Abstract
Background and Objective
Fluvoxamine, a potent CYP1A2 inhibitor, increases clozapine serum concentrations by inhibiting its N-dealkylation to norclozapine, thus reducing norclozapine formation and increasing the clozapine/norclozapine ratio. Clinically, fluvoxamine may reduce clozapine tablet burden and mitigate norclozapine-related metabolic side-effects. However, clinical guidance on this co-administration is limited. The current study evaluates the effect of fluvoxamine and its dose on clozapine and norclozapine concentrations and their ratio, while exploring potential influencing factors.
Methods
Patients from long-stay psychiatric wards were included if they had been or were currently receiving clozapine and fluvoxamine, with available steady-state concentrations with and without fluvoxamine coadministraton. Dose-adjusted clozapine and norclozapine concentrations (C/D, ng/mL per mg/day) and their ratios were compared among the two conditions using the Wilcoxon signed-rank test. Median fold increases and associations with clinical variables (e.g. gender, smoking, dosing frequency, baseline clozapine level, fluvoxamine dose), were analysed using Mann–Whitney U tests.
Results
Sixty-seven patients were included. During fluvoxamine co-administration, median C/D clozapine increased from 0.70 to 1.72, C/D norclozapine from 0.43 to 0.80 and the clozapine/norclozapine ratio from 1.66 to 2.16 (all p < 0.001). Median fold increases were 2.51 (clozapine), 1.92 (norclozapine) and 1.27 (clozapine/norclozapine ratio). Greater increases were observed with fluvoxamine doses > 25 mg and baseline clozapine levels < 350 ng/mL, without a significant increase in clozapine/norclozapine ratio. Other factors showed no significant association.
Conclusion
Fluvoxamine significantly increases clozapine and norclozapine concentrations, and their ratio. Doses > 25 mg lead to greater fold increases and more variability. Initiation at 25 mg with a 50% clozapine dose reduction is recommended.
Key Points
| Co-administration of fluvoxamine with clozapine increases serum concentrations of both clozapine and norclozapine. |
| Current study contributes real-world data to help guide clinicians in optimizing clozapine therapy. |
Introduction
Clozapine is the only antipsychotic drug with regulatory approval for the treatment of treatment-resistant schizophrenia (TRS), referring to patients with ongoing symptoms and impaired functioning after at least two trials of other antipsychotics at an adequate dose and duration [1]. Since the landmark “Study 30” [2] clozapine has been considered the gold standard for TRS.
Therapeutic Drug Monitoring (TDM) of clozapine is strongly recommended, due to its established concentration-response relationship and the considerable interindividual variability in serum concentrations [3]. Women or non-smokers generally require lower doses than men or smokers to achieve comparable serum levels [4–7]. The commonly accepted therapeutic reference range for clozapine is 350–600 ng/mL [3]. However, good clinical responses have also been observed at concentrations both below 350 ng/mL and above 600 ng/mL. While concentrations exceeding 1000 ng/mL are potentially more effective, they are also associated with an increased risk of central nervous system adverse effects [8]. Therefore, most clinical laboratories apply an alert threshold of 1000 ng/mL.
The two main metabolic pathways of clozapine are N-dealkylation and N-oxidation, yielding the metabolites N-desmethylclozapine (norclozapine) and clozapine-N-oxide, respectively. N-dealkylation is predominantly mediated by CYP1A2, with also contributions by CYP2C19 and other CYP-enzymes, while N-oxidation is primarily mediated by CYP3A4 [9, 10].
Case-reports and small studies have shown that fluvoxamine can influence clozapine serum levels [11–14]. Fluvoxamine is a strong inhibitor of the cytochrome P450 isoenzymes CYP1A2 and CYP2C19, and a less potent inhibitor of CYP2C9, CYP2D6 and CYP3A4 [15]. As a result, fluvoxamine primarily interferes with the N-dealkylation pathway of clozapine, thus reducing norclozapine formation and increasing the clozapine/norclozapine ratio. In clinical practice, co-administration of fluvoxamine is employed to reduce the number of tablets of clozapine needed to reach therapeutic concentrations. This improves patient medication adherence and can also reduce costs [14]. Moreover, fluvoxamine-induced increase in the clozapine/norclozapine ratio may also improve clozapine’s side effect profile as norclozapine is associated with metabolic side effects [16–19]. Currently, clear guidelines on adjunctive fluvoxamine are lacking, highlighting the need for one [20].
In current study focussing on the pharmacokinetic interaction of fluvoxamine and clozapine we aim:
To assess the impact of fluvoxamine and fluvoxamine dose on serum concentrations of clozapine and norclozapine and the clozapine/norclozapine ratio.
