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1.  Levels-of-processing effect on internal source monitoring in schizophrenia 
Psychological medicine  2006;36(5):641-648.
Recognition can be normalized in schizophrenia by providing patients with semantic organizational strategies through a levels-of-processing (LOP) framework. However, patients may rely primarily on familiarity effects, making recognition less sensitive than source monitoring to the strength of the episodic memory trace. The current study investigates whether providing semantic organizational strategies can also normalize patients’ internal source-monitoring performance.
Sixteen clinically stable medicated patients with schizophrenia and 15 demographically matched healthy controls were asked to identify the source of remembered words following an LOP-encoding paradigm in which they alternated between processing words on a ‘shallow’ perceptual versus a ‘deep’ semantic level. A multinomial analysis provided orthogonal measures of item recognition and source discrimination, and bootstrapping generated variance to allow for parametric analyses. LOP and group effects were tested by contrasting recognition and source-monitoring parameters for words that had been encoded during deep versus shallow processing conditions.
As in a previous study there were no group differences in LOP effects on recognition performance, with patients and controls benefiting equally from deep versus shallow processing. Although there were no group differences in internal source monitoring, only controls had significantly better performance for words processed during the deep encoding condition. Patient performance did not correlate with clinical symptoms or medication dose.
Providing a deep processing semantic encoding strategy significantly improved patients’ recognition performance only. The lack of a significant LOP effect on internal source monitoring in patients may reffect subtle problems in the relational binding of semantic information that are independent of strategic memory processes.
PMCID: PMC4332577  PMID: 16608558
2.  Online peer support for mental health problems in the United States: 2004–2010 
Psychological medicine  2013;43(11):2277-2288.
Help seeking for online peer and other social support in response to depression and other mental health problems offers an electronic technology alternative to traditional mental health care. Here, with nationally representative samples of adult community residents in the USA, we study online peer support help seeking, estimate its occurrence, and investigate depression and other suspected predictors and correlates, some of which might prove to be causal influences.
The data are from nationally representative probability sample surveys of the non-institutionalized US adult population, with a new independent sample assessed via confidential computerized self-assessment modules each year from 2004 to 2010, yielding estimates about online peer support. A total of 264 431 adults participated in these years.
An estimated three per 1000 adults (0.3%) seek online peer support for mental health problems each year (95% confidence interval 0.0022–0.0036). Individuals with depression and/or serious psychological distress are strongly over-represented among these adult online peer support help seekers (odds ratio >7, p<0.001). Associations with college education, being non-Hispanic white, being female, and age are also noteworthy (p<0.05).
Online help seeking for mental health social support is becoming frequent enough for study in large sample national surveys, and might well be fostered by active neuropsychiatric ailments such as depression or other serious psychological distress. Open questions remain about whether the result is beneficial, or conditions required for efficacious online peer support, as might be disclosed in definitive evidence from randomized controlled trials.
PMCID: PMC4327823  PMID: 23410539
Internet self help; major depression; mental health treatment; online discussion forums; online social support; serious psychological distress
3.  Controlled cross-over study in normal subjects of naloxone-preceding-lactate infusions; respiratory and subjective responses: relationship to endogenous opioid system, suffocation false alarm theory and childhood parental loss 
Psychological medicine  2010;41(2):385-393.
The expanded suffocation false alarm theory (SFA) hypothesizes that dysfunction in endogenous opioidergic regulation increases sensitivity to CO2, separation distress and panic attacks. In panic disorder (PD) patients, both spontaneous clinical panics and lactate-induced panics markedly increase tidal volume (TV), whereas normals have a lesser effect, possibly due to their intact endogenous opioid system. We hypothesized that impairing the opioidergic system by naloxone could make normal controls parallel PD patients' response when lactate challenged. Whether actual separations and losses during childhood (childhood parental loss, CPL) affected naloxone-induced respiratory contrasts was explored. Subjective panic-like symptoms were analyzed although pilot work indicated that the subjective aspect of anxious panic was not well modeled by this specific protocol.
Randomized cross-over sequences of intravenous naloxone (2 mg/kg) followed by lactate (10 mg/kg), or saline followed by lactate, were given to 25 volunteers. Respiratory physiology was objectively recorded by the LifeShirt. Subjective symptomatology was also recorded.
