[Antipsychotics for treatment of neuropsychiatric disorders in dementia]. / Antipsychotika zur Behandlung neuropsychiatrischer Störungen bei Demenz.

Antipsychotics, when used to treat neuropsychological symptoms associated with dementia, are associated with low effectiveness but a high risk of side effects. Some of these unwanted effects are severe and include an increased rate of cerebrovascular events and increased mortality. Although neuropsychiatric symptoms are frequently associated with dementia, it appears that antipsychotics are often used without clear indications and for too long time periods. Antipsychotics should be used only when all non-pharmacological strategies have failed. A clear definition of the treatment target in advance and a continuous monitoring of the therapy are mandatory.

Evaluating depressive symptoms and their impact on outcome in schizophrenia applying the Calgary Depression Scale.

OBJECTIVE: To examine depressive symptoms, their course during treatment, and influence on outcome. METHOD: Weekly Calgary Depression Scale for Schizophrenia ratings were performed in 249 inpatients with schizophrenia. Early response was defined as a 20% reduction in the total score of the Positive and Negative Syndrome Scale for Schizophrenia from admission to week 2, response as a 50% reduction in the total score of the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) from admission to discharge and remission according to the consensus criteria. RESULTS: Thirty six per cent of the patients were depressed at admission, with 23% of them still being depressed at discharge. Depressed patients scored significantly higher on the PANSS negative and general psychopathology subscore, featured more impairments in subjective well-being (P < 0.0001) and functioning (P < 0.0001). They suffered from more suicidality (P = 0.0021), and had greater insight into their illness (P = 0.0105). No significant differences were found regarding early response, response, and remission. CONCLUSION: Patients with depressive symptoms should be monitored closely, given the burden of negative symptoms, their impairments in well-being and functioning and the threat of suicidality.

Outcome of suicidal patients with schizophrenia: results from a naturalistic study.

OBJECTIVE: Purpose was to assess suicidality before and at the time of admission in patients with schizophrenia and compare outcome differences. METHOD: Biweekly PANSS (Positive and Negative Syndrome Scale), HAMD (Hamilton Depression Rating Scale) and UKU (Udvalg for Klinske Undersogelser Side Effect Rating Scale) ratings were evaluated in 339 in-patients with schizophrenic spectrum disorders. Response was defined as an initial 20% PANSS total score reduction at discharge, remission was defined according to the proposed consensus criteria by the Remission in Schizophrenia Working Group. RESULTS: Suicidal patients (22%) scored significantly higher on the PANSS negative subscore, PANSS insight item and HAMD total score at admission and at discharge. They developed significantly more side effects. No differences were found concerning response and remission between the two patient subgroups. CONCLUSION: Despite receiving significantly more antidepressants the suicidal patients suffered from significantly more depressive symptoms up to discharge, yet without differing regarding response and remission.

A critical analysis and discussion of the appropriateness of the schizophrenia consensus remission criteria in clinical pharmaceutical trials.

BACKGROUND: The aim of this paper is to apply the proposed consensus remission criteria to an acutely ill inpatient sample at admission and evaluate their adaptability in this patient population and pharmaceutical trials. METHODS: The Remission in Schizophrenia Working Group's consensus criteria were applied to 272 acutely ill schizophrenia patients. Patients were examined using the PANSS, HAMD, UKU and SWN-K total scales at admission as well as the GAF, SOFAS and the Strauss-Carpenter Prognostic Scale. Sociodemographic and clinical baseline variables were assessed using a standardized documentation system. RESULTS: 33 patients (12%) fulfilled the symptom severity component of the proposed remission criteria already at baseline. Almost no significant differences were found when comparing patients with achieved and failed symptom severity component that would explain the hospitalization of the patients with achieved criteria despite their apparently mild psychopathological symptoms. The only explainable difference was that patients with an achieved symptom severity component had received significantly more antipsychotics and had suffered from significantly more life events before admission. CONCLUSION: The present results raise the question whether the symptom severity threshold is adequate to identify patients in remission when applied in clinical trials.

Galantamine: a cholinergic patch in the treatment of alcoholism: a randomized, placebo-controlled trial.

