Dimensions in major depressive disorder and their relevance for treatment outcome

doi:10.1016/j.jad.2013.10.020

Journal of Affective Disorders

Volume 155, February 2014, Pages 35-41

https://doi.org/10.1016/j.jad.2013.10.020 Get rights and content

Abstract

Background

Major depressive disorder (MDD) is a heterogeneous disease. More homogeneous psycho(patho)logical dimensions would facilitate MDD research as well as clinical practice. The first aim of this study was to find potential dimensions within a broad psychopathological assessment in depressed patients. Second, we aimed at examining how these dimensions predicted course in MDD.

Methods

Ten psychopathological variables were assessed in 75 MDD inpatients. Factor and regression analyses assessed putative relations between psychopathological factors and depression severity and outcome after 8 weeks of treatment.

Results

A 3-factor model (eigenvalue: 54.4%) was found, representing a psychomotor change, anhedonia and negative affect factor. Anhedonia and negative affect predicted depression severity (R²=0.37, F=20.86, p<0.0001). Anhedonia predicted non-response (OR 6.00, CI 1.46–24.59) and both negative affect (OR 5.69, CI 1.19–27.20) and anhedonia predicted non-remission (OR 9.28, CI 1.85–46.51).

Limitations

The sample size of the study was relatively modest, limiting the number of variables included in the analysis.

Conclusions

Results confirm that psychomotor change, anhedonia and negative affect are key MDD dimensions, two of which are related to treatment outcome.

Introduction

Current neurobiological and behavioral research on the psychopathology of Major depressive disorder (MDD), as well as common clinical practice, increasingly considers MDD as a multidimensional and heterogeneous concept (Hasler et al., 2004, Zimmerman, 2009). Affected individuals are associated with a wide variety of risk factors, symptoms and other clinically relevant variables, such as demographic characteristics, comorbidity, personality traits and characteristics of depressive episodes (Kendler, 1999). A data-driven approach to identify meaningful components or latent dimensions within a heterogeneous diagnostic construct is factor analysis (Comrey et al., 1978). In the past, several studies have used factor analytic strategies to identify subdimensions of MDD, based on clinical rating scales for depression and other symptom measures reflecting DSM-IV criteria (e.g., Carragher et al., 2009, Cassano et al., 2009, Harald and Gordon, 2012). The most commonly identified factors in MDD are a depression severity factor and a somatic factor (Shafer, 2006). A few studies report a positive affect factor and a psychomotor factor (Schrijvers et al., 2008).

However, most of the studies using factor analysis in MDD research have important limitations. First, the proposed factors have been largely limited to clinical symptoms without attempts to correlate the factors with variables across different units of analysis, such as etiological characteristics of MDD. Classifying psychopathology based on dimensions of observable behavior, risk factors as well as psychobiological measures would define dimensions on their basic functions and cutting across categorical disorders as traditionally defined. It seems clear that clusters of self-reported symptoms is constraining advances in understanding the pathophysiology of mental illnesses and in addition hampers the development of better treatments (Insel and Charney, 2003). Second, the clinical relevance in terms of the influence of these factors on outcome in MDD patients has often not been examined in detail. Identifying reliable predictors of outcome in research may allow for the development of novel and more specified interventions (Chen et al., 2000, Insel et al., 2010).

The primary effort of this study was to discover basic dimensions of functioning within MDD, by including variables across different units of analysis, from core MDD symptoms to potentially important underlying risk factors and behaviors. In addition, we evaluated the clinical relevance of these dimensions by investigating their relation to depression severity and their ability to predicting outcome.

To achieve our aims, we conducted a factor analysis based on a broad range of psychopathological characteristics, assessed in 75 depressed inpatients. Ten clinical symptoms of MDD, as well as additional features representing underlying psychopathological vulnerability and environmental factors involved in the development of MDD were included in the factor analysis. In an additional analysis, potential latent dimensions were evaluated with regard to their relationship to outcome after 8 weeks of treatment using logistic regression models. Outcome was operationalized using response and remission rates.

