Never-depressed Subjects Research Articles

Structural brain changes and neuroticism in late-life depression: a neural basis for depression subtypes

The neurobiological basis of neuroticism in late-life depression (LLD) is understudied. We hypothesized that older depressed subjects scoring high in measures of neuroticism would have smaller hippocampal and prefrontal volumes compared with non-neurotic older depressed subjects and with nondepressed comparison subjects based on previous research. Non-demented subjects were recruited and were either depressed with high neuroticism (n = 65), depressed with low neuroticism (n = 36), or never depressed (n = 27). For imaging outcomes focused on volumetric analyses, we found no significant between-group differences in hippocampal volume. However, we found several frontal lobe regions for which depressed subjects with high neuroticism scores had smaller volumes compared with non-neurotic older depressed subjects and with nondepressed comparison subjects, controlling for age and gender. These regions included the frontal pole, medial orbitofrontal cortex, and left pars orbitalis. In addition, we found that non-neurotic depressed subjects had a higher volume of non-white matter hypointensities on T1-weighted images (possibly related to cerebrovascular disease) than did neurotic depressed subjects. Our finding that depressed subjects low in neuroticism had higher volumes of non-white matter hypointensities is consistent with prior literature on "vascular depression." In contrast, the finding that those high in neuroticism had smaller frontal volume than depressed subjects low in neuroticism and never-depressed subjects highlight the importance of frontal circuitry in the subgroup of older depressed individuals with comorbid neuroticism. Together, these results implicate different neural mechanisms in older neurotic and non-neurotic depressed groups and suggest that multiple biological pathologies may lead to different clinical expressions of LLD.

Accelerated brain aging predicts impaired cognitive performance and greater disability in geriatric but not midlife adult depression

Depression is associated with markers of accelerated aging, but it is unclear how this relationship changes across the lifespan. We examined whether a brain-based measure of accelerated aging differed between depressed and never-depressed subjects across the adult lifespan and whether it was related to cognitive performance and disability. We applied a machine-learning approach that estimated brain age from structural MRI data in two depressed cohorts, respectively 170 midlife adults and 154 older adults enrolled in studies with common entry criteria. Both cohorts completed broad cognitive batteries and the older subgroup completed a disability assessment. The machine-learning model estimated brain age from MRI data, which was compared to chronological age to determine the brain–age gap (BAG; estimated age-chronological age). BAG did not differ between midlife depressed and nondepressed adults. Older depressed adults exhibited significantly higher BAG than nondepressed elders (Wald χ2 = 8.84, p = 0.0029), indicating a higher estimated brain age than chronological age. BAG was not associated with midlife cognitive performance. In the older cohort, higher BAG was associated with poorer episodic memory performance (Wald χ2 = 4.10, p = 0.0430) and, in the older depressed group alone, slower processing speed (Wald χ2 = 4.43, p = 0.0354). We also observed a statistical interaction where greater depressive symptom severity in context of higher BAG was associated with poorer executive function (Wald χ2 = 5.89, p = 0.0152) and working memory performance (Wald χ2 = 4.47, p = 0.0346). Increased BAG was associated with greater disability (Wald χ2 = 6.00, p = 0.0143). Unlike midlife depression, geriatric depression exhibits accelerated brain aging, which in turn is associated with cognitive and functional deficits.

Functional Brain Response to Emotional Musical Stimuli in Depression, Using INLA Approach for Approximate Bayesian Inference.

