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Biomedical subjects

W Z Potter

Publications and source records attributed to W Z Potter.

At least 19 recordsLinked to original sources
PubMed2001

The double-blind variable placebo lead-in period: results from two antidepressant clinical trials.

The 1-week single-blind placebo lead-in has long been a standard in double-blind psychopharmacology clinical trials. Although a lead-in period is often necessary (e.g., to receive laboratory results before randomization), some authors have demonstrated that the standard single-blind placebo lead-in's performance was similar to having a lead-in in which placebo was not administered. The single-blind placebo lead-in did not decrease postrandomization placebo response, nor did it increase drug-placebo differences. To eliminate a higher percentage of placebo responders before randomization and to reduce potential biases in baseline ratings, the authors designed and implemented two depression studies with a double-blind variable placebo lead-in period. In these designs, both the patients and personnel at the investigative sites were blinded to the length of the placebo lead-in period and the start of the active treatment period. Approximately 28% of the patients in the double-blind placebo lead-in studies met criteria to be placebo lead-in responders, as compared with fewer than 10% from two single-blind placebo lead-in studies conducted in a similar time frame. Although all patients continued in the study (including placebo lead-in responders), the primary efficacy analysis prospectively excluded double-blind placebo lead-in responders. Analysis of postrandomization changes revealed that double-blind placebo lead-in responders, even when continuing to receive placebo treatment, maintained their response. At the study endpoint, these placebo lead-in responders had significantly lower severity scores than their counterparts who were not lead-in responders. The prospective removal of lead-in responders thus resulted in an increase in mean endpoint placebo group severity scores. This resulted in an increased drug-placebo treatment difference in one of the two studies but had no effect on the treatment difference in the other study.

Antidepressive Agents↗
PubMed2001

The effects of ECT on brain glucose: a pilot FDG PET study.

BACKGROUND: Regional brain activity was measured before and after electroconvulsive therapy (ECT) using [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). METHODS: 6 patients (4 females) with major depression were free of psychotropic medications for at least 2 weeks prior to baseline FDG scans. Patients were treated with bifrontotemporal ECT, and posttreatment scans were obtained after the last treatment. RESULTS: A region of interest (ROI) analysis of absolute metabolic rate showed a decrease in CMRglu after ECT in all 61 regions examined. In 17 of the 61 regions, the decrease was significant at the p < 0.05 level. In the right parietal lobe, and the right anterior and left posterior frontal lobes, the decrease in CMRglu significantly correlated with the decrease in Hamilton Depression Rating Scale (HDRS) scores (r = 0.83, 0.82, and 0.84, respectively). The analysis of CMRglu normalized to global metabolic rate showed significant increases in 8 of 61 regions, including basal ganglia, upper brainstem, and occipital lobe. DISCUSSION: The decreases in global glucose metabolism and correlation of changes in frontal metabolism with decreases in HDRS are consistent with earlier brain imaging studies of ECT. The relative increases in CMRglu observed in regions with known dopaminergic innervation (caudate and upper brainstem) have not been previously reported.

Adult↗
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

Catecholamines in depression: a cumulative study of urinary norepinephrine and its major metabolites in unipolar and bipolar depressed patients versus healthy volunteers at the NIMH.

Studies comparing urinary norepinephrine (NE) and its metabolites in unipolar or bipolar depressed patients and healthy volunteers have not yielded consistent findings. However, in unipolar depressed patients, most studies in non-elderly populations consistently report elevated concentrations of plasma NE, at least following an orthostatic challenge. Expanding upon previous studies which showed elevated plasma NE in depression, we compared the urinary excretion of NE, normetanephrine (NMN), 3-methoxy-4-hydroxyphenylglycol (MHPG), and vanillylmandelic acid (VMA) in age- and sex-matched unipolar and bipolar depressed patients versus healthy volunteers hospitalized at an inpatient unit at the National Institute of Mental Health. Only depressed subjects with a minimum 4-week drug-free period were included. Total turnover (NE + NMN + MHPG + VMA) was reduced in this sample of unipolar and bipolar depressed patients. MHPG concentration did not distinguish unipolar from bipolar depressed patients and was not significantly different from that in healthy volunteers. A construct of the average fractional extraneuronal concentration of NE (NE + NMN/NE + NMN + MHPG + VMA) was significantly higher in unipolar and bipolar depressed patients than in healthy volunteers. This finding extends data suggesting that unmedicated unipolar and bipolar depressed patients have a 'hyperresponsive' noradrenergic system and provides a framework which ties together plasma and urinary findings.

Adult↗
PubMed1999

Cerebral glucose metabolic and plasma catecholamine responses to the alpha(2) adrenoceptor antagonist ethoxyidazoxan given to healthy volunteers.

