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 treatment with olanzapine for four weeks. Additionally, spectral power analysis of the EEG signal in distinct frequency bands was computed for different sleep stages. Psychopathology (PANSS, HAMD-17, HAMA) and side effects were assessed weekly. RESULTS: All patients improved, as measured by PANSS global scores. Compared to baseline, there was a significant improvement of parameters of sleep efficiency and an increase of delta sleep as well as REM sleep. Regarding spectral power values, no significant differences between baseline and treatment conditions were found. CONCLUSIONS: Sleep improvement was due to parameters of sleep efficiency and delta sleep, which may be related to serotonin antagonistic properties of olanzapine.

[Standardized documentation procedure as a basis for improvement of process quality of treatment in psychiatric hospitals]. / Standardisierte Verlaufsdokumentation als Grundlage zur Verbesserung der Prozessqualität der stationären psychiatrischen Behandlung.

A standardized documentation system is presented for detailed description and analysis of treatment procedure for psychiatric inpatients. In the first step of a pilot study limited to patients with depressive syndromes at the Department of Psychiatry, University of Mainz, for each subject the clinical status was assessed weekly using psychopathological ratings and depicted in its temporal course along with therapeutic activities. Visualization of the treatment process turned out to be useful for everyday work by supporting the application of practice guidelines for clinical decisions. Beyond optimization of the individual treatment process, aggregation of the data also allows global assessment of treatment processes in the clinic. Thus, in addition to established basic documentation, the presented documentation procedure allows the development of a powerful quality management system in psychiatric clinics, due to its process orientation. Moreover, in psychiatric care research, it is an adequate basis for evaluating the effectiveness and efficiency of treatment procedures.

An overview of the clinical efficacy of mirtazapine.

Mirtazapine is at least as effective as the tricyclic antidepressants and trazodone in a wide range of patient subgroups including in- and out-patients with moderate to severe depression. It also appears to be at least as effective as the serotonin and noradrenaline reuptake inhibitor venlafaxine in the treatment of severely depressed melancholic patients. When compared with the selective serotonin reuptake inhibitors (SSRIs), mirtazapine shows a significantly earlier onset of action. Further analysis of a study comparing mirtazapine with the SSRI paroxetine indicated that early improvement was a highly sensitive predictor of later stable response for both drugs. The positive predictive value of an early improvement was significantly higher during mirtazapine treatment compared with paroxetine. The negative predictive value approached maximum values as early as week 2 with mirtazapine and week 3 with paroxetine. This suggests that the predictability of the response to treatment is better with mirtazapine than with paroxetine.

Long-term effects of the substituted benzamide derivative amisulpride on baseline and stimulated prolactin levels.

In the present study, we investigated the long-term effects of treatment with amisulpride, a substituted benzamide derivative, as compared with the effects of treatment with flupenthixol, a thioxanthene, on the prolactin levels in schizophrenic patients. After completing 6 weeks of medication with either amisulpride or flupenthixol, the patients entered a long-term maintenance treatment with amisulpride 200-600 mg/day or flupenthixol 5-15 mg/day for a maximum of 12 months with a subsequent drug-free follow-up until month 15. Eighteen initially included patients were still participating in the study at month 6. In the flupenthixol group, only 1 patient treated reached month 12, and none of the patients reached month 15. For the amisulpride treatment group, months 12 and 15 were completed by 9 and 6 patients, respectively. After 1, 3, 6, and 12 months of treatment, and finally 3 months after cessation of treatment, the basal and thyrotropin-releasing hormone-stimulated secretions of prolactin were investigated. The prolactin plasma levels were elevated in both treatment groups during the course of maintenance treatment with a maximum effect at month 1. Flupenthixol treatment initially raised the prolactin levels about two- or threefold, and a subsequent decline during months 3 and 6 occurred. However, only the changes for month 1 reached the level of a statistical trend. The prolactin secretion was initially increased over tenfold by amisulpride. The prolactin levels at months 1, 3, 6, and 12 were significantly elevated as compared with the baseline values. A continuous decline of prolactin levels in both treatment groups occurred over the course of the next months. The prolactin response after the thyrotropin-releasing hormone challenge was not significantly changed over the long-term course. Notably, in the amisulpride group, 3 months after cessation of treatment at month 12, the elevated levels of prolactin returned to baseline at month 15. In summary, amisulpride demonstrated more pronounced effects than flupenthixol on the prolactin levels. However, the findings indicate also that treatment with amisulpride at clinically effective doses can be achieved at significantly lower prolactin levels during the long-term maintenance phase than during the prior acute phase.

