Nefazodone Tricyclic antidepressants

Drugs that can increase carbamazepine serum levels include cimetidine, danazol, diltiazem, erythromycin, felbamate, clarithromycin, fluoxetine, isoniazid, niacinamide, propoxyphene, ketaconazole, itraconazole, verapamil, valproate, troleandomycin, loratadine, nicotinamide, tricyclic antidepressants, SSRIs, nefazodone, protease inhibitors. 

Nefazodone, sertraline, mirtazapine, tricyclic antidepressants Mood stabilizers... 

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. 

Although the efficacy of tricyclic antidepressants in the treatment of unipolar depression is beyond reproach, the side-effect profile of these agents makes them less desirable as first-line therapeutic agents. Introduction of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine in the past decade has revolutionized the treatment of depression universally. The side-effect profile of SSRIs, such as nausea, diarrhea and sexual dysfunction, is considerably more benign than that of tricyclic drugs. Multiple controlled trials have proven the efficacy of SSRIs vs. placebo (Nemeroff, 1994). Recently, a number of SNRIs (serotonin and noradrenaline reuptake inhibitors) and so-called atypical antidepressants have been marketed that may have additional advantages over SSRIs, such as more rapid onset of action (venlafaxine. mirtazapine) and low sexual side-effect potential ( bupropion, nefazodone). Additionally, it appears that venlafaxine may be more efficacious in cases of treatment-refractory depression (Clerc et al., 1994 Fatemi et al., 1999). Finally, in a recent report (Thase et al., 2001),... 

First-pass metabolism (first-pass effect) The passage of the drug from the portal circulation into hepatocytes and conversion there into metabolites. These metabolites may have a pharmacological profile different from that of the parent drug. They are typically then excreted by the hepatocytes into the biliary system and pass back into the small bowel where enterohepatic recirculation may occur (e.g., benzodiazepines, bupropion, nefazodone, neuroleptics, tricyclic antidepressants). 

FIGURE 9-6. Various treatments can be given in combination for panic disorder (i.e., panic combos). The basis of all many combination treatments is a serotonin selective reuptake inhibitor (SSRI). Other antidepressants such as venlafaxine, nefazodone, mirtazapine, tricyclic antidepressants, and monoamine oxidase inhibitors can all have antipanic actions, although they are second-line treatments, as are the benzodiazepines. On the other hand, benzodiazepines are often added to SSRIs, particularly at the initiation of an SSRI and intermittently when there is breakthrough panic. Cognitive and behavioral psychotherapies can also be added to any of these drug treatments. 

Peterman, S. M., Duczak, N., Jr., Kalgutkar, A. S., Lame, M. E., and Soglia, J. R. (2006). Application of a linear ion trap/orbitrap mass spectrometer in metabohte characterization studies Examination of the human liver microsomal metabolism of the non-tricyclic antidepressant nefazodone using data-dependent accurate mass measurements. J. Am. Soc. Mass Spectrom. 17 363-375. 

Carbamazepine + phenytoin, tricyclic antidepressants, typical neuroleptics, valproate, clonazepam, warfarin, nefazodone and propoxyphene —> reduced plasma concentration of carbamazepine due to increased metabolism. 

Cyt 3A3/4 metabolizes clozapine, sertindole, quetiapine common substrates -tricyclic antidepressants, nefazodone, sertraline, carbamazepine, ethosuximide, terfenadine, benzodiazepines, diltiazem, nifedipine, verapamil, erythromycin, cyclosporine, lidocaine, quinidine, cisapride, paracetamol. Common inhibitors -nefazodone, fluvoxamine, fluoxetine, ketoconazole. 

The cumulative incidence of hepatic adverse reactions associated with antidepressant treatment has been estimated through spontaneous reports to the Spanish Pharmacovigilance System (12). For classical tricyclic antidepressants and SSRIs the estimated rate of adverse hepatic reactions was 1.28-4.00 per 100 000 patient years. However, the rate with nefazodone was much higher (29 per 100 000 patient years). This report supports concerns that nefazodone may be more hepatotoxic than other antidepressants. Significant hepatic reactions to nefazodone are relatively rare but can be serious. 

