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Objective: Identifying modifiable predictors of outcomes following treatment for eating disorders may help to tailor interventions to patients' individual needs, improve treatment efficacy, and develop new interventions. The goal of this meta‐analysis was to quantify the association between pretreatment motivation and posttreatment changes in eating disorder symptomology. Method: We reviewed 196 longitudinal studies reporting on change on indices of overall eating‐disorder symptomatology, weight gain, binge‐eating, vomiting, anxiety/depression, and treatment adherence. Meta‐analyses were performed using two complementary approaches: (a) combined probability analysis using the added Z's method; (b) effect size analyses. Using random‐effect models, effect sizes were pooled when there were at least three studies with the same type of statistical design and reporting statistics on the same outcome. Heterogeneity in study outcome was evaluated using Q and I2 statistics. Studies were reviewed qualitatively when the number of studies or reported data were insufficient to perform a meta‐analysis. Results: Forty‐two articles were included. Although samples and treatments differed substantially across studies, results across studies were remarkably consistent. Both combined‐probability and effect‐size analyses indicated positive effects of pretreatment motivation on improvement in general eating‐disorder symptoms (Cohen's r =.17), and an absence of effects on anxiety/depression symptoms. Remaining outcome indices were subject to selective reporting and/or small sample size bias. Discussion: Our findings underscore the importance of incorporating treatment engagement approaches in the treatment of eating disorders. Optimal reporting of study findings and improving study quality would improve future efforts to obtain an in‐depth understanding of the relationship between motivation and eating disorder symptoms. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Evidence associates anorexia nervosa (AN) with epigenetic alterations that could contribute to illness risk or entrenchment. We investigated the extent to which AN is associated with a distinct methylation profile compared to that seen in normal-eater women. Method Genome-wide methylation profiles, obtained using DNA from whole blood, were determined in 29 women currently ill with AN (10 with AN-restrictive type, 19 with AN-binge/purge type) and 15 normal-weight, normal-eater control women, using 450 K Illumina bead arrays. Results Regardless of type, AN patients showed higher and less-variable global methylation patterns than controls. False Discovery Rate corrected comparisons identified 14 probes that were hypermethylated in women with AN relative to levels obtained in normal-eater controls, representing genes thought to be associated with histone acetylation, RNA modification, cholesterol storage and lipid transport, and dopamine and glutamate signaling. Age of onset was significantly associated with differential methylation in gene pathways involved in development of the brain and spinal cord, while chronicity of illness was significantly linked to differential methylation in pathways involved with synaptogenesis, neurocognitive deficits, anxiety, altered social functioning, and bowel, kidney, liver and immune function. Discussion Although pre-existing differences cannot be ruled out, our findings are consistent with the idea of secondary alterations in methylation at genomic regions pertaining to social-emotional impairments and physical sequelae that are commonly seen in AN patients. Further investigation is needed to establish the clinical relevance of the affected genes in AN, and, importantly, reversibility of effects observed with nutritional rehabilitation and treatment. © 2015 Wiley Periodicals, Inc. (Int J Eat Disord 2015; 48:874-882) [ABSTRACT FROM AUTHOR]

The functioning of the hypothalamic-pituitary-adrenal (HPA) axis and serotonergic (5-HT) system are known to be intertwined with mood. Alterations in these systems are often associated with depression. However, neither are sufficient to cause depression in and of themselves. It is now becoming increasingly clear that the environment plays a crucial role, particularly, the perinatal environment. In this review, we posit that early environmental stress triggers a series of epigenetic mechanisms that adapt the genome and programme the HPA axis and 5-HT system for survival in a harsh environment. We focus on DNA methylation as it is the most stable epigenetic mark. Given that DNA methylation patterns are in large part set within the perinatal period, long-term gene expression programming by DNA methylation is especially vulnerable to environmental insults during this period. We discuss specific examples of genes in the 5-HT system (serotonin transporter) and HPA axis (glucocorticoid receptor and arginine vasopressin enhancer) whose DNA methylation state is associated with early life experience and may potentially lead to depression vulnerability. We conclude with a discussion on the relevance of studying epigenetic mechanisms in peripheral tissue as a proxy for those occurring in the human brain and suggest avenues for future research. [ABSTRACT FROM AUTHOR]

