A phenotype-based genetic association study reveals the contribution of neuregulin1 gene variants to age of onset and positive symptom severity in schizophrenia.

By pure endpoint diagnosis of the disease, the risk of developing schizophrenia has been repeatedly associated with specific variants of the neuregulin1 (NRG1) gene. However, the role of NRG1 in the etiology of schizophrenia has remained unclear. Since Nrg1 serves vital functions in early brain development of mice, we hypothesized that human NRG1 alleles codetermine developmentally influenced readouts of the disease: age of onset and positive symptom severity. We analyzed 1,071 comprehensively phenotyped schizophrenic/schizoaffective patients, diagnosed according to DSM-IV-TR, from the GRAS (Göttingen Research Association for Schizophrenia) Data Collection for genetic variability in the Icelandic region of risk in the NRG1 gene. For the case-control analysis part of the study, we included 1,056 healthy individuals with comparable ethnicity. The phenotype-based genetic association study (PGAS) was performed on the GRAS sample. Instead of a risk constellation, we detected that several haplotypic variants of NRG1 were, unexpectedly, less frequent in the schizophrenic than in the control sample (mean OR=0.78, range between 0.68 and 0.85). In the PGAS we found that these "protective" NRG1 variants are specifically underrepresented in subgroups of schizophrenic subjects with early age of onset and high positive symptom load. The GRAS Data Collection as a prerequisite for PGAS has enabled us to associate protective NRG1 genotypes with later onset and milder course of schizophrenia.

Substantial decrease of psychiatric comorbidity in chronic alcoholics upon integrated outpatient treatment - results of a prospective study.

It is far from clear how comorbidity changes during alcoholism treatment. This study investigates: (1) the course of comorbid Axis I disorders in chronic alcoholics over 2 years of controlled abstinence in the outpatient long-term intensive therapy for alcoholics (OLITA) and (2) the effect of comorbid Axis I and II disorders in this group of patients on subsequent drinking outcome over a four-year follow-up. This prospective treatment study evaluates psychiatric variables of 89 severely affected chronic alcohol dependent patients on admission (t(1)), month 6 (t(2)), 12 (t(3)) and 24 (t(4)). Drinking outcomes have been analyzed from 1998 to 2002. On admission, 61.8% of the patients met criteria for a comorbid Axis I disorder, 63.2% for a comorbid personality disorder. Axis I disorders remit from t(1) (59.0% ill), t(2) (38.5%), t(3) (28.2%) to t(4) (12.8%) (p < 0.0001). Anxiety disorders remit more slowly from t(1) (43.6%) to t(3) (20.5%, p = 0.0086), whereas mood disorders remit early between t(1) (23.1%) and t(2) (5.1%, p = 0.0387) with a slight transient increase at t(3) (10.3%). During the four-year follow-up, the cumulative probability of not having relapsed amounts to 0.59. Two predictors have a strong negative impact on abstinence probability: number of inpatient detoxifications (p = 0.0013) and personality disorders (p = 0.0106). The present study demonstrates a striking remission of comorbid Axis I disorders upon abstinence during comprehensive long-term outpatient alcoholism treatment. The presence of an Axis II rather than an Axis I disorder on admission strongly predicts drinking outcome over a four-year follow-up.

[Comparison of "home treatment" with traditional inpatient treatment in a mental hospital in rural southern Germany]. / Vergleich stationär-psychiatrischer Routinebehandlung mit wohnfeldbasierter psychiatrischer Akutbehandlung ("Home Treatment").

OBJECTIVE: To investigate the clinical effectiveness of "Home Treatment" (HT) in comparison to the usual inpatient treatment in patients with acute psychiatric illness. METHODS: In a prospective observational study we compared 60 of our HT patients to 18 patients receiving inpatient treatment as usual (TAU) with regard to psychopathological symptoms (PANSS, HAM-D 21), global functioning (GAF), symptom severity (HoNOS-D) and sociodemographic parameters at admission and discharge. RESULTS: HT was a feasible alternative in patients with several different psychiatric diagnoses and appeared to be similar to TAU in view of clinical effectiveness. CONCLUSIONS: In potentially suitable patients fulfilling criteria of hospital admission, the alternative of HT can be actively considered.

Preserved vasopressin response to osmostimulation despite decreased basal vasopressin levels in long-term abstinent alcoholics.

