Recurrent Major Depressive Disorder Research Articles

Treatment of Patient with Recurrent Major Depressive Disorder: A Case Report

Introduction: The alteration of biogenic amines, in particular norepinephrine and serotonin, is a hypothesis that is frequently put forward in relation to the etiology of major depressive disorder. This study was aimed to present the recurrent major depressive disorder in a forty years old woman. Case presentation: A 40-year-old woman, presented to our mental health unit with symptoms of a low mood, which she described as similar to previous episodes of depression. Two decades ago, she underwent an evaluation and received a diagnosis of severe depression for the first time. Throughout that duration, she received imipramine (tricyclic antidepressant/TCA) at dosages of up to 150 mg per day, resulting in favorable outcomes. She claimed that she abstained from illicit substances and has not undergone any distressing events in the recent past. Although she was confident that she was experiencing another severe depression, she expressed a desire to avoid using imipramine this time due to its adverse effects, including dry mouth, dry eyes, and diarrhea. The patient was diagnosed as recurrent major depressive disorder without psychotic symptoms. Conclusion: The likelihood of experiencing additional bouts of major depression is higher when there have been multiple prior episodes, residual symptoms of depression between episodes, and the coexistence of other psychiatric or chronic medical conditions. Prior episodes of serious depression that responded well to treatment have a greater probability of reaching remission in future episodes. First-line treatment options for major depressive disorder include selective serotonin reuptake inhibitors (SSRIs) such as bupropion, venlafaxine, mirtazapine, and duloxetine.

Abstract PS04-06: Breast cancer recurrence among women with pre-diagnostic major depression and co-existing substance abuse disorder: A retrospective study in the United States Veterans Health Administration Cohort

Abstract Background: Our prior study observed a 34% higher risk of breast cancer (BC) recurrence among women with major depressive disorder (MDD) at the time of their BC diagnosis compared to women without MDD after adjusting for sociodemographic, clinical, and prognostic factors. Given the high prevalence of substance abuse disorders among individuals with MDD and the positive association between alcohol use and mortality among BC survivors, we were interested to examine whether the risk of BC recurrence was compounded for women with both conditions. Objective: To investigate whether pre-diagnostic substance abuse disorders modify the association between MDD and BC recurrence. Methods: We established a retrospective cohort of women (age ≥ 18 years) with incident, early-stage BC diagnosed from 2010 through 2019 using the VHA’s electronic medical record database. A two-year window was used to identify women with MDD and co-existing substance abuse disorders prior to their BC diagnosis. We examined potential interactions between MDD and alcohol abuse and MDD and other substance abuse using multivariable proportional hazards regression, accounting for competing risk of death. Our outcome of interest was BC recurrence. The reference group for all analyses was women with BC alone. The models were adjusted for patient characteristics including age, race, ethnicity, marital status, rurality of primary residence, priority group rating (proxy for socioeconomic status), any homelessness or economic problems, comorbidity burden, body mass index, smoking status, receipt of a screening mammography, year of BC diagnosis, cancer stage, cancer subtype, and cancer treatment. Subgroup analyses were conducted by cancer subtype. Results: Our cohort comprised 6,045 women with BC, of whom 1,754 (29%) had a pre-diagnostic MDD diagnosis and 1,509 (25%) had a substance abuse disorder. Among women with MDD, 386 (22%) abused alcohol and 336 (19%) abused other substances. The median length of follow-up from BC diagnosis was 4.5 years (IQR=4.8 years). The average age at BC diagnosis was 57 years (SD=11 years) overall, 56 years (SD=10 years) among women with MDD, and 57 years (SD=9 years) among women with substance abuse disorders. On multivariable analysis, MDD (HR=1.33; 95% CI: 1.14, 1.53), alcohol abuse disorder (HR=1.37; 95% CI: 1.12, 1.68), and other substance abuse disorders (HR=1.33; 95% CI: 1.13, 1.56) were independent risk factors for BC recurrence. Further, there was a statistically significant interaction between pre-diagnostic MDD and alcohol abuse disorder (p-interaction=0.003). Women with BC who had both pre-diagnostic MDD and alcohol abuse disorder were at a 65% (HR=1.65; 95% CI: 1.29, 2.11) higher risk of BC recurrence compared to women with BC alone. A statistically significant interaction was also observed between pre-diagnostic MDD and other substance abuse disorders (p-interaction < 0.001). Women with BC who had both pre-diagnostic MDD and other substance abuse disorders were at a 90% (HR=1.90; 95% CI: 1.50, 2.42) higher risk of BC recurrence compared to women with BC alone. In subgroup analyses, the interaction between MDD and alcohol abuse disorders (p-interaction=0.001) and MDD and other substance abuse disorders (p-interaction < 0.001) was limited to women with estrogen receptor positive cancer but not estrogen receptor negative cancer. Conclusion: Women with incident BC who have prior diagnoses of both MDD and substance abuse disorder are at higher risk of recurrence than women with either exposure independently. Further research is needed to examine the etiology of our findings and to evaluate whether this newly defined risk group would benefit from closer monitoring and more tailored treatment options. Citation Format: Maya Aboumrad, Kala Visvanathan. Breast cancer recurrence among women with pre-diagnostic major depression and co-existing substance abuse disorder: A retrospective study in the United States Veterans Health Administration Cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS04-06.

