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Biomedical subjects

Linda L Carpenter

Publications and source records attributed to Linda L Carpenter.

At least 19 recordsLinked to original sources
PubMed2006

Temperament and hypothalamic-pituitary-adrenal axis function in healthy adults.

BACKGROUND: Traits such as behavioral inhibition and neuroticism have been linked to the development of mood and anxiety disorders. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, a manifestation of the stress response, is often seen in major depression and has also been demonstrated in animals and humans with inhibited temperaments. A recent study found HPA hyperactivity in adults with high levels of neuroticism. The present study investigated associations of temperament and HPA function in 31 healthy adults. METHODS AND MATERIALS: Subjects completed diagnostic interviews, questionnaires, and the dexamethasone-/corticotropin-releasing hormone (Dex/CRH) test. Temperament was assessed using the Tridimensional Personality Questionnaire (TPQ). RESULTS: Novelty Seeking was inversely related to plasma cortisol concentrations in the Dex/CRH test. Harm Avoidance and Reward Dependence were not significantly associated with cortisol responses in the Dex/CRH test. The results were not accounted for by psychiatric symptoms or a history of stress or childhood maltreatment. CONCLUSIONS: These findings are consistent with previous reports associating temperament factors with HPA axis hyperactivity. Further work is needed to replicate these observations and determine whether HPA axis dysfunction might account for some of the previously reported association of personality factors with mood and anxiety disorders.

Adolescent↗
PubMed2006

Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression.

BACKGROUND: Abnormalities in the hypothalamic pituitary adrenal axis have been implicated in the pathophysiology of psychotic major depression (PMD). Recent studies have suggested that the antiglucocorticoid, mifepristone might have a role in the treatment of PMD. The current study tested the efficacy of mifepristone treatment of the psychotic symptoms of PMD. METHODS: 221 patients, aged 19 to 75 years, who met DSM-IV and SCID criteria for PMD and were not receiving antidepressants or antipsychotics, participated in a double blind, randomized, placebo controlled study. Patients were randomly assigned to either 7 days of mifepristone (n = 105) or placebo (n = 116) followed by 21 days of usual treatment. RESULTS: Patients treated with mifepristone were significantly more likely to achieve response, defined as a 30% reduction in the Brief Psychiatric Rating Scale (BPRS). In addition, mifepristone treated patients were significantly more likely to achieve a 50% reduction in the BPRS Positive Symptom Scale (PSS). No significant differences were observed on measures of depression. CONCLUSION: A seven day course of mifepristone followed by usual treatment appears to be effective and well tolerated in the treatment of psychosis in PMD. This study suggests that the antiglucocorticoid, mifepristone, might represent an alternative to traditional treatments of psychosis in psychotic depression.

Adult↗
PubMed2006

Number of risk genotypes is a risk factor for major depressive disorder: a case control study.

BACKGROUND: The objective of the study was to determine the genetic basis of Major Depressive Disorder, and the capacity to respond to antidepressant treatment. An association study of 21 candidate polymorphisms relevant to monoamine function and the mechanism of antidepressant response was conducted in 3 phenotypically distinct samples: a group with chronic or recurrent depression unable to respond to antidepressants (non-responders) (n = 58), a group capable of symptomatic improvement with or without treatment (responders) (n = 39), and volunteer controls (n = 85). The responders and non-responders constituted a larger group of depressed subjects. METHODS: A candidate gene approach was employed to asses the genetics basis of Major Depressive Disorder. The genotypic frequencies of selected polymorphisms were compared between the controls and depressed subjects. To asses the genetics basis of the capacity to respond to antidepressant treatment, the responders were compared to the non-responders. Candidate genes were chosen based on functional studies and proximity to whole genome linkage findings in the literature. Risk genotypes were identified by previous functional studies and association studies. RESULTS: A statistically significant difference in genotype frequency for the SLC6A4 intron 2 VNTR was detected between the subjects with a history of depression and controls (p = 0.004). Surprisingly, a statistically significant difference was detected between responders and non-responders for the DRD4 exon III VNTR genotype frequencies (p = 0.009). Furthermore, a difference between the controls and depressed subjects as well as between the controls and non-responders was detected for the number and distribution of risk genotypes in each group. CONCLUSION: An association between several monoamine-related genes and Major Depressive Disorder is supported. The data suggest that the two depressive phenotypes are genetically different, inferring that the genetic basis for the capacity to respond to standard antidepressant treatment, and the genetic susceptibility to Major Depressive Disorder may be independent. In addition, a proof of concept is provided demonstrating that the number of risk genotypes may be an indication of susceptibility of major depressive disorder and the severity of the disorder.

Journal Article↗
PubMed2006

Elevated cerebrospinal fluid substance p concentrations in posttraumatic stress disorder and major depression.

