Pharmacometabolomic mapping of early biochemical changes induced by sertraline and placebo.

In this study, we characterized early biochemical changes associated with sertraline and placebo administration and changes associated with a reduction in depressive symptoms in patients with major depressive disorder (MDD). MDD patients received sertraline or placebo in a double-blind 4-week trial; baseline, 1 week, and 4 weeks serum samples were profiled using a gas chromatography time of flight mass spectrometry metabolomics platform. Intermediates of TCA and urea cycles, fatty acids and intermediates of lipid biosynthesis, amino acids, sugars and gut-derived metabolites were changed after 1 and 4 weeks of treatment. Some of the changes were common to the sertraline- and placebo-treated groups. Changes after 4 weeks of treatment in both groups were more extensive. Pathway analysis in the sertraline group suggested an effect of drug on ABC and solute transporters, fatty acid receptors and transporters, G signaling molecules and regulation of lipid metabolism. Correlation between biochemical changes and treatment outcomes in the sertraline group suggested a strong association with changes in levels of branched chain amino acids (BCAAs), lower BCAAs levels correlated with better treatment outcomes; pathway analysis in this group revealed that methionine and tyrosine correlated with BCAAs. Lower levels of lactic acid, higher levels of TCA/urea cycle intermediates, and 3-hydroxybutanoic acid correlated with better treatment outcomes in placebo group. Results of this study indicate that biochemical changes induced by drug continue to evolve over 4 weeks of treatment and that might explain partially delayed response. Response to drug and response to placebo share common pathways but some pathways are more affected by drug treatment. BCAAs seem to be implicated in mechanisms of recovery from a depressed state following sertraline treatment.

Pretreatment metabotype as a predictor of response to sertraline or placebo in depressed outpatients: a proof of concept.

The purpose of this study was to determine whether the baseline metabolic profile (that is, metabotype) of a patient with major depressive disorder (MDD) would define how an individual will respond to treatment. Outpatients with MDD were randomly assigned to sertraline (up to 150 mg per day) (N=43) or placebo (N=46) in a double-blind 4-week trial. Baseline serum samples were profiled using the liquid chromatography electrochemical array; the output was digitized to create a 'digital map' of the entire measurable response for a particular sample. Response was defined as ≥50% reduction baseline to week 4 in the 17-item Hamilton Rating Scale for Depression total score. Models were built using the one-out method for cross-validation. Multivariate analyses showed that metabolic profiles partially separated responders and non-responders to sertraline or to placebo. For the sertraline models, the overall correct classification rate was 81% whereas it was 72% for the placebo models. Several pathways were implicated in separation of responders and non-responders on sertraline and on placebo including phenylalanine, tryptophan, purine and tocopherol. Dihydroxyphenylacetic acid, tocopherols and serotonin were common metabolites in separating responders and non-responders to both drug and placebo. Pretreatment metabotypes may predict which depressed patients will respond to acute treatment (4 weeks) with sertraline or placebo. Some pathways were informative for both treatments whereas other pathways were unique in predicting response to either sertraline or placebo. Metabolomics may inform the biochemical basis for the early efficacy of sertraline.

Hierarchical temporal processing deficit model of reality distortion and psychoses.

We posit in this article that hierarchical temporal processing deficit is the underlying basis of reality distortion and psychoses. Schizophrenia is a prototypical reality distortion disorder in which the patient manifests with auditory hallucinations, delusions, disorganized speech and thinking, cognitive impairment, avolition and social and occupational dysfunction. Reality distortion can be present in many other disorders including bipolar disorder, major depression and even dementia. Conceptually, schizophrenia is a heterogeneous entity likely to be because of numerous causes similar to dementia. Although no single symptom or set of symptoms is pathognomonic, a cardinal feature in all patients with schizophrenia is chronic distortion of reality. The model that we have proposed accounts for the varied manifestations of reality distortion including hallucinations and delusions. In this paper we consider the implications of this model for the underlying biology of psychoses and also for the neurobiology of schizophrenia and suggest potential targets to consider for the etiology and pathophysiology of reality distortion, especially in the context of schizophrenia.

BDNF Val66Met genotype and 6-month remission rates in late-life depression.

