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Biomedical subjects

D L Garver

Publications and source records attributed to D L Garver.

At least 37 records · Page 2Linked to original sources
PubMed1995

Risk factors for clozapine discontinuation among 805 patients in the VA hospital system.

The goal of this study was to determine if demographic or clinical factors collected at baseline on patients treated with clozapine would increase the risk of having clozapine discontinued for (a) lack of response, (b) side effects, (c) noncompliance, (d) concomitant illness, or (e) death. The subjects were 805 patients treated with clozapine at 96 Department of Veterans Affairs Hospital System facilities. Multiple logistic regression was used to determine if any of the baseline variables predisposed patients to discontinuation from treatment. Factors which were studied include age, race, history of inadequate response to traditional neuroleptics, history of substance abuse, and DSM-III-R Axis I diagnosis. Of the 805 patients started on clozapine 167 (20.7%) were discontinued from treatment. The only significant variable in the logistic regression model was race. This study finds that African American patients are more likely to have clozapine discontinued than non-African American patients, and there is a trend for prior history of inadequate response to traditional neuroleptics to predict clozapine discontinuation. We found no effect of substance abuse or dependence, diagnosis, or age on outcome in the overall patient group. In a post hoc analysis the African American patients had a significantly lower baseline white blood count than the non-African American patients, which could have explained the difference in clozapine discontinuation. The findings of this study support further investigation into the causes of ethnic differences in treatment outcome with clozapine.

Adult↗
PubMed1994

Serotonin and impulsive/aggressive behavior in cocaine dependent subjects.

1. 10 male cocaine dependent patients and 10 sex matched controls were administered several behavioral measures of aggression including the Buss-Durkee Hostility Inventory, and The Brown-Goodwin Life History of Aggression. 2. All subjects were also administered a buspirone neuroendocrine challenge as a measure of serotonin function. 3. The cocaine dependent subjects were significantly more aggressive than the controls. 4. There was a significant correlation between the growth hormone response to buspirone and behavioral measures of aggression in the cocaine dependent subjects, but not in the controls. 5. There was no difference in the overall growth hormone response between the controls and cocaine dependent subjects, possibly due to differences in metabolism of buspirone. 6. This study supports a role for serotonin in aggression in cocaine dependent subjects.

Adult↗
PubMed1993

Serum homovanillic acid levels in schizophrenic patients and normal control subjects.

Schizophrenic patients with an early age at onset of illness had low baseline levels of homovanillic acid (HVA) in serum compared with schizophrenic patients with a late age at onset. After adjustments were made for age at onset, there was a significant partial correlation between positive symptoms and serum HVA. The relationship between positive symptom scores and serum HVA was shifted to the left in the early onset patients, suggesting a relatively increased sensitivity of dopamine-associated response. Patients with severe negative symptoms also had an earlier age at onset and a trend toward lower serum HVA. This study found no difference between mean serum HVA values in schizophrenic patients and normal control subjects.

Adult↗
PubMed1991

Heterogeneity of schizophrenia: relationship to latency of neuroleptic response.

Patients with an index diagnosis of schizophrenia were compared to patients with an index diagnosis of schizophreniform disorder to determine if they differed in latency to therapeutic response to haloperidol. The results of a survival analysis showed that patients with a diagnosis of schizophreniform disorder responded to haloperidol significantly more rapidly than did patients with a diagnosis of schizophrenia. Inspection of time-to-response slopes revealed that approximately 75% of the schizophreniform patients responded to neuroleptics on or before day 8 of treatment, whereas only 20% of the schizophrenic patients responded this rapidly. Forty percent of schizophrenic patients responded between day 8 and day 18, and 30% between day 18 and day 36. These results indicate that schizophreniform disorder has been successfully separated from schizophrenia in DSM-III, at least in relationship to drug response.

Adult↗
PubMed1991

Concentration of cholecystokinin in cerebrospinal fluid is decreased in psychosis: relationship to symptoms and drug response.

1. Cholecystokinin (CCK) is a neuropeptide which is co-localized within some mesolimbic and mesocortical dopamine neurons. 2. CCK resembles an antipsychotic drug in some pharmacological and behavioral tests. 3. Levels of CCK in the cerebrospinal fluid (CSF) are reduced in eleven drug-free schizophrenics in comparison with six controls. 4. Schizophrenic males have lower CSF CCK levels than females. 5. Rapidity of antipsychotic response to haloperidol appeared to be inversely related to drug-free baseline CSF CCK levels.

