Baroreflex mechanisms in major depression

BACKGROUND: Recent studies have shown that depressive disorder is associated with impaired baroreceptor or baroreflex sensitivity, which is proposed to be a predisposing factor for sudden death in patients with manifest cardiac disease. These studies have not evaluated the afferent and efferent components of the cardiac baroreflex loop or other baroreflex mechanisms that regulate target processes (cardiac metabolism and blood pressure variability) related to the impairment. The objective of this study was to gain more insight into autonomic functioning in depressive disorder to more fully examine the potential basis for increased cardiac mortality. METHODS: The subjects were 28 women and men with unipolar major depression who were taking antidepressant medications and who were in partial remission and free of cardiovascular or other serious disease, and 28 healthy control subjects matched for sex, age, and ethnicity. The two samples were compared for negative affective dispositions (anger expression, hostility, defensiveness, anxiety), spontaneous (closed-loop) baroreflex activity, heart rate, heart rate variability, systolic blood pressure, and heart rate-systolic blood pressure double product under resting conditions. RESULTS: Depressed patients showed a general disposition to anger suppression coupled with higher hostility and anxiety, and lower defensiveness. The patients showed higher general sympathetic activity (high levels of blood pressure, low-frequency heart rate variability) and lower parasympathetic-related activity (high heart rate and reduced high frequency heart rate variability) with affected cardiac metabolism estimated by the double product. Depressed patients had lower baroreflex sensitivity related to a higher gain of the afferent component of the baroreflex without respective gain adjustment of its efferent component (reflex gain 'de-afferentation'). It was coupled with a compensatory higher number of effective baroreflex reactions (reflex gating 're-afferentation'). Antidepressant agents and depressed mood had additional independent effects on baroreflex sensitivity through the efferent component of the cardiac baroreflex loop. CONCLUSIONS: The data indicate that different baroreflex components and mechanisms may be impaired in patients with depression and may contribute to their increased cardiac risk.     

Clinical characteristics and treatment outcome in a representative sample of depressed inpatients - findings from the Munich Antidepressant Response Signature (MARS) project

Depression is a common and often difficult-to-treat clinical condition with a high rate of patients showing insufficient treatment response and persistence of symptoms. We report the characteristics of a representative sample of depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Eight hundred and forty-two inpatients admitted to a psychiatric hospital for treatment of a major depressive episode, recurrent or bipolar depression were thoroughly characterized with respect to demographic factors, clinical history, and the degree of HPA-axis dysregulation evaluated by means of combined dex/CRH tests, and the predictive value of these factors for treatment outcome is investigated. 80.8% of patients responded to treatment (i.e., improvement in symptom severity of at least 50%) and 57.9% reached remission (i.e., near absence of residual depressive symptoms) at discharge after a mean treatment period of 11.8 weeks. Regression analysis identified early partial response (within 2 weeks) as the most important positive predictor for achieving remission. Previous ineffective treatment trials in the current episode and presence of a migration background are potent negative predictors for treatment outcome. In addition, remitters were characterized by a more pronounced normalization of an initially dysregulated HPA-axis. We could show that a large majority of inpatients suffering from depression benefits from antidepressant treatment during hospitalization. However, a considerable number of patients failed to achieve remission. We demonstrated that this subgroup can be characterized by a set of demographic, clinical and neuroendocrine variables allowing to predict unfavorable outcome at an early stage of treatment.     

Decreased dopamine transporter availability in male smokers -- a dual isotope SPECT study

Introduction

Although the mesolimbic dopaminergic system has been shown to play a role in reinforcing tobacco smoking, results of imaging studies that examine the relationship between tobacco smoking and the central dopamine system remain discrepant. To delineate the role of tobacco addiction in central pre- and post-synaptic dopaminergic activities, we analyzed the central D₂-family receptors, the dopamine transporters (DAT), and degrees of dependence in male smokers.

Methods

Eleven male smokers and 11 healthy non-smokers were recruited. The striatal dopamine D₂/D₃ receptor availability was approximated using SPECT and [¹²³I] IBZM while the DAT availability was approximated using SPECT and [^99mTc] TRODAT-1. All of the smokers completed the Fagerström Test for Nicotine Dependence (FTND) and other related questionnaires.

Results

A decrease in DAT availability in the striatum of male smokers is noted (p < 05). However, the striatal D₂/D₃ receptor availability in male smokers does not differ from that of non-smokers.

Conclusions

These findings suggest that cigarette smoking may alter central dopamine functions in males, particularly at the pre-synaptic sites.     

