Primary enduring negative symptoms in schizophrenia and major depression.

Abstract Primary enduring negative symptoms (PENS) were studied in 26 patients with DSM-III-R schizophrenia and in 94 patients with unipolar major depressive episodes 5 years after the index episode. PENS were assessed with the Schedule for Deficit Syndrome (SDS). Negative symptoms were also assessed with the Scale for Assessment of Negative Symptoms (SANS) and subclassified into primary and secondary according to the SDS. The frequency of PENS did not differ significantly between schizophrenics and non-schizophrenic patients. Enduring negative symptoms (regardless of whether primary or not) were more frequently observed in schizophrenia (65% according to the SDS, and 88% according to the S…

Roxindole, a dopamine autoreceptor agonist, in the treatment of major depression

Roxindole is a potent autoreceptor-“selective” dopamine agonist originally developed for the treatment of schizophrenic syndromes. The drug also inhibits 5-HT uptake and has 5-HT1A agonistic actions. In this open clinical trial 12 in-patients suffering from a major depressive episode (DSM-III-R) were treated with roxindole for 28 days in a fixed dosage of 15 mg per day. A reduction of at least 50% in HAMD-17 total scores was observed in 8 out of 12 patients after 4 weeks (mean HAMD-17 reduction of 56% in all patients), while 4 patients did not respond to roxindole treatment. Half of the patients showed a complete psychopathological remission (HAMD-17 <8). Roxindole's onset of antidepressant…

Carbohydrate-deficient transferrin (CDT) and HDL cholesterol (HDL) are highly correlated in male alcohol dependent patients.

Background: Serum levels of total HDL cholesterol (HDL) are reportedly influenced by recent alcohol intake. We examined the correlation between HDL cholesterol and widely used markers of excessive alcohol intake, such as carbohydrate-deficient transferrin (CDT), γ-glutamyl-transferase (GGT), or mean corpuscular volume of erythrocytes (MCV), of which CDT is thought to be the most specific. Methods: Several serological markers [i.e., CDT, GGT, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), MCV, and HDL] were determined in 100 actively drinking male patients with alcohol dependence (DSM-IV) and in 27 non-alcohol-dependent controls, according to routine procedures. Spearman…

Determination of benperidol and its reduced metabolite in human plasma by high-performance liquid chromatography and electrochemical detection.

An isocratic high-performance liquid chromatographic method with electrochemical detection for the quantification of benperidol and its suggested reduced metabolite TVX Q 5402 in human plasma is described. The method included a two-step solid-phase extraction on reversed-phase and cation-exchange material, followed by separation on a cyanopropyl silica gel column (5 microns; 250 mm x 4.6 mm I.D.). The eluent was 0.15 M acetate buffer (pH 4.7) containing 25% acetonitrile (w/w). Spiperone served as internal standard. The inclusion of the cation-exchange step provided sample purity higher than those achieved with other methods. After extraction of 1 ml of plasma, concentrations as low as 0.5 n…

Dimensionality of depression in acute schizophrenia: a methodological study using the Bech-Rafaelsen Melancholia Scale (BRMES).

Abstract Despite the great clinical importance of depressive symptoms in schizophrenia there is a lack of studies on the assessment and evaluation of depression in acutely psychotic patients. For the Bech-Rafaelsen Melancholia Scale (BRMES), among other advantages, the concept of unidimensionality was confirmed in patients with major depression by different methodological approaches including Rasch analysis. The present evaluation was designed to investigate the scale properties of the BRMES in acutely schizophrenic patients with particular emphasis on the dimensionality of the scale. Three different statistical approaches were used: principal component analysis in combination with computer…

Blood ethanol levels and adenylyl cyclase activity in lymphocytes of alcoholic patients

Abstract Background: The adenylyl cyclase (AC) signal transduction pathway is a target of acute and chronic ethanol actions. This study examined whether AC activity in lymphocyte membranes of male alcoholic patients correlated with blood concentrations of ethanol. Methods: Patients ( n = 13; mean age: 40 ± 8 years) were studied on the day of admission (day 0) and 2 days later under detoxification. Moreover, 13 age-matched male healthy controls (mean age 40 ± 9 years) were included. Lymphocyte membranes were prepared by differential centrifugation whereby blood ethanol was washed out. As a measure of AC activity the formation of cyclic adenosine monophosphate (cAMP) from adenosine triphospha…

Seroquel (ICI 204 636), a putative "atypical" antipsychotic, in schizophrenia with positive symptomatology: results of an open clinical trial and changes of neuroendocrinological and EEG parameters.

