1Ther Drug Monit 2000 Aug 22: 392-6
PMID10942177
TitleCYP2D6*10 alleles are not the determinant of the plasma haloperidol concentrations in Asian patients.
AbstractThe authors we investigated the relationship between plasma levels of HALoperidol (HAL) and the number of CYP2D6*10 (*10) alleles in 66 Japanese inpatients with schizophrenia (male = 61, female = 5) on HAL. Plasma HAL level was determined by an enzyme immunoassay method. Daily dose of HAL was 1.5-36 (mean +/- SD = 12.3 +/- 7.6) mg or 0.02-0.49 (0.21 +/- 0.13) mg/kg body weight. Plasma HAL levels ranged from 1.4 to 47.4 (12.4 +/- 9.5) ng/mL. No significant difference in the plasma HAL levels was observed between the subjects with no, one, and two *10 alleles (one-way analysis of variance: 56.1 +/- 20.3, 61.0 +/- 20.3, and 63.3 +/- 20.3 ng/mL/mg/kg, respectively, F(2,63) = 0.65, p = 0.52). These results are not supportive of the previous report that plasma HAL levels can be predicted by the number of *10 alleles in Asian patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
2J Clin Pharmacol 2000 Nov 40: 1296-7
PMID11075316
TitleEffect of chlorpromazine and clozapine on plasma concentrations of haloperidol in a patient with schizophrenia.
AbstractA 40-year-old patient being treated for schizophrenia developed elevated plasma levels of HALoperidol (HAL) in combination with chlorpromazine (CPZ) and during overlap treatment with clozapine. Competitive inhibition of HAL by first CPZ and then clozapine is discussed as a possible mechanism.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
3J Clin Psychopharmacol 2000 Apr 20: 175-80
PMID10770455
TitleInterindividual variation in bromperidol metabolism and relationship to therapeutic effects.
AbstractPlasma concentrations of bromperidol (BRP) and reduced bromperidol (RBRP) were determined in 31 patients with schizophrenia who were administered BRP for their psychiatric symptoms. Activities of carbonyl reductase in red blood cells were assayed using BRP as a substrate. Plasma concentrations of BRP and RBRP ranged from 2.2 to 23.5 ng/mL and from 0.2 to 8.2 ng/mL, respectively. RBRP-to-BRP ratios in plasma ranged from 0.01 to 0.94 (mean +/- SD: 0.31 +/- 0.20), values notably lower than the previously reported values of reduced HALoperidol to HALoperidol (HAL) in the plasma from patients on HAL. The activity of BRP reductase in red blood cells was determined as 6.8-12.3 pmol/hr/10(6) red blood cells, which was at approximately the same level as that of HAL reductase. Patients with positive responses to BRP treatment were evaluated using the Brief Psychiatric Rating Scale. We found that the number of patients who had a positive response to BRP did not increase after BRP plasma levels had reached the level of 12 ng/mL. This finding suggests that a therapeutic plateau in BRP pharmacotherapy of schizophrenia occurs, and there is no advantage to raising the dose once this plateau is reached.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
4Clin Ther 2000 May 22: 583-99
PMID10868556
TitleDoses of olanzapine, risperidone, and haloperidol used in clinical practice: results of a prospective pharmacoepidemiologic study. EFESO Study Group. Estudio Farmacoepidemiologico en la Esquizofrenia con Olanzapina.
AbstractThe objectives of this study were to determine the doses of olanzapine (OLZ), risperidone (RIS), and HALoperidol (HAL) used in clinical practice in outpatients with schizophrenia and the rates of occurrence of extrapyramidal symptoms (EPS) and other adverse events, clinical response, and use of concomitant medications.
The present study involved a subset of patients from a 6-month, open-label, prospective observational study. Data were collected by 293 psychiatrists at mental health centers and other outpatient treatment facilities in Spain. Medications and doses used, occurrence of EPS and other adverse events, and scores on the Clinical Global Impression (CGI) of Severity Scale and Global Assessment of Function (GAF) were recorded. Clinical response was defined as a decrease of > or = 2 points on the CGI, with a final CGI score < or = 4.
A total of 2657 patients were included in the analysis. The initial and overall mean daily doses for the 3 groups were as follows: OLZ, 12.2 and 13.0 mg, respectively; RIS, 5.2 and 5.4 mg; and HAL, 13.9 and 13.6 mg. Initial and overall median daily doses were the same in each group: OLZ, 10 mg; RIS, 6 mg; and HAL, 10 mg. A significantly lower proportion of OLZ-treated patients (36.9%) experienced EPS compared with RIS-treated (49.6%) and HAL-treated (76.0%) patients (P < or = 0.001). A significantly lower proportion of patients in the OLZ group (47.8%) experienced adverse events compared with patients in the RIS (57.2%) and HAL (79.8%) groups (P < or = 0.001). A significantly greater proportion of OLZ-treated patients (37.3%) were responders compared with RIS-treated patients (31.5%) (P < 0.05). In all 3 groups, patients who had an initial CGI score > or = 5 received significantly higher overall mean daily doses than did patients with an initial CGI score < 5 (P < 0.001). A significantly lower proportion of OLZ-treated patients (10.2%) were receiving concomitant anticholinergic medication at the end of the study (month 6) compared with RIS-treated (19.9%) and HAL-treated (44.0%) patients (P < 0.001).
The mean daily doses recorded in this analysis based on data from a naturalistic setting are consistent with recommendations based on clinical trials. Compared with both RIS- and HAL-treated patients, OLZ-treated patients were less likely to experience EPS or other adverse events, and less likely to use concomitant anticholinergic medications. OLZ-treated patients were also more likely to respond to treatment than were RIS-treated patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
5Prog. Neuropsychopharmacol. Biol. Psychiatry 2001 Apr 25: 507-18
PMID11370994
TitleDopamine receptor responsivity in schizophrenic patients in a drug-free state and after treatment with olanzapine.
Abstract1. 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.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
6Prog. Neuropsychopharmacol. Biol. Psychiatry 2001 Apr 25: 507-18
PMID11370994
TitleDopamine receptor responsivity in schizophrenic patients in a drug-free state and after treatment with olanzapine.
Abstract1. 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.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
7Can. J. Physiol. Pharmacol. 2002 Jan 80: 36-41
PMID11911224
TitleNo change in dopamine D1 receptor in vivo binding in rats after sub-chronic haloperidol treatment.
AbstractA frequent side effect in the long-term treatment of schizophrenia with the dopamine D2 antagonist HALoperidol (HAL) is the appearance of tardive dyskinesia or, in animals, of repetitive involuntary vacuous chewing movements (VCMs). In rats, chronic HAL-induced or D1 receptor-stimulated VCMs are suppressed by D1 antagonists, suggesting that this behavioral supersensitivity is mediated by D1 receptors. The goal of this study was to investigate in vivo the possible relationship between D1 receptor binding and D1-mediated behavioral supersensitivity, after subchronic HAL treatments. D1 agonist R-SKF 82957 and antagonist SCH 23390, both labeled with carbon-11, were used to assess in vivo D1 receptor binding. Rats were treated with HAL (1.5 mg/kg, i.p.) or vehicle for 21 days, followed by a 4 day washout period. No significant difference was found in the regional brain binding of either radioligand. D1 receptor-mediated behaviors including VCMs, grooming, and rearing were measured in control or HAL-treated rats. VCMs were significantly increased in HAL-treated rats, suggesting D1 receptor stimulation and possibly receptor supersensitivity. This study failed to link the purported D1 receptor-mediated behaviors with in vivo receptor binding measures of R-[11C]SKF 82957 or [11C]SCH 23390 in rat brain regions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
8Prog. Neuropsychopharmacol. Biol. Psychiatry 2002 Feb 26: 261-5
PMID11817502
TitleLack of impact of CYP1A2 genetic polymorphism (C/A polymorphism at position 734 in intron 1 and G/A polymorphism at position -2964 in the 5'-flanking region of CYP1A2) on the plasma concentration of haloperidol in smoking male Japanese with schizophrenia.
AbstractThe impact of genetic polymorphism of CYP1A2 that are related to the induction of the isozyme on the plasma levels of HALoperidol (HAL) in 40 male smokers with schizophrenia was investigated. A point mutation from C to A in intron 1 at position 734 and a point mutation from G to A at position -2964 in the 5'-flanking region of CYP1A2 were identified by polymerase chain-reaction-restricted fragment length polymorphism method. Regarding C/A polymorphism in intron 1 at position 734, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight among the subjects with A/A (n = 21), A/C (n = 14) and C/C (n = 5) genotypes (one-way analysis of variance: 63.1 +/- 18.5, 47.8 +/- 12.5 and 50.8 +/- 15.1 ng/ml/mg/kg, respectively, F(2,37) = 2.556, P = .09). Regarding G/A polymorphism at position -2964 in the 5'-flanking region, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight between subjects with G/G (n = 24) and G/A (n = 15) (two-tailed t test: G/G and G/A = 51.2 +/- 16.6 and 59.0 +/- 17.6 ng/ml/mg/kg, respectively, df = 28, P = .22). The present study suggests that the genotyping of CYP1A2 cannot predict the steady state plasma levels of HAL in male smoking schizophrenics.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
9J Med Assoc Thai 2002 Dec 85: 1301-8
PMID12678168
TitleComparative study of the effectiveness of zuclopenthixol acetate and haloperidol in acutely disturbed psychotic patients.
AbstractTo study the effectiveness, frequency of administration and side effects of zuclopenthixol acetate (ZPTA) and HALoperidol (HAL) in the treatment of acute psychotic disturbance with aggression.
Purposive sampling method was employed in a group of psychotic patients with aggression admitted to Songkla Neuropsychiatric Hospital, they were randomly divided into 2 groups: ZPTA group and HAL group. All of the patients were evaluated daily for 7 consecutive days using the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression Scale (CGI). Statistical analysis was performed by using the Student t-test and Linear regression.
There were 70 patients with diagnosis of schizophrenia, mania and acute psychosis. Thirty-eight patients were randomly assigned to the ZPTA group and were given 50-100 mg of the drug, while 32 patients received HAL 5-10 mg. The result showed a significant reduction in BPRS or CGI scores in both groups. Patients treated with ZPTA required less frequent administration than did those on HAL (p < 0.05). There was no statistically significant difference in the reduction in scores between the two groups. Nor was there a statistical difference in reduction of aggression based on BPRS rating. Each group of patients showed a few side effects of mild degree.
Both ZPTA and HAL were effective in the treatment of acute psychosis with aggression, but frequency of administration was lower in the ZPTA group
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
10Schizophr. Res. 2002 Jul 56: 25-30
PMID12084416
TitleSexual side effects of novel antipsychotic medications.
AbstractThe novel antipsychotic medications offer a more favorable extrapyramidal side effect profile than conventional agents. It is uncertain that the novel antipsychotics have a benefit in terms of sexual side effects.
We prospectively administered a survey of sexual functioning to 25 male patients with DSM-IV schizophrenia, taking conventional and novel antipsychotics. Contrasts were made between three treatment groups: clozapine (CLOZ), risperidone (RIS), and a combined HALoperidol/fluphenazine (HAL/FLU) group.
A decrease in overall sexual functioning was reported in all medication groups (40-71%). The majority of subjects taking RIS or HAL/FLU reported a decline in one or more aspects of sexual functioning. Examining specific aspects of sexual functioning revealed that, a decline in sexual interest was significantly less common on CLOZ compared to RIS (0 vs. 64%; chi(2)=6.1, df=1, p=0.01) or HAL/FLU (0 vs. 67%; chi(2)=5.2, df=1, p=0.02), while a decline in the erectile frequency was significantly more common on RIS compared to CLOZ (40 vs. 93%; chi(2)=6.2, df=1, p=0.01) or HAL/FLU (50 vs. 93%; chi(2)=4.8, df=1, p=0.03) (0%). For enjoyment of orgasm and ejaculatory volume, significantly fewer CLOZ compared to RIS subjects reported a decline (20 vs. 86%; chi(2)=7.4, df=1, p=0.01).
Sexual side effects are common clinically pertinent adverse effects associated with both novel and conventional antipsychotic medications. They deserve increased attention in clinical work and future research with emerging antipsychotic drugs.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
11Psychiatry Res 2002 May 110: 27-37
PMID12007591
TitleSex differences in clinical response to olanzapine compared with haloperidol.
AbstractThere is current disagreement over whether men and women respond differently to typical or atypical antipsychotic medications. This study reanalyzed a large international clinical trial of olanzapine (Olz) compared with HALoperidol (HAL) to test for sex differences in treatment response, controlling for illness chronicity and menopausal status. We hypothesized that women would show a greater response to either medication than men, particularly among first admission, premenopausal women. DSM-III-R schizophrenia inpatients (700 women and 1295 men) were randomly assigned to a 6-week trial of Olz vs. HAL. Longitudinal random effect models were used to test for interactions of sex with medication, chronicity and menopausal status on treatment response. Findings showed that women on olanzapine had a greater drop in overall symptomatology by week 4 than any other group, and their level of symptomatology remained lower throughout the 6-week trial. The sex differences in treatment response in olanzapine compared with HALoperidol were, in part, dependent on chronicity and, in women, menopausal status. That is, first episode women on HALoperidol exhibited an increase in symptomatology over the 6-week trial compared to their male counterparts, while multiply hospitalized women had a better treatment response on HALoperidol than their male counterparts. Women on olanzapine had a significantly better treatment response than men, regardless of chronicity. Finally, premenopausal women had a significantly better treatment response than postmenopausal women, regardless of treatment and chronicity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
12Prog. Neuropsychopharmacol. Biol. Psychiatry 2002 Feb 26: 261-5
PMID11817502
TitleLack of impact of CYP1A2 genetic polymorphism (C/A polymorphism at position 734 in intron 1 and G/A polymorphism at position -2964 in the 5'-flanking region of CYP1A2) on the plasma concentration of haloperidol in smoking male Japanese with schizophrenia.
AbstractThe impact of genetic polymorphism of CYP1A2 that are related to the induction of the isozyme on the plasma levels of HALoperidol (HAL) in 40 male smokers with schizophrenia was investigated. A point mutation from C to A in intron 1 at position 734 and a point mutation from G to A at position -2964 in the 5'-flanking region of CYP1A2 were identified by polymerase chain-reaction-restricted fragment length polymorphism method. Regarding C/A polymorphism in intron 1 at position 734, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight among the subjects with A/A (n = 21), A/C (n = 14) and C/C (n = 5) genotypes (one-way analysis of variance: 63.1 +/- 18.5, 47.8 +/- 12.5 and 50.8 +/- 15.1 ng/ml/mg/kg, respectively, F(2,37) = 2.556, P = .09). Regarding G/A polymorphism at position -2964 in the 5'-flanking region, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight between subjects with G/G (n = 24) and G/A (n = 15) (two-tailed t test: G/G and G/A = 51.2 +/- 16.6 and 59.0 +/- 17.6 ng/ml/mg/kg, respectively, df = 28, P = .22). The present study suggests that the genotyping of CYP1A2 cannot predict the steady state plasma levels of HAL in male smoking schizophrenics.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
13Prog. Neuropsychopharmacol. Biol. Psychiatry 2003 Sep 27: 945-9
PMID14499311
TitleEffects of smoking and cytochrome P450 2D6*10 allele on the plasma haloperidol concentration/dose ratio.
