Therapeutic effect and safety of increasing doses of risperidone (R 64766) in psychotic patients.

Risperidone (R 64766) was administered during 4 weeks in increasing doses to 17 psychotic patients, to evaluate the hematological and cardiovascular safety, the therapeutic effect, side effects, effects upon endocrinological parameters and the pharmacokinetic profile. Following a placebo wash-out period of 1 week, the initial dose was 10 mg daily, increasing with 5 mg per week until the maximal dose of 25 mg daily was reached during the 4th week of treatment. Doses up to 20 mg daily resulted in a significant improvement of the total BPRS score and of the different BPRS factor scores; with higher doses, no further clinical benefit was achieved except for the hostility and anxiety-depression factor, while sedation became more prominent. No increase of extrapyramidal symptoms was noticed. Except for the sedation observed with higher doses, risperidone was well tolerated. No clinically relevant effects on cardiovascular and ECG parameters were noticed, and except for a slight increase of aspartate aminotransferase and alanine aminotransferase in one patient, no laboratory abnormalities were observed. Prolactin showed an expected increase, while the other endocrinological parameters revealed no changes. Risperidone had a linear pharmacokinetic profile.

Effect of serotonin antagonism in schizophrenia: a pilot study with setoperone.

The new antipsychotic drug setoperone is pharmacologically characterized by its potent serotonin and moderate dopamine receptor blocking properties. Forty chronic schizophrenic patients were included and 34 completed this pilot study. Following a drug-free period of 1 week the patients received setoperone 5 mg t.i.d. After 1 month of treatment, the psychotic symptoms, as measured by the BPRS, improved by approximately 50% (P less than 0.001) as compared with the condition under previous neuroleptic medication. Blockade of serotonin receptors may be related to improvement of autistic behaviour, dysphoria, and parkinson-like symptoms. In residual schizophrenic patients, the need for dopamine blockade, which is normally correlated with the therapeutic effect on positive symptoms, can be reduced substantially.

The efficacy of the D2 and 5-HT2 antagonist risperidone (R 64,766) in the treatment of chronic psychosis. An open dose-finding study.

After a wash-out period of 1 week, 20 patients suffering from schizophrenia were treated for 4 weeks in an open dose-finding study with a new serotonin-dopamine antagonist risperidone. All patients completed the trial. The mean daily dose of risperidone was 4.6 mg (range 2-10 mg) at completion. Risperiodone had a rapid onset of action: a highly significant decrease of the total BPRS score (Brief Psychiatric Rating Scale) was already noticed at the end of the second week. This decrease was found in all BPRS factors after 4 weeks. In spite of the withdrawal of antiparkinson medication at selection, a clear decrease of EPS (extrapyramidal symptoms), assessed on the Simpson and Angus Scale, was observed. The Global Therapeutic Impression agreed to the BPRS scores, showing a highly significant improvement after 2 weeks of treatment. Risperidone was very well tolerated, only mild side effects were reported. Vital signs, electrocardiographic parameters and laboratory values remained normal during the trial. This study indicates that risperidone can be an effective and well-tolerated alternative in the treatment of chronic schizophrenia, combining an antipsychotic activity, a beneficial effect on anergia and anxiety depression and a low EPS-inducing profile.

Pharmacology, pharmacokinetics and clinical development of haloperidol decanoate.

The absorption mechanism of haloperidol decanoate from the intramuscular depot was studied in dogs. Haloperidol, a pharmacologically active molecule characterised by selective dopamine antagonism, was detectable in plasma within one hour after dosing. Peak plasma levels were obtained within three to seven days. After single and repeated doses of haloperidol decanoate, plasma levels were found to be dose related. Human pharmacokinetics in schizophrenic patients were studied by giving four-weekly deep intramuscular injections of haloperidol decanoate at doses equivalent to the patients' previous antipsychotic medication. Within each interval between doses, haloperidol plasma levels were maximal within the first week after each dose, decaying with an average half-life of three weeks. Steady-state was reached within three months giving therapeutic plasma levels in the same range as those found during oral treatment with haloperidol. Open and double-blind clinical trials have demonstrated the clinical efficacy of haloperidol decanoate given four-weekly by deep intramuscular injection over a dose range from 50 to 300 mg, principally in schizophrenic patients. Low incidences of extrapyramidal side effects were noted, often allowing a reduction of antiparkinsonian medication required through previous antipsychotic treatment.

