Alterations In Major Depressive Disorder Research Articles

Nitric oxide synthase and nitric oxide alterations in chronically stressed rats: A model for nitric oxide in major depressive disorder

Nitric oxide (NO) and NO synthase-1 (NOS1) are involved in the stress response and in depression. We compared NOS-NO alterations in rats exposed to chronic unpredictable stress (CUS) with alterations in major depressive disorder (MDD) in humans. In the hypothalamus of male CUS rats we determined NOS activity, and in the paraventricular nucleus (PVN) we determined NOS1-immunoreactive (ir) cell densities and co-localization of NOS1 with stress-related neuropeptides corticotropin-releasing hormone (CRH), vasopressin (AVP) or oxytocin (OXT). We measured plasma NO levels and cortisol in male medicine-naïve MDD patients and plasma NO and corticosterone (CORT) in CUS rats. In the CUS rat total NOS activity in the hypothalamus (P=0.018) and NOS1-ir cell density in the PVN were both significantly decreased (P=0.018), while NOS1 staining was mainly expressed in OXT-ir neurons in this nucleus. Interestingly, plasma NO levels were significantly increased both in male CUS rats (P=0.001) and in male MDD patients (P<0.001). Plasma CORT levels were increased in male CUS rats (P=0.001), while male MDD patients did not show a significant change in cortisol levels. In conclusion, the changes in plasma and hypothalamic NOS-NO of CUS rats and MDD were similar. The male CUS rat model may thus help us with our investigation of the mechanism underlying NOS-NO alterations in depression.

The one-carbon-cycle and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in recurrent major depressive disorder; influence of antidepressant use and depressive state?

BackgroundAn important biological factor suggested in the pathophysiology of (recurrent) Major Depressive Disorder (MDD) concerns a polymorphism in a gene encoding for the MTHFR-enzyme of the one-carbon (1-C)-metabolism. Integratively investigating key 1-C-components (folate, homocysteine, vitamin B6 and B12), including the possible effects of antidepressant medication and depressive state, could provide more insight in the possible association between the MTHFR-polymorphism and recurrent MDD. MethodsWe compared the MTHFR C677T-polymorphism together with the key 1-C-components in clinically ascertained patients with recurrent MDD (n=137) to age- and gender-matched healthy controls (n=73). ResultsFirst, patients had lower folate (t=2.25; p=.025) as compared to controls; a difference that resolved after correction for demographics (t=1.22; p=.223). Second, patients that were depressed during sampling had lower vitamin B6 (t=−2.070; p=.038) and higher homocysteine (t=2.404; p=.016) compared to those in remission. Finally, current use of antidepressants had no influence on the 1-C-components. ConclusionsDespite investigation of a specific recurrently depressed patient population, we found no clear associations with the 1-C-cycle, except for higher homocysteine and lower vitamin B6 during the depressed state. This suggests that 1-C-cycle alterations in MDD are state-associated, possibly resulting from high levels of acute (psychological) stress, and may provide a treatment target to reduce cardiovascular risk in this population.

Association between Glucocorticoid Receptor Methylation and Hippocampal Subfields in Major Depressive Disorder

BackgroundDNA methylation in the promoter region of the glucocorticoid receptor gene (NR3C1) is closely associated with childhood adversity and suicide. However, few studies have examined NR3C1 methylation in relation to major depressive disorder (MDD) and hippocampal subfield volumes. We investigated the possible association between NR3C1 methylation and structural brain alterations in MDD in comparison with healthy controls.MethodsWe compared the degree of NR3C1 promoter methylation in the peripheral blood of non-psychotic outpatients with MDD and that of healthy controls. Correlations among NR3C1 promoter methylation, structural abnormalities in hippocampal subfield volumes and whole-brain cortical thickness, and clinical variables were also analyzed.ResultsIn total, 117 participants (45 with MDD and 72 healthy controls) were recruited. Patients with MDD had significantly lower methylation than healthy controls at 2 CpG sites. In MDD, methylations had positive correlations with the bilateral cornu ammonis (CA) 2–3 and CA4-dentate gyrus (DG) subfields. However, in healthy controls, methylations had positive correlation with the subiculum and presubiculum. There were no differences in total and subfield volumes of the hippocampus between patients with MDD and healthy controls. Compared with healthy controls, patients with MDD had a significantly thinner cortex in the left rostromiddle frontal, right lateral orbitofrontal, and right pars triangularis areas.ConclusionsLower methylation in the NR3C1 promoter, which might have compensatory effects relating to CA2-3 and CA4-DG, is a distinct epigenetic characteristic in non-psychotic outpatients with MDD. Future studies with a longitudinal design and a comprehensive neurobiological approach are warranted in order to elucidate the effects of NR3C1 methylation.

