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Biomedical subjects

M A Demitrack

Publications and source records attributed to M A Demitrack.

At least 19 recordsLinked to original sources
PubMed2005

Clinical perspectives on antidepressant drug development: a critical discussion.

Improving our knowledge of the development, course and treatment of major depression is among the most pressing public health concerns in medicine. It is therefore satisfying to observe that critical advances have been made in our fundamental understanding of this illness and related conditions in the past several years. Among the areas of major change have been advances in nosology and disease classification, an improved understanding of risk factors for the development of major depression, advances in the standards of clinical practice, enhanced societal acceptance of patients with the disease and their treatment, and a substantial increase in our understanding of the underlying neurobiology of this common, disabling, and potentially lethal illness. It is sobering, in contrast, to observe that we still use methods of clinical study to explore new treatments with this condition that employ study designs and measurement tools which have changed very little over the past three decades. In this selective review, several key areas of interest relevant to the clinical development of antidepressants are examined. These areas point to some suggested topics for attention in the future.

Antidepressive Agents↗
PubMed2001

Abnormalities in response to vasopressin infusion in chronic fatigue syndrome.

Several neuroendocrine studies have suggested hypoactivation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. One possible determinant of this neuroendocrine abnormality, as well as the primary symptom of fatigue, is reduced hypothalamic secretion of corticotropin-releasing hormone (CRH). Because CRH and vasopressin secreted from the hypothalamus act synergistically at the pituitary to activate ACTH secretion, the ACTH response to peripheral infusion of vasopressin can provide an indirect measure of hypothalamic CRH secretion. We measured the ACTH and cortisol response to a one hour infusion of arginine vasopressin in 19 patients with chronic fatigue syndrome and 19 age and sex matched healthy volunteers. Patients with chronic fatigue syndrome had a reduced ACTH response to the vasopressin infusion and a more rapid cortisol response to the infusion. These results provide further evidence of reduced hypothalamic CRH secretion in patients with chronic fatigue syndrome.

Adrenocorticotropic Hormone↗
PubMed2000

The impact of restrictive entry criterion during the placebo lead-in period.

In the study of depression, most randomized clinical trials have design features that attempt to sample from a stable patient population. One commonly used design feature is to require patients to maintain some minimum baseline symptom severity score during a placebo lead-in period. One intent of this design feature is to evaluate the behavior of patients prior to administration of active medication. If, during the lead-in period, patients do not maintain minimum symptom severity, the patients are excluded from the remainder of the study, the theory being that the excluded patients are not part of a stable patient population and hence are not likely to demonstrate efficacy of a truly effective treatment. This presentation investigates the effectiveness of a restrictive entry criterion and proposes an alternative explanation for what is usually defined as placebo response.

Antidepressive Agents↗
PubMed1999

Melatonin levels in women with fibromyalgia and chronic fatigue syndrome.

OBJECTIVE: Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are stress associated disorders mainly affecting women. FM is characterized primarily by widespread musculoskeletal pain, and CFS by profound debilitating fatigue, but there is considerable overlap of clinical symptoms between these 2 syndromes. Neuroendocrine abnormalities have been noted in both FM and CFS and desynchronization of circadian systems has been postulated in their etiology. The pineal hormone melatonin is involved in synchronizing circadian systems and the use of exogenous melatonin has become widespread in patients with FM and CFS. METHODS: We examined the characteristics and relationship of melatonin and cortisol levels in premenopausal women with FM (n = 9) or CFS (n = 8), compared to age and menstrual cycle phase matched controls. Blood was collected from an indwelling intravenous catheter every 10 min over 24 h, and plasma melatonin and cortisol were determined by radioimmunoassay at 60 and 10 min intervals, respectively. RESULTS: Night time (23:00-06:50) plasma melatonin levels were significantly higher in FM patients compared to controls (p<0.05), but there was no significant difference in melatonin levels between CFS patients and controls. No differences in the timing of cortisol and melatonin secretory patterns and no internal desynchronization of the 2 rhythms were found in either patient group, compared to controls. CONCLUSION: Raised plasma melatonin concentrations have been documented in several other conditions that are associated with dysregulation of neuroendocrine axes. Increased melatonin levels may represent a marker of increased susceptibility to stress induced hypothalamic disruptions. These data indicate that there is no rationale for melatonin replacement therapy in patients with FM and CFS.

