PubMed Health⌕ Search

Biomedical subjects

K Ranga R Krishnan

Publications and source records attributed to K Ranga R Krishnan.

At least 19 recordsLinked to original sources
PubMed2007

A preliminary metabolomic analysis of older adults with and without depression.

BACKGROUND: Metabolomics, the global science of biochemistry, is an emerging field that enables detection and quantification of small molecules involved in metabolic and signaling pathways. Metabolic signatures for disease and its treatment could provide valuable biomarkers and insights about disease mechanisms. In this pilot study, we evaluate the potential of metabolomics in the study of older depressed patients. METHODS: We performed a metabolomic analysis of blood plasma from nine depressed, 11 remitted, and ten never-depressed older adults. Approximately 800 metabolites were analyzed, with comparisons made among the three groups. RESULTS: Metabolites that were altered in currently depressed patients when compared with controls included several fatty acids, glycerol and gamma-aminobutyric acid (GABA). Analyses comparing concentrations in remitted and currently depressed patients revealed a pattern of metabolite alterations similar to the control vs currently depressed analyses. One difference observed in the remitted patients relative to the depressed patients was elevation of the concentration of the ketone 3-hydroxybutanoic acid. CONCLUSION: These observations suggest that the depressed state may be associated with alterations in the metabolism of lipids and neurotransmitters, and that treatment with antidepressants adjusts some of the aberrant pathways in disease so that the patients in remission have a metabolic profile more similar to controls than to the depressed population. These results will need to be examined and validated in larger longitudinal cohorts.

Aged↗
PubMed2006

Predicting memory decline in normal elderly: genetics, MRI, and cognitive reserve.

Major predictors of Alzheimer's disease (AD) include apolipoprotein E (APOE)-epsilon4, hippocampal atrophy on magnetic resonance imaging (MRI), and memory dysfunction prior to diagnosis. We examined 159 normal elderly subjects with MRI and the California Verbal Learning Test (CVLT); 84 returned for longitudinal follow-up 5 years later. Analyses at baseline revealed significant variance in hippocampal volume accounted for by cerebral volume and age but not by APOE isoform. However, interactions involving APOE isoform and laterality were observed. As hypothesized, an APOE x time interaction was revealed for CVLT long-delay free recall: APOE-epsilon3/4 subjects had significantly poorer performance than APOE-epsilon3/3 subjects at follow-up. Forward stepwise multiple regression analysis predicting follow-up long-delay free recall selected baseline recall, followed by number of APOE-epsilon4 alleles, followed by left-hippocampal volume. Age and sex did not enter into the model. We conclude that APOE-epsilon4 predicts longitudinal memory decline in healthy controls and that MRI morphometry of hippocampus adds slightly to predictive value.

Aged↗
PubMed2006

Dorsolateral prefrontal cortex and anterior cingulate cortex white matter alterations in late-life depression.

BACKGROUND: The dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) are critical for mood regulation. Alterations in the white matter connections of these regions may impair their role in mood regulation and increase the risk of developing depression. This study used diffusion tensor imaging to examine for white matter microstructural abnormalities of these regions and of central white matter structures in late-life depression. METHODS: One hundred six elderly depressed subjects and eighty-four elderly nondepressed subjects underwent clinical assessment and diffusion tensor imaging. The apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in regions of interest placed in the white matter of the DLPFC, ACC, corpus callosum, and internal capsule. Differences between groups were assessed, controlling for age, sex, and total cerebral volume. RESULTS: After controlling for covariates, depressed subjects had significantly lower FA values in white matter of the right ACC, bilateral superior frontal gyri, and left middle frontal gyrus. There were no significant differences in ADC values. CONCLUSIONS: Lower FA, representing lower tissue organization, is observed in depressed elders in the DLPFC and right ACC. These findings support the hypothesis that altered connectivity between brain regions contributes to the risk of depression.

Aged↗
PubMed2006

Prognosis of patients taking selective serotonin reuptake inhibitors before coronary artery bypass grafting.