Impairment of the endogenous opioid system by naloxone accentuates TV and symptomatic response to lactate. This interaction is substantially lessened by CPL.
Opioidergic dysregulation may underlie respiratory pathophysiology and suffocation sensitivity in PD. Comparing specific anti-panic medications with ineffective anti-panic agents (e.g. propranolol) can test the specificity of the naloxone + lactate model. A screen for putative anti-panic agents and a new pharmacotherapeutic approach are suggested. Heuristically, the experimental unveiling of the endogenous opioid system impairing effects of CPL and separation in normal adults opens a new experimental, investigatory area.
PMCID: PMC4319711  PMID: 20444308
Affective neuroscience; childhood parental loss (CPL); endogenous opioids; panic disorder pathophysiology
4.  [No title available] 
PMCID: PMC3825740  PMID: 23574685
5.  [No title available] 
PMCID: PMC3795869  PMID: 23689064
6.  White-matter tract integrity in late-life depression: associations with severity and cognition 
Psychological medicine  2013;44(7):1427-1437.
Although significant changes in both gray and white matter have been noted in late-life depression (LLD), the pathophysiology of implicated white-matter tracts has not been fully described. In this study we examined the integrity of specific white-matter tracts in LLD versus healthy controls (HC).
Participants aged ≥60 years were recruited from the community. The sample included 23 clinically diagnosed individuals with LLD and 23 HC. White-matter integrity metrics [fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD)] were calculated in the bilateral cingulum and uncinate fasciculus. Depression severity was measured using the Center for Epidemiological Studies Depression Scale (CESD). Composite scores for learning and memory and executive function were created using standardized neuropsychological assessments.
White-matter integrity was lower in LLD versus HC in the bilateral cingulum and right uncinate fasciculus (p≤0.05). In the whole sample, depression severity correlated with integrity in the bilateral cingulum and right uncinate fasciculus (p ≤0.05). In patients, depression severity correlated with the integrity of the left uncinate fasciculus (p=0.03); this tract also correlated with executive function (p=0.02). Among HC, tract integrity did not correlate with depression scores; however, learning and memory correlated with integrity of the bilateral uncinate fasciculus and bilateral cingulum; executive function correlated with the right uncinate and left cingulum (p ≤0.05).
White-matter tract integrity was lower in LLD than in HC and was associated with depression severity across all participants. Tract integrity was associated with cognition in both groups but more robustly among HC.
PMCID: PMC4310501  PMID: 24041297
Aging; cognition; depression; diffusion tensor imaging; late-life depression; white matter
7.  Prefrontal Dysfunction during Emotion Regulation in Generalized Anxiety and Panic Disorder 
Psychological medicine  2012;43(7):1475-1486.
The mechanisms that contribute to emotion dysregulation in anxiety disorders are not well understood. Two common disorders, Generalized Anxiety Disorder (GAD) and Panic Disorder (PD), were examined to test the hypothesis that both disorders are characterized by hypo-activation in prefrontal cortex (PFC) during emotion regulation. A competing hypothesis that GAD in particular is characterized by PFC hyper-activation during emotion regulation (reflecting overactive top-down control) also was evaluated.
Twenty-two medication-free Healthy Control (HC), 23 GAD, and 18 PD participants underwent functional magnetic resonance imaging (fMRI) during a task that required them to reappraise (i.e., reduce) or maintain emotional responses to negative images.
GAD participants reported the least reappraisal use in daily life, and reappraisal use was inversely associated with anxiety severity and functional impairment in these participants. During fMRI, HC demonstrated greater activation during both reappraisal and maintenance than either GAD or PD (who did not differ) in brain areas important for emotion regulation (e.g., dorsolateral and dorsomedial PFC). Furthermore, across all anxious participants, activation during reappraisal in dorsolateral and dorsomedial PFC was inversely associated with anxiety severity and functional impairment.
Emotion dysregulation in GAD and PD may be the consequence of PFC hypo-activation during emotion regulation, consistent with insufficient top-down control. The relationship between PFC hypo-activation and functional impairment suggests that the failure to engage PFC during emotion regulation may be part of the critical transition from dispositionally high anxiety to an anxiety disorder.