Adult↗
PubMed1991

Relation of CSF neurotensin concentrations to symptoms and drug response of psychotic patients.

OBJECTIVE: The authors investigated the putative endogenous antipsychotic neurotensin in relation to both psychotic symptoms and patterns of response during treatment with an antipsychotic drug. METHOD: Twenty recently admitted patients with mood-incongruent psychoses underwent 1) interviews with the Schedule for Affective Disorders and Schizophrenia for diagnostic evaluation and symptom profiles, 2) drug-free baseline measurements of CSF neurotensin and homovanillic acid, and 3) close monitoring of a therapeutic trial of haloperidol to determine latency of antipsychotic response. RESULTS: A relative deficiency in CSF neurotensin was found in a subgroup of psychotic women whose clinical response to haloperidol was delayed for 11 to 35 days after initiation of the neuroleptic. These patients had greater thought disorder, delusions-hallucinations, behavioral disorganization, and impaired functioning than did psychotic patients with higher CSF concentrations of neurotensin. Neurotensin concentrations increased during treatment with haloperidol. CONCLUSIONS: The study provides further evidence that there is diminished availability of neurotensin in some psychotic patients, with increases in neurotensin early in neuroleptic treatment. Exploration of neurotensin receptor agonists as a potentially novel class of antipsychotic compounds is suggested.

Adult↗
PubMed1990

Enlargement of cerebral third ventricle in psychotic patients with delayed response to neuroleptics.

Enlargement of the cerebral third ventricle appears to be a replicable finding in groups of patients with psychotic illnesses, and there is evidence for an association of third ventricle enlargement with poorer response to treatment. Third ventricle area and width were measured from computed tomography (CT) scans in 24 mood-incongruent psychotic patients and 14 controls age and gender matched to schizophrenic patients. Patients were treated with a fixed dose of haloperidol and classified as rapid responders (55% symptom reduction on New Haven Schizophrenic Index (NHSI) within 4.5 +/- 1.3 days) or delayed responders (55% symptom reduction on NHSI within 18.6 +/- 10.5 days). The significant enlargement of third ventricle area was isolated among the 12 delayed neuroleptic responders (19.3 +/- 9.0 mm2) compared with the 14 controls (11.7 +/- 4.8 mm2, p = 0.01), and 12 other mood-incongruent psychotics. Third ventricle width also showed a trend towards larger width in the delayed responders. There was a clear positive correlation between ventricular size and patient's age exclusively in the delayed responders (r = 0.78); a comparable relationship between ventricular size and age was not present in controls, or in the other psychotics. This finding is consistent with an age-related progressive degenerative process in the central nervous system (CNS) isolated to the neuroleptic-delayed responsive psychotics.

Adult↗
PubMed1990

A family study of lithium-responsive psychosis.

Psychiatric life histories of 487 first-degree family members of 24 lithium-responsive (mood-incongruent) psychotics, 54 lithium-nonresponsive (mood-incongruent) psychotics, and 18 lithium-responsive patients with bipolar (manic-depressive) disorder were contrasted. While the morbid risk of schizophrenic-spectrum was 11.1% in relatives of lithium-nonresponsive probands, the morbid risk for such disorders was only 2.4% in relatives of lithium-responsive (mood-incongruent) psychotics (P less than 0.05). This lithium-responsive illness appears to be familially, and perhaps genetically, distinct from the bulk of the schizophrenias.

Adult↗
PubMed1990

Depression and antidepressant therapy: receptor dynamics.