Evaluation of treatment response in depression studies using a Bayesian parametric cure rate model

Efficacy trials with antidepressant drugs often fail to show significant treatment effect even though efficacious treatments are investigated. This failure can, amongst other factors, be attributed to the lack of sensitivity of the statistical method as well as of the endpoints to pharmacological activity. For regulatory purposes the most widely used efficacy endpoint is still the mean change in HAM-D score at the end of the study, despite evidence from literature showing that the HAM-D scale might not be a sensitive tool to assess drug effect and that changes from baseline at the end of treatment may not reflect the extent of response. In the current study, we evaluate the prospect of applying a Bayesian parametric cure rate model (CRM) to analyse antidepressant effect in efficacy trials with paroxetine. The model is based on a survival approach, which allows for a fraction of surviving patients indefinitely after completion of treatment. Data was extracted from GlaxoSmithKline's clinical databases. Response was defined as a 50% change from baseline HAM-D at any assessment time after start of therapy. Survival times were described by a log-normal distribution and drug effect was parameterised as a covariate on the fraction of non-responders. The model was able to fit the data from different studies accurately and results show that response to treatment does not lag for two weeks, as is mythically believed. In conclusion, we demonstrate how parameterisation of a survival model can be used to characterise treatment response in depression trials. The method contrasts with the long-established snapshot on changes from baseline, as it incorporates the time course of response throughout treatment.     

WHAT DEPRESSIVE SYMPTOMS ARE REPORTED IN ALZHEIMER'S PATIENTS?

Purpose. To ascertain the nature of depression-related symptoms in AD. Method. The Hamilton Rating Scale for Depression (HAM-D) was administered as a semi-structured interview to 30 consecutive Alzheimer's disease (AD) patients who also underwent independent psychiatric evaluation. The HAM-D was also administered with a caregiver as the informant. Results. There was no relationship between the number of symptoms reported by patients or caregivers and patients' level of cognitive impairment. Symptom reports by caregivers living in the same household did not differ significantly from symptom reports by caregivers living elsewhere. Caregivers rated AD patients as having significantly more depressive symptoms than did patients themselves. The items most frequently endorsed by caregivers were psychic anxiety (77%), suspiciousness (50%), low energy (50%) and depression (43%). The items most frequently endorsed by AD patients were weight loss (36%), psychic anxiety (33%) and somatic anxiety (33%). Depression was endorsed by 20% of patients. Caregiver-respondent HAM-D scores suggested clinically significant depression in 27% of cases, but AD patients' scores suggested clinically significant depression in only 7% of cases. No case of major depression was found on psychiatric examination. Conclusions. Depressive symptoms seemed more an executive function loss than of primary mood disturbance in that guilt, suicidal rumination and self-perceived loss of interest were uncommon, suggesting that simple environmental measures might be the most appropriate treatment of these symptoms.     

Shared impairment in associative learning in schizophrenia and bipolar disorder

Background

Schizophrenia (SCZ) and bipolar disorder (BD) share some cognitive commonalities. However, the role of associative learning, which is a cornerstone of human cognition mainly relying on hippocampus, has been under-investigated. We assessed behavioral performance during associative learning in a group of SCZ, BD and healthy controls (HC).

Methods

Nineteen patients with SCZ (36 ± 8.1 years; 13 males, 6 females; all Caucasians), 14 patients with BD (41 ± 9.6 years; 5 males, 9 females; all Caucasians) and 45 HC (27.7 ± 6.9 years; 18 males, 27 females; all Caucasians) were studied. Learning was assessed using an established object-location paired-associative learning paradigm. Subjects learned associations between nine equi-familiar common objects and locations in a nine-location grid. Performance data were analyzed in a repeated measures analysis of variance with time (repeated) and group as factors.

Results

Learning curves (performance = 1−e^−k?time) fitted to average performance data in the three groups revealed lower learning rates in SCZ and BD (k = 0.17 and k = 0.34) than HC (k = 0.78). Significant effects of group (F = 11.05, p < 0.001) and time (F = 122.06, p < 0.001) on learning performance were observed.

Conclusions

Our study showed that associative learning is impaired in both SCZ and BD, being potentially not affected by medication. Future studies should investigate the neural substrates of learning deficits in SCZ and BD, particularly focusing on hippocampus function and glutamatergic transmission.     

Increased methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of patients with generalized anxiety disorder

Previous findings on the dysfunction of hypothalamic-pituitary-adrenal (HPA) axis in generalized anxiety disorder (GAD) are controversial, and the molecular mechanisms underlying such dysfunction remain unclear. We analyzed the methylation status of the NR3C1 1_F promoter and the expression of glucocorticoid receptor-α isoform (GRα) in peripheral blood mononuclear cells (PMBCs), the basal cortisol level in serum, and a functional neuroendocrine marker for GR sensitivity in the PMBCs in 64 patients with current GAD and 85 healthy controls. We found that patients with GAD had significantly elevated levels of morning basal serum cortisol (P < 0.0001) and diminished GR sensitivity in the PBMCs (P < 0.0001) compared with healthy controls. The overall methylation levels across NR3C1 1_F promoter (P < 0.0001) and percent methylation at each of the 5 CpG sites including CpG12, 21, 30, 31, and 32 (P < 0.001) significantly increased. Accordingly, the mRNA levels of GRα significantly decreased (P < 0.0001) in the PBMCs in patients with GAD compared with healthy controls, with the effects specific in patients without childhood traumatic experience. Moreover, both serum basal cortisol levels and GR sensitivity in the PBMCs were negatively correlated with the overall methylation levels of the NR3C1 1_F promoter (P < 0.0001) and positively correlated with GRα mRNA levels (P = 0.007) in the PBMCs. In sum, our study revealed the increased activity of the HPA axis and diminished peripheral glucocorticoid responsiveness of GR underlying episodes of GAD. Furthermore, such dysfunction of the HPA axis is associated with both increased DNA methylation of NR3C1 1_F promoter and decreased GRα expression.     

