The Tryptophan Catabolite or Kynurenine Pathway’s Role in Major Depression

Kynurenine or tryptophan catabolite (TRYCAT) pathway contributes to the pathophysiology of major depression disorder (MDD) and major depressive episodes (MDE) in bipolar disorder and suicidal behaviors. The consequences of the overactivation of this pathway large reduced tryptophan (TRP) levels in peripheral blood and the CNS and increased levels of neurotoxic TRYCATs including kynurenine (KYN), 3-hydroxy kynurenine (3HK), quinolinic acid (QA), xanthurenic acid (XA), and picolinic acid (PA). However, other TRYCATs are protective, such as kynurenic acid (KA) and anthranilic acid (AA). Inflammation and cell-mediated immune activation along with oxidative and nitrosative stress (O&NS) may stimulate the first and rate-limiting enzyme of this pathway, namely indoleamine-2,3-dioxygenase (IDO). Therefore, during depression, balancing neuroprotective versus neurotoxic TRYCATs and balancing activation of the immune response system (IRS) versus the compensatory immune response system is crucial for achieving better treatment outcomes. Furthermore, targeting the causes of TRYCAT pathway activation (immune activation and O&NS) is probably the most effective strategy to treat depression. In the present review, we aim to provide a comprehensive explanation of the impact of TRYCATs in terms of pathophysiology and treatment of MDD and MDE.

Lifetime use of MDMA/ecstasy and psilocybin is associated with reduced odds of major depressive episodes

Background: Depression is a major mental health issue worldwide, with high rates of chronicity and non-recovery associated with the condition. Existing treatments such as antidepressant medication and psychological treatments have modest effectiveness, suggesting the need for alternative interventions. Aim: The aim of this study was to examine the relationships between MDMA (3,4-methylenedioxymethamphetamine)/ecstasy and psilocybin use and major depressive episodes (MDEs). Methods: This observational study used data from a large ( N = 213,437) nationally representative sample of US adults to test the association of lifetime use of MDMA/ecstasy, psilocybin and other classic psychedelics (lysergic acid diethylamide (LSD), peyote, mescaline), other illegal substances (e.g. cocaine, phencyclidine (PCP)), and legal/medicinal substances of misuse (e.g. pain relievers, tranquilizers) with lifetime, past year, and past year severe MDEs. Results: Results revealed that lifetime MDMA/ecstasy use was associated with significantly lowered odds of a lifetime MDE (adjusted odds ratio (aOR) = 0.84; p < 0.001), past year MDE (aOR = 0.84; p < 0.001), and past year severe MDE (aOR = 0.82; p < 0.001). Psilocybin was associated with significantly lowered odds of a past year MDE (aOR = 0.90; p < 0.05) and past year severe MDE (aOR = 0.87; p < 0.05). All other substances either shared no relationship with a MDE or conferred increased odds of an MDE. Conclusions: These results suggest that MDMA/ecstasy and psilocybin use is associated with lower risk of depression. Experimental studies are needed to test whether there is a causal association between use of these compounds and the alleviation of depressive symptoms.

Association Between Frontal Alpha Asymmetry With Cognitive Symptoms, Depression Severity, and Insomnia

Objective: Previous studies have compared depressive episodes between bipolar disorder (BD) and major depressive disorder (MDD) using quantitative electroencephalogram (QEEG); however, there are no distinct discriminating feature between them. Here, we used QEEG to directly compare the alpha asymmetry and absolute power of each band between patients with BD and MDD.Methods: Fifty in-patients with major depressive episodes between 2019 and 2021 were retrospectively enrolled. Self-reported questionnaires including the Beck Depression Inventory (BDI), Korean version of the Childhood Trauma Questionnaire, and Adult Attention-Deficit/Hyperactivity Disorder Self Report Scale (ASRS) were used to evaluate the symptoms. The absolute power of QEEG delta, theta, alpha, beta, high beta waves, and the Z-scores of frontal alpha asymmetry were collected. A t-test and Pearson’s correlation test were conducted using these data and based on these results, an analysis of covariance was conducted.Results: There were no significant differences between MDD and BD in QEEG power or alpha asymmetry. Patients with severe depression (BDI ≥29) had higher alpha power at FP1 (p=0.037), FP2 (p=0.028), F3 (p=0.047), F4 (p=0.016), and higher right frontal alpha asymmetry at F3–F4 (p=0.039). Adult patients with features consistent with ADHD (ASRS ≥4) had higher right frontal alpha asymmetry at F3–F4 (p=0.046). Patients with insomnia had higher left frontal alpha asymmetry at F3–F4 (p=0.003).Conclusion: QEEG limited the differential diagnosis of MDD and BD. However, frontal alpha asymmetry did exist in depression and affected cognitive impairment, insomnia, and depression severity in particular. Future studies with improved methodologies are needed for a better comparison.

