138 Journal of Clinical Psychopharmacology • Volume 23, Number 2, April 2003 Initial Platelet Serotonin (5-HT) Transport Kinetics Predict Nortriptyline Treatment Outcome Jeffrey L. Rausch, MD,* Frederick G. Moeller, MD,† and Maria E. Johnson, MD* Abstract: According to the hypothesis of initial conditions, drug response may be determined by different initial states of neurotransmitter protein recognition systems. Platelet serotonin (5-HT) transport kinetics were studied as initial-conditions pre- dictors of antidepressant response in 24 depressed patients before and after 3 weeks of treatment with nortriptyline (75 mg). The ini- tial affinity of the 5-HT transporter (5-HTT) correctly predicted 71% of the outcome. The pretreatment affinity constant (K m ) cor- related (r = 0.61; p  0.002) with that measured after 3 weeks of treatment (Kapp). Responding patients had a significantly higher initial K m before treatment and a significantly higher Kapp after treatment. Nonresponders had an initial K m significantly lower than that of 24 controls. Nortriptyline plasma levels were not sta- tistically different between response groups. These results are consistent with two previously published observations, which in- dicate that the initial affinity of the 5-HTT predicted response to fluvoxamine or fluoxetine in the same way. Insofar as all three drugs increase the apparent affinity of the 5-HTT, it appears that a better response is related to those cases where the initial affin- ity is already higher before treatment. (J Clin Psychopharmacol 2003:23: 138–144) A lthough it is clear that antidepressants are effective for the treatment of major depression, responses to these drugs vary considerably in different patients. The biological factors related to different responses are not well under- stood. 1 The present study was prompted from the observa- tion that some depressed patients may respond dramati- cally, while others do not respond to the same initial doses and blood levels of antidepressant drug treatment. The pres- ent investigation sought to examine whether differences in the initial conditions 2 of the 5-HTT’s kinetic function might account for differences in response. Considerable evidence previously had suggested that platelet serotonin (5-HT) neurons might be important com- ponents in the process of an antidepressant response. 3–5 Elec- trophysiological and receptor binding studies indicated that different classes of antidepressant treatments might enhance 5-HT signal transfer. 6 In contrast, interventions depleting 5- HT stores have been shown to reverse the therapeutic effects of antidepressants: both depletion of serotonin stores with PCPA administration and depletion of the amino acid pre- cursor to serotonin, tryptophan, have been demonstrated to prompt relapses of depression. 7–9 Conversely, treatments that increase the extracellular concentrations of serotonin are well known to have antidepressant effects. 9–11 The extracellular concentrations of 5-HT are regu- lated, in part, by the 5-HTT, an active-transport protein present on the cell membrane of both serotonin neurons and platelets. 12–14 The neuronal transporter can be con- ceptualized as part of the “off signal” of serotonergic neu- rotransmission, sequestering 5-HT from other serotonin receptors in the extracellular environment. The presence of the transporter on the platelet cell membranes has prompted numerous studies of depressed patients, al- though the clinical significance of this measure has re- mained largely elusive. 15 Previous observations suggest that heterocyclic anti- depressants inhibit 5-HT transport similarly in platelets and synaptosomes. 16, 17 A high correlation is found across the different potencies of 5-HT-uptake-inhibiting drugs be- tween synaptosomes and platelets (r = 0.99). 18, 19 These data suggest that platelets may model certain aspects of central 5-HT transport in response to 5-HT-uptake- inhibiting drugs. In the present study we sought to examine whether platelet 5-HT transport kinetics would correlate with treat- ment response for a given dose of an antidepressant, com- petitively inhibiting 5-HT transport. Nortriptyline was chosen for study because its efficacy is well established and there is ample literature on the relationship between nor- triptyline levels and response to treatment. 20–24 In addition, ample evidence has shown that nortripty- line inhibits 5-HTT. Nortriptyline has been shown to com- petitively inhibit 5-HTT in platelets of nortriptyline-treated patients. 25 The K i of nortriptyline for 5-HTT inhibition is ORIGINAL CONTRIBUTION *Department of Psychiatry, Veterans Affairs Medical Center, and The Medical College of Georgia, Augusta, Georgia; and †Department of Psychiatry and Behavioral Sciences, University of Texas Houston Health Science Center, Houston, Texas Received February 14 2002; accepted after revision July 10, 2002. Address reprint requests to: Jeffrey L. Rausch, MD, Department of Psychiatry and Health Behavior, The Medical College of Georgia, Au- gusta, GA 30912–3800. Address e-mail to: jeffreyr@mail.mcg.edu.