To explore whether variables, such as gender, smoking status, clozapine baseline serum levels, and dosing regimen, influence the effect of fluvoxamine on serum concentrations of clozapine and norclozapine.
Methods
Study Context
This study was conducted at the Arkin Institute for Mental Healthcare in Amsterdam. Patients from various long-term clinical services were included: inpatient mental health rehabilitation units (IMRU’s), forensic wards and specialized long-term closed wards for patients with serious mental illness and extremely disruptive/aggressive or otherwise dangerous behaviour (total capacity: 238 beds). All three types of wards offer treatment for patients with serious mental illness who have treatment-resistant symptoms, often comorbid problems and a low level of functioning. Many patients have complex psychosis [21].
Inclusion and Exclusion Criteria
Patients were included if they had been or were currently receiving clozapine with adjunctive fluvoxamine and if steady-state serum levels of clozapine and norclozapine were available at time points before and after fluvoxamine initiation or discontinuation. Data assessed between November 2015 and August 2023 were used. There were no exclusion criteria regarding gender, age, diagnosis, co-morbidity or comedication. All included patients were aged 18 or older.
Data Collection
Only data recorded for routine clinical practice were used. The retrievement of these data from the electronic case files was conducted by the first author (GvW), hospital pharmacist, who was involved in treatment of all enrolled patients and performed the annual medication reviews together with a psychiatrist, residents and a psychiatric nurse. During these medication reviews that were conducted between August 2016 and August 2023, patients were identified who were prescribed clozapine in combination with fluvoxamine. Retrospectively, steady state concentrations of clozapine and N-desmethylclozapine (norclozapine) were extracted from a TDM database, at time points before and after the initiation or discontinuation of fluvoxamine.
Steady-state was defined as at least 5 days on a stable clozapine dose during monotherapy, or at least 10 days on a stable dose of both clozapine and fluvoxamine during co-administration, to account for fluvoxamine’s effect on prolonging clozapine’s half-life. For each patient, the last available steady-state concentration before fluvoxamine initiation or discontinuation and the first available steady-state level after the change were used for analysis. Prescribed clozapine doses were retrieved from the electronic patients records.
Information regarding the patient’s ancestry and smoking status was obtained from the treating psychiatrist or psychiatric nurse during the medication review, because this information was not always correctly recorded in the electronic patient files.
The study protocol was reviewed by the Medical research Ethics Committees United (MEC-U, study-reference W17.058), and was granted an exemption from approval based on the fact that participants in the study were not subject to procedures or interventions, and were not required to follow rules of behaviour. According to Dutch legislation and privacy rules of the institute, an informed consent procedure was not deemed necessary because of the following arguments: (1) data were retrieved from the electronic patients’ record by the hospital pharmacist (GvW) who already had access because of her involvement in treatment; (2) data were coded and stored in a secured database; (3) data were analysed by GvW herself [22].
Quantification of Clozapine and Norclozapine
All blood samples were collected in the morning at 12 h after the evening dose, representing mid-point or trough levels, depending on whether patients were on a once-daily or twice-daily clozapine regimen.
Serum concentrations of clozapine and norclozapine were quantified using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Analyses were conducted at two different clinical laboratories, with a transition from the first to the second occurring in May 2022. Both laboratories were ISO 15189 accredited and participated in external quality assurance programs (SKML or LGC), ensuring comparability of results over time.
Statistical Analysis
Dose-adjusted concentrations of clozapine and norclozapine (C/D) were calculated as the ratio of drug concentration (C) to the administered daily dose of clozapine (D), expressed in ng/mL per mg/day.
All statistical analyses were conducted with SPSS software version 29.0.0.0. The Wilcoxon signed-rank test for related samples was performed to compare dose-adjusted concentrations of clozapine and norclozapine (C/D) as well as the clozapine/norclozapine ratio, at two time points (with and without fluvoxamine). A two-sided test was used for conventional reasons.
The fold increase was calculated as the ratio of the dose-adjusted concentrations during concomitant fluvoxamine to dose-adjusted concentrations when fluvoxamine was not used ({C/D}/{C/D}). The fold increase in the clozapine/norclozapine ratio was determined by dividing the ratio during concomitant fluvoxamine use by the ratio when fluvoxamine was not used.