RATIONALE: Methods that test for the central effects of alpha(2)-adrenoceptor antagonists can facilitate the clinical development of such compounds. Recently we evaluated the effects of idazoxan (IDX), an alpha(2)-adrenoceptor antagonist with high affinity for imidazoline sites, on a variety of measures potentially sensitive to blockade of alpha(2)-adrenoceptors including regional brain glucose metabolic rate. OBJECTIVE: To test whether these effects on brain metabolic rate could have been mediated by imidazoline binding sites, single dose challenges of 9 or 12 mcg/kg ethoxyidazoxan (ETX; an alpha(2)-adrenoceptor antagonist which does not bind to imidazoline sites) were given to healthy male volunteers. METHODS: The effects on brain glucose metabolism, blood pressure, catecholamines, and behavior were assessed. RESULTS: Blood pressure increased 10-15% after both doses. Plasma catecholamines increased 2- to 2.5-fold and responses were dose dependent. There was no evidence of either dose being anxiogenic. Both doses of ETX produced diffuse increases in brain glucose metabolism. CONCLUSIONS: Brain glucose metabolic responses were more widespread and monotonic than we had observed with IDX. ETX also produced robust increases in glucose metabolism in cerebellum. While we were unable to exclude the possibility that some of the brain metabolic responses we had observed with IDX were mediated by imidazoline sites, ETX may be sufficiently distinct from IDX in alpha(2)-adrenoceptor affinity that differences in acute metabolic responses occurred.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1999

A double-blind study comparing idazoxan and bupropion in bipolar depressed patients.

BACKGROUND: There is a small body of evidence indicating that idazoxan, a potent and selective alpha-2 antagonist, may be effective in treating bipolar depressive disorder. The purpose of this prospective controlled study is to compare idazoxan to bupropion, an antidepressant which has been suggested to have some advantages over other antidepressants in treating bipolar depressed patients. METHODS: Bipolar I depressed patients were randomly assigned in this 6-week double-blind out-patient study to receive either idazoxan, titrated to 240 mg/day and placebo bupropion, or bupropion, titrated to 450 mg/day and placebo idazoxan. These doses were achieved after 2 weeks. Depression severity was assessed with the Hamilton Depression Rating Scale and possible psychosis with the Brief Psychiatric Rating Scale. Side effects, heart rate, weight, and orthostatic blood pressure were also monitored. RESULTS: Fourteen patients completed this study (seven in each group). Both idazoxan and bupropion demonstrated significant improvement over time with reductions in Hamilton scores of 50%. LIMITATIONS: Limitations of this study include lack of a placebo group and small sample size. CONCLUSION: In light of our preliminary findings suggesting the usefulness of idazoxan in bipolar depression, larger more rigorous studies are indicated.

Adrenergic alpha-Antagonists↗
PubMed1999

Metabolism of tricyclic antidepressants.

1. Despite the considerable advances in the treatments available for mood disorders over the past generation, tricyclic antidepressants (TCAs) remain an important option for the pharmacotherapy of depression. 2. The pharmacokinetics of TCAs are characterized by substantial presystemic first-pass metabolism, a large volume of distribution, extensive protein binding, and an elimination half-life averaging about 1 day (up to 3 days for protriptyline). 3. Clearance of tricyclics is dependent primarily on hepatic cytochrome P450 (CYP) oxidative enzymes. Although the activities of some P450 isoenzymes are largely under genetic control, they may be influenced by external factors, such as the concomitant use of other medications or substances. Patient variables, such as ethnicity and age, also affect TCA metabolism. The impact of gender and related reproductive issues is coming under increased scrutiny. 4. Metabolism of TCAs, especially their hydroxylation, results in the formation of active metabolites, which contribute to both the therapeutic and the adverse effects of these compounds. 5. Renal clearance of the polar metabolites of TCAs is reduced by normal aging, accounting for much of the increased risk of toxicity in older patients. 6. Knowledge of factors affecting the metabolism of TCAs can further the development and understanding of newer antidepressant medications.

Antidepressive Agents, Tricyclic↗
PubMed1999

Methodological considerations for the development of new treatments for bipolar disorder.

Lithium has been the drug of choice in treating bipolar disorder for 50 years and, therefore, patterns of response associated with its use define what we expect from treatment. Although efforts to establish some other agents as antimanic have been successful, it is difficult to assess their overall efficacy in relation to that of lithium without a better understanding of inclusion/exclusion criteria, subtypes, definitions of remission, relapse and recurrence, and duration of study. All of these factors need to be carefully addressed to identify the most important clinical targets for new drug development. Additional relevant information emerges from studies on combinations of mood stabilisers, efficacy of antimanic agents in different patient populations, analysis of rates of drop-out, non-compliance, suicide, drug abuse, and discontinuation especially with long-term treatment. Agents other than lithium that are effective in the acute phase treatment are still not well characterised as mood stabilisers. New agents need to be evaluated in the context of long-term treatment and the targeting of specific components of the syndrome beyond mania.

