Episode-specific differential gene expression of peripheral blood mononuclear cells in rapid cycling supports novel treatment approaches.

Molecular mechanisms underlying bipolar affective disorders are unknown. Difficulties arise from genetic and phenotypic heterogeneity of patients and the lack of animal models. Thus, we focused on only one patient (n = 1) with an extreme form of rapid cycling. Ribonucleic acid (RNA) from peripheral blood mononuclear cells (PBMC) was analyzed in a three-tiered approach under widely standardized conditions. Firstly, RNA was extracted from PBMC of eight blood samples, obtained on two consecutive days within one particular episode, including two different consecutive depressive and two different consecutive manic episodes, and submitted to (1) screening by microarray hybridizations, followed by (2) detailed bioinformatic analysis, and (3) confirmation of episode-specific regulation of genes by quantitative real-time polymerase chain reaction (qRT-PCR).Secondly, results were validated in additional blood samples obtained one to two years later. Among gene transcripts elevated in depressed episodes were prostaglandin D synthetase (PTGDS) and prostaglandin D2 11-ketoreductase (AKR1C3), both involved in hibernation. We hypothesized them to account for some of the rapid cycling symptoms. A subsequent treatment approach over 5 months applying the cyclooxygenase inhibitor celecoxib (2 x 200 mg daily) resulted in reduced severity rating of both depressed and manic episodes. This case suggests that rapid cycling is a systemic disease, resembling hibernation, with prostaglandins playing a mediator role.

Development of an outcome prediction measure for alcoholism therapy by multimodal monitoring of treatment processes.

Outcome prediction in alcoholism therapy is of major sociopolitical and economic significance. Instruments based on psychotherapeutic processes are lacking. Therefore, treatment processes of 64 chronic alcohol dependent patients have been investigated at three time-points, t(1) (week 3), t(2) (month 6), and t(3) (month 12) during the first year of a comprehensive outpatient treatment program, guaranteeing strictly controlled alcohol abstinence. Main focus of the study was the prediction of cumulative abstinence probability over a follow-up period of up to 4 years based on these treatment processes. One hundred and seventy-five video recordings of therapy sessions were analyzed with the behavior observational system VAMP (Video-Assisted Monitoring of Psychotherapeutic Processes in Chronic Psychiatric Disease). Patients' self-rating of treatment processes was measured with questionnaires for self-efficacy, abstinence confidence, self-consciousness and stress coping. Prediction of cumulative abstinence probability was determined with Cox regression analysis. By integrating the observer rated process variables with the highest predictive validity, the composite score TOPPS (Therapy Orientation by Process Prediction Score) was constructed. It includes the process variables experience of resources, abstinence self-efficacy, implicit craving, relapse alertness, relapse risk, disease concept, dysfunctional therapeutic engagement, and dysfunctional problem solving of current problems. Whereas patients' self-rating of treatment processes was insufficiently predictive, the TOPPS strongly predicted four-year abstinence probability at any of the 3 time-points (p<0.001). The results suggest to validate the item combination described in the TOPPS in addiction therapy as a treatment guideline of individual relapse prevention strategies.

Recombinant human erythropoietin in the treatment of human brain disease: focus on cognition.

Treatment of human brain disease with erythropoietin (EPO) in order to achieve neuroprotection and/or neuroregeneration represents a totally new frontier in translational neuroscience. Rather than specifically targeting the cause of a particular disease entity, EPO nonspecifically influences components of the "final common pathway" that determine disease severity and progression in a number of entirely different brain diseases. EPO acts in an antiapoptotic, anti-inflammatory, antioxidant, neurotrophic, angiogenetic, stem cell-modulatory fashion. Importantly, it appears to influence neural plasticity. Most likely due to these properties, EPO has been found by many investigators to be protective or regenerative and to improve cognitive performance in various rodent models of neurological and psychiatric disease. The "Göttingen-EPO-stroke trial" has provided first promising data on humans for a neuroprotective therapy of an acute brain disease. Experimental EPO treatment to improve cognitive function in patients with schizophrenia represents a novel neuroregenerative strategy for a chronic brain disease. An exploratory trial in chronic progressive multiple sclerosis as an example of an inflammatory disease of the nervous system yielded first positive results of EPO treatment on both motor function and cognition. These promising results are just the beginning and will hopefully stimulate further work along these lines.

