Biomedical subjects

K M Malone

Publications and source records attributed to K M Malone.

32 records · Page 2Linked to original sources

PubMed1997

Blunted serotonin response to fenfluramine challenge in premenstrual dysphoric disorder.

OBJECTIVE: Indirect evidence suggests that abnormalities in serotonergic function may be involved in the pathogenesis of premenstrual dysphoric disorder. The goal of this study was to test the hypothesis of serotonergic deficiency in premenstrual dysphoric disorder by measuring the prolactin response to fenfluramine. METHOD: The authors administered the serotonin-releasing drug dl-fenfluramine in a placebo-controlled protocol to nine women with premenstrual dysphoric disorder and 11 healthy female volunteers in the luteal phase of the menstrual cycle. RESULTS: Compared to the normal subjects, the women with premenstrual dysphoric disorder had a significantly blunted prolactin response to fenfluramine. CONCLUSIONS: Premenstrual dysphoric disorder appears to be associated with serotonergic deficiency.

Adult↗

PubMed1997

Low use of neuroleptic drugs in the treatment of psychotic major depression.

OBJECTIVE: The adequacy of pharmacologic treatment received by patients with psychotic major depression was evaluated. METHOD: The authors systematically assessed the pharmacotherapy received by 187 depressed patients before initiation of ECT and compared the medication trials of those with psychotic (N = 53) and nonpsychotic (N = 134) depression. RESULTS: Despite a median of four medication trials and median index episode duration of 20 weeks, only two (4%) of the patients with psychotic depression received at least one adequate pharmacotherapy trial. In contrast, 70 (52%) of the patients with nonpsychotic depression received at least one adequate trial. Twenty-five (47%) of the patients with psychotic depression received either no neuroleptic treatment (N = 11) or treatment for less than 3 weeks (N = 14). Only eight (15%) received a daily neuroleptic dose higher than 200 mg of chlorpromazine equivalents. CONCLUSIONS: These findings suggest that many patients with psychotic major depression referred for ECT receive inadequate pharmacotherapy because of either the absence or the inadequate use of neuroleptic medication.

Antidepressive Agents↗

PubMed1997

Suicide: risk factors and prevention in refractory major depression.

The literature regarding risk factors for suicidal behavior in the context of major depressive episode is reviewed. An organized framework for prevention strategies is provided. Risk factors for suicide in major depression can be organized according to whether their effect is on the threshold for suicidal acts or whether they serve mainly as triggers or precipitants of suicidal acts. For patients sufficiently depressed to present for evaluation and treatment, severity of depression is a poor guide to risk for suicidal acts. The best predictors relate to the threshold or predisposition to suicidal acts in response to major depression. Although available literature on suicidal behavior focuses on major depression in general, the findings may be usefully applied in refractory depression. Guidelines for assessment and management of suicidal behavior in major depression are offered.

Antidepressive Agents↗

PubMed1996

Suicidal behavior in patients with major depression and comorbid personality disorders.

We investigated the relationship of DSM-III-R personality disorder (PD) diagnoses and traits to suicidal behavior in patients with Major Depressive Disorder (MDD). Axis I and Axis II criteria and suicidal behavior were assessed using structured interviews of 102 psychiatric inpatients. Subjects with comorbid MDD and Borderline PD (BPD: n = 30) were more likely than other patients to have a history of multiple suicide attempts, and were equally likely to have made a highly lethal attempt. Number of BPD and other Cluster B (dramatic/erratic) criteria were better predictors of past suicidal behavior than were depressive symptoms. We conclude that patients with BPD symptomatology are at risk for serious suicide attempts. Moreover, severity of comorbid Cluster B PD psychopathology should be considered when assessing suicide risk in MDD patients even in those without a PD diagnosis.

Adolescent↗

PubMed1996

Attempted suicide characteristics and cerebrospinal fluid amine metabolites in depressed inpatients.

