Biomedical subjects

R Ranjan

Publications and source records attributed to R Ranjan.

At least 37 records · Page 2Linked to original sources

PubMed1999

Ethanol-induced macrophage apoptosis: the role of TGF-beta.

Both clinical and laboratory reports indicate that ethanol addicts are prone to recurrent infections. We hypothesize that ethanol promotes macrophage apoptosis, thus compromising the efficiency of the mononuclear phagocyte system in dealing with infection. We studied the effect of ethanol on macrophage apoptosis. Human monocytes isolated from healthy subjects after an alcohol drinking binge showed enhanced apoptosis (before, 1.2 +/- 0.3% vs after, 28.4 +/- 3.7% apoptotic cells/field). Peritoneal macrophages harvested from ethanol-treated rats also showed increased (p < 0.0001) apoptosis. DNA isolated from peritoneal macrophages of ethanol-treated rats displayed integer multiples of 200 base pairs (ladder pattern). Furthermore, macrophages harvested from ethanol-treated rats had an enhanced expression as well as accumulation of TGF-beta. In in vitro studies, ethanol promoted apoptosis of human monocytes as well as rat peritoneal macrophages. In addition, ethanol enhanced apoptosis of murine macrophages (J774) in a time-dependent manner. The ethanol-induced apoptosis was amplified by LPS and partly attenuated (p < 0.001) by anti-TGF-beta Ab. TGF-beta also promoted macrophage apoptosis in a dose-dependent manner. Moreover, ethanol enhanced TGF-beta protein production by macrophages. These results indicate that ethanol promotes macrophage apoptosis. This effect of ethanol seems to be partly mediated through the generation of TGF-beta by macrophages.

Animals↗

PubMed1999

A novel mechanism of anode-break stimulation predicted by bidomain modeling.

-Anodal stimulation by external pacemakers has been explained on the basis of bidomain models of cardiac tissue. Bidomain models predict that anodal stimuli will hyperpolarize the underlying tissue while adjacent regions become depolarized (virtual cathodes), initiating excitation. We investigated the contribution of active cellular properties to anode-break stimulation. A bidomain model was implemented in which each cell contained realistic ionic currents, including those recruited by hyperpolarization. Simulations reveal that anode-break excitation can originate at the site of stimulation itself and not only from adjacent regions of induced depolarization. The threshold for initiating excitation at the site of stimulation is lower than that for stimulation initiating from adjacent depolarized regions. Thus, incorporation of active cellular properties into a bidomain model predicts a novel mechanism for anode-break stimulation of the heart. The results will improve our understanding of anodal pacing and its risks and benefits in patients.

Action Potentials↗

PubMed1998

Cysteine string protein is required for calcium secretion coupling of evoked neurotransmission in drosophila but not for vesicle recycling.

The entire deletion of the cysteine string protein (CSP) gene causes a temperature-sensitive (ts) block of evoked neurotransmission in Drosophila. CSP has been found to interact in vitro with the clathrin-uncoating ATPase HSC70, suggesting a potential role of CSP in vesicle recycling. Using FM1-43 imaging, we analyzed whether the ts block of neurotransmission in csp mutants is caused by a defect in vesicle exocytosis or vesicle recycling. We determined that FM1-43-labeled synaptic boutons of csp mutant neuromuscular junctions fail to destain at 32 degrees C after K+ depolarization, and that FM1-43 dye uptake cannot be evoked by K+ stimulation at 32 degrees C. However, when we stimulated dye uptake independent of depolarization by using black widow spider venom (BWSV), we observed endocytotic uptake of FM1-43. This suggests that endocytosis exhibits no primary ts defect. In addition, we found no ts defect of vesicle recycling at 32 degrees C that would correlate with the ts block of neurotransmission. We also discovered that BWSV and the calcium ionophore calcimycin stimulate FM1-43 destaining and quantal release in csp mutants at 32 degrees C when depolarization fails to evoke any response. The wild-type-like, calcimycin-induced response in csp null mutants indicates that some aspect of the depolarization-dependent calcium signaling pathway must be impaired, either calcium entry, calcium action, or both. Collectively, our results indicate that the csp mutation affects calcium secretion coupling of evoked exocytosis but not vesicle recycling. This supports the hypothesis that CSP links synaptic vesicles to calcium secretion coupling.