OBJECTIVES: The involvement of the central cholinergic system in alcohol abuse behavior is well known. It is possible that the reinforcing effects of ethanol are partially mediated by nicotinic receptors, which modulate neurotransmitter release. It was demonstrated that the application of a cholinesterase inhibitor reduces alcohol consumption in alcohol-preferring rats. This suggests that galantamine (GAL), a cholinesterase inhibitor, could be effective when seeking to prolong abstinence in recently detoxified alcoholics. This study represents the first reported clinical trial of a cholinergic drug in alcohol-relapse prevention. PATIENTS AND METHODS: We investigated the efficacy and safety of GAL by conducting a 24-week randomized, placebo-controlled, multicentric clinical trial on 149 recently detoxified alcoholics. Survival analyses (Kaplan-Meier) were performed to reveal evidence of prolonged abstinence periods in patients who received GAL. RESULTS: Our findings did not support our hypothesis. GAL did not extend the time to first severe relapse. However, additional post hoc analyses suggest that relapsed patients treated with GAL consume less ethanol per drinking day than patients treated with placebo. CONCLUSIONS: GAL seems to be ineffective when used in relapse prevention of detoxified alcoholics. It is possible that alcohol needs to be "on board" for GAL to be beneficial. This could explain why our post hoc analysis showed that GAL possibly reduces the alcohol consumption of relapsers. If confirmed, GAL could play a role in the reduction of harmful alcohol use and at-risk consumption.

Psychopathological and behavioral correlates of dopaminergic sensitivity in alcohol-dependent patients.

OBJECTIVES: To explore 2 facets of dopamine receptor sensitivity in alcoholics: (1) whether reduced sensitivity of central dopamine receptors is correlated with anxiety, depression, or novelty seeking and (2) whether this reduction is associated with poor treatment outcome. METHOD: Sixty-four alcohol-dependent patients were assessed according to their clinical outcome, sensitivity of central dopamine receptors (apomorphine-induced growth hormone secretion), mood states, and personality traits before and after detoxification. RESULTS: Patients with poor treatment outcome displayed a blunted growth hormone response before, but not after, detoxification. Growth hormone response was not significantly correlated with novelty seeking. Relapsing patients tended to be less depressed than patients who remained abstinent during observation. CONCLUSION: This study did not support the hypothesis that reduced sensitivity of dopamine receptors is associated with anxiety, depressed mood, or high novelty seeking in alcoholism.

Prescribing practices in German and Swiss psychiatric university and in non-university hospitals: national differences.

OBJECTIVE: There are great variations between hospitals in the way drugs are prescribed, and these variations may be due to multiple factors such as local prescribing traditions, pharmacoeconomic considerations, drug availability, regional differences of population, disease prevalence etc. Available studies on prescribing habits, apart from studies performed in a unique center, have until now been mainly restricted to single countries or regions and the comparisons across countries or regions have often been limited by the use of diverse methodologies and definitions. The aim of the present study was to compare drug prescriptions between German and Swiss psychiatric services with regard to their preference of newer psychotropics. MATERIAL AND METHODS: Five psychiatric hospitals, associated to the AMSP project, were chosen to represent Swiss and German clinics, university and non-university settings. Data were available from one index day on 572 patients and 1,745 prescriptions. The comparisons were adjusted for age and gender. RESULTS: There was a significant difference (p < 0.001) with regard to the prescription of newer antidepressants (NAD), Swiss clinicians giving proportionally more (65.2%) than the German psychiatrists (48.3%). No significant difference was, on the other hand, found as to the proportion of atypical antipsychotics, the lack of difference being due to the higher proportion of clozapine among the atypical antipsychotics in Germany. CONCLUSION: There seems, therefore, to be a higher propensity for Swiss hospital psychiatrists to prescribe newer antidepressants. This seems to be due to national or regional prescribing traditions. Further studies are needed to investigate the economical influences on antidepressant prescribing in Swiss and German clinics.

What are depressive symptoms in acutely ill patients with schizophrenia spectrum disorder?

BACKGROUND: Aim was to examine depressive symptoms in acutely ill schizophrenia patients on a single symptom basis and to evaluate their relationship with positive, negative and general psychopathological symptoms. METHODS: Two hundred and seventy-eight patients suffering from a schizophrenia spectrum disorder were analysed within a naturalistic study by the German Research Network on Schizophrenia. Using the Calgary Depression Scale for Schizophrenia (CDSS) depressive symptoms were examined and the Positive and Negative Syndrome Scale (PANSS) was applied to assess positive, negative and general symptoms. Correlation and factor analyses were calculated to detect the underlying structure and relationship of the patient's symptoms. RESULTS: The most prevalent depressive symptoms identified were depressed mood (80%), observed depression (62%) and hopelessness (54%). Thirty-nine percent of the patients suffered from depressive symptoms when applying the recommended cut-off of a CDSS total score of >6 points at admission. Negligible correlations were found between depressive and positive symptoms as well as most PANSS negative and global symptoms despite items on depression, guilt and social withdrawal. The factor analysis revealed that the factor loading with the PANSS negative items accounted for most of the data variance followed by a factor with positive symptoms and three depression-associated factors. LIMITATIONS: The naturalistic study design does not allow a sufficient control of study results for the effect of different pharmacological treatments possibly influencing the appearance of depressive symptoms. CONCLUSION: Results suggest that depressive symptoms measured with the CDSS are a discrete symptom domain with only partial overlap with positive or negative symptoms.

