[Guideline-oriented treatment of alcohol-related disorders]. / Leitlinienorientierte Behandlung alkoholbezogener Störungen.

Alcohol use disorders (e.g. abuse and dependence) account for a plethora of consequences for affected individuals and for a substantial proportion of the overall burden of disease for the community. To date, existing treatment options are either poorly known by doctors or they are not fully applied and only approximately 15% of potential patients are treated with a mean latent period of 10 years between early symptoms and the first intervention. So-called S3 treatment guidelines were recently developed to close this gap. Representatives of more than 50 learned societies, families and patients were involved. A systematic literature search from 2005 to 2012 was performed and more than 120 recommendations were made. Financing came exclusively from those societies and the academic and treatment institutes involved.This article summarizes the recommendations pertinent for psychiatrists and include early detection and intervention, acute withdrawal and long-term psychotherapy and pharmacotherapy. Classical and new treatment goals are discussed. If the new guidelines were properly applied an increase in patients receiving treatment to 30-40% could be expected, which would improve the quality of lives of affected persons and their families and in Germany would save several thousand lives per year.

Genetic risk prediction and neurobiological understanding of alcoholism.

We have used a translational Convergent Functional Genomics (CFG) approach to discover genes involved in alcoholism, by gene-level integration of genome-wide association study (GWAS) data from a German alcohol dependence cohort with other genetic and gene expression data, from human and animal model studies, similar to our previous work in bipolar disorder and schizophrenia. A panel of all the nominally significant P-value SNPs in the top candidate genes discovered by CFG  (n=135 genes, 713 SNPs) was used to generate a genetic  risk prediction score (GRPS), which showed a trend towards significance (P=0.053) in separating  alcohol dependent individuals from controls in an independent German test cohort. We then validated and prioritized our top findings from this discovery work, and subsequently tested them in three independent cohorts, from two continents. A panel of all the nominally significant P-value single-nucleotide length polymorphisms (SNPs) in the top candidate genes discovered by CFG (n=135 genes, 713 SNPs) were used to generate a Genetic Risk Prediction Score (GRPS), which showed a trend towards significance (P=0.053) in separating alcohol-dependent individuals from controls in an independent German test cohort. In order to validate and prioritize the key genes that drive behavior without some of the pleiotropic environmental confounds present in humans, we used a stress-reactive animal model of alcoholism developed by our group, the D-box binding protein (DBP) knockout mouse, consistent with the surfeit of stress theory of addiction proposed by Koob and colleagues. A much smaller panel (n=11 genes, 66 SNPs) of the top CFG-discovered genes for alcoholism, cross-validated and prioritized by this stress-reactive animal model showed better predictive ability in the independent German test cohort (P=0.041). The top CFG scoring gene for alcoholism from the initial discovery step, synuclein alpha (SNCA) remained the top gene after the stress-reactive animal model cross-validation. We also tested this small panel of genes in two other independent test cohorts from the United States, one with alcohol dependence (P=0.00012) and one with alcohol abuse (a less severe form of alcoholism; P=0.0094). SNCA by itself was able to separate alcoholics from controls in the alcohol-dependent cohort (P=0.000013) and the alcohol abuse cohort (P=0.023). So did eight other genes from the panel of 11 genes taken individually, albeit to a lesser extent and/or less broadly across cohorts. SNCA, GRM3 and MBP survived strict Bonferroni correction for multiple comparisons. Taken together, these results suggest that our stress-reactive DBP animal model helped to validate and prioritize from the CFG-discovered genes some of the key behaviorally relevant genes for alcoholism. These genes fall into a series of biological pathways involved in signal transduction, transmission of nerve impulse (including myelination) and cocaine addiction. Overall, our work provides leads towards a better understanding of illness, diagnostics and therapeutics, including treatment with omega-3 fatty acids. We also examined the overlap between the top candidate genes for alcoholism from this work and the top candidate genes for bipolar disorder, schizophrenia, anxiety from previous CFG analyses conducted by us, as well as cross-tested genetic risk predictions. This revealed the significant genetic overlap with other major psychiatric disorder domains, providing a basis for comorbidity and dual diagnosis, and placing alcohol use in the broader context of modulating the mental landscape.

Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci.