BACKGROUND: Basal arginine vasopressin (AVP) plasma levels in alcoholic patients are persistently decreased over months of controlled alcohol abstinence. As a potential explanation of this phenomenon, a reduction of AVP immunoreactive neurons was described in the hypothalamus of alcohol-dependent humans and rodents. This study was therefore designed to examine whether long-term abstinent alcoholics have a compromised response of AVP to osmostimulation. METHODS: Fifteen male alcoholics, aged 42 +/- 2 years, were examined (1) over 12 months of strictly controlled abstinence (longitudinal study) and (2) during an osmostimulation test (5% NaCl infusion at 0.06 ml/kg/min over 2 hr) and were compared with 15 healthy male subjects, aged 41 +/- 2 years. AVP and routine laboratory parameters, including electrolytes and osmolality, were measured. RESULTS: Starting from lower basal concentrations, alcoholics showed increases similar to those of controls in AVP and plasma osmolality after osmostimulation. The first sensation of thirst was announced significantly later by alcoholics than by controls. Twenty-hour-posttest urine volume and sodium excretion were reduced in alcoholics compared with controls. CONCLUSIONS: Despite their persistently decreased basal AVP plasma levels, long-term abstinent alcoholics have a well preserved AVP response to osmostimulation. This finding indicates a peripheral suppression of AVP levels that is most likely due to a regulatory set-point shift toward hypotonic hyperhydration, rather than to a reduced central capacity of AVP secretion.

Erythropoietin: novel approaches to neuroprotection in human brain disease.

With the increased life expectancy in western industrialized countries, the incidence and prevalence of brain diseases dramatically increased. Stroke and a wide spectrum of neuropsychiatric illnesses such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, traumatic head injury, and schizophrenia all lead to severe disability. However, targeted effective therapies for treatment of these diseases are lacking. Even more frustrating is the fact that we do not yet clearly understand the basic mechanisms underlying the disease processes in these conditions. We propose a hypothesis of loss of neuronal function via a final common deleterious pathway in this clinically very heterogeneous disease group. This review presents a novel neuroprotective concept for treatment of brain disease: Erythropoietin (EPO). EPO is a natural body-own-protein hormone that has been used for treatment of anemia for more than a decade. The neuroprotective approach using EPO in brain disease represents a totally new frontier. The "Göttingen EPO-stroke trial" represents the first effective use in man of a neuroprotective therapy in an acute brain disease while the experimental EPO therapy to combat cognitive decline in patients with schizophrenia will be introduced as an example of a neuroprotective strategy for a chronic brain disease.

Therapist rotation--a new element in the outpatient treatment of alcoholism.

For nine years, the so-called "therapist rotation" has been a central part of OLITA, the Outpatient Longterm Intensive Therapy for Alcoholics. Thus far, the participation of several equally responsible therapists in the treatment of a patient has rarely been seen as a specific therapeutic approach. The present article analyzes the therapist rotation from a theoretical and clinical perspective. Articles concerned with the therapeutic alliance in the treatment of substance use disorders are reviewed. Furthermore, the literature on multiple psychotherapy, which may be seen as the precedent of the therapist rotation is surveyed. Based on the efficacy of multiple psychotherapy and the importance of the therapeutic alliance in the treatment of substance use disorders, the present work discusses the therapist rotation as an essential factor for the success of OLITA. It considers both potential advantages and disadvantages for patients and therapists and tries to identify conditions under which this approach appears to promote therapeutic interactions. Finally, the implementation of therapist rotation into OLITA is described, including the theoretical background of the program itself and the treatment procedure. New areas of application for the therapist rotation are discussed.

Persistent alterations of vasopressin and N-terminal proatrial natriuretic peptide plasma levels in long-term abstinent alcoholics.

BACKGROUND: During alcohol withdrawal and early abstinence, severe alterations of electrolyte and water homeostasis and their regulating hormones are well recognized. Almost nothing is known about regeneration of these functions with long-term abstinence. This cohort study was designed to monitor determinants of electrolyte and water balance over 280 days of abstinence in alcohol-dependent men compared with healthy controls. METHODS: Vasopressin (AVP), N-terminal proatrial natriuretic peptide, aldosterone, angiotensin II, and electrolytes, together with major parameters of kidney and liver function, were monitored in 35 male alcoholics aged 44 +/- 8 years. Of these, 21 could be followed up to 280 days of strictly controlled abstinence due to their participation in the Outpatient Long-Term Intensive Therapy for Alcoholics. The control group comprised 20 healthy male volunteers aged 39 +/- 7 years. RESULTS: Basal AVP levels were found to be suppressed over the whole study period. In contrast, N-terminal proatrial natriuretic peptide remained increased over all 280 days. No persistent alterations were found for aldosterone or angiotensin II. Sodium and potassium in plasma and urine returned to normal within a few weeks. Creatinine clearance, urea nitrogen in plasma and urine, urinary osmolality, hematocrit, and hemoglobin remained low as compared with controls over the entire study. CONCLUSIONS: Chronic alcohol abuse causes severe and persistent alterations in the hormonal regulatory systems of electrolyte and water balance. The suppressed basal secretion of AVP may reflect a dysregulation in the brain that influences the hypothalamic-pituitary-adrenal axis function, mood, memory, addiction behavior, and craving during alcohol abstinence. These findings may provide a ground for future therapeutic approaches to stable abstinence.