Adolescent↗
PubMed1998

Evidence for and pathophysiologic implications of hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is characterized by profound fatigue and an array of diffuse somatic symptoms. Our group has established that impaired activation of the hypothalamic-pituitary-adrenal (HPA) axis is an essential neuroendocrine feature of this condition. The relevance of this finding to the pathophysiology of CFS is supported by the observation that the onset and course of this illness is excerbated by physical and emotional stressors. It is also notable that this HPA dysregulation differs from that seen in melancholic depression, but shares features with other clinical syndromes (e.g., fibromyalgia). How the HPA axis dysfunction develops is unclear, though recent work suggests disturbances in serotonergic neurotransmission and alterations in the activity of AVP, an important co-secretagogue that, along with CRH, influences HPA axis function. In order to provide a more refined view of the nature of the HPA dusturbance in patients with CFS, we have studied the detailed, pulsatile characteristics of the HPA axis in a group of patients meeting the 1994 CDC case criteria for CFS. Results of that work are consistent with the view that patients with CFS have a reduction of HPA axis activity due, in part, to impaired central nervous system drive. These observations provide an important clue to the development of more effective treatment to this disabling condition.

Fatigue Syndrome, Chronic↗
PubMed1998

Chronic fatigue syndrome and fibromyalgia. Dilemmas in diagnosis and clinical management.

There has been a resurgence of interest in recent years in both chronic fatigue syndrome and fibromyalgia. These perplexing and common clinical conditions are a source of significant patient morbidity and frame one of the more enduring dilemmas of contemporary Western medical thought, namely the ambiguous interface between mind and body. In this article, the current definitions are reviewed, and a framework for an emerging psychobiological model of these syndromes is presented. These issues are synthesized into a pragmatic approach to clinical management.

Behavior Therapy↗
PubMed1998

Outcome assessment and clinical improvement in panic disorder: evidence from a randomized controlled trial of fluoxetine and placebo. The Fluoxetine Panic Disorder Study Group.

OBJECTIVE: Although panic attacks account for only a portion of the morbidity of panic disorder and panic attack frequency assessments are unreliable, studies of drug efficacy in panic disorder have generally used reduction in panic attack frequency as the primary measure of improvement. The authors studied the efficacy of fluoxetine treatment in panic disorder and measured the relative contributions of changes in symptoms to overall improvement. METHOD: Patients with a diagnosis of panic disorder (N = 243) were randomly assigned to treatment with 10 or 20 mg/day of fluoxetine or placebo. Primary outcome measures were change in panic attack frequency and clinician-rated Clinical Global Impression improvement scores. Other assessments included a panic attack inventory, clinician-rated and patient-rated versions of the Panic and Phobic Disorder Change Scale, a phobia rating scale, the Hamilton Anxiety Rating Scale, the 21-item Hamilton Depression Rating Scale, and the Sheehan Disability Scale. Correlations were determined between outcomes in individual symptom domains and overall clinical outcome. RESULTS: Fluoxetine, particularly the 20-mg/day dose, was associated with more improvement than was placebo in patients with panic disorder across multiple symptom measures, including global improvement, total panic attack frequency, phobic symptoms, and functional impairment. Global improvement was most highly correlated with reductions in overall anxiety and phobic symptoms and least correlated with reduction in panic attacks. Fluoxetine treatment for panic disorder was well tolerated, with a safety profile consistent with that observed for fluoxetine in other disorders. CONCLUSIONS: These data provide support for the efficacy and safety of fluoxetine treatment in reducing panic attacks, phobic symptoms, anxiety, and depressive symptoms in patients with panic disorder. Reductions in panic attack frequency in subjects given either fluoxetine or placebo were less closely related to overall clinical improvement than reductions in phobic avoidance, anxiety, depressive symptoms, and functional impairment, suggesting that outcome measures in this disorder should be more broadly based.

Adult↗
PubMed1998

The problem of measurement error in multisite clinical trials.

The implementation of a multisite, randomized, clinical psychopharmacologic trial involves a substantial investment of time and effort on the part of all participants. Because of their complexity, such clinical trials present unique methodological and design challenges. Indeed, it is not uncommon for such studies to conclude with uninterpretable results, due in part to such methodological pitfalls. It has been suggested that clarification of such methodologic dilemmas is one of the most important challenges facing the future of industry-sponsored psychopharmacologic drug development. Among the many factors that may contribute to problematic clinical trial results, error in measuring the phenomena being studied is of particular concern. In this article, we describe the outcome of an intensive series of interrater reliability training sessions for the 17-item Hamilton Depression Rating Scale conducted at the start of a Phase II multisite clinical drug trial. The data underscore the magnitude of error present in such a test setting and provide preliminary evidence for the potential effect of this problem on the detection of clinical change.