Animals↗

PubMed1998

Mechanism of anode break stimulation in the heart.

Anodal stimulation is routinely observed in cardiac tissue, but only recently has a mechanism been proposed. The bidomain cardiac tissue model proposes that virtual cathodes induced at sites distant from the electrode initiate the depolarization. In contrast, none of the existing cardiac action potential models (Luo-Rudy phase I and II, or Oxsoft) predict anodal stimulation at the single-cell level. To determine whether anodal stimulation has a cellular basis, we measured membrane potential and membrane current in mammalian ventricular myocytes by using whole-cell patch clamp. Anode break responses can be readily elicited in single ventricular cells. The basis of this anodal stimulation in single cells is recruitment of the hyperpolarization-activated inward current I(f). The threshold of activation for I(f) is -80 mV in rat cells and -120 mV in guinea pig or canine cells. Persistent I(f) "tail" current upon release of the hyperpolarization drives the transmembrane potential toward the threshold of sodium channels, initiating an action potential. Time-dependent block of the inward rectifier, I(K1), at hyperpolarized potentials decreases membrane conductance and thereby potentiates the ability of I(f) to depolarize the cell on the break of an anodal pulse. Inclusion of I(f), as well as the block and unblock kinetics of I(K1), in the existing Luo-Rudy action potential model faithfully reproduces anode break stimulation. Thus active cellular properties suffice to explain anode break stimulation in cardiac tissue.

Action Potentials↗

PubMed1998

Morphine modulates proliferation of kidney fibroblasts.

Renal interstitial scarring is an important component of heroin-associated nephropathy. Kidney fibroblasts have been demonstrated to play a role in the development of renal scarring in a variety of renal diseases. We studied the effect of morphine, an active metabolite of heroin, on the proliferation of kidney fibroblasts. Morphine at a concentration of 10(-12) M enhanced (P < 0.001) the proliferation of kidney fibroblasts (control, 67.5 +/- 2.0 vs. morphine, 112.2 +/- 10.1 x 10(4) cells/well). [3H]thymidine incorporation studies further confirmed these results. Morphine at concentrations of 10(-12) M to 10(-10) M also modulated mRNA expression of early growth related genes (c-fos, c-jun and c-myc). Morphine at concentrations of 10(-8) to 10(-4) M promoted apoptosis of kidney fibroblasts and also enhanced the synthesis of p53 by kidney fibroblasts. We speculate that morphine-induced kidney fibroblast proliferation may be mediated through the activation of early growth related genes, whereas morphine induced kidney fibroblast apoptosis may be mediated through the generation of p53. The present in vitro study provides a hypothetical basis for the role of morphine in the development of renal interstitial scarring in patients with heroin-associated nephropathy.

Animals↗

PubMed1998

HIV-1 gp120 envelope protein and morphine-tubular cell interaction products modulate kidney fibroblast proliferation.

