Melancholic Depressive Subtypes Research Articles

HPA Axis Function as Biomarker for Atypical and Melancholic Depression

HPA Axis Function as Biomarker for Atypical and Melancholic Depression

Serum proteomic profiles of depressive subtypes.

Depression is a highly heterogeneous disorder. Accumulating evidence suggests biological and genetic differences between subtypes of depression that are homogeneous in symptom presentation. We aimed to evaluate differences in serum protein profiles between persons with atypical and melancholic depressive subtypes, and compare these profiles with serum protein levels of healthy controls. We used the baseline data from the Netherlands Study of Depression and Anxiety on 414 controls, 231 persons with a melancholic depressive subtype and 128 persons with an atypical depressive subtype for whom the proteomic data were available. Depressive subtypes were previously established using a data-driven analysis, and 171 serum proteins were measured on a multi-analyte profiling platform. Linear regression models were adjusted for several covariates and corrected for multiple testing using false discovery rate q-values. We observed differences in analytes between the atypical and melancholic subtypes (9 analytes, q<0.05) and between atypical depression and controls (23 analytes, q<0.05). Eight of the nine markers differing between the atypical and melancholic subtype overlapped with markers from the comparison between atypical subtype and controls (mesothelin, leptin, IGFBP1, IGFBP2, FABPa, insulin, C3 and B2M), and were mainly involved in cellular communication and signal transduction, and immune response. No markers differed significantly between the melancholic subtype and controls. To conclude, although some uncertainties exist in our results as a result of missing data imputation and lack of proteomic replication samples, many of the identified analytes are inflammatory or metabolic markers, which supports the notion of atypical depression as a syndrome characterized by metabolic disturbances and inflammation, and underline the importance and relevance of subtypes of depression in biological and genetic research, and potentially in the treatment of depression.

Evidence for increased motor cortical facilitation and decreased inhibition in atypical depression.

Major depressive disorder (MDD) is a clinically heterogeneous condition. However, the role of cortical glutamate and gamma-aminobutyric acid (GABA) receptor-mediated activity, implicated in MDD pathophysiology, has not been explored in different MDD subtypes. Our aim was to assess the atypical and melancholic depression subtypes regarding potential differences in GABA and glutamate receptor-mediated activity through established transcranial magnetic stimulation (TMS) neurophysiological measures from the motor cortex. We evaluated 81 subjects free of antidepressant medication, including 21 healthy controls and 20 patients with atypical, 20 with melancholic, and 20 with undifferentiated MDD. Single and paired-pulse TMS paradigms were used to evaluate intracortical facilitation (ICF), cortical silent period (CSP), and short intracortical inhibition (SICI), which index glutamate, GABAB receptor-, and GABAA receptor-mediated activity respectively. Patients with MDD demonstrated significantly decreased mean CSP values than healthy controls (Cohen's d = 0.22-0.3, P < 0.01 for all comparisons). Atypical depression presented a distinct cortical excitability pattern of decreased cortical inhibition and increased cortical facilitation, that is, an increased mean ICF and SICI ratios than other depression subtypes (d = 0.22-0.33, P < 0.01 for all comparisons). Different MDD subtypes may demonstrate different neurophysiology in relation to GABAA and glutamatergic activity. TMS as an investigational tool might be useful to distinguish between different MDD subtypes.

Melancholia in later life: late and early onset differences in presentation, course, and dementia risk

Depression is a risk factor for cognitive decline and dementia. This risk may vary with age of onset and depression subtype. Late onset depression (LOD, 60 years and older) is associated with more cognitive decline, whereas early onset depression (EOD, before 60 years) is associated with more residual depressive symptoms. Potential differences may reflect divergent etiologies. These onset differences, however, have not been examined in the melancholic subtype of depression in older adults. Data were obtained from the Neurocognitive Outcomes of Depression in the Elderly study. Participants (N = 284, 73% EOD-melancholic (EOD-M) and 27% LOD-melancholic (LOD-M)) were followed up over 3 years. Factor analyses examined differences in baseline depressive symptoms. Hierarchical linear growth curve models examined changes in depressive symptoms (Montgomery-Asberg Depression Rating Scale) and cognition (mini mental state examination). An annual clinical review panel assigned diagnoses of dementia. The LOD-M participants had more vegetative symptoms at baseline. LOD-M exhibited greater cognitive decline but fewer residual depressive symptoms than EOD-M. Among participants who remained in the study for at least 1 year, in uncontrolled analyses, a greater percentage of LOD-M compared with EOD-M developed dementia (23.0% vs. 7.8%). Whereas in logistic analyses, controlling for baseline demographics, age at onset remained a predictor of dementia, the odds ratio suggested that the effect was relatively small. The EOD-M and LOD-M participants have a different presentation and course. LOD-M may represent a syndrome of neuropsychiatric deterioration with expression of both depressive symptoms and cognitive decline.

