are ascribed to aberrant filtering of sensory inputs leading to sensory overload and enhanced “noise” in neural structures. Here we examined auditory evoked potentials in a rodent model of schizophrenia (MAM-GD17) during an auditory PPI paradigm to better understand this phenomenon. MAM rats exhibited reductions in specific components of auditory evoked potentials in the orbtiofrontal cortex and an abolition of the graded response to stimuli of differing intensities indicating deficient intensity processing in the orbitofrontal cortex. These data indicate that aberrant sensory information processing, rather than being attributable to enhanced noise in neural structures, may be better attributed to diminished evoked amplitudes resulting in a reduction in the “signal-to-noise” ratio. Therefore, the ability for sensory input to modulate the ongoing background activity may be severely disrupted in schizophrenia yielding an internal state which is insufficiently responsive to external input.
PMCID: PMC3786048  PMID: 23932574
MAM; schizophrenia; prepulse inhibition; auditory evoked potentials; intensity processing
19.  Exposure to Herpes Simplex Virus, type 1 and reduced cognitive function 
Journal of psychiatric research  2013;47(11):10.1016/j.jpsychires.2013.07.010.
Herpes Simplex virus, type 1 (HSV-1) causes cold sores, keratitis and rarely, fatal encephalitis. The infection is life long, with sensory ganglia serving as reservoirs of latent infection. Recently, exposure to HSV-1 has also been repeatedly associated with reduced cognitive function among healthy individuals without prior encephalitis. Though HSV-1 does not elevate risk for schizophrenia (SZ) per se, exposure is likewise associated with impaired cognitive functions among SZ patients. The range of cognitive changes observed in HSV-1 exposed persons has not been investigated systematically, nor is it known whether interaction between HSV-1 exposure and SZ related factors contributes to the impairment among SZ patients. Persons with or without schizophrenia/schizophreniform disorder (N = 298 total, DSM IV criteria) were assessed for HSV-1 exposure using serum HSV-1 antibody titers. The Penn Computerized Neurocognitive battery was used to assess eight cognitive domains with respect to accuracy and speed. There were no significant case-control differences in HSV-1 exposure. The SZ/schizophreniform disorder cases were significantly impaired in all cognitive domains compared with the controls. HSV-1 exposure was also associated with reduced cognitive function in the entire sample, but the magnitude of the effects and their patterns differed from the SZ related changes. Further, statistically significant interactions between HSV-1 exposure and SZ case status were not detected. HSV-1 exposure does not elevate risk for SZ, but it is associated with reduced function in specific cognitive domains regardless of SZ diagnostic status. An ‘epidiagnostic’ model for the association is proposed to explain the results.
PMCID: PMC3809147  PMID: 23920011
schizophrenia; herpes simplex; virus; cognition; HSV-1; memory
20.  Dopaminergic gene polymorphisms and cognitive function in a north Indian schizophrenia cohort 
Journal of psychiatric research  2013;47(11):10.1016/j.jpsychires.2013.07.007.
Associations of polymorphisms from dopaminergic neurotransmitter pathway genes have been reported in Caucasian ancestry schizophrenia (SZ) samples. As studies investigating single SNPs with SZ have been inconsistent, more detailed analyses utilizing multiple SNPs with the diagnostic phenotype as well as cognitive function may be more informative. The analyses were conducted in a north Indian sample.
Indian SZ case-parent trios (n = 601 families); unscreened controls (n= 468) and an independent set of 118 trio families were analyzed. Representative SNPs in the Dopamine D3 receptor (DRD3), dopamine transporter (SLC6A3), vesicular monoamine transporter 2 (SLC18A2), catechol-o-methyltransferase (COMT) and dopamine beta hydroxylase (DBH) were genotyped using SNaPshot/SNPlex assays (n=59 SNPs). The Trail Making Test (TMT) was administered to a subset of the sample (n=260 cases and_n=302 parents).
Eight SNPs were nominally associated with SZ in either case-control or family based analyses (p<0.05, rs7631540 and rs2046496 in DRD3; rs363399 and rs10082463 in SLC18A2; rs4680, rs4646315 and rs9332377 in COMT). rs6271 at DBH was associated in both analyses. Haplotypes of DRD3 SNPs incorporating rs7631540-rs2134655-rs3773678-rs324030-rs6280-rs905568 showed suggestive associations in both case-parent and trio samples. At SLC18A2, rs10082463 was nominally associated with psychomotor performance and rs363285 with executive functions using the TMT but did not withstand multiple corrections.
