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[Therapy of subclinical (subdiagnostic) syndromes of schizophrenia spectrum].

Since 1911, when E. Bleuler thought of the so-called latent schizophrenia as the most frequent type of schizophrenia, but most seldom diagnosed as such, the question, whether there exist abortive forms of schizophrenia, was discussed again and again; so in 1932 by Mayer-Gross, who devoted to the uncharacteristic onset of schizophrenia a special chapter, in 1938 by Stern (so-called borderline neuroses) und in 1949 by Hoch and Polatin (pseudoneurotic schizophrenias). Since the 50s Huber had described by means of follow-up studies the uncharacteristic basic stages occurring long before the onset and after remission of the florid symptomatology, in 1957 the cenesthetic schizophrenia and in 1961 and 1966 the asthenic or pure defect of schizophrenia, which he also counts to the subclinical syndromes or formes frustes of endogenous psychoses just as the endogenous juvenile-asthenic failure syndromes, the larvate schizophrenia, the endogenous obsessive-compulsive disorder and the circumscribed cenesthopathy. The recognition of these subthreshold stages and types of the schizophrenia spectrum, which cannot be diagnosed by valid diagnostic criteria for schizophrenia, is the presupposition for an adequate therapy. The patients complain about subjectively experienced mainly dynamic, affective, cognitive (thought, perception and action disturbances), cenesthetic and vegetative basic symptoms, can be registered and documented by the Bonn Scale BSABS. We will deal with symptomatology, course and therapy of the mentioned sublinical syndromes. The psychopharmacological treatment is chosen according to the psychopathological cross-section picture and will be continued until improvement or remission of the symptomatology and after stepwise reduction stopped. If dynamic and affective basic symptoms predominate, we prefer antidepressants (e. g. amitriptyline-type or the newer SSRIs), in case of prevailing cognitive and cenethetic basic symptoms neuroleptics, today mainly atypical ones. In the past also classical neuroleptics, e. g. haloperidol, fluphenazine or pimozide in low dosage of or low potent drugs as thioridazine or perazine have proved to be worthwhile.

Adult↗

The AMUP study for drug surveillance in psychiatry - a summary of inpatient data.

From 1979 to 1989 the AMUP study (AMUP = Arzneimittelüberwachung in der Psychiatrie) was conducted in two psychiatric hospitals in Germany with the aim to provide a systematic and standardized assessment of all adverse reactions to psychotropic drugs under conditions of routine practice. A total of 60.7 % of patients experienced at least one adverse drug reaction (ADR) with probable or definite causality during their stay in the hospital; 37.1 % of patients exhibited ADRs that had some therapeutic impact on further treatment. ADRs that led to drug discontinuation were observed in 8.6 %. This rate ranged from 9.5 to 5.1 % for haloperidol and perazine, the most common neuroleptics at that time; sedating antidepressants (AD) rated lower than non-sedating (amitriptyline 5.1 %, clomipramine 10.4 %). Lithium salts, antiparkinson drugs, and benzodiazepines were associated with considerably lower rates of ADRs than neuroleptics or antidepressants. Severe ADRs occurred in 1.4 % of exposed patients (e. g., toxic delirium, grand mal seizures, malignant neuroleptic syndrome, or agranulocytosis). The AMUP data suggest that administration of psychotropic drugs in psychiatric hospitals at that time was a safe, but also inconvenient treatment for many patients due to a wide range of bothersome side effects that compromised patient compliance. The data can serve as a reference base for comparisons with newer compounds introduced to the market over the last decade such as serotonin reuptake inhibitors (SSRIs) and other new AD, atypical neuroleptics, or other new generation psychotropic drugs.

Adverse Drug Reaction Reporting Systems↗

Blood dyscrasias induced by psychotropic drugs.