Prevalence of Psychotic Symptoms in Those With Melancholic and Nonmelancholic Depression

The best classification of depressive disorders is still to be established. A melancholic subtype has a lengthy history, and recent research demonstrates its relevance. This study compares the prevalence of psychotic symptoms in nonmelancholic and melancholic depression and assesses whether there is a dimensional pattern in the severity of symptoms among the subtypes. Patients with unipolar depression were assessed for melancholic status, psychotic symptoms, and severity of depression. The diagnosis of melancholia was made by both Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), criteria and CORE measure. The DSM criteria assigned a much higher percentage of patients as melancholics (67.4%) than did the CORE (24.9%). Prevalence of psychosis was distinctly higher in the melancholics. Symptoms severity was higher among the melancholics when compared with the nonmelancholics. The presence of psychotic symptoms was not associated with an increase in the intensity of depressive symptoms. Psychotic symptoms are more frequently associated with the melancholic subtype of depression. This suggests clinical contiguity between the melancholic and psychotic subtypes and the clinical relevance of identifying melancholia.

Psychostimulants for managing unipolar and bipolar treatment-resistant melancholic depression: A medium-term evaluation of cost benefits

BackgroundWe earlier reported an open study of 50 unipolar and bipolar treatment resistant depressed patients indicating that psychostimulants may have differential superiority for the melancholic depressive sub-type. We designed an extension study to examine cost benefits of psychostimulants more closely for those only with melancholic depression. MethodThe sample comprised patients clinically diagnosed with melancholic depression who had failed to respond to and/or experienced significant side-effects with at least two antidepressants. Data were collected for 61 unipolar and 51 bipolar II patients receiving a psyschostimulant for a mean interval of 69 weeks. Benefits and side-effects were assessed. ResultsEffectiveness ratings were similar across unipolar and bipolar sub-sets. Psychostimulants were judged as ‘very’ effective for 20% of patients and ‘somewhat’ effective for 50%. Forty percent judged the psychostimulant as being ‘as effective’ or as ‘superior’ to previously prescribed antidepressants, and worthy of being maintained. Significant side-effects were experienced by 40% of patients, requiring medication to be ceased in 12%. Twenty percent of the bipolar patients experienced a worsening of highs. LimitationsThe study was uncontrolled and retrospective, no formal rater-completed or patient-completed interval measures of severity were completed, while diagnostic judgments about melancholic depression and bipolar disorder were clinically judged. ConclusionsThis open study suggests that psychostimulants may be efficacious antidepressant options for managing unipolar and bipolar melancholia, often seemingly having very rapid onset and generally requiring only low doses, and arguing the need for controlled studies in melancholic patients.

A Case for Reprising and Redefining Melancholia

To identify limitations to severity-based classifications of depression, and to argue for positioning melancholia as a distinct melancholic subtype. An overview of relevant literature was conducted. First, dimensionalizing depressive disorders effectively aggregates multiple heterogeneous depressive types and syndromes, and thus limits, if not prevents, identification of differential causes and treatments. Second, the melancholic depressive subtype can be defined with some relative precision, and that as it shows quite distinct differential treatment responsiveness, identification should be a clinical priority. Melancholia can be positioned and classified as a distinct depressive subtype.

Discrimination between patients with melancholic depression and healthy controls: Comparison between 24-h cortisol profiles, the DST and the Dex/CRH test

Diurnal (24-h) cortisol profiles were compared to DST and Dex/CRH test outcomes with regard to their discriminative power in depressive disorder. With regard to several statistical measures (effect sizes, area under the curve) we found 24-h cortisol profiles to better discriminate between healthy controls and inpatients with the melancholic subtype of depression compared to the DST and Dex/CRH test. In search of a shortened time interval we found the 2-h time window 1000-1200 h of the cortisol profile to be the one with the highest sensitivity (83.3%) and specificity (87.9%). The specificity of the DST was 93.3% and somewhat higher than that of the cortisol profiles and the Dex/CRH test (87.9% and 78.8.%, respectively). However, the sensitivity of the DST was very low (30.8%), in fact similar to that of the Dex/CRH test (30.8%), but much lower than that of the 1000-1200 h interval (83.3%). The assessment of cortisol in plasma is an easy to perform, cost-saving method for the evaluation of the HPA system activity, which may have a series of clinical and scientific implications for the depressive disorder.