AbstractThis 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.
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.
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.
Our results suggest that the effect of smoking on the HAL C/D ratio depends on the CYP2D6*10 genotype.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
14J. Neurochem. 2003 Sep 86: 1089-100
PMID12911617
TitleAntipsychotic drugs differentially modulate apolipoprotein D in rat brain.
AbstractApolipoprotein-D (apoD), a member of the lipocalin family of proteins, binds to arachidonic acid and cholesterol among other hydrophobic molecules. Recently, elevated apoD levels have been reported in the post-mortem brains, as well as plasma, of schizophrenic patients and in rodent brains after chronic treatment with clozapine (CLOZ). These findings and the evidence for altered membrane lipid metabolism in schizophrenia suggest that apoD may have a role in the pathophysiology of illness, and also in the differential clinical outcome following treatment with typical and atypical antipsychotic drugs. Here, we compared the effects of these antipsychotics on the expression of apoD in rat brain. Chronic treatment with typical antipsychotic, HALoperidol (HAL) reduced apoD expression in hippocampus, piriform cortex and caudate-putamen (p = 0.027-0.002), whereas atypical antipsychotics, risperidone (RISP) and olanzapine (OLZ) increased (p = 0.051 to < 0.001 and p = 0.048 to < 0.001, respectively) apoD expression. In hippocampus, HAL-induced changes were present in CA1, CA3 and dentate gyrus, however, apoD levels in motor cortex were unchanged. There were also very dramatic effects of HAL on the neuronal morphology, particularly, cellular shrinkage and disorganization with the loss of neuropil. Post-treatment, either with RISP or OLZ, was very effective in restoring the HAL-induced reduction of apoD, as well as cellular morphology. Similarly, pre-treatments were also effective, but slightly less than post-treatment, in preventing HAL-induced reduction of apoD. The increased expression of apoD by atypical antipsychotics may reflect a novel molecular mechanism underlying their favorable effects compared with HAL on cognition, negative symptoms and extra-pyramidal symptoms in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
15J. Neurochem. 2003 Sep 86: 1089-100
PMID12911617
TitleAntipsychotic drugs differentially modulate apolipoprotein D in rat brain.
AbstractApolipoprotein-D (apoD), a member of the lipocalin family of proteins, binds to arachidonic acid and cholesterol among other hydrophobic molecules. Recently, elevated apoD levels have been reported in the post-mortem brains, as well as plasma, of schizophrenic patients and in rodent brains after chronic treatment with clozapine (CLOZ). These findings and the evidence for altered membrane lipid metabolism in schizophrenia suggest that apoD may have a role in the pathophysiology of illness, and also in the differential clinical outcome following treatment with typical and atypical antipsychotic drugs. Here, we compared the effects of these antipsychotics on the expression of apoD in rat brain. Chronic treatment with typical antipsychotic, HALoperidol (HAL) reduced apoD expression in hippocampus, piriform cortex and caudate-putamen (p = 0.027-0.002), whereas atypical antipsychotics, risperidone (RISP) and olanzapine (OLZ) increased (p = 0.051 to < 0.001 and p = 0.048 to < 0.001, respectively) apoD expression. In hippocampus, HAL-induced changes were present in CA1, CA3 and dentate gyrus, however, apoD levels in motor cortex were unchanged. There were also very dramatic effects of HAL on the neuronal morphology, particularly, cellular shrinkage and disorganization with the loss of neuropil. Post-treatment, either with RISP or OLZ, was very effective in restoring the HAL-induced reduction of apoD, as well as cellular morphology. Similarly, pre-treatments were also effective, but slightly less than post-treatment, in preventing HAL-induced reduction of apoD. The increased expression of apoD by atypical antipsychotics may reflect a novel molecular mechanism underlying their favorable effects compared with HAL on cognition, negative symptoms and extra-pyramidal symptoms in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
16Neuropsychopharmacology 2003 Feb 28: 300-9
PMID12589383
TitleDifferential effects of haloperidol, risperidone, and clozapine exposure on cholinergic markers and spatial learning performance in rats.
AbstractHALoperidol (HAL), a potent typical antipsychotic, continues to be a frequently prescribed medication for behavioral disturbances associated particularly with schizophrenia despite well-documented adverse effects associated with its chronic use. Animal experiments have even indicated that HAL can damage cholinergic pathways and thus could be especially deleterious to those experiencing cognitive deficits. However, several recent clinical studies indicate that atypical antipsychotics may actually improve cognitive function in some patients, although this assertion requires further investigation. The purpose of this study was to compare the effects of prior chronic (45- or 90-day) oral exposure to HAL and the atypical antipsychotics risperidone (RISP) and clozapine (CLOZ) on cognitive performance and central cholinergic markers in rats. All analyses were done after 4 days of drug washout in order to minimize direct drug effects. Learning performance and choline acetyltransferase (ChAT) levels were assessed in a water maze task and with immunofluorescence staining, respectively. HAL significantly impaired learning performance after 90 but not after 45 days of treatment when compared to both vehicle controls and the atypical agents, while RISP slightly improved task performance. Both 45 and 90 days of previous HAL exposure reduced ChAT staining in several brain regions, including the cortex, caudate-putamen, and hippocampus. ChAT staining in the caudate-putamen and hippocampus was also decreased after 90 days of RISP exposure, raising the possibility of deleterious cognitive effects after exposure to this dosage for longer periods of time. The results suggest that antipsychotic drugs exert differential and temporally dependent effects on central cholinergic neurons and learning performance.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
17Neuropsychopharmacology 2003 Aug 28: 1501-5
PMID12784098
TitleEffect of CYP2D6 genotypes on the metabolism of haloperidol in a Japanese psychiatric population.
AbstractWe investigated the effect of CYP2D6 genotypes on plasma levels of HALoperidol (HAL) and reduced HALoperidol (RHAL) in 88 Japanese schizophrenic inpatients being treated with HAL. Some subjects carrying CYP2D6*5 allele (CYP2D6*1/CYP2D6*5, CYP2D6*5/CYP2D6*10) showed extremely high concentrations of both HAL and RHAL, and the groups with CYP2D6*5 allele seemed to have higher plasma concentrations of HAL (1.14+/-0.69 ng/ml/mg) and RHAL (1.10+/-1.05 ng/ml/mg) than the other groups. Among those without CYP2D6*5 allele, there were no significant differences in plasma concentrations of HAL and RHAL between those without CYP2D6*10 allele (HAL=0.68+/-0.31 ng/ml/mg, RHAL=0.28+/-0.37 ng/ml/mg), those with one CYP2D6*10 (HAL=0.70+/-0.23 ng/ml/mg, RHAL=0.31+/-0.16 ng/ml/mg) and those with two CYP2D6*10 alleles (HAL=0.69+/-0.14 ng/ml/mg, RHAL=0.40+/-0.09 ng/ml/mg), although there was a tendency of higher plasma concentration of RHAL in those with two CYP2D6*10 alleles. At a lower daily dosage of HAL (<10 mg/day), the subjects with two or one CYP2D6*10 allele(s) showed significantly higher plasma concentrations of RHAL (0.43+/-0.23 ng/ml/mg, 0.34+/-0.16 ng/ml/mg) than those without CYP2D6*10 allele (0.18+/-0.16 ng/ml/mg). The results of this study indicate that CYP2D6*10 allele plays significant but modest role in HAL metabolism in Japanese; nevertheless, we should not lump CYP2D6*10 allele with CYP2D6*5 allele because these two mutated alleles seem to have different impacts in the metabolism of HAL.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
18Int J Geriatr Psychiatry 2003 Nov 18: 1013-20
PMID14618553
TitleOlanzapine vs haloperidol in geriatric schizophrenia: analysis of data from a double-blind controlled trial.
AbstractTo compare the six-week clinical response and safety profile of schizophrenia patients, age > or =60 years, receiving olanzapine (OLZ) vs HALoperidol (HAL) in a double blind, randomized trial.
Double-blind data on patients age > or =60 randomized to 5 mg/d OLZ (n=83) or 5 mg/d HAL (n=34) (Week 1) then flexibly dosed to 5-20 mg/d over six weeks, with a 48-week extension for responders, were analyzed post-hoc. Efficacy indices included the PANSS Total and PANSS Psychosis Core Total (PPCT). Safety measures included the Simpson-Angus Scale (SAS), Barnes Akathisia Scale (BAS), Abnormal Involuntary Movement Scale (AIMS), treatment-emergent adverse events, and laboratory values. Mixed model, repeated measures (MMRM) analyses were applied to all continuous data measured at each visit. Continuous data recorded only at phase completion or termination were analyzed with a fixed effect last observation carried forward (LOCF) model. Frequencies of categorical response data were analyzed using Fisher's exact methods. Differences were tested for significance at Week 6 using a two-sided alpha value of 0.05.
HAL group (n=34; age range 60-80) received a mean modal dose 9.4 mg/d while OLZ group (n=83; age range 60-86) received a mean modal dose 11.9 mg/d. At Week 6, OLZ was superior to HAL on both the PANSS Total (p=0.015) and PPCT (p=0.043). Considering safety, OLZ was superior to HAL for the SAS and BAS (p<0.001; p<0.001). No spontaneous adverse event occurred more frequently with OLZ than with HAL. In patients never receiving adjunct anticholinergic therapy, no significant differences were present for anticholinergic-like side effects including blurred vision, dry mouth, constipation, or urinary difficulties.
In elderly schizophrenia patients, olanzapine was more efficacious and better tolerated for extrapyramidal signs than was HALoperidol. Olanzapine was equivalent to HALoperidol for anticholinergic-like side effects when corrected for anticholingergic agents.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
19Neuropsychopharmacology 2003 Jul 28: 1227-34
PMID12700705
TitleRegulation of glutamate carboxypeptidase II function in corticolimbic regions of rat brain by phencyclidine, haloperidol, and clozapine.
AbstractMounting evidence indicates that hypofunction of NMDA glutamate receptors causes or contributes to the full symptomatology of schizophrenia. N-acetyl-aspartyl-glutamate (NAAG), an endogenous neuropeptide, blocks NMDA receptors and inhibits glutamate release by activating metabotropic mGluR3 receptors. NAAG is catabolized to glutamate and N-acetyl-aspartate by the astrocytic enzyme glutamate carboxypeptidase II (GCP II). Changes in GCP II activity may be critically linked to changes in glutamatergic neurotransmission especially at NMDA receptors. We examined whether GCP II function is altered by treatment with the noncompetitive antagonist and psychotomimetic drug phencyclidine (PCP) and with the neuroleptics HALoperidol (HAL) and clozapine (CLOZ), in corticolimbic brain regions of the adult rat. Chronic exposure to PCP produced significant increases in GCP II protein expression and activity in the prefrontal cortex (PFC) and hippocampus (HIPP). This effect may be explained by a compensatory response to persistent blockade of NMDA receptors. In addition, chronic treatment with neuroleptics upregulated GCP II activity, but not protein expression, in the PFC. In contrast, GCP II activity was decreased after acute exposure to HAL or CLOZ and was not changed after acute PCP treatment. These findings provide support for a role of GCP II function in the control of glutamatergic neurotransmission and suggest that some of the therapeutic actions of neuroleptic drugs may be mediated through their effects on GCP II activity. These results demonstrate that psychotomimetic and neuroleptic drugs modulate GCP II function in brain regions that are widely involved in the neuropathology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
20Nihon Shinkei Seishin Yakurigaku Zasshi 2004 Apr 24: 67-70
PMID15164612
Title[Effect of smoking on pharmacokinetics of antipsychotics].
AbstractThe population of Japanese smokers has decreased; however, the prevalence of smokers among psychiatric patients has been reported to be as high as 80% in schizophrenic patients. Although the impact of smoking on the pharmacokinetics of antipsychotics has been reported, results have been controversial. At first, the impact of smoking on plasma HALoperidol (HAL) concentrations was investigated in Japanese male schizophrenic inpatients treated with HAL per os. Smokers had approximately 20% lower HAL concentrations/daily dose of HAL/kg body weight than non-smokers. The impact of genetic polymorphism of CYP1A2 that are related to the induction of the isozyme on the plasma levels of HAL in male smokers with schizophrenia was also investigated. A point mutation from C to A in intron 1 at position 734 and a point mutation from G to A at position--2964 in the 5'-flanking region of CYP1A2 were identified by the PCR-RFLP method. Regarding C/A polymorphism in intron 1 at position 734, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight among the subjects with A/A, A/C and C/C genotypes. Regarding G/A polymorphism at position--2964 in the 5'-flanking region, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight between subjects with G/G and G/A.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
21Nihon Shinkei Seishin Yakurigaku Zasshi 2004 Apr 24: 67-70
PMID15164612
Title[Effect of smoking on pharmacokinetics of antipsychotics].
AbstractThe population of Japanese smokers has decreased; however, the prevalence of smokers among psychiatric patients has been reported to be as high as 80% in schizophrenic patients. Although the impact of smoking on the pharmacokinetics of antipsychotics has been reported, results have been controversial. At first, the impact of smoking on plasma HALoperidol (HAL) concentrations was investigated in Japanese male schizophrenic inpatients treated with HAL per os. Smokers had approximately 20% lower HAL concentrations/daily dose of HAL/kg body weight than non-smokers. The impact of genetic polymorphism of CYP1A2 that are related to the induction of the isozyme on the plasma levels of HAL in male smokers with schizophrenia was also investigated. A point mutation from C to A in intron 1 at position 734 and a point mutation from G to A at position--2964 in the 5'-flanking region of CYP1A2 were identified by the PCR-RFLP method. Regarding C/A polymorphism in intron 1 at position 734, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight among the subjects with A/A, A/C and C/C genotypes. Regarding G/A polymorphism at position--2964 in the 5'-flanking region, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight between subjects with G/G and G/A.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
22Drug Alcohol Depend 2005 Oct 80: 23-33
PMID15894433
TitleRating the severity and character of transient cocaine-induced delusions and hallucinations with a new instrument, the Scale for Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SAPS-CIP).
AbstractCocaine can induce transient psychotic symptoms. We examined the phenomenology of such cocaine-induced psychosis (CIP) using a modified version of the Scale for Assessment of Positive Symptoms (SAPS), a well-validated instrument for the assessment of schizophrenic psychosis.