Though suggestive associations with dopaminergic genes were detected in this study, but convincing links between dopaminergic polymorphisms and SZ or cognitive function were not observed.
PMCID: PMC3831060  PMID: 23932573
Schizophrenia; Dopamine genes; SNPs; association; Haplotypes; cognition
21.  DSM-IV Personality Disorders and Associations with Externalizing and Internalizing Disorders: Results from the National Epidemiologic Survey on Alcohol and Related Conditions 
Journal of psychiatric research  2013;47(11):10.1016/j.jpsychires.2013.07.016.
Although associations between personality disorders and psychiatric disorders are well established in general population studies, their association with liability dimensions for externalizing and internalizing disorders has not been fully assessed. The purpose of this study is to examine associations between personality disorders (PDs) and lifetime externalizing and internalizing Axis I disorders.
Data were obtained from the total sample of 34,653 respondents from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drawing on the literature, a 3-factor exploratory structural equation model was selected to simultaneously assess the measurement relations among DSM-IV Axis I substance use and mood and anxiety disorders and the structural relations between the latent internalizing-externalizing dimensions and DSM-IV PDs, adjusting for gender, age, race/ethnicity, and marital status.
Antisocial, histrionic, and borderline PDs were strong predictors for the externalizing factor, while schizotypal, borderline, avoidant, and obsessive-compulsive PDs had significantly larger effects on the internalizing fear factor when compared to the internalizing misery factor. Paranoid, schizoid, narcissistic, and dependent PDs provided limited discrimination between and among the three factors. An overarching latent factor representing general personality dysfunction was significantly greater on the internalizing fear factor followed by the externalizing factor, and weakest for the internalizing misery factor.
Personality disorders offer important opportunities for studies on the externalizing-internalizing spectrum of common psychiatric disorders. Future studies based on panic, anxiety, and depressive symptoms may elucidate PD associations with the internalizing spectrum of disorders.
PMCID: PMC3881358  PMID: 23932575
DSM-IV personality disorders; DSM-IV substance use, mood, and anxiety disorders; epidemiology; structural equation modeling
22.  The Effect of Odor Valence on Olfactory Performance in Schizophrenia Patients, Unaffected Relatives and At-Risk Youth 
Journal of psychiatric research  2013;47(11):1636-1641.
Given the presence of odor identification impairment in individuals with schizophrenia and recent evidence of aberrant odor hedonic processing, the aim of this investigation was to examine the influence of valence and intensity on odor identification in schizophrenia patients, their first-degree family members, and young persons at clinical risk for psychosis. Participants completed the 16-item Sniffin’ Stick Odor Identification Test. A logistic regression was conducted to assess the influence of valence and intensity on odor identification accuracy. Identification performance in the schizophrenia patients and youths at clinical risk for psychosis was significantly influenced by odor valence, but not intensity. Identification accuracy in first-degree family members was not influenced by valence or intensity. These data suggest that abnormalities in odor valence perception may represent an environmentally-mediated marker for hedonic disturbance that could have predictive utility in future conversion to psychosis. Further research examining the utility of odor valence measures as markers for psychosis risk are warranted.
PMCID: PMC4198303  PMID: 23953754
olfaction; anhedonia; emotion; schizophrenia prodrome; smell identification
23.  Comorbidity of Borderline Personality Disorder and Posttraumatic Stress Disorder in the U.S. Population 
Journal of psychiatric research  2010;44(16):1190-1198.