Tissue-specific gene expression of genome-wide significant loci associated with major depressive disorder subtypes

Major depressive disorder (MDD) is a clinically and genetically heterogeneous disorder. To reduce heterogeneity, large-scale genome-wide association studies have recently identified genome-wide significant loci associated with seven MDD subtypes. However, it was unclear in which tissues the genes near those loci are specifically expressed. We investigated whether genes related to specific MDD subtypes would be preferably expressed in a specific tissue. At 14 novel subtype-specific loci related to seven MDD subtypes—(1) non-atypical-like features MDD, (2) early-onset MDD, (3) recurrent MDD, (4) MDD with suicidal thoughts, (5) MDD without suicidal thoughts, (6) MDD with moderate impairment, and (7) postpartum depression, we investigated whether 22 genome-wide significant genetic variant-mapped genes were tissue-specifically expressed in brain, female reproductive, male specific, cardiovascular, gastrointestinal, or urinary tissues in the Genotype-Tissue Expression (GTEx) subjects (n ≤ 948). To confirm the tissue-specific expression in the GTEx, we used independent Human Protein Atlas (HPA) RNA-seq subjects (n ≤ 95). Of 22 genes, nine and five genes were tissue-specifically expressed in brain and female reproductive tissues, respectively (p < 2.27 × 10−3). RTN1, ERBB4, and AMIGO1 related to early-onset MDD, recurrent MDD, or MDD with suicidal thoughts were highly expressed in brain tissues (d = 1.19–2.71), while OAS1, LRRC9, DHRS7, PSMA5, SYPL2, and GULP1 related to non-atypical-like features MDD, early-onset MDD, MDD with suicidal thoughts, or postpartum depression were expressed at low levels in brain tissues (d = −0.17−−1.48). DFNA5, CTBP2, PCNX4, SDCCAG8, and GULP1, which are related to early-onset MDD, MDD with moderate impairment, or postpartum depression, were highly expressed in female reproductive tissues (d = 0.80–2.08). Brain and female reproductive tissue-specific expression was confirmed in the HPA RNA-seq subjects. Our findings suggest that brain and female reproductive tissue-specific expression might contribute to the pathogenesis of MDD subtypes.

Vulnerability to risky sexual behavior among patients with severe mental illness in Uganda

BackgroundThe relationship between severe mental illness and risky sexual behaviors, defined as acts associated with a higher risk level is notably significant in sub-Saharan Africa. In Uganda, mental disorders have been substantially correlated with unsafe sexual practices, contributing to the global burden of risky sexual behaviors. The consequential outcomes, such as sexually transmitted diseases, has resulted into a significant challenge in managing severe mental illness and potentially increased risky sexual behaviour. There is an urgent need to identify and understand factors specific to Uganda that amplify the vulnerability of severe mental illness patients to risky sexual behaviors. This study aimed to understand the vulnerability factors to risky sexual behaviour in severe mental illness in central and south-western Uganda, seeking to inform the development of tailored and effective intervention strategies to address this critical issue.MethodsThis was a qualitative descriptive study that was carried out at Butabika and Masaka hospitals in Uganda, involving a varied group of 32 individuals, comprising 12 persons with diagnosed Severe Mental Illness (Schizophrenia, Bipolar Affective Disorder, or Recurrent Major Depressive Disorder) and to risky sexual behaviors, 8 caregivers (who had patients with severe mental illness and to risky sexual behaviors) and 12 mental health specialists, (who had treated these participants). Purposive sampling was done by intentionally selecting participants based on specific attributes relevant to the research question and the objective of the study which was to explore the factors contributing vulnerability to risky sexual behaviour in severe mental illness in central and south-western Uganda. The interviews were conducted, centered on personal experiences and influences on risky sexual behaviors for the persons with severe mental illness, targeting insights into the nuanced interplay of severe mental illness and sexual behavior. For caregivers and mental health specialists, the interviews were conducted to gain a comprehensive understanding of the unique challenges, perspectives, and experiences they encounter in providing support and treatment respectively. The interviews were tape-recorded and transcribed verbatim. Framework analysis of transcribed interviews, using NVivo11 software that helped to systematically organize and code data within the predetermined and emergent thematic framework, we were able to identify patterns and themes to address the research question and objective.ResultsThe study findings underscored a pervasive pattern of engaging in risky sexual behavior among individuals coping with severe mental illness, a growing concern traditionally associated with sexually transmitted infections like HIV and AIDS, unwanted pregnancies, and sexual encounters with strangers. This problem was largely attributed to factors such as compromised judgment due to underlying morbidity, abnormally high libido, poverty, desperation, and inadequate social support. Additionally, sexual deprivation, often a result of stigma, discrimination, and prolonged periods of hospitalization, was found to contribute to irresponsible and risky sexual acts. Respondents also highlighted certain practices and structural weaknesses within hospital environments, such as stripping patients naked when going to seclusion rooms and inadequate patient monitoring.ConclusionsThe findings underscore the need for targeted interventions addressing both individual and structural factors to alleviate the risks associated with sexual behavior among individuals with severe mental illness.