Introduction:One of the vital skills which has an impact on emotional health and well-being is the regulation of emotions. In recent years, the neural basis of this process has been considered widely. One of the powerful tools for eliciting and regulating emotion is music. The Anterior Cingulate Cortex (ACC) is part of the emotional neural circuitry involved in Major Depressive Disorder (MDD). The current study uses functional Magnetic Resonance Imaging (fMRI) to examine how neural processing of emotional musical auditory stimuli is changed within the ACC in depression. Statistical inference is conducted using a Bayesian Generalized Linear Model (GLM) approach with an Integrated Nested Laplace Approximation (INLA) algorithm.Methods:A new proposed Bayesian approach was applied for assessing functional response to emotional musical auditory stimuli in a block design fMRI data with 105 scans of two healthy and depressed women. In this Bayesian approach, Unweighted Graph-Laplacian (UGL) prior was chosen for spatial dependency, and autoregressive (AR) (1) process was used for temporal correlation via pre-weighting residuals. Finally, the inference was conducted using the Integrated Nested Laplace Approximation (INLA) algorithm in the R-INLA package.Results:The results revealed that positive music, as compared to negative music, elicits stronger activation within the ACC area in both healthy and depressed subjects. In comparing MDD and Never-Depressed (ND) individuals, a significant difference was found between MDD and ND groups in response to positive music vs negative music stimuli. The activations increase from baseline to positive stimuli and decrease from baseline to negative stimuli in ND subjects. Also, a significant decrease from baseline to positive stimuli was observed in MDD subjects, but there was no significant difference between baseline and negative stimuli.Conclusion:Assessing the pattern of activations within ACC in a depressed individual may be useful in retraining the ACC and improving its function, and lead to more effective therapeutic interventions.

Do prefrontal midline electrodes provide unique neurophysiologic information in Major Depressive Disorder?

Brain oscillatory activity from the midline prefrontal region has been shown to reflect brain dysfunction in subjects with Major Depressive Disorder (MDD). It is not known, however, whether electrodes from this area provide unique information about brain function in MDD. We examined a set of midline sites and two other prefrontal locations for detecting cerebral activity differences between subjects with MDD and healthy controls. Resting awake quantitative EEG (qEEG) data were recorded from 168 subjects: 47 never-depressed adults and 121 with a current major depressive episode. Individual midline electrodes (Fpz, Fz, Cz, Pz, and Oz) and prefrontal electrodes outside the hairline (Fp1, Fp2) were examined with absolute and relative power and cordance in the theta band. We found that MDD subjects exhibited higher values of cordance (p = 0.0066) at Fpz than controls; no significant differences were found at other locations, and power measures showed trend-level differences. Depressed adults showed higher midline cordance than did never-depressed subjects at the most-anterior midline channel. Salient abnormalities in MDD may be detectable by focusing on the prefrontal midline region, and EEG metrics from focused electrode arrays may offer clinical practicality for clinical monitoring.

Hippocampus Atrophy and the Longitudinal Course of Late-life Depression

Smaller hippocampal volumes are observed in depression but it remains unclear how antidepressant response and persistent depression relate to changes in hippocampal volume. We examined the longitudinal relationship between hippocampal atrophy and course of late-life depression. Academic medical center. Depressed and never-depressed cognitively intact subjects age 60 years or older. Depression severity was measured every three months withthe Montgomery-Asberg Depression Rating Scale (MADRS). Participants also completed cranial 1.5-T magnetic resonance imaging every 2 years. We compared 2-year change in hippocampal volume based on remission status, then in expanded analyses examined how hippocampal volumes predicted MADRS score. In analyses of 92 depressed and 70 never-depressed subjects, over 2 years the cohort whose depression never remitted exhibited greater hippocampal atrophy than the never-depressed cohort. In expanded analyses of a broader sample of 152 depressed elders, depression severity was significantly predicted by a hippocampus× time interaction where smaller hippocampus volumes over time were associated with greater depression severity. Hippocampal atrophy is associated with greater and persistent depression severity. Neuropathological studies are needed to determine if this atrophy is related to the toxic effects of persistent depression or related to underlying Alzheimer disease.