To explore which factors influenced the observed fold-increase in clozapine concentrations, comparisons were made between relevant subgroups. The two-sided Mann–Whitney U test was used to assess differences based on gender, smoking status, baseline concentration of clozapine (< 350 ng/mL vs ≥ 350 ng/mL), dose frequency (once daily vs other), fluvoxamine dose (≤ 25 mg vs > 25 mg) and administration time of fluvoxamine (evening vs other).
Categorical variables are presented as n (percentage, %), and non-normally distributed continuous data as median (interquartile range, IQR). The significance threshold (α) was set at 0.05. No correction for multiple comparisons was applied.
Results
A total of 97 patients treated with the combination of clozapine and fluvoxamine were identified. Thirteen patients were excluded because fluvoxamine was initiated prior to November 2015, when norclozapine measurements were not yet routinely performed. Another 17 patients were excluded due to missing clozapine concentrations before fluvoxamine initiation, either because fluvoxamine was already prescribed at hospital admission or because the available concentrations did not meet steady-state criteria. The remaining 67 patients for whom serum levels of clozapine and norclozapine were available around the time of fluvoxamine initiation or discontinuation were included in the study.
Among the 67 included patients, 12 were women and 55 were men. The majority were smokers. The main primary diagnoses were schizophrenia or schizoaffective disorder. Sixty patients started fluvoxamine, while seven patients discontinued it. Fluvoxamine doses at steady-state ranged from 12.5 to 100 mg. Patient characteristics are presented in Table 1.
Table 1.
Patient characteristics
| n = 67 | |
|---|---|
| Male | 55 (82.1%) |
| Age (mean years ± SD) | 39.1 ± 9.1 |
| Smokers | 62 (92.5%) |
| Ancestry | |
| Caucasian | 37 (55.2%) |
| Africana | 9 (13.4%) |
| Asian | 2 (3.0%) |
| Other | 19 (28.3%) |
| Primary diagnosis (DSM-5) | |
| Schizophrenia | 36 (53.7%) |
| Schizoaffective disorder | 25 (37.3%) |
| Unspecified schizophrenia spectrum disorder | 1 (1.5%) |
| Bipolar disorder | 2 (3%) |
| Other | 3 (4.5%) |
| Time between start clozapine therapy and start/stop fluvoxamine | < 6 months: 22 |
| 6–12 months: 7 | |
| 1–2 years: 11 | |
| 2–5 years: 9 | |
| 5–10 years: 11 | |
| > 10 years: 7 | |
| Clozapine concentration (ng/mL) without fluvoxamine | |
| ≤ 350 ng/mL | 35 |
| > 350 ng/mL | 32 |
| Clozapine dose without fluvoxamine (median, IQR) | |
| All 67 patients | 475 (300–575) |
| ≤ 350 ng/mL | 325 (200–450) |
| > 350 ng/mL | 588 (478–788) |
| Clozapine dose frequency | |
| Once daily | 59 |
| > Once daily | 8 |
| Fluvoxamine dose | |
| 12.5 mg | 4 (6%) |
| 25 mg | 39 (58.2%) |
| 37.5 mg | 1 (1.5%) |
| 50 mg | 20 (29.9%) |
| 75 mg | 2 (3%) |
| 100 mg | 1 (1.5%) |
aSub-Saharan African, including Surinamese Creole
Table 2 presents the median serum concentrations (ng/mL) and median C/D ratios of clozapine and norclozapine under both conditions (clozapine monotherapy and clozapine combined with fluvoxamine), as well as the median within-subject difference in C/D ratios between these two conditions. A substantial proportion of patients (n = 50, 74.6%) underwent (preventive) clozapine dose adjustments after starting or discontinuing fluvoxamine. Consequently, statistical analysis was restricted to dose-adjusted concentrations (C/D, ng/mL per mg/day). At group level, C/D clozapine increased from 0.70 (IQR 0.52–0.96) to 1.72 (IQR 1.40–2.38), C/D norclozapine from 0.43 (IQR 0.30–0.56) to 0.80 (IQR 0.65–0.96), and the clozapine/norclozapine ratio from 1.66 (IQR 1.35–2.09) to 2.16 (IQR 1.83–2.63) during the addition of fluvoxamine (all p < 0.001, Wilcoxon signed-rank test for related samples, Table 2)
Table 2.