Outpatient Long-term Intensive Therapy for Alcoholics (OLITA): a successful biopsychosocial approach to the treatment of alcoholism.

Alcohol dependence is a frequent, chronic, relapsing, and incurable disease with enormous societal costs. Thus, alcoholism therapy and research into its outcome are of major importance for public health. The present article will: (i) give a brief overview of the epidemiology, pathogenesis, and treatment outcomes of alcohol dependence; (ii) introduce the basic principles of outpatient long-term therapy of alcohol-dependent patients; and (iii) discuss in detail process-outcome research on Outpatient Long-term Intensive Therapy for Alcoholics (OLITA). This successful biopsychosocial approach to the treatment of alcoholism shows a 9-year abstinence rate of over 50%, a re-employment rate of 60%, and a dramatic recovery from comorbid depression, anxiety disorders, and physical sequelae. The outcome data are empirically based on treatment processes that have proven high predictive validity and give concrete information about where to focus the therapeutic efforts. Thus, process-outcome research on OLITA can serve for the development of new therapeutic guidelines on adapting individual relapse prevention strategies.

Personality disorder and chronicity of addiction as independent outcome predictors in alcoholism treatment.

OBJECTIVE: A prospective four-year study examined which components of addiction severity predicted time to relapse among 112 adults with chronic alcoholism who participated in a comprehensive outpatient treatment program. METHODS: Recruited from emergency, inpatient, and outpatient facilities, patients were admitted into the program consecutively between March 1998 and June 2002. Alcohol abstinence was carefully monitored for four years from admission by regular contacts and urine and blood analyses. Alcoholism characteristics and personality disorders were assessed with structured interviews and the International Diagnostic Checklists for Personality Disorders. RESULTS: Among a variety of potential variables, only presence of a personality disorder and chronicity of addiction were independently associated with a decrease of cumulative four-year abstinence probability. CONCLUSIONS: Their high predictive values suggest that chronicity and personality disorder rank among the most important characteristics of addiction severity.

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.

Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms.

CONTEXT: Schizophrenia is the collective term for a heterogeneous group of mental disorders with a still obscure biological basis. In particular, the specific contribution of risk or candidate gene variants to the complex schizophrenic phenotype is largely unknown. OBJECTIVE: To prepare the ground for a novel "phenomics" approach, a unique schizophrenia patient database was established by GRAS (Göttingen Research Association for Schizophrenia), designed to allow association of genetic information with quantifiable phenotypes.Because synaptic dysfunction plays a key role in schizophrenia, the complexin 2 gene (CPLX2) was examined in the first phenotype-based genetic association study (PGAS) of GRAS [corrected] DESIGN: Subsequent to a classic case-control approach, we analyzed the contribution of CPLX2 polymorphisms to discrete cognitive domains within the schizophrenic population. To gain mechanistic insight into how certain CPLX2 variants influence gene expression and function, peripheral blood mononuclear cells of patients, Cplx -null mutant mice, and transfected cells were investigated. SETTING: Coordinating research center (Max Planck Institute of Experimental Medicine) and 23 collaborating psychiatric centers all over Germany. PARTICIPANTS: One thousand seventy-one patients with schizophrenia (DSM-IV) examined by an invariant investigator team, resulting in the GRAS database with more than 3000 phenotypic data points per patient, and 1079 healthy control subjects of comparable ethnicity. Main Outcome Measure Cognitive performance including executive functioning, reasoning, and verbal learning/memory. RESULTS: Six single-nucleotide polymorphisms, distributed over the whole CPLX2 gene, were found to be highly associated with current cognition of schizophrenic subjects but only marginally with premorbid intelligence. Correspondingly, in Cplx2 -null mutant mice, prominent cognitive loss of function was obtained only in combination with a minor brain lesion applied during puberty, modeling a clinically relevant environmental risk ("second hit") for schizophrenia. In the human CPLX2 gene, 1 of the identified 6 cognition-relevant single-nucleotide polymorphisms, rs3822674 in the 3' untranslated region, was detected to influence microRNA-498 binding and gene expression. The same marker was associated with differential expression of CPLX2 in peripheral blood mononuclear cells. CONCLUSIONS: The PGAS allows identification of marker-associated clinical/biological traits. Current cognitive performance in schizophrenic patients is modified by CPLX2 variants modulating posttranscriptional gene expression.

