Henning Krampe

Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin

Schizophrenia is increasingly recognized as a neurodevelopmental disease with an additional degenerative component, comprising cognitive decline and loss of cortical gray matter. We hypothesized that a neuroprotective/neurotrophic add-on strategy, recombinant human erythropoietin (rhEPO) in addition to stable antipsychotic medication, may be able to improve cognitive function even in chronic schizophrenic patients. Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter, proof-of-principle (phase II) study. This study had a total duration of 2 years and an individual duration of 12 weeks with an additional safety visit at 16 weeks. Chronic schizophrenic men (N=39) with defined cognitive deficit (⩾1 s.d. below normal in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)), stable medication and disease state, were treated for 3 months with a weekly short (15 min) intravenous infusion of 40 000 IU rhEPO (N=20) or placebo (N=19). Main outcome measure was schizophrenia-relevant cognitive function at week 12. The neuropsychological test set (RBANS subtests delayed memory, language–semantic fluency, attention and Wisconsin Card Sorting Test (WCST-64) – perseverative errors) was applied over 2 days at baseline, 2 weeks, 4 weeks and 12 weeks of study participation. Both placebo and rhEPO patients improved in all evaluated categories. Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia-related cognitive performance (RBANS subtests, WCST-64), but no effects on psychopathology or social functioning. Also, a significant decline in serum levels of S100B, a glial damage marker, occurred upon rhEPO. The fact that rhEPO is the first compound to exert a selective and lasting beneficial effect on cognition should encourage new treatment strategies for schizophrenia.

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 Alzheimers disease, Parkinsons 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.

Recombinant Human Erythropoietin: Novel Strategies for Neuroprotective/Neuro-regenerative Treatment of Multiple Sclerosis

Treatment of multiple sclerosis (MS) is still unsatisfactory and essentially non-existing for the progressive course of the disease. Recombinant human erythropoietin (EPO) may be a promising neuroprotective/neuroregenerative treatment of MS. In the nervous system, EPO acts anti-apoptotic, antioxidative, anti-inflammatory, neurotrophic and plasticity-modulating. Beneficial effects have been shown in animal models of various neurological and psychiatric diseases, including different models of experimental autoimmune encephalomyelitis. EPO is also effective in human brain disease, as shown in double-blind placebo-controlled clinical studies on ischemic stroke and chronic schizophrenia. An exploratory study on chronic progressive MS yielded lasting improvement in motor and cognitive performance upon high-dose long-term EPO treatment.

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.

The influence of personality factors on disease progression and health‐related quality of life in people with ALS

We aimed to perform a prospective long‐term follow‐up of health‐related quality of life (QOL) in ALS and to investigate the relationship of personality factors with changes in QOL and disease progression. Data on QOL were collected prospectively for 12 months from 31 ALS patients. Personality factors were studied using the NEO‐FFI (NEO Five Factor Inventory). Monthly self‐ratings of global QOL, and seven health‐related QOL functions, as well as ALSFRS (ALS Functional Rating Scale) scores were analyzed using a linear mixed model approach. QOL and ALSFRS scores decreased during follow‐up. Patients who scored higher on the agreeableness personality dimension, despite similar total duration of disease, had higher QOL at the beginning of the follow‐up period but the reduction of QOL over time was significantly steeper than in patients who scored lower on agreeableness, associated with faster disease progression. These findings suggest that being less agreeable might serve as a protective factor with respect to QOL and disease progression in ALS.

Postoperative delirium is an independent risk factor for posttraumatic stress disorder in the elderly patient: a prospective observational study.