Preclinical data indicated that seroquel (ICI 204 636), a dibenzothiazepine with 5-HT2 and D2-like receptor antagonistic properties, might be an effective antipsychotic agent, causing fewer extrapyramidal side effects than typical neuroleptics. In the present study, 12 patients suffering from schizophrenia or schizophreniform disorder with predominantly positive symptomatology were treated in an open clinical trial for 4 weeks with seroquel at a maximum dosage of 750 mg/day. The drug was generally well tolerated, and virtually no adverse extrapyramidal side effects such as acute dystonia, parkinsonism or akathisia were observed. Total scores for BPRS (item score 0–6; baseline: 42.0±2.3; mea…

Effects of subchronic paroxetine administration on night-time endocrinological profiles in healthy male volunteers

Abstract To evaluate the subchronic effects of paroxetine, a selective serotonin reuptake inhibitor, on nocturnal endocrinological profiles, eight healthy male volunteers with no personal or family history of a psychiatric or neurological disease were administered paroxetine (30 mg/day) or placebo in a double-blind cross-over design. Drugs were given as a single dose at 10:00 h for a period of 4 weeks each. Between days 21 and 28 of each treatment period, sleep EEG was registered for four consecutive nights from 23:00 to 07:00 h. During the last night, hormonal profiles for prolactin, growth hormone (GH), cortisol, corticotropin (ACTH), luteinizing hormone (LH), testosterone and melatonin w…

Genetic polymorphisms of the dopamine D2 and D3 receptor and neuroleptic drug effects in schizophrenic patients

SEQUENTIALLY ADJUSTED RANDOMIZATION TO FORCE BALANCE IN CONTROLLED TRIALS WITH UNKNOWN PREVALENCE OF COVARIATES: APPLICATION TO ALCOHOLISM RESEARCH

In treatment outcome studies with small to medium sample sizes (n200), the balance of groups with regard to important factors, which sometimes occur at low prevalence, is indispensable for adequate interpretation. This study tested a method for use in clinical alcoholism research, an uncomplicated procedure for satisfactory randomization of patients to different treatments, taking into account relevant background variables.An easily applicable modification of Efron's biased coin method for the randomization of treatments within strata of unknown but low prevalence was compared with the original approach and alternative methods by computer simulation (10,000 runs). An application example for…

Dose-Related Effects of Amisulpride on Five Dimensions of Psychopathology in Patients With Acute Exacerbation of Schizophrenia

The present analysis investigated symptom-specific dose-response relationships of the atypical antipsychotic amisulpride (AMI) in schizophrenic patients. The effects of different AMI doses on five different symptom dimensions of the Brief Psychiatric Rating Scale (BPRS) were analyzed. Results on global efficacy and safety parameters have been previously published. Four AMI doses (100 mg/day [AMI100], 400 mg/day [AMI400], 800 mg/day [AMI800], 1200 mg/day) were compared with 16 mg haloperidol (HAL16) in a multicenter, double-blind, randomized, parallel-group, 4-week trial. A total of 319 patients with acute exacerbation of schizophrenia (DSM-III-R) were included. AMI100 was compared with the …

Savoxepine: invalidation of an "atypical" neuroleptic response pattern predicted by animal models in an open clinical trial with schizophrenic patients.

The new tetracyclic compound savoxepine exhibits potent antidopaminergic effects with preferential activity in the hippocampus as compared to striatum in rat brain. As a result of behavioural animal models and regional differences in dopamine receptor binding characteristics, it has been suggested to possess an "atypical" neuroleptic response pattern. In an open clinical trial, savoxepine was administered to 12 in-patients suffering from paranoid schizophrenia and schizophreniform disorder (DSM-III). Eight patients were treated with a stable dose of 0.5 mg per day throughout the study, while in the remaining patients higher doses up to 20 mg/day were administered. Mean total BPRS scores and…

Combination treatment with clozapine and paroxetine in schizophrenia: safety and tolerability data from a prospective open clinical trial.

Clozapine is a drug with many side effects, some of them with potentially hazardous outcome (e.g. seizures, agranulocytosis), if not carefully monitored. It has been shown that the metabolism of clozapine may be affected by concomitant treatment with selective serotonin reuptake inhibitors (SSRIs), while there have been reports of improved efficacy on negative symptomatology of clozapine in combination with SSRIs. Therefore, this prospective open clinical trial was performed to investigate the safety and tolerability of the coadministration of clozapine and paroxetine under control of serum concentrations of clozapine and its metabolites and the effect of this combination treatment on psych…

Zotepin versus Perazin bei Patienten mit paranoider Schizophrenie: eine doppelblind-kontrollierte Wirksamkeitsprüfung

The dibenzothiepine zotepine is a new potential "atypical" neuroleptic exhibiting powerful antiserotonergic and antidopaminergic properties. The efficacy of zotepine was evaluated in a double-blind controlled trial versus the tricyclic neuroleptic perazine in 41 patients suffering mainly from the paranoid-hallucinatory type of schizophrenia. The key outcome variable was the extent of mental disturbance as defined by the total score of the BPRS. Additional outcome variables were GAS and CGI. In addition, adverse reactions and extrapyramidal side effects were assessed according to the FSUCL scale and the Gerlach and AIMS rating scale, respectively. Additional variables recorded were blood pre…

Dose escalation vs. continued doses of paroxetine and maprotiline: a prospective study in depressed out-patients with inadequate treatment response

In view of the fact that controlled prospective studies on the benefits of dose escalation of the selective serotonin re-uptake inhibitor (SSRI) paroxetine are lacking, we conducted a double-blind, randomized, parallel-group multicentre study designed to compare the possible benefits of dose escalation of paroxetine and maprotiline in patients suffering from major or minor depression according to modified Research Diagnostic Criteria (RDC) with inadequate treatment response. The study sample consisted of 544 out-patients with different degrees of severity of depression. Patients received either 20 mg paroxetine (n = 271) or 100 mg maprotiline (n = 273) for the first 3 weeks in a double-blin…

A randomized, double-blind comparison of a rapidly escalating dose of venlafaxine and imipramine in inpatients with major depression and melancholia.