Impaired implicit learning and reduced pre-supplementary motor cortex size in early-onset major depression with melancholic features

Background:Major depression is a heterogeneous disorder. Biological markers and cognitive tasks have been employed to distinguish clinical subtypes but results have been inconclusive. Methods:The current study assessed implicit learning with the Serial Reaction Time Task (SRTT) known to be sensitive to frontostriatal dysfunctions and regional brain volumes of the anterior supplementary motor area (pre-SMA) in participants with early-onset major depression (MD) of either melancholic (n=26) or non-melancholic (n=9) subtype, and 26 matched controls. Results:Depressive subjects with melancholic features but not those with non-melancholic depression showed implicit learning deficits. This deficit could not be explained in terms of more severe depression or psychomotor retardation. Regional volumes of the right pre-SMA were reduced in depressive subjects with melancholic features. Limitations:Medication effects in depressive subjects and the small size of the non-melancholic sample should be taken into consideration when reviewing the implications of these results. Conclusions:Deficits in implicit motor sequence learning seem to be an additional characteristic of the melancholic subtype of depression. It might be linked to dysfunction within structural or functionally altered frontostriatal circuits. Use of implicit sequence learning tasks could offer useful diagnostic and aetiological cues for future research.

Serotonin receptor 1A −1019C/G variant: Impact on antidepressant pharmacoresponse in melancholic depression?

Previous studies on the effects of serotonin receptor 1A (5-HT1A) gene variation on treatment response in depression revealed inconsistent results with studies pointing towards a detrimental influence of the 5-HT1A-1019G allele on antidepressant treatment response, while others did not discern any involvement of 5-HT1A variants. In order to further delineate the impact of 5-HT1A gene variation on pharmacoresponse in depression over 6 weeks of antidepressant treatment, the influence of the 5-HT1A-1019C/G (rs6295) polymorphism was investigated in 340 Caucasian patients with a Major Depressive Episode (DSM-IV) with particular attention to the subtype of depression (major depression and melancholic depression). Antidepressant treatment response across 5-HT1A-1019C/G genotype groups showed no differences in either Major Depressive Episode or major depression between genotype groups, whereas stratification for the melancholic subtype of depression revealed a significantly worse treatment response as conferred by the -1019CC genotype (p=0.02). The poorer treatment response in melancholic depression could first be detected in week 2 (p=0.03), continuing until week 6 and showing a maximum effect in week 3 (p=0.01). The present study adds to the clarification of the role of 5-HT1A variation in treatment response in major depression by providing preliminary support for poor treatment response mediated by the 5-HT1A-1019C allele repressing 5-HT1A activity specifically in the melancholic subtype of depression.

Serotonin transporter polymorphism (5-HTTLPR) association with melancholic depression: a female specific effect?

Earlier studies yielded inconsistent results on the association between variation in the serotonin transporter (5-HTT) gene and depression, with evidence for a differential effect of the 5-HTTLPR on melancholic versus atypical depression. To further delineate the impact of 5-HTT gene variation on psychopathology in depression, in this analysis the influence of the 5-HTTLPR and the functionally closely related 5-HTT rs25531 was investigated in 340 Caucasian patients with a major depressive episode (DSM-IV) with particular attention to the subtype of depression (melancholic depression versus atypical depression) applying logistic regression models adjusted for age and gender. The homozygous, more active 5-HTTLPR LL genotype was significantly associated with melancholic depression (odds ratio, OR, 1.7; 95% confidence interval, CI, 1.1-2.6; P=0.04), with the effect originating in the female subgroup of patients (OR 1.9; 95%CI 1.0-3.4; P=0.05). Also, the more active 5-HTTLPR/5-HTT rs25531 haplotype L(A)L(A) conveyed a significant risk for melancholic depression (OR 2.0; 95%CI 1.3-3.1; P=0.001), again only in the female subsample of patients (OR 2.1; 95%CI 1.1-4.1; P=0.02). The present results provide further support for an association of genetic variation increasing serotonin transporter activity with the melancholic subtype of depression as well as evidence for a potential female-specific mechanism underlying this effect.

