Nefazodone MAOIs

Many commonly used medications also contain substances that are eliminated by the MAOIs and must not be taken by these patients. The list of medications to be avoided inclndes the narcotic pain reliever meperidine (Demerol), and many over-the-connter cold remedies containing dextromethorphan or pseudoephedrine. Finally, patients taking MAOIs must also avoid medications that elevate serotonin levels. This inclndes certain appetite snppressants and antidepressants including the SSRIs, venlafaxine, duloxetine, mirtazapine, nefazodone, and trazodone. Medications that interact with the MAOIs cannot be taken until at least 2 weeks after the MAOI has been stopped. 

Serotonin-Boosting Antidepressants. The SSRIs have also been studied in the treatment of generalized social anxiety disorder, and paroxetine, sertraline, and venlafaxine are effective. Preliminary data suggests that the serotonin-boosting atypical antidepressants (mirtazapine and nefazodone) may also be helpful. Like the MAOIs, they appear to be effective at doses comparable to those used to treat depression. They may help avoidant patients to gradually increase their social interaction and become more assertive. 

Serotonin-boosting antidepressants or longer-acting benzodiazepines are also both suitable first-line treatments for APD. For APD patients who are also troubled by depression, an antidepressant is obviously preferable. We also prefer to use antidepressants rather than benzodiazepines to treat APD patients who have a history of substance abuse. The current data suggests that any of the SSRls as well as nefazodone, mirtazapine, and venlafaxine may be helpful. When these do not work, a MAOI is a reasonable alternative provided the patient is willing to commit to the dietary regimen. 

Maintenance/Continuation/Extended treatment There is no evidence to indicate how long the depressed patient should be treated with nefazodone. However, it is generally agreed that pharmacologic treatment for acute episodes of depression should continue for at least 6 months. Whether the dose of antidepressant needed to induce remission is identical to the dose needed to maintain euthymia is unknown. In clinical trials, more than 250 patients were treated for at least 1 year. Switching to or from a monoamine oxidase inhibitor (MAOi) At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with nefazodone. In addition, wait at least 7 days after stopping nefazodone before starting an MAOI. 

MAOis- Because nefazodone is an inhibitor of both serotonin and norepinephrine reuptake, it is recommended that nefazodone not be used in combination with an MAOl, or within 14 days of discontinuing treatment with an MAOI. Allow at least 1 week after stopping nefazodone before starting an MAOl. 

Drugs that affect nefazodone include general anesthetics, sibutramine, sumatriptan, buspirone, carbamazepine, and propranolol. Drugs that may be affected by nefazodone include alcohol, benzodiazepines, buspirone, carbamazepine, cisapride, digoxin, haloperidol, HMG-CoA reductase inhibitors, MAOIs, propranolol, St. John s wort, cyclosporine, and tacrolimus. 

Contraindications Co-administration of terfenadine, astemizole, cisapride, pimozide, or carbamazepine hypersensitivity to other phenylpiperazine antidepressants those who were withdrawn from nefazodone due to evidence of hepatic injury use within 14 days of MAOIs... 

Most child and adolescent studies published thus far have focused on the effects of the tricyclic antidepressants (TCAs) and, more recently, the SSRIs. A few open studies have also shown that monoamine oxidase inhibitors (MAOIs) can be used safely with children and adolescents (Ryan et ah, 1988b), but noncompliance with dietary requirements may present a significant problem for minors. Other antidepressants, including the heterocyclics (HTC) (e.g., amoxapine, maprotiline), buproprion, venlafaxine, and nefazodone, have been found to be efficacious for the treatment of depressed adults (APA, 2000), but they have not been well studied for the treatment of MDD in children and adolescents. Therefore, this chapter mainly describes the use of SSRIs and TCAs for youth with MDD. 

Coadministration with most medications that are metabolized by CYP 3A3/4 should be undertaken with caution, and the doses of the other medications that are CYP 3A3/4 substrates (see Table 1-1) should be reduced. The interaction between nefazodone and MAOIs has not yet been evaluated, but it may be as dangerous as... 

