S-47-01

Pharmacokinetics and -dynamics in dose-response trials with antidepressants

L. F. Gram. Univ. Southern Denmark IST, Clinical Pharmacology, Odense C, Denmark

Objective: Dose-effect studies with antidepressants define, in groups of patients, the probabilty of a certain degree of therapeutic response and/or tolerability problems for different doses and duration of drug therapy. Such studies thus describe the inter patient variability and the therapeutic range of the drug.

Methods: Systematic reviews and a 5-dose study with clomipramine (DUAG 1999) have shown that for both tricyclic and SSRI antidepressants, the dose effect curves for therapeutic response and tolerability are flat and overlapping. High doses yield better response, but with higher risk of tolerabilty problems.

Results: The clomipramine study (DUAG 1999) suggested that all doses may be effective, but that high doses (125 - 200 mg/d) result in faster reponse than the low doses (25 - 50 mg/d). Genetic polymorphism and dose dependent kinetics for clomipramine enhanced the inter patient variation from a factor 8 for dose to a factor 100 for steady state blood concentrations (clomipramine + desmehtylclominpramine). However the correlations for dose versus rating score and concentration versus rating score were not significantly different (R(S) about - 0.25, p= 0.01 - 0,05).

Conclusion: In conclusion clinical dosing should be based on a judgement of the individual patient's need for rapid and effective cure against the importance of good tolerability. Dose is an important, but not the only determinant of the clinical effects of antidepressant drugs. However, for further studies on the other factors of importance including pharmacokinetics, the dose-effect study design remains essential.

S-47-02

Receptor binding problems in dose-response trials of antidepressants

B. Leonhard. National University of Ireland Pharmacology Dept., Galway, Ireland

The presentation will consider the following problems that arise in correlating the concentration of an antidepressant with the therapeutic response to treatment: 1) Most therapeutically active antidepressants have active metabolites with different pharmacokinetic and pharmacodynamic properties to the parent compound. For example, dual action antidepressants such as arnitriptyline and imipramine have metabolites with a high affinity for the noradrenaline transporter; fluoxetine has a potent, long halflife metabolite norfluoxetine; lofepramine produces several metabolites that (unlike the parent drug) show selectivity for the noradrenaline transporter. These metabolites play a major role in the therapeutic actions of the parent drug. 2) There is little evidence that a correlation exists between the transporter or receptor binding properties of an antidepressants in peripheral tissues (for example platelets) and the therapeutic effect. Unless the binding properties of the antidepressants in the brain of the before and following a therapeutic response is known, there seems little value in trying to extrapolate from data obtained from peripheral tissues to the brain. 3) There is now substantial evidence that the therapeutic effects of antidepressants occur "down-stream" from aminergic transporters and receptors. This implies that until methods are available to determine changes in such tertiary messengers and neurotrophic factors such as brain-derived neurotrophic factor from the brains of depressed patients being treated with antidepressants, it seems unlikely that a meaningful relationship between the local drug concentration and the therapeutic effect will be understood. 4) With the limitation of the techniques presently available, it appears that determining the time of onset of an antidepressant response will depend on inexact rating scales. As appropriate ligands become available, imaging methods may be of more value in the future. For example, in schizophrenia research it has been demonstrated that antipsychotic drugs are most likely to cause extrapyramidal side-effects when they occupy more than 80% of D2 receptors in the striatum.

S-47-03

A linear dose-response relationship of venlafaxine in major depression

P. Boyer. Ottawa, Canada

S-47-04

Dose-response relationship of other antidepressants using unidimensional depression scales

P. Bech. WHO Collaborating Centre Psychiatric Research Unit, Hillerod, Denmark

Among the new generation antidepressants, the first SNRI, venlafaxine, has been investigated intensively concerning doseresponse relationship. The results have not been quite clear, because the two depression scales HAM-D17 and MADRS10 showed divergent results when used as indicators of clinical response. However, when looking at all controlled venlafaxine trials it has been shown that the depression factor of HAM-D17 containing the six core depression items (HAM-D6), emerged as being the most sensitive in discriminating between venlafaxine and placebo. For the other SNRI, duloxetine, the HAM-D6 was able to show dose-response relationship in the dose range between 40mg and 120 mg dally (higher dose showing better outcome). HAM-D6 and its counterpart, the MADRS6, were able to demonstrate a doseresponse relationship for the two SSRIs citalopram (in the dose range from 10 to 60 mg) and escitalopram (where 20rag was significantly superior to 10mg in severely depressed patients). In conclusion, the gold standard for measuring dose-response relationship both for SNRIs and SSRIs is the HAM-D6 subscale, which is a scale that is unidimensional, indicating that its total score is a sufficient statistic.