Impact of aripiprazole discontinuation in remitted major depressive disorder: a randomized placebo-controlled trial.

The efficacy and safety of antidepressant augmentation therapy with aripiprazole (AATA) has been established; however, the ongoing effects of continuing aripiprazole after remission remain unclear because no studies have examined this issue. We aimed to explore the effect of AATA discontinuation on the major depressive disorder (MDD) recurrence risk in patients with remitted MDD after AATA. This 24-week, multicenter, placebo-controlled, double-blind, randomized trial evaluated recurrence risk in patients with MDD who achieved remission with AATA. Differences in MDD recurrence, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, between the two groups were compared using survival analysis. The differences in depressive symptom severity and social functioning between the two groups were compared using a mixed model with repeated measures. Extrapyramidal symptoms and akathisia were also assessed. Twenty-three participants were randomized and treated. Two patients in each group experienced recurrence during the study. Kaplan-Meier analysis with Log-rank comparison showed no difference in recurrence between groups (p = 0.642). No significant difference in interactions between group and period was observed in the 17-item Hamilton depression rating scale (p = 0.492) or the Social and Occupational Functioning Assessment Scale (p = 0.638). No patients developed extrapyramidal symptoms or akathisia. Definitive conclusions could not be drawn owing to the small sample size. This study represents a starting point for investigating the safety of aripiprazole discontinuation on recurrence in patients with MDD who have achieved remission with AATA. Future studies with appropriate sample sizes calculated based on this study are needed.

The Effectiveness of Mindfulness-Based Cognitive Therapy for Major Depressive Disorder and Relapse Prevention

Due to the prevalence and severity of Major Depressive Disorder (MDD), it is essential to examine the effectiveness of Mindfulness-Based Cognitive Therapy (MBCT) when treating and preventing the recurrence of MDD. This paper evaluated recent research in this area. First, this article described the importance of research on MDD, which has led to considering MBCT techniques for treating MDD. In addition, this article presented previous literature which explored the symptoms and causes of MDD, as well as the mechanisms and theories of mindfulness training and Cognitive Behavioral Therapy (CBT). Moreover, the paper reviewed recent findings in this area and compared the overall effectiveness of MBCT, Active Control Condition (ACC), and medical therapy when treating MDD. Plus, this paper identified the core components of MBCT, including self-compassion cultivation, meditation training, attentional bias improvement, and meta-cognitive skill enhancement. Finally, this paper also proposed that future research should involve large and diverse samples, longer-term studies, subgroup analyses, and qualitative research to understand MBCT’s effectiveness and applications more comprehensively.

Single arketamine in treatment resistant depression: Presentation of 3 cases with regard to sick-leave duration