1. The classical norepinephrine (NE) and serotonin (5-HT) theories of depression have been abandoned in light of recent chronic antidepressant drug studies. 2. The new NE and 5-HT theories of depression focus on the dynamics of receptor subtypes in depression and chronic antidepressant treatments. 3. Recent studies in molecular genetics suggest a reclassification of monoamine receptors based on receptor structural homologies in DNA and amino acid sequences rather than receptor affinity for ligands. 4. Electrophysiologic studies in rats suggest that 5-HT1 receptor function is facilitated by chronic antidepressant treatment. 5. Preclinical studies employing a range of 5-HT1 mediated behavioral models also suggest that chronic antidepressant treatment facilitates transmission at central 5-HT1 receptors. 6. Patient studies, employing a 5-HT1 mediated neuroendocrine model, suggest that depression is associated with decreased transmission at CNS 5-HT1 receptors; and that chronic antidepressant treatment facilitates 5-HT1 receptor responsiveness in depressed patients. 7. New 5-HT1 selective agonists have been developed and found to be clinically effective antidepressants. 8. The above clinical and preclinical data suggest that some forms of depression are related to a decreased responsiveness of 5-HT1 receptors which is reversed by chronic antidepressant treatment. 9. Beta adrenergic and NE-stimulated cyclic AMP studies suggest that chronic antidepressant treatment decreases the responsiveness of central beta-adrenergic receptors, particularly beta-1 receptors. 10. A novel approach to antidepressant drug development focuses on identifying centrally active beta-1 agonists, which like clinically proven antidepressants, decrease beta-1 receptor responsiveness with chronic treatment. 11. 5-HT2 receptor binding studies and initial studies of 5-HT2 receptor coupled PI turnover suggest that chronic antidepressant treatment decreases 5-HT2 receptor number and function. 12. The development of new atypical antidepressants with 5-HT2 receptor related mechanisms of action suggest that 5-HT2 receptors may be associated with certain types of depression and their clinical treatment.

Animals↗
PubMed1990

No evidence for linkage between chromosome 5 markers and schizophrenia.

Linkage between chromosome 5 markers and schizophrenia has been proposed for a small number of Icelandic and English families. Three subsequent reports have failed to replicate this report. To increase the number of tested kindreds, we collected seven North American families with schizophrenia and genotyped them at 4 loci that span the region 5p13-5q11-14, including the two markers used in the single positive linkage report. The data were analyzed with models of affection status similar to those utilized in the positive report. We observed no evidence of linkage between these markers and psychiatric disorders, regardless of the definition of affection status. Additionally, we can exclude most of the region for linkage with schizophrenia in these families. This and other negative reports of linkage between schizophrenia and chromosome 5 markers suggest that genetic defects in this region are rarely, if ever, etiologically related to schizophrenia.

Chromosomes, Human, Pair 5↗
PubMed1990

Cholecystokinin, dopamine and schizophrenia.

Immunoreactive-cholecystokinin (CCK) in cerebrospinal fluid (CSF) was examined in 11 drug-free DSM-III schizophrenic patients and 6 age-matched controls. CSF CCK was significantly lower (p less than .002) in schizophrenic subjects than in controls and was significantly lower (p less than .01) in male than female schizophrenic subjects. CSF CCK was significantly lower (p less than .04) in schizophrenic subjects whose antipsychotic response was delayed 28 or more days after initiation of haloperidol compared with earlier drug responders. CCK appears to be required for neuroleptic-induced depolarization-inactivation of dopamine neurons and associated antipsychotic response; therefore, schizophrenic patients with low CCK may be resistant to the antipsychotic effects of neuroleptics.

Adult↗
PubMed1990

Length of psychiatric hospitalization and prediction of antipsychotic response.

1. Clinical variables determining length of psychiatric hospitalization for psychotic inpatients were explored. Forty psychotic inpatients received a 14 day fixed dose neuroleptic trial. 2. Neuroleptic responders (25/40) were discharged 15 +/- 2 days after initiation of pharmacotherapy. For neuroleptic non-responders (15/40) antipsychotic medication was then altered as clinically indicated. Patients requiring one change in medication (N = 8) were discharged after 27 +/- 5 days; those requiring two medication adjustments (N = 4) were discharged after 33 +/- 3 days and those requiring three alterations in pharmacotherapy (N = 3) were discharged after 42 +/- 12 days. 3. Statistical analysis of clinical and diagnostic variables indicated that 84% of the variation in length of hospitalization was accounted for by the number of alterations in pharmacotherapy required for symptom remission and discharge. It is suggested that length of hospitalization may be decreased by decreasing the length of time a clinician prescribes pharmacotherapy that subsequently proves not effective. 4. Bayesian analysis was employed to identify the minimum length of pharmacotherapy which accurately predicts subsequent antipsychotic response/non-response. During the fixed dose neuroleptic trial response/non-response could be accurately predicted for 65% of the patients by Day 3 of the trial while by Day 7 response/non-response could be predicted for 80% of the patients. 5. The present data indicate that a three to seven day trial of antipsychotics may be sufficient for making pharmacotherapy decisions as such a trial demonstrates a diagnostic efficiency similar to other predictive tests employed in clinical medicine.