Median concentrations (IQR), median dose-adjusted (C/D) concentrations (IQR) of clozapine (CLZ) and norclozapine (NCLZ) and CLZ/NCLZ ratio, measured with and without fluvoxamine (FLV)
| N = 67a | CLZ without FLV | CLZ + FLV | Individual differenceb | p* |
|---|---|---|---|---|
| CLZ (ng/mL) | 328 (195–490) | 598 (419–850) | ||
| C/D CLZ (ng/mL per mg/day) | 0.70 (0.52–0.96) | 1.72 (1.40–2.38) | 0.97 (0.65–1.54) | < 0.001 |
| NCLZ (ng/mL) | 190 (107.5–280) | 290 (200–410) | ||
| C/D NCLZ (ng/mL per mg/day) | 0.43 (0.30–0.56) | 0.80 (0.65–0.96) | 0.37 (0.2–0.53) | < 0.001 |
| CLZ/NCLZ ratio | 1.66 (1.35–2.09) | 2.16 (1.83–2.63) | 0.46 (0.25–0.76) | < 0.001 |
aN = 66 for NCLZ and CLZ/NCLZ ratio (one missing value NCLZ)
bMedian within subject difference in dose adjusted CLZ and NCLZ concentrations and CLZ/NCLZ ratio
*Wilcoxon signed rank test for related samples
Figure 1 presents the fold-increase in C/D clozapine, C/D norclozapine and the clozapine/norclozapine ratio. The median fold increase was 2.51 (IQR 1.89–3.33) for clozapine, 1.92 (IQR 1.47–2.39) for norclozapine and 1.27 (IQR 1.12–1.52) for the clozapine/norclozapine ratio. The data exhibited a considerable spread; the maximum observed fold increase in C/D clozapine observed was 7.43.
Fig. 1.
Fold increase in C/D clozapine, C/D norclozapine and clozapine/norclozapine ratio (n = 67)
The median time between the two timepoints was 33 days (IQR 21–56). Due to frequent dose adjustments in both clozapine and fluvoxamine, it took relatively long before a new steady-state serum level was reached. Nine patients taking clozapine in combination with fluvoxamine had clozapine concentrations exceeding 1000 ng/mL, with the highest recorded level reaching 1410 ng/mL. In six of these cases, no or only minor (< 50 mg) clozapine dose adjustments were made following fluvoxamine addition.
Fluvoxamine Dose
Figure 2 presents the relationship between fluvoxamine dose and the fold increase in clozapine C/D ratios. Even at low fluvoxamine doses (12.5 mg) a substantial fold increase in C/D clozapine was observed. With increasing fluvoxamine doses, the fold increase became more pronounced but this seemed to plateau at higher doses (above 50 mg).The majority of patients received a fluvoxamine dose of either 25 mg or 50 mg. To further analyze the effect of fluvoxamine dose, patients were categorized in two fluvoxamine dose groups: patients with fluvoxamine doses ≤ 25 mg (n = 43) and patients with fluvoxamine doses > 25 mg (n = 24). The median fold increase in C/D clozapine was higher in the > 25 mg group than in the ≤ 25 mg group (3.52 (IQR 2.4–4.45) vs 2.52 (IQR 1.62–2.81), p < 0.001, Mann–Whitney U test, Fig. 3). For C/D norclozapine, the median fold increase was also higher in the > 25 mg group than in the ≤ 25 mg group (2.29 (IQR 1.93–3.06) vs 1.57 (IQR 1.30–2.27), p < 0.001, Mann–Whitney U test). The median norclozapine/clozapine ratio did not differ significantly between > 25 mg group and ≤ 25 mg group (1.31 (IQR 1.13–1.64) vs 1.24 (IQR 1.10–1.48, p = 0.371, Mann–Whitney U test).
Fig. 2.
Fold increase in C/D clozapine at different fluvoxamine doses
Fig. 3.
Fold increase in C/D clozapine at fluvoxamine doses ≤ 25 mg (n = 43) versus fluvoxamine > 25 mg (n = 24)
To explore whether specific patient characteristics might explain greater fold increases, we examined the outliers in Fig. 3. Two of the three were patients of African ancestry. For one of these patients, pharmacogenetic data were available, indicating a CYP2D6*1/*13 genotype consistent with intermediate metabolizer status. CYP1A2 activity was not assessed, while CYP2C19, CYP2C9, and CYP3A4 activity were normal in this patient.
