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.
Similar content being viewed by others
References
Anderson GM, Teff KL, Young SN (1987a) Serotonin in cisternal cerebrospinal fluid of the rat: measurement and use as an index of functionally active serotonin. Life Sci 40:2253–2260
Anderson GM, Feibel FC, Cohen DJ (1987b) Determination of serotonin in whole blood, PRP, PPP and plasma ultrafiltrate. Life Sci 40:1063–1070
Anderson GM, Mefford IN, Tolliver TJ, Riddle MA, Ocame DM, Leckman JF, Cohen DJ (1990) Serotonin in human lumbar cerebrospinal fluid: a reassessment. Life Sci 46:247–255
Anderson GM, Bennett AJ, Weld KP, Pushkas JG, Ocame DM, Higley JD (2002) Serotonin in cisternal cerebrospinal fluid of rhesus monkeys: basal levels and effects of sertraline administration. Psychopharmacology 161:95–99
Aronoff GR, Bergstrom RF, Poltratz ST, Sloan RS, Wolen RL, Lemberger L (1984) Fluoxetine kinetics and protein binding in normal and impaired renal function. Clin Pharmacol Ther 36:138–144
Barr CS, Newman TK, Shannon C, Parker C, Dvoskin RL, Becker ML, Schwandt M, Champoux M, Lesch KP, Goldman D, Suomi SJ, Higley JD (2004) Rearing condition and rh5-HTTLPR interact to influence limbic-hypothalamic-pituitary-adrenal axis response to stress in infant macaques. Biol Psychiatry 55:733–738
Bel N, Artigas F (1992) Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: an in vivo microdialysis study. Eur J Pharmacol 278:1064–1072
Bel N, Artigas F (1993) Chronic treatment with fluvoxamine increases extracellular serotonin in frontal cortex but not in raphe nuclei. Synapse 15:243–245
Benmansour S, Cecchi M, Morilak DA, Gerhardt GA, Javors MA, Gould GG, Frazer A (1999) Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level. J Neurosci 19:10494–10501
Benmansour S, Owens WA, Cecchi M, Morilak DA, Frazer A (2002) Serotonin clearance in vivo is altered to a greater extent by antidepressant-induced downregulation of the serotonin transporter than by acute blockade of this transporter. J Neurosci 22:6766–6772
Bennett AJ, Lesch KP, Heils A, Long JC, Lorenz JG, Shoaf SE et al (2002) Early experience and serotonin transporter gene variation interact to influence primate CNS function. Mol Psychiatry 7:118–122
Black K, Shea C, Dursun S, Kutcher S (2000) Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria. J Psychiatry Neurosci 25:255–261
Blier P, De Montigny C (1994) Current advances and trends in the treatment of depression. Trends Pharmacol Sci 15:220–226
Brammer GL, Raleigh MJ, McGuire MT, Rubinstein EH (1987) Comparison of ketamine, physical restraint, halothane and pentobarbital: lack of influence on serotonergic measures in monkeys and rats. Neuropharmacology 26:1615–1621
Bunin MA, Wightman RM (1999) Paracrine neurotransmission in the CNS: involvement of 5-HT. Trends Neurosci 22:377–382
Carpenter L, Anderson GM, Siniscalchi JM, Chappell PB, Price LP (2003) Acute changes in cerebrospinal fluid 5-HIAA following oral paroxetine challenge in healthy humans. Neuropsychopharmacology 28:339–347
Catterson ML, Preskorn SH (1996) Pharmacokinetics of selective serotonin reuptake inhibitors: clinical relevance. Pharmacol Toxicol 78:203–208
Clarke AS, Ebert MH, Schmidt DE, McKinney WT, Kraemer GW (1999) Biogenic amine activity in response to fluoxetine and desipramine in differentially reared rhesus monkeys. Biol Psychiatry 46:221–228
Collins JM, Dedrick RL (1983) Distributed model for drug delivery to CSF and brain tissue. Am J Physiol 245:R303–R310
DeVane CL, Liston HL, Markowitz JS (2002) Clinical pharmacokinetics of sertraline. Clin Pharmacokinet 41:1247–1266
Eccleston D, Ashcroft GW, Moir ATB, Parker-Rhodes A, Lutz W, Mahoney DP (1968) A comparison of 5-hydroxyindoles in various regions of dog brain and cerebrospinal fluid. J Neurochem 15:947–957
Epperson N, Czarkowski KA, Ward-O’Brien D, Weiss E, Gueorguieva R, Jatlow P, Anderson GM (2001) Maternal sertraline treatment and serotonin transport in breast-feeding mother-infant pairs. Am J Psychiatry. 158:1631–1637
Frazer A, Benmansour S (2002) Delayed pharmacological effects of antidepressants. Mol Psychiatry 7:S23–S28
Gur E, Dremencov E, Lerer B, Newman ME (1999a) Venlafaxine: acute and chronic effects on 5-hydroxytryptamine levels in rat brain in vivo. Eur J Pharmacol 372:17–24
Gur E, Lerer B, Newman ME (1999b) Chronic clomipramine and triiodothyronine increase serotonin levels in rat frontal cortex in vivo: relationship to serotonin autoreceptor activity. J Pharmacol Exp Ther 288:81–87
Hammarlund-Udenaes M (2000) The use of microdialysis in CNS drug delivery studies pharmacokinetic perspectives and results with analgesics and antiepileptics. Adv Drug Deliv Rev 45:283–294
Higley JD, Suomi SJ, Linnoila M (1991) Development, rearing history, and sex differences in CSF monoamine metabolites. Psychopharmacology 103:551–556
Higley JD, Suomi SJ, Linnoila M (1992) A longitudinal study of CSF monoamine metabolite and plasma cortisol concentrations in young rhesus monkeys: effects of early experience, age, sex and stress on continuity of interindividual differences. Biol Psychiatry 32:127–145
Invernizzi R, Bramante M, Samanin R (1996) Role of 5-HT(1A) receptors in the effects of acute and chronic fluoxetine on extracellular serotonin in the frontal cortex. Pharmacol Biochem Behav 54:143–147
Katz MM, Koslow SH, Frazer A (1997) Onset of antidepressant activity: reexamining the structure of depression and multiple actions of drugs. Depress Anxiety 4:257–267
Kihara T, Ikeda M (1995) Effects of duloxetine, a new serotonin and norepinephrine uptake inhibitor, on extracellular monoamine levels in rat frontal cortex. J Pharmacol Exp Ther 272:177–183
Kornhuber J, Retz W, Rieder P (1995) Slow accumulation of psychotropic substances in the human brain. Relationship to therapeutic latency of neuropletic and antidepressant drugs? J Neural Transm 46:315–323
Landen M, Eriksson E (2003) How does premenstrual dysphoric disorder relate to depression and anxiety disorders? Depress Anxiety 17:122–129
Martensson B, Nyberg S, Toresson G, Brodin E, Bertilsson L (1989) Fluoxetine treatment of depression. Acta Scand Psychiatr 79:589–596
Matsumoto M, Togashi H, Yoshioka M, Morii K, Hirokami M, Tochihara M, Ikeda T, Saito Y, Saito H (1991) Significant correlation between cerebrospinal fluid and brain levels of norepinephrine, serotonin, and acetylcholine in anesthetized rats. Life Sci 48:823–829
Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ, Ginovart N, Spencer EP, Cheok A, Houle S (2004) Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry 16:826–835
Mulder EJ, Anderson GM, Kema IP, Minderaa RB (2002) Reactivity of whole blood serotonin. Biol Psychiatry 51:266–268
Nutt DJ (2003) Death and dependence: current controversies over the selective serotonin reuptake inhibitors. J Psychopharmacol 17:355–364
Perry KW, Fuller RW (1992) Effect of fluoxetine on serotonin and dopamine concentration in microdialysis fluid from rat striatum. Life Sci 50:1683–1690
Renshaw P, Guimaraes A, Fava M, Rosenbaum J, Pearlman J et al (1992) Accumulation of fluoxetine and norfluoxetine in human brain during therapeutic administration. Am J Psychiatry 149:1592–1594
Riddle MA, Anderson GM, McIntosh S, Harcherik DF, Shaywitz BA, Cohen DJ (1986) Cerebrospinal fluid monoamine precursor and metabolite levels in children treated for leukemia: age and sex effects and individual variability. Biol Psychiatry 21:69–83
Rollema H, Clarke T, Sprouse JS, Schulz DW (1996) Combined administration of a 5-hydroxytryptamine [5-HT(1D)] antagonist and a 5-HT reuptake inhibitor synergistically increases 5-HT release in Guinea pig hypothalamus in vivo. J Neurochem 67:2204–2207
Ronfeld RA, Tremaine LM, Wilner KD (1997) Pharmacokinetics of sertraline and its N-demethyl metabolite in elderly and young male and female volunteers. Clin Pharmacokinet 32(Suppl 1):22–30
Rosen R, Menza M, Lane R (1999) Effects of SSRIs on sexual dysfunction: critical review. J Clin Psychopharmacol 19:67–85
Rutter J, Gundlah C, Auerbach SB (1994) Increase in extracellular serotonin produced by uptake inhibitors is enhanced after chronic treatment with fluoxetine. Neurosci Lett 171:183–186
Sarkissian CF, Wurtman RJ, Morse AN, Gleason R (1990) Effects of fluoxetine or d-fenfluramine on serotonin release from, and levels in, rat frontal cortex. Brain Res 529:294–301
Schatzberg AF, Haddad P, Kaplan EM, Lejoyeux M, Rosenbaum JF, Young AH, Zajecka J (1997) Serotonin reuptake inhibitor discontinuation syndrome: a hypothetical definition. Discontinuation consensus panel. J Clin Psychiatry 58(Suppl 7):5–10
Selim M, Bradberry CW (1996) Effect of ethanol on extracellular 5-HT and glutamate in the nucleus accumbens and prefrontal cortex: comparison between the Lewis and Fischer 344 rat strains. Brain Res 716:157–164
Sheline Y, Bardgett ME, Csernansky JG (1997) Correlated reductions in cerebrospinal fluid 5-HIAA and MHPG concentrations after treatment with selective serotonin reuptake inhibitors. J Clin Psychopharmacol 17:11–14
Smith T, Kuczenski R, George-Friedman K, Malley JD, Foote SL (2000) In vivo microdialysis assessment of extracellular serotonin and dopamine levels in awake monkeys during sustained fluoxetine administration. Synapse 38:460–470
Sprouse J, Clarke T, Reynolds L, Heym J, Rollema H (1996) Comparison of the effects of sertraline and its metabolite desmethylsertraline on blockade of central 5-HT reuptake in vivo. Neuropsychopharmacology 14:225–231
Sprouse J, Braselton J, Reynolds L, Clarke T, Rollema H (2001) Activation of postsynaptic 5-HT(1A) receptors by fluoxetine despite the loss of firing-dependent serotonergic input: electrophysiological and neurochemical studies. Synapse 41:49–57
Steiner M, Pearlstein T (2000) Premenstrual dysphoria and the serotonin system: pathophysiology and treatment. J Clin Psychiatry 61(Suppl 12):17–21
Walker MC, Tong X, Perry H, Alavijeh MS, Patsalos PN (2000) Comparison of serum, cerebrospinal fluid and brain extracellular fluid pharmacokinetics of lamotrigine. Br J Pharmacol 130:242–248
Wood JH (1980) Neurobiology of cerebrospinal fluid. Plenum, New York, pp 1–16
Yonkers K (1997) The association between premenstrual dysphoric disorder and other mood disorders. J Clin Psychiatry 58(Suppl 15):19–25
Zhou FC, Tao-Cheng J, Segu L, Patel T, Wang Y (1998) Serotonin transporters are located on the axons beyond the synaptic junctions: anatomical and functional evidence. Brain Res 805:241–254
Acknowledgments
Supported by the National Institute of Mental Health, the National Institute of Alcohol Abuse & Alcoholism, and the Gettner Research Fund.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-004-2011-7