Risperidone (R64 766) in psychotic patients. A first clinical therapeutic exploration.

Seventeen therapy-resistant adult male psychotic inpatients were treated in an exploratory open study with the new combined serotonin-S2 and dopamine-D2 antagonist risperidone (R 64 766). The mean daily dose was 4.5 mg orally, and the mean duration of treatment 6 months. There were 11 responders, 5 non-responders and 1 drop-out. Risperidone combined an effective antidelusional potency with important contact- and mood-improving properties, while at the same time it reduced existing extrapyramidal symptoms (EPS). Three out of the 5 non-responders were probably underdosed. Risperidone was very well tolerated, reported side effects were mild and transient, and no reason for premature interruption of the therapy.

Pilot study of a specific serotonergic antagonist, pirenperone, in the treatment of anxiety disorders.

Pirenperone (R 47465) is the prototype of a new class of psychotropic drugs, selective serotonin 5-HT2 receptor blocking agents. In an open pilot study, the anxiolytic properties of pirenperone were evaluated in a sample of five anxious inpatients who met Research Diagnostic Criteria for current Generalized Anxiety Disorder and who had a score of at least 25 on the Hamilton Anxiety Scale (HAS). Three dosage levels were tested: 15, 30 and 60 mg/a day in 3 divided doses. Each dosage period lasted at least 5 days, at the end of which patients were reassessed by HAS, Clinical Global Impression and a side-effects checklist. Results suggested a modest anxiolytic activity, without a clear dose-response relationship and with good tolerance. Subsequent treatment by lorazepam (7.5 mg/d) seemed to result in more specific improvement.

Milenperone. A selective drug for the control of behavioral disorders in epileptic and alcoholic patients.

Thirty-four patients took part in an 8-week open investigation aimed at evaluating the efficacy of low oral doses of milenperone as non-sedative neuroleptic drug in the management of aggressive behavior in alcoholics and epileptics. Significant improvements were recorded for respectively 11 and 13 out of 16 evaluable symptoms in alcoholics and epileptics. The symptoms tyrannical and rebellious behavior, aggressive speech and actions, impulsivity, egotism, irritability, use of bad language and bad temper improved in both groups of patients. Out and inpatients, the latter being on milenperone as either adjuvant or monotherapy, responded comparably well. No important side-effects were reported.

[Development of new antipsychotic drugs]. / El desarrollo de nuevas drogas antipsicóticas.

As far as schizophrenia is concerned, therapeutical effects of neuroleptics based on brain-located dopamine receptor blockers are taken for granted. It is also admitted, however, that classical neuroleptics have inconveniences, namely: Their relative lack of effect on negative symptoms, and their liability to induce extrapyramidal symptoms (EPS). Pipamperone-based clinical studies evidenced that an antagonist combining serotonin 5-HT2, and dopamine D2 was successful in the treatment of schizophrenia--which could be clearly observed in (a) anti-autistic effects, (b) regulating disrupted sleep-wake rhythms, and (c) a lesser tendency to EPS. Setoperone-based studies--a compound with a comparable pharmacological profile--confirmed the above observations. Until, however, the synthesis of ritanserin--a specific, and selective antagonistic receptor--was not achieved, no exact implication of 5-HT2 antagonist in psychopharmacological treatments of schizophrenia could be explored further. Indeed, double-blind trials evidenced a remarkable improvement in negative as well as extrapyramidal symptoms. Since a monotherapy appeared as undeniably called for in the treatment of schizophrenia, the next logical step to be taken was selecting a compound with a central antagonism comparable to ritanserin's, and a central D2 antagonism comparable to haloperidol's. Among a chemical range of benzisoxazole derivatives, risperidone was thus selected. The first double-blind trials on chronic schizophrenic patients seem indeed to confirm that this substance is likely to get over the above mentioned inconveniences, so typical of classical neuroleptics.

12-month study of haloperidol decanoate in chronic schizophrenic patients.

239 psychotic patients entered a 52-week open study comparing the efficacy and safety of intramuscular haloperidol decanoate, injected once every 4 weeks, with that of their previous maintenance therapy. Haloperidol decanoate, given at a medium monthly dose of 100 mg provided a suitable substitute for oral neuroleptic mono- and polytherapy and intramuscular fluphenazine decanoate. Stabilization or slight improvement was observed for all ten symptoms selected from the BPRS. The drug provoked a low incidence of side-effects allowing reduction of antiparkinsonian medication and there were no significant haematological or biochemical changes.

