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Objective To examine characteristics of placebo responders and seek optimal criteria of early improvement with placebo for predicting subsequent placebo response in patients with schizophrenia. Method Data of 672 patients with schizophrenia randomized to placebo in nine double-blind antipsychotic trials were analyzed. Multiple logistic regression analyses were conducted to examine associations between placebo response at week 6 (i.e., a ≥ 25% reduction in the Positive and Negative Syndrome Scale [PANSS] score) and gender, age, study locations, baseline PANSS total or Marder 5-Factor scores, and per cent PANSS score reduction at week 1. Predictive power of improvement at week 1 for subsequent response was investigated; sensitivity and specificity of incremental 5% cutoff points between 5% and 25% reduction in the PANSS total score at week 1 were calculated. Results Per cent PANSS total score reduction at week 1 and lower PANSS Marder disorganized thought scores at baseline were significantly associated with subsequent placebo response. A 10% reduction in a per-protocol analysis or a 15% reduction in last-observation-carried-forward analysis in the PANSS total score at week 1 showed the highest predictive power. Conclusion These findings are informative to identify potential placebo responders at the earliest opportunity for optimal trial design for schizophrenia.

Background Mild cognitive impairment (MCI) has been suggested to represent a prodromal stage of dementia and to confer a high risk for conversion to dementia Alzheimer's type (DAT). Objectives In this study, we examined the predictive value of depressive symptoms and neuropsychological variables on conversion of MCI to DAT. Methods Neuropsychological and clinical follow-up data of 260 MCI patients seen at the Psychiatric Memory Clinic of the Medical University of Innsbruck between 2005 and 2015 were analyzed retrospectively. Depression was assessed using the Geriatric Depression Scale (GDS). Potential predictors of conversion from MCI to DAT were analyzed by logistic regression analyses and additional survival-analytic methods. Results Of the 260 patients (mean age 71.5±7.7 years), 83 (32%) converted to DAT within a mean follow-up time of 3.2±2.2 years and estimated one-year conversion rate of 10.1%. The univariate analysis showed with few exceptions (gender, use of antidepressants, low GDS score) group differences at baseline in patients converted to DAT compared to stable MCI patients. Logistic regression analysis as well as survival analysis revealed moderate to severe depression together with higher age and specific cognitive deficits as predictors of conversion from MCI to DAT. Conclusion Our results support the predictive value of different neuropsychological measures on the progression of DAT. In addition, we found a strong negative influence of depression on conversion to DAT in MCI patients. These results emphasize the importance of assessing depressive symptoms in the early stages of DAT when evaluating the conversion from MCI to DAT.

Objective Improving quality of life (QoL) is an important objective in the treatment of schizophrenia. The aim of the current study was to examine to what extent resilience, self-esteem, hopelessness, and psychopathology are correlated with QoL. Method We recruited 52 out-patients diagnosed with schizophrenia according to DSM-IV criteria and 77 healthy control subjects from the general community. In patients, psychopathology was quantified by the Positive and Negative Syndrome Scale. The following scales were used in both patients and control subjects: the Berliner Lebensqualitatsprofil, the Resilience Scale, the Rosenberg Self-Esteem Scale, and the Beck Hopelessness Scale to assess QoL, resilience, self-esteem, and hopelessness respectively. Results Patients with schizophrenia presented with significantly less QoL, resilience, self-esteem, and hope compared to healthy control subjects. In patients, QoL correlated moderately with resilience, self-esteem, and hopelessness and weakly with symptoms. With respect to the latter, particularly depression and positive symptoms were negatively correlated with QoL. Conclusion Our results highlight the complex nature of QoL in patients suffering from schizophrenia. They underscore that significant efforts are necessary to enhance resilience and self-esteem and to diminish hopelessness as well as affective and positive symptoms in patients with schizophrenia.

Objective The impact of religious/spiritual activities on clinical outcomes in patients with serious mental illnesses remains controversial, which was addressed in this international cross-sectional study. Method Three-hundred sixty-nine subjects were recruited from Austria (n = 189) and Japan (n = 180), consisting of 112 outpatients with paranoid schizophrenia, 120 with bipolar I disorder (DSM-IV), and 137 healthy controls. Religiosity was assessed in terms of attendance and importance of religious/spiritual activities, while resilience was assessed using the 25-item Resilience Scale. General linear models were used to test whether higher religiosity will be associated with higher resilience, higher social functioning, and lower psychopathology. The association between levels of spiritual well-being and resilience was also examined. Results Attendance of religious services (F[4,365] = 0.827, P = 0.509) and importance of religion/spirituality (F[3,365] = 1.513, P = 0.211) did not show significant associations with resilience. Regarding clinical measures, a modest association between higher importance of religion/spirituality and residual manic symptoms was observed in bipolar patients (F[3,118] = 3.120, P = 0.029). In contrast to the findings regarding religiosity, spiritual well-being showed a strong positive correlation with resilience (r = 0.584, P < 0.001). Conclusion The protective effect of religiosity in terms of resilience, social functioning, and psychopathology was not evident in our sample. Spiritual well-being appears more relevant to resilience than religiosity.

