Sex differences in allelic frequencies of the 5-HT2C Cys23Ser polymorphism in psychiatric patients and healthy volunteers: findings from an association study

Polymorphisms in the serotonergic system are believed to play a role in the etiology and treatment of different psychiatric illnesses. The 5-HT2C receptor gene is X-linked, with a frequent mutation at nucleotide 68 leading to a Ser-->Cys transition at amino acid 23. Recent studies have demonstrated an impaired function of 5-HT2C receptors and an increased production of the major noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol in the cerebrospinal fluid among the subjects carrying the Ser23 allele (Lappalainen et al., 1999). Biol. Psychiatry 46:821). We genotyped patients with alcohol dependence, panic disorder without agoraphobia, generalized anxiety disorder, narcolepsy an…

Carbohydrate-deficient transferrin (CDT) and HDL cholesterol (HDL) are highly correlated in male alcohol dependent patients.

Background: Serum levels of total HDL cholesterol (HDL) are reportedly influenced by recent alcohol intake. We examined the correlation between HDL cholesterol and widely used markers of excessive alcohol intake, such as carbohydrate-deficient transferrin (CDT), γ-glutamyl-transferase (GGT), or mean corpuscular volume of erythrocytes (MCV), of which CDT is thought to be the most specific. Methods: Several serological markers [i.e., CDT, GGT, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), MCV, and HDL] were determined in 100 actively drinking male patients with alcohol dependence (DSM-IV) and in 27 non-alcohol-dependent controls, according to routine procedures. Spearman…

Confirmation of association of the GABRA2 gene with alcohol dependence by subtype-specific analysis

Objectives: Three recent studies revealed a haplotypic association of alcohol dependence with the gene encoding the {alpha}2 subunit of the {gamma}-aminobutyric acid type A (GABAA) receptor (GABRA2). The present study examined whether variation of the GABRA2 gene confers susceptibility to different subtypes of alcohol dependence in the German population. Methods: A total of 257 German alcohol-dependent patients and 88 healthy population controls were genotyped for six single-nucleotide polymorphisms covering the middle part and the 3′ end of GABRA2. Allelic, genotypic and haplotypic comparisons were done for subgroups of alcohol-dependent patients with a presumed high genetic load. Results:…

Genetic polymorphisms of the dopamine D2 and D3 receptor and neuroleptic drug effects in schizophrenic patients

Distigmine bromide induced acute psychotic disorder in a patient with multiple sclerosis.

AbstractA female patient with multiple sclerosis (MS) suffered from an acute psychotic disorder after taking distigmine bromide for detrusor dysfunction. She showed a dramatic relief of her symptoms after the medication, distigmine bromide, was stopped. Distigmine is not supposed to penetrate the blood-brain barrier (BBB). However, in MS patients a leakage of the BBB could be hypothesized.

Combination treatment with clozapine and paroxetine in schizophrenia: safety and tolerability data from a prospective open clinical trial.

Clozapine is a drug with many side effects, some of them with potentially hazardous outcome (e.g. seizures, agranulocytosis), if not carefully monitored. It has been shown that the metabolism of clozapine may be affected by concomitant treatment with selective serotonin reuptake inhibitors (SSRIs), while there have been reports of improved efficacy on negative symptomatology of clozapine in combination with SSRIs. Therefore, this prospective open clinical trial was performed to investigate the safety and tolerability of the coadministration of clozapine and paroxetine under control of serum concentrations of clozapine and its metabolites and the effect of this combination treatment on psych…

Association study of suicidal behavior and affective disorders with a genetic polymorphism in ABCG1, a positional candidate on chromosome 21q22.3

The gene that codes for the ABC transporter ABCG1 is located in a chromosomal susceptibility region (21q22.3) for affective disorders. Genetic variations in ABCG1 have been associated with affective disorders in Japanese males. In this study, we investigated the distribution of a G2457A polymorphism in patients with affective disorders, suicide attempters with various psychiatric diagnoses and healthy subjects. We initially found a trend towards a modest association with affective disorders in males (p = 0.046 for allele frequencies and p = 0.046 for AA versus GG). We conducted a replication study with independent patients and controls. There was no association with affective disorders, eit…

Pharmacokinetic Interactions of Clozapine With Selective Serotonin Reuptake Inhibitors

Pharmacokinetic interactions of clozapine and its metabolites N-desmethylclozapine and clozapine N-oxide with the selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and paroxetine were investigated in a prospective study in schizophrenic patients under steady-state conditions. Thirty patients were treated with clozapine at a target dose of 2.5 to 3.0 mg/kg of body weight. After gradual dose escalation, serum concentrations of clozapine and two metabolites were determined twice at 7-day intervals after steady-state conditions had been reached. Then, fluvoxamine (50 mg/day) or paroxetine (20 mg/day) was added in 16 and 14 patients, respectively. Serum concentrations of clozapine and …

Adenylyl cyclase activity is increased in younger, but decreased in older, alcoholic patients after detoxification.