Clinically important, potentially hazardous interactions with alcohol, cimetidine, CNS depressant, erythromycin, ethanol, ketoconazole, nefazodone, nelfinavir, olanzapine, rifampin, ritonavir, tricyclic antidepressants... 

Clinically important, potentially hazardous interactions with amitriptyline, amoxapine, amphetamines, bupropion, citalopram, clomipramine, cyproheptadine, desipramine, dextroamphetamine, dextromethorphan, diethylpropion, dopamine, doxepin, entacapone, ephedra, ephedrine, epinephrine, fluoxetine, fluvoxamine, ginseng, imipramine, levodopa, mazindol, meperidine, methamphetamine, nefazodone, nortriptyline, paroxetine, phendimetrazine, phentermine, phenylephrine, pizotifen, propoxyphene, protriptyline, pseudoephedrine, rizatriptan, sertraline, sibutramine, sumatriptan, sympathomimetics, tramadol, tricyclic antidepressants, trimipramine, tryptophan, venlafaxine, zolmitriptan... 

Clinically important, potentially hazardous interactions with amphetamines, aprepitant, astemizole, atazanavir, azithromycin, azole antifungals, clarithromycin, darunavir, dirithromycin, erythromycin, fluoxetine, fosamprenavir, grapefruit juice, imatinib, indinavir, itraconazole, ketoconazole, methylphenidate, nefazodone, nelfinavir, nilotinib, pemoline, phenothiazines, protease inhibitors, quinidine, ritonavir, saquinavir, sertraline, sparfloxacin, sulpiride, telithromycin, thioridazine, tipranavir, tricyclic antidepressants, troleandomycin, voriconazole, zileuton, ziprasidone... 

HT, antagonist with antidepressant activity (123) it binds with high affinity (if < 10 nM) at 5-HT, receptors (124). Hence, trazodone (24), nefazodone (16), and mianserin (27) represent atypical antidepressants that have in common a high affinity for S-HTgA receptors and S-HTg antagonist action. It might be noted that certain tricyclic antidepressants also bind at 5-HT, receptors imipramine (11), desipramine (6), nortriptyline (17), and maprotiline (13), for example, bind with submicromolar Ki values (124) (Table 8.6). 

For patients who are unable to tolerate a tricyclic antidepressant, the choice of agent should consider the patients underlying mental state. If the patient has concomitant depression, another antidepressant such as ven-lafaxine, nefazodone, or mirtazapine may be the appropriate choice. If the patient does not have concomitant depression, an anticonvulsant agent such as gabapentin may be an acceptable alternative. 

Potentially clinically significant interactions include the tendency for fluvoxamine to increase circulating concentrations of oxidatively metabolized benzodiazepines, clozapine, theophylline, and warfarin. Sertraline and fluoxetine can increase levels of benzodiazepines, clozapine, and warfarin. Paroxetine increases levels of clozapine, theophylline, and warfarin. Fluoxetine also potentiates tricyclic antidepressants and some class 1C antiarrhythmics with a narrow therapeutic index (including encainide, flecainide, and propafenone). Nefazodone potentiates benzodiazepines other than lorazepam and oxazepam. 

Another risk of antidepressants in vulnerable patients (particularly those with unrecognized bipolar depression) is switching, sometimes suddenly, from depression to hypomanic or manic excitement, or mixed, dysphoric-agitated, manic-depressive states. To some extent this effect is dose-related and is somewhat more likely in adults treated with tricyclic antidepressants than with serotonin reuptake inhibitors, bupropion, and perhaps with MAO inhibitors. Risk of mania with newer sedating antidepressants, including nefazodone and mirtazapine, also may be relatively low, but some risk of inducing mania can be expected with any treatment that elevates mood, including in children with unsuspected bipolar disorder. 

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