Remitted Major Depressive Disorder Group Research Articles

Association of Lower Rostral Anterior Cingulate GABA+ and Dysregulated Cortisol Stress Response With Altered Functional Connectivity in Young Adults With Lifetime Depression: A Multimodal Imaging Investigation of Trait and State Effects.

Preclinical work suggests that excess glucocorticoids and reduced cortical γ-aminobutyric acid (GABA) may affect sex-dependent differences in brain regions implicated in stress regulation and depressive phenotypes. The authors sought to address a critical gap in knowledge, namely, how stress circuitry is functionally affected by glucocorticoids and GABA in current or remitted major depressive disorder (MDD). Multimodal imaging data were collected from 130 young adults (ages 18-25), of whom 44 had current MDD, 42 had remitted MDD, and 44 were healthy comparison subjects. GABA+ (γ-aminobutyric acid and macromolecules) was assessed using magnetic resonance spectroscopy, and task-related functional MRI data were collected under acute stress and analyzed using data-driven network modeling. Across modalities, trait-related abnormalities emerged. Relative to healthy comparison subjects, both clinical groups were characterized by lower rostral anterior cingulate cortex (rACC) GABA+ and frontoparietal network amplitude but higher amplitude in salience and stress-related networks. For the remitted MDD group, differences from the healthy comparison group emerged in the context of elevated cortisol levels, whereas the MDD group had lower cortisol levels than the healthy comparison group. In the comparison group, frontoparietal and stress-related network connectivity was positively associated with cortisol level (highlighting putative top-down regulation of stress), but the opposite relationship emerged in the MDD and remitted MDD groups. Finally, rACC GABA+ was associated with stress-induced changes in connectivity between overlapping default mode and salience networks. Lifetime MDD was characterized by reduced rACC GABA+ as well as dysregulated cortisol-related interactions between top-down control (frontoparietal) and threat (task-related) networks. These findings warrant further investigation of the role of GABA in the vulnerability to and treatment of MDD.

Everyday emotion regulation goals, motives, and strategies in current and remitted major depressive disorder: An experience sampling study.

People with major depressive disorder (MDD) report difficulties with emotion regulation (ER), particularly in habitual strategy use. We examined ER strategy use and other aspects of ER-desired emotional states (emotion goals) and reasons for ER (ER motives)-in current and remitted MDD. In a 2-week experience sampling study, adults with current MDD (n = 48), remitted MDD (n = 80), and healthy controls (n = 87) reported their negative affect (NA) and positive affect (PA), emotion goals (frequency, direction), ER motives (hedonic, instrumental), and ER strategy use (social sharing, acceptance, savoring, reappraisal, suppression, distraction). Multilevel modeling and Bayes factors were used to assess differences and similarities across groups. Compared to the remitted MDD and control groups, the current MDD group regulated emotion more frequently in general but showed weakened associations between initiating regulation and momentary affect and reported different emotion goal directions. Although all groups mostly reported emotion goals to regulate prohedonically (decrease NA, increase or maintain PA), the current MDD group was the most likely to try to amplify NA and PA simultaneously. Current MDD and remitted MDD groups endorsed hedonic motives more than controls, but the three groups did not differ in instrumental motives. The only group difference in ER strategy use was that the current MDD group used distraction more than controls. Most group differences in ER were between the current MDD group and controls, with the remitted MDD group and controls being quite similar. ER in current MDD is characterized by frequent regulation, weakened association between initiating regulation and momentary affect, increased hedonic-focused ER motives, and a greater use of distraction. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