BACKGROUND: Renal interstitial scarring is an important feature of HIV-associated nephropathy. Intravenous drug abuse has been demonstrated to be a risk factor for the development of HIV-associated nephropathy in patients with HIV infection. We studied the effect of tubular cell-morphine and/or HIV-1 gp120 envelope protein interaction products on kidney fibroblast (KF) proliferation and apoptosis. METHODS: Tubular cell-morphine and/or gp120 interaction products were prepared by incubating confluent human proximal tubular cells with buffer (TCP), morphine (10(-3) mol/L) (TCM-IP), gp120 (0.01 microgram/mL)(TC-120IP), or morphine (10(-3) mol/L) + gpl20 (0.01 microgram/mL) (TCM-120IP). To evaluate the effect of tubular cell interaction products (TCIP) on KF proliferation, growth arrested kidney fibroblasts were treated with variable concentrations (5%, 10%, 20%, 30%, and 50%) of TCP, TCM-IP, TC-120IP, or TCM-120IP for 48 hours. To evaluate the role of cytokines in TCIP-induced KF proliferation, cells were incubated with TCIP with or without cytokine neutralizing antibodies to TGF-beta, TNF-alpha, FGF, or IL-6 for 48 hours. Subsequently, cells were counted in a hemocytometer (n = 3). To evaluate the effect of TCIP on KF apoptosis, cells were treated with 50% TCP, 50% TCM-IP, 50% TC-120IP, or 50% TCM-120IP for 24 hours and stained with H-33342 and propidium iodide. In parallel experiments KFs were harvested under identical conditions, DNA was isolated and run on gel electrophoresis. To evaluate the role of early growth genes in TCM-120-induced KF proliferation, TCM-120IP-treated cells were probed with cDNA for c-fos and c-jun. RESULTS: TC-120IP at a lower concentration (20%) enhanced (P < 0.001) proliferation of KF when compared with TCP. TCM-IP did not stimulate KF proliferation. On the contrary, TCM-120IP at a lower concentration (20%) promoted (P < 0.001) KF proliferation when compared with TCP, TCM-IP and TC-120IP. TCM-120IP at a lower concentration (20%) also enhanced KF mRNA expression of c-fos and c-jun. TCM-120IP enhanced KF proliferation in a dose-dependent manner. All tubular cell interaction products at a higher concentration (50%) promoted apoptosis of KF. CONCLUSIONS: Tubular cell-gp120 interaction products stimulated KF proliferation. Morphine amplified the effect of tubular cell-gp120 interaction on the proliferation of KF. TCM-120IP-induced KF proliferation may be mediated through the expression of early growth genes; whereas TCM-120IP-induced KF growth suppression may be mediated through the induction of apoptosis.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Effect of varying pacing waveform shapes on propagation and hemodynamics in the rabbit heart.

The propagation characteristics of myocardium stimulated with anodal, cathodal, and equiphasic biphasic pacing pulses were examined in Langendorff-perfused rabbit hearts. Conduction velocity measurements were made using an array of bipolar extracellular electrodes, transmembrane potentials recorded using floating intracellular microelectrodes, and hemodynamics measured by fluid-filled catheter transducer systems. Anodal (A) stimulation pulses improved the electrical conduction at all the stimulus amplitudes tested in both longitudinal (e.g., 5 V 2-msec pulse: [A] 54.9 +/- 0.7 cm/sec; cathodal [C] 49.7 +/- 1.5 cm/sec) and transverse (e.g., 5 V 2 msec pulse: [A] 31.3 +/- 1.7 cm/sec; [C] 23.3 +/- 2.9 cm/sec) directions. Microelectrode recordings verified that increased conduction velocities of the anodal pulses were associated with faster upstrokes of the action potentials. The increased threshold associated with anodal pulses may be overcome by using a biphasic (B) waveform, in effect adding a second phase (e.g., 2-msec pulse: [A] 2.03 +/- 1.3 V; [C] 3.85 +/- 1.5 V; [B] 2.15 +/- 0.9 V). The conduction speeds achieved by the biphasic pulses were found to be comparable to the equivalent anodal pulses (e.g., 5 V 2-msec pulse: [B] 55.2 +/- 1.7 cm/sec longitudinal and 32.4 +/- 2.1 cm/sec transverse). It is postulated that the enhanced conduction by anodal and biphasic pulses may be due to preconditioning of the myocardium before stimulation, resulting in more vigorous action potential upstrokes. In preliminary experiments, it was observed that improved conduction elicited by these pulses also resulted in enhanced contractility as measured by shortened electromechanical delays and faster rate of rise of pressure development (dP/dtmax: [A] 25.4 +/- 0.4 mm Hg/sec; [C] 19.4 +/- 0.8 mm Hg/sec; [B] 25.7 +/- 1.2 mm Hg/sec, respectively). Use of novel hybrid pulses involving an anodal component may offer a way for implanted pacemakers to enhance the electro-mechanical response of the heart.