BACKGROUND: Serotonin abnormalities have been reported in the brain of suicide victims. Evidence of a serotonin deficiency in suicide attempters is less consistent. We hypothesized that a serotonin deficiency may be present in suicide attempters whose attempt behavior more closely approximates completed suicide. METHOD: Sixty-seven (67) drug-free depressed inpatients (46 suicide attempters, 21 nonattempters) underwent research clinical assessments and a lumbar puncture. Cerebrospinal fluid (CSF) monoamine metabolites were assayed. Degree of medical damage and intent of the most recent suicide attempt were rated. RESULTS: CSF amine metabolites did not differentiate suicide attempters as a group from nonattempters. However, reduced serotonergic activity, as indicated by lower levels of CSF-5-hydroxyindoleacetic acid (5-HIAA) was associated with a history of planned suicide attempts and with suicide attempts that resulted in greater medical damage. Other monoamine metabolites did not correlate with seriousness of suicidal behavior, except for low CSF homovanillic acid and higher medical damage. No correlation was found with violent method. CONCLUSIONS: Planned and more medically damaging suicide attempts appear to be associated specifically with low serotonergic activity and, therefore, resemble completed suicide both behaviorally and biochemically. It remains to be determined whether low levels of CSF 5-HIAA can predict greater medical damage in future suicide attempts.

Adult↗

PubMed1996

Positron emission tomographic imaging of serotonin activation effects on prefrontal cortex in healthy volunteers.

Serotonergic system abnormalities have been implicated in major depression, suicide, violence, alcoholism, and other psychopathologies. The prolactin response to fenfluramine has been widely used as a neuroendocrine probe to study brain serotonin responsivity. We have extended this methodology by using the positron emission tomography (PET) 18F-fluorodeoxyglucose (18FDG) method to examine the fenfluramine-induced changes in regional cerebral glucose metabolism (rCMRglu), an indicator of changes in regional neuronal activity. We report results on 16 healthy controls, each of whom underwent two PET studies. One group of six subjects had a placebo on day 1 and a single 60 mg oral dose of fenfluramine on day 2. The second group, of 10 subjects, was tested on two consecutive occasions without drug or placebo. Data were analyzed for significant rCMRglu changes on day 2 vs day 1 using the statistical parametric mapping method (p < 0.01). Subjects who did not receive drugs showed no statistically significant areas of rCMRglu increase or decrease on day 2 versus day 1. In contrast, the group that received fenfluramine showed significant fenfluramine-induced responses. Areas of rCMRglu increases involved mainly the left prefrontal and left temperoparietal cortex. Within the prefrontal cortex, two major areas of rCMRglu increase included, first, an area centered on the anterior cingulate and, second, an area in the lateral prefrontal cortex involving principally the inferior, middle, and superior frontal gyri. Some decreases in rCMRglu were observed, principally in the right hemisphere. This PET-fenfluramine paradigm is a potentially useful method for studying abnormalities of serotonin function in the prefrontal cortex.

Adult↗

PubMed1996

Demonstration in vivo of reduced serotonin responsivity in the brain of untreated depressed patients.

OBJECTIVE: For over 25 years, it has been hypothesized that major depression is due to a deficiency of available serotonin or subsensitivity of key serotonin receptors in relevant brain regions. Direct evidence supporting this hypothesis has been lacking because of the difficulty in studying regional brain serotonergic function. The authors have developed a method for visualizing in vivo regional brain responses to serotonin release by comparing regional brain glucose metabolism after administration of the serotonin-releasing drug dl-fenfluramine, relative to placebo. METHOD: Results with healthy subjects (N = 6) were compared to those obtained with drug-free inpatients with moderately severe major depression (N = 6). RESULTS: Healthy subjects had several areas of statistically significant increases in metabolism, mostly in the left prefrontal and temporoparietal cortex, and areas of decreased metabolism, such as in the right prefrontal cortex. In contrast, the depressed patients had no areas of increase or decrease in metabolism, differing significantly from healthy subjects. Results with patients resembled those with healthy subjects (N = 10) who were scanned twice without active drug on either occasion. CONCLUSIONS: This study provides the first direct visualization of blunted regional brain responses to serotonin release in the brain of patients with major depression, a finding that supports the hypothesis of impaired serotonergic transmission in depression.