We report a GWAS of alcohol dependence (AD) in European-American (EA) and African-American (AA) populations, with replication in independent samples of EAs, AAs and Germans. Our sample for discovery and replication was 16 087 subjects, the largest sample for AD GWAS to date. Numerous genome-wide significant (GWS) associations were identified, many novel. Most associations were population specific, but in several cases were GWS in EAs and AAs for different SNPs at the same locus,showing biological convergence across populations. We confirmed well-known risk loci mapped to alcohol-metabolizing enzyme genes, notably ADH1B (EAs: Arg48His, P=1.17 × 10(-31); AAs: Arg369Cys, P=6.33 × 10(-17)) and ADH1C in AAs (Thr151Thr, P=4.94 × 10(-10)), and identified novel risk loci mapping to the ADH gene cluster on chromosome 4 and extending centromerically beyond it to include GWS associations at LOC100507053 in AAs (P=2.63 × 10(-11)), PDLIM5 in EAs (P=2.01 × 10(-8)), and METAP in AAs (P=3.35 × 10(-8)). We also identified a novel GWS association (1.17 × 10(-10)) mapped to chromosome 2 at rs1437396, between MTIF2 and CCDC88A, across all of the EA and AA cohorts, with supportive gene expression evidence, and population-specific GWS for markers on chromosomes 5, 9 and 19. Several of the novel associations implicate direct involvement of, or interaction with, genes previously identified as schizophrenia risk loci. Confirmation of known AD risk loci supports the overall validity of the study; the novel loci are worthy of genetic and biological follow-up. The findings support a convergence of risk genes (but not necessarily risk alleles) between populations, and, to a lesser extent, between psychiatric traits.

Association of functional DBH genetic variants with alcohol dependence risk and related depression and suicide attempt phenotypes: results from a large multicenter association study.

OBJECTIVE: Dopamine-beta-hydroxylase (DBH) metabolizes the conversion of dopamine to noradrenaline. DBH, located on chromosome 9q34.2 has variants with potential functional consequences which may be related to alterations of neurotransmitter function and several psychiatric phenotypes, including alcohol dependence (AD), depression (MD) and suicidal behavior (SA). The aim of this association study in a large multicenter sample of alcohol-dependent individuals and controls is to investigate the role of DBH SNPs and haplotypes in AD risk and associated phenotypes (AD with MD or SA). METHOD: 1606 inpatient subjects with DSM-IV AD from four addiction treatment centers and 1866 control subjects were included. Characteristics of AD, MD and SA were obtained using standardized structured interviews. After subjects were genotyped for 4 DBH polymorphisms, single SNP case-control and haplotype analyses were conducted. RESULTS: rs1611115 (near 5') C-allele and related haplotypes were significantly associated with alcohol dependence in females. This association with female alcohol dependence also accounts for the significant relationship between this variant and comorbid conditions and traits. CONCLUSIONS: This study presents evidence for a potentially functional DBH variant influencing the risk for alcohol dependence while other comorbid conditions are not independently influenced by this SNP. However, the study also supports the possible role of the dopamine system in the etiology of female alcohol dependence.

Involvement of the atrial natriuretic peptide transcription factor GATA4 in alcohol dependence, relapse risk and treatment response to acamprosate.

In alcoholism, both relapse to alcohol drinking and treatment response are suggested to be genetically modulated. This study set out to determine whether the top 15 single nucleotide polymorphisms (SNPs) of a recent genome-wide association (GWA) and follow-up study of alcohol dependence are associated with relapse behavior and pharmacological treatment response in 374 alcohol-dependent subjects who underwent a randomized, double-blind, placebo-controlled trial with acamprosate, naltrexone or placebo. The single nucleotide polymorphism, rs13273672, an intronic SNP in the gene for GATA-binding protein 4 (GATA4), was associated with relapse within the 90-day medical treatment period (P<0.01). Subsequent pharmacogenetic analyses showed that this association was mainly based on patients treated with acamprosate (P<0.01). In line with the observation that natriuretic peptide promoters are modulated by GATA4, a significant gene dose effect on the variance of atrial natriuretic peptide (ANP) plasma concentration in the different GATA4 genotypes (P<0.01) was found. Hence, genetic variations in GATA4 might influence relapse and treatment response to acamprosate in alcohol-dependent patients via modulation of ANP plasma levels. These results could help to identify those alcohol-dependent patients who may be at an increased risk of relapse and who may better respond to treatment with acamprosate.

No association of alcohol dependence with HOMER 1 and 2 genetic variants.

