Paroxetine clozapine

Clozapine 1A2 3A3/4, 2D6, 2C19 Fluvoxamine, ciprofloxacin, paroxetine Cigarette smoking... 

Antidepressants tricyclics, fluoxetine, paroxetine, sertraline, mirtazepine, venlafaxine, mianserin Antipsychotics phenothiazines, haloperidol, clozapine, olanzapine, quetiapine... 

Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300 mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure. 

In most cases, SSRIs are the first choice for drugs to combat OCD. Clomipramine, fluvoxamine, fluoxetine, paroxetine, sertraline, and citalopram are all SSRIs that have been proven effective in reducing OCD symptoms. However, in about 40 to 60% of patients, these drugs do not completely alleviate all the symptoms. When this is the case, a second type of drug called a neuroleptic is often added. Neuroleptic drugs, such as haloperidol, clozapine, risperidone, and chlorpromazine... 

P450 IID6 -fin women Inhibited by OCs Hydroxylation of nortriptyline and desipramine, haloperidol, clozapine, risperidone, venlafaxine Fluoxetine, fluvoxamine, paroxetine, sertraline... 

Wetzel H, Anghelescu 1, Szegedi A, et al Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors differential effects of fluvoxamine and paroxetine in a prospective study. J Clin Psy-chopharmacol 18 2-9, 1998... 

D6 Bufuralol, bupranolol, clomipramine, clozapine, codeine, debrisoquin, dextromethorphan, encainide, flecainide, fluoxetine, guanoxan, haloperidol, hydrocodone, 4-methoxy-amphetamine, metoprolol, mexile-tine, oxycodone, paroxetine, phenformin, propafenone, propoxyphene, risperidone, selegiline (deprenyl), sparteine, thioridazine, timolol, tricyclic antidepressants Unknown Quinidine, paroxetine... 

D6 Tricyclic antidepressants (TCAs), benztropine, perphenazine, clozapine, haloperidol, codeine/oxycodone, risperidone, class Ic antiarrhythmics, 3 blockers, trazodone, paroxetine, maprotiline, amoxapine, duloxetine, mirtazapine (partly), venlafaxine, bupropion Fluoxetine, paroxetine, duloxetine, hydroxybupropion, methadone, cimetidine, haloperidol, quinidine, ritonavir Phenobarbital, rifampin... 

According to the FDA reports, painkillers are the most commonly reported cause of adverse reactions. The five drugs causing the most adverse reactions include oxycodone, fentanyl, morphine, acetaminophen, and methadone—all painkillers. The sixth most common cause of adverse reactions, clozapine is an antipsychosis drug. Other drugs reported to the FDA for adverse reactions include estrogens, insulin, paroxetine (the active ingre-... 

Cyt 1A2 metabolizes clozapine common substrates - amitriptyline, clomipramine, propranolol, theophylline, warfarin, caffeine. Common inhibitors - fluvoxamine, paroxetine. 

Cyt 2D6 metabolizes haloperidol, risperidone, thioridazine, sertindole, olanzapine and clozapine common substrates - fluoxetine, paroxetine, sertraline, venlafaxine, amitriptyline, clomipramine, desipramine, imipramine, nortriptyline, propranolol, metoprolol, timolol, codeine, encainide, flecanide. Common inhibitors - paroxetine, sertraline, fluoxetine. 

Clozapine and SSRIs are often used together, because depressive syndromes are common in patients with schizophrenia. Clozapine carries a relatively high risk of agranulocytosis, but this adverse effect is very rarely seen with SSRIs, although a case of possible fluoxetine-induced neutropenia has been described (SEDA-22, 15). Two cases in which the addition of paroxetine to clozapine was associated with neutropenia have been reported (11). The patients had been taking stable doses of clozapine for 6-12 months and had previously tolerated other SSRIs without adverse hematological consequences. In both cases the white cell count recovered when clozapine was withdrawn, although paroxetine was continued. 

