Tardive dyskinesia--diagnostic issues, subsyndromes, and concurrent movement disorders: a study of state hospital inpatients referred to a movement disorder consultation service.

Of 49 state hospital patients referred for movement disorder consultation for tardive dyskinesia (TD), 11 (23.9%) of 46 meeting inclusion criteria had movement disorders other than TD. These other disorders led to a false diagnosis of TD in 6 subjects (12.2%). Between-day dyskinesia variability affected TD ascertainment in only 3.2 percent of subjects. Prevalences of other neurological conditions in the 30 patients identified with definite TD were parkinsonism (90%), dystonia (25%), akathisia (16%), cerebellar signs (40%), dysmetria (23%), cerebellar tremor (17%), tardive dystonia (3.3%), and tardive akathisia (3.3%). Concurrence rates of parkinsonism with TD varied significantly according to which clinical signs were used to define parkinsonism. Using a rating score threshold of at least mild, rigidity occurred in 79.3 percent, bradykinesia in 55.2 percent, and resting tremor in 41.4 percent of subjects with TD; more significant rigidity occurred in 41.4 percent, bradykinesia in 31.0 percent, and resting tremor in 20.7 percent. Concurrence rates of neurological conditions with TD subsyndromes were distributed rather evenly according to condition prevalences, except for an association of cervicotruncal TD with bradykinesia (perhaps because of ventromedial striatal presynaptic and postsynaptic D2 blockade, respectively). These findings, as well as the occurrence of equal gender ratio and relative under-representation of bipolar and alcohol disorders in subjects with definite TD, are discussed.

P300 delay and attenuation in schizophrenia: reversal by neuroleptic medication.

BACKGROUND: P300 amplitude reduction in schizophrenia has been found by many investigators, but P300 latency generally has been reported to be normal; however, conflicting findings are present in the literature, and interpretation has been confounded by medication effects and methodological differences. METHODS: This study used a standard auditory oddball paradigm to compare the latency, amplitude, and topographic distribution of P300s in neuroleptic-free schizophrenic patients with those of healthy controls. The patients then were treated for 6 weeks with either remoxipride or haloperidol, and their P300s were reassessed. RESULTS: P300s were attenuated and delayed among neuroleptic-free patients. There was no evidence of peak lateralization or amplitude asymmetry over temporal areas. Subsequent neuroleptic medication normalized P300 latencies and increased P300 amplitudes, but the latter remained below normal limits over all except frontal areas. There were no correlations between P300 latency or amplitude and clinical symptomatology either before or after treatment. CONCLUSIONS: The finding of a P300 delay in neuroleptic-free schizophrenics that is normalized by neuroleptic medication has not been reported previously. Neuroleptic effects on P300 amplitude and latency appear to be independent of effects on clinical symptoms, and cannot be attributed to anticholinergic activity.

Response of cultured cerebral artery smooth muscle cells to the nitric oxide vasodilators, nitroglycerin and sodium nitroprusside.

We characterized the response of soluble guanylyl cyclase in smooth muscle cells cultured from cerebral vessels to the nitric oxide (NO)-producing vasodilators, nitroglycerin (NTG) and sodium nitroprusside (SNP) and determined the ability of these agents to induce tolerance. Smooth muscle cells were isolated from porcine basilar, anterior and middle cerebral, and internal carotid arteries. Following an initial series of experiments using NTG at various concentrations and times of exposure to determine conditions, concentration-response curves of intracellular guanosine 3',5'-cyclic monophosphate (cGMP) to NTG and SNP were determined in cells pretreated for 1 h with 100 mumol NTG to induce tolerance and compared with response curves in control cells. Basal cGMP levels were 2.1 +/- 0.4 pmol/mg cell protein (n = 16). Both NTG and SNP increased cGMP in nontolerant cells, and SNP was more effective. Maximum concentrations of SNP (1 mmol/L) increased cGMP to 163 +/- 5.9 pmol/mg versus 21 +/- 2.4 pmol/mg for 1 mmol/L NTG (p < 0.01). Cells made tolerant to NTG were unresponsive to NTG up to 1 mmol/L but remained responsive to SNP. However, the response curve to SNP was significantly depressed by approximately 25%. Following washout of NTG in tolerant cells, the response of cGMP to SNP returned to control within 12 h, while response to NTG required 36 h. Similar experiments were conducted in cells initially made tolerant to SNP. These results indicate that cerebral artery smooth muscle cells in culture express a functioning soluble guanylyl cyclase and the enzymes that are necessary to metabolize NTG to NO. Prolonged exposure of the cells to NTG induced tolerance as well as cross-tolerance to SNP.