Influence of the dopamine D2 receptor (DRD2) genotype on neuroadaptive effects of alcohol and the clinical outcome of alcoholism.

The present study was performed to test the hypotheses that allelic variants at the human dopamine D2 receptor gene locus (DRD2) confer susceptibility to alcoholism or are associated with clinical subtypes of alcoholism. We investigated an A --> G substitution polymorphism in the 3'-untranslated region of exon 8 (E8) of DRD2 with allele frequencies of f(G) = 0.295 - 0.329. No significant association of the DRD2 genotype or allele frequencies with alcoholism was found in an association study including 283 alcoholics and 146 non-alcoholic controls. However, the frequent homozygous E8 A/A genotype with f(AA) = 0.47 - 0.48 was associated with increased anxiety and depression scores in alcoholics during the follow up after clinical detoxification treatment. In addition, E8 A/A was associated with increased suicide attempts and showed a tendency towards more severe withdrawal symptoms, early relapse and reduced responsiveness to the dopaminergic agonist apomorphine. Regression analysis revealed the DRD2 E8 genotype as the only significant factor determining withdrawal severity in female alcoholics. The findings suggest an influence of the DRD2 genotype on the neuropharmacological effects of chronic alcohol exposure and the clinical course of alcoholism.

The Tridimensional Personality Questionnaire and the intensity dependence of auditory evoked dipole source activity.

The relationship between the tridimensional personality questionnaire's (TPQ) dimensions "novelty seeking," "harm avoidance," and "reward dependence" and the intensity dependence of the auditory evoked N1/P2-component was investigated in healthy subjects. Using dipole source analysis, evoked activity of the primary auditory cortex (tangential dipole) could be analyzed at least in part separately from that of secondary auditory areas (radial dipole). It was found that the intensity dependence of the tangential dipole was positively correlated to the TPQ dimension "novelty seeking," but not to "harm avoidance" and "reward dependence." This is in line with findings concerning similar personality traits like "sensation seeking," "impulsivity," or "extraversion." It is therefore concluded that a strong intensity dependence may characterize subjects with an action-oriented and extroverted personality style. The results are discussed within the concept that a low central serotonergic neurotransmission is underlying both an impulsive personality type and a strong intensity dependence of the tangential dipole.

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.

Serotonin transporter gene variants in alcohol-dependent subjects with dissocial personality disorder.

BACKGROUND: We tested the hypothesis that a functional biallelic repetitive element in the 5' regulatory region of the human serotonin transporter gene (SLC6A4) confers susceptibility to serotonin-related personality traits underlying alcohol dependence with dissocial behavior. METHODS: The association study was focused on 64 alcohol-dependent subjects with a dissocial personality disorder (according to ICD-10) who were derived from 315 German alcohol-dependent subjects. The Tridimensional Personality Questionnaire (TPQ) was applied to assess personality dimensions in 101 alcohol-dependent men, including 39 dissocial alcoholics. RESULTS: Our association analyses revealed a trend towards a higher frequency of the short (S) allele of the SLC6A4 polymorphism in dissocial alcoholics compared to 216 German controls (chi 2 = 2.81, df = 1, p = 0.094). Dissocial alcoholics carrying the S/S genotype exhibited significant lower scores of harm avoidance compared to those lacking it (U-test, p = 0.015). Significantly higher novelty seeking scores were obtained in dissocial alcoholics carrying the S allele relative to those lacking it (U-test, p = 0.021). CONCLUSIONS: Our tentative association findings in dissocial alcoholics suggest that the S allele of the 5' regulatory SLC6A4 polymorphism confers susceptibility to a temperamental profile of high novelty seeking and low harm avoidance that has been postulated to underlie dissocial (type-2) alcoholism according to Cloninger's neurogenetic theory of personality.

Allelic association of a dopamine transporter gene polymorphism in alcohol dependence with withdrawal seizures or delirium.