Objective Patients with schizophrenia often experience sexual dysfunction (SD), to which disorder-related factors like negative symptoms and nondisorder-related factors can theoretically contribute. Thus, we investigated the correlation of SD and serum prolactin level in patients with schizophrenia during antipsychotic treatment. Methods We included 39 patients with schizophrenia with a mean age of 34.6 years who were switched to second-generation antipsychotics into the study. Sexual adverse effects (via a specific scale) and serum prolactin levels were measured at baseline and week 4. Results In males, mean prolactin levels increased over 4 weeks at a trend level of significance. Although a high incidence of SD was reported at baseline, there were no statistically significant changes over the course of 4 weeks. At baseline, a positive correlation between diminished sexual desire and prolactin levels could be found in men, which was not found in women; at week 4, both male and female patients demonstrated a positive correlation between orgastic dysfunction and prolactin levels. We found significant positive correlations between changes in prolactin levels over 4 weeks and changes in orgastic dysfunction for both sexes. Regression analyses showed prolactin levels at baseline to be a predictor of diminished sexual desire in men. Change in prolactin level was found to be a predictor of change for diminished sexual desire in women and for orgastic dysfunction in both sexes. Conclusion We conclude that the potential of antipsychotics to increase serum prolactin levels imposes a certain risk that patients will experience SD of varying severity.

Background: Antipsychotic-induced metabolic adversities are often difficult to manage. Using concomitant medications to counteract these adversities may be a rational option. Objective: To systematically determine the effectiveness of medications to counteract antipsychotic-induced metabolic adversities in patients with schizophrenia. Data Sources: Published articles until November 2013 were searched using 5 electronic databases. Clinical trial registries were searched for unpublished trials. Study Selection: Double-blind randomized placebo-controlled trials focusing on patients with schizophrenia were included if they evaluated the effects of concomitant medications on antipsychotic-induced metabolic adversities as a primary outcome. Data Extraction: Variables relating to participants, interventions, comparisons, outcomes, and study design were extracted. The primary outcome was change in body weight. Secondary outcomes included clinically relevant weight change, fasting glucose, hemoglobin A1c, fasting insulin, insulin resistance, cholesterol, and triglycerides. Data Synthesis: Forty trials representing 19 unique interventions were included in this meta-analysis. Metformin was the most extensively studied drug in regard to body weight, the mean difference amounting to −3.17 kg (95% CI: −4.44 to −1.90 kg) compared to placebo. Pooled effects for topiramate, sibutramine, aripiprazole, and reboxetine were also different from placebo. Furthermore, metformin and rosiglitazone improved insulin resistance, while aripiprazole, metformin, and sibutramine decreased blood lipids. Conclusion: When nonpharmacological strategies alone are insufficient, and switching antipsychotics to relatively weight-neutral agents is not feasible, the literature supports the use of concomitant metformin as first choice among pharmacological interventions to counteract antipsychotic-induced weight gain and other metabolic adversities in schizophrenia.

The population with schizophrenia is characterised by a leftward shift in handedness-sinistrality. However, findings are inconsistent in chronic patients, and familial sinistrality (FS), defined as the presence of left-handed close relatives, might contribute to the discrepancies. Therefore the aim of this study was to investigate the strength of manual lateralisation in patients with first episode schizophrenia, taking into account familial sinistrality. The Edinburgh Inventory (EI) allowed us to categorise 179 patients from the EUFEST study and 189 controls presenting "strong handedness" (SH: EI absolute value between ∣81∣ and ∣100∣) or "weak-handedness" (WH: EI value between -80 and +80). The nominal logistic regression did not show an FS effect, but a nearly significant interaction between illness and FS (p =.07). There were fewer participants without FS presenting SH among patients (99/151: 65.6%) than among controls (134/164: 81.7%, p =.001). In contrast, the number of participants with FS presenting SH was similar between controls (68%) and patients (75%, p =.57). The presence of left-handed relatives (FS + ) tended to reduce manual lateralisation, but only in controls. This supports the notion that reduced manual lateralisation in schizophrenia is related to the illness rather than to familial left-handedness.

