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Background: The aim of our study was to evaluate the expression of the CASP3 gene at both mRNA and protein levels in patients with depressive disorders and to determine the impact of caspase 3 in the pathogenesis of depression; Methods: A total of 290 subjects, including 190 depressed patients and 100 healthy controls, participated in the study. Socio-demographic and clinical data were collected, and the severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale. Venous blood was collected and gene expression was evaluated using RT-PCR and ELISA at the mRNA and protein levels, respectively; Results: The expression of the CASP3 gene was significantly lower in depressed patients compared to healthy controls at both the mRNA and protein levels. Additionally, a positive correlation was observed between CASP3 gene expression and disease duration as well as the number of depressive episodes; Conclusions: Further studies are needed to investigate the role of caspase 3 in depressive disorders. [ABSTRACT FROM AUTHOR]

• Patients with CVDs with comorbid MDD often comorbid somatic and fatigue symptoms. • N-3 PUFAs reduced fatigue symptoms in patients with CVDs comorbid MDD. • N-3 PUFAs reduced somatic symptoms in younger patients with CVDs comorbid MDD. • Changes of EPA and n-3 PUFAs correlate negatively with changes of somatic symptoms. • Changes of BDNF correlate negatively with changes of somatic symptoms. Cardiovascular diseases (CVDs) and major depressive disorder (MDD) are the two most disabling diseases. Patients with CVDs comorbid depression had somatic and fatigue symptoms and were associated with chronic inflammation and omega-3 polyunsaturated fatty acid (n-3 PUFA) deficits. However, there have been limited studies on the effects of n-3 PUFAs on somatic and fatigue symptoms in patients with CVDs comorbid MDD. Forty patients with CVDs comorbid MDD (58% males, mean age of 60 ± 9 years) were enrolled and randomised to receive either n-3 PUFAs (2 g of eicosapentaenoic acid [EPA] and 1 g of docosahexaenoic acid [DHA] per day) or placebo in a 12-week double-blind clinical trial. We assessed the somatic symptoms with Neurotoxicity Rating Scale (NRS) and fatigue symptoms with Fatigue Scale at baseline, weeks 1, 2, 4, 8 and 12, as well as blood levels of Brain-Derived Neurotrophic Factor (BDNF), inflammatory biomarkers and PUFAs, at the baseline and week 12. The n-3 PUFAs group had a greater reduction in Fatigue scores than the placebo group at Week 4 (p =.042), while there were no differences in the changes of NRS scores. N-3 PUFAs group also had a greater increase in EPA (p =.001) and a greater decrease in total n-6 PUFAs (p =.030). Moreover, in the subgroup analyses in the younger age group (age < 55), the n-3 PUFAs group had a greater reduction on NRS total scores at Week 12 (p =.012) and NRS Somatic scores at Week 2 (p =.010), Week 8 (p =.027), Week 12 (p =.012) than the placebo group. In addition, the pre- and post-treatment changes of EPA and total n-3 PUFAs levels were negatively associated with the changes of NRS scores at Weeks 2, 4, and 8 (all p <.05), and the changes of BDNF levels were negatively associated with NRS scores at Weeks 8 and 12 (both p <.05) in the younger age group. In the older age group (age ≥ 55), there were a lesser reduction on NRS scores at Weeks 1, 2 and 4 (all p <.05), but a greater reduction on Fatigue score at Week 4 (p =.026), compared to the placebo group. There was no significant correlation between the changes of blood BDNF, inflammation, PUFAs and NRS and Fatigue scores in general and in the older age group. Overall, n-3 PUFAs improved the fatigue symptoms in patients with CVDs comorbid MDD and the general somatic symptoms in specific subpopulation of younger age patients, and perhaps via the interplay between BDNF and EPA. Our findings provide promising rationales for future studies to investigate the treatment effects of omega-3 fatty acids on fatigue and somatic symptoms of chronic mental and medical diseases. [ABSTRACT FROM AUTHOR]