0647 Rest-activity pattern in Major depressive disorder - a case control study

Abstract Introduction Disruption of rest-activity pattern are important behavioral manifestations in patients with major depressive disorder (MDD). Actigraphy provides accessible and objective measurement on physical activity, sleep, and circadian rhythm, but it was not widely used in studying patients with MDD, especially among Asian population. Methods Rest-activity pattern was recorded by Actiwatch Spectrum Plus/PRO for 7 continuous days. Physical activity and sleep estimation was processed by Philips Actiware software 6. Circadian rhythm characteristics were generated by using the “cosinor” and “nparACT” packages in R to perform the cosinor and nonparametric analysis respectively. Results A total of 70 MDD subjects, and 59 age- and sex-comparable controls were included in the actigraphy data analysis. The mean age of MDD subjects was 51.24 ± 10.39 years, and 71.4% of MDD subjects were female. Of these MDD subjects, 54.3% were unremitted for their depressive illness. For sleep and circadian features, MDD subjects had higher Insomnia Severity Index (ISI score, MDD: 10.29 ± 5.70; controls: 6.05 ± 5.20, P < 0.001) and lower reduced Morningness-Eveningness questionnaire (rMEQ score, MDD: 13.19 ± 4.62; controls: 16.07 ± 3.28, P < 0.001) than controls. The percentage of mobility measured by actigraphy was significantly lower in MDD patients than controls (MDD: 58.58%; controls: 62.27%, P < 0.001), albeit the difference only occurred during rest period. MDD subjects had later acrophase (P = 0.024), M10 midpoint (P = 0.040) and a trend of delayed sleep midpoint (P = 0.076) and longer sleep duration (P = 0.067) than controls. When the comparison was performed among three groups, unremitted MDD subjects showed a higher intra-individual variability of sleep midpoint than remitted MDD group (P = 0.021) and higher intra-individual variability for sleep duration than controls (P = 0.016). Conclusion MDD subjects had increased insomnia and eveningness than controls, which was supported by the acitgraphy data at which MDD had a tendency of longer major rest interval and delayed circadian phase. Unremitted MDD subjects showed a higher intra-individual variability of sleep midpoint and sleep duration. These actigraphy parameters may be useful markers for phenotyping and monitoring of MDD. Support (if any)

Different retrieval mechanisms of overgeneral autobiographical memory for positive and negative cues in remitted major depressive disorder

Background and objectivesOvergeneral autobiographical memory (OGM) has been shown to occur in depressed and previously depressed populations regardless of the emotional valence of cues. However, recent research has pointed out that the retrieval process underlying OGM, generative retrieval (i.e., retrieval requiring effort or additional information) or direct retrieval (i.e., memory that comes to consciousness without effort or additional information), may differ depending on the emotional valence of cues. We examined the hypotheses that a remitted MDD (major depressive disorder), group compared with a control group, would show (a) more direct retrieval of categoric memories for negative cues, (b) more generative retrieval of categoric memories for positive cues, and (c) less direct retrieval of specific memories for positive cues. MethodsA remitted clinical MDD group (n = 21) and control group (n = 21) completed the Autobiographical Memory Test with minimal instruction, and were required to subjectively judge generative retrieval and direct retrieval. ResultsAs expected, results showed that the remitted MDD group reported more frequent direct retrieval of categoric memory for negative cues and more generative retrieval of categoric memory for positive cues than the control group. LimitationsOur paradigm for distinguishing between generative and direct retrieval relied on subjective judgements. ConclusionsThis extends the findings from student sample in previous studies to a help-seeking population. Increased availability of negative categoric memories and the attenuation of positive specific recall represent vulnerabilities for MDD. We discuss how these findings provide further rationale for memory therapeutics for MDD and refinement of those techniques.

Set Shifting and Inhibition Deficits as Potential Endophenotypes for Depression

The etiology of Major Depressive Disorder (MDD) is poorly understood, and identifying endophenotypes, or intermediate processes implicated in pathophysiology, for MDD may inform treatment and identification/prevention efforts. Impaired set-shifting and inhibition are commonly observed in MDD; however, few studies have examined they are endophenotypes for MDD. Thus, the present study tested whether set-shifting and/or inhibition satisfy several endophenotype criteria: specifically, whether they were (1) impaired in current MDD, (2) impaired in remitted MDD, and (3) familial (i.e., correlated within sibling pairs). Set-shifting and inhibition were assessed using subtests from the Delis-Kaplan Executive Function System. Psychopathology was assessed using the Structured Clinical Interview for DSM-5. Results indicated set-shifting deficits were familial and present in both current MDD and in remitted MDD individuals who had no current disorders, suggesting they may be state-independent. Inhibition was familial, but was generally not impaired in current nor remitted MDD (although the remitted MDD group with no current disorders exhibited impairments on one of the two inhibition tasks). These findings indicate that impaired set-shifting is a promising endophenotype candidate for MDD. Findings are limited to young adults, and further research is needed to test generalizability to other populations, evaluate longitudinal relationships, and examine other endophenotype criteria.