Psychological Medicine, 42 (7), ISSN:0033-2917, ISSN:1469-8978

The use of second-generation antipsychotics (SGAs) is associated with metabolic side effects including weight gain, diabetes mellitus and an atherogenic lipid profile. These adverse effects are not only the risk factors for cardiovascular disease, insulin resistance and diabetes mellitus leading to increased morbidity and mortality but may also impair the patient's adherence to treatment. SGAs in particular are associated with significant weight gain with clozapine and olanzapine carrying the highest risk, whereas newer agents, such as risperidone and aripiprazole, are considered to be less prone to cause weight gain. Consequently, a consensus development conference convened issuing recommendations on patient monitoring when treated with SGAs. The metabolic effects of antipsychotic drugs should be of concern when planning a patient's treatment strategy. Baseline screening and regular follow-up monitoring whose intervals should depend on the individual predisposition are advised. Possible therapeutical strategies for the management of drug-induced obesity include therapeutic approaches, such as life style change and pharmaceutical intervention. Drugs with a weight reducing effect become more important because of the lack of compliance with behavioural intervention. Topiramate, histamine-antagonists, dopaminergic- and serotoninergic agents have shown positive results in the management of psychotropic medication induced weight gain. However, further trials are required to support a specific therapeutical approach as well as studies to investigate the underlying mechanisms for future drug development.

The management of schizophrenia patients remains one of the great challenges in psychiatry. Despite the undisputed effectiveness of antipsychotic drugs, patients and their physicians still face considerable difficulties mainly related to incomplete or lacking treatment response and the inability to predict the individual efficacy and tolerability. In this manuscript we review the key elements of pharmacological treatment of this disorder, encompassing acute and long-term management as well as specific management problems ranging from acutely violent patients to treatment-resistant subjects. Along with general treatment principles, the document provides specific information regarding efficacy and safety features of antipsychotics. Many of the currently available treatment recommendations/guidelines are based on the evidence reviewed here. This review is meant to serve as a guide for clinicians involved in managing schizophrenia, whether in a psychiatric hospital setting or as family physicians in private practice.

Schizophrenia is a severe psychiatric illness with a lifetime morbidity risk of around 1 %. Symptoms include hallucinations, delusions, poverty of thought and emotion and social withdrawal and cognitive deficits. Although newer antipsychotics affecting multiple neurotransmitter receptors facilitate therapy, many patients still do not achieve full response. Despite intensive study, the molecular etiology of schizophrenia remains enigmatic in many ways. The dopamine hypothesis of schizophrenia still plays an important role, although pharmacological studies, brain imaging analyses and genetic research indicate additional dysfunctions of glutamate, GABA and serotonin transmission. This article reviews the pathophysiological background of the disorder, its implications for pharmacological treatment and possible directions for future research.

This review summarizes current key research strategies and the most prominently pursued new potential treatments for schizophrenia. First, new routes of administration for second generation antipsychotics are presented. These include rapidly dissolving tablets, drops and sirups as well as new intramuscular formulations. Newly available short acting and long acting (depot) antipsychotics complement oral antipsychotics so that the full spectrum of routes of administration is now available for second generation antipsychotics. Next to antipsychotic polypharmacy, in which two or more antipsychotics are combined, pharmacological add-on treatments, mainly with benzodiazepines, antidepressants and mood stabilizers enjoy increasing popularity. Most of this practice is driven by personal preferences, clinical experience and marketing rather than evidence based medicine. New pharmacological mechanisms currently utilized in advanced states of development include partial dopamine D2-receptor agonism, supplementation with glutamatergic agents, estrogen and omega-3-fatty acids. While the concept of partial D1-agonism has already led to the successful launch of a new antipsychotic, aripiprazole, the other attempts to improve therapeutic response in schizophrenia patients have so far provided equivocal results. It is argued that they may be helpful for certain subgroups or specific symptoms of schizophrenia patients. In conclusion, many exciting new pharmacological leads are currently pursued and this will very likely augment the options for treating patients with schizophrenia.

