Zacopride in schizophrenia: a single-blind serotonin type 3 antagonist trial.
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Adult↗
Biomedical subjects
J G Csernansky
Publications and source records attributed to J G Csernansky.
Plasma prolactin and homovanillic acid as markers for psychopathology and abnormal movements during maintenance haloperidol treatment in male patients with schizophrenia.
Measurement of plasma prolactin (PRL) concentration and plasma homovanillic acid (HVA) concentration was performed in 24 patients with schizophrenia during maintenance haloperidol treatment. A significant inverse correlation was found between plasma PRL and ratings of both dyskinesia and thought disorder. Plasma PRL was also correlated with negative symptoms. No relationship was found between plasma HVA and any symptom grouping. Twelve patients received an apomorphine challenge; a trend toward a significant inverse relationship was found between baseline dyskinesia and apomorphine-induced decreases in plasma PRL. Plasma PRL and plasma HVA may reflect different elements of dopamine function in the central nervous system during maintenance treatment; plasma PRL may be the useful marker under these conditions.
Adult↗
Fenfluramine stimulation of prolactin in obsessive-compulsive disorder.
The success of serotonergic reuptake inhibitors in the treatment of obsessive-compulsive disorder (OCD) has suggested that serotonergic neurotransmission may play a role in the pathogenisis of this disorder. Prolactin responses to a 60-mg oral dose of fenfluramine in 26 medication-free patients with a DSM-III-R diagnosis of OCD were compared with those of 20 controls subjects. Fenfluramine produced a significant elevation of prolactin levels in both OCD patients and controls. Prolactin responses were significantly blunted in OCD patients compared with responses in control subjects. Female subjects in both groups showed greater prolactin responses to fenfluramine than did their male counterparts. There was a significant interaction between sex and the presence of OCD such that female patients had lower prolactin responses than their controls, while the difference between male patients and controls was not significant. Prolactin responses were not correlated with age, weight, drug level, depression, anxiety, or degree of OCD symptoms. The results are consistent with a relative reduction in serotonergic efficacy in the setting of OCD.
Adult↗
Season of birth and neuropsychological impairment in schizophrenia.
Repeated studies suggest a relationship between winter birth and increased incidence of schizophrenia. Furthermore, there may be seasonal fluctuations in schizophrenia risk factors (e.g., influenza epidemics) and the severity of biological anomalies (e.g., enlarged cerebral ventricles in neuroimaging studies). In order to assess whether winter-born schizophrenics show greater neuropsychological impairment, 112 males meeting Research Diagnostic criteria for schizophrenia were administered the Luria-Nebraska Neuropsychological Battery, a thorough measure of higher cortical functioning deficit. Sixty-four of these 112 patients were also administered the Wechsler Adult Intelligence Scale-Revised, the Benton Visual Retention Test, and the Rey Auditory Verbal Learning Test. Despite the use of several definitions of winter and nonwinter birth, there was no evidence of elevated rates of neuropsychological dysfunction among winter-born patients on any measure. The current study contains certain limitations (e.g., variable medication status at testing), but the results suggest no strong season of birth relationship with neuropsychological impairment in a reasonably large, research-diagnosed sample of schizophrenic patients.
Adult↗
Placebo-controlled, double-blind study of the effects of proglumide in the treatment of schizophrenia.
A double-blind, placebo-controlled, randomized study was performed to determine whether proglumide added to ongoing neuroleptic medication was efficacious in the treatment of 32 patients with persistent positive and negative schizophrenic symptoms. Patients treated with both proglumide and placebo showed a significant improvement over the 8 weeks of the study, but no significant difference between the patients taking proglumide and those taking placebo could be demonstrated. In addition, proglumide had no effect on plasma homovanillic acid concentrations or neuroleptic drug activity. The results suggest that, at least for the dose of proglumide used in this study (15 mg/day), the addition of this particular cholecystokinin antagonist does not potentiate the antipsychotic efficacy of neuroleptic medication in patients with persistent schizophrenic symptoms.
Adult↗
Plasma prolactin and homovanillic acid as markers for psychopathology and abnormal movements after neuroleptic dose decrease.
Plasma prolactin concentration (pPRL), plasma homovanillic acid concentration (pHVA), and symptomatology were measured in 24 male subjects with schizophrenia during maintenance haloperidol treatment. Fourteen subjects subsequently underwent 50 percent dose decreases under placebo-controlled, double-blind conditions. At baseline, a significant inverse correlation was found between pPRL and both tardive dyskinesia (TD) and "thinking disorder"; pPRL was directly correlated with negative symptoms. No such relationship was found with pHVA. In the patients who underwent a dose decrease, no relationship was found between baseline pPRL or pHVA and any clinical variable after the decrease. These data do not support the use of baseline pPRL or pHVA as markers of central dopamine function subsequent to a neuroleptic dose decrease.