A double-blind, randomized, parallel study in 167 hospitalized patients with major depression and melancholia was conducted to determine if rapidly escalated doses of venlafaxine produced an earlier response, compared with rapidly escalated doses of imipramine. The daily dose of venlafaxine was rapidly increased to 375 mg/day over a five-day period, was maintained at this level for 10 days, and then was reduced to 150 mg/day for the remainder of the study. The imipramine dose was rapidly increased to 200 mg/day over five days and was maintained at this level to the end of the study. The primary efficacy variables were time to response and time to sustained response on the HAM-D and MADRS. N…

Pharmacokinetic Interactions of Clozapine With Selective Serotonin Reuptake Inhibitors

Pharmacokinetic interactions of clozapine and its metabolites N-desmethylclozapine and clozapine N-oxide with the selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and paroxetine were investigated in a prospective study in schizophrenic patients under steady-state conditions. Thirty patients were treated with clozapine at a target dose of 2.5 to 3.0 mg/kg of body weight. After gradual dose escalation, serum concentrations of clozapine and two metabolites were determined twice at 7-day intervals after steady-state conditions had been reached. Then, fluvoxamine (50 mg/day) or paroxetine (20 mg/day) was added in 16 and 14 patients, respectively. Serum concentrations of clozapine and …

Adenylyl cyclase activity is increased in younger, but decreased in older, alcoholic patients after detoxification.

Acute and chronic administration of ethanol leads to alterations of the adenylyl cyclase (AC) signal transduction pathway. This study examined whether the formation of cAMP by AC in lymphocytes correlates with age in alcoholic patients and in healthy controls. Blood was drawn for preparation of lymphocyte membranes and for determination of basal, GTPgammaS-stimulated, and forskolin-stimulated AC activity from 68 actively drinking alcoholic patients (age, mean +/- SD: 45 +/- 10; range: 26-69 years) after ethanol detoxification. The patients' AC activity correlated negatively with age. In contrast, no effect of age was observed in the healthy controls (age, mean +/- SD: 42 +/- 11; range: 24-6…

Roxindole, a dopamine autoreceptor agonist, in the treatment of positive and negative schizophrenic symptoms

Twenty schizophrenic inpatients with either predominantly positive or predominantly negative symptoms were treated with the dopamine autoreceptor agonist roxindole in prospective open clinical trials. There was no antipsychotic effect in the subgroup with positive symptoms, whereas the subgroup with negative symptoms, especially those with the residual type of schizophrenia, showed a moderate but significant 20% reduction in total scores on the Scale for the Assessment of Negative Symptoms.

Improvement of inter-rater reliability of PANSS items and subscales by a standardized rater training.

The present evaluation focused on the inter-rater reliability of single items and subscales of the Positive and Negative Syndrome Scale (PANSS) before and after a standardized rater training. The results of two independent studies comprising n=23 (study I) and n=12 (study II) psychiatrists and videotaped interviews with schizophrenic patients were analysed. Chance-corrected coefficients of rating agreement with expert standards (weighted kappa) were computed for single items and subscales of the PANSS. The results clearly demonstrate the importance of rater trainings. After three training sessions, 90% of the PANSS items reached an acceptable level of reliability (kappa(w)>0.40) in both eva…

Evaluation eines standardisierten Trainings für die "Positive and Negative Syndrome Scale" (PANSS)

Die vorliegende Arbeit umfasst 3 Untersuchungen zur Interrater-Reliabilitat der deutschen Version der “Positive and Negative Syndrome Scale for Schizophrenia” (PANSS). Zur Interrater-Reliabilitat und Trainierbarkeit der PANSS liegen im deutschen Sprachraum trotz der weiten Verbreitung der Skala bisher keine empirischen Daten vor. Bei 3 Stichproben mit insgesamt 47 Teilnehmern unterschiedlicher klinischer Erfahrung wurde ein standardisiertes PANSS-Rater-Training durchgefuhrt und evaluiert. Als Qualitatsmase fur das Training wurden die Ubereinstimmung mit einem Expertenstandard (K) und gewichtete Kappa-Koeffizienten (κw) berechnet. Als ein Hauptergebnis lasst sich feststellen, dass zur Erreic…

Antipsychotic effects and tolerability of the sigma ligand EMD 57445 (panamesine) and its metabolites in acute schizophrenia: an open clinical trial.