Differential effects of high-dose amisulpride versus flupentixol on latent dimensions of depressive and negative symptomatology in acute schizophrenia: an evaluation using confirmatory factor analysis.

While many acutely ill schizophrenic patients suffer from depressive symptoms, most studies on the efficacy of antipsychotic drugs focus on positive and negative symptoms. Dimensional models of schizophrenic symptoms, based on confirmatory factor analysis (CFA) using structural equation modelling, offer a methodological alternative to compare antipsychotics on empirically justified latent factors. The present report is a refined analysis of a published double-blind study on the D2/D3-selective antagonist amisulpride (ASP) versus the mixed D1-5/5-HT2 antagonist flupentixol (FPX). CFA was applied to Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, Bech-Rafaelsen Melancholia Scale and Simpson-Angus Scale subscores to examine differential effects of high doses of ASP and FPX on negative and depressive symptom dimensions in 126 acutely ill schizophrenic patients. A four-factor model comprising the full spectrum of acute symptomatology and a three-factor model ('negative', 'anhedonia-apathy', 'depressive') restricted to negative and depressive symptoms were yielded with an identical 'depressive' dimension in both models. Analyses of CFA-derived factor scores showed that ASP was significantly superior to FPX regarding the latent 'depressive' dimension, independent of baseline scores, dosage and changes in akinesia. Neither the negative' dimension nor 'anhedonia-apathy' showed significantly different treatment effects. CFA-based analyses appear to be suitable for psychotropic drug evaluation when more refined and data-related information on drug efficacy profiles are required.

Lower self-reported depression in patients with erectile dysfunction after treatment with sildenafil.

BACKGROUND: Depressive symptoms in men with erectile dysfunction (ED) may improve under successful ED treatment. Self-reported depressive symptoms were compared in men with ED after sildenafil treatment to a group of untreated patients. METHODS: In an open study, self-reported depressive symptoms of 54 men after successful treatment with sildenafil (>4 weeks) and 51 men awaiting ED treatment were investigated with the Center of Epidemiologic Studies-Depression Scale (CES-D). CES-D items were subjected to an exploratory factor analysis and group differences in CES-D items and factors were analyzed. RESULTS: Groups were comparable with respect to demographic characteristics and illness duration. CES-D total scores were lower in the group treated with sildenafil. Substantial differences were found in favor of the group treated with sildenafil, particularly in scores on a "positive affect" factor. CONCLUSIONS: The findings emphasize the relevance of depression associated with ED and the importance of effective ED treatment. Although depression was generally low in this sample, hedonistic aspects were substantially enhanced in the group of ED patients after sildenafil treatment. LIMITATIONS: The open and cross-sectional study design does not permit causal inference. Selection bias and motivational aspects to participate in the study can not completely be ruled out.

Effects of moclobemide on sexual performance and nocturnal erections in psychogenic erectile dysfunction.

RATIONALE AND OBJECTIVES: We tested the hypothesis that the selective reversible MAO-A inhibitor moclobemide has a specific therapeutic effect on erectile dysfunction independent of its antidepressive properties. METHODS: In a double-blind placebo controlled study, 12 male outpatients suffering from psychogenic erectile dysfunction without any other psychiatric disorder were investigated. Based on comprehensive diagnosis before the beginning of the study, organic factors relevant for sexual function were excluded. The treatment period was 8 weeks. Half the patients received 450 mg moclobemide during the first week, and 600 mg afterwards; the others received placebo. Apart from assessment of erectile function by means of the Clinical Global Impression (CGI) scale, nocturnal erections were measured under polysomnographic control at baseline and at the end of the treatment period. RESULTS: The evaluation of the CGI scale revealed a clearly stronger improvement under moclobemide compared to placebo during the study period. The therapeutic efficacy found on the subjective level had no clear correlate on the neurophysiological level. No alterations of nocturnal erectile parameters were obvious under treatment, neither were clinically relevant alterations found regarding sleep EEG parameters. The medication was well tolerated without serious adverse events. CONCLUSIONS: The findings support the hypothesis that moclobemide has a specific effect on erectile dysfunction. Thus, patients suffering from psychogenic erectile dysfunction who are not depressed might benefit from moclobemide without relevant side effects.

