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Schizophrenia is a severe neuropsychiatric disease associated with substantially higher mortality. Reduced life expectancy in schizophrenia relates to an increased prevalence of metabolic disturbance, and antipsychotic medication is a major contributor. Molecular mechanisms underlying adverse metabolic effects of antipsychotics are not fully understood; however, adipose tissue homeostasis deregulation appears to be a critical factor. We employed mass spectrometry-based untargeted proteomics to assess the effect of chronic olanzapine, risperidone, and haloperidol treatment in visceral adipose tissue of prenatally methylazoxymethanol (MAM) acetate exposed rats, a well-validated neurodevelopmental animal model of schizophrenia. Bioinformatics analysis of differentially expressed proteins was performed to highlight the pathways affected by MAM and the antipsychotics treatment. MAM model was associated with the deregulation of the TOR (target of rapamycin) signalling pathway. Notably, alterations in protein expression triggered by antipsychotics were observed only in schizophrenia-like MAM animals where we revealed hundreds of affected proteins according to our two-fold threshold, but not in control animals. Treatments with all antipsychotics in MAM rats resulted in the downregulation of mRNA processing and splicing, while drug-specific effects included among others upregulation of insulin resistance (olanzapine), upregulation of fatty acid metabolism (risperidone), and upregulation of nucleic acid metabolism (haloperidol). Our data indicate that deregulation of several energetic and metabolic pathways in adipose tissue is associated with APs administration and is prominent in MAM schizophrenia-like model but not in control animals., (Copyright © 2020. Published by Elsevier Inc.)

