Silexan does not cause withdrawal symptoms even when abruptly discontinued.

OBJECTIVE: Subsequent to a randomised, double-blind, double dummy clinical trial assessing the efficacy of silexan compared to placebo and paroxetine in patients suffering from generalised anxiety disorder (GAD), a 1week follow-up phase was added in order to assess possible withdrawal symptoms of silexan after abrupt discontinuation. METHODS: Participants received silexan 80 mg/d, silexan 160 mg/d, paroxetine 20 mg/d, or placebo at a ratio of 1:1:1:1. Study medication was discontinued after the 10 week active treatment phase of the original trial. Whereas paroxetine was tapered as indicated, silexan administration was discontinued abruptly. Assessment of possible withdrawal effects was done using the Physician Withdrawal Checklist questionnaire (PWC-20). RESULTS: During the 1 week down-titration phase, mean total PWC-20 scores had reduced by 0.19 in placebo, 0.23 in silexan 80, 0.65 in silexan 160, and 0.51 in paroxetine. The median change in all four groups was 0.00. In none of the treatment groups withdrawal effects occurred after discontinuation. CONCLUSIONS: Values assessed for the silexan groups indicate the absence of a dependency potential of this preparation.

Should early improvement be re-defined to better predict the maintenance of response in first-episode schizophrenia patients?

OBJECTIVE: To evaluate the predictive validity of early response in first-episode schizophrenia within a 1-year follow-up trial and to compare the resulting cutoff to the currently proposed early response definition (20% improvement by week 2). METHOD: Receiver operator characteristic (ROC) analyses were used to identify the predictive validity of the psychopathological improvement of treatment from week 1 to week 8, regarding the maintenance of response until week 52 as well as to define the most reasonable cutoff in 132 first-episode patients. The Youden Index (maximum of sensitivity and specificity) was used to compare the newly developed and the commonly used early response definition. RESULTS: Starting with week 6, a reasonable validity to predict the maintenance of response was found (area under the curve = 0.721) with the best fitting cutoff being a 51.6% PANSS total score improvement. Using this cutoff 74 patients (56%) were correctly identified to become responder and maintain response during follow-up (sensitivity: 0.747). The Youden Index was higher applying the newly developed early response cutoff featuring higher specificity compared to the commonly used early response definition. CONCLUSION: Regarding long-term treatment, it seems more appropriate to base predictions of the patient's maintenance of response not before 6 weeks of treatment.

Evaluating depressive symptoms and their impact on outcome in schizophrenia applying the Calgary Depression Scale.

OBJECTIVE: To examine depressive symptoms, their course during treatment, and influence on outcome. METHOD: Weekly Calgary Depression Scale for Schizophrenia ratings were performed in 249 inpatients with schizophrenia. Early response was defined as a 20% reduction in the total score of the Positive and Negative Syndrome Scale for Schizophrenia from admission to week 2, response as a 50% reduction in the total score of the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) from admission to discharge and remission according to the consensus criteria. RESULTS: Thirty six per cent of the patients were depressed at admission, with 23% of them still being depressed at discharge. Depressed patients scored significantly higher on the PANSS negative and general psychopathology subscore, featured more impairments in subjective well-being (P < 0.0001) and functioning (P < 0.0001). They suffered from more suicidality (P = 0.0021), and had greater insight into their illness (P = 0.0105). No significant differences were found regarding early response, response, and remission. CONCLUSION: Patients with depressive symptoms should be monitored closely, given the burden of negative symptoms, their impairments in well-being and functioning and the threat of suicidality.

Outcome of suicidal patients with schizophrenia: results from a naturalistic study.

