Assessment of plasma creatine kinase as biomarker for levodopa-induced dyskinesia in Parkinson's disease.

We tested in a translational approach the usefulness of plasma creatine kinase (CK) as an objective biomarker for levodopa-induced dyskinesia (LID). Plasma CK levels were measured in five dyskinetic parkinsonian non-human primates (NHP) and in ten PD patients with LID who participated in a treatment trial with simvastatin. Plasma CK levels were increased in dyskinetic NHP and correlated with LID severity while they were not affected by LID severity in PD patients.

Changes in kynurenine pathway metabolism in Parkinson patients with L-DOPA-induced dyskinesia.

L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective drug in the symptomatic treatment of Parkinson's disease, but chronic use is associated with L-DOPA-induced dyskinesia in more than half the patients after 10 years of treatment. L-DOPA treatment may affect tryptophan metabolism via the kynurenine pathway. Altered levels of kynurenine metabolites can affect glutamatergic transmission and may play a role in the development of L-DOPA-induced dyskinesia. In this study, we assessed kynurenine metabolites in plasma and cerebrospinal fluid of Parkinson's disease patients and controls. Parkinson patients (n = 26) were clinically assessed for severity of motor symptoms (UPDRS) and L-DOPA-induced dyskinesia (UDysRS). Plasma and cerebrospinal fluid samples were collected after overnight fasting and 1-2 h after intake of L-DOPA or other anti-Parkinson medication. Metabolites were analyzed in plasma and cerebrospinal fluid of controls (n = 14), Parkinson patients receiving no L-DOPA (n = 8), patients treated with L-DOPA without dyskinesia (n = 8), and patients with L-DOPA-induced dyskinesia (n = 10) using liquid chromatography-mass spectrometry. We observed approximately fourfold increase in the 3-hydroxykynurenine/kynurenic acid ratio in plasma of Parkinson's patients with L-DOPA-induced dyskinesia. Anthranilic acid levels were decreased in plasma and cerebrospinal fluid of this patient group. 5-Hydroxytryptophan levels were twofold increased in all L-DOPA-treated Parkinson's patients. We conclude that a higher 3-hydroxykynurenine/kynurenic acid ratio in plasma may serve as a biomarker for L-DOPA-induced dyskinesia. Longitudinal studies including larger patients cohorts are needed to verify whether the changes observed here may serve as a prognostic marker for L-DOPA-induced dyskinesia.

Potential diagnostic markers of olanzapine efficiency for acute psychosis: a focus on peripheral biogenic amines.

BACKGROUND: Biomarkers are now widely used in many fields of medicine, and the identification of biomarkers that predict antipsychotic efficacy and adverse reactions is a growing area of psychiatric research. Monoamine molecules of the peripheral bloodstream are possible prospective biomarkers based on a growing body of evidence indicating that they may reflect specific changes in neurotransmitters in the brain. The aim of this study was to detect peripheral biogenic amine indicators of patients with acute psychosis and to test the correlations between the biological measures studied and the psychopathological status of the patients. METHODS: This research included 60 patients with acute psychosis treated with olanzapine (n = 30) or haloperidol (n = 30). Here, we measured biogenic amine indicators, including mRNA levels of dopamine receptor D4 (DRD4) and the serotonin 2A receptor (5HTR2A), in peripheral blood mononuclear cells (PBMCs) using quantitative real-time polymerase chain reaction and serum dopamine concentrations by enzyme linked immunosorbent assay (ELISA). Psychopathological status was evaluated using psychometric scales. The assessments were conducted prior to and after 14 and 28 days of treatment. RESULTS: The administration of haloperidol, but not olanzapine, up-regulated 5HTR2A mRNA in a linear manner, albeit without statistical significance (p = 0.052). Both drugs had non-significant effects on DRD4 mRNA levels. Nevertheless, a positive correlation was found between DRD4 and 5HTR2A mRNA levels over a longitudinal trajectory, suggesting co-expression of the two genes. A significant positive correlation was observed between 5HTR2A mRNA levels and total Positive and Negative Syndrome Scale (PANSS) scores in both groups of patients before treatment. A significant correlation between baseline 5HTR2A mRNA levels and PANSS scores on days 14 and 28 of treatment remained for patients treated with olanzapine only. Moreover, a significant positive correlation was observed between blood serum dopamine levels and scores on extrapyramidal symptom scales in the olanzapine group. CONCLUSIONS: The DRD4 and 5HTR2A genes are co-expressed in PBMCs during antipsychotic administration. Despite a correlation between the studied biogenic amine indicators and the psychopathological status of patients, reliable biomarkers of treatment response could not be determined.