Characteristics of Depressed Preschoolers With and Without Anhedonia: Evidence for a Melancholic Depressive Subtype in Young Children

Characteristics of Depressed Preschoolers With and Without Anhedonia: Evidence for a Melancholic Depressive Subtype in Young Children

Characteristics of Depressed Preschoolers With and Without Anhedonia: Evidence for a Melancholic Depressive Subtype in Young Children

This study investigated whether a melancholic subtype similar to that established in depressed adults can be identified in depressed preschool children. A final group total of 156 preschool children between the ages of 3.0 and 5.6 years and their caregivers underwent a comprehensive psychiatric assessment that included a structured psychiatric interview modified for young children. The clinical characteristics of four study groups (N=156) were compared: depressed preschoolers with anhedonia, depressed preschoolers without anhedonia ("hedonic"), a psychiatric comparison group with DSM-IV attention deficit hyperactivity disorder and/or oppositional defiant disorder, and a healthy comparison group. Fifty-four depressed preschoolers were identified, and 57% of this depressed group was anhedonic, a symptom deemed to be highly developmentally and clinically significant when arising in the preschool period. The anhedonic depressed subgroup identified was characterized by greater depression severity, alterations in stress cortisol reactivity, increased family history of major depressive disorder, and increased frequency of psychomotor retardation as well as other melancholic symptoms, such as a lack of brightening in response to joyful events. The clinical characteristics of this depressed subgroup are consistent with those described in melancholic depressed adults and suggest that a melancholic depressed subtype can be manifest in children as young as age 3.

Alterations in Stress Cortisol Reactivity in Depressed Preschoolers Relative to Psychiatric and No-Disorder Comparison Groups

Despite the robust and widely replicated finding of elevated hypothalamic-pituitary-adrenal (HPA) axis reactivity in depressed adults, studies of depressed children have yielded ambiguous findings. Animal models of early depression and studies of children experiencing early psychosocial deprivation have suggested that alterations in HPA axis reactivity are evident in early "depressive-like" conditions. The current study is, to our knowledge, the first investigation of HPA axis reactivity in very young children with a clinical depressive syndrome for which content validity has been established. Depressed, psychiatric, and no-disorder comparison children aged 3 through 5.6 years were studied for HPA axis reactivity in response to experimental psychosocial stressors. The children were diagnosed using a developmentally appropriate, structured psychiatric interview. Salivary cortisol was obtained at 3 time points during a laboratory assessment before and after stressors involving separation from the parent and frustrating tasks. Repeated measures of multivariate analysis of variance revealed a significant interaction between the diagnostic group and 2 cortisol percent change scores. Depressed preschoolers displayed a pattern of increasing cortisol levels throughout the assessment in response to both separation and frustration stressors. In contrast, both comparison groups showed decreasing cortisol levels in response to the separation stressor. All groups displayed increasing cortisol levels in response to frustrating tasks. Preschoolers with a presumptive melancholic depressive subtype displayed these alterations at a greater magnitude relative to comparison groups. To our knowledge, these findings are the first to demonstrate altered HPA axis reactivity in depressed preschoolers. These alterations are consistent with those described in depressed adults and in animal models of early depression. These findings provide evidence for possible continuity of HPA axis alterations in depressive disorders across the lifespan and are discussed in the context of prior studies of HPA axis reactivity in clinically depressed children and adolescents, suggesting that younger age and inpatient status are features associated with altered HPA axis reactivity.

Assessing the comparative effectiveness of antidepressant therapies: a prospective clinical practice study.