Drugs can cause a variety of blood dyscrasias, e. g., by interfering with hematopoiesis in the bone marrow or damaging mature blood cells by antibodies. Although numerous reports on the risks of adverse hematological effects associated with psychotropic drugs have led to stringent monitoring requirements for some compounds, particularly neuroleptics, it is still difficult to estimate the true prevalence of such risks. Sixteen episodes of thrombocytopenia, 63 of neutropenia, 22 of agranulocytosis, 4 episodes of severe neutro- and thrombocytopenia, and 2 of pancytopenia were documented by the drug safety program in psychiatry AMSP (Arzneimittelsicherheit in der Psychiatrie) in a population of 122,562 patients between 1993 and 2000. All cases were related to the epidemiological data provided for this population and systematically analyzed as regards history of medication, co-medication, and the clinical course. Putative risk rates for the main groups of medications and a number of drugs could be estimated with this database. Most changes in the white blood cell counts, which were rated as probably or definitely drug-induced, were attributed to clozapine (0.18 % of patients exposed), carbamazepine (0.14 %) and perazine (0.09 %). In patients on newer atypical neuroleptics, we documented neutropenia assumed to be probably or definitely drug-related in five patients during treatment with olanzapine and in one case with risperidone. In all five olanzapine-related cases, the drugs were the sole cause of the adverse drug reactions. All surveyed patients who received clozapine showed no difference in age and gender distribution from those who developed hematological changes. Incidences of hematological changes for antidepressants were much lower (about 0.01 %). Although the methodological accuracy of these findings has to be critically discussed these data could be of considerable clinical relevance and should be helpful in making clinical treatment decisions.

Adult↗

Adverse psychic reactions to psychotropic drugs--a report from the AMUP study.

The AMUP study (AMUP = Arzneimittelüberwachung in der Psychiatrie (Drug Monitoring in Psychiatry)) was conducted from 1979 to 1989 in order to provide for a systematic and standardized assessment of all adverse reactions to psychotropic drugs under the conditions of routine clinical treatment at two psychiatric hospitals. This paper presents data from the AMUP study on the type and frequency of adverse psychic reactions to psychotropic drug groups and relevant single drugs. Psychic ADR leading to drug discontinuation were observed in 4.5% of 15,264 inpatients monitored over an eight-year period. Only neurological ADR were more frequent (4.9%). Neuroleptics and antidepressants were involved with similar frequencies in ADR that were at least "probably" drug-related (3.3 and 3.5%). Lithium salts and benzodiazepines were only rarely involved in psychic ADR. Toxic delirium (1.0%), agitation (0.9%), and sedation (0.8%) were the most frequent single events, usually rated as "probably" drug-related. Depression and psychotic states were next in frequency, but judged as only "possibly" drug-related in a considerable proportion of cases. Haloperidol, the most common high-potency neuroleptic, was imputed mainly for depression, sedation, agitation, and (malignant) neuroleptic syndrome; with medium-potency perazine, toxic delirium and sedation prevailed; among the most common antidepressants, amitriptyline was above all connected with toxic delirium, while with clomipramine agitation predominated. The paper discusses the particular difficulties encountered in the field of psychic ADR in psychiatric patients regarding causality assessment, and emphasizes the need for continuous ADR assessment studies including state hospitals.

Adult↗

Tricyclic neuroleptic and antidepressant overdose: epidemiological, electrocardiographic, and clinical features--a survey of 92 cases.

From 1976 to 1980, there were 3,193 admissions due to acute drug overdosage at the resuscitation centre of the Rudolf-Virchow-Hospital, Free University of Berlin. The frequency and the characteristics of selfpoisoning with antidepressants and low-potency neuroleptic drugs (mainly perazine and thioridazine) were determined. These drugs were involved in 92 cases (3%) during this five-year period. Amitriptyline--in combination with a benzodiazepine--was the most common antidepressant taken by the patients. Ten of the patients required assisted ventilation. Complete ECG recordings were carried out in 24 patients. The most common abnormality was a prolonged QTc interval (21 patients) followed by a QRS duration of 0.11 seconds or longer (17 patients). Sinus tachycardia was present in half of the cases. In no cases did the medical records describe convulsions or cardiac arrhythmias requiring special treatment. The percentage of patients showing ECG changes and respiratory depression was higher when other drugs such as ethanol were ingested along with antidepressants than when only antidepressants were taken. One patient died after six weeks in hospital due to a complicated abscess. From 1976 to 1980, the incidence of antidepressant selfpoisoning was relatively low compared with findings from other studies. Data from other studies suggest that, in the period 1980-1987, there was an increase in the incidence of antidepressant selfpoisoning, at least in the West Berlin and Munich areas. However, these figures are much lower than those reported by British, American, and Australian authors.