Affect↗
PubMed1998

Effect of IL-1alpha on the release of norepinephrine in rat hypothalamus.

The increased release of norepinephrine (NE) in the brain as part of the 'acute phase response' has been postulated to result from a direct action of IL-1 on the hypothalamus. To test whether the effects of IL-1alpha were direct, we carried out in vivo experiments using microdialysis and measured NE release in the hypothalamus using high pressure liquid chromatography (HPLC). Two groups of male Sprague Dawley rats were either injected intraperitoneally with 1 ml of IL-1alpha (2 microg/ml) or had IL-1alpha 2 microl (100 ng/ml) infused directly into the medial hypothalamus. A significant increase in extracellular hypothalamic NE was observed in the animal group treated with IL-1alpha intraperitoneally and not in the controls or the group treated with IL-1alpha intracerebrally. One-way ANOVA showed a significant effect of drug and route of administration with the ip IL-1alpha treated group, differing from all other groups (vehicle ip, IL-1alpha ic, and vehicle ic). Therefore these findings suggest that some aspects of IL-1alpha actions on the HPA may be indirect requiring other intermediate steps or mediators outside the central nervous system.

Animals↗
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↗
PubMed1998

Bipolar depression: specific treatments.

From the perspective of pharmacologic treatment, bipolar depression is considered in this article as belonging to a spectrum of affective disorders. Insufficient controlled data permit only general recommendations for treatment of the spectrum of affective disorders, except perhaps for the classic form of bipolar I disorder. While the field waits for prospective controlled trials, a wide range of drugs is currently available for the treatment of bipolar depression. The potential advantages of having an increasing number of agents with different mechanisms of actions are suggested by the many small studies claiming some degree of advantage in one or another subgroup of patients with bipolar depression. Several antidepressants and one anticonvulsant have the virtue of clinical experience that contributes to a body of information about side effects and the potential for producing benefit in at least some bipolar depressed patients. By default, and because they appear to have less chance of precipitating mania and are otherwise safe, selective serotonin reuptake inhibitors are probably the most comfortable first-line treatment for bipolar depression.

Antidepressive Agents↗
PubMed1997

Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease.

OBJECTIVE: To evaluate the therapeutic effects of selective cholinergic replacement with xanomeline tartrate, an m1 and m4 selective muscarinic receptor (mAChR) agonist in patients with probable Alzheimer disease (AD). DESIGN: A 6-month, randomized, double-blind, placebo-controlled, parallel-group trial followed by a 1-month, single-blind, placebo washout. SETTING: Outpatients at 17 centers in the United States and Canada. PARTICIPANTS: A total of 343 men and women at least 60 years of age with mild to moderate AD. INTERVENTIONS: Patients received 75, 150, or 225 mg (low, medium, and high doses) of xanomeline per day or placebo for 6 months. OUTCOME MEASURES: Scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change (CIBIC+), the Alzheimer's Disease Symptomatology Scale (ADSS), and the Nurses' Observational Scale for Geriatric Patients (NOSGER). RESULTS: A significant treatment effect existed for ADAS-Cog (high dose vs placebo; P < or = .05), and CIBIC+ (high dose vs placebo; P < or = .02). Treatment Emergent Signs and Symptoms analysis of the ADSS, which assesses behavioral symptoms in patients with AD, disclosed significant (P < or = .002) dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, NOSGER, which assesses memory, instrumental activities of daily living, self-care, mood, social behavior, and disturbing behavior in the elderly, also showed a significant dose-response relationship (P < or = .02). In the high-dose arm, 52% of patients discontinued treatment because of adverse events; dose-dependent adverse events were predominantly gastrointestinal in nature. Syncope, defined as loss of consciousness and muscle tone, occurred in 12.6% of patients in the high-dose group. CONCLUSIONS: The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD. Furthermore, the dramatic and favorable effects on disturbing behaviors in AD suggest a novel approach for treatment of noncognitive symptoms.

Alzheimer Disease↗
PubMed1997

Responses to alpha 2-adrenoceptor blockade by idazoxan in healthy male and female volunteers.

Seven male and five female volunteers underwent double-blind infusions of the alpha 2-adrenoceptor antagonist idazoxan (100 and 200 micrograms/mg) and placebo in random order. Blood pressure, plasma norepinephrine, growth hormone and subjective responses were measured. The higher dose of idazoxan produced increases in blood pressure, norepinephrine and growth hormone and slight increases in anxiety. Both subject age and sex appeared to influence the magnitude of responses.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1997

Increase in AP-1 transcription factor DNA binding activity by valproic acid.

