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Background: Extrapyramidal symptoms (EPS) can cause significant morbidity and impact negatively on patients' quality of life. Clinical guidelines provide recommendations regarding screening frequency and the use of structured tools to ensure adequate monitoring of EPS. Despite this, the literature indicates that the documentation and monitoring of EPS remain suboptimal. Aims: To devise an intervention that would lead to the improvement in the documentation and hence monitoring of EPS. Methods: An initial paper chart survey was conducted to assess the current extent of documentation and monitoring of EPS carried out in patient files of three distinct settings in our Mental Health Service (MHS): inpatient, rehabilitation, and assertive outreach. An intervention aimed at improving practice was subsequently designed and implemented. This involved adoption by the MHS of a new EPS monitoring tool and delivery of an educational session regarding its use. The extent of documentation and monitoring of EPS was re-surveyed post-intervention. Results: Initially, only 14.8% of inpatient records contained evidence of EPS documentation while no evidence at all was found across the other two MHS settings. Following the intervention, there was evidence of guideline concordant EPS monitoring using a structured tool in the clinical records of 75% of inpatients, 79.6% in the rehabilitation setting, and 18% in the assertive outreach programme. Conclusion: Documentation of EPS monitoring improved significantly across several settings affiliated with a Dublin North City MHS following the systematic adoption of the Extrapyramidal Symptom Scale (EPSS) and clinician education regarding its use. [ABSTRACT FROM AUTHOR]

Rationale: There is a debate about whether doctors should prophylactically use benzhexol in schizophrenic patients to reduce the occurrence of extrapyramidal side effects (EPS) after risperidone treatment.We conducted a prospective animal model to explore the efficacy and safety of the prophylactic use of benzhexol after risperidone treatment and the mechanism of the process.C57/BL mice were injected with MK-801 (0.5 mg/kg, i.p.) once a day for two weeks. The open field test (OFT) and the novel object recognition test (NORT) assessed the schizophrenia-like behavior of mice. After four weeks of treatment with benzhexol (10 mg/kg, i.g.) and risperidone (3 mg/kg, i.g.), the inclined screen test (IST), rotarod test (RT), open field test (OFT), novel object recognition test (NORT) and the Morris water maze test (MWM) were conducted successively. The expression of BDNF, p-Tau, and Tau in the hippocampus was detected by Western blot assay.We showed that benzhexol can significantly attenuate risperidone-induced motor coordination impairments and catalepsy and did not affect the efficacy of risperidone in reducing spontaneous activity. Notably, the prophylactic use of benzhexol reduced the recognition memory and spatial memory in MK-801-induced model mice after risperidone. In addition, benzhexol increased the ratio of p-Tau/Tau and decreased BDNF expression levels in the hippocampus.We found that the prophylactic use of benzhexol can reduce the occurrence of EPS and does not affect the efficacy of risperidone in the treatment of positive symptoms. Benzhexol may impair cognitive function but did not cause further deterioration of cognitive function in MK-801 mice.Objectives: There is a debate about whether doctors should prophylactically use benzhexol in schizophrenic patients to reduce the occurrence of extrapyramidal side effects (EPS) after risperidone treatment.We conducted a prospective animal model to explore the efficacy and safety of the prophylactic use of benzhexol after risperidone treatment and the mechanism of the process.C57/BL mice were injected with MK-801 (0.5 mg/kg, i.p.) once a day for two weeks. The open field test (OFT) and the novel object recognition test (NORT) assessed the schizophrenia-like behavior of mice. After four weeks of treatment with benzhexol (10 mg/kg, i.g.) and risperidone (3 mg/kg, i.g.), the inclined screen test (IST), rotarod test (RT), open field test (OFT), novel object recognition test (NORT) and the Morris water maze test (MWM) were conducted successively. The expression of BDNF, p-Tau, and Tau in the hippocampus was detected by Western blot assay.We showed that benzhexol can significantly attenuate risperidone-induced motor coordination impairments and catalepsy and did not affect the efficacy of risperidone in reducing spontaneous activity. Notably, the prophylactic use of benzhexol reduced the recognition memory and spatial memory in MK-801-induced model mice after risperidone. In addition, benzhexol increased the ratio of p-Tau/Tau and decreased BDNF expression levels in the hippocampus.We found that the prophylactic use of benzhexol can reduce the occurrence of EPS and does not affect the efficacy of risperidone in the treatment of positive symptoms. Benzhexol may impair cognitive function but did not cause further deterioration of cognitive function in MK-801 mice.Methods: There is a debate about whether doctors should prophylactically use benzhexol in schizophrenic patients to reduce the occurrence of extrapyramidal side effects (EPS) after risperidone treatment.We conducted a prospective animal model to explore the efficacy and safety of the prophylactic use of benzhexol after risperidone treatment and the mechanism of the process.C57/BL mice were injected with MK-801 (0.5 mg/kg, i.p.) once a day for two weeks. The open field test (OFT) and the novel object recognition test (NORT) assessed the schizophrenia-like behavior of mice. After four weeks of treatment with benzhexol (10 mg/kg, i.g.) and risperidone (3 mg/kg, i.g.), the inclined screen test (IST), rotarod test (RT), open field test (OFT), novel object recognition test (NORT) and the Morris water maze test (MWM) were conducted successively. The expression of BDNF, p-Tau, and Tau in the hippocampus was detected by Western blot assay.We showed that benzhexol can significantly attenuate risperidone-induced motor coordination impairments and catalepsy and did not affect the efficacy of risperidone in reducing spontaneous activity. Notably, the prophylactic use of benzhexol reduced the recognition memory and spatial memory in MK-801-induced model mice after risperidone. In addition, benzhexol increased the ratio of p-Tau/Tau and decreased BDNF expression levels in the hippocampus.We found that the prophylactic use of benzhexol can reduce the occurrence of EPS and does not affect the efficacy of risperidone in the treatment of positive symptoms. Benzhexol may impair cognitive function but did not cause further deterioration of cognitive function in MK-801 mice.Results: There is a debate about whether doctors should prophylactically use benzhexol in schizophrenic patients to reduce the occurrence of extrapyramidal side effects (EPS) after risperidone treatment.We conducted a prospective animal model to explore the efficacy and safety of the prophylactic use of benzhexol after risperidone treatment and the mechanism of the process.C57/BL mice were injected with MK-801 (0.5 mg/kg, i.p.) once a day for two weeks. The open field test (OFT) and the novel object recognition test (NORT) assessed the schizophrenia-like behavior of mice. After four weeks of treatment with benzhexol (10 mg/kg, i.g.) and risperidone (3 mg/kg, i.g.), the inclined screen test (IST), rotarod test (RT), open field test (OFT), novel object recognition test (NORT) and the Morris water maze test (MWM) were conducted successively. The expression of BDNF, p-Tau, and Tau in the hippocampus was detected by Western blot assay.We showed that benzhexol can significantly attenuate risperidone-induced motor coordination impairments and catalepsy and did not affect the efficacy of risperidone in reducing spontaneous activity. Notably, the prophylactic use of benzhexol reduced the recognition memory and spatial memory in MK-801-induced model mice after risperidone. In addition, benzhexol increased the ratio of p-Tau/Tau and decreased BDNF expression levels in the hippocampus.We found that the prophylactic use of benzhexol can reduce the occurrence of EPS and does not affect the efficacy of risperidone in the treatment of positive symptoms. Benzhexol may impair cognitive function but did not cause further deterioration of cognitive function in MK-801 mice.Conclusions: There is a debate about whether doctors should prophylactically use benzhexol in schizophrenic patients to reduce the occurrence of extrapyramidal side effects (EPS) after risperidone treatment.We conducted a prospective animal model to explore the efficacy and safety of the prophylactic use of benzhexol after risperidone treatment and the mechanism of the process.C57/BL mice were injected with MK-801 (0.5 mg/kg, i.p.) once a day for two weeks. The open field test (OFT) and the novel object recognition test (NORT) assessed the schizophrenia-like behavior of mice. After four weeks of treatment with benzhexol (10 mg/kg, i.g.) and risperidone (3 mg/kg, i.g.), the inclined screen test (IST), rotarod test (RT), open field test (OFT), novel object recognition test (NORT) and the Morris water maze test (MWM) were conducted successively. The expression of BDNF, p-Tau, and Tau in the hippocampus was detected by Western blot assay.We showed that benzhexol can significantly attenuate risperidone-induced motor coordination impairments and catalepsy and did not affect the efficacy of risperidone in reducing spontaneous activity. Notably, the prophylactic use of benzhexol reduced the recognition memory and spatial memory in MK-801-induced model mice after risperidone. In addition, benzhexol increased the ratio of p-Tau/Tau and decreased BDNF expression levels in the hippocampus.We found that the prophylactic use of benzhexol can reduce the occurrence of EPS and does not affect the efficacy of risperidone in the treatment of positive symptoms. Benzhexol may impair cognitive function but did not cause further deterioration of cognitive function in MK-801 mice. [ABSTRACT FROM AUTHOR]