Self-Compassion in Depression: Associations With Depressive Symptoms, Rumination, and Avoidance in Depressed Outpatients

Self-compassion involves being kind to oneself when challenged with personal weaknesses or hardship and has been claimed to be associated with resilience in various areas. So far, there are only a handful of studies that investigate self-compassion and its relation to clinical depression. Therefore, the principal goals of the present study were (a) to compare self-compassion in clinically depressed patients and never-depressed subjects, (b) to investigate self-compassion and its relation to cognitive-behavioral avoidance and rumination in depressed outpatients, and (c) to investigate rumination and avoidance as mediators of the relationship between self-compassion and depressive symptoms. One hundred and forty-two depressed outpatients and 120 never-depressed individuals from a community sample completed a self-report measure of self-compassion along with other measures. Results indicate that depressed patients showed lower levels of self-compassion than never-depressed individuals, even when controlled for depressive symptoms. In depressed outpatients, self-compassion was negatively related to depressive symptoms, symptom-focused rumination, as well as cognitive and behavioral avoidance. Additionally, symptom-focused rumination and cognitive and behavioral avoidance mediated the relationship between self-compassion and depressive symptoms. These findings extend previous research on self-compassion, its relation to depression, as well as processes mediating this relationship, and highlight the importance of self-compassion in clinically depressed patients. Since depressed patients seem to have difficulties adopting a self-compassionate attitude, psychotherapists are well advised to explore and address how depressed patients treat themselves.

Decreased frontal regulation during pain anticipation in unmedicated subjects with major depressive disorder

Major depressive disorder (MDD) is characterized by impaired processing of negative information, possibly due to dysfunction in both, the bottom-up emotional network and top-down modulatory network. By acquiring functional magnetic resonance imaging (fMRI) on a pain-anticipation task, we tested the hypothesis that individuals with MDD would show increased negative biasing that may be associated with reduced frontal connectivity. Thirty-one (15 females) unmedicated young adults with current MDD and 22 (11 females) healthy subjects with no history of MDD were recruited. Groups did not differ significantly in age, race, level of education, marital status or gender distribution. fMRI data were collected during an event-related pain-anticipation paradigm, during which subjects were cued to anticipate painful heat stimuli of high or low intensity. All temperature stimuli were applied to each subject's left forearm. We found that relative to healthy comparison subjects, participants with MDD showed significantly stronger responses to high versus low pain anticipation within right ventral anterior insula (AI), but overlapping response within right dorsal AI, which correlated positively with the depression symptoms severity in the MDD group. Functional connectivity analyses showed increased functional connectivity between dorsal insula and posterior thalamus and decreased functional connectivity between dorsal insula and the right inferior frontal gyrus in the MDD compared with the non-MDD group. Our results demonstrate that unmedicated individuals with current MDD compared with healthy never-depressed subjects show both differential and overlapping response within AI during anticipation of pain. Furthermore, the overlapping insular response is less regulated by frontal brain systems and is more subservient to affective processing regions in the posterior thalamus in MDD. These results support and provide functional validation of the co-occurring enhanced ‘bottom-up' and attenuated ‘top-down' processing of salient, unpleasant emotional information in MDD.

Are Specific Symptoms of Depression Predictive of Alzheimer’s Dementia?

To investigate whether specific symptoms of major depression are associated with later development of possible or probable Alzheimer's dementia. The analysis is part of the Vienna Transdanube Aging Study, a prospective, community-based cohort study of all 75-year-old inhabitants of 2 Viennese districts. Current depressive symptoms were captured with a DSM-IV-TR-based questionnaire. Diagnosis of possible or probable Alzheimer's dementia was performed according to criteria by the National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. The baseline sample included 437 not-demented and not previously depressed individuals. At 60-month follow-up, 65 of the remaining 296 subjects had possible or probable Alzheimer's dementia. The primary outcome measure was the probability of diagnosis of Alzheimer's dementia related to baseline depressive symptoms. Baseline data were collected between May 2000 and December 2002; 60-month follow-up data were collected between June 2005 and February 2008. 10.8% of those who were diagnosed with possible or probable Alzheimer's dementia at 60-month follow-up had shown loss of interest versus 2.2% in the nondemented group. The analysis showed a significant association of loss of interest only with the later occurrence of possible or probable Alzheimer's dementia (adjusted P value <.05, OR = 5.27 [95% CI, 1.62-17.2], area under the receiver operating characteristic curve = 0.541). The specificity of this symptom in predicting Alzheimer's dementia was 97.8, and the sensitivity was 10.4. Of 9 symptoms of depression, only loss of interest was associated with the development of Alzheimer's dementia over a period of 5 years in a sample of 75-year-old not-demented, never-depressed subjects, suggesting that depressive symptoms in the elderly are mostly symptoms of genuine depression.