OBJECTIVE: The authors tested the hypothesis that concentrations of the pain-transmitting neuropeptide substance P are elevated in the CSF of patients with major depression or posttraumatic stress disorder (PTSD), which have overlapping symptoms. The authors also sought to determine if CNS substance P concentrations change on provocation of symptoms in PTSD patients. METHOD: The authors measured CSF substance P concentrations in medication-free patients with either major depression or PTSD and in healthy comparison subjects. Next, using a within-subject, crossover design, the authors sampled CSF for 6 hours through an indwelling subarachnoid catheter in PTSD patients before, during, and after exposure to a 60-minute traumatic or neutral videotape stimulus. RESULTS: Both depressed and PTSD patients had significantly elevated basal CSF substance P concentrations. In the challenge study, marked increases in CSF substance P concentrations were found only after precipitation of PTSD symptoms. CSF substance P concentrations increased by 169% and 90.6% of baseline levels at 10 and 70 minutes, respectively, after the start of the traumatic videotape but changed by only 1.1% and -8.1% of baseline levels 10 and 70 minutes after the start of the neutral videotape. CONCLUSIONS: These results suggest that elevated CNS substance P concentrations are involved in both major depression and PTSD. The marked increase in CSF substance P concentrations during and after the symptom-provoking stimulus, but not after the neutral stimulus, implicates CNS release of substance P in the mechanism of acute PTSD symptoms. These data also reveal that CNS substance P responds acutely to psychological stress in humans.

Acute Disease↗
PubMed2006

Neurostimulation in resistant depression.

Drugs and psychotherapy are inadequate for relieving depressive symptoms in a substantial portion of severely depressed patients. In that patient group, neurostimulation techniques such as electroconvulsive therapy, transcranial magnetic stimulation, magnetic seizure therapy, vagus nerve stimulation and deep brain stimulation could be lifesaving therapies. Neurostimulation is a physical intervention that utilizes application of either electric current or a magnetic field to directly stimulate the brain or central nervous system. This article presents an overview of currently available neurostimulatory techniques for depression, including a review of their efficacy and safety. Further development and evaluation of non-pharmacological antidepressant therapies are needed, with the hope of improving treatment of refactory depression.

Antidepressive Agents↗
PubMed2006

Psychotic major depression: a benefit-risk assessment of treatment options.

Numerous studies in the past three decades have characterised 'psychotic major depression', a subtype of major depression which is accompanied by delusions or other psychotic features. Evidence from phenomenological and neurobiological investigations indicates that this is a unique disorder with clinical and biological characteristics that are distinct from those of nonpsychotic depression and from other psychotic disorders. Treatment studies have provided evidence of small placebo effects and good responses to electroconvulsive therapy or combination treatment with an antidepressant plus an antipsychotic agent. However, until recently, there were only a few small, prospective, double-blind, controlled trials investigating the efficacy of antidepressant-antipsychotic combination pharmacotherapy, yet this constitutes the currently accepted and most universally applied 'standard of care' for psychotic depression. Treatment guidelines have been based largely on uncontrolled investigations of electroconvulsive therapy and studies using tricyclic antidepressants and first-generation antipsychotic drugs, which are not frequently chosen as first-line agents today because of concerns regarding tolerability and risks. However, recent open-label studies and large controlled trials of newer antidepressants and antipsychotics have yielded very divergent results thus far, so that the best treatment approach remains elusive. This review discusses the phenomenology and treatment of psychotic depression with a focus on the benefits and risks of various treatment approaches. Problems with this literature are highlighted, and strategies for future research are suggested.

Antidepressive Agents↗
PubMed2006

Open-label tiagabine monotherapy for major depressive disorder with anxiety.

OBJECTIVE: Gamma-aminobutyric acid (GABA) plays a key role in the pathophysiology and treatment of depression and anxiety. Tiagabine, a selective GABA reuptake inhibitor (SGRI) that enhances normal GABA tone, was evaluated for its efficacy and safety in the treatment of depression comorbid with significant anxiety. METHOD: In this 8-week, single-center, open-label study, adults with DSM-IV-diagnosed major depressive disorder and significant anxiety (i.e., "anxious depression") received tiagabine monotherapy, initiated at 4 mg/day and titrated for optimum response as tolerated to a maximum dose of 20 mg/day. Symptoms, function, and adverse events were assessed at regular intervals. Patients were entered from April 2002 to February 2003. RESULTS: Nineteen patients entered the study and 15 met criteria for intent-to-treat analyses. Of those, 6 (40%) discontinued treatment and 9 (60%) completed the 8-week protocol. Tiagabine significantly improved depression, as shown by a reduction in mean +/- SD Hamilton Rating Scale for Depression scores from baseline (31.9 +/- 6.1) to endpoint (17.0 +/- 12.4; p = .002). Categorical response rate was 47% (N = 7). Tiagabine also significantly improved anxiety (Hamilton Rating Scale for Anxiety baseline score of 22.7 +/- 4.9 vs. endpoint score of 12.5 +/- 8.8; p = .002). The mean +/- SD final daily dose was 12.8 +/- 5.8 mg. The most commonly reported adverse events were dizziness, headache, and gastrointestinal upset/nausea. CONCLUSION: These results suggest the potential of the SGRI tiagabine in the treatment of depression with anxiety. Large, placebo-controlled trials are needed.

