Ion Anghelescu

Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors: differential effects of fluvoxamine and paroxetine in a prospective study.

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 its metabolites were measured after 1, 7, and 14 days of coadministration with the SSRI. Mean trough concentrations of steady-state serum concentrations of clozapine, N-desmethylclozapine, and clozapine N-oxide were markedly elevated under fluvoxamine by about threefold of baseline concentrations whereas paroxetine induced only minor, nonsignificant changes. Estimation of the mean elimination half-life of clozapine 2 weeks after start of fluvoxamine comedication revealed an increase from 17 hours to about 50 hours whereas there was no change under paroxetine coadministration. The N-desmethylclozapine/clozapine ratio did not change significantly with either SSRI. Under monotherapy, clozapine mean serum concentrations in smokers were significantly lower by 32% compared with nonsmokers. Similarly, N-demethylation ratios were about 20 to 50% higher in smokers. Thus, in all patients, fluvoxamine induced relevant increases in serum concentrations of clozapine and its metabolites, probably by the inhibition of enzymes catalyzing the degradation of clozapine and N-desmethylclozapine, whereas paroxetine, at a usual clinically effective dosage of 20 mg/day, did not cause significant pharmacokinetic interactions.

The HTR1B 861G>C receptor polymorphism among patients suffering from alcoholism, major depression, anxiety disorders and narcolepsy

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 (chi(2)=4.02, d.f.=2, P=0.04). However, the association resulted from higher frequencies of the opposite alleles (HTR1B 861G), as originally reported by Lappalainen et al. (1998). Although the association in our study might be due to a type I error, the higher degree of HTR1B allele sharing within both populations could also argue for another alcoholism-relevant gene within the proximity of the HTR1B gene on human chromosome 6.

Neuroendocrine response to antipsychotics : Effects of drug type and gender

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 D2-like dopamine antagonist; and a thioxanthene, flupenthixol, a mixed D1/D2-like antagonist also blocking serotonin, H1, and D1 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 hormone (TRH) was injected i.v. to investigate drug effects on TRH-stimulated secretion of prolactin, TSH, and GH. RESULTS Prolactin plasma levels were markedly elevated in both treatment groups. In female, but not in male patients, this elevation was significantly more pronounced under amisulpride than under flupenthixol. The prolactin response to TRH was significantly blunted by amisulpride only in male subjects. While basal TSH secretion was significantly increased by both compounds, TRH-stimulated TSH secretion was elevated only in patients treated with amisulpride. Low basal prolactin levels predicted improvement of negative symptoms in patients treated with amisulpride. CONCLUSIONS Amisulprides more pronounced endocrine effects may be a reflection of its distinguished pharmacology and pharmacokinetics.

Association of the dopamine D2 receptor gene with alcohol dependence: haplotypes and subgroups of alcoholics as key factors for understanding receptor function.

Objectives The dopamine D2 receptor (DRD2) plays an important role in the reinforcing and motivating effects of ethanol. Several polymorphisms have been reported to affect receptor expression. The amount of DRD2, expressed in a given individual, is the result of the expression of both alleles, each representing a distinct haplotype. We examined the hypothesis that haplotypes composed of polymorphisms, associated with reduced receptor expression, are more frequent in alcoholics compared with healthy individuals. Methods The polymorphisms −141ins/del, C957T, A1385G, and TaqIA were genotyped in a case–control sample comprising 360 alcoholics and 368 controls, and in a family-based sample of 65 trios. To investigate more homogenous groups, we constructed two subgroups with respect to age at onset and antisocial personality disorder. In addition, a subgroup with positive family history of alcoholism was investigated. Results The haplotypes I-C-G-A2 and I-C-A-A1 occurred with a higher frequency in alcoholics [P = 0.026, odds ratio (OR): 1.340; P = 0.010, OR: 1.521, respectively]. The rare haplotype I-C-A-A2 occurred less often in alcoholics (P = 0.010, OR: 0.507), and was also less often transmitted from parents to their affected offspring (1 vs. 7). Among the subgroups, I-C-G-A2 and I-C-A-A1 had a higher frequency in Cloninger 1 alcoholics (P = 0.083 and 0.001, OR: 1.917, respectively) and in alcoholics with a positive family history (P = 0.031, OR: 1.478; P = 0.073, respectively). Cloninger 2 alcoholics had a higher frequency of the rare haplotype D-T-A-A2 (P<0.001, OR: 4.614) always compared with controls. In patients with positive family history haplotype I-C-A-A2 (P = 0.004, OR: 0.209), and in Cloninger 1 alcoholics haplotype I-T-A-A1 (P = 0.045, OR: 0.460) were less often present. Conclusion We confirmed the hypothesis that haplotypes, which are supposed to induce a low DRD2 expression, are associated with alcohol dependence. Furthermore, supposedly high-expressing haplotype weakened or neutralized the action of low-expressing haplotypes.