Extrapyramidal (EP) symptoms are a known feature in a subpopulation of patients with behavioral variant frontotemporal dementia (bvFTD). Concomitant EP symptoms with FTD-like neuropsychiatric symptoms are also core features in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). This complicates the early diagnosis of these disorders. Our retrospective register study aimed to discover imaging (MRI and FDG-PET) biomarkers to differentiate PSP, CBD, and bvFTD patients with extrapyramidal symptoms (EP +) from bvFTD patients without EP symptoms (EP-). The records of 2751 patients were screened for the diagnoses and presence of EP symptoms. A total of 222 patients were submitted to imaging analysis and applicable imaging data were recovered from 139 patients. Neuroimaging data were analyzed using Freesurfer software. In the whole cohort, EP + patients showed lower volumes of gray matter compared to EP- patients in the putamen (p = 0.002), bilateral globus pallidum (p = 0.002, p = 0.042), ventral diencephalon (p = 0.002) and brain stem (p < 0.001). In the bvFTD subgroup, there was volumetric difference between EP + and EP− patients in the brain stem. FDG-PET scans in the bvFTD patient subgroup showed that EP + patients had comparative hypometabolism of the superior cerebellar peduncle (SCP) and the frontal lobes. We discovered that EP symptoms are linked to brainstem atrophy in bvFTD patients and the whole cohort. Also, evident hypometabolism in the SCP of bvFTD EP + patients was detected as compared to bvFTD EP− patients. This could indicate that the EP symptoms in these diseases have a more caudal origin in the brainstem than in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Researchers have used elements of administrative healthcare claims data (e.g., diagnosis codes and medications) to calculate rates of extrapyramidal symptoms (EPS) in patients with schizophrenia who utilize second-generation antipsychotics (SGAs). However, a detailed description of claims-based EPS evidence has not been previously provided, which is the objective of the current study. This descriptive study, using 2016–2020 de-identified multi-state Medicaid administrative claims data, followed patients diagnosed with schizophrenia for 12 months after initiation of SGA therapy to identify and describe the first evidence of EPS. Time to EPS evidence was calculated and continuously-eligible patients were followed for an additional 12 months to examine EPS medication utilization and costs. Following SGA initiation, 13.6% (n = 2,288) of patients had evidence of EPS during the 12-month follow-up period. Mean time to first evidence of EPS after SGA initiation was 103.7 days (sd = 112.2, median = 58). For a majority of patients (n = 1,636, 71.5%), an EPS medication claim was the initial evidence of EPS, rather than an EPS diagnostic claim. Additionally, a quarter of patients (25.3%) in the EPS evidence cohort had a claim for an EPS medication on the same date as SGA initiation, possibly indicating prophylactic prescribing to prevent EPS development. Nearly 93% of those with EPS medication claims were treated with benztropine, while less than 2% received deutetrabenazine or valbenazine (indicated for tardive dyskinesia (TD)). Annual per patient EPS medication expenditures were $804 (sd = 7,080) overall, but only $40 (sd = 104) when excluding the higher-cost TD medications. Nearly 14% of Medicaid patients with schizophrenia who initiated SGA treatment had evidence of EPS based on claims data. The majority of the time, this evidence was derived from a prescription claim for a medication to treat EPS, rather than an EPS diagnostic claim. Prophylactic prescribing for EPS occurred more often than expected and should be explored more fully. While the cost of traditional EPS medications minimally contributes to the overall cost of care in schizophrenia, use of newer TD drugs can substantially increase spending. [ABSTRACT FROM AUTHOR]

