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Psychotropic drugs are often liable to unwanted anticholinergic effects that reduce tolerance and compliance. Especially, in certain patient groups, such as elderly patients, anticholinergic adverse effects may be hazardous. There are also occasions in therapy when antimuscarinic activity is desired, e. g. in the treatment of neuroleptic-induced extrapyramidal symptoms with biperiden and other potent anticholinergic drugs. In this review, we describe various techniques to evaluate the anticholinergic influences of psychotropic drugs in vivo and also provide examples of previous human studies where these methods have been applied. By combining subjective ratings of anticholinergic effects to in vitro measurements of antimuscarinic activity in blood, as well as the functional state of salivary glands, sweat glands, heart and eye, a researcher can obtain a detailed anticholinergic profile of the drug in question, or a clinician can estimate the anticholinergic burden of his/her psychiatric patient who often uses multiple medications.

Introduction: The use of aripiprazole (APZ) has increased in the pediatric population. Its pharmacological profile differs from other antipsychotics being generally considered to have a good safety and tolerability profile with a lower risk of metabolic adverse events and a low to moderate risk for extrapyramidal symptoms. Objective: Two adolescents with severe APZ induced extrapyramidal symptoms are presented. Outcomes (i.a. assessed with the global assessment of functioning scale, GAF) and other data were documented within an online patient-registry (www.tdm-kjp.de). Case 1: A 17-year-old female with schizoaffective disorder (GAF-score 5) was treated with APZ (GAF-score 40) for four weeks. After five days at the maximum dosage of 15 mg daily she developed rest tremor, stiffness, and akinesia. The APZ serum concentration was 456 ng/ml (recommended range for adults 150 – 500 ng/ml). After a single administration of 4 mg long acting biperiden (anticholinergic) symptoms immediately decreased. Under a reduced APZ dose of 12,5 mg (corresponding serum concentration of 407 ng/ml) and 2 mg biperiden daily the girl was discharged free of extrapyramidal symptoms with significantly improved clinical presentation (GAF-score 70). Case 2: A 16-year-old boy with paranoid schizophrenia (GAF-score 26) was treated with APZ after he had developed extrapyramidal symptoms under 10 mg haloperidol. Under concomitant medication with biperiden 8 mg daily APZ was increased up to a maximum of 30 mg daily (serum concentration 327 ng/ml; GAF-score 32) for 24 days. After biperiden was tapered off the patient developed a massive attack of extrapyramidal symptoms with cogwheel phenomenon, blepharospasm, dystonia, tremor, and ataxic gait. Symptoms remitted by administration of 4 mg biperiden orally and additional intravenous injection of 6 mg biperiden. Finally the adolescent was discharged after 23 weeks with 200 mg clozapine per day (GAF-score 39). Discussion: Few cases of APZ induced extrapyramidal symptoms in minors have been published. In the two patients presented APZ was approved for diagnosis and age, however due to the severity of illness administered in higher than the recommended dose of 10 mg daily (maximum 30 mg). If the claimed advantage, that APZ has a lower potential for developing extrapyramidal symptoms really exists, this advantage may disappear with higher dosages.

We report the case of a bipolar patient developing severe delirium and extrapyramidal signs shortly after initiation of a lithium-neuroleptic combination therapy. Clinical presentation, EEG changes and lithium plasma levels showed a close correlation. The delirium was reversible when all drugs were stopped; however, dyskinesia was found to be persistent after a period of 6 months. This rare syndrome is difficult to differentiate from lithium intoxication and neuroleptic malignant syndrome. Given the additional use of valproate and biperiden in this patient, valproate encephalopathy and anticholinergic delirium are further differential diagnoses. To avoid this serious pharmacodynamic drug interaction, patients should be closely monitored when lithium-neuroleptic comedication is started.