The frequent co-occurrence of degenerative cerebellar pathology and schizophrenia, as well as the recently reported increased association rate between autosomal dominant ataxias and major psychosis, strongly suggests the involvement of the cerebellum in the pathophysiology of schizophrenia.1–3 The analysis of associations between psychosis and neurodegenerative diseases may improve our understanding of the pathophysiology of schizophrenia and facilitate the search for susceptibility genes for this disorder.4 To our best knowledge, there have been no previous reports about an association between schizophrenia and the periodic autosomal dominant ataxias, such as episodic ataxia type 1 and type 2 (EA1 and EA2). We present a case of a young man who has been diagnosed with paranoid schizophrenia (ICD-10: F20.0) and episodic ataxia type 2. The patient, a man aged 27 years, was first admitted to our hospital with psychotic symptoms in June 1995. He presented with paranoid delusions and delusions of reference, acoustic hallucinations (commenting voices), formal thought disorder, and behaviour disorganisation, as well as negative symptoms such as blunted affect, poor rapport, and lack of spontaneity. At this time, he was diagnosed as having paranoid schizophrenia (ICD-10: F20.0) and showed a PANSS (positive and negative symptom scale) total score of 137 (fig …

This review summarizes current key research strategies and the most prominently pursued new potential treatments for schizophrenia. First, new routes of administration for second generation antipsychotics are presented. These include rapidly dissolving tablets, drops and sirups as well as new intramuscular formulations. Newly available short acting and long acting (depot) antipsychotics complement oral antipsychotics so that the full spectrum of routes of administration is now available for second generation antipsychotics.

To review the available literature on depressive symptomatology in schizophrenia in order to establish a diagnostic algorithm of depressive syndromes in schizophrenia.A literature search was performed using PubMed and Medline. Additional information was gained by cross-referencing from papers found in the database. Data from controlled studies as well as supplementary information from review articles and psychiatric manuals pertinent to the topic were used. Depressive symptoms were classified with respect to their temporal relationship to acute psychotic symptoms before the background of nosological entities as operationalized by Diagnostic Statistical Manual IV (DSM IV).Depression is a common and devastating comorbid syndrome in patients suffering from schizophrenic disorder. The paper summarizes the relevant diagnostic steps to guide the clinician towards therapeutic interventions, which differ depending on the nature of the depressive syndrome.Differentiating depressives states in schizophrenia has consequences in terms of choosing therapeutic strategies. An algorithm which leads the practitioner to a reliable diagnosis and in consequence to a valid therapy is presented.

The tendency of most of the second generation antipsychotics to induce weight gain to a larger extent than that of traditional neuroleptics has renewed the interest in weight problems of patients with schizophrenia. Drug-induced weight gain has been identified as a major risk factor for various medical disorders that might be responsible for the increased morbidity and mortality rates of patients suffering from schizophrenia. Also, it has a major impact on compliance. This article focuses on the clinical relevance of increased body weight in schizophrenia. It outlines screening and management options to prevent and/or manage weight gain associated with schizophrenia in everyday clinical practice. The first strategies should be to identify obesity-prone patients at the beginning of treatment and provide information (to patients and caregivers) about the risks of weight gain and its consequences. Additionally, the possibility of weight gain calls for a regular monitoring of weight and weight-related laboratory parameters. The patients should also be offered dietary advice as well as regular exercise and behavior modification programs. Physicians must be aware of the problem of weight gain associated with schizophrenia and choose antipsychotic medication carefully, especially in patients at high risk for weight gain.

Despite the demonstrated efficacy of antipsychotics the relapse rate among patients with schizophrenia remains high. One major reason for this is non-compliance. In this article we review different factors influencing compliance and discuss possibilities to enhance compliance among schizophrenic patients.This review is based on a systematic literature search in Medline.We summarize the four main factors (patient-, environment-, physician- and treatment-related) that influence compliance and discuss possible measures to enhance compliance. Next to many other variables discussed in more detail, it is crucial to ensure a positive doctor-patient relationship and to provide sufficient information about the benefit/risk ratio of the medication as well as about the illness itself to build up and sustain compliance. Significant others should be included into the therapeutic alliance whenever possible.Despite many published reports on compliance, it remains to be a problem of eminent clinical relevance. Clinicians must not underestimate it in order to optimize the treatment of patients with schizophrenia.

In-patient suicides continue to be a matter of concern in hospital psychiatry. In-patients at risk for suicide need to be identified.In-patient suicides in two psychiatric hospitals were assessed over a time-span of 8 years. Cases were detected by comparing police suicide data with the hospitals' admission and discharge records. Further information was then gathered from patients' records.During the period under investigation 44 in-patients committed suicide, the majority of them being diagnosed with affective disorders (45.4%) or schizophrenia (27.3%). The most commonly used method was 'jumping in front of a vehicle' (34.1%); 79.5% were treated in an open ward at the time of their suicide, 15.9% in a locked unit. The majority of open ward suicides happened outside the hospital; 39.4% of patients had left the ward without giving notice.Additional cautionary measures are warranted especially for patients in open wards.