PMCID: PMC4308620  PMID: 23111120
8.  Height, weight and body mass index (BMI) in psychiatrically ill US Armed Forces personnel 
Psychological medicine  2003;33(2):363-368.
In both psychiatrically ill and psychiatrically healthy adults, the connection between health and individuals’ height and weight has long been examined. Specifically, research on the idea that individuals with certain body types were prone to particular psychiatric diseases has been explored sporadically for centuries. The hypothesis that psychiatrically ill individuals were shorter and weighed less than psychiatrically healthy counterparts would correspond with the neurodevelopmental model of psychiatric disease.
To evaluate possible links between psychiatric illness and physique, the height, weight and BMI of 7514 patients and 85 940 controls were compared. All subjects were part of the National Collaborative Study of Early Psychosis and Suicide (NCSEPS). Patients were US military active duty personnel hospitalized for either bipolar disorder, major depressive disorder, or schizophrenia and controls were psychiatrically-healthy US military active duty personnel matched for date of entry into the service.
No consistent differences in height, weight or BMI were found between patients and controls, or between patient groups. Some weak ANOVA differences were found between age at the time of entering active duty and weight, as well as BMI, but not height.
Unlike most previous studies that have looked at the links between height and psychiatric illness, this study of the NCSEPS cohort found that, at entry into the US Armed Forces, there were no consistent decreases in height for patients with bipolar disorder, major depressive disorder or schizophrenia compared with a large control group. Furthermore, there were no consistent differences for weight or BMI.
PMCID: PMC4306342  PMID: 12622316
9.  [No title available] 
PMCID: PMC4292836  PMID: 16879759
10.  [No title available] 
PMCID: PMC4291029  PMID: 20346191
11.  Lifetime Prevalence and Comorbidity of Externalizing Disorders and Depression in Prospective Assessment 
Psychological medicine  2013;44(2):10.1017/S0033291713000627.
Epidemiological research is believed to underestimate the lifetime prevalence of mental illness due to recall failure and a lack of rapport between researchers and participants.
In this prospective study, we examined lifetime prevalence and comorbidity rates of substance use disorders, antisocial personality disorder (ASPD), and major depressive disorder (MDD) in a representative, statewide Minnesota sample (N=1252) assessed four times between the ages of 17 and 29 with very low attrition.
Lifetime prevalence rates of all disorders more than doubled from age 17 to age 29 in both men and women, and our prospective rates at age 29 were consistently higher than rates from leading epidemiological surveys. Although there was some variation, the general trend was for lifetime comorbidity to increase between ages 17 and 29, and this trend was significant for MDD-alcohol dependence, MDD-nicotine dependence, and ASPD-nicotine dependence.
Overall, our results show that emerging adulthood is a high-risk period for the development of mental illness, with increases in the lifetime prevalence and comorbidity of mental disorders during this time. More than a quarter of individuals had met criteria for MDD and over a fifth had experienced alcohol dependence by age 29, indicating that mental illness is more common than is estimated in cross-sectional mental health surveys. These findings have important implications for the measurement of economic burden, resource allocation toward mental health services and research, advocacy organizations for the mentally ill, and etiological theories of mental disorders.
PMCID: PMC3797261  PMID: 23590946
12.  Offspring psychopathology following preconception, prenatal, and postnatal maternal bereavement stress 
Psychological medicine  2013;44(1):10.1017/S0033291713000780.
Preconception, prenatal, and postnatal maternal stress are associated with increased offspring psychopathology, but findings are inconsistent and need replication. We estimated associations between maternal bereavement stress and offspring autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, schizophrenia, suicide attempt, and completed suicide.
Using Swedish registers, we conducted the largest population-based study to date examining associations between stress exposure in 738,144 offspring born 1992–2000 for childhood outcomes and 2,155,221 offspring born 1973–1997 for adult outcomes with follow-up through 2009. Maternal stress was defined as death of a first degree relative during 6 months before conception, across pregnancy, or the first two postnatal years. Cox proportional survival analyses were used to obtain hazard ratios (HR) in unadjusted and adjusted analyses.
