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Biomedical subjects

O M Wolkowitz

Publications and source records attributed to O M Wolkowitz.

At least 37 records · Page 2Linked to original sources
PubMed1996

Novel strategies for treatment-resistant depression.

This article describes a highly selective constellation of the more unique strategies for managing the treatment-resistant patient. In light of the often-devastating toll that treatment-resistant depression takes on an individual's life, it behooves us to continue the search for more effective strategies for those patients that fail more traditional interventions. As each successive move down the treatment algorithm flowchart becomes necessary, the risk/benefit ratio may shift toward less well-substantiated, but still biologically informed, strategies. Although some of the more unusual treatments described in this article represent minimally charted territories, the more promising techniques are deserving of further careful exploration.

Antidepressive Agents↗
PubMed1994

Prospective controlled studies of the behavioral and biological effects of exogenous corticosteroids.

The brain is an important target organ for both endogenous and synthetic corticosteroid hormones, but the nature of steroid action there is complex. We review a series of studies that was designed to elucidate possible relationships between the behavioral and biological effects of exogenous corticosteroids. In these studies, corticosteroids were administered to intact animals or to currently healthy volunteers, and behavioral and biological indices of corticosteroid effects were jointly assessed. In the first study, chronic corticosterone administration to intact rats resulted in increased locomotor activity (consistent with increased caudate or nucleus accumbens dopamine activity) and increased caudate homovanillic acid (HVA) levels. In the second study, acute dexamethasone administration to healthy human volunteers resulted in increased plasma HVA levels. These findings in animals and humans may help explain vulnerability factors for experiencing psychotic reactions during chronic corticosteroid treatment. To more closely mimic clinical conditions in which "steroid psychoses" develop, we administered a higher dose and more chronic corticosteroid medication (prednisone, 80 mg/day for 5 days) in a double-blind manner to healthy volunteers. Consistent with prior clinical observations, behavioral changes were variable across subjects. Seventy-five percent of the individual volunteers developed mild behavioral side effects during prednisone administration; in addition, significant, specific deterioration in cognitive performance was observed. Prednisone administration was also associated with significant decreases in plasma levels of adrenocorticotropic hormone (ACTH), cortisol, and 3-methoxy,4-hydroxyphenyl glycol (MHPG) and in cerebrospinal fluid (CSF) levels of ACTH, beta-endorphin (BE), beta-lipotropin (BLPH), somatostatin-like immunoreactivity (SLI), and norepinephrine (NE). It was also associated with significant slowing of brain wave electrical activity (viz., an increase in theta wave activity) on quantitative electroencephalography. Several behavioral changes, particularly those relating to mood or cognition, were related to changes in CSF levels of NE, MHPG, ACTH, BE, BLPH, and SLI and to the slowing of brain wave activity. Our preliminary data raise the possibility that the behavioral effects of exogenous corticosteroids have specific neural concomitants and that the pattern of biological changes produced contributes to the behavioral variability observed. Steroid effects on levels of biogenic amines, pro-opiomelanocortin (POMC)-related peptides and somatostatin, among others, as well as on brain electrophysiology, may be behaviorally relevant and are highlighted as being worthy of further investigation.

Adrenal Cortex Hormones↗
PubMed1994

Differences in CSF concentrations of thyrotropin-releasing hormone in depressed patients and normal subjects: negative findings.

Since there have been reports of elevated CSF concentrations of thyrotropin-releasing hormone (TRH) in depression, the authors compared the TRH levels of 17 depressed patients and 19 normal subjects. All subjects underwent lumbar punctures after fasting overnight, and CSF concentrations of TRH were determined by radioimmunoassay. CSF concentrations of norepinephrine and monoamine metabolites were also measured. There was no significant difference between the two groups on any measure, and in the depressed patients there was no significant relation between CSF concentrations of TRH and thyrotropin-stimulating hormone responses to TRH infusion.

Adult↗
PubMed1993

Quantitative electroencephalographic correlates of steroid administration in man.

Elevated levels of circulating corticosteroids are frequently associated with behavioral alterations in man, although the mechanisms by which corticosteroids may affect behavior are poorly understood. To evaluate possible effects of exogenous corticosteroids on brain electrophysiological functioning and the relationship of such effects to behavioral and biochemical changes, we administered prednisone (80 mg p.o. daily for 5 days) in a double-blind manner to 11 medically healthy volunteers. Quantitative electroencephalogram analysis was performed following 4 days of prednisone administration and during the preceding and ensuing placebo administration periods. Central theta wave brain electrical activity significantly increased following prednisone administration and returned to baseline following prednisone withdrawal. This effect was directly correlated with prednisone-induced increases in subjective sadness ratings and with decreases in self-rated energy and well-being. Prednisone-induced reductions in peak alpha wave activity were also directly correlated with increases in subjective sadness and Symptom Checklist-90 ratings and with decreases in self-rated 'hypomanic' symptoms. Further, prednisone-induced increases in theta activity were significantly correlated with prednisone-induced decreases in CSF levels of somatostatin-like immunoreactivity, and prednisone-induced decreases in peak alpha activity were significantly correlated with decreases in CSF levels of norepinephrine and with relative increases (or lesser decreases) in CSF levels of beta-endorphin and beta-lipotropic hormone. This preliminary report of the concomitant development of prednisone-induced changes in brain electrical activity, neurochemistry and behavior highlights areas for future exploration in the study of corticosteroid effects on behavior in man.

