Clozapine serum concentrations in dopamimetic psychosis in Parkinson's disease and related disorders.

PURPOSE: Psychotic symptoms in Parkinson's disease (PD) caused by dopamimetic treatment are a relevant clinical problem. As clozapine does not cause extrapyramidal side effects, it is suitable for treatment of dopamimetic psychosis. The main aim of the present study was (1) to establish an indication-specific recommendation for therapeutic reference range of clozapine among patients with dopamimetic psychosis in PD and related disorders. Secondary goals were (2) to test whether clozapine therapy is safe and calculable despite pharmacokinetic changes expected in the study population and (3) to assess influencing variables on clozapine serum levels. METHODS: We carried out a retrospective chart review of patients suffering from dopamimetic psychosis as well as Lewy body dementia treated with clozapine. We extracted demographic and clinical data as well as results from therapeutic drug monitoring that was carried out via high-performance liquid chromatography in order to analyse clozapine and norclozapine serum concentrations. RESULTS: n = 35 patients could be identified and were included in the study. Mean age was 72.4 years. Clozapine treatment for patients with dopamimetic psychosis in PD and related disorders seems to be safe and calculable. Mean clozapine serum concentration was 77.9 ng/ml (SD 63.4 ng/ml). Clozapine dose is significantly correlated with serum clozapine concentration (r = 0.35; R (2) = 0.122). Women showed lower clozapine serum concentrations although they received higher weight-corrected clozapine doses. CONCLUSIONS: We suggest an orienting indication-specific therapeutic reference range of 15-141 ng/ml among PD patients with dopamimetic psychosis. Therapeutic drug monitoring is recommended and might help to minimize the risk of adverse events by screening for unexpectedly high serum concentrations of clozapine.

How smoking affects sleep: a polysomnographical analysis.

OBJECTIVE: Subjective quality of sleep is impaired in smokers compared with non-smokers, but there is only limited evidence from methodologically sound studies about differences in polysomnography (PSG) sleep characteristics. Therefore, this study used PSG to evaluate sleep in smokers and non-smokers while controlling for other parameters that affect sleep. METHODS: After an adaptation night, PSG sleep laboratory data were obtained from 44 smokers (29 men and 15 women, median age 29.6 years) and compared with PSG data from 44 healthy, sex- and age-matched never smokers. Exclusion criteria were alcohol or other substance abuse, psychiatric or endocrine diseases, and treatment with any kind of psychotropic medication. Nicotine and cotinine plasma levels were measured (in the smoking group) and subjective sleep quality assessed in both groups. RESULTS: The smokers had a Fagerström tolerance score of 6.4, consumed an average of 21.2 cigarettes per day and had been smoking for 13.1 years (median). Smokers had a shorter sleep period time, longer sleep latency, higher rapid eye movement sleep density, more sleep apneas and leg movements in sleep than non-smokers. There were no differences regarding parameters of spectral analysis of the sleep electroencephalogram as well as in the sleep efficiency measured by PSG. Nevertheless smokers rated their sleep efficiency lower on the Pittsburgh Sleep Quality Index compared with non-smoking individuals, but no differences were detected on the SF-A. Plasma cotinine level correlated negatively with slow wave sleep in the smoking group. CONCLUSIONS: Smokers showed a number of insomnia-like sleep impairments. The findings suggest that it is important for sleep researchers to control smoking status in their analyses. Further research should focus on the causes and consequences of impaired sleep during tobacco cessation, as sleep disturbances are a known risk factor for early relapse after initial tobacco abstinence.

[Diagnostics and therapy of alcohol withdrawal syndrome: focus on delirium tremens and withdrawal seizure]. / Diagnostik und Therapie des Alkoholentzugssyndroms: Fokus auf Delirium tremens und Entzugskrampfanfall.

INTRODUCTION: Delirium tremens and withdrawal seizures are serious complications of an alcohol withdrawal syndrome. This review presents the diagnostic procedures required in case of the occurrence of a withdrawal seizure and delirium tremens as well as possible treatment options including prophylactic medication regimen for alcohol withdrawal syndrome. Furthermore non-pharmacological procedures accompanying delirium tremens and a potential integration of viewing videotapes of delirium tremens in the course of alcohol-specific therapy are discussed. METHODS: A systematic literature research using Pubmed has been carried out to find recent studies and review articles dealing with alcohol withdrawal syndrome. RESULTS AND DISCUSSION: Regarding the diagnostic algorithm in case of the occurrence of a withdrawal seizure or a delirium tremens basic diagnostic procedures and special diagnostics including neuro-imaging or cerebrospinal fluid puncture depending on patients' clinical condition have to be considered. Sedatives are important in treatment of alcohol withdrawal seizures and delirium tremens as well as in the prophylaxis of alcohol withdrawal syndrome. A long-lasting prescription of anticonvulsant medication in patients suffering from withdrawal seizure should be considered critically and can be carried out only under certain conditions.

Olanzapine treatment during breast feeding: a case report.

Postpartum psychosis constitutes a severe complication that entails risk for both mother and child. Little is known about the use of olanzapine in the treatment of postpartum psychosis. In previous studies, it has been reported on mothers receiving relatively low doses of olanzapine. We report a 38-year-old patient who was admitted to the hospital for an acute psychotic exacerbation. She was breast feeding her 5-month-old child, and she wished to continue breast feeding. Olanzapine treatment was started with a daily dosage of 15 mg. The weight-corrected maternal dose was 270 mug/kg. The olanzapine concentration in the mother's plasma was 24 ng/mL. The analysis of olanzapine in breast milk applying two different high-performance liquid chromatography procedures revealed similar results: 12.2 ng/g without and 11.5 ng/g with additional hydrochloric acid extraction, respectively. In addition, breast milk of an unmedicated mother was used for establishing the analytical procedure so that the validity of the results was better confirmed. The milk-plasma ratio arising from our data was 0.5, and the relative infant dose was 0.3%. The olanzapine concentration was below the limit of detection (<5 ng/mL) in the infant's plasma sample. No adverse effects were noticed, and the mother experienced a rapid improvement in her psychopathology during her hospital stay. In future studies, long-term follow-up of both mother and child would be useful.

