Lutz G. Schmidt

Ultrastructural Hippocampal and White Matter Alterations in Mild Cognitive Impairment: A Diffusion Tensor Imaging Study

Mild cognitive impairment (MCI) is considered to be a transitional stage between normal aging and dementia. In Alzheimer’s disease (AD), white matter structural pathology is due to Wallerian degeneration and central angiopathy. However, in MCI patients, the presence and extent of white matter alterations as a possible correlate of impaired memory function and as predictor of subsequent progression to AD is not clarified yet. Diffusion tensor imaging (DTI) reveals the ultrastructural integrity of cerebral white matter tracts. Therefore, it could detect pathological processes that modify tissue integrity in patients with MCI. In our prospective study, conventional and diffusion tensor MR scans were obtained from 14 patients with MCI, 19 patients with AD, and 10 healthy controls. Mean diffusivity (MD) and fractional anisotropy (FA) were measured in temporal, frontal, parietal and occipital white matter regions as well as in the corpus callosum (genu and splenium) and the hippocampus. MCI patients showed higher MD values in the left centrum semiovale (p = 0.013; right: p = 0.026), in the left temporal (p = 0.006), the right temporal (p = 0.014) and the left hippocampal (p = 0.002) region as compared to the control group. FA values of MCI patients and controls did not differ significantly in any region. Compared to controls, AD patients had increased MD values in the left centrum semiovale (p = 0.012), the left parietal (p = 0.001), the right parietal (p = 0.028), the left temporal (p = 0.018), the right temporal (p = 0.011) and the left hippocampal region (p = 0.002). Decreased FA values were measured in the left temporal area (p = 0.017) and in the left hippocampus (p = 0.031) in AD patients compared to controls. FA and MD values did not differ significantly between AD and MCI patients. Elevated MD values indicating brain tissue alterations in MCI patients were found in regions that are typically involved in early changes due to AD, particularly the left hippocampus. The sensitivity of distinguishing MCI patients from controls was 71.4% (with a specificity set at 80%). Therefore, the DTI technique validates the MCI concept, and diffusion tensor MR measurement can be a helpful tool to quantify MCI pathology in vivo.

Association of Low Striatal Dopamine D2 Receptor Availability With Nicotine Dependence Similar to That Seen With Other Drugs of Abuse

OBJECTIVE All drugs of abuse induce a phasic dopamine release within the striatum that does not undergo habituation. Prolonged substance consumption impairs the natural function of the mesolimbic dopamine system, as shown by a decrease in the availability of striatal dopamine 2 (D(2)) receptors in patients suffering from cocaine, heroin, amphetamine, and alcohol dependence. However, it is unclear whether similar changes can also be observed in heavy-smoking nicotine-dependent smokers. METHOD In vivo D(2)/D(3) receptor availability was determined with [ (18)F]fallypride positron emission tomography in 17 heavy-smoking nicotine-dependent subjects and in 21 age-matched never-smoking comparison subjects. The smokers were scanned twice: first, during a period of usual consumption and second, 24 hours after smoking cessation. RESULTS Independent of the withdrawal status, the nicotine-dependent smokers displayed significantly less availability of D(2)/D(3) receptors within the bilateral putamen functionally covering parts of the dorsal striatum, as compared to the never-smoking subjects. Nicotine craving under the consumption condition correlated positively with D(2)/D(3) receptor availability within the ventral striatum but negatively with D(2)/D(3) receptor availability within the anterior cingulate and inferior temporal cortex. CONCLUSIONS Similar to other types of substance abuse, nicotine dependence is associated with low availability of dorsal striatal D(2)/D(3) receptors. In contrast to previous findings on abstinent alcohol-dependent patients, nicotine craving seems to be maintained by a region-specific shift in D(2)/D(3) receptor availabilities, with higher availability within the ventral striatum but lower availability within the anterior cingulate and inferior temporal cortex.

Association of a regulatory polymorphism in the promoter region of the monoamine oxidase A gene with antisocial alcoholism

We analyzed a novel functional 30-bp repeat polymorphism in the promoter region of the X-chromosomal monoamine oxidase A gene (MAOA) to test whether length variation of the repeat polymorphism contributes to variation in the individual vulnerability to antisocial behavior and liability to alcohol dependence. The repeat number (3-5) of the MAOA polymorphism was assessed in 488 male subjects of German descent, a sample comprising 185 psychiatrically screened control subjects and 303 alcohol-dependent subjects including 59 alcoholics with antisocial personality disorder. The frequency of the low-activity 3-repeat allele was significantly increased in 59 antisocial alcoholics compared to 185 control subjects (51 vs. 35%; P = 0.031) and to 244 alcoholics without antisocial personality disorder (51 vs. 32%; P = 0.008), respectively. We found no significant difference in the frequency of the 3-repeat allele between 244 alcoholics without an antisocial personality disorder and the control subjects. Our findings suggest that the low-activity 3-repeat allele of the MAOA promoter polymorphism confers increased susceptibility to antisocial behavior rather than alcohol dependence per se in alcohol-dependent males.