In accordance with a previous study of adjuvant effects of the anticonvulsant carbamazepine (CBZ) on the neuroleptic treatment of schizophrenic psychoses, the effects of valproate (VPA) were tested in a randomly assigned double-blind, placebo-controlled study. Apart from a (statistically nonsignificant) psychopathological deterioration following discontinuation of VPA while on continuous neuroleptic mediation after four weeks and a statistically significant effect on "hostile belligerence", no overall therapeutic effects of the combination of haloperidol (HPD) with VPA were observed under controlled conditions. Unlike the results with CBZ, concomitant use of VPA led to an even higher consumption of haloperidol and biperiden and to a higher rate of extrapyramidal symptoms compared with the corresponding placebo group, although these differences did not attain statistical significance. In regard to use of the sedative neuroleptic chlorprothixene, there was a trend toward lower doses in the VPA group than in the placebo group. From these results, adjuvant effects like those of carbamazepine in the neuroleptic treatment of schizophrenic psychoses could not be confirmed for valproate in the present study. However, the trend toward lower doses of sedative medication and observed effects on "hostile belligerence" may indicate sedative and/or antimanic properties of valproate which have recently been demonstrated in several controlled studies.

In contrast to several authors who found hepatic cytochrome P 450 2D6 (CYP2D6) metabolising status to be clinically unimportant in treatment with the CYP2D6 substrate, risperidone, we report on a 17-year-old schizophrenic patient who suffered from severe extrapyramidal side effects (EPS) while being treated with risperidone at 4 mg per day. He was genotyped as a CYP2D6 poor metaboliser (PM). The active moiety of risperidone (sum of risperidone and 9-hydroxyrisperidone) was elevated and increased even further under co-medication with haloperidol and biperiden. We conclude that the PM phenotype for CYP2D6 of this patient had major clinical importance in treatment with risperidone. Most likely metabolic pathways other than CYP2D6 were also involved that are probably inhibited by haloperidol.

In vitro receptor-binding profiles and in vivo pharmacological studies have shown risperidone to be a potent mixed serotonin-S2 dopamine-D2-like receptor antagonist. While anti-D2 activity may relate to the antipsychotic potency of neuroleptic drugs, an antidepressive efficacy of substances with anti-S2 activity has been suggested. In an open pilot-study, ten patients with schizodepressive disorders or a DSM-III-R diagnosis of psychotic major depressive episodes were treated with risperidone (2-10 mg/d) for six weeks. Weekly psychopathological evaluation was performed, including BPRS, SANS, SAPS, VAS scales, and AIMS and UKU for the assessment of side-effects. Generally, the psychotic syndrome (BPRS, SANS and SAPS) decreased markedly in all patients; seven patients also showed a clinically significant improvement of depressive symptoms (BPRS). Except for two patients who needed biperiden because of extrapyramidal side-effects, the tolerance of risperidone was good. The antipsychotic and antidepressive properties of risperidone shown in our pilot study are promising enough to merit full double-blind controlled trials for further evaluation of its therapeutic value in this broad spectrum of psychiatric disorders.

INTRODUCTION: Amisulpride appears to be an effective atypical agent for treating schizophrenia in a dose-dependent manner. METHODS: 29 patients suffering from schizophrenia or schizoaffective disorder were treated with a broad dose range of amisulpride (50-1 200 mg/day, mean: 455.2±278.8 mg/day). After 2 weeks, brain single photon emission tomography (SPET) scans were performed two hours after intravenous injection of 185 MBq [ 123 I]IBZM. Clinical evaluations and ratings of extrapyramidal symptoms were performed at baseline and after steady state treatment of two weeks with amisulpride. RESULTS: In patients treated with amisulpride, specific binding of [ 123 I]IBZM to D2 receptors was significantly decreased (p

The aim of the present study was to seek a CYP2D6 genotypic-phenotypic discordance possibility in Japanese patients under psychotropic drug treatment where the CYP2D6 status and pharmacodynamic responses differ from those in Caucasian psychiatric patients. Ninety drug-free, healthy volunteers and 14 patients undergoing psychotropic drug treatment were phenotyped for their individual CYP2D6 activity using dextromethorphan as a probe, and then the metabolic ratio (MR) was calculated. For the genotyping, eight mutant alleles of the CYP2D6 genes were identified. Serum concentrations of two frequently co-medicated psychotropic drugs, biperiden and levomepromazine, were determined by GC/MS. Genotyping revealed no poor metabolizers (PMs) enrolled in our study. Healthy volunteers exhibited an identical phenotype-genotype concordance, whereas 7 of the 14 patients had significantly high (p < 0.05) MRs compared with genotype-matched volunteers. Three of the patients who had the extensive metabolizer (EM) genotype had extremely high MRs and were classified as phenotypic PMs. Five patients plus all of the seven high MR patients were treated with levomepromazine and/or biperiden, respectively. Their mean serum steady-state concentrations were 27.4 and 7.6 ng/ml, respectively. A CYP2D6 phenotype-genotype mismatch (phenocopying) can occur in Japanese psychiatric patients receiving clinical doses of some psychotropic drugs where the prevalence of PMs is low and the pharmacodynamic responses to those drugs are enhanced compared to Caucasian patients.