Fluphenazine↗
PubMed1989

Neuroleptic-induced emotional defecation: effects of scopolamine and haloperidol.

Most investigators have found a decrease in emotional defecation in rats given neuroleptics in novel environments, supporting their action as a major tranquilizer. We have found, however, that in rats a profound increase in emotional defecation can result from neuroleptic administration in well habituated environments, such as the homecage. Anticholinergics are known to be effective in treating the side effects associated with neuroleptic administration in humans. Therefore the present study determined the effects of anticholinergic treatment in this animal model. In male rats, defecation was measured for a 1-h test period in their homecage following various doses of the central and peripheral anticholinergics, scopolamine, and n-methylscopolamine, respectively. A decrease in fecal excretions and an attenuation of haloperidol-induced defecation was found following administration of scopolamine. n-Methylscopolamine reduced defecation at all doses. When n-methylscopolamine was combined with haloperidol, both fecal mass and number decreased significantly. Since both anticholinergic agents reduced haloperidol-induced defecation it is suggested that their effectiveness is mediated through peripheral mechanisms.

Animals↗
PubMed1989

Schizophrenia and the question of genetic heterogeneity.

Despite major advances in psychiatric diagnosis during the past 20 years, boundaries of the schizophrenic syndrome remain elusive. Moreover, in pedigrees containing cases of schizophrenia there are marked between-pedigree differences with respect to prognosis, familial patterns of psychiatric illness, drug response, and especially association of affected status with a specific chromosomal locus. Such between-pedigree differences suggest the syndrome may be made up of several different diseases. Linkage of affected status to specific loci may aid in resolving genetic heterogeneity. Large multigenerational informative pedigrees may permit the separation into those that do and do not link to a genomic locus of interest. Admixture analysis of smaller informative pedigrees may permit separation of linked and unlinked pedigrees on the basis of differences in the recombination fraction. Finally, biological "markers" can be used before the genetic analysis to separate putative linked and unlinked pedigrees. The combined study of genetic linkage and clinical heterogeneity will aid in the resolution of etiological heterogeneity of schizophrenia and the delineation of meaningful diagnostic boundaries.

Genetic Linkage↗
PubMed1989

Neuroleptic drug levels and antipsychotic effects: a difficult correlation; potential advantage of free (or derivative) versus total plasma levels.

Attempts to demonstrate relationships between neuroleptic plasma levels and antipsychotic response have met with mixed results. Eight studies have attempted to clarify such discrepancies by contrasting drug level-response relationships in which the fit of plasma neuroleptic concentrations with response could be contrasted to the fit with antipsychotic response found with free (unbound) neuroleptic (or close derivations of free drug, such as cerebrospinal fluid or erythrocyte neuroleptic concentrations). In describing such drug level-response relationships, seven of eight studies show superiority of free, cerebrospinal fluid or erythrocyte concentrations of drug, as compared with plasma neuroleptic levels (p less than 0.05). Variance between neuroleptic blood levels and therapeutic response was reduced 12.0% +/- 17.7% (SD) by the use of free, cerebrospinal fluid or erythrocyte neuroleptic concentrations rather than plasma drug concentrations. Neuroleptic assays that monitor metabolites as well as parent neuroleptic may also reduce variance between drug level and response. The state of present information is such that routine monitoring of neuroleptic drug concentrations to guide dosage adjustment is premature.

Antipsychotic Agents↗
PubMed1988

TSH response to TRH and haloperidol response latency in psychoses.

Thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) was measured in 19 acutely psychotic (DSM-III schizophrenia, 7; schizophreniform, 2; schizoaffective, 3; affective, mood-incongruent psychosis, 5; manic, mood-congruent psychosis, 2) drug-free patients prior to systematic trials of lithium and/or haloperidol. TSH response was not associated with sex, age, baseline T4, or baseline TSH. A reduced TSH response was associated with affective diagnosis and was a significant predictor of a positive, rapid response to neuroleptic treatment.

Adult↗