Efficacy of high doses of classical neuroleptics in the treatmentresistant patient

There is no published evidence for the efficacy of high dose medication as an effective strategy either to accelerate therapeutic response or to increase the number of patients who respond to medication. Neither is there any objective evidence to show that escalating the dose of a ''classical'' neuroleptic is likely to produce a beneficial response in chronically resistant patients. Furthermore, there are anecdotal reports that high dose neuroleptics can cause sudden death (due to cardiotoxicity), severe Parkinsonism and/or akathisia with the possibility of paradoxical and violent behaviour (possibly associated with akathisia). The possibility of the neuroleptic malignant syndrome occurring following high dose neurolep-tics is more closely related to the rate of dose escalation than to the quantity of neuroleptic administered.

However, despite the absence of firm evidence for efficacy because of the real dangers that may arise, it is occasionally justified to consider administering a high therapeutic dose of a ''classical'' neuroleptic to a patient who is responding poorly to a normal dose of the drug. It is well established that the blood concentration of a neuroleptic varies considerably between patients given the same oral dose. Such variation probably arises from differences in compliance, in first-pass metabolism and in the rate of elimination. Where possible, the plasma concentrations should be determined before proceeding with the dose escalation of a standard neuroleptic. Assuming that pharmacologically active concentrations of the drug have been achieved, it is possible that poor therapeutic response is due to an insufficient population of the D2 receptors in the mesocortical areas of the brain being blocked by the neuroleptics. However, it must be emphasized that the use of high doses of neuroleptics should be the last resort for carefully selected and supervised patients. It may be argued that as the new atypical neuroleptics are equi-effective with the ''classical'' antipsychotics, and certainly superior in their tolerability and side-effect profile, such drugs (despite their high unit cost) should be considered before escalating the dose of a non-response patient on a ''classical'' neuroleptic.

Treatment decisions for schizophrenia are shown in Table 11.10.

Figure 11.11. Chemical structure of the benzamide neuroleptic sulpiride.

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