Selective Serotonin Reuptake Inhibitors and Clozapine: Clinically Relevant Interactions and Considerations.

Amber N Edinoff,Adam M Kaye,Elyse M Cornett,Christopher D Causey,Caroline R Burroughs,Juliana M Fort,Alan D Kaye,Joshua J Woo

doi:10.3390/neurolint13030044

Abstract

The monoamine hypothesis of depression attributes the symptoms of major depressive disorders to imbalances of serotonin, noradrenaline, and dopamine in the limbic areas of the brain. The preferential targeting of serotonin receptor (SERT) by selective serotonin reuptake inhibitors (SSRIs) has offered an opportunity to reduce the range of these side effects and improve patient adherence to pharmacotherapy. Clozapine remains an effective drug against treatment-resistant schizophrenia, defined as failing treatment with at least two different antipsychotic medications. Patients with schizophrenia who display a constellation of negative symptoms respond poorly to antipsychotic monotherapy. Negative symptoms include the diminution of motivation, interest, or expression. Conversely to the depressive symptomology of interest presently, supplementation of antipsychotics with SSRIs in schizophrenic patients with negative symptoms lead to synergistic improvements in the function of these patients. Fluvoxamine is one of the most potent inhibitors of CYP1A2 and can lead to an increase in clozapine levels. Similar increases in serum clozapine were detected in two patients taking sertraline. However, studies have been contradictory as well, showing no such increases, which are worrying. Clinicians should be aware that clozapine levels should be monitored with any coadministration with SSRIs.

Highlights

The monoamine neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), dopamine, and norepinephrine are each generated exclusively by their respective populations of neurons
The findings from this study suggest sertraline may be an acceptable treatment option for patients taking clozapine, but strongly advise when paroxetine is co-administered with clozapine that clinicians provide patients with careful clinical observation and monitoring
Findings suggest metabolism of clozapine is not affected by sertraline, while paroxetine, a potent inhibitor of CYP2D6, does have an effect and appears to inhibit metabolism of clozapine

Summary

Introduction

The monoamine neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), dopamine, and norepinephrine are each generated exclusively by their respective populations of neurons. The monoamine transporters serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transport (DAT) regulate the concentrations of serotonin, norepinephrine, and dopamine, respectively. NET is located in the plasma membrane of noradrenergic neurons, and its function is to take up released norepinephrine, which was released from the synapse [1]. DAT is responsible for the clearance of dopamine from the extraneuronal space after it is released from vesicles [2]. These transporters are frequent targets of psychoactive medications and drugs of abuse. Pharmacologic manipulation is usually achieved by competitively or allosterically inhibiting the conformational changes of the transporter, preventing the intracellular uptake of neurotransmitter, and causing it to remain available in the synapse at higher concentrations

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