Inflammatory biomarkers in 70 depressed inpatients with and without the metabolic syndrome.

OBJECTIVE Chronic subclinical inflammation may be associated with the metabolic syndrome as well as with depression. We examined the impact of the metabolic syndrome on concentrations of inflammatory biomarkers in major depression. METHOD Data for 70 inpatients with major depressive disorder (diagnosed according to ICD-10 and DSM-IV), and with or without the metabolic syndrome, were assessed 4 to 5 weeks after admission to the clinic of the Department of Psychiatry, Charité-University Medicine, Berlin, between 2005 and 2007. The metabolic syndrome was defined according to the criteria of the International Diabetes Federation (2005). Immunologic biomarkers assessed included adiponectin, resistin, serum amyloid A (SAA), C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), soluble E-selectin, and CD40 ligand (CD40L). Severity of depression was measured with the 17-item Hamilton Depression Rating Scale. RESULTS After regressional correction for confounding variables and covariates, a 2-factorial analysis of variance (metabolic syndrome x time) revealed that the metabolic syndromes presence affected adiponectin (F(43,1) = 5.56; P < .05) and IL-6 levels (F(25,1) = 6.80; P < .05) significantly. There was also a trend for effects on fibrinogen levels (F(47,1) = 3.66; P = .06). CONCLUSIONS This is the first study to evaluate the putative additive effect of the metabolic syndrome on a panel of 9 inflammatory biomarkers in depression. Our findings support an additive effect on some (adiponectin, IL-6, and trendwise for fibrinogen) markers. Patients with the metabolic syndrome and major depression are at higher risk for more frequent and more severe cardiovascular side effects than their counterparts without the metabolic syndrome.

Lithium versus lamotrigine augmentation in treatment resistant unipolar depression: a randomized, open-label study.

Treatment-resistant depression affects up to 70% of patients. In our 8-week, randomized, open-label, prospective study of 34 treatment-resistant depression patients lamotrigine-add-on was compared with lithium-augmentation. Both treatments resulted in clinically significant reduction in Hamilton rating scale for depression score: mean Hamilton rating scale for depression-score declined from 22.7 (SD 3.9) to 11.7 (SD 4.2) in the lamotrigine group and from 21.5 (SD 3.8) to 13.3 (SD 5.7) in the lithium (Li) group. No significant differences were seen in Hamilton rating scale for depression scores between treatment groups at baseline (P=0.82) and after 8 weeks (P=0.11). Twenty-three percent of the lamotrigine group (n=4) and 18% (n=3) of the Li group achieved remission, 53% of the lamotrigine group (n=9) responded to treatment vs. 41% in the Li group (n=7) and 47% of the lamotrigine group (n=8) vs. 35% of the Li group (n=6) showed at least a partial response. Lamotrigine-augmentation was well tolerated. In conclusion, this study demonstrated that the add-on of lamotrigine to antidepressive medication revealed comparable results in most outcome measures as a lithium augmentation. Owing to small sample size no conclusions regarding similar efficacy can be drawn from our data. Larger trials that should include a placebo arm are needed to further investigate lamotriginés role in treatment-resistant depression.