Although efficacy studies suggest equal potency among antidepressant treatments, their effectiveness in clinical practice appears more variable, particularly in that the newer antidepressants may be less effective in either more severe depression or the melancholic subtype of depression. We pursue some factors that may impact the effectiveness of antidepressant treatments in a clinical sample. A sample of 182 patients with DSM-IV major depressive disorder was assessed at baseline and 12 months later to establish treatments provided, identify patients who had recovered from the index episode, and quantify likely treatment determinants. Four systems for distinguishing patients with melancholic and non-melancholic depression were examined to assess for differential effects of the antidepressant strategies across those subtypes. Multimodal therapy (commonly, psychotherapy combined with an antidepressant drug) and patients' frequent attribution of recovery to spontaneous improvement made for difficulty in disentangling recovery determinants. After excluding a spontaneous improvement component, electroconvulsive therapy (ECT) and the irreversible monoamine oxidase inhibitors (MAOIs) appeared to be the most effective therapies across the sample, while the reversible inhibitor of monoamine oxidase-A (RIMA) appeared to be the least effective. The distinct gradient of suggested effectiveness of various strategies appeared to be contributed to principally by the varied effectiveness of alternate treatments across the melancholic subtype, whereby ECT, tricyclic antidepressants, and MAOIs were the most effective, and the selective serotonin reuptake inhibitors (SSRIs), RIMAs, and antipsychotic drugs were much less effective. For the nonmelancholic disorders, the effectiveness of SSRIs appeared to be comparable with that of older antidepressants. Although most patients received a physical treatment, they commonly judged psychotherapy and spontaneous improvement to be influential in their recovery. Reasons for such attributions are worthy of clarifying studies. Despite patients' concerns about the side effects and stigma of ECT as well as the side effects associated with the older antidepressants, these therapies were rated as more helpful by patients-and were more strongly associated with recovery-than the newer antidepressant drugs. Such overall results are compatible with an earlier study undertaken by us involving an independent sample and retrospective data. The overall gradient is clarified by studying depressive subtypes, allowing an important conclusion. Although the newer and older antidepressant drugs may be of similar effectiveness in nonmelancholic depression, the newer agents appear comparatively inferior for the treatment of melancholia, findings that have clinical implications and perhaps inform us about the pathogenesis of melancholia.

Clinical comparison of selective serotonin reuptake inhibitors in the treatment of geriatric depression: a review of literature

IntroductionWith their ease of administration, relatively benign side-effect profile and safety in overdose, in the United States the selective serotonin reuptake inhibitors (SSRIs) have become de facto first choice in the treatment of geriatric depression, displacing tricyclic antidepressants (TCAs). In this paper, the relevant literature regarding neurochemistry, kinetics, dosing, efficacy and differential side-effect profiles of citalopram, fluvoxamine, fluoxetine, sertraline, and paroxetine, the five currently available SSRIs in the USA, will be reviewed with special emphasis on geriatric data. Of late, considerable controversy has been generated regarding whether SSRIs are as effective as TCAs in severe and melancholic depressive subtypes. This important issue will be explored and the relative utility of all the SSRIs in the elderly patient compared and contrasted. Finally, reasons for difficulties in comparing results across studies will be elucidated.

Defining Melancholia: Properties of a Refined Sign-Based Measure

We hypothesised that psychomotor disturbance is specific to the melancholic subtype of depression and capable of defining melancholia more precisely than symptom-based criteria sets. We studied 413 depressed patients, and examined the utility of a refined, operationally driven set of clinician-rated signs, principally against a set of historically accepted symptoms of endogeneity. We specified items defining psychomotor disturbance generally as well as those weighted either to agitation or to retardation. We demonstrated the system's capacity to differentiate 'melancholic' and 'non-melancholic' depression (and the comparable success of DSM-III-R and Newcastle criteria systems) by reference to several patient, illness and treatment response variables, to an independent measure of psychomotor disturbance (reaction time) and to a biological marker (the dexamethasone suppression test).

DSM-III-R: En oversikt

The article reviews the major differences between DSM-III and DSM-III-R. In DSM-III-R the elimination of many of the diagnostic hierarchies which occurred in DSM-Ill makes multiple diagnoses a probability in anyone episode of illness. This renders the use of decision-trees less exclusive to the clinician and increases the need for good knowledge of all the diagnostic possibilities of one episode of illness. Thus, from a research point of view, the appropriate use of DSM-III-R in clinical studies is difficult without the application of structured interviews covering all diagnostic possibilities. Although several of the revisions made in the diagnostic criteria in DSM-III-R compared with DSM-III appear clinically valid, the majority made in DSM-III-R have not been sufficiently validated by clinical research. It is also important to note that some of the diagnostic criteria in DSM-III-R differ from those in DSM-III to such an extent that comparisons between DSM-III and DSM-III-R diagnoses with equal » label « are rendered meaningless (e.g. melancholic subtype of depression). These facts suggest the need for the provision of diagnoses of mental disorders according to additional classification systems in future clinical and research reports.