Depression is increasingly recognized as an independent prognostic risk factor in patients with coronary artery disease and coronary artery bypass grafting (CABG). The use of selective serotonin reuptake inhibitors (SSRIs) for depression in patients with cardiac disease is becoming more prevalent. We examined the long-term outcomes of patients on SSRIs before CABG. We prospectively examined collected data in the Duke Databank for Cardiovascular Disease from January 1, 1999 to December 31, 2003. The median and maximum follow-up periods were 3 and 6 years, respectively. We screened patients who underwent CABG (n = 5,364) and excluded those who underwent simultaneous CABG and valvular surgery (n = 570). SSRI antidepressants included fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, venlafaxine, and clomipramine, and their use was determined from the inpatient pharmacy records during the index hospitalization. Outcomes included event-free survival from all-cause mortality, rehospitalization, and a composite end point of all-cause mortality or rehospitalization. Of 4,794 CABG-only patients, 246 (5.1%) took SSRIs before CABG. The SSRI group had a higher prevalence of diabetes, hypercholesterolemia, hypertension, cerebrovascular disease, peripheral vascular disease, and previous cardiovascular intervention. After adjustment for baseline differences, patients on SSRIs before CABG had increased risks of mortality, rehospitalization, and the composite end point (hazard ratio 1.61, 95% confidence interval 1.17 to 2.21, p = 0.003; hazard ratio 1.52, 95% confidence interval 1.30 to 1.77, p <0.0001; and hazard ratio 1.46, 95% confidence interval 1.26 to 1.70, p <0.0001, respectively). In conclusion, SSRI use before CABG was associated with a higher risk of long-term post-CABG mortality and rehospitalization. The explanation behind these findings requires further research.

Aged↗
PubMed2006

White matter lesion volumes and caudate volumes in late-life depression.

BACKGROUND: Decreased caudate volumes and increased white matter lesions (WMLs) are associated both with aging and late-life depression, but the relationship between the two is unclear. We examined the association between WML and caudate volume, hypothesizing there would be a negative association, which would be stronger for WMLs located in anterior regions. We additionally hypothesized that this association would be stronger in depressed subjects. METHOD: This MRI study included 182 elderly depressed and 64 elderly control subjects. Our imaging analysis procedures divided the brain into anterior and posterior halves. WML volume in each half was calculated, as were left and right caudate volumes. A statistical model incorporating WML volumes, age, total brain volume, diagnosis, and gender was used to examine caudate volumes. RESULTS: WML volume was negatively associated with total and right caudate volume. This association was stronger for WMLs in the anterior half of the brain. Anterior WML volume was additionally negatively associated with right caudate volume in depressed subjects, but not in controls. CONCLUSIONS: Using unadjusted levels of significance, WML volume is negatively associated with right caudate volume in both older populations, but with left caudate volume only in depressed individuals. When statistical corrections for multiple comparisons are used, the finding is limited to a negative association between WML volume and right caudate volume, primarily in depressed subjects. This study demonstrates one mechanism by which WMLs may disrupt frontostriatal circuits.

Age of Onset↗
PubMed2006

The relation of free plasma tryptophan to anger, hostility, and aggression in a nonpatient sample of adult men and women.

BACKGROUND: Dysregulation of central nervous system serotonergic (5-HT) activity is implicated in behavioral states and psychological traits associated with depression and aggression, with some studies suggesting possible gender-related differences. PURPOSE: This study examined the relation of free plasma tryptophan (TRP) to aggression and depression in a sample of 138 nonsmoking adults recruited from the general community. It was hypothesized that TRP would be associated with anger, hostility, and aggression. METHODS: To minimize effects of diurnal variation and menstrual cycle, fasting blood samples were collected in the morning, and, for women, during the follicular phase of the menstrual cycle. Participants were administered questionnaires following blood draw. Plasma TRP was determined by high performance liquid chromatography. RESULTS: In women, but not men, higher levels of TRP were associated with trait hostility, propensity for anger, a tendency to express anger outwardly, and an antagonistic interpersonal style. For men and women, greater severity of depressive symptoms, anger, and the verbal expression of anger were associated with higher TRP. These associations were independent of age, body mass index, fasting albumin, and race and ethnicity. CONCLUSIONS: These data suggest that in women, but not men, higher plasma levels of TRP, the precursor to 5-HT, are associated with anger-hostility-aggression and that these associations are independent of various potential confounds. Implications of these observations to studies employing acute TRP depletion studies are discussed.

Adolescent↗
PubMed2005

Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression.

Dysregulation of central serotonin neurotransmission has been widely suspected as an important contributor to major depression. Here, we identify a (G1463A) single nucleotide polymorphism (SNP) in the rate-limiting enzyme of neuronal serotonin synthesis, human tryptophan hydroxylase-2 (hTPH2). The functional SNP in hTPH2 replaces the highly conserved Arg441 with His, which results in approximately 80% loss of function in serotonin production when hTPH2 is expressed in PC12 cells. Strikingly, SNP analysis in a cohort of 87 patients with unipolar major depression revealed that nine patients carried the mutant (1463A) allele, while among 219 controls, three subjects carried this mutation. In addition, this functional SNP was not found in a cohort of 60 bipolar disorder patients. Identification of a loss-of-function mutation in hTPH2 suggests that defect in brain serotonin synthesis may represent an important risk factor for unipolar major depression.

