[The significance of depot medication in the long-term-treatment of schizophrenia]. / Stellenwert von Depotformulierungen in der Langzeittherapie der Schizophrenie.

Relapse prevention in schizophrenia is a key aim in therapy. However, it is estimated that approximately 75% of patients with schizophrenia relapse within five years. Each relapse might worsen the disease and increase the risk of psychosocial and work-related disadvantages. A continuous long-term therapy is able to reduce this risk, but medical non-adherence, which is influenced by numerous factors, is a limitation. Naturalistic studies show that depot-antipsychotics compared with oral antipsychotics lead consistently to a better outcome, for example by reducing relapse rates or hospitalisation. Numerous meta-analyses of randomised controlled trials comparing oral versus depot-antipsychotics also show this advantages. However these results are not consistent in all meta-analyses. Results of controlled studies do not appropriately reflect the reality of daily practice. The advantages of depot-antipsychotics are shown more distinctly in naturalistic studies. The following review reflects the current therapy of schizophrenia and discusses adequately a broad application of depot-antipsychotics based on existing data. In addition, concerns and prejudices of physicians and patients against antipsychotic long-term therapy and depot-formulation are discussed and a recommendation is provided.

[Modafinil for the treatment of cancer-related fatigue : an intervention study]. / Modafinil zur behandlung der tumorfatigue : eine interventionsstudie.

AIM: the authors conducted an open-label investigation examining the effects of modafinil in reducing fatigue in patients with cancer, undergoing cancer treatment, and receiving opioid therapy. METHODS: after approval by the local Ethics Committee and informed consent cancer patients who reported fatigue - defined as persistent tiredness interfering with usual functioning - were enrolled in the study. Once daily, patients received 100 mg open-label modafinil. The Fatigue Severity Scale (FSS), Epworth Sleepiness Scale (ESS), and a visual analogue scale (VAS, 0-10) were performed at baseline (t1), day 7 (t2), and day 28 (t3). Further assessment comprised the d2 Test of Attention (d2), the Hamilton Depression Scale (HAMD), the Eastern Cooperative Oncology Group-Score (ECOG), side effects, and patients' satisfaction with modafinil treatment. RESULTS: of the 37 patients who were enrolled, 29 completed all assessments in the study. Modafinil had a significant effect on the FSS (t1 44.6+/-12.2, t2 39+/-12.4, t3 35.3+/-13.8 (p=0.015), on the VAS (t1 6+/-3.1), t2 4.5+/-2.8, t3 3.7+/-2.8 (p=0.005), and an insignificant effect on d2 parameters of neurophysiological functioning and ESS. No differences were seen for ECOG and patients' satisfaction. No severe adverse effects were detected. CONCLUSION: modafinil improved alertness and cognitive skills in patients receiving cancer pain treatment by enhancing vigilance and cognitive performance. Although confirmation of this preliminary result is needed, these findings suggest that modafinil may improve quality of life in this patient population. However, in Germany the use of modafinil for fatigue is off-label and careful assessment of fatigue is needed prior to treatment. Randomized controlled trials are needed to confirm this evidence.

[Adverse side-effect on sexual function caused by psychotropic drugs and psychotropic substances]. / Beeinträchtigung der Sexualfunktion durch Psychopharmaka und psychotrope Substanzen.

Unhindered sexuality plays an important role in the quality of life and this also holds true for patients with psychiatric illnesses. Knowledge concerning the complex neuronal and endocrine control mechanisms of sexual function reveals areas of possible dysfunction caused by the interactions between the control system, psychiatric drugs and addictive psychoactive substances. The differentiation of the cause of the dysfunction between being caused by the underlying illness and caused by other factors is difficult in practice. Both classical tri-cyclic antidepressants and selective serotonin uptake inhibitors can frequently cause adverse effects in multiple dimensions of sexual function. This same is true for neuroleptics, whereby the differentiation between symptoms of schizophrenia and side-effects from the medication can make an evaluation difficult. The medication-based strategy used to treat opiate dependency by administration of methadone causes sexual dysfunction in many cases. The consideration of medication-induced sexual dysfunction has a great importance with regard to compliance. Possible solutions can be modification of the medication regime, additional medication, e.g. partial antagonists and PD5 inhibitors, as well as dysfunction-specific psychotherapy and psychoeducation.

Time course of antipsychotic treatment response in schizophrenia: results from a naturalistic study in 280 patients.

