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Biomedical subjects

R C Shelton

Publications and source records attributed to R C Shelton.

At least 19 recordsLinked to original sources
PubMed2002

Noradrenergic antidepressants: does chronic treatment increase or decrease nuclear CREB-P?

Chronic administration of noradrenergic antidepressants causes a desensitization of the beta adrenoceptor coupled adenylate cyclase system. In the present studies, we attempted to answer the question of whether or not this deamplification is reflected beyond the second messenger system. Nuclear CREB-P was determined in frontal cortex of rats following acute and chronic administration of desipramine (DMI) or reboxetine and in human fibroblasts following incubation for 48 hours with DMI, reboxetine or venlafaxine. Nuclear CREB-P in the frontal cortex was significantly decreased following chronic administration of DMI or reboxetine. Moreover, incubation of human fibroblasts with DMI or reboxetine, but not with venlafaxine, caused a highly significant reduction in nuclear CREB-P suggesting that the noradrenergic antidepressants exert direct effects beyond beta adrenoceptors. The results are consistent with the view that chronic treatment with antidepressants causes a net deamplification of the norepinephrine mediated signal transduction cascade which might "normalize" the increased noradrenergic activity evident in major depression.

Animals↗
PubMed2001

Effectiveness of St John's wort in major depression: a randomized controlled trial.

CONTEXT: Extracts of St John's wort are widely used to treat depression. Although more than 2 dozen clinical trials have been conducted with St John's wort, most have significant flaws in design and do not enable meaningful interpretation. OBJECTIVE: To compare the efficacy and safety of a standardized extract of St John's wort with placebo in outpatients with major depression. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled clinical trial conducted between November 1998 and January 2000 in 11 academic medical centers in the United States. PARTICIPANTS: Two hundred adult outpatients (mean age, 42.4 years; 67.0% female; 85.9% white) diagnosed as having major depression and having a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 20. INTERVENTION: Participants completed a 1-week, single-blind run-in of placebo, then were randomly assigned to receive either St John's wort extract (n = 98; 900 mg/d for 4 weeks, increased to 1200 mg/d in the absence of an adequate response thereafter) or placebo (n = 102) for 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was rate of change on the HAM-D over the treatment period. Secondary measures included the Beck Depression Inventory (BDI), Hamilton Rating Scale for Anxiety (HAM-A), the Global Assessment of Function (GAF) scale, and the Clinical Global Impression-Severity and -Improvement scales (CGI-S and CGI-I). RESULTS: The random coefficient analyses for the HAM-D, HAM-A, CGI-S, and CGI-I all showed significant effects for time but not for treatment or time-by-treatment interaction (for HAM-D scores, P<.001, P =.16, and P =.58, respectively). Analysis of covariance showed nonsignificant effects for BDI and GAF scores. The proportion of participants achieving an a priori definition of response did not differ between groups. The number reaching remission of illness was significantly higher with St John's wort than with placebo (P =.02), but the rates were very low in the full intention-to-treat analysis (14/98 [14.3%] vs 5/102 [4.9%], respectively). St John's wort was safe and well tolerated. Headache was the only adverse event that occurred with greater frequency with St John's wort than placebo (39/95 [41%] vs 25/100 [25%], respectively). CONCLUSION: In this study, St John's wort was not effective for treatment of major depression.

Adult↗
PubMed2001

Serum thyrotropin concentrations and bioactivity during sleep deprivation in depression.

