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Biomedical subjects

P J Orsulak

Publications and source records attributed to P J Orsulak.

At least 19 recordsLinked to original sources
PubMed2001

Doxepin plasma concentrations: is there really a therapeutic range?

Despite the introduction of numerous new agents, tricyclic antidepressants remain an important option for the treatment of depression. Doxepin is still in wide use, and determining its concentration is a standard procedure in many psychiatric clinics. Some widely cited reviews indicate a therapeutic range from 150 to 250 ng/mL (parent plus desmethyl metabolite). The vast majority of the authors' patients fell short of these concentrations under customary doses. To resolve this issue, the authors' serum-level databank was analyzed, a questionnaire was sent to U.S. and German psychiatric university departments and laboratories, and the literature was reviewed. The main results were the following: (1) Only 9% of all samples analyzed (N = 217) displayed plasma levels (high-performance liquid chromatography) between 150 and 250 ng/mL; 88% were subtherapeutic. The mean doxepin + desmethyldoxepin steady-state serum concentration was 89+/-75 ng/mL (N = 32, doxepin >3 weeks). The mean daily dose was 143+/-30 mg. There was no correlation between concentrations and improvement. (2) A wide variety of recommendations is given by the different university departments (10-1,000 ng/mL). (3) According to the studies published to date, there is not enough evidence for recommending a therapeutic range. The preliminary suggestions given in some influential reviews have been widely adopted without critical re-evaluation. Compared with the concentrations found in the original studies, the therapeutic ranges suggested are too high. A methodologically sound study to determine a therapeutic range is required for the rational monitoring of this drug. Meanwhile, a preliminary working range of 50 to 250 ng/mL is proposed on the basis of critical reassessment of published data.

Aged↗
PubMed2000

Stand-alone automated solutions can enhance laboratory operations.

Clinical laboratory automation has developed over the past decade as one means of consolidating testing, reducing costs, and improving the effectiveness of laboratory testing. Most of the developments have been aimed at core clinical laboratory operations, and have primarily addressed preanalytical and analytical processing of traditional specimens arriving in blood collection or similar aliquot tubes. Much less attention has been given to specialized applications such as processing specimens for urine toxicology, and only recently have vendors attacked the problems associated with sorting and maintaining the laboratory's inventory of specimens. This report highlights selected developments in these areas, describes one approach to cost-effective custom platform development, and discusses the advantages and pitfalls to solving problems with laboratory automation.

Autoanalysis↗
PubMed1999

Characteristics of norepinephrine and clonidine displacement of [3H]yohimbine binding to platelet alpha2-adrenoreceptors in healthy volunteers.

Clonidine's estimates of platelet alpha2-adrenoreceptor (alpha2AR) density are substantially lower than yohimbine's. This discrepancy could have contributed to inconsistent results from studies on the role of alpha2AR in depression. Furthermore, few studies have investigated the relative distribution of alpha2AR between the high- and low-affinity states or their Gi protein coupling. [3H]yohimbine saturable binding to platelet alpha2AR, its displacement by norepinephrine and clonidine, and the effects of Gpp(NH)p on agonist displacement curves were investigated in 11 healthy volunteers. Clonidine estimates of alpha2AR density were close to norepinephrine estimates, and both were strongly correlated. Clonidine's K(L)/K(H) ratio was lower than norepinephrine's, consistent with its partial agonist nature. Norepinephrine and clonidine displacement curves revealed two affinity states. Gpp(NH)p induced a significant rightward shift to a single low-affinity state. When used in combination with a specific antagonist, clonidine's estimates of alpha2AR density were similar to those of norepinephrine's, and both were higher than previously reported, when clonidine was used alone. Re-evaluation of previous studies on alpha2AR in depression using clonidine is needed. The combined use of antagonist-saturation and agonist-displacement experiments to examine possible dysregulation in alpha2AR coupling to Gi protein in psychiatric disorders is recommended.

Adult↗
PubMed1999

Platelet alpha2-adrenergic receptor coupling efficiency to Gi protein in subjects with post-traumatic stress disorder and normal controls.