Extrapyramidal symptoms (EP) are not uncommon in Alzheimer's Disease (AD); when present, they negatively influence the course of the disorder. A large proportion of AD patients shows concomitant Lewy bodies' pathology post mortem. Total α Synuclein (αSyn) concentrations are frequently increased in the cerebrospinal fluid (CSF) of AD patients, but are decreased in Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB). αSyn CSF concentrations in AD patients with EP (EP+) have not been reported so far. αSyn and the four Neurochemical Dementia Diagnostics (NDD) CSF biomarkers, (Aβ1-42, Aβ42/40, Tau, and pTau181), interpreted according to the Erlangen Score algorithm, were measured in patients with positive NDD results and presence of extrapyramidal symptoms (NDD + / EP+; n = 26), in patients with positive NDD results and absence of extrapyramidal symptoms (NDD+ / EP−; n = 54), and in subjects with negative NDD results (NDD−; n = 34). Compared to the NDD− controls (379.8 ± 125.2 pg/mL), NDD+ patients showed, on average, highly significantly increased CSF αSyn (519 ± 141.3 pg/mL, p < 0.01), but without differences between NDD+ / EP+ and NDD+ / EP− subgroups (p = 0. 38). Moderate but highly significant association was observed between concentrations of αSyn and Tau (r = 0.47, p < 0.01) and pTau181 (r = 0.65, p < 0.01). Adjusted for diagnoses, age, and sex, subjects with more advanced neurodegeneration on neuroimaging showed significantly lower αSyn concentrations (p < 0.02). In the setting AD versus controls, the area under the receiver operating characteristic (ROC) curve was 0.804 [0.712; 0.896] with the sensitivity and the specificity of 0.863 and 0.618, respectively. αSyn in AD patients does not differentiate between subjects with- and without EP. Its increased average concentration reflects probably neurodegenerative process, and is not specific for any pathophysiologic mechanisms. Further studies are necessary to explain the role of CSF αSyn as a potential biomarker. [ABSTRACT FROM AUTHOR]

Introduction: We explore the transcription factors involved in the molecular mechanism of antipsychotic (AP)-induced acute extrapyramidalsymptoms (EPS) in order to identify new candidate genes for pharmacogenetic studies. Methods: Protein-protein interaction (PPI) networks previously created from three pharmacogenomic models (in vitro, animal, and peripheral blood inhumans) were used to, by means of several bioinformatic tools; identify key transcription factors (TFs) that regulate each network. Once the TFs wereidentified, SNPs disrupting the binding sites (TFBS) of these TFs in the genes of each network were selected for genotyping. Finally, SNP-basedassociations with EPS were analyzed in a sample of 356 psychiatric patients receiving AP. Results: Our analysis identified 33 TFs expressed in the striatum, and 125 SNPs disrupting TFBS in 50 genes of our initial networks. Two SNPs (rs938112,rs2987902) in two genes (LSMAP and ABL1) were significantly associated with AP induced EPS (p < 0.001). These SNPs disrupt TFBS regulated byPOU2F1. Conclusion: Our results highlight the possible role of the disruption of TFBS by SNPs in the pharmacological response to AP. [ABSTRACT FROM AUTHOR]

Introduction: Drug-induced parkinsonism (DIP) and tardive dyskinesia (TD) are stigmatizing movement disorders associated with exposure to dopamine receptor blocking agents such as antipsychotics, but they differ in their pathophysiology and clinical management. Treatment for one may worsen the other, and there are important diagnostic clues that assist in making an accurate assessment and instituting a rational treatment plan.Methods: A literature review was executed to identify articles relating to the presentation, pathophysiology, epidemiology, and management of DIP and TD.Results: DIP and TD prevalence estimates range from approximately 20 to 35% among antipsychotic users, but may be higher in select populations. DIP often presents as bradykinesia and rigidity, as well as rhythmic tremor, and the majority of cases appear within hours to weeks of initiation of therapy with an antipsychotic, or if dosage of the antipsychotic is increased. TD onset is delayed, typically appearing after at least 3 months or longer of treatment, and patients will commonly present with involuntary, abnormal facial movements such as lip smacking, puckering, chewing, or tongue protrusion. DIP often resolves with discontinuation of the causative agent, but TD may be permanent. Broadly, proposed mechanisms underlying these adverse events include decreased dopamine concentrations in the nigrostriatal pathway of the striatum and dopamine hypersensitivity, for DIP and TD, respectively. Pharmacologic treatment approaches for DIP have commonly included anticholinergic agents such as benztropine; however, anticholinergic medications can make TD worse. Switching the antipsychotic medication to one with lower propensity for DIP is an option for some patients. Amantadine, a non-anticholinergic agent used for the treatment of DIP, may be preferred in patients with comorbid DIP and TD. In TD, treatment options include the new reversible vesicular monoamine 2 transporter inhibitors, valbenazine and deutetrabenazine.Conclusions: It is important for clinicians to be able to recognize DIP and TD in patients using antipsychotics so that they can minimize the impact of these adverse events on their patients' quality of life. Accurate diagnosis will drive the selection of the correct treatment.Plain Language Summary: Plain language summary available for this article. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate factors associated with the occurrence of extrapyramidal symptoms (EPS) in users of second-generation antipsychotics (SGA). Methods: Observational cross-sectional study based on a random sample of subjects from three outpatient clinics. Inclusion criteria were age between 18 and 65 years, of both genders, with a diagnosis of schizophrenia and under the use of a single SGA agent. Subjects who had received i.m. long-acting antipsychotics in the past were excluded. The families of eligible patients were contacted by phone and, if willing to participate in the study, a household visit was scheduled. Informed consent was obtained from all study subjects and their next of kin. The risk of EPS associated with sociodemographic, clinical features and medications used was analyzed by logistic regression. Results: The study population consisted of 213 subjects. EPS were observed in 38.0% of subjects. The more commonly used SGA were olanzapine (76, 35.7%), risperidone (74, 34.3%), quetiapine (26, 12.2%), and ziprasidone (23, 10.8%). Among the drugs used as adjunctive therapy for schizophrenia, benzodiazepines were the most prevalent (31.5%), followed by carbamazepine (24.4%) and antidepressants (20.2%). Multivariate analysis showed that the risk of EPS was associated with the use of carbamazepine (odds ratio 3.677, 95% CI 1.627-8.310). We found no evidence that the type of SGA modified the risk of EPS. Conclusion: The occurrence of EPS in SGA users is a common finding, with no difference of antipsychotics studied in relation to the risk of extrapyramidal manifestations. The adjunctive use of carbamazepine may predispose the user of SGA to the occurrence of EPS. [ABSTRACT FROM AUTHOR]