The co-occurrence of depression and obesity has become a significant public health concern worldwide. Recent studies have shown that metabolic dysfunction, which is commonly observed in obese individuals and is characterized by inflammation, insulin resistance, leptin resistance, and hypertension, is a critical risk factor for depression. This dysfunction may induce structural and functional changes in the brain, ultimately contributing to depression's development. Given that obesity and depression mutually increase each other's risk of development by 50–60%, there is a need for effective interventions that address both conditions. The comorbidity of depression with obesity and metabolic dysregulation is thought to be related to chronic low-grade inflammation, characterized by increased circulating levels of pro-inflammatory cytokines and C-reactive protein (CRP). As pharmacotherapy fails in at least 30–40% of cases to adequately treat major depressive disorder, a nutritional approach is emerging as a promising alternative. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are a promising dietary intervention that can reduce inflammatory biomarkers, particularly in patients with high levels of inflammation, including pregnant women with gestational diabetes, patients with type 2 diabetes mellitus, and overweight individuals with major depressive disorder. Further efforts directed at implementing these strategies in clinical practice could contribute to improved outcomes in patients with depression, comorbid obesity, and/or metabolic dysregulation. [ABSTRACT FROM AUTHOR]

Background and Objectives: Nicotinamide adenine dinucleotide (NAD) is an important coenzyme in various physiological processes, including sirtuins (SIRTs) and kynurenine pathway (KP). Previous studies have shown that lower NAD levels can be indicative of increased risks of cancer and psychiatric disorders. However, there has been no prior study exploring the link between NAD homeostasis and psychiatric disorders from a genetic perspective. Therefore, we aimed to investigate the association of genetic polymorphism in the pathways of NAD biosynthesis with major depressive disorder (MDD). Methods: A total of 317 patients were included in the case group and were compared with sex-matched control group of 1268 participants (1:4 ratio) from Taiwan Biobank (TWB). All subjects in the control group were over 65 years old, which is well past the average age of onset of MDD. Genomic DNA extracted from patients' blood buffy coat was analyzed using the Affymetrix TWB array. Full-model tests were conducted for the analysis of single nucleotide polymorphism (SNPs) in all candidate genes. We focused on genes within the NAD-related candidate pathways, including 15 in KP, 12 in nicotinate metabolism, 7 in SIRTs, and 19 in aldehyde dehydrogenases (ALDHs). A total of 508 SNPs were analyzed in this study. After significant SNPs were determined, 5000 genome-wide max(T) permutations were performed in Plink. Finally, we built a predictive model with logistic regression and assessed the interactions of SNPs with the haplotype association tests. Results: We found three SNPs that were significantly associated with MDD in our NAD-related candidate pathways, one within the KP (rs12622574 in ACMSD) and two within the nicotinate metabolism (rs28532698 in BST1 and rs3733593 in CD38). The observed association with MDD was significant in the dominant model of inheritance with marital status, education level, and body mass index (BMI) adjusted as covariates. Lastly, in haplotype analysis, the three associated SNPs consisted of one haploblock in ACMSD, four haploblocks in BST1, and two haploblocks in CD38. Conclusions: This study provides the first evidence that genetic variations involved in NAD homeostasis in the KP and nicotinate metabolism may be associated with the occurrence of MDD. [ABSTRACT FROM AUTHOR]

Background: Endocannabinoids (ECs) are one type of bioactive endogenous neuroinflammatory mediator derived from polyunsaturated fatty acids (PUFAs), which may regulate the emotional processes. Here, we assessed the effect of ω-3 PUFAs on EC levels, which may be the novel targets for the ω-3 PUFAs' antidepressive effects.Methods: We conducted a 12-week double-blind, nonplacebo, randomized controlled trial. Eighty-eight major depressive disorder (MDD) participants were randomly assigned to receive eicosapentaenoic acid (EPA, 3.0 g/day), docosahexaenoic acid (DHA, 1.4 g/day), or a combination of EPA (1.5 g/d) and DHA (0.7 g/day). Eighty-five participants completed the trial, and their clinical remission and plasma PUFA-derived EC levels (pmol/mL) were measured.Results: The cumulative rates of clinical remission were significantly higher in the EPA and EPA + DHA groups than the DHA group (51.85 and 53.84 vs. 34.37%; p =0.027 and p =0.024, respectively). EPA and EPA + DHA treatments increased the eicosapentaenoylethanolamide (EPEA) levels compared to DHA treatment (0.33 ± 0.18 and 0.35 ± 0.24 vs. 0.08 ± 0.12; p =0.002 and p =0.001, respectively), while EPA + DHA treatment increased the docosahexaenoylethanolamide levels more than EPA treatment (1.34 ± 2.09 vs. 0.01 ± 1.79; p =0.006). Plasma EPEA levels were positively correlated with rates of clinical remission (hazard ratio: 1.60, 95% confidence interval: 1.08-2.39).Conclusions: Treatments enriched with EPA increased plasma EPEA levels, which was positively associated with clinical remission. This finding may suggest that levels of plasma EPEA play a potential novel endogenous therapeutic target in MDD. [ABSTRACT FROM AUTHOR]