Adult↗
PubMed2005

Brain morphometry, T2-weighted hyperintensities, and IQ in children with neurofibromatosis type 1.

BACKGROUND: Larger gray matter (GM) volume in healthy children is correlated with higher IQ. Children with neurofibromatosis type 1 (NF1) have larger brains, their magnetic resonance images frequently show T2-weighted hyperintensities, and their IQs are lower. OBJECTIVES: To confirm the hypotheses that (1) children with NF1 have larger GM and white matter volumes, (2) the greatest volume differences are in the frontal and parietal regions and in children with NF1 with hyperintensities, and (3) GM volume is inversely related to IQ in children with NF1. DESIGN: Wechsler Intelligence Scale for Children-Third Edition IQ testing and measurement of cerebral volumes and hyperintensities in brain magnetic resonance images were performed on 36 children with NF1 and on 36 matched relatives who served as control subjects. RESULTS: Gray matter and white matter volumes were significantly larger in children with NF1. The greatest difference was observed in cerebral white matter volume, predominantly in the frontal lobes, whereas the greatest difference in GM volume was in the temporal, parietal, and occipital regions. In controls, IQ was significantly related to GM volume, but in children with NF1, IQ was not inversely associated with GM volume, although IQs of children with NF1 were significantly lower. CONCLUSIONS: Children with NF1 do not have the normal relationship between GM volume and IQ. Larger GM volume in the posterior brain regions and larger white matter volumes in the frontal brain regions contribute to the larger brain volume in children with NF1.

Brain↗
PubMed2005

Influence of serotonin transporter promoter region polymorphisms on hippocampal volumes in late-life depression.

CONTEXT: Polymorphisms in the promoter region of the serotonin transporter gene (5-HTTLPR) influence transcription and may play a role in the pathogenesis and course of depression. Recent research demonstrates that specific polymorphisms may be associated with differences in hippocampal volumes in subjects with depression. OBJECTIVE: To examine associations between 5-HTTLPR genotype and hippocampal volumes in elderly control subjects and elderly subjects classified as having early or late onset of depression. DESIGN: Cohort study examining baseline characteristics. PARTICIPANTS: Subjects were community dwelling and 60 years or older. Using a definition of early-onset depression as depression first occurring at 50 years or younger, we examined 72 subjects with early-onset depression, 63 subjects with late-onset depression, and 83 healthy control subjects. MAIN OUTCOME MEASURES: All subjects underwent genotyping for the 5-HTTLPR and underwent brain magnetic resonance imaging. Analyses of hippocampal volumes were controlled for total cerebral volume, age, and sex. RESULTS: The interaction between diagnosis and 5-HTTLPR genotype was statistically significant for the right hippocampus (P = .04). Subjects with late-onset depression who were homozygous for the long (L) allele (L /L genotype) had significantly smaller right hippocampal volumes than did L /L subjects with early-onset depression (P = .046) or L /L control subjects (P = .01). Post hoc analyses showed that later age of depression onset was associated with smaller hippocampal volumes in subjects with the L /L genotype, but earlier age of onset was associated with smaller hippocampal volumes in subjects who were homozygous for the short (S) allele (S/S genotype). CONCLUSIONS: Subjects with late-onset depression who were homozygous for the L allele exhibited smaller hippocampal volumes than other groups. Genotype also mediated the effect of age of onset on hippocampal volumes. Our findings differ from previous work; however, we examined an older and larger cohort of subjects than previous studies. Possible explanations for these findings include interactions between the serotonergic system and neurotrophic factors or cortisol response to stresses, each of which may affect hippocampal volumes.

Age Factors↗
PubMed2005

Biological and social predictors of long-term geriatric depression outcome.