OBJECTIVE: Purpose was to assess suicidality before and at the time of admission in patients with schizophrenia and compare outcome differences. METHOD: Biweekly PANSS (Positive and Negative Syndrome Scale), HAMD (Hamilton Depression Rating Scale) and UKU (Udvalg for Klinske Undersogelser Side Effect Rating Scale) ratings were evaluated in 339 in-patients with schizophrenic spectrum disorders. Response was defined as an initial 20% PANSS total score reduction at discharge, remission was defined according to the proposed consensus criteria by the Remission in Schizophrenia Working Group. RESULTS: Suicidal patients (22%) scored significantly higher on the PANSS negative subscore, PANSS insight item and HAMD total score at admission and at discharge. They developed significantly more side effects. No differences were found concerning response and remission between the two patient subgroups. CONCLUSION: Despite receiving significantly more antidepressants the suicidal patients suffered from significantly more depressive symptoms up to discharge, yet without differing regarding response and remission.

A critical analysis and discussion of the appropriateness of the schizophrenia consensus remission criteria in clinical pharmaceutical trials.

BACKGROUND: The aim of this paper is to apply the proposed consensus remission criteria to an acutely ill inpatient sample at admission and evaluate their adaptability in this patient population and pharmaceutical trials. METHODS: The Remission in Schizophrenia Working Group's consensus criteria were applied to 272 acutely ill schizophrenia patients. Patients were examined using the PANSS, HAMD, UKU and SWN-K total scales at admission as well as the GAF, SOFAS and the Strauss-Carpenter Prognostic Scale. Sociodemographic and clinical baseline variables were assessed using a standardized documentation system. RESULTS: 33 patients (12%) fulfilled the symptom severity component of the proposed remission criteria already at baseline. Almost no significant differences were found when comparing patients with achieved and failed symptom severity component that would explain the hospitalization of the patients with achieved criteria despite their apparently mild psychopathological symptoms. The only explainable difference was that patients with an achieved symptom severity component had received significantly more antipsychotics and had suffered from significantly more life events before admission. CONCLUSION: The present results raise the question whether the symptom severity threshold is adequate to identify patients in remission when applied in clinical trials.

Levo-alpha-acetylmethadol (LAAM) induced QTc-prolongation - results from a controlled clinical trial.

BACKGROUND: Due to potential proarrhythmic side-effects levo-alpha-Acetylmethadol (LAAM) is currently not available in EU countries as maintenance drug in the treatment of opiate addiction. However, recent studies and meta-analyses underline the clinical advantages of LAAM with respect to the reduction of heroin use. Thus a reappraisal of LAAM has been demanded. The aim of the present study was to evaluate the relative impact of LAAM on QTc-interval, as a measure of pro-arrhythmic risk, in comparison to methadone, the current standard in substitution therapy. METHODS: ECG recordings were analysed within a randomized, controlled clinical trial evaluating the efficacy and tolerability of maintenance treatment with LAAM compared with racemic methadone. Recordings were done at two points: 1) during a run-in period with all patients on methadone and 2) 24 weeks after randomisation into methadone or LAAM treatment group. These ECG recordings were analysed with respect to QTc-values and QTc-dispersion. Mean values as well as individual changes compared to baseline parameters were evaluated. QTc-intervals were classified according to CPMP-guidelines. RESULTS: Complete ECG data sets could be obtained in 53 patients (31 LAAM-group, 22 methadone-group). No clinical cardiac complications were observed in either group. After 24 weeks, patients receiving LAAM showed a significant increase in QTc-interval (0.409s +/- 0.022s versus 0.418s +/- 0.028s, p = 0.046), whereas no significant changes could be observed in patients remaining on methadone. There was no statistically significant change in QTc-dispersion in either group. More patients with borderline prolonged and prolonged QTc-intervals were observed in the LAAM than in the methadone treatment group (n = 7 vs. n = 1; p = 0.1). CONCLUSIONS: In this controlled trial LAAM induced QTc-prolongation in a higher degree than methadone. Given reports of severe arrhythmic events, careful ECG-monitoring is recommended under LAAM medication.

Chronic mu-opioid receptor stimulation in humans decreases muscle sympathetic nerve activity.

