Olav Spigset

Effect of cigarette smoking on fluvoxamine pharmacokinetics in humans

Although fluvoxamine inhibits the biotransformation of drugs known to be metabolized by CYP1A2, there are no data available with regard to the importance of CYP1A2 for the metabolism of fluvoxamine itself. Because smoking induces the metabolism of drugs catalyzed by CYP1A2, this study investigated the pharmacokinetics of fluvoxamine in smokers and nonsmokers.

Relationship between fluvoxamine pharmacokinetics and CYP2D6/CYP2C19 phenotype polymorphisms

Objective: The purpose of this study was to investigate whether the disposition of fluvoxamine is associated with the CYP2D6 and CYP2C19 phenotype polymorphisms. Methods: The serum concentration of fluvoxamine was followed for 48 h after oral administration of a single dose of 50 mg fluvoxamine to five poor metabolizers of the CYP2D6 test drug dextromethorphan, five poor metabolizers of the CYP2C19 test drug mephenytoin, and five extensive metabolizers of both test drugs. Results: Poor metabolizers of dextromethorphan had significantly higher areas under the serum concentration-time curve than extensive metabolizers of dextromethorphan (mean 1.31 vs 1.00 μmol · h · l−1). There were no differences between poor and extensive metabolizers of mephenytoin (mean, 1.00 vs 1.15 μmol · h · l−1). Conclusion: The results are consistent with a possible minor to moderate role of CYP2D6, but not CYP2C19, in fluvoxamine metabolism.

Seizures and myoclonus associated with antidepressant treatment: assessment of potential risk factors, including CYP2D6 and CYP2C19 polymorphisms, and treatment with CYP2D6 inhibitors

All adverse drug reaction reports labelled seizures or myoclonus during treatment with antidepressants and stored in the Swedish national database for spontaneous reporting of adverse drug reactions were reviewed in order to evaluate possible risk factors. The reporting physicians were contacted and asked for complementary information, and blood samples for determination of the CYP2D6 and CYP2C19 genotypes were obtained from patients available. In total, 25 cases of seizures and 7 cases of myoclonus were studied. The drugs included were maprotiline (n=8), mianserin (n=7), fluvoxamine (n=6), amitriptyline (n=3), clomipramine (n=3), citalopram (n=2), paroxetine (n=2) and lofepramine (n= 1). Previously suggested predisposing factors were identified in all but four cases (87%). None of the 11 patients genotyped were found to be poor metabolizers with respect to the enzymes CYP2D6 or CYP2C19. Thus, neither the CYP2D6 nor the CYP2C19 genotype were found to be associated with the occurrence of seizures/myoclonus during treatment with antidepressants. However, 15 patients (47%) were concomitantly treated with drugs with potential inhibitory effects on CYP2D6, such as neuroleptics and dextropropoxyphene, and the patients might thus have been converted from the extensive metabolizer to the poor metabolizer phenotype during this treatment. Concomitant treatment with drugs decreasing the seizure threshold and/or inhibiting the metabolism of antidepressants appeared to be an important risk factor for the occurrence of seizures/myoclonus.

Influence of menstrual cycle on platelet serotonin uptake site and serotonin2A receptor binding

Depression and anxiety are common health problems affecting women, particularly during the reproductive years. Major depression is two to three times as common in women than in men. Neuroendocrine factors are likely to contribute to this overall increased risk for developing mood disorders in women, and the neuroendocrine influence is most obviously seen in women with premenstrual dysphoric disorder (PMDD) as these women experience depressed mood and anxiety premenstrually only during ovulatory cycles. Moreover, dysfunction of serotonergic transmission has been regarded as an important mechanism in several psychiatric disorders and ovarian steroids have been shown to profoundly influence the activity of the serotonergic system. Given these facts, the purpose of this study was to examine whether binding of [3H]paroxetine to the platelet serotonin transporter or binding of [3H]lysergic acid diethylamide ([3H]LSD) to the platelet 5-HT2A receptor are influenced by the cyclical changes in circulating estradiol and progesterone that occur during the menstrual cycle. We examined 28 healthy women, without oral contraceptives and with regular menstrual cycles. In the late follicular phase, Bmax for [3H]paroxetine binding was significantly higher than in the ovulatory (p<0.01), early luteal phase (p<0.05) and mid-luteal phase (p<0.01). Bmax for [3H]LSD binding was significantly higher in the early follicular phase and the early luteal phase compared to the mid-luteal phase (p<0.001 and p<0.05, respectively). In the early follicular phase and the ovulatory phase, significant correlations between estradiol serum concentrations and Kd for [3H]paroxetine were obtained (p<0.001, respectively). In the luteal phase, significant inverse correlations between progesterone as well as estradiol serum concentrations and Kd for [3H]LSD binding were found (p<0.05, respectively).