Antipsychotic efficacy and side effects of the selective sigma ligand EMD 57445 (panamesine) were investigated in 12 patients (6 males, 6 females) who met DSM-III-R criteria for schizophrenia. A 4-week open clinical study revealed only modest effects of EMD 57445 and its metabolites on positive and negative symptoms of schizophrenia. Extrapyramidal and other side effects were moderate, although a significant increase in mild dyskinetic movements was found. Five patients, four of whom were females, completed the trial. Dropouts were mainly due to treatment failure. Antipsychotic effects were significantly greater in female than male patients.

Serum Concentrations of Fluvoxamine and Clinical Effects: A prospective open clinical trial

This pilot study examined prospectively blood serum concentrations of fluvoxamine, side effects and therapeutic response after a fixed dosage of 100 mg fluvoxamine/day for 14 days. Twenty male and female patients who met the DSM-IV criteria of a major depression received 50 mg fluvoxamine b.i.d. for two weeks. On days 7 and 14 side effects and therapeutic response were registered and serum concentrations of fluvoxamine were determined. A Receiver Operating Characteristic (ROC) curve was constructed to determine a possible relationship between serum concentrations and clinical effects. The serum concentrations of fluvoxamine were highly variable, even when dosages were corrected for body wei…

Evaluation of standardized rater training for the Positive and Negative Syndrome Scale (PANSS)

The Positive and Negative Syndrome Scale (PANSS) is employed increasingly for the evaluation of therapeutic outcome in studies on schizophrenia. Rater training is important to improve the concordance and accuracy of ratings; however, there are no established guidelines for carrying out such training. We conducted rater training, under clinical conditions, of psychiatrists and clinical psychologists who were rather unfamiliar with the PANSS. Based on videotapes of PANSS interviews, all participants were trained during five successive standardized weekly sessions. The results were analyzed with respect to conventional criteria of concordance with standard expert ratings and interrater reliabi…

Reliability and validity of the German version of the European Addiction Severity Index (EuropASI).

This study provides data on the psychometric characteristics of the German version of the European Addiction Severity Index (EuropASI). The ASI is a frequently used clinical and research instrument that measures problem severity among people with substance dependence.The German ASI was used in a sample of 112 consecutively admitted male psychiatric inpatients seeking treatment for severe alcohol problems. The conceptual structure of the German ASI subscales was investigated by analyzing the intercorrelations of the severity ratings and composite scores. Internal consistency, interrater reliability and concurrent validity in terms of correlations with other assessment instruments were evalua…

Three dimensions of depression in patients with acute psychotic disorders: A replication study

Depressive symptoms in psychotic disorders are of high relevance but seem to be heterogeneous when assessed with a standard rating scale. The present analysis is a replication study on the dimensionality of the Bech-Rafaelsen Melancholia Scale (BRMES) in acutely psychotic patients with substantial depression defined according to a functional approach across the nosological borders of schizophrenia with major affective symptoms, schizoaffective disorder, depressed subtype, and major depression with psychotic features. The baseline data of 123 patients participating in a multicenter pharmacological trial were evaluated with structural equation models. A previously reported three-dimensional m…

Psychopharmakotherapie in Schwangerschaft und Stillzeit

The primary purpose of this article is to review critically the literature on the use of psychotropic medications in pregnancy and during breast feeding in order to suggest strategies for the clinical management of these periods. Use of psychotropic medications during pregnancy may cause three complications: 1. teratogenicity, 2. perinatal syndromes (neonatal toxicity), and 3. postnatal behavioural sequelae (behavioural toxicity). The literature features few well-controlled studies concerning these points, so that the available information allows only few conclusions. Exposure to certain psychotropic drugs in utero may increase the risk for some specific congenital anomalies; there is mostl…

The neuroendocrinological profile of roxindole, a dopamine autoreceptor agonist, in schizophrenic patients

Roxindole is a potent autoreceptor-selective dopamine agonist with additional properties as a serotonin reuptake inhibitor and 5-HT1A agonist. In order to get more insight into its mode of action in various psychiatric populations, we evaluated the effects of subchronic roxindole treatment on pituitary and adrenal hormone secretion, i.e. release of prolactin, thyroid stimulating hormone (TSH), growth hormone (GH), luteinizing hormone (LH), and cortisol. Fifteen schizophrenic patients with positive and negative symptomatology, respectively, were treated with roxindole for 28 days. Both basal and thyrotropin releasing hormone (TRH) -induced prolactin secretion diminished significantly to 26.4…

Acute, subchronic and discontinuation effects of zopiclone on sleep EEG and nocturnal melatonin secretion

Zopiclone is a new short half-life cyclopyrrolone hypnotic agent acting at the GABA-benzodiazepine receptor complex. In order to characterize its pharmacological profile, the effects of 7.5 mg zopiclone on nocturnal melatonin secretion were investigated under polysomnographic control in 11 healthy subjects following acute and subchronic administration as well as after abrupt discontinuation of the drug. No effect of zopiclone on the melatonin plasma levels could be observed. Regarding both total melatonin production and the temporal pattern of melatonin secretion during the night, there was no difference between placebo baseline condition, acute and subchronic administration, and discontinu…

Dopamine Autoreceptor Agonists in the Treatment of Schizophrenia and Major Depression*