Adult↗

PubMed1996

Resistance to antidepressant medications and short-term clinical response to ECT.

OBJECTIVE: Traditionally, it has been widely assumed that the likelihood of response to ECT is independent of the adequacy of previous treatment with antidepressant medications. However, recent research has raised the possibility that medication-resistant patients with depression have a poorer clinical ECT outcome than patients who have not failed previous adequate medication trials. METHOD: Medication resistance of 100 patients with primary, unipolar, nonpsychotic major depression was evaluated during the index episode with the Antidepressant Treatment History Form. Patients were recruited and treated with ECT at three sites; standardized ECT and clinical assessment procedures were used. Clinical outcome was assessed immediately and 1 week after completion of the ECT course. RESULTS: Patients who previously had failed one or more adequate antidepressant medication trials were less likely to respond to subsequent ECT than patients not known to be medication resistant. This finding held within each study site, whether clinical response was assessed categorically or in terms of the magnitude of symptomatic improvement and after the authors accounted for other potential predictors of clinical outcome. Resistance to heterocyclic antidepressants predicted poorer outcome after ECT, while resistance to selective serotonin reuptake inhibitors and monoamine oxidase inhibitors did not show significant predictive relations. CONCLUSIONS: While a substantial percentage of medication-resistant patients respond to ECT, clinical outcome in this group is inferior to that of patients without established medication resistance. The predictive power of medication resistance is generalizable across diverse clinical settings, particularly for heterocyclic antidepressants, which perhaps suggests an overlap in the mechanisms of actions of ECT and this medication class.

Aged↗

PubMed1996

Prolactin response to fenfluramine and suicide attempt lethality in major depression.

BACKGROUND: This study employed an alternative method for assessing serotonergic function to further evaluate our finding that cerebrospinal fluid (CSF) 5-hydroxyindole acetic acid (5-HIAA) in depressed suicide attempters with a lifetime history of higher lethality suicide attempts is significantly lower compared to depressed patients who have a history of low lethality suicide attempts. METHOD: We used dl-fenfluramine (60 mg) as a neuroendocrine probe to examine the serotonin system in 41 in-patients with a DSM-III-R major depressive episode, divided into two groups on the basis of a lifetime history of high or low lethality suicide attempts. Fenfluramine challenge test outcome was defined as the maximum prolactin response in the five hours following fenfluramine. RESULTS: Patients with a history of a higher lethality suicide attempt had a significantly lower prolactin response to fenfluramine, even when controlling for cortisol, age, sex, weight, comorbid cluster B personality disorder, pharmacokinetic and menstrual cycle effects. CONCLUSIONS: The data provide further support for the hypothesis that serotonin dysfunction is associated with more lethal suicide attempts, and suggests that higher lethality suicide attempters or failed suicides resemble completed suicides both behaviourally and biochemically.

Adult↗

PubMed1995

Major depression and the risk of attempted suicide.

We examined the risk of attempted suicide in 100 inpatients during a major depressive episode. We hypothesized that patients who attempt suicide have a vulnerability for suicidal behavior independent of severity or duration of depression, manifested by suicide attempts early in the course of a depressive episode. The first 3 months after the onset of an MDE and the first 5 years after the lifetime onset of major depressive disorder represented the highest-risk period for attempted suicide, independent of the severity or duration of depression. Familial, genetic, early-life loss experiences and comorbid alcoholism may be causal factors.

Adolescent↗

PubMed1995

Blunted serotonergic responsivity in depressed inpatients.

We found a 38% lower maximal prolactin response to an oral challenge dose of 60 mg of dl-fenfluramine relative to placebo in younger (< 30 years) depressed inpatients compared with the response in age-matched healthy controls (p < .03). Severity of depression did not correlate with prolactin response. Prolactin responses in older depressed patients (> or = 30 years) did not differ from older controls. Younger depressed patients differed from older depressed patients in terms of earlier age of onset of first lifetime episode of major depression, greater degree of suicidal intent during a recent suicide attempt, double the level of hopelessness on admission to hospital, and a higher rate of comorbid borderline personality disorder. A blunted prolactin response to fenfluramine may be interpreted as evidence for reduced serotonergic function in younger depressed patients and may underlie their observed greater suicidality and hopelessness.