Several lines of evidence indicate that alterations of the central cortico-accumbens glutamate pathway are involved in the development and maintenance of alcohol- and substance-use disorders. The HOMER protein family is encoded by 3 genes HOMER (1-3) which are components of the excitatory postsynaptic density complex and function to modulate synaptic activity by the regulation of glutamate signaling. HOMER 1 and 2 have been reported to contribute to chronic alcohol-induced long-term neurochemical changes in the endogenous reward system. Data from animal models suggest a potential role of the Homer protein family in the development of alcohol and substance use. The aim of this study is to assess potential associations between HOMER 1 and 2 genetic variants in a larger sample of alcohol-dependent individuals and unrelated controls. Five genetic variants of HOMER 1 and 3 of HOMER 2 were genotyped in a multi-site sample of 1,923 German healthy controls and 2,039 alcohol-dependent subjects. Neither single SNP nor haplotype analysis could detect significant associations with alcohol dependence (AD) and related phenotypes. While most of the HOMER 1 and 2 SNPs are in low-to-moderate linkage disequilibrium, three major haplotypes of HOMER 1 and 4 haplotypes of HOMER 2 are present in the majority of alcohol-dependent and control subjects. In conclusion, our results suggest that single SNPs, respectively, haplotypes of the HOMER 1 and 2 genes are unlikely to play a major role in the pathophysiology of AD.

Personality disorders in alcohol-dependent individuals: relationship with alcohol dependence severity.

The rate of axis II disorders in alcohol-dependent individuals is suggested to be high. The aim of this investigation is to assess the rate of DSM-IV axis II diagnoses in alcohol-dependent inpatients and their correlation with clinical characteristics of alcohol dependence (AD). 1,079 inpatients with DSM-IV AD from three inpatient addiction treatment centers ('qualified detoxification', open psychiatric university hospital wards) were included. Characteristics of AD were obtained using standardized structured interviews. Diagnoses of DSM-IV personality disorders (PDs) were generated with SCID-II-PQ and SCID-II interviews. Alcoholism severity was measured using the number of DSM-IV criteria endorsed and age at first drinking. Approximately 60% of the sample had at least one PD. However, rates of Axis II disorders differed significantly across centers. The most frequent PDs were obsessive-compulsive, borderline, narcissistic and paranoid PD. Diagnosis of any PD was related to a more severe clinical profile of AD. Regression analyses revealed that obsessive-compulsive PD was related to the number of DSM-IV criteria endorsed while antisocial PD was related to early age at first drinking. The majority of alcohol-dependent individuals had one or more comorbid axis II disorders. Univariate and multivariate analyses indicate that different PDs are related to age at first dinking and alcoholism severity.

[The impact of attachment styles and ADHD on alcohol dependence]. / Einfluss unsicherer Bindungsstile und ADHS auf Alkoholabhängigkeit.

BACKGROUND: Insecure attachment (IA) and attention-deficit/hyperactivity disorder (ADHD) are discussed as risk factors for increased alcohol intake and the development of alcoholism. METHODS: Among a sample of 517 consecutively admitted German inpatients with alcohol dependence we investigated the contribution of IA to alcoholism phenotypes, taking into consideration comorbid ADHD. RESULTS: IA was significantly associated with increased alcohol consumption, increased frequency of withdrawal symptoms, increased frequency of physical or psychological problems that are likely to have been worsened by alcohol, and reduced social activities because of alcohol use. ADHD has no significant effect on these parameters. CONCLUSIONS: IA developed as a result of social interactions during childhood long before alcohol dependence. The results point to an important effect of IA on the severity and acceleration of alcohol dependence. Therefore, it might be helpful to improve efforts in primary prevention and psychotherapy of alcohol dependence by considering the specific needs of subjects with an IA.

Different effects of a CD14 gene polymorphism on disease outcome in patients with alcoholic liver disease and chronic hepatitis C infection.