Hereditary factors confer susceptibility to alcohol dependence. Alcohol mediates its reinforcing effects by enhancing dopamine activity in the mesolimbic dopamine system. The role of the dopamine transporter in terminating dopaminergic activity in synaptic neurotransmission suggests that variants of the dopamine transporter gene (DAT1) might contribute to individual differences in vulnerability to addictive behavior. Our population-based association study investigated whether variants of DAT1 confer susceptibility to alcohol dependence in 293 alcoholics and clinically more homogeneous subgroups formed by: positive family history, early age-at-onset, delirium, withdrawal seizures, antisocial tendencies, type 1 and 2 alcoholics. Analyzing a VNTR polymorphism in the 3' untranslated region of DAT1, we found a significantly increased prevalence of the nine-repeat allele in 93 alcoholics displaying withdrawal seizures or delirium, compared with 93 ethnically matched nonalcoholic controls (p = 0.003; OR = 2.44; 95% confidence interval: 1.35-4.43). Our data provide evidence that a major genetic determinant of DAT1 influences vulnerability to severe alcohol withdrawal symptoms.

Dopamine D2 receptor gene (DRD2) haplotypes in Caucasians.

The human dopamine D2 receptor gene (DRD2) is considered a candidate gene for neuro-psychiatric diseases. We typed three new DNA sequence variants in DRD2 intron 4, intron 6 and exon 8, in combination with the known TaqI A restriction fragment length polymorphism (RFLP) and exon 7 311Ser/Cys in 106 unrelated psychiatrically healthy Caucasians. Based on the genotypic data we delineated 10 distinct DRD2 haplotypes and their genetic relationship. Our data provide evidence that the Taq A1 allele and the 311Cys variant are components of different groups of haplotypes though both variants have been speculated to be associated with alcoholism or schizophrenia in recent studies. Therefore we conclude that the prior knowledge of the frequencies and genetic relationships of DRD2 haplotypes will lead to the selection of more suitable intragenic markers for future association studies.

Modification of alcohol withdrawal by the A9 allele of the dopamine transporter gene.

OBJECTIVE: Determinants of individual vulnerability to alcohol withdrawal symptoms are largely unknown. Because of the substantial role of monoaminergic transporters in limiting time and space effects of synaptic neurotransmission, the dopamine transporter gene (DAT1; locus symbol: SLC6A3) was studied as a candidate gene possibly related to symptoms of uncomplicated alcohol withdrawal. METHOD: In 48 chronically intoxicated alcoholics (diagnosed according to ICD-10), withdrawal symptoms were examined and the presence of a variable-number tandem repeat in the 3' untranslated region of the DAT1 gene was determined. RESULTS: Withdrawal syndromes were more pronounced in the 22 patients carrying the nine-copy repeat than in the 26 patients without this variant. Multiple regression analysis revealed that 4% of the variance of withdrawal was explained by this genotype, whereas 16% was due to the amount of alcohol the patients reported having consumed in the month before detoxification. CONCLUSIONS: The A9 allele of the dopamine transporter gene is associated with more severe effects of alcohol withdrawal, possibly because of modifications of the brain's capacity to compensate for long-term effects of ethanol on cerebral function.

Dopaminergic responsivity in alcoholism: trait, state, or residual marker?

OBJECTIVE: In order to classify neuroendocrine abnormalities in alcohol-dependent patients as trait, state, or residual markers, growth hormone (GH) secretion was assessed longitudinally. METHOD: GH secretion, stimulated by the dopaminergic agonist apomorphine, was evaluated in 21 alcohol-dependent patients (16 men, five women) and 10 healthy comparison subjects (eight men, two women). The patients were tested during early withdrawal, after 8 days of abstinence, and after 3 months. RESULTS: Patients who relapsed within 3 months (N = 8) showed significantly less GH secretion in all neuroendocrine tests than did either the patients who abstained from ethanol consumption for 6 months (N = 13) or the healthy comparison subjects. The relapsers and abstainers did not differ significantly in any of their clinical or pathophysiological data, in the severity of their withdrawal symptoms, or in antecedent or concomitant illnesses associated with alcoholism. CONCLUSIONS: GH blunting appears to be a residual marker of clinical relevance in alcoholism.

Superiority of carbohydrate-deficient transferrin to gamma-glutamyltransferase in detecting relapse in alcoholism.