Adult↗
PubMed2006

Vagus nerve stimulation and deep brain stimulation for treatment resistant depression.

Neurostimulation techniques are potentially useful options for severely depressed patients who have failed trial after trial of medication and psychotherapy. Cervical VNS therapy for chronic or recurrent depression which does not resolve with pharmacotherapy was recently approved by the FDA. DBS for severe intractable depression has been studied in two pilot studies with very few patients to date. Further investigations are currently underway in order to more fully evaluate both of these neurostimulation therapies, with the hope of substantially improving the treatment of refractory depression.

Deep Brain Stimulation↗
PubMed2005

Service expectations and clinical characteristics of patients receiving psychiatric emergency services.

Previous studies suggest that patients use medical emergency departments for nonurgent care. However, relatively little has been published about the use of psychiatric emergency services. Eighty-two patients who visited the psychiatric emergency department in a free-standing psychiatric hospital during July 2003 participated in a self-report survey about patients' expectations. Almost all respondents had acute psychiatric needs on presentation to the psychiatric emergency department, and 45 (75 percent) had urgent needs that required inpatient or partial hospitalization. However, there was considerable mismatch between some patients' expectations and the types of services available. Patients' use of this psychiatric emergency department was generally consistent with the department's mission, but many respondents endorsed a need for a service that was not available, such as family therapy. These findings suggest the importance of efforts to educate the public about how to obtain mental health services.

Adolescent↗
PubMed2005

Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants.

BACKGROUND: Atomoxetine is a selective nor-epinephrine reuptake inhibitor currently approved for the treatment of attention-deficit/hyperactivity disorder. Other compounds that enhance synaptic norepinephrine have shown efficacy as antidepressant monotherapies and as augmentation agents. This case series study examined the role of atomoxetine in antidepressant augmentation. METHOD: Fifteen adult outpatients with primary DSM-IV Axis I depressive disorders received open-label atomoxetine augmentation following partial response or nonresponse to at least 8 weeks of standard antidepressant pharmacotherapy. Atomoxetine 40 mg/day was added to ongoing medication regimens and titrated according to clinical response. Atomoxetine was systematically offered to patients from July through October 2003. RESULTS: Eleven patients (73%) completed at least 6 weeks of atomoxetine augmentation. Mean endpoint dose was approximately 80 mg/day. Nine patients (60%) met criteria for positive categorical response. Inventory of Depressive Symptomatology-Self-Report scores decreased significantly from baseline to endpoint, and clinician ratings of social and occupational functioning increased. There were no significant changes in heart rate or blood pressure, and the most common side effect was activation. A modest but significant drop in body mass index was observed (p = .025), and a subset (6/15; 40%) of patients reported improved sexual function. CONCLUSION: More studies are warranted to evaluate the potential utility of atomoxetine for antidepressant augmentation.

Adrenergic Uptake Inhibitors↗
PubMed2004

Increased cerebrospinal fluid corticotropin-releasing factor concentrations during tryptophan depletion in healthy adults.

BACKGROUND: Brain serotonin neurotransmission and hypothalamic-pituitary-adrenal axis function are implicated in the pathophysiology of depression, and these systems interact in a reciprocal modulatory fashion. This study examined the effect of tryptophan depletion, which acutely reduces brain serotonin concentrations, on serial cerebrospinal fluid concentrations of corticotropin-releasing factor in healthy humans. METHODS: Five subjects completed a standard tryptophan depletion protocol, and four subjects participated in a comparison condition. Subjects underwent continuous sampling of cerebrospinal fluid via lumbar peristaltic pump. Concentrations of cerebrospinal fluid corticotropin-releasing factor were measured by radioimmunoassay. RESULTS: No mood changes were observed in either group. Tryptophan-depleted subjects exhibited significantly greater increases in corticotropin-releasing factor concentrations over time than subjects in the comparison condition. CONCLUSIONS: These findings highlight the potential importance of corticotropin-releasing factor and serotonin interactions and suggest that activation of corticotropin-releasing-factor-containing neurons could play a role in the emergence of mood symptoms following tryptophan depletion in vulnerable individuals.

Adult↗
PubMed2004

Effect of vagus nerve stimulation on cerebrospinal fluid monoamine metabolites, norepinephrine, and gamma-aminobutyric acid concentrations in depressed patients.

