Hans-Peter Volz’s research while affiliated with Friedrich Schiller University Jena and other places

Im Rahmen der Schizophrenieforschung der letzten Jahre hat die 31Phosphor-Magnetresonanzspektroskopie (31P-MRS) erheblich an Bedeutung gewonnen, da diese Methode einen nichtinvasiven Einblick in den Stoffwechsel der Phospholipide und energiereichen Phosphate des lebenden Gehirns erlaubt. In verschiedenen Studien wurden Unterschiede im zerebralen Metabolismus zwischen schizophrenen Patienten und gesunden Kontrollen gefunden. Darüberhinaus wurde über Lateralisierungseffekte und Einflüsse epidemiologischer und psychopathologischer Faktoren berichtet. Dieser Übersichtsartikel soll die Möglichkeiten der 31P-MRS in der Schizophrenieforschung darlegen und die bisherigen Befunde kritisch besprechen. Besonders diskutiert werden Alterationen der Phospholipide im Kontext der Membranlipidhypothese der Schizophrenie, die Frage des energetischen Hypometabolismus und der Einfluss der Neuroleptika. 31Phosphorus nuclear magnetic resonance spectroscopy (31P-MRS) has gained much interest in schizophrenia research in the last years, since it allows noninvasive measurement of high energy phosphates and phospholipids of the human brain in vivo. Thus, several studies have reported cerebral metabolic differences between patients and healthy controls as well as on lateralization effects and influences of epidemiological and psychopathological factors. This review gives a survey of the potential of 31P-MRS in schizophrenia research and summarizes and comments on the results of preceding studies. The discussion covers the reduction of phospholipids in patients in the context of the membrane phospholipid hypotheses, the question of an energetic hypometabolism in schizophrenics, and the influence of neuroleptic medication.

The noradrenaline-selective antidepressant reboxetine in vitro is a weak inhibitor of both cytochrome P450 (CYP) 2D6 and CYP3A4. Thus, in this study the pharmacokinetics of reboxetine in relation to pharmacogenetics and the effects of reboxetine compared to paroxetine treatment on the CYP2D6 and CYP3A4 phenotype were analyzed in healthy control subjects. Healthy male volunteers were treated with either 6 mg reboxetine (n = 26) or 30 mg paroxetine (n = 25). On Days 10/11 of treatment, serum concentrations of the antidepressants were measured and pharmacokinetic parameters calculated. Volunteers were phenotyped at the end of treatment and after at least 3 weeks washout (true phenotype) using 30 mg dextromethorphan (DM) hydrobromide given orally and measuring DM and metabolites in serum 2 h after intake. CYP2D6 and CYP2C19 genotypes were determined in parallel. Reboxetine serum concentrations showed no correlation with the CYP2D6 genotype and the CYP2D6 phenotype, whereas paroxetine concentrations showed some dependence on CYP2D6. In contrast to in vitro investigations, indicating a major role of CYP3A4 in reboxetine metabolism, reboxetine concentrations in serum showed no correlation with the respective DM metabolic ratios. There was also no correlation between paroxetine concentrations and the CYP3A4 phenotype data. The CYP2C19 genotype (only heterozygosity) had no influence on reboxetine and paroxetine pharmacokinetics. There were only minor changes in the DM metabolite pattern on treatment with reboxetine and no evidence of enzyme inhibition was obtained. In contrast and as expected, paroxetine strongly inhibited CYP2D6. Thus, reboxetine treatment has no effect on the CYP2D6 genotype and no clinically relevant drug interactions involving CYP2D6 are anticipated.

Background: The psychopharmacotherapy of somatoform disorders (SD; ICD-10: F45) has been less frequently investigated and is not as well established as in other (neurotic) disorders of ICD-10 section F4, i.e. generalized anxiety disorder (GAD; ICD-10: F41.1). The atypical compound opipramol is very often used to treat SD and GAD in clinical practice in Germany. However, state-of-the-art controlled clinical trials have not yet been performed. Objectives: Two clinical trials were performed with the aim of confirming the efficacy and tolerability of opipramol in SD and GAD. Methods: Both trials were performed as randomized, double-blind, placebo-controlled, multicenter studies. While the GAD trial was a three-arm study with opipramol (200 mg/day) vs. placebo and alprazolam (2 mg/day) for 28 days, the SD trial was a placebo-controlled two-arm study with a treatment duration of 42 days. Each group consisted of about 100 patients. Results: Significant differences (alpha = 0.05) were found for the primary efficacy criteria (HAMA total score in GAD, HAMA somatic subscore in SD) and most of the secondary criteria in favor of the active drug therapies. Considerable differences between the psychopathology of SD and GAD were detected. Conclusion: The well-tolerated anxiolytic opipramol is the first psychotropic drug with proven efficacy in somatoform disorders with effects on symptoms of somatization, anxiety, and depression. The compound is also effective and safe in GAD.