Adult↗

Recent trends in prescribing psychotropic drugs at a psychiatric university hospital (1981-84).

Analysis of the prescribing of psychotropic drugs in the psychiatric hospital of the Free University of Berlin revealed a slight decrease in the mean number of prescriptions to our patients over recent years. As a response to intensified psychopharmacological pretreatment the proportion of patients who had initially been treated drug-free (up to the 10th day after admission) rose steadily every year. The use of neuroleptics increased significantly, mainly due to increased prescriptions of this group of compounds to endogenous depressives. The use of benzodiazepines, however, decreased in all groups of patients. Simultaneous use of neuroleptics was a clear leader in the category of drug combinations. Low-potent neuroleptics (i.e. perazine, clozapine), clomipramine, and the MAO-inhibitor tranylcypromine were preferred increasingly in recent years; reduced prescription rates were found for haloperidol, clomethiazol, and metamizol. These changes may be related to an ongoing process of reevaluating benefits and risks of available treatments. The systematic updating of prescribing patterns is an essential tool for quality control of psychiatric pharmacotherapy.

Adult↗

Drug prescribing pattern of a psychiatric university hospital in Germany.

1. The drug treatment of 1,263 psychiatric patients (= 96% of all in-patients admitted during a period of 2 years) was analyzed by means of case histories. During hospitalization 7.4% of all patients were treated completely drug-free; 12.5% received no psychoactive drugs. 2. The patients were hospitalized for 50 days on the average, and received psychoactive drugs on 43 days. During the total treatment period, they were prescribed an average of 4.3 (median 3.8) different drugs; of these, 2.7 (median 2.3) were various psychoactive drugs. Neuroleptics were the most frequently used drugs; they were prescribed at least once during treatment for 62% of all patients. Antidepressants were prescribed for almost 30% of the patients. 3. For the neuroleptics prescriptions decreased with patient's age; they increased for the antidepressants. Antiparkinsonian agents were prescribed to 51% of neuroleptic-treated patients under 45 years of age, and to 26% of these patients over 45. 4. Neuroleptics were prescribed more frequently in male patients, antidepressants in female patients. 5. Among the individual prescriptions, perazine was the most favoured of the neuroleptics, and amitriptyline of the antidepressants. Clozapine was prescribed for the longest period among all psychotropic agents except lithium salts. Antiparkinsonian agents were used for shorter periods than the neuroleptics administered simultaneously. One-fifth of the patients were given analgesics for brief periods. 6. Medication pattern is related to specific nosology. 95% of schizophrenic patients received neuroleptics for at least an average of 41 days; every second patient in this group received antiparkinsonian agents. 90% of unipolar depressed patients were given antidepressants; during one course of treatment at least 2 different antipressant drugs were prescribed for 32% of these patients. 43% of unipolar depressed patients received neuroleptics for an average of 33 days. Lithium salts were administered for an average of 45 days to 43% of the patients with affective disorders. 7. Treatment surveys of this kind supplement the collection of data on adverse drug reactions by drug monitoring systems. The relationship between the side effects of drugs and the prescription pattern of individual drugs allows one to determine the incidence rates of drug side effects.

Age Factors↗

[Gabapentin in the treatment of mania].