For 14 patients, steady-state concentrations were available at two different fluvoxamine doses (25 mg and 50 mg). Figure 4 presents individual patient graphs for C/D clozapine, C/D norclozapine, and the clozapine/norclozapine ratio across these two dose points, illustrating substantial inter-individual variability in the magnitude of fluvoxamine’s effect on clozapine metabolism. The median C/D clozapine was significantly higher at 50 mg than at 25 mg fluvoxamine (2.25 (IQR 1.50–2.73) vs 1.39 (IQR 1.16–1.99), p < 0.01, Wilcoxon signed-rank test). The C/D norclozapine was also higher at 50 mg than at 25 mg fluvoxamine, although this effect was less pronounced (0.80 (IQR 0.69–1.22) vs 0.67 (IQR 0.50–0.79), p < 0.001, Wilcoxon signed-rank test). The median clozapine/norclozapine ratio did not differ significantly among the 50 mg and 25 mg fluvoxamine dose points (2.26 (IQR 1.85–3.04) vs 2.05 (IQR 1.74–2.95), p = 0.157, Wilcoxon signed-rank test). However, at 25 mg fluvoxamine, the clozapine/norclozapine ratio was significantly higher compared to baseline, without fluvoxamine co-administration (2.05 (IQR 1.74–2.95) vs 1.77 (IQR 1.44–2.02), p = 0.005, Wilcoxon signed-rank test)
Fig. 4.
a Individual patient graphs of C/D clozapine at different fluvoxamine doses. b Individual patient graphs of C/D norclozapine at different fluvoxamine doses. c Individual patient graphs of clozapine/norclozapine ratio at different fluvoxamine doses
Other Factors
We examined the influence of gender, smoking status, dosing frequency, baseline serum level (i.e., concentration in the absence of fluvoxamine) and the timing of fluvoxamine administration on the fold-increase of dose-adjusted concentrations of clozapine, norclozapine and their ratio (Table 3). Given the small number of non-smokers (n = 5) and patients on a multiple daily clozapine dosing regimen (n = 8), the variables smoking status and dosing frequency were excluded from statistical analysis. Ethnic differences were also not formally analyzed due to the small subgroup sizes. For reference, data from patients of Caucasian and African ancestry have been included in Table 3.
Table 3.
Median fold increase clozapine (CLZ) dose adjusted concentrations, norclozapine (NCLZ) dose adjusted concentrations and CLZ/NCLZ ratio
| N | Fold increase clozapine Median (IQR) |
p | Fold increase norclozapine Median (IQR) |
p | Fold increase ratio CLZ:NCLZ Median (IQR) |
p | |
|---|---|---|---|---|---|---|---|
| Total | 67 | 2.51 (1.89–3.33) | 1.92 (1.47–2.39) | 1.27 (1.12–1.52) | |||
| Gender | |||||||
| Female | 12 | 2.51 (1.33–4.36) | 0.896 | 1.82 (1.19–2.54) | 0.777 | 1.38 (1.15–1.75) | 0.245 |
| Male | 55a | 2.51 (1.92–3.33) | 1.95 (1.49–2.39) | 1.24 (1.12–1.48) | |||
| Smoking status | |||||||
| Smoker | 62a | 2.48 (1.89–3.31) | 1.91 (1.49–2.33) | 1.27 (1.12–1.48) | |||
| Non smoker | 5 | 3.56 (1.78–5.66) | 2.50 (1.29–4.80) | 1.43 (0.87–1.77) | |||
| Baselineconcentration | |||||||
| ≤ 350 ng/mL | 35a | 3.04 (2.46–4.18) | < 0.001 | 2.28 (1.72–2.99) | < 0.001 | 1.29 (1.20–1.64) | 0.158 |
| > 350 ng/mL | 32 | 2.12 (1.52–2.50) | 1.56 (1.17–2.12) | 1.23 (1.04–1.39) | |||
| Dose frequency | |||||||
| Once daily | 59a | 2.52 (1.89–3.5) | 1.96 (1.47–2.58) | 1.27 (1.12–1.52) | |||
| ≥ once daily | 8 | 2.40 (1.70–2.75) | 1.58 (1.30–2.25) | 1.22 (1.10–1.62) | |||
| Fluvoxamine dose | |||||||
| ≤ 25 mg | 43 | 2.32 (1.62–2.81) | < 0.001 | 1.57 (1.30–2.27) | < 0.001 | 1.24 (1.10–1.48) | 0.371 |
| > 25 mg | 24a | 3.52 (2.4–4.45) | 2.29 (1.93–3.06) | 1.31 (1.13–1.64) | |||
| Fluvoxamine time | |||||||
| 21.00/22.00 evening | 31a | 2.59 (2.09–3.56) | 0.242 | 2.13 (1.49–2.52) | 0.318 | 1.31 (1.16–1.51) | 0.279 |
| Other | 36 | 2.50(1.62–3.24) | 1.68 (1.45–2.30) | 1.23 (1.10–1.58) | |||
| Ancestry | |||||||
| Caucasian | 37 | 2.46 (1.90–3.19) | 1.92 (1.50–2.35) | 1.28 (1.12–1.47) | |||
| Africanb | 9 | 2.62 (2.06–5.62) | 2.18 (1.55–4.85) | 1.22(1.11–1.40) |
Fold increase = dose adjusted concentration on CLZ + FLV divided by dose adjusted concentration on CLZ
aCalculation median fold increase NCLZ and ratio CLZ:NCLZ based on n = 54, 61, 34, 58, 23 and 30 (one missing value norclozapine), Mann–Whitney U test based on N = 66
bSub-Saharan African, including Surinamese Creole
When compared to patients with therapeutic clozapine concentrations (≥ 350 ng/mL), those with subtherapeutic baseline levels (< 350 ng/mL) exhibited significantly greater fold increases in both C/D clozapine (3.04 (IQR 2.46–4.18) vs 2.12 (IQR 1.52–2.50), p < 0.001) and C/D norclozapine (2.28 (IQR 1.72–2.99) vs. 1.56 (IQR 1.17–2.12), p < 0.001). However, no significant difference was observed in the fold increase of the norclozapine/clozapine ratio between patients with subtherapeutic and therapeutic baseline levels (1.29 (IQR 1.20–1.64) vs 1.23 (IQR 1.04–1.39), p = 0.158). No significant differences in clozapine or norclozapine levels were observed for gender and timing of fluvoxamine administration.