In an open study the cholinolytic biperiden was administered to 10 severely depressed inpatients in an average dose of 12 mg per day for 30 days. Patients were classified according to the International Classification of Diseases, the research Diagnostic Criteria and the Newcastle Scale. A significant improvement was demonstrated in the global score of the Hamilton Depression Scale (p less than 0.001). Especially the factors retardation (p less than 0.001) and agitation (p less than 0.001) and the items depressed mood (p less than 0.001), initial insomnia (p less than 0.05), work and interest (p less than 0.001) and gastrointestinal symptoms (p less than 0.001) could favorably be influenced. Nevertheless, biperiden treatment had to be discontinued after three weeks in two patients because of a paranoid syndrome in one case and symptoms of inner restlessness and disturbances of vital feelings in the other case. There was a positive correlation between the clinical response and the cortisol non-suppressability to dexamethasone prior to the study (p less than 0.03). These results taken together with other findings from the literature suggest that cholinergic mechanisms may have an important impact on the pathogenesis of certain forms of depression.

Zotepine, a new neuroleptic, was administered to 23 hospitalized patients with schizophrenia at doses of 75 to 600 mg/d for 21 to 42 days. Based upon analysis of conventional rating scales we observed a significant improvement (P less than 0.001) during week 1, which compound throughout the study period. After 21 days we identified 17 responders and 6 nonresponders, 2 of whom dropped out of the study because of a tonic-clonic seizure in one case and withdrawal of consent to further participation in the second case. During further treatment the improvement remaind stable in the responder group, while 1 nonresponder improved after 3 weeks of treatment. In 9 patients extrapyramidal symptoms were observed (6 parkinsonism, 2 early dyskinesia, 1 parkinsonism and early dyskinesia), which required sporadic (n = 3) or continuous (n = 2) treatment with biperiden in 5 cases. This low incidence of extrapyramidal symptoms necessitating coadministration of anticholinergic drugs suggests that the risk of inducing parkinsonism and dyskinesias during zotepine treatment is low. Comparison of cortisol, growth hormone and prolactin release in normal controls challenged with 25 mg zotepine showed that only prolactin secretion is increased, while secretion of cortisol and growth hormone remains unaffected. The clinical effects observed in the present study show that zotepine has potential value in the treatment of schizophrenia. The findings warrant further study in controlled trials.

A young man with a previously untreated schizophrenia developed a neuroleptic malignant syndrome (NMS) on the second day of neuroleptic treatment. The dominant symptom was deep coma. The NMS occurred on the second day of neuroleptic therapy with rapidly progressing mental deterioration, temperature elevation, and extrapyramidal signs. After anticholinergics were injected the patient regained consciousness. This suggests that a cholinergic hyperactivity in the central nervous system (rather than hyperthermia) is responsible for the disturbance of consciousness in NMS. The experimental evidence that central cholinergic systems are stimulated by neuroleptics is discussed. It is concluded that anticholinergics might be helpful in treating coma during NMS.

In pharmacological screening amisulpride produces no catalepsy, no inhibition of stereotypic movements, yet a blockade of drug-induced vomiting. During an open clinical trial lasting 4 weeks, 14 patients (13 schizophrenics) were treated with the compound. The (BPRS-) syndromes anxiety/depression, thought disorder, activity, hostility and the global score showed significant improvement. With the AMDP system significant changes were seen in the paranoid-hallucinatory, manic, depressive and hostility syndromes as well as in the global score. No changes were revealed in anergia (BPRS) and apathia (AMDP). In the EEG a significant decrease in the frequency of alpha-rhythms was found. The scores of the Simpson-scale for extrapyramidal side effects were low, but there was an acute dystonic reaction in one patient. In three cases akathisia occurred; biperiden administration was necessary three times. In conclusion, amisulpride showed good antipsychotic efficacy without sedation. Contrary to expectations based on the pharmacological screening, we did find extrapyramidal side effects.