Early studies suggest that selective α2C-adrenoceptor (AR)-antagonism has anti-psychotic-like and pro-cognitive properties. However, this has not been demonstrated in an animal model of schizophrenia with a neurodevelopmental construct. The beneficial effects of clozapine in refractory schizophrenia and associated cognitive deficits have, among others, been associated with its α2C-AR modulating activity. Altered brain-derived neurotrophic factor (BDNF) has been linked to schizophrenia and cognitive deficits. We investigated whether the α2C-AR antagonist, ORM-10921, could modulate sensorimotor gating and cognitive deficits, as well as alter striatal BDNF levels in the social isolation reared (SIR) model of schizophrenia, comparing its effects to clozapine and the typical antipsychotic, haloperidol, the latter being devoid of α2C-AR-activity. Moreover, the ability of ORM-10921 to augment the effects of haloperidol on the above parameters was also investigated. Animals received subcutaneous injection of either ORM-10921 (0.01mg/kg), clozapine (5mg/kg), haloperidol (0.2mg/kg), haloperidol (0.2mg/kg)+ORM-10921 (0.01mg/kg) or vehicle once daily for 14days, followed by assessment of novel object recognition (NOR), prepulse inhibition (PPI) of startle response and striatal BDNF levels. SIR significantly attenuated NOR memory as well as PPI, and reduced striatal BDNF levels vs. social controls. Clozapine, ORM-10921 and haloperidol+ORM-10921, but not haloperidol alone, significantly improved SIR-associated deficits in PPI and NOR, with ORM-10921 also significantly improving PPI deficits vs. haloperidol-treated SIR animals. Haloperidol+ORM-10921 significantly reversed reduced striatal BDNF levels in SIR rats. α2C-AR-antagonism improves deficits in cognition and sensorimotor gating in a neurodevelopmental animal model of schizophrenia and bolsters the effects of a typical antipsychotic, supporting a therapeutic role for α2C-AR-antagonism in schizophrenia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Pleckstrin homology domain (PH domain) comprises approximately 120 amino acids and is integrated in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton. This domain can bind phosphatidylinositol (3,4,5)-triphosphate and phosphatidylinositol (4,5)-biphosphate and proteins such as the βγ-subunits of heterotrimeric G proteins and protein kinase C. Associations with psychiatric diseases have not been investigated yet. To identify genes involved in response to antipsychotics, mice were treated with haloperidol (1mg/kg, n = 11) or saline (n = 12) for one week. By analyzing microarray data, we observed an increase of pleckstrin homology domain containing 6 (PLEKHA6) gene expression. Furthermore, we genotyped 263 schizophrenic patients, who were treated monotherapeutically with different antipsychotics within randomized-controlled trials. Psychopathology was measured weekly using the PANSS for a minimum of four and a maximum of twelve weeks. Correlations between PANSS subscale scores at baseline and PANSS improvement scores after four weeks of treatment and genotypes were calculated by using a linear model for all investigated SNPs. We found associations between four PLEKHA6 polymorphisms (rs17333933 (T/G), rs3126209 (C/T), rs4951338 (A/G) and rs100900571 (T/C)) and different PANSS subscales at baseline. Furthermore two different polymorphisms (rs7513240 (T/C), rs4951353 (A/G)) were found to be associated with therapy response in terms of a significant correlation with different PANSS improvement subscores after four weeks of antipsychotic treatment. Our observation of an association between genetic polymorphisms of a protein of the PH domain and psychopathology data in schizophrenic patients might be indicative for an involvement of PLEKHA6 in the pathophysiology of schizophrenia and the therapy response towards antipsychotics., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Clinical observations suggest that antipsychotic effect starts early and increases progressively over time. This time course of antipsychotic effect can be captured in a rat phencyclidine (PCP)-induced hyperlocomotion model, as repeated antipsychotic treatment progressively increases its inhibition of the repeated PCP-induced hyperlocomotion. Although the neural basis of acute antipsychotic action has been studied extensively, the system that mediates the potentiated effect of repeated antipsychotic treatment has not been elucidated. In the present study, we investigated the neuroanatomical basis of the potentiated action of haloperidol (HAL) and clozapine (CLZ) treatment in the repeated PCP-induced hyperlocomotion. Once daily for five consecutive days, adult Sprague-Dawley male rats were first injected with HAL (0.05 mg/kg, sc), CLZ (10.0 mg/kg, sc) or saline, followed by an injection of PCP (3.2 mg/kg, sc) or saline 30 min later, and motor activity was measured for 90 min after the PCP injection. C-Fos immunoreactivity was assessed either after the acute (day 1) or repeated (day 5) drug tests. Behaviorally, repeated HAL or CLZ treatment progressively increased the inhibition of PCP-induced hyperlocomotion throughout the five days of drug testing. Neuroanatomically, both acute and repeated treatment of HAL significantly increased PCP-induced c-Fos expression in the nucleus accumbens shell (NAs) and the ventral tegmental area (VTA), but reduced it in the central amygdaloid nucleus (CeA). Acute and repeated CLZ treatment significantly increased PCP-induced c-Fos expression in the ventral part of lateral septal nucleus (LSv) and VTA, but reduced it in the medial prefrontal cortex (mPFC). More importantly, the effects of HAL and CLZ in these brain areas underwent a time-dependent reduction from day 1 to day 5. These findings suggest that repeated HAL achieves its potentiated inhibition of the PCP-induced hyperlocomotion by acting on the NAs, CeA and VTA, while CLZ does so by acting on the mPFC, LSv and VTA., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Schizophrenia is a chronic and highly complex psychiatric disorder characterised by cognitive dysfunctions, negative and positive symptoms. The major challenge in schizophrenia research is lack of suitable animal models that mimic the core behavioural aspects and symptoms of this devastating psychiatric disorder. In this study, we used classical and atypical antipsychotic drugs to examine the predictive validity of ketamine-enhanced immobility in forced swim test (FST) as a possible animal model for the negative symptoms of schizophrenia. We also evaluated the effects of a selective serotonin reuptake inhibitor (SSRI) on the ketamine-enhanced immobility in FST. Repeated administration of a subanaesthetic dose of ketamine (30 mg kg(-1), i.p., daily for 5 days) enhanced the duration of immobility in FST 24 h after the final injection. The effect, which persisted for at least 21 days after withdrawal of the drug, was neither observed by single treatment with ketamine (30 mg kg(-1) i.p.) nor repeated treatment with amphetamine (1 and 2 mg kg(-1) i.p., daily for 5 days). The enhancing effects of ketamine (30 mg kg(-1) day(-1) i.p.) on the duration of immobility in the FST were attenuated by clozapine (1, 5 and 10 mg kg(-1) i.p.), risperidone (0.25 and 0.5 mg kg(-1) i.p.) and paroxetine (1 and 5 mg kg(-1) i.p.). Haloperidol (0.25 and 0.50 mg kg(-1) day(-1) i.p.) failed to attenuate the ketamine-enhanced immobility in the FST. The repeated ketamine administration neither affects locomotor activity nor motor coordination in rats under the same treatment conditions with the FST, suggesting that the effects of ketamine on the duration of immobility in this study was neither due to motor dysfunction nor peripheral neuromuscular blockade. Our results suggest that repeated treatment with subanaesthetic doses of ketamine enhance the duration of immobility in FST, which might be a useful animal model for the negative symptoms (particularly the depressive features) of schizophrenia., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Hyperprolinemia is an inherited disorder of proline metabolism and patients affected by this disease may present neurological manifestations, including seizures and cognitive dysfunctions. Moreover, an association between adulthood schizoaffective disorders and moderate hyperprolinemia has been reported. However, the mechanisms underlying these behavioral phenotypes still remain unclear. In the present study, we investigated the effect of proline treatments on behavioral parameters in zebrafish, such as locomotor activity, anxiety, and social interaction. Adult zebrafish (Danio rerio) were exposed to proline (1.5 and 3.0 mM) during 1h or 7 days (short- or long-term treatments, respectively). Short-term proline exposure did not promote significant changes on the behavioral parameters observed. Long-term exposure at 1.5 mM proline significantly increased the number of line crossing (47%), the total distance (29%), and the mean speed (33%) when compared to control group. A significant increase in the time spent in the upper portion of the test tank was also observed after this treatment (91%), which may be interpreted as an indicator of anxiolytic behavior. Proline at 1.5 mM also induced social interaction impairment (78%), when compared to the untreated group after long-term treatment. Moreover, these proline-induced behavioral changes in zebrafish were completely reversed by acute administration of an atypical antipsychotic drug (sulpiride), but not by a typical (haloperidol). These findings demonstrate that proline is able to induce schizophrenia-like symptoms in zebrafish, which reinforce the use of this species as a complementary vertebrate model for studying behavioral phenotypes associated with neurological dysfunctions characteristic of metabolic diseases., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The neurotoxicity of antipsychotic (AP) drugs seems to be linked with neurological side effects like extrapyramidal symptoms (EPS). On the other hand, neuroprotective effects can mitigate or slow the progressive degenerative structural changes in the brain leading to improved outcome of schizophrenia. First and second-generation antipsychotics may differ in their neurotoxic and neuroprotective properties. The aim of this study was to compare the neurotoxic/neuroprotective activity of haloperidol, a first-generation antipsychotic, and risperidone, a second-generation one, with paliperidone, a relatively new second-generation antipsychotic, in SK-N-SH cells. Haloperidol, risperidone and paliperidone (10, 50, 100 μM) were administered, either alone or in combination with dopamine (100 μM), to human neuroblastoma SK-N-SH. We examined the effects of the drugs on cell viability (measured by alamarBlue®), caspase-3 activity (measured by fluorimetric assay) and cell death (by measuring the externalization of phosphatidylserine). Haloperidol significantly decreased cell viability and increased caspase-3 activity and cell death. Risperidone and paliperidone did not affect cell viability or cell death. Both second-generation APs decreased caspase-3 activity, especially paliperidone. In cells treated with dopamine in combination with antipsychotics, only paliperidone (10 μM) induced a slight improvement in cell viability. While haloperidol potentiated the dopamine-induced increase in caspase-3 activity, risperidone and paliperidone reduced this effect. The results indicate that haloperidol induces apoptosis, whereas risperidone and paliperidone may afford protection against it. Of the APs tested, paliperidone always showed the strongest neuroprotective effect. The different antipsychotic effects on survival and cell death might be related to differences in their capacity to induce EPS., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Metabolic adversities are prevalent in patients with schizophrenia. Retinol-binding protein 4 (RBP4) and high molecular weight (HMW) adiponectin have been recently found to be associated with metabolic features in non-psychiatric population. The study aimed to evaluate the associations between metabolic features and RBP4, total adiponectin, and HMW adiponectin in patients with schizophrenia., Methods: We recruited 109 patients with schizophrenia treated with clozapine or haloperidol and evaluated their body mass index (BMI), waist circumference, blood pressure, and fasting triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose, insulin, RBP4, total adiponectin, and HMW adiponectin levels., Results: We found that patients with metabolic syndrome (MS) had higher RBP4 level, and lower total adiponectin and HMW adiponectin levels than those without MS. There were no significant differences in metabolic features and adipocytokine levels between patients treated with clozapine and haloperidol. Most of the metabolic indexes were significantly correlated with the levels of adipocytokines. After adjusting the effects of age, gender, and BMI, marginal significant correlations existed between TG and RBP4 levels; HDL-C and total adiponectin and HMW adiponectin; insulin and HOMA-IR and HMW adiponectin. Receiver operating curve analysis showed that all of the three adipocytokines could differentiate patients with MS from those without MS. Meanwhile, total adiponectin and HMW adiponectin, but not RBP4, had the differentiating power for insulin resistance., Conclusion: Higher RBP4 and lower total adiponectin and HMW adiponectin levels were observed in schizophrenic patients with MS. Only HMW adiponectin is marginally correlated with insulin sensitivity. The finding that metabolic profiles, but not the antipsychotic types, are associated with adipocytokine levels should be confirmed in longitudinal studies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Schizophrenic patients are heterogeneous with respect to voluntary eye movement performance, with some showing impairment (e.g., high antisaccade error rates) and others having intact performance. To investigate how this heterogeneity may correlate with different cognitive outcomes after treatment, we used a prosaccade and antisaccade task to investigate the effects of haloperidol in schizophrenic subjects at three time points: baseline (before medication), 3-5 days post-medication, and 12-14 days post-medication. We also investigated changes on the Stroop Task and the Positive and Negative Syndrome Scale (PANSS) in these same subjects. Results were compared to matched controls. When considered as a single patient group, haloperidol had no effects across sessions on reflexive and voluntary saccadic eye movements of schizophrenic patients. In contrast, the performance of the Control group improved slightly but significantly across sessions on the voluntary eye movement task. When each subject was considered separately, interestingly, for schizophrenic patients change in voluntary eye movement performance across sessions depended on the baseline performance in a non-monotonic manner. That is, there was maximal worsening of voluntary eye movement performance at an intermediate level of baseline performance and the worsening decreased on either side of this intermediate baseline level. When patients were divided into categorical subgroups (nonimpaired and impaired), consistent with the non-monotonic relationship, haloperidol worsened voluntary eye movement performance in the nonimpaired patients and improved performance in the impaired patients. These results were only partially reflected in the Stroop Test. Both patient subgroups showed clinically significant improvement over time as measured by the PANSS. These findings suggest that haloperidol has different effects on cognitive performance in impaired and nonimpaired schizophrenic patients that are not evident in clinical ratings based on the PANSS. Given that good cognitive function is important for long-term prognosis and that there is heterogeneity in schizophrenia, these findings are critical for optimal evaluation and treatment of schizophrenic patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The effect of antipsychotic drugs on brain morphology is under debate. Here we investigate the effects of risperidone, olanzapine and low doses of haloperidol on cortical and subcortical morphometry in first episode drug naïve patients with non-affective psychosis., Methods: Morphological variables were measured in three treatment groups (haloperidol=18; risperidone=16; olanzapine=18) and in healthy subjects (N=38) at baseline and after one year. The relationship between brain morphometric changes and changes in clinical scores was also assessed., Results: At one year, the three antipsychotics had had an equal effect on the gray matter cortical structure, overall and lobes (all p's>0.121.). A significant time-by-group interaction was found in lateral ventricle volume (F2,47=5.65; p=0.006). Post-hoc comparisons revealed a significant increase in lateral ventricles in patients treated with risperidone (p=0.009). Patients exposed to atypicals (olanzapine and risperidone) exhibited a decrease in caudate nucleus volume (p=0.001). In general, brain changes did not account in any significant manner for clinical changes over time in any treatment group., Conclusions: We conclude that low doses of haloperidol, risperidone and olanzapine seem to have an equal effect on the gray matter cortical structure after 1 year of treatment. In contrast to typical antipsychotics, atypicals have differential effects on lateral ventricle and caudate nucleus volumes.