Section snippets

Participants

Eighty-two depressed patients participated in this study. All patients were hospitalized at the University Psychiatric Center of the University of Leuven, Belgium. The Structured Clinical Interview for DSM-IV-TR (SCID-I) (Spitzer et al., 1992) was used to make DSM-IV diagnoses of MDD. Patients with other mood spectrum disorders, addiction, psychotic disorders or any other unstable medical condition were excluded. All patients received pharmacological and/or psychotherapy treatment, as

Demographic and clinical data

Eighty-two depressed patients were included in the study. Five participants were excluded from the final statistical analysis because of invalid performance on the reward task. Two participants were excluded due to other missing data. Thirteen participants dropped out before the follow-up assessment. Sociodemographic and clinical data at baseline of our baseline sample (n=75) are reported in Table 1. Pearson correlations showed that HDRS scores were significantly correlated with SHAPS (r=0.46, p

Discussion

The first aim of the present study was to identify latent factors, based on variables across different units of analysis, within an inpatient MDD sample. Second, we examined the clinical validity of these factors by assessing their relationship with overall depression severity and their ability to predict clinical outcome. A principal component analysis revealed three independent latent factors. Psychomotor change was extracted as the first factor, characterized by non-interactiveness,

Role of funding source

This project was supported by a unrestricted research grant from Johnson and Johnson, by a research grant (OT06/60) from the University of Leuven (KUL) and by a grant (ELG-B5588-G.0193.07) from the Fund for Scientific Research, Flanders, Belgium (FWO).

Conflict of interest

Prof. Claes is Senior Clinical Investigator of the FWO. Dr Schmidt and de Boer are employees of Janssen Research and Development. Dr. Pizzagalli was supported by NIMH grant R01MH68376 and R21MH078979 and over the past 3 years has received consulting fees from Shire, AstraZeneca, Ono Pharma USA and Johnson & Johnson as well as honoraria from AstraZeneca for projects unrelated to the current study. Koen Demytennaere reports no conflict of interest directly related to the submitted manuscript. He

Acknowledgement

This paper has no Acknowledgement.

References (48)

H.M. Burke et al.
Depression and cortisol responses to psychological stress: a meta-analysis
Psychoneuroendocrinology
(2005)
N. Carragher et al.
Subtypes of depression in a nationally representative sample
J. Affect. Disord.
(2009)
G.B. Cassano et al.
The factor structure of lifetime depressive spectrum in patients with unipolar depression
J. Affect. Disord.
(2009)
L. Chen et al.
Understanding the heterogeneity of depression through the triad of symptoms, course and risk factors: a longitudinal, population-based study
J. Affect. Disord.
(2000)
N. Eshel et al.
Reward and punishment processing in depression
Biol. Psychiatry.
(2010)
I.H. Franken et al.
The assessment of anhedonia in clinical and non-clinical populations: further validation of the Snaith–Hamilton Pleasure Scale (SHAPS)
J. Affect. Disord
(2007)
N. Geschwind et al.
Early improvement in positive rather than negative emotion predicts remission from depression after pharmacotherapy
Eur. Neuropsychopharmacol.
(2011)
B. Harald et al.
Meta-review of depressive subtyping models
J. Affect. Disord.
(2012)
P.A. Keedwell et al.
The neural correlates of anhedonia in major depressive disorder
Biol. Psychiatry.
(2005)
A.T. Konkle et al.
Evaluation of the effects of chronic mild stressors on hedonic and physiological responses: sex and strain compared
Brain Res.
(2003)

G. Loas

Vulnerability to depression: a model centered on anhedonia

J. Affect. Disord.

(1996)

D.A. Pizzagalli et al.

Toward an objective characterization of an anhedonic phenotype: a signal-detection approach

Biol. Psychiatry.

(2005)

DA Pizzagalli et al.

Reduced hedonic capacity in major depressive disorder: evidence from a probabilistic reward task

J. Psychiatr. Res

(2008)

J.K. Rilling

The neural and hormonal bases of human parental care

Neuropsychologia

(2013)

D. Schrijvers et al.

Psychomotor symptoms in depression: a diagnostic, pathophysiological and therapeutic tool

J. Affect. Disord.

(2008)

M.A. Taylor et al.

Restoring melancholia in the classification of mood disorders

J. Affect. Disord.

(2008)

E. Vrieze et al.

Reduced reward learning predicts outcome in major depressive disorder

Biol. Psychiatry.

(2013)

American Psychiatric Association (A.P.A.)

Diagnostic and Statistical Manual of Mental Disorders

(1994)

A.L. Comrey et al.