Action Potentials↗

PubMed1997

Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs.

Recently, an acute phase (AP) protein response has been reported in major depression. In order to examine whether an AP response occurs in other psychiatric disorders, such as schizophrenia and mania, the authors measured plasma AP reactants, such as haptoglobin (Hp), immunoglobulin G (IgG), IgM, fibrinogen (Fb), complement component 3 (C3C), C4, alpha 1-antitrypsin (alpha 1 AT), alpha 1-acid-glycoprotein (alpha 1S) and hemopexin (Hpx), in 27 schizophrenic, 23 manic, 29 major depressed and 21 normal subjects. Schizophrenic patients had significantly higher plasma Hp, Fb, C3C, C4, alpha 1S and Hpx than normal controls. Manic subjects showed significantly higher plasma Hp, Fb, alpha 1S and Hpx than normal volunteers. Depressed subjects had significantly higher plasma Hp, Fb, C3C, C4 and alpha 1S than normal controls. Overall, the above disorders in AP reactants were more pronounced in schizophrenic than in depressed subjects. No significant differences in the above AP reactants could be found between normal volunteers, and schizophrenic, manic or depressed patients who underwent chronic treatment with psychotropic drugs. Plasma Hp, Fb, C3C, C4, alpha 1S, and Hpx were significantly higher in schizophrenic, manic and depressed patients who were non-medicated than in those who were treated with antidepressants, antipsychotics or lithium. The results suggest that not only major depression but also schizophrenia and mania are accompanied by an AP response, and that the latter may be suppressed by (sub)chronic treatment with psychotropic drugs.

Acute-Phase Proteins↗

PubMed1997

Molecular motions within the pore of voltage-dependent sodium channels.

The pores of ion channel proteins are often modeled as static structures. In this view, selectivity reflects rigidly constrained backbone orientations. Such a picture is at variance with the generalization that biological proteins are flexible, capable of major internal motions on biologically relevant time scales. We tested for motions in the sodium channel pore by systematically introducing pairs of cysteine residues throughout the pore-lining segments. Two distinct pairs of residues spontaneously formed disulfide bonds bridging domains I and II. Nine other permutations, involving all four domains, were capable of disulfide bonding in the presence of a redox catalyst. The results are inconsistent with a single fixed backbone structure for the pore; instead, the segments that line the permeation pathway appear capable of sizable motions.

Amino Acid Sequence↗

PubMed1997

Mechanisms of sodium/calcium selectivity in sodium channels probed by cysteine mutagenesis and sulfhydryl modification.

A conserved lysine residue in the "P loop" of domain III renders sodium channels highly selective. Conversion of this residue to glutamate, to mimic the homologous position in calcium channels, enables Ca2+ to permeate sodium channels. Because the lysine-to-glutamate mutation converts a positively charged side chain to a negative one, it has been proposed that a positive charge at this position suffices for Na+ selectivity. We tested this idea by converting the critical lysine to cysteine (K1237C) in mu 1 rat skeletal sodium channels expressed in Xenopus oocytes. Selectivity of the mutant channels was then characterized before and after chemical modification to alter side-chain charge. Wild-type channels are highly selective for Na+ over Ca2+ (PCa/PNa < 0.01). The K1237C mutation significantly increases permeability to Ca2+ (PCa/PNa = 0.6) and Sr2+. Analogous mutations in domains I (D400C), II (E755C), and IV (A1529C) did not alter the selectivity for Na+ over Ca2+, nor did any of the domain IV mutations (G1530C, W1531C, and D1532C) that are known to affect monovalent selectivity. Interestingly, the increase in permeability to Ca2+ in K1237C cannot be reversed by simply restoring the positive charge to the side chain by using the sulfhydryl modifying reagent methanethiosulfonate ethylammonium. Single-channel studies confirmed that modified K1237C channels, which exhibit a reduced unitary conductance, remain permeable to Ca2+, with a PCa/PNa of 0.6. We conclude that the chemical identity of the residue at position 1237 is crucial for channel selectivity. Simply rendering the 1237 side chain positive does not suffice to restore selectivity to the channel.