Adult↗
PubMed1993

Ketoconazole administration in hypercortisolemic depression.

Ketoconazole, an antiglucocorticoid drug, was administered to 10 hypercortisolemic depressed patients for up to 6 weeks. Three patients dropped out because of side effects or intercurrent illness. The remaining seven had significant ketoconazole-associated decreases in serum cortisol levels and in depression ratings. Antiglucocorticoid agents may be useful probes for investigating the sequelae of hypercortisolemia in patients with major depression.

Adult↗
PubMed1993

Rational polypharmacy in schizophrenia.

Approximately 10 to 30% of patients with schizophrenia show poor response to neuroleptics alone. An initial evaluative and treatment approach to these patients is outlined, and the literature on adjunctive treatments, which seek to augment neuroleptic effects, is reviewed. The greatest evidence for efficacy has been shown for lithium, benzodiazepines, carbamazepine, reserpine, and electroconvulsive therapy, although individual patients may also respond to propranolol, clonidine, valproic acid, and L-dopa. Antidepressants may also be useful for treating comorbid depression in nonacutely psychotic patients. One general theme is that no one adjunctive treatment benefits all patients; indeed, only a minority of patients responds to any given agent. Therefore, the choice of specific treatments is best guided by the clinical characteristics of the individual patient. These observations raise the possibility that subgroups of schizophrenia exist; delineation of differences in clinical response to biochemically distinct agents may help elucidate such underlying differences between patient groups.

Antidepressive Agents↗
PubMed1992

Plasma levels of catecholamines and corticotrophin during acute glucopenia induced by 2-deoxy-D-glucose in normal man.

Acute cellular glucopenia after 2-deoxy-D-glucose administration profoundly stimulates hypothalamic-pituitary-adrenocortical and adrenomedullary activity. Whether glucopenia stimulates sympathoneural release of noradrenaline is unclear. We studied 20 healthy subjects who received 2-deoxy-D-glucose (50 mg/kg in 100 ml isotonic saline) or isotonic saline (100 ml) i.v. for 30 min on each of 2 test days. Heart rate and blood pressure were measured with antecubital venous blood obtained via an indwelling catheter for assays of plasma catecholamines (noradrenaline; adrenaline; dihydroxyphenylalanine; dihydroxyphenylglycol; and dihydroxyphenylacetic acid), corticotrophin, cortisol, and glucose. 2-deoxy-D-glucose decreased diastolic blood pressure by 20% (from 69 +/- 2 to 55 +/- 2 mmHg) and increased adrenaline levels by 30-fold [21 +/- 6 (SEM) to 634 +/- 73 pg/ml], corticotrophin by sevenfold (5.1 +/- 1.2 to 35.8 +/- 4.9 pg/ml), glucose and cortisol by two-fold (82 +/- 5 to 163 +/- 9 mg/dl and 15 +/- 2 to 31 +/- 2 micrograms/dl), and noradrenaline by about 30% (224 +/- 15 to 295 +/- 24 pg/ml, p < 0.05), whereas plasma dihydroxyphenylglycol levels decreased (765 +/- 56 to 628 +/- 42 pg/ml). Small decreases in dihydroxyphenylalanine and dihydroxyphenylacetic acid levels after 2-deoxy-D-glucose did not differ from those after saline. Responses of adrenaline levels were positively correlated with those of noradrenaline (r = 0.47, p < 0.05) and glucose (r = 0.45, p = 0.06), but not of corticotrophin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1992

Benzodiazepine augmentation of neuroleptics in treatment-resistant schizophrenia.