Lack of efficacy of naltrexone in the prevention of alcohol relapse: results from a German multicenter study.

In a placebo-controlled, double-blind German multicenter study (seven sites) the efficacy of naltrexone as an adjunctive treatment in alcoholism to maintain abstinence was assessed for 12 weeks. A total of 171 detoxified patients (97.7% met the DSM-III-R criteria for alcohol dependence) were included. Patients had been abstinent for a mean of 19.5 ± 9.4 days at study entry. Eighty-four and 87 patients were randomized to receive naltrexone (50 mg/day) and placebo, respectively. Each site was instructed to provide its usual psychosocial alcohol treatment program. The primary effectiveness measure was the time to first heavy drinking as derived from self-reports of drinking (timeline-follow-back method). Secondary effectiveness measures included time to first drink, amount of alcohol consumption, intensity of craving, severity of alcoholism problems, and liver enzymes. Thirty-three (38%) placebo patients and 28 (33%) naltrexone patients discontinued the study. At endpoint, 62% of the patients in each group did not have an episode of heavy drinking. Also, there were no significant differences between the study groups concerning secondary effectiveness measures as well as compliance and adverse clinical events—with the exception of the γ-GT, which was significantly greater reduced in the naltrexone group throughout the study. Based upon an intention-to-treat population, this study confirms the safety but not the efficacy of naltrexone in prevention of alcohol relapse. Nevertheless, the question arises whether self-reports of drinking are more reliable than γ-GT as a measure of recent alcohol consumption.

Adverse effects of clozapine

Adverse effects related to clozapine were assessed within a post-marketing drug surveillance program, the AMÜP study, in two university psychiatric departments. In a randomly selected sample of patients (intensive drug monitoring) ADRs of any type were observed in 76% of clozapine-treated inpatients. Sedation, hypersalivation, increase in transaminases, and EEG changes were most frequently observed, but only rarely required changes in therapy. In 8.1% of 959 patients exposed to clozapine in the total inpatient population of the participating hospitals ADR led to withdrawal of clozapine; in 3.9% reactions judged as severe and potentially life-threatening occurred. Among these latter toxic delirium prevailed. In addition, four cases of severe cardiovascular and respiratory dysregulation were observed with the combination of clozapine and benzodiazepines. These cases and one case of sudden death under clozapine and haloperidol treatment are presented in some detail. The results obtained for clozapine are compared to data from this drug surveillance program for other neuroleptics.

Different allele distribution of a regulatory MAOA gene promoter polymorphism in antisocial and anxious-depressive alcoholics

Summary. Heritable factors account for approximately 40–60% of the total variance of liability to alcohol dependence. The present study tested whether a novel functional polymorphism in the promotor region of the X-chromosomal monoamine oxidase A gene (MAOA) was related to antisocial and anxious-depressive traits in alcoholics. Due to the X-chromosomal localization of the MAOA gene, psychobiological traits were compared separately for both genders of 298 male and 66 female alcoholics.In males, 30 of 59 alcoholics with antisocial personality disorder carried the low-activity 3-repeat allele in contrast to only 7 of 31 anxious-depressive alcoholics (51% vs. 23%; p = 0.02). Likewise, female anxious-depressive alcoholics showed a trend towards a low frequency of genotypes with the 3 repeat allele compared to female alcoholics without these symptoms (29% vs. 53%; p = 0.09). Taken together, these findings suggest that the 3-repeat allele of the MAOA polymorphism contributes modestly to the dimension of over- and underreactive behaviors as possible antecedents of alcoholism.