Low platelet membrane alpha2-adrenergic receptor (alpha2AR) density and low basal and forskolin-stimulated cyclic adenosine monophosphate responses, which have been reported in post-traumatic stress disorder (PTSD), suggest either abnormal alpha2AR coupling to G(i) protein or dysregulation in post-receptor signal transduction mechanisms. alpha2AR density in the high- and low-conformational states, agonist affinity in both states and coupling to G(i) protein were investigated in 23 drug-free combat PTSD patients and 25 normal controls. alpha2AR coupling measures were not different between PTSD patients and controls. Total alpha2AR density was higher in PTSD patients than controls, due to a higher density of the receptor in the high-conformational state. There were no differences in agonist affinity to the receptor in either conformational state. Results rule out dysregulation in alpha2AR coupling to G(i) protein. Studies of post-receptor signal transduction mechanisms are warranted.

Adult↗
PubMed1999

Neutrophil beta2-adrenergic receptor coupling efficiency to Gs protein in subjects with post-traumatic stress disorder and normal controls.

The symptomatology of post-traumatic stress disorder (PTSD) involves sympathetic hyperarousal. Several of these sympathetic symptoms are mediated through end-organ beta2-adrenergic receptors (beta2AR). Increased sympathetic activity in PTSD could therefore be due to increased betaAR function. This study investigated betaAR function in 30 healthy controls and 20 drug-free PTSD patients. BetaAR binding studies were conducted using antagonist-saturation and agonist-displacement experiments. Measures of beta2AR coupling to Gs protein were derived from agonist-displacement experiments. PTSD patients had significantly higher beta2AR density particularly in the high-conformational state and higher beta2AR coupling than controls, as reflected in a higher percentage of receptors in the high conformational state and a higher ratio of the agonist dissociaton constant from the receptor in the low/high-conformational state. Increased betaAR function in PTSD is consistent with the symptomatology of this disorder. Increased betaAR density and coupling may be consistent with downregulation of betaAR density and uncoupling by antidepressants and may underlie their partial efficacy in PTSD. Dysregulation in Gs protein function is postulated and, agonist-mediated regulation of betaAR expression and/or betaAR kinase activity in PTSD should be investigated in future studies.

Adult↗
PubMed1999

Prehospital stability of diazepam and lorazepam.

Injectable benzodiazepines are commonly stocked on ambulances for use by paramedics. We evaluated the stability of lorazepam and diazepam as a function of storage temperature. Diazepam (5 mg/mL) and lorazepam (2 mg/mL) injectable solutions were stored for up to 210 days in clear glass syringes at three conditions: 4 degrees C to 10 degrees C (refrigerated); 15 degrees C to 30 degrees C (on-ambulance ambient temperature); and 37 degrees C (oven-heated). High-performance liquid chromatography (HPLC) analyses of syringe contents were performed at 30-day intervals. After 210 days, the reduction in diazepam concentration was 7% refrigerated, 15% at ambient temperature, and 25% at 37 degrees C. The reduction in lorazepam concentration was 0% refrigerated, 10% at ambient temperature, and 75% at 37 degrees C. Whereas diazepam retained 90% of its original concentration for 30 days of on-ambulance storage, lorazepam retained 90% of its original concentration for 150 days. The decrease in lorazepam concentration correlated with an increase in the maximum ambient temperature in San Francisco. These results suggest that diazepam and lorazepam can be stored on ambulances. When ambient storage temperatures are 30 degrees C or less, ambulances carrying lorazepam and diazepam should be restocked every 30 to 60 days. When drug storage temperatures exceed 30 degrees C, more frequent stocking or refrigeration is required.

Ambulances↗
PubMed1999

Adrenergic receptor function in panic disorder. I. Platelet alpha 2 receptors: Gi protein coupling, effects of imipramine, and relationship to treatment outcome.