Clinical studies with clozapine have clearly demonstrated its superior efficacy over that of conventional antipsychotics in treatment-resistant schizophrenic patients. In comparative trials with these drugs, considerably more patients respond to treatment with clozapine than to conventional antipsychotic medication. Recently, new antipsychotics, such as olanzapine, quetiapine, risperidone, sertindole, and zotepine, have been introduced, but extensive data on their effects in treatment-resistant patients are not yet available. Published studies have drawn criticism in terms of inappropriate titration schedules, nonequivalent dosing between treatment groups, short treatment duration, and inadequate sample sizes. Further research will be needed to determine whether novel antipsychotics may substitute for clozapine in the future or whether clozapine will retain its unique role in the management of patients suffering from difficult-to-treat schizophrenic disorders.

Until the mid 20th century the pharmacological management of patients suffering from schizophrenia consisted exclusively of unspecific sedative measures. This situation changed dramatically with the advent of chlorpromazine which had been synthesized by chemists at Rhone-Poulenc in 1950. Originally found successful in manic patients, it was quickly realized that this drug was also very useful to treat agitated patients with schizophrenia and that its effect went way beyond mere sedation (Deniker 1988). After a number of scientific reports in the early 1950s, the term neuroleptic, signifying a “softening of the nervous system” was coined in 1955. The year before, Steck and Haase had independently described the “extrapyramidal and diencephalic syndrome” (Steck 1954) and the “psychomotor Parkinson syndrome” (Haase 1954), thereby recognizing a specific side effect profile of these new medications. In 1958 researchers at Janssen synthesized haloperidol (Niemegeers 1988), which was licensed in 1959. In the same year chlorprothixene, the first thioxanthene neuroleptic, was introduced by Lundbeck (Lassen 1988). The preclinical screening of clozapine started in 1960. Scientists at Dr. Wander AG suggested at first that this drug might be a strongly sedating analgesic (Stille and Fischer-Cornelssen 1988).

Compliance is the degree of adherence to an appropriate medical advise. Especially in longterm treatment, therapeutic success depends largely on patient compliance. In the treatment of schizophrenia with antipsychotic agents a non-compliance rate up to 80% is the reason for the difference between the relatively good outcome of controlled treatment studies and the bad results in clinical reality. 4 groups of variables can be identified, which influence compliant behaviour: patient-related factors, factors related to the patients environment, physician-related factors, and medication-related factors. Possibilities to ameliorate the compliance of schizophrenic patients during long-term therapy are discussed.

A number of novel antipsychotics were registered and introduced into clinical practice in the last decade. These include olanzapine, quetiapine, risperidone, sertindole and zotepine as well as ziprasidone, which is still in the registration process. It quickly became apparent, that it is not always easy to translate results from phase II and III clinical trials into everyday clinical practice. In this context, we discuss methodological aspects that mainly deal with selection of patients for clinical trials and clinical trial methodology. Next to that, an overview of the current knowledge concerning novel antipsychotics is given. There is no doubt that these drugs broaden the therapeutic spectrum made available to patients suffering from schizophrenia. On the other hand, it is evident that there is still a need for a critical evaluation of the risk-benefit-ratio of novel antipsychotics. Clinical psychiatrists also face the challenge to modify some of the traditional treatment approaches. These prerequisites will allow the embedding of novel antipsychotics into modern integrative treatment concepts of schizophrenia.

These guidelines for depot antipsychotic treatment in schizophrenia were developed during a two-day consensus conference held on July 29 and 30, 1995 in Siena, Italy. Depot antipsychotic medications were developed in the 1960s as an attempt to improve the long-term treatment of schizophrenia (and potentially other disorders benefiting from long-term antipsychotic medication). Depot drugs as distinguishable from shorter acting intramuscularly administered agents can provide a therapeutic concentration of at least a seven day duration in one parenteral dose. The prevention of relapse in schizophrenia remains an enormous public health challenge worldwide and improvements in this area can have tremendous impact on morbidity, mortality and quality of life, as well as direct and indirect health care costs. Though there has been debate as to what extent depot (long-acting injectable) antipsychotics are associated with significantly fewer relapses and rehospitalizations, in our view when all of the data from individual trials and metaanalyses are taken together, the findings are extremely compelling in favor of depot drugs. However in many countries throughout the world fewer than 20% of individuals with schizophrenia receive these medications. The major advantage of depot antipsychotics over oral medication is facilitation of compliance in medication taking. Non-compliance is very common among patients with schizophrenia and is a frequent cause of relapse. In terms of adverse effects, there are not convincing data that depot drugs are associated with a significantly higher incidence of adverse effects than oral drugs. Therefore in our opinion any patient for whom long-term antipsychotic treatment is indicated should be considered for depot drugs. In choosing which drug the clinician should consider previous experience, personal patient preference, patients history of response (both therapeutic and adverse effects) and pharmacokinetic properties. In conclusion the use of depot antipsychotics has important advantages in facilitating relapse prevention. Certainly pharmacotherapy must be combined with other treatment modalities as needed, but the consistent administration of the former is often what enables the latter.