Eltoprazine counteracts l-DOPA-induced dyskinesias in Parkinson's disease: a dose-finding study.

In advanced stages of Parkinson's disease, serotonergic terminals take up L-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of L-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks L-DOPA-induced dyskinesias in animal models of dopamine depletion, justifying a clinical study with eltoprazine, a 5-HT1A/B receptor agonist, against L-DOPA-induced dyskinesias in patients with Parkinson's disease. A double-blind, randomized, placebo-controlled and dose-finding phase I/IIa study was conducted. Single oral treatment with placebo or eltoprazine, at 2.5, 5 and 7.5 mg, was tested in combination with a suprathreshold dose of L-DOPA (Sinemet®) in 22 patients with Parkinson's disease (16 male/six female; 66.6 ± 8.8 years old) with L-DOPA-induced dyskinesias. A Wilcoxon Signed Ranked Test was used to compare each eltoprazine dose level to paired randomized placebo on the prespecified primary efficacy variables; area under the curve scores on Clinical Dyskinesia Rating Scale for 3 h post-dose and maximum change of Unified Parkinson's Disease Rating Scale part III for 3 h post-dose. Secondary objectives included effects on maximum Clinical Dyskinesia Rating Scale score, area under the curve of Rush Dyskinesia Rating Scale score for 3 h post-dose, mood parameters measured by Hospital Anxiety Depression Scale and Montgomery Asberg Depression Rating Scale along with the pharmacokinetics, safety and tolerability profile of eltoprazine. A mixed model repeated measures was used for post hoc analyses of the area under the curve and peak Clinical Dyskinesia Rating Scale scores. It was found that serum concentrations of eltoprazine increased in a dose-proportional manner. Following levodopa challenge, 5 mg eltoprazine caused a significant reduction of L-DOPA-induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale [-1.02(1.49); P = 0.004] and Rush Dyskinesia Rating Scale [-0.15(0.23); P = 0.003]; and maximum Clinical Dyskinesia Rating Scale score [-1.14(1.59); P = 0.005]. The post hoc analysis confirmed these results and also showed an antidyskinetic effect of 7.5 mg eltoprazine. Unified Parkinson's Disease Rating Scale part III scores did not differ between the placebo and eltoprazine treatments. The most frequent adverse effects after eltoprazine were nausea and dizziness. It can be concluded that a single dose, oral treatment with eltoprazine has beneficial antidyskinetic effects without altering normal motor responses to L-DOPA. All doses of eltoprazine were well tolerated, with no major adverse effects. Eltoprazine has a favourable risk-benefit and pharmacokinetic profile in patients with Parkinson's disease. The data support further clinical studies with chronic oral eltoprazine to treat l-DOPA-induced-dyskinesias.

Dyskinesia detection and monitoring by a single sensor in patients with Parkinson's disease.

OBJECTIVE: In current clinical practice, assessment of levodopa-induced dyskinesias (LIDs) in Parkinson's disease (PD) is based on semiquantitative scales or patients' diaries. We aimed to assess the feasibility, clinical validity, and usability of a waist-worn inertial sensor for discriminating between LIDs and physiological sway in both supervised and unsupervised settings. METHODS: Forty-six PD patients on L-dopa therapy, 18 de novo PD patients, and 18 healthy controls were enrolled. Patients underwent clinical assessment of motor signs and dyskinesias and kinetic-dynamic L-dopa monitoring, tracked by serial measurements of plasma drug concentrations and motor and postural tests. RESULTS: A subset of features was selected, which showed excellent reliability. Sensitivity and specificity of the selected features for dyskinesia recognition were assessed in both supervised and unsupervised settings with an accuracy of 95% and 86%, respectively. CONCLUSIONS: Our preliminary findings suggest that it is feasible to design a reliable sensor-based application for dyskinesia monitoring at home.

The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model.