We developed a new instrument, the Scale for Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SAPS-CIP), based on the well-validated SAPS. We interviewed 243 unrelated cocaine-dependent adults using both the SAPS-CIP and an instrument for the identification of cocaine-induced paranoia, the Cocaine Experience Questionnaire (CEQ).
One hundred and eighty-one (75%) of the subjects endorsed CIP using the CEQ. With the SAPS-CIP, HALlucination (HAL) and delusion (DEL) scores correlated strongly, and the DEL domain showed excellent concurrent validity with the CEQ. We observed significant positive correlations, respectively, between severity of HAL and DEL, and lifetime number of episodes of cocaine use, and negative correlations with age at onset of cocaine use.
The results suggest that CIP consists of transient delusional and HALlucinatory symptoms, which tend to occur together and co-vary in severity. It appears that rating cocaine-induced paranoia alone (e.g., with the CEQ) can identify most subjects experiencing CIP. However, the SAPS-CIP is useful for quantifying the severity of CIP according to operational criteria. Our data provide additional evidence that CIP is a sensitizing response.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
23Behav. Brain Res. 2006 Jan 166: 177-83
PMID16188330
TitlePharmacological treatment to augment hole board habituation in prenatal Vitamin D-deficient rats.
AbstractNeurocognitive impairment has consistently been considered a central and stable feature of schizophrenia. There is much controversy about the effects of neuroleptics on neurocognitive deficits. Thus, further investigations are needed to clarify the pathological substrate of cognitive deficits in schizophrenia as well as to identify pharmacological tools for treatment. Transient prenatal Vitamin D deficiency is considered a developmental model in schizophrenia research. Recently, it was reported that prenatal Vitamin D-depleted rats showed a habituation deficit in the hole board. Here, we tested the effect on hole board habituation of HALoperidol (HAL, 0.075 mg/kg, i.p.), risperidone (Ris, 0.2 mg/kg, i.p.) and the mGluR5 agonist CHPG (0.1 mg, i.c.v.) after subchronic treatment. HAL was found to impair habituation in control animals, Ris restored hole board habituation, whereas HAL and CHPG normalised hole board habituation in the deplete animals completely. The results of the study demonstrate that (i) the Vitamin D model might be a valuable tool in the study of neurodevelopmental aspects of schizophrenia, (ii) the model is sensitive in detecting the effect of antipsychotic drugs and (iii) the model appears to be sensitive in differentiating between typical and atypical antipsychotic drug.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
24Schizophr. Res. 2006 Feb 82: 95-106
PMID16442781
TitleDifferential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus.
AbstractThe results of mostly short-term treatment studies in human patients and animals suggest that second-generation antipsychotics (SGAs) such as risperidone (RISP) and olanzapine (OLZ) compared to first-generation antipsychotics (FGAs) such as HALoperidol (HAL) and chlorpromazine (CPZ) have neuroprotective effects. The animal studies indicate that these effects are probably mediated through increased expression of neurotrophic factors such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). However, since antipsychotics are commonly used for very long-term treatment periods, particularly in schizophrenic patients, it is important to measure the effects of chronic administration of antipsychotic drugs on the aforementioned growth factors. This study determined the effects of 90- and 180-day treatments with two FGAs, HAL and CPZ, and two SGAs, RISP and OLZ, on the levels of NGF and BDNF protein in hippocampus and striatum of rat. Furthermore, since a preliminary study showed that 90-day treatment of HAL caused significant reductions in the expression of both NGF and BDNF the HAL-treated animals were then switched to SGAs for the next 90 days to assess the potential for restoration of trophic factor levels. After the 90-day treatment, NGF levels in the hippocampus were reduced by 60-70% with HAL or CPZ, and by only 25-30% with RISP or OLZ compared to levels with vehicle only. After the 180-day treatment, NGF levels were further reduced with HAL, RISP, and OLZ, but not with CPZ. The magnitude of the NGF decreases in the striatum was larger (70-90%) with all the antipsychotics compared to the hippocampus. However, the pattern of BDNF changes in the hippocampus differed significantly from the striatum after 90- or 180-day treatment with the antipsychotics. In hippocampus, compared to controls, BDNF levels remained unchanged with OLZ both after 90 and 180 days of treatment. Whereas, larger decreases in BDNF levels were observed with HAL or CPZ and intermediate decreases were observed with RISP after 90 days of treatment that continued to decline up to 180 days. Furthermore, switching HAL animals after 90 days of treatment to either RISP or OLZ for the next 90 days significantly restored levels of both NGF and BDNF in both the brain regions. These data indicate that SGAs compared to FGAs induce less deleterious effects on neurotrophic factor levels in the brain and may also offer ability to reverse the more pronounced negative effects of FGAs as well. These data may have significant clinical implications for long-term antipsychotic selection as well as the common practice of antipsychotic switchover.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
25Naunyn Schmiedebergs Arch. Pharmacol. 2006 Dec 374: 177-93
PMID17103144
TitleRole of the simultaneous enhancement of NMDA and dopamine D1 receptor-mediated neurotransmission in the effects of clozapine on phencyclidine-induced acute increases in glutamate levels in the rat medial prefrontal cortex.
AbstractClozapine (CLZ) can improve both the positive and negative symptoms of treatment-resistant schizophrenia (TRS), which does not respond to typical antipsychotics. This suggests that elucidation of the pharmacological mechanism for CLZ could lead to further clarification of the pathophysiology of TRS. This study examined the effects of CLZ on phencyclidine (PCP)-induced hyperlocomotion and on the acute increases in glutamate levels that occur in the medial prefrontal cortex (mPFC) in order to test the hypothesis that CLZ effect is associated with the simultaneous enhancement of N-methyl-D: -aspartate (NMDA) and dopamine D(1) receptor-mediated neurotransmission. CLZ effect on PCP-induced hyperlocomotion and increases in glutamate levels were examined by using behavioral rating scores and in vivo microdialysis, respectively. CLZ and HALoperidol (HAL) dose-relatedly attenuated PCP-induced hyperlocomotion, and concentration-relatedly blocked PCP-induced acute increases in glutamate levels in the mPFC, with the decrease in saline-induced locomotor activity induced by CLZ being much weaker than that induced by HAL. CLZ also blocked, in a dose-related manner, acute increases in glutamate levels in the mPFC that were induced by local perfusion with a competitive NMDA receptor antagonist, CPP, in this region. Although an enhanced blocking effect of the sub-threshold concentration of NMDA perfusion on PCP-induced acute increases in glutamate levels in the mPFC was noted after co-perfusion with a dopamine D(1) receptor agonist, SKF-38393, perfusion with SKF-38393 did not reverse the CLZ blocking of PCP-induced increases in glutamate levels. Therefore, CLZ may block PCP-induced acute increases in glutamate levels in the mPFC by an enhancement of the NMDA receptor-mediated neurotransmission that is not accelerated by an enhanced dopaminergic transmission via dopamine D(1) receptors. This blocking effect may partially explain the CLZ-induced attenuation of PCP-induced hyperlocomotion.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
26Psychopharmacology (Berl.) 2006 Oct 188: 183-92
PMID16944104
TitleDifferential attenuation of d-amphetamine-induced disruption of conditional discrimination performance by dopamine and serotonin antagonists.
AbstractRecent experimental findings suggest that a core cognitive deficit of schizophrenia is the degraded ability to use task-setting cues to guide goal-directed behaviour, that this deficit is evident in acute as well as chronic schizophrenia, and that such deficits can me modelled in animals using conditional discrimination tasks.
To establish the reversal potential of D1, D2 and 5-HT receptor antagonists acutely, and D1 and D2 receptor antagonists chronically, on d-amphetamine-induced disruption of a conditional discrimination task that depends on the ability to use task-setting cues to direct goal directed performance.
A conditional discrimination paradigm was employed in which rats learned to respond on an appropriate lever, conditional upon specific auditory stimuli.
d-Amphetamine (1.5 mg/kg) disruption of conditional discrimination was attenuated by acute pre-treatment with the selective D1 antagonist SCH 23390 and the atypical anti-psychotic clozapine (Cloz). Acute pre-treatment with the selective D2 antagonist eticlopride (Eti) and the anti-psychotic HALoperidol (HAL) failed to reverse d-amphetamine disruption, as did pre-treatment with the selective 5HT1A antagonist WAY 100635 and the selective 5HT2A/C antagonist ritanserin. However, Eti and HAL did reverse d-amphetamine-induced task disruption when administered chronically (as did SCH 23390, alpha-flupenthixol and Cloz).
These results suggest that D1 receptors are involved in tasks that require the use of conditional relationships and that D2 receptor antagonism can come to exert a similar influence after chronic treatment.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
27J Psychiatry Neurosci 2006 Jul 31: 271-9
PMID16862245
TitleLevomepromazine versus chlorpromazine in treatment-resistant schizophrenia: a double-blind randomized trial.
AbstractWe compared the effect of levomepromazine (LMP) with chlorpromazine (CPZ) in treatment-resistant schizophrenia (TRS).
We carried out a double-blind, parallel group study (n = 19/arm) with balanced randomization in blocks of 4 and stratification by sex. Subjects entered a 30-week trial, of which phases I-III were open: phase I (wk 0-6) baseline; phase II (wk 7-9) stepwise transition to HALoperidol (HAL), 30 mg/d, plus benztropine (BT), 4 mg/d; phase III (wk 10-15) HAL, 40-60 mg/d, plus BT, 4-6 mg/d; phase IV (wk 16-20) stepwise transition to LMP or CPZ (500 mg/d) following randomization; phase V (wk 21-28) stepwise increase of LMP or CPZ (600-1000 mg/d, dose reduction permitted) to establish optimum dose; and phase VI (wk 29-30) optimized dose maintained. Criteria for TRS were based on those established by Kane et al in 1988. The criterion for a response to treatment was a reduction of 25% or more in total Brief Psychiatric Rating Scale score.
Both LMP (p = 0.007) and CPZ (p = 0.030) improved TRS relative to baseline. Although there was no significant difference between the 2 groups in treatment response at study end point, hierarchical linear modelling of longitudinal outcome revealed a significant (p = 0.006) advantage of LMP over CPZ for the BPRS total score. Ten of 19 participants on LMP and 8 of 19 on CPZ met the criterion for treatment response, and 9 of the 18 responders did so on 200-700 mg/d phenothiazine. The mean dose of responders was 710 (standard deviation [SD] 265) mg/d (LMP) and 722 (SD 272) mg/d (CPZ). Akathisia was associated with a nonresponse to phenothiazines (p = 0.010). BPRS scores increased significantly on HAL (p = 0.006). Two of 19 participants on LMP and 5 of 19 on CPZ withdrew early from the study.
LMP and CPZ may be useful in the management of TRS. A modest advantage of LMP compared with CPZ was seen in longitudinal analysis. High doses of neuroleptics may contribute to TRS; reduction of neuroleptics to modest or moderate doses should be considered before categorizing a patient as treatment resistant.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
28J Neural Transm (Vienna) 2006 Oct 113: 1355-65
PMID16465454
TitleChronic neuroleptic treatment reduces endogenous kynurenic acid levels in rat brain.
AbstractThe brain and cerebrospinal fluid levels of kynurenic acid (KYNA), a metabolite of the kynurenine pathway of tryptophan degradation and antagonist of the glycine(B) receptor and the alpha7 nicotinic acetylcholine receptor, are elevated in persons with schizophrenia. To evaluate whether this increase is related to antipsychotic medication, we examined the effects of HALoperidol (HAL), clozapine (CLOZ) or raclopride (RAC) on brain KYNA levels in rats. Animals received either acute drug injections or ingested the drugs chronically with the drinking water. Acute application or one-week drug exposure had no effect on brain KYNA levels. After one month, HAL, CLOZ and RAC all caused significant reductions in KYNA levels in striatum, hippocampus and frontal cortex. Quantitatively similar reductions in the brain tissue content of KYNA were observed after one year of HAL administration. All these effects were accompanied by equivalent decreases in the extracellular concentration of KYNA, measured by striatal microdialysis. Separate animals received an intrastriatal infusion of (3)H-kynurenine to probe the entire kynurenine pathway acutely in rats treated with HAL for one year. These animals showed reduced (3)H-KYNA production, but no changes in the formation of other kynurenine pathway metabolites. By enhancing glutamatergic and cholinergic neurotransmission, reduced brain KYNA levels may play a role in the clinical effects of prolonged antipsychotic medication.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
29J Psychiatr Res 2007 Aug 41: 372-86
PMID16564057
TitleLong-term antipsychotic treatments and crossover studies in rats: differential effects of typical and atypical agents on the expression of antioxidant enzymes and membrane lipid peroxidation in rat brain.
AbstractShort-term (<45 days) treatment studies in rats have reported increased oxidative stress and oxidative (i.e., oxygen free radical-mediated) neural cell injury with typical antipsychotics such as HALoperidol, but not with the atypicals such as clozapine, olanzapine or risperidone. However, now these and several other atypical antipsychotics that differ in their neurotransmitter receptor affinity profiles are being used for a long-term treatment of schizophrenia. Therefore, understanding of their long-term treatment effects on the expression of antioxidant enzymes and oxidative neural cell injury in rats may be important to explain the possible differential mechanisms underlying their long-term clinical and side effects profiles. The effect of 90 and 180 day exposure to HALoperidol (HAL, 2mg/kg/day), a representative typical antipsychotic was compared to exposure to chlorpromazine (CPZ, 10mg/kg/day), ziprasidone (ZIP, 12mg/kg/day), risperidone (RISP, 2.5mg/kg/day), clozapine (CLOZ, 20mg/kg/day) or olanzapine (OLZ, 10mg/kg/day) on the expression of antioxidant defense enzymes and levels of lipid peroxidation in the rat brain. The drug-induced effects on various antioxidant defense enzymes; manganese-superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD) and catalase (CAT) were assessed by determination of their enzymatic activity and protein content. Immunohistochemical analysis was also carried out to assess the cellular levels of MnSOD and CuZnSOD and cellular morphology. The oxidative membrane damage was assessed by determination of levels of the lipid peroxidation product, hydroxyalkanals (HAEs) in the rat brain. Both 90 and 180 days of HAL treatment very significantly decreased the levels of MnSOD (50%) and CuZnSOD (80%) and increased the levels of HAEs compared to vehicle treatment. Smaller reduction was found in CAT (25%) and no change in the glutathione peroxidase (GSHPx). The levels of enzymatic activity correlated generally well with the levels of enzyme protein indicating that the changes were in the expression of net protein. Though atypical antipsychotics like ZIP, RISP and OLZ did not show any change in the HAEs levels up to 90 days, further treatment up to 180 days resulted in significantly increased levels of HAEs in CPZ, ZIP and RISP, but not in OLZ treated rats. Post-treatment with several atypical antipsychotics (OLZ=CLOZ>RISP) for 90 days after 90 day of HAL treatment significantly restored the HAL-induced loss in MnSOD and CuZnSOD activities and increase in lipid peroxidation products as well as cellular morphology. These data may be very helpful in planning long-term use as well as switch over of these antipsychotics for the management of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
30Neurochem. Res. 2007 Aug 32: 1343-50
PMID17401650
TitleEffects of chronic haloperidol and/or clozapine on oxidative stress parameters in rat brain.