Die Gruppe der sogenannten atypischen Antipsychotika ist pharmakologisch und klinisch heterogen. Es existiert kein verbindlicher Konsens daruber, wann ein Antipsychotikum als „atypisch“ zu kennzeichnen ist (Meltzer 1991). Letztlich umschreibt die Atypika-Definition klinisch festgestellte Besonderheiten der „Muttersubstanz“ Clozapin im Vergleich zu typischen Neuroleptika. Hierbei wurde in der Vergangenheit zunachst auf das Fehlen signifikanter extrapyramidalmotorischer Nebenwirkungen bei Gabe einer antipsychotisch wirksamen Dosis abgehoben, weiterhin auf das Fehlen von Spatdyskinesien und -dystonien. Im Gefolge der wegweisenden Studie von Kane et al. (1988) stand danach im Mittelpunkt des klinischen Interesses die Moglichkeit, mit atypischen Antipsychotika die als „schizophrenes Negativsyndrom“ (Andreasen 1982) zusammengefaste Symptomgruppe besser als mit typischen Neuroleptika beeinflussen zu konnen (siehe Exkurs: Atypische Eigenschaften klassischer Substanzen).

Suicide on railways (either by being run over by or jumping in front of a train) is one of the "hardest' suicide methods. In Austria, 617 suicides or attempted suicides on railways were registered between 1990 and 1994. This amounts to 5.73% of all suicides committed in this period with women showing a higher percentage than men. In both men and women there was a predominance of younger age groups; the mean age was higher in women than in men (48.0 vs 40.4 years). There was a significant increase in suicides or attempted suicides on railways after a television report on the stress suffered by train drivers concerning possible suicides. Persuading the mass media to treat the subject of "suicide' with reserve and with greater caution, even when not presenting a distinct suicide model, may be of importance in general suicide prevention.

Es wird uber die Schwangerschaft einer 31 jahrigen Patientin, die seit ihrem 24 Lebensjahr an Schizophrenie erkrankt ist, berichtet. Die Patientin steht unter Clozapin-Dauermedikation, herkommliche Neuroleptika wurden nicht toleriert. Mit einer Tagesdosis von 100mg war die Patientin die letzten 5 Jahre vor ihrer Schwangerschaft symptomfrei. Wegen Kinderwunsch versuchte die Patientin Clozapin vor einer geplanten Schwangerschaft abzusetzen, das Wiederauftreten von Halluzinationen zwang jedoch zur Beibehaltung der Medikation. Nach eingehender medizinischer Beratung entschlos sich die Patientin zur Schwangerschaft unter Clozapin-Medikation.

We present a comparison of the results from two studies of patients on clozapine. The American study (n = 84; Hillside Hospital, Glen Oaks, NY) and the European study (n = 63; Innsbruck University Clinics, Innsbruck, Austria) both examine efficacy and side effects in schizophrenic patients on this atypical neuroleptic. There is a very substantial difference in the dosing regimen used on both continents and this is reflected in the studies reported. A question with major clinical implications is whether the higher doses commonly used in the United States lead to a better outcome or a different profile of side effects. Outcome as a function of serum concentration will be examined. Results confirm a lower dose, lower clozapine blood level, and a lesser degree of side effects in the Austrian cohort when compared to the American sample. Surprisingly, the clinical efficacy of the lower dosing regimen was superior to the higher dose. Reasons for this anomaly are explored.

The side effects of antipsychotic drugs have always been a major concern for clinicians and the appreciation of their importance in the treatment of schizophrenia has increased steadily over the years. Epidemiological studies as well as trials of the prevention and treatment of antipsychotic side effects are the consequences of this development. Results of these studies also have important implications for improving compliance and quality of life in schizophrenic patients. Thus, side effects research has made the treatment of schizophrenia not only safer but also more effective. Next to a brief overview of some of the more important adverse events and their treatment, we will also discuss these effects in the context of compliance, treatment response and the influence of anti-EPS drugs.

