Inflammatory cytokines,complement factor H and anhedonia in drug-naïve major depressive disorder

ObjectiveAnhedonia is a core symptom of major depressive disorder (MDD) and often associated with poor prognosis. The main objective of the present study was to explore the relationship between complement factor H (CFH), inflammatory cytokines and anhedonia in drug-naïve MDD patients.MethodsA total of 215 participants (61 MDD patients with anhedonia, 78 MDD patients without anhedonia, and 76 control subjects) were included. Severity of depression and levels of anhedonia were evaluated by Hamilton Rating Scale for Depression-17 (HAMD-17) and SHAPS (Snaith-Hamilton Pleasure Scale). Plasma levels of CFH, interleukin-6 (IL-6), IL-10 and tumor necrosis factor-α (TNF-α) were measured.ResultsThe plasma levels of CFH, IL-10 and TNF-α were higher in drug-naïve MDD patients than control subjects. Compared to MDD patients without anhedonia, patients with anhedonia showed higher levels of CFH and IL-6. The stepwise regression analysis revealed that IL-10, TNF-α, as well as IL-10 × TNF-α were associated with depressive symptoms measured by HAMD-17 in drug-naïve MDD patients, while only CFH levels were identified as a mediator factor for the severity of anhedonia in the patients.ConclusionMDD patients with anhedonia showed different inflammatory characteristics compared to patients without anhedonia. Our results provide novel evidence suggesting that increased plasma CFH levels may be a potential biomarker of anhedonia of subtyping MDD.     

The clinical picture of depression in preschool children

OBJECTIVE: To investigate the clinical characteristics of depression in preschool children. METHOD: One hundred seventy-four subjects between the ages of 3.0 and 5.6 years were ascertained from community and clinical sites for a comprehensive assessment that included an age-appropriate psychiatric interview for parents. Modifications were made to the assessment of major depressive disorder (MDD) criteria so that age-appropriate manifestations of symptom states could be captured. Typical and "masked" symptoms of depression were investigated in three groups: depressed (who met all MDD criteria except duration criterion), those with nonaffective psychiatric disorders (who met criteria for attention-deficit/hyperactivity disorder and/or oppositional defiant disorder), and those who did not meet criteria for any psychiatric disorder. RESULTS: Depressed preschool children displayed "typical" symptoms and vegetative signs of depression more frequently than other nonaffective or "masked" symptoms. Anhedonia appeared to be a specific symptom and sadness/irritability appeared to be a sensitive symptom of preschool MDD. CONCLUSIONS: Clinicians should be alert to age-appropriate manifestations of typical MDD symptoms and vegetative signs when assessing preschool children for depression. "Masked" symptoms of depression occur in preschool children but do not predominate the clinical picture. Future studies specifically designed to investigate the specificity and sensitivity of the symptoms of preschool depression are now warranted.     

Reconsidering anhedonia in depression: Lessons from translational neuroscience

Anhedonia is a core symptom of major depressive disorder (MDD), the neurobiological mechanisms of which remain poorly understood. Despite decades of speculation regarding the role of dopamine (DA) in anhedonic symptoms, empirical evidence has remained elusive, with frequent reports of contradictory findings. In the present review, we argue that this has resulted from an underspecified definition of anhedonia, which has failed to dissociate between consummatory and motivational aspects of reward behavior. Given substantial preclinical evidence that DA is involved primarily in motivational aspects of reward, we suggest that a refined definition of anhedonia that distinguishes between deficits in pleasure and motivation is essential for the purposes of identifying its neurobiological substrates. Moreover, bridging the gap between preclinical and clinical models of anhedonia may require moving away from the conceptualization of anhedonia as a steady-state, mood-like phenomena. Consequently, we introduce the term “decisional anhedonia” to address the influence of anhedonia on reward decision-making. These proposed modifications to the theoretical definition of anhedonia have implications for research, assessment and treatment of MDD.     