Dopamine autoreceptor agonists reduce the firing rate, synthesis, and release of dopamine in dopaminergic neurons by means of a negative feedback mechanism via stimulation of autoreceptors. Moreover, dopamine autoreceptor agonists are able to stimulate supersensitive but not normosensitive postsynaptic receptors. For dopamine autoreceptor agonists, therapeutic effects by readjustment of excessive or deficient dopaminergic function have been postulated for positive and negative schizophrenic symptomatology as well as for subtypes of depressive disorders. Investigations on the therapeutic effects of autoreceptor-nonselective dopamine agonists in schizophrenia or depression have yielded incons…

Subchronic Effects of Olanzapine on Sleep EEG in Schizophrenic Patients with Predominantly Negative Symptoms

Background It is well known that sleep disturbance is an integral symptom of schizophrenia. In recent studies, a deficit of delta sleep has been observed in schizophrenic patients. Antipsychotic drugs with serotonin (5-HT2) receptor-antagonistic properties are considered to have delta sleep promoting effects. We have investigated the effects of subchronic olanzapine treatment on sleep EEG in schizophrenic patients. Methods The effects of administration of olanzapine (15 to 20 mg) on sleep were studied for four weeks in 10 male, drug-free patients suffering from schizophrenia with predominantly negative symptoms. Conventional sleep EEG parameters were investigated at baseline and after treat…

Dopamine autoreceptor agonists in the treatment of schizophrenic disorders

Abstract 1. Synthesis and release of dopamine as well as firing rates of dopaminergic neurons are controlled by stimulation of autoreceptors via a negative feedback regulation, investigations on therapeutic effects of autoreceptor-nonselective dopamine agonists in schizophrenia have yielded inconsistent results. 2. With respect to the dopamine hypothesis of schizophrenia, dopamine autoreceptor agonists have been tested in positive schizophrenic symptomatology in order to reduce the postulated excess of central dopaminergic activity. However, administration of selective dopamine autoreceptor agonists like talipexole or roxindole did not result in a significant improvement of psychopathologic…

Automated Determination of Fluvoxamine in Plasma by Column-Switching High-Performance Liquid Chromatography

Abstract A column-switching system with high-performance liquid-chromatographic separation and ultraviolet detection is described for automated determination of fluvoxamine in human plasma or serum. Samples were injected and the drug was retained in a clean-up column [20 x 4.6 mm (i.d.)] filled with C8 reversed-phase material (10-micron particles). After unwanted material was washed out, the drug was eluted and separated with an analytical chromatography column, 4.6 x 250 mm (i.d.), filled with Nucleosil 100 CN (5-micron particles) with an acetonitrile:methanol:0.01 mol/L phosphate buffer eluent (188:578:235 by vol) at a flow rate of 1.5 mL/min for &amp;lt; 20 min and detected by spectromet…

Is There an Advantage to Venlafaxine in Comparison with Other Antidepressants?

The purpose of this article is to compare and contrast the benefits and limitations of antidepressant drugs. Several different classes of antidepressants are available for treatment of major depressive disorder, each with its own benefits and limitations as a result of its pharmacological profile. Tricyclic antidepressants (TCAs) and monoamine oxidase (MAO) inhibitors are effective in a large proportion of depressed patients, but their use is often limited by short- and long-term safety/tolerability problems. Selective serotonin reuptake inhibitors (SSRIs) exhibit comparable efficacy to TCAs in most patients, but may be less effective in certain patients. Additionally, SSRI use may by impac…

Amisulpride versus flupentixol in schizophrenia with predominantly positive symptomatology - a double-blind controlled study comparing a selective D 2 -like antagonist to a mixed D 1 -/D 2 -like antagonist

The benzamide amisulpride (ASP) is a selective D2-like dopamine antagonist, while flupentixol (FPX), a thioxanthene, blocks D2-like, D1-like and 5-HT2 receptors. To evaluate efficacy and safety of ASP and to investigate the importance of an additional D1-like antagonism for antipsychotic effects and extrapyramidal tolerability, a randomized double-blind multi-center study versus FPX as reference drug was performed for 6 weeks in 132 patients suffering from acute schizophrenia (DSM-III-R) with predominant positive symptomatology. Doses were initially fixed (ASP: 1000 mg/day; FPX: 25 mg/day) but could be reduced by 40% in case of side effects (mean daily doses: ASP: 956 mg; FPX: 22.6 mg). Int…

Inhibition of antidepressant demethylation and hydroxylation by fluvoxamine in depressed patients.

Bidirectional drug interactions between fluvoxamine and classical antidepressants were studied in depressed patients. A column switching technique combined with high performance liquid chromatography (HPLC) enabled automated analyses of plasma for simultaneous determination of fluvoxamine, tricyclic and tetracyclic antidepressants and demethylated and major hydroxylated metabolites in a single HPLC run. The measurements revealed that fluvoxamine inhibited N-demethylation of imipramine, clomipramine, amitriptyline and maprotiline whereas interferences with hydroxylation reactions were restricted to aromatic 8-hydroxylation of clomipramine. In patients under fluvoxamine monotherapy before com…

Dopamine agonists in schizophrenia: a review.