C-natriuretic peptide but not atrial natriuretic peptide increases cyclic GMP in cerebral arterial smooth muscle cells.

A-type natriuretic peptide (ANP) is found primarily in the heart and is released into the circulation. C-type (CNP) is found principally in the brain and has also been detected in the systemic circulation. When injected, both peptides produce vasodilatation most likely by elevation of guanosine 3'5'-cyclic monophosphate (cGMP) in smooth muscle cells via two distinct receptors, NPR-A and NPR-B. In this present study, we determined the effects of these two peptides on intracellular cGMP in smooth muscle cells cultured from pig cerebral and peripheral arteries. In smooth muscle cells cultured from the left anterior descending coronary artery, ANP and CNP increased cGMP with equal potency and efficacy (EC50 for ANP and CNP, 3.6 +/- 0.2 x 10(-8) M and 6.7 +/- 0.8 x 10(-8) M, respectively). In contrast, in smooth muscle cells from cerebral arteries, ANP was without effect while CNP increased cGMP in a concentration dependent manner (EC50: 9.6 +/- 1.7 x 10(-8) M). Stimulation of the soluble guanylyl cyclase with either nitroglycerin or nitroprusside was equivalent in the two cell types. The pattern of response of intracellular cGMP to CNP and ANP in isolated intact arteries from brain and heart was similar to that found in the cultured cells. These results suggest that smooth muscle cells in cerebral arteries express only NPR-B while cells from peripheral arteries can express both NPR-A and NPR-B.

Measurement of blood levels of neuroleptics and metabolites by combined high performance liquid chromatography-radioreceptor assay for D2 and sigma sites.

The dopamine (D2) receptor blocking property of antipsychotic medications has been proposed as the mechanism of the therapeutic activity of this class of drugs. This property has also been exploited as a method to quantify therapeutic levels of these drugs in patients. However, the lack of correlation among dosage, blood levels and clinical response has resulted in a contradictory literature on both mechanism and quantification of these drugs. Bioactivity and chemical identity of the commonly prescribed neuroleptic drug fluphenazine and its metabolites in human plasma were determined by a new method which combines the selectivity of chemical methods with the sensitivity and bioassay of the radioreceptor assay (RRA) method. Fluphenazine and its metabolites were separated and identified in human plasma by an ion-pairing reverse phase high performance liquid chromatographic method with electrochemical detection. A volatile buffer system was employed which was compatible with facile sample preparation for post-column analyses, and which provided sharp, symmetrical chromatographic peaks of parent compound and metabolites. Post chromatography, HPLC fractions were assayed by RRA for D2, alpha 1 and sigma receptors. More than one pattern of metabolism of the drug was seen, including biosynthesis of drug metabolites with biological activities at these receptor types. The individual differences with which this occurs may contribute to the variabilities seen in clinical response to neuroleptics, and to difficulties in neuroleptic blood level determinations.

Human metabolism of phenothiazines to sulfoxides determined by a new high performance liquid chromatography--electrochemical detection method.

The metabolism of phenothiazine drugs may contribute to both their therapeutic and toxic actions by production of active metabolites in vivo. Idiosyncratic reactions or treatment failure may be a consequence of differing patterns of metabolism in different patients. In this report, a modification of our method for the detection of metabolites of phenothiazines is described, which also permits the simultaneous determination of sulfoxide metabolites in human plasma. Application of this method to human plasma identifies marked individual differences in patterns of phenothiazine metabolism.