Although not observed in younger adult cohorts, in older individuals the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with major depressive disorder (MDD) risk. It is further associated with subjective social support and magnetic resonance imaging (MRI) hyperintense lesions, clinical features independently related to MDD. We examined the relationship between this polymorphism and antidepressant remission rates in an elderly sample with MDD, while also testing for mediation effects of social support and hyperintensities. A total of 229 elderly Caucasian subjects with MDD completed baseline assessments, 1.5 T MRI, and BDNF genotyping. They received antidepressant medication under a structured treatment algorithm and were evaluated for remission at 3 and 6 months. At the 3-month evaluation, BDNF Val66Met genotype was not associated with remission (Wald's χ²=2.51, P=0.1131). When not controlling for multiple comparisons, Met66 allele carriers were more likely to be remitted at 6 months (χ²=4.32, P=0.0377) with an odds ratio of 1.82 (95% CI: 1.04, 3.22). This effect persisted after controlling for lesion volume and social support, neither of which mediated this relationship. Thus in this exploratory analysis, the Met66 allele may be associated with increased odds of remission in older subjects, but also with increased time to remission as there was no 3-month effect.

Altered interactions of tryptophan metabolites in first-episode neuroleptic-naive patients with schizophrenia.

Schizophrenia is characterized by complex and dynamically interacting perturbations in multiple neurochemical systems. In the past, evidence for these alterations has been collected piecemeal, limiting our understanding of the interactions among relevant biological systems. Earlier, both hyper- and hyposerotonemia were variously associated with the longitudinal course of schizophrenia, suggesting a disturbance in the central serotonin (5-hydroxytryptamine (5-HT)) function. Using a targeted electrochemistry-based metabolomics platform, we compared metabolic signatures consisting of 13 plasma tryptophan (Trp) metabolites simultaneously between first-episode neuroleptic-naive patients with schizophrenia (FENNS, n=25) and healthy controls (HC, n=30). We also compared these metabolites between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. N-acetylserotonin was increased in FENNS-BL compared with HC (P=0.0077, which remained nearly significant after Bonferroni correction). N-acetylserotonin/Trp and melatonin (Mel)/serotonin ratios were higher, and Mel/N-acetylserotonin ratio was lower in FENNS-BL (all P-values<0.0029), but not after treatment, compared with HC volunteers. All three groups had highly significant correlations between Trp and its metabolites, Mel, kynurenine, 3-hydroxykynurenine and tryptamine. However, in the HC, but in neither of the FENNS groups, serotonin was highly correlated with Trp, Mel, kynurenine or tryptamine, and 5-hydroxyindoleacetic acid (5HIAA) was highly correlated with Trp, Mel, kynurenine or 3-hydroxykynurenine. A significant difference between HC and FENNS-BL was further shown only for the Trp-5HIAA correlation. Thus, some metabolite interactions within the Trp pathway seem to be altered in the FENNS-BL patients. Conversion of serotonin to N-acetylserotonin by serotonin N-acetyltransferase may be upregulated in FENNS patients, possibly related to the observed alteration in Trp-5HIAA correlation. Considering N-acetylserotonin as a potent antioxidant, such increases in N-acetylserotonin might be a compensatory response to increased oxidative stress, implicated in the pathogenesis of schizophrenia.

Relationship of depression to increased risk of mortality and rehospitalization in patients with congestive heart failure.

BACKGROUND: Patients with congestive heart failure (CHF) may have a high prevalence of depression, which may increase the risk of adverse outcomes. OBJECTIVE: To determine the prevalence and relationship of depression to outcomes of patients hospitalized with CHF. METHODS: We screened patients aged 18 years or older having New York Heart Association class II or greater CHF, an ejection fraction of 35% or less, or both, admitted between March 1, 1997, and June 30, 1998, to the cardiology service of one hospital. Patients with a Beck Depression Inventory score of 10 or higher underwent a modified National Institute of Mental Health Diagnostic Interview Schedule to identify major depressive disorder. Primary care providers coordinated standard treatment for CHF and other medical and psychiatric disorders. We assessed all-cause mortality and readmission (rehospitalization) rates 3 months and 1 year after depression assessment. Logistic regression analyses were used to evaluate the independent prognostic value of depression after adjustment for clinical risk factors. RESULTS: Of 374 patients screened, 35.3% had a Beck Depression Inventory score of 10 or higher and 13.9% had major depressive disorder. Overall mortality was 7.9% at 3 months and 16.2% at 1 year. Major depression was associated with increased mortality at 3 months (odds ratio, 2.5 vs no depression; P =.08) and at 1 year (odds ratio, 2.23; P =.04) and readmission at 3 months (odds ratio, 1.90; P =.04) and at 1 year (odds ratio, 3.07; P =.005). These increased risks were independent of age, New York Heart Association class, baseline ejection fraction, and ischemic etiology of CHF. CONCLUSIONS: Major depression is common in patients hospitalized with CHF and is independently associated with a poor prognosis.

