Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary immunizing infections with LCM virus result in a transient depression of the in vitro proliferative responses of splenic lymphocytes to mitogens specifically reactive with T cells or B cells. This depression of lymphocyte function is the result of a virus-induced defect in an adherent, phagocytic cell population required for in vitro lymphocyte activation. Depressed responses persist for about 1 week after virus clearance and can be corrected by the addition of normal PEM or 2-ME to infected spleen cell cultures. Although the precise nature of this defect remains unclear, it is postulated that it is due to a productive infection of macrophages and their precursors that renders them dysfunctional. Secondary LCM virus infections do not result in depressed in vitro responses to mitogens, presumably because of rapid virus clearance and limited numbers of infected cells. Primary infections of immunologically immature mice, mice rendered functionally athymic, or mice treated with nonspecific immunosuppressive agents result in LCM virus persistence. Shortly after infection, these animals show a similar depression of immunologic reactivity that returns to normal as the virus carrier state becomes established. Despite virus persistence, few PEM from established LCM virus carrier mice contain viral antigens and these cells function normally. Thus, LCM virus-induced immunosuppression appears to reflect a subtle cytopathic effect of LCM virus replication that is not mediated by the virus-specific cell-mediated immune mechanisms responsible for acute LCM virus disease.
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PMID:Lymphocytic choriomeningitis virus-induced immunosuppression: a virus-induced macrophage defect. 95 45

This article describes the use of the NIMH prospective life-charting methodology (NIMH LCM-p) in the context of a formal double-blind, clinical trial and provides preliminary evidence of its reliability and validity. Subjects included in this report were 30 outpatients with bipolar I and II disorder who completed the first 2 years of a long-term maintenance study: 1 year on carbamazepine or lithium and a crossover to the other in the second year. The LCM-p follows the same types of guidelines and principles utilized in the previously described retrospective life-chart process, allowing for continuity of illness assessment prior and subsequent to study entry. In the LCM-p, daily ratings of severity of mood symptoms based on the degree of associated functional incapacity, provide a more detailed topography of manic and depressive fluctuations. Inter-rater reliability was examined by comparing the severity of daily LCM-p ratings assigned by two raters. In order to assess the validity, we correlated the LCM-p ratings with well-standardized scales, including Hamilton and Beck Depression Ratings, Young Mania Ratings and the Global Assessment Scale (GAS). The Kappa scores for inter-rater reliability demonstrated significant and satisfactory strength of agreement with no fall off over 14 days prior to the rating interview. Strong correlations were found: (1) between the LCM-p average severity for depression rating and the mean Hamilton Depression Rating (r = 0.86, p < .001), and the Beck Depression Inventory (r = 0.73, p < .001); 2) between the LCM-p average severity for mania rating and the Young Mania Rating Scale (r = 0.61, p < .001); and (3) between the LCM-p average severity and the GAS (r = -0.81, p < .001). These preliminary data suggest the reliability and validity of the NIMH-LCM-p in assessing manic and depressive episode severity. It also provides a useful continuous daily measure of affective illness-related symptom fluctuations that allows for detailed prospective assessment of frequency and pattern of illness, treatment response, and continuity with retrospective life chart assessments.
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PMID:Preliminary evidence of the reliability and validity of the prospective life-chart methodology (LCM-p). 936

This study examined the construct validity of the functional impairment scales of the National Institute of Mental Health (NIMH) prospective life-charting methodology (LCM-p(TM)). Twelve male and 28 female bipolar participants were recruited from the community through advertisements. Diagnoses of bipolar I or II were confirmed using Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Patients completed life charts for three consecutive months. At the end of each month, a trained clinician administered the Hamilton Depression Rating Scale (HDRS) and the Young Mania Rating Scale YMRS by telephone, followed by ratings using the Global Asessment of Functioning (GAF), and Clinical Global Impression (CGI) for bipolar disorder. Data was analyzed separately for each month (time 1, time 2, and time 3). Complete data was available for 35 participants at time 1, 36 at time 2 and 32 at time 3. Spearman correlations demonstrated significant convergent validity at times 2 and 3 for life chart measures of mania (HIGH) and CGI-mania, and at all three times for life chart depression (LOW) and CGI-depression, with corresponding discriminant validities. The GAF was positively correlated with HIGH and negatively correlated with LOW at time 2 and 3 only. HAM-D and LOW also showed convergent and discriminant validity for all three times. For HIGH and YMRS, however, there was a strong significant correlation at time 3 only. While the use of heterogeneous methods maximizes differences between measures, it also appears that bipolar patients are less consistent in reporting functional impairment due to mania than due to depression. The construct of life chart dysfunction due to mania does not consistently measure the same construct as similar clinician ratings of mania. Life chart dysfunction due to depression shows higher construct validity.
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PMID:Construct validity of life chart functioning scales for use in naturalistic studies of bipolar disorder. 1086 13