Mapping the depressed brain: A meta-analysis of structural and functional alterations in major depressive disorder

Depression has a lifetime prevalence of up to 20%. Neuroimaging methods have revealed various structural and functional changes that occur in a human brain during a depressive episode. However, we still lack information concerning the extent to which structural and functional changes co-occur in a depressed brain. Furthermore, it is difficult to evaluate from a merely qualitative literature review what regional brain changes in volume and activation are robust across depressed patient samples and consistent across imaging centers. This study is a meta-analysis from 10 selected studies published previously. We applied the statistical anatomical/activation likelihood estimate method (ALE) in a total of 176 depressed patients and 175 controls for the MRI modality and in a total of 102 depressed patients and 94 controls for the PET modality to quantitatively identify those brain regions that show concordant alteration in the midst of a depressive episode across imaging modalities and study sites. We find a convergent change in the limbic-cortical brain circuit in depression compared to controls of both Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) data. The specific changes include lower gray matter volumes in the amygdala, the dorsal frontomedian cortex, and the right paracingulate cortex, as well as increases in glucose metabolism in the right subgenual and pregenual anterior cingulate cortices. Our current findings represent an important first step towards a more focused approach to neuroimaging unipolar depression. The regions identified could serve as a specific region-of-interest-for-disease template for both individual in vivo imaging studies and postmortem histopathologic exploration.

Altered Negative Unconscious Processing in Major Depressive Disorder: An Exploratory Neuropsychological Study

ObjectiveMajor depressive disorder (MDD) has been characterized by abnormalities in emotional processing. However, what remains unclear is whether MDD also shows deficits in the unconscious processing of either positive or negative emotions. We conducted a psychological study in healthy and MDD subjects to investigate unconscious emotion processing and its valence-specific alterations in MDD patients.MethodsWe combined a well established paradigm for unconscious visual processing, the continuous flash suppression, with positive and negative emotional valences to detect the attentional preference evoked by the invisible emotional facial expressions.ResultsHealthy subjects showed an attentional bias for negative emotions in the unconscious condition while this valence bias remained absent in MDD patients. In contrast, this attentional bias diminished in the conscious condition for both healthy subjects and MDD.ConclusionOur findings demonstrate for the first time valence-specific deficits specifically in the unconscious processing of emotions in MDD; this may have major implications for subsequent neurobiological investigations as well as for clinical diagnosis and therapy.

P02-04 - Area-specific occupancy of the serotonin transporter by escitalopram and citalopram in major depressive disorder

IntroductionThe serotonin transporter (SERT) occupancy after long-term antidepressant treatment (steady-state) at minimum clinical doses has been reported to be approximately 80% (e.g., Meyer 2007, J.Psychiatry Neurosci;32(2):86-102, review). However, this value is mostly calculated in the striatum, therefore the occupancy values in other brain areas might be better associated to clinical parameters.ObjectivesTo compare the SERT occupancy of the striatum to occupancy values in six other brain areas.Methods18 patients with major depressive disorder (MDD) received either escitalpram (10mg/d) or citalopram (20mg/d) in a double-blind, longitudinal study. They underwent three PET scans using the radioligand [11C]DASB: PET1 baseline, PET2 six hours after the first drug intake and PET3 after three weeks of treatment. Occupancy of SERT at PET3 was analyzed in seven regions partly associated with alterations in MDD: striatum, subgenual part of the anterior cingulate cortex (sgACC), ACC, amygdala, inferior frontal cortex (IFC), superior frontal cortex (SFC), superior parietal cortex (SPC). ROI-based quantification was performed in PMOD.ResultsThere was a huge range in occupancy values of different areas: amygdala (93.5% ± 6.9%, mean ± SD), SPC (90.8% ± 8.0%), ACC (86.0% ± 13.2%), sgACC (79.1% ± 23.6%), striatum (78.8% ± 4.9%), SPF (64.0% ± 26.4%), IFC (54.4% ± 21.7%). We found significant differences in occupancy values between striatum and the ACC, amygdala, IFC, SFC, SPC (t-test, p &lt; 0.05).ConclusionsIn this study we show significant differences in SERT occupancy between brain areas ranging between 54.4% and 93.5%. According to the area-specific effects of changes in serotonergic neurotransmission, regional occupancy values, especially in limbic areas, might be considered in the association to clinical response.