Potential structural trait markers of depression in the form of alterations in the structures of subcortical nuclei and structural covariance network properties

It has been proposed recently that major depressive disorder (MDD) could represent an adaptation to conserve energy after the perceived loss of an investment in a vital source, such as group identity, personal assets, or relationships. Energy conserving behaviors associated with MDD may form a persistent marker in brain regions and networks involved in cognition and emotion regulation. In this study, we examined whether subcortical regions and volume-based structural covariance networks (SCNs) have state-independent alterations (trait markers).First-episode drug-naïve currently depressed (cMDD) patients (N = 131), remitted MDD (RD) patients (N = 67), and healthy controls (HCs, N = 235) underwent structural magnetic resonance imaging (MRI). Subcortical gray matter volumes (GMVs) were calculated in FreeSurfer software, and group differences in GMVs and SCN were analyzed.Compared to HCs, major findings were decreased GMVs of left pallidum and pulvinar anterior of thalamus in the cMDD and RD groups, indicative of a trait marker. Relative to HCs, subcortical SCNs of both cMDD and RD patients were found to have reduced small-world-ness and path length, which together may represent a trait-like topological feature of depression.In sum, the left pallidum, left pulvinar anterior of thalamus volumetric alterations may represent trait marker and reduced small-world-ness, path length may represent trait-like topological feature of MDD.

State-Dependent and Trait-Like Characteristics of Dysfunctional Attitudes in Patients With Major Depressive Disorder.

BackgroundStudies have shown that patients with major depressive disorder (MDD) exhibit elevated dysfunctional attitudes (DAs). However, it remains controversial whether the DAs are state-dependent or trait-like features of MDD.MethodsThis study recruited 172 patients and 159 healthy controls (HCs) at baseline. DAs were respectively assessed by the 24-item Hamilton Depression Rating Scale (HAMD24) and the Chinese version of Dysfunctional Attitude Scale form A (C-DAS-A). After baseline, patients received a 6-month antidepressant treatment. General linear models were used to analyze the differences in the C-DAS-A total and factor scores between the acute and remitted MDD groups and the HC group. Paired t tests were used to assess the changes of C-DAS-A total and factor scores in the remitted MDD group before and after treatment.ResultsAt baseline, patients with MDD showed significantly higher scores in C-DAS-A and its subscales than HCs (all P < 0.05). After treatment, the C-DAS-A total and factor scores decreased significantly in the remitted MDD group (all P < 0.05). However, the C-DAS-A total (P = 0.005) and five factors’ scores (vulnerability, attraction and repulsion, perfectionism, compulsion, and dependence) remained elevated in the remitted MDD group as compared with HCs (all P < 0.05). There were moderate correlations between the baseline and remission phase C-DAS-A total and five factors’ scores (all P < 0.05).ConclusionDAs show a mixture of state-dependent and trait-like characteristics in MDD with partial improvement in the remission phase. Special attention should be paid to the residual DAs in the remitted MDD for the prevention of relapse.

Neuroendocrine and Inflammatory Effects of Childhood Trauma Following Psychosocial and Inflammatory Stress in Women with Remitted Major Depressive Disorder

The dysregulation of the inflammatory and neuroendocrine systems seen in major depressive disorder (MDD) may persist after remission and this is associated with a higher risk of relapse. This vulnerable subgroup may be characterized by a history of childhood trauma. In a single-blind randomized placebo-controlled crossover study, 21 women with remitted recurrent MDD and 18 healthy controls were exposed to psychosocial stress (Trier social stress test) or inflammatory stress (typhoid vaccine), or both, to investigate the effects of childhood trauma on the neuroendocrine and inflammatory responses. Childhood trauma was assessed using the Childhood Trauma Questionnaire and participants were dichotomized into a traumatized and non-traumatized group. Serum adrenocorticotropic hormone (ACTH), cortisol, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were measured at regular intervals after each intervention. The effects of trauma, time, and intervention on these parameters were modeled by fitting linear mixed models. Childhood trauma in itself did not have a main effect on the outcome measurements. However, an interactional effect of trauma with stressor type was found in the remitted MDD group: trauma was associated with higher cortisol levels only after adding immunological to psychosocial stress, and with lower TNF-α levels in response to vaccination. This suggests the existence of a vulnerable trauma-associated MDD endophenotype.