We present the case of a 60-year old bipolar-I-patient showing a rapid antimanic response to gabapentin after having been non-responsive to lithium and perazine. This case encouraged us to further evaluate the antimanic potency of gabapentin in an open label trial. 20 patients with acute mania were treated for up to 21 days with gabapentin in a dose range from 1200 to 4800 mg/day. Ten patients were treated with gabapentin as add-on medication and ten patients were treated with a high dose of gabapentin alone. The BRMAS score declined significantly in patients with moderate mania, whereas gabapentin alone was not efficacious in patients with very severe mania. Keeping in mind the limitations of an open study, it can still be said that gabapentin as add-on medication with other effective mood stabilizers appears to be safe and efficacious in the treatment of moderate mania.

Acetates↗

Specificity data of the tricyclic antidepressants assay by fluorescent polarization immunoassay.

Additional specificity data of the fluorescent polarization immunoassay (FPIA) for tricyclic antidepressants (TCA) in serum were evaluated. The TDx TCA assay exhibits cross-reactivities for a variety of the tricyclic antidepressants, tetracyclic antidepressants, phenothiazines, and several metabolites from these compounds. Significant cross-reactivities were found for dixyrazine (20-40%), alimemazine (20-47%), perazine (23-33%), Iofepramine (27-30%), desmethyltrimipramine (40-57%), opipramol (60-77%), amitriptylinoxide (73-85%), and dothiepin (97-113%).

Antidepressive Agents, Tricyclic↗

Characterization of human cytochrome p450 enzymes involved in the metabolism of the piperidine-type phenothiazine neuroleptic thioridazine.

The aim of the present study was to identify human cytochrome P450 enzymes (P450s) involved in mono-2-, di-2-, and 5-sulfoxidation, and N-demethylation of the piperidine-type phenothiazine neuroleptic thioridazine in the human liver. The experiments were performed in vitro using cDNA-expressed human P450s (Supersomes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4), liver microsomes from different donors, and P450-selective inhibitors. The results indicate that CYP1A2 and CYP3A4 are the main enzymes responsible for 5-sulfoxidation and N-demethylation (34-52%), whereas CYP2D6 is the basic enzyme that catalyzes mono-2- and di-2-sulfoxidation of thioridazine in human liver (49 and 64%, respectively). Besides CYP2D6, CYP3A4 contributes to a noticeable degree to thioridazine mono-2-sulfoxidation (22%). Therefore, the sulforidazine/mesoridazine ratio may be an additional and more specific marker than the mesoridazine/thioridazine ratio for assessing the activity of CYP2D6. In contrast to promazine and perazine, CYP2C19 insignificantly contributes to the N-demethylation of thioridazine. Considering serious side-effects of thioridazine and its 5-sulfoxide (cardiotoxicity), as well as strong dopaminergic D2 and noradrenergic alpha1 receptor-blocking properties of mono-2- and di-2-sulfoxides, the obtained results are of pharmacological and clinical importance, in particular, in a combined therapy. Knowledge of the catalysis of thioridazine metabolism helps to choose optimum conditions (a proper coadministered drug and dosage) to avoid undesirable drug interactions.

Animals↗

Renal impairment as a possible side effect of gabapentin. A single case report.

A bipolar I manic patient was treated successfully by adding gabapentin to perazine and clonazepam. Also initially tolerated well, an increase of creatinine after several weeks of GP (2000 mg) was observed which was reversible after discontinuation of GP. It is suggested that the possibility of renal dysfunction should be kept in mind with the usage of gabapentin.

Acetates↗

Acetazolamide in the treatment of acute mania. A case report.

Several antiepileptic drugs are also being used in affective disorders. There are some hints that also the carbonic anhydrase inhibitor acetazolamide might be useful in the treatment of bipolar affective disorder. We report a 39-year-old male patient with a history of bipolar affective disorder who presented with his second manic episode. Acetazolamide was added to a low dose of valproic acid and to perazine. A marked decrease of the BRMAS score was achieved. The implications of this case are discussed.

Acetazolamide↗

Effect of phenylhydrazine-induced structural alterations of human erythrocytes on basic drug penetration.

