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Biomedical subjects

D Pickar

Publications and source records attributed to D Pickar.

At least 145 records · Page 8Linked to original sources
PubMed1988

A central 6-hydroxydopamine lesion prevents fluphenazine-induced increase in plasma homovanillic acid.

Plasma and brain levels of the dopamine metabolite, homovanillic acid, were measured in rats after acute and chronic treatment with fluphenazine. After acute administration, homovanillic acid levels were increased in the whole frontal cortex, caudate nucleus, nucleus accumbens, anterior cingulate (supragenual) cortex, prefrontal cortex and plasma. Following chronic administration, the effects of single doses of fluphenazine in increasing homovanillic acid were markedly attenuated in the caudate nucleus, nucleus accumbens, the whole frontal cortex, anterior cigulate cortex and plasma, but not in the prefrontal (anteromedial) cortex. Following fluphenazine administration plasma homovanillic acid levels were correlated with homovanillic acid concentrations in whole frontal cortex (r = 0.63, p less than 0.01) and caudate nucleus (r = 0.51, p less than 0.05). Further, prior intracerebroventricular administration of 6-hydroxydopamine prevented the fluphenazine-induced increase in plasma homovanillic acid. These data suggest that in the rat, plasma and brain (caudate nucleus and whole frontal cortex) homovanillic acid levels change in a similar fashion during acute and chronic neuroleptic administration.

Animals↗
PubMed1988

Urinary-free cortisol in depressed patients and controls: relationship to urinary indices of noradrenergic function.

We measured urinary outputs of urinary-free cortisol in 28 medication-free depressed patients and 32 normal controls. Depressed patients had significantly greater urinary outputs of urinary-free cortisol than controls. Also, there were significant correlations among depressed patients, but not among controls, between urinary-free cortisol and urinary outputs of norepinephrine and its metabolite vanillylmandelic acid (VMA). These urinary data extend recent findings suggesting that dysregulation of both the hypothalamic-pituitary-adrenal axis and noradrenergic system occur together in depression.

Adult↗
PubMed1988

Steady-state cerebrospinal fluid transfer of verapamil and metabolites in patients with schizophrenia.

Cerebrospinal fluid (CSF) and plasma levels of verapamil and its two metabolites, norverapamil and D-620, were measured in seven patients with schizophrenia under steady-state conditions. Simultaneous sampling of CSF and plasma just before the dose during week 4 of the trial showed that verapamil, norverapamil, and D-620 partition in the CSF and reflect 7%, 5%, and 12% of the corresponding levels in plasma, respectively. There was a significant decrease in the mean unbound fraction of verapamil in schizophrenic patients as compared with normal subjects (0.058 vs. 0.11; p less than 0.001). Estimates of the mean unbound fraction obtained from CSF/plasma verapamil concentrations and the pH partition hypothesis showed excellent agreement with that measured by equilibrium dialysis (0.055 vs. 0.058) in these patients. Although systemic pool protein concentrations in schizophrenic patients were within normal range, an excellent positive correlation was observed between the ratio of the bound/free verapamil concentration and alpha 1-acid glycoprotein levels (r = 0.86; p less than 0.05). Determination and development of correlations between plasma and CSF may enhance our understanding of the central nervous system effects of verapamil.

Administration, Oral↗
PubMed1988

Perspectives on a time-dependent model of neuroleptic action.

The best support for the hypothesized involvement of central nervous system dopamine systems in the pathophysiology of schizophrenia is the association between the affinity of neuroleptic drugs for the D2 dopamine receptor and their potency as antipsychotics. Discrepancy between the time course of receptor binding and the development of antipsychotic effects, however, limits this model. Preclinical studies have now shown that activation of presynaptic nigrostriatal and mesolimbic dopamine neurons by acute neuroleptic administration is reversed during chronic administration. Clinically, neuroleptic-induced time-dependent reductions in plasma levels of the dopamine metabolite, homovanillic acid (HVA), have been linked to the antipsychotic response in schizophrenic patients. These data support the notion that slowly developing alterations in presynaptic dopamine activity play a role in the mechanism of action of neuroleptic drugs. Differences between plasma and cerebrospinal fluid (CSF) HVA responses to neuroleptic treatment, although not fully explained, may be related to prominent contributions of mesocortical metabolism to CSF levels of HVA. A time-dependent dopaminergic model of neuroleptic action with implications for the pharmacotherapy of schizophrenia is presented.