Absence of interaction between erythromycin and a single dose of clozapine.

AbstractObjective: To study the suggested pharmacokinetic interaction between erythromycin, a strong inhibitor of CYP3A4, and clozapine. Methods: Twelve healthy male volunteers received a single dose of 12.5 mg of clozapine alone or in combination with a daily dose of 1500 mg erythromycin in a randomised crossover study. Clozapine and its metabolites clozapine-N-oxide and desmethyl-clozapine were measured in serum samples which were collected during a 48 h period and in a sample of the urine secreted over the interval 0–12 h. Results: There were no significant differences in mean area under the serum concentration time curves (1348 (633) nmol h · 1−1 in the control phase and 1180 (659) nmol h · 1−1 in the erythromycin phase), terminal half-lives (19 (13) h and 15 (6) h, respectively), peak serum concentrations (92 (53) nmol · 1−1 and 77 (40) nmol · 1−1, respectively), time to peak serum concentrations (1.4 (0.7) h and 1.5 (1.0) h, respectively) or apparent oral clearances of clozapine (34 (15) l · h−1 and 46 (37) l · h−1, respectively). There were no significant differences in partial metabolic clearances to clozapine-N-oxide (5.1 (3.6) l · h−1 and 7.8 (9.4) l · h−1, respectively) or to desmethyl-clozapine (1.5 (1.3) l · h−1 and 1.8 (1.7) l · h−1, respectively) or in renal clearances of clozapine (0.8 (0.5) l · h−1 and 1.0 (0.7) l · h−1, respectively) between the two phases. Conclusion: These results demonstrate that erythromycin at a clinically relevant dosage does not inhibit the metabolism of clozapine. Hence, CYP3A4 seems to be of minor importance in the disposition of clozapine in humans at least when clozapine is taken at a low single dose.

Serotonin 5-HT2A Receptor Binding in Platelets from Healthy Subjects as Studied by [3H]-Lysergic Acid Diethylamide ([3H]-LSD): Intra- and Interindividual Variability

In studies on platelet 5-HT2A receptor binding in patients with neuropsychiatric disorders, there has been a marked variability and a considerable overlap of values between patients and controls. The causes of the large variability in 5-HT2A receptor parameters is still unsettled. In the present study, we have quantified the intra- and interindividual variability of platelet 5-HT2A receptor binding in 112 healthy subjects and explored factors that may influence 5-HT2A receptor binding, using [3H]-lysergic acid diethylamide as radioligand. Age, gender, blood pressure, and metabolic capacity of the liver enzymes CYP2D6 and CYP2C19 did not influence Bmax and Kd values. Body weight and body mass index (BMI) showed a negative correlation with Kd (p =. 04 and. 03, respectively), but not with Bmax. Bmax was significantly lower in the light half of the year than in the dark half of the year (p =. 001), and Kd was significantly lower in the fall than in the summer and winter (p <. 001). In females, there was a significant increase in Bmax from week 1 to week 2 of the menstrual cycle (p =. 03). Females taking contraceptive pills had significantly higher Kd than drug-free females in weeks 1 and 4 of the menstrual cycle (p =. 04). This study shows that a number of factors should be taken into account when using platelet 5-HT2A receptor binding in studies of neuropsychiatric disorders.

Circannual variations in the binding of [3H]lysergic acid diethylamide to serotonin2A receptors and of [3H]paroxetine to serotonin uptake sites in platelets from healthy volunteers.