Marginal increased risk of bipolar disorder and schizophrenia following preconception bereavement stress was not significant. Third trimester prenatal stress increased risk of ASD (adjusted HR=1.58, 95% CI: 1.15–2.17) and ADHD (adjusted HR=1.31, 95% CI: 1.04–1.66). First postnatal year stress increased risk for offspring suicide attempt (adjusted HR=1.13, 95% CI: 1.02–1.25) and completed suicide (adjusted HR=1.51, 95% CI: 1.08–2.11). Bereavement stress during the second postnatal year increased risk of ASD (adjusted HR=1.30, 95% CI: 1.09–1.55).
Further research is needed on associations between preconception stress and psychopathological outcomes. Prenatal bereavement stress increases risk of offspring ASD and ADHD. Postnatal bereavement stress moderately increases risk of offspring suicide attempt, completed suicide, and ASD. Smaller previous studies may have overestimated associations between early stress and psychopathological outcomes.
PMCID: PMC3766407  PMID: 23591021
stress; preconception; prenatal; postnatal; psychiatric; psychopathology; autism; attention-deficit/hyperactivity disorder; schizophrenia; suicide
13.  Natural Course of Cannabis Use Disorders 
Psychological medicine  2014;45(1):63-72.
Despite its importance as a public health concern, relatively little is known about the natural course of cannabis use disorders (CUDs). The primary objective of this research is to provide descriptive data on the onset, recovery, and recurrence functions of CUDs during the high-risk periods of adolescence, emerging adulthood, and young adulthood based on data from a large prospective community sample.
Probands (N = 816) from the Oregon Adolescent Depression Project (OADP) participated in four diagnostic assessments (T1 – T4) between ages 16 and 30, during which current and past CUDs were assessed.
The weighted lifetime prevalence of CUDs was 19.1% with an average onset age of 18.6 years. Although gender was not significantly related to age of initial CUD onset, men were more likely to be diagnosed with a lifetime CUD. Of those diagnosed with a CUD episode, 81.8% eventually achieved recovery during the study period. Women achieved recovery significantly more quickly than men. The recurrence rate (27.7%) was relatively modest, and most likely to occur within the first 36 months following the offset of the first CUD episode. CUD recurrence was uncommon after 72 months of remission and recovery.
CUDs are relatively common, affecting about 1 out of 5 persons in the OADP sample prior to age 30. Eventual recovery from index CUD episodes is the norm, although about 30% of those with a CUD exhibit a generally persistent pattern of problematic use extending 7 years or longer.
PMCID: PMC4229487  PMID: 25066537
Cannabis use disorders; marijuana; natural course; onset; recovery; recurrence; gender differences
14.  The causes of parent–offspring transmission of drug abuse: a Swedish population-based study 
Psychological medicine  2014;45(1):87-95.
While drug abuse (DA) is strongly familial, we still have limited knowledge about the causes of its cross-generational transmission.
We examined DA ascertained from national registers in offspring of three family types from the Swedish population [intact (n=2111074), ‘not-lived-with’ (n = 165315, where biological parents never lived with their offspring) and ‘step’ (n = 124800 offspring)], which reflected, respectively, the effects of genes+rearing, genes only and rearing only. We replicated these results in three high-risk co-relative designs.
Combined across mothers and fathers, the hazard ratio (HR) for DA in offspring given DA in parents was 3.52 in intact, 2.73 in ‘not-lived-with’ and 1.79 in stepfamilies. In 968 biological full or half-sibling pairs one of whom was reared by and the other never lived with their parent with DA, the HR for DA was greater in the reared than ‘not-lived-with’ child (HR 1.57). In 64 offspring pairs of a parent with DA, the HR for DA was greater in a reared biological v. step-parented non-biological child (HR 3.33). In 321 pairs of offspring of a parent with DA one of whom was a not-lived-with biological child and the second a step-parented non-biological child, the HR for DA was greater in the biological v. stepchild (HR 1.80).
Both genetic and environmental factors contribute substantially to parent–offspring resemblance for DA. The general population contains informative family constellations that can complement more traditional adoption designs in clarifying the sources of parent–offspring resemblance.
PMCID: PMC4232482  PMID: 25066684
Adoption; drug abuse; environment; genetics; parent-offspring transmission; Sweden
15.  Reduced gray matter volume in the anterior cingulate, orbitofrontal cortex and thalamus as a function of mild depressive symptoms: a voxel-based morphometric analysis 
Psychological medicine  2014;44(13):2833-2843.