BackgroundKetamine is the prototypal rapid-acting antidepressant (RAAD) for TRD with approved indication for esketamine-nasal spray (ESK-NS). Distinctly, arketamine (R-KET) demonstrates enhanced antidepressant effects and neuroplasticity changes compared to esketamine, with fewer dissociative side effects and abuse potential. This study focuses on R-ketamine's therapeutic implications, safety, and tolerability in TRD treatment. MethodsWe report on a year-long follow-up of three TRD patients post-single IV R-KET administration. The study, conducted under the clinical trial PCN-101 (NCT05414422), observed these subjects for healthcare resource utilization and social support system impact. Participants, adults diagnosed with recurrent major depressive disorder without psychotic features, were observed in a year-long follow-up period for safety. ResultsCase analyses revealed significant symptom reduction and improved social and vocational functioning, with reduced sick leaves and hospitalizations post-treatment. However, one case developed a substance use disorder, underscoring the need for vigilant monitoring. The study highlights R-KET's transformative potential in managing depression, indicating a shift in TRD treatment strategies towards early, aggressive interventions. ConclusionsDespite promising findings, the study faces limitations due to its small sample size, lack of randomization, and potential observational design biases. The results, while aligning with existing ketamine research, require cautious interpretation and warrant further investigation with larger, more robust studies. This exploration of R-KET's role in home-based TRD treatment opens avenues for future research, particularly focusing on its long-term effectiveness and safety in diverse patient populations. This study is registered in clinicaltrials.gov: NCT06232291.

Divorce, genetic risk, and suicidal thoughts and behaviors in a sample with recurrent major depressive disorder

BackgroundTheories of risk for suicidal thoughts and behaviors (STB) implicate both interpersonal and biological factors. Divorce/separation and aggregate genetic liability are robustly associated with STB, but have seldom been evaluated in conjunction with one another. Furthermore, whether these factors are effective predictors in high-risk populations is not clear. MethodsAnalyses were conducted in a sample of Han Chinese women with severe recurrent major depressive disorder (maximum N = 4380). Logistic regressions were used to evaluate the associations between divorce/separation and polygenic scores (PGS) for suicidal ideation or behavior with STB. Where appropriate, additive interactions between divorce and PGS were tested. ResultsDivorce/separation was significantly associated with increased risk of suicidal ideation, plans, and attempts (odds ratios = 1.28–1.61). PGS for suicidal ideation were not associated with STB, while PGS for suicidal behavior were associated with ideation and plans (odds ratios = 1.08–1.09). There were no significant interactions between divorce/separation and PGS. ConclusionsConsistent with theories of suicidality, the disruption or end of an important interpersonal relationship is an indicator of risk for STB. Aggregate genetic liability for suicidal behavior more modestly contributes to risk, but does not exacerbate the negative impact of divorce. Thus, even within a high-risk sample, interpersonal and biological exposures distinguish between those who do and do not experience STB, and could motivate targeted screening. Further research is necessary to evaluate whether and how the context of divorce contributes to variation in its effect on STB risk.

Lower odds of successful community discharge after medical hospitalization for Veterans with schizophrenia: A retrospective cohort study of national data

Medical comorbidity, particularly cardiovascular diseases, contributes to high rates of hospital admission and early mortality in people with schizophrenia. The 30 days following hospital discharge represents a critical period for mitigating adverse outcomes. This study examined the odds of successful community discharge among Veterans with schizophrenia compared to those with major affective disorders and those without serious mental illness (SMI) after a heart failure hospital admission. Data for Veterans hospitalized for heart failure were obtained from the Veterans Health Administration (VHA) and Centers for Medicare & Medicaid Services between 2011 and 2019. Psychiatric diagnoses and medical comorbidities were assessed in the year prior to hospitalization. Successful community discharge was defined as remaining in the community without hospital readmission, death, or hospice for 30 days after hospital discharge. Logistic regression analyses adjusting for relevant factors were used to examine whether individuals with a schizophrenia diagnosis showed lower odds of successful community discharge versus both comparison groups. Out of 309,750 total Veterans in the sample, 7377 (2.4%) had schizophrenia or schizoaffective disorder and 32,472 (10.5%) had major affective disorders (bipolar disorder or recurrent major depressive disorder). Results from adjusted logistic regression analyses demonstrated significantly lower odds of successful community discharge for Veterans with schizophrenia compared to the non-SMI (Odds Ratio [OR]: 0.63; 95% Confidence Interval [CI]: 0.60, 0.66) and major affective disorders (OR: 0.65, 95%; CI: 0.62, 0.69) groups. Intervention efforts should target the transition from hospital to home in the subgroup of Veterans with schizophrenia.