AIM: Clinical and experimental data suggest that gut-derived endotoxins are an important pathogenic factors for progression of chronic liver disease. Recently, a C-T (-159) polymorphism in the promoter region of the CD14 gene was detected and found to confer increased CD14 expression and to be associated with advanced alcoholic liver damage. Here, we investigated this polymorphism in patients with less advanced alcoholic liver disease (ALD) and chronic hepatitis C virus (HCV) infection. METHODS: CD14 genotyping was performed by PCR-RFLP analysis in (a) 121 HCV patients, (b) 62 patients with alcohol-associated cirrhosis (Alc-Ci), (c) 118 individuals with heavy alcohol abuse without evidence of advanced liver damage (Alc-w/o Ci), and (d) 247 healthy controls. Furthermore, serum levels of soluble CD14 (sCD14) and transaminases were determined. RESULTS: The TT genotype was significantly more frequent in Alc-Ci compared to Alc-w/o Ci or controls (40.3% vs 23.7% or 24.0%, respectively). In Alc-w/o Ci, serum levels of transaminases did not differ significantly between patients with different CD14 genotypes. In HCV patients, TT-homozygotes had significantly higher sCD14 levels and sCD14 serum levels were significantly higher in patients with advanced fibrosis or cirrhosis. However, no association was found between CD14 genotypes and histological staging or grading. CONCLUSION: Considering serum transaminases as surrogate markers for alcoholic liver damage, the CD14 polymorphism seems to exhibit different effects during the course of ALD. Differences in genotype distribution between cirrhotic HCV patients and alcoholics and the known functional impact of this polymorphism on CD14 expression levels further indicate differences in the pathophysiological role of CD14 and CD14-mediated lipopolysaccharides signal transduction with regard to the stage as well as the type of the underlying liver disease.

The candidate gene approach in alcoholism: are there gender-specific differences?

It is well established that genetic factors play a major role in the development of alcoholism in both sexes. Several twin studies demonstrated a nearly equally high magnitude of genetic influence for men and women. However, the genetic sources of vulnerability are supposed to only partially overlap in men and women. Therefore, we evaluated the gender-specific effects of two single nucleotide polymorphisms affecting dopaminergic neurotransmission (dopamine D2 receptor: -141C Ins/Del polymorphism; Dopamine D3 receptor: Bal I) in our large sample of primary alcoholics. Only a gender-specific analysis of subgroups with a putatively high genetic load, e.g., family-history-positive or presence of severe withdrawal complications, revealed significant differences in allele-/genotype-frequency. Our results demonstrate that a varying sex distribution in the samples investigated might contribute to the heterogeneous results reported in association studies for candidate genes in alcoholism and, therefore, should be taken into account in future studies.

Gender and personality in alcoholism.

The topic gender and personality in alcoholism is discussed on the background of a research project on clinical aspects of alcoholism at the University of Würzburg, Germany. The data of this study are presented in the context of two questions: Which personality differences are there between women and men dependent on alcohol, and is there a connection between these personality differences and features of the alcohol dependence? Additionally, we take a look at gender-related differences in the development of alcoholism. In a first step, gender differences in the development and the course of alcoholism are investigated. The data revealed only weak differences between female and male alcoholics when important confounding variables like age and education are taken into consideration. Secondly, the female and male alcoholics are matched according to age and education and their personality structures are compared by using several well-established and standardized self-report questionnaires. No serious gender differences concerning the main characteristics of alcohol dependence could be discovered. However, some remarkable personality differences between female and male alcoholics are found: women scored significantly higher on Neuroticism and Harm-Avoidance while men reached significantly higher scores on Venturesomeness and Sensation-Seeking. In order to detect a possible connection between alcoholism and gender-related personality differences, both males and females are subdivided into two groups using the scores of Neuroticism, Harm-Avoidance, Venturesomeness and Sensation-Seeking, respectively. We have found no indication for a gender-specific relevance of personality differences between female and male alcoholics with regard to Harm-Avoidance, Venturesomeness or Sensation-Seeking. However, differences in Neuroticism have revealed a greater relevance in alcohol-dependent women than in men.

Gender-related differences in pharmacological relapse prevention with flupenthixol decanoate in detoxified alcoholics.

A study recently finished by our research group elucidated the effectiveness of flupenthixol decanoate (FLX) in maintaining abstinence in detoxified alcoholics. Flupenthixol decanoate is an established antipsychotic drug, which is well known for its mild antidepressant and anxiolytic activity as well as for its minimal sedation at low doses. It blocks dopamine binding at a number of receptor subtypes, primarily at D-1, D-2, D-3 and with less affinity at D4-receptors. It also affects serotonin binding at 5-HT2A and 5-HT2C receptors. In a double-blind placebo-controlled multicenter trial, 77 women and 204 men suffering from moderate or severe DSM-II-R alcohol dependence were randomly assigned to either 10 mg FLX or placebo both injected every second week over a period of 24 weeks (treatment phase) succeeded by a medication-free 24-weeks follow-up period. In the overall analysis the number of patients relapsed after 24 weeks of treatment (=main criterion of efficacy) was significantly higher in the FLX treated group (85.2%) than under placebo (65.5%). However, when differentiating this result according to sex the analysis revealed a gender-related discrepancy: while male patients had an almost 4-fold higher risk to relapse under FLX than under placebo (OR=3.95) this risk was barely elevated for female patients (OR=1.51). A significantly negative outcome due to FLX treatment was restricted to male alcoholics solely. In conclusion, gender-related differences to pharmacological relapse prevention with FLX have probably contributed to a better treatment outcome in women than in men.