Recovery of hippocampus-related functions in chronic alcoholics during monitored long-term abstinence.

AIMS: The hippocampus (HC) is characterized by high vulnerability to noxious influence, but also by a considerable regenerative potential. Although deficits in HC-related functions are among the most commonly reported cognitive sequelae in alcoholism, little and conflicting information is available concerning regeneration upon abstinence. The present study has been designed to evaluate (i) the frequency of measurable dysfunction in so called HC tests and (ii) its predictive value for risk to relapse in a cohort of 50 severely affected chronic alcoholic patients and (iii) to monitor recovery of HC-related functions upon strict abstention from alcohol. METHODS: Patients underwent a 2-year neuropsychological follow-up including HC-associated tests (Verbal Learning Test, VLT; Nonverbal Learning Test, NVLT; 'City Map Test' of Learning and Memory Test, LGT-3), as well as tests of intelligence and attention in the framework of OLITA (Outpatient Long-Term Intensive Therapy for Alcoholics), a programme with careful abstinence monitoring. RESULTS: At study entry, 30/50 (60%) alcoholics had HC dysfunction which tended to predict a lower long-term abstinence probability (P = 0.058). Of the subgroup that could be followed under conditions of strictly monitored alcohol abstinence (n = 32; age 44.7 +/- 6.2 years; 23 men, 9 women), 53% (17/32) exhibited distinct HC dysfunction at inclusion which returned to normal after 2 years. Patients with initially normal HC function (9/32) and patients with additional brain damage of different aetiologies (6/32) failed to show improvement on HC-related tests. While the former displayed stably normal HC test performance, the latter remained on a performance level below normal. CONCLUSIONS: Demonstrating slow but remarkable regeneration of HC functions upon strict abstention from alcohol, our data strongly support abstinence-oriented long-term treatment of alcoholics. The absence of functional recovery in patients with additional causes of brain damage might be explained by the 'dual hit' exhausting the regenerative potential of the HC.

Follow-up of 180 alcoholic patients for up to 7 years after outpatient treatment: impact of alcohol deterrents on outcome.

OBJECTIVE: (1) To perform a 9-year study of abstinence, lapse, and relapse in 180 chronic alcoholic patients, participants of the Outpatient Longterm Intensive Therapy for Alcoholics (OLITA); (2) To investigate the role of supervised alcohol deterrents (AD) in relapse prevention and as an adjunct for maintenance of long-term abstinence. METHOD: This prospective open treatment study evaluates the long-term course of drinking outcomes and AD use of 180 chronic alcoholics consecutively admitted from 1993 to 2002. Subsamples are compared for (1) sham-AD versus verum-AD (disulfiram/calcium carbimide), (2) coped lapses versus finally detrimental lapses versus malignant relapses, and (3) AD use for 13 to 20 versus >20 months. RESULTS: In this 9-year study, the cumulative probability of not having relapsed was 0.52, and that of not having consumed any alcohol was 0.26. Despite long-term use, disulfiram/calcium carbimide was well tolerated. Patients on sham-AD (due to contraindications to verum-AD) showed higher cumulative abstinence probability than patients on verum (S = 0.86 vs. S = 0.49, p = 0.03). Detrimental lapses and malignant relapses occurred earlier than successfully coped lapses (p < 0.001); patients with detrimental lapse and with malignant relapse had fewer days of AD intake and less subsequent days without AD than patients with coped lapse (p < 0.001). The cumulative abstinence probability was S = 0.75 for patients with long-term intake compared with S = 0.50 for patients who stopped AD between months 13 and 20 (p < 0.001). CONCLUSIONS: An abstinence rate of >50% in this 9-year study strongly supports the concept of comprehensive, long-term outpatient treatment of alcoholics. Supervised, guided intake of AD, also over extended periods, can be used as a predominantly psychologically acting ingredient of successful alcoholism therapy.

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.