MRI signal hyperintensities in geriatric depression.

OBJECTIVE: The authors rated periventricular and subcortical signal hyperintensities on magnetic resonance imaging (MRI) scans in elderly patients with depression and in normal subjects with similar demographic features to examine whether such changes discriminate patients with depression from normal subjects and whether they are associated with any clinical variables. METHOD: Two established hyperintensity rating systems were used to compare the MRI brain scans of 48 elderly patients with depression diagnosed according to DSM-III-R with the scans of 39 normal elderly subjects. RESULTS: Elderly depressed patients manifested significantly more severe hyperintensity ratings in the subcortical gray matter than age-matched comparison subjects. Significant differences were not identified between patients with similar current ages and cerebrovascular disease risk who had early-onset or late-onset depression. CONCLUSIONS: These findings support those of neuroimaging studies implicating the basal ganglia in depression and geriatric depression. The data suggest that the relationship observed in some reports between late-onset depression and MRI hyperintensities is most likely a function of cerebrovascular disease risk and age.

MRI changes in schizophrenia in late life: a preliminary controlled study.

The aim of this pilot study was to compare cerebral changes on magnetic resonance imaging (MRI) scans in elderly schizophrenic subjects with those in psychiatric and normal control subjects. We compared the MRIs of 19 subjects with schizophrenia, 19 age- and gender-matched subjects with recurrent major depression, and 19 age- and gender-matched nonpsychiatric control subjects. Deep white matter hyperintensities (DWMH) in right posterior regions were significantly more prominent in the schizophrenic group than in the two comparison groups. Total ratings of MRI abnormalities were significantly related to age in both the normal control and schizophrenic groups, but not in the depressive group. Age of onset was positively associated with total ratings in the depressive group, but not in the schizophrenic group. Thus, a subset of elderly patients with schizophrenia appear to have cerebral white matter abnormalities; such abnormalities may not be confined to late-onset schizophrenia. Systematic MRI studies of early- and late-onset schizophrenia in late life are needed to resolve this question.

Pharmacokinetics of growth hormone secretion in humans induced by growth hormone releasing hormone.

This investigation compares the age- and sex-related changes in growth hormone (GH) response to growth hormone releasing hormone (GHRH) in normal subjects using an appropriate pharmacokinetic model. Twenty-five subjects (14 males and 11 females) aged 23-89 yr received a single intravenous bolus dose (1 microgram/kg) of GHRH-40 solution. Plasma GH concentration-time profiles are best characterized by a biexponential equation (or one-compartment model) with first-order release and disappearance rates and an equilibration lag time. The harmonic mean release rate half-life is similar for both sexes (males: 12.6 min vs. females; 11.4 min) but significantly different across age groups (23-35 yr: 7.2 min vs. 50-89 yr: 16.8 min). The mean disappearance rate half-life and GHRH-equilibration time lag for females (33.6 and 20.4 min, respectively) and the higher age group subjects (32.4 and 21.6 min, respectively) are significantly longer than those of males (22.8 and 9 min, respectively) and the lower age-group subjects (21.6 and 8.4 min, respectively). The mean metabolic clearance rate of GH is significantly lower (p less than 0.02) for females than for males (3.1 vs. 4.83 ml/hr.m2). However, the production rate and the amount of GH released by the pituitary for our subjects appear to be very similar for both males (8.7 micrograms/hr.m2 and 4.65 micrograms/m2) and females (9.33 micrograms/hr.m2 and 5.11 micrograms/m2).

Marked reduction in the number of platelet-tritiated imipramine binding sites in geriatric depression.