Cognitive appraisal and life stress moderate the effects of the 5‐HTTLPR polymorphism on amygdala reactivity

The short allele of the serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism is associated with increased amygdala activation in response to emotional stimuli. Although top-down processes may moderate this association, available evidence is conflicting, showing the genotype influence on amygdala reactivity to be either decreased or increased during emotion regulation. Because the effects of the 5-HTTLPR polymorphism on amygdala reactivity are also conditional on self-reported life stress, differences in life stress exposure may account for this apparent discrepancy. Here, we hypothesized that self-reported life stress would moderate the relationships between genotype, cognitive appraisal, and amygdala reactivity. Forty-five healthy never-depressed subjects were presented with emotional stimuli and performed two cognitive tasks: a self-referential task and an emotion-labeling task. Life-stress exposure was measured through a semistructured interview. First, there was a genotype × condition interaction in the right amygdala: short allele carriers displayed increased amygdala activation and decreased functional connectivity with the subgenual anterior cingulate cortex in self-referential processing versus emotion labeling. Second, in line with our hypothesis, there was a genotype × condition × stress interaction in bilateral amygdala the amygdala activation during self-referential processing was negatively correlated with self-reported life stress in short allele carriers and positively in individuals homozygous for the long allele, whereas an opposite pattern was observed during emotion labeling. These results confirm that the influence of the 5-HTTLPR polymorphism on amygdala reactivity is at least partially under cognitive control. Additionally, they suggest that measuring life stress exposure is a critical step when imaging genetics.

Stability of dysfunctional attitudes and early maladaptive schemas: A 9-year follow-up study of clinically depressed subjects

The Dysfunctional Attitude Scale (DAS) and the Young Schema Questionnaire (YSQ) have been suggested as relatively stable vulnerability markers for depression and entrenched psychological disorders, respectively. One-hundred-and-forty-nine clinically depressed (CDs), previously depressed (PDs) and never-depressed subjects (NDs) completed the DAS, the YSQ and the Beck Depression Inventory in the index study and were followed-up nine years later. Results showed: (1) Elevated scores in CDs and PDs as compared to NDs; (2) Some stability of depressive symptoms; (3) Significant moderate test–retest correlations for DAS scales and YSQ scales Disconnection and Impaired Limits, also after controlling for depression severity; (4) A significant reduction in mean score for DAS total, Approval by Others and YSQ scales Disconnection and Impaired Limits; (5) Significant correlations between DAS and YSQ scales. Our results support a state-trait vulnerability model of depression comprising stable differences in availability of dysfunctional attitudes and early maladaptive schemas, but also fluctuating differences in accessibility of those schemas during the course of depression. The findings point to the significance of the YSQ scales as vulnerability markers for depression in addition to the more established DAS scales.

Genetics and personality affect visual perspective in autobiographical memory

Major depression is associated with a decrease of 1st person (versus 3rd person) visual perspective in autobiographical memory, even after full remission. This study aimed to examine visual perspective in healthy never-depressed subjects presenting with either genetic or psychological vulnerability for depression. Sixty healthy participants performed the Autobiographical Memory Test with an assessment of visual perspective. Genetic vulnerability was defined by the presence of at least one S or L G allele of the polymorphism of the serotonin-transporter-linked promoter region (5-HTTLPR). Psychological vulnerability was defined by high scores of harm avoidance measured by the Temperament and Character Inventory. Life stress exposure, depressive mood, rumination, and familial history of depression were assessed through standardized procedures. Visual perspective for positive memories was independently predicted by both harm avoidance and a gene by environment interaction between the 5-HTTLPR polymorphism and life stress exposure. Visual perspective and vulnerability for depression may share some biological bases.