In a prospective study, paroxetine (20 mg/day), a potent inhibitor of CYP2D6, did not increase clozapine concentrations (n = 14), and the authors therefore suggested that CYP2D6 is not an important pathway of metabolism of clozapine (20). However, other studies (SEDA-21, 22) have shown that paroxetine can increase clozapine concentrations, suggesting that this combination should be used with caution. 

The effect of paroxetine on steady-state plasma concentrations of clozapine and its metabolites has been studied in 17 patients taking clozapine (200 -00 mg/ day), nine of whom took additional paroxetine (20-40 mg/day) (21). Paroxetine, a potent inhibitor of CYP2D6, inhibited the metabolism of clozapine, possibly by affecting a pathway other than N-desmethylation and N-oxidation. After 3 weeks of paroxetine, mean plasma concentrations of clozapine and norclozapine increased significantly by 31% and 20% respectively, while concentrations of clozapine N-oxide were unchanged. 

George TP, Innamorato L, Sernyak MJ, Baldessarini RJ, Centorrino F. Leukopenia associated with addition of paroxetine to clozapine. J Clin Psychiatry 1998 59(1) 31. 

Spina E, Avenoso A, Salemi M, Facciola G, Scordo MG, Ancione M, Madia A. Plasma concentrations of clozapine and its major metabohtes during combined treatment with paroxetine or sertraline. Pharmacopsychiatry 2000 33(6) 213-7. 

IMATINIB 1. ANTIARRHYTHMICS -flecainide, mexiletine, propafenone 2. ANTIDEPRESSANTS - fluoxetine, paroxetine, TCAs, trazodone, venlafaxine 3. ANTIPSYCHOTICS -clozapine, haloperidol, perphenazine, risperidone, thioridazine 4. BETA-BLOCKERS - metoprolol, propanolol, timolol 5. DONEPEZIL 6. METHAMPHETAMINE Imatinib may cause t plasma concentrations of these drugs, with a risk of toxic effects Inhibition of CYP2D6-mediated metabolism of these drugs Watch for early features of toxicity of these drugs... 

CYP450 2D6 inhibitors (e.g., paroxetine, fluoxetine, duloxetine) can raise clozapine levels, but dosage adjustment usually not necessary... 

Clozapine Fluoxetine, paroxetine, sertraline, and possibly citalopram can raise serum clozapine levels. Particularly large increases can occur with fluvoxamine. Toxicity has been seen in some patients. 

CYP2D6 Antidepressants amitriptyline, clomipramine, imipramine, desipramine, nortriptyline, trimipramine, N-desmethyl-clomipramine, fluoxetine, norfluoxetine, paroxetine, venlafaxine, sertraline Neuroleptics chlorpromazine, thioridazine, perphenazine, haloperidol, reduced haloperidol, risperidone, clozapine, sertindole Others codeine, opiate, propranolol, dextromethorphan 4 no activity 25% in Caucasians 0%-10% in others 5 no activity 2%-10% in all groups 10 reduced activity 47%-70% in Asians <5% in others 17 reduced activity 25%-40% in blacks 0% in others 2XN increased activity 19%-29% in Arabs and Ethiopians <5% in others... 

The future of psychopharmacotherapy may include creative dietary or other pharmacological manipulations of the CYP enzyme system to achieve a positive treatment response. Recently, it was demonstrated that levels of cyclosporine (an expensive immunosuppressive agent) were dramatically increased in patients who were concomitantly administered grapefruit juice (Hollander et al. 1995). In other studies, paroxetine and fluoxetine were used to raise desipramine levels in superextensive me-tabolizers who were nonresponsive to standard doses (Kraus et al. 1996). Also, the authors used fluvoxamine to augment olanzapine and clozapine concentrations when a lack of response was obtained at standard or upper-level doses. Because per-pill costs of many of today s newer-generation psychoactive compounds often prove prohibitive, use of dietary and pharmacological CYP inhibitors could have significant pharmacoeconomic implications. 

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