The aim of the study was to shed more light on the incidence and course of clozapine-induced transient white blood count (WBC) disorders.In an analysis of our clozapine drug monitoring program, we evaluated the data of 68 patients receiving clozapine for the first time. Incidence rates were calculated by actuarial life table analysis. The potential influence of sex, age, dose, and plasma level was evaluated using discriminant analysis.Two patients developed progressive neutropenia, leading to agranulocytosis in one case. We also found the following transient hematologic dysfunctions: neutropenia (22.0%), eosinophilia (61.7%), and leukocytosis (40.9%). One patient showed chronic leukocytosis. Additionally, minor changes in the number of lymphocytes, monocytes, and basophilic granulocytes were detected in the study population.Hematologic side effects are frequently induced by the atypical antipsychotic clozapine. Next to agranulocytosis, a progressive and potentially lethal hematologic adverse effect, most of the WBC disorders are transient and appear to be harmless.

The report (1) provides an overview of clozapine doses used in trials conducted in Europe and the United States, (2) compares data on efficacy, and (3) compares side effects of clozapine from recent European and U.S. investigations. The reviewed European trials used a mean dose of 283.7 mg/day, while the mean dose in the U.S. studies was 444 mg/day. Even though the mean doses used in the United States are considerably higher than those used in Europe, the response rates for the two continents are strikingly similar. The main differences in a comparison of two samples evaluated in New York and Innsbruck were found in the prevalence of seizures (Innsbruck, 0%; United States, 7.1%) and confusion (Innsbruck, 0%; United States, 14%). Excitement was less prevalent in the U.S. study. The data presented appear to suggest that a lower dose of clozapine may be as effective as a higher dose in the management of treatment-resistant schizophrenic patients and may cause fewer side effects.

The phenylpiperidine derivative paroxetine is a selective serotonin reuptake inhibitor. In a double-blind 6-week trial, paroxetine was compared with amitriptyline in hospitalized patients suffering from major depression (DSM-III). One hundred fifty-three patients were enrolled in the study in seven centers in Austria and Germany. Results showed similar efficacy of both drugs after 6 weeks. The differences between groups in Montgomery-Asberg Depression Rating Scale and Clinical Global Impression ratings did not reach statistical significance at any time. Side effects were distributed similarly but with a significantly higher incidence of anticholinergic effects in patients treated with amitriptyline (por = 0.001), whereas agitation and insomnia were registered more often in the paroxetine group. This study supports the antidepressive efficacy of paroxetine in a sample of severely depressed inpatients.

The prophylaxis of unipolar depression is still controversial. Some physicians prefer lithium, others maintenance treatment with antidepressants. The role of carbamazepine remains unclear. Only a few patients have been described in the literature; most are lithium nonresponders or rapid cyclers.In an open-label naturalistic study, 15 patients suffering from major depression with melancholia (DSM-III, 296.2, 296.3) and receiving long-term prophylaxis with carbamazepine were followed for 5 years. Four had been pretreated with lithium without satisfactory effects, 11 were prophylaxis naive. We compared the number of depressive episodes before and during carbamazepine treatment.The mean time span patients received carbamazepine was 49.5 months. Seventy-three percent (11 of 15) of the patients gained substantial benefit from carbamazepine. Side effects were infrequent.Our results encourage further controlled and prospective studies using carbamazepine for maintenance treatment of patients with unipolar major mood disorder.

Clozapin ist ein Antipsychotikum, das nunmehr seit uber 30 Jahren in verschiedenen europaischen Landern und seit kurzer Zeit auch in den USA registriert ist. Die Wirksamkeit sowie gewisse Vorteile gegenuber herkommlichen Antipsychotika (v. a. im Bereich extrapyramidalmotorischer Nebenwirkungen) sind gut dokumentiert (Baldessarini u. Frankenburg 1991; Claghorn et al. 1987; Goodwin 1991; Kane et al. 1981, 1988; Meltzer et al. 1991; Naber u. Hippius 1990; Perez Urdaniz et al. 1990; Pilowsky et al. 1992).

When antipsychotics were introduced into clinical psychiatry in the 1950’s extrapyramidal motor side effects (EPS) were felt to be an integral part of their profile of action. The propensity to induce EPS in animal models was an important part of the screening procedures in the development of antipsychotics. The term “neuroleptic” that was coined to characterize this new class of drugs had to do with their impact on motor functions. It wasn’t until the development of clozapine that psychopharmacologists realized that antipsychotic efficacy is not necessarily linked to EPS.