Association of different adverse life events with distinct patterns of depressive symptoms

OBJECTIVE: The authors sought to determine whether, in a general population sample, different categories of adverse life events were associated with different patterns of depressive symptoms. METHOD: A total of 4,856 individuals (53% female) who experienced depressive symptoms in the previous year were assessed in up to four waves over a maximum of 12 years. At each wave, participants reported the severity of 12 symptoms disaggregated from the nine DSM-III-R criteria for major depression and the self-identified cause of these symptoms, which were classified into nine categories of adverse life events. RESULTS: The patterns of depressive symptoms associated with the nine categories of adverse life events differed significantly. Deaths of loved ones and romantic breakups were marked by high levels of sadness, anhedonia, appetite loss, and (for romantic breakups) guilt. Chronic stress and, to a lesser degree, failures were associated with fatigue and hypersomnia, but less so with sadness, anhedonia, and appetite loss. Those who reported that no adverse life events caused their dysphoric episodes reported fatigue, appetite gain, and thoughts of self-harm, but less sadness or trouble concentrating. These symptom patterns were found in a between-persons analysis of participants who had a single dysphoric episode, and they were replicated in an independent within-persons analysis of episode-specific symptom deviations among individuals with multiple episodes. Similar results were obtained when the sample was restricted to those meeting DSM-III-R diagnostic criteria for major depression. CONCLUSIONS: Depression is a pathoplastic syndrome. Different types of life events are related to different depressive symptom profiles. The results from the within-persons analysis suggest that these relationships are causal.     

Progress and challenges in research of the mechanisms of anhedonia in major depressive disorder

There is an increasing heavy disease burden of major depressive disorder (MDD) globally. Both high diagnostic heterogeneity and complicated pathological mechanisms of MDD pose significant challenges. There is much evidence to support anhedonia as a core feature of MDD. In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, anhedonia is further emphasised as a key item in the diagnosis of major depression with melancholic features. Anhedonia is a multifaceted symptom that includes deficits in various aspects of reward processing, such as anticipatory anhedonia, consummatory anhedonia, and decision-making anhedonia. Anhedonia is expected to become an important clinicopathological sign for predicting the treatment outcome of MDD and assisting clinical decision making. However, the precise neurobiological mechanisms of anhedonia in MDD are not clearly understood. In this paper, we reviewed (1) the current understanding of the link between anhedonia and MDD; (2) the biological basis of the pathological mechanism of anhedonia in MDD; and (3) challenges in research on the pathological mechanisms of anhedonia in MDD. A more in-depth understanding of anhedonia associated with MDD will improve the diagnosis, prediction, and treatment of patients with MDD in the future.     

Posttraumatic stress disorder and major depressive disorder: investigating the role of overlapping symptoms in diagnostic comorbidity

Studies of posttraumatic stress disorder (PTSD) have found high levels of comorbid major depressive disorder (MDD). One reason suggested for the comorbidity is the symptom overlap (contaminated symptoms) between the disorders. The present study investigated the contribution of contaminated symptoms (anhedonia, concentration, and sleep problems) to the comorbidity of PTSD and MDD. PTSD symptoms were subdivided into two groups: the contaminated symptoms and the 14 unique symptoms. It was speculated that if the contaminated symptoms are responsible for the comorbidity, then they will show less specificity than the unique symptoms, will be less highly correlated with a PTSD symptom total count, and be more frequently endorsed in PTSD patients with than without MDD. These hypotheses were tested in a sample (N = 1300) of psychiatric outpatients, 260 of whom had lifetime PTSD. None of the hypotheses were supported, thereby suggesting that the comorbidity between PTSD and MDD is not an artifact of symptom overlap.     

Is peripartum anhedonia a missing target?

The perinatal period is an extremely delicate phase that can involve a high risk for onset of depressive disorders. The Edinburgh Postnatal Depression Scale (EPDS) is a widely validated instrument for assessing perinatal depressive symptoms, including the dimension of anhedonia. There are studies suggesting that the neural mechanism underlying the occurrence of anhedonia in patients with major depressive disorder (MDD) and bipolar depression (BD) might be distinct. Anhedonia seems to represent a more stable and frequent symptom in women with postpartum bipolar relative to unipolar depressive disorder and is associated with significantly higher depressive symptom severity. Perinatal medicine is an important component of women's health. Treatment of anhedonia can be challenging, and the most effective treatment can be a combination of psychotherapy and medication, but the screening of anhedonia in peripartum women can prevent the development of other psychiatric disorders and maladaptive behaviors.     