OBJECTIVE: To describe the course of positive and negative symptoms during inpatient treatment and examine remission and response rates under routine clinical care conditions. METHODS: Two hundred and eighty inpatients with schizophrenia (DSM-IV criteria) were assessed with the Positive and Negative Syndrome Scale (PANSS) at admission and at biweekly intervals until discharge from hospital. Remission was defined according to the symptom-severity component of the consensus criteria (Remission in Schizophrenia Working Group) as a rating of three or less in the relevant PANSS items at discharge, and response as a reduction of at least 20% in the PANSS total score from admission to discharge. RESULTS: The mean duration of inpatient treatment was 54.8 days. Of the total sample, 78.5% achieved the criteria for response and 44.6% those for remission. Mean PANSS total scores decreased from 72.4 at admission to 52.5 at discharge (p<0.001). A reduction in PANSS total scores was found from visit to visit, up to week 8. The most pronounced decline was observed within the first two weeks of treatment. CONCLUSION: Response rates were comparable to those found in efficacy studies, and remission rates were slightly higher. This may be explained by differences in the selection and the treatment of patients. Nevertheless, the findings might indicate that a complex naturalistic treatment approach is beneficial in terms of effectiveness.

Sexuality in male psychiatric inpatients. a descriptive comparison of psychiatric patients, patients with epilepsy and healthy volunteers.

INTRODUCTION: The majority of psychiatric patients suffer from sexual dysfunction. Although sexual impairment is a major cause for non-compliance in psychiatric patients, it remains underdiagnosed by the attending physician. Therefore, the aim of the following study was to examine sexual behaviour and sexual dysfunction in a large sample of psychiatric patients. METHODS: Male psychiatric inpatients received a questionnaire for sexuality ("Sexualitätsfragebogen für Männer", SFM) examining various aspects of sexual behaviour (e.g., value of sexuality, sexual dysfunction). Questionnaires from 351 patients were analysed. Additionally, 55 male healthy controls and 52 male patients with epilepsy were recruited. RESULTS: Psychiatric patients demonstrated more severe sexual dysfunction in the acute phase of their illness as well as in the premorbid time period compared with healthy controls. Patients with epilepsy showed only mild current sexual dysfunction (in the acute phase of the illness), with the exception of persisting erectile dysfunction. When comparing the two groups of patients, the psychiatric patients reported more current sexual impairments. DISCUSSION: Sexual dysfunction is not limited to the acute phase of psychiatric illnesses. Hence, treatment and follow-up must be geared towards such aspects of the quality of life while focussing on coping strategies.

Sexual dysfunction in psychiatric inpatients the role of antipsychotic medication.

INTRODUCTION: Sexual dysfunction is a common side effect of antipsychotic medication. Although increased prolactin levels caused by antipsychotic agents are believed to play a major role with regard to sexual side effects, the underlying mechanism of antipsychotic agent-induced sexual dysfunction remains poorly understood. METHODS: In a multicentric study 587 psychiatric inpatients were assessed by means of a self-rating sexual questionnaire. Focussing on antipsychotic treatment three subgroups were drawn from the original sample. One group was treated with prolactin-increasing antipsychotics (n=119), the other with prolactin-neutral medication (n=109) and the third patient group was comprised of non-medicated clinical controls (n=105). RESULTS: The majority of all patients (50-75%) reported at least minor sexual dysfunction. On comparison of the subgroups, only female patients treated with prolactin-increasing medication reported more severe sexual dysfunction. However, multiple regression analysis did not confirm an association between the type of treatment and sexual impairment. DISCUSSION: Sexual dysfunction frequently occurs in psychiatric inpatients treated with antipsychotics. Our findings only partly support the assumptions concerning a major role of prolactin-increasing neuroleptics for medication-induced sexual impairment.

Sexual impairment in psychiatric inpatients: focus on depression.

INTRODUCTION: Although sexual side effects are a common reason for noncompliance with medication, information on impairment of sexuality in psychiatric inpatients is scarce. METHODS: In the present multi-center study, data on several aspects of sexual functioning were collected in psychiatric inpatients using a previously validated questionnaire. RESULTS: A high overall prevalence of sexual dysfunction was reported by participants and was highest in depressed subjects. Patients receiving antidepressants suffered from more frequent and more severe impairment of sexuality than did subjects receiving neither antidepressants nor antipsychotics or opioids. DISCUSSION: Judging from this data, sexual impairment appears to be a frequent and underestimated problem in psychiatric inpatients with a high prevalence across all diagnostic groups, particularly in depressed subjects. Female patients attribute this impairment mainly to their mental illness, whereas male patients tend to assign their impairments primarily to their medication.