BACKGROUND: Blocking metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for levodopa-induced dyskinesias (LID) in Parkinson's disease (PD). We assessed the effect on LID of dipraglurant, a potent selective mGluR5 receptor negative allosteric modulator in the gold-standard LID macaque model. METHODS: Dipraglurant (3, 10, and 30 mg/kg, by mouth) was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque model of LID in a four-way crossover, single-dose, controlled study (n = 8). RESULTS: Dipraglurant inhibited dyskinesias in the LID macaque model, with best effect reached at 30 mg/kg dose with no alteration of levodopa efficacy. CONCLUSION: Acute challenges of dipraglurant were efficacious on choreic and dystonic LID in the MPTP-macaque model. Dipraglurant pharmacokinetic variables were similar to those of levodopa, suggesting that both drugs can be co-administered simultaneously in further studies.

The outcome of the movement disorder in methcathinone abusers: clinical, MRI and manganesemia changes, and neuropathology.

BACKGROUND AND PURPOSE: There is limited knowledge regarding the long-term outcome of the methcathinone/manganese-induced movement disorder. Our purpose was to define prognosis in intravenous methcathinone abusers affected by this distinctive disorder attributed to manganese (Mn) toxicity. Also, neuropathology from a globus pallidus region biopsy from a former user is reported. METHODS: Eighteen methcathinone abusers were categorized as active (five), discontinued (four) or former (nine) users. They were reassessed after a median of 32.5 months (range 3.4-59.6) clinically, on rating scales, and with MRI and blood Mn levels. The biopsy was examined ultrastructurally. RESULTS: Overall the group showed a slight tendency to deterioration at follow-up on clinical assessment of motor functioning, especially the active users. No significant change occurred on parkinsonian rating scale reassessment. Significant reduction in Mn levels occurred in former users, and decreased T1-weighted hyperintensity on basal ganglia MRI occurred in 3 of 4 former and 2 of 3 discontinued users, despite lack of clinical improvement. The biopsy consisted of white matter showing decompacted myelin sheaths and frequent abnormalities of mitochondria. CONCLUSIONS: No improvement in this Mn-induced movement disorder occurs after cessation of methcathinone abuse despite improvement of Mn blood levels and/or MRI abnormalities. Ultrastructural abnormalities in a former user confirm structural damage to white matter is associated with the disorder. Methcathinone/Mn toxicity is an important, disabling and permanent medical sequel of intravenous drug abuse in the former Soviet Union.

The relationship between the plasma concentration of blonanserin, and its plasma anti-serotonin 5-HT(2A) activity/anti-dopamine D2 activity ratio and drug-induced extrapyramidal symptoms.

AIMS: Blonanserin is a second-generation antipsychotic that was developed in Japan. We investigated the relationships between plasma concentration, the plasma anti-5-HT(2A) activity/anti-D2 activity (S/D) ratio and extrapyramidal symptoms (EPS) in blonanserin dosing. METHODS: The subjects were 29 outpatients with schizophrenia. We assessed EPS using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The plasma concentrations were measured by high performance liquid chromatography, and the plasma anti-D2 and anti-5-HT(2A) activities were measured by [³H]-spiperone and [³H]-ketanserin radioreceptor assays. RESULTS: The results revealed that there were significant correlations between both the plasma concentration and the DIEPSS total score (P<0.05). A negative correlative tendency was found between the S/D ratio and the DIEPSS total score. Furthermore, the plasma concentrations were divided into a low plasma concentration group and a high plasma concentration group, and the S/D ratios were divided into a low S/D ratio group and a high S/D ratio group. We then compared each group based on the DIEPSS total scores. The score in the high plasma concentration-low S/D ratio group was significantly higher than in the high plasma concentration-high S/D ratio, low plasma concentration-high S/D ratio and low plasma concentration-low S/D ratio groups (P<0.05 for all). CONCLUSIONS: These findings indicate that the incidence of EPS during treatment with blonanserin is mainly determined by plasma concentration, but the incidence of EPS may be inhibited when anti-5HT(2A) activity is predominant over anti-D2 activity.

Investigation of the effects of cannabidiol on vacuous chewing movements, locomotion, oxidative stress and blood glucose in rats treated with oral haloperidol.