AbstractDecreased antioxidant activity is considered as one of the causes of tardive dyskinesia in schizophrenic patients in a prolonged neuroleptic treatment course. HALoperidol (HAL) has been hypothesized to increase oxidative stress, while clozapine (CLO) would produce less oxidative damage. The objective was to determine whether CLO for 28 days could reverse or attenuate HAL-induced oxidative damage in animals previously treated with HAL for 28 days. HAL significantly increased thiobarbituric acid reactive substances levels in the cortex (CX) and striatum and increased protein carbonyls in hippocampus (HP) and CX and this was not attenuated by CLO treatment. In the total radical trapping antioxidant parameter assay there was a decrease in the HP total antioxidant potential induced by HAL and by treatment with HAL + CLO. Our findings demonstrated that the atypical antipsychotic CLO could not revert oxidative damage caused by HAL.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
31Neurosci. Lett. 2007 Jun 420: 66-71
PMID17466452
TitleQuetiapine reverses altered locomotor activity and tyrosine hydroxylase immunoreactivity in rat caudate putamen following long-term haloperidol treatment.
AbstractHALoperidol (HAL) is a typical antipsychotic drug and known to cause extrapyramidal symptoms (EPS) that may be associated with the blockade of dopamine D2-receptors in nigrostriatal pathway by the drug. In contrast, quetiapine (QTP) is an atypical antipsychotic drug that has the lowest incidence of producing EPS in patients with schizophrenia, while improving psychosis symptoms. In the present study, we investigated the possibility of reversing the HAL-induced changes in locomotor activity and in striatal tyrosine hydroxylase (TH) of rats. Rats were administered HAL (2mg/kg/day, p.o.) for 3 months, followed by vehicle (VEH), QTP (10mg/kg/day), HAL, or HAL+QTP for another 5 weeks. The locomotor activity and TH immunoreactivity of the rats were measured. Chronic administration of HAL caused significant increase in locomotor activity and lower levels of TH immunoreactivity in the caudate putamen of the striatum. When the long-term HALoperidol treatment was removed, the change in TH immunoreactivity was normalized, while the HAL induced high level of locomotor activity was returned to normal level only in the rats that stopped HAL consumption and received QTP treatment. In the substantia nigra and ventral tegmental areas, all rats showed comparable numbers of TH-positive cell bodies, which had no shrinkage. These results support a previously proposed relationship between EPS and TH levels in the striatum and provide valuable preclinical information towards understanding why QTP produces a lowest incidence of EPS among antipsychotics and has been used to treat EPS caused by other antipsychotics, and eventually establish a principle of treating EPS.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
32Neuropsychopharmacology 2007 Aug 32: 1791-804
PMID17180123
TitleNeurobehavioral and immunological consequences of prenatal immune activation in rats. Influence of antipsychotics.
AbstractIncreasing evidence suggests that pre- or perinatal events that influence the immune system contribute to the development of behavioral or neuropsychiatric disorders. For instance, exposure of pregnant rats to the bacterial endotoxin lipopolysaccharide (LPS) disrupts sensorimotor information processing, as assessed by the prepulse inhibition test (PPI), and also the immune function in adult offspring, which might be of particular relevance as regards schizophrenia. However, the consequences of maternal LPS exposure during pregnancy on synaptic functioning in adult offspring and, more importantly, the therapeutic opportunity to re-establish PPI and immune function have still to be demonstrated. In this work, we analyzed the consequences of prenatal LPS exposure on dopaminergic neurotransmission and presynaptic markers in adult brain areas related to PPI circuitry. In addition, we tested whether oral treatment with the typical antipsychotic drug HALoperidol (HAL) could reinstate PPI performances and cytokine serum levels in six-month-old male rats with prenatal LPS exposure. Both sensory information processing deficits and immune anomalies induced by prenatal exposure to LPS were accompanied by changes in dopaminergic neurotransmission and synaptophysin expression. It is important to note that PPI disruption and serum increases in cytokines induced by prenatal LPS exposure were both reversed by HAL. Taken together, these results demonstrate the critical influence of prenatal immune events on the functioning of adult nervous and immune systems, in association with the putative role of the immune system in the development of behavior relevant to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
33Psychopharmacology (Berl.) 2007 Feb 190: 241-9
PMID17111172
TitleOccupancy of dopamine D(1), D (2) and serotonin (2A) receptors in schizophrenic patients treated with flupentixol in comparison with risperidone and haloperidol.
AbstractFlupentixol (FLX) has been used as a neuroleptic for nearly 4 decades. In vitro data show comparable affinity to dopamine D(2), D(1) and 5-HT(2A) receptors and recently, FLX showed to be not inferior to risperidone in schizophrenic patients with predominant negative symptomatology, which was implicated with flupentixol's interaction with 5-HT(2A) and/or D(1) receptors.
To assess in vivo receptor occupancy (RO) in patients clinically treated with FLX (n = 13, 5.7 +/- 1.4 mg/day) in comparison with risperidone (RIS, n = 11, 3.6 +/- 1.3 mg/day) and HALoperidol (HAL, n = 11, 8.5 +/- 5.5 mg/day).
Each patient underwent two PET scans with 3-N-[(11)C]methylspiperone (target: frontal 5-HT(2A)), [(11)C]SCH23390 (striatal D(1)) or [(11)C]raclopride (striatal D(2)). RO was calculated as the percentage reduction of specific binding in comparison with healthy controls.
D(2)-RO under FLX was between 50% and 70%, indicating an ED(50) of about 0.7 ng/ml serum. 5-HT(2A) and D(1)-RO was 20 +/- 10% and 20 +/- 5% (mean, SEM). Under HAL, D(1)-RO was 14 +/- 6% and under RIS not significantly different from zero.
We were able to demonstrate a moderate 5-HT(2A) and D(1) occupancy under clinically relevant doses of flupentixol, albeit lower than expected from in vitro data and clearly below saturation. Therefore, if flupentixol's efficacy on negative symptoms is based on its interaction with 5-HT(2A) and/or D(1) receptors, it should be highly dependent on serum concentration and thus on dosage and metabolism. However, these data suggest that mechanisms other than D(1) or 5-HT(2A) antagonism may contribute to flupentixol's efficacy on negative symptoms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
34Metab Brain Dis 2008 Jun 23: 213-9
PMID18496748
TitleLack of effect of antipsychotics on BNDF and NGF levels in hippocampus of Wistar rats.
Abstractschizophrenia is a common and serious mental disorder, in which the majority of patients require long-term antipsychotic treatment. Several studies have suggested that schizophrenia is associated with decreased neurotrophins such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Investigation of the mechanisms of pharmacological agents that are used in the treatment of schizophrenia has been used to better understand the basis of the pathology associated with this mental illness. The present study aims to investigate the effect of chronic treatment with antipsychotics, named HALoperidol (HAL), clozapine (CLO), olanzapine (OLZ) or aripiprazole (ARI) on BDNF and NGF levels in rat hippocampus. Adult male Wistar rats received daily injections of HAL (1.5 mg/kg), CLO (25 mg/kg), OLZ (2.5, 5 or 10 mg/kg) or ARI (2, 10 or 20 mg/kg), whereas control animals were given vehicle. BDNF and NGF levels were measured in rat hippocampus by sandwich-ELISA. The results showed that chronic administration of antipsychotics did not modify BDNF and NGF levels in rat hippocampus, suggesting that their therapeutic properties are not mediated by stimulation of these neurotrophins.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
35Neuropsychopharmacology 2008 Dec 33: 3146-56
PMID18354385
TitleAntipsychotic-like properties of 5-alpha-reductase inhibitors.
AbstractRecent evidence indicates that neuroactive steroids may participate in the pathogenesis of schizophrenia spectrum disorders, yet the mechanisms of this involvement are elusive. As 5-alpha-reductase (5AR) is the rate-limiting enzyme of one of the two major metabolic pathways in brain steroidogenesis, we investigated the effects of its blockade in several rat models of psychotic-like behavior. The 5AR inhibitor finasteride (FIN, 60 or 100 mg/kg, intraperitoneal, i.p.) dose- and time-dependently antagonized prepulse inhibition (PPI) deficits induced by apomorphine (APO, 0.25 mg/kg, subcutaneous, s.c.) and d-amphetamine (AMPH, 5 mg/kg, s.c.), in a manner analogous to HALoperidol (HAL, 0.1 mg/kg, i.p.) and clozapine (CLO, 5 mg/kg, i.p.). Similar results were observed with the other 5AR inhibitors dutasteride (DUT, 40 or 80 mg/kg, i.p.) and SKF 105111 (30 mg/kg, i.p.). FIN (60 or 100 mg/kg, i.p.) also reduced hyperlocomotion induced by AMPH (1 or 3 mg/kg, s.c.) and attenuated stereotyped behaviors induced by APO (0.25 mg/kg, s.c.). Nevertheless, FIN (100 mg/kg, i.p.) did not reverse the PPI disruption induced by the N-methyl-d-aspartate receptor antagonist dizocilpine (0.1 mg/kg, s.c.). FIN (60-300 mg/kg, i.p.) induced no catalepsy in either the bar test or the paw test. Our results suggest that 5AR inhibitors elicit antipsychotic-like effects in animals and may be proposed as a putative novel target in the management of psychotic disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
36J. Neurochem. 2008 Nov 107: 941-51
PMID18786174
TitleCystamine prevents haloperidol-induced decrease of BDNF/TrkB signaling in mouse frontal cortex.
AbstractThe role of brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology as well as treatment outcome of schizophrenia. Rodent studies indicate that several antipsychotic drugs have time-dependent (and differential) effects on BDNF levels in the brain. Earlier studies from our laboratory have indicated that long-term treatment with HALoperidol (HAL) decreases BDNF, reduced GSH and anti-apoptotic marker, Bcl-xl protein levels and increases the expression of pro-apoptotic proteins in rat frontal cortex. Furthermore, findings from human as well as rodent studies suggest that treatment of schizophrenia must involve the neuroprotective strategies to improve the neuropathology and thereby clinical outcome. In the present study, we investigated the potential of cystamine (CYS), an anti-oxidant and anti-apoptotic compound, to prevent HAL-induced reduction in BDNF, GSH, and Bcl-xl protein levels in mice and the signaling mechanism(s) involved in the beneficial effects of CYS. The results indicated that CYS as well as cysteamine (the FDA-approved precursor of CYS) increased BDNF protein levels in mouse frontal cortex 7 days after treatment. CYS co-treatment prevented chronic HAL treatment-induced reduction in BDNF, GSH, and Bcl-xl protein levels. CYS treatment enhanced TrkB-tyrosine phosphorylation and activated Akt and extracellular signal-regulated kinase (ERK)1/2, downstream molecules of TrkB signaling. In addition, in vitro experiments with mouse cortical neurons showed that CYS prevented the HAL-induced reduction in neuronal cell viability and BDNF protein levels, and increase in apoptosis. BDNF-neutralizing antibody as well as K252a, a selective inhibitor of neurotrophin signaling blocked the CYS-mediated neuroprotection. Moreover, CYS-mediated neuroprotection is also blocked by LY294002, a phosphatidylinositol 3-kinase inhibitor or PD98059, a mitogen-activated protein kinase kinase (MEK) inhibitor. Thus, CYS protects cortical neurons through a mechanism involving TrkB receptor activation, and a signaling pathway involving phosphatidylinositol 3-kinase and MAPK. The findings from the present study may be helpful for the development of novel neuroprotective strategies to improve the treatment outcome of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
37Proc. Natl. Acad. Sci. U.S.A. 2008 Sep 105: 13614-9
PMID18757738
TitleClozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation.
AbstractCortical GABAergic dysfunction, a HALlmark of both schizophrenia (SZ) and bipolar (BP) disorder pathophysiologies may relate to the hypermethylation of GABAergic gene promoters (i.e., reelin and GAD67). Benefits elicited by a combination of atypical antipsychotics with valproate (VPA) (a histone deacetylase inhibitor that may also activate brain DNA demethylation) in SZ or BP disorder treatment prompted us to investigate whether the beneficial action of this association depends on induction of a putative DNA demethylase activity. To monitor this activity, we measured the ratio of 5-methyl cytosine to unmethylated cytosine in reelin and GAD67 promoters in the mouse frontal cortex and striatum. We compared normal mice with mice pretreated with l-methionine (5.2 mmol/kg s.c. twice a day for 7 days) to hypermethylate promoters, including reelin and GAD67. Clinically relevant doses of clozapine (CLZ) (3.8 to 15 micromol/kg twice a day s.c. for 3 days) and sulpiride (SULP) (12.5 to 50 micromol/kg twice a day for 3 days) but not clinically relevant doses of HALoperidol (HAL) (1.3 to 4 micromol/kg twice a day s.c. for 3 days) or olanzapine (OLZ) (4 to 15 micromol/kg twice a day for 3 days) exhibited dose-related increases in the cortical and striatal demethylation of hypermethylated reelin and GAD67 promoters. These effects of CLZ and SULP were dramatically potentiated by a clinically relevant VPA dose (0.5 mmol/kg twice a day for 3 days). By activating a DNA demethylase, the association of CLZ or SULP with VPA may facilitate a chromatin remodeling that normalizes the GABAergic gene expression down-regulation detected in the telencepHALic regions of SZ and BP patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
38Psychopharmacology (Berl.) 2009 May 203: 723-35
PMID19066855
TitleEvaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine.
AbstractPrepulse inhibition (PPI) is an operational measure of sensorimotor gating that is deficient in schizophrenia patients. In rats, PPI deficits induced by dopamine (DA) agonists are reversed by antipsychotics. Inhibition of the striatum-rich phosphodiesterase (PDE)10A may represent a novel antipsychotic mechanism. Previous studies were controversial, showing antipsychotic-like profiles in measures of PPI for the preferential PDE10A inhibitor papaverine (PAP) but not the novel PDE10A inhibitor TP-10.
The aim of the study was to evaluate the antipsychotic profile of PAP in rats using PPI.
PPI deficits were induced in rats by apomorphine (APO; 0.1, 0.5 mg/kg) or D: -amphetamine (AMPH; 4 mg/kg). PAP (3, 10, 30 mg/kg) or HALoperidol (HAL; 0.1 mg/kg) was tested against these agonists in Sprague-Dawley (SD) or Wistar (WI) rats. Prepulse intervals ranged from 10 to 120 ms. Further tests evaluated the effects of PAP on spontaneous locomotion, AMPH (1 mg/kg)-induced hyperlocomotion, and core body temperature (T degrees ).