Administration, Oral↗

PubMed1995

Clinical assessment versus research methods in the assessment of suicidal behavior.

OBJECTIVE: This study examined how accurately routine inpatient clinical assessments documented a history of overt suicidal behavior in inpatients with a diagnosis of major depressive episode. Secondary questions involved the exploration of possible factors influencing the quality of routine clinical documentation of suicidal behavior, such as lethality of attempts, axis II comorbidity, and presence of recent suicidal behavior. METHOD: Hospital records for 50 patients, known to have a history of suicidal behavior on the basis of research ratings, were reviewed to assess reporting of the number of lifetime suicide attempts, suicidal ideation and planning behavior, most medically lethal suicide attempt, and family history of suicidal behavior. These measures of suicidal behavior were compared with a comprehensive research assessment, completed concurrently and independently. RESULTS: At admission clinicians failed to document a history of suicidal behavior in 12 of 50 patients identified by research assessment as depressed and as having attempted suicide. Fewer total suicide attempts were clinically reported than in research data. Documentation of suicidal behavior was least accurate in the physician discharge summary and was most accurate on hospital intake assessment, which employed a semistructured format for recording clinical information including suicidal behavior. CONCLUSIONS: A significant degree of past suicidal behavior is not recorded during routine clinical assessment, and the use of semistructured screening instruments may improve documentation and detection of lifetime suicidal behavior. The physician discharge summary must accurately document suicidal behavior, since it best identified a high-risk population for out-patient clinicians responsible for follow-up.

Adolescent↗

PubMed1994

Fixed low-dose versus adjusted higher-dose warfarin following orthopedic surgery. A randomized prospective trial.

Orthopedic patients are at a high risk for developing venous thromboembolism, yet only a fraction of eligible patients receive anticoagulation prophylaxis after hospital discharge. This pilot study compared the efficacy of a fixed 2 mg/d dose of warfarin versus an adjusted higher dose of warfarin for 1 month after discharge to prevent the development of proximal leg deep venous thrombosis among recently discharged orthopedic patients. After standard inhospital treatment with adjusted higher-dose warfarin and a predischarge leg ultrasound to exclude deep venous thrombosis, 96 orthopedic patients were randomized just prior to discharge to either fixed low-dose (n = 49) or adjusted higher-dose warfarin (n = 47). At the 6-week follow-up evaluation, ultrasonographically confirmed, asymptomatic, proximal leg deep venous thrombosis occurred in two patients (4%). Both patients were randomized to the fixed low-dose group, although one remained on adjusted higher-dose warfarin throughout the trial. No patient in either group developed major bleeding complications. Further studies should be undertaken to further test fixed low-dose warfarin for venous thromboembolic prevention in high-risk orthopedic patients.

Female↗

PubMed1993

Fenfluramine challenge test as a predictor of outcome in major depression.

It has been reported that low pretreatment cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) levels may correlate with better clinical response to selective serotonin reuptake inhibitors (SSRI) compared to non-serotonergic antidepressant drugs. We examined the hypothesis that serotonergic system status, as measured by the prolactin (PRL) response to fenfluramine (FEN), may predict outcome in a heterogenous sample treated with various types of antidepressant treatment. Higher PRL response predicted a favorable outcome for males and females treated with either pharmacotherapy, psychotherapy [milieu therapy with or without cognitive behavior therapy (CBT)], or electroconvulsive therapy (ECT). All patients in the high PRL response group responded to antidepressant therapies. Patients receiving ECT had the highest proportion of treatment responders, the highest degree of treatment response, and, unlike drug or psychotherapy treatment, improved significantly whether in the high or low PRL response group. PRL response to a single dose fenfluramine challenge may be a useful predictor of response to pharmacological or psychotherapeutic treatments in major depression. By contrast, ECT is an effective short-term treatment independent of pretreatment serotonergic responsivity.

Adolescent↗