Amino Acid Sequence↗

PubMed1997

Components of biological variation, including seasonality, in blood concentrations of TSH, TT3, FT4, PRL, cortisol and testosterone in healthy volunteers.

OBJECTIVE: There are few detailed studies of annual or seasonal variations in hormone concentrations in man. This study examines the components of biological variation, including seasonality, in plasma TSH, total T3 (TT3), free T4 (FT4), PRL, cortisol and testosterone in healthy volunteers. DESIGN: Monthly blood samplings for the assay of the above hormones were collected during one calendar year. SUBJECTS: Thirteen normal men and 13 normal women participated in the present study (mean age 38.7 +/- 13.4 years). MEASUREMENTS: Assays of TSH, TT3 and FT4 were carried out by means of immunoradiometric assays (IRMA), PRL by ELISA, cortisol by a fluorescence immunoassay, and testosterone with RIA. The time series were analysed by means of (bivariate or multivariate) spectral and cosinor analyses. RESULTS: Significant annual, four-monthly and biannual rhythms were detected in serum TSH; the lowest TSH values were observed in spring. A significant annual rhythm was detected in TT3, with lower values in spring and summer than in the other seasons. The peak-trough differences in the yearly variation expressed as a percentage of the mean were 29.1% and 8.2% for TSH and TT3, respectively. The yearly variation in plasma cortisol was significantly different between men and women: in men, 5.9% of the variation was explained by an annual rhythm, while in women 14.7% was explained by the fourth and seventh harmonical wave. The peak-trough differences in the yearly variation in plasma cortisol were 17.6% and 31.8% in men and women, respectively. There were no significant seasonal rhythms in PRL, FT4 or testosterone. The intraindividual/interindividual CV values were: TSH 29.3/48.4%, TT3 9.4/ 18.5%, FT4 7.1/9.1%, PRL 39.2/65.0%, cortisol 21.7/ 46.2%, and testosterone 12.6/40.8%. CONCLUSIONS: The degree of individuality measured in the plasma hormones is such that conventional population-based reference ranges may not correctly identify major alterations in these hormones in individual subjects.

Adult↗

PubMed1997

Estimation of the ventricular fibrillation duration by autoregressive modeling.

An accurate estimation of ventricular fibrillation (VF) duration could be critical in selecting the most effective therapeutic intervention. We test the hypothesis that changes in frequency content of VF signals can be quantified by using autoregressive (AR) modeling, and the duration since the onset of VF can be estimated by using this method. VF signals were recorded for up to 300 s in five isolated rabbit hearts. Fourth-order AR parameters of successive segments were estimated, and frequencies of the first poles (the pole with lower frequency) were pooled together and a curve was fitted: F(t) = A exp (-alpha t) + B, where F(t) is the estimated frequency of the first pole at t'th time instant, alpha is the decay constant, B is the offset frequency, and A is the frequency at time zero minus the offset frequency. The utility of this curve in estimating the VF duration was tested in four new experiments, and the difference between the actual and the estimated VF duration (estimation error) was calculated. F(t), the frequency of the first pole, decreased from 12 to 6 Hz with duration of:VF, while the frequency of the other pole decreased from 25 to 20 Hz. Parameters of the fitted curve were calculated as A = 7.8, alpha = 0.0041 and B was selected as four. Testing on a new set of VF signals produced very little estimation error for the first 100 s of VF, although this error increased with VF duration. For these new signals, the mean value of the absolute estimation error was 26 s. Results of this study show that changes in the frequency content of electrocardiogram (ECG) during VF can be quantified by AR modeling and that the frequency changes associated with a pole of this model can be used to estimate the VF duration.