BACKGROUND: Opioid-addicted patients undergoing detoxification provide a unique opportunity to assess the effects of chronic opioid receptor stimulation on the sympathetic nervous system. We tested the hypothesis that chronic oral methadone intake decreases resting efferent sympathetic nerve activity to muscle (MSA). Furthermore, we assessed whether this effect is reversed by mu-opioid receptor blockade during antagonist-supported detoxification under general anesthesia. METHODS AND RESULTS: Fifteen young patients (30+/-1 years old, mean+/-SEM) with a long history of mono-opioid addiction and under oral methadone substitution therapy (65+/-10 mg/d for 21+/-6 months) were selected. Peroneal MSA (microneurography) and catecholamine plasma concentrations (high-performance liquid chromatography) were assessed in the awake state and compared with those of age-matched healthy control subjects. The effects of mu-opioid receptor blockade by naloxone (12.4 mg IV) were determined during propofol anesthesia. Compared with healthy volunteers, resting MSA (4+/-2 versus 22+/-2 bursts/min, P<0.0001) and antecubital venous norepinephrine plasma concentration (100+/-64 versus 256+/-48 pg/mL, P=0.01) were markedly decreased in addicted patients despite similar arterial blood pressure and heart rate. Opioid receptor blockade markedly increased MSA (5+/-2 to 24+/-3 bursts/min) and norepinephrine (49+/-12 to 305+/-48 pg/mL) and epinephrine (13+/-2 to 482+/-67 pg/mL) arterial plasma concentrations as well as mean arterial pressure (82+/-4 to 108+/-3 mm Hg) and heart rate (70+/-3 to 86+/-4 beats/min). CONCLUSIONS: Chronic mu-opioid receptor stimulation by methadone decreases resting MSA in humans.

Short-term naloxone administration in schizophrenic and manic patients. A World Health Organization Collaborative Study.

A double-blind study of the behavioral effects of short-term naloxone hydrochloride administration was performed in 32 schizophrenic and 26 manic patients in a World Health Organization collaborative project. There was a significant naloxone-associated reduction in overall physician-rated symptoms in schizophrenic patients concurrently treated with neuroleptic medication (N = 19) but not in medication-free schizophrenics (N = 13). Physician rating of auditory hallucinations showed significant naloxone-associated improvement for the total schizophrenic population, while self-ratings of auditory hallucinations showed improvement only in neuroleptic-treated schizophrenics. While further studies are needed to delineate these effects as to clinical significance, they may bear etiological implications for the psychobiology of schizophrenia, including the possibility of synergistic effects of dopamine and endorphin blockade. Naloxone produced no significant behavioral effects in manic patients. These findings are discussed with relationship to the hypotheses of endorphin involvement in schizophrenia and mania.

Sustained improvement of clinical outcome with risperidone long-acting injectable in psychotic patients previously treated with olanzapine.

The efficacy and tolerability of risperidone long-acting injectable were investigated in patients with schizophrenia or other psychotic disorders who had previously been symptomatically stable on olanzapine treatment. Patients received risperidone long-acting injectable, 25 mg, by intramuscular injection every 2 weeks; the dose could be increased to 37.5 or 50 mg if necessary. Patients were transferred directly from their previous medication to risperidone long-acting injectable without a run-in period of oral risperidone treatment. Of 192 patients recruited, 134 patients (70%) completed the study. The principal reasons for discontinuation were withdrawal of consent (8%), adverse events (6%), insufficient response (5%) and non-compliance (4%). Risperidone long-acting injectable produced a significant improvement (p = 0.0001) in Positive and Negative Syndrome Scale (PANSS) total scores, from 74.2+/-21.3 at baseline to 65.8+/-21.4 at endpoint. There were also significant reductions in PANSS subscales (positive symptoms, negative symptoms, general psycho-pharmacology) and Marder factor scores. The Clinical Global Impression increased significantly from baseline to endpoint (p = 0.0001), as reflected by the increase in the proportion of patients rated as 'not ill' or 'borderline ill' from 10% at baseline to 21% at endpoint. Risperidone long-acting injectable was also associated with significant improvements in Global Assessment of Function, patient satisfaction with treatment, and quality of life, measured on the SF-36 scale. Movement disorders, measured on the Extrapyramidal Symptom Rating Scale, were significantly reduced following the change to risperidone long-acting injectable. Treatment with risperidone long-acting injectable was well tolerated, and no significant weight gain occurred during the study. This open study suggests that risperidone long-acting injectable produces symptomatic improvement in schizophrenia patients previously considered symptomatically stable with olanzapine, along with improvement in movement disorders. The combination of improved efficacy and good tolerability may have important implications for patient adherence to therapy and subsequent long-term outcomes.