Psychiatric screening with the Comrey personality scales

Psychol. Rep.

(1978)

P.T. Costa et al.

Revised NEO Personality Inventory (NEO-PI-R) and NEO Five-Factor Inventory (NEO-FFI) manual

(1992)

R.J. Davidson

Affective neuroscience and psychophysiology: toward a synthesis

Psychophysiology

(2003)

N. Draijer et al.

Childhood trauma and perceived parental dysfunction in the etiology of dissociative symptoms in psychiatric inpatients

Am. J. Psychiatry

(1999)

J. Fawcett et al.

Differences between anhedonic and normally hedonic depressive states

Am. J. Psychiatry.

(1983)

G.L. Flett et al.

The continuity of depression in clinical and nonclinical samples

Psychol. Bull.

(1997)

Cited by (95)

Efficacy of transcranial direct current stimulation for treating anhedonia in patients with depression: A randomized, double-blind, sham-controlled clinical trial
2024, Journal of Affective Disorders
Anhedonia, the core symptom of major depressive disorder (MDD), is highly prevalent in patients with depression. Anhedonia is associated with low efficacy of drug treatment, high suicide rates, and poor social function. Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technology that uses constant, low-intensity direct current to treat MDD by regulating cortical activity and neuronal excitability. However, little is known about the efficacy of tDCS for treating anhedonia in patients with depression, and even the existing results of clinical trials are conflicting. In addition, there is no consensus on what brain regions should be targeted by tDCS during the treatment of anhedonia in patients with depression.
This study aimed to evaluate the efficacy and safety of tDCS over the left dorsolateral prefrontal cortex (DLPFC) and right orbitofrontal cortex (OFC) in the improvement of anhedonia in patients with depression and finally identified suitable brain regions to be stimulated during treatment.
This randomized, double-blind, sham-controlled clinical trial recruited 70 patients with anhedonia and depressive episodes. Patients were randomly assigned to three groups according to the stimulation site: right orbitofrontal cortex (OFC), left dorsolateral prefrontal cortex (DLPFC), and sham stimulation. Each group received twelve 20-min interventions (ten as primary treatment and two for consolidation). The primary outcome was a decrease in Snaith-Hamilton Pleasure Scale (SHAPS) scores after primary treatment. Evaluations were performed at baseline, post-treatment, and 8-week follow-up.
The depression mood of the three groups of patients at each time point was better than the baseline, but there was no significant difference in the efficacy between the groups (p>0.05). On the basis of the improvement of depression, this study found that tDCS of the DLPFC significantly improved anhedonia (p = 0.028) after primary treatment (2 weeks), and tDCS of the DLPFC and OFC significantly improved social functioning (p = 0.005) at 8-week follow-up.
The sample size of this study was small, with only about 23/24 patients in each group completing the intervention assessments; due to the impact of the COVID-19 epidemic, data analysis was limited by the lack of patients during the follow-up period.
tDCS of the DLPFC significantly improves anhedonia in depressed patients and is thus a potential adjuvant therapy for anhedonia in these patients.
Personality characteristics, not clinical symptoms, are associated with anhedonia in a community sample: A preliminary investigation
2023, Journal of Psychiatric Research
Anhedonia is a salient transdiagnostic psychiatric symptom associated with increased illness severity and chronicity. Anhedonia is also present to varying degrees in non-clinical cohorts. Here, we sought to examine factors influencing expression of anhedonia. Participants (N = 335) were recruited through the Nathan Kline Institute-Rockland Sample, an initiative to deeply phenotype a large community sample across the lifespan. Utilizing a data-driven approach, we evaluated associations between anhedonia severity, indexed by Snaith-Hamilton Pleasure Scale (SHAPS), and 20 physical, developmental, and clinical measures, including Structured Clinical Interview for DSM-IV, Beck Depression Inventory, State-Trait Anxiety Inventory, NEO Five-Factor Inventory-3 (NEO–FFI–3), BMI, Hemoglobin A1C, and demography. Using a bootstrapped AIC-based backward selection algorithm, seven variables were retained in the final model: NEO–FFI–3 agreeableness, extraversion, and openness to experience; BMI; sex; ethnicity; and race. Though median SHAPS scores were greater in participants with psychiatric diagnoses (18.5) than those without (17.0) (U = 12238.5, z = 2.473, p = 0.013), diagnosis and symptom measures were not retained as significant predictors in the final robust linear model. Participants scoring higher on agreeableness, extraversion, and openness to experience reported significantly lower anhedonia. These results demonstrate personality as a mild-to-moderate but significant driver of differences in experiencing pleasure in a community sample.
Fluoxetine combined with swimming exercise synergistically reduces lipopolysaccharide-induced depressive-like behavior by normalizing the HPA axis and brain inflammation in mice
2023, Pharmacology Biochemistry and Behavior
Major depression disorder is a debilitating psychiatric disease affecting millions of people worldwide. This disorder is the leading cause of morbidity and mortality in high-income countries. Selective serotonin reuptake inhibitors such as fluoxetine are first-line drugs for treating depression-related disorders, but not all patients respond well to these antidepressants. This study aimed to evaluate whether fluoxetine combined with aerobic exercise can affect lipopolysaccharide (LPS)-induced depressive-like behavior, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and brain inflammation in mice. Male mice were exposed to fluoxetine, swimming exercise, or a combination of both and finally treated with LPS. We measured depression-related symptoms such as anhedonia, behavioral despair, weight gain, and food intake. Hormones (corticosterone and testosterone) and cytokines (IL-1β, IL-6, TNF-α, IL-10) were also measured in serum and brain (hippocampus and prefrontal cortex), respectively. The findings indicated that LPS induced anhedonia and behavioral despair and increased corticosterone, hippocampal IL-1β, TNF-α, and decreased testosterone and hippocampal IL-10 in mice. Fluoxetine and exercise separately reduced LPS-induced depressive-like behavior, while their combination synergistically reduced these symptoms in LPS-treated mice. We found fluoxetine alone increased food intake and body weight in LPS-treated mice. Fluoxetine and exercise combination reduced corticosterone, hippocampal TNF-α, and prefrontal IL-6 and TNF-α levels and increased testosterone and hippocampal and prefrontal IL-10 levels more effectively than fluoxetine alone in LPS-treated mice. This study suggests that swimming exercise combined with fluoxetine can affect depression-related behavior, HPA axis, and brain inflammation more effectively than when they are used separately.
