SLOW ACCUMULATION OF PSYCHOTROPIC SUBSTANCES IN THE HUMAN BRAIN - RELATIONSHIP TO THERAPEUTIC LATENCY OF NEUROLEPTIC AND ANTIDEPRESSANT DRUGS

The mechanism of therapeutic latency of antidepressant and neuroleptic drugs is not clearly understood. Current hypotheses include slow adap tive processes after fast access to primary drug targets. Here, we pre sent a hypothesis explaining therapeutic latency by slow accumulation of the drugs in acidic intracellular compartments. We have studied the pharmacokinetics of amantadine, a lysosomotropic model substance. It' s fast therapeutic response is mediated by fast access to cell surface receptors. However, it slowly accumulates intracellularly in human br ain tissue. Half-maximal and plateau concentrations are reached after 8 and at least 70 days of treatment, respectively. The concentration i n brain tissue relative to CSF and serum is about 20:1. The high stora ge capacity of brain tissue is probably related to lysosomotropic prop erties of amantadine. This means that amantadine, as other lysosomotro pic substances, is trapped by protonation in acidic intracellular comp artments and may disturb biochemical processes that require an acidic milieu, such as the proton-driven transport of monoamines into synapti c vesicles. The mean daily oral dose of amantadine is low compared to the high storage capacity of brain and other tissues thus explaining t he slow accumulation. Many psychotropic drugs including antidepressant and neuroleptic substances also have lysosomotropic properties. A slo w accumulation in brain tissue is therefore likely for many antidepres sant and neuroleptic drugs and has been directly demonstrated for fluo xetine. While lysosomotropism alone is not a sufficient explanation fo r antidepressant or neuroleptic properties of a certain drug, it contr ibutes to high storage capacity and slow accumulation in brain tissue and results in disturbances of several biochemical processes. Slow acc umulation in brain tissue might be related to the therapeutic latency of neuroleptic and antidepressant drugs.