Although it is unlikely that the different types of course and severity of schizophrenia are caused by one neurochemical abnormality alone, indirect pharmacological evidence still suggests a relative excess of dopaminergic activity being implicated in the pathogenesis of most of the schizophrenic symptoms, e.g. positive symptomatology. Synthesis and release of dopamine as well as firing rates of dopaminergic neurons are controlled by stimulation of autoreceptors via a negative feedback regulation. Investigations on therapeutic effects of autoreceptor-nonselective dopamine agonists in schizophrenia have yielded inconsistent results. Dopamine autoreceptor agonists like pramipexole, roxindole,…

Combination treatment with nefazodone and cognitive-behavioral therapy for relapse prevention in alcohol-dependent men: a randomized controlled study.

Background This study evaluated the serotonergic antidepressant nefazodone versus placebo and specific cognitive-behavioral therapy (CBT) versus nondirective group counseling (GC) for relapse prevention in alcohol dependence in a large prospective, randomized, and placebo-controlled double-blind study at 3 German university centers. Method 242 male patients fulfilling at least 5 criteria for alcohol dependence according to DSM-IV and ICD-10 were eligible, after detoxification, for one of the following treatment combinations: nefazodone + CBT, nefazodone + GC, placebo + CBT, and placebo + GC. Either nefazodone or placebo was administered throughout the evaluation period of 15 months. Either …

Neuroendocrine response to antipsychotics: effects of drug type and gender

Abstract Background: To study the influences of drug type and gender on the neuroendocrine response to neuroleptic treatment, we compared the endocrine actions of two neuroleptics with different receptor affinity profiles—a substituted benzamide, amisulpride, a selective D 2 -like dopamine antagonist; and a thioxanthene, flupenthixol, a mixed D 1 /D 2 -like antagonist also blocking serotonin, H 1 , and D 1 receptors—on anterior pituitary hormone secretion in schizophrenic patients (DSM-III-R). Methods: Blood was withdrawn at 15-min intervals to assess basal secretion of prolactin, growth hormone (GH), and thyroid-stimulating hormone (TSH). Four hundred micrograms of thyrotropin-releasing ho…

Risperidone in the Treatment of Disorders with a combined Psychotic and Depressive Syndrome - A Functional Approach

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 syndr…

Pharmacokinetics and bioavailability of benperidol in schizophrenic patients after intravenous and two different kinds of oral application

Pharmacokinetics and bioavailability of benperidol were determined in 13 schizophrenic patients after acute administration of 6 mg benperidol as an intravenous (i.v.) bolus injection, orally as liquid, and orally as tablets using a partially randomized cross-over design. Drug plasma levels were determined by high performance liquid chromatography with electrochemical detection and subjected to model independent pharmacokinetic analyses. After i.v. dosing the geometric means (mean-g) were 3.2 min for the distribution half-life, 5.80 h for the elimination half-life (t1/2 beta), 4.21 l/kg for the distribution volume, 7.50 h for the mean residence time (MRT), and 0.50 l/(h*kg) for the clearance…

Medikamente zur Behandlung von Persönlichkeitsstörungen

Die Therapie von Personlichkeitsstorungen war lange Zeit ausschlieslich eine Domane psychotherapeutischer Interventionen. Mittlerweile existieren einige kontrollierte Studien auch zum Einsatz von Psychopharmaka bei Personlichkeitsstorungen Die Ergebnisse sind aber fur allgemeine Empfehlungen noch zu wenig abgesichert. Die Diagnose von Personlichkeitsstorungen (z. B. Achse-Il-Storungen nach DSM-IV) ist fehleranfallig. Die diagnostischen Kategorien sind uneinheitlich und derzeit noch im Flus; selbst strukturierte Interviews erfahrener Untersucher zeigen nur begrenzte Verlaslichkeit. Wichtig ist die Erfassung und — wenn moglich — Abgrenzung von gleichzeitig vorhandenen Achse-I-Storungen nach D…

IBZM-SPECT bei Neuroleptikatherapie

Mit IBZM — einem mit Jod-123 markierten Benzamid — ist es erstmalig moglich, die Dopamin-D2-Rezeptoren mit der Single-Photonen-Emissions-Computertomographie (SPECT) darzustellen. Das trotz der fehlenden ab-soluten Quantifizierung mit SPECT diese Methode hilfreich sein kann fur die Messung der D2-Rezeptoren, wurde schon von der Arbeitsgruppe von Brucke [1] dargestellt. Gegenstand unserer eigenen Studien war die Untersuchung der D2-Rezeptorbesetzung (RB) unter Haloperidol, Benperidol und Clozapin im Zusammenhang mit klinischen Daten und Prolaktinspiegeln.