Rationale: Several pre-clinical studies suggest that antipsychotic medications cause secondary negative symptoms. However, direct evidence for a relationship among antipsychotic medications, their direct effects on neurotransmitter systems, and negative symptoms in schizophrenia remains controversial. Objective: The objective of this study was to examine the relationship between antipsychotic-related dopamine D receptor occupancy and negative symptoms in patients with schizophrenia. Methods: Forty-one clinically stable outpatients with schizophrenia participated in this prospective dose reduction positron emission tomography (PET) study. Clinical assessments and [C]-raclopride PET scans were performed before and after participants underwent gradual dose reduction of their antipsychotic medication by up to 40 % from the baseline dose. Results: No significant relationship was found between antipsychotic-related dopamine D receptor occupancy and negative symptom severity at baseline or follow-up. Similar null findings were found for subdomains of negative symptoms (amotivation and diminished expression). Occupancy was significantly lower following dose reduction; however, negative symptom severity did not change significantly, though a trend toward reduction was noted. Examination of change scores between these two variables revealed no systematic relationship. Conclusions: Our cross-sectional and longitudinal results failed to find a significant dose-dependent relationship between severity of negative symptoms and antipsychotic-related dopaminergic antagonism in schizophrenia. These findings argue against the notion that antipsychotics necessarily cause secondary negative symptoms. Our results are also in contrast with the behavioral effects of dopaminergic antagonism routinely reported in pre-clinical investigations, suggesting that the role of this variable in the context of chronic treatment and schizophrenia needs to be re-examined. [ABSTRACT FROM AUTHOR]

Haloperidol is an effective antipsychotic drug for treatment of schizophrenia, but prolonged use can lead to debilitating side effects. To better understand the effects of long-term administration, we measured global metabolic changes in mouse brain following 3 mg/kg/day haloperidol for 28 days. These conditions lead to movement-related side effects in mice akin to those observed in patients after prolonged use. Brain tissue was collected following microwave tissue fixation to arrest metabolism and extracted metabolites were assessed using both liquid and gas chromatography mass spectrometry (MS). Over 300 unique compounds were identified across MS platforms. Haloperidol was found to be present in all test samples and not in controls, indicating experimental validity. Twenty-one compounds differed significantly between test and control groups at the p < 0.05 level. Top compounds were robust to analytical method, also being identified via partial least squares discriminant analysis. Four compounds (sphinganine, N-acetylornithine, leucine and adenosine diphosphate) survived correction for multiple testing in a non-parametric analysis using false discovery rate threshold < 0.1. Pathway analysis of nominally significant compounds ( p < 0.05) revealed significant findings for sphingolipid metabolism ( p = 0.015) and protein biosynthesis ( p = 0.024). Altered sphingolipid metabolism is suggestive of disruptions to myelin. This interpretation is supported by our observation of elevated N-acetyl-aspartyl-glutamate in the haloperidol-treated mice ( p = 0.004), a marker previously associated with demyelination. This study further demonstrates the utility of murine neurochemical metabolomics as a method to advance understanding of CNS drug effects. [ABSTRACT FROM AUTHOR]

There is a growing body of evidence confirming the involvement of oxidative stress and inflammation in pathogenesis of schizophrenia. Inter-individual variation in antioxidant capacity caused by different genetic profile could potentially influence patient's susceptibility to oxidative damage. In this study we evaluated the polymorphisms of manganese superoxide dismutase SOD2Val16Ala, glutathione peroxidase GPX1Pro200Leu, catalase CAT-262C>T and CATc.66+78C>T, and tumour necrosis factor-alpha TNF-308G>A by assessing their association with biomarkers of oxidative stress, neurochemistry, psychopathology of schizophrenia and extrapyramidal symptoms in Caucasian schizophrenia patients treated with haloperidol depot. TNF-308G>A was associated with the increased risk of parkinsonism. No major role of polymorphism of SOD2Val16Ala, CAT-262C>T nor GPX1Pro200Leu in psychopathology of schizophrenia or extrapyramidal symptoms was observed. SOD2Val16Ala polymorphism was associated with dopamine plasma concentration and blood concentration ratio between reduced and oxidised form of glutathione, while GPX1Pro200Leu was related with concentration of reduced glutathione. CATc.66+78C>T was associated with noradrenaline plasma concentration and PANSS negative score. PANSS positive and general scores, were associated with the increased risk of tardive dyskinesia. PANSS positive, negative, and general scores, and GAF score were all associated with the increased risk of akathisia. [ABSTRACT FROM AUTHOR]

Rationale: It has previously been shown that impairment of postural stability is a side effect of typical antipsychotic drugs, which are largely administered to control psychosis and behavioral symptoms in elderly patients. Surprisingly, no study has yet addressed this problem with second-generation antipsychotics. Objective: The objective of this study was to determine the extent to which risperidone at low doses altered balance control in healthy participants. Methods: Twelve healthy young adults received, following a randomized double-blind crossover design, a single oral dose of placebo, 1 and 3 mg of risperidone on separate days at least 14 days apart. Evaluation of extrapyramidal symptoms using the Extrapyramidal Symptom Rating Scale-abbreviated scoring form (ESRS-A) and measures of postural sway using a force platform were assessed over 9 h following drug ingestion. Results: There is a significant increase in the postural stability item of the ESRS-A parkinsonism subscale at 3 and 6 h following 3 mg of risperidone only when compared to placebo. With regard to balance control, body sway measures were increased at 1 mg of risperidone but more pronounced at 3 mg. The peak effects were observed at 3 h after administration of the drug and had not completely returned to baseline after 9 h. Conclusions: Risperidone administered at low doses did not elicit clinically detectable EPS but had significant effects on balance control. A dose-response effect on impairment of balance was observed that followed the expected time course of the drug pharmacokinetics. These results are likely to apply to older or demented individuals who have pre-existing balance control deficit. [ABSTRACT FROM AUTHOR]