BACKGROUND: One night of sleep deprivation induces a brief remission in about half of depressed patients. Subclinical hypothyroidism may be associated with depression, and changes in hypothalamic-pituitary-thyroid function may affect the mood response to sleep deprivation. We wished to define precisely the status of the hypothalamic-pituitary-thyroid axis of depressed patients during sleep deprivation and the possible relationship of hypothalamic-pituitary-thyroid function to the mood response. METHODS: We studied 18 patients with major depressive disorder and 10 normal volunteers. We assessed mood before and after sleep. We measured serum thyrotropin every 15 minutes during the night of sleep deprivation, thyrotropin bioactivity, the thyrotropin response to protirelin the next afternoon, and other indexes of hypothalamic-pituitary-thyroid function. To determine if the changes were limited to the hypothalamic-pituitary-thyroid axis, we measured serum cortisol, which also has a circadian secretory pattern. RESULTS: Nocturnal serum thyrotropin concentrations were consistently higher in responders, entirely because of elevated levels in the women reponders. Responders had exaggerated responses to protirelin the next afternoon. The bioactivity of thyrotropin in nonresponders was significantly greater than in responders (F(1,8. 99) = 7.52; P =.02). Other thyroid indexes and serum cortisol concentrations were similar among groups. CONCLUSIONS: Depressed patients have mild compensated thyroid resistance to thyrotropin action, not subclinical autoimmune primary hypothyroidism. Sleep deprivation responders compensate by secreting more thyrotropin with normal bioactivity; nonresponders compensate by secreting thyrotropin with increased bioactivity.

Adult↗
PubMed2001

Cross-talk between PKA and PKC in human fibroblasts: what are the pharmacotherapeutic implications?

BACKGROUND: The present study was designed to confirm or refute in human fibroblasts the hypothesized cross-talk elicited via neurotransmitter transduction cascades at the level of protein kinase mediated phosphorylation of the nuclear transcription factor CREB. METHODS: Human fibroblasts from normal control subjects were subcultured and incubated at confluency after five growth passages with isoproterenol (stimulation of PKA mediated phosphorylation) and/or phorbol 12-myristate 13-acetate (PMA) (stimulation of PKC mediated phosphorylation) followed by the determination of nuclear CREB-P by immunoblotting, enhanced chemiluminescence and quantitation of the autoradiograms by laser densitometry. RESULTS: Using the nuclear transcription factor CREB as a target, both the activation of the cyclic AMP-PKA pathway by isoproterenol and the activation of the PKC pathway by PMA caused phosphorylation of nuclear CREB. This phosphorylation is additive in nature and appears to occur at the same molecular site, serine133 of CREB. CONCLUSIONS: The present results in human fibroblasts demonstrate that the hypothesized cross-talk at the level of protein kinase mediated phosphorylation of transcription factors is no longer hypothetical. Since it is the phosphorylation of nuclear CREB that determines its dimerization and transcriptional activation of programs of CRE containing genes, the results suggest that this convergence of the neurotransmitter signals may be the critical mechanism in gene expression following the administration of antidepressant drugs that affect noradrenergic, serotonergic or both transduction cascades. The results may also provide a rationale for the apparent superior clinical efficacy of dual uptake inhibitors.

Activating Transcription Factor 2↗
PubMed2001

A novel augmentation strategy for treating resistant major depression.

OBJECTIVE: Treatment-resistant depression is a significant public health concern; drug switching or augmentation often produce limited results. The authors hypothesized that fluoxetine could be augmented with olanzapine to successfully treat resistant depression. METHOD: An 8-week double-blind study was conducted with 28 patients who were diagnosed with recurrent, nonbipolar, treatment-resistant depression without psychotic features. Subjects were randomly assigned to one of three groups: olanzapine plus placebo, fluoxetine plus placebo, or olanzapine plus fluoxetine. RESULTS: Fluoxetine monotherapy produced minimal improvement on various scales that rate severity of depression. The benefits of olanzapine monotherapy were modest. Olanzapine plus fluoxetine produced significantly greater improvement than either monotherapy on one measure and significantly greater improvement than olanzapine monotherapy on the other measures after 1 week. There were no significant differences between treatment groups on extrapyramidal measures nor significant adverse drug interactions. CONCLUSIONS: Olanzapine plus fluoxetine demonstrated superior efficacy for treating resistant depression compared to either agent alone.

Ambulatory Care↗
PubMed2001

Can recovery from depression be achieved?