Studies investigating structural brain abnormalities in depression have typically employed a categorical rather than dimensional approach to depression [i.e. comparing subjects with Diagnostic and Statistical Manual of Mental Disorders (DSM)-defined major depressive disorder (MDD) v. healthy controls]. The National Institute of Mental Health, through their Research Domain Criteria initiative, has encouraged a dimensional approach to the study of psychopathology as opposed to an over-reliance on categorical (e.g. DSM-based) diagnostic approaches. Moreover, subthreshold levels of depressive symptoms (i.e. severity levels below DSM criteria) have been found to be associated with a range of negative outcomes, yet have been relatively neglected in neuroimaging research.
To examine the extent to which depressive symptoms – even at subclinical levels – are linearly related to gray matter volume reductions in theoretically important brain regions, we employed whole-brain voxel-based morphometry in a sample of 54 participants.
The severity of mild depressive symptoms, even in a subclinical population, was associated with reduced gray matter volume in the orbitofrontal cortex, anterior cingulate, thalamus, superior temporal gyrus/temporal pole and superior frontal gyrus. A conjunction analysis revealed concordance across two separate measures of depression.
Reduced gray matter volume in theoretically important brain regions can be observed even in a sample that does not meet DSM criteria for MDD, but who nevertheless report relatively elevated levels of depressive symptoms. Overall, these findings highlight the need for additional research using dimensional conceptual and analytic approaches, as well as further investigation of subclinical populations.
PMCID: PMC4280261  PMID: 25066703
Depressive symptoms; DSM; gray matter volume; research domain criteria; voxel-based morphometry
16.  Moderating effects of childhood maltreatment on associations between social information processing and adult aggression 
Psychological medicine  2011;42(6):1293-1304.
Associations between early life maltreatment, social information processing (SIP) and aggression in childhood and adolescence have been widely documented. Few studies have examined the importance of childhood maltreatment independent of SIP in the etiology of adult aggression. Furthermore, moderating effects of childhood maltreatment on the SIP–aggression links have not been explored.
Hierarchical, multi-level models were fitted to data from n=2752 twins aged 20–55 years from the PennTwins Cohort. Adult aggression was assessed with the Life History of Aggression questionnaire. Childhood maltreatment was measured using the Childhood Trauma Questionnaire. Two aspects of SIP were examined : hostile attribution biases (HAB) ; negative emotional responses (NER).
Childhood maltreatment was positively correlated with adult aggression, independently of HAB and NER. In addition, childhood maltreatment moderated the relationships between both aspects of SIP and adult aggression. Specifically, the relationship between NER and aggression was stronger among individuals with higher levels of childhood maltreatment and NER was not associated with aggression for adults who experienced low levels of childhood maltreatment. Moderating effects of childhood maltreatment on the NER–aggression link were supported for total childhood maltreatment, emotional neglect and emotional abuse. In contrast, HAB was more strongly associated with adult aggression at lower levels of emotional abuse and physical neglect.
The current study provides insight into the mechanisms by which early life experiences influence adult aggression. Our findings suggest that childhood maltreatment may not only lead to increased levels of aggression in adulthood but may also modify the associations between SIP and adult aggression.
PMCID: PMC4255557  PMID: 22008562
Adult aggression; childhood maltreatment; hostile attribution biases; moderation; negative emotional responses
17.  Chronic stressors and trauma: prospective influences on the course of bipolar disorder 
Psychological medicine  2013;43(12):10.1017/S0033291713000147.
Exposure to life stress is known to adversely impact the course of bipolar disorder. Few studies have disentangled the effects of multiple types of stressors on the longitudinal course of bipolar I disorder. This study examines whether severity of chronic stressors and exposure to trauma are prospectively associated with course of illness among bipolar patients.
One hundred and thirty-one participants diagnosed with bipolar I disorder were recruited through treatment centers, support groups and community advertisements. Severity of chronic stressors and exposure to trauma were assessed at study entry with in-person interviews using the Bedford College Life Event and Difficulty Schedule (LEDS). Course of illness was assessed by monthly interviews conducted over the course of 24 months (over 3000 assessments).