The pharmacodynamic and kinetic profiles of two oral biperiden formulations (tablet with instant-release and sugar-coated tablet with slow-release) were studied in a total of 12 healthy subjects after the administration of a 4 mg dose and compared in part to placebo. Biperiden as slow-release formulation showed much slower absorption than the instant-release tablet; whereas plasma levels peaked as early as 1-2 h after administration of the tablet, with the slow-release formulation a first peak was seen approximately 4.5 h after intake in the majority of the subjects. In some subjects this was followed by a trough, in others by formation of a shoulder at around 0.5 ng/ml. In all subjects a peak of about 1.0 ng/ml was reached after 10-12 h. The instant-release tablet and the slow-release formulation showed comparable bioavailability. Plasma concentrations for the slow-release formulation at 24 h were around 0.5 ng/ml, about twice as high as those for the instant-release formulation. The ratio of peak to 24 h values showed the marked reduction which is characteristic for a slow-release formulation compared with the instant-release tablet. The subjective well-being of the volunteers was not influenced by the slow-release formulation, whereas after the instant-release tablet slight CNS effects (dizziness, drowsiness and fatigue) were reported up to 6 h after ingestion. Furthermore, objectively quantifiable pharmacodynamic ocular parameters (near-point accomodation, pupil size) and the secretion of saliva proved to be less affected by the slow-release formulation than by the instant release tablet, or not affected at all. Das pharmakodynamisch-kinetische Profil von zwei oralen Biperiden- Formulierungen (Tablette mit schneller und Dragee mit verzogerter Wirkstoff-Freisetzung) wurde bei insgesamt 12 gesunden Probanden nach Gabe einer Dosis von 4 mg und zum Teil im Vergleich mit Plazebo untersucht. Biperiden wird aus der Retard-Form im Vergleich zur schnell freisetzenden Tablette stark verlangsamt resorbiert: Wahrend die Plasmakonzentrationen bereits 1-2 h nach Gabe der Tablette ihre Gipfelwerte erreichen, ist bei der Retard-Form bei den meisten Probanden rund 4,5 h p.a. ein erstes Maximum erkennbar, dem zum Teil nach Durchlaufen eines Minimums bzw. zum Teil nach einer Schulterbildung bei rund 0,5 ng/ml bei allen Probanden ein Maximum um 1 ng/ml 10-12 p.a. folgt. Tablette und Retard-Form zeigen vergleichbare Bioverfugbarkeit. 24 h p.a. sind die Plasmakonzentrationen bei der Retard-Form mit rund 0,5 ng/ml etwa doppelt so hoch wie bei der Tablette; der Quotient aus Gipfel und 24 h-Wert zeigt die fur eine Retardform typische deutliche Verminderung gegenuber der Tablette. Das subjektive Befinden der Probanden ist durch die Retardform nicht verandert, wahrend nach der Tablette bis zur 6. Stunde leichte zentralnervose Symptome (Schwindel, Benommenheit, Mudigkeit) angegeben werden. Auch die objektiv quantifizierten, pharmakodynamischen okularen Parameter (Nahakkomodation, Pupillengrose) sowie die Speichelsekretion zeigen bei der Retardform im Vergleich zurTablette geringere oder keine Veranderungen.

In a 38-year-old male patient suffering from a severe postzosteric trigeminal neuralgia, intravenous application of 10 mg biperiden lactate led to a long-lasting paradoxical reaction characterized by considerable bradycardia, dysarthria, and dysphagia. The heart rate was back to normal within 12 hours upon administration of orciprenaline under cardiac monitoring in an intensive care unit. Bradycardia induced by biperiden is attributed to the speed of injection and to a dose-related dual effect of atropine-like drugs on muscarine receptors.