Comorbid major depression in obsessive-compulsive disorder patients

Although major depressive disorder (MDD) has been consistently considered the most frequent complication of obsessive-compulsive disorder (OCD), little is known about the clinical characteristics of patients with both disorders. This study assessed 815 Brazilian OCD patients using a comprehensive psychiatric evaluation. Clinical and demographic variables, including OCD symptom dimensions, were compared among OCD patients with and without MDD. Our findings showed that prevalence rates of current MDD (32%) and lifetime MDD (67.5%) were similar for both sexes in this study. In addition, patients with comorbid MDD had higher severity scores of OCD symptoms. There was no preferential association of MDD with any particular OCD symptom dimension. This study supports the notion that depressed OCD patients present more severe general psychopathology.     

Unipolar depression does not moderate responses to the Sweet Taste Test

Background: The Sweet Taste Test (STT) measures hedonic responses to sweet tastes and has been linked to both alcoholism and to a family history of alcoholism. However, STT response profiles in unipolar major depressive disorder (MDD), a disorder characterized by anhedonia, have been minimally investigated. Methods: Twelve adults with and 15 adults without MDD participated in two identical STT assessments separated by approximately 12 weeks. Between assessments, MDD outpatients received Behavioral Activation Therapy for Depression, a psychotherapy modality designed to increase engagement with rewarding stimuli and reduce avoidance behaviors. Primary‐dependent measures included sensitivity to sucrose, hedonic response to sucrose, and designation as a Sweet‐Liker or Sweet‐Disliker. Results: A total of 75% of adults with MDD were treatment responders. There were no significant differences in STT response profiles between groups overall or at either timepoint. Furthermore, STT profiles of MDD participants did not differ after psychotherapy, relative to baseline. Conclusions: Findings suggest that although anhedonia is a symptom of MDD, the disorder is not characterized by altered responses to sweet tastes. Implications and future directions are discussed. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

A three-factor model of the MADRS in major depressive disorder

Major Depressive Disorder (MDD) may be composed of some symptom clusters with distinct neurochemical disturbances, suggesting the importance of the factor analysis of depressive symptoms; however, the results of previous studies using the Montgomery-Asberg Depression Rating Scale (MADRS) have been inconsistent. In the present study, factor analysis of the MADRS was performed in 132 Japanese patients (range 23-74 years, mean 47.6 years) with MDD without any psychiatric comorbidity. The principal component analysis with Varimax rotation identified three factors, accounting for 61% of the total variance: The first factor, labeled dysphoria, included pessimistic thoughts, suicidal thoughts, and reported sadness; the second factor, labeled retardation, included lassitude, inability to feel, apparent sadness, and concentration difficulties; and the third factor, labeled vegetative symptoms, included reduced sleep, reduced appetite, and inner tension. The score of the vegetative factor showed a significant positive correlation with age and was significantly higher in females than in males. This study suggests that the symptoms of MDD, as assessed by the MADRS, cluster into three factors (dysphoria, retardation, and vegetative symptoms).     

Childhood trauma is associated with elevated anhedonia and altered core reward circuitry in major depression patients and controls

Childhood trauma (CT) is a well‐established risk factor for major depressive disorder (MDD). However, the underlying mechanism linking CT and MDD remains not fully understood. The present study tested the hypothesis that CT have effects on specific types of anhedonia in depression via reward system. To do so, we evaluated different aspects of anhedonia and resting‐state functional connectivity (FC) in reward system among 66 patients with MDD (44 with moderate‐to‐severe and 22 with no or low CT), and 57 healthy controls (HC; 23 with moderate‐to‐severe and 34 with no or low CT). Results showed that MDD patients with moderate‐to‐severe CT suffered more severe state anhedonic depression than patients with no or low level of CT. Individuals with moderate‐to‐severe CT, irrespective of MDD diagnosis, had elevated physical, social and anticipatory but not consummatory trait anhedonia, and demonstrated decreased left nucleus accumbens (NAcc)‐right orbital frontal cortex (OFC) and left ventral caudate‐left OFC connectivity compared to those with no or low exposure. Left NAcc‐right OFC connectivity mediated relationship between CT and state anhedonia in MDD. The total altered ventral striatum (VS)‐OFC connectivity mediated links between CT and physical trait anhedonia in HC. These findings highlight specific types of anhedonia and the core reward system as targets of CT. Blunted hedonic responses via decreased coupling within core reward system may be involved in the mechanism of depression following CT. Implications for clinical interventions are also discussed.     