Classification of recurrent major depressive disorder using a residual denoising autoencoder framework: Insights from large-scale multisite fMRI data

Background and objectiveRecurrent major depressive disorder (rMDD) has a high recurrence rate, and symptoms often worsen with each episode. Classifying rMDD using functional magnetic resonance imaging (fMRI) can enhance understanding of brain activity and aid diagnosis and treatment of this disorder. MethodsWe developed a Residual Denoising Autoencoder (Res-DAE) framework for the classification of rMDD. The functional connectivity (FC) was extracted from fMRI data as features. The framework addresses site heterogeneity by employing the Combat method to harmonize feature distribution differences. A feature selection method based on Fisher scores was used to reduce redundant information in the features. A data augmentation strategy using a Synthetic Minority Over-sampling Technique algorithm based on Extended Frobenius Norm measure was incorporated to increase the sample size. Furthermore, a residual module was integrated into the autoencoder network to preserve important features and improve the classification accuracy. ResultsWe tested our framework on a large-scale, multisite fMRI dataset, which includes 189 rMDD patients and 427 healthy controls. The Res-DAE achieved an average accuracy of 75.1 % (sensitivity = 69 %, specificity = 77.8 %) in cross-validation, thereby outperforming comparison methods. In a larger dataset that also includes first-episode depression (comprising 832 MDD patients and 779 healthy controls), the accuracy reached 70 %. ConclusionsWe proposed a deep learning framework that can effectively classify rMDD and 33 identify the altered FC associated with rMDD. Our study may reveal changes in brain function 34 associated with rMDD and provide assistance for the diagnosis and treatment of rMDD.

Gender differences in prevalence and associations between cognitive symptoms and suicidal ideation in patients with recurrent major depressive disorder: findings from the Chinese NSSD study

BackgroundThis study aimed to explore gender differences in associations between cognitive symptoms and suicidal ideation (SI) among patients with recurrent major depressive disorder (MDD).MethodsWe recruited 1222 patients with recurrent MDD from the National Survey on Symptomatology of Depression (NSSD), a survey designed to investigate the symptoms experienced during current major depressive episodes in China. A four-point Likert questionnaire was used to assess the frequency of cognitive symptoms and SI in the past two weeks.ResultsGender differences in clinical features and cognitive symptoms of participants with recurrent MDD were found. Specifically, male patients had a higher prevalence of memory loss, decreased verbal output, indecisiveness, and impaired interpersonal relationships, while female patients exhibited a higher prevalence of impaired social and occupational functioning (all P < 0.05). No significant difference in SI prevalence was found between male and female patients. The logistic regression analysis revealed that in male patients, SI was associated with indecisiveness and impaired interpersonal relationships. In female patients, reduced verbal output and impaired social and professional functions were also associated with SI in addition to the above-mentioned variables.ConclusionThe findings of gender differences in associations between cognitive symptoms and SI highlight the need to carefully assess gender-specific cognitive predictors of SI in patients with recurrent MDD. This has further implications for more targeted prevention and treatment strategies for SI based on gender.

Distinct effects of first-episode and recurrent major depressive disorder on brain changes related to suicidal ideation: Evidence from the REST-meta-MDD Project

BackgroundSignificant differences in clinical manifestations between first-episode and recurrent major depression disorder (FE-MDD/R-MDD) have been demonstrated in previous studies, including the degree of suicide attempt. However, the potential brain mechanism underlying the effect of depressive episode frequency on suicidal ideation (SI) remains unclear. MethodsIn this study, 102 patients with FE-MDD (SI/non-SI: N = 70/32) and 71 matched normal controls (NCs), as well as 75 patients with R-MDD (SI/non-SI: N = 37/38) and 49 matched NCs were screened from the Chinese REST-meta-MDD consortium. T1-weighted and resting-state fMRI images were used to calculate gray matter volume (GMV) and fractional amplitude of low-frequency fluctuations (fALFF), respectively. ResultsGroup comparisons revealed that FE-MDD showed changes only in GMV, while R-MDD showed changes in both GMV and fALFF compared to NCs. SI-specific GMV decreases were observed in the right cerebellum, superior marginal gyrus, and left middle temporal gyrus in FE-MDD patients, while SI-specific fALFF decreases in bilateral superior frontal gyrus and increases in bilateral cerebellum and left parahippocampal gyrus were obserevd in R-MDD patients. Moreover, a negative correlation was found between GMV value in right cerebellum and HAMD score. ConclusionsThese findings suggest that first-episode and recurrent MDD show different effects on brain structure and function in patients with SI, providing a potential explanation for the distinct clinical manifestations of MDD patients from a brain mechanisms perspective.