Adult↗
Limbic/mesolimbic connections and the pathogenesis of schizophrenia.
The development of models of the pathogenesis of neuropsychiatric diseases that build on recent advances in chemical neuroanatomy will help to guide future research. The interconnections among limbic, basal ganglia, and cortical structures are used to form the basis of a hypothesis of the pathogenesis of schizophrenia. The adaptive capacity of subcortical dopamine systems is advanced as an explanation of the many states of the disease.
Humans↗
Symptomatology and cognitive impairment associate independently with post-dexamethasone cortisol concentrations in unmedicated schizophrenic patients.
Serum cortisol concentrations were measured after dexamethasone administration (1 mg) in 21 neuroleptic-free schizophrenic inpatients. Patients were assessed using the Brief Psychiatric Rating Scale and a battery of cognitive tests. A significant correlation was found between negative symptoms and both 8:00 AM and 4:00 PM post-dexamethasone cortisol concentration (PDC). Cognitive impairment on several measures was also correlated with 8 AM PDC, but in an independent manner. Although positive and negative symptoms were unrelated, exploratory analysis revealed a significant inverse correlation between a positive symptom grouping and both 8:00 AM and 4:00 PM PDC.
Adult↗
MMPI measures of impulsivity and depression correlate with CSF 5-HIAA and HVA in depression but not schizophrenia.
Recent studies have linked impulsivity with CSF concentrations of both 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA). One work found a negative correlation between the MMPI psychopathic deviate (Pd) scale and 5-HIAA in personality disordered men (Brown et al., 1982). We found that the 5-HIAA/Pd correlation extends (P less than 0.05) to unmedicated depressed patients (n = 21). A trend was found between HVA and Pd in depression. There was no relationship between either metabolite and the Pd scale in unmedicated schizophrenics (n = 24). A significant inverse correlation was found between the MMPI depression scale and CSF HVA but not 5-HIAA in the depressed patients.
Adult↗
Evaluating cognitive impairment in depression with the Luria-Nebraska Neuropsychological Battery: severity correlates and comparisons with nonpsychiatric controls.
Depressed patients often complain of memory and attentional difficulties, and some research suggests an increased incidence of neuropsychological impairment in depression. Yet, many prior studies contain methodological problems, including the following: (1) inclusion of medicated patients, (2) small sample sizes, and (3) tests with unknown psychometric properties. We administered the Luria-Nebraska Neuropsychological Battery (LNNB) to 28 unmedicated inpatients who met Research Diagnostic Criteria for major depression. Twenty of the 28 patients were given additional cognitive measures (e.g., Wechsler Adult Intelligence Scale-Revised, Benton Tests). The depressed patients performed similarly to an age- and education-matched nonpsychiatric reference sample. When data for a subset of the most severely depressed patients were analyzed separately, these patients too were found to perform similarly to matched controls. There were no relationships between Hamilton rating scale measures of depression severity and any cognitive measures among the depressed patients. The results suggest that cognitive functioning in depressed patients does not differ significantly from that in carefully matched controls and is independent of symptom severity.
Adult↗
Estimation of haloperidol concentrations in rat striatum after chronic treatment.
3H-Spiroperidol association and dissociation rate constants were determined in rat striatal homogenates in the presence of known concentrations of unlabelled haloperidol. The rate of 3H-spiroperidol association was progressively decreased in the presence of increasing concentrations of haloperidol and no changes were seen in 3H-spiroperidol dissociation rate constants. Measuring changes in 3H-spiroperidol association rate constants permitted detection of 0.1 pmol/ml unlabelled haloperidol in assay homogenates. Then, male Sprague-Dawley rats received daily injections of haloperidol (1.5 mg/kg) for 1-21 days. Twenty-four hours after the last injection, 3H-spiroperidol kinetic rate constants and Kd values were measured and found to be unchanged in all treatment groups. These findings suggest that, under these conditions of drug withdrawal and tissue preparation, which are widely employed in studies of chronic neuroleptic administration, residual haloperidol does not interfere with the estimation of 3H-spiroperidol binding parameters.
Animals↗
Clinical factors that may confound the assessment of drug efficacy.