Background: The serotonin transporter (5-HTT) plays an important role in serotonergic neurotransmission. In the present study, we investigated the effects of the 44 bp insertion/deletion polymorphism in the promoter region of 5-HTT gene (5-HTTLPR) on symptomatology of psychosis and clinical response to antipsychotic drugs., Methods: In total 56 patients acutely treated with haloperidol or risperidone either for the first episode of schizophrenia, schizophreniform or schizoaffective disorders, or for the relapse of these psychotic disorders after tapering their maintenance treatment, were genotyped for the 5-HTTLPR L and S alleles and for the new A/G functional variant within the L alelle (La/g). Psychopathological symptoms were assessed with the Brief Psychiatric Rating Scale (BPRS) and with Clinical Global Impression (CGI) twice: at 8-12 days after the first dose of antipsychotic and after 4 weeks. Extrapyramidal side effects were assessed with the Simpson-Angus Extrapyramidal Side Effects Scale (EPS), the Barnes Akathisia Scale (BARS) and the Abnormal Involuntary Movement Scale (AIMS)., Results: Age, body mass index (BMI), illness duration, drug type and dosage were considered as covariates when analysing association with genetic variants as they were associated with baseline or final BPRS and CGI scores and/or extrapyramidal side effects. 5-HTTLPR was not associated with baseline and final BPRS and CGI scores or with the CGI% reduction. However, the 5-HTTLPR S allele was associated with a lower improvement in BPRS scores (P=0.022) and this effect was even stronger after pooling subjects with S or Lg containing alleles (P=0.006). We did not observe any effect of 5-HTTLPR on acute antipsychotics side effects., Conclusion: Present result supports a contribution of serotonin system to neuroleptics efficacy for the treatment of schizophrenia. The analysis of the La/g functional variant may significantly improve the predictive power of 5-HTTLPR genotyping and represent a step further towards the development of the personalized antipsychotic treatment.

Negative symptoms of schizophrenia are particularly problematic due to their deleterious impact on a patient's social life. The indol alkaloid alstonine, the major component of traditional remedies used for treating mental illnesses in Nigeria, presents a clear antipsychotic-like profile in mice, as well as anxiolytic properties. Considering that social interaction is the core of negative symptoms, and that anxiolytic drugs can improve social interaction behavior, the aim of this study was to evaluate the effects of alstonine in the social interaction and MK801-induced social withdrawal models in mice. Sub-chronic (but not acute) treatment with alstonine 0.5 mg/kg (but not 1.0 mg/kg) significantly increased social interaction in mice. Moreover, MK801-induced social withdrawal was completely prevented by sulpiride (10 mg/kg) and alstonine 1.0 mg/kg, and partially prevented by alstonine 0.5 mg/kg. The study indicates that alstonine not only increases social interaction in normal mice, but also averts social deficits attributable to negative symptoms of schizophrenia. This study reinforces and complements the antipsychotic-like profile of alstonine, and emphasizes its potential as a drug useful for the management of negative symptoms in schizophrenia.

Background: Previous reports show different cerebral activity patterns during treatment with clozapine and typical neuroleptics. However, to date no study has directly compared the brain activity patterns while subjects are undergoing treatment with clozapine and other atypical antipsychotics. This comparison is of interest, given the probably different mechanism of action of clozapine in comparison with other atypicals., Objective: To assess the effect of clozapine on perfusion deviations still evident during treatment with risperidone., Methods: Here we used hexamethylene-propylenaminoxime single photon emission computed tomography to compare the perfusion patterns observed during the performance of a Stroop test in 10 patients sequentially treated with risperidone and clozapine, owing to a lack of response to the former, and in 10 healthy controls., Results: Patients on risperidone showed decreased perfusion as compared to controls in the medial prefrontal, middle cingulate and insular regions, as well as increased activities in brain stem and the posterior hippocampus. After receiving clozapine, the same patients showed an even wider prefrontal perfusion deficit and the brain stem was still hyperactive, but the abnormalities in the cingulate cortex, insula and hippocampus had disappeared. Clinical improvement was directly related to an increase in thalamic perfusion., Conclusion: Clozapine may alleviate hyperactivity in the limbic system in schizophrenia and may facilitate activation of the regions involved in cognitive tasks to a greater degree than risperidone, as well as eliciting greater inhibition of the PF region.

Purpose: Acute agitation is a common presentation in emergency departments and is often secondary to an underlying psychotic condition. The aim of this study was to compare the effectiveness of three second generation antipsychotics (risperidone, olanzapine, quetiapine) versus haloperidol in the treatment of psychotic agitation for up to 72 h., General Methods: We recruited 101 patients with acute psychosis who were admitted at the Mental Health Department 1 South of Turin, Psychiatric Emergency Service of San Giovanni Battista Hospital, from June 2004 to June 2005., Findings: Aggressive behavior, as measured by Modified Overt Aggression Scale and Hostility-suspiciousness factor derived from the Brief Psychiatric Rating Scale, significantly improved in all groups, with no significant between-group differences. Extrapyramidal symptoms were more common in haloperidol treated patients compared with patients receiving risperidone, olanzapine or quetiapine., Conclusions: Our results show that in the clinical practice setting of emergency psychiatry olanzapine, risperidone, quetiapine are as effective as haloperidol and better tolerated.

A significant body of data suggests that GABA(A) receptors are altered in the CNS of subjects with schizophrenia. However, subjects with schizophrenia are treated with antipsychotic drugs and, in some cases, antipsychotic drugs and benzodiazepines. It has therefore been suggested that the changes in GABA(A) receptors in the CNS of subjects with schizophrenia are due to such drug treatments. Surprisingly, there appear to be no studies to determine the effect of a combined antipsychotic-benzodiazepine treatment on GABA(A) receptors. We therefore measured both the GABA binding site ([3H]muscimol) and the benzodiazepine binding site ([3H]flumazenil) in the CNS of rats treated with either haloperidol, diazepam or a combination of the two drugs. The main findings of our study are that treatment with diazepam or the combination of diazepam and haloperidol results in regionally selective increases GABA binding sites but treatment with haloperidol alone decreases the GABA binding site in the thalamus but increases these sites in the hypothalamus. By contrast, treatment with diazepam, haloperidol and a combination of the two drugs resulted in widespread decreases in the number of benzodiazepine binding sites in the rat CNS. The notable exception to this outcome was increased numbers of benzodiazepine binding sites in the frontal cortex of rats that had received diazepam. Our data suggests that there are complex changes in the GABA(A) receptor following treatment with haloperidol, diazepam or a combination of these drugs. This outcome may be relevant to the therapeutic benefits of using both drugs in conjunction early in the treatment of a psychotic episode.