OBJECTIVE: In this study, we examined 204 older depressed individuals for up to 64 months to determine factors related to depression outcome. We hypothesized that both presence of vascular brain lesions seen on baseline magnetic resonance imaging (MRI) scans and lower baseline social support measures would be related to worse depression outcome. METHOD: At study entry, all subjects were at least 59 years old, had a diagnosis of major depression, and were free of other major psychiatric illness and primary neurological illness, including dementia and stroke. Depression was diagnosed via structured interview and clinical assessment by a geriatric psychiatrist who completed a Montgomery Asberg Depression Rating Scale (MADRS) to determine severity of depression. Subjects provided self-report data on social support variables and ability to perform basic and instrumental activities of daily living (ADL, IADL). All subjects agreed to have a baseline standardized MRI brain scan. Ratings of severity of hyperintensities were determined for the periventricular white matter, deep white matter, and subcortical gray matter by two readers who decided by consensus. Treatment was provided by geropsychiatrists following clinical guidelines. Using mixed models to analyze the data, we determined the effect of a variety of demographic, social and imaging variables on the trajectory of MADRS score, the outcome variable of interest. RESULTS: MADRS scores decreased steadily over time. In a final HLM model, in which time since entry, a baseline time indicator, age, gender, education and Mini-mental State Examination score were controlled, subjective social support, instrumental ADL impairment, subcortical gray matter severity, and the interactions of time with social network and with subcortical gray matter lesions remained significantly associated with MADRS score. CONCLUSIONS: Both social and biological factors at baseline are associated with longitudinal depression severity in geriatric depression.

Aged↗
PubMed2005

Medical comorbidity in a bipolar outpatient clinical population.

The presence of medical illnesses among inpatients with bipolar disorder is known to complicate treatment and lengthen hospital stay. However, except for a few specific diseases, little is known about prevalence of medical illnesses in bipolar outpatients and the effect it may have on treatment. The authors sought to assess the presence of medical illnesses in a large outpatient clinical sample of bipolar patients, and the effect that medical illnesses may have on the clinical assessment and treatment of the underlying bipolar disorder. Using the Duke University Medical Center clinical database, the authors categorized the medical diagnoses of 1379 patients who were treated with bipolar disorder from 2001 to 2002 through outpatient psychiatric clinics. The prevalence of medical comorbidities was examined, as well as the effect their presence had on the clinician's assessment of disease severity and time to improvement. As expected, medical comorbidities increased with age. The most common systemic illnesses in bipolar outpatients were Endocrine and Metabolic Diseases (13.6% of the sample), Diseases of the Circulatory System (13.0%), and Diseases of the Nervous System and Sense Organs (10.7%). Significant specific diseases included cardiovascular diseases/hypertension (10.7%), COPD/asthma (6.1%), diabetes (4.3%), HIV infection (2.8%), and hepatitis C infection (1.9%). Clinicians assessed greater severity of illness in patients with increasing numbers of comorbid conditions; however, the time to recovery was not significantly effected by the presence of medical comorbidity. In conclusion, comorbid medical illnesses are common in bipolar outpatients, increasing with age. HIV rates may be increased relative to population norms. Their presence compounds the severity of the illness at time of presentation.

Adult↗
PubMed2005

Cortical white matter microstructural abnormalities in bipolar disorder.

This article reports on preliminary findings describing microstructural abnormalities in the white matter of cortical areas thought to be associated with bipolar disorder. In all, 14 patients with bipolar disorder and 21 nonpsychiatrically ill control subjects underwent MR imaging including a diffusion tensor imaging (DTI) pulse sequence (six directions, b=1000 mm(2)/s). DTI data were analyzed on a workstation using a program that allowed calculation of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) within the following three white matter fiber tracts bilaterally: the orbital frontal cortex, and the superior and middle frontal gyri. These values were compared across patient groups. The left and right orbital frontal white matter exhibited significantly higher ADC values in bipolar subjects than control subjects on both the left (p=0.028) and right (p=0.011). Microstructural changes in the white matter of the orbital frontal areas as reflected by increased ADC values appear to be associated with bipolar disorder. Further research is needed to better understand the interaction of microstructural changes and bipolar symptoms and whether these changes are specific to bipolar disorder.

Adult↗
PubMed2005

Hyperforin plasma level as a marker of treatment adherence in the National Institutes of Health Hypericum Depression Trial.