Gustatory and olfactory function in patients with unipolar and bipolar depression

Although the crucial distinction between unipolar depressive disorder and bipolar disorder is the presence of mania (or hypomania) in the course of the latter, significant differences between unipolar and bipolar depression have also been found in clinical studies. The primary aim of the present investigation was to assess pleasantness/unpleasantness ratings of chemosensory stimuli in depressed patients, including subjects with unipolar and bipolar depression. Sensory aspects (thresholds and identification abilities) of gustatory and olfactory function were also assessed. There were no major differences between a depression group, as a whole, and healthy controls in terms of gustatory and olfactory thresholds and identification abilities. Similarly, pleasantness ratings of various gustatory and olfactory stimuli did not differ between the control and depression group. Gustatory and olfactory thresholds and identification abilities did not differ between individuals with unipolar and bipolar depression. Bipolar patients tended to rate less gustatory stimuli as unpleasant and more olfactory stimuli as pleasant compared to unipolar patients. The present results suggest that: i) depression is not associated with any major deficit in sensory aspects of gustatory and olfactory function or altered hedonic ratings of chemosensory stimuli; ii) hedonic responses to chemosensory stimuli tend to be increased in bipolar as compared to unipolar depressed patients.     

Lithium increases platelet serine-9 phosphorylated GSK-3β levels in drug-free bipolar disorder during depressive episodes

BackgroundGlycogen synthase kinase-3 β (GSK3β) is an intracellular enzyme directly implicated in several neural processes relevant to bipolar disorder (BD) pathophysiology. GSK3β is also an important target for lithium and antidepressants. When phosphorylated at serine-9, GSK3β becomes inactive. Few studies evaluated serine-9 phosphorylated GSK3β (phospho-GSK3β) levels in BD subjects in vivo and no study has assessed it specifically in bipolar depression. Also, the effect of lithium monotherapy on GSK3β has never been studied in humans.MethodsIn 27 patients with bipolar depression, total GSK3β and phospho-GSK3β were assessed in platelets by enzyme immunometric assay. Subjects were evaluated before and after 6 weeks of lithium treatment at therapeutic levels. Healthy subjects (n = 22) were used as a control group.ResultsNo differences in phospho-GSK3β or total GSK3β were observed when comparing drug-free BD subjects in depression and healthy controls. Baseline HAM-D scores were not correlated with phospho-GSK3β and total GSK3β levels. From baseline to endpoint, lithium treatment inactivated GSK3β by significantly increasing phospho-GSK3β levels (p = 0.010). Clinical improvement (baseline HAM-D — endpoint HAM-D) negatively correlated with the increase in phospho-GSK3β (p = 0.03).ConclusionThe present results show that lithium inactivates platelet GSK3β in BD during mood episodes. No direct association with pathophysiology of BD was observed. Further studies are needed to clarify the role of GSK3β as a key biomarker in BD and its association with treatment response as well as the relevance of GSK3β in other neuropsychiatric disorders and as a new therapeutic target per se.     

Accelerating response to antidepressant treatment in depression: A review and clinical suggestions

Objective

The primary objective of this article is to review the literature regarding the speed of response to antidepressant drugs and potential strategies to accelerate the antidepressant response in new antidepressant-free patients with depression. Based on these data, we try to propose both an effective and safe antidepressant treatment strategy to alleviate depressive symptoms at the earliest opportunity.

Data sources

Data were identified by searches of Medline (1966 to September 2009) and references from relevant articles and books. Search terms included depression, antidepressant, predictor, response, onset, acceleration, and augmentation. As our focus was on the acute phase treatment of depression, articles relevant to treatment-resistant depression were excluded. Only articles written in English or Japanese were consulted.

Data selection

Studies, reviews, and books pertaining to the treatment of depression with a special regard to accelerating therapeutic effects were selected.

Data synthesis

Most of the available treatment guidelines for major depressive disorders recommend the continuous use of antidepressants for 4 to 8 weeks based on the idea of a delayed onset of response to these drugs. Contrary to this conventional belief, the recent data indicate that antidepressants start to exert their effects within 2 weeks and early non-response could predict a subsequent unfavorable outcome.

Conclusions

These findings suggest the need of revisiting the timing of an antidepressant switch for early non-responders, whereby switching could be commenced in as early as 2 weeks.