Post-mortem studies of the human brain indicate that certain GABA(A) receptor subtypes may be differentially altered in schizophrenia. Increased binding to the total population of GABA(A) receptors using [3H]muscimol is observed in the post-mortem schizophrenic brain, yet a proportion of these receptors which bind benzodiazepines and are labelled with [3H]flunitrazepam, show decreased or unaltered expression. Data from animal studies suggest that antipsychotic drugs alter GABA(A) receptor expression in a subtype selective manner, but in the opposite direction to that observed in schizophrenia. To broaden our understanding of the effects of antipsychotic drugs on GABA(A) receptors, we examined the saturation binding maximum (B(max)) and binding affinity (K(D)) of [3H]muscimol and [3H]flunitrazepam in the prefrontal cortex (PFC), hippocampus and thalamus of male SD rats that received a sucrose solution containing either haloperidol (1.5 mg/kg), olanzapine (6.5 mg/kg) or no drug daily for up to 28 days using quantitative receptor autoradiography. [3H]Muscimol binding density was increased most prominently in the PFC after 7 days, with larger and more prolonged effects being induced by the atypical antipsychotic drug olanzapine in subcortical regions. While no changes were observed in [3H]muscimol binding in any region after 28 days of drug administration, [3H]flunitrazepam binding density (B(max)) was increased for both antipsychotic treatments in the PFC only. These findings confirm that the subset of GABA(A) receptors sensitive to benzodiazepines are regulated differently from other GABA(A) receptor subtypes following antipsychotic drug administration, in a time- and region-dependent manner.

Classical antipsychotics like haloperidol are suggested to increase oxidative stress and oxidative cell injury in the brain. Pro-oxidant effect of haloperidol may influence the course and treatment outcomes of schizophrenia. Dietary supplementation of either antioxidants or omega-3 fatty acids was found to improve symptoms of schizophrenia. Thus we decided to assess the impact of combining omega-3 fatty acids, vitamins E and C supplementation on treatment outcome and side effects in schizophrenia patients treated with haloperidol. Ongoing haloperidol treatment of 17 schizophrenia patients was supplemented with 1000 mg capsule of omega-3 fatty acids (180 mg EPA+120 mg DHA) bid, vitamin E 400 IU bid and vitamin C 1000 mg/day. Patients were assessed with Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS), Simpson Angus Scale (SAS) and Barnes Akathisia Rating Scale (BARS) over a 4 month period. Gluthatione peroxidase, superoxide dismutase, malondialdehyde, vitamin E and C levels were also evaluated at baseline and at the end of study. BPRS, SANS, SAS and BARS scores obtained at follow-up visits were significantly lower compared to baseline. Superoxide dismutase level was significantly lower at the end of study. No significant differences were detected in other laboratory parameters. Our results support the beneficial effect of the supplementation on positive and negative symptoms of schizophrenia as well as the severity of side effects induced by haloperidol. The effect of supplementation on akathisia is especially noteworthy and it has not been investigated in previous studies.

It has been reported that antipsychotics may improve cognitive function in the treatment of schizophrenia. The present study examined the effect of haloperidol and risperidone on cognitive performance in schizophrenic patients. 95 healthy subjects and 68 schizophrenic patients were recruited for comparison of cognitive function. As 20 of the 68 schizophrenic patients were drug-naive, they were randomly divided into two groups and double-blinded for treatment with either haloperidol or risperidone for an 8-week period. Each subject received Wisconsin Card Sorting Test (WCST) and Maze paradigms for cognitive function performance. For schizophrenic patients, the Positive and Negative Syndrome Scale (PANSS) was used for evaluation of clinical symptoms. Results demonstrated that in both WCST and Maze paradigms the 68 schizophrenic patients had worse cognitive performance compared with healthy subjects. Of the 20 drug-naive schizophrenic patients from the 68 in-patients, both haloperidol and risperidone improved the clinical symptoms. Maze tasks performance was improved progressively after haloperidol and risperidone treatment, although improvement was greatest with risperidone. Both haloperidol and risperidone had no evident effect on WCST performance. Our findings suggest that Maze paradigms may be an ideal tool for evaluation of pharmacological treatment effects on cognitive function in schizophrenic patients. Furthermore, risperidone may have more treatment benefits than haloperidol on cognitive performance in drug-naive schizophrenic patients.

We present two cases of patients with schizophrenia treated with minocycline. Minocycline (a second-generation tetracycline) is an established and safe broad-spectrum antibiotic that crosses the blood-brain barrier, with additional efficacy for diseases such as acne and rheumatoid arthritis. Animal studies have suggested that minocycline may prevent progression of some neurological disorders. Moreover, it has been reported that minocycline might have antidepressant effects. We report two cases of acute schizophrenia with predominant catatonic symptoms that responded to minocycline.

Purpose: Intracerebroventricular (ICV) administration of ouabain, a potent sodium pump inhibitor, has been used to model mania. Antipsychotic agents have demonstrated efficacy in the management of acute mania. This study was undertaken to determine the prophylactic efficacy of olanzapine and haloperidol in the ouabain mania model., Methods: Male Sprague-Dawley rats (4-8/group) were treated with two haloperidol decanoate intramuscular shots one week apart (21 mg/kg) or twice daily olanzapine intraperitoneal injections at low dose (1 mg/kg/day) or high dose (6 mg/kg/day) for 7 days prior to ICV administration of ouabain. Open field locomotion was quantified at baseline and after ouabain administration., Results: Ouabain caused a significant increase in open field locomotion (253.7+/-SEM 55.12 vs control 53.1+/-12.13 squares traversed in 30 min in the olanzapine experiments, P<0.05; and 236.5+/-41.42 vs 129.3+/-38.23, P<0.05 in the haloperidol experiments). Olanzapine alone at low dose (102.2+/-37.7) or high dose (151.2+/-49.2) did not alter open field activity. Low dose olanzapine (176.6+/-73.27) but not high dose (307.5+/-167.32) caused a modest reduction of the ouabain effect. Haloperidol alone significantly reduced motoric activity compared to control (55.6+/-18.0, P<0.05), and prevented ouabain-induced hyperactivity (60.3+/-33.1, P<0.05)., Conclusion: Haloperidol, but not olanzapine, demonstrated efficacy in this mania model, but methodological details may have reduced the effect of olanzapine.

There is strong evidence that oxygen free radicals may play an important role in the pathophysiology of schizophrenia. Impaired antioxidant defense and increased lipid peroxidation have been previously reported in drug-naïve, first episode and chronically medicated schizophrenic patients using typical neuroleptics. We measured serum SOD and TBARS in two groups of chronic medicated DSM-IV schizophrenic patients, under haloperidol (n = 10) or clozapine (n = 7) and a group of healthy controls (n = 15). Serum SOD and TBARS were significantly higher (p = 0.001) in schizophrenic patients (7.1 +/- 3.0 and 3.8 +/- 0.8) than in controls (4.0 +/- 1.6 and 2.5 +/- 0.7). Among patients, serum TBARS was significantly higher (p = 0.008) in those under clozapine (4.4 +/- 0.7) than in those under haloperidol treatment (3.4 +/- 0.7). For SOD levels the difference between groups was not found. It is reasonable to argue that the difference found in TBARS levels might be due to the course of the disease, instead of medication. Further investigation on the role of oxidative tonus and lipid peroxidation in different schizophrenia subtypes and different outcome patterns in this disorder is warranted. Additionally it could also address questions concerning a possible oxidant/antioxidant imbalance in schizophrenia.

