Major depressive disorder with melancholia displays robust alterations in resting state heart rate and its variability: implications for future morbidity and mortality.

BACKGROUND: Major depressive disorder (MDD) is associated with increased heart rate and reductions in its variability (heart rate variability, HRV) - markers of future morbidity and mortality - yet prior studies have reported contradictory effects. We hypothesized that increases in heart rate and reductions in HRV would be more robust in melancholia relative to controls, than in patients with non-melancholia. METHODS: A total of 72 patients with a primary diagnosis of MDD (age M: 36.26, SE: 1.34; 42 females) and 94 controls (age M: 35.69, SE: 1.16; 52 females) were included in this study. Heart rate and measures of its variability (HRV) were calculated from two 2-min electrocardiogram recordings during resting state. Propensity score matching controlled imbalance on potential confounds between patients with melancholia (n = 40) and non-melancholia (n = 32) including age, gender, disorder severity, and comorbid anxiety disorders. RESULTS: MDD patients with melancholia displayed significantly increased heart rate and lower resting-state HRV (including the square root of the mean squared differences between successive N-N intervals, the absolute power of high frequency and standard deviation of the Poincaré plot perpendicular to the line of identity measures of HRV) relative to controls, findings associated with a moderate effect size (Cohens d's = 0.56-0.58). Patients with melancholia also displayed an increased heart rate relative to those with non-melancholia (Cohen's d = 0.20). CONCLUSION: MDD patients with melancholia - but not non-melancholia - display robust increases in heart rate and decreases in HRV. These findings may underpin a variety of behavioral impairments in patients with melancholia including somatic symptoms, cognitive impairment, reduced responsiveness to the environment, and over the longer-term, morbidity and mortality.

The impact of melancholia versus non-melancholia on resting-state, EEG alpha asymmetry: electrophysiological evidence for depression heterogeneity.

While depression has been associated with relatively greater right than left frontal cortical activity - a neurophysiological marker reflecting greater activation of the withdrawal system - contradictory findings have been reported. It was hypothesised that melancholia would be associated with relative right frontal activation, in comparison to non-melancholia and controls. We collected 2-min of resting-state, eyes closed, electroencephalographic activity from a total of 237 participants including 117 patients with major depressive disorder (57 with melancholia, 60 with non-melancholia) and 120 healthy controls. In contrast to hypotheses, patients with non-melancholia displayed relative left frontal activation in comparison to controls and those with melancholia. These findings were associated with a small to moderate effect size (Cohen's d=0.30-0.34). Critically, patients with melancholic subtype did not differ from controls despite increased severity - relative to those with non-melancholia - on clinical measures. These results may reflect an increase in approach tendencies in patients with non-melancholia including reassurance seeking, anger or irritable aggression. Findings highlight the need for further research on the heterogeneity MDD.

The impact of depression heterogeneity on cognitive control in major depressive disorder.

OBJECTIVE: Depressed patients display a variety of deficits in neuropsychological function, and contradictory findings in the literature may be due to disorder heterogeneity. The aim of this study was to examine the impact of severity, subtype and symptoms on cognitive control. METHODS: Neuropsychological function across a range of cognitive control tasks was examined in melancholic (n = 65) and non-melancholic depressed patients (n = 59) relative to controls (n = 124). The relationship between subtype (melancholia vs non-melancholia) and anxiety was also examined. RESULTS: Melancholia was characterised by attention and working memory deficits typically associated with the dorsolateral prefrontal cortex, while non-melancholia was characterised by verbal memory recall deficits indicative of left frontal lobe and medial temporal lobe function. The severity of anxious arousal and psychomotor disturbance contributed to cognitive impairment more than the severity of depression symptoms and anxious apprehension. CONCLUSIONS: Findings highlight a differential impact of depression subtype and severity, and suggest that anxious arousal and psychomotor disturbance may contribute to poorer performance on neuropsychological tasks associated with dorsolateral prefrontal cortex function.

The impact of depression heterogeneity on inhibitory control.

OBJECTIVE: Major depressive disorder (MDD) is associated with deficits in executive cognitive function, including inhibitory control. However, inconsistencies have been found across studies. Depression is a heterogeneous disorder and these inconsistencies may therefore relate to heterogeneity in relatively small samples. METHOD: Here we sought to examine event-related potentials (ERPs) during a cognitive Go/No-Go task in melancholic (n = 60) and non-melancholic depressed patients (n = 54) relative to controls (n = 114). RESULTS: Behavioural responses indicate that inhibitory control processes are differentially affected by subtypes of depression such that melancholic patients exhibit a greater number of commission errors and more variable response rates in comparison to non-melancholic patients and controls respectively. However, ERPs do not differ during a cognitive Go/No-Go task when ERPs associated with correct responses are examined. CONCLUSIONS: These findings indicate that while patients with melancholia differ from patients without melancholia and controls, no neurophysiological differences are observed when controlling for observable behavioural impairment.

The contribution of BDNF and 5-HTT polymorphisms and early life stress to the heterogeneity of major depressive disorder: a preliminary study.

OBJECTIVE: Two reported genetic polymorphisms related to the production of brain-derived neurotrophic factor (BNDF) and reuptake by the serotonin transporter (5-HTT) appear to contribute to depression in combination with stressful life events. The aim of the current study was to investigate the contribution of early life stress (ELS), BDNF (Val versus Met alleles) and 5-HTT polymorphisms (L versus S alleles) to melancholic (n = 65) and non-melancholic depression (n = 59). METHODS: A mediation approach ((G × G) × E mediation model) was employed to confirm the indirect effects of ELS on the relationship between 5-HTTPLR × BDNF polymorphism combinations and depression subtype. A series of binary logistic regressions were then conducted to determine whether genotype, ELS, and their interaction were able to predict depression subtype. RESULTS: Key findings indicated that BDNF and 5-HTT polymorphisms in combination with ELS contributed to the development of non-melancholic depression. An interaction between BDNF and ELS increased the risk of non-melancholia by 3.327, whereas the interaction between 5-HTT and ELS increased risk by 2.406. CONCLUSION: The results support a role for genetic factors in the development of non-melancholia. The lack of findings in melancholia indicates that other mechanisms may underlie the subtype. Alternatively, null findings may reflect a Type II error associated with a small sample size. Future studies should consider further examination of differential gene-environment interactions for melancholia versus non-melancholia.