Substance use disorder comorbidity in major depressive disorder: an exploratory analysis of the Sequenced Treatment Alternatives to Relieve Depression cohort

Patients with major depressive disorder (MDD) often present with concurrent substance use disorders (SUD) involving alcohol and/or illicit drugs. This analysis compares the depressive symptomatic presentation and a range of clinical and demographic features of patients with MDD and concurrent SUD symptoms vs those without SUD symptoms, to clarify how these two differ and to determine whether concurrent SUD symptoms may alter the clinical presentation of MDD. The first 1500 outpatients with nonpsychotic MDD enrolled in the Sequenced Treatment Alternatives to Relieve Depression study were divided into those with and without concurrent SUD symptoms as ascertained by a self-report instrument, the Psychiatric Diagnostic Screening Questionnaire (PDSQ). Of the 1484 cases with completed baseline PDSQ, 28% (n = 419) of patients with MDD were found to endorse symptoms consistent with current SUD. Patients with symptoms consistent with SUD were more likely to be men (P < .0001), to be either divorced or never married (P = .018), to have a younger age of onset of depression (P = .014), and to have a higher rate of previous suicide attempts (P = .014) than those without SUD symptoms. Patients with major depressive disorder who have symptoms consistent with SUD endorsed greater functional impairment attributable to their illness than those without concurrent SUD symptoms (P = .0111). The presence of SUD symptoms did not alter the overall depressive symptom pattern of presentation, except that the dual-diagnosed patients had higher levels of hypersomnia (P = .006), anxious mood (P = .047), and suicidal ideation (P = .036) compared to those without SUD symptoms. In conclusion, gender, marital status, age of onset of major depression, functional impairment, and suicide risk factors differ in depressed patients with concurrent SUD symptoms compared to those without SUD comorbidity.     

Correlation of major depressive disorder symptoms with FKBP5 but not FKBP4 expression in human immunodeficiency virus-infected individuals

Major depressive disorder (MDD) is a significant cause of morbidity in people living with the human immunodeficiency virus (HIV). FKBP5 is a candidate gene with single-nucleotide polymorphisms (SNPs) rs1360780 and rs3800373 associated with MDD. This gene product and its relative, FKBP4, physically associate with the glucocorticoid receptor whose function is implicated in MDD pathophysiology. Because these genes are expressed in blood and brain and elevated in HIV infection, we explored the relationship between gene expression, genotype, and MDD symptoms. Longitudinally followed subjects (N = 57) as part of the CNS HIV AntiRetroviral Effects Research study, with diagnosed MDD and who donated blood for genotyping and gene expression analysis, were assessed. Subjects donated blood on adjacent visits with and without meeting criteria for MDD episode. Changes in clinical parameters were compared changes in gene expression. Change in FKBP5 expression correlated with change in Beck Depression Inventory (BDI) for MDD » euthymic comparison in GG genotype of rs3800373 (P = .013) and TT carriers of rs1360780 (P = .02). In euthymic » MDD comparison, GG homozygous, FKBP5 expression correlated with more severe change in BDI. Change in FKBP4 expression did not correlate with changes in clinical or depression measurements. Higher FKBP5 expression correlated with greater symptom change for GG carriers of rs3800373.     

Depression and Employment Status in Primary and Tertiary Care Settings

Objective:

Major depressive disorder (MDD) is a leading cause of disability. Impairment in work function considerably adds to symptom burden and increases the economic impact of this disorder. Our study aimed to investigate the factors associated with work status in MDD within primary and tertiary care.