In addition to other factors such as type and duration of treatment, patient- and illness-related variables and other psychosocial features, side effects are known to exert a significant influence on the compliance with antipsychotic treatment. This has been demonstrated for extrapyramidal motor side effects and akathisia, sedation, weight gain and sexual dysfunctions. Other adverse events interfering with the patients' social roles also interfere with the patients' willingness to comply with treatment. It is important to acknowledge this not only in the acute treatment of schizophrenia but especially during maintenance and prophylactic treatment. Compliance can be considerably improved by a) adequately informing the patient about the risks and nature of side effects and b) by recognizing and treating side effects, since prevention of adverse events is not easily achieved. An underestimation of the influence of side effects on compliance will often lead to treatment failures that are erroneously attributed to treatment resistance.

Clozapine has advantages over standard antipsychotics in refractory schizophrenia. Studies on the efficacy of clozapine in the maintenance treatment are sparse and suffer from methodological limitations. Despite this fact clozapine ranked second in a survey dealing with the preference of this antipsychotic in the long-term treatment of schizophrenia. Doctors report on using a mean of 130 mg/d in this indication which is considerably less than the doses used in most of the published long-term trials. The discrepancy between the popularity of clozapine and the lack of sound empirical data on its long-term efficacy is discussed.

Schon kurz nach der Markteinfuhrung von Clozapin machten Norris et al. [6] auf eine vermehrte Gewichtszunahme aufmerksam. Wahrend der letzten Jahre beschrieben immer mehr Autoren diese Nebenwirkung. Bisher existiert jedoch nur eine Studie, welche den Unterschied zu Standardneuroleptika untersucht [4]. Diese Arbeitsgruppe beschreibt eine signifikant grosere Gewichtszunahme bei mit Clozapin behandelten Patienten im Vergleich zu Fluphenazin.

Die vorliegende Arbeit beschreibt den Zusammenhang zwischen Dosis und Plasmaspiegel und den Einflus von Nikotin und Geschlecht bei 148 Patienten. Die Regressionsanalyse ergab einen linearen Zusammenhang zwischen verabreichter Tagesdosis (12,5–700 mg/die) und Plasmaspiegel. Mannliche Patienten erreichten bei einer bestimmten Dosis nur 69,3% der Plasmakonzentrationen weiblicher Patienten. Die durchschnittlichen Plasmaspiegel von Rauchern waren um 18,2% niedriger als die der Nichtraucher.

Patienten, die uber langere Zeit Benzodiazepine (BZD) konsumieren, laufen in Gefahr, davon abhangig zu werden. Rickels et al. [6] berichteten von Entzugssymptomen bei 40% der Patienten, die langer als ein Jahr BZD einnahmen. Ein Grosteil der BZD-Verwender nehmen diese Substanzen allerdings regelmasig uber grose Zeitraume ein [2,4].

Seit Einfuhrung der trizyklischen Antidepressiva in die Behandlung der Depression beschaftigte sich eine Vielzahl von Arbeiten mit den Problemen unterschiedlicher Wirkungen und Nebenwirkungen in bezug auf Plasmaspiegel, Applikationsart und Dosierung.

In den letzten Jahren konnten uber 50 Peptide im Gehirn von Saugetieren entdeckt werden, die zur elektrochemischen Reizubertragung in der Lage sind. Die Rolle, die Neuropeptide im Rahmen psychiatrischer Erkrankungen spielen, ist allerdings bislang weitgehend unklar. Im letzten Jahrzehnt mehrten sich die Hinweise fur eine Uberaktivitat oder eine Dysregulation im zentralen Endorphinsystem schizophrener Patienten [2], wobei die Ergebnisse allerdings heterogen sind. Van Kammen und Mitarbeiter [3] beschrieben eine signifikante Verminderung von Vasopressin bei mannlichen Schizophrenen im Vergleich zu gesunden Kontrollpersonen. Von anderen Autoren [1] wurden Veranderungen im Neurotensin-System Schizophrener beschrieben. Zusammenfassend last sich beim derzeitigen Stand der Forschung keine klare Aussage uber regelhafte Veranderungen von Neuropeptiden bei schizophrenen Patienten machen, ganz zu schweigen von Aussagen zur Rolle der Neuropeptide in der Pathophysiologie und Pathogenese schizophrener Erkrankungen.