What are depressive symptoms in acutely ill patients with schizophrenia spectrum disorder?

BACKGROUND: Aim was to examine depressive symptoms in acutely ill schizophrenia patients on a single symptom basis and to evaluate their relationship with positive, negative and general psychopathological symptoms. METHODS: Two hundred and seventy-eight patients suffering from a schizophrenia spectrum disorder were analysed within a naturalistic study by the German Research Network on Schizophrenia. Using the Calgary Depression Scale for Schizophrenia (CDSS) depressive symptoms were examined and the Positive and Negative Syndrome Scale (PANSS) was applied to assess positive, negative and general symptoms. Correlation and factor analyses were calculated to detect the underlying structure and relationship of the patient's symptoms. RESULTS: The most prevalent depressive symptoms identified were depressed mood (80%), observed depression (62%) and hopelessness (54%). Thirty-nine percent of the patients suffered from depressive symptoms when applying the recommended cut-off of a CDSS total score of >6 points at admission. Negligible correlations were found between depressive and positive symptoms as well as most PANSS negative and global symptoms despite items on depression, guilt and social withdrawal. The factor analysis revealed that the factor loading with the PANSS negative items accounted for most of the data variance followed by a factor with positive symptoms and three depression-associated factors. LIMITATIONS: The naturalistic study design does not allow a sufficient control of study results for the effect of different pharmacological treatments possibly influencing the appearance of depressive symptoms. CONCLUSION: Results suggest that depressive symptoms measured with the CDSS are a discrete symptom domain with only partial overlap with positive or negative symptoms.

Trimipramine: pharmacological reevaluation and comparison with clozapine.

Trimipramine has been reported to differ from other typical tricyclic antidepressant drugs in several aspects, for instance it does not inhibit neuronal transmitter uptake and does not cause down-regulation of beta-adrenoceptors. Moreover, it may possess antipsychotic activity in schizophrenic patients. In the present investigation it was found that trimipramine did not alter the electrically-induced release of [3H]noradrenaline and [3H]5-hydroxytryptamine, from slices of the cerebral cortex of the rat, in concentrations of less than 1 microM. It did not antagonize the inhibitory effect of noradrenaline and 5-hydroxytryptamine on the release of transmitter, mediated by presynaptic autoreceptors. In radioligand binding studies, D,L-trimipramine showed fairly high affinities (KI 10-60 nM) for some dopamine (DA), noradrenaline and 5-hydroxytryptamine (5-HT) receptor subtypes (5-HT2 receptors = alpha 1A/B-adrenoceptors greater than or equal to D2 receptors), intermediate affinities (300-550 nM) for D1 receptors, alpha 2B-adrenoceptors and 5-HT1C receptors but only low affinities (greater than 1000 nM) for alpha 2A-adrenoceptors, 5-HT1A, 5-HT1D and 5-HT3 receptors. It may thus be classified as an atypical neuroleptic drug. Especially, its affinities for dopamine receptors, alpha 1-adrenoceptors and 5-HT2 receptors closely resembled the values measured for clozapine. The L-enantiomer of trimipramine showed higher affinities for these binding sites than D-trimipramine. The present findings may explain the mechanism of the potential antipsychotic action but not the antidepressant effect of trimipramine.

Clinical originality and new biology of trimipramine.

