Effect of fluvoxamine augmentation and smoking on clozapine serum concentrations.

BACKGROUND: Clozapine (CLZ) is metabolized via cytochrome P450 CYP1A2 to N-desmethylclozapine (NCLZ). Smoking induces CYP1A2 thereby increasing clozapine metabolism whereas fluvoxamine inhibits CYP1A2. Studies suggest that the beneficial effect of fluvoxamine augmentation in raising serum clozapine concentrations also occurs when serum concentrations are low due to smoking. Yet, little is known about the influence of fluvoxamine augmentation on clozapine serum concentrations in smoking versus non-smoking patients. METHODS: A TDM database was analyzed. Serum concentrations of CLZ, NCLZ, dose-adjusted serum concentrations (C/D) and metabolite-to-parent ratios (MPR) were compared using non-parametrical tests in four groups: clozapine-monotherapy in non-smokers (VNS, n = 28) and smokers (VS, n = 43); combined treatment with clozapine and fluvoxamine in non-smokers (VNS+F, n = 11) and smokers (VS+F, n = 43). RESULTS: The CLZ monotherapy smoking group showed lower values of C/D CLZ of -38.6% (p < 0.001), C/D NCLZ -35.6% (p < 0.001) and a higher MPR (p = 0.021) than in the non-smoking group. The combination of CLZ and fluvoxamine in non-smoking patients led to higher C/D values: C/D CLZ +117.9% (p < 0.001), C/D NCLZ +60.8% (p = 0.029) while the MPR did not differ between groups (p = 0.089). Changes were comparable to fluvoxamine augmentation in the smoking group with increased C/D CLZ of +120.1% (p < 0.001), C/D NCLZ of +85.8% (p < 0.001) and lower MPR (p = 0.006). CONCLUSIONS: Smoking in clozapine monotherapy reduced median dose-adjusted serum concentrations more than a third. Combined treatment with fluvoxamine and clozapine led to higher median C/D values in both, smokers and non-smokers. The opposing effects of CYP1A2 induction by smoking and inhibition by fluvoxamine on clozapine serum concentrations balanced out.

Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies.

BACKGROUND: Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogeneous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with multisystemic involvement. METHODS: We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives (n = 43) and particularly focused on the associated multisystemic symptoms. RESULTS: We identified 14 heterozygous mutations (diagnostic yield of 37%), among them the novel p.Pro209Gln mutation in the BAG3 gene, which was associated with onset in adulthood, a mild phenotype and an axonal sensorimotor polyneuropathy, in the absence of giant axons at the nerve biopsy. We revealed several novel clinical phenotypes and unusual multisystemic presentations with previously described mutations: hearing impairment with a FLNC mutation, dysphonia with a mutation in DES and the first patient with a FLNC mutation presenting respiratory insufficiency as the initial symptom. Moreover, we described for the first time respiratory insufficiency occurring in a patient with the p.Gly154Ser mutation in CRYAB. Interestingly, we detected a polyneuropathy in 28% of the MFM patients, including a BAG3 and a MYOT case, and hearing impairment in 13%, including one patient with a FLNC mutation and two with mutations in the DES gene. In four index patients with a mutation in one of the MFM genes, typical histological findings were only identified at the ultrastructural level (29%). CONCLUSIONS: We conclude that extraskeletal symptoms frequently occur in MFM, particularly cardiac and respiratory involvement, polyneuropathy and/or deafness. BAG3 mutations should be considered even in cases with a mild phenotype or an adult onset. We identified a genetic defect in one of the known genes in less than half of the MFM patients, indicating that more causative genes are still to be found. Next generation sequencing techniques should be helpful in achieving this aim.