Negative symptomatology: psychopharmacological strategies and methodological aspects for drug evaluation

The Calgary Depression Rating Scale for Schizophrenia: development and interrater reliability of a German version (CDSS-G)

A German version of the Calgary Depression Rating Scale for Schizophrenia (CDSS-G) approved by the author of the original scale is presented comprising a semi-structured interview for 9 items to sensitively and specifically assess depression in schizophrenia and related disorders. The process of translation is outlined and the finally derived CDSS-G was investigated with respect to interrater reliability in three studies. To keep comparability with the CDSS source version a standard procedure was used. Two trained raters jointly assessed ten schizophrenic patients (study I). In a second study, videotapes with the CDSS-G were presented to clinically inexperienced raters (study II, N = 14/15)…

Medikamente zur Phasenprophylaxe affektiver Psychosen und zur Behandlung manischer Syndrome

Folgende Substanzgruppen sind in der Therapie manischer Syndrome und/oder in der Phasenprophylaxe affektiver Storungen etabliert (Im folgenden werden die Begriffe affektive bzw. schizoaffektive „Storung“ bzw. „Psychose“ weitgehend synonym verwendet.)

No Association Between the Dopamine D2 Receptor Taq I A1 Allele and Earlier Age of Onset of Alcohol Dependence According to Different Specified Criteria

BACKGROUND: The presence of the A1 allele of the dopamine D2 receptor TaqI restriction fragment length polymorphism has been reported to be associated with an earlier age of onset of alcohol dependence as a marker for severity. METHODS: We tested this hypothesis with special regard to the definition of the age of onset of alcoholism in 243 patients with alcohol dependence, according to DSM-IV criteria assessed by the standardized interview Munchner Composite International Diagnostic Interview (M-CIDI), consecutively admitted for detoxification. Additionally, the Addiction Severity Index (ASI) was performed. The TaqIA polymorphism was amplified by polymerase chain reaction (PCR), and the PCR…

Symptom-Triggered versus Standard Chlormethiazole Treatment of Inpatient Alcohol Withdrawal: Clinical Implications from a Chart Analysis

To evaluate clinical effectiveness and safety of 2 different detoxification treatment protocols, a chart analysis of hospital inpatients consecutively admitted for alcohol withdrawal during one year was undertaken. Records of 33 patients receiving symptom-triggered treatment (using a modified version of the revised Clinical Institute Withdrawal Assessment for Alcohol Scale) were compared with those of patients treated by applying a fixed-dose regimen (n = 32). Patients (45.3 ± 9.8 years, 21% female) of both groups were comparable regarding illness severity, epidemiologic parameters as well as complications during the observed treatment period. Under symptom-triggered therapy, chlormethiazol…

Moderate and severe depression

Background: Despite its importance, no distinction between moderate and severe depression using the Montgomery–Asberg Depression Rating Scale (MADRS) based on a direct comparison with the Hamilton Depression Rating Scale (HAMD-17) is available. Methods: HAMD-17 and MADRS ratings from N=40 at least moderately depressed inpatients with major depression (DSM-III-R) were analyzed. Linear and non-parametric correlations were computed and a MADRS cut-off score for severe depression using an HAMD-17 score of at least 28 points as reference was estimated. Results: HAMD-17 and MADRS mean scores were 24.6±4.3 and 32.6±5.0 points, respectively. Linear correlation of both scores was r=0.70 (P<0.0005). …

Response to treatment in minor and major depression: results of a double-blind comparative study with paroxetine and maprotiline.

Several concepts of minor depression in the sense of acute but less severe symptomatology than major depression have been proposed in the literature, but currently none of them is generally accepted. For the treatment of these conditions, only few recommendations based on empirical data are available. We conducted a randomized double-blind multicentre study in depressed outpatients comparing paroxetine and maprotiline in both patients with minor (n = 245) and major depression (n = 298). For the diagnosis, Research Diagnostic Criteria were used in a modified version. Two response criteria were applied: a reduction of 50% or more in total HAMD-17 scores from baseline (criterion 1), and a redu…

Occupancy of striatal D 2 -like dopamine receptors after treatment with the sigma ligand EMD 57445, a putative atypical antipsychotic

Rationale: EMD 57445 (panamesine) is a high affinity sigma ligand with the profile of an atypical antipsychotic in animal studies. It has been reported recently to have antipsychotic activity in schizophrenia. However, its metabolite, EMD 59983, binds also to D2 and D3 dopamine (DA) receptors. Objectives: The aim of this study was to test, using single photon emission computed tomography (SPECT) and [123I]iodobenzamide (IBZM) as the radiotracer, whether EMD 59983 would pass the blood-brain barrier and to what extent it would contribute to the effects of EMD 57445 in schizophrenia. Methods: Two IBZM SPECT-scans were performed in five neuroleptic-free schizophrenic patients (DSM IV), one befo…

Addition of Low-Dose Fluvoxamine to Low-Dose Clozapine Monotherapy in Schizophrenia: Drug Monitoring and Tolerability Data from a Prospective Clinical Trial

Combining fluvoxamine and clozapine may be a strategy to improve therapeutic effects on negative symptoms in schizophrenic patients. Fluvoxamine, however, markedly inhibits the metabolism of clozapine, and hazardous side effects may result. This study prospectively investigated the safety and tolerability of an add-on therapy with fluvoxamine to a clozapine monotherapy in schizophrenic patients. Sixteen schizophrenic patients received 50 mg fluvoxamine as a comedication after having reached steady-state conditions under clozapine monotherapy. Patients were monitored for subjective adverse events, laboratory parameters, EEG and ECG recordings, orthostatic hypotension and their psychopatholog…

Cue exposure in alcohol dependent patients: preliminary evidence for different types of cue reactivity.