Association between food insecurity and major depressive episodes amid Covid-19 pandemic: results of four consecutive epidemiological surveys from southern Brazil

Objective: To assess the association between household food insecurity (FI) and major depressive episodes (MDE) amid Covid-19 pandemic in Brazil. Design: Cross-sectional study carried out with data from four consecutive population-based studies. Setting: The study was conducted between May and June 2020, in Bagé, a Brazilian southern city. Household FI was measured using the short-form version of the Brazilian Food Insecurity Scale. Utilizing the Patient Health Questionnaire-9, we used two different approaches to define MDE: the cut-off point of ≥9 and the diagnostic criteria proposed by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-R). Association between FI and MDE was analysed using crude and adjusted Poisson regression models. Participants: 1550 adults (≥20 years old). Results: The prevalence of household FI was 29.4% (95%C.I 25.0; 34.4). MDE prevalence varied from 4.4% (95%C.I. 3.1 to 6.0), when we used the DSM-IV-R criteria to define this condition, to 9.6% (95%C.I 7.3; 12.5) of the sample, when we used the cut-off point of ≥9 as definition. Prevalence of MDE was more than two times higher in those individuals living with FI, independent of the criteria adopted to define the outcome. Adjustment for potential confounders did not change the association’s magnitude. Conclusion: Household FI has been positively associated with MDE amid Covid-19 pandemic, independent of sociodemographic characteristics of participants. Actions are needed to warrant basic living conditions to avoid food insecurity and hunger and its consequences for the Brazilian population, especially those consequences linked to mental health disorders.

A Controlled Study of Major Depressive Episodes in Long-Term Childhood, Adolescence, and Young Adult Cancer Survivors (The NOR-CAYACS Study)

Background: A major depressive episode (MDE) is typically self-rated by screening forms identifying probable MDE (pMDE). This population-based cross-sectional questionnaire study examined the prevalence rates of pMDE identified by the PHQ-9 screener in long-term survivors of childhood and adolescence (CACSs) and young adult cancer (YACSs) and a normative sample (NORMs). Methods: Data from 488 CACSs, 1202 YACSs, and 1453 NORMs were analyzed, and pMDE was defined both by cut-off ≥10 on the total PHQ-9 score and by an algorithm. Results: The prevalence rates of pMDE among CACSs were 21.5%, 16.6% in YACSs, and 9.2% among NORMs using the cut-off definition. With the algorithm, the prevalence rates of pMDE were 8.0% among CACSs, 8.1% among YACSs, and 3.9% among NORMs. Independent of definition, CACSs and YACSs had significantly increased prevalence rates of pMDE compared to NORMs. Psychosocial factors and self-rated health were significantly associated with both definitions of pMDE in multivariable analyses, while survivor groups, cancer types, and adverse events were not. Conclusion: Since pMDE has negative health consequences and is amenable to treatment, healthcare providers should be attentive and screen for pMDE in young cancer survivors. For PHQ-9, the preferred type of definition of pMDE should be determined.

Accuracy in detecting major depressive episodes in older adults using the Swedish versions of the GDS-15 and PHQ-9

Objectives: The purpose of this study was to evaluate the diagnostic accuracy at different cut-off values for the Swedish versions of the 15-item Geriatric Depression Scale (GDS-15) and Patient Health Questionnaire (PHQ-9) compared with a structured clinical psychiatric interview in older adults. Methods: Community-dwelling participants (N = 113) aged 65 years or older completed the Swedish versions of the GDS-15 and PHQ-9 and were then interviewed using the Mini International Neuropsychiatric Interview (MINI) to establish the presence or absence of current major depressive episodes (MDEs). Areas under the curve (AUC) were calculated for each scale, as well as the sensitivity, specificity, and Youden’s index for different cut-off values. Results: Seventeen participants met the criteria for MDEs. The AUC was 0.97 for the GDS-15 and 0.95 for the PHQ-9. A cut-off of ≥6 on the GDS-15 yielded a sensitivity of 94%, a specificity of 88%, and a Youden’s index of 0.82. A cut-off of ≥5 on the PHQ-9 yielded a sensitivity of 100%, a specificity of 81%, and a Youden’s index of 0.81. The proposed cut-off of ≥10 on the PHQ-9 produced excellent specificity of 95% but a lower sensitivity of 71%. Conclusions: This study indicates that the Swedish versions of the GDS-15 and PHQ-9 have comparable accuracy as screening instruments for older adults with MDEs. However, the proposed cut-off of 10 on the PHQ-9 might be too high when applied to older individuals in Sweden, and further investigations in larger samples in different healthcare settings are warranted.

