Antidepressant drugs antidepressants pharmacokinetics

Tanaka E, Hisawa S. Clinically significant pharmacokinetic drug interactions with psychoactive drugs antidepressants and antipsychotics and the cytochrome P450 system. J Clin Pharm Ther 1999 24 7-16. 

In this chapter, we have discussed the mechanisms of action of the major antidepressant drugs. The acute pharmacological actions of these agents on receptors and enzymes have been described, as well as the major hypothesis that attempts to explain how all current antidepressants ultimately work. That hypothesis is known as the neurotransmitter receptor hypothesis of antidepressant action. We have also introduced pharmacokinetic concepts relating to the metabolism of antidepressants and mood stabilizers by the cytochrome P450 enzyme system. 

Ereshefsky L, Riesenman C, Lam YW. Antidepressant drug interactions and the cytochrome P450 system—the role of cytochrome P4502D6. Clin Pharmacokinet 1995 29(suppl 1) 10-19. 

Interestingly, in the learned helplessness animal model of depression, reversal of helpless behavior may be obtained acutely by direct intracerebral drug administration into frontal cortex, though reversal of helpless behavior by systemic drug administration requires several days (Sherman and Petty, 1980). This suggests that the reversal of depressive symptoms by antidepressant drugs may involve pharmacokinetic as well as pharmacodynamic effects (Petty et al., 1982). 

Fig. 2. CYP2D6 genotype dependent quantitative changes in pharmacokinetics of antidepressant drugs expressed as percent dose adaptations. CYP2D6 PM (whit, IM (gray), EM (dark gray), UM (black). Dose adaptations were calculated as described in [1]. Dose adaptations are based on an average dose of 100% and are aimed for the Caucasian population. Data from studies in Asiatic or African or other populations were not incorporated because PM data are lacking. (From Kirchheiner J, Nickchen K, Bauer M, et al. Pharmacogenetics of antidepressants and antipsychotics the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004 9f.5) 442 7.3 with permission.)...

Impact of CYP2D6 and CYP2C19 polymorphisms on pharmacokinetics and outcome of antidepressant drugs... 

A. Classification and Pharmacokinetics The major classes of antidepressant drugs are shown in Figure 30-1 tricyclic antidepressants, heterocyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors. 

Pisani F, Fazio A, Spina E, Artesi C, Pisani B, Russo M, Trio R, Perucca E, Pharmacokinetics of the antidepressant drug viloxazine in normal subjects and in epileptic patients receiving chronic anticonvulsant treatment. Psychopharmacology (Berl) (1986) 90, 295-8. 

Therapeutic drug management (TDM) of most antidepressants is not widely available or widely utilized, for any clinical indication. The primary benefits of TDM in the management of antidepressant therapy could include assessment of patient compliance, detection of drug-drug interactions or altered pharmacokinetics, and evaluating the concentration relationship of individual patient response and/or thresholds for dose-related side effects. Of all the classes of antidepressant drugs, TDM of TCAs is most common. 

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Differentiate antidepressants according to pharmacologic properties, adverse-effect profiles, pharmacokinetic profiles, drug interaction profiles, and dosing features. 

The major drug interactions of antidepressants are shown in Table 35—6.9,19,30 Antidepressants cause both pharmacodynamic (e.g., additive pharmacologic effects) and pharmacokinetic (e.g., changes in drug levels) interactions with other medications. 

Compared to antipsychotics, there are even fewer studies on the prescribing patterns of antidepressants done in Asian countries. Pi etal. (1985) conducted a survey of psychotropic prescribing practices reported by psychiatrists in 29 medical schools in 9 Asian countries. Daily dose range of tricyclic antidepressants (TCAs) such as amitriptyline, imipramine, and nortriptyline in Asian countries was comparable to the practice in USA. This is despite differences found between Asian and non-Asian populations in the pharmacokinetics of TCAs (Pi et al, 1993). A questionnaire on the practical prescribing approaches in mood disorders administered to 298 Japanese psychiatrists was reported by Oshima et al. (1999). As first-line treatment, the majority of respondents chose newer TCAs or non-TCAs for moderate depression and older TCAs for severe depression. Combination of antidepressants and anxiolytics was preferred in moderate depression, while an antidepressant and antipsychotic combination was common in severe psychotic depression. Surprisingly, sulpiride was the most favored drug for dysthymia. In a naturalistic, prospective follow-up of 95 patients with major depression in Japan, the proportion of patients receiving 125 mg/day or less of imipramine was 69% at one month and 67% at six months (Furukawa et al., 2000). 

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