Dopamine D2 (DAD2) and dopamine D3 (DAD3) receptor gene polymorphisms and treatment outcome in alcohol dependence.

The dopaminergic system is critically involved in reward mechanisms mediating the reinforcing effects of alcohol. The intention of this study was to investigate the genotypic frequencies of the -141C Ins/Del polymorphism of the DAD2 receptor gene as well as the Bal I polymorphism of the DAD3 receptor and their potential association with treatment outcome in alcoholism. Therefore, individuals suffering from primary alcohol dependence were clinically and genetically characterized and followed prospectively over a period of one year after inpatient treatment. No association was found between DAD2 or DAD3 receptor gene variants and treatment outcome as reflected by abstinence/relapse after one year. Taking into account potential stratification effects, such as family history, gender, age of onset, or severity of the disease an association with DAD2 or DAD3 gene variants could neither be found. In conclusion, we found no evidence that the DAD2 or DAD3 gene variants investigated have a major influence on treatment outcome in primary alcohol dependence.

Growth hormone response to placebo, apomorphine and growth hormone releasing hormone in abstinent alcoholics and control subjects.

Abstinent alcoholics and control subjects were challenged with placebo (saline), growth hormone releasing hormone (GHRH) and apomorphine (APO). While both groups did not differ in their growth hormone response (HGH) to placebo and GHRH, the alcoholics revealed a significant lower HGH response to dopamine receptor stimulation with APO. These findings provide no evidence that in abstinent alcoholics HGH blunting after dopamine receptor stimulation could be related to an alteration at the pituitary level but they give neuroendocrinological support to the hypothesis of a lower dopamine receptor sensitivity in abstinent alcoholics.

Peripheral-type benzodiazepine receptors in diagnostic subtypes of schizophrenic patients.

The peripheral-type benzodiazepine receptor (pBZD-R; also called the omega-3 receptor or the mitochondrial benzodiazepine receptor) seems to play a critical role in the production of neurosteroids, which are able to alter the electrical properties of neuronal membranes and thus the firing patterns of neurons. Putative endogenous ligands are the diazepam-binding inhibitor and its processing products, as well as porphyrins, some of them, in the case of porphyria, are well known to give rise to certain aspects of neuropsychiatric disorders, such as schizophrenic-like symptoms. Previous findings of altered benzodiazepine binding sites in post-mortem brain samples and platelets from small samples of schizophrenic patients have been inconclusive. Therefore we investigated characteristic binding parameters (Bmax, Kd) of the granulocytic pBZD-R by using the selective ligand PK11.195 in 53 subjects, fulfilling ICD-10 and DSM-IV criteria of schizophrenia. The binding parameters in our total group of 53 schizophrenic patients did not differ from those in healthy subjects. However, Bmax values were significantly reduced in schizophrenic patients with predominantly negative symptoms (residual type) compared to schizophrenic patients with predominantly positive symptoms, i.e. paranoid (-50%) and catatonic subtype (-38%). Moreover, only residual type schizophrenics exhibited a significantly reduced binding capacity compared to healthy subjects (-38%). More studies are warranted to clarify the functional significance of this binding site in the pathogenesis of negative symptoms.

Increased concentrations of manganese superoxide dismutase in serum of alcohol-dependent patients.

Oxidative stress-associated parameters [concentrations of lactoferrin, Cu,Zn-superoxide dismutase (SOD) and Mn-SOD] were determined in sera of 20 patients suffering from alcohol dependence immediately after detoxification and in 15 non-dependent healthy subjects as controls. In the patient group, the mean Mn-SOD concentration reached almost double the values of those from the control group (142.9 vs 76.0 ng/ml, P < 0.01). The other parameters tended to be increased in patients, but did not differ significantly between index and control groups. The findings are consistent with increased oxidative stress due to chronic alcohol intake, which might be responsible for secondary diseases such as brain atrophy, peripheral polyneuropathy and liver fibrinogenesis.