Antipsychotic Agents↗
PubMed1988

Thyrotropin releasing hormone test in unipolar depressed patients and controls: relationship to clinical and biologic variables.

We compared unipolar depressed patients (n = 31) with controls (n = 38) for their responses to the thyrotropin releasing hormone (TRH) test. Depressed patients showed significantly smaller thyrotropin stimulating hormone (TSH) responses to TRH which correlated negatively with post-dexamethasone plasma cortisol levels. Depressed patients also showed significant negative correlations between delta max TSH and urinary outputs of norepinephrine and normetanephrine with similar trends with plasma levels of norepinephrine and 3-methoxy-4-hydroxyphenylglycol. Patients who showed a blunted TSH response, compared with those who did not, had significantly lower platelet serotonin uptake values. These results suggest that the blunted TSH response to TRH seen in depression may be associated with dysregulation of the cortisol, noradrenergic and serotonin systems.

Adult↗
PubMed1988

Plasma homovanillic acid as an index of central dopaminergic activity: studies in schizophrenic patients.

Despite the limitations of the dopamine hypothesis, compelling evidence remains that implicates dysfunction of CNS dopamine systems in the pathophysiology of schizophrenia. The longitudinal measurement of levels of plasma HVA has proved a useful tool in studying neuroleptic effects and has highlighted time-dependent effects as a potentially important facet of the mechanism of antipsychotic action of these drugs. Despite the good clinical correlates of plasma HVA levels, caution is needed in interpreting plasma levels of HVA with regard to CNS dopamine activity. The peripheral nervous system significantly contributes to levels of HVA that circulate in plasma. This issue is underscored by the fact that CSF HVA shows different neuroleptic response patterns than that seen in plasma. The administration of a peripherally acting MAO inhibitor to enhance the CNS "signal" in circulating levels of HVA does not resolve the "problem" of different CSF-plasma HVA neuroleptic response patterns. The possibility that mesocortical dopamine activity is reflected by CSF HVA is suggested by indirect evidence from clinical and preclinical studies. Future studies in which attempts are made at using both plasma and CSF HVA to enhance neurochemical and clinical correlates may help to advance our understanding of the contributions of specific CNS dopamine systems to schizophrenia.

Animals↗
PubMed1988

Cerebral structural pathology in schizophrenia: evidence for a selective prefrontal cortical defect.

To replicate earlier findings of central and cortical cerebral structural abnormalities and to further examine specific prefrontal cortical irregularities in schizophrenia, the authors examined computerized tomographic (CT) scans of 71 patients with chronic schizophrenia and 30 normal volunteer control subjects for ventricle-brain ratio (VBR), third ventricle width, and prominence of cortical markings in a generalized (parieto-occipital) distribution compared with the prefrontal area. Patients showed significantly larger VBRs and third ventricle widths than control subjects. Patients also showed significantly greater prefrontal markings in terms of both the number of individuals affected and the degree of difference. The relative differences on measures of VBR and prefrontal atrophy did not appear gender related, but the difference in third ventricle width between schizophrenic and control women was greater than that between schizophrenic and control men.

Adult↗
PubMed1987

Prednisone decreases CSF somatostatin in healthy humans: implications for neuropsychiatric illness.

Several neuropsychiatric illnesses, including depression and Alzheimer's disease, are reported to be characterized by hypercortisolemia and by reduced levels of cerebrospinal fluid somatostatin-like immunoreactivity (CSF-SLI). To investigate a possible causal linkage between these abnormalities we administered prednisone, 80 mg orally per day for 5 days, to 9 healthy volunteers. We observed significant prednisone-induced reductions in CSF-SLI. Moreover, the magnitude of these reductions was inversely related to the magnitude of prednisone-induced reductions in plasma ACTH levels, suggesting a functional interaction between circulating corticosteroids, central somatostatin and pituitary ACTH release.

Adrenocorticotropic Hormone↗
PubMed1987

Effects of psychotropic drugs on neurotransmitters in man.