Abstract: Acute tryptophan depletion (ATD) in currently depressed patients has no immediate effect on symptoms, but leads to transient symptom improvement or worsening the next day. In view of recent findings concerning the cognitive effects of serotonin manipulations, we used ATD in fourteen depressed patients to investigate whether cognitive effects following ATD predict symptom changes. We found that symptom improvement 24h after ATD was associated with an improved recall of positive words and with less attentional bias and recall of negative words, 5h after ATD. These results indicate that serotonergic alterations affect emotional processing which may subsequently lead to symptom changes. [Copyright &y& Elsevier]

Objective. Irritable and nonirritable depressed patients differ on demographic and clinical characteristics.We investigated whether this extends to psychological and physiological measures. Method. We compared irritable and nonirritable unipolar depressed patients on symptomatology, personality, and (psycho)physiological measures (cortisol, cholesterol, and heart rate variability). Symptomatology was reassessed after one year, and we also compared depressed patients who were irritable or non-irritable at both time points (Irr++ versus Irr--). Results. Almost half (46%; N = 420) of the sample was classified as irritable. These patients scored higher on depression severity, anxiety, hypomanic symptoms, and psychological variables. No differences were observed on physiological markers after correction for depression severity. The same pattern was found when comparing Irr++ and Irr-- groups. Conclusion. Irritable and non-irritable depressed patients differ on clinical and psychological variables, but not on the currently investigated physiological markers. The clinical relevance of the distinction and the significance of the hypomanic symptoms remain to be demonstrated. [ABSTRACT FROM AUTHOR]

Depressive disorders are associated with various cognitive impairments. Studies on whether or not these impairments persist into the euthymic phase have shown conflicting results, due to differences in test versions and in study samples. In this paper, we aimed to compare the cognitive performance of remitted depressed patients with that of age- and gender-matched healthy volunteers across a wide range of cognitive domains. In two studies, we found few differences on neutral as well as emotional information processing tests. The findings indicate that remitted depressed patients who use antidepressant medication still show an increased recognition of facial expression of fear compared to healthy controls. Patients also performed worse on a test of recognition of abstract visual information from long-term memory. No other residual cognitive impairments were found. These results indicate that most of the cognitive impairments associated with depression resolve with recovery through medication, even when recovery is incomplete. Considering the finding that remitted depressed patients have higher levels of cognitive reactivity, future studies may investigate the possibility that these cognitive impairments have not resolved but have become latent, and may therefore easily be triggered by small changes in mood state. Depression and Anxiety 0:1–10, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Cognitive reactivity (CR) is a psychological vulnerability marker of depression, whereas response to acute tryptophan depletion (ATD; a serotonergic challenge procedure) is a biological vulnerability marker. The aim of this study was to investigate the relationship between these markers. Thirty-nine remitted depressed patients participated in 2 ATD sessions in a double-blind crossover design. CR, assessed prior to the ATD sessions, predicted depressive response to high-dose ATD. CR also diminished the effects of 2 known predictors of ATD response: gender and residual symptoms. Neuroticism and behavioral inhibition were unrelated to ATD response. CR is associated with an increased sensitivity to reductions of serotonin concentrations. These findings present a small step toward unifying cognitive and neurobiological theories of depression. [ABSTRACT FROM AUTHOR]

Background: Depression is a major risk factor for cardiovascular disease. An important risk factor for cardiovascular disease, low heart rate variability, often has been found in depressed patients and has been associated with impulsivity. The present study investigated whether experimental lowering of serotonin would decrease heart rate variability and increase impulsivity in remitted depressed patients, in particular in those patients with disturbed impulse control. Methods: Nineteen patients in remission from depression received high-dose and low-dose acute tryptophan depletion in a randomized, counterbalanced, double-blind crossover design. Heart rate variability and impulsivity were assessed during each acute tryptophan depletion session and during a baseline session. Suicidal ideation during past depression was used as an index for individual differences in impulse control. Results: High-dose acute tryptophan depletion led to a larger increase in depressive symptoms than did low-dose acute tryptophan depletion. High-dose acute tryptophan depletion decreased heart rate variability and increased impulsivity and anxiety, but only in patients with a history of suicidal ideation. Symptom effects of high-dose acute tryptophan depletion correlated with low heart rate variability at baseline. Conclusions: Depressed patients who have problems with controlling impulsivity might be more at risk for developing cardiovascular disease, possibly related to increased vulnerability to impaired 5-hydroxytryptamine function. [Copyright &y& Elsevier]