Alterations in homocysteine metabolism among alcohol dependent patients--clinical, pathobiochemical and genetic aspects.

Addiction research focusing on homocysteine metabolism and its association with aspects of alcohol dependence has revealed important findings. Recent literature on this topic has been taken into account for the review provided. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the homocysteine metabolism. Plasma homocysteine levels are influenced by the single-nucleotide polymorphism (SNP) MTHFR C677T. Besides genetic factors, environmental factors have an impact on homocysteine plasma levels too. Thus, chronic alcohol intake is associated with elevated homocysteine plasma concentrations. Elevation of plasma homocysteine concentration is considered as a predictor for the occurrence of alcohol withdrawal seizures and--as homocysteine is a cardiovascular risk factor--might contribute to the higher risk for myocardial infarction among alcohol dependent patients. Homocysteine acts as an N-methyl-D-aspartate (NMDA) receptor agonist and has excitotoxic effects. Furthermore, it has been demonstrated that homocysteine has neurotoxic effects especially on dopaminergic neurons. As the rewarding effects of alcohol are mediated by the dopaminergic system, a homocysteine-dependent impairment of the reward system possibly leads to an altered drinking behaviour according to the deficit hypothesis of addiction. Homocysteine is involved in the metabolism of methyl groups and DNA-methylation plays a role in regulation of gene expression. Therefore it has been suggested that homocysteine is an important epigenetic factor. It remains to be determined whether alcohol dependent patients benefit from homocysteine lowering strategies, e.g., via supplementation of folate, vitamin B6 and B12. In this respect it is not clear yet, if a supplementation therapy can reduce the risk for the occurrence of alcohol withdrawal seizures.

Significant impact of MTHFR C677T polymorphism on plasma homovanillic acid (HVA) levels among alcohol-dependent patients.

The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate. It plays a critical role in homocysteine metabolism. A high impact of MTHFR C677T polymorphism on plasma homocysteine levels has been observed among alcoholics. Recent studies indicate that homocysteine has toxic effects on dopaminergic neurons. Thus it lowers levels of homovanillic acid (HVA) in the striatal region in rats. Alcoholics had significantly lower plasma HVA concentrations compared with healthy controls. Aim of this study is to elucidate whether HVA plasma levels in alcoholics are influenced by MTHFR C677T polymorphism. A total of 142 alcohol-dependent patients and 101 healthy controls were examined regarding plasma HVA concentration and MTHFR C677T genotype. Blood samples of alcoholics were obtained after a minimum of 22 days of abstinence. Among alcohol-dependent patients MTHFR C677T polymorphism was significantly associated with plasma HVA levels: carriers of MTHFR C677T T-allele had significantly lower HVA plasma levels compared with homozygote carriers of C-allele: 11.9 ng/ml versus 14.4 ng/ml (chi2: 5.39; P = 0.02). In healthy control subjects plasma HVA levels did not differ significantly between MTHFR C677T T-allele carriers and homozygote carriers of C-allele: 15.1 ng/ml versus 15.3 ng/ml (chi2: 0.04; P = 0.82). The data suggest an influence of MTHFR C677T polymorphism on plasma HVA among alcohol-dependent patients. This might be due to neurotoxic effects of homocysteine on the dopaminergic system or direct impairment of monoamine metabolism. Future studies should try to elucidate whether this effect is reversible during alcohol abstinence.

Methylenetetrahydrofolate reductase C677T-polymorphism and its association with alcohol withdrawal seizure.

BACKGROUND: Elevated homocysteine plasma levels are considered as a risk factor for the occurrence of seizures during alcohol withdrawal. Homocysteine plasma concentrations seem to be influenced by the methylenetetrahydrofolate reductase (MTHFR) C677T-polymorphism. It was investigated whether the T-allele of the MTHFR C677T-polymorphism is associated with alcohol dependence, alcohol withdrawal seizure (WS), or the daily amount of alcohol consumption. METHODS: A group of 102 healthy controls and 221 alcoholic patients, including 97 patients with a history of mild withdrawal symptoms (MWS) and 70 patients with a history of alcohol WS, were genotyped, and personal data were collected for statistical evaluation in a case-control design. RESULTS: The T-allele is significantly associated with WS by comparing alcoholic patients with a history of WS (T-allele frequency: 0.39) and healthy controls (T-allele frequency: 0.28) (p=0.03). Although there was no significant difference between alcoholic patients with only MWS and alcoholic patients with a history of WS, a trend for the T-allele frequency among the analyzed subgroups was noticed: T-allele frequency increased from f(T)=0.28 in healthy controls to f(T)=0.33 in alcoholic patients with MWS up to f(T)=0.40 in alcohol-dependent men having a WS. Differences between healthy male controls and male alcoholic patients concerning the T-allele frequency also turned out to be significant [f(T)=0.27 vs f(T)=0.37; p=0.03]. Daily alcohol intake was independent of T-allele carrier status in alcohol-dependent patients. CONCLUSION: The present study suggests an influence of the MTHFR C677T-polymorphism on the etiology of alcohol WS and alcohol dependence in men in a western European population. An influence of MTHFR C677T on the daily amount of alcohol intake before admission among alcohol-dependent patients could not be shown.