HAL reversed APO-induced PPI deficits but PAP failed to reverse APO- and AMPH-induced PPI deficits at all doses, strains, pretreatment times, and prepulse intervals. PAP (30 mg/kg) significantly reduced AMPH hyperlocomotion in SD rats, and a similar pattern was detected in WI rats. This PAP dose also strongly reduced spontaneous locomotion and T degrees in SD rats.
Our study does not support an antipsychotic-like profile of PAP in dopaminergic PPI models.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
39Toxicol In Vitro 2009 Feb 23: 78-82
PMID18996465
TitleAntipsychotic drugs inhibit nucleotide hydrolysis in zebrafish (Danio rerio) brain membranes.
AbstractHALoperidol (HAL), olanzapine (OLZ), and sulpiride (SULP) are antipsychotic drugs widely used in the pharmacotherapy of psychopathological symptoms observed in schizophrenia or mood-related psychotic symptoms in affective disorders. Here, we tested the in vitro effects of different concentrations of a typical (HAL) and two atypical (OLZ and SULP) antipsychotic drugs on ectonucleotidase activities from zebrafish brain membranes. HAL inhibited ATP (28.9%) and ADP (26.5%) hydrolysis only at 250 microM. OLZ decreased ATPase activity at all concentrations tested (23.8-60.7%). SULP did not promote significant changes on ATP hydrolysis but inhibited ADP hydrolysis at 250 microM (25.6%). All drugs tested, HAL, OLZ, and SULP, did not promote any significant changes on 5'-nucleotidase activity in the brain membranes of zebrafish. These findings demonstrated that antipsychotic drugs could inhibit NTPDase activities whereas did not change 5'-nucleotidase. Such modulation can alter the adenosine levels, since the ectonucleotidase pathway is an important source of extracellular adenosine. Thus, it is possible to suggest that changes promoted by antipsychotic drugs in the bilayer membrane could alter the NTPDase activities, modulating extracellular ATP and adenosine levels.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
40Psychoneuroendocrinology 2009 Dec 34 Suppl 1: S258-64
PMID19647946
TitleTransient prenatal vitamin D deficiency is associated with changes of synaptic plasticity in the dentate gyrus in adult rats.
AbstractTransient prenatal vitamin D deficiency is considered a neurodevelopmental animal model in schizophrenia research. Vitamin D deficiency in female rats causes morphological, cellular and molecular changes in the brain and alters behaviour and nerve growth factors expression in their offspring. Prenatal depleted animals showed a significant impairment of latent inhibition, a feature often associated with schizophrenia and of hole board habituation. Interestingly, memory consolidation of brightness discrimination was improved. Possible functional effects of altered brain development that results from prenatal vitamin D deficiency were characterized by investigation of potentiation phenomena in the hippocampus in freely moving rats. Transient prenatal vitamin D deficiency induced an enhancement of long-term potentiation (LTP) using either weak tetanic or strong tetanic stimulation, whereas the response to test stimuli was not changed. The classic neuroleptic drug HALoperidol (HAL) and the atypical neuroleptic risperidone (Ris) in doses, which normalized behavioural disturbances in prenatal vitamin D-deficient animals without any side effects on the normal behaviour decreased the enhanced LTP in the experimental group to control level. Interestingly, the effect of the substances was different in experimental and control rats. The LTP was enhanced in control animals by the low doses of the drugs effective in our behavioural experiments. It can be suggested, that changes in brain development induced by prenatal vitamin D deficiency lead to specific functional alterations in hippocampal synaptic plasticity. LTP is considered a cellular correlate of learning and memory. The better retention performance in brightness discrimination seems in accordance with enhanced potentiation level.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
41Cereb. Cortex 2009 May 19: 1107-23
PMID18842668
TitleTime-lapse mapping of cortical changes in schizophrenia with different treatments.
AbstractUsing time-lapse maps, we visualized the dynamics of schizophrenia progression, revealing spreading cortical changes that depend on the type of antipsychotic treatment. Dynamic, 4-dimensional models of disease progression were created from 4 repeated high-resolution brain magnetic resonance imaging scans of 36 first-episode schizophrenia patients (30 men/6 women; mean age: 24.2 +/- 5.1 SD years) randomized to HALoperidol (HAL) (n = 15) or olanzapine (OLZ) treatment (n = 21), imaged at baseline, 3, 6, and 12 months (144 scans). Based on surface-based cortical models and point-by-point measures of gray matter volume, we generated time-lapse maps for each treatment. Disease trajectories differed for atypical versus typical neuroleptic drugs. A rapidly advancing parietal-to-frontal deficit trajectory, in HAL-treated patients, mirrored normal cortical maturation but greatly intensified. The disease trajectory advanced even after symptom normalization, involving the frontal cortex within 12 months with typical drug treatment. Areas with fastest tissue loss shifted anteriorly in the first year of psychosis. This trajectory was not seen with OLZ. Whether this association reflects either reduced neurotoxicity or neuroprotection cannot be addressed with neuroimaging; changes may relate to glial rather than neural components. These maps revise current models of schizophrenia progression; due to power limitations, the findings require confirmation in a sample large enough to model group x time interactions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
42Psychopharmacology (Berl.) 2009 Mar 202: 579-87
PMID18810393
TitleHaloperidol and risperidone have specific effects on altered pain sensitivity in the ketamine model of schizophrenia.
AbstractThe ketamine (ket) model reflects features of schizophrenia as well as secondary symptoms such as altered pain sensitivity.
In the present study, we investigated the effect of subchronic oral treatment with HALoperidol (HAL, 0.075 mg/kg) and risperidone (ris, 0.2 mg/kg) on altered pain perception and locomotor activity in this model.
In reaction to 5 mg/kg morphine, ket pretreated animals showed a diminished analgesic response. HAL had no analgesic effect per se, but the compound normalised the analgesic reaction to morphine in the ket pretreated animals. The effect of ris was complex. First, there was no analgesic effect per se, and control animals showed a dose-dependent increase in the analgesic index after morphine injection. In the ket group treated with ris, the analgesic response to 5 mg/kg morphine was attenuated and in response to 10 mg/kg analgesia was comparable with that measured in controls. The reduced analgesic effect was not due to pharmacokinetic differences in morphine metabolism. After administration via drinking water in saline-injected control animals, the HAL blood serum concentration was 2.6 +/- 0.45 ng/ml. In ket-injected animals, the mean serum concentration of HAL amounted to 1.2 +/- 0.44 ng/ml. In the experiment using ris, animals in the control group had higher ris serum concentrations compared with ket-injected animals. In control animals, morphine dose dependently decreased locomotor activity. This effect was significantly stronger in the ket pretreated groups.
HAL and ris had different effects on altered pain sensitivity. It was hypothesised that these results are connected with alterations in dopamine D2 and mu opioid receptor binding.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
43Addict Biol 2009 Jul 14: 283-93
PMID19298320
TitleLong-term haloperidol treatment (but not risperidone) enhances addiction-related behaviors in mice: role of dopamine D2 receptors.
AbstractThe high prevalence of psychostimulant abuse observed in schizophrenic patients may be related to the development of mesolimbic dopaminergic supersensitivity (MDS) or nigrostriatal dopaminergic supersensitivity (NDS) in response to the chronic blockade of dopamine receptors produced by typical neuroleptic treatment. We compared the effects of withdrawal from long-term administration of the typical neuroleptic HALoperidol (HAL) and/or the atypical agent risperidone (Ris) on MDS and NDS, behaviorally evaluated by amphetamine-induced locomotor stimulation (AILS) and apomorphine-induced stereotypy (AIS) in mice, respectively. We further evaluated the duration of MDS and investigated the specific role of dopamine D2 receptors in this phenomenon by administering the D2 agonist quinpirole (Quin) to mice withdrawn from long-term treatment with these neuroleptics. Withdrawal (48 hours) from long-term (20 days) HAL (0.5 mg/kg i.p.) (but not 0.5 mg/kg Ris i.p.) treatment potentiated both AILS and AIS. Ris co-administration abolished the potentiation of AILS and AIS observed in HAL-withdrawn mice. Ten days after withdrawal from long-term treatment with HAL (but not with Ris or Ris + HAL), a potentiation in AILS was still observed. Only HAL-withdrawn mice presented an attenuation of locomotor inhibition produced by Quin. Our data suggest that the atypical neuroleptic Ris has a pharmacological property that counteracts the compensatory MDS and NDS developed in response to the chronic blockade of dopamine receptors imposed by Ris itself or by typical neuroleptics such as HAL. They also indicate that MDS may be long lasting and suggest that an upregulation of dopamine D2 receptors in response to long-term treatment with the typical neuroleptic is involved in this phenomenon.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
44Schizophr. Res. 2010 Jun 119: 164-74
PMID20346631
TitleHaloperidol activates quiescent oligodendroglia precursor cells in the adult mouse brain.
AbstractRecent human studies suggest that abnormal development of oligodendrocytes (OLs) is an important component in the pathophysiology of schizophrenia. However, less information is available regarding effects of antipsychotics on OLs' development. In the present study, young adult C57BL/6 mice were given HALoperidol (HAL; 2mg/kg/day) in their drinking water for three or six weeks. At the conclusion of the drug treatment, mice were sacrificed and the numbers of NG2- and Olig2-expressing cells in the brain regions of the corpus callosum, hippocampus and cerebral cortex were quantified. NG2 is a specific marker for oligodendroglia precursor cells (OPCs); Olig2 marks glial progenitors. HAL treatment for three weeks increased the number of NG2-expressing cells in the corpus callosum; HAL treatment for three and six weeks increased the numbers of Olig2-expressing cells in all three brain regions and increased the levels of Olig2 expression in the same brain regions. These results suggest that HAL treatment activates adult OPCs, which divide infrequently under normal conditions but respond to a variety of insulting factors by proliferation and differentiation. However, our further observations showed no changes in the number of mature OLs and the amount of myelin basic protein in HAL-treated mice, suggesting the drug treatment has no effect on the maturation of OLs. In addition, HAL treatment did not increase the numbers of GFAP- and CD68-expressing cells, suggesting that no gliosis and inflammatory responses occurred while the drug activated the quiescent OPCs in adult brain. These results suggest that HAL treatment may target the development of OLs.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
45Psychopharmacology (Berl.) 2010 Aug 211: 355-66
PMID20552172
TitleOpposite roles of dopamine and orexin in quinpirole-induced excessive drinking: a rat model of psychotic polydipsia.
AbstractRepeated administration of the dopamine D2/D3 agonist quinpirole (QNP) progressively increases non-regulatory water intake. This effect may model psychotic polydipsia, a potentially fatal but poorly understood condition.
The growing evidence for a role of orexin in mediating arousal and cognition has linked this peptide to schizophrenia, hence we examined whether manipulations of dopaminergic and orexinergic systems, as well as of setting, would further characterize the model.
Water intake was measured in rats sequentially tested in home and then operant conditioning setting, with chronic administration of D2 antagonist HALoperidol (HAL) prior to QNP treatment. A group of rats similarly treated was also assessed for orexin A (OxA) expression in the cortex. Finally, the effect of the orexin-1 receptor antagonist SB-334867 on QNP-induced polydipsia was evaluated.
In rats made polydipsic by QNP the amount of water drank during the first 4 h was strongly correlated with the degree of dissociation between appetitive and consummatory components of drinking behavior in the following hour of operant access to water. HAL 0.2 mg/kg prevented both polydipsia and the dissociation, while 0.1 mg/kg only blocked the dissociation. Chronic QNP treatment increased, in a HAL-reversible way, OxA expression in the somatosensory cortex (SI). Moreover, pretreatment with SB-334867 sped up and potentiated QNP-induced polydipsia.
Results disclose compulsive components in QNP-induced polydipsia that are mediated by dopamine D2 receptors. QNP also regulates OxA expression in the SI, while the block of orexin-1 receptors enhances QNP-induced polydipsia. We suggest that dopamine and OxA play opposite roles in QNP-induced polydipsia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
46Hum Psychopharmacol 2011 Oct 26: 517-25
PMID22031266
TitleEffects of adjunct valproic acid on clinical symptoms and saccadic eye movements in schizophrenia.
AbstractValproic acid (VPA) has been suggested as a potential adjunct therapy in schizophrenia for the treatment of clinical symptoms and cognitive deficits. Here, we investigate the effects of VPA on clinical symptoms and saccadic eye movements while controlling for multiple medication effects.
Remitted and first-episode schizophrenia patients taking HALoperidol were given adjunct VPA for approximately 2 weeks and tested using a measure of clinical symptoms (Positive and Negative Syndrome Scale) and saccadic eye movement tasks over three testing periods. The effects of VPA were compared with schizophrenia patients medicated with equivalent doses of HALoperidol alone (HAL group) and normal controls.
schizophrenia patients had higher error rates on the antisaccade task (AS task) compared with normal controls. Adjunct VPA did not affect AS task error rates but was associated with an increase in response times for both saccade and AS tasks, with a significantly greater and dose-dependent increase in response times for the AS task. There were no differences in clinical improvement between VPA and HAL schizophrenia patient groups when controlling for HALoperidol medication state.
These results suggest that adjuvant VPA therapy results in both sensorimotor and cognitive slowing but does not either help or further impair inhibitory control in schizophrenia, as measured by the elevated AS task errors.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
47BMC Psychiatry 2011 -1 11: 87
PMID21586165
TitleChange in level of productivity in the treatment of schizophrenia with olanzapine or other antipsychotics.
AbstractWhen treating schizophrenia, improving patients' productivity level is a major goal considering schizophrenia is a leading cause of functional disability. Productivity level has been identified as the most preferred treatment outcome by patients with schizophrenia. However, little has been done to systematically investigate productivity levels in schizophrenia. We set out to better understand the change in productivity level among chronically ill patients with schizophrenia treated with olanzapine compared with other antipsychotic medications. We also assessed the links between productivity level and other clinical outcomes.
This post hoc analysis used data from 6 randomized, double-blind clinical trials of patients with schizophrenia or schizoaffective disorder, with each trial being of approximately 6 months duration. Change in productivity level was compared between olanzapine-treated patients (HGBG, n = 172; HGHJ, n = 277; HGJB, n = 171; HGLB, n = 281; HGGN, n = 159; HGDH, n = 131) and patients treated with other antipsychotic medications (separately vs. HALoperidol [HGGN, n = 97; HGDH, n = 132], risperidone [HGBG, n = 167; HGGN, n = 158], quetiapine [HGJB, n = 175], ziprasidone [HGHJ, n = 271] and aripiprazole [HGLB, n = 285]). Productivity was defined as functional activities/work including working for pay, studying, housekeeping and volunteer work. Productivity level in the prior 3 months was assessed on a 5-point scale ranging from no useful functioning to functional activity/work 75% to 100% of the time.