No data are available on the safety or efficacy of combining mirtazapine or nefazodone with MAOIs. Until studies are available, it is prudent to avoid such combinations. 

There is a great disparity of current knowledge regarding the effects of antidepressants on GYP enzymes. There have been almost no studies to test the potential effects of TCAs, MAOIs, and trazodone on GYP enzymes. There has only been one study with bupropion but it demonstrated that bupropion produces substantial inhibition of GYP 2D6 comparable with the effect of fluoxetine and paroxetine. In contrast to studies in these antidepressants, there have been extensive in vitro and in vivo studies of SSRIs, nefazodone, and venlafaxine. 

The novel compounds nefazodone and trazodone usually require titration to a minimum therapeutic dose of at least 200 mg/day. Response to reboxetine, venlafaxine and mirtazapine may occur at the starting dose but some dose titration is commonly required. Venlafaxine is licensed for treatment-resistant depression by gradual titration from 75 to 375 mg/day. There is some need for dose titration when using MAOIs although recommended starting doses (e.g. phenelzine 15 mg t.d.s.) may be effective. Unlike other drug classes, reduction to a lower maintenance dose is recommended after a response is achieved. 

Drugs that inhibit cytochrome P450 3A4 (e.g., verapamil, dUtiazem, itraconazole, fluvoxamine, nefazodone, and erythromycin) can increase buspirone levels. Rifampin caused a 10-fold reduction in buspirone levels. Buspirone reportedly increases haloperidol levels and elevates blood pressure in patients taking a monoamine oxidase inhibitor (MAOI). 

DA agonists levodopa, bromocriptine, ropinirole, pramipexole, selegiline AAAD inhibitor carbidopa M-blockers benztropine, trihexiphenidyl MAOIs phenelzine, tranylcypromine TCAs amitriptyline, imipramine, clomipramine SSRIs fluoxetine, paroxetine, sertraline Others bupropion, mirtazapine, nefazodone, trazodone... 

Nefazodone is a phenylpiperazine antidepressant structurally related to trazodone, but it differs pharmacologically from trazodone, the SSRIs, the MAOIs, and the TCAs (Fig. 21.22). When compared with trazodone, nefazodone displays approximately twice the affinity potency for SERT. Nefazodone therapy, however, was associated with life-threatening cases of idiosyncratic hepatotoxicity, and as a result, nefazodone was withdrawn from both the North American and European markets in 2003. The mechanism of hepatotoxicity remains unknown, but nefazodone, being structurally similar to trazodone (Fig. 21.23), is metabolized to p-hydroxynefazodone, m-CPP, and phenoxyethyltriazoledione. In turn, p-hydroxynefazodone is thought to be oxidized to an iminoquinone and/or an epoxide reactive metabolite, which may play a role in the initiation of nefazodone-mediated hepatotoxicity (76). 

An isolated report describes a woman who developed marked and acute hypotension and weakness when desipramine, fluoxetine and venlafaxine were replaced by nefazodone. Isolated cases describe the serotonin syndrome in patients given nefazodone together, or sequentially, with another serotonei c drug (amitriptyline, paroxetine, St John s wort, or trazodone). The manufacturer recommended that nefazodone should not be used with an MAOI or within 14 days of discontinuing an MAOL Note that, due to adverse hepatic effects nefazodone was widely withdrawn from the market. 

The manufacturer stated that nefazodone should not be used with an MAOI or within 2 weeks of discontinuing treatment with an MAOI. Conversely at least one week should be allowed after stopping nefazodone before starting an MAOI. There appears to be no direct clinical evidence that an adverse interaction occurs. 

Carbamazepine should not be used in patients with a history of previous bone m arrow depression, or known hypersensitivity to carbamazepine or tricyclic compounds. It is contraindicated with concomitant use of an MAOI or within 14 days of discontinuing an MAOI. Co-administration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and decreased drug effectiveness. Coadministration of carbamazepine with nefazodone is contraindicated. 

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