Even though a variety of treatments are available for depression, many patients experience an incomplete response, resulting in chronic functional impairment. The authors present a therapeutic heuristic that derives, in part, from a body of research that suggests that symptoms of mood disorders can be separated into three distinct components: somatic anxiety, which is most prominent in anxiety disorders, such as panic; anhedonia or low positive affect, which is most specific to depression; and general distress, which is present with both anxiety and depressive disorders. General distress and somatic anxiety appear to be significantly modulated by serotonin, and serotonergic drugs may exert their effects most significantly on these symptoms. On the other hand, positive affect, the dimension of reward-oriented motivation and enjoyment, appears to be most dependent on dopamine and, indirectly, norepinephrine. Thus a theoretical heuristic can be derived on the basis of the predominance of residual symptoms. Serotonergic agents would be chosen for monotherapy or augmentation for symptoms of distress. Alternatively, catecholaminergic drugs would be the first choice for anhedonia and decreased motivation.

Antidepressive Agents↗
PubMed2001

Detection of an mRNA polymorphism by differential display.

Differential Display (DD) technology was utilized to compare programs of gene expression in primary cultures of human skin fibroblasts from normal volunteers and patients diagnosed with melancholic depression. Polymorphic transcripts of a single gene differing by one tandem repeat sequence of four nucleotides (TGAT) in the 3' noncoding region were detected.

3' Untranslated Regions↗
PubMed2001

Mechanisms of action in the treatment of anxiety.

Anxiety and depressive disorders share many features, suggesting a common set of physiologic substrates. Recent research has indicated that mood can be categorized into 3 components by factor analysis: (1) somatic anxiety (a factor relatively specific to panic disorder), (2) anhedonic depression (which includes symptoms related to motivation and enjoyment and found to be specific to depression), and (3) general distress (a factor that cuts across all depressive and anxiety disorders studied). Antidepressant drugs, particularly serotonin reuptake inhibitors and serotonin receptor modulators, are effective for a wide variety of anxiety and depressive disorders. The impact on both anxiety and depression may be a result of an effect on a common set of physiologic targets relevant to the general distress dimension. At a cellular level, the antidepressants target components of the stress-adaptation system in brain, which may explain these common effects. On the other hand, there appear to be differences in the relative impact of serotonergic and noradrenergic drugs on the spectrum of distress and motivational symptoms. Basic research and clinical research suggest that serotonergic agents may be preferentially effective for symptoms of general distress, whereas catecholaminergic agents may target anhedonic depression symptoms.

Affect↗
PubMed2000

Human fibroblasts as a relevant model to study signal transduction in affective disorders.

BACKGROUND: Previous studies have demonstrated a blunted beta adrenoceptor-linked protein kinase A (PKA) response in the 900xg supernatant fraction of human fibroblasts cultured from patients with major depression. RESULTS: Results of the present studies demonstrate a significant reduction in the B(max) value of [3H]cyclic AMP binding to the regulatory subunit of PKA in the supernatant fraction of fibroblasts from patients with major depression with no change in the K(d) values. The data are consistent with the previous observation that the maximal stimulation of PKA by cyclic AMP is reduced without a change in the EC(50) value. The blunted beta adrenoceptor-mediated PKA response in fibroblasts from patients with major depression is reflected in a significant reduction in the isoproterenol-stimulated phosphorylation of the nuclear transcription factor CREB. Both, the isoproterenol-mediated phosphorylation of nuclear CREB and the activation of the stably transfected luciferase reporter gene, pAD neo2-C12-BGL, were inhibited by the beta(2) adrenoceptor antagonist ICI 118551, thus indicating that the gene activating action of isoproterenol in human fibroblasts is mediated via the beta(2) adrenoceptor cascade. The low EC(50) value of 1 nM isoproterenol for activation of gene expression in stably transfected human fibroblasts appears to be a reflection of the amplification mechanism occurring via the beta adrenoceptor-cyclic AMP-PKA-CREB transduction cascade. CONCLUSIONS: The results support the notion that human fibroblasts represent a relevant model for studying processes of signal transduction in patients with affective disorders.

Adrenergic beta-Agonists↗
PubMed2000

Cellular mechanisms in the vulnerability to depression and response to antidepressants.