The phospholipid organization, lipid fluidity and spectrin degradation were measured in human erythrocytes oxidized with phenylhydrazine, and the contribution of these structural alterations to the penetration of perazine and promethazine into the membrane was estimated. It was found that exposure of erythrocytes to phenylhydrazine (0.2--0.4 mg/ml) produced a 35--40% decrease in the amount of spectrin, with resultant gross morphological changes to the echinocyte conformation. The phosphatidylethanolamine content in the treated erythrocytes was greatly lowered compared with that in the untreated cells. Treatment with phenylhydrazine (0.05--0.2 mg/ml) dramatically diminished the lipid fluidity of the membrane, as estimated by electron spin resonance (ESR) spectrometry, and the ESR study revealed increased restriction of the molecular motion of the hydrophobic core in the treated membrane. These results suggest a drastic alteration of the erythrocyte membrane structure. The amount of drugs which penetrated into the treated erythrocytes increased markedly with increasing phenylhydrazine concentration, suggesting enhanced membrane permeability and facilitated localization of the drugs in the hydrophobic regions due to the structural changes and partial disturbance of the lipid organization.

Erythrocytes↗

Studies on anti-platelet agents. V. Synthesis and structure-activity relationship of 3-substituted 5,6-bis(4-methoxyphenyl)-1,2,4-triazines.

The syntheses and structure-activity relationships of a series of 3-substituted 5,6-bis(4-methoxyphenyl)-1,2,4-triazines as anti-platelet agents based on cyclooxygenase (CO) inhibition are described. Of these compounds, 1-[5,6-bis(4-methoxyphenyl)-1,2,4-triazin-3-yl]carbonyl-4-methylpi perazine (10) exhibited potent CO inhibition in vitro (IC50 = 2.8 x 10(-7) M) with vasodilatory activity (ED50 = 4.5 x 10(-5) M). Compound 10 also showed potent ex vivo activities, completely preventing platelet aggregation induced by arachidonic acid and collagen at 6 h after oral administration of 3.2 and 1.0 mg/kg. The ex vivo potency of 10 is more than three times that of aspirin. Moreover, 10 demonstrated no gastrointestinal side effect in rats even at 100 mg/kg in spite of its potent CO inhibition activity, while aspirin, the most widely-used anti-platelet drug, showed gastrointestinal side effects in a dose-dependent manner (32, 100, and 320 mg/kg) in our study. These results suggested that 10 is a very attractive candidate for development as an anti-platelet drug since an aspirin-like anti-platelet agent, based on CO inhibition and being free from gastrointestinal side effects, is a major goal of thromboembolic research.

Animals↗

Anabolic effect of genistein in osteoblastic MC3T3-E1 cells.

Genistein is a natural isoflavone found in Leguminosae. The effect of genistein on osteoblastic MC3T3-E1 cells was investigated. Cells were cultured for 48 h in the presence of genistein (10(-7)-10(-5) M). Genistein (10(-6) and 10(-5) M) caused a significant elevation of protein content, alkaline phosphatase activity, and deoxyriboncleic acid (DNA) content in the cells. The effect of genistein (10-5 M) in increasing protein content, alkaline phosphatase activity and DNA content in the cells was completely prevented by the presence of cycloheximide (10(-6) M), an inhibitor of protein synthesis, suggesting that the isoflavone's effect results from a newly synthesized protein component. The effect of genistein (10(-5) M) in elevating cellular protein content and alkaline phosphatase activity was completely inhibited by the presence of trifluo-perazine (10(-5) M), staurosporine (10(-7) M) or vanadate (10(-6) M), various protein kinase inhibitors. Moreover, genistein (10(-5) M)-increased protein content and alkaline phosphatase activity in the cells was clearly abolished by the presence of anti-estrogen tamoxifen (10(-6) M). The effect of 17beta-estradiol (10(-9) M) in elevating protein and alkaline phosphatase activity in the cells was not enhanced by the presence of genistein (10(-5) M). Genistein's effect might be partly involved in estrogen action. The present study demonstrates that genistein has an anabolic effect on osteoblastic MC3T3-E1 cells.