Various studies suggest alpha 2-adrenergic receptor (alpha 2AR) dysregulation in panic disorder (PD). Platelet alpha 2-AR exist in high- and low-conformational states as a function of their coupling to Gi protein. alpha 2AR coupling is important in signal transduction and is modulated by antidepressants. alpha 2AR density in the high- and low-conformational states, agonist affinity, and coupling efficiency were investigated in 21 healthy controls, 21 drug-free PD patients, and eight imipramine-treated patients using norepinephrine displacement of 3H-yohimbine binding. Percentage of receptors in the high-conformational state (%RH) and the ratio of the agonist dissociation constant to the receptor in the low-/high-conformational state (KL/KH), calculated from displacement experiments, were used as coupling indices. Patients had high alpha 2AR density in both conformational states. %RH and KL/KH ratio were significantly different, particularly in patients with Hamilton scale for depression (HAMD) scores > or = 15. Imipramine treatment (29 weeks) had no effect on alpha 2AR density or coupling, despite improvement in anxiety ratings. High pretreatment alpha 2AR density and coupling predicted low severity of anxiety after treatment. Increased alpha 2AR density and abnormal coupling may represent an adaptive mechanism or trait marker in PD.

Adult↗
PubMed1999

Effects of fluoxetine on the polysomnogram in outpatients with major depression.

This study investigated the effects of open-label fluoxetine (20 mg/d) on the polysomnogram (PSG) in depressed outpatients (n = 58) who were treated for 5 weeks, after which dose escalation was available (< or = 40 mg/d), based on clinical judgment. Thirty-six patients completed all 10 weeks of acute phase treatment and responded (HRS-D < or = 10). PSG assessments were conducted and subjective sleep evaluations were gathered at baseline and at weeks 1, 5, and 10. Of the 36 subjects who completed the acute phase, 17 were reevaluated after 30 weeks on continuation phase treatment and 13 after approximately 7 weeks (range 6-8 weeks) following medication discontinuation. Acute phase treatment in responders was associated with significant increases in REM latency, Stage 1 sleep, and REM density, as well as significant decreases in sleep efficiency, total REM sleep, and Stage 2 sleep. Conversely, subjective measures of sleep indicated a steady improvement during acute phase treatment. After fluoxetine was discontinued, total REM sleep and sleep efficiency were found to be increased as compared to baseline.

Adolescent↗
PubMed1997

Dexamethasone response, thyrotropin-releasing hormone stimulation, rapid eye movement latency, and subtypes of depression.

Most prior studies of mood disorders have used a single laboratory test to assist in differential diagnosis, prediction of treatment response, and prediction of relapse. This study compared three laboratory measures in a combined in- and outpatient sample of depressed patients. Dexamethasone suppression test (DST) nonsuppression occurred in 46% of patients with endogenous major depression, in 15% with nonendogenous major depression, and in 56% with bipolar, depressed phase disorder. A blunted thyrotropin-releasing hormone stimulation test (TRH-ST) occurred in 25% of patients with endogenous, 10% with nonendogenous, and 44% with bipolar, depressed phase disorder. Reduced REM latency was found in 65% of endogenous major depressions, in 34% of nonendogenous major depressions, and in 53% of bipolar, depressed phase disorders. Fifty-one percent of those with reduced REM latency also evidenced DST nonsuppression. When the endogenous major depression and bipolar, depressed phase groups were combined, 28% had no laboratory abnormality, whereas 8% evidenced all three. These findings suggest that 1) endogenous/nonendogenous unipolar groups are distinguished by all three laboratory tests; 2) most patients with a blunted TRH-ST also evidence DST nonsuppression; and 3) one half of patients with reduced REM latency evidence DST nonsuppression. Sensitivity is greatest and specificity is lowest for REM latency, followed by the DST and then the TRH-ST.

Adult↗
PubMed1996

Growth hormone response to baclofen: a comparison of 10-mg and 20-mg doses in healthy men.