Serum level of nerve growth factor is a potential biomarker of conversion to bipolar disorder in women with major depressive disorder

The aim of this study was to identify biomarkers associated with major depressive disorder (MDD) and conversion from MDD to bipolar disorder (BD) in an outpatient sample of women. This was a longitudinal study including women diagnosed with MDD and aged 18 to 60 years. The follow-up was 3 years. The diagnosis was performed using the Mini International Neuropsychiatric Interview Plus. Blood collection was just performed in the first phase. Serum interleukin-6, tumor necrosis factor-α, brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, and nerve growth factor (NGF) levels were measured using a commercial immunoassay kit. We included 156 women. The conversion rate from MDD to BD was 15.4% (n = 24). NGF serum levels were increased in patients who converted to BD compared to the remitted MDD group and current MDD group (P = 0.013). The Bonferroni post-hoc test for multiple comparisons revealed significant differences for higher NGF levels in patients who converted to BD compared to patients with current MDD (P = 0.037). Interleukin-6, tumor necrosis factor-α, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor serum levels did not differ among the groups. Our results suggest that NGF might be a useful biomarker associated with early detection of conversion to BD, helping clinicians in the clinical diagnosis.

State-independent alterations of intrinsic brain network in current and remitted depression

BackgroundIt has been proposed that state-independent, or trait, neurobiological alterations across illness phases may contribute to the high recurrence of major depressive disorder (MDD). Although intrinsic brain network abnormalities have been implicated consistently in MDD neuropathology, MDD state-independent and -dependent resting-state network alterations have not been clearly studied. MethodsResting-state functional magnetic resonance imaging (fMRI) data were collected from 57 medication-naive first-episode current MDD patients, 35 remitted MDD patients, and 66 healthy controls (HCs). Independent component analysis (ICA) was used to extract subnetworks of the default mode network (DMN), central executive network (CEN), and salience network (SN). ResultsRelative to HCs, the current MDD and remitted MDD groups had decreased intra-intrinsic functional connectivity (iFC) in the dorsal lateral prefrontal cortex (dlPFC) of the left CEN, increased inter-FC between the SN and right CEN (rCEN), and decreased inter-FC between the anterior DMN (aDMN) and rCEN. The altered intra-iFC in the left CEN were correlated negatively with the depressive level in the remitted MDD. ConclusionsHypoactivity of the dlPFC in the left CEN, increased inter-FC between the SN and rCEN, and decreased inter-FC between the aDMN and rCEN may reflect state-independent biomarkers of MDD.

Electroencephalography Source Functional Connectivity Reveals Abnormal High-Frequency Communication Among Large-Scale Functional Networks in Depression

BackgroundFunctional magnetic resonance imaging studies of resting-state functional connectivity have shown that major depressive disorder (MDD) is characterized by increased connectivity within the default mode network (DMN) and between the DMN and the frontoparietal network (FPN). However, much remains unknown about abnormalities in higher frequency (>1 Hz) synchronization. Findings of abnormal synchronization in specific frequencies would contribute to a better understanding of the potential neurophysiological origins of disrupted functional connectivity in MDD. MethodsWe used the high temporal resolution of electroencephalography to compare the spectral properties of resting-state functional connectivity in individuals with MDD (n = 65) with healthy control subjects (n = 79) and examined the extent to which connectivity disturbances were evident in a third sample of individuals in remission from depression (n = 30). Exact low resolution electromagnetic tomography was used to compute intracortical activity from regions within the DMN and FPN, and functional connectivity was computed using lagged phase synchronization. ResultsCompared to control subjects, the MDD group showed greater within-DMN beta 2 band (18.5–21 Hz) connectivity and greater beta 1 band (12.5–18 Hz) connectivity between the DMN and FPN. This hyperconnectivity was not observed in the remitted MDD group. However, greater beta 1 band DMN–FPN connectivity was associated with more frequent depressive episodes since first depression onset, even after controlling for current symptom severity. ConclusionsThese findings extend our understanding of the neurophysiological basis of abnormal resting-state functional connectivity in MDD and indicate that elevations in high-frequency DMN–FPN connectivity may be a neural marker linked to a more recurrent illness course.