Cognitive vulnerability to depression in never depressed subjects

The purpose of this study was to investigate whether dysfunctional cognitions could be measured in never-depressed individuals after a sad mood prime, and if these dysfunctional cognitions would predict future depression. Subjects were first screened for current or past depression. Never-depressed subjects were randomly assigned to a prime or no-prime condition and completed the Dysfunctional Attitudes Scale. After one month, subjects completed the Beck Depression Inventory. The mood induction was successful in producing a sad mood, but had no effect on accessibility of dysfunctional cognition. Dysfunctional cognitions did predict depressive symptoms one month later, for the women in the sample, but not the men. These results were actually stronger for the unprimed subjects. The results provide some support for the cognitive diathesis-stress model, and suggest that cognitive vulnerability to depression may exist prior to a clinically significant depressive episode. However, mood priming does not appear to be a useful strategy with never-depressed subjects.

Relationship between perceived stigma and depression severity.

The purpose of this study was to explore the relationship between perceived stigma and being in treatment for depression and current depression severity. Face-to-face interviews were conducted with a convenience sample of depressed subjects from a Veterans Administration outpatient mental health clinic (N = 54) and never-depressed subjects from a Veterans Administration primary care clinic (N = 50). Depression severity was measured using the 9-item Primary Care Evaluation of Mental Disorders depression measure. Stigma was measured using the 5-item Stigma Scale for Receiving Psychological Help modified for depression treatment. Statistical analyses included Spearman correlation and multivariate regression. In the correlation analysis, being in treatment for depression compared with never experiencing depression was associated with significantly higher levels of perceived stigma (p <.001). In separate multivariate models controlling for significant univariate correlates, greater depression severity (p <.001) and meeting criteria for current major depression (p <.001) were significant predictors of perceived stigma. Greater depression severity appears to be a strong predictor of perceived stigma.

Understanding Emotion Regulation in Borderline Personality Disorder: Contributions of Neuroimaging

Understanding Emotion Regulation in Borderline Personality Disorder: Contributions of Neuroimaging

Depression and Folate Status in the US Population

Background: Folate deficiency and low folate status have been linked in clinic studies to depression, persistent depressive symptoms, and poor antidepressant response. These relationships have not been demonstrated in general populations. This study examined associations between depression and folate status indicators in an ethnically diverse general US population sample aged 15–39 years. Methods: Healthy subjects whose red blood cell (RBC) folate concentrations had been measured were determined to have no depression (n = 2,526), major depression (n = 301 ), or dysthymia (n = 121) using a diagnostic interview schedule. Serum concentrations of folate and total homocysteine (tHcy) were also measured. Results: After adjustment for sociodemographic factors, serum vitamin B₁₂ concentration, alcohol consumption over the past year and current status as to overweight and use of vitamin/mineral supplements, cigarettes and illegal drugs, subjects who met criteria for a lifetime diagnosis of major depression had folate concentrations in serum and RBCs that were lower than those of subjects who had never been depressed. Subjects who met criteria for dysthymia alone had lower RBC folate concentrations than never-depressed subjects, but the serum folate concentrations of the two groups were comparable. Serum tHcy concentration was not related to lifetime depression diagnoses. Low folate status was found to be most characteristic of recently recovered subjects, and a large proportion of such subjects were folate deficient. Conclusions: Low folate status was detectable in depressed members of the general US population. Folate supplementation may be indicated during the year following a depressive episode.

The Cardiff sib-pair study: suicidal ideation in depressed and healthy subjects and their siblings.

