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

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.

Assessing Adherence to Clozapine

“…Of the 3933 samples in which clozapine was not detected, summary information on the reason for the request was provided in 1367 instances (4 reasons, 4; 3, 53; 2: 206; 1, 780). By way of comparison, of 33,303 samples with plasma clozapine 0.01–0.16 mg L −1 (10 th percentile of the results in which clozapine was detected and dose information was provided), 16 information on the reason for the request was provided for 10,702 samples (4 reasons, 51; 3: 473; 2, 2656, 1: 7522; Table 2). Information on the administration of crushed tablets suspended in an appropriate medium or a proprietary suspension and of tablets for the groups of samples compared in Table 2 is given in Table 3.…”

“…13 With clozapine, dose assessment is complicated because (1) there is a 45-fold interpatient variation in the rate of clozapine metabolism and (2) alteration in smoking habit or coprescription of drugs such as fluvoxamine, for example, can have a large effect on an individual's clozapine dose requirement. [14][15][16] There may also be patient factors such as partial adherence to consider. If no clozapine is present in a TDM sample (limit of accurate measurement 0.01 mg L −1 ), this finding may have especially important implications because of the likely requirement to reinitiate clozapine.…”

“…With clozapine, dose assessment is complicated because (1) there is a 45-fold interpatient variation in the rate of clozapine metabolism and (2) alteration in smoking habit or coprescription of drugs such as fluvoxamine, for example, can have a large effect on an individual's clozapine dose requirement 14–16 . There may also be patient factors such as partial adherence to consider.…”

Clozapine Use in 22q11.2 Deletion Syndrome

“…It is also important that clinicians consider the effect that other factors, including the use of concurrent medications, may have on the metabolism of clozapine, 45 particularly given that seizure risk is dose (or more accurately, concentration) dependent. Specifically, numerous anticonvulsants (eg, phenytoin and carbamazepine) induce the metabolism of clozapine 50 and lower blood levels as a result, whereas numerous antidepressants (eg, fluvoxamine, fluoxetine, and paroxetine) 51 can inhibit its metabolism and increase blood levels, thereby theoretically increasing seizure risk. Valproate is unique, as it may both induce and inhibit clozapine metabolism, 46 which further highlights the importance of obtaining regular clozapine levels when using these medications concurrently.…”

Pharmacokinetics and Pharmacodynamics: A Comprehensive Analysis of the Absorption, Distribution, Metabolism, and Excretion of Psychiatric Drugs

“…Paroxetine metabolism occurs mainly in the liver and is predominantly facilitated by the cytochrome enzyme CYP2D6, with additional involvement from CYP3A4 and potentially other cytochrome enzymes. The pharmacokinetics of this medicine may be affected by genetic variations in the CYP2D6 enzyme [ 15 , 16 , 17 ].…”