Discussion
Current study aimed to assess the effect of fluvoxamine and its dose on serum concentrations of clozapine and norclozapine, the clozapine/norclozapine ratio, and to explore additional factors that may influence this effect in a naturalistic setting.
Impact of Fluvoxamine on (Nor)clozapine Concentration
Co-administration of fluvoxamine with clozapine was associated with a 2.51 fold higher C/D clozapine, a 1.92-fold higher C/D norclozapine and a 1.27 fold higher clozapine/norclozapine ratio compared to treatment without fluvoxamine. These findings are consistent with previous studies involving smaller sample sizes [12–14]. A more recent study compared four groups differing in smoking status and co-medication with fluvoxamine. In this study, the group of 43 smokers receiving fluvoxamine showed + 120.1% (i.e. 2.2 fold) higher median C/D clozapine and + 85.8% (i.e. 1.86 fold) higher C/D norclozapine compared to 43 smokers receiving clozapine without fluvoxamine. While this study used a between-group design, in contrast to our within-subject repeated measures approach, its findings align well with ours [23].
The increase in norclozapine levels is notable, given that fluvoxamine inhibits the N-dealkylation pathway responsible for its formation. This suggests that fluvoxamine not only inhibits the metabolism of clozapine, but also the metabolism and/or elimination of norclozapine. A possible explanation may be the inhibition of norclozapine hydroxylation, as norclozapine is first hydroxylated and subsequently conjugated via glucuronidation and sulfation. This metabolic pathway results in urinary excretion of metabolites such as 8-deschloro-8-hydroxydesmethylclozapine-O-glucuronide and 7-hydroxydesmethylclozapine sulfate [24]. The exact enzymatic pathways remain unclear and direct evidence for the involvement of CYP enzymes inhibited by fluvoxamine is lacking. However, CYP2C19 and CYP2C9—both inhibited by fluvoxamine—are involved in the metabolism of other compounds that undergo similar phase I hydroxylation, such as cannabidiol [25]. Renal clearance of unbound norclozapine represents an alternative elimination pathway, primarily mediated by active renal transport [26, 27]. However, inhibition of this route is unlikely to account for the observed increase in norclozapine concentrations, as urinary concentrations of free norclozapine rise following fluvoxamine co-administration [13], and this pathway contributes only approximately 5% of total clozapine elimination [27]. Another potential explanation for the elevated norclozapine levels is that co-administration of fluvoxamine inhibits pre-systemic metabolism and increases clozapine bioavailability, resulting in increased formation of norclozapine through N-dealkylation mediated by alternative CYP isoenzymes.
Inhibition of pre-systemic intestinal metabolism is less likely, considering the negligible expression of CYP1A2 and the low expression of CYP2C19 in the intestinal wall [28]. Clozapine, however, undergoes substantial pre-systemic first-pass hepatic metabolism [27, 29], which may also be subject to inhibition. This is supported by a study in healthy volunteers, evaluating the interaction of fluvoxamine with a single dose of clozapine, in which addition of fluvoxamine resulted in higher clozapine and lower norclozapine concentrations in the initial 3 h compared with clozapine monotherapy, indicating presystemic inhibition of N-dealkylation [30]. Moreover, concentration–time profiles demonstrated that co-administration with fluvoxamine was associated with increased overall clozapine exposure and increasing norclozapine concentrations from 3 h onward, reaching levels exceeding those observed with clozapine monotherapy. In conclusion, inhibition of pre-systemic hepatic metabolism and therefore increased bioavailability of clozapine, might contribute to the observed increase in norclozapine concentrations.
