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 adaptive processes after fast access to primary drug targets. Here, we present 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 brain tissue. Half-maximal and plateau concentrations are reached after 8 and at least 70 days of treatment, respectively. The concentration in brain tissue relative to CSF and serum is about 20:1. The high storage capacity of brain tissue is probably related to lysosomotropic properties of amantadine. This means that amantadine, as other lysosomotropic substances, is trapped by protonation in acidic intracellular compartments and may disturb biochemical processes that require an acidic milieu, such as the proton-driven transport of monoamines into synaptic vesicles. The mean daily oral dose of amantadine is low compared to the high storage capacity of brain and other tissues thus explaining the slow accumulation. Many psychotropic drugs including antidepressant and neuroleptic substances also have lysosomotropic properties. A slow accumulation in brain tissue is therefore likely for many antidepressant and neuroleptic drugs and has been directly demonstrated for fluoxetine. While lysosomotropism alone is not a sufficient explanation for antidepressant or neuroleptic properties of a certain drug, it contributes to high storage capacity and slow accumulation in brain tissue and results in disturbances of several biochemical processes. Slow accumulation in brain tissue might be related to the therapeutic latency of neuroleptic and antidepressant drugs.
Kornhuber
J
J
Department of Psychiatry, University of Würzburg, Federal Republic of Germany.
Retz
W
W
Riederer
P
P
D000547:Amantadine / Q000493:pharmacokinetics; D000928:Antidepressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics; D006801:Humans; D011619:Psychotropic Drugs / Q000493:pharmacokinetics*; D011930:Reaction Time; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D011619:Psychotropic Drugs; D016194:Receptors, N-Methyl-D-Aspartate; D000547:Amantadine