Rationale: Fundamental questions remain regarding the actions of the selective serotonin reuptake inhibitors (SSRIs).
Objectives: To examine the time course of central and peripheral neurochemical effects of sertraline (SER) in non-human primates.
Methods: SER (20 mg/kg, p.o.) or placebo were administered daily for 4 weeks to two groups of six young adult male rhesus monkeys. Both groups received placebo during a 3-week baseline lead-in period and for 6 weeks after discontinuation. Blood and cisternal cerebrospinal fluid (cCSF) samples were obtained on days -21, -14, -7, 0, +3, +7, +14, +21, +28, +35 and +70.
Results: In animals receiving SER, mean (+/-SD) levels of cCSF serotonin (5-HT) increased from 38.6+/-9.0 pg/ml at baseline to 128+/-46.4 pg/ml during treatment (paired t=4.17, P=0.014). Concentrations of cCSF 5-HT were 290% of baseline on day 0 (+3 h), ranged from 260% to 436% of baseline during treatment, and returned to baseline 7 days after discontinuation. Levels of cCSF 5-hydroxyindoleacetic acid declined to 51+/-2.0% of baseline by day +3 and remained at similarly reduced levels during treatment. Plasma drug levels and decrements in platelet 5-HT were similar to those seen in patients.
Conclusions: SER rapidly and substantially increases cCSF levels of 5-HT in primates, the extent of elevation is relatively constant during prolonged administration, and values return to baseline shortly after discontinuation. The results suggest that response latency for SSRIs in depression is not due to gradually increasing brain extracellular fluid 5-HT levels and tend not to support theories that posit SSRI response latency as being due to autoreceptor desensitization, transporter downregulation, or drug accumulation.