• Cardiovascular diseases (CVDs) commonly comorbid with depression. • Omega-3 fatty acids (n-3 PUFAs) are compared with placebo in CVDs with depression. • N-3 PUFAs did not improve total HAMD or BDI scores in CVDs with depression. • N-3 PUFAs did not have an effect on CVDs markers as secondary outcome. • N-3 PUFAs improved Core depression symptoms in the severe depression group. Cardiovascular diseases (CVDs) and major depressive disorder (MDD) will be the two most disabling diseases by 2030. Patients with CVDs comorbid depression had lower levels of total omega-3 polyunsaturated fatty acids (n-3 PUFAs), docosahexaenoic acid (DHA), and a higher omega-6 to omega-3 ratio. However, there have been limited studies on the effects n-3 PUFAs on MDD in patients with CVDs. We have enrolled a total of 59 patients (64% males, mean age of 61.5 ± 9.0 years and mean education of 10.2 ± 4.2 years) with CVDs comorbid MDD. They were randomized into either receiving n-3 PUFAs (2 g per day of eicosapentaenoic acid (EPA) and 1 g of DHA) or placebo for 12 weeks. We assessed depression symptom severity with Hamilton Depression Rating Scale (HAMD) and Beck Depression Inventory (BDI), as well as blood fatty acid levels, electrocardiogram and blood biochemistry, at the baseline and at the endpoint. There were no differences between the n-3 PUFAs and placebo group in the changes of HAMD and BDI total scores, while PUFAs group had a greater reduction in HAMD Cognition subscale scores than the placebo group at week 8 (p < 0.05). Moreover, subgroup analyses found that the n-3 group had a greater reduction of HAMD Core subscale scores than the placebo group at the end of week 12 (p < 0.05) for the very severe DEP group (HAMD ≥ 23). Overall, n-3 PUFAs did not show a beneficial effect on depressive symptoms when compared with placebo. However, when stratified with depression severity, n-3 PUFAs supplementation improved core depression symptoms in the very severe MDD group. N-3 PUFAs supplementation may provide a treatment option for a subpopulation of patients with CVDs comorbid MDD. [ABSTRACT FROM AUTHOR]

Introduction Prenatal depression (PND) is a common psychiatric disorder in pregnant women and leads to psychosocial dysfunction, high suicidal rate, and adverse childcare. Patients with PND have omega-3 polyunsaturated fatty acid (omega-3 or n-3 PUFAs) deficits, which might link to chronic low-grade inflammatory process and the pathophysiological mechanisms of depression. In this case-control study, we examined the levels of PUFAs and inflammatory cytokines in PND. Method Blood samples were obtained and analyzed from 16 healthy controls and 17 depressed cases (PND group) diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Independent sample t -test and correlation analysis were performed with Statistical Package for the Social Sciences (SPSS) logistics correlation analysis. Results PND group had significantly lower levels of total n-3 (p = 0.026), docosahexaenoic acid (DHA) (p = 0.020) and eicosapentaenoic (EPA) (p = 0.019) but a higher omega-6 (n-6)/n-3 PUFAs ratio (p = 0.007) and tumor necrosis factor alpha (TNF-α) (p = 0.016) level. Moreover, the duration of current PND episodes were also significantly correlated with DHA, EPA, n-3 PUFAs, n-6/n-3 ratio and TNF-α. In terms of PUFAs and cytokine levels, only DHA was inversely correlated with TNF-α. Conclusion PND is significantly associated with lower DHA, EPA, and total n-3 PUFAs levels and an increased n-6/n-3 PUFAs ratio, while the duration of PND is associated with lower levels of n-3 PUFAs, including DHA and EPA. The correlation of PUFAs levels with depression and TNF-α level grant further investigation into the inflammatory process underlying PND, mediated by PUFAs. [ABSTRACT FROM AUTHOR]