Quality of partnership in patients with erectile dysfunction after sildenafil treatment.

OBJECTIVE: A comprehensive investigation on the quality of partnership of male patients with erectile dysfunction (ED) after treatment with sildenafil vs. untreated patients, as perceived by both the patients and their female partners. METHODS: This report describes an observational, cross-sectional exploratory study comparing ED patients responsive to sildenafil with ED patients prior to therapy. Assessments included the 'International Index of Erectile Function' (IIEF) and the 'Partnerschaftsfragebogen' (PFB), a partnership questionnaire used in German-speaking countries. The comparability of the two study groups was examined using a stepwise logit model. Significant intergroup differences regarding demographics and history were identified and included as confounding variables in the assessment of Quality of Partnership differences using ANCOVA. A regression analysis was performed to determine the association between the mean total IIEF scores and Quality of Partnership measures. RESULTS: 105 patients were included in the study. After adjustment for confounding variables, the groups varied significantly with respect to Quality of Partnership as perceived by men (mean score PFB 61.8 +/- 13.9 vs. 54.4 +/- 15.5; p<0.001) and women (mean score PFB 63.1 +/- 13.6 vs. 57.0 +/- 14.7; p = 0.006). In men, all three PFB subscales (quarreling, tenderness, togetherness) differed significantly between the two study groups. In the female partners, the tenderness and togetherness domains varied significantly. Erectile function correlated highly significantly with tenderness and togetherness in both the male patients and their partners. CONCLUSION: Our data indicate that the Quality of Partnership reported by both the men and their female partners is significantly better in appropriately treated ED patients than in untreated controls.

Depressive factors and their relationships with other symptom domains in schizophrenia, schizoaffective disorder, and psychotic depression.

Relationships among different symptom domains were investigated in patients with acute exacerbation of schizophrenia with depressive symptoms, psychotic depression, or schizoaffective disorder, depressive subtype. Scores for depression and depressive factors were correlated with positive, negative, and extrapyramidal symptoms within diagnostic categories. No between-group differences in the relationship of different symptom domains could be found, and no substantial relationship between depression and positive symptoms could be revealed in any diagnostic subgroup. Only the retardation factor of depression showed a significant overlap with negative symptoms; depressive core symptoms did not. Core symptoms of depression were independent from other symptoms in all investigated diagnostic groups. Depression seems to represent a heterogeneous symptom domain with unique relationships of components to positive and negative symptoms across nosological borders. A more differentiated assessment, analysis, and treatment of depressive symptoms is therefore recommended for patients with combined depressive and psychotic symptoms.

[Which properties make a neuroleptic "atypical"?]. / Welche Eigenschaften machen ein Neuroleptikum "atypisch"?

The group of "atypical" neuroleptics is not a homogeneous class of drugs, but pharmacologically as well as clinically disparate. Furthermore, there seems to be a continuum between "conventional" and "atypical" neuroleptics. Based on preclinical findings with these drugs and their characteristics in SPECT- and PET-studies, the most common concepts of neuroleptic "atypicality" are discussed. Combined D2-like dopamine/5-HT2-serotonin antagonism and preferential binding to mesolimbic dopamine neurons are believed to be the main pharmacological features of "atypical" compounds. For certain substances, affinities for specific neurotransmitter receptors as well as interactions with other non-dopaminergic systems may be essential. A relatively low affinity for D2-like dopamine receptors and binding to dopamine autoreceptors are probably of some importance for other compounds. The diversity of possible mechanisms suggests that there is not a single, pharmacologically established concept of "atypicality". A variety of biological mechanisms characterizes a heterogeneous group of substances, which also substantially differ in their clinical properties.

[Clinical applications of single photon emission tomography in neuromedicine. 1. Neuro-oncology, epilepsy, movement disorders, cerebrovascular disease]. / Klinische Anwendungen der Single-Photon-Emissionstomographie in der Neuromedizin. Teil 1: Neuroonkologie, Epilepsien, Basalganglienerkrankungen, zerebrovaskuläre Erkrankungen.