Dynamic risk factors of psychiatric readmission for major depressive disorder: A longitudinal study on patients treated with mono-antidepressant

In this comprehensive study, we sought to unravel the risk factors for recurrence in Major Depressive Disorder (MDD), uniquely focusing on patients undergoing mono-antidepressant treatment. By considering psychiatric readmission as a direct indicator of MDD recurrence, we meticulously analyzed the records of 1,456 inpatients from a Chinese mental health center from 2012 to 2020. Our follow-up periods, spanning 90, 180, and 365 days post-discharge, allowed for a nuanced understanding of the recurrence dynamics. We identified four critical risk factors: thyroid function (FT3 and TSH), high-density lipoprotein (HDL) levels, and region of residence. Notably, the study revealed an increasing risk of readmission associated with decreased FT3 and HDL over time, while elevated TSH and residing in another province 's impact diminished. The antidepressant type did not significantly alter readmission risks, providing a unique perspective on MDD management. This research contributes to the field by offering a deeper understanding of how demographic and biochemical factors influence the likelihood of MDD recurrence, guiding more effective treatment approaches.

Effects of lockdowns on neurobiological and psychometric parameters in unipolar depression during the COVID-19 pandemic

Defying the COVID-19 pandemic required restriction measures of unprecedented scale, that may induce and exacerbate psychiatric symptoms across the population. We aimed to assess in vivo dynamic effects of mitigation strategies on human brain neurobiology, neuroplastic as well as psychometric parameters. Three structural magnetic resonance imaging measurements, serum brain-derived neurotrophic factor (sBDNF) analyses, and psychometric assessments (Beck Depression Inventory-II and Perceived Stress Questionnaire-20) were performed in healthy individuals and patients with a recurrent major depressive disorder in the period from September 2020 to July 2021. Group differences and changes over time in structural imaging, neuroplastic and psychometric parameters were assessed with linear mixed models. Analysis of data from 18 patients with a recurrent major depressive disorder and 28 healthy individuals showed clinically relevant scores for depression and stress in the patient group as well as significant cross-sectional differences in depression scores (F = 30.89, p < 0.001) and three subscales of the Perceived Stress Questionnaire (Worries: F = 19.19, p < 0.001, Tension: F = 34.44, p < 0.001, Joy: F = 12.05, p = 0.001). Linear mixed models revealed no significant changes over time in cortical thickness of the prefrontal cortex, anterior cingulate cortex, hippocampus, and amygdala (F = 0.29, p > 0.1) and no interaction with group (F = 0.28, p > 0.1). Further, analysis revealed no main effect of time and no interaction of time x group in depressive symptoms, perceived stress subscales, and sBDNF (all p > 0.1). Despite the limited sample size, the strength of this investigation lies in the multimodal assessment of peri-pandemic lockdown effects. Nine months of varying restrictions measures did not result in observable changes in brain morphology nor impact depressive symptoms in either psychiatric patients with a recurrent major depressive disorder or healthy individuals. While these neurobiological and psychometric data stand in contrast to initial expectations about the effects of restriction measures, they might inform future investigations of longitudinal effects of restriction measures on mental health.

Active versus sham DLPFC-NAc rTMS for depressed adolescents with anhedonia using resting-state functional magnetic resonance imaging (fMRI): a study protocol for a randomized placebo-controlled trial

BackgroundAnhedonia, which is defined as the inability to feel pleasure, is considered a core symptom of major depressive disorder (MDD). It can lead to several adverse outcomes in adolescents, including heightened disease severity, resistance to antidepressants, recurrence of MDD, and even suicide. Specifically, patients who suffer from anhedonia may exhibit a limited response to selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT). Previous researches have revealed a link between anhedonia and abnormalities within the reward circuitry, making the nucleus accumbens (NAc) a potential target for treatment. However, since the NAc is deep within the brain, repetitive transcranial magnetic stimulation (rTMS) has the potential to modulate this specific region. Recent advances have enabled treatment technology to precisely target the left dorsolateral prefrontal cortex (DLPFC) and modify the functional connectivity (FC) between DLPFC and NAc in adolescent patients with anhedonia. Therefore, we plan to conduct a study to explore the safety and effectiveness of using resting-state functional connectivity magnetic resonance imaging (fcMRI)-guided rTMS to alleviate anhedonia in adolescents diagnosed with MDD.MethodsThe aim of this article is to provide a study protocol for a parallel-group randomized, double-blind, placebo-controlled experiment. The study will involve 88 participants who will be randomly assigned to receive either active rTMS or sham rTMS. The primary object is to measure the percentage change in the severity of anhedonia, using the Snaith-Hamilton Pleasure Scale (SHAPS). The assessment will be conducted from the baseline to 8-week post-treatment period. The secondary outcome includes encompassing fMRI measurements, scores on the 17-item Hamilton Rating Scale for Depression (HAMD-17), the Montgomery Asberg Depression Rating Scale (MADRS), the Chinese Version of Temporal Experience of Pleasure Scale (CV-TEPS), and the Chinese Version of Beck Scale for Suicide Ideation (BSI-CV). The Clinical Global Impression (CGI) scores will also be taken into account, and adverse events will be monitored. These evaluations will be conducted at baseline, as well as at 1, 2, 4, and 8 weeks.DiscussionIf the hypothesis of the current study is confirmed, (fcMRI)-guided rTMS could be a powerful tool to alleviate the core symptoms of MDD and provide essential data to explore the mechanism of anhedonia.Trial registrationClinicalTrials.gov NCT05544071. Registered on 16 September 2022.