Depression is associated with high rates of suicidal ideation, which varies in intensity from transient thoughts of wishing to be dead to the making of plans and, Finally, to attempts to kill oneself. There is limited evidence from family, twin, and adoption studies that completed suicide is familial and has a genetic etiological component. However, it is unclear whether suicidal ideation is also familial. The familiality of suicidal ideation has been examined in the subjects who participated in the Cardiff Depression Study, namely, 108 depressed probands. their nearest-aged siblings, and 105 healthy control subjects and their siblings. The study showed that 66% of depressed subjects had experienced suicidal ideation in the week prior to the interview, and that this was significantly associated with recurrent illness. Suicidal ideation was not shown to be familial. However, somewhat surprisingly, 6% of healthy, never-depressed subjects admitted to having had transient suicidal thoughts. Suicidal ideation was significantly associated with high neuroticism and psychoticism scores and severe threatening life events.

First-cycle REM density in never-depressed subjects with borderline personality disorder

Background: There is much interest in the identification of polysomnographic markers of liability to the mood disorders that may predate the onset of illness in high-risk subjects, and/or remain altered after remission. One such putative marker is rapid eye movement (REM) density during the first REM period.Methods: Never-depressed subjects with borderline personality disorder (BPD) as a group at high risk for the mood disorders were compared by continuous 48-hour ambulatory electroencephalographic monitoring to age- and gender-matched controls.Results: Subjects with BPD had significantly higher REM density during the first REM period. One man with BPD who later committed suicide had REM density values exceeding the mean value of his group by 2 SD.Conclusions: These data extend the view that REM density in the first REM period can be a marker of liability to the mood disorders, as it is present in a group of young subjects at heightened risk for depression. Biol Psychiatry 1999;45:1056–1058 © 1999 Society of Biological Psychiatry

Cardiac autonomic function during sleep of never-depressed borderline subjects: A pilot study

In a controlled 48 h ambulatory polysomnographic study of never-depressed subjects with DSM-III-R borderline (BDL) personality disorder (PD) we obtained measures of tonic and phasic heart rate variability. Subjects with BDL PD showed a significantly smaller index of tonic heart rate decrease during NREM sleep than normal controls. This is unlikely to be a state-dependent finding and it may derive from relative augmentation of adrenergic function compared to cholinergic function between wakefulness and NREM sleep. Hyperadrenergic states in BDL PD have already been suggested by studies of other biological indicators: a smaller index of tonic heart rate decrease may be a further correlate of core psychobiological dimensions such as impulsivity and affective instability.

Attentional allocation processes in individuals at risk for depression

Cognitive models of depression typically emphasize cognitive schemas as important variables in the depression process. To date, evidence of these schemas is difficult to detect in remitted depressed individuals unless they have specifically been activated by factors such as negative moods. The present study tested one aspect of schema activation, attentional allocation, in individuals who had previously experienced a major depressive episode. Using a dichotic listening task to assess attention to negative and positive stimuli, results indicated no differences in non-mood-primed subjects. For subjects who had been primed by a negative mood induction, formerly depressed individuals evidenced greater error rates for both negative and positive stimuli, while never-depressed subjects evidenced decreased error rates for negative and positive stimuli. These results appear to suggest a schema activation process that is emotionally diffuse but unique to individuals at risk for depression.

Major depression in a nonclinical sample. Demographic and clinical risk factors for first onset.

The relatives, controls, and spouses of affectively ill probands underwent diagnostic examinations on two occasions, 6 years apart. Of 965 subjects who had never been mentally ill when first examined, 11.8% had development of at least one episode of major depression as defined by the Research Diagnostic Criteria during the ensuing 6 years. Subjects younger than 40 years were three times more likely than older subjects to develop depression and women were approximately twice as likely as men to develop depression regardless of age. Marital disruption, a farm setting, and high educational achievement substantially increased the risk of depression among female subjects. Of 214 never-depressed subjects with a history of nonaffective mental disorder, 62 (29.0%) developed major depression. Age and sex were again powerful determinants. The course of prospectively observed secondary depression was more severe than that for primary depression.