Depression is associated with reduced brain serotonin (5-hydroxytryptamine; 5-HT) function and with cognitive dysfunctions. A diet rich in α-lactalbumin protein has been found to increase the ratio tryptophan/large neutral amino acids (Trp/∑LNAA), and to improve cognitive functioning in individuals with high neuroticism scores. Since cognitive dysfunctions sometimes persist after remission of depression, the present study investigated the effects of α-lactalbumin-enriched diet on cognition in recovered depressed patients. Twenty-three recovered depressed patients and 20 healthy matched controls without a history of depression consumed meals rich in α-lactalbumin or casein protein in a double-blind crossover design. Mood, cognitive function and plasma amino acids were assessed at both sessions before and after dietary intake. Alpha-lactalbumin protein had no effect on mood, but improved abstract visual memory and impaired simple motor performance. These effects were independent of history of depression. Supplements of α-lactalbumin may be useful for nutrition research in relation to age- or disease-related memory decline. The present findings should be further examined in different (e.g. medicated) samples. The long-term effects of α-lactalbumin should also be investigated. [ABSTRACT FROM AUTHOR]

It has frequently been demonstrated that acute tryptophan depletion (ATD) induces a transient depressed mood in some patients who are in remission from depression. However, the effects of ATD on cognitive processes in remitted depressed patients have not been investigated. The aim of the present study was to investigate the effects of different extents of depletion on mood and cognitive tasks involving neutral and emotional stimuli. Twenty patients in remission or in partial remission from depression received ATD in a double-blind, crossover design. Mood was assessed at both sessions before, at +6.5 h and +24 h after depletion. Cognitive assessment in both sessions started at +4.75 h, and also before and after the whore procedure. The ATD mixtures induced the expected reductions of plasma tryptophan levels. High-dose ATD induced a depressive response in a subsample of patients and impaired the processing of positive information independent of mood change. Attention for neutral stimuli (Stroop interference) improved in a dose-dependent manner. ATD may affect mood and cognition via different pathways: one implicated in mood regulation and the processing of emotional information, and one for the processing of neutral information. The first pathway may be more important for discriminating vulnerability to impaired serotonin function. The comparison of the effects of high-dose and low-dose ATD is useful for those studies aiming to investigate the relationships among 5-HT, mood and cognition. [ABSTRACT FROM AUTHOR]

Acute tryptophan depletion (ATD) induces depressive symptoms in 50-60% of selective serotonin reuptake inhibitor (SSRI) treated, recovered depressed patients. However, no reliable predictors of mood response to ATD have been established. In the present study, individual subject data of six ATD studies were pooled (‘mega-analysis’) in order to investigate the mediating role of clinical, demographic and biochemical characteristics in the mood response to ATD. A procedure was developed to make different versions of the Hamilton scale comparable. Recurrent depressive episodes, female gender, prior exposure to SSRI antidepressant treatment and previous serious suicidal thoughts/attempts all appear to be independent predictors of mood response to ATD. Chronicity of illness is the most powerful predictor. Residual symptoms of depression were not found to predict response to ATD. ATD may be useful to study the mechanism of action of SSRI antidepressants and individual biological vulnerability of the serotonin system. Whether the effects of ATD represent a reversal of the action of SSRI antidepressants or individual vulnerability probably depends upon the timing of the procedure in the course of remission of a depressive episode. [Copyright &y& Elsevier]

Despite intense ongoing research efforts, the etiology of psychiatric disorders remains incompletely understood. Among biological factors playing a role in Major Depressive Disorder (MDD) and Anxiety Disorders (ANX), emerging evidence points to the relevance of different types of glia cells and efficient neuron-glia interactions. Here, we review recent findings highlighting the involvement of central nervous system (CNS) glia in MDD and ANX etiology and treatment response. Additionally, several relatively underexplored topics will be discussed: (1) glial response to non-pharmacological therapies, (2) impact of early life adversity on glia, (3) influence of lifestyle factors on glia in the context of MDD and ANX, and (4) monitoring glial functions in patients. It can be concluded that despite the sequence of events is still unclear, alterations in glial cell types are common and somewhat overlapping in ANX, MDD and corresponding animal models. Furthermore, glia are responsive to a variety of treatment and lifestyle options. Looking forward, new research developments can lead to novel types of therapeutic or symptom-relieving approaches targeting glia. [ABSTRACT FROM AUTHOR]

