Diencephalic Serotonin Transporter Availability Predicts Both Transporter Occupancy and Treatment Response to Sertraline in Obsessive-Compulsive Checkers Werner Zitterl, Thomas Stompe, Martin Aigner, Karin Zitterl-Eglseer, Kristina Ritter, Georg Zettinig, Kurt Hornik, Susanne Asenbaum, Walter Pirker, and Kenneth Thau Background: To our knowledge, no studies have investigated the predictive value of central serotonin transporter (SERT) availability for treatment response to serotonin reuptake inhibitors (SSRIs) in patients with obsessive– compulsive disorder (OCD). This study used brain imaging to examine the relationship between pretreatment SERT availability and transporter occupancy as well as treatment response by sertraline in patients displaying prominent behavioral checking compulsions (OC checkers). Methods: Single photon emission computed tomography (SPECT) was used to measure thalamic-hypothalamic SERT availability with [ 123 I]-2-carbomethoxy-3-(4-iodophenyl)-tropane in 28 nondepressed OC checkers at baseline and after 14 weeks of treatment with sertraline (175 mg daily). SERT availability was correlated with OC severity and treatment response as assessed with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Associations between individual transporter occupancies and clinical parameters were investigated. Results: 1) Correlation analyses between thalamic-hypothalamic SERT availability and OC severity showed significant negative associations at baseline and after treatment with sertraline. 2) Pretreatment SERT availability correlated significantly with both transporter occupancy and treatment response; in addition, a positive association was found between transporter occupancy and treatment response directly. 3) Using multivariate statistical models, the data demonstrated that higher pretreatment SERT availability significantly predicted higher occupancy rates as well as better treatment response 14 weeks later. Conclusions: Higher pretreatment thalamic-hypothalamic SERT availability may predict both higher occupancy rates and better treatment response to sertraline. The data suggest a strong connection between transporter occupancy and treatment response. Key Words: Obsessive-compulsive disorder, serotonin transporter, sertraline, SPECT, thalamus, treatment response A lthough obsessive-compulsive disorder (OCD) was once considered rare, recent epidemiologic data have demon- strated a prevalence of 1.5%–3.5% (1–3). Increasing evi- dence supports a neurobiological basis of OCD with the ad- vances in neuroimaging techniques and neurophysiologic and pharmacologic studies over the past 2 decades (4–9). Currently, pathophysiologic concepts suggest neurochemical abnormalities in central serotonergic functioning. In general, OCD symptoms can best be managed with the serotonin reuptake inhibitor clomipramine, the selective serotonin reuptake inhibitors (SSRIs), or behavioral therapy (10 –12). The selective response to clomipra- mine or SSRIs observed in OCD patients has led to the hypothesis that these compounds may function by causing changes in the central serotonergic systems (4,10,13,14). There is, however, little direct evidence supporting the role of serotonergic disturbances in the neurobiology of OCD (15). Neuroimaging studies have played a major role in forming neurobiological models of OCD. A network of brain regions, including the orbitofrontal cortex, striatum, and thalamus, have been implicated in the pathophysiology of OCD by concurring data. Most of the regions believed to be involved in OCD are densely innervated by serotonergic or dopaminergic neurons (6). However, the exact functioning of these neurotransmitter sys- tems in OCD has undergone little investigation, even though several ligands for dopaminergic and serotonergic binding sites suitable for positron emission tomography (PET) or single pho- ton emission computed tomography (SPECT) have been identi- fied. A commonly used ligand is [ 123 I]-2-carbomethoxy-3-(4- iodophenyl)-tropane ([ 123 I] -CIT), a SPECT ligand allowing for both serotonin (5-HT) and dopamine transporter visualization in the brain (16 –20). [ 123 I] -CIT has already been widely imple- mented to investigate several psychiatric and neuropsychiatric disorders (21–27). In the striatal region, binding of [ 123 I] -CIT has proven to represent mostly binding to dopamine transporter, whereas binding to serotonin transporter takes place mainly in the thalamus, midbrain, and pons. To our knowledge, there have been eight studies investigat- ing SERT availability in untreated OCD patients published to date: two PET studies and six -CIT SPECT studies (28 –35). The results of these studies are summarized in Table 1. The authors are aware of only two studies examining SERT availability in treated OCD patients: a small pilot study of Stengler-Wenzke et al.(36), who treated five OCD patients with citalopram and elements of cognitive-behavioral therapy (CBT), finding that higher occupancy of SERT seemed to be associated with better clinical response after 1 year of treatment, and a study of Zitterl et al.(37) that included 24 patients treated with clomipramine, which showed that higher pretreatment SERT availability signif- icantly predicted better treatment response 3 months later. The rationale to conduct the present study arose from various factors: From the Departments of Psychiatry and Psychotherapy (WZ, TS, MA, KR, KT), Nuclear Medicine (GZ), and