Fluvoxamine Dose
Even at a low dose of 12.5 mg, a substantial fold-increase in C/D clozapine was observed. This is in line with a study in which doses as low as 10 mg and 20 mg fluvoxamine were used to investigate the kinetics of caffeine (a CYP1A2 substrate) and omeprazole (a CYP2C19 substrate). At a daily dose of 20 mg, fluvoxamine produced a 40–50% inhibitory effect on these probe drugs [31]. In clinical practice, fluvoxamine is often initiated at 25 mg or 50 mg, which may be too high if no dose-adjustments are made for clozapine, potentially resulting in concentrations exceeding the laboratory alert level. In Europe, the lowest available tablet strength of fluvoxamine is 50 mg, making a 12.5 mg dose impractical.
With increasing fluvoxamine doses, the fold increase became more pronounced but this seemed to plateau at higher doses (above 50 mg). As only a few patients in our cohort received doses above this threshold, this observation should be interpreted with caution. Nonetheless, such a plateau may indicate that maximum inhibition of CYP1A2 is reached, which is expected beyond a certain fluvoxamine dose. When CYP1A2 is (maximally) inhibited, clozapine metabolism will be redirected to alternative pathways, including N-dealkylation mediated by other CYP-enzymes [13].
In our cohort, both clozapine and norclozapine dose-adjusted concentrations were higher in the > 25 mg dose group compared to the ≤ 25 mg group. However, despite the association between fluvoxamine co-administration and higher clozapine/norclozapine ratios, no difference in this ratio was observed between these fluvoxamine dose groups. Similarly, among the 14 patients with concentration data available at both 25 mg and 50 mg fluvoxamine, the clozapine/norclozapine ratios remained comparable at the two dose levels. This intriguing finding deserves replication and further investigation. The greater variability in C/D clozapine in the higher fluvoxamine dose group suggests that the effect of fluvoxamine on clozapine metabolism becomes less predictable at fluvoxamine doses > 25 mg. This, combined with the marked interindividual variation in clozapine/norclozapine ratio changes among 14 patients with data at both 25 mg and 50 mg, further suggests that if the clinical goal is to increase this ratio and reduce norclozapine concentrations to minimize (metabolic) side effects, the optimal fluvoxamine dose may differ between individuals.
Other Factors
Among the factors explored, only baseline clozapine concentrations were significantly associated with the fold increase in serum levels. Patients with subtherapeutic baseline clozapine concentrations exhibited a greater fold increase in both C/D clozapine and C/D norclozapine compared to those with therapeutic clozapine baseline levels. One possible explanation is that these patients may be rapid metabolizers, in whom the extent of inhibition is apparently greater than in poor metabolizers. Alternatively, low baseline levels may reflect poor medication adherence, which could have improved following the initiation of fluvoxamine, thereby contributing to the observed increase.
Our sample included only 12 women and 5 non-smokers. The limited number of female patients is notable. Although clozapine use shows a male preponderance, a study across 17 countries reported a male-to-female ratio of 1.5 among clozapine users, which closely mirrors the gender distribution in adults with schizophrenia (1.4), suggesting only a narrow or non-existent gender gap in treatment [32]. In contrast, our cohort of 97 identified clozapine–fluvoxamine users showed a markedly higher male-to-female ratio of 4.1 (78 males, 19 females). This discrepancy may largely be explained by a male preponderance in the included psychiatric wards. Another possible explanation is that women (as well as non-smokers)—due to their generally slower clozapine metabolism—may be less likely to require adjunctive fluvoxamine.
Dose frequency of clozapine was explored as a confounding variable, given that clozapine concentrations are known to be higher 12 h post-dose when clozapine is administered as a single evening dose compared with twice- (or multiple-) daily regimens [33]. In our sample, the majority of patients (59/67) received a once-daily regimen. Although the sample size was too small to draw firm conclusions, the data did not indicate major differences in fold-increase in concentrations between the two dosing regimens.