The drug-transporting P-glycoprotein transports drugs against a concentration gradient across the blood-brain barrier back into the plasma and thereby reduces the bioavailability in the brain. Polymorphisms in the MDR1 gene regulating P-glycoprotein expression can be associated with differences in drug disposition in the brain. The present study was therefore designed to examine whether the major polymorphisms of MDR1 gene, C3435T and G2677T/A are related to therapeutic response to neuroleptics in the treatment of schizophrenia. Subjects consisted of 31 acutely exacerbated schizophrenic inpatients treated with bromperidol (6-18 mg/day). Plasma drug concentrations were monitored and clinical symptoms were evaluated using the Brief Psychiatric Rating Scale (BPRS) before and 3 weeks after the treatment. The C3435T and G2677T/A genotypes were determined by a polymerase chain reaction method. Schizophrenic symptoms were allocated into 5 clusters: positive, excitement, cognitive, negative, and anxiety-depression symptoms. Patients were C/C in 12, C/T in 12 and T/T in 7 cases for C3435T genotype and G/G in 3, G/T or A in 17 and T or A/T or A in 11 cases for G2677T/A genotype. There were a tendency of difference, but not statistically different, in the percentage improvement or the improved scores of 5 sub-grouped symptoms after the 3-week treatment between C3435T genotypes and between G2677T/A genotypes. Multiple regression analyses including age, body weight, gender and drug concentration showed significant correlations between the percentage improvement and the improved scores of cognitive symptoms and C3435T genotypes. The present results suggest that the C3435T polymorphism is associated with some therapeutic response to bromperidol in schizophrenic patients, possibly by different drug concentration in the brain.

Background: This study investigated safety and effectiveness of olanzapine in monotherapy compared with conventional antipsychotics in treatment of acute inpatients with schizophrenia., Method: This was a prospective, comparative, nonrandomized, open-label, multisite, observational study of Spanish inpatients with an acute episode of schizophrenia. Data included safety assessments with an extrapyramidal symptoms (EPS) questionnaire and the report of spontaneous adverse events, plus clinical assessments with the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impressions-Severity of Illness (CGI-S). A multivariate methodology was used to more adequately determine which factors can influence safety and effectiveness of olanzapine in monotherapy., Results: 339 patients treated with olanzapine in monotherapy (OGm) and 385 patients treated with conventional antipsychotics (CG) were included in the analysis. Treatment-emergent EPS were significantly higher in the CG (p<0.0001). Response rate was significantly higher in the OGm (p=0.005). Logistic regression analyses revealed that the only variable significantly correlated with treatment-emergent EPS and clinical response was treatment strategy, with patients in OGm having 1.5 times the probability of obtaining a clinical response and patients in CG having 5 times the risk of developing EPS., Conclusion: In this naturalistic study olanzapine in monotherapy was better-tolerated and at least as effective as conventional antipsychotics.

McEvoy et al.'s study in 1999, which used cotinine levels but had limited power, suggested that clozapine treatment may be associated with a mild smoking decrease (particularly when plasma clozapine levels are > 150 ng/ml). Some naturalistic studies also suggest that clozapine treatment may be associated with a mild smoking decrease. The present study included 38 schizophrenic daily smokers from a double-blind clozapine trial. Five analyses were tested for significant decreases in plasma cotinine levels from a haloperidol baseline to: (1) the end of clozapine trials regarding clozapine doses (100, 300 or 600 mg/day), (2) the end of the clozapine trial where the highest plasma clozapine level was achieved, (3) the end of the clozapine trial where a clozapine level in the 150-450 ng/ml range was achieved, (4) the end of the first clozapine trial regardless of clozapine dose, and (5) the end of the last clozapine trial in the study. The first and straightforward analysis by dose showed no clozapine effects on smoking. The second and the third analyses (an attempt to mimic the design by McEvoy et al. [McEvoy, J.P., Freudenreich, O., Wilson, W.H., 1999. Smoking and therapeutic response to clozapine in patients with schizophrenia. Biol. Psychiat. 46, 125-129.]) also indicated that there was not a significant effect of clozapine on smoking. The fourth and five analyses were also negative. None of the five analyses in our clozapine trial demonstrated that clozapine had major effects on smoking. This study cannot rule out that in some subjects, clozapine treatment may be associated with a small decrease in smoking. New prospective longitudinal studies using repeated cotinine and clozapine levels are needed to explore whether clozapine may reduce smoking in some patients.

There is a large amount of data showing that adenosine plays a role opposite to dopamine in the brain. Adenosine agonists and antagonists produce behavioral effects similar to dopamine antagonists and dopamine agonists, respectively. Allopurinol, a well-known hypouricemic drug that inhibits xantine oxidase, has been used as an add-on drug in the treatment of poorly responsive schizophrenic patients. Indeed, the neuropsychiatric effects of allopurinol in schizophrenia have been suggested to be secondary to its inhibitory effect of purine degradation, enhancing adenosinergic activity. The purpose of the present investigation was to assess the efficacy of allopurinol as an adjuvant agent in the treatment of chronic schizophrenia in an 8-week double blind and placebo controlled trial. Eligible participations in the study were 46 patients with schizophrenia. All patients were inpatients and were in the active phase of the illness, and met DSM-IV criteria for chronic schizophrenia. Patients were allocated in a random fashion, 23 to haloperidol 15 mg/day plus allopurinol 300 mg/day and 23 to haloperidol 15 mg/day plus placebo. Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of haloperidol and allopurinol showed a significant superiority over haloperidol alone in the treatment of positive symptoms, general psychopathology symptoms as well as PANSS total scores. The means of Extrapyramidal Symptoms Rating Scale for the placebo group were higher than in the allopurinol group over the trial, and the differences were significant in weeks 6 and 8. A significant difference was observed between the overall mean biperiden dosages in two groups. The results of this study suggest that allopurinol may be an effective adjuvant agent in the management of patients with chronic schizophrenia. Nevertheless, results of larger controlled trials are needed, before recommendations for a broad clinical application can be made.

The authors report a case of a patient, who in a few days after an abrupt discontinuation of clozapine and haloperidol developed agitated and confused state resembling neuroleptic malignant syndrome (NMS) and clozapine withdrawal symptoms at the same time. Data obtained from family members led to gradual reintroduction of clozapine and to subsequent recovery. The case illustrates the importance for clinicians to be familiar with the variety of discontinuation symptoms, so they can recognize them and offer effective treatment.

Objective: The aim of this study was to compare striatal dopaminergic D2 receptor occupancy (D2 RO) induced by ziprasidone and haloperidol and its relationship with clinical response and extrapyramidal side effects (EPS) in patients with acute psychosis exacerbation., Method: Twenty patients hospitalized with an acute psychosis exacerbation were randomised in a single-blind study to receive either ziprasidone (80-120 mg/day) or haloperidol (5-20 mg/day) for more than 2 weeks. When stable doses were achieved, data on 123I-IBZM single-photon emission computed tomography (SPECT), as well as data on clinical efficacy (positive and negative symptoms scale [PANSS]) and EPS (Simpson Angus scale [SAS]), were compared between the two groups of patients. Clinical response was defined as a percentage of change of >30% in PANSS. Striatal D2 RO and clinical data were also compared between responders and nonresponders on each treatment group., Results: All patients on haloperidol and four patients on ziprasidone showed EPS. Mean D2 RO was significantly higher in the haloperidol (74.7+/-3.5) than in the ziprasidone (60.2+/-14.4) group (Mann Whitney U-test [M-W U-test] 8.50; p=0.002). Five patients were responders, and five were nonresponders on each group of treatment. Haloperidol responders and nonresponders did not differ in D2 RO, duration of treatment, doses or EPS. Ziprasidone responders were on higher doses than nonresponders and showed higher D2 RO although below 74%. A positive correlation of ziprasidone D2 RO was found with dose (r Spearman 0.87; p=0.001) and with SAS scores (r Spearman 0.88; p=0.001)., Conclusions: Ziprasidone induces lower D2 RO and EPS than haloperidol, which is consistent with an atypical antipsychotic profile. A direct relationship of ziprasidone D2 RO with dose, clinical efficacy and EPS has been found in this study. These data suggest that high ziprasidone doses might be more beneficial in patients with psychosis exacerbation and claim for caution regarding EPS appearance with such high dosages.