Objectives: Accurate and complete study reporting allows evidence users to critically appraise studies, evaluate possible bias, and assess generalizability and applicability. We evaluated the extent to which recent studies on depression screening accuracy were reported consistent with Standards for Reporting of Diagnostic Accuracy Studies (STARD) statement requirements. Methods: MEDLINE was searched from January 1, 2018 through May 21, 2021 for depression screening accuracy studies. Results: 106 studies were included. Of 34 STARD items or sub‐items, the number of adequately reported items per study ranged from 7 to 18 (mean = 11.5, standard deviation [SD] = 2.5; median = 11.5), and the number inadequately reported ranged from 3 to 17 (mean = 10.1, SD = 2.5; median = 10.0). There were eight items adequately reported, seven partially reported, 11 inadequately reported, and four not applicable in ≥50% of studies; the remaining four items had mixed reporting. Items inadequately reported in ≥70% of studies related to the rationale for index test cut‐offs examined, missing data management, analyses of variability in accuracy results, sample size determination, participant flow, study registration, and study protocol. Conclusion: Recently published depression screening accuracy studies are not optimally reported. Journals should endorse and implement STARD adherence. [ABSTRACT FROM AUTHOR]

Background: Subthreshold depression is highly prevalent in adolescence, but compared to major depressive disorder, the clinical impact is under-researched. The aim of this review was to compare subthreshold depression and major depressive disorder in adolescents by reviewing available literature on epidemiology, risk factors, illness trajectories, brain anatomy and function, genetics, and treatment response.Methods: We conducted a scoping review of papers on subthreshold depression and major depressive disorder in adolescence published in English. Studies in adults were included when research in adolescence was not available.Results: We found that individuals with subthreshold depression were similar to individuals with major depressive disorder in several regards, including female/male ratio, onset, functional impairment, comorbidity, health care utilization, suicidal ideation, genetic predisposition, brain alterations, and treatment response. Further, subthreshold depression was about two times more common than major depressive disorder.Limitations: The definition of subthreshold depression is highly variable across studies. Adolescent-specific data are limited in the areas of neurobiology and treatment.Conclusions: The findings of the current review support the idea that subthreshold depression is of clinical importance and provide evidence for a spectrum, versus categorical model, for depressive symptomatology. Given the frequency of subthreshold depression escalating to major depressive disorder, a greater recognition and awareness of the significance of subthreshold depression in research, clinical practice and policy-making may facilitate the development and application of early prevention and intervention. [ABSTRACT FROM AUTHOR]

Objectives: Depression screening tool accuracy studies should be conducted with large enough sample sizes to generate precise accuracy estimates. We assessed the proportion of recently published depression screening tool diagnostic accuracy studies that reported sample size calculations; the proportion that provided confidence intervals (CIs); and precision, based on the width and lower bounds of 95% CIs for sensitivity and specificity. In addition, we assessed whether these results have improved since a previous review of studies published in 2013–2015. Methods: MEDLINE was searched from January 1, 2018, through May 21, 2021. Results: Twelve of 106 primary studies (11%) described a viable sample size calculation, which represented an improvement of 8% since the last review. Thirty‐six studies (34%) provided reasonably accurate CIs. Of 103 studies where 95% CIs were provided or could be calculated, seven (7%) had sensitivity CI widths of ≤10%, whereas 58 (56%) had widths of ≥21%. Eighty‐four studies (82%) had lower bounds of CIs <80% for sensitivity and 77 studies (75%) for specificity. These results were similar to those reported previously. Conclusion: Few studies reported sample size calculations, and the number of included individuals in most studies was too small to generate reasonably precise accuracy estimates. [ABSTRACT FROM AUTHOR]

Screening is done to improve health outcomes by identifying and effectively treating individuals with unrecognized conditions. Depression screening has been proposed to identify previously unrecognized depression cases. Including individuals already diagnosed or treated for depression in screening test accuracy studies could exaggerate accuracy and the yield of new cases from screening. The present study investigated (1) the proportion of depression screening tool accuracy primary studies published in 2018–2021 that excluded individuals with a confirmed depression diagnosis or who were already undergoing treatment; and (2) whether this has improved since the last review of studies published in 2013–2015, which found that five of 89 (5.6%) primary studies appropriately excluded such individuals. MEDLINE was searched from January 1, 2018 through May 21, 2021 for primary studies on depression screening tool accuracy. Eighteen of 106 (17.0%; 95% Confidence Interval [CI], 11.0% to 25.3%) primary studies excluded currently diagnosed or treated individuals. This was 11.4% (95% CI, 2.8% to 20.0%) greater than in similar studies published in 2013–2015. There has been an improvement since 2015, but the proportion of studies that exclude individuals already known to have depression remains low. This may bias research findings intended to inform clinical practice. [ABSTRACT FROM AUTHOR]