BACKGROUND: Vagus nerve stimulation (VNS) has shown promising antidepressant effects in treatment-resistant depression, but the mechanisms of action are not known. Cerebrospinal fluid (CSF) studies in epilepsy patients show that VNS alters concentrations of monamines and gamma-aminobutyric acid (GABA), neurotransmitter systems possibly involved in the pathogenesis of depression. METHODS: Twenty-one adults with treatment-resistant, recurrent, or chronic major depression underwent standardized lumbar puncture for collection of 12 mL CSF on three separate but identical procedure days during participation in the VNS D-02 clinical trial. All subjects remained on stable regimens of mood medications. Collections were made at baseline (2 weeks after surgical implantation but before device activation), week 12 (end of the acute-phase study), and week 24. Cerebrospinal fluid concentrations of norepinephrine (NE), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were determined with high-performance liquid chromatography. Concentrations of GABA were assayed with mass spectrometry. RESULTS: Comparison of sham versus active VNS revealed a significant (mean 21%) VNS-associated increase in CSF HVA. Mean CSF concentrations of NE, 5-HIAA, MHPG, and GABA did not change significantly. Higher baseline HVA/5-HIAA ratio predicted worse clinical outcome. CONCLUSIONS: Although several of the CSF neurochemical effects we observed in this VNS study were similar to those described in the literature for antidepressants and electroconvulsive therapy, the results do not suggest a putative antidepressant mechanism of action for VNS.

Adult↗
PubMed2004

Update on stress and depression: the role of the hypothalamic-pituitary-adrenal (HPA) axis.

Over the past 50 years, relationships between stress and the neurobiological changes seen in psychiatric disorders have been well-documented. A major focus of investigations in this area has been the role of the hypothalamic-pituitary-adrenal (HPA) axis, both as a marker of stress response and as a mediator of additional downstream pathophysiologic changes. This review examines the emerging literature concerning the relationship between stress, HPA axis function, and depression, as well as the role of early life stress as an important risk factor for HPA axis dysregulation. The more recent studies reviewed suggest that the prominence of HPA axis hyperactivity in adults with depressive and anxiety disorders may constitute a link between the occurrence of adversity in childhood and the development of adult psychopathology.

Adrenocorticotropic Hormone↗
PubMed2004

Cerebrospinal fluid interleukin (IL)-6 in unipolar major depression.

BACKGROUND: Previous studies have suggested that regulation of the proinflammatory cytokine interleukin (IL)-6 is abnormal in patients with major depression. This study was undertaken to determine whether IL-6 concentrations in cerebrospinal fluid (CSF) differ between depressed patients and healthy control subjects. METHODS: Lumbar puncture with a standardized procedure was performed on 18 drug-free patients meeting DSM-IV criteria for unipolar major depression and 26 age- and sex-matched healthy volunteers. CSF was assayed for IL-6 using a quantitative 'sandwich' enzyme immunoassay technique. RESULTS: Mean+/-S.D. CSF IL-6 levels did not differ between depressed (2.2+/-1.0 pg/ml) and healthy control (2.4+/-1.9 pg/ml) subjects. LIMITATIONS: This study had adequate power (0.8) to detect a large (d=0.88) effect size at alpha = 0.05. Although sample sizes were comparable to or larger than those of previous CSF studies, it is possible that a less robust difference between depressed and healthy subjects was not detected. CONCLUSIONS: These findings fail to support speculation that immune activation may be causally involved in the pathogenesis of depression.

Adolescent↗
PubMed2004

Cerebrospinal fluid corticotropin-releasing factor and perceived early-life stress in depressed patients and healthy control subjects.

Previous studies have reported elevated concentrations of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF) in patients with major depression. Elevations of CSF CRF have also been reported in adult laboratory animals exposed to the stress of brief maternal deprivation or maternal neglect in the neonatal or preweaning period. The present study was designed to determine whether major depression and a history of perceived early adversity in childhood are independently associated with elevated CSF CRF concentrations in adults. In this case-control study, 27 medication-free adults with major depression and 25 matched controls underwent standardized lumbar puncture for collection of a single CSF sample at 1200. Subjects provided data about significant adverse early-life experiences and rated their global perceived level of stress during pre-school and preteen years on a six-point Likert scale. The mean difference in CSF CRF between depressed patients and controls did not reach statistical significance. In a regression model, perceived early-life stress was a significant predictor of CSF CRF, but depression was not. Perinatal adversity and perceived adversity in the preteen adversity years (ages 6-13 years) were both independently associated with decreasing CSF CRF concentrations. The relationship observed between perceived early-life stress and adult CSF CRF concentrations in this study closely parallels recent preclinical findings. More work is needed to elucidate the critical nature and timing of early events that may be associated with enduring neuroendocrine changes in humans.

Adult↗