Plasma acetyl-l-carnitine and l-carnitine in major depressive episodes: a case–control study before and after treatment

Background Major depressive disorder (MDD) is the main cause of disability worldwide, its outcome is poor, and its underlying mechanisms deserve a better understanding. Recently, peripheral acetyl-l-carnitine (ALC) has been shown to be lower in patients with major depressive episodes (MDEs) than in controls. l-Carnitine is involved in mitochondrial function and ALC is its short-chain acetyl-ester. Our first aim was to compare the plasma levels of l-carnitine and ALC, and the l-carnitine/ALC ratio in patients with a current MDE and healthy controls (HCs). Our second aim was to assess their changes after antidepressant treatment. Methods l-Carnitine and ALC levels and the carnitine/ALC ratio were measured in 460 patients with an MDE in a context of MDD and in 893 HCs. Depressed patients were re-assessed after 3 and 6 months of antidepressant treatment for biology and clinical outcome. Results As compared to HC, depressed patients had lower ALC levels (p < 0.00001), higher l-carnitine levels (p < 0.00001) and higher l-carnitine/ALC ratios (p < 0.00001). ALC levels increased [coefficient: 0.18; 95% confidence interval (CI) 0.12–0.24; p < 0.00001], and l-carnitine levels (coefficient: −0.58; 95% CI −0.75 to −0.41; p < 0.00001) and l-carnitine/ALC ratios (coefficient: −0.41; 95% CI −0.47 to −0.34; p < 0.00001), decreased after treatment. These parameters were completely restored after 6 months of antidepressant. Moreover, the baseline l-carnitine/ALC ratio predicted remission after 3 months of treatment (odds ratio = 1.14; 95% CI 1.03–1.27; p = 0.015). Conclusions Our data suggest a decreased mitochondrial metabolism of l-carnitine into ALC during MDE. This decreased mitochondrial metabolism is restored after a 6-month antidepressant treatment. Moreover, the magnitude of mitochondrial dysfunction may predict remission after 3 months of antidepressant treatment. New strategies targeting mitochondria should be explored to improve treatments of MDD.

Sensitivity and concurrent validity of the Japanese version of the Euthymia scale: a clinimetric analysis

Background Euthymia is characterized by the lack of mood disorders, the presence of positive affects, psychological flexibility and well-being, a unifying outlook on life, and resistance to stress. The Euthymia Scale (ES) is a 10-item self-rating clinimetric index assessing euthymia. Objectives The present study was conducted to examine the clinimetric sensitivity and concurrent validity of the Japanese version of the Euthymia Scale (ES-J). Methods A cross-sectional online survey was conducted. The Mini-International Neuropsychiatric Interview was used to determine the presence of past or current major depressive episodes (MDE). The clinimetric sensitivity was evaluated using the Analysis of Variance (ANOVA). Pearson’s correlation coefficients were performed to examine the concurrent validity of the ES-J. Results A total of 1030 eligible participants completed the survey. The ES-J differentiated healthy subjects from complete remission (i.e., those with a past history of MDE without current MDE) (p < 0.001), from those with past or current history of MDE (p < 0.001), subjects with current MDE from those with sub-threshold symptoms of depression (p < 0.001), and healthy participants from subjects with moderate to severe symptoms of psychological distress (p < 0.001). The associations between the ES-J and measures of psychological well-being, resilience, life satisfaction, and social support were significantly positive (0.353 < r < 0.666, p < 0.001). A negative relationship between the ES-J and measures of psychological distress was also found (r = − 0.595, p < 0.001). Conclusions The findings of the present study indicated that the ES-J is a valid and highly sensitive clinimetric index, which can be used as a screening measure in the clinical process of assessment of recovery, particularly when symptoms are expected to be mild and/or when dealing with subclinical symptoms of psychological distress and depression. The findings of this study also support the use of the ES-J to detect vulnerability to depression and to identify subjects at higher risk of relapse.