Objectives: Somatic symptoms are common in depressive disorder and are similar to sickness behaviors due to inflammatory activation after cytokine administration. Omega-3 polyunsaturated fatty acids (PUFAs) are natural anti-inflammatory agents and may reduce inflammation-induced behavioral changes. The aim of this study was to investigate the role of PUFAs on the development of somatic symptoms and depression in patients of hepatitis C virus infection (HCV) receiving interferon-alpha therapy (IFN-α) in a prospective manner. Methods: In this 24-week, prospective cohort study, 43 patients with chronic HCV ongoing IFN-α therapy were assessed with the mini-international neuropsychiatric interview for major depressive episodes and neurotoxicity rating scale (NRS) for somatic symptoms. Results: One-third later developed IFN-α-induced depression (depression (DEP) group). As compared to subjects without depression, DEP group had higher NRS scores (P < 0.001), lower eicosapentaenoic acid (EPA) levels (P = 0.038) at week 2. Somatic symptoms, regardless of painful/non-painful characteristics, had positive association with arachidonic acid (P < 0.05), and negative association with EPA (P < 0.05). Conclusion: This study implies that early intervention with omega-3 PUFAs might be a promising strategy to prevent depression and somatic symptoms in patients receiving cytokine therapy. [ABSTRACT FROM PUBLISHER]

The article discuses the efficacy of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) for pregnant women who suffered from mental depression. It conducted a double-blind randomized controlled trial (RCT) to determine the efficacy of omega-3 PUFAs for depressive symptoms among pregnant women. It mentions that the RCT found no evidence for the superiority of omega-3 PUFAs however the efficacy might be greatly affected by the study site and participant characteristics.

Background: Cardiovascular diseases (CVDs) are commonly comorbid with depression and vice versa. Polyunsaturated fatty acids (PUFAs) have been suggested to mediate in CVDs and depression in cross-sectional and observational studies. With the patients of CVDs, we investigated the role of depression on the effect of PUFAs. Methods: Forty-four patients with CVDs were recruited and assessed with Hamilton depression rating scale (HAMD). Patients’ CVDs markers were measured by electrocardiogram and their red blood cell (RBC) samples were collected for PUFAs analyses. Results: The data of 44 subjects were analyzed; where 10 participants (23%) with CVDs had moderate or severe depression, defined by a HAMD score more than 19 points. The moderate depression group had lower docosahexaenoic acid (DHA), omega-3 (N3) and omega-6(N6) to N3 (N6/N3) ratio than non-depression group (HAMD score less than 8), while no differences between the 2 groups in terms of corrected QT (QTc) intervals and high sensitivity C-reactive protein (hsCRP) levels. Furthermore, when we analyzed the data with an inclusion of a more heterogeneous depression group, where HAMD score is greater than or equal to 10 (mild depression group, N = 24), the differences in PUFAs levels between the 2 groups disappear. Secondary analysis of the moderate depression group showed a positive correlation between DHA, N3 PUFAs, and N6/N3 ratio and total HAMD scores, a positive correlation between N3 PUFAs and QTc intervals in non-depression group. Conclusion: Moderate depression group of patients with CVDs had lower levels of DHA, N3, and N6/N3 ratio than non-depression group, while both groups had no differences in QTc and hsCRP. On the other hand, the differences in PUFAs levels disappear in the mild depression group after inclusion of patients with CVDs with greater heterogeneity of depression. Hence, the role of N3 PUFAs is implicated in depression of patients with CVDs if the depression status is more strictly defined. [ABSTRACT FROM AUTHOR]