Alcohol withdrawal and dopamine receptor sensitivity after prolonged abstinence.

1. Forty-four male inpatients suffering from moderate to severe alcohol dependence (DSM-III-R and ICD-10) as well as 14 healthy controls entered this study. Individuals were classified according to the severity of their withdrawal symptoms during detoxification i.e. group 1) no withdrawal, group 2) autonomic hyperactivity, group 3) withdrawal delirium and group 4) controls. 2. During the 6th week of treatment, that is, when all patients were recovered, controlled abstinent, and several weeks away from the end of their withdrawal syndrome, dopamine receptor sensitivity was neuroendocrinologically assessed by stimulating human growth hormone (HGH) with apomorphine (APO). 3. In a repeated measures model ANOVA, the four groups differed significantly in their HGH release. However, when excluding the controls from the analysis and focusing on alcoholics only (group 1 - 3), the significant difference disappeared. Covariates such as age, weight, quantity of drinking and duration of dependence were not related to the dependent variable. 4. In conclusion, the first significant result (with controls) reflects a blunted HGH response in alcoholics. It confirms earlier reports. The second, non significant result with the alcohol dependents only, suggests that the severity of withdrawal is not reflected by the amount of HGH released. Therefore, in alcoholics, a reduced dopamine receptor function after six weeks of abstinence, as neuro-endocrinologically assessed with apomorphine, seems to be related to alcohol dependence rather than to the severity of alcohol withdrawal.

Excretion of beta-carbolines harman and norharman in 24-hour urine of chronic alcoholics during withdrawal and controlled abstinence.

Animal experiments suggest that endogenous substances that could result from the interaction between neurotransmitters (dopamine and indoleamines) and ethanol and its metabolite acetaldehyde might be involved in the pathogenesis and maintenance of alcohol dependence. Therefore, aromatic beta-carbolines (norharman and harman) were investigated repeatedly in 24-hr urine of 13 male severe alcoholics without any psychiatric comorbidity during a controlled inpatient abstention program of up to 8 weeks. Harman excretion was approximately 2-fold above levels in control subjects, with a steady decline after 3 weeks of abstinence and lower levels in patients with a longer duration of alcohol dependence. Severity of withdrawal symptoms and actual feelings of anxiety/depression were negatively associated with urinary harman excretion. Positive associations could be established with daily ethanol consumption the month before admission and the score on the scale "reward dependence" according to Cloninger's Tridimensional Personality Questionnaire. Moreover, patients without alcohol-dependent first-degree relatives and higher "reward dependence" exhibited an increased excretion of harman. Therefore, harman levels might characterize a distinct subgroup of alcoholic patients, who in part resemble the so-called type l alcoholics of Cloninger. However, this awaits further study in a larger number of individuals. In contrast, norharman excretion was elevated up to 6-fold, compared with nonalcoholics over 6 to 8 weeks of controlled abstention. No correlations to demographic or clinical variables could be observed. Therefore, increased norharman levels might be proposed as a "residual marker" or a trait variable. Whether the observed changes are specific markers of at least certain aspects of alcoholism or dependence remain to be elucidated.

3H-spiperone binding to peripheral mononuclear cells in psychiatric in-patients.

1. There is an ongoing controversy, if increased binding of 3H-spiperone to lymphocytes might discriminate between schizophrenia and other psychiatric diseases or even be a genetic vulnerability marker for schizophrenia, or predict the response to neuroleptic treatment. 2. Some critical methodological details which might contribute to this controversy are described. 3. 3H-spiperone binding was evaluated in 31 patients with schizophrenia, 7 patients with schizoaffective disorder, bipolar type, 6 patients with a manic episode and 6 patients with a depressive episode of bipolar major affective disorder (DSM-III-R criteria), and in 19 healthy subjects. 4. There were no significant differences in characteristic binding parameters (KD, Bmax) between all groups of psychiatric in-patients and in comparison to healthy subjects. Moreover, there was no relation of binding parameters to any of the subtypes of schizopherenia or to the course of illness according to DSM-III-R-criteria. 5. Neuroleptic treatment or clinical response to treatment had no consistent effect on binding parameters intra-individually. 6. In summary, 3H-spiperone binding to lymphocytes failed to differentiate between the diagnostic subgroups (DSM-III-R) and between treatment responders and non-responders in our sample of patients.