Acute and chronic administration of ethanol leads to alterations of the adenylyl cyclase (AC) signal transduction pathway. This study examined whether the formation of cAMP by AC in lymphocytes correlates with age in alcoholic patients and in healthy controls. Blood was drawn for preparation of lymphocyte membranes and for determination of basal, GTPgammaS-stimulated, and forskolin-stimulated AC activity from 68 actively drinking alcoholic patients (age, mean +/- SD: 45 +/- 10; range: 26-69 years) after ethanol detoxification. The patients' AC activity correlated negatively with age. In contrast, no effect of age was observed in the healthy controls (age, mean +/- SD: 42 +/- 11; range: 24-6…

Reliability and validity of the German version of the European Addiction Severity Index (EuropASI).

This study provides data on the psychometric characteristics of the German version of the European Addiction Severity Index (EuropASI). The ASI is a frequently used clinical and research instrument that measures problem severity among people with substance dependence.The German ASI was used in a sample of 112 consecutively admitted male psychiatric inpatients seeking treatment for severe alcohol problems. The conceptual structure of the German ASI subscales was investigated by analyzing the intercorrelations of the severity ratings and composite scores. Internal consistency, interrater reliability and concurrent validity in terms of correlations with other assessment instruments were evalua…

No association of alcohol dependence with a NMDA-receptor 2B gene variant

Long-Term Effects of the Substituted Benzamide Derivative Amisulpride on Baseline and Stimulated Prolactin Levels

In the present study, we investigated the long-term effects of treatment with amisulpride, a substituted benzamide derivative, as compared with the effects of treatment with flupenthixol, a thioxanthene, on the prolactin levels in schizophrenic patients. After completing 6 weeks of medication with either amisulpride or flupenthixol, the patients entered a long-term maintenance treatment with amisulpride 200–600 mg/day or flupenthixol 5–15 mg/day for a maximum of 12 months with a subsequent drug-free follow-up until month 15. Eighteen initially included patients were still participating in the study at month 6. In the flupenthixol group, only 1 patient treated reached month 12, and none of t…

Association study of affective disorders with genetic polymorphisms of monoamine oxidases

Introduction: Monoamine oxidases (MAO) catalyze the oxidative deamination of monoamines like norepinephrine, serotonin and dopamine. The existing MAOs (A and B) have distinct although partially overlapping biological functions and distributions in the brain. MAO A is mainly expressed in catecholaminergic neurons. Thirty-fold differences in enzyme activity of MAO A can be found in cultured cells from different individuals suggesting a genetic determination of enzyme activity. Indeed, a point mutation in the coding region of the gene which creates a restriction site for Fnu4HI alters the activity. Moreover, the pharmacological inhibition of monoamine oxidase A activity is one of the most effe…

Combination treatment with nefazodone and cognitive-behavioral therapy for relapse prevention in alcohol-dependent men: a randomized controlled study.

Background This study evaluated the serotonergic antidepressant nefazodone versus placebo and specific cognitive-behavioral therapy (CBT) versus nondirective group counseling (GC) for relapse prevention in alcohol dependence in a large prospective, randomized, and placebo-controlled double-blind study at 3 German university centers. Method 242 male patients fulfilling at least 5 criteria for alcohol dependence according to DSM-IV and ICD-10 were eligible, after detoxification, for one of the following treatment combinations: nefazodone + CBT, nefazodone + GC, placebo + CBT, and placebo + GC. Either nefazodone or placebo was administered throughout the evaluation period of 15 months. Either …

Vitamin B12 and hepatic enzyme serum levels correlate in male alcohol-dependent patients.

- Vitamin B12 serum levels and markers for alcohol consumption were determined in 80 male alcohol-dependent patients. Spearman correlation coefficients (r(S)) were calculated. Significant positive correlations between vitamin B12 and hepatic enzyme values were found (gamma-glutamyltransferase: r(S) = 0.58; alanine aminotransferase: r(S) = 0.43; aspartate aminotransferase: r(S) = 0.47; glutamate dehydrogenase: r(S) = 0.43; all P:0.001). Therefore, for a proper interpretation of vitamin B12 levels, it may be clinically relevant to take markers of hepatocellular damage into account.