Adult↗
PubMed1997

Sleep-onset rapid eye movement after electroconvulsive therapy is more frequent in patients who respond less well to electroconvulsive therapy.

The response to electroconvulsive therapy (ECT) was monitored with sleep polysomnography studies (SPS) performed pre- and post-ECT, in 25 patients with major depressive disorder (MDD). Patients included in this study met research diagnostic criteria for MDD and had been free of psychotropic medication for at least 10 days before SPS were performed. We compared ECT responders and nonresponders on SPS, demographic, and clinical parameters. Many SPS parameters, regardless of the clinical response, changed significantly with ECT. The presence of delusions was significantly associated with SOREM post-ECT. The presence of sleep-onset REM periods post-ECT was associated with poor response to ECT. SPS performed during a course of ECT may help identify patients at risk of responding less well to this modality of treatment.

Adult↗
PubMed1996

Eating pathology, fat avoidance, and serum estradiol concentrations in young women.

OBJECTIVE: Pathological dieting in young women is a continuum of behavior, with bulimia nervosa representing the extreme end of the continuum. This cross-sectional study was conducted to describe the relationship between the degree of eating pathology and dietary intake of college-age women. The relationship between dietary intake and serum estradiol concentrations was also examined. METHOD: We evaluated the dietary intake of 69 women, defined according to degree of eating pathology with a questionnaire instrument. Three-day food records at follicular and luteal phases of one menstrual cycle, and serum estradiol concentrations at approximate menstrual cycle days 6, 21, and 28, were evaluated. RESULTS: Greater degree of eating pathology was associated with significantly lower dietary fat and energy intake (p < .05). A trend for luteal phase energy intake to be related to serum estradiol concentration at day 28 (p = .06) was also observed. DISCUSSION: Fat avoidance may be a useful indicator of increased risk for an eating disorder in young women.

Adult↗
PubMed1996

Evidence that abnormalities of central neurohormonal systems are key to understanding fibromyalgia and chronic fatigue syndrome.

Fibromyalgia (FM) and chronic fatigue syndrome (CFS) fall into the spectrum of what might be termed stress-associated syndromes by virtue of frequent onset after acute or chronic stressors and apparent exacerbation of symptoms during periods of physical or emotional stress. These illnesses also share perturbation of the hypothalamic-pituitary-adrenal axis and sympathetic stress response systems. In this article, the authors discuss the specific neurohormonal abnormalities found in FM and CFS and potential mechanisms by which dysfunction of neurohormonal stress-response systems could contribute to vulnerability to stress-associated syndromes and to the symptoms of FM and CFS.

Humans↗
PubMed1996

Neurohormonal perturbations in fibromyalgia.

Fibromyalgia (FM) falls into the spectrum of what might be termed 'stress-associated syndromes' by virtue of frequent onset after acute or chronic stressors and apparent exacerbation of symptoms during periods of physical or emotional stress. Patients with FM exhibit disturbances of the major stress-response systems, the HPA axis and the sympathetic nervous system. Integrated basal cortisol levels measured by 24-hour urine-free cortisol are low. FM patients display a unique pattern of HPA axis perturbation characterized by exaggerated ACTH response to exogenous CRH or to endogenous activators of CRH such as insulin-induced hypoglycaemia. The cortisol response to increased ACTH in these stress paradigms is blunted, as is the the cortisol response to exercise. Functional analysis suggests that FM patients may also exhibit disturbed autonomic system activity. For example, plasma NPY, a peptide co-localized with norepinephrine in the sympathetic nervous system, is low in patients with FM. Abnormalities of related neuronal systems, particularly decreased serotonergic activity, may contribute to the observed neuroendocrine perturbations in FM. Finally, other neuroendocrine systems, including the growth hormone axis, are also abnormal in FM patients. Many clinical features of FM and related disorders, such as widespread pain and fatigue, could be related to the observed neuroendocrine perturbations. This hypothesis is supported by the observation that many useful treatments for FM affect the function of these central nervous system centres. Further clarification of the role of neuroendocrine abnormalities in patients with FM, and the relationship of these disturbances with particular symptoms, may lead to improved therapeutic strategies.