Objectives: Tardive dyskinesia (TD) unlike acute dystonia may be irreversible. This study investigated the effects of oral cannabidiol (CBD) on haloperidol-induced vacuous chewing movement (VCM) model of TD. Methods: There were six experimental groups with different combinations of oral cannabidiol with 5 mg/kg of haloperidol given orally. Behavioural assays and FBS were measured. VCMs were assessed after the last dose of medication. Blood for oxidative stress assays was collected on the 8th day after the administration of the last dose of medication. Results: This study found that CBD co-administration with haloperidol attenuated the VCMs and increased motor tone produced by haloperidol. CBD alone at 5 mg/kg appears to have anxiolytic properties but may not be as effective as haloperidol which exhibited a greater anxiolytic effect at 5 mg/kg. Treatment with CBD alone at 5 mg/kg also appeared to enhance brain DPPH scavenging activity. Conclusions: We confirmed that CBD can ameliorate motor impairments produced by haloperidol. Our data suggest that CBD can be combined with haloperidol to prevent the emergent of extrapyramidal side effects and long-term movement disorders, such as acute dystonic disorder and TD.

Efficacy and safety of bifeprunox in patients with an acute exacerbation of schizophrenia: results from a randomized, double-blind, placebo-controlled, multicenter, dose-finding study.

RATIONALE: Bifeprunox is a partial dopamine agonist with a unique receptor-binding profile and potential antipsychotic properties. OBJECTIVES: The current study evaluated the efficacy and safety of bifeprunox in patients with an acute exacerbation of schizophrenia. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Association of metals with the risk and clinical characteristics of Parkinson's disease.

INTRODUCTION: While metals have been implicated in the pathophysiology of Parkinson's disease (PD), the clinical evidence is scarce. Further, the contribution of metals for the risk or clinical presentation of PD remains to be explored. METHODS: To investigate the associations between the level of metals in blood serum and PD risk or clinical presentation, including sex-related differences, we studied 325 PD patients and age- and sex-matched 304 controls. We collected clinical data of the PD patients, including age at onset, PD duration, levodopa-equivalent dose (LED), Hoehn and Yahr stage (H-Y stage), presence of motor fluctuation, levodopa-induced dyskinesia (LID), freezing of gait, hallucination, and Mini-Mental State Examination (MMSE) score. Iron, copper, and zinc levels in serum were assayed by inductively coupled plasma mass spectrometry. Statistical analyses were performed to determine the sex-related differences in metal levels. RESULTS: Among the three metal elements tested, serum copper levels showed significant correlations with PD risk or clinical presentation. Higher copper levels were associated with a decreased PD risk. Higher copper or lower iron levels were associated with the risk of LID in women. Serum copper levels were negatively correlated with MMSE scores in PD patients. CONCLUSIONS: This clinical study suggests significant associations between serum metal levels and PD risk or essential clinical features, demonstrating the possible roles of metals in PD pathogenesis or symptom development.

Therapeutic drug monitoring for optimizing amisulpride therapy in patients with schizophrenia.

Amisulpride is a clinically effective antipsychotic drug in a broad dose range with low propensity for extrapyramidal symptoms (EPS). Daily doses and plasma levels of amisulpride were analyzed within a large-scale therapeutic drug monitoring (TDM) survey to find plasma level ranges for optimized treatment under naturalistic conditions. Data of 378 schizophrenic patients treated with amisulpride (100-1550 mg) were included (40% female). Amisulpride plasma levels were analyzed at steady state; assessment comprised improvement (CGI-I) and side-effects, particularly EPS. For detection of cut-off values regarding non-response or EPS, receiver operating characteristics (ROC) curves were applied and the area under the ROC curve (AUC) was calculated. Amisulpride daily doses (594+/-262 mg) and plasma levels (315+/-277 ng/ml) were significantly correlated (r=0.53; P<0.0001). Patients with non-response to amisulpride (8.9%) had significantly (P<0.05) lower plasma levels (248+/-291 ng/ml) than patients with at least moderate improvement (316+/-253 ng/ml) despite comparable amisulpride doses (628+/-253 vs. 590+/-263 mg). Patients with EPS (14.6%) had significantly (P<0.05) higher amisulpride plasma levels (377+/-290 ng/ml) than patients without EPS (305+/-274 ng/ml) despite similar doses in both groups (595+/-266 vs. 594+/-246 mg). ROC analyses revealed significant predictive properties of amisulpride plasma levels (P<0.05) for non-response (AUC=0.65+/-0.05) and EPS (AUC=0.62+/-0.05), respectively. Daily amisulpride doses did not significantly predict non-response or EPS. Optimal amisulpride plasma level values to avoid non-response and EPS were 100 or 320 ng/ml, respectively. Analysis of clinical utility revealed that blood levels must be analyzed in 7 patients until one patient benefits from the TDM procedure by avoiding non-response or EPS. Although our results were mainly explorative, TDM of amisulpride seems very useful for clinical decision making.