Neuroendocrine response to antipsychotics: effects of drug type and gender

Abstract Background: To study the influences of drug type and gender on the neuroendocrine response to neuroleptic treatment, we compared the endocrine actions of two neuroleptics with different receptor affinity profiles—a substituted benzamide, amisulpride, a selective D 2 -like dopamine antagonist; and a thioxanthene, flupenthixol, a mixed D 1 /D 2 -like antagonist also blocking serotonin, H 1 , and D 1 receptors—on anterior pituitary hormone secretion in schizophrenic patients (DSM-III-R). Methods: Blood was withdrawn at 15-min intervals to assess basal secretion of prolactin, growth hormone (GH), and thyroid-stimulating hormone (TSH). Four hundred micrograms of thyrotropin-releasing ho…

Medikamente zur Behandlung von Persönlichkeitsstörungen

Die Therapie von Personlichkeitsstorungen war lange Zeit ausschlieslich eine Domane psychotherapeutischer Interventionen. Mittlerweile existieren einige kontrollierte Studien auch zum Einsatz von Psychopharmaka bei Personlichkeitsstorungen Die Ergebnisse sind aber fur allgemeine Empfehlungen noch zu wenig abgesichert. Die Diagnose von Personlichkeitsstorungen (z. B. Achse-Il-Storungen nach DSM-IV) ist fehleranfallig. Die diagnostischen Kategorien sind uneinheitlich und derzeit noch im Flus; selbst strukturierte Interviews erfahrener Untersucher zeigen nur begrenzte Verlaslichkeit. Wichtig ist die Erfassung und — wenn moglich — Abgrenzung von gleichzeitig vorhandenen Achse-I-Storungen nach D…

Analysis of genetic variations of protein tyrosine kinase fyn and their association with alcohol dependence in two independent cohorts.

Abstract Background Decreased sensitivity to and increased tolerance for the effects of alcohol is a phenotype, which was shown to be associated with an increased risk for alcoholism in humans and was observed in protein tyrosine kinase (PTK) fyn knockout mice. Methods We performed an association study of genetic variations of PTK fyn in 430 alcohol-dependent patients and 365 unrelated control subjects from two independent samples. Results In a combined analysis, we found an association of alcohol dependence with the single nucleotide polymorphism (SNP) T137346C in the 5′ untranslated region (UTR) of the gene. A relevant association could be excluded for the remaining two informative SNPs. …

Medikamente zur Phasenprophylaxe affektiver Psychosen und zur Behandlung manischer Syndrome

Folgende Substanzgruppen sind in der Therapie manischer Syndrome und/oder in der Phasenprophylaxe affektiver Storungen etabliert (Im folgenden werden die Begriffe affektive bzw. schizoaffektive „Storung“ bzw. „Psychose“ weitgehend synonym verwendet.)

No Association Between the Dopamine D2 Receptor Taq I A1 Allele and Earlier Age of Onset of Alcohol Dependence According to Different Specified Criteria

BACKGROUND: The presence of the A1 allele of the dopamine D2 receptor TaqI restriction fragment length polymorphism has been reported to be associated with an earlier age of onset of alcohol dependence as a marker for severity. METHODS: We tested this hypothesis with special regard to the definition of the age of onset of alcoholism in 243 patients with alcohol dependence, according to DSM-IV criteria assessed by the standardized interview Munchner Composite International Diagnostic Interview (M-CIDI), consecutively admitted for detoxification. Additionally, the Addiction Severity Index (ASI) was performed. The TaqIA polymorphism was amplified by polymerase chain reaction (PCR), and the PCR…

Symptom-Triggered versus Standard Chlormethiazole Treatment of Inpatient Alcohol Withdrawal: Clinical Implications from a Chart Analysis

To evaluate clinical effectiveness and safety of 2 different detoxification treatment protocols, a chart analysis of hospital inpatients consecutively admitted for alcohol withdrawal during one year was undertaken. Records of 33 patients receiving symptom-triggered treatment (using a modified version of the revised Clinical Institute Withdrawal Assessment for Alcohol Scale) were compared with those of patients treated by applying a fixed-dose regimen (n = 32). Patients (45.3 ± 9.8 years, 21% female) of both groups were comparable regarding illness severity, epidemiologic parameters as well as complications during the observed treatment period. Under symptom-triggered therapy, chlormethiazol…

The HTR1B 861GC receptor polymorphism among patients suffering from alcoholism, major depression, anxiety disorders and narcolepsy.

Abstract The HTR1B receptor gene has been linked to antisocial alcoholism in a Finnish population and an American Indian tribe [Lappalainen et al., Arch. Gen. Psychiatry, 55 (1998) 989]. Using a candidate gene approach, we genotyped 209 patients with alcoholism, 108 patients with major depression, 32 patients with panic disorder, 50 patients with generalized anxiety disorder, 58 patients with narcolepsy and 74 healthy volunteers for the HTR1B 861G>C polymorphism. There was a higher frequency of the HTR1B 861G alleles among the alcohol-dependent patients as compared to the control subjects (χ 2 =4.02, d.f.=2, P =0.04). However, the association resulted from higher frequencies of the opposite…

Addition of Low-Dose Fluvoxamine to Low-Dose Clozapine Monotherapy in Schizophrenia: Drug Monitoring and Tolerability Data from a Prospective Clinical Trial