Antipsychotic-induced parkinsonism (AIP) is a severe adverse affect of neuroleptic treatment. Interindividual heterogeneity in AIP development and severity is associated with risk factors such as antipsychotic drug type, old age, and female gender. There is evidence for genetic predisposition to develop AIP but the variants that confer susceptibility or protection are mostly unknown. To identify genes related to AIP susceptibility, we performed a pharmacogenomic genome-wide association study (GWAS) for AIP severity. Three hundred ninety-seven American schizophrenia patients who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)-GWAS project were included in our analysis. Patients had been randomized to treatment with antipsychotic monotherapy for periods ranging from 2 weeks to 18 months during phase 1 of the CATIE trial. They were regularly assessed for AIP severity using the modified Simpson–Angus Scale (SAS). For statistical analysis, patients were dichotomized as cases (average SAS mean global score > 0.3 during CATIE phase 1, N = 199) or controls (average SAS mean global score 0, N = 198). Using logistic regression and controlling for population stratification, age, gender, SAS score at baseline, and concomitant use of anticholinergic drugs, we identified several single-nucleotide polymorphisms associated with AIP severity. Although none reached the GWAS significance level of P < 4.2 × 10−7, some promising candidate genes for further research on genetic predisposition to AIP were identified including EPF1, NOVA1, and FIGN. Our finding may contribute to understanding of the pathophysiology of AIP as well as to a priori identification of patients vulnerable for development of AIP. [ABSTRACT FROM AUTHOR]

RGS2 (regulator of G-protein signaling 2) modulates dopamine receptor signal transduction. Functional variants in the gene may influence susceptibility to extrapyramidal symptoms (EPS) induced by antipsychotic drugs. To further investigate our previous report of association of the RGS2 gene with susceptibility to antipsychotic-induced EPS, we performed a replication study. EPS were rated in 184 US patients with schizophrenia (115 African Americans, 69 Caucasian) treated for at least a month with typical antipsychotic drugs (n=45), risperidone (n=46), olanzapine (n=50) or clozapine (n=43). Six single nucleotide polymorphisms (SNPs) within or flanking RGS2 were genotyped (rs1933695, rs2179652, rs2746073, rs4606, rs1819741 and rs1152746). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. Our results indicate association of SNP rs4606 with antipsychotic-induced parkinsonism (AIP), as measured by the Simpson Angus scale, in the overall sample and in the African-American subsample, the G (minor) allele having a protective effect. ORs for AIP among rs4606 G-allele carriers were 0.23 (95% CI 0.10–0.54, P=0.001) in the overall sample, and 0.20 (0.07–0.57, P=0.003) in the African-American subsample. In the previously studied Israeli sample the OR was 0.31 (0.11–0.84, P=0.02). We completely sequenced the RGS2 gene in nine patients with AIP and nine patients without, from the Israeli sample. No common coding polymorphisms or additional regulatory variants were revealed, suggesting that association of the rs4606 C/G polymorphism with AIP is biologically meaningful and not a consequence of linkage disequilibrium with another functional variant. Taken together, the findings of the current study support the association of RGS2 with AIP and focus on a possible protective effect of the minor G allele of SNP rs4606. This SNP is located in the 3′-regulatory region of the gene, and is known to influence RGS2 mRNA levels and protein expression.The Pharmacogenomics Journal (2009) 9, 103–110; doi:10.1038/tpj.2008.6; published online 18 March 2008 [ABSTRACT FROM AUTHOR]

Bifeprunox is a partial dopamine agonist with a unique receptor-binding profile and potential antipsychotic properties. The current study evaluated the efficacy and safety of bifeprunox in patients with an acute exacerbation of schizophrenia. In this 6-week, double-blind, placebo-controlled study, 589 patients were randomly assigned to once-daily treatment with bifeprunox 5, 10, or 20 mg, placebo, or risperidone 6 mg. Efficacy was assessed by changes in symptom rating scales [Positive and Negative Syndrome Scale (PANSS) total and subscale scores; PANSS-derived BPRS scores; Clinical Global Impression—Severity (CGI—S) and Clinical Global Impression—Improvement (CGI—I) scores]. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms (EPS), laboratory values, electrocardiograms, prolactin levels, and weight. Compared with placebo, bifeprunox 20 mg produced a statistically significantly greater reduction from baseline to last assessment in the primary efficacy variable (PANSS total score; effect size = −0.339), as well as most secondary efficacy measures. No statistically significant differences in efficacy were seen with lower doses of bifeprunox. The most common treatment-emergent adverse events (TEAEs) noted with bifeprunox were gastrointestinal; no clear dose-related trend in the incidence of any TEAE was observed in the bifeprunox groups. Compared to placebo, treatment with bifeprunox led to small but statistically significant decreases in weight and prolactin levels. EPS were comparable between bifeprunox and placebo. The active reference in this study, risperidone 6 mg, showed statistically significant differences from placebo for the primary efficacy parameter (effect size = −0.628) and all secondary efficacy parameters. These data suggest that 20 mg of bifeprunox may be efficacious in improving symptoms in patients with an acute exacerbation of schizophrenia. Bifeprunox appeared to be safe and well tolerated by patients in this 6-week study. [ABSTRACT FROM AUTHOR]

In Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) α-synuclein (αS) pathology is seen that displays a predictable topographic distribution. There are two staging/categorization systems, i.e. Braak’s and McKeith’s, currently in use for the assessment of αS pathology. The aim of these diagnostic strategies in pathology is, in addition to assess the stage/severity of pathology, to assess the probabilities of the related clinical symptomatology i.e. dementia and extrapyramidal symptoms (EPS). Herein, we assessed the applicability of these two staging/categorization systems and the frequency of dementia and EPS in a cohort of 226 αS-positive-subjects. These subject were selected from a large autopsy sample ( n = 1,720), irrespective of the clinical presentation, based on the detection of αS-immunoreactivity (IR) in one of the most vulnerable nuclei; in the dorsal motor nucleus of vagus, substantia nigra and basal forebrain. The frequency of αS-IR lesions in this large cohort was 14% (248 out of 1,720). If applicable, each of the 226 subjects with all required material available was assigned a neuropathological stage/category of PD/DLB and finally the neuropathological data was analyzed in relation to dementia and EPS. 83% of subjects showed a distribution pattern of αS-IR that was compatible with the current staging/categorization systems. Around 55% of subjects with widespread αS pathology (Braak’s PD stages 5–6) lacked clinical signs of dementia or EPS. Similarly, in respect to those subjects that fulfilled the McKeith criteria for diffuse neocortical category and displaying only mild concomitant Alzheimer’s disease-related pathology, only 48% were demented and 54% displayed EPS. It is noteworthy that some subjects (17%) deviated from the suggested caudo-rostral propagation suggesting alternative routes of progression, perhaps due to concomitant diseases and genetic predisposition. In conclusion, our results do indeed confirm that current staging/categorization systems can readily be applied to most of the subjects with αS pathology. However, finding that around half of the subjects with abundant αS pathology remain neurologically intact is intriguing and raises the question whether we do assess the actual disease process. [ABSTRACT FROM AUTHOR]