Anhedonia, Depression, and Motor Functioning in Parkinson’s Disease During Treatment With Pramipexole

Anhedonia, a core symptom of depression, correlates with motor alterations in major depressive disorder and has been assumed to be frequent in depressed patients with Parkinson's disease (PD). In the present study, the authors assessed for the first time frequency of anhedonia in patients with idiopathic Parkinson's disease (N = 657) and the relationship of anhedonia and parkinsonian motor deficits during treatment with pramipexole. Mild depression was present in 47% of the patients and moderate to severe depression in 22%. Anhedonic individuals included 45.7% of all patients and 79.7% of depressed Parkinson's disease patients. Anhedonic Parkinson's disease patients had greater motor deficits, restrictions in activities of daily living, and depression compared to nonanhedonic patients. Frequency of anhedonia and depression was significantly reduced during treatment with pramipexole. Future studies should further investigate antianhedonic efficacy of dopamine agonists including pramipexole in depressed patients with Parkinson's disease.

Anhedonia, Depression, and Motor Functioning in Parkinson's Disease During Treatment With Pramipexole

Anhedonia, a core symptom of depression, correlates with motor alterations in major depressive disorder and has been assumed to be frequent in depressed patients with Parkinson's disease (PD). In the present study, the authors assessed for the first time frequency of anhedonia in patients with idiopathic Parkinson's disease (N=657) and the relationship of anhedonia and parkinsonian motor deficits during treatment with pramipexole. Mild depression was present in 47% of the patients and moderate to severe depression in 22%. Anhedonic individuals included 45.7% of all patients and 79.7% of depressed Parkinson's disease patients. Anhedonic Parkinson's disease patients had greater motor deficits, restrictions in activities of daily living, and depression compared to nonanhedonic patients. Frequency of anhedonia and depression was significantly reduced during treatment with pramipexole. Future studies should further investigate antianhedonic efficacy of dopamine agonists including pramipexole in depressed patients with Parkinson's disease.

Somatization and the recognition of depression and anxiety in primary care.

The authors examined the effect of patients' style of clinical presentation on primary care physicians' recognition of depression and anxiety. The subjects were 685 patients attending family medicine clinics on self-initiated visits. They completed structured interviews assessing presenting complaints, self-report measures of symptoms and hypochondriacal worry, the Diagnostic Interview Schedule (DIS), and the Center for Epidemiologic Studies Depression Scale (CES-D). Physician recognition was determined by notation of any psychiatric condition in the medical chart over the ensuing 12 months. The authors identified three progressively more persistent forms of somatic presentations, labeled "initial," "facultative," and "true" somatization. Of 215 patients with CES-D scores of 16 or higher, 80% made somatized presentations; of 75 patients with DIS-diagnosed major depression or anxiety disorder, 76% made somatic presentations. Among patients with DIS major depression or anxiety disorder, somatization reduced physician recognition from 77%, for psychosocial presenters, to 22%, for true somatizers. The same pattern was found for patients with high CES-D scores. In logistic regression models education, seriousness of concurrent medical illness, hypochondriacal worry, and number of lifetime medically unexplained symptoms each increased the likelihood of recognition, while somatized presentations decreased the rate of recognition. While physician recognition of psychiatric distress in primary care varied widely with different criteria for recognition, the same pattern of reduction of recognition with increasing level of somatization was found for all criteria. In contrast, hypochondriacal worry and medically unexplained somatic symptoms increased the rate of recognition.