Background: Cognitive reactivity to sad mood is a vulnerability marker of depression. Implicit self-depressed associations are related to depression status and reduced remission probability. It is unknown whether these cognitive vulnerabilities precede the first onset of depression. Aim: To test the predictive value of cognitive reactivity and implicit self-depressed associations for the incidence of depressive disorders. Methods: Prospective cohort study of 834 never-depressed individuals, followed over a two-year period. The predictive value of cognitive reactivity and implicit self-depressed associations for the onset of depressive disorders was assessed using binomial logistic regression. The multivariate model corrected for baseline levels of subclinical depressive symptoms, neuroticism, for the presence of a history of anxiety disorders, for family history of depressive or anxiety disorders, and for the incidence of negative life events. Results: As single predictors, both cognitive reactivity and implicit self-depressed associations were significantly associated with depression incidence. In the multivariate model, cognitive reactivity was significantly associated with depression incidence, together with baseline depressive symptoms and the number of negative life events, whereas implicit self-depressed associations were not. Conclusion: Cognitive reactivity to sad mood is associated with the incidence of depressive disorders, also when various other depression-related variables are controlled for. Implicit self-depressed associations predicted depression incidence in a bivariate test, but not when controlling for other predictors. [ABSTRACT FROM AUTHOR]

Peer victimization is associated with increased risk for mental health problems. These adverse psychological outcomes are linked with altered cognitive and emotional processes and their related neural functioning. In the present study, by using functional magnetic resonance imaging (fMRI), we examined whether peer victimization was associated with heightened neural response to social exclusion. Participants (N = 45; M age = 17.7 years, SD = 0.60; 36 women) included three mutually exclusive groups: peer-victimized individuals (targets of bullying), cyberdefenders (defended peers who were being cyberbullied), and controls (not involved as targets or cyberdefenders). All participants underwent an fMRI scan while playing Cyberball, an experimental paradigm that simulates social exclusion. Peer victimization was associated with increased neural response in the left amygdala, left parahippocampal gyrus, left inferior frontal operculum, and right fusiform gyrus. Understanding the acute neural response to social exclusion in peer-victimized individuals may provide insight into their increased risk for poor mental health. [End Page 135] [ABSTRACT FROM AUTHOR]

Background: Difficult temperament in infancy is a risk factor for forms of later internalizing and externalizing psychopathology, including depression and anxiety. A better understanding of the roots of difficult temperament requires assessment of its early development with a genetically informative design. The goal of this study was to estimate genetic and environmental contributions to individual differences in infant negative emotionality, their persistence over time and their influences on stability between 5 and 18 months of age. Method: Participants were 244 monozygotic and 394 dizygotic twin pairs (49.7% male) recruited from birth. Mothers rated their twins for negative emotionality at 5 and 18 months. Longitudinal analysis of stability and innovation between the two time points was performed in Mplus. Results: There were substantial and similar heritability (approximately 31%) and shared environmental (57.3%) contributions to negative emotionality at both 5 and 18 months. The trait’s interindividual stability across time was both genetically- and environmentally- mediated. Evidence of innovative effects (i.e., variance at 18 months independent from variance at 5 months) indicated that negative emotionality is developmentally dynamic and affected by persistent and new genetic and environmental factors at 18 months. Conclusions: In the first two years of life, ongoing genetic and environmental influences support temperamental negative emotionality but new genetic and environmental factors also indicate dynamic change of those factors across time. A better understanding of the source and timing of factors on temperament in early development, and role of sex, could improve efforts to prevent related psychopathology. [ABSTRACT FROM AUTHOR]

Objectives: About 50% of patients with unipolar depression suffer from treatment-resistant depression (TRD). Animal studies have suggested potential antidepressant properties of valproate (VPA) possibly due to its implication in epigenetic programming.Methods: Fourteen TRD patients (seven males and seven females; age 19–59) received VPA (375–1000 mg/day) in addition to their treatment regimen after previously failing to respond to two or more antidepressant trials and/or different combinations. Clinical response to VPA was investigated prior the treatment (T-0) and after 1 (T-1), 4 (T-4) and 7 (T-7) months of therapy using the Montgomery–Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI).Results: Compared to T-0, VPA significantly decreased MADRS score at T-1 (P < 0.001), T-4 (P < 0.001) and T-7 (P < 0.001) (partial η2=0.86). Importantly, MADRS score at T-7 (13.6 ± 1.6, mean ± SEM) was closer to the reported value of remission (MADRS <10), and none of the patients relapsed during the observational period. Compared to T-0, VPA also decreased CGI-Severity of illness score at T-1 (p = 0.03), T-4 (p < 0.001) and T-7 (p < 0.001) (partial η2 = 0.74).Conclusions: Antidepressant augmentation with VPA provided substantial clinical improvement and maintenance over a relatively long-term period in a subgroup of patients with severe TRD. VPA thus deserves further exploration in large double-blind clinical trials. [ABSTRACT FROM PUBLISHER]