Associations between insomnia symptoms and inflammatory cytokines in adolescents with first-episode and recurrent major depressive disorder

BackgroundInsomnia symptoms are often associated with increased levels of inflammatory biomarkers. However, such associations have not been adequately explored in adolescents with major depressive disorder (MDD). This study aimed to examine the associations between insomnia symptoms with inflammatory cytokines in adolescents with first-episode and recurrent MDD. MethodsFrom January to December 2021, this study included 164 adolescents with MDD and 76 healthy controls (HCs). The Center for Epidemiological Studies Depression Scale (CES—D) and the Insomnia Severity Index Scale (ISI) were used to assess depressive and insomnia symptoms, respectively. Also, plasma levels of interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-17 A and tumor necrosis factor-α (TNF-α) were measured. ResultsThe prevalence of mild, moderate and severe insomnia in adolescents with MDD was 40.24 %, 36.59 % and 6.71 %, respectively. The patients had higher levels of IL-1β, IL-6 and TNF-α than HCs (all p < 0.05). ISI score was positively correlated with CES-D score and levels of IL-1β, IL-6 and TNF-α in first-episode patients but not in recurrent patients. A further multivariate stepwise linear regression analysis showed that ISI score was independently associated with CES-D score (beta = 0.523, t = 5.833, p < 0.001) and TNF-α levels (beta = 0.254, t = 2.832, p = 0.006). LimitationsThe cross-sectional design leads to failure to make causal inferences. ConclusionInsomnia symptoms are common in adolescents with MDD and associated with elevated levels of inflammatory cytokines in first-episode patients. The findings suggest that inflammatory cytokines may relate to the pathogenesis of insomnia symptoms in adolescents with MDD, but further longitudinal studies are needed to explore the causal association between insomnia symptoms and inflammatory cytokines in MDD.

Aberrant resting-state co-activation network dynamics in major depressive disorder

Major depressive disorder (MDD) is a globally prevalent and highly disabling disease characterized by dysfunction of large-scale brain networks. Previous studies have found that static functional connectivity is not sufficient to reflect the complicated and time-varying properties of the brain. The underlying dynamic interactions between brain functional networks of MDD remain largely unknown, and it is also unclear whether neuroimaging-based dynamic properties are sufficiently robust to discriminate individuals with MDD from healthy controls since the diagnosis of MDD mainly depends on symptom-based criteria evaluated by clinical observation. Resting-state functional magnetic resonance imaging (fMRI) data of 221 MDD patients and 215 healthy controls were shared by REST-meta-MDD consortium. We investigated the spatial-temporal dynamics of MDD using co-activation pattern analysis and made individual diagnoses using support vector machine (SVM). We found that MDD patients exhibited aberrant dynamic properties (such as dwell time, occurrence rate, transition probability, and entropy of Markov trajectories) in some transient networks including subcortical network (SCN), activated default mode network (DMN), de-activated SCN-cerebellum network, a joint network, activated attention network (ATN), and de-activated DMN-ATN, where some dynamic properties were indicative of depressive symptoms. The trajectories of other networks to deactivated DMN-ATN were more accessible in MDD patients. Subgroup analyses also showed subtle dynamic changes in first-episode drug-naïve (FEDN) MDD patients. Finally, SVM achieved preferable accuracies of 84.69%, 76.77%, and 88.10% in discriminating patients with MDD, FEDN MDD, and recurrent MDD from healthy controls with their dynamic metrics. Our findings reveal that MDD is characterized by aberrant dynamic fluctuations of brain network and the feasibility of discriminating MDD patients using dynamic properties, which provide novel insights into the neural mechanism of MDD.

Connectome architecture modulates the gray matter atrophy in major depression disorder patients with diverse suicidal ideations.