The impacts of anhedonia on brain functional alterations in patients with major depressive disorder: A resting-state functional magnetic resonance imaging study of regional homogeneity
2022, Journal of Psychiatric Research
Anhedonia, as one of the core manifestations of major depressive disorder (MDD), has an effect on prognosis of the disease. However, the neuropathology of MDD is complex and the neural basis of anhedonia remains unclear. The aim of the present study was to investigate the impacts of anhedonia on brain functional alterations in patients with MDD.
A total of 62 individuals including MDD patients with anhedonia (n = 22), MDD patients without anhedonia (n = 20), and healthy controls (HCs, n = 20) were recruited. All participants underwent resting-state functional magnetic resonance imaging scanning and intrinsic brain function was explored by using regional homogeneity (ReHo) method. A two-sample t-test was performed to explore ReHo differences between MDD patients and HCs, then analysis of variance (ANOVA) was introduced to obtain brain regions with significant differences among three groups, and finally post hoc tests were calculated for inter-group comparisons. Correlations between ReHo values of each survived area and clinical characteristics in MDD patients were further analyzed.
Compared with HCs, MDD showed increased ReHo in the left superior temporal gyrus (STG) and bilateral inferior frontal gyrus (IFG), as well as decreased ReHo in the left superior frontal gyrus (SFG). Interestingly, this relationship was attenuated and no longer significant after consideration for the effect of anhedonia in MDD patients. MDD patients with anhedonia were more likely to exhibit decreased ReHo in the left SFG and left middle cingulate gyrus (MCG) when comparing to HCs. No significant difference was found between MDD patients without anhedonia and HCs, either the two groups of MDD patients. There was no significant association between ReHo values of each survived area and clinical characteristics in MDD patients.
The present results suggest that the impacts of anhedonia on brain functional alterations in MDD should be emphasized and disturbed intrinsic brain function in the frontal-limbic regions may be associated with anhedonia in MDD patients.
Tetrahydrobiopterin modulates the behavioral neuroinflammatory response to an LPS challenge in mice
2022, Brain, Behavior, and Immunity
Tetrahydrobiopterin (BH4) is a necessary cofactor for the synthesis of monoamines from essential amino-acids, phenylalanine, tyrosine and tryptophan. The BH4 synthesis pathway is induced by inflammatory factors but highly regulated processes maintain levels in a physiological range. However, BH4 activity can be durably altered in inflammation-related pathologies, such as certain types of depression, potentially involving impairment of dopaminergic neurotransmission. The purpose of this study was to investigate the response of the brain BH4 pathway to the inflammatory stimulus induced by lipopolysaccharide (LPS) in mice. Brain expression of genes related to BH4 synthesis, levels of BH4, changes in L-aromatic amino acid precursors of monoamines and dopamine levels were determined. As secondary aim, the effect of acute BH4 supply under the inflammatory challenge was tested on these parameters and on the expression of inflammatory cytokines. Mice were also submitted to the sucrose preference test and to the open-field in order to asses hedonic and locomotor responses to LPS, in addition to their modulation by BH4 supply. The LPS challenge resulted in decreased striatal DA levels and increased Phenylalanine/Tyrosine ratio, suggesting reduced BH4 activity. BH4 supply was effective to increase striatal BH4 levels, to restore the LPS-induced decreased in DA levels in striatum and to dampen the LPS-induced expression of inflammatory cytokines. At the behavioral level, BH4 supply was able to restore the loss of locomotor response to amphetamine in the LPS treated mice, suggesting a modulation of the dopaminergic neurotransmission.
These data suggest that BH4 can be considered as a potential add-on molecule, helping to maintain or restore dopaminergic neurotransmission in neuroinflammatory conditions..
Repeated testing modulates chronic unpredictable mild stress effects in male rats
2022, Behavioural Brain Research
Depression is a highly prevalent, debilitating mental disorder. Chronic unpredictable mild stress (CUMS) is the most widely applied model to study this affliction in rodents. While studies incorporating CUMS prior to an intervention often require long-lasting stress effects that persist after exposure is ceased, the longevity of these effects is rarely studied. Additionally, it is unclear whether behavioural assessments can be performed before and after interventions without repeated testing effects. In rats, we investigated CUMS effects on components of depressive-like behaviour both acutely after stress cessation and after a recovery period, as well as effects of repeated testing. We observed acute disruptions of the circadian locomotor rhythm and a reduced sucrose preference immediately after CUMS exposure. While circadian locomotor rhythm effects persisted up until four weeks after stress cessation, independently of repeated testing, sucrose preference effects did not. Interestingly, CUMS animals tested once after a recovery period of four weeks showed reduced anxiety-like behaviour in the open field and elevated plus maze compared to their control group and repeatedly-tested CUMS animals. These findings suggest that distinct CUMS-induced components of depressive-like behaviour are affected differentially by recovery time and repeated testing; these aspects should be considered carefully in future study designs.

