Antidepressants serum levels

A study found that carbamazepine reduced the serum levels of nortriptyi-ine by 58% and of amitriptyline plus its metabolite, nortriptyline, by 60% in 8 psychiatric patients. In 17 other patients carbamazepine reduced serum doxepin levels by 54% and doxepin plus its metabolite, nordox-epin, by 55%. A retrospective study of very large numbers of patients confirmed that carbamazepine approximately halves the serum levels of amitriptyline and nortriptyline. An elderly woman needed her nortriptyline dosage to be inereased from 75 to 150 mg daily to achieve effective antidepressant serum levels when carbamazepine 500 to 600 mg daily was added. ... 

TABLE 3.9. Doses and Serum Levels of Tricyclic Antidepressants... 

The TCAs are the only antidepressant class in which effectiveness is dependent on serum level. Attainment of the minimal therapeutic level is typically required for effectiveness. Exceeding the maximum treatment level usually provides no additional benefit and risks toxicity. Unique in this regard is nortriptyline, which is the only TCA with a therapeutic window. This means that beyond the maximum therapeutic level of 150ng/mL nortriptyline not only risks toxicity but is actually less effective at treating depression. Please refer to Table 3.9 for a summary of dosing guidelines and therapeutic levels. 

An adequate trial of an antidepressant requires 4-6 weeks of treatment at a recognized therapeutic dose or serum level. If a patient exhibits no response or an nnsatisfactory partial response after an adequate trial, then several options are available. These are discussed in Section 3.2.7 Refractory Depression. 

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. 

Drugs that can decrease carbamazepine serum levels include charcoal, cisplatin, doxorubicin, felbamate, hydantoins, rifampin, phenobarbital, primidone, theophylline. The serum levels of oral contraceptives, haloperidol, bupropion, anticoagulants, felbamate, valproic acid, felodipine, tricyclic antidepressants, acetaminophen, ziprasidone, voriconazole, topiramate, tiagabine, olanzapine, and lamotrigine can be lowered by carbamazepine. 

Lithium has numerous pharmacologic effects. It is able to cross through sodium channels, competing with monovalent and divalent cations in cell membranes (AHFS, 2000). Animal studies have shown that lithium at a serum level of 0.66 + — 0.08 mEq/L can increase the amphetamine-induced release of serotonin (5-hydroxytryptamine [5-HT]) and the concentrations of a serotonin metabolite (e.g., 5-hydroxyindoleacetic acid [5-HIAA]) in the perifornical hypothalamus (PFH) of rats before and after chronic lithium chloride administration (Baptista et ah, 1990), a mechanism possibly involved in lithium s antidepressant effect. The precise neurobiological mechanisms through which lithium reduces acute mania and protects against recurrence of illness remain uncertain (Lenox and Hahn,... 

Antacids reduce the absorption and enzyme-inducing drugs may decrease serum levels. Cimetidine and propranolol both increase serum levels. There can be competition for metabolic pathways by some tricyclic antidepressants (TCAs) and SSRIs (especially fluoxetine) which may increase serum levels. 

Leucht S, Hackl HJ, Steimer W, Angersbach D, Zimmer R. Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients. Psychopharmacology (Berl) 2000 147(4) 378-83. 

CALCIUM CHANNEL BLOCKERS SSRIs Reports oft serum levels of nimodipine and episodes of adverse effects of nifedipine and verapamil (oedema, flushing and i BP) attributed to t levels when co-administered with fluoxetine Fluoxetine inhibits CYP3A4-mediated metabolism of calcium channel blockers. It also inhibits intestinal P-gp, which may t the bioavailability of verapamil Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (lightheadedness, dizziness on standing, etc.). Consider reducing the dose of calcium channel blocker or using an alternative antidepressant... 

Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nazakato M, Watanabe H, Shinoda N, Okada S, lyo M. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol. Psychiatry 2003 54 70-75. 