A significant minority of patients with schizophrenia fail to respond to neuroleptic medication alone. In some of these patients, adjunctive treatment with benzodiazepines may prove beneficial. Preclinical studies suggest that benzodiazepines significantly decrease brain dopamine release and turnover, perhaps by augmenting gamma-aminobutyric acid (GABA) inhibition of dopamine neuron activity. Double-blind clinical studies, however, have not conclusively established a role for benzodiazepines in the treatment of schizophrenia, and it seems likely that some patients respond favorably, whereas others do not. We review preliminary new observations that approximately half of a group of treatment-resistant patients, studied in a double-blind treatment protocol, demonstrated clinically significant antipsychotic responses to adjunctive alprazolam. We also briefly describe long-term efficacy of alprazolam in several patients whom we have followed in open-label clinical settings. Possible predictors or biological concomitants of benzodiazepine responsivity, which may aid in delineating distinct subgroups of patients, are discussed, and recommendations for future research are presented.

Anti-Anxiety Agents↗
PubMed1992

Antiglucocorticoid strategies in hypercortisolemic states.

Major depressive illness is frequently associated with cortisol hypersecretion. The pathophysiologic significance of this is unknown, although it is possible that hypercortisolemia exacerbates or perpetuates depressive symptoms. In both depression and Cushing's syndrome, certain depressive symptoms are correlated with cortisol levels and, in the latter condition, therapeutic lowering of cortisol levels is associated with remission of psychiatric symptomatology. We review the behavioral effects of anticortisolemic drug administration in Cushing's syndrome and major depression. Preliminary data from small-scale studies suggest that ratings of depressive symptoms in hypercortisolemic major depression may be lowered by such interventions. Such results, if confirmed in larger scale, double-blind studies, might help clarify the role of endocrinologic disturbance in psychiatric symptomatology and might lead to the development of a novel class of antidepressant agent for hypercortisolemic depressed patients.

Depressive Disorder↗
PubMed1991

MRI deep white matter hyperintensity in a psychiatric population.

The authors evaluated magnetic resonance imaging (MRI) of deep white matter hyperintensity (DWMH) in 90 adult psychiatric inpatients in whom MRIs were clinically indicated and 25 age-matched, medically healthy controls. Forty-two percent of the psychiatric patients and 12% of the controls had evidence of DWMH on MRI. Both incidence and severity of DWMH were significantly correlated with age in both groups. Even after controlling for age in the psychiatric population, DWMH was significantly associated with hypertension, history of myocardial infarction or angina, abnormal electrocardiogram, and abnormal neurological examinations.

Adult↗
PubMed1991

Benzodiazepines in the treatment of schizophrenia: a review and reappraisal.

OBJECTIVE: Benzodiazepines, either alone or added to neuroleptics, have been studied extensively as treatments for schizophrenia, but no consensus regarding their efficacy has been reached. The authors review the double-blind trials in the literature and relate the findings to the neurobiology of benzodiazepine actions. METHOD: The clinical review included all double-blind studies through 1989 that could be identified by means of Index Medicus and computer-assisted searches and by the cross-referencing of articles. The findings from the 14 studies of benzodiazepines used alone and the 16 studies of adjunctive therapy are presented separately. RESULTS: The studies reviewed suggest that 1) response is highly variable, and about one-third to one-half of patients improve; 2) benzodiazepines are potentially most useful as adjuncts to neuroleptics in the acute management of psychotic agitation, although actual antipsychotic effects have also been observed in some patients; 3) relatively higher doses of benzodiazepines may be associated with better response; and 4) therapeutic effects, when seen, develop rapidly but diminish after several weeks in some patients. The authors explore the neurobiological bases of benzodiazepine action, which presumably underlie their efficacy in schizophrenia and may help explain the variability of response. CONCLUSIONS: Future research on benzodiazepines in the treatment of schizophrenia should focus on features that predict response, the relation of dopamine or other neurotransmitter systems to therapeutic effects, the schizophrenic symptoms most amenable to benzodiazepine treatment, changes in neuroleptic dose during benzodiazepine augmentation, the role of benzodiazepines in maintenance therapy, and the optimal characteristics of benzodiazepine treatment.

Antipsychotic Agents↗
PubMed1990

Circadian variation of plasma homovanillic acid levels is attenuated by fluphenazine in patients with schizophrenia.

Plasma homovanillic acid (HVA) levels were measured hourly for a 24-hour period in 10 patients with schizophrenia during treatment with placebo and fluphenazine. Ten age- and sex-matched normal volunteers were similarly studied. Diet and activity were carefully controlled and monitored in both patients and controls. A circadian rhythm of the plasma HVA level was found in controls with a nadir in the afternoon and peak values in the early morning hours; when the patients were free from drugs, they showed a similar rhythm with lower amplitudes. Fluphenazine treatment significantly reduced the plasma concentrations of HVA and abolished the 24-hour rhythm. These data suggest that a 24-hour rhythm of the plasma HVA level exists in humans and that the amplitude of this rhythm may be less pronounced in patients with schizophrenia. Treatment with neuroleptic drugs reduces both the absolute levels and the normal circadian rhythm of the plasma HVA level.

Adult↗