Age-related differences in levodopa dynamics in Parkinson's: implications for motor complications.

Treatment-related motor complications in Parkinson's disease have been previously linked to disease-induced pre-synaptic alterations: dopaminergic denervation and changes in dopamine (DA) release patterns. The occurrence of such complications is also known to be partly dependent on the age of disease onset, occurring more frequently in patients with disease onset at a younger age. Using positron emission tomography (PET) and 4-h-long 18F-fluorodopa (FD) scans we have investigated in vivo an age dependence of disease-induced changes in DA turnover as a possible contributing factor to the age-related differences in treatment-related motor complications. We evaluated the relative changes in DA turnover (measured by its direct inverse, effective DA distribution volume--EDV) and DA synthesis and vesicular storage capacity (quantified by the plasma input uptake rate constant Ki) in Parkinson's disease patients as a function of age (n = 27, age range 38-79 years). After correcting for disease severity, a significant negative correlation was found between age and magnitude of disease-induced decrease in EDV and in Ki in the putamen (P < 0.001, P = 0.02, respectively). However, the difference between the disease-induced decrease in EDV and that in Ki also exhibited an age dependence (P < 0.001), indicating a relatively higher disease-induced increase in DA turnover (inverse of EDV) compared with the decrease in DA synthesis and storage rate in patients of younger age compared with older patients. This finding implies that DA turnover in younger-onset patients undergoes a relatively greater alteration and thus likely contributes to a greater imbalance between DA synthesis, storage and release, which could lead to larger swings in synaptic DA levels. It has indeed been suggested on theoretical grounds that such imbalance may contribute to the greater propensity for motor fluctuations. These results provide one possible explanation for the age-dependent occurrence of complications and support the existence of a pre-synaptic contribution to the occurrence of motor complications.

A Phase Ib Randomized Controlled Study to Evaluate the Effectiveness of a Single-Dose of the NR2B Selective N-Methyl-D-Aspartate Antagonist MK-0657 on Levodopa-Induced Dyskinesias and Motor Symptoms in Patients With Parkinson Disease.

OBJECTIVES: Blockade of N-methyl-D-aspartate receptors containing the NR2B subunit has been shown to be therapeutic in animal models of Parkinson disease (PD). However, findings with investigational NR2B receptor antagonists in PD patients have been mixed. The objective of this study was to evaluate the effects of the NR2B selective N-methyl-D-aspartate receptor antagonist MK-0657 on levodopa-induced dyskinesias and motor symptoms in PD patients. METHODS: A randomized, double-blind, single-dose, 2-period crossover study was conducted in 22 patients with PD and levodopa-induced peak-dose dyskinesias. Patients received oral MK-0657 (7 mg) or placebo, in randomized order, on each of 2 test days. On both days, levodopa was administered as a 2-hour intravenous infusion at greater than or equal to 1 mg/kg per hour with frequent assessments of dyskinesia, motor function, and pharmacokinetics. RESULTS: MK-0657 7 mg had no significant effect on dyskinesias (difference versus placebo in modified Abnormal Involuntary Movement Scale mean change from baseline area under the curve over 5 hours, -2.3; 95% confidence interval, -5.1 to 0.4) or motor function (difference versus placebo in Unified Parkinson's Disease Rating Scale Part III mean change from baseline area under the curve over 5 hours, 13.9; 95% confidence interval, -1.7 to 29.5). MK-0657 7 mg achieved the target mean maximum plasma concentration of 400 nM. CONCLUSIONS: These data suggest that a single dose of MK-0657 7 mg is not effective in improving levodopa-induced dyskinesias and motor symptoms in PD patients. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT00505843.

Tardive dyskinesia in schizophrenia is associated with prolactin-related sexual disturbances.