Animals↗
PubMed1996

Nutritional characteristics, eating pathology, and hormonal status in young women.

Ovulatory dysfunction is common in patients with eating disorders. However, many women engage in pathologic dieting behaviors without meeting the current diagnostic criteria for anorexia or bulimia nervosa. Clinical eating disorders are only the most extreme form of pathologic eating attitudes and behaviors that are present in many young women. Specific food choices and nutrient intakes may be associated with altered gonadal hormone status of these dieters. This cross-sectional study was conducted to describe the nutritional characteristics of college-aged women defined by their eating attitudes and behaviors with a previously described questionnaire. We evaluated dietary intake, body composition, and selected biochemical indicators in 76 undergraduate women. Serum concentrations of estradiol, progesterone, lipids, and carotenoids were measured on days 6, 21, and 28 of one menstrual cycle. Dietary assessment was based on food records at two 3-d intervals during the cycle. Ovulatory status was definitively determined on the basis of biochemical data for 46 of the women. Increased degree of pathologic dieting was associated with a significantly lower intake of dietary fat (P < 0.02), despite similar mean body mass index and body composition across the eating pathology groups. Serum concentration of alpha-carotene was significantly greater (P < 0.005) in association with a greater degree of eating pathology. With ovulation as a between-group factor, serum lutein concentration and dietary intake of energy and fat differed significantly between groups (P < 0.003). Nutritional characteristics associated with pathologic dieting behavior may also be associated with menstrual irregularities in young women.

Adolescent↗
PubMed1995

Cerebrospinal fluid levels of kynurenine pathway metabolites in patients with eating disorders: relation to clinical and biochemical variable.

In brain, most L-tryptophan is metabolized to indoleamines, whereas in systemic tissues L-tryptophan is catabolized to kynurenine pathway metabolites. Among these latter compounds are: quinolinic acid, an N-methyl-D-aspartate receptor agonist; kynurenic acid, an antagonist of excitatory amino acid receptors that also reduces quinolinic acid-mediated neurotoxicity; and L-kynurenine, a possible convulsant. Because the metabolism of L-tryptophan through the kynurenine pathway is dependent upon adequate nutrition, we sought to determine whether the impaired nutrition characteristic of eating-disordered patients might be associated with specific disturbances in this metabolic pathway. Cerebrospinal fluid levels of L-tryptophan, quinolinic acid, kynurenic acid, L-kynurenine, and 5-hydroxyindoleacetic acid were measured in medication-free female patients meeting DSM-III-R criteria for either anorexia nervosa (n = 10) or normal-weight bulimia nervosa (n = 22), studied at varying stages of nutritional recovery. Eight healthy, normal-weight females served as a comparison group. Cerebrospinal fluid levels of kynurenic acid were significantly reduced in underweight anorectics, compared to normal females, but returned to normal values with restoration of normal body weight. Although cerebrospinal fluid quinolinic acid levels were not different from controls, the ratio of quinolinic acid to kynurenic acid was significantly increased during the underweight phase of anorexia nervosa. Furthermore, in the eating-disordered patients, kynurenic acid levels in cerebrospinal fluid correlated positively with percent-of-population average body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Naloxone, an opiate blocker, reduces the consumption of sweet high-fat foods in obese and lean female binge eaters.

To test the hypothesis that endogenous opiate peptides selectively influence hedonic response to sweet and high-fat foods, the opiate antagonist naloxone, opiate agonist butorphanol, and a saline placebo were administered by intravenous infusion to 16 obese and 25 normal-weight women. Twenty of the women (10 obese, 10 lean) fulfilled DSM-III-R diagnostic criteria for bulimia nervosa, as determined by psychiatric interview. During drug infusion the women tasted and rated 20 sweetened dairy products and were presented with eight snack foods of varying sugar and fat content. Naloxone suppressed hedonic responses in all subject groups and suppressed the consumption of sweet and high-fat foods in binge eaters, but not in nonbingers. Food intakes of obese women were not affected by naloxone. Butorphanol had no effect on either hedonic response or on food consumption in any group. Although opiate blockade is not a viable strategy for weight reduction in the treatment of obesity, it may be useful in the clinical management of the binge-eating disorder.

Adult↗