Based on a previous report [9] on alterations of membrane phosphorus metabolism in asymptomatic family members of schizophrenic patients, the aim of the present study was to extend and improve the evaluation and data processing of (31)P spectroscopic data obtained from a larger study population by including an analysis of the broad spectral component (BC) of membrane phospholipids (PL). Eighteen children and siblings of patients with schizophrenia and a gender- and age-matched control group of 18 healthy subjects without familial schizophrenia were investigated with phosphorus magnetic resonance spectroscopy ((31)P-MRS) by using image selected in vivo spectroscopy (ISIS) in the dorsolateral prefrontal regions (DLPFR) of the brain. Spectral analysis was performed by using both the full and truncated FID to estimate metabolic peak ratios of different (31)P metabolites and the intensity and linewidth of the broad component. A significantly higher PDE level (p<0.01) and increased linewidth of the PDE components were observed for the high-risk group compared with the control group (p=0.02). No significant differences were observed for PME as well as for other (31)P-metabolites. No differences were observed between the left and right hemispheres for different normalised (31)P-metabolic levels. Decreased intensities (p=0.03) and smaller linewidths (p=0.01) were obtained for the broad component in the high-risk group. Impairments of membrane metabolism that are typical for schizophrenic patients are partially observed in adolescent asymptomatic family members of schizophrenics, including increased levels of low molecular PDE compounds indicating increased membrane degradation processes, no changes for PME, and decreased intensities and linewidths of the BC indicating changes in the composition and fluidity of membrane phospholipids. Despite limitations to completely suppress fast-relaxing components by dismissing initial FID data points, the spectroscopic results indicate additional changes in the membrane metabolism of high-risk subjects beyond changes of synthesis and degradation.

Zellulär vermittelte Nebenwirkungen der Psychopharmakotherapie Antidepressiva und Neuroleptika gehören zu den am häufigsten in der Psychopharmakotherapie eingesetzten Substanzen. Aufgrund der häufig vergleichbaren Wirksamkeit von Substanzen derselben Gruppe, bestimmen zunehmend die möglichen Nebenwirkungen die Auswahl einer bestimmten Substanz. Der antidepressive Effekt wird durch eine Hemmung der Wiederaufnahme der Transmitter Noradrenalin und Serotonin vermittelt. Unerwünschte Nebenwirkungen entstehen durch die zusätzliche Blockade von Rezeptoren, die nicht für die therapeutische Wirkung verantwortlich sind, im wesentlichen durch den muskarini-schen (M) Acetylcholinrezeptor, den Histamin (H1) Rezeptor und den alpha-1 (α1) adrenergen Rezeptor. Im Gegensatz zu den klassischen trizyklischen Antidepressiva, blockieren die neueren selektiven Serotonin Wiederaufnahmehemmer weder den M1- noch den H1- oder den α1 Rezeptor. Wenngleich hierdurch die Häufigkeit von Nebenwirkungen im Vergleich zu den trizyklischen Antidepressiva deutlich geringer ist, können unerwünschte Wirkungen durch die Stimulation verschiedener Serotonin Rezeptorsubtypen entstehen (5-HT2A, 5-HT2B und 5-HT3) und zu ängstlicher Unruhe, Schlafstörungen und Übelkeit führen. Neuroleptika werden häufig im Rahmen der Behandlung der Schizophrenie oder der schizoaffektiven Störung über Jahre, z. T. über Jahrzehnte eingenommen. Die wesentlichen Nebenwirkungen sind extrapyramidal-motorische Symptome, z. B. das Neuroleptika-induzierte Parkinsonoid, die Akathisie, Dystonien und tardive Dyskinesien. Mit der Einführung der atypischen Neuroleptika (z. B. Clozapin, Risperidon, Olanzapin) wurde deutlich, daß der antipsychotische Effekt und die extrapyramidalmotorischen Ne-benwirkungen nicht notwendigerweise miteinander verbunden sein müssen. Es werden die Grundlagen der unterschiedlichen pathogenetischen Hypothesen vorgestellt. Sowohl die Hypothese der Dop-aminrezeptor Hypersensitivität als auch die Hypothese der Hemmung der mito-chondrialen Atmungskette gründen sich bislang auf indirekte Hinweise. Wenn jedoch, wie die Untersuchungen des mitochondrialen Energiestoffwechsels zeigen, der antipsychotische Effekt und die uner-wünschten Wirkungen voneinander un-abhängige Eigenschaften der Neuroleptika darstellen, sollte ein neues Vorgehen bei der Entwicklung neuartiger Neuroleptika gewählt werden. Neuroleptika können dann entwickelt werden, die antipsychotisch wirksam sind bei einer gleichzeitig nur sehr geringen Wahrscheinlichkeit von einschränkenden extrapyramidal-motorischen Nebenwirkungen.