Alkaline Phosphatase↗

Reversal of morphine-induced apnea in the anesthetized rat by drugs that activate 5-hydroxytryptamine(1A) receptors.

The purpose of our study was to test the hypothesis that 5-hydroxytryptamine (5-HT)(1A) receptor agonists counteract morphine-induced respiratory depression. Studies were conducted in anesthetized rats, and respiratory activity was monitored with diaphragm electromyography. Morphine was administered i.v. in doses that produce apnea. Once apnea was established, i.v. administration of the 5-HT(1A) receptor agonist drug 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) at 10 or 100 microgram/kg restored normal breathing in each animal (n = 24). This antagonistic effect of 8-OH-DPAT on morphine-induced respiratory depression was observed in both spontaneously breathing and artificially ventilated animals. Results obtained with 8-OH-DPAT were mimicked by buspirone (50 microgram/kg i.v.), another 5-HT(1A) receptor agonist drug. Pretreatment with 4-(2'-methoxyphenyl)-1-[2'[N-(2'-pyridinyl]-p-iodo-benzamido]ethyl]pi perazine, an antagonist of 5-HT(1A) receptors, prevented 8-OH-DPAT from counteracting morphine-induced apnea. These results indicate that activation of central nervous system 5-HT(1A) receptors is an effective way of reversing morphine-induced respiratory depression. Most important, this is the third model of disturbed respiratory function in which drugs that stimulate 5-HT(1A) receptors have been shown to restore breathing to near-normal levels.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

[Obsessive-compulsive disorders in adolescents with diagnosed schizophrenia].

The aim of the study was to assess the prevalence of OCD among 200 outpatients and inpatients (102 girls and 88 boys), 15-19 years old (mean age = 17.1 +/- 0.29) with schizophrenia (DSM-III-R, DSM-IV) and to determinate the time of onset of OCD: at least 6 months before schizophrenic symptoms, together with schizophrenic symptoms, while treatment with neuroleptics (name of drug, doses, duration of pharmacotherapy). Patients were examined with SCID-P for DSM-III-R and DSM-IV, version for patient, Y-BOCS and a specially prepared questionnaire for determining the age of onset, duration of OCD and a clinical picture of OCD. OCD was diagnosed in 13% adolescent patients with schizophrenia. Primary OCD--before schizophrenic symptoms was noted in 2.0% of patients, OCD together with schizophrenic symptoms in 4.5% of subjects, and while pharmacotherapy with various atypical neuroleptics: clozapine, risperidone, olanzapine in 6.0% of young patients. The most of assessed patients received clozapine (35 subjects), 24 subjects were treated with risperidone and 17 patients with olanzapine. It was determined that 14.3% of subjects used clozapine, 12.5% of subjects treated with risperidone and 5.9% treated with olanzapine presented OCD, where symptoms had appeared while in pharmacotherapy with these atypical neuroleptics. The differences were not statistically significant. OCD was not observed in these patients who had earlier treatment with classical neuroleptics (for example: haloperidol, perazine). It is possible that part of OCD in schizophrenic patients is induced by medication with new atypical neuroleptics, their influence on serotoninergic system, other, maybe the partial symptomatology of schizophrenia in a special subgroup of patients.

Adolescent↗

Kinetics of drug decomposition. Part XXXVI. Stability of 10-(1'-methyl-4'-piperazinylpropyl)-phenothiazine derivatives on the grounds of kinetics of thermal degradation and Hammett equation.

Thermal degradation of aqueous and buffered solutions of perazine, prochlorperazine, trifluoperazine, thioproperazine, thiethylperazine and butaperazine salts was examined by kinetic method using an accelerated testing of pharmaceutical preparations. The order, rate constants and activation parameters (Q100, E, delta H not equal to, delta S not equal to, delta G not equal to ) of the reaction given were discussed. The predicted stability of the examined derivatives was compared on the grounds of a calculated time t10% and K293 kappa. A dependence between the stability and kind of substituent in the C2 positions was discussed in terms of the Hammett equation.

Chemical Phenomena↗