Studies addressing the relationship between a history of obstetric complications (OCs) and neurological abnormalities in schizophrenia have produced contradictory findings. Using a pre-posttreatment design in a neuroleptic-naive sample of psychotic patients, we examined the relationship of a history of OC to primary and drug-induced neurological signs. Fifty neuroleptic-naive non-affective psychotic inpatients were assessed for a history of OC by using the McNeil-Sjöström scale, and for neurological signs including parkinsonism, dyskinesia, akathisia and catatonia, which were rated before and after inception of neuroleptic treatment. A subsample of 28 patients were also examined for neurological soft-signs. Ratings of OCs were related to admission levels of parkinsonism, dyskinesia, akathisia and neurological soft-signs, but not to levels of catatonia. By obstetric period, pregnancy complications were related to levels of parkinsonism, dyskinesia, and neurological soft-signs, and neonatal complications were related to levels of akathisia. Drug-induced neurological signs were not associated with a history of OCs. We argue that the association pattern between a history of OCs and primary neurological signs from several domains suggests a causal link among these variables. Having a history of OCs does not convey a vulnerability for developing drug-induced neurological signs in the short term. [ABSTRACT FROM AUTHOR]

Despite extensive investigation, the cellular mechanisms responsible for neuroleptic actions remain elusive. We have previously shown that neuroleptics modulated the expression of some members of the ligand-activated transcription factors (nuclear receptors) including the nerve-growth factor inducible gene B (NGFI-B or Nur77) and retinoid X receptor (RXR) isoforms. Using genetic and pharmacological approaches, we investigated the role of NGFI-B and retinoids in acute behavioral and biochemical responses to dopamine antagonists. NGFI-B knockout (KO) mice display a profound alteration of haloperidol-induced catalepsy and striatal neuropeptide gene expression. Haloperidol-induced increase of striatal enkephalin mRNA is totally abolished in NGFI-B KO mice whereas the increase of neurotensin mRNA expression is reduced by 50%. Interestingly, catalepsy induced by raclopride, a specific dopamine D2/D3 antagonist is completely abolished in NGFI-B-deficient mice whereas the cataleptic response to SCH 23390, a dopamine D1 agonist, is preserved. Accordingly, the effects of haloperidol on striatal c-fos, Nor-1, and dynorphin mRNA expression are also preserved in NGFI-B-deficient mice. The cataleptic response and the increase of enkephalin mRNA expression induced by haloperidol can also be suppressed by administration of retinoid ligands 9-cis retinoic acid and docosahexaenoic acid. In addition, we demonstrate that haloperidol enhances colocalization of NGFI-B and RXRγ1 isoform mRNAs, suggesting that both NGFI-B and a RXR isoform are highly coexpressed after haloperidol administration. Our data demonstrate, for the first time, that NGFI-B and retinoids are actively involved in the molecular cascade induced by neuroleptic drugs. [ABSTRACT FROM AUTHOR]

A series of typical (chlorpromazine, haloperidol and thioridazine) and atypical (risperidone, quetiapine, clozapine and olanzapine) antipsychotics were tested for effects on integrated bioenergetic functions of isolated rat liver mitochondria. Polarographic measurement of oxygen consumption in freshly isolated mitochondria showed that electron transfer activity at respiratory complex I is inhibited by chlorpromazine, haloperidol, risperidone, and quetiapine, but not by clozapine, olanzapine, or thioridazine. Chlorpromazine and thioridazine act as modest uncouplers of oxidative phosphorylation. The typical neuroleptics inhibited NADH-coenzyme Q reductase in freeze-thawed mitochondria, which is a direct measure of complex I enzyme activity. The inhibition of NADH-coenzyme Q reductase activity by the atypicals risperidone and quetiapine was 2-4 fold less than that for the typical neuroleptics. Clozapine and olanzapine had only slight effects on NADH-coenzyme Q reductase activity, even at 200 μM. The relative potencies of these neuroleptic drugs as inhibitors of mitochondrial bioenergetic function is similar to their relative potencies as risk factors in the reported incidence of extrapyramidal symptoms, including tardive dyskinesia (TD). This suggests that compromised bioenergetic function may be involved in the cellular pathology underlying TD. [ABSTRACT FROM AUTHOR]

Depression, negative symptoms, and extrapyramidal signs (EPS) frequently occur together in schizophrenia. Their overlap is due partly to the lack of specificity of assessment instruments. However, to disentangle the three syndromes is clinically important as treatment of schizophrenia requires a differentiated approach. This study investigated the overlap between depression, emotional blunting as a core part of the negative syndrome, and akinesia as manifestation of EPS, using the Calgary Depression Rating Scale (CDSS), the Rating Scale for Emotional Blunting (SEB), and the akinesia score of the Simpson-Angus Scale (SAS) as the most specific assessment instruments presently available. We investigated 57 medicated schizophrenic patients before discharge from hospitalization. Mutual relationships were assessed with linear and partial correlations. Substantial linear associations emerged between SEB and SAS scores. The correlation between CDSS and SAS scores was significantly lower, but also different from zero. When SEB scores were statistically controlled, the association between CDSS and SAS scores dropped to nonsignificance; the correlation between SEB and SAS scores remained nearly unchanged when controlling for depression. The correlation between CDSS and SEB scores decreased to nonsignificance when controlling for SAS scores. Neither gender, age, illness duration, nor type of medication had an influence on the findings. High levels of akinesia were related to emotional blunting but not independently to depressive symptoms in medicated schizophrenic patients. Although the results cannot be assumed to be specific for schizophrenia, they corroborate the partial independence of depression and affective blunting in schizophrenia and the relationship of negative symptoms to EPS. [ABSTRACT FROM AUTHOR]

