Pharmacokinetics antidepressants

Similarly, covert substance abuse is also common in depression (Akiskal 1982 MacEwan and Remick 1988) and a leading cause of TRD. In a survey of 6,355 patients with substance abuse, M. S. Gold et al. (1994) found that 43.7% had a lifetime prevalence of major depression. Not only does comorbid substance abuse lead to TRD, but the presence of resulting hepatic disease alters antidepressant pharmacokinetics, making these patients more difficult to treat (Ciraulo and Jaffe 1981 Ciraulo et al. 1988 Mason and Kocsis 1991). In this regard, SSRls may offer some advantages over other antidepressants. One recent study of alcoholic patients with depression found a modest advantage for an SSRI over a TCA (G. Invernizzi et al. 1994). 

Cohen LJ, De Vane CL Clinical implications of antidepressant pharmacokinetics and pharmacogenetics. Ann Pharmacother 1996 30(12) 1471. [PMID 8968460]... 

Frackiewicz EJ, Sramek JJ, Cutler NR. Gender differences in depression and antidepressant pharmacokinetics and adverse events. Ann Pharma-cother 2000 34 80-88. 

Medications that have been used as treatment for anxiety and depression in the postwithdrawal state include antidepressants, benzodia2epines and other anxiolytics, antipsychotics, and lithium. In general, the indications for use of these medications in alcoholic patients are similar to those for use in nonalcoholic patients with psychiatric illness. However, following careful differential diagnosis, the choice of medications should take into account the increased potential for adverse effects when the medications are prescribed to alcoholic patients. For example, adverse effects can result from pharmacodynamic interactions with medical disorders commonly present in alcoholic patients, as well as from pharmacokinetic interactions with medications prescribed to treat these disorders (Sullivan and O Connor 2004). 

Ciraulo DA, Jaffe JH Tricyclic antidepressants in the treatment of depression associated with alcoholism. Clin Psychopharmacol 1 146—150, 1981 Ciraulo DA, Nace E Benzodiazepine treatment of anxiety or insomnia in substance abuse patients. Am J Addict 9 276—284, 2000 Ciraulo DA, Barnhill JG, Jaffe JH, et al Intravenous pharmacokinetics of 2-hydroxy-imipramine in alcoholics and normal controls. J StudAlcohol 51 366-372, 1990 Ciraulo DA, Knapp CM, LoCastro J, et al A benzodiazepine mood effect scale reliability and validity determined for alcohol-dependent subjects and adults with a parental history of alcoholism. Am J Drug Alcohol Abuse 27 339—347, 2001 Collins MA Tetrahydropapaveroline in Parkinson s disease and alcoholism a look back in honor of Merton Sandler. Neurotoxicology 25 117-120, 2004 COMBINE Study Research Group Testing combined pharmacotherapies and behavioral interventions in alcohol dependence rationale and methods. Alcohol Clin Exp Res 27 1107-1122, 2003a... 

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

Pharmacokinetic parameters of the newer antidepressants are shown in Table 35— 5.9,29 Several antidepressants are not very highly protein bound, and the most notable of these is venlafaxine. The elimination half-lives of nefazodone and... 

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. 

Table 4.1 Some pharmacokinetic studies of antidepressants in different ethnic groups...

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). 

Pharmacokinetic Drug Interactions Involving Tricyclic Antidepressants (TCAs)... 

The ability of an SSRI, or any antidepressant, to inhibit or induce the activity of the cytochrome P450 (CYP450) enzymes can be a significant contributory factor in determining its capability to cause a pharmacokinetic drug-drug interaction. 

Ding GH, Naora K, Hayashibara M, Katagiri Y, Kano Y, Iwamoto K. (1991). Pharmacokinetics of [6]-gingerol after intravenous administration in rats. Chem Pharm Bull (Tokyo). 39(6) 1612-14. Dziedzicka-Wasylewska M, Willner P, Papp M. (1997). Changes in dopamine receptor mRNA expression following chronic mild stress and chronic antidepressant treatment. Behav Pharmacol. 8(6-7) 607-18. 

Tricyclic antidepressants Despite the numerous publications over the past 30 years on the determination of the TCAs (Tricyclic Antidepressants) by HPLC to establish possible therapeutic windows, both therapeutic drug monitoring and pharmacokinetic calculations have revealed there is considerable variation (10- to 50-fold) in plasma concentrations between individuals with these drugs. The plasma concentrations are usually in the range of 50-300 ng/ml. 

It may be concluded that, so far, a pharmacokinetic analysis of antidepressants is of limited clinical value because of ... 

The effects of variables such as age, sex, race and drug interactions on the pharmacokinetics of the antidepressant. 

In contrast to the limited value of pharmacokinetics to the use of antidepressants, knowledge of the kinetics of lithium has been important in defining the therapeutic and toxic range in unipolar or bipolar manic patients. Prediction of the dose required by the individual patient by giving a single dose of the drug and measuring the erythrocyte/plasma lithium... 

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 SUMMARY, it would appear that a detailed knowledge of the pharmacokinetics of the main groups of psychotropic drugs is only of very limited clinical use. This is due to limitations in the methods for the detection of some drugs (e.g. the neuroleptics), the presence of active metabolites which make an important contribution to the therapeutic effect, particularly after chronic administration (e.g. many antidepressants, neuroleptics and anxiolytics), and the lack of a direct correlation between the plasma concentration of the drug and its therapeutic effect. Perhaps the only real advances will be made in this area with the development of brain imaging techniques whereby the concentrations of the active drug in the... 

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