Aripiprazole is a new atypical antipsychotic with a mode of action that is distinct from currently available antipsychotic drugs. In phase III comparative clinical studies, aripiprazole 15-30 mg/day was at least as effective as haloperidol and risperidone in short term treatment of acute exacerbation of schizophrenia but superior to haloperidol in long term maintenance therapy. Consistent with an atypical profile, aripiprazole is effective against positive, negative and cognitive symptoms of schizophrenia and has a favourable side effect profile with the incidence of extrapyramidal symptoms (EPS) comparable to placebo. It is also devoid of side effects such as clinically significant hyperprolactinaemia, hypercholesterolaemia and cardiotoxicity, and has a low propensity for weight gain. Symptom relief is achieved without significant sedation. These clinical data suggest its usefulness in psychosocial rehabilitation, as well as in long-term prevention of schizophrenic relapse. Recent results from a multicentre, open-label study in a general psychiatric setting provide the first evidence that aripiprazole is also effective under naturalistic conditions. However, only post-marketing experience will show whether the positive results of these controlled trials can be replicated in everyday practice.

Long-term pharmacotherapy with antipsychotic agents is an important aspect of the management of schizophrenia. In patients responsive to the chosen treatment, maintenance therapy is usually conducted by halving the drug dose that has proven effective during the acute phase. This strategy is suitable for maintaining remission; moreover, it can improve the patients' quality of life. Records from over 1000 patients treated with clozapine during the past 22 years were examined; 782 of these patients were diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Text Revision (DSM-IV-TR) criteria (with the modification in early years). From this group, 181 patients were treated with clozapine for at least a year. The mean duration of long-term maintenance treatment with clozapine was 12.2+/-4.25 years (range: from 14.5 months to 18 years). Clozapine was administered in a daily dose of 50-200 mg (mean: 71.5+/-14.12 mg). In 76 schizophrenics, treatment was initiated with clozapine, whereas 105 patients were switched over from other treatments after their failure. The control group comprised 152 patients on long-term maintenance therapy with haloperidol. Clozapine administered for long-term maintenance therapy was effective both in paranoid and in catatonic schizophrenia. It also accomplished good results in patients with disorganized or residual schizophrenia, as well as in individuals with schizoaffective psychosis. Relapse rate was similar to that observed in the haloperidol group; however, patient compliance, side-effect profile, and therapeutic efficacy were all superior in the clozapine group. Long-term maintenance therapy with clozapine is successful. Compliance is good; schizophrenic patients are willing to take this atypical antipsychotic for years on end. Clozapine treatment is associated with a low relapse rate and a favorable safety profile.

The estrogen hypothesis of schizophrenia postulates that estrogen exerts a protective effect against schizophrenia and that this partly explains the observed sex differences in premorbid adjustment, onset age, treatment response, and illness course. It has been suggested that estrogen supplementation can augment the treatment effects of antipsychotics. The purpose of the present investigation was to access the efficacy of ethinyl estradiol as an adjuvant agent in the treatment of premenopausal women with chronic schizophrenia in an 8-week, double-blind, and placebo-controlled trial. Eligible participants in the study were 32 women of childbearing age with schizophrenia. All patients were inpatients, in the active phase of illness, and met DSM-IV criteria for chronic schizophrenia. Patients were allocated in a random fashion, 16 to haloperidol 15 mg/day plus ethinyl estradiol 0.05 mg/day and 16 to haloperidol 15 mg/day plus placebo for an 8-week, double-blind, placebo-controlled study. Although both protocols significantly decreased the score of the positive, negative, and general psychopathological symptoms over the trial period, the combination of haloperidol and ethinyl estradiol showed a significant superiority over haloperidol alone in the treatment of positive and general psychopathology symptoms as well as Positive and Negative Syndrome Scale (PANSS) total scores. Although the means Extrapyramidal Symptoms Rating Scale (ESRS) for the placebo group were higher than ethinyl estradiol group, the differences were not significant over the trial. A significant difference was observed between the overall mean biperiden dosages in the two groups. The results of this study suggest that estrogen may be an effective adjuvant agent in the management of women of childbearing age with chronic schizophrenia. Nevertheless, results of larger controlled trials are needed before recommendation for a broad clinical application can be made.

Objective: This study was carried out to evaluate the influence of CYP2D6 polymorphism and smoking on the plasma clearance of haloperidol (HAL) levels, accounting for the antipsychotic dose, body weight, and coadministration of other drugs., Methods: Subjects were 110 Japanese patients (66 male, 44 female) diagnosed with schizophrenia, dementia, or mood disorder and treated orally with HAL. Venous blood was obtained from each patient to determine the HAL concentration/dose (C/D) ratio (plasma concentration of HAL divided by the daily dose of HAL per body weight) and for CYP2D6 genotyping., Results: There was no significant difference in the HAL C/D ratio between nonsmokers and smokers. In patients with a non-2D6*10 homozygous genotype, smokers had a significantly lower HAL C/D ratio than nonsmokers, whereas smokers with a 2D6*10 homozygous genotype had a significantly higher HAL C/D ratio than those with a non-2D6*10 homozygous genotype., Conclusion: Our results suggest that the effect of smoking on the HAL C/D ratio depends on the CYP2D6*10 genotype.

Objective: Most of the data supporting the use of atypical antipsychotics (AA) is based on studies in young adult patients. The present study is an open-label naturalistic follow-up study of olanzapine treatment vs. haloperidol for elderly chronic schizophrenia patients. MEHTOD: 20 patients (mean age 72.7+/-5.9 years, mean disease duration 33.1+/-12.0 years) who met the DSM-IV criteria for schizophrenia were randomly assigned to olanzapine (n=10) or haloperidol (n=10) treatment during acute exacerbation. Primary outcome measure was rating on the Clinical Global Impression (CGI) scale and the Positive and Negative Symptom Scale (PANSS)., Results: Between-group differences were computed using analysis of covariance. PANSS Total score decreased from 84 at baseline to 65 after treatment with olanzapine while decreased only from 79 to 74 with haloperidol treatment (F= 6.66, P=.02). PANSS Negative subscale decreased from 19 at baseline to 15 with olanzapine treatment while increased (deteriorated) from 18 to 20 with haloperidol treatment (F=23.37, P=.0003). CGI decreased from baseline with both olanzapine and haloperidol treatments (1.1 vs. 0.4) but the decrease in the olanzapine group was significantly greater (F=4.63, P=.05). Mean weight increased in both groups but without statistical difference between groups., Conclusions: In elderly chronic schizophrenia patients, olanzapine treatment is superior to haloperidol in reducing negative symptoms as well as less induction of extrapyramidal symptoms (EPS).

Motor symptoms including neurological soft signs have been found to be more prevalent in schizophrenic patients. In addition, catatonic symptoms and neuroleptic treatment as well may influence cortical and subcortical motor organization in schizophrenia. The results of previous neuroimaging studies exploring motor function in patients with schizophrenia are inhomogenous reporting on a decreased activity in cortical motor regions in some studies and normal activity in others. Using fMRI, we studied 40 subjects performing a unilateral self-paced fingertapping task. Analyzing a general linear model of four groups, we compared patients with schizophrenia according to DSM-IV treated with olanzapine (OL; 10) or haloperidol (HA; 10) to healthy controls (HC; 10) and untreated patients (UN; 10). Brainvoyager software was used for data analyzing. In all groups, the contralateral motor cortex was significantly activated. Significant activation of the ipsilateral cerebellum was found in the UN group, the control group and the OL group. The contralateral basal ganglia were activated in UN and in controls. Motor-induced cortical and subcortical brain activation in HC was significantly higher than in patients with schizophrenia. UN with schizophrenia showed a significant overactivation than the other groups. In conclusion, we revealed a diminished activation in the patient group treated with neuroleptic drugs. This study outlines the importance of further fMRI studies to investigate interindividual activation differences under different conditions especially focusing on basal ganglia.