BACKGROUND Posttraumatic stress disorder (PTSD) may appear after hospitalisation for surgery with general anaesthesia in elderly patients. Prevalence and risk factors in this setting are unknown. Postoperative delirium could be a risk factor. OBJECTIVE The purpose of this study was to identify the prevalence of, and risk factors for, PTSD 3 months after surgery with general anaesthesia in elderly patients. DESIGN A prospective, clinical observational study. SETTING This study was carried out between March 2009 and May 2010 in a German university hospital in Berlin and was part of a larger study focusing on depth of anaesthesia. PATIENTS Inclusion criteria: at least 60 years of age; noncardiac surgery with general anaesthesia. Exclusion criteria: impaired preoperative cognitive function [mini-mental state examination (MMSE) score <24]; expected surgery time less than 1 h; nonproficiency in the German language. INTERVENTIONS None. MAIN OUTCOME MEASURES Screening for PTSD 3 months after surgery using the screening instrument Post-Traumatic Stress Syndrome 14-Questions Inventory Score (PTSS-14). The following risk factors for PTSD 3 months after surgery were tested: age; American Society of Anesthesiologists physical status; sex; duration of anaesthesia; postoperative delirium; PTSS-14 score 7 days after surgery; postoperative vomiting and nausea; postoperative pain; and preoperative depression. STATISTICS Univariate statistical analysis was performed with Fishers exact test and Spearman correlation. A backward logistic regression was performed. RESULTS A total of 559 out of 1277 patients were included. Sixty-six patients (12%) were identified with PTSD 3 months after surgery. Seventy-seven patients (14%) were identified with postoperative delirium. Independent associated factors in the backward logistic regression were postoperative delirium (risk factor) and preoperative depression (protective factor). CONCLUSION The prevalence of PTSD 3 months after surgery in elderly patients was high using the screening instrument PTSS-14. Postoperative delirium is a risk factor for PTSD 3 months after surgery. TRIAL REGISTRATION ISRCTN Register: 36437985. http://www.controlled-trials.com/ISRCTN36437985/

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.

Depression and essential health risk factors in surgical patients in the preoperative anaesthesiological assessment clinic.

Background and objective Depression is common in patients with medical illness. However, little is known about frequency and clinical relevance of preoperative depression in surgical patients. The objective of this study was to investigate the frequency of depression, essential health risk factors and hospital length of stay (LOS) of patients in preoperative anaesthesiological assessment. Methods Patients were consecutively screened in the preoperative anaesthesiological assessment clinics. In total, 5429 patients gave written informed consent to perform a computerised self-assessment of lifestyle factors, including alcohol use, tobacco smoking, weight, physical status, physical exercise, sleeping disturbance, subjective health and sense of coherence (SOC). Depression was defined by a WHO-5 well-being score of 13 or less. LOS was obtained from the electronic patient management system. Results A clinically relevant depressive state was found in 29.7% of the patients. Patients with depression had a median LOS of 6.0 days as compared to patients with positive well-being who had a LOS of 4.8 days (P < 0.001). Worse subjective health, less physical exercise and experience of SOC, as well as more severe sleeping disturbances were independently and significantly associated with depression (P < 0.001). Conclusion Clinically significant depressive states are frequent conditions in surgical patients of preoperative anaesthesiological assessment and are associated with an increased LOS. Different clinical pathways delivering adequate preoperative information according to the needs, considering subjective health and SOC of the patient as well as avoiding immobilisation and sleep disturbances during hospital stay should be considered. Long-term treatment programmes including brief intervention in the hospital and an outpatient concept should be offered.

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.

Effects of an Innovative Psychotherapy Program for Surgical Patients: Bridging Intervention in Anesthesiology--A Randomized Controlled Trial.

Background:The stepped care program Bridging Intervention in Anesthesiology (BRIA) aims at motivating and supporting surgical patients with comorbid mental disorders to engage in psychosocial mental healthcare options. This study examined the efficacy of BRIA. Methods:This randomized, parallel-group, open-label, controlled trial was conducted in the preoperative anesthesiological assessment clinics and surgical wards of a large university hospital in Germany. A total of 220 surgical patients with comorbid mental disorders were randomized by using the computer-generated lists to one of two intervention groups: BRIA psychotherapy sessions up to 3 months postoperatively (BRIA) versus no psychotherapy/computerized brief written advice (BWA) only. Primary outcome was participation in psychosocial mental healthcare options at month 6. Secondary outcome was change of self-reported general psychological distress (Global Severity Index of the Brief Symptom Inventory) between baseline and month 6. Results:At 6-month follow-up, the rate of patients who engaged in psychosocial mental healthcare options was 30% (33 of 110) in BRIA compared with 11.8% (13 of 110) in BWA (P = 0.001). Number needed to treat and relative risk reduction were 6 (95% CI, 4 to 13) and 0.21 (0.09 to 0.31), respectively. In BRIA, Global Severity Index decreased between baseline and month 6 (P < 0.001), whereas it did not change significantly in BWA (P = 0.197). Conclusions:Among surgical patients with comorbid mental disorders, BRIA results in an increased engagement in subsequent therapy options and a decrease of general psychological distress. These data suggest that it is reasonable to integrate innovative psychotherapy programs into the context of interdisciplinary surgical care.