Valproic acid (VPA), a simple branched fatty acid anticonvulsant, has been demonstrated to have clinical efficacy in the treatment of manic-depressive illness (Bowden et al., 1994), but the mechanism(s) by which VPA produces its therapeutic effects remain to be elucidated. VPA's clinical antimanic action require a lag period for onset and are not immediately reversed upon discontinuation of treatment, effects that suggest alterations at the genomic level; we therefore investigated the effects of VPA on the modulation of the DNA binding activity of key transcription factors. DNA binding activities of activator protein 1 (AP-1) and cAMP responsive element binding protein (CREB) were studied in acute (hours) and chronic (days) VPA-treated rat C6 glioma cells. VPA did not affect CREB DNA binding activity, but concentration- and time-dependently increased AP-1 DNA binding activity. The activity was raised at 2 hours (the shortest time examined) and remained high after 6 days (the longest time used) of continuing VPA treatment. VPA also enhanced AP-1 DNA binding activity in human neuroblastoma (SH-SY5Y) cells. Because the effects of VPA were markedly inhibited by cycloheximide, they appear to require new protein synthesis. Taken together, the data suggest that antimanic agents may affect gene expression by modulation of the activity of major transcription factors; in view of the key roles of these nuclear transcription regulatory factors in long-term neuronal plasticity and cellular responsiveness, these effects may play a major role in VPA's therapeutic efficacy and are worthy of further study.

Activating Transcription Factor 2↗
PubMed1997

Gender differences in brain metabolic and plasma catecholamine responses to alpha 2-adrenoceptor blockade.

alpha 2-Adrenergic receptors modulate the release of several neurotransmitters implicated in the treatment and pathophysiology of mood and anxiety disorders. Significant sex differences occur in the prevalence of both disorders. To test whether gender affects alpha 2 function, the plasma catecholamine and brain metabolic responses to alpha 2 blockade were measured in male and female volunteers. Ten female and thirteen male volunteers underwent [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans before and after infusion of idazoxan (200 micrograms/kg). Measures of plasma catecholamines, blood pressure, and anxiety were obtained. Norepinephrine responses were larger in males. Women showed global increases in metabolism, whereas males had no global changes and some regional decreases in FDG uptake following idazoxan administration. The differences in norepinephrine increases are consistent with previously reported effects of gender on sympathetic activation. The PET data suggest gender differences in responses to alpha 2-receptor blockade in brain as well.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1997

Cerebrospinal fluid monoamine metabolites in childhood-onset schizophrenia.

OBJECTIVE: Pediatric studies of cerebrospinal fluid (CSF) monoamine metabolites in childhood-onset schizophrenia may help to elucidate both pathophysiology and treatment response in early-onset psychosis. METHOD: CSF homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) and serum prolactin were measured during drug-free and antipsychotic medication conditions in 18 patients (mean age = 14.2 years, SD = 1.7) who had onset of schizophrenia by age 12 (mean age at onset = 9.9 years, SD = 1.8). Relationships between changes in CSF monoamines and serum prolactin and clinical outcome were examined, and the degree of change in CSF monoamines in response to clozapine treatment was compared with that for 16 patients with later-onset schizophrenia. RESULTS: Despite patients' significant clinical improvement with treatment, CSF monoamine concentrations and ratios of HVA/5-HIAA and HVA/MHPG did not significantly change with 6 weeks of either haloperidol or clozapine treatment. Serum prolactin levels increased during haloperidol treatment. Clozapine had similar effects on CSF monoamines in patients with childhood- and later-onset schizophrenia. CONCLUSIONS: While these data are compatible with continuity between childhood- and later-onset schizophrenia, they also highlight the complexity of the biochemical events mediating clinical changes in schizophrenia.

Adolescent↗
PubMed1997

High levels of Gs alpha in platelets of euthymic patients with bipolar affective disorder.

OBJECTIVE: Previous investigations have suggested the involvement of signal-transducing guanine-nucleotide-binding proteins (G proteins) both in the mechanism of action of lithium and in the pathophysiology of bipolar affective disorder. To determine whether such G protein abnormalities are a trait phenomenon, the authors investigated the levels of G protein alpha subunits in platelets and lymphocytes of euthymic patients with bipolar affective disorder. METHOD: Selective antibodies were used to quantitate levels of G protein alpha subunits regulating adenylylcyclase activity (Gs alpha-both 45- and 52-kDa forms- and Gil-2 alpha) and those regulating phosphoinositide turnover (Gq/11 alpha) in both platelets and lymphocytes of 44 euthymic patients with bipolar affective disorder and 27 matched comparison subjects. RESULTS: Levels of both Gs alpha 45 and Gs alpha 52 were higher in the platelets of the euthymic bipolar patients (both bipolar I and bipolar II) than in those of the comparison subjects. CONCLUSIONS: These findings are consistent with previous reports of high Gs alpha levels in bipolar affective disorder and, furthermore, suggest that such levels may be a trait abnormality for this condition.

Adult↗