Trimipramine differs from other antidepressant drugs in a number of ways. Although trimipramine shares equivalent efficacy with doxepin, imipramine, maprotiline and amitriptyline, as evidenced by double-blind studies, it possesses a different side-effect profile. Trimipramine is considered to be less cardiotoxic, and data presented in this paper support its minimal effect on orthostatic hypotension, as compared with clomipramine. In addition, trimipramine has less epileptogenic potential than other antidepressants such as imipramine, amitriptyline and maprotiline. Besides this different side-effect profile, trimipramine exerts differing effects on neurotransmitter functions and their reuptake. For example, trimipramine does not inhibit reuptake of noradrenaline and serotonin, and does not down-regulate beta 1-adrenoceptors. Furthermore, in common with lithium, trimipramine produces enhancement of antidepressant action in treatment-resistant depressed patients. There is evidence that trimipramine enhances the sensitivity of cortical neurons to noradrenaline after prolonged administration and may also increase the activity of serotonin neurons.

EEG, blood level, and behavioral effects of the antidepressant mianserin (ORG GB-94).

A pharmacokinetic analysis of a new antidepressant drug, mianserin (ORG GB-94), was undertaken in 4 male volunteers, each of whom received 15 mg mianserin on two occasions. Plasma levels peak at 2 h with a median level of 11.0 ng/ml, a median beta-phase half-life of 10.0 h, and a median apparent volume of distribution of 3.3 X 10(3) 1. EEG profile analysis shows mianserin to increase frequencies below 6 Hz, decrease those from 7.5 to 15 Hz, and increase frequencies above 18 Hz, a pattern similar to amitriptyline. Peak EEG effects range from 2 to 5 h with a pattern of measured changes that parallels plasma levels with varying latency. Decreases in vigilance measures and in critical flicker-fusion frequency show a similar time course. Mianserin is a putative thymoleptic on EEG profile analysis with high cerebral penetrance.

Altered fronto-central PINV topography and the primary negative syndrome in schizophrenia.

Postimperative negative variation (PINV) was recorded during a warned reaction time paradigm in 16 chronic DSM-IIIR schizophrenics in remission. Clinical symptoms were assessed by BPRS, SANS and the anhedonia scale of the Chapman Questionnaire. Ten healthy controls were studied in the same manner. Over the fronto-central area we found a significantly elevated PINV amplitude with an altered topographical distribution in the patient group. The difference values 'PINV Cz-PINV Fz' were correlated negatively with primary negative symptoms of schizophrenia.

Ethacrynic acid: effects on postsynaptic GABA responses and electric activity of CA3 neurones.

Ethacrynic acid (ETA) inhibits somatic Cl(-)-extrusion from hippocampal pyramidal neurones. We analysed the dependence of postsynaptic gamma-aminobutyric acid (GABA) responses on this Cl- extrusion. ETA irreversibly reduced the 'somatic' hyperpolarizing GABAA response (hGABAA) within a few minutes, without altering the following depolarizing GABAA (dGABAA) and hyperpolarizing GABAB responses. GABA-induced changes of the membrane resistance were not affected by ETA, indicating that ETA does not act primarily on receptor-operated channels. In about 50% of the tested CA3 neurones spontaneous activity and caffeine-induced epileptiform discharges increased initially after adding ETA. All neurones lost their activity during prolonged ETA exposure. The early ETA-induced increase of neuronal activity coincided with the decrease of hGABAA (disinhibition). The late suppressive action may be caused by intracellular acidosis.

Preliminary studies with citalopram (LU 10-171), a specific 5-HT-reuptake inhibitor, as antidepressant.

1. Ten hospitalized, depressive, female patients above the age of 50 have been treated in a 3 week open trial with citalopram, a specific 5-HT-uptake inhibitor. 2. Six full and two partial responders demonstrate a recovery rate within the well known range for tricyclic antidepressant drugs. 3. Early onset of clinical effect and minimal side effects indicate that citalopram is possible a new effective antidepressant.

Clinical correlates of response to DST. The Dexamethasone Suppression test in depression: a World Health Organisation collaborative study.