Tardive dyskinesia (TD) may occur in never-medicated patients with psychotic illness, indicating the existence of non-medication, possibly disease-related, causes. We tested the hypothesis that, independent of the antipsychotic-induced rise in prolactin, the incidence of TD would be associated with the incidence of prolactin-related sexual disturbances (PRSD), which would be suggestive of a common pathology involving multiple dopamine tracts. Simple, global measures of TD and PRSD (loss of libido, amenorrhea, gynaecomastia, impotence, and galactorrhea) were rated in a prospective, observational European Health Outcomes Study (SOHO). New onset of TD and new onset of PRSD at 3, 6, and 12 months was analyzed in a risk set of 4263 patients using a Cox proportional hazard model yielding adjusted hazard ratios (aHR). Incidence of TD was significantly and linearly comorbid with the incidence of PRSD in both men and women. Compared to those with no PRSD, the risk for TD was 2.0 (95% CI: 1.1, 3.7) with one PRSD, 2.4 (95% CI: 1.3, 4.5) with two PRSD, and 3.6 (95% CI: 1.1, 11.8) with three PRSD. Associations were stronger in those who only had received prolactin-sparing medications (aHR per unit PRSD increase=2.0, 95% CI: 1.2, 3.3) than in those who only had received prolactin-raising medications (aHR=1.3, 95% CI: 0.9, 1.9). In people with schizophrenia, TD and PRSD show comorbidities that are independent of antipsychotic-induced alterations in plasma prolactin. This may suggest a shared, pandopaminergic pathological mechanism associated with schizophrenia itself, rather than only a medication effect.

Alterations in DHEA metabolism in schizophrenia: two-month case-control study.

OBJECTIVE: The goals of this study were to determine whether alterations in serum dehydroepiandrosterone (DHEA), its sulfated conjugate (DHEAS), androstenedione, testosterone, and progesterone concentrations occur in schizophrenia patients compared with healthy controls over two months, and their associations with psychopathology, emotional distress, and antipsychotic treatment. METHOD: Serum hormones were repeatedly determined for 21 antipsychotic-treated male DSM-IV schizophrenia patients and 14 healthy controls. Observations were at four time points: upon entry into the study, and after 2, 4 and 8 weeks. RESULTS: In schizophrenia patients compared with healthy controls serum concentration of DHEA and androstenedione found increased, but that of DHEAS decreased, while progesterone and testosterone showed normal levels. Schizophrenia patients were also characterized by elevated androstenedione/DHEAS molar ratios, and reduced DHEAS/DHEA and testosterone/androstenedione molar ratios compared with healthy controls. Concentrations and molar ratios of serum hormones did not significantly change during the study either among schizophrenia patients, or healthy controls. Among patients alterations in DHEA, DHEAS and androstenedione were associated with emotional distress, anxiety, dysphoric mood, positive and activation symptoms, serum prolactin levels, but were not related to age, antipsychotic agents, and extrapyramidal side effects. CONCLUSIONS: Alterations in DHEA metabolism in schizophrenia are attributed to the distress, anxiety, severity of symptoms, prolactin levels, and may represent a marker for impaired hormonal responses to stress. These findings should be considered when evaluating the discrepancies in DHEA studies in schizophrenia.

Risperidone-induced extrapyramidal side effects: is the need for anticholinergics the consequence of high plasma concentrations?

Antipsychotic drugs can induce various undesirable adverse motor reactions, such as extrapyramidal side effects (EPS). A widely accepted pharmacodynamic mechanism underlying EPS includes an increase in striatal D2-receptor occupancy. However, less is known about the pharmacokinetic background of EPS. The aim of this study was to analyze in-vivo possible pharmacokinetic patterns underlying biperiden-treated EPS in risperidone (RIS)-medicated patients. A large therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-hydroxyrisperidone (9-OH-RIS) of 2293 adult inpatients and outpatients was analyzed. Two groups were compared: a group receiving RIS (n=772) and a group comedicated with biperiden (n=68). Plasma concentrations, dose-adjusted plasma concentrations (C/D) of RIS, 9-OH-RIS, and active moiety (AM) (RIS+9-OH-RIS) as well as ratios of concentrations for metabolite to parent drug (9-OH-RIS/RIS) were computed. We compared the plasma concentrations of the different compounds between the two groups considering the prescription of biperiden as an indirect report of EPS. The daily dosage of RIS did not differ between groups. No differences were detected in case of plasma concentrations and C/D of RIS and active metabolite between the groups. However, plasma concentrations of the AM were significantly higher in the comedicated group (P=0.032) and showed a trend in terms of the active metabolite 9-OH-RIS (P=0.053). Data indicate enhanced AM plasma concentrations of RIS in patients comedicated with biperiden as an EPS treatment. This might underscore an association between higher plasma concentrations of the AM and treatment-requiring EPS.

Blood lactate levels as a biomarker of antipsychotic side effects in patients with schizophrenia.