Reliability and Validity of the Form 90 Interview

Objective: 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. Method: 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. Results: Form 90 demonstrated good to excellent retest reliability for the central variables of alcohol consumption. Retest reliability Pearson correlation coefficients (r) ranged from 0.76 to 0.99 and Intraclass Correlation Coefficients (ICC) ranged from 0.74 to 0.98. Reliability coefficients proved to be stable throughout the whole assessment window (90 days). Confidence intervals demonstrated sufficient precision of measures of alcohol consumption. Validity was supported by significant correlations of the amount of alcohol consumed with outcome parameters of the Lifetime Drinking History Interview (r = 0.47 and 0.58), γ-glutamyltransferase on admission to detoxification treatment (r = 0.37), physical withdrawal symptoms (r = 0.56) and the withdrawal symptom index (r = 0.48). Conclusions: Form 90 presented evidence of good to excellent psychometric properties, and its applicability to clinical populations of alcohol-dependent patients in German-speaking countries could be confirmed.

Cognitive-Behavioral Therapy as Continuation Treatment to Sustain Response After Electroconvulsive Therapy in Depression: A Randomized Controlled Trial

BACKGROUND Although electroconvulsive therapy (ECT) is the most effective acute antidepressant intervention, sustained response rates are low. It has never been systematically assessed whether psychotherapy, continuation ECT, or antidepressant medication is the most efficacious intervention to maintain initial treatment response. METHODS In a prospective, randomized clinical trial, 90 inpatients with major depressive disorder (MDD) were treated with right unilateral ultra-brief acute ECT. Electroconvulsive therapy responders received 6 months guideline-based antidepressant medication (MED) and were randomly assigned to add-on therapy with cognitive-behavioral group therapy (CBT-arm), add-on therapy with ultra-brief pulse continuation electroconvulsive therapy (ECT-arm), or no add-on therapy (MED-arm). After the 6 months of continuation treatment, patients were followed-up for another 6 months. The primary outcome parameter was the proportion of patients who remained well after 12 months. RESULTS Of 90 MDD patients starting the acute phase, 70% responded and 47% remitted to acute ECT. After 6 months of continuation treatment, significant differences were observed in the three treatment arms with sustained response rates of 77% in the CBT-arm, 40% in the ECT-arm, and 44% in the MED-arm. After 12 months, these differences remained stable with sustained response rates of 65% in the CBT-arm, 28% in the ECT-arm, and 33% in the MED-arm. CONCLUSIONS These results suggest that ultra-brief pulse ECT as a continuation treatment correlates with low sustained response rates. However, the main finding implicates cognitive-behavioral group therapy in combination with antidepressants might be an effective continuation treatment to sustain response after successful ECT in MDD patients.

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

&NA; 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 patientswith alcohol dependence, panic disorder without agoraphobia, generalized anxiety disorder, narcolepsy and normal healthy volunteers for the 5‐HT2C Cys23Ser polymorphism. 5‐HT2C Cys23Ser allele frequencies and genotypes did not differ among patients with alcohol dependence, panic disorder, generalized anxiety disorder, narcolepsy and normal healthy volunteers. In an overall analysis, female subjects (n = 173) displayed a higher frequency of 5‐HT2C Ser23 alleles as compared to males (n = 298, P = 0.0178). The potential mechanisms of the observed gender difference in allele frequencies, including transmission ratio distortion, are discussed.

Aripiprazole as adjunct to a mood stabilizer and citalopram in bipolar depression: a randomized placebo-controlled pilot study

The use of atypical antipsychotics (AAPs) for the treatment of unipolar and bipolar depression has been more and more frequently evaluated, and aripiprazole showed positive effects in the treatment of unipolar depression. However, no placebo‐controlled studies of adjunctive aripiprazole for the treatment of bipolar depression have been performed yet.