Trauma exposure was related to more severe interpersonal chronic stressors. Multiple regression models provided evidence that severity of overall chronic stressors predicted depressive but not manic symptoms, accounting for 7.5% of explained variance.
Overall chronic stressors seem to be an important determinant of depressive symptoms within bipolar disorder, highlighting the importance of studying multiple forms of life stress.
PMCID: PMC3748240  PMID: 23419615
Bipolar disorder; disease progression; prospective studies; social environment; stress
18.  Cognition in schizophrenia and schizo-affective disorder: impairments that are more similar than different 
Psychological medicine  2013;43(12):2535-2545.
Cognition is increasingly being recognized as an important aspect of psychotic disorders and a key contributor to functional outcome. In the past, comparative studies have been performed in schizophrenia and schizo-affective disorder with regard to cognitive performance, but the results have been mixed and the cognitive measures used have not always assessed the cognitive deficits found to be specific to psychosis. A set of optimized cognitive paradigms designed by the Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRACS) Consortium to assess deficits specific to schizophrenia was used to measure cognition in a large group of individuals with schizophrenia and schizo-affective disorder.
A total of 519 participants (188 with schizophrenia, 63 with schizo-affective disorder and 268 controls) were administered three cognitive paradigms assessing the domains of goal maintenance in working memory, relational encoding and retrieval in episodic memory and visual integration.
Across the three domains, the results showed no major quantitative differences between patient groups, with both groups uniformly performing worse than healthy subjects.
The findings of this study suggests that, with regard to deficits in cognition, considered a major aspect of psychotic disorder, schizophrenia and schizo-affective disorder do not demonstrate major significant distinctions. These results have important implications for our understanding of the nosological structure of major psychopathology, providing evidence consistent with the hypothesis that there is no natural distinction between cognitive functioning in schizophrenia and schizo-affective disorder.
PMCID: PMC4149253  PMID: 23522057
Cognitive performance; diagnostic validity; goal maintenance; memory encoding; nosology; psychosis; visual processing
19.  A genetically informative developmental study of the relationship between conduct disorder and peer deviance in males 
Psychological medicine  2007;38(7):1001-1011.
Conduct disorder (CD) and peer deviance (PD) both powerfully predict future externalizing behaviors. Although levels of CD and PD are strongly correlated, the causal relationship between them has remained controversial and has not been examined by a genetically informative study.
Levels of CD and PD were assessed in 746 adult male–male twin pairs at personal interview for ages 8–11, 12–14 and 15–17 years using a life history calendar. Model fitting was performed using the Mx program.
The best-fit model indicated an active developmental relationship between CD and PD including forward transmission of both traits over time and strong causal relationships between CD and PD within time periods. The best-fit model indicated that the causal relationship for genetic risk factors was from CD to PD and was constant over time. For common environmental factors, the causal pathways ran from PD to CD and were stronger in earlier than later age periods.
A genetically informative model revealed causal pathways difficult to elucidate by other methods. Genes influence risk for CD, which, through social selection, impacts on the deviance of peers. Shared environment, through family and community processes, encourages or discourages adolescent deviant behavior, which, via social influence, alters risk for CD. Social influence is more important than social selection in childhood, but by late adolescence social selection becomes predominant. These findings have implications for prevention efforts for CD and associated externalizing disorders.
PMCID: PMC4248600  PMID: 17935643
Conduct disorder; genetics; peer deviance; twin studies
20.  Associations of current and remitted major depressive disorder with brain atrophy: the AGES-Reykjavik Study 
Psychological medicine  2012;43(2):317-328.
To examine whether lifetime DSM-IV diagnosis of major depressive disorder (MDD), including age at onset and number of episodes, is associated with brain atrophy in older persons without dementia.
Within the population-based AGES-Reykjavik Study 4,354 persons (mean age 76±5 years, 58% women) without dementia had a 1.5Tesla brain MRI. Automated brain segmentation total and regional brain volumes were calculated. History of MDD, including age at onset and number of episodes, and MDD in the past 2 weeks was diagnosed according to DSM-IV criteria using the MINI International Neuropsychiatric Interview.