As a testable heuristic, the concept of stress response and adaptation is highly appealing, and the support for the concept is strong. This explanatory model of depression may account for hitherto apparently discordant facts--contradictory symptoms, antidepressant drugs that act on differing systems, facilitation of antidepressant response by augmentation, and response to psychotherapy and pharmacotherapy. This article has focused narrowly on specific cellular elements of the stress-adaptational mechanisms, including the AC-PKA and PLC-PKC transductional cascades, together with specific response elements, such as the HPA axis, BDNF, and NMDA receptors; however, other important mechanisms, including specific receptor subtypes (e.g., 5-HT1A and NE alpha 2), transmitter systems (e.g., acetylcholine and depamine), and hormones (e.g., thyroid and growth hormones and prolactin), which may be important, have not been discussed. As the complex interactions of these systems gradually yield to investigation, not only will new treatments be developed, but better matching of treatment to patient may become an achievable goal.

Antidepressive Agents↗
PubMed2000

Intracellular mechanisms of antidepressant drug action.

The action of antidepressant drugs on monoamines such as norepinephrine and serotonin has been described for three decades. However, more-recent research has looked beyond cell surface receptors to transductional cascades and gene expression. Antidepressant drug therapies seem to share several mechanisms involved in either activating the adenylyl cyclase-protein kinase A cascade or inhibiting the phospholipase C-protein kinase C mechanisms. These effects, ultimately, combine to regulate the expression of target genes. Several specific genes are known to be activated or inhibited by antidepressant therapies. Steady-state levels of mRNA for glucocorticoid and mineralocorticoid receptors, brain-derived neurotrophic factor and its receptor trkB, and preproenkephalin are enhanced, whereas those for corticotropin-releasing hormone, c-fos,N-methyl-D-aspartate receptor subunits, and nerve-growth factor 1A are reduced. New molecular genetic methods for identifying differentially expressed genes will aid in the development of targets for wholly new generations of antidepressant drug therapies.

Antidepressive Agents↗
PubMed1999

Treatment options for refractory depression.

A significant proportion of patients with depressive disorders do not experience a full response with antidepressant treatment. Fortunately, most eventually remit, even though the time to response may be significantly delayed in many patients. A variety of options exist to deal with these difficult clinical situations. Established strategies include switching to an antidepressant of an alternative class (e.g., tricyclic to a monoamine oxidase inhibitor [MAOI] or selective serotonin reuptake inhibitor [SSRI]), electroconvulsive therapy (ECT), and augmentation with lithium or thyroid hormone. Promising alternatives include combined serotonin and norepinephrine enhancement strategies (e.g., SSRI plus serotonin norepinephrine reuptake inhibitor [NSRI] or higher doses of venlafaxine or fluoxetine), steroid suppression therapy, augmentation with atypical antipsychotics, and psychotherapy.

Antidepressive Agents↗
PubMed1999

Mood-stabilizing drugs in depression.

Mood-stabilizing drugs including lithium, anticonvulsants, and antipsychotics have established effects in the management of bipolar disorder, especially in mania. However, these drugs also have been shown to be effective in depressed patients. For example, lithium is well established as an effective augmenting strategy with tricyclic antidepressants in refractory depression. This article will review a variety of effects of mood-stabilizing drugs in bipolar and unipolar depressed patients, which will include acute treatment, prevention of relapse and recurrence, and the management of refractory patients. The effects of antipsychotics (especially atypicals) and new research directions also will be reviewed.

Acute Disease↗
PubMed1997

The undertreatment of dysthymia.

BACKGROUND: Dysthymia is a chronic depressive condition that is quite prevalent. This condition can exact a significant toll on the general health and quality of life in the affected individual. Despite the frequency and consequences of dysthymia, however, the condition is often not diagnosed or treated. We present data on prior treatment from 410 patients with DSM-III-R dysthymia, primary type, early onset without concurrent major depression. METHOD: Axis I and II diagnoses were made by using the Structured Clinical Interviews for DSM-III-R, Patient Version (SCID-P) and SCID II for Personality Disorders. The Hamilton Rating Scale for Depression and the Clinical Global Impressions scale were also completed. Prior treatment was assessed, with special attention paid to previous antidepressant drug therapy and psychotherapy. RESULTS: Although the mean duration of dysthymia was about 30 years and almost half of the patients had previous episodes of major depression, only 41.3% had been treated with antidepressants and 56.1% with psychotherapy. A past history of major depression increased the frequency of prior antidepressant pharmacotherapy (45.7%) and psychotherapy (59.4%) compared with no history of major depression (36.8% and 40.9%, respectively). Comorbid personality disorder increased the likelihood of prior psychotherapy (70.7% vs. 49.6%) while having no effect on past pharmacotherapy. A history of substance abuse did not affect the history of antidepressant or psychotherapy treatment. In this study, dysthymia and psychosocial outcomes improved with sertraline and imipramine treatment. CONCLUSION: Dysthymic patients in this sample were significantly undertreated. Newer antidepressant agents may alter the potential for pharmacotherapy interventions in this vulnerable population.