OBJECTIVE: The usefulness of carbohydrate-deficient transferrin is widely accepted in screening (male) population samples for heavy alcohol consumption, but its role in relapse detection is not convincingly established. The authors therefore compared the diagnostic value of carbohydrate-deficient transferrin with the commonly used gamma-glutamyltransferase in identifying relapsed alcoholics during outpatient aftercare. METHOD: The patients were 101 male alcoholics who entered a 6-month rehabilitation program after hospital detoxification. Drinking status was assessed by means of self- and collateral reports obtained during regular contacts with the rehabilitation team; relapse was defined as consumption of any alcohol. Visits occurred weekly during month 1, biweekly during month 2, and every 4 weeks during months 3-6. At every visit a blood sample was taken for measurement of carbohydrate-deficient transferrin and gamma-glutamyltransferase. RESULTS: The proportion of men who reported relapse was 25.6% per scheduled contact on average. Positive predictive values indicated that relapse was identified with a 76.2% probability by carbohydrate-deficient transferrin values above the upper normal limit, in contrast to a 32.9% chance with gamma-glutamyltransferase. Carbohydrate-deficient transferrin was especially useful in detecting early relapses during the initial rehabilitation phase, when gamma-glutamyltransferase values had not normalized. Because of the longer half-life of gamma-glutamyltransferase, it had some value with a 4-week monitoring schedule in detecting new drinking episodes in alcoholics whose previous results had been normal. CONCLUSIONS: Carbohydrate-deficient transferrin proved to be superior to gamma-glutamyltransferase in relapse detection in an outpatient care setting for alcoholics.

Long-term changes of markers of alcoholism after orthotopic liver transplantation (OLT).

Both physical rehabilitation and the course of the alcoholism improve after orthotopic liver transplantation (OLT) in patients with end-stage alcoholic liver cirrhosis. In the present study including 17 alcoholics and 14 nonalcoholics, after OLT, three of the alcoholic patients resumed their pre-OLT alcohol drinking habits, 4 consumed alcohol occasionally, 10 remained abstinent over the observation period of 13 to 36 months. The laboratory parameters before OLT did not discriminate alcoholics from nonalcoholic patients. Furthermore, the blood levels of two so-called alcogens (harman and norharman) were determined to investigate whether they discriminate between the two groups. Alcogens are natural compounds that are presumed to induce alcohol abuse in predisposed individuals. Both alcogens measured were elevated in plasma from nonalcoholics and alcoholics before OLT, suggesting a disturbance in inactivation in end-stage liver disease. Following OLT, the alcogens normalized but in the alcoholics this process was slower with respect to harman. The present exploratory study suggests that the normalized metabolic capacity of the liver after OLT causes a normalization of the levels of alcogens, for which harman and norharman are representative. These changes could contribute to the observed benefit to the outcome in alcoholics with respect to the alcohol dependence.

Association analysis between a Cys23Ser substitution polymorphism of the human 5-HT2c receptor gene and neuronal hyperexcitability.

Transgenic mice lacking a functional 5-HT2c receptor gene are extremely susceptible to audiogenic seizures, suggesting that 5-HT2c receptors mediate inhibition of neuronal network excitability. The present association study tested the hypothesis that a Cys23Ser substitution polymorphism within the human 5-HT2c receptor gene modulates neuronal excitability. Genotypes of the Cys23Ser polymorphism were assessed in 454 subjects of German descent, comprising: 1) 93 severely affected alcohol-dependent males with a history of alcohol withdrawal seizure or delirium, 2) 119 patients affected by an idiopathic generalized epilepsy, and 3) 242 controls. Both sexes were analyzed separately because of the X-chromosomal location of the 5-HT2c receptor gene. The allele frequencies of the Cys23Ser variants did not differ significantly between the controls and either the severely affected alcohol-dependent males (P = 0.34), or patients with idiopathic generalized epilepsy (P > 0.57). Our results suggest that the common Cys23Ser substitution polymorphism of the human 5-HT2c receptor gene does not confer susceptibility to neuronal hyperexcitability in either idiopathic generalized epilepsy or alcohol withdrawal seizure or delirium.

Dopamine D4 receptor exon III alleles and variation of novelty seeking in alcoholics.

A dysfunction of dopaminergic neurotansmission has been implicated in alcohol-seeking behavior. Recently, a significant association between the seven-repeat allele (DRD4*7R) of a 16 amino acid motif in the third exon of the dopamine D4 receptor gene (DRD4) and the personality trait of novelty seeking has been reported. Our population-based association study tested the hypothesis that the DRD4*7R variant predisposes to high levels of novelty seeking, which may underlie alcohol-seeking behavior. The genotypes of the expressed DRD4 exon III polymorphism were determined in 197 German controls and 252 German alcohol-dependent males, of whom 92 alcoholics completed the tridimensional personality questionnaire. We found no significant differences in the DRD4*7R frequencies between controls and alcoholics, including two subgroups (56 alcoholics with dissocial personality disorder according to ICD-10 and 89 alcoholics with severe withdrawal symptoms) with a high level of novelty seeking. The novelty-seeking scores did not differ significantly between alcoholics (including both subgroups) carrying long alleles with six or more repeats compared with those lacking long alleles. The present results do not provide evidence that the DRD4*7R allele contributes a common and relevant effect to alcohol-seeking behavior in our sample of alcoholics.