Single photon emission tomography is, because of its availability and the relatively low costs, the functional imaging modality currently most widely used for clinical applications in the brain. Beside the application of radiopharmaceuticals for the assessment of regional cerebral blood flow there is an increasing clinical use of more selective SPECT-radiopharmaceuticals, like amino acid analogs or receptor ligands. This article gives in his first part a critical review of the clinical applications of SPECT in neuro-oncology, epilepsy, basal ganglia disorders and cerebrovascular disease.

Mirtazapine compared with paroxetine in major depression.

BACKGROUND: The aim was to compare the efficacy and tolerability of mirtazapine with those of paroxetine. METHOD: 275 outpatients with a diagnosis of major depressive episode (DSM-IV) and a score > or = 18 on the 17-item Hamilton Rating Scale for Depression (HAM-D-17) were randomly assigned to 6 weeks of treatment with mirtazapine (15-45 mg/day) or paroxetine (20-40 mg/day). Efficacy was assessed by the HAM-D-17, Hamilton Rating Scale for Anxiety (HAM-A), and Clinical Global Impressions scales (Severity and Improvement), and analyses were performed on the intent-to-treat sample (127 mirtazapine-treated patients and 123 paroxetine-treated patients). RESULTS: Mean daily doses were 32.7 mg of mirtazapine and 22.9 mg of paroxetine. Thirty patients in the mirtazapine group and 33 in the paroxetine group dropped out. Both drugs were equally effective in reducing symptoms of depression. At week 1, the mean HAM-D-17 total score was significantly lower in mirtazapine- than paroxetine-treated patients (16.5 vs. 18.8, p = .0032). Similarly, significantly more mirtazapine-treated patients were HAM-D-17 responders (> or = 50% decrease from baseline) at weeks 1 (23.2% vs. 8.9%, p = .002) and 4 (58.3% vs. 44.5%, p = .04). Both treatments were equally effective in reducing anxiety. However, the reduction in mean HAM-A total score was significantly greater with mirtazapine than with paroxetine at week 1 (-5.1 vs. -3.5, p = .0435). Tolerability of both treatments was good, with more nausea, vomiting, tremor, and sweating in the paroxetine group and more weight increase and influenza-like symptoms in the mirtazapine group. CONCLUSION: Mirtazapine and paroxetine were equally effective after 6 weeks of therapy and were both well tolerated. A potentially faster onset of overall therapeutic efficacy of mirtazapine was suggested by significant differences between treatments after 1 week of therapy that were due to slightly larger improvements of several core symptoms of depression as well as distinct prevention of treatment-emergent worsening of anxiety and physical components of depression.

Moderate and severe depression. Gradations for the Montgomery-Asberg Depression Rating Scale.

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). A MADRS cut-off score of at least 35 points was estimated to separate 'moderate' from 'severe' depression corresponding to a HAMD-17 cut-off of 28 points with sufficient sensitivity and specificity. LIMITATIONS: The sample size was limited and no observer ratings directly assessing the severity of depression were used. CONCLUSIONS: The preliminary findings are in line with previous findings and suggest a cut-off score of 35 points to separate moderate from severe depression with the MADRS accepting an HAMD-17 score of >/=28 point as reference. Further studies on this issue are warranted.

The primary care evaluation of mental disorders (PRIME-MD), German version: a comparison with the CIDI.

There is a need for the development and evaluation of diagnostic instruments suitable for daily use in primary care offices that can improve recognition rates of psychopathology. The objective of this study is the comparison of the German version of the Primary Care Evaluation of Mental Disorders (PRIME-MD), a short structured diagnostic instrument, with the Composite International Diagnostic Interview (CIDI) and to gather some information on the usefulness of the PRIME-MD. Seven hundred and four patients were assessed three times, once using the physician's clinical judgement, subsequently, administering the PRIME-MD, DSM-IV version and finally, with the CIDI. The CIDI was administered on a different occasion within 1 week after the PRIME-MD evaluation by independent interviewers over the telephone. At the end of the study, the participating physicians answered a few feedback questions on the usefulness of PRIME-MD. Sensitivity (0.73), specificity (0.67), overall accuracy (0.70) were good for any psychiatric disorder. According to the diagnostic categories of mood disorders, anxiety disorders, eating disorders, and alcohol-related disorders, the sensitivity of PRIME-MD was good (0.67-0.80). For somatoform disorders, sensitivity was poor. Specificity, accuracy, and negative predictive values were good-to-excellent for all diagnostic categories. Kappas range from poor (0.12 somatoform disorders) to satisfactory (0.62 alcohol related disorders). Average time for administering PRIME-MD was 11 min. The results demonstrated that the German version of the PRIME-MD may be useful in primary care settings to enhance recognition of mental disorders by primary care physicians, even without being formally trained in diagnosing mental disorders.

