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Drug‐Resistance Phenomena in Major Psychoses: Their Discrimination and Causal Mechanisms

Summary: Drug‐resistance phenomena are commonly encountered in psychiatric practice and are of particular concern in the treatment of major psychoses. Of paramount importance is the need to discriminate between drug‐resistance problems due to pharmacodynamic factors (i.e., receptor sensitivity) or pharmacokinetic factors (inadequate plasma concentration of the drugs at receptor sites). To exclude the former, plasma level measurements of antidepressant and neuroleptic compounds are desirable. Actually, lack of or poor compliance is a peculiarity (often underestimated) when treating psychotic patients, and the use of the drug plasma level/dose ratio (L/D) approach is useful, particularly with outpatients. Another source of drug resistance stems from the interindividual metabolic variability, as with haloperidol or anticholinergic drugs, which are used to counteract neuroleptic‐induced extrapyramidal side effects. In general, plasma‐level measurement is advisable whenever no or poor response is obtained during standard treatments with neuroleptic, antidepressant, or anticholinergic drugs. Finally, this author suggests a four‐level discrimination process to determine drug resistance in major psychoses, which includes clinical, pharmacological, pharmacokinetic, and pharmacodynamic factors.