Relationship between plasma neuroleptic concentrations and the therapeutic response

Controversy still rages regarding the value of measuring the plasma drug concentrations of psychotropic drugs as a means of assessing the therapeutic response of the patient to treatment. A number of factors determine the value of such information. These include:

1. The reliability of the assay method used to determine the concentration of the drug and its possible metabolites.

2. The homogeneous nature of the patient population and the number of patients in the sample.

3. The use of fixed doses of the drugs so that the plasma levels remain independent of clinical impression or improvement.

4. The use of double-blind conditions and ensuring that the drug is administered for an adequate period of time.

5. Ensuring that other drugs or treatments are not administered which may interact with the psychotropic drug under investigation (e.g. lithium, electroconvulsive therapy).

6. Use of appropriate statistical methods for the analysis of the data.

Unfortunately, few of the studies that have attempted to relate the blood concentrations of neuroleptics to therapeutic response have fulfilled all these criteria. There is a suggestion that a ''therapeutic window'' exists for some phenothiazine neuroleptics. A therapeutic window is a range of concentrations of a drug measured in the blood that are associated with a good therapeutic response. Plasma concentrations outside this range are either too low to ensure a therapeutic response or so high that they induce toxic side effects. Despite the numerous studies of the relationship between the plasma concentration and the therapeutic response for a number of ''standard'' neuroleptics, it would appear that such correlations rarely account for more than 25% of the variance in clinical response to treatment. The existence of a therapeutic window for neuroleptics would therefore appear to be unproven. However, there could be ranges of plasma concentrations associated with optimal antipsychotic action, but these must be defined separately for each drug. There is also evidence that some non-responders to treatment may improve when the plasma drug concentration is reduced rather than raised.

Besides the poor specificity of many of the assays used to determine plasma drug concentrations, another problem which has arisen from these studies has been the length of the ''wash-out'' period necessary before the patient is given the neuroleptic under investigation. As a result of the prolonged duration of blockade of dopamine receptors in the brain by conventional neuroleptics and their metabolites, it is necessary to allow a wash-out period of several weeks before the patients are subject to a pharmacokinetic study. This raises serious ethical questions. Perhaps with the advent of new imaging techniques it may be possible in the near future actually to determine the rate of disappearance of neuroleptics from the brain of the patient. This may enable the relationship between plasma concentration and clinical response to be accurately determined.

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