Background: The aim of the present study was to investigate the association of fMRI blood oxygen--level dependent (BOLD) reactivity with the level of epigenetic methylation of SLC6A4 in blood DNA from a sample of healthy participants and patients with major depressive disorder (MDD). Methods: We investigated patients with MDD and healthy controls using fMRI and an emotional attention-shifting task. We assessed site-specific DNA methylation of a previously characterized SLC6A4 region in peripheral blood DNA using pyro-sequencing. Results: Our study involved 25 patients with MDD and 35 healthy controls. Activation in the anterior insula elicited by negative emotional content was significantly positively associated with the degree of SLC6A4 methylation. Significantly negative associations were observed between activation in the posterior insula and the degree of SLC6A4 methylation when judging the geometry of pictures after seeing negative in contrast to positive emotional stimuli. Healthy controls with a high degree of SLC6A4 methylation depicted significantly more activity elicited by positive stimuli in limbic regions and more activity elicited by negative stimuli in limbic as well as cognitive control regions than those with a low degree of SLC6A4 methylation. Limitations: It is impossible to measure methylation directly in the brain and thus we assessed peripheral methylation of SLC6A4. Since the association was cross-sectional, no conclusion about cause and effect can be drawn. Conclusion: Our study provides further support to the hypothesis that particular DNA methylation states that are associated with brain function during emotion processing are detectable in the periphery. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: We used functional magnetic resonance imaging (fMRI) to investigate the neural correlates of sadness, the prevailing mood in major depression (MD), in a prospective, well-documented community sample followed since birth. Methods: The children, comprising 136 children (65 boys and 71 girls) of mothers with varying levels of depressive symptomatology, were scanned – using a 1.5-Tesla system – while they watched 5 blocks of both sad and neutral film excerpts. Following scanning, they rated the emotions they experienced, and if they identified sadness, they were also asked to rate its intensity. Results: In children whose mothers exhibited higher depressive symptomatology, compared to children whose mothers displayed lower depressive symptomatology, altered neural responses to sad film excerpts were noted in brain regions known to be involved in sadness and MD, notably the insula, anterior cingulate cortex and caudate nucleus, even though the children did not differ in current mood. Limitations: Whether this represents genetic vulnerability or a consequence of exposure to maternal depressive symptoms at a young age is unknown. Discussion: The results are consistent with the results of studies in healthy adults and MD patients. The present study suggests that an altered pattern of regional brain responses to sad stimuli, is already present in childhood and might represent vulnerability for MD later in life. [Copyright &y& Elsevier]

Background: Some authors have hypothesized that Treatment-Resistant Unipolar Depression (TRD-UP) should be considered within the bipolar spectrum disorders and that hidden bipolarity may be a risk factor for TRD-UP. However, there are neither studies comparing clinical and sociodemographic data of patients with TRD-UP versus Bipolar (BP) disorders nor are there any examining differences versus Bipolar type I (BP-I) and Bipolar type II (BP-II). Methods: Charts analysis was conducted on 194 patients followed at the Mood Disorders Clinic of the McGill University Health Center. Sociodemographic, clinical features and depression scales were collected from patients meeting DSM-IV criteria for TRD-UP (n = 100) and BP (n = 94). Binary logistic regression analysis was conducted to examine clinical predictors independently associated with the two disorders. Results: Compared to BP, TRD-UP patients exhibited greater severity of depression, prevalence of anxiety and panic disorders, melancholic features, Cluster-C personality disorders, later onset of depression and fewer hospitalizations. Binary logistic regression indicated that higher comorbidity with anxiety disorders, higher depression scale scores and lower global assessment of functioning (GAF) scores, and lower number of hospitalizations and psychotherapies differentiated TRD-UP from BP patients. We also found that the rate of unemployment and the number of hospitalizations for depression was higher in BP-I than in BP-II, while the rate of suicide attempts was lower in BP-I than in BP-II depressed patients. Conclusions: These results suggest that TRD-UP constitutes a distinct psychopathological condition and not necessarily a prodromal state of BP depression. [ABSTRACT FROM AUTHOR]