Introduction Omega-3 polyunsaturated fatty acids (PUFAs) have been proven critical in the development and management of major depressive disorder (MDD) by a number of epidemiological, clinical and preclinical studies, but the molecular mechanisms underlying this therapeutic action are yet to be understood. Although eicosapentaenoic acid (EPA) seems to be the active component of omega-3 PUFAs' antidepressant effects, the biological research about the difference of specific genetic regulations between EPA and docosahexaenoic acid (DHA), the two main components of omega-3 PUFAs, is still lacking in human subjects. Methods We conducted a 12-week randomized-controlled trial comparing the effects of EPA and DHA on gene expressions of phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX2), serotonin transporter (5HTT), and Tryptophan hydroxylase 2 (TPH-2) in 27 MDD patients. In addition, the erythrocyte PUFA compositions and the candidate gene expressions were also compared between these 27 MDD patients and 22 healthy controls. Results EPA was associated with a significant decrease in HAM-D scores (CI: − 13 to − 21, p < 0.001) and significant increases in erythrocyte levels of EPA (CI: + 1.0% to + 2.9%, p = 0.001) and DHA (CI: + 2.9% to + 5.6%, p = 0.007). DHA treatment was associated with a significant decrease in HAM-D scores (CI: − 6 to − 14, p < 0.001) and a significant increase in DHA levels (CI: + 0.2% to + 2.3%, p = 0.047), but not of EPA levels. The cPLA2 gene expression levels were significantly increased in patients received EPA (1.9 folds, p = 0.038), but not DHA (1.08 folds, p = 0.92). There was a tendency for both EPA and DHA groups to decrease COX-2 gene expressions. The gene expressions of COX-2, cPLA2, TPH-2 and 5-HTT did not differ between MDD cases and healthy controls. Conclusions EPA differentiates from DHA in clinical antidepressant efficacy and in upregulating cPLA2 gene regulations, which supports the clinical observation showing the superiority of EPA's antidepressant effects. Trial registration: ClinicalTrials.gov identifier: NCT02615405 [ABSTRACT FROM AUTHOR]

• We conducted a cohort study of chronic HCV patients who received IFN-α therapy. • Patients free from depression after IFN-α therapy have a lower risk of developing depression. • A new direction for developing pharmacological prophylaxis strategy against depression. IFN-α-induced depression in patients undergoing hepatitis C virus (HCV) treatment provides powerful support for the inflammation hypothesis of depression. Most studies have focused on the occurrence of depressive symptoms, but there has been no study yet in depression-free HCV patients receiving IFN-α. We hypothesized that HCV patients who did not develop depression after IFN-α exposure might have a lower incidence of depressive disorders after the IFN-α treatment. We conducted a twelve-year population-based cohort study of chronic HCV patients who received IFN-α therapy. The data were obtained from the Taiwan National Health Insurance Research Database. The study cohort was patients without any depressive disorder nor antidepressant use before and during IFN-α therapy. They were matched randomly by age, sex income and urbanization at a ratio of 1:4 with the control cohort of HCV patients without IFN-α therapy. The follow-up started after the last administration of IFN-α, and the primary outcome was the incidence of depressive disorders after IFN-α therapy. A total of 20,468 depression-free subjects were identified from records of HCV patients receiving IFN-α therapy. Patients without IFN-α-induced depression were associated with a significantly lower incidence (per 10,000 person-years) of new-onset depressive disorders (126.8, 95% Confidential Interval [CI] of 118.5–135.6) as compared to the control cohort (145.2, 95% CI of 140.0–150.6) (p < 0.001). After adjusting for age, sex, income, urbanization and comorbid diseases, the crude hazard ratio for the incident depressive disorder was 0.87 (95% CI, 0.80–0.87) and the adjusted hazard ratios was 0.79 (95% CI, 0.72–0.87) for IFN-α-induced depression-free subjects as compared to the controls. Our study indicates that IFN-α treated depression-free patients have a lower risk for depressive disorders. This hypothesized mechanism might derive from an IFN-α-induced resilience factor as yet to be defined. Our study might suggest a new possibility for a new pharmacological strategy against depression. [ABSTRACT FROM AUTHOR]