Acute effects of treatment for prodromal symptoms for people putatively in a late initial prodromal state of psychosis.

BACKGROUND: People in a putatively late prodromal state not only have an enhanced risk for psychosis but already suffer from mental and functional disturbances. AIMS: To evaluate the acute effects of a combined supportive and antipsychotic treatment on prodromal symptoms. METHOD: Putatively prodromal individuals were randomly assigned to a needs-focused intervention without (n=59) or with amisulpride (n=65). Outcome measures at 12-weeks effects were prodromal symptoms, global functioning and extrapyramidal side-effects. RESULTS: Amisulpride plus the needs-focused intervention produced superior effects on attenuated and full-blown psychotic symptoms, basic, depressive and negative symptoms, and global functioning. Main side-effects were prolactin associated. CONCLUSIONS: Coadministration of amisulpride yielded a marked symptomatic benefit. Effects require confirmation by a placebo-controlled study.

Relationship between mirtazapine dose, plasma concentration, response, and side effects in clinical practice.

OBJECTIVE: The aim of this study was to evaluate the benefit of mirtazapine plasma concentration monitoring in a typical clinical setting. METHODS: The relationship between mirtazapine plasma concentration, dose, response, and side effects was studied in 65 inpatients presenting with a depressive episode according to ICD-10. Plasma concentrations, the 17-item Hamilton Depression Rating (HAMD), and the UKU side effect rating were performed weekly. A subgroup of 45 patients was evaluated for a concentration-response relationship. RESULTS: We found a low positive correlation between plasma concentration and dose. A low negative correlation between plasma concentration and increased duration of sleep was noted in the first week of mirtazapine treatment, but not during the entire observation time. Responders to mirtazapine treatment presented with higher plasma concentrations than non-responders, revealing a threshold concentration of 30 ng/mL. CONCLUSION: The mirtazapine dose is a weak predictor of mirtazapine plasma concentrations. Plasma concentration measurements may therefore be useful to adjust mirtazapine doses in non-responders with plasma concentrations below 30 ng/mL. Sedative effects appear temporary and require no plasma concentration control when standard doses are administered.

Randomized double blind comparison of olanzapine vs. clozapine on subjective well-being and clinical outcome in patients with schizophrenia.

OBJECTIVE: This randomized double-blind multicenter trial evaluated the effects of olanzapine vs. clozapine on subjective well-being, quality of life (QOL) and clinical outcome. METHOD: The primary objective was to demonstrate non-inferiority of olanzapine, mean dosage 16.2 +/- 4.8 (5-25 mg/day) vs. clozapine, mean dosage 209 +/- 91 (100-400 mg/day) regarding improvement on the 'Subjective Well-Being under Neuroleptic Treatment' (SWN) Scale after 26 treatment weeks in 114 patients with schizophrenia. Secondary outcome parameters included: Munich QOL Dimension List (MLDL), Positive and Negative Symptom Scale (PANSS), Clinical Global Impression (CGI). RESULTS: SWN scores improved significantly in both groups, olanzapine was non-inferior to clozapine (group difference 3.2 points in favor of olanzapine; 95% CI: 4.2;10.5). MLDL-satisfaction, PANSS and CGI-S improved similarly, olanzapine yielded a higher CGI Therapeutic Index. Individual SWN and PANSS changes correlated only moderately (r = -0.45). CONCLUSION: Olanzapine was non-inferior to clozapine. The lack of a marked correlation between PANSS and SWN improvements indicates that patients and psychiatrists perceive treatment differently.

Neuroimaging and 5-HT2C receptor polymorphism: a HMPAO-SPECT study in healthy male probands using mCPP-challenge of the 5-HT2C receptor.