BACKGROUND: Antipsychotic drugs (APs) are widely prescribed in psychiatry primarily for the treatment of psychosis in schizophrenia and bipolar disorders. An issue related to poor prognosis in patients with chronic illness relates to the accumulation of lactate levels in blood, leading to patients that become critically ill. It is suggested that haloperidol and olanzapine, as common therapy for schizophrenia, are associated with increased levels of blood lactate, which may contribute towards the extra-pyramidal side effects. AIMS AND METHOD: In this study, 88 patients attending the psychiatry outpatient clinic of Mansoura University Hospital, under treatment with typical APs (chlorpromazine or haloperidol) or the atypical APs (risperidone, olanzapine or quetiapine) were followed over a three-month period. Blood lactate levels were assessed at diagnosis, ten days and 90 days after the start of AP treatment. Extra-pyramidal symptoms (EPSs) were studied in participants during the course of this study. RESULTS: Chlorpromazine and haloperidol caused significant increases in lactate levels within the first ten days of therapy, while after 90 days, all APs showed significant increases in arterial blood lactate levels in comparison with the first baseline measurement (for all APs, p-values <0.0001). Dystonia was reported by patients on chlorpromazine, haloperidol and risperidone therapies, while Parkinsonian-like manifestations were reported with all APs tested except for quetiapine. Both dystonia and Parkinsonian-like manifestations were also observed alongside the significant increases in arterial blood lactate levels in comparison to patients on therapy not displaying EPSs. CONCLUSION: These findings suggest elevated blood lactate levels may serve as early biomarkers for occurrence of extra-pyramidal symptoms in patients on chronic APs treatment.

High serum homocysteine levels in young male schizophrenic and schizoaffective patients with tardive parkinsonism and/or tardive dyskinesia.

BACKGROUND: The pathogenesis of neuroleptic-induced tardive movement disorders (TMD), including tardive parkinsonism and tardive dyskinesia (TD), has not yet been established. An elevated serum level of total homocysteine has been implicated as a risk factor for various neuropathologic states and some movement disorders. The aim of our study was to determine whether there is an association between serum total homocysteine level and the presence of TMD among schizophrenic and schizoaffective patients. METHOD: This study was conducted in Be'er Sheva Mental Health Center from August 2002 to May 2004. Fifty-eight patients with schizophrenia or schizoaffective disorder (DSM-IV) and TMD for at least 1 year (38 men, 20 women; age range, 28-73 years) were compared to a control group of 188 patients with DSM-IV-diagnosed schizophrenia or schizoaffective disorder without TMD (123 men, 65 women; age range, 19-66 years) regarding serum total homocysteine levels. RESULTS: Men with TMD (demonstrating tardive parkinsonism and/or TD) had significantly higher mean serum total homocysteine levels compared to sex- and age group-matched controls. The difference between groups was almost entirely attributable to the homocysteine levels of young male patients (age group, 19-40 years old) with TMD. CONCLUSION: High serum total homocysteine level may constitute a risk factor for certain variants of TMD, especially in young schizophrenic or schizo-affective male patients. Further prospective studies are needed to clarify these findings.

Decreased plasma brain-derived neurotrophic factor levels in schizophrenic patients with tardive dyskinesia: association with dyskinetic movements.

Neurodegenerative processes may be involved in the pathogenesis of tardive dyskinesia (TD). Accumulating evidence suggests that brain-derived neurotrophic factor (BDNF) plays a critical role in the maintenance of functional neurons. The present study was to examine plasma BDNF levels and the relationship among BDNF level, psychopathological and tardive dyskinesia symptoms in schizophrenic patients with TD. Eighty schizophrenic patients with TD were compared with 45 schizophrenic patients without TD, as well as with 45 age-, sex-matched normal controls. The severity of TD was assessed using the Abnormal Involuntary Movement Scale (AIMS). The psychopathology of patients was assessed by the Positive and Negative Syndrome Scale (PANSS). Plasma BDNF levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA). The results showed that the patients with TD had lower plasma BDNF levels than those without TD, and than that of normal controls. In the patients with TD, plasma BDNF levels was inversely correlated with AIMS total score, and with PANSS negative subscore. Female patients had significantly lower plasma BDNF levels than male TD patients. Our results suggest that decreased BDNF may play an important role in the pathophysiology of TD. There may be a relationship between decreased BDNF levels and dyskinetic movements associated with TD.