View all citing articles on Scopus

View full text

Research reportDimensions in major depressive disorder and their relevance for treatment outcome

Abstract

Background

Methods

Results

Limitations

Conclusions

Introduction

Section snippets

Participants

Demographic and clinical data

Discussion

Role of funding source

Conflict of interest

Acknowledgement

Psychoneuroendocrinology

J. Affect. Disord.

J. Affect. Disord.

J. Affect. Disord.

Biol. Psychiatry.

J. Affect. Disord

Eur. Neuropsychopharmacol.

J. Affect. Disord.

Biol. Psychiatry.

Brain Res.

J. Affect. Disord.

Biol. Psychiatry.

J. Psychiatr. Res

Neuropsychologia

J. Affect. Disord.

J. Affect. Disord.

Biol. Psychiatry.

Diagnostic and Statistical Manual of Mental Disorders

Psychiatric screening with the Comrey personality scales

Psychol. Rep.

Revised NEO Personality Inventory (NEO-PI-R) and NEO Five-Factor Inventory (NEO-FFI) manual

Affective neuroscience and psychophysiology: toward a synthesis

Psychophysiology

Childhood trauma and perceived parental dysfunction in the etiology of dissociative symptoms in psychiatric inpatients

Am. J. Psychiatry

Differences between anhedonic and normally hedonic depressive states

Am. J. Psychiatry.

The continuity of depression in clinical and nonclinical samples

Psychol. Bull.

Research report
Dimensions in major depressive disorder and their relevance for treatment outcome