Growth hormone (GH) response and baclofen levels were measured in seven healthy adult men following a 10-mg and a 20-mg dose of oral baclofen (gamma-aminobutyric acidB agonist) to determine the preferred dose in baclofen challenge studies. Multivariate analysis of variance (ANOVA) with repeated measures revealed no differences between the doses. However, when a univariate ANOVA with repeated measures was performed for each dose, the 10-mg dose showed no significant GH response over time, whereas the 20-mg dose showed a significant GH response over time. The average delta GH (change in GH from baseline) was 7.84 ng/ml (SD = 10.17) for the 10-mg dose and 3.34 ng/ml (SD = 3.64) for the 20-mg dose. The variability in the delta GH response to the 10-mg dose was significantly greater than the response to the 20-mg dose of baclofen. This variance in GH response was not explained by the differences in serum baclofen levels. Thus, a 20-mg baclofen dose appears to be preferable to a 10 mg-dose in baclofen challenge studies.

Adult↗
PubMed1996

Plasma GABA predicts acute response to divalproex in mania.

Bipolar I, manic phase inpatients were treated with divalproex sodium, lithium, or placebo in a previously reported parallel group multicenter, double-blind, randomized, controlled acute phase treatment trial. Plasma concentrations of gamma aminobutyric acid (GABA) were measured before and after treatment. Higher pretreatment plasma GABA levels were significantly (p = .04) related to a better clinical response to divalproex (n = 19). Pretreatment plasma GABA levels did not correlate with response to either lithium (n = 13) or placebo (n = 31). Following treatment with divalproex sodium, plasma GABA levels decreased significantly (p < .05), compared to placebo. Pretreatment plasma GABA levels were not related to overall severity of manic symptoms. Plasma GABA may predict response to pharmacologic agents acting on the GABA system.

Adult↗
PubMed1996

The dexamethasone suppression test in patients with mood disorders.

BACKGROUND: This study was undertaken to (1) determine whether the endogenous/nonendogenous mood disorder dichotomy is validated by the dexamethasone suppression test (DST); (2) determine whether other subtyping schemes (unipolar/bipolar, DSM-III melancholic/nonmelancholic, Winokur's family history subtypes) relate to the DST; (3) evaluate the relative contributions of symptom severity, weight loss, and other factors to DST status; and (4) assess the relative sensitivity of various post-dexamethasone cortisol determinations in the detection of dexamethasone nonsuppression. METHOD: 487 consecutive adult inpatients (N = 131) and outpatients (N = 356) with unipolar (N = 422) or bipolar disorder (N = 65) underwent the 1.0-mg DST. Nonsuppression was defined as at least one post-dexamethasone cortisol measurement > 4.0 micrograms/dL. RESULTS: Nonsuppression occurred in 27% of all patients with major depression and 43% of all bipolar depressed phase patients. For outpatients, dexamethasone nonsuppression occurred in 35.2% of subjects with endogenous (unipolar + bipolar; N = 145) and 9.0% of those with nonendogenous (unipolar only; N = 211) depressions (single 4 p.m. post-dexamethasone cortisol). For inpatients, dexamethasone nonsuppression was found in 61.5% of subjects with endogenous (N = 104) and 18.5% of those with nonendogenous (N = 27) depressions (three post-dexamethasone cortisol determinations). For the inpatient and outpatient sample together, the DST had a sensitivity of 46.2% and a specificity of 89.9% in differentiating endogenous from nonendogenous major depressive episodes. Weight loss, gender, and symptom severity added little to the endogenous/nonendogenous dichotomy. The Research Diagnostic Criteria (RDC) primary/secondary and Winokur and colleagues' family history subtypes for unipolar depression were not strongly validated by the DST. The 4 p.m. and 11 p.m. samples together detected 91.0% of those inpatients with abnormal three-sample DST results. The 8 a.m. sample alone detected 30% of those, the 4 p.m. sample alone detected 67%, and the 11 p.m. sample alone detected 62%. CONCLUSION: The RDC endogenous/nonendogenous dichotomy was validated by the DST.

Adult↗
PubMed1995

Depression spectrum disease with and without depression in first-degree relatives.