Decreased Resting-State Activity in the Precuneus Is Associated With Depressive Episodes in Recurrent Depression.

To investigate alterations in resting-state spontaneous brain activity in patients with major depressive disorder (MDD) experiencing multiple episodes. Between May 2007 and September 2014, 24 recurrent and 22 remitted patients diagnosed with MDD with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), and 69 healthy controls matched for age, sex, and educational level participated in this study. Among them, 1 healthy control was excluded due to excessive head motion. The fractional amplitude of low-frequency fluctuation (fALFF) was assessed for all recruited subjects during the completion of resting-state functional magnetic resonance imaging. Relationships between fALFF and clinical measurements, including number of depressive episodes and illness duration, were examined. Compared to patients with remitted MDD and to healthy controls, patients with recurrent MDD exhibited decreased fALFF in the right posterior insula and right precuneus and increased fALFF in the left ventral anterior cingulate cortex. Decreased fALFF in the right precuneus and increased fALFF in the right middle insula were correlated with the number of depressive episodes in the recurrent MDD groups (r = -0.75, P < .01 and r = 0.78, P < .01, respectively) and remitted MDD groups (r = -0.63, P < .01 and r = 0.41, P = .03, respectively). In addition to regions in the default mode network (DMN) and salience network, the altered resting-state activity in the middle temporal and visual cortices was also identified. Altered resting-state activity was observed across several neural networks in patients with recurrent MDD. Consistent with the emerging theory that altered DMN activity is a risk factor for depression relapses, the association between reduced fALFF in the right precuneus and number of depressive episodes supports the role of the DMN in the pathology of recurrent depression.

Olfactory sulcus morphology in patients with current and past major depression

Olfactory deficits have been reported in major depressive disorder (MDD). However, it remains largely unknown whether MDD is associated with abnormalities in olfactory sulcus morphology, a potential marker of olfactory system development. This magnetic resonance imaging study investigated the length and depth of the olfactory sulcus in 29 currently depressed patients, 27 remitted depressed patients, and 33 age- and gender-matched healthy control subjects. Both current and remitted MDD patients had significantly shallower olfactory sulci bilaterally as compared with controls. Only for male subjects, the right olfactory sulcus was significantly shorter in remitted MDD patients than in controls. The right sulcus depth was negatively correlated with number of depressive episodes in the entire MDD group and with residual depressive symptoms in the remitted MDD group. Medication status, presence of melancholia, and comorbidity with anxiety disorders did not affect the sulcus morphology. These findings suggest that abnormality of the olfactory sulcus morphology, especially its depth, may be a trait-related marker of vulnerability to major depression.

Enhanced subgenual cingulate response to altruistic decisions in remitted major depressive disorder.

BackgroundMajor depressive disorder (MDD) is associated with functional abnormalities in fronto-meso-limbic networks contributing to decision-making, affective and reward processing impairments. Such functional disturbances may underlie a tendency for enhanced altruism driven by empathy-based guilt observed in some patients. However, despite the relevance of altruistic decisions to understanding vulnerability, as well as everyday psychosocial functioning, in MDD, their functional neuroanatomy is unknown.MethodsUsing a charitable donations experiment with fMRI, we compared 14 medication-free participants with fully remitted MDD and 15 demographically-matched control participants without MDD.ResultsCompared with the control group, the remitted MDD group exhibited enhanced BOLD response in a septal/subgenual cingulate cortex (sgACC) region for charitable donation relative to receiving simple rewards and higher striatum activation for both charitable donation and simple reward relative to a low level baseline. The groups did not differ in demographics, frequency of donations or response times, demonstrating only a difference in neural architecture.ConclusionsWe showed that altruistic decisions probe residual sgACC hypersensitivity in MDD even after symptoms are fully remitted. The sgACC has previously been shown to be associated with guilt which promotes altruistic decisions. In contrast, the striatum showed common activation to both simple and altruistic rewards and could be involved in the so-called “warm glow” of donation. Enhanced neural response in the depression group, in areas previously linked to altruistic decisions, supports the hypothesis of a possible association between hyper-altruism and depression vulnerability, as shown by recent epidemiological studies.