BACKGROUND: A previously reported clinical trial of Hypericum perforatum (St John's wort) in depression did not demonstrate efficacy. We assessed treatment adherence by measuring plasma hyperforin and evaluated the possible impact of adherence on study results. METHODS: Outpatients with major depression (N = 340) were randomized to an 8-week trial of H. perforatum (900-1500 mg/d), sertraline (50-100 mg/d) as active comparator, or placebo. Plasma was available from 292 patients (86% of randomized). Samples from the placebo and H. perforatum groups were assayed for hyperforin, and samples from the sertraline group for sertraline/N-desmethyl-sertraline. RESULTS: Of the 104 patients randomized to placebo, 18 (17%) had detectable plasma hyperforin. Of the 97 patients randomized to H. perforatum, 17 (17%) had no detectable plasma hyperforin. All the assayed sertraline patients (N = 91) had plasma sertraline/N-desmethyl-sertraline. The clinical trial conclusions remained unchanged when only patients with plasma assay consistent with random assignment were included in the analyses. CONCLUSIONS: One of every 6 patients assigned to placebo had plasma hyperforin, and 1 of every 6 patients assigned to H. perforatum had no detectable plasma hyperforin. The finding underscores the difficulty of enforcing treatment adherence in clinical trials of preparations that are readily available in the community.

Adult↗
PubMed2005

Relationship between release of platelet/endothelial biomarkers and plasma levels of sertraline and N-desmethylsertraline in acute coronary syndrome patients receiving SSRI treatment for depression.

OBJECTIVE: In a platelet/endothelial biomarker substudy of the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART), the authors sought to determine whether plasma levels of sertraline and its primary metabolite N-desmethylsertraline affect the release of platelet/endothelial biomarkers. METHOD: Fifty-five acute coronary syndrome patients with depression were randomly assigned to receive sertraline (N=23) or placebo (N=32). Twenty-six serial plasma samples collected at week 6 (N=12) and week 16 (N=14) were analyzed. Platelet factor 4 (PF4), beta-thromboglobulin (beta-TG), platelet/endothelial cell adhesion molecule 1 (PECAM-1), P-selectin, thromboxane B(2) (TxB(2)), prostacyclin (6-keto-PGF1alpha), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin were measured by enzyme-linked immunosorbent assay. Concentrations of sertraline and N-desmethylsertraline were determined by liquid chromatography with fluorescence detection in autologous samples. RESULTS: Strong, mostly time-dependent negative correlations were found for the plasma levels of sertraline and N-desmethylsertraline with PF4 (week 6: r=-0.69 and -0.33, respectively; week 16: r=-0.63 for both), beta-TG (week 6: r=-0.43 and -0.29; week 16: r=-0.66 and -0.57), PECAM-1 (week 6: r=-0.82 and -0.49; week 16: r=-0.60 for both), P-selectin (week 6: r=-0.82 and -0.49; week 16: r=-0.73 and -0.43), and TxB(2) (week 6: r=-0.66 and -0.59; and week 16: r=-0.64 and -0.41). Regression analysis revealed some borderline correlations for endothelial markers such as 6-keto- PGF1alpha and E-selectin and a positive correlation for VCAM-1. CONCLUSIONS: This is the first documented evidence that plasma release of platelet/endothelial biomarkers is directly related to the levels of sertraline and N-desmethylsertraline in acute coronary syndrome patients receiving SSRI treatment for depression. The clinical significance of these findings should be assessed in the setting of a randomized clinical trial.

Biomarkers↗
PubMed2004

Caudate volume measurement in older adults with bipolar disorder.

BACKGROUND: Decreased caudate volumes have been noted in unipolar depressed subjects, especially in the elderly and those with cognitive impairment. No differences have been noted in initial studies of multi-aged bipolar subjects; however, this region has not been examined in older bipolar subjects. METHODS: We examined the caudate nuclei volumes of 36 older bipolar subjects (mean age 58) and 35 older controls (mean age 62) using logistic regression analyses to control for age and gender differences. Differences between late- and early-onset (age-of-onset before age 45) bipolar subjects were also examined, as well as the effect of length of illness. RESULTS: The right caudate was noted to be smaller in older bipolar subjects compared with older controls when controlled for sex and age (p = 0.0448). No differences were noted in overall brain volume nor lateral ventricular volume between the bipolar and control subjects. Late-onset bipolar subjects had a decrease in brain volume (p = 0.035) compared with early-onset bipolar subjects. Late-onset bipolar subjects had a decrease in the right (p = 0.044) and total (p = 0.04) caudate size compared with older controls. CONCLUSIONS: Right caudate volume is decreased in older bipolar subjects compared to controls. Bipolar subjects with late-onset illness have significantly decreased right and total caudate volumes compared to controls. This is affected by neither the length of illness nor the age of onset. Late-onset bipolar subjects have decreased total brain volume compared with early-onset bipolar subjects.

Age of Onset↗