Family history was assessed in 211 outpatients with unipolar major depression and diagnoses were rendered according to Winokur et al. (Winokur et al. (1978) J. Nerv. Ment. Dis. 166, 764-768) family history typology. The subclassification of Depression Spectrum Disease with Alcoholism and Depression (DSDA + D) was applied to those patients reporting at least one first-degree relative suffering from alcoholism and another first-degree relative suffering from depression (n = 103), while Depression Spectrum Disease with Alcoholism (DSDA) was applied to those patients with at least one first-degree relative suffering from alcoholism, but none suffering from depression (n = 108). These two groups were compared on demographic, clinical and biological characteristics. They were also compared with 162 patients who reported the presence of depression and absence of alcoholism in first-degree relatives, designated as Familial Pure Depressive Disease (FPDD) by the Winokur et al. (1978) classification. Results revealed that the DSDA + D group was younger, had an earlier age at onset of depression and experienced more episodes of depression than did the DSDA group. No differences were found between the two groups on biological measures. The FPDD group was more similar to the DSDA + D group than the DSDA group in terms of age at onset and number of depressives episodes. However, the FPDD group had a longer length of illness than either of the DSD groups. These data suggest that the DSD group should be more narrowly defined (excluding those with a positive family history of depression) in future clinical research studies.

Adult↗
PubMed1995

Arecoline reverses dexamethasone suppression of cortisol in normal males: a pilot study.

Six normal controls participated in two or three individual, intravenous challenges (each separated by 1 week) of saline or one of two doses of arecoline at 8 AM following ingestion of 1 mg dexamethasone at 12 midnight the previous evening. Individuals differed in their subjective and neuroendocrine responses to arecoline. At 2.1 micrograms/kg (n = 4) or 2.8 micrograms/kg (n = 1), four of five subjects evidenced dexamethone suppression test (DST) nonsuppression, which followed the rise in prolactin. Cholinergic side effects and nausea were minimal. At a dose of 4.2 micrograms/kg, four of five subjects evidenced cortisol escape from dexamethasone suppression, which was associated with a substantial rise in prolactin, some subjective cholinergic symptoms, and little to modest nausea. These data are consistent with the notion that cholinergic mechanisms are involved in the escape from dexamethasone suppression. Further, arecoline may be preferable to physostigmine as a cholinergic agonist, since it appears less likely to cause marked cholinergic side effects and significant nausea.

Adult↗
PubMed1994

The effects of fluoxetine on the polysomnogram of depressed outpatients: a pilot study.

The effects of fluoxetine (FLU) and its active metabolite, norfluoxetine (NFLU), on the polysomnogram (PSG) of nine depressed outpatients (eight with major depression; one with bipolar II, depressed phase disorder) were investigated by contrasting PSG values prior to treatment and during administration of FLU. The PSG changes were correlated with daily dose, cumulative dosage, single serum concentrations, and the total area under the serum concentration curve (AUC) of both FLU and NFLU. Fluoxetine clearly increased both stage 1 sleep time and rapid-eye-movement (REM) latency and decreased both percent REM and REM density. With a few exceptions, the cumulative dosage of FLU and the AUC of FLU and NFLU were better predictors of the changes in awake and movement time in the PSG than single-sample concentrations of FLU and NFLU taken at the time of PSG assessment.

Adult↗
PubMed1993

Effects of tricyclic antidepressant treatment on tyramine-O-sulfate excretion in depressed patients.

The urinary excretion of tyramine-O-sulfate following an oral load of tyramine (Tyramine Challenge Test, 'TCT') was measured in a group of fourteen inpatients with unipolar and bipolar major depressive episode. TCT was done both during a pretreatment baseline period and following four weeks of treatment with tricyclic antidepressants. The change in TCT values after treatment correlated with improvement in depression. The previously described ability of TCT to discriminate between endogenous and nonendogenous depressed patients was confirmed at baseline. However, following tricyclic antidepressant treatment, TCT values were not significantly different between endogenous and nonendogenous patients.

Adult↗