Chronically ill patients treated with olanzapine (OLZ) experienced significantly greater improvement in productivity when compared to patients treated with risperidone (RISP) (OLZ = 0.22 1.19, RISP = -0.03 1.17, p = 0.033) or ziprasidone (ZIP) (OLZ = 0.50 1.38, ZIP = 0.25 1.27, p = 0.026), but did not significantly differ from the quetiapine, aripiprazole or HALoperidol treatment groups. Among first episode patients, OLZ therapy was associated with greater improvements in productivity levels compared to HALoperidol (HAL), during the acute phase (OLZ = -0.31 1.59, HAL = -0.69 1.56, p = 0.011) and over the long-term (OLZ = 0.10 1.50, HAL = -0.32 1.91, p = 0.008). Significantly more chronically ill and first episode patients treated with olanzapine showed moderately high (>50%-75% of the time) and high levels of productivity (>75%-100% of the time) at endpoint, when compared to risperidone or HALoperidol-treated patients (p < .05), respectively. Higher productivity level was associated with significantly higher study completion rates and better scores on the positive, negative, disorganized thoughts, hostility and depression subscales of the Positive and Negative Symptom Scale (PANSS).
Some antipsychotic medications significantly differed in beneficial impact on productivity level in the long-term treatment of patients with schizophrenia. Findings further highlight the link between clinical and functional outcomes, showing significant associations between higher productivity, lower symptom severity and better persistence on therapy.
clinicaltrials.gov identifier NCT00088049; NCT00036088.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
48Neuropsychobiology 2011 -1 63: 197-201
PMID21422766
TitleQuetiapine, olanzapine and haloperidol affect human plasma lipid peroxidation in vitro.
AbstractOxidative injury in schizophrenia may be caused not only by pathophysiological processes but partly also by treatment with antipsychotics. The purpose of the present study was to examine and to compare the effects of quetiapine (QUE), olanzapine (OLA) and HALoperidol (HAL), at final concentrations corresponding to doses used for treatment of acute episodes of schizophrenia, on plasma lipid peroxidation in vitro, measured by the level of thiobarbituric acid-reactive substances (TBARS).
Blood from 30 healthy volunteers was collected into ACD (citric acid/citrate/dextrose) solution. The drugs in form of active substances were dissolved in 0.01% dimethyl sulfoxide, added to plasma at the final concentrations [QUE (175 and 275 ng/ml), OLA (20 and 40 ng/ml), HAL (4 and 20 ng/ml)] and incubated for 1 and 24 h at 37 C. The level of TBARS was measured spectrophotometrically (according to the Rice-Evans method, 1991).
The comparative study in vitro showed that QUE causes a decrease in the TBARS level in plasma, whereas HAL increases the plasma TBARS level. After 24 h of incubation of plasma with QUE or HAL (at lower and higher concentrations),thedifferences in TBARS levels between the drugs were significant (p = 5.9 10??, p = 2.2 10??, respectively).
QUE and OLA, contrary to the prooxidative action of HAL, did not induce oxidative stress; moreover, QUE has antioxidant properties.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
49Int. J. Neuropsychopharmacol. 2011 Jun 14: 644-54
PMID20701827
TitleEffects of adjunct galantamine to risperidone, or haloperidol, in animal models of antipsychotic activity and extrapyramidal side-effect liability: involvement of the cholinergic muscarinic receptor.
AbstractThe acetylcholine esterase inhibitor/cholinergic nicotinic receptor (nAChR) allosteric modulator galantamine (Gal) is used against cognitive impairment in Alzheimer's disease. Negative/cognitive and psychotic symptom improvement in schizophrenia by adjunct Gal to antipsychotic drugs (APDs) has been reported. Cognitive symptoms in schizophrenia may involve brain prefrontal hypo-dopaminergia. Experimental data by others indicate nAChR involvement in animal pro-cognitive effects of Gal. The role of nAChRs in antipsychotic effects by Gal has, however, not been elucidated. Using the conditioned avoidance response (CAR) and the catalepsy tests for antipsychotic activity and extrapyramidal side-effect (EPS) liability, respectively, we here investigated the effects of adjunct Gal (1.25 mg/kg) to the typical APD HALoperidol (HAL) (0.05 mg/kg), or the atypical APD risperidone (Ris) (0.2 mg/kg), in rats. Adjunct Gal significantly enhanced APD-like effects by low doses of HAL or Ris, but showed a safe EPS liability profile only in combination with Ris. Pretreatment with the muscarinic receptor (mAChR) antagonist scopolamine, but not the nAChR antagonist mecamylamine, completely reversed the enhancing effects of adjunct Gal to HAL treatment, in the CAR test. While the nAChR-modulating properties of Gal probably contribute to pro-cognitive activity, as shown by others, the present data suggest that any contribution to antipsychotic activity by Gal is mediated primarily via mAChRs. This property combination of Gal may offer a unique, favourable therapeutic profile for schizophrenia treatment.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
50Int. J. Neuropsychopharmacol. 2011 Mar 14: 143-55
PMID20181299
TitleThe involvement of GABA(A) receptor in the molecular mechanisms of combined selective serotonin reuptake inhibitor-antipsychotic treatment.
AbstractThere is evidence that combining selective serotonin reuptake inhibitor (SSRI) antidepressant and antipsychotic drugs may improve negative symptoms in schizophrenia and resistant symptoms in obsessive-compulsive and affective disorders. To examine the mechanism of action of this treatment we investigated the molecular modulation of ?-aminobutyric acid-A (GABA(A)) receptor components and biochemical pathways associated with GABA(A) receptor function following administration of the SSRI fluvoxamine (Flu) combined with the first-generation antipsychotic HALoperidol (HAL) and compared it to the individual drugs and the atypical antipsychotic clozapine (Clz). We analysed prefrontal cortices of Sprague-Dawley rats injected intraperitoneally (i.p.) with the combination of Flu (10 mg/kg) and HAL (1 mg/kg), each drug alone, or Clz (10 mg/kg) after 30 min and 1 h. We found that HALoperidol plus fluvoxamine (HAL-Flu) co-administration, and Clz, decreased the level of GABAA?2/3 receptor subunit in the cytosolic fraction, and increased it in the membrane compartment in rat PFC. Flu or HAL alone did not produce changes in GABAA?2/3 receptor protein expression. Additionally, HAL-Flu and Clz regulated molecular signalling pathways that modulate GABA(A) receptor function, including protein kinase C (PKC) and extracellular signal-regulated kinase-2 (ERK2). In primary cortical culture, short-term treatment (15 min) with HAL-Flu combination and Clz increased GABAA? subunit phosphorylation levels. Pretreatment of the cells with PKC inhibitor abolished the effect of the combined treatment, or Clz on phosphorylation of GABA(A) receptor. Inhibition of ERK2 did not alter the effect of drugs on GABA(A) receptor phosphorylation levels. Our findings provide evidence that the combined treatment regulates GABA(A) receptor function and does so via a PKC-dependent pathway.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
51Front Psychiatry 2012 -1 3: 96
PMID23162479
TitleHippocampal shape and volume changes with antipsychotics in early stage psychotic illness.
AbstractProgression of hippocampal shape and volume abnormalities has been described in psychotic disorders such as schizophrenia. However it is unclear how specific antipsychotic medications influence the development of hippocampal structure. We conducted a longitudinal, randomized, controlled, multisite, double-blind study involving 14 academic medical centers (United States 11, Canada 1, Netherlands 1, and England 1). One hundred thirty-four first-episode psychosis patients (receiving either HALoperidol [HAL] or olanzapine [OLZ]) and 51 healthy controls were followed for up to 104?weeks using magnetic resonance imaging and large-deformation high-dimensional brain mapping of the hippocampus. Changes in hippocampal volume and shape metrics (i.e., percentage of negative surface vertex slopes, and surface deformation) were evaluated. Mixed-models analysis did not show a significant group-by-time interaction for hippocampal volume. However, the cumulative distribution function of hippocampal surface vertex slopes showed a notable left shift with HAL treatment compared to OLZ treatment and to controls. OLZ treatment was associated with a significantly lower percentage of "large magnitude" negative surface vertex slopes compared to HAL treatment (p?=?0.004). Surface deformation maps however did not localize any hippocampal regions that differentially contracted over time with OLZ treatment, after FDR correction. These results indicate that surface analysis provides supplementary information to volumetry in detecting differential treatment effects of the hippocampus. Our results suggest that OLZ is associated with less longitudinal hippocampal surface deformation than HAL, however the hippocampal regions affected appear to be variable across patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
52Schizophr. Res. 2012 Nov 141: 144-52
PMID22954754
TitlePimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day: comparison with reference dose risperidone, 6mg/day.
AbstractMost atypical antipsychotic drugs (APDs), e.g. risperidone (RIS), produce more extensive blockade of brain serotonin (5-HT)(2A) than dopamine (DA) D(2) receptors. This distinguishes them from typical APDs, e.g. HALoperidol (HAL). Our objective was to test the hypothesis that augmentation of low doses of RIS or HAL (2mg/day) with pimavanserin (PIM), a selective 5-HT(2A) inverse agonist, to enhance 5-HT(2A) receptor blockade, can achieve efficacy comparable to RIS, 6mg/day, but with lesser side effects. In a multi-center, randomized, double-blind, 6week trial, 423 patients with chronic schizophrenia experiencing a recent exacerbation of psychotic symptoms were randomized to RIS2mg+placebo (RIS2PBO), RIS2mg+PIM20mg (RIS2PIM), RIS6mg+PBO (RIS6PBO), HAL2mg+PBO (HAL2PBO), or HAL2mg+PIM20mg (HAL2PIM). Improvement in psychopathology was measured by the PANSS and CGI-S. The reduction in PANSS Total Score with RIS2PIM at endpoint was significantly greater than RIS2PBO: -23.0 vs. -16.3 (p=0.007), and not significantly different from the RIS6PBO group: -23.2 points. The percentage of patients with ?20% improvement at day 15 in the RIS2PIM group was 62.3%, significantly greater than the RIS6PBO (42.1%; p=0.01) and the RIS2PBO groups (37.7%; p=0.002). Weight gain and hyperprolactinemia were greater in the RIS6PBO group than the RIS2PIM group but there was no difference in extrapyramidal side effects (EPS). HAL2PBO and HAL2PIM were not significantly different from each other in efficacy but HAL2PIM had less EPS at end point. Both HAL groups and RIS6PBO showed equal improvement in psychopathology at endpoint, indicating HAL 2mg/day is effective to treat an acute exacerbation in chronic schizophrenia patients. In conclusion, a sub-effective RIS dose combined with PIM to enhance 5-HT(2A) receptor blockade provided faster onset of action, and at endpoint, equal efficacy and better safety, compared to standard dose RIS. These results support the conclusion that 5-HT(2A) receptor blockade is a key component of the action of some atypical APDs and can reduce EPS due to a typical APD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
53Prog. Neuropsychopharmacol. Biol. Psychiatry 2012 Aug 38: 252-9
PMID22542492
TitleModulation of antipsychotic-induced extrapyramidal side effects by medications for mood disorders.
AbstractAntipsychotic drugs are widely used not only for schizophrenia, but also for mood disorders such as bipolar disorder and depression. To evaluate the interactions between antipsychotics and drugs for mood disorders in modulating extrapyramidal side effects (EPS), we examined the effects of antidepressants and mood-stabilizing drugs on HALoperidol (HAL)-induced bradykinesia and catalepsy in mice and rats. The selective serotonin reuptake inhibitors (SSRIs), fluoxetine and paroxetine, and the tricyclic antidepressant (TCA) clomipramine, which showed no EPS by themselves, significantly potentiated HAL-induced bradykinesia and catalepsy in a dose-dependent manner. In contrast, the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine failed to augment, but rather attenuated HAL-induced bradykinesia and catalepsy. Mianserin also tended to reduce the EPS induction. In addition, neither treatment with lithium, sodium valproate nor carbamazepine potentiated HAL-induced EPS. Furthermore, treatment of animals with ritanserin (5-HT2A/2C antagonist), ondansetron (5-HT3 antagonist), and SB-258585 (5-HT6 antagonist) significantly antagonized the EPS augmentation by fluoxetine. Intrastriatal injection of ritanserin or SB-258585, but not ondansetron, also attenuated the EPS induction. The present study suggests that NaSSAs are superior to SSRIs or TCAs in combined therapy for mood disorders with antipsychotics in terms of EPS induction. In addition, 5-HT2A/2C, 5-HT3 and 5-HT6 receptors seem to be responsible for the augmentation of antipsychotic-induced EPS by serotonin reuptake inhibitors.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
54Biol. Psychiatry 2012 May 71: 855-63
PMID22244831
TitleContrasting effects of haloperidol and lithium on rodent brain structure: a magnetic resonance imaging study with postmortem confirmation.
AbstractMagnetic resonance imaging (MRI) studies suggest that antipsychotic -treated patients with schizophrenia show a decrease in gray-matter volumes, whereas lithium-treated patients with bipolar disorder show marginal increases in gray-matter volumes. Although these clinical data are confounded by illness, chronicity, and other medications, they do suggest that typical antipsychotic drugs and lithium have contrasting effects on brain volume.
Rodent models offer a tractable system to test this hypothesis, and we therefore examined the effect of chronic treatment (8 weeks) and subsequent withdrawal (8 weeks) with clinically relevant dosing of an antipsychotic (HALoperidol, HAL) or lithium (Li) on brain volume using longitudinal in vivo structural MRI and confirmed the findings postmortem using unbiased stereology.
Chronic HAL treatment induced decreases in whole brain volume (-4%) and cortical gray matter (-6%), accompanied by hypertrophy of the corpus striatum (+14%). In contrast, chronic Li treatment induced increases in whole-brain volume (+5%) and cortical gray matter (+3%) without a significant effect on striatal volume. Following 8 weeks of drug withdrawal, HAL-induced changes in brain volumes normalized, whereas Li-treated animals retained significantly greater total brain volumes, as confirmed postmortem. However, the distribution of these contrasting changes was topographically distinct: with the HALoperidol decreases more prominent rostral, the lithium increases were more prominent caudal.
The implications of these findings for the clinic, potential mitigation strategies, and further drug development are discussed.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
55Schizophr Bull 2012 Sep 38: 1012-20
PMID21402722
TitleChronic treatment with aripiprazole prevents development of dopamine supersensitivity and potentially supersensitivity psychosis.
AbstractLong-term treatment of schizophrenia with antipsychotics is crucial for relapse prevention, but a prolonged blockade of D(2) dopamine receptors may lead to the development of supersensitivity psychosis. We investigated the chronic effects of aripiprazole (ARI) on dopamine sensitivity.
