Antidepressant-induced lipidosis with special reference to tricyclic compounds

Cationic amphiphilic drugs, in general, induce phospholipid disturbances. T ricyclic: as well as other antidepressants belongs to this group. In experi mental animals, antidepressants induce lipid storage disorders in cells of most organs: a so-called generalized phospholipidosis. This disorder is con veniently detected by electron microscopic examination revealing myelin fig ures. Myelin figures or myeloid bodies are subcellular organelles containin g unicentric lamellar layers. The lipidotic induction potency during in viv o is related to the apolarity of the compound. Metabolism of phospholipids takes place within the cell continuously. Several underlying mechanisms may be responsible for the induction of the phospholipid disturbance. For inst ance, it has been suggested that the compounds bind to phospholipids and su ch binding may alter the phospholipid's suitability as a substrate for phos pholipases. Free TCA or metabolites thereof may also inhibit phospholipases directly, as has been demonstrated for sphingomyelinase in glioma and neur oblastoma cells. Both these mechanisms might result in phospholipidosis. In teraction between drug and phospholipid bilayer has been investigated by nu clear magnetic resonance technique. There seems to be large differences in the sensitivities amongst different organs. Steroid-producing cells of the adrenal cortex, testis and ovaries are in particular susceptible to drug-in duced lipidosis. The so-called foam cells are lung macrophages located in t he interstitium which become densely packed with myelin figures during TCA exposure. It requires about 3-6 weeks of treatment to develop this converte d cell. In cell cultures however, phospholipidosis is demonstrated already after 24 h only. It appears that the cells that undergo TCA-induced lipidos is may recover after withdrawal of the drug. The time required to achieve c omplete recovery ranges from 3-4 weeks to several months, depending on the organ affected. Little is known about the functional significance of lipido sis. Even if TCA and other antidepressants show other effects, it has not b een possible to exclusively relate it to phospholipidosis. However, few att empts have been made to correlate the physiological effects of TCAs in expe rimental animals to the morphological changes associated with phospholipido sis. There is an increasing evidence however, that cationic amphiphilic dru gs may have effects on immune function, signal transduction and receptor-me diated events, effects that to some extent might be related to disturbances in phospholipid metabolism. (C) 2000 Elsevier Science Ltd. All rights rese rved.