Of the total sample, 4.5% reported a lifetime history of MDD; 1.5% had a current diagnosis of MDD (including 75% with a prior history of depression) and 3.0% had a past but no current diagnosis (remission). After adjusting for multiple covariates, compared to participants never depressed, those with current MDD (irrespective of past) had more global brain atrophy (B=−1.25%; 95%CI −2.05 to −0.44%), including more gray and white matter atrophy in most lobes as well as more atrophy of the hippocampus and thalamus. Participants with current, first onset, MDD also had more brain atrophy (B=−1.62%; 95%CI −3.30 to 0.05%), while those remitted did not (B=0.06%; 95%CI −0.54 to 0.66%).
In older persons without dementia, current MDD, irrespective of prior history, but not remitted MDD, was associated with widespread gray and white matter brain atrophy. Prospective studies should examine whether MDD is a consequence of or contributes to brain volume loss and development of dementia.
PMCID: PMC4244840  PMID: 22647536
22.  Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twins 
Psychological medicine  2012;43(9):1813-1823.
Childhood adverse experiences are known to induce persistent changes in the hypothalamic–pituitary–adrenal (HPA) axis reactivity to stress. However, the mechanisms by which these experiences shape the neuroendocrine response to stress remain unclear.
We tested whether bullying victimization influenced serotonin transporter gene (SERT) DNA methylation using a discordant monozygotic (MZ) twin design. A subsample of 28 MZ twin pairs discordant for bullying victimization, with data on cortisol and DNA methylation, were identified in the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative 1994–1995 cohort of families with twins.
Bullied twins had higher SERT DNA methylation at the age of 10 years compared with their non-bullied MZ co-twins. This group difference cannot be attributed to the children’s genetic makeup or their shared familial environments because of the study design. Bullied twins also showed increasing methylation levels between the age of 5 years, prior to bullying victimization, and the age of 10 years whereas no such increase was detected in non-bullied twins across time. Moreover, children with higher SERT methylation levels had blunted cortisol responses to stress.
Our study extends findings drawn from animal models, supports the hypothesis that early-life stress modifies DNA methylation at a specific cytosine–phosphate–guanine (CpG) site in the SERT promoter and HPA functioning and suggests that these two systems may be functionally associated.
PMCID: PMC4231789  PMID: 23217646
Bullying; childhood victimization; cortisol; DNA methylation; hypothalamic–pituitary–adrenal axis; SERT
23.  The structure of depression, anxiety and somatic symptoms in primary care 
Psychological medicine  2011;42(1):15-28.
Observed co-morbidity among the mood and anxiety disorders has led to the development of increasingly sophisticated dimensional models to represent the common and unique features of these disorders. Patients often present to primary care settings with a complex mixture of anxiety, depression and somatic symptoms. However, relatively little is known about how somatic symptoms fit into existing dimensional models.
We examined the structure of 91 anxiety, depression and somatic symptoms in a sample of 5433 primary care patients drawn from 14 countries. One-, two- and three-factor lower-order models were considered; higher-order and hierarchical variants were studied for the best-fitting lower-order model.
A hierarchical, bifactor model with all symptoms loading simultaneously on a general factor, along with one of three specific anxiety, depression and somatic factors, was the best-fitting model. The general factor accounted for the bulk of symptom variance and was associated with psychosocial dysfunction. Specific depression and somatic symptom factors accounted for meaningful incremental variance in diagnosis and dysfunction, whereas anxiety variance was associated primarily with the general factor.
The results (a) are consistent with previous studies showing the presence and importance of a broad internalizing or distress factor linking diverse emotional disorders, and (b) extend the bounds of internalizing to include somatic complaints with non-physical etiologies.
PMCID: PMC4221083  PMID: 21682948
Anxiety; bifactor model; depression; diagnosis; somatization
24.  A Population-based Longitudinal Study of Childhood Neurodevelopmental Disorders, IQ and Subsequent Risk of Psychotic Experiences in Adolescence 
Psychological medicine  2014;44(15):3229-3238.
Schizophrenia has a neurodevelopmental component to its origin, and may share overlapping pathogenic mechanisms with childhood neurodevelopmental disorders (ND). Yet longitudinal studies of psychotic outcomes among individuals with ND are limited. We report a population-based prospective study of six common childhood ND, subsequent neurocognitive performance and the risk of psychotic experiences (PEs) in early adolescence.