Method:

We used data from 2 large databases for our analysis—Study 1: the InSight database, a chart review of MDD patients treated by primary care physicians across Canada (n = 986); and Study 2: the International Mood Disorders Collaborative Project, a cross-sectional study of mood disorder patients (Canadian data only: n = 274).

Results:

Both studies demonstrated high rates of unemployment and disability (30.3% to 42.1%). Quebec showed the highest rate of unemployment (21%) and British Columbia had the greatest percentage of patients on disability (15%). Employed and unemployed groups were similar based on clinical characteristics; however, unemployed people may have higher age, prevalence of medical comorbidity, and greater likelihood of receiving a benzodiazepine. Increased disability rates were associated with history of childhood abuse, duration of current major depressive episode, comorbidity, benzodiazepine use, as well as greater depression and anxiety severity. The unemployed–disability groups had greater somatic symptoms and anhedonia. In keeping with this, anhedonia was the strongest predictor of disability. Absenteeism was also high across both studies.

Conclusions:

Unemployment and disability rates in MDD are high. The presence of anhedonia and medical comorbidity significantly influenced work status, emphasizing the need for treatment strategies to alleviate the additional symptom burden in this subpopulation.     

Examining the relation between posttraumatic stress disorder and suicidal ideation in an OEF/OIF veteran sample

This study examined the relation between posttraumatic stress disorder (PTSD) and suicidal ideation among U.S. military veterans deployed during Operation Enduring Freedom and/or Operation Iraqi Freedom. Specific aims included investigation of (1) whether PTSD was associated with suicidal ideation after controlling for combat exposure and history of suicide attempt(s), (2) whether PTSD was associated with suicidal ideation absent a co-occurring depressive disorder (MDD) or alcohol use disorder (AUD), (3) whether co-occurring MDD or AUD increased risk of suicidal ideation among those with PTSD and (4) whether PTSD/MDD symptom clusters were differentially associated with suicidal ideation. Results pointed to unique effects associated with prior suicide attempt(s), PTSD and MDD. PTSD-diagnosed participants with co-occurring MDD or AUD were not significantly more likely to endorse suicidal ideation than PTSD-diagnosed participants without such comorbidity. The ‘emotional numbing’ cluster of PTSD symptoms and the ‘cognitive-affective’ cluster of MDD symptoms were uniquely associated with suicidal ideation.     

Diagnosing major depressive disorder V: applying the DSM-IV exclusion criteria in clinical practice

To be diagnosed with DSM-IV major depressive disorder (MDD), a patient must meet five out of nine symptom criteria, one of which is depressed mood or pervasive loss of interest or pleasure. Once a patient has reached this symptom threshold, there are several exclusionary criteria that need to be passed to receive the diagnosis. The symptoms must cause significant distress or impairment in functioning, the symptoms cannot be caused by substance use or a general medical condition, and the symptoms cannot be better accounted for by bereavement. Finally, the presence of psychotic symptoms not coincident with the depressive symptoms excludes the diagnosis. We are not aware of any studies of psychiatric patients that have examined the impact of all of these exclusionary rules on the diagnosis of MDD in clinical practice. It is important for clinicians to know how often each of these factors might exclude the diagnosis of MDD so that they can be more or less vigilant to their presence. The goal of the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services project was to examine the impact of the DSM-IV exclusion rules on the diagnosis of MDD. In total, 38 (3.0%) of the 947 patients meeting the DSM-IV symptom inclusion criteria were excluded from a diagnosis of MDD or bipolar depression. These results suggest that the DSM-IV exclusion criteria for MDD had only a modest impact on diagnosis in psychiatric outpatients. It is likely that the results of a study of the impact of the DSM-IV depression exclusion criteria will depend on where the study is conducted. The potential influence of different settings on diagnostic exclusion is discussed.     

