The effects of amitriptyline, lithium, and electroconvulsive shock on cerebral permeability and blood flow were tested. These three treatments share in common (i) the ability to influence the functional activity of central adrenergic neurons by way of effects on the release, reuptake, or metabolism of norepinephrine and (ii) therapeutic efficacy in mood disturbances. Under control conditions, cerebral permeability increases linealy with increasing arterial partial pressure of carbon dioxide and hence cerebral blood flow. All three treatments altered this relationship in a manner consistent with their adrenergic effects. Amitriptyline potentiated this increase in cerebral permeability whereas lithium and electroconvulsive shock blunted this phenomenon. These results support the hypothesis that one function of central adrenergic neurons is regulation of the blood-brain barrier and raise the possibility that a related effect may underlie the clinical usefulness of such treatment.
The traditional dose-response method of medication adjustment depends on several assumptions that are not met in the case of tricyclic antidepressants (TCAs), which makes therapeutic drug monitoring (TDM) particularly useful with these drugs. TDM can facilitate treatment by providing objective guidelines for dose adjustment. It provides a means of assessing compliance, ensuring an effective concentration, and avoiding toxicity. The latter is an often-overlooked benefit of therapeutic monitoring of TCAs and yet is just as important as improving response. The cardiac and central nervous system toxicity of TCAs is concentration-dependent and potentially life-threatening. Such toxicity will predictably occur in up to 5% of patients on standard antidepressant doses of TCAs when TDM is not used to rationally adjust the dose. Without TDM, such toxicity is difficult to detect early. A cost/benefit analysis supports the cost effectiveness of TDM as a standard part of TCA chemotherapy when doses in the 100-300 ng/day range are used.
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