The influence of ritanserin, a serotonin antagonist, in anxiety disorders: a double-blind placebo-controlled study versus lorazepam.

A double-blind study was performed in 83 patients with generalized anxiety disorder comparing daily doses of 5 and 10 mg ritanserin (a selective antagonist of serotonine S2 receptors) versus placebo and 4 mg lorazepam as reference drug. Patients treated with 10 mg ritanserin or 4 mg lorazepam improved significantly better (p less than 0.05) after two weeks than those treated with placebo. On the other hand a daily dose of 5 mg ritanserin appeared to be not superior to placebo. Patients treated with 4 mg lorazepam complained significantly more about sedation and dizziness than patients treated with 10 mg ritanserin (p less than 0.05).

Pharmacokinetics of haloperidol decanoate. A 2-year follow-up.

Plasma haloperidol levels were assayed in 181 chronic schizophrenic inpatients, who were monthly injected intramuscularly with haloperidol decanoate. Steady state levels are reached after the third monthly injection and then remain constant, being associated with a remarkably stable control of the psychotic condition. Between two subsequent injections the haloperidol levels decrease gradually by about half their initial value. The haloperidol plasma levels strongly correlate with the injected doses of the decanoate form. For a single dose of 100 mg haloperidol decanoate monthly the minimal steady state value is about 4 ng/ml.

Pilot clinical investigation of risperidone in the treatment of psychotic patients.

Sixty-one adult psychotic patients were treated for four weeks in an open dose-finding study with the new combined serotonin-dopamine antagonist risperidone (R 64 766). Risperidone had a rapid onset of action; a highly significant decrease in the total score on the Brief Psychiatric Rating Scale (BPRS) was already noticed after the first week of treatment. There was also a significant decrease in score for individual BPRS items related to positive, negative, and affective symptoms. In spite of the withdrawal of antiparkinson medication at selection, a significant decrease in extra-pyramidal symptoms (EPS) was observed, as assessed on the Simpson and Angus Scale. The Clinical Global Impression of therapeutic effect was consistent with the BPRS scores, showing a constant improvement throughout the study. The mean daily dose of risperidone at the end of the study was 3.7 mg. Tolerance was excellent and only mild side-effects were reported. Vital signs, ECG-parameters, and laboratory values remained within normal limits. This study demonstrates that risperidone has great potential as an effective and well-tolerated alternative for the treatment of chronically psychotic patients. It has potent antipsychotic effects, a low EPS-inducing profile, and, at the same time, it improves the negative and affective symptoms of schizophrenia.

El desarrollo de nuevas drogas antipsicoticas / Development of new antipsychotic drugs

Se da por sentado que en la esquizofrenia, los efectos terapéuticos de los neurolépticos se basan en el bloqueo de los receptores de dopamina situados en el cerebro. Sin embargo, también se admite que los neurolépticos "clásicos" presentan algunos incovenientes importantes: su relativa falta de efectos sobre los síntomas negativos y su capacidad de inducción de síntomas extrapoiramidales (SEP). Experiencias clínicas llevadas a cabo con pipamperona mostraron que un antagonista combinado de serotinina 5-HT2 y dopamina D2 presentaba ventajas en el tratamiento de la esquizofrenia. Esto se hizo patente a través de los efectos antiautísticos observados, de la regulación de los ritmos de sueño y de vigilia perturbados y de la baja tendencia a la inducción de SEP. Los estudios realizados con setoperona, compuesto de perfil farmacológico comparable, confirmaron estas observaciones. No se pudo explorar la exacta implicación del antagnista 5-HT2 en los tratamientos psicofarmacológicos de la esquizofrenia hasta no haberse realizado la síntesis del receptor antagonista selectivo y específico: la ritanserina. En efecto las pruebas de doble ciego efectuadas demostraron una majoría sensible de los síntomas negativos y extrapiramidales. Puesto que las ventajas de la monoterapia en el tratamiento de la esquizofrenia son innegables, lo lógico era pasar a la selección de un compuesto con un antagonismo central comparable al de...