Peripheral and central neurochemical effects of the selective serotonin reuptake inhibitors (SSRIs) in humans and nonhuman primates: assessing bioeffect and mechanisms of action.

It is clear that selective serotonin reuptake inhibitors (SSRIs) act powerfully to inhibit serotonin (5-hydroxytryptamine, 5-HT) uptake centrally and peripherally. However, there are a number of critical unanswered questions concerning the effects of the drugs in adults and children. The influence of age and duration of treatment on the extent of uptake inhibition and on the enhancement of central serotonergic functioning are unclear. In addition, the relationship of these factors and effects to the therapeutic and adverse effects of the SSRIs remain to be clarified. The general clinical utility of platelet 5-HT measurement is reviewed and studies assessing central and peripheral uptake blockade in infants and children and non-human primates are discussed. Recent investigations of central neurochemical effects of the SSRIs in primates assessed through measurement of 5-HT and related compounds in cisternal cerebrospinal fluid (CSF) of the rhesus monkey are presented. In summary, the studies described have found that: human fetal exposure to SSRIs has substantial effects on 5-HT transport in utero; exposure to SSRIs through breastmilk of mothers treated for postpartum depression usually has negligible effects on 5-HT uptake; prescribed SSRIs appear to exert similar effects on 5-HT transporter blockade in children and adults; and rapid and sustained increases are seen in monkey cisternal CSF levels of 5-HT upon initiation of SSRI administration. The implications of the observations in terms of behavioral effects, clinical practice, and underlying mechanisms of action of the SSRIs are discussed.