Genetic analysis of the μ-opioid receptor in alcohol-dependent individuals

On the basis of various study results, it is suggested that the ethanol-induced activation of the endogenous opioid system may play an important role in mediating the reinforcing effects of ethanol. The mesolimbic dopamine reward system is activated by both ethanol and opioids, and genetic differences in the sensitivity of the endogenous opioid system to alcohol may be an important factor determining the risk for the development of excessive alcohol consumption. Thus, variants of the mu-opioid receptor (muOR) gene may confer vulnerability to alcohol dependence. Five exon 1 variants of the muOR were investigated in 327 alcohol-dependent and 340 healthy control subjects. The Val6 variant of the +17C/T polymorphism and the Asp40 variant of the +118A/G polymorphism showed a trend to an increased allele frequency in alcohol-dependent subjects. The latter polymorphism was investigated in more detail. The dopamine receptor agonist apomorphine causes an increase in growth hormone (GH) levels in the blood by stimulating the release of growth hormone-releasing hormone. beta-endorphin also activates this regulatory circuit. We found a blunted response in intoxicated alcohol-dependent subjects, but no difference in GH response between the groups of alcohol-dependent subjects with and without the variant Asp allele. However, alcohol-dependent subjects with the Asp allele showed a significantly higher GH response at day 7 after alcohol withdrawal and a tendency to lower novelty seeking. These results suggest to us that there is reduced dopaminergic neuronal activity in alcohol-dependent subjects with the muOR Asp40 allele, along with a compensating increase in dopamine receptor activity. The difference between the two groups of alcohol-dependent subjects can be demonstrated only under certain conditions such as alcohol withdrawal, which necessitates the adaptation of the neurones to a new homeostasis.

μ-Opioid receptor variants and dopaminergic sensitivity in alcohol withdrawal

OBJECT The endogenous opioid system plays an important role in the reinforcing properties of alcohol by an interconnected activation of the mesolimbic dopamine system. The Asn40Asp substitution polymorphism of the human mu-opioid-receptor (OPRM) influences binding of opioids and signal transduction and may, thereby, contribute to the development of alcoholism. The present study tested whether the Asn40Asp substitution polymorphism of the OPRM gene is associated with a variation in central dopaminergic sensitivity during alcohol withdrawal in alcoholics. METHOD Sensitivity of central dopamine receptors was assessed by apomorphine-induced growth hormone (GH) secretion in 97 alcohol-dependent patients before and 1 week after alcohol cessation, and in a subgroup of 19 alcoholics after 3 months of abstinence. GH response was defined as area under the hormone/time curve. Comparisons of the GH response were conducted between alcoholics carrying the Asn40Asp genotype versus those with the Asn40Asn genotype using U-test statistics. RESULTS Marginal differences in apomorphine-induced GH response were found between both genotype groups before detoxification (P = 0.799 (n = 97)/P = 0.459 (n = 19)) and after 3 months of abstinence (P = 0.331 (n = 19)). In contrast, the GH response measured seven days after alcohol withdrawal was significantly increased in alcoholics with the Asn40Asp genotype compared with those carrying the Asn40Asn genotype (P = 0.013 (n = 97)/P = 0.026 (n = 19)). CONCLUSION Our results suggest that genetic variation of the mu-opioid receptor modulates the central dopaminergic sensitivity during acute alcohol withdrawal.

Reduced dopaminergic function in alcoholics is related to severe dependence

With a view to the role of dopamine (DA) systems in reward processes and considering recent studies linking specific alleles at the DA-D2 receptor gene locus with alcoholism (especially with severe types) dopaminergic functions were evaluated in 49 alcoholics using growth hormone (GH) response to DA receptor agonist apomorphine (0.01 mg/kg subcutaneously). neuroendocrine testing was performed (during intoxication) at the time of admission to an inpatient alcohol treatment program and was repeated 7 days later (in a postintoxicated state). Patients underwent clinical examination, detoxification treatment and a subsequent rehabilitation program for abstinence including follow-up evaluation of outcome for 6 months. A two-factor analysis of variance (ANOVA) revealed a significant change of GH response (peak values corrected for baseline) over time (between intoxication and postintoxication; p < 0.001) and between abstainers and relapsers (p = 0.032). Relapse was also associated with paternal alcoholism, early onset of disease, and a more complete dependence syndrome and cerebellar atrophy. Standardized canonical discriminant coefficient was highest for reduced GH response compared to other relapse predictors in the model used. It is concluded that reduced GH response to dopaminergic stimulation corresponds to a progressed stage or syndrome of severe alcohol dependence; however, if reduced, dopaminergic function is one cause or consequence of addiction in this particular subgroup of patients that remains to be elucidated.

Predictors of Relapse in the Year After Hospital Discharge Among Patients With Schizophrenia

OBJECTIVE Relapse and its predictors were examined among patients with schizophrenia in the year after hospital discharge. METHODS The sample included 200 patients with schizophrenia participating in a German multicenter study. Relapse was defined as a worsening of psychopathological symptoms or rehospitalization in the year after hospital discharge. Predictors examined were variables related to course of illness and to response and remission at discharge. RESULTS Fifty-two percent of participants had a relapse. Patients whose symptoms were not in remission at discharge were more likely to have a relapse, as were those who had more severe symptoms and more side effects at discharge. Those who experienced a relapse were less likely to be taking a second-generation antipsychotic at discharge, less likely to have a positive attitude toward treatment adherence, and less likely to be employed. CONCLUSIONS The high rate of relapse among patients with schizophrenia highlights the need to improve current treatment strategies.