clinicians worked with antipsychotic drugs (conventional or typical) that almost invariably caused extrapyramidal symptoms (EPS) at clinically effective doses. This led to the false impression that all antipsychotics were the same, and that EPS were an unavoidable consequence of effective antipsychotic therapy. EPS adversely impact several aspects of antipsychotic efficacy and tolerability, thereby worsening outcome of afflicted individuals. EPS reduce beneficial effects of antipsychotic treatment on the negative, cognitive, and mood symptom domains, while increasing the risk of tardive dyskinesia and reducing compliance. By definition, the newer generation of “atypical” antipsychotic agents are significantly better than conventional agents with regard to EPS (i.e., they are clinically effective at doses at which they do not cause EPS). Pharmacologically, this difference is expressed in the greater degree of separation between respective dose response curves for antipsychotic and EPS effects observed for “atypical” in contrast to conventional agents. Clinically, this EPS advantage of atypical antipsychotics translates into several important benefits, including better negative symptom efficacy, less dysphoria, less impaired cognition, a lower risk of TD, and better overall outcome. [ABSTRACT FROM AUTHOR]

This is the first study to use the unbiased stereological method, the disector, to estimate the total number of pigmented neurons in the pars compacta of the substantia nigra (SNpc) in Alzheimer's disease (AD) patients as compared to healthy controls. The right half of the SNpc of 11 AD patients and 24 controls was studied. We also used single sections to determine the neuronal number and area in different subregions of the SNpc. The results showed that there was no significant difference in the total number of pigmented neurons in the SNpc (154415±13593 for AD and 160163±8027 for controls) or in the volume of the SNpc between the patients with AD and controls. Studies on single sections revealed that even subregionally there was no significant difference in the neuronal number or area in the SNpc between AD patients and controls. [ABSTRACT FROM AUTHOR]

Haloperidol persists in brain tissue long after discontinuation while haloperidol -induced tardive dyskinesia often worsens after withdrawal of the drug. The mechanism of haloperidol -associated tardive dyskinesia is unknown, although neurotoxic pathways are suspected. Nitric oxide (NO) synthase (NOS) inhibitors exacerbate haloperidol -induced catalepsy, while haloperidol itself is a potent neuronal NOS inhibitor in vitro. Since NO and cGMP are involved in striatal neural plasticity, this study investigates a possible relation between cGMP and extrapyramidal symptoms as early predictors of haloperidol -associated tardive dyskinesia. Sprague-Dawley rats were administered either water or oral haloperidol (0.25mg/kg/d po) for 17 weeks, followed by 3 weeks withdrawal. Saline (ip) or the nNOS/guanylate cyclase inhibitor, methylene blue (5mg/kg/d ip), were co-administered with haloperidol for the first three weeks of treatment. Vacous chewing movements (VCM's) were continuously monitored, followed by the determination of striatal cGMP and peripheral serum nitrogen oxide (NOx) levels. Chronic haloperidol engendered significant VCM's, with acute withdrawal associated with significantly reduced striatal cGMP levels as well as reduced serum NOx. Furthermore, suppressed cGMP levels were maintained and VCM's were significantly worse after early administration of methylene blue to the chronic haloperidol group. However, serum NOx was unchanged from control. We conclude that the central effects of chronic haloperidol on striatal NO-cGMP function persist for up to 3 weeks post-withdrawal. Moreover, suppression of striatal cGMP constitutes an early neuronal insult that determines the presence and intensity of haloperidol -associated motor dysfunction. [ABSTRACT FROM AUTHOR]

Five Cebus apella monkeys were treated with biweekly injections of fluphenazine enanthate (0.1-3.2 mg/kg IM). Three of these completed 1 full year of treatment, one injured its leg after 6 months of treatment and was killed, and another died of unknown causes after 9 months of treatment. All monkeys displayed abnormal movements corresponding to the early appearing extrapyramidal symptoms of neuroleptic-treated patients. These consisted initially of slowing or absence of volitional movement, trembling of the hands, trembling of the entire body, and general drowsy behavior. As treatment progessed, a variety of abnormal postures and movements appeared after each injection that were not exacerbated by drug withdrawal and, as tested at the end of the year, could be abolished or prevented with benztropine mesylate (0.2-0.5 mg/kg IM). The three monkeys that completed 1 year of treatment with fluphenazine were then withdrawn from the drug. After withdrawal, all three developed movements similar in appearance to those of patients with tardive dyskinesia (TD). Reinstitution of fluphenazine treatment, as tested in one monkey, abolished all movements resembling TD. [ABSTRACT FROM AUTHOR]

Neurological side effects associated with neuroleptic drugs result from a complex interaction of multiple neurotransmitters. To clarify the etiology of neuroleptic-induced acute dystonic reactions, monkeys ( Cercopithecus aethiops) were treated with haloperidol at doses sufficient to evoke dystonia, and the effects of agents that influenced dopaminergic, cholinergic, or GABAergic neurotransmitters were evaluated. Apomorphine, a dopamine (DA) agonist, and biperiden, an acetylcholine (ACh) antagonist, decreased acute dystonia, whereas α-methyl- p-tyrosine (AMPT), an inhibitor of DA synthesis, and physostigmine, and ACh agonist, increased the symptoms. Muscimol, a GABA agonist, increased the dystonias in a dose-dependent way, and GABA inhibition with picrotoxin also aggravated dystonia, complicated by systemic intoxication and seizures. The reciprocal interaction between DA and ACh influences is consistent with clinical findings and animal models of dyskinesias. Dystonia may also be modulated by GABAergic substrates, but the results suggest complex interactions among DA, ACh, and GABA neurotransmission. Symptoms involving the orofacial, limb, and trunk regions, and purposeless overactivity are discussed in comparison with acute and tardive neuroleptic-induced movement disorders. [ABSTRACT FROM AUTHOR]