PEs were assessed by semi-structured interviews at age 13 years. IQ and working memory were measured between ages 9 and 11 years. The presence of six neurodevelopmental disorders (autism spectrum, dyslexia, dyspraxia, dysgraphia, dysorthographia, dyscalculia) was determined from parent-completed questionnaire at age 9 years. Linear regression calculated mean difference in cognitive scores between those with and without ND. The association between ND and PEs was expressed as odds ratio (OR); effects of cognitive deficits were examined. Potential confounders included age, gender, father’s social class, ethnicity and maternal education.
Out of 8,220 children, 487 (5.9%) were reported to have ND at age 9 years. Children with, compared with those without ND performed worse on all cognitive measures; adjusted mean difference in total IQ 6.84 (95% CI 5.00- 8.69). The association between total IQ and ND was linear (p<0.0001). The risk of PEs was higher in those with, compared with those without ND; adjusted OR for definite PEs 1.76 (95% CI 1.11- 2.79). IQ (but not working memory) deficit partly explained this association.
Higher risk of PEs in early adolescence among individuals with childhood ND is consistent with the neurodevelopmental hypothesis of schizophrenia.
PMCID: PMC4180723  PMID: 25066026
Neurodevelopmental Disorder; Dyslexia; Dyspraxia; Autism; Autism Spectrum Disorder; Dyscalculia; Dysgraphia; Dysorthographia; Childhood; Psychotic Experiences; Psychotic Symptoms; IQ; Working Memory; Neurodevelopment; Neurocognitive Performance; Schizophrenia; Psychotic Disorder; Mediation Analysis; Risk; Birth Cohort Study; ALSPAC
25.  Remission, continuation, and incidence of eating disorders during early pregnancy: A validation study on a population-based birth cohort 
Psychological medicine  2012;43(8):1723-1734.
The objective of this study was to validate previously published rates of remission, continuation, and incidence of broadly defined eating disorders during pregnancy. The previous rate modeling was done by our group (Bulik et al. 2007) and yielded participants halfway into recruitment of the planned 100,000 pregnancies in the Norwegian Mother and Child (MoBa) Cohort at the Norwegian Institute of Public Health. This study aimed to internally validate the findings with the completed cohort.
77267 pregnant women enrolled at 17 weeks gestation between 2001 and 2009 were included. Participants were split into a “training” sample (n=41243) based on participants in the MoBa version 2 dataset of the original study and a “validation” sample (n=36024) comprising individuals in the MoBa version 5 dataset that were not in the original study (Bulik et al. 2007). Internal validation of all original rate models involved fitting a calibration model to compare model parameters between the “training” and “validation” samples as well as bootstrap estimates of bias in the entire version 5 dataset.
Remission, continuation, and incidence estimates from the “training” sample remained stable when evaluated via a split sample validation procedure. Pre-pregnancy prevalence estimates in the “validation” sample were 0.1% for anorexia nervosa, 1.0% for bulimia nervosa (BN), 3.3% for binge eating disorder (BED), and 0.1% for purging disorder (EDNOS-P). In early pregnancy, estimates were 0.2% for BN, 4.8% for BED, and <0.01% for EDNOS-P. Consistent with the original study, incident BN and EDNOS-P during pregnancy were rare. For BED, the adjusted incidence rate in the “validation” sample was 1.17 per 1000 person-weeks. The highest rates were for full or partial remission for BN and EDNOS-P, and continuation for BED.
This study provides evidence of validity of previously estimated rates of remission, continuation, and incidence of eating disorders during pregnancy. Eating disorders during pregnancy were relatively common, occurring in nearly 1 in every 20 women, although almost all were cases of BED. Pregnancy was a window of remission from BN but a window of vulnerability for onset and continuation of BED. Training to detect the signs and symptoms of eating disorders by obstetricians/gynecologists and interventions to enhance pregnancy and neonatal outcomes warrant attention.
PMCID: PMC4206832  PMID: 23164164
Eating disorders; epidemiology; incidence; pregnancy; prospective; remission; The Norwegian Mother and Child Cohort Study

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