The clinical potentials of adjunctive fluvoxamine to clozapine treatment: a systematic review

  title={The clinical potentials of adjunctive fluvoxamine to clozapine treatment: a systematic review},
  author={Christoffer Polcwiartek and Jimmi Nielsen},
RationaleNew clozapine optimization strategies are warranted, as some patients do not achieve sufficient response and experience various adverse effects. Fluvoxamine is a potent CYP1A2 inhibitor and may increase the ratio of clozapine to its primary metabolite N-desmethylclozapine (NDMC).ObjectivesThis study aims to review all pharmacodynamic effects and the adverse effect profile of changing the clozapine/NDMC ratio with adjunctive fluvoxamine.MethodsMEDLINE, Embase, and the Cochrane Library… 

The clozapine to norclozapine ratio: a narrative review of the clinical utility to minimize metabolic risk and enhance clozapine efficacy

A narrative review comprehensively examines the clinical utility of the CLZ:NDMC ratio to reduce metabolic risk and increase treatment efficacy and suggests it may be useful for predicting and monitoring cardiometabolic adverse effects and optimizing potential cognitive benefits of clozapine.

A systematic review and meta-analysis of the association between clozapine and norclozapine serum levels and peripheral adverse drug reactions

Heart rate, triglycerides and combined ADRs are significantly correlated with clozapine levels, and triglycerides, total cholesterol and weight gain with norclozAPine levels.

Comedication of Valproic Acid Is Associated With Increased Metabolism of Clozapine

Comedication with valproic acid accelerated metabolism of clozapine with predominant effects on the degradation of norclozapines, andTherapeutic drug monitoring should be applied to guide individual patient responses upon initiation of comedication.

High-Dose Fluvoxamine Augmentation to Clozapine in Treatment-Resistant Psychosis

Although high variability of responses and adverse effects were observed during fluvoxamine augmentation to clozapine, this strategy was successful in increasing clozAPine serum levels and may confer benefit to residual negative, obsessive, and anxiety symptoms.

Potential Role of Patients’ CYP3A-Status in Clozapine Pharmacokinetics

Prospective assaying of CYP3A-status may better identify the patients with higher risk of inefficiency or adverse reactions and may facilitate the improvement of personalized clozapine therapy; however, further clinical studies are required to prove the benefit of CYp3A testing for patients under clozAPine therapy.

Treatment of Clozapine Nonresponders

Electroconvulsive therapy (ECT) is possibly the most effective augmentation strategy in patients not responding or partially responding to clozapine and require augmentation of clozAPine with another treatment strategy.

When Clozapine Fails: Augmentation Strategies in the Management of Clozapine-Resistant Schizophrenia

The aim of this chapter was to provide an overview of the managing strategies of clozapine-resistant schizophrenia with a particular focus on augmentation strategies aimed to improve efficacy on schizophrenia symptoms.



Adjunctive fluvoxamine inhibits clozapine-related weight gain and metabolic disturbances.

It is suggested that fluvoxamine cotreatment can attenuate weight gain and metabolic disturbances in clozapine-treated patients and conservative introduction with reduced clozabine dosage and careful therapeutic drug monitoring of clozAPine concentration is recommended.

Fluvoxamine Inhibition and Carbamazepine Induction of the Metabolism of Clozapine: Evidence from a Therapeutic Drug Monitoring Service

It is concluded that carbamazepine causes decreased clozapine plasma levels, while fluvoxamine increases the levels.

Olanzapine plus fluvoxamine and olanzapine alone for the treatment of an acute exacerbation of schizophrenia

Fluvoxamine augmentation to olanzapine is well tolerated and more effective than olanZapine alone for short‐term (6‐week) treatment of an acute exacerbation of schizophrenia.

Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided?

Results suggest that prompt discontinuation of clozapine without rechallenge is indicated for agranulocytosis, myocarditis, cardiomyopathy, and a QTc interval > 500 milliseconds that is confirmed and derived using the appropriate correction method.

Clozapine treatment of childhood-onset schizophrenia: evaluation of effectiveness, adverse effects, and long-term outcome.

Clinical improvement after 6 weeks of clozapine treatment, as measured by the percentage of improvement on the Brief Psychiatric Rating Scale and the Scale for the Assessment of Positive Symptoms, was strongly associated with the NDMC/clozAPine ratio at the 6-week time point.

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

In all patients, fluvoxamine induced relevant increases in serum concentrations ofClozapine and its metabolites, probably by the inhibition of enzymes catalyzing the degradation of clozapines and N-desmethylclozabine, whereas paroxetine, at a usual clinically effective dosage of 20 mg/day, did not cause significant pharmacokinetic interactions.

Fluvoxamine Augmentation of Olanzapine in Chronic Schizophrenia: Pharmacokinetic Interactions and Clinical Effects

Although the combination was well tolerated in this sample and the negative symptom response appeared to be favorable in at least five patients, the combination therapy of olanzapine and fluvoxamine should be used cautiously and should be controlled by therapeutic drug monitoring to avoid olanZapine-induced side effects or intoxications.

Clozapine-induced sialorrhea: pathophysiology and management strategies

Judicious use of pharmacological agents along with behavioral methods will reduce this troublesome side effect and enhance compliance and no drug has been found to be superior.

Nonresponse to Clozapine and Ultrarapid CYP1A2 Activity: Clinical Data and Analysis of CYP1A2 Gene

The sequencing of the entire CYP1A2 gene from genomic DNA of these patients suggests that the −164C > A mutation (CYP1A 2*1F) in intron 1, which confers a high inducibility of CYP 1A2 in smokers, is the most likely explanation for their ultrarapid CYP2A2 activity.