An intercalation mechanism as a mode of action exerted by psychotropic drugs: results of altered phospholipid substrate availabilities in membranes?

Abstract

Patients respond differently to psychotropic drugs, and this is currently a controversial theme among psychiatrists. The effects of 16 psychotropics on cell membrane parameters have been reported. These drugs belong to three major groups used in therapeutic psychiatry: antipsychotics, antidepressants, and anxiolytic/hypnotics. Human platelets, lacking dopamine (D 2 ) receptors (proposed targets of most psychotropics), have been used as a cell model. Here we discuss the effects of these drugs on three metabolic phenomena and also results from Langmuir experiments. Diazepam, in contrast to the remaining drugs, had negligible effects on metabolic phenomena and had no effects in Langmuir experiments. Psychotropic drugs may work through intercalation in membrane phospholipids. It is possible that the fluidity of membranes, rich in essential fatty acids, the content being influenced by diet, could be a contributing factor to the action of psychotropics. This might in turn explain the observed major differences in therapeutic response among patients.

Neuroleptic malignant syndrome: an easily overlooked neurologic emergency

“…Another aspect is, can we explain the pathophysiology of psychosis dependent only on the basis of receptor and ligand (neurotransmitter) interaction alone and treatment based on the receptor–drug theory of pharmacology? Furthermore, what about the intercalation mechanism of psychotropics into the membranal phospholipids of neurons and myocytes118 and the biomembranes of internal cellular organelles of these excitable cells, such as endoplasmic reticulum that releases intracellular calcium? The majority of agents that can initiate the onset of NMS, listed in Table 1 have amphiphilic chemical structures,119,120 that is, they have lipophilic and hydrophilic moieties (Figure 1).…”

Atypical antipsychotics alter cholesterol and fatty acid metabolism in vitro

“…Antipsychotics interact with lipids and show higher affi nity for sphingomyelin than for phosphatidylcholine, and they alter liquid-ordered domain formation and bilayer thickness ( 36 ). Moreover, antipsychotics have been shown to intercalate among anionic glycerophospholipids in cellular membranes and to alter the relative spatial positioning of PLs, affecting the activity of membranebound proteins ( 37,38 ).…”

Etiopathogenesis of metabolic syndrome in schizophrenia – recent findings

“…S obzirom na to da je nedavno pronađeno da u stanicama humanih monocita inzulin inducira aktivnost enzima D6-i D5-desaturaza koji sudjeluju u sintezi PUFA-a iz prekursorskih molekula linolne kiseline (LA; 18:2n-6) i alfa-linolenske kiseline (ALA; 18:3n-3) unesenih prehranom, inzulinska bi rezistencija mogla dodatno pogoršati postojeći deficit PUFA-a u shizofreniji 87 . Bilo bi zanimljivo spomenuti da novije spoznaje proizašle iz in vitro studija ukazuju na mogućnost da bi smanjena koncentracija PUFA-a u membranama pacijenata sa shizofrenijom mogla imati za posljedicu i slabiji terapijski učinak atipičnih antipsihotičnih lijekova 88,89 . Naime, istraživanja su pokazala da su atipični antipsihotici amfifilne molekule koje se ugrađuju u unutrašnji (citosolni) dio fosfolipidnog dvosloja, a čini se da molekule PUFA ubrzavaju proces njihove ugradnje olakša-vajući interakciju lijekova s membranskim glicerofosfolipidima.…”

“…Naime, istraživanja su pokazala da su atipični antipsihotici amfifilne molekule koje se ugrađuju u unutrašnji (citosolni) dio fosfolipidnog dvosloja, a čini se da molekule PUFA ubrzavaju proces njihove ugradnje olakša-vajući interakciju lijekova s membranskim glicerofosfolipidima. Nadalje, promjena prostornog položaja receptora za pojedine neurotransmiterske sustave, nastala zbog ugradnje antipsihotič-nih lijekova u membranu, mogla bi također utjecati na procese neurotransmisije u središ-njem živčanom sustavu 88 . Unatoč tome što je veći broj studija istražio razlike u značajkama prehrane između oboljelih od shizofrenije i pripadnika opće populacije, još uvijek se nedovoljno zna o direktnoj povezanosti prehrane s metaboličkim sindromom ili njegovim pojedinač-nim komponentama u pacijenata 39,66 .…”