BACKGROUND: The human 5-HT (2C) receptor gene has been localized on the X chromosome and is expressed in two genetic variants. Whereas previous investigations have suggested that the 5-HT (2C) receptor gene polymorphism is critically involved in the pathogenesis of affective and eating disorders, as yet the functional consequences being associated with the rare serine variant of the 5-HT (2C) receptor in humans are unclear. METHODS: We explored by HMPAO-SPECT if a challenge with the serotonin agonist mCPP, that interacts mainly with the 5-HT (2C) receptor, provokes different patterns of regional cerebral bloodflow (rCBF) as a function of the genetic variant of the receptor. Thus we studied its action in 16 healthy male volunteers carrying the common 5-HT (2C)-cys-23 receptor gene and 16 healthy male volunteers carrying the less frequent 5-HT (2C)-ser-23 receptor gene. RESULTS: We found significant differences in rCBF between the two genotypes after mCPP infusion compared to placebo: In the cysteine group rCBF was increased in the left medial prefrontal cortex and decreased in the left anterior cingulate and right medio-temporal cortex, whereas the serine group showed an increase of rCBF in the left medio- and superior-temporal cortex and in cerebellum and a reduced rCBF in the right medial prefrontal cortex. In addition, there was a significant disordinal interaction of the genotype factors and challenge with an increase of rCBF in the serine group and a decrease in the cysteine group in the left motor cortex and calcarine cortex. Additionally, a decrease of rCBF in the serine-group and a simultaneous increase in the cysteine group was found in the right anterior and the left posterior cingulate cortex. CONCLUSION: These findings suggest that differences in the 5-HT (2C) receptor gene polymorphism has functional consequences due to a different responsiveness of the expressed 5-HT (2C) receptor variants.

Pharmacokinetics of m-chlorophenylpiperazine after intravenous and oral administration in healthy male volunteers: implication for the pharmacodynamic profile.

INTRODUCTION: Serotonin plays an important role in psychiatric diseases, most notably in depression and anxiety. Seven different major serotonin receptor subtypes have been described. Receptor-selective agonists and antagonists have been searched for to find a suitable drug to test the in vivo receptor sensitivity. Different serotonin receptor subtypes take part in the control of neuroendocrine function. m-Chlorophenylpiperazine (mCPP) acts as an agonist to serotonin 2C, 1A, 1B, and 1D receptor subtypes and is applied in challenge tests. The object of this study was to develop a pharmacokinetic-pharmacodynamic model to describe the effects of mCPP on pituitary hormone secretion. METHODS: The hormone and mCPP plasma concentrations were determined after intravenous and oral administration of mCPP to 12 healthy men. The kinetic parameters of mCPP were compared to the drug's effect on hormonal response. RESULTS: After mCPP treatment, ACTH, cortisol, and prolactin levels were significantly increased compared to placebo. There was also a significant increase in clinical response (anxiety, shivering, dizziness, heightened sensitivity toward light and noise, and fear of losing control). Maximum mCPP concentrations varied 2.3-fold after intravenous infusion and 8-fold after oral administration. The absolute bioavailability ranged from 12% to 84%. mCPP's elimination half-life ranged from 2.4 h to 6.8 h after intravenous infusion and from 2.6 h to 6.1 h after oral application. However, the kinetic data as well as the pharmacodynamic response varied to an extent that precluded pharmacokinetic-pharmacodynamic modeling. The wide interindividual variability in mCPP's disposition kinetics could not be fully explained by genetic variation of the mCPP-metabolizing enzyme cytochrome P4502D6, which was determined in all probands. DISCUSSION: Other factors contributing to the variability in disposition kinetics could not be ruled out in this study, suggesting that mCPP is not a suitable model drug to test serotonin 2C receptor activity in vivo.

[Quality of life and therapeutic result in outpatients with schizophrenia under flupenthixol treatment]. / Lebensqualität und Therapieerfolg in der ambulanten Schizophrenie-Therapie mit Flupentixol: Eine Anwendungsbeobachtung.

The objective of this phase IV surveillance study was to document the efficacy and tolerability of flupenthixol as well as the quality of life of patients suffering from schizophrenia and to gain insights into which doses were actually used in specialists outpatients care. The observational variables in this study include demographic variables, details of the diagnosis as well as concomitant diseases. Further evaluations included the assessment of CGI-Scale and subjective patient quality of live assessment using a standardised questionnaire. This questionnaire SWN-K (subjective well-being under neuroleptic treatment; short version) includes 20 items on the state of health with a six-point scale from "absolutely not" to "very strong" respectively. 66.3 % Patients were treated with the depot form of flupenthixol, the rest with oral medication with mean doses of 9.2 mg/d i. m. and 6.3 mg/d p. o. respectively. 78.8 % of patients improved on the CGI-Scale, 5.5 % had an adverse event and in 4.6 % of patients this event was related to the medication. 0.3 % of patients had a serious adverse event. The mean of SWN-K improved from 61.2 to 78.5 in the course of study. The CGI improved from 5.83 to 3.43 in the course of treatment.

[Chronic course and psychosocial disability caused by depressive illnesses in general practice patients during a one year period. Results of a study by the World Health Organization]. / Chronifizierung und psychosoziale Behinderung durch depressive Erkrankungen bei Patienten in der Allgemeinarztpraxis im Einjahresverlauf. Ergebnisse aus einer Studie der Weltgesundheitsorganisation.