The development of new chemical classes of psychotherapeutic drugs offers the potential for new patterns of drug efficacy as well as decreases in side effects. However, the determination of drug efficacy can be confounded by sample selection and outcome determination factors. The ability of selected clinical factors of both types to affect the outcome of antipsychotic drug trials is reviewed. Suggestions for future clinical drug trials are made.
Clinical Trials as Topic↗
Intercorrelations among monoamine metabolite concentrations in human lumbar CSF are not due to a shared acid transport system.
Intercorrelations among homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-hydroxy-phenylglycol (MHPG) concentrations in lumbar cerebrospinal fluid (CSF) were examined before and after blockade of the acid transport system by probenecid in 59 psychiatric inpatients. The three compounds remained intercorrelated despite acid transport blockade, suggesting that the common transport system does not account for their covariance. Other possibilities to explain the interrelationship among these compounds are discussed.
Acid-Base Equilibrium↗
Olfactory functioning in schizophrenia and depression.
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Adult↗
CSF 5-HIAA, serum cortisol, and age differentially predict vegetative and cognitive symptoms in depression.
Prior studies have shown that both cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5-HIAA) and serum cortisol levels are related to overall symptom severity in depression. In the present study, 30 unmedicated inpatients meeting Research Diagnostic Criteria (RDC) criteria for depression participated in serum cortisol collection and a lumbar puncture for CSF. A multiple regression evaluated the ability of CSF 5-HIAA, serum cortisol, and age to predict cognitive and vegetative symptom clusters of the Hamilton Rating Scale for Depression. The multiple regression to predict the vegetative symptom cluster was highly significant overall (p = 0.002) and found that age and cortisol but not 5-HIAA predicted vegetative symptoms. The regression to predict the cognitive cluster narrowly missed overall significance (p = 0.06). Both CSF 5-HIAA and serum cortisol predicted cognitive symptoms and 5-HIAA predicted the cognitive cluster more strongly than cortisol. Age did not predict cognitive symptoms. The results suggest a dissociation between serum cortisol levels and CSF 5-HIAA in predicting vegetative and cognitive symptom clusters in depression.
Adult↗
Sensitization versus tolerance to the dopamine turnover-elevating effects of haloperidol: the effect of regular/intermittent dosing.
Recent clinical research suggests that particular patterns of changes in presynaptic dopamine (DA) turnover accompany the therapeutic response to neuroleptics. We sought to determine whether daily versus weekly dosing of haloperidol for 3 weeks produced distinct effects on DA, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) concentrations in multiple brain areas. Daily dosing favored the development of tolerance to the DA-turnover elevating effects of haloperidol in the striatum and nucleus accumbens. Weekly dosing favored the development of sensitization in the striatum, posterior olfactory tubercle, and ventral tegmental area. These results suggest that dosing schedules may determine, at least in part, the effects of chronic neuroleptic administration on presynaptic DA function.
3,4-Dihydroxyphenylacetic Acid↗
Interrelationships between plasma homovanillic acid and indices of dopamine turnover in multiple brain areas during haloperidol and saline administration.
Haloperidol or saline was administered to rats daily for 1, 8, 15 or 22 days. During haloperidol, but not saline administration, changes in plasma homovanillic acid (HVA) concentrations were correlated with changes in nucleus accumbens HVA. Haloperidol administration also had a significant effect on the intercorrelation of dopamine (DA) concentrations and indices of DA turnover across multiple brain areas. In particular, intercorrelations of HVA concentrations among DA terminal brain areas (i.e. striatum, nucleus accumbens, and olfactory tubercle) occurred only during haloperidol treatment.
3,4-Dihydroxyphenylacetic Acid↗
Sensitization versus tolerance to haloperidol-induced catalepsy: multiple determinants.
The effects of dose, administration frequency, and behavioral testing conditions on the development of tolerance versus sensitization to haloperidol-induced catalepsy were tested in rats. Animals received daily or weekly injections of haloperidol (0.05-5.00 mg/kg SC) for up to 22 days. Catalepsy assessments were made either once or repeatedly using two tests: the horizontal bar and the inclined screen. Tolerance was found only in animals treated daily with haloperidol (1.5 mg/kg) and tested repeatedly on the horizontal bar. In contrast, sensitization was observed with various haloperidol doses, daily or weekly administration schedules (for most doses), either horizontal bar or inclined screen catalepsy tests, and repeated or single testing. Sensitization developed most strongly following weekly drug administration and repeated testing on the horizontal bar. No single experimental variable produced a definitive pattern of change in catalepsy over time. Dose, drug administration schedule, and behavioral test conditions all influenced the evolution of catalepsy during chronic haloperidol treatment.
Animals↗