The antipsychotic drug, bromperidol, is a close structural analogue of haloperidol. These two drugs also have similarities in metabolic pathways and pharmacological properties. In the present study, the prolactin concentrations in plasma during bromperidol versus haloperidol treatments were compared in the same individuals. The subjects were 22 schizophrenic inpatients, who first received bromperidol 12 mg/day for at least 2 weeks followed by haloperidol 12 mg/day. The prolactin concentration in plasma during bromperidol treatment (median and range; 24 and 7-93 ng/ml, respectively) was significantly (P< .01) lower than during haloperidol treatment (32 and 8-102 ng/ml), although the difference was small. The mean (+/- S.D.) plasma concentration of bromperidol was significantly lower than that of haloperidol (20.8+/-8.0 vs. 28.0+/-13.1 nmol/l, P<.05). Prolactin concentrations during both treatment phases correlated well in individuals (r's=.813, P<.001), while no correlation was observed between plasma concentrations of haloperidol and bromperidol (r=.053, ns). These findings suggest that slightly higher prolactin concentration does not necessarily lead to increased risk of hyperprolactinemia during bromperidol treatment compared with haloperidol treatment. In addition, it is suggested that both drugs show similar pharmacodynamic response despite the difference in pharmacokinetics in the same individuals.

Therapeutic profiles of bromperidol and their relationship with plasma drug concentration and prolactin response were investigated in 30 acutely exacerbated schizophrenic patients treated with randomly allocated fixed-doses of bromperidol (6, 12 or 18 mg/day) for 3 weeks. The mean values (+/- S.D.) of percentage improvement at 3 weeks in total Brief Psychiatric Rating Scale (BPRS) and five subgrouped symptoms were 59.8+/-29.2% for total, 64.6+/-37.5% for positive, 73.3+/-33.7% for excitement, 80.2+/-45.5% for cognitive, 43.1+/-46.5% for negative and 49.6+/-46.8% for anxiety-depression symptoms, respectively. Twenty (67%) of 30 patients were responders defined as having 50% or more symptom reduction significantly greater in responders than those in nonresponders after 2 weeks. Mean plasma bromperidol concentration in patients with 50% or more reduction in positive symptoms was significantly higher than in the others (8.2+/-4.7 vs. 4.1+/-1.8 ng/ml, P< .05). Percentage improvement in total BPRS at 1 and 2 weeks were correlated well with that at 3 weeks. These findings suggest that an early improvement in positive and anxiety-depression symptoms results in favorable outcome of total response to bromperidol treatment. Plasma drug monitoring may have a limited predictive value for improvement in positive symptoms.

1. Olanzapine is a novel atypical antipsychotic with affinity for a number of neurotransmitter receptors including dopamine D1, D2, D4, serotonin 5HT2A, 5HT2C, histamine H1, a1-adrenergic, and muscarinic receptors. 2. A neuroendocrinological method to check the degree of dopamine receptor blocking is by measuring the prolactin (PRL) responses to acute (i.m.) administration of haloperidol (HAL). The authors applied this test in a group of male patients with DSM-IV schizophrenia in the drug-free state. The patients were subsequently treated with olanzapine (OLZ) (mean daily dose: 22.5+/-5.8) and the test was repeated six weeks later. For the HAL-test, 5mg HAL were injected i.m. and blood samples were taken at times 0, 30, 60, 90 and 120 minutes. Fourteen patients enrolled in the study. Psychopathology was assessed by means of the Brief Psychiatric Rating Scale (BPRS). 3. Six weeks treatment with OLZ resulted in significant decreases in the total BPRS score and on the score of its subscales for positive, negative, and general psychopathology. Comparison of the PRL response patterns, after HAL administration by analysis of variance for repeated measures (ANOVAR) for drug treatment and time, revealed a highly significant time effect (F=28.98, p=0.000) and a significant treatment by time interaction (F=8.27, p=0.000008). Namely, in the drug-free state significant increases were found in the PRL levels after i.m. HAL administration which were significantly reduced during treatment with OLZ, indicating moderate receptor blockade.

1. In a group of schizophrenic patients, the effect and selected parameters of biological markers were evaluated during the index hospitalisation in the acute phase of schizophrenia (n = 30) and then after one year of ambulatory treatment. 2. During the acute treatment, a significant drop in symptomatology was recorded in average; an analogical tendency was observed further on, too. Apart from that, a significant change was observed in 5/41 parameters being monitored (the pair t-test): I) decrease in the total NES score, II) decrease in the sensorial integration subscale NES score, III) increase in psychomotor speed, IV) decrease in auditory reaction time, V) increase in basal cortisol. 3. In the comparison of the successfully (severity of illness after one year = 1, 2) and unsuccessfully (severity of illness after one year > or =3) treated patients in the beginning of treatment in the acute phase, the unsuccessful group had a significantly higher score of negative symptomatology, and by the end of the acute treatment, again, a significantly higher score of negative symptomatology, a higher total PANSS score and a greater severity of illness. 4. In the acute phase, the successful group had a significantly better score in individual items of the Contemporary Memory Scale and a significantly worse performance and goal-aimed concentration in the Bourdon test than the unsuccessfully treated one; apart from that, it had a significantly higher cortisol level after dexamethasone, which was also reflected in the lower percentage rate of dexamethasone nonsupression. 5. In the course of the year, a drop in the total NES score for the individual subscales occurred; a significant drop was observed in the sensory integration subscale. The worse concentration items improved significantly in the successful group in contrast to the unsuccessful group, where they showed a downgrade tendency. Changes in Contemporary Memory Scale were negligible and mostly below statistical significance. Apart from that, a drop in basal cortisolemia occurred in the successful group and an increase in cortisolemia after administering dexamethasone was registered in the unsuccessful group. 6. The more successful group had a significantly lower NES score, a significantly better visual reaction time and a smaller forgetting item (in percentiles) after the one-year period.

1. Since the development of a kit for the assay of haloperidol by enzyme immunoassay, therapeutic monitoring of haloperidol has been utilised in Japan for several years. By retrospectively analysing the accumulated data, this study was carried out to investigate the factors affecting haloperidol level. Especially, the effects of enzyme-inducing comedications were analysed in relation to serum gamma-glutamyltransferase (GGT) level, which has been measured simultaneously with haloperidol. Serum haloperidol level measurements were obtained from medical records of inpatients on multiple medications (n = 102). For each subject, average haloperidol level was computed during the same prescription and doses. The effects of age, sex, smoking status, and the coadministration of carbamazepine and barbiturates (including phenobarbital, amobarbital and pentobarbital) were analysed using correlation, between-group comparison and multiple regression analysis. Separately, the effect of comedications on haloperidol and GGT levels were analysed individually in a small number of patients (n = 5) who had received those comedications intermittently. Significant lowering of serum haloperidol level by the coadministration of carbamazepine and/or barbiturates was observed. The coadministration was also correlated with the elevated GGT level in between-group comparison. In the separate analysis, the change in haloperidol level was correlated with the change in GGT level in some individuals but not in others. None of the other clinical factors investigated in the study showed significant effect on haloperidol level. This study suggests that the lowering of haloperidol level and the elevation of GGT level may often occur coincidentally by the coadministration of enzyme-inducing drugs. However, whether there is a causal relationship between these phenomena and whether elevated serum GGT level could serve as a clinically useful marker need to be clarified by further basic pharmacological research.