Gray matter (GM) atrophy is well documented in patients with major depressive disorder (MDD), but its underlying mechanism remains unknown. This study aimed to examine the GM atrophy in MDD patients with diverse suicidal ideations (SIs) and to explore whether those alterations were driven by connections.GM volume was estimated in 163 patients with recurrent MDD (comprising 122 with SI [MDDSI] and 41 without SI [MDDNSI]) and 134 health controls (HCs). A two-sample t-test was used to identify GM volume abnormalities in MDD patients and their subgroups. Functional connectivity was computed between pairs of aberrant GM in both patients and HCs, which were further compared with the connectivity of random brain regions. A permutation test was performed to assess its significance. Propensity score matching (PSM) was further performed to validate the main results.Compared with HCs, the MDDNSI group exhibited GM atrophy in 24 regions, with the largest effect sizes found in the frontal and parietal lobes, while the MDDSI group exhibited more widespread GM atrophy involving 49 regions, with the largest effect sizes in the frontal lobe, parietal lobe, temporal lobe, and the limbic system. Furthermore, patients and HCs exhibited significantly increased functional connectivity between regions with GM atrophy compared with randomly selected regions (p < 0.05). PSM analysis presented similar results to the main analysis.MDD patients had diverse GM atrophy features according to their SI tendency. Moreover, connectome architecture modulates the GM atrophy in MDD patients, implying the possibility that connections drive these pathological changes.

Stress exposure in at-risk, depressed, and suicidal adolescents.

Stress exposure contributes to the onset, maintenance, and recurrence of major depressive disorder (MDD) in adolescents. However, the precise stress facets (e.g. chronicity, domain) most strongly linked to outcomes at different stages along the depression severity continuum remain unclear. Across two studies, chronic and episodic stressors were comprehensively assessed among: (a) healthy youth with (High-Risk [HR]) and without (Low-Risk [LR]) a maternal history of MDD and (b) adolescents with current MDD and suicide ideation and healthy controls (HC). Study 1 included LR (n = 65) and HR (n = 22) 12- to 14-year-olds (49 females; 56.32%) with no lifetime history of mental disorders. Study 2 enrolled 87 mid-to-late adolescents (64 females; 73.56%), including 57 MDD youth from a short-term intensive treatment service and 30 HCs from the community. All depressed youth reported recent suicide ideation; some had no lifetime history suicide attempts (SI; n = 31) and others reported at least one past year attempt (SA; n = 26). The Life Events and Difficulties Schedule was used to capture stressor severity in both studies. We used multiple linear regression models that adjusted for demographic and clinical covariates. Being in the HR versus LR group was associated with more severe chronic (β = .22, CI95 = 0.01-0.42, p = .041), independent (β = .34, CI95 = 0.12-0.56, p = .003), and interpersonal (β = .23, CI95 = 0.004-0.45, p = .047) stress severity. By contrast, the MDD group reported significantly more severe chronic (β = .62, CI95 = 0.45-0.79, p < .001) and dependent (β = .41, CI95 = 0.21-0.61, p < .001) stress than the HC group, but not independent (p = .083) stress. Stress severity did not differ between recent attempters versus youth who reported suicide ideation alone (SA vs. SI contrast). However, the SA group reported a higher rate of targeted rejection events (RR = 3.53, CI95 = 1.17-10.70, p = .026). Our findings clarify the stressor features that may most strongly contribute to adolescent depression and its clinical correlates at two important points along depression's clinical course.

Classification of MDD using a Transformer classifier with large-scale multisite resting-state fMRI data.

Major depressive disorder (MDD) is one of the most common psychiatric disorders worldwide with high recurrence rate. Identifying MDD patients, particularly those with recurrent episodes with resting-state fMRI, may reveal the relationship between MDD and brain function. We proposed a Transformer-Encoder model, which utilized functional connectivity extracted from large-scale multisite rs-fMRI datasets to classify MDD and HC. The model discarded the Transformer's Decoder part, reducing the model's complexity and decreasing the number of parameters to adapt to the limited sample size and it does not require a complex feature selection process and achieves end-to-end classification. Additionally, our model is suitable for classifying data combined from multiple brain atlases and has an optional unsupervised pre-training module to acquire optimal initial parameters and speed up the training process. The model's performance was tested on a large-scale multisite dataset and identified brain regions affected by MDD using the Grad-CAM method. After conducting five-fold cross-validation, our model achieved an average classification accuracy of 68.61% on a dataset consisting of 1611 samples. For the selected recurrent MDD dataset, the model reached an average classification accuracy of 78.11%. Abnormalities were detected in the frontal gyri and cerebral cortex of MDD patients in both datasets. Furthermore, the identified brain regions in the recurrent MDD dataset generally exhibited a higher contribution to the model's performance.