Primary biochemical profiles of antidepressants and neuroleptics are summarized in comparison to their actual effects on monoamine neurotransmitters in humans during the time period when clinical response emerges. Even the most biochemically specific of these drugs produces effects on at least two monoamines by three to four weeks. Interestingly, taking into account relative changes in dopamine and serotonin metabolites in cerebrospinal fluid relates better to the primary biochemical action(s) of each drug than do absolute changes. Moreover, monoamine changes after drugs are in the opposite direction to those after ECT, suggesting that balance among rather than shifts in single neurotransmitters is the relevant target of major psychotropic drugs.

Antidepressive Agents↗
PubMed1987

Dysfunction in a prefrontal substrate of sustained attention in schizophrenia.

Regional brain metabolism was measured in normal subjects and patients with schizophrenia while they performed an auditory discrimination task designed to emphasize sustained attention. A direct relationship was found in the normal subjects between metabolic rate in the middle prefrontal cortex and accuracy of performance. The metabolic rate in the middle prefrontal cortex of patients with schizophrenia, even those who performed as well as normals, was found to be significantly lower than normal and unrelated to performance. The findings point to a role of the mid-prefrontal region in sustained attention and to dysfunction of this region in schizophrenia.

Adult↗
PubMed1987

Clinical and biochemical effects of verapamil administration to schizophrenic patients.

We administered verapamil hydrochloride, a calcium channel antagonist, to seven chronically ill schizophrenic patients for five weeks under double-blind, placebo-controlled conditions. No therapeutic effect was noted. Worsening in hostile and uncooperative behaviors and a syndrome of heightened emotional tone was observed during verapamil treatment and during the postverapamil placebo period. Verapamil produced significant increases in cerebrospinal fluid (CSF) and plasma levels of homovanillic acid and in plasma levels of prolactin, as well as significant decreases in plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol. Verapamil and its active metabolite, norverapamil, were partitioned into CSF with CSF/plasma ratios of 0.06 and 0.04, respectively. The lack of therapeutic effects of verapamil in schizophrenic patients differs from earlier reports of its usefulness in treating manic patients. The biochemical and clinical data from our study suggest the possibility that verapamil exerts behaviorally relevant central nervous system activity in schizophrenic patients.

Adult↗
PubMed1987

Platelet tritiated imipramine binding and serotonin uptake in depressed patients and controls. Relationship to plasma cortisol levels before and after dexamethasone administration.

We measured platelet tritiated imipramine binding and serotonin uptake in 51 depressed patients and 43 normal controls. Although there were no significant differences in platelet 3H-imipramine binding or serotonin uptake when the total group of depressed patients was compared with controls, depressed women (n = 32) had a significantly lower maximal density of 3H-imipramine binding sites (beta max) than control women (n = 25). Moreover, among the total group of depressed patients, there were significant negative correlations between the beta max values and plasma cortisol levels at 4 PM (n = 41) and 11 PM (n = 41) following dexamethasone administration. These negative correlations between beta max and cortisol levels were strongest among melancholic patients both at 4 PM before dexamethasone administration (n = 14) and at 11 PM after dexamethasone administration (n = 15). These data suggest that the reported decrease in beta max found among depressed patients may be related to and is perhaps secondary to the hypercortisolemia of depression.

Adult↗
PubMed1987

The effects of dexamethasone on plasma homovanillic acid and 3-methoxy-4-hydroxyphenylglycol. Evidence for abnormal corticosteroid-catecholamine interactions in major depression.

We investigated the possible interactions between corticosteroids and catecholamines in depression by studying the effects of the synthetic glucocorticoid dexamethasone on plasma levels of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) in a group of depressed patients and normal controls. In comparison with metabolite levels on a control day, normal controls showed a significant dexamethasone-induced increase in the plasma HVA level and a trend toward a decrease in the plasma MHPG level at 4 PM following dexamethasone administration (1 mg orally at 11 PM). Conversely, depressed patients, particularly those with psychotic features, showed a significant dexamethasone-induced increase in the plasma MHPG level and a blunting of the plasma HVA response relative to the normal controls. Dexamethasone-induced increases in the plasma MHPG level were directly correlated with the severity of depressive symptoms and with postdexamethasone cortisol levels in the depressed patients. These data suggest abnormal corticosteroid-catecholamine interactions in depression and, specifically, in depressed patients with psychotic features.

Adult↗