Algorithms↗

PubMed1997

Age at onset and gender of schizophrenic patients in relation to neuroleptic resistance.

OBJECTIVE: The age at onset of schizophrenia for males has usually but not always been reported to be less than that for females. Early onset has also been associated with poor response to neuroleptic treatment and worse long-term outcome. The authors compared age at onset in neuroleptic-resistant and -responsive schizophrenic patients to determine whether the gender difference in age at onset is related to response to neuroleptic treatment. METHOD: The subjects were 322 patients with schizophrenia or schizoaffective disorder who were consecutively admitted to a university hospital-based research program. RESULTS: Analysis of variance showed significant relationship between age at onset and both gender and longterm responsivity to neuroleptic drugs. The mean ages at onset in the neuroleptic-responsive men (mean = 21.2 years, SD = 6.1, N = 75), neuroleptic-resistant men (mean = 19.4 years, SD = 4.7, N = 119), and neuroleptic-resistant women (mean = 20.1 years, SD = 6.3, N = 77) were fairly similar, whereas that of the neuroleptic-responsive women (mean = 24.2 years, SD = 8.7, N = 51) was significantly greater than for all other groups. A simple effects model indicated that male and female neuroleptic-resistant patients did not differ significantly in mean age at onset, whereas male and female neuroleptic-responsive patients did. The effect of gender and neuroleptic responsivity on age at onset was related to schizophrenic subtype. CONCLUSIONS: These results confirm previous data indicating neuroleptic resistance is associated with early onset. The finding that the difference in age at onset between males and females is smaller in neuroleptic-resistant patients than in neuroleptic-responsive patients suggests that neuroleptic-resistant patients differ premorbidly as well as after onset of illness.

Adolescent↗

PubMed1996

Increased serum soluble CD8 or suppressor/cytotoxic antigen concentrations in depression: suppressive effects of glucocorticoids.

There is now some evidence that depression and, in particular, major depression, is accompanied by signs of an immune response, and that there are reciprocal relationships between immune function and increased hypothalamic-pituitary-adrenal (HPA) axis activity in depression. To further examine the above phenomena, this study has assayed serum soluble CD8 (sCD8) concentrations in 22 normal controls, 27 minor depressed, 37 major depressed, and 26 melancholic depressed patients. Serum sCD8 was significantly higher in depressed patients versus normal controls. Thirty-five percent of the depressed subjects had increased sCD8 serum levels (i.e., > 560 U/mL) with a specificity of 95.4%. Dexamethasone administration (1 mg PO) had a significant suppressive effect on serum sCD8. In depressed subjects, there were significant and negative relationships between serum sCD8 and postdexamethasone cortisol values. The results suggest the presence of an ongoing lymphocyte activation in depression, which may be down-regulated by increased HPA axis activity in that illness.

Adult↗

PubMed1996

Acute and long-term effectiveness of clozapine in treatment-resistant psychotic depression.

The treatment of refractory major depression, including the psychotic subtype, is a therapeutic challenge. Three cases of resistant psychotic depression were treated with clozapine monotherapy, an atypical antipsychotic drug effective in treatment-resistant schizophrenia and mania. Both psychotic and mood symptoms responded well to clozapine monotherapy, although response was delayed in one case. Tardive dyskinesia improved markedly, and tardive dystonia improved moderately in one patient. No patient relapsed during a follow-up period of 4-6 years of clozapine treatment. Clozapine was well-tolerated with few side effects. These observations suggest controlled trials of clozapine in the treatment of psychotic depression that fails to respond to electroconvulsive therapy or typical neuroleptics plus tricyclic antidepressants are indicated. The same is true for the use of clozapine in maintenance treatment for psychotic depression in those cases in which typical neuroleptic drugs are required, in order to reduce the risk of tardive dyskinesia and dystonia.