1-Naphthylamine↗
PubMed1996

Beta-adrenoceptor-linked protein kinase A (PKA) activity in human fibroblasts from normal subjects and from patients with major depression.

Human fibroblasts from normal subjects and from patients with major depression are cultured and their beta-adrenoreceptor-cyclic AMP-protein kinase A (PKA) system characterized. The results indicate that the beta-adrenoreceptor-mediated activation of PKA in the 900 g supernatant fraction of human fibroblasts is mediated via beta-adrenoreceptors. The activation of PKA by isoproterenol is very rapid with maximal stimulation occurring at 5 seconds. The time course of PKA activation by isoproterenol in fibroblasts from patients with major depression is identical to that in fibroblasts from normal subjects but the magnitude of activation is significantly reduced in fibroblasts from patients with major depression. Dose-response curves on cyclic AMP mediated activation of PKA confirmed the previously reported reduction in activation of PKA in patients with major depression but demonstrated that this reduction occurs without a change in the EC50 values of cyclic AMP (approximately 20 nmol/L). The blunted beta-adrenoceptor-linked PKA responses in patients with major depression occur without a change in the expression of the PKA catalytic subunit C alpha. The studies suggest that the beta-adrenoceptor-coupled adenylate cyclase PKA system in human fibroblasts may represent a valid model to explore possible abnormalities in the fine tuning of the beta-adrenergic transduction cascade in patients with affective disorders.

Adrenergic beta-Agonists↗
PubMed1996

cAMP-dependent protein kinase activity in major depression.

OBJECTIVE: The author's intent was to evaluate the activity of the beta-adrenoceptor-linked, cAMP-dependent protein kinase (protein kinase A) in patients with major depression compared with a group of nondepressed volunteer subjects. METHOD: Skin fibroblast samples were obtained by 2-mm punch biopsy from 12 patients (11 were women) who had major depression diagnosed according to the Structured Clinical Interview for DSM-III-R and from 10 nondepressed volunteers (seven were women). Fibroblasts were cultured in Dulbecco's modified Eagle medium. Baseline and cAMP-stimulated activities of protein kinase A were determined in both particulate and supernatant fractions (900g). Linkage of the finding to beta adrenergic receptor function was evaluated by determination of protein kinase A activity after incubation of the confluent cultures for 30 minutes with 10 microM isoproterenol. RESULTS: There were significant differences between groups in the baseline and cAMP-stimulated phosphorylation in the supernatant fraction. Moreover, the attenuated protein kinase A response was accompanied by a blunted isoproterenol response. CONCLUSIONS: Patients with depression exhibit significantly less activity of beta-adrenoceptor-linked protein kinase A than do normal subjects. The reductions in protein kinase A activity support the significance of beta-receptor-mediated events in depression.

Adult↗
PubMed1995

Effects of a safe person on induced distress following a biological challenge in panic disorder with agoraphobia.

This study examined the effect of having a safe person present on artificially induced anxiety following a biological challenge among panic-disordered patients. Anxiety symptoms were induced using a 5.5% CO2-inhalation procedure. Panic patients underwent the inhalation procedure either in the presence or absence of their safe person. Nonanxious controls underwent the procedure without a safe person. Panic patients exposed to CO2 without their safe person present reported greater distress, a greater number of catastrophic cognitions, and a greater level of physiological arousal than did panic patients exposed with their safe person. The latter group did not differ from controls on most measures at postexposure. The attenuation of self-reported anxiety and catastrophic cognitions is consistent with the safety-signal theory and the cognitive model of panic, respectively. The results, however, are inconsistent with a biological model of panic.

Adult↗