We administered ARI (1.5 mg/kg/d), HALoperidol (HAL; 0.75 mg/kg/d), or vehicle (VEH) via minipump for 14 days to drug-naive rats or to rats pretreated with HAL (0.75 mg/kg/d) or VEH via minipump for 14 days. On the seventh day following treatment cessation, we examined the effects of the treatment conditions on the locomotor response to methamphetamine and on striatal D(2) receptor density (N = 4-10/condition/experiment).
Chronic treatment with HAL led to significant increases in locomotor response and D(2) receptor density, compared with the effects of chronic treatment with either VEH or ARI; there were no significant differences in either locomotor response or D(2) density between the VEH- and ARI-treated groups. We also investigated the effects of chronic treatment with HAL, ARI, or VEH preceded by HAL or VEH treatment on locomotor response and D(2) density. ANOVA analysis indicated that the rank ordering of groups for both locomotor response and D(2) density was HAL-HAL > HAL-VEH > HAL-ARI > VEH-VEH.
Chronic treatment with ARI prevents development of dopamine supersensitivity and potentially supersensitivity psychosis, suggesting that by reducing excessive sensitivity to dopamine and by stabilizing sensitivity for an extended period of time, ARI may be helpful for some patients with treatment-resistant schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
56Schizophr Bull 2013 May 39: 692-702
PMID22927669
TitlePrior haloperidol, but not olanzapine, exposure augments the pursuit of reward cues: implications for substance abuse in schizophrenia.
AbstractDrug abuse and addiction are excessively common in schizophrenia. Chronic antipsychotic treatment might contribute to this comorbidity by inducing supersensitivity within the brain's dopamine system. Dopamine supersensitivity can enhance the incentive motivational properties of reward cues, and reward cues contribute to the maintenance and severity of drug addiction. We have shown previously that rats withdrawn from continuous HALoperidol (HAL) treatment (via subcutaneous minipump) develop dopamine supersensitivity and pursue reward cues more vigorously than HAL-naive rats following an amphetamine (AMPH) cHALlenge. Atypical antipsychotic drugs are thought to be less likely than typicals to produce dopamine supersensitivity. Thus, we compared the effects of HAL and the atypical antipsychotic olanzapine (OLZ) on the pursuit of reward cues. Rats were trained to associate a light-tone cue with water then treated with HAL or OLZ. Following antipsychotic withdrawal, we assessed AMPH-induced enhancement of lever pressing for the cue. Withdrawal from HAL, but not from OLZ, enhanced this effect. HAL, but not OLZ, also enhanced AMPH-induced psychomotor activation and c-fos mRNA expression in the caudate-putamen. Thus, prior HAL, but not OLZ, enhanced conditioned reward following an AMPH cHALlenge, and this was potentially linked to enhanced behavioral sensitivity to AMPH and AMPH-induced engagement of the caudate-putamen. These findings suggest that HAL, but not an atypical like OLZ, modifies reward circuitry in ways that increase responsiveness to reward cues. Because enhanced responsiveness to reward cues can promote drug-seeking behavior, it should be investigated whether atypical antipsychotics might be a preferential option in schizophrenic patients at risk for drug abuse or addiction.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
57Schizophr Bull 2013 May 39: 692-702
PMID22927669
TitlePrior haloperidol, but not olanzapine, exposure augments the pursuit of reward cues: implications for substance abuse in schizophrenia.
AbstractDrug abuse and addiction are excessively common in schizophrenia. Chronic antipsychotic treatment might contribute to this comorbidity by inducing supersensitivity within the brain's dopamine system. Dopamine supersensitivity can enhance the incentive motivational properties of reward cues, and reward cues contribute to the maintenance and severity of drug addiction. We have shown previously that rats withdrawn from continuous HALoperidol (HAL) treatment (via subcutaneous minipump) develop dopamine supersensitivity and pursue reward cues more vigorously than HAL-naive rats following an amphetamine (AMPH) cHALlenge. Atypical antipsychotic drugs are thought to be less likely than typicals to produce dopamine supersensitivity. Thus, we compared the effects of HAL and the atypical antipsychotic olanzapine (OLZ) on the pursuit of reward cues. Rats were trained to associate a light-tone cue with water then treated with HAL or OLZ. Following antipsychotic withdrawal, we assessed AMPH-induced enhancement of lever pressing for the cue. Withdrawal from HAL, but not from OLZ, enhanced this effect. HAL, but not OLZ, also enhanced AMPH-induced psychomotor activation and c-fos mRNA expression in the caudate-putamen. Thus, prior HAL, but not OLZ, enhanced conditioned reward following an AMPH cHALlenge, and this was potentially linked to enhanced behavioral sensitivity to AMPH and AMPH-induced engagement of the caudate-putamen. These findings suggest that HAL, but not an atypical like OLZ, modifies reward circuitry in ways that increase responsiveness to reward cues. Because enhanced responsiveness to reward cues can promote drug-seeking behavior, it should be investigated whether atypical antipsychotics might be a preferential option in schizophrenic patients at risk for drug abuse or addiction.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
58Life Sci. 2013 Oct 93: 429-34
PMID23973956
TitleAntipsychotics promote the differentiation of oligodendrocyte progenitor cells by regulating oligodendrocyte lineage transcription factors 1 and 2.
AbstractOligodendrocyte/myelin abnormalities may be an important component of the pathogenesis found in schizophrenia. The aim of this current study was to examine the possible effects of the antipsychotic drugs (APDs) HALoperidol (HAL), olanzapine (OLA), and quetiapine (QUE) on the development of oligodendroglial lineage cells.
CG4 cells, an oligodendrocyte progenitor cell line, were treated with various concentrations of HAL, OLA, or QUE for specific periods. The proliferation and differentiation of the CG4 cells were measured. The regulation of CG4 cell differentiation by oligodendrocyte lineage transcription factors 1 and 2 (Olig1 and Olig2) was examined.
The APDs used in this study had no effect on the proliferation of CG4 cells. The APDs elevated the expression of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), a specific marker of oligodendrocytes, and promoted the CG4 cells to differentiate into CNP positive oligodendrocytes. QUE and OLA increased the expression of both Olig1 and Olig2 whereas HAL only increased the expression of Olig2.
Our findings suggest that oligodendrocyte development is a target of HAL, OLA, and QUE and provide further evidence of the important role of oligodendrocytes in the pathophysiology and treatment of schizophrenia. They also indicate that the expression level of oligodendrocyte/myelin-related genes could be profoundly affected by APDs, which should be considered in future studies aiming to measure the oligodendrocyte/myelin-related gene expressions in schizophrenia patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
59Front Behav Neurosci 2013 -1 7: 136
PMID24101897
TitleDeficits in latent inhibition induced by estradiol replacement are ameliorated by haloperidol treatment.
AbstractThere are sex differences in the symptomatology of schizophrenia, and in the response to antipsychotic treatments. One HALlmark symptom of schizophrenia is a deficit in selective attention. Selective attention can be measured using a latent inhibition (LI) paradigm in humans; LI can be measured in rodents, and is used as an animal model of the selective attention deficits observed in schizophrenia. In the current experiments LI was used to clarify whether selective attention differs between male rats and ovariectomized (OVX) female rats receiving different estradiol (E2) replacement regimens. An additional aim was to determine whether HALoperidol's (HAL) facilitation of LI is enhanced by E2. Males and OVX female rats were trained in a conditioned emotional response LI paradigm. Females received no E2 replacement, a chronic low dose of E2 via silastic capsule, or a high phasic dose of E2 via silastic capsule accompanied by E2 (10 g/kg subcutaneous (SC)) injections every 4th day. Actual plasma levels of E2 were determined using an enzyme linked immunosorbent assay. Rats were also administered a vehicle treatment, a 0.05 mg/kg, or a 0.1 mg/kg IP injection of HAL. Males and OVX females that did not receive E2 replacement both exhibited LI, but LI was not observed in the low and high E2 replacement groups. HAL restored LI at a lower dose in the females receiving high E2 replacement compared to females receiving low E2 replacement, indicating that E2 replacement facilitates HAL in restoring LI.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
60J Med Econ 2013 Nov 16: 1267-74
PMID24003857
TitleValidation of an economic model of paliperidone palmitate for chronic schizophrenia.
AbstractModel validation is important, but seldom applied in chronic schizophrenia. Validation consists of verifying the model itself for face validity (i.e., structure and inputs), cross-validation with other models assessing the same issue, and comparison with real-life outcomes. The primary purpose was to cross-validate a recent pharmacoeconomic model comparing long-acting injectable (LAI) antipsychotics for treating chronic schizophrenia in Sweden. The secondary purpose was to provide external validation.
The model of interest was a decision tree analysis with a 1-year time horizon with costs in 2011 Swedish kroner. Drugs analyzed included paliperidone palmitate (PP-LAI), olanzapine pamoate (OLZ-LAI), risperidone (RIS-LAI), HALoperidol (HAL-LAI), and oral olanzapine (oral-OLZ). Embase and Medline were searched from 1990-2012 for models examining LAIs. Articles were retrieved, with data extracted for all drugs compared including: expected costs, rates of hospitalization, proportion of time not in relapse, and associated QALYs. Outcomes from the model of interest were compared with those from other articles; costs were projected to 2012 using the consumer price index.
Twenty-six studies were used for validation; 14 of them provided evidence for cross-validation, 13 for external validation, and four for cost. In cross-validation, cost estimates varied -1.8% (range: -12.4-20.1%), hospitalizations 5.2% (-12.1-3.1%), stable disease 2.5% (-5.6-1.5%), QALYs 9.0% (4.3% after removing outliers). All estimates of clinical outcomes were within 15%. In external validation, hospitalization rates varied by 6.3% (-0.7-11.3%). The research was limited by data availability and validity of the original results.
Other models validated the outputs of our model very well.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
61Schizophr. Res. 2014 Nov 159: 376-84
PMID25219486
TitleGlutamate receptor 1 phosphorylation at serine 845 contributes to the therapeutic effect of olanzapine on schizophrenia-like cognitive impairments.
Abstractschizophrenia patients exhibit a wide range of impairments in cognitive functions. Clinically, atypical antipsychotic drugs (AAPs) such as olanzapine (OLZ) have a therapeutic effect on memory function among schizophrenia patients rather than typical antipsychotics, e.g., HALoperidol. To date, however, little is known about the neuroplasticity mechanism underlying the effect of AAPs on the impairment of cognitive functions. Here, we treated schizophrenia rat models with a systematic injection of MK-801 (0.1mg/kg) and chose the drug OLZ as a tool to investigate the mechanisms of AAPs when used to alter cognitive function. The results showed that the systematic administration of MK-801 results in the impairment of spatial learning and memory as well as spatial working memory in a Morris water maze task. OLZ but not HAL improved these MK-801-induced cognitive dysfunctions. After MK-801 application, the hippocampal LTP was profoundly impaired. In conjunction with the results of the behavioral test, the administration of OLZ but not of HAL resulted in a significant reversal effect on the impaired LTP induced via MK-801 application. Furthermore, we found that OLZ but not HAL can upregulate the phosphorylation of GluR1 Ser845. These data suggest that the therapeutic effect of OLZ on cognitive dysfunctions may be due to its contribution to synaptic plasticity via the ability to upregulate the state of GluR1 Ser845 phosphorylation. We therefore suggest that the upregulated state of GluR1 Ser845 phosphorylation may be a promising target for developing novel therapeutics for treating schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
62Psychopharmacology (Berl.) 2014 Jun 231: 2237-49
PMID24752659
TitleOxidative stress and the antipsychotic-induced vacuous chewing movement model of tardive dyskinesia: evidence for antioxidant-based prevention strategies.
AbstractDespite decades of research, tardive dyskinesia (TD) remains a poorly understood iatrogenic movement disorder with few effective treatments and no known cure. Accordingly, the development of an innocuous strategy to prevent or mitigate antipsychotic (AP)-associated TD would represent an important clinical advance. Supporting evidence for antioxidant (AX)-based treatment regimens can be found in the preclinical literature, where AP-induced vacuous chewing movements (VCMs) in rats are attenuated by the concurrent administration of direct and indirect AXs.
Our aim was to review the preclinical literature examining the role of AX-promoting treatments in the prevention of AP-induced VCMs in rats.
A literature search using Google Scholar and PubMed was performed. Relevant results were qualitatively reviewed.
Studies featuring a variety of naturally occurring and synthetic AX treatments were identified and included in the review. The majority of studies used HALoperidol (HAL), a typical AP, to induce VCMs. Studies revealed reduced VCMs in co-treated rats, with favorable changes seen in markers of oxidative stress (OS) and AX status, but were limited by their short durations.
Some preclinical evidence suggests that the inclusion of a naturally occurring and benign AX compound as an adjunct to AP treatment may help guard patients against TD, but additional long-duration studies are needed. This AX-based strategy is further substantiated by accumulating evidence of preexisting OS abnormalities in schizophrenia (SZ).
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
63Schizophr Bull 2014 Mar 40: 341-50
PMID24464874
TitlePrior antipsychotic drug treatment prevents response to novel antipsychotic agent in the methylazoxymethanol acetate model of schizophrenia.
AbstractTrials of novel compounds for the treatment of schizophrenia are typically tested in patients following brief withdrawal of ongoing medication despite known long-term changes in the dopamine (DA) system following chronic antipsychotic drug therapy. The present study explored the impact of withdrawal from repeated HALoperidol (HAL) treatment, as well as the response to a novel ?5 gamma-aminobutyric acid (GABA(A)) receptor positive allosteric modulator (?5PAM), on the activity of the DA system in the methylazoxymethanol acetate (MAM) neurodevelopmental model of schizophrenia. Electrophysiological recordings were conducted from DA neurons in the ventral tegmental area of MAM and saline (SAL) rats following 7-day withdrawal from repeated HAL (21 d, 0.6 mg/kg, orally). In separate animals, amphetamine-induced locomotion was measured to assess changes in DA behavioral sensitivity. SAL rats withdrawn from HAL demonstrated reduced spontaneous DA neuron activity along with an enhanced locomotor response to amphetamine, indicative of the development of DA supersensitivity. Both ?5PAM treatment and ventral hippocampal (vHPC) inactivation reversed the DA neuron depolarization block following HAL withdrawal in SAL rats. In contrast, MAM rats withdrawn from HAL exhibited reduced spontaneous DA activity and enhanced locomotor response to amphetamine compared with untreated SAL rats; however, this condition was unresponsive to ?5PAM treatment or vHPC inactivation. Withdrawal from prior HAL treatment interferes with the therapeutic actions of this novel treatment in the MAM model of schizophrenia. Consequently, testing novel compounds on chronically treated schizophrenia patients may be ineffective.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
64J. Psychopharmacol. (Oxford) 2014 Apr 28: 387-94
PMID24429222
TitleEarly improvement as a predictor of treatment response and remission in patients with schizophrenia: a pooled, post-hoc analysis from the asenapine development program.