Craving is considered to be an important phenomenon in addictive behaviours. However, there is still an unresolved debate on what craving for alcohol means, how it is best measured and which clinical and therapeutical consequences its presence or absence may imply. Cue reactivity paradigms have been developed to elicit craving under standardized experimental conditions. Here we present preliminary results characterizing alcohol-dependent patients with regard to subjective and psychophysiological aspects of exposure to alcohol-associated cues in a cue reactivity paradigm. Thirty-six patients fulfilling at least 5 criteria of alcohol dependence according to DSM-IV criteria were studied after …

Risperidone Versus Haloperidol and Amitriptyline in the Treatment of Patients With a Combined Psychotic and Depressive Syndrome

In a multicenter, double-blind, parallel group trial, the efficacy of risperidone (RIS) was compared with a combination of haloperidol and amitriptyline (HAL/AMI) over 6 weeks in patients with coexisting psychotic and depressive symptoms with either a schizoaffective disorder, depressive type, a major depression with psychotic features, or a nonresidual schizophrenia with major depressive symptoms according to DSM-III-R criteria. A total of 123 patients (62 RIS; 61 HAL/AMI) were included; the mean daily dosage at endpoint was 6.9 mg RIS versus 9 mg HAL combined with 180 mg AMI. Efficacy results for those 98 patients (47 RIS; 51 HAL/AMI) who completed at least 3 weeks of double-blind treatme…

Subchronic Antidepressant Treatment with Venlafaxine or Imipramine and Effects on Blood Pressure and Heart Rate: Assessment by Automatic 24-Hour Monitoring

Venlafaxine is a new nontricyclic antidepressant inhibiting the reuptake of serotonin, noradrenaline, and, to a lesser extent, dopamine without antagonizing cholinergic, histaminergic, or noradrenergic receptors. Significantly, in a first placebo-controlled safety and efficacy study, high doses of venlafaxine increased blood pressure in some study subjects. In order to investigate further the effect of subchronic antidepressant drug treatment on blood pressure and heart rate, the effects of a conventional tricyclic (imipramine) and a structurally different phenethylamine antidepressant (venlafaxine) were compared. Sixteen inpatients with major depression (melancholic type) were treated for …

Activity of the adenylyl cyclase in lymphocytes of male alcoholic patients is state dependent.

A decreased basal and/or stimulated activity of the G-protein/adenylyl cyclase (AC) system in peripheral blood cells has been proposed to represent a trait marker for alcoholism. However, AC activity may underlie state-dependent changes, which may impair a proper interpretation of AC activity measurements. Our study examined systematically the AC activity in peripheral lymphocytes of 73 male alcohol-dependent patients (according to DSM-IV criteria) at three different time points of measurement during the clinical course of detoxification (day 0 = at admission, while still ethanol-affected; day 2 = at the presumed peak of withdrawal symptoms; day E = after detoxification). Basal and stimulat…

Andere Pharmaka für psychiatrische Indikationen

Drei z. Z. noch nicht klassifizierte Pharmaka, die in der psychiatrischen Pharmakotherapie eine wichtige Bedeutung haben, sollen hier ausfuhrlich beschrieben werden: Clomethiazol (Distraneurin) Cyproteronazetat (Androcur) Disulfifram (Antabus)

Plasma levels of benperidol, prolactin, and homovanillic acid after intravenous versus two different kinds of oral application of the neuroleptic in schizophrenic patients

Plasma levels of prolactin (PRL) and the butyrophenone neuroleptic benperidol (BPD) were closely followed 0 to 48 h after acute application of 6 mg BPD as intravenous injection, orally as liquid, and orally as tablets in 12 schizophrenic patients using a partially randomized cross over design. Drug concentrations showed application specific pharmacokinetic behavior with complete elimination within 48 h. All three applications led to a biphasic PRL response with pronounced initial plasma PRL peaks returning to baseline levels within 48 h. The results suggest that after acute neuroleptic challenge BPD plasma levels as low as 2-3 ng/ml can be sufficient for complete depletion of pituitary PRL …

Benzodiazepines for catatonic symptoms, stupor, and mutism.

A double-blind study comparing paroxetine and maprotiline in depressed outpatients.

A double-blind multicenter randomized parallel group study comparing paroxetine and maprotiline was carried out in a total of 544 outpatients. Included were patients with varying degrees of severity of depressive symptoms who fulfilled modified RDC criteria for either Minor or Major Depression and showed a HAMD-17 score of > or = 13. No concomitant benzodiazepine treatment was allowed. Duration of treatment was 6 weeks, after an initial wash-out period. Doses were fixed during the first 3 weeks of treatment, patients receiving either 20 mg paroxetine or 100 mg maprotiline daily. An option for dose escalation was provided for insufficient responders after 3 weeks. The weekly assessments comp…