• This is the largest study to examine interferon-induced psychopathology at different onset stages and with major depression (MDD). • Compared to MDD, IFN-induced depression was associated with more somatic symptoms and fewer symptoms of mood, anxiety and negative cognition. • More somatic symptoms were also found in those who became clinically depressed at early stage of IFN-alpha therapy. Interferon (IFN)-alpha, until recently the standard treatment of hepatitis C virus (HCV) infection, is associated with a significant risk of major depressive episode (MDE, or IFN-alpha-induced depression). However, it is little studied the comparisons of clinical manifestations between IFN-alpha-induced depression and major depressive disorder (MDD). In addition, IFN-alpha induces different neuroinflammation and neuroendocrine status throughput the HCV treatment course; however, the clinical presentations have never been compared between early-onset and later-onset IFN-alpha-induced depression. We assessed 200 HCV patients starting IFN-alpha therapy bi-weekly for 24 weeks, with the structured interview for confirmation of diagnosis of IFN-alpha-induced depression and with clinical rating scales for depressive symptoms and neuropsychiatric symptoms. Subjects developed IFN-alpha-induced depression (n = 59, 30%) during the first 6 weeks of IFN-alpha therapy were defined as the early-onset group (n = 32), while those developed depression after the 6th week were defined as the late-onset group (n = 27). A matched group of MDD patients (n = 60) was used to compare specific clusters of depressive symptoms with early- and late-onset IFN-alpha-induced depression. Compared to the matched group of MDD patients, IFN-alpha-induced depression was significantly associated with more somatic symptoms and fewer symptoms of mood, anxiety and negative cognition. More somatic symptoms were also found in those who became clinically depressed at early stage of IFN-alpha therapy. We suggest that the specific somatic features of interferon-alpha-induced depression, and especially of early-onset depression, characterise individuals who are more sensitive to cytokines-induced changes in mood. [ABSTRACT FROM AUTHOR]

Background Interferon (IFN)-α therapy for chronic hepatitis C virus infection is frequently associated with depression. The routine prophylaxis with antidepressants might expose patients to adverse effects, hence, the need for alternative preventive interventions. Omega-3 polyunsaturated fatty acids are safe and effective essential nutritional compounds used for the treatment of depression, putatively through an anti-inflammatory action. In addition, lower erythrocyte levels of omega-3 polyunsaturated fatty acids have been associated with an increased risk of IFN-induced depression. Methods We conducted a 2-week, double-blind, placebo-controlled trial comparing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and placebo for the prevention of IFN-α-induced depression. A total of 162 patients consented to participate and were randomized to the study. All of the patients completed the 2-week trial; 152 participants were followed throughout the 24 weeks of IFN-α treatment and were included in the analysis. Results Compared with placebo, the incident rates of IFN-α-induced depression were significantly lower in EPA-treated but not in DHA-treated patients (10% and 28%, respectively, versus 30% for placebo, p = .037). Both EPA and DHA significantly delayed the onset of IFN-induced depression (week of onset: 12.0 and 11.7, respectively, versus 5.3 for placebo, p = .002). EPA and DHA were both well tolerated in this population. EPA treatment increased both EPA and DHA erythrocyte levels, but DHA only increased DHA erythrocyte levels. Conclusions EPA is effective in the prevention of depression in hepatitis C virus patients received IFN-α therapy. Our study confirms the notion that anti-inflammatory strategies are effective antidepressants in the context of depression associated with inflammation. [ABSTRACT FROM AUTHOR]

Abstract: Aim: Japanese psychiatrists have increasingly reported patients with depression that does not seem to fit the criteria of the ICD-10 and the DSM-IV, and which has recently been called modern type depression (MTD). We explored whether MTD is frequently seen in Japan and also in other countries, and if so, how patients with MTD are diagnosed and treated. Methods: The questionnaires, with two case vignettes (traditional type depression (TTD) and MTD), were sent to psychiatrists in Australia, Bangladesh, India, Iran, Japan, Korea, Taiwan, Thailand and the USA. Participants rated their opinions about each case''s prevalence in their country, etiology, diagnosis, suicide risk, and treatment using Likert scales. Results: Out of 247 responses (123 from Japan and 124 from other countries), two hundred thirty-nine valid responses were received. MTD was recognized in all participating countries, and especially in urban areas. Generally, the factor of personality was regarded as the most probable cause of MTD. Whereas about 90% of Japanese psychiatrists applied the ICD/DSM criteria to TTD, only about 60% applied the criteria to MTD. Conclusion: Our results indicate that Japan''s MTD seems to be occurring in many other countries, and that the present ICD/DSM criteria may not be sufficient to diagnose MTD. Therefore, it could be an important candidate for a new international diagnostic criterion as a subtype of depression. A clear diagnostic framework and consensus on the interventions to treat MTD would be valuable. Further clinical, psychopathological and international epidemiological studies are needed to confirm our preliminary findings of MTD. [Copyright &y& Elsevier]