Regarding serum levels, several researchers observed a reduction of IL-6 during treatment with the serotonin reuptake inhibitor fluoxetine (Sluzewska et al., 1995). A decrease of IL-6 serum levels during therapy with different antidepressants has been observed by other researchers (Frommberger et al., 1997). On the other hand, other groups cUcl not find any effect of certain antidepressants on serum levels of different cytokines (Maes et al., 1995a, 1997). 

Maes M, Verkerk R, Vandoolaeglie E, Lin A, Schai-pe S (1998) Serum levels of excitatory amino acids, serine, glycine, histidine, threonme, tauiine, alanine and ai giniiie in ti eatment-resistant depression Modulation by ti eatment witli antidepressants and prediction of clinical responsivity. Acta Psycliiati Scand 97 302—308. 

This behavior is characteristic of Frank, and you respond in a calm and nondefensive way. You acknowledge his need to thoroughly understand the medication and that it can be frustrating to wait for indicators that the drug is working. However, you remind him that the typical response time for most antidepressants is three to four weeks and is not absolutely related to serum level of the medication. You suggest other sources of information, written for patients. 

Differences in biotransformation capacities have been identified for at least two distinct groups poor metabolizers and extensive metabolizers. Poor metabolizers demonstrate a deficiency in one or more pathways of the cytochrome P/450 enzyme system. Since the metabolism of antidepressants and neuroleptics depends on this system (see appendix A), poor metabolizers may be at risk for complications of therapy. For certain tricyclic antidepressants and neuroleptics, it has been established that these individuals will demonstrate increased serum levels and exaggerated medication response. Additionally, they wiU be more susceptible to side effects. Although data is limited on the SSRIs, similar patterns are evident. 

Tobacco smoke reduces serum levels of a wide range of drugs and dose adjustment may be necessary when smokers have given up, particularly with theophylline, beta-blockers, adrenergic agonists, nifedipine, tricyclic antidepressants, phenothiazines, benzodiazepines and insulin. 

Side Effects and Toxicity. Adverse effects to the tricyclic antidepressants, primarily the result of the actions of these compounds on either the autonomic, cardiovascular, or central nervous systems, are summarized in Table 3. The most serious side effects of the tricyclics concern the cardiovascular system. Arrhythmias, which are dose-dependent and rarely occur at therapeutic plasma levels, can be life-threatening. In order to prevent adverse effects, as well as to be certain that the patient has taken enough drug to be effective, the steady-state serum levels of tricyclic antidepressant drugs are monitored as a matter of good practice. A comprehensive review of structure—activity relationships among the tricyclic antidepressants is available (42). 

DISTRIBUTION AND SERUM LEVEL MONITORING Once absorbed, tricychc antide pressants are widely distributed. They are relatively lipophilic and strongly bind to plasma proteins and constituents of tissues, leading to apparent volumes of distribution as high as 10-50 L g. The tendency of tricyclic antidepressants and their ring-hydroxy metabolites to accumulate in cardiac tissue adds to their cardiotoxicity. Serum concentrations of antidepressants that correlate meaningfully with clinical effects are only established for a few tricychc antidepressants (particularly amitriptyline. 

Drugs that can increase the serum levels/effects of tricyclic antidepressants... 

Drugs whose serum levels/effects can be Increased by tricyclic antidepressants... 

Chronic abuse of alcohol can lead to enhanced activity of cytochrome P450 enzymes and a consequent decrease in tricyclic antidepressant (TCA) serum levels. Central receptor interactions between alcohol and TCAs can cause impaired motor abilities (evident with amitriptyline, clomipramine, doxepin, and nortriptyline). 

Fluvoxamine inhibits the cytochrome P450 liver catabolic enzymes (predominantly this is inhibition of N-demethylation), leading to an increase in tricyclic antidepressant (TCA) serum levels. Plasma levels of several antidepressant drugs (e.g. amitriptyline, clomipramine, desipramine, imipramine, maprotiline, and nortriptyline) have been reported to increase by up to 4-fold during co-administration with fluvoxamine. Fluvoxamine at a daily dose of 50-100 mg causes a 3-4-fold increase in the plasma concentration of mirtazapine. 

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