The number (Bmax) and affinity (Kd) of platelet-tritiated imipramine binding sites was determined in young and middle-aged controls 50 years of age and younger (n = 25), elderly normal controls over 60 years of age (n = 18), patients who fulfilled DSM-III criteria for major depression who were under 50 years of age (n = 29), patients who fulfilled DSM-III criteria for major depression who were 60 years of age and older (n = 19), and patients who fulfilled both DSM-III criteria for primary degenerative dementia and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer's disease (n = 13). Both groups of depressed patients (under 50 and over 60 years of age) exhibited significant reductions (decreases 42%) in the number of platelet-tritiated imipramine binding sites with no change in affinity, when compared with their age-matched controls. There was little overlap in Bmax values between the elderly depressed patients and their controls. The patients with probable Alzheimer's disease showed no alteration in platelet-tritiated imipramine binding. There was no statistically significant relationship between postdexamethasone plasma cortisol concentrations and tritiated imipramine binding. These results indicate that platelet-tritiated imipramine binding may have potential utility as a diagnostic adjunct in geriatric depression, and moreover that the reduction in the number of platelet-tritiated imipramine binding sites is not due to hypercortisolemia.

The Newcastle Anxiety Depression Diagnostic Index in relationship to the effects of monoamine oxidase inhibitors and tricyclic antidepressants.

The Newcastle Anxiety Depression Diagnostic Index (NADDI) was applied to 151 patients who received a monoamine oxidase inhibitor (MAOI) or a tricyclic antidepressant (TCA) drug. The pretreatment presence of a physical stressor and absence of agoraphobia were associated with superior MAOI effects. In women nine of the 13 NADDI items were associated with superior response to the MAOI drugs: these items comprised the absence of childhood anxiety, agoraphobia, compulsive symptoms, early awaking, and retardation, and the presence of dependent traits, neuroticism, physical stress, and panic attacks. In men the absence of suicidal tendencies and retardation, and the presence of dependent traits and panic attacks were associated with superior TCA effects. A within-treatment analysis indicated that depressed men responded better to MAOI than did anxious men.

A diagnostic and family study of posttraumatic stress disorder.

A family history study of 36 patients with chronic posttraumatic stress disorder revealed a positive history of familial psychopathology in 66% of the patients. Alcoholism, depression, and anxiety disorders were the disorders most commonly found. The patients also had a higher prevalence of alcoholic siblings than did a retrospectively derived control group of depressed and anxious male patients. With respect to the proportion of familial anxiety to familial depression, the probands with posttraumatic stress disorder more closely resembled probands with generalized anxiety than probands with depression. Every patient had experienced at least one significant psychiatric illness during his lifetime, most commonly alcohol abuse or depression.

MAO inhibitor therapy in trichotillomania associated with depression: case report.

Trichotillomania may sometimes be an atypical variant of depressive illness. A case is reported in which the MAO inhibitor isocarboxazid was successfully used to treat both depression and associated trichotillomania. The symptoms recurred upon discontinuation of the drug and were ameliorated by reintroduction of isocarboxazid .

Effects of single and repeated alcohol withdrawal on kindling.

It has been hypothesized that an electrophysiological reorganization of the limbic system takes place with repeated episodes of alcohol withdrawal which leaves the individual more susceptible to withdrawal effects, including delirium tremens and seizures. We examined the effects of two alcohol-dosing paradigms on the rate of kindling. Levels of ethanol below 300 mg/dl clearly did not accelerate the rate of kindling nor appear to affect the afterdischarge threshold, in spite of the fact that these levels have produced short-term withdrawal symptoms in other studies. Higher levels appeared to accelerate kindling. In the second experiment kindling was accelerated in animals with blood alcohol levels between 300 and 500 mg/dl. These findings are discussed in relation to clinical studies of alcohol withdrawal.

Narcolepsy: preliminary retrospective study of psychiatric and psychosocial aspects.

A review of the charts of 24 ambulatory male veterans with narcolepsy or narcolepsy/cataplexy showed an impressive number of psychiatric and psychosocial difficulties in these patients, such as poor adjustment to the illness, high unemployability, and disturbed intrafamily relationships. Sixteen of the patients had psychiatric disorders according to DSM-III criteria, including adjustment disorder, major depressive episode, alcohol dependence, and personality disorder, but excluding any type of psychotic disorder. The study suggests that narcoleptic/cataplectic patients have more of these difficulties than narcoleptic patients do.

Abnormal cortisol suppression in bipolar patients with simultaneous manic and depressive symptoms.

The authors studied the cortisol response to 1 mg of dexamethasone in 10 patients who simultaneously manifested manic and depressive symptoms. All patients showed some evidence that normal cortisol suppression was lacking. When 3 patients were randomly retested after recovery, the results suggested the normalization of suppression.