The frequency and degree of stiatopallidonigral (SPN) degeneration were examined in 41 autopsy cases of Pick's disease. Based on the degree of SPN degeneration, these cases were arranged into four groups: 1) group I (severely degenerate; 19.5%), 2) group II (moderately degenerate; 22.0%), 3) group III (mildly degenerate; 36.5%), and 4) group IV (non-degenerate; 22.0%). 17 of the 41 cases had a definite (moderate to severe) SPN degeneration. The striatum, especially the caudate nucleus, was most frequently and most severely affected, while the internal segment of the globus pallidus was least frequently and least severely affected. In general, the oral portions of the SPN nuclei were more severely involved. In addition, in the putamen and globus pallidus the dorsomedial portions adjacent to the internal capsule were apt to be affected more markedly than the other portions. In the substantia nigra the degeneration tended to be more predominant in the pars reticulata than in the pars compacta, although both were usually involved. In addition, the medial to central portions of the substantia nigra were more vulnerable. In comparing the severely and moderately degenerate groups (groups I and II) with the mildly and non degenerate groups (groups III and IV), the former had more female cases, longer duration of illness, and more third-stage cases. In addition, the former contained more cases with lower brain weight and (predominant) frontal atrophy type, and more atypical cases without Pick bodies, or with symmetrical pyramidal tract degeneration or with combined traumatic lesions. It is notable that in all cases with definite SPN degeneration no extrapyramidal involuntary movements had been detected. [ABSTRACT FROM AUTHOR]

Hyperammonemia and changes in brain monoamine metabolism have been proposed to contribute to the pathogenesis of the neuropsychiatric symptoms characteristic of human portal-systemic encephalopathy (PSE) resulting from chronic liver disease. Portacaval anastomosis (PCA) in the rat leads to sustained hyperammonemia and mild encephalopathy. In order to evaluate the role of dopamine (DA) metabolism in PSE, levels of DA and its metabolites were measured by HPLC with electrochemical detection in brain regions of rats with PCA at various stages of encephalopathy precipitated by ammonium acetate administration. Following ammonium acetate administration, rats with PCA rapidly develop severe neurological signs of encephalopathy progressing through loss of righting reflex to coma; sham-operated control animals administered ammonium acetate showed no such neurological deterioration. Concentrations of the DA metabolites DOPAC and HVA as well as [DA metabolites]/[DA] ratios, an indirect measure of DA turnover in brain, were increased in caudate-putamen, in cingulate and pyriform entorhinal cortices as well as in raphe nucleus and locus coeruleus. Increased DA metabolites, however, did not worsen at coma states of PSE. Increased DA turnover thus appears to relate to early neuropsychiatric and extrapyramidal symptoms of PSE. [ABSTRACT FROM AUTHOR]

Two adult female cebus apella monkeys with persistent tardive dyskinesia (TD) were given acute i.m. injections of reference neuroleptics (chlorpromazine, haloperidol, thioridazine, and clozapine) or of potential new antipsychotic agents (MJ 13859-1 and MJ 13980-1). The drugs were assessed for their ability to modify TD symptoms or to produce acute neurologic reactions. Effects of three doses of MJ 13859-1 administered orally were also examined. At the doses used, thioridazine and clozapine had little or no effect. Chlorpromazine, haloperidol, MJ 13859-1 and MJ 13980-1 reduced or abolished TD and concomitantly produced hypokinesia, akinesia, mask expression, trembling, and reduced response to stimuli. Haloperidol also produced a mildly abnormal posture. In addition to the above effects, MJ 13859-1 also produced 'slow motion' movement, sustained bizarre postures, sudden falls, and episodes of severe rigidity with trembling. [ABSTRACT FROM AUTHOR]

Patients with chronic liver disease manifest a high incidence (>75%) of pallidal signal hyperintensity on T-weighted Magnetic Resonance Imaging (MRI), the intensity of which correlates with blood manganese levels and the presence of extrapyramidal symptoms. A major cause of pallidal hyperintensity on T-weighted MRI is manganese deposition; chronic manganese intoxication in the absence of liver disease results in pallidal MR signal hyperintensity, in extrapyramidal symptoms and in selective effects on the dopaminergic neurotransmitter system in basal ganglia. Direct measurements in globus pallidus obtained at autopsy from patients with chronic liver disease who died in hepatic coma reveal 2 to 7-fold increases of pallidal manganese and a concomitant loss of dopamine D binding sites. Liver transplantation results in normalization of pallidal MR signals and of blood manganese levels. These findings suggest that (1) pallidal MR signal hyperintensity in patients with chronic liver disease is the result of manganese deposition and (2) alterations of dopaminergic function due to the toxic effects of manganese may contribute to the extrapyramidal symptoms in these patients. [ABSTRACT FROM AUTHOR]

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Tardive dyskinesia (TD) is a severe and potential irreversible side effect of antipsychotic treatment. Treatment of established TD is often unsuccessful. In this article, we report three cases of psychogeriatric patients who suffered from TD as a side effect of long-term treatment with haloperidol that resolved after switching treatment to aripiprazole. Potential psychopharmacological mechanisms explaining this finding are briefly discussed. [ABSTRACT FROM AUTHOR]

A single oral intake of 10 mg of Bromocriptine can modify both plasma renin activity (PRA) and arterial blood pressure (BP). The changes in both variables depend on the integrity of the central dopaminergic systems. The parkinsonians whose extrapyramidal symptoms are markedly improved by l-Dopa in association with a decarboxylase inhibitor (IDC) and the untreated parkinsonians are the only patients whose PRA and BP are lowered 1 h after Bromocriptine ingestion. The results obtained in the l-dopainduced dyskinetic parkinsonians are similar to those obtained in the group of l-Dopa-resistant patients. This points to the paradoxical hypothesis of dopaminergic hyposensitivity in the dyskinetic patients. In spite of the absence of correlation between PRA and BP, it is possible that lowering of BP by Bromocriptine is linked to the parallel decrease of PRA. An increase of the BP may be obtained in the dyskinetic and l-Dopa-resistant groups. These data point to a possible involvement of central dopaminergic systems in some aspects of hypertension. [ABSTRACT FROM AUTHOR]

A 64-year-old female patient with spinocerebellar ataxia type 6 was referred to our department for pancreatic cancer and anesthetized with volatile anesthesia combined with epidural anesthesia for pancreaticoduodenectomy. No complications arose during surgery. On postoperative day 4, a head tremor was noticed at the time of mobilization. The tremor was a postural and “no-no” tremor rather than an intention or resting tremor. The head tremor caused difficulty in eating and in other activities of daily living. No abnormal results were obtained by magnetic resonance imaging of the brain. The tremor was resistant to drugs, including anti-Parkinson drugs and benzodiazepines, and was therefore difficult to treat. [ABSTRACT FROM AUTHOR]