Difference in amplitude of low-frequency fluctuation between currently depressed and remitted females with major depressive disorder

Medical intervention for major depressive disorder (MDD) can be more appropriately focused through the identification and characterization of neurobiological markers that are specific to the disorder, and this study aims to examine the abnormality in the fractional amplitude of low-frequency fluctuation (fALFF) and the amplitude of low-frequency fluctuation (ALFF) in currently depressed and remitted female MDD patients and to correlate these fluctuations with clinical markers of MDD. Nineteen currently depressed female patients, 19 remitted female patients, as well as 19 age- and education-matched healthy females participated in the resting-state functional magnetic resonance imaging (fMRI) analysis. We compared the fALFF/ALFF maps among the three groups and investigated the correlation between clinical measurements and statistically significant differences in the fALFF/ALFF of various brain regions. Compared with healthy controls, both currently depressed and remitted patients showed increased fALFF/ALFF in the right putamen. Currently depressed MDD patients showed increased fALFF/ALFF in the right ventral median frontal gyrus relative to both the remitted MDD group and the healthy control group. The ALFF of the right precuneus was found to be positively correlated with the number of depressive episodes and the fALFF of the right precuneus to be positively correlated with the disease duration in currently depressed MDD patients. An abnormal fALFF/ALFF in the right ventral median frontal gyrus was found only in currently depressed patients, suggesting that such an anomaly may play a critical role in depressive symptomatology and may be a therapeutic target for MDD. An abnormal fALFF/ALFF in the right putamen is a potential candidate as a trait-related marker of vulnerability to major depression.

Sex differences in physiological and affective responses to stress in remitted depression

Major depressive disorder (MDD) is associated with alterations in stress physiology. Severe melancholic depression is characterized by hypercortisolism, but community dwelling mildly depressed individuals and those with remitted MDD have shown reduced or normal reactivity to stress. There are also pronounced sex differences both in the incidence of MDD and in stress reactivity. To explore the relationships among depression history, sex differences, and stress, we examined stress reactivity in people with and without a history of MDD. Twenty-two participants with remitted MDD (12 men and 10 women) and 36 never depressed comparison participants (22 men and 14 women) participated in the study. Cortisol and alpha-amylase (sAA) were sampled from saliva before, 10 min after, and 30 min after the Trier Social Stress Test (TSST). Participants filled out the Positive Affect Negative Affect Schedule (PANAS) before and after they underwent the TSST. Women with remitted MDD showed reduced cortisol response to the TSST compared with the never MDD women, while men with remitted MDD showed comparable cortisol reactivity to the never depressed men. The groups did not differ on sAA reactivity to stress. The remitted MDD group (overall and men and women separately) reported greater negative affect both before and after stress compared to the never depressed group. Women from both groups reported greater post-stress negative affect than men. In contrast, men from both groups reported higher positive affect before and after stress than women. Given that the sex difference findings were not dependent on depression history, self-reported affective differences in response to stress may predate depressive symptoms and contribute to sex differences in depression incidence.

The structure of past and future lives in depression.

This study assessed the organization of past autobiographical knowledge in individuals with either current major depressive disorder (MDD), MDD in remission, or no history of MDD (the control group). Participants generated personal lists of "life chapters," dividing both their past and potential future into subjectively meaningful episodes or themes (e.g., "married life"). They were then given a list of potentially chapter-descriptive positive or negative attributes and sorted them according to the different chapters. Results revealed that, relative to the control group, MDD participants selected more negative attributes overall, showed greater redundancy for negative attributes (i.e., using the same ones repeatedly across chapters) and reduced redundancy for positive attributes, and exhibited greater compartmentalization (i.e., the negative and positive attributes were clustered separately across different chapters). A similar pattern emerged for the remitted MDD group relative to controls, with the exception of negative redundancy, which was not elevated. For future chapters, there were no group differences. Finally, a greater number of past depressive episodes was associated with increasingly reduced positive redundancy. These data reveal a "depressogenic" structuring of past (but not future) knowledge in MDD that is also evident in a remitted MDD group, with the exception of negative redundancy, which appears to be a marker of the acute state. These findings shed light on important aspects of the organization of past knowledge that are likely to be linked to maladaptive processing biases in those with a depression history.