BACKGROUND Circannual variations occur in several serotonergic parameters, including platelet serotonin uptake and platelet [3H]imipramine binding. METHODS Binding of [3H]lysergic acid diethylamide ([3H]LSD) to platelet serotonin (5-HT)2A receptors and binding of [3H]paroxetine to platelet serotonin uptake sites were studied longitudinally for 1 year in 12 healthy volunteers. RESULTS For [3H]LSD, the number of binding sites (Bmax) showed no significant seasonal variation (two-way analysis of variance), although Bmax was significantly higher during the months October through February than during the months April through August (32.6 vs. 29.8 fmol/mg protein; p = .015). For [3H]paroxetine, Bmax showed a significant seasonal variation (p = .003) with maximum in August (1322 fmol/mg protein) and minimum in February (1168 fmol/mg protein). The affinity constant (Kd) showed a significant seasonal variation for [3H]LSD binding (p = .046), but not for [3H]paroxetine binding. The seasonal fluctuations in [3H]LSD binding and in paroxetine binding tended to be inversely correlated for Bmax (r = -.70; p = .08) and were significantly negatively correlated for Kd (r = -.88; p = .009). CONCLUSIONS The present study demonstrates a seasonal effect on platelet serotonin uptake site binding and indicates a possible seasonal effect on 5-HT2A receptor binding. The results imply that circannual fluctuations should be taken into account when these platelet serotonin markers are studied.

Oral symptoms in bulimia nervosa A survey of 34 cases

Bulimia nervosa is increasingly recognized as an eating disorder with significant medical and dental complications, including increased caries rate, thermal hypersensitivity, enamel erosion, xerostomia, and parotid gland hypertrophy. This article reviews the oral manifestations in bulimia nervosa and presents a questionnaire study of oral symptoms in 34 women with bulimia nervosa. Twenty-three (68%) of the subjects reported dental symptoms, such as hypersensitive teeth (47%), tooth pain (18%), dental fractures (6%), and subjectively increased caries rate (29%). Twelve women (35%) reported dry mouth or dry eyes as a daily experience, and 10 (29%) reported intermittent parotid gland swelling. To the authors knowledge, this is the first report that evaluates the frequency of subjectively experienced oral symptoms in bulimia nervosa.

Binding of [3H]paroxetine to serotonin uptake sites and of [3H]lysergic acid diethylamide to 5-HT2A receptors in platelets from women with premenstrual dysphoric disorder during gonadotropin releasing hormone treatment

Changes in serotonergic parameters have been reported in psychiatric conditions such as depression but also in the premenstrual dysphoric disorder (PMDD). In addition, hormonal effects on serotonergic activity have been established. In the present study, binding of [3H]paroxetine to platelet serotonin uptake sites and binding of [3H]lysergic acid diethylamide ([3H]LSD) to platelet serotonin (5-HT)2A receptors were studied in patients with PMDD treated with a low dose of a gonadotropin releasing hormone (GnRH) agonist (buserelin) or placebo and compared to controls. The PMDD patients were relieved of premenstrual symptoms like depression and irritability during buserelin treatment. The number of [3H]paroxetine binding sites (Bmax) were significantly higher in the follicular phase in untreated PMDD patients compared to controls. When treated with buserelin the difference disappeared. No differences in [3H]LSD binding between the three groups were shown. The present study demonstrated altered platelet [3H]paroxetine binding characteristics in women with PMDD compared to controls. Furthermore, [3H]paroxetine binding was affected by PMDD treatment with a low dose of buserelin. The results are consistent with the hypothesis that changes in serotonergic transmission could be a trait in the premenstrual dysphoric disorder.

Enhanced platelet serotonin 5-HT2A receptor binding in anorexia nervosa and bulimia nervosa

Some evidence exists to suggest that serotonin 5-HT2A receptor function is altered in anorexia nervosa and bulimia nervosa. In order to further investigate the 5-HT2A receptor in eating disorders, platelet [3H]lysergic acid diethylamide ([3H]LSD) binding was studied in ten patients with anorexia nervosa, 23 patients with bulimia nervosa and 33 healthy controls. At admission, Bmax for platelet [3H]LSD binding was significantly higher both in the anorexia nervosa group (30.6+/-4.2 fmol/mg protein; mean+/-S.D.) and in the bulimia nervosa group (30.8+/-7.6 fmol/mg protein) than in the control group (23.5+/-6.3 fmol/mg protein; p=0.01 and p=0.003, respectively). Kd was borderline significantly higher among anorexics (median 1.45 nM) and significantly higher among bulimics (median 1.66 nM) than among controls (median 0.95 nM; p=0.05 and 0.003, respectively). The Global Assessment of Functioning score and the body mass index were both significantly negatively correlated to Kd (r=-0.40; p=0.03 and r=-0.41 p=0.03, respectively), but not to Bmax. The present study indicates that patients with anorexia nervosa as well as patients with bulimia nervosa have an enhanced 5-HT2A receptor binding and provides further evidence for a serotonergic dysfunction in eating disorders.