As part of an international WHO study on psychological disorders in primary health care, patients were examined for mental disorders and especially depression and social disability in the course of 1 year. Depression is common in primary care (8.6%) and frequently associated with recurring or chronic courses (33.3%). Depression at baseline leads to a 100% increase of lost working days (3.2 per month) 1 year later as compared to patients without depression (1.7). The diagnosis of depression at baseline poses a greater risk for a relevant and lasting psychosocial disability (28.2%) than e.g. chronic somatic illnesses (8.6%). Even the diagnosis of a subthreshold depression leads comparatively to a higher degree of psychosocial disability (15.6% of patients) and days of absenteeism at work during the last month (2.9 days).

Allelic variants of the serotonin(2C) receptor and neuroendocrinological responses to the serotonin(2C) receptor agonist m-chlorophenylpiperazine in healthy male volunteers.

The neurotransmitter serotonin (5-HT) possesses several receptors and their subtypes, some of which are polymorphic, such as the 5-HT(2C) receptor. The latter has been implicated in the control of neuroendocrine function, and has been discussed in the pathophysiology and pharmacotherapy of psychiatric disorders such as obsessive-compulsive disorder, panic disorder and bipolar affective disorder. To investigate whether the 5-HT(2C) receptor polymorphism contributes to the variation of neuroendocrinological responses elicited by activation of the hypothalamic-pituitary axis, we performed an m-chlorophenylpiperazine (m-CPP) challenge and monitored m-CPP and ACTH, cortisol and prolactin plasma levels in 16 healthy male volunteers carrying the common 5-HT(2C)-cys-23 receptor gene and 16 healthy male volunteers carrying the less frequent 5-HT(2C)-ser-23 receptor gene. The 5-HT(2C) polymorphism contributed little to the variation of the scores regarding hormonal responses of ACTH, cortisol and prolactin to the m-CPP challenge. The group carrying the rare 5-HT(2C)-ser-23 receptor gene showed a faster and stronger but not statistically significant ACTH response to the challenge. However, it is noteworthy that there is a 'medium' effect size of the ACTH response according to the conventions of Cohen, and thus comparable to other studies. Both groups show similar major scores in the Temperament and Character Inventory (TCI).

[Flupenthixol--a partial atypical neuroleptic?]. / Flupentixol--ein partiell atypisches Neuroleptikum?

There is no really clear-cut definition for "atypical" neuroleptics. The most convincing definition is draft by characterization of the receptor-binding profile. Most important are: the combined antagonism of D2 and 5-HT2 receptors, the preferential binding to D4 and D3 receptors and a balanced relation of D2 to D1 antagonism. Flupentixol fits into this description as well as some modern neuroleptics widely considered as "atypical" neuroleptics. Clinical criteria--like the absence of EPMS and the improvement of negative symptoms--offer no clear-cut distinction between "typical" and "atypical" neuroleptics, too, because some modern "atypical" neuroleptics lead--dose-dependent--to EPMS, and there is no proven efficacy for some atypical neuroleptics in the treatment of negative symptoms. So, neuroleptics are labelled "atypical" if there is a favourable relation between antipsychotic activity and the degree of EPMS, and if there is at least some efficacy in the treatment of negative symptoms. In this regard, Flupentixol has to be labelled at least a "partial atypical neuroleptic".

Allelic variants of dopamine receptor D4 (DRD4) and serotonin receptor 5HT2c (HTR2c) and temperament factors: replication tests.

The contribution of genetic factors to personality differences between individuals is evidenced by twin and adoption studies. Ebstein et al. [1996, 1997a, 1997b] reported an association between the long repeat allele of the dopamine D4-exon-III receptor polymorphism and the human personality dimension novelty seeking (NS), between the 5HT2c-ser-23 allele and reward dependence, and an interaction between both receptor polymorphisms and reward dependence. Subsequent replication tests mainly reported controversial results for the association between DRD4-exon-III long repeat and NS. We examined a homogeneous study population of 190 healthy male students of middle European descent, aged between 20 and 30 years using Cloninger's TPQ in order to replicate Ebstein's findings. Using a significance level of 1%, no association between the long repeat of the DRD4-exon-III polymorphism and NS and between the 5HT2c receptor polymorphism and reward dependence was found, but a significant interaction effect of DRD4 and 5HT2c receptor polymorphisms on reward dependence was observed in accordance to Ebstein's report.