From 9 centres 293 patients took part in the WHO-collaborative study on Dexamethasone-Suppression-Test (DST) in depression to examine the relationship of psychopathological and psychiatric history information to cortisol-levels and suppression/non-suppression status. Differences between the centres were large and significant on nearly all of the measures. The predictor analyses generally suffered from numerically weak correlations with many variables correlating to sex and age. Therefore analyses of the data were adjusted for centre-, sex-, and age-influences. The best predicting features of cortisol were 'fitful, restless sleep', 'change of bodyweight' and 'affective disorders in blood relatives'. The last 2 items together with 'hypersomnia' and 'ideas of insufficiency' were the best predictors of suppression/nonsuppression status. However, statistical evidence did not seem to be strong enough to describe a typical symptom profile of a depressive cortisol suppressor or nonsuppressor.

Platelet 3H-imipramine binding sites in depressed patients and healthy controls: a comparison between morning and afternoon samples.

Platelet 3H-imipramine binding was compared between 19 hospitalized, depressed patients and age-matched controls (n = 11). For each individual person blood samples were withdrawn at 8 a.m. and 3 p.m. on two separate occasions (day 0 and day 28). Mean Bmax and Kd values did not differ between depressed patients and healthy controls at any of the four time-points tested, and no significant differences could be established between the different time-points, though there were irregular intraindividual variations.

Determination of human plasma levels of levo-alpha-acetylmethadol and its metabolites by gas chromatography-mass spectrometry.

A gas chromatography-mass spectrometry (GC-MS) method is presented which allows the simultaneous determination of the plasma concentrations of the levo-alpha-acetylmethadol (LAAM) and of its active metabolites (NorLAAM and DiNorLAAM), after derivatization with the reagent trifluoroacetic anhydride (TFAA). No interferences from endogenous compounds were observed following the extraction of plasma samples from 11 different human subjects. The standard curves were linear over a working range of 5-200ng/ml for the three compounds. Recoveries measured at three concentrations ranged from 47 to 67% for LAAM, from 50 to 69% for NorLAAM and from 28 to 50% for DiNorLAAM. Intra- and interday coefficients of variation determined at three concentrations ranged from 5 to 13% for LAAM, from 3 to 9% for NorLAAM and from 5 to 13% for DiNorLAAM. The limits of quantitation of the method were found to be 4ng/ml for the three compounds. No interference was noted from methadone. This sensitive and specific analytical method could be useful for assessing the in vivo relationship between LAAM's blood levels, clinical efficacy and/or cardiotoxicity

DEPRES II (Depression Research in European Society II): a patient survey of the symptoms, disability and current management of depression in the community. DEPRES Steering Committee.

The first pan-European survey of depression in the community (DEPRES I) demonstrated that 17% of the general population suffer from depression (major depression, minor depression, or depressive symptoms). This article describes findings from a second phase of DEPRES (DEPRES II), in which detailed interviews based on a semi-structured questionnaire (78 questions) were conducted with 1884 DEPRES I participants who had suffered from depression and who consulted a healthcare professional about their symptoms during the previous 6 months. The mean time from onset of depression was 45 months, and the most commonly experienced symptoms during the latest period were low mood (76%), tiredness (73%) and sleep problems (63%). During the previous 6 months, respondents had been unable to undertake normal activities because of their depression for a mean of 30 days, and a mean of 20 days of work had been lost to depression by those in paid employment. Approximately one-third of respondents (30%) had received an antidepressant during the latest period of depression. Significantly more respondents given a selective serotonin reputake inhibitor found that their treatment made them feel more like their normal self than those given a tricyclic antidepressant, and fewer reported treatment-related concentration lapses, weight problems, and heavy-headedness (all P < 0.05). Approximately two-thirds of respondents (70%) had received no antidepressant therapy during the latest period of depression, and prescription of benzodiazepines alone, which are not effective against depression, was widespread (17%). There is a need for education of healthcare professionals to encourage appropriate treatment of depression.