While placed on different axes of the DSM classification system, borderline personality disorder (BPD) and posttraumatic stress disorder (PTSD) have important relationships with trauma, and overlap between these disorders has long been recognized. The current study is the first to examine comorbidity of PTSD and BPD in a large nationally representative sample using a reliable and valid method of assessing Axis I and II mental disorders. Data came from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) Wave II (N=34,653; response rate 70.2%). Multiple regression models were used to examine differences in psychopathology, traumatic events and health-related quality of life across individuals with PTSD alone (n=1820), BPD alone (n=1290) and those with comorbid PTSD-BPD (n=643). The lifetime prevalence of PTSD and BPD were 6.6% and 5.9%, respectively. Of individuals with BPD, 30.2% were also diagnosed with PTSD, whereas 24.2% of individuals with PTSD were also diagnosed with BPD. Individuals with comorbid PTSD-BPD had a poorer quality of life, more comorbidity with other Axis I conditions, increased odds of a lifetime suicide attempt, and a higher prevalence of repeated childhood traumatic events than individuals with either condition alone. These results show that PTSD and BPD have a high degree of lifetime co-occurrence but are not entirely overlapping. Their concurrence is associated with poorer functioning compared to either diagnosis alone, emphasizing the clinical utility of diagnosing both conditions. Future research should explore the determinants of having either or both diagnoses with an aim toward improved identification, prevention, and intervention.
PMCID: PMC4209725  PMID: 20537660
posttraumatic stress disorder; borderline personality disorder; comorbidity; epidemiology; suicide attempt
24.  Disrupted amygdala-prefrontal functional connectivity in civilian women with posttraumatic stress disorder 
Journal of psychiatric research  2013;47(10):1469-1478.
Many features of posttraumatic stress disorder (PTSD) can be linked to exaggerated and dysregulated emotional responses. Central to the neurocircuitry regulating emotion are functional interactions between the amygdala and the ventromedial prefrontal cortex (vmPFC). Findings from human and animal studies suggest that disruption of this circuit predicts individual differences in emotion regulation. However, only a few studies have examined amygdala-vmPFC connectivity in the context of emotional processing in PTSD. The aim of the present research was to investigate the hypothesis that PTSD is associated with disrupted functional connectivity of the amygdala and vmPFC in response to emotional stimuli, extending previous findings by demonstrating such links in an understudied, highly traumatized, civilian population. 40 African-American women with civilian trauma (20 with PTSD and 20 non-PTSD controls) were recruited from a large urban hospital. Participants viewed fearful and neutral face stimuli during functional magnetic resonance imaging (fMRI). Relative to controls, participants with PTSD showed an increased right amygdala response to fearful stimuli (pcorr<.05). Right amygdala activation correlated positively with the severity of hyperarousal symptoms in the PTSD group. Participants with PTSD showed decreased functional connectivity between the right amygdala and left vmPFC (pcorr <.05). The findings are consistent with previous findings showing PTSD is associated with an exaggerated response of amygdala-mediated emotional arousal systems. This is the first study to show that the amygdala response may be accompanied by disruption of an amygdala-vmPFC functional circuit that is hypothesized to be involved in prefrontal cortical regulation of amygdala responsivity.
PMCID: PMC3743923  PMID: 23827769
PTSD; amygdala; fMRI; functional connectivity; medial prefrontal cortex; emotion
25.  Latent Subtypes of Depression in a Community Sample of Older Adults: Can Depression Clusters Predict Future Depression Trajectories? 
Journal of psychiatric research  2013;47(10):1288-1297.
Identifying sources of heterogeneity in late life depression remains an important focus of psychiatric investigation. Community samples are particularly informative since many older adults have clinically significant depressive symptoms but fail to meet criteria for major depression and older adults generally do not seek treatment for their depressive symptoms. The primary data used for these analyses were those collected in a community-based survey of over 3000 adults age 65 or older followed for up to ten years. Depressive symptoms were measured by the Center for Epidemiologic Studies-Depression scale (CES-D). Latent class analysis was used to identify clusters of participants based on their symptom profiles at baseline. Mixed models were used to examine trajectories of CES-D scores based on cluster assignment. A model with three unique clusters best fit the data. Cluster 1 (59%) had a low probability of any symptom endorsement. Cluster 2 (31%) endorsed as a group some negative affect and somatic symptoms but their endorsement of low positive affect did not differ from Cluster 1. Participants in Cluster 3 (10%) had a higher probability of endorsement of all symptoms compared to Clusters 1 and 2. The results did not appreciably differ when symptom severity was included. Cluster assignment was a significant predictor of change in CES-D score over the ten-year follow-up period, and the effects over time differed by sex. Depressive symptom profiles predict the longitudinal course of depression in a community sample of older adults, findings that are important especially in primary care settings.
PMCID: PMC3743925  PMID: 23806578

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