Combining fluvoxamine and clozapine may be a strategy to improve therapeutic effects on negative symptoms in schizophrenic patients. Fluvoxamine, however, markedly inhibits the metabolism of clozapine, and hazardous side effects may result. This study prospectively investigated the safety and tolerability of an add-on therapy with fluvoxamine to a clozapine monotherapy in schizophrenic patients. Sixteen schizophrenic patients received 50 mg fluvoxamine as a comedication after having reached steady-state conditions under clozapine monotherapy. Patients were monitored for subjective adverse events, laboratory parameters, EEG and ECG recordings, orthostatic hypotension and their psychopatholog…

Furosemide action on cerebellar GABA(A) receptors in alcohol-sensitive ANT rats.

Furosemide increases the basal tert-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding and reverses the inhibition of the binding by gamma-aminobutyric acid (GABA) in the cerebellar GABA(A) receptors containing the alpha6 and beta2/beta3 subunits. These effects are less pronounced in the alcohol-sensitive (ANT) than in the alcohol-insensitive (AT) rat line. The difference between the rat lines in the increase of basal [35S]TBPS binding was removed after a longer preincubation with ethylendiaminetetraacetic acid (EDTA) containing buffer, but long preincubation did not reduce the GABA content of the incubation fluid or remove the difference in GABA antagonism by furosemide. The GABA sensi…

Activity of the adenylyl cyclase in lymphocytes of male alcoholic patients is state dependent.

A decreased basal and/or stimulated activity of the G-protein/adenylyl cyclase (AC) system in peripheral blood cells has been proposed to represent a trait marker for alcoholism. However, AC activity may underlie state-dependent changes, which may impair a proper interpretation of AC activity measurements. Our study examined systematically the AC activity in peripheral lymphocytes of 73 male alcohol-dependent patients (according to DSM-IV criteria) at three different time points of measurement during the clinical course of detoxification (day 0 = at admission, while still ethanol-affected; day 2 = at the presumed peak of withdrawal symptoms; day E = after detoxification). Basal and stimulat…

Reliability and validity of the form 90 interview.

<i>Objective:</i> Alcohol consumption is a central variable in substance abuse research and treatment. The study reports the psychometric characteristics of the German version of the Form 90 interview for the assessment of recent alcohol consumption. <i>Method:</i> Reliability was evaluated in a test-retest study (7 days) with 30 consecutively admitted psychiatric inpatients with alcohol dependence. Validity of Form 90 was assessed with a second sample of 60 alcohol-dependent inpatients. <i>Results:</i> Form 90 demonstrated good to excellent retest reliability for the central variables of alcohol consumption. Retest reliability Pearson correlation coeffic…

The TPH intron 7 A218C polymorphism and TCI dimension scores in alcohol-dependent patients: hints to nonspecific psychopathology

Abstract Aims A linkage of certain alleles of the tryptophan hydroxylase (TPH) intron 7 A218C polymorphism to suicidality and antisocial behaviour has been described. The aim of our study was to find any association between dimensions of the Temperament and Character Inventory (TCI) indicating impulsivity and the TPH polymorphism alleles in unselected alcohol-dependent patients and age-matched controls. Methods We examined 159 alcohol-dependent patients and 161 controls with the TCI and genotyped them for the TPH intron 7 A218C polymorphism alleles. Results Although homozygous TPH genotypes were found more often in alcohol-dependent patients than in controls, an association between TCI dime…

Early improvement under mirtazapine and paroxetine predicts later stable response and remission with high sensitivity in patients with major depression

OBJECTIVE Current clinical knowledge holds that antidepressants have a delayed onset of efficacy. However, the delayed onset hypothesis has been questioned recently by survival analytical approaches. We aimed to test whether early improvement under antidepressant treatment is a clinically useful predictor of later stable response and remission. METHOD We analyzed data from a randomized double-blind controlled trial with mirtazapine and paroxetine in patients with major depression (DSM-IV). Improvement was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D-17) score reduction of > or = 20%. Stable response was defined as > or = 50% HAM-D-17 score reduction at week 4 and week 6,…

Neuropsychological status of alcohol-dependent patients: increased performance through goal-setting instructions.

Aims: The effects of goal-setting instructions on neuropsychological performance of alcohol-dependent patients and control subjects were assessed. Methods: 57 alcohol-dependent patients and 59 carefully age- and education-matched healthy control subjects underwent standard neuropsychological investigation. In addition, the goal-setting paradigm was used to systematically manipulate motivation. Participants were requested to calculate simple mathematical problems repeatedly within phases of a 2-min duration receiving normal or goal setting-instructions (to increase performance in the next phase by 20%). Results: The patients demonstrated deficits in standard neuropsychological tests. Patient…