AbstractThe purpose of this study was to assess whether early symptom improvement predicts later treatment outcome in patients with schizophrenia.
Data were pooled from intent-to-treat (ITT) populations of three six-week randomized controlled studies with fixed doses of asenapine (ASE; n=470), olanzapine (OLA; n=95), risperidone (RIS; n=56), HALoperidol (HAL; n=112), or placebo (PLA; n=275). Early improvement was defined as a 20% reduction of Positive and Negative Syndrome Scale (PANSS) total score at week 2, compared to baseline (primary criterion). Treatment outcome at week 6 was defined as response (PANSS: ?50% score reduction) or remission (PANSS item score ?3 on selected items at week 6). Odds ratios (ORs) and predictive performance statistics were calculated.
Statistically significant associations between early improvement (at week 2) and treatment outcome (at week 6) were observed for all treatment groups except OLA; as evidenced by increased ORs for response. Analysis of associations between early improvement and remission, as defined by Andreasen et al. (2005), revealed a statistically significant relationship for ASE and PLA-treated patients only. Predictive performance statistics revealed higher negative predictive value (NPV) and sensitivity rates, and comparably lower positive predictive value (PPV) and specificity rates across treatment groups for both response and remission.
It is suggested that absence of improvement within two weeks of treatment may predict the unlikely success of subsequent pharmacological intervention.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
65Nord J Psychiatry 2014 Aug 68: 416-27
PMID24274837
TitlePharmacoeconomics of depot antipsychotics for treating chronic schizophrenia in Sweden.
AbstractTo determine the cost-effectiveness of long-acting injectable (LAI) antipsychotics for chronic schizophrenia in Sweden.
A 1-year decision tree was developed for Sweden using published data and expert opinion. Five treatment strategies lasting 1 year were compared: paliperidone palmitate (PP-LAI), olanzapine pamoate (OLZ-LAI), risperidone (RIS-LAI), HALoperidol decanoate (HAL-LAI) and olanzapine tablets (oral-OLZ). Patients intolerant/failing drugs switched to another depot; subsequent failures received clozapine. Resources and employment time lost (indirect costs) were costed in 2011 Swedish kroner (SEK), from standard government lists. The model calculated the average cost/patient and quality-adjusted life-years (QALYs), which were combined into incremental cost-effectiveness ratios. Multivariate and 1-way sensitivity analyses tested model stability.
PP-LAI followed by OLZ-LAI had the lowest cost/patient (189,696 SEK) and highest QALYs (0.817), dominating in the base case. OLZ-LAI followed by PP-LAI cost 229,775 SEK (0.812 QALY), RIS-LAI followed by HAL-LAI cost 221,062 SEK (0.804 QALY), HAL-LAI followed by oral-OLZ cost 243,411 SEK (0.776 QALY), and oral-OLZ followed by HAL-LAI cost 249,422 SEK (0.773 QALY). The greatest proportions of costs (52.5-83.8%) were for institutional care; indirect costs were minor (2.4-3.8%). RESULTS were sensitive to adherence and hospitalization rates, but not drug cost. PP-LAI followed by OLZ-LAI dominated OLZ-LAI followed by PP-LAI in 59.4% of simulations, RIS-LAI followed by HAL-LAI in 65.8%, HAL-LAI followed by oral-OLZ in 94.0% and oral-OLZ followed by HAL-LAI in 95.9%; PP-LAI followed by OLZ-LAI was dominated in 1.1% of the 40,000 iterations.
PP-LAI followed by OLZ-LAI was cost-effective in Sweden for chronic schizophrenia and cost-saving overall to the healthcare system.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
66Brain Res. 2015 Aug 1618: 100-10
PMID26032742
TitleChanges in brain volume in response to estradiol levels, amphetamine sensitization and haloperidol treatment in awake female rats.
AbstractEstrogen has been shown to further ameliorate symptoms when administered in conjunction with antipsychotics in patients with schizophrenia. We have previously shown that chronic HALoperidol (HAL) treatment reduces amphetamine (AMPH)-induced locomotor activity in AMPH-sensitized rats, but only when paired with high levels of the estrogen, 17-? estradiol. In addition, we reported estradiol-dependent responses to AMPH in AMPH-sensitized rats as measured by functional magnetic resonance imaging. It is thus clear that estradiol and antipsychotics both affect the rat brain, however the mechanism by which this occurs is unknown. The aim of the current study was to assess this interaction by investigating the effects of estradiol, AMPH and HAL on brain volume changes in awake female rats. Repeated exposure to AMPH resulted in an overall reduction in brain volume, regardless of hormonal status (i.e. no, low or high estradiol). Similarly, chronic HAL treatment further reduced brain volume compared to acute treatment. Hormonal status affected hippocampal volume with rats receiving low estradiol replacement showing larger volume; this difference was no longer significant after repeated exposure to AMPH. Finally, we found changes in volume in response to AMPH throughout hippocampal components (i.e. CA1-CA3 and dentate) as well as components of the mesocortical system. In conclusion, brain volume seems to be influenced by hormonal status, as well as exposure to AMPH and HALoperidol treatment. These findings implicate areas where estradiol, amphetamine and antipsychotics may be producing volumetric changes in the brain, pointing the way to where future studies should focus.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
67Neuropharmacology 2015 Dec 99: 715-25
PMID25823912
TitleAntipsychotic treatment leading to dopamine supersensitivity persistently alters nucleus accumbens function.
AbstractChronic exposure to some antipsychotic medications can induce supersensitivity to dopamine receptor stimulation. This is linked to a worsening of clinical outcome and to antipsychotic treatment failure. Here we investigated the role of striatal subregions [nucleus accumbens (NAc) and caudate-putamen (CPu)] in the expression of antipsychotic-induced dopamine supersensitivity. We treated rats with HALoperidol (HAL) or olanzapine (OLZ), using regimens that achieve clinically relevant kinetics of striatal D2 receptor occupancy. Under these conditions, HAL produces dopamine supersensitivity whereas OLZ does not. We then assessed behaviors evoked by the dopamine agonist amphetamine (AMPH). We either injected AMPH into the striatum or inhibited striatal function with microinjections of GABA receptor agonists prior to injecting AMPH systemically. HAL-treated rats were dopamine supersensitive, as indicated by sensitization to systemic AMPH-induced potentiation of both locomotor activity and operant responding for a conditioned reward (CR). Intra-CPu injections of AMPH had no effect on these behaviors, in any group. Intra-NAc injections of AMPH enhanced operant responding for CR in OLZ-treated and control rats, but not in HAL-treated rats. In HAL-treated rats, inhibition of the NAc also failed to disrupt systemic AMPH-induced potentiation of operant responding for CR. Furthermore, while intra-NAc AMPH enhanced locomotion in both HAL-treated and control animals, inhibition of the NAc disrupted systemic AMPH-induced locomotion only in control rats. Thus, antipsychotic-induced dopamine supersensitivity persistently disrupts NAc function, such that some behaviors that normally depend upon NAc dopamine no longer do so. This has implications for understanding dysfunctions in dopamine-mediated behaviors in patients undergoing chronic antipsychotic treatment.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
68Pharmacol. Biochem. Behav. 2015 Nov 138: 14-9
PMID26363311
TitleAtypical antipsychotic properties of AD-6048, a primary metabolite of blonanserin.
AbstractBlonanserin is a new atypical antipsychotic drug that shows high affinities to dopamine D2 and 5-HT2 receptors; however, the mechanisms underlying its atypicality are not fully understood. In this study, we evaluated the antipsychotic properties of AD-6048, a primary metabolite of blonanserin, to determine if it contributes to the atypicality of blonanserin. Subcutaneous administration of AD-6048 (0.3-1mg/kg) significantly inhibited apomorphine (APO)-induced climbing behavior with an ED50 value of 0.200mg/kg, the potency being 1/3-1/5 times that of HALoperidol (HAL). AD-6048 did not cause extrapyramidal side effects (EPS) even at high doses (up to 10mg/kg, s.c.), whereas HAL at doses of 0.1-3mg/kg (s.c.) significantly induced bradykinesia and catalepsy in a dose-dependent manner. Thus, the therapeutic index (potency ratios of anti-APO action to that of EPS induction) of AD-6048 was much higher than that of HALoperidol, illustrating that AD-6048 per se possesses atypical antipsychotic properties. In addition, immunohistochemical analysis of Fos protein expression revealed that both AD-6048 and HAL significantly increased Fos expression in the shell part of the nucleus accumbens and the striatum. However, in contrast to HAL which preferentially enhanced striatal Fos expression, AD-6048 showed a preferential action to the nucleus accumbens. These results indicate that AD-6048 acts as an atypical antipsychotic, which seems to at least partly contribute to the atypicality of blonanserin.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
69Eur Neuropsychopharmacol 2015 Nov 25: 2098-107
PMID26321204
TitleMicroglial activation in the rat brain following chronic antipsychotic treatment at clinically relevant doses.
AbstractNeuroinflammation is increasingly implicated in the pathogenesis of schizophrenia (SCZ). In addition, there is increasing evidence for a relationship between the dose and duration of antipsychotic drug (APD) treatment and reductions in grey matter volume. The potential contribution of microglia to these phenomena is however not yet defined. Adult rats were treated with a common vehicle, HALoperidol (HAL, 2 mg/kg/day) or olanzapine (OLZ, 10 mg/kg/day) for 8 weeks via an osmotic mini-pump implanted subcutaneously. Microglial cells, identified by their Iba-1 immunoreactivity, were quantified in four regions of interest chosen based on previous neuroimaging data: the hippocampus, anterior cingulate cortex, corpus striatum, and secondary somatosensory cortex. Those cells were also analysed according to their morphology, providing an index of their activation state. Chronic APD treatment resulted in increased density of total microglia in the hippocampus, striatum, and somatosensory cortex, but not in the ACC. Importantly, in all brain regions studied, both APD tested led to a dramatic shift towards an amoeboid, reactive, microglial morphology after chronic treatment compared to vehicle-treated controls. These data provide the first in vivo evidence that chronic APD treatment at clinically relevant doses leads to microglial proliferation and morphological changes indicative of activated microglia in the nave rat brain. Although caution needs to be exerted when extrapolating results from animals to patients, these data suggest a potential contribution of antipsychotic medication to markers of brain inflammation. Further investigation of the links between antipsychotic treatment and the immune system are warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
70Clin Schizophr Relat Psychoses 2015 Apr 9: 13-20
PMID25367164
TitleManagement of depressive symptoms in schizophrenia.
AbstractAlthough depressive symptoms are a frequently occurring phenomenon in schizophrenia, effective treatments remain an area of clinical need.
To assess the benefit of short-term treatment with the atypical antipsychotic asenapine versus placebo on depressive symptoms in patients with acute schizophrenia in an exacerbated state.
Data were pooled from intent-to-treat (ITT) populations of three 6-week, randomized controlled studies with fixed doses of asenapine (ASE; n=427), olanzapine (OLA; n=82), risperidone (RIS; n=54), HALoperidol (HAL; n=97), or placebo (PLA; n=254). Change from baseline Calgary Depression Scale for schizophrenia (CDSS) total score and individual item scores were assessed at Day 21 and Day 42 in the total patient population (n=914), and in patients presenting with a CDSS total score of .6 at baseline (n=248). Mixed model repeated measures (MMRM) analyses were performed on patient data.
The observed change from baseline in CDSS total score was significantly larger with ASE.compared to PLA.at both Day 21 (p<0.05) and Day 42 (p<0.01) for the total patient population group, and at Day 21 (p<0.05) in patients with baseline CDSS total score .6. For both populations, there was a significant change from baseline in the CDSS depression item score with ASE.compared to PLA.at Day 21 (p<0.01, all patient population; p<0.05, patients with baseline CDSS .6), and at Day 42 (p<0.01) in the all patient population. Statistically significant changes from baseline, in favor of ASE versus PLA, were also observed in other individual CDSS item scores including hopelessness (p<0.05, Day 21, patients with baseline CDSS .6), self-depreciation (p<0.05, Day 42, all patient population), guilty ideas of reference (p<0.01, Day 42, all patient population), pathological guilt (p<0.01, Day 21, all patient population; p<0.05, Day 21 and Day 42, patients with baseline CDSS score .6), and observed depression (p<0.05, Day 21, all patient population).
ASE significantly improved a range of depressive symptoms in people with an acute exacerbation of schizophrenia, as measured by the CDSS. ASE may represent a beneficial treatment option for the management of depressive symptoms in patients with schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics
71J Med Econ 2016 May -1: 1-9
PMID27124697
TitleEconomic analysis of paliperidone long-acting injectable for chronic schizophrenia in Portugal.
AbstractPatients with chronic schizophrenia suffer a huge burden, as do their families/caregivers. Treating schizophrenia is costly for health systems. The European Medicines Agency has approved paliperidone palmitate (PP-LAI; Xeplion), an atypical antipsychotic depot; however, its pharmacoeconomic profile in Portugal is unknown. A cost-effectiveness analysis was conducted from the viewpoint of the Portuguese National Health Service.
PP-LAI was compared with long acting injectables risperidone (RIS-LAI) and HALoperidol (HAL-LAI) and oral drugs (olanzapine; oral-OLZ) adapting a 1-year decision tree to Portugal, guided by local experts. Clinical information and costs were obtained from literature sources and published lists. Outcomes included relapses (both requiring and not requiring hospitalization) and quality-adjusted life-years (QALYs). Costs were expressed in 2014 euros. Economic outcomes were incremental cost-effectiveness ratios (ICERs); including cost-utility (outcome?=?QALYs) and cost-effectiveness analyses (outcomes?=?relapse/hospitalization/emergency room (ER) visit avoided).
The base-case cost of oral-OLZ was 4447? (20% drugs/20% medical/60% hospital); HAL-LAI cost 4474? (13% drugs/13% medical/74% hospital); PP-LAI cost 5326? (49% drugs/12% medical/39% hospital); RIS-LAI cost 6223? (44% drugs/12% medical/44% hospital). Respective QALYs/hospitalizations/ER visits were oral-OLZ: 0.761/0.615/0.242; HAL-LAI: 0.758/0.623/0.250; PP-LAI: 0.823/0.288/0.122; RIS-LAI: 0.799/0.394/0.168. HAL-LAI was dominated by oral-OLZ and RIS-LAI by PP-LAI for all outcomes. The ICER of PP-LAI over oral-OLZ was 14,247?/QALY, well below NICE/Portuguese thresholds (?24,800?/30,000?/QALY). ICERs were 1973?/relapse avoided and 2697?/hospitalization avoided. Analyses were robust against most variations in input values, as PP-LAI was cost-effective over oral-OLZ in >99% of 10,000 simulations.
In Portugal, PP-LAI dominated HAL-LAI and RIS-LAI and was cost-effective over oral-OLZ with respect to QALYs gained, relapses avoided, and hospitalizations avoided.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics