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Time course of the effects of the serotonin-selective reuptake inhibitor sertraline on central and peripheral serotonin neurochemistry in the rhesus monkey

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Abstract

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.

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Acknowledgments

Supported by the National Institute of Mental Health, the National Institute of Alcohol Abuse & Alcoholism, and the Gettner Research Fund.

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Authors and Affiliations

  1. Departments of Child Psychiatry and Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA

    George M. Anderson & Ilya Shifrovich

  2. Laboratory of Clinical Studies-Primate Unit, The National Institute of Alcohol Abuse & Alcoholism (NIAAA), Poolesville, MD, USA

    Christina S. Barr, Stephen Lindell, Amy C. Durham & J. Dee Higley

Authors
  1. George M. Anderson
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  2. Christina S. Barr
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  3. Stephen Lindell
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  4. Amy C. Durham
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Correspondence to George M. Anderson.

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Anderson, G.M., Barr, C.S., Lindell, S. et al. Time course of the effects of the serotonin-selective reuptake inhibitor sertraline on central and peripheral serotonin neurochemistry in the rhesus monkey. Psychopharmacology 178, 339–346 (2005). https://doi.org/10.1007/s00213-004-2011-7

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  • DOI: https://doi.org/10.1007/s00213-004-2011-7

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