This study investigated the assets of the daily prospective National Institute of Mental Health Life-Chart Method (NIMH-LCM-p or LCM-p) for use in clinical trials in bipolar disorder. Fifty-two outpatients, who met DSM-III-R criteria for bipolar disorder, were randomly assigned in a double-blind design to an intended 1 year of treatment with lithium or carbamazepine, a crossover to the opposite drug in the second year, and then to a combination of both agents in the third year. For each patient, the LCM-p was initiated upon admission and was continued on a daily basis. Overall therapeutic effect for each phase (intended year) was assessed by using the Clinical Global Impressions-Bipolar Version (CGI-BP) scale. Kruskal-Wallis analysis of variance was used to examine the detailed course-of-illness variables derived from the LCM-p (e.g., percentage of time ill, average severity of illness, episodes per year, and mood switches per year) in relation to the global assessments of treatment response (CGI-BP). Most of the individual LCM-p-derived illness variables varied significantly (P <.05) as a function of global treatment response. Since global ratings of the degree of improvement can represent very different proportions of improvement in percentage of time ill, average severity of mania or depression, or frequency of manic and depressive episodes, the LCM-p provides the basis for a comprehensive description of both the illness course and the response to treatment. The LCM-p appears to have considerable utility in clinical trials of pharmacological and other interventions of bipolar disorder. It provides a detailed characterization of the severity, frequency, and duration of manic and depressive episodes, which facilitates the assessment of global improvement and allows for the quantification of separate components of the illness, which are or are not responsive to a given treatment.
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PMID:Utility of the daily prospective National Institute of Mental Health Life-Chart Method (NIMH-LCM-p) ratings in clinical trials of bipolar disorder. 1181 46

Chronic pain affects the life of millions of people. Current treatments have deleterious side effects. We have advanced a strategy for targeting protein interactions which regulate the N-type voltage-gated calcium (CaV2.2) channel as an alternative to direct channel block. Peptides uncoupling CaV2.2 interactions with the axonal collapsin response mediator protein 2 (CRMP2) were antinociceptive without effects on memory, depression, and reward/addiction. A search for small molecules that could recapitulate uncoupling of the CaV2.2-CRMP2 interaction identified (S)-lacosamide [(S)-LCM], the inactive enantiomer of the Food and Drug Administration-approved antiepileptic drug (R)-lacosamide [(R)-LCM, Vimpat]. We show that (S)-LCM, but not (R)-LCM, inhibits CRMP2 phosphorylation by cyclin dependent kinase 5, a step necessary for driving CaV2.2 activity, in sensory neurons. (S)-lacosamide inhibited depolarization-induced Ca influx with a low micromolar IC50. Voltage-clamp electrophysiology experiments demonstrated a commensurate reduction in Ca currents in sensory neurons after an acute application of (S)-LCM. Using constellation pharmacology, a recently described high content phenotypic screening platform for functional fingerprinting of neurons that uses subtype-selective pharmacological agents to elucidate cell-specific combinations (constellations) of key signaling proteins that define specific cell types, we investigated if (S)-LCM preferentially acts on certain types of neurons. (S)-lacosamide decreased the dorsal root ganglion neurons responding to mustard oil, and increased the number of cells responding to menthol. Finally, (S)-LCM reversed thermal hypersensitivity and mechanical allodynia in a model of postoperative pain, and 2 models of neuropathic pain. Thus, using (S)-LCM to inhibit CRMP2 phosphorylation is a novel and efficient strategy to treat pain, which works by targeting specific sensory neuron populations.
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PMID:(S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology. 2696 96