Self rated depression in relation to DSM-III classification: a statistical isolinear multiple components analysis

The Zung Self-Rating Depression Scale (SDS) was presented to 99 depressed inpatients. The patients were categorized according to DSM-III as suffering from minor depression, major depression without melancholia and major depression with melancholia and/or with psychotic features. Differences in self-reported symptoms between these categories were studied with multivariate statistical techniques including linear discriminant analysis (LDA) and statistical isolinear multiple components analysis (SIMCA). Patients with minor depression rate themselves significantly less depressed than those with major depression. Patients with major depression without melancholia are less depressed than those with melancholia and/or psychotic features. The three DSM-III depressive categories can be regarded as belonging to a clinical continuum in which they form relevant levels with quantitative differences in self-reported symptoms. These differences are not only defined by gradual shiftings in the overall severity of illness, but also by quantitative differences in the severity of some target symptoms, i.e. agitation, retardation, diurnal variation, loss of libido, fatiguability, insomnia, anorexia, sadness and anhedonia.     

Stability of DSM-IV criterion symptoms for major depressive disorder

Given the chronic and recurrent nature of major depressive disorder (MDD), it is important to understand whether specific symptoms are stable over time or vary over the course of the disorder. This is the first longitudinal investigation examining the stability of the nine criterion symptoms of depression, as specified in the DSM-IV, among diagnosed depressed adults who were not recovered at follow-up. In this study, participants were assessed twice, ten months apart, with the structured clinical interview for DSM-IV, and stability of the nine criterion symptoms of MDD was examined. Findings indicate strong stability in individuals' symptom profiles. Among individuals who were clinically depressed at both assessments, there were no statistically significant fluctuations in specific symptoms endorsed. Changes in symptom endorsement among individuals who no longer met diagnostic criteria for MDD at Time 2 were attributable to reduced severity (i.e., number of symptoms) rather than to inconsistency of symptom endorsement. These results indicate that depressed individuals experience essentially the same pattern of specific symptoms over the course of a year. Variation in clinical course is likely to be attributable more to fluctuations in overall severity than to changes in specific symptoms of depression.     

Residual symptoms in older patients treated for major depression

OBJECTIVE: The purpose of this study was to identify residual symptoms in a sample of older adults treated for major depression and compare individual symptoms present at baseline with those at three months by remission status. METHODS: The sample was comprised of 229 patients with DSM-IV major depression who were participants in the NIMH Mental Health Clinical Research Center at Duke University. Symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: At three months, 86 patients (37.6%) had remitted, or had a MADRS score less than or equal to 9. In the remitted group, the most frequently reported symptoms at three months were inner tension and lassitude. Among nonremitters, the most frequently reported symptoms were reported and apparent sadness, as well as lassitude and inner tension. In the sample as a whole, the symptoms most likely to be present at baseline but not three months were pessimistic and suicidal thoughts, while the most frequently reported emergent symptoms were reduced appetite and inner tension. Patients were much more likely to no longer have a particular symptom than to acquire a new symptom. Overall, the symptoms present at three months were not severe in either group. CONCLUSIONS: In older adults treated for major depression, residual symptoms at three months may include emergent symptoms as well as persistent symptoms, and are likely to include symptoms of anxiety as well as sadness. These findings have clinical implications for the treatment of late-life depression.     

Factors that differentiate early vs. later onset of major depression disorder

This report explores the relationship between age of first onset of major depression and other demographic and clinical features in the first 1500 patients entering the Sequenced Treatment Alternative to Relieving Depression (STAR*D) study. Outpatients, 18-75 years of age, with nonpsychotic major depressive disorder (MDD) from either primary care or psychiatric practices constitute the population. Age of onset was defined at study intake by asking patients to estimate the age at which they experienced the onset of their first major depressive episode. This report divides the population in terms of pre-adult (before age 18) onset and adult (age 18 or later) onset. The results suggest that MDD that begins before age 18 has a distinct set of demographic (female gender) and clinical correlates (longer duration of illness; longer current episodes; more episodes; more suicidality; greater symptom severity; more psychiatric symptoms associated with Axis I comorbidity; and more sadness, irritability, agitation and atypical symptom features), and it appears associated with significant psychosocial consequences (lower educational attainment and marriage rates). Thus, pre-adulthood onset MDD is a particularly severe and chronic condition.