1. The aim of the study was to replicate our earlier finding of elevated cerebrospinal fluid (CSF) angiotensin-converting enzyme (ACE) in neuroleptic-treated schizophrenia and to elucidate the correlations between CSF ACE, neuroleptic treatment, and psychotic symptoms in a longitudinal study. 2. Levels of ACE were measured in CSF and serum from 9 acutely psychotic schizophrenic patients at two separate points of time; within a few days of admission and at follow-up after 3-4 weeks. CSF ACE was also determined from 9 healthy controls. 3. The schizophrenic patients showed non-significantly higher levels of CSF ACE than the controls. Although a significant clinical improvement was observed and the neuroleptic medication was reduced during the follow-up period, there were no significant differences in serum or CSF ACE between the two observation points in the schizophrenia group.

1. The case of a schizophrenic patient taking bromperidol (18 mg/day), whose psychotic symptoms deteriorated markedly after addition of cisapride (7.5 mg/day), is presented. 2. Retrospective determination of drug concentrations revealed that plasma concentrations of bromperidol and its reduced metabolite were increased after cisapride addition. 3. The present study thus suggests that there is an interaction between cisapride and bromperidol.

1. There is an ongoing controversy, if increased binding of 3H-spiperone to lymphocytes might discriminate between schizophrenia and other psychiatric diseases or even be a genetic vulnerability marker for schizophrenia, or predict the response to neuroleptic treatment. 2. Some critical methodological details which might contribute to this controversy are described. 3. 3H-spiperone binding was evaluated in 31 patients with schizophrenia, 7 patients with schizoaffective disorder, bipolar type, 6 patients with a manic episode and 6 patients with a depressive episode of bipolar major affective disorder (DSM-III-R criteria), and in 19 healthy subjects. 4. There were no significant differences in characteristic binding parameters (KD, Bmax) between all groups of psychiatric in-patients and in comparison to healthy subjects. Moreover, there was no relation of binding parameters to any of the subtypes of schizopherenia or to the course of illness according to DSM-III-R-criteria. 5. Neuroleptic treatment or clinical response to treatment had no consistent effect on binding parameters intra-individually. 6. In summary, 3H-spiperone binding to lymphocytes failed to differentiate between the diagnostic subgroups (DSM-III-R) and between treatment responders and non-responders in our sample of patients.

1. The aim of this open study was to determine whether a more rational therapeutic approach could be devised for psychotic patients (n = 11) treated for long periods with long-acting (LA) haloperidol. The mean multiplication factor for the transition from the oral formulation to the long-acting one was 12.8 (10.4, standard deviation), lower than the theoretically recommended factor of 20. 2. The best dose (mg/kg)-concentration correlations were found for haloperidol (HAL) and reduced HAL (RHAL) in the red blood cells (RBC) (representative of the free drug fraction) rather than in the plasma of patients that had attained the steady state (at the third cycle and afterwards) 3. Pharmacokinetic analyses were conducted at the same time as clinical evaluations, grading using the BPRS and determinations of plasma levels of total, free and conjugated homovanillic acid (HVA), a marker of central dopaminergic activity. 4. A between groups comparison at the steady state (patients (n = 20) with oral administration and the above patients (n = 11) with long-acting form of HAL), showed that the plasma and RBC RHAL/HAL ratios of long-acting HAL decreased significantly (p < 0,005) in comparison with oral administration, at least by half. 5. Plasma HVA values complete the information provided by plasma and more especially RBC HAL and RHAL levels. All these results taken together, as substantiated by the clinical assessment scales (BPRS), assure a better pharmacoclinical surveillance and can be predictive of a patient's response.

1. Plasma levels were monitored for about 18 months during therapy with haloperidol decanoate. When steady-state was reached, patients treated without enzyme inducers showed in their plasma concentrations a stable plateau and a very low fluctuation. Furthermore, doses were correlated to plasma levels (r = 0.9). 2. Contrary, patients treated with both haloperidol decanoate and enzyme inducers seemed to present in their plasma concentration a very large fluctuation with C min (plasma concentrations measured just before the injection) significantly lower than those of the other group. Moreover their C min values were excluded from the linear regression curve calculated between plasma levels and doses in patients without enzyme inducers. 3. Our data suggest a shortening of the absorption half-time of haloperidol. In this case, it seems necessary to diminish the interval between injections than to give higher dosage in order to maintain plasma concentrations.

1. The authors attempted to correlate plasma concentrations in H/rH and clinical efficacy from 8 schizophrenic patients (DSM IIIR) on H. 2. No significant correlations were found between H, rH plasma levels and positive and negative subscale for each patient. 3. The authors observed an opposite evolution concerning the mean results between plasma concentrations and PANSS total score.

1. Clinical response to treatment with haloperidol was studied in 20 schizophrenic inpatients with acute exacerbation (DSM-IIIR). 2. Patients were assigned to fixed doses of haloperidol (10, 20 or 30 mg/day) for three weeks. Clinical assessment was made using scales SAPS, SANS, BPRS and Simpson-Angus Scale for rating of extrapyramidal side effects. 3. Sixteen patients showed forty per cent or more decrease in positive symptoms assessed by SAPS, being considered the group of responders. Six out of the twenty patients showed improvement in negative symptoms assessed by SANS (improvement above 30%). 4. Clinical predictors of response were only identified for SAPS. The group of responders showed higher basal scores in total scale and formal thought disorder. 5. Negative symptoms responsive to treatment were affective flattening and alogia. Improvement in negative symptoms was independent from that in positive ones. 6. Socio-demographic predictors of clinical response were not found. No differences in clinical response were found in relation to the dose administered. 7. The results of our study suggest that negative symptomatology improves in a scheduled treatment with haloperidol. Assessment of negative symptoms may be useful in the evaluation of treatment of acute schizophrenia.

1. Schizophrenic patients have been investigated electroencephalographically to describe disturbed information processing mechanisms. 2. 16-channel quantitative EEG and P300 were recorded at resting conditions before and during neuroleptic depot injection. 3. Reduced occipital alpha-power and alpha-power dependent P300-amplitudes were found in the schizophrenics. 4. Hippocampal structures are involved in the disturbed information processing mechanisms.

1. Plasma haloperidol and reduced haloperidol concentration were measured in four ethnic populations. 2. Plasma samples were obtained under steady-state conditions and obtained 10-12 hours post bedtime dose and prior to the morning dose. 3. Haloperidol and reduced haloperidol plasma levels were assayed by radioimmunoassay and liquid chromatography. 4. A wide interpatient variability between haloperidol dose and plasma concentration was observed for each ethnic group. 5. The Chinese group differed from the other ethnic populations. 6. A nonlinear relationship was observed between haloperidol and reduced haloperidol plasma levels in each ethnic group. Further, the relationship of haloperidol to reduced haloperidol plasma levels differed for each ethnic group. These results suggest that various ethnic groups could metabolize haloperidol and reduced haloperidol differently.

1. Patterns of fluid intake and urine output was examined in schizophrenia and normal controls. 2. Fluid intake and urine output were significantly higher in schizophrenic patients. 3. Bouts of drinking correlated significantly with fluid intake but did not differ significantly between schizophrenic patients and normal controls. 4. Schizophrenic patients drink more per bout compared to normal controls.

1. We measured haloperidol reductase activity in red blood cells in 87 samples collected from 50 Japanese psychiatric patients on HAL. HAL reductase activities in the patients were in a range of 7.9-26.1 pmol/hr/10(6) RBC (mean = 13.4, S.D. = 3.4). Interindividual variability was as large as 25.4% (CVs), while intraindividual CVs were small (8.9%). 2. Distribution of HAL reductase activities was normal but their values were slightly lower in the patients than those in the normal controls, though the difference between these two groups was not significant. 3. No significant correlations were found between HAL reductase activity in RBC vs dose of HAL per body weight, or plasma and RBC RHAL/HAL ratio.