Adult↗

PubMed1996

Lower serum transcortin (CBG) in major depressed females: relationships with baseline and postdexamethasone cortisol values.

This study has been carried out to examine (i) transcortin or corticosteroid binding globulin (CBG), the major glucocorticoid transport protein, in major depressed versus minor depressed and normal subjects; and (ii) the relationships between CBG and basal and postdexamethasone cortisol or adrenocorticotropic hormone (ACTH) values. Serum CBG was significantly lower in major depressed than in minor depressed subjects and normal controls. The significant decrease in serum CBG was observed in major depressed women but not in major depressed men. In depressed subjects, there was a significant and negative relationship between serum CBG and severity of illness. There were significant positive relationships between serum CBG and basal 8:00 a.m. plasma cortisol in normal volunteers (r = 0.87, P < 10(-4)) and depressed subjects (r = 0.40, P = 0.0002). There was no significant relationship between serum CBG and 24-h urinary cortisol. In depressed patients, there was a positive relationship between serum CBG and postdexamethasone cortisol (r = 0.31, P = 0.003). It is concluded that, in depression, serum CBG levels should be taken into consideration for the interpretation of baseline and postdexamethasone plasma total cortisol levels.

Adjustment Disorders↗

PubMed1996

Relapse following clozapine withdrawal: effect of neuroleptic drugs and cyproheptadine.

The objective of this study was to report the effect of the slow withdrawal of clozapine from 19 patients with neuroleptic-responsive schizophrenia at the end of a 2-year clinical trial of clozapine and to compare this with the results of naturalistic discontinuation of clozapine treatment in 64 neuroleptic-resistant schizophrenic patients. Nineteen neuroleptic-responsive schizophrenic patients who received clozapine were withdrawn from clozapine by tapering it over 3-week period with and without the addition of a typical neuroleptic. Fifteen of the 19 neuroleptic-responsive patients experienced the return of psychotic symptoms during or after the clozapine taper, which were most severe in the ten patients in whom the withdrawal of clozapine was carried out without prior addition of neuroleptic treatment. Addition of a neuroleptic prior to clozapine withdrawal prevented the emergence of positive symptoms during clozapine withdrawal in each of eight patients. Nevertheless, psychotic symptoms emerged, usually within a week after discontinuing clozapine, in six of the eight patients. Neuroleptic treatment, with or without an anticholingergic drug, was much less effective in treating positive symptoms in these patients immediately after the clozapine withdrawal than it had been 2 years previously. Cyproheptadine, a non-selective serotonin receptor antagonist, augmented the antipsychotic effect of neuroleptics in each of four patients who relapsed following withdrawal from clozapine and relieved extrapyramidal symptoms in a fifth patient. The frequency of relapse following withdrawal of clozapine in 64 neuroleptic-resistant patients was significantly lower (25/64, 39.1%) than in the neuroleptic-responsive patients.

Adult↗

PubMed1996

Neuropsychologic deficits in schizophrenia: relation to social function and effect of antipsychotic drug treatment.

Cognitive impairment is present in the majority of schizophrenic patients, even at the onset of psychosis. It is a relatively stable characteristic in most patients, usually with little progression over the course of illness, but sometimes progresses to severe dementia. The results of studies of the effects of typical neuroleptic drugs on cognitive functioning in schizophrenia are conflicting. Clozapine, which has superior antipsychotic effects compared to typical neuroleptic drugs, has been reported to improve executive function, verbal fluency, attention, and recall memory in two of three studies. Cognitive measures predict work function and overall outcome on clozapine as assessed by the Global Assessment Scale and Quality-of-Life Scale in neuroleptic--resistant schizophrenia. Improvement in cognitive function by clozapine may be a major reason for expanding its currently limited utilization.

Antipsychotic Agents↗