[Evaluation of standardized training for the "Positive and Negative Syndrome Scale" (PANSS)]. / Evaluation eines standardisierten Trainings für die "Positive and Negative Syndrome Scale" (PANSS).

The present analysis comprises 3 studies on the interrater reliability of the Positive and Negative Syndrome Scale for Schizophrenia (PANSS; German version). To our knowledge this is the first empirical report on interrater reliability and on results of rater training of the German version of the PANSS despite the widespread use of the scale. In a total of 47 training participants with different clinical experience standardized PANSS rater training was carried out and subsequently evaluated. Therefore, concordance rates with an expert standard (C) and weighted coefficients kappa (kappa W) were calculated. As a main outcome of the studies, at least 3 training sessions were necessary but also sufficient to reach acceptable interrater reliability of the PANSS (C > 80%, kw > 0.60). In training participants with low psychiatric experience the level of interrater reliability of schizophrenic negative symptoms did not reach the results of positive symptoms after the training. Despite some conceptual limitations with respect to negative symptoms, the German version of the PANSS seems highly suitable to assess a broad spectrum of schizophrenic psychopathology in a reliable and economic manner. The present results also underline the practicability of our recommendations for conducting PANSS rater training in the clinical and scientific field as part of quality control and quality assurance in psychopathological assessment.

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

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 were determined, and area-under-the-curve values were calculated. None of the endocrinological parameters revealed any statistically significant changes. A trend could be found for an increased cortisol production under paroxetine (P = 0.069). ACTH, LH, and melatonin showed slight and non-significant decreases. Prolactin release was only marginally elevated (+7%). The mean sleep onset GH release (as measured for a time period of 180 min after sleep onset) was decreased by about 30% under paroxetine. However, statistical significance could not be reached. For hGH, there was a delayed mean GH-peak under paroxetine. Nocturnal testosterone secretion remained almost unaltered. The lack of significant endocrinological alterations might be partially explained by both adaptational phenomena under subchronic treatment conditions and the extended time span between the single morning dose and the registration period, respectively.

[Clinical applications of single photon emission tomography in neurology. 2. Dementia, psychoses, inflammation, skull and brain injuries]. / Klinische Anwendungen der Single-Photon-Emissionstomographie in der Neuromedizin. Teil 2: Dementielle Erkrankungen, Psychosen, Entzündungen, Schädelhirntraumata.

This article gives in his second part a critical review of the clinical applications of SPECT with perfusion markers and receptor ligands in dementing disorders and psychosis. In addition this review discusses clinical applications of SPECT investigations with perfusion markers in inflammatory diseases of the central nervous system and in brain trauma.

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 model of the BRMES comprising the facets retardation, depressive core symptoms, and accessory depressive symptoms was cross-validated by confirmatory factor analysis (CFA). The three-dimensional model proved to be superior to one-, two-, or four-factor models with respect to goodness-of-fit (goodness-of-fit index [GFI] = 0.91 and comparative fit index [CFI] = 0.89) and parsimony (adjusted GFI [AGFI] = 0.85). When comparing the present model with the previously reported model, a highly satisfactory correspondence emerged (CFI = 0.87). The results corroborate our previous findings that depression-like symptoms in acutely psychotic patients assessed by the BRMES can best be represented by a three-dimensional model and should not be treated as a homogeneous syndrome.

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 D(2) and D(3) dopamine (DA) receptors. OBJECTIVES: The aim of this study was to test, using single photon emission computed tomography (SPECT) and [(123)I]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 before and one after treatment with 60 mg panamesine daily for a treatment duration of 12-26 days. RESULTS: A high occupancy of striatal D(2)-like DA receptors similar to that induced by typical neuroleptics was observed in all patients treated with EMD 57445. CONCLUSIONS: Our results suggest that a possible antipsychotic activity of EMD 57445 in schizophrenia is not necessarily attributable to its affinity for sigma receptors, but could be simply due to the potent antidopaminergic effects of EMD 59983, its main metabolite.