Ethnic differences were not formally analyzed due to the small subgroup sizes. For reference, data from patients of Caucasian and African ancestry have been included in Table 3. Few TDM studies have been conducted in patients of African ancestry, and both higher and lower clozapine metabolism have been reported [20, 29]. To our knowledge, no studies have addressed the interaction of fluvoxamine and clozapine in this population. Notably, two of the three outliers with extreme clozapine increases in our cohort were patients of African ancestry. For one of these patients, pharmacogenetic data were available, indicating an intermediate CYP2D6 metabolizer status. As intermediate CYP2D6 metabolizers are more prevalent in African populations, one possible explanation is that fewer alternative metabolic pathways are available in this group, leading to greater fold-increases in clozapine concentrations following the addition of fluvoxamine. Furthermore, fluvoxamine itself is a CYP2D6 substrate, and exposure may be higher in CYP2D6 intermediate metabolizers. This observation deserves further investigation.
Strengths and Limitations
A major strength of current study is its relatively large sample size in a naturalistic setting, without exclusion criteria, reflecting real-world clinical practice. To our knowledge, our study is the largest naturalistic study to date comparing clozapine concentrations with and without fluvoxamine in the same individuals.
A limitation is that no comedication was registered at both time-points. Because the median interval between the two measurements was 33 days, changes in comedication may have occurred during this period, potentially influencing clozapine concentrations. However, the large sample size may have mitigated this effect, by averaging out individual variations. Second, we assumed that steady-state clozapine concentrations are reached 10 days after initiating fluvoxamine and this is based on the reported increase in clozapine half-life from 17.3–50.6 h following fluvoxamine co-administration [12]. While five half-lives (approximately 250 h or 10 days) is a standard estimate for reaching steady-state, interindividual pharmacokinetic variability may result in longer half-lives, meaning that steady-state may not have been achieved in all patients. This may have resulted in underestimation of the effect, particularly among Asian patients and poor metabolizers. However, given the median interval of 33 (IQR 21–56) days between measurements, even individuals with a clozapine half-life of up to 5 days would be expected to have attained steady-state concentrations by that time. Pharmacogenetic profiles were not available for all patients, and we did not investigate this variable. This is a third limitation, as it could provide insight into the varying degrees of inhibition between the different groups of metabolizers. Fourth, clozapine-N-oxide was not measured, as it is not part of routine clinical practice. Measuring of this metabolite could have provided additional insight into shifts in metabolic pathways, when N-dealkylation is inhibited by fluvoxamine. And last, fluvoxamine concentrations were not measured, so the real systemic exposure to fluvoxamine is not known. Fluvoxamine is a substrate of CYP2D6 and exhibits non-linear kinetics [34, 35], particularly at doses exceeding 50 mg. However, as 64 out of 67 patients in our cohort received fluvoxamine at doses of 50 mg or less, it’s impact may have been limited. Additionally, differences in CYP2D6 phenotype may have influenced fluvoxamine disposition.
Conclusion
Co-administration with fluvoxamine significantly increases concentrations of both clozapine and norclozapine, while also increasing the clozapine/norclozapine ratio. The primary factors influencing this effect are the fluvoxamine dose and baseline concentrations. While patients receiving fluvoxamine doses > 25 mg exhibit a greater fold increase in both C/D clozapine and C/D norclozapine compared to those receiving ≤ 25 mg, the clozapine/norclozapine ratio does not significantly differ between the two dose groups. Additionally, variability in concentrations is greater at doses > 25 mg. Therefore, we recommend to initiate fluvoxamine at a low dose of 25 mg and to proactively reduce the clozapine dose by 50%. Subsequent dose adjustments should be guided by therapeutic drug monitoring. Even when clozapine concentrations are still subtherapeutic at the time of fluvoxamine initiation, clozapine dose adjustment is recommended to avoid side effects associated with a rapid rise in concentrations, including sedation and, during initial clozapine titration, myocarditis [36]. To optimise the clozapine/norclozapine ratio and decrease norclozapine concentrations in order to minimize (metabolic) side effects, careful fine-tuning of both clozapine and fluvoxamine doses is needed.
Funding
Not applicable.
Declarations
Conflict of interest
The authors declare that there is no conflict of interest
Ethics approval
The study protocol was reviewed by the Medical research Ethics Committees United (MEC-U, study-reference W17.058)
Consent to participate
Not applicable
Consent for publication
Not applicable
Code availability
Not applicable
Data availability
Data will be made available on reasonable request
Author contributions
GvW: conceptualization, data curation, formal analysis, investigation, writing-original draft, writing-review and editing. HdH: conceptualization, writing—original draft, writing-review and editing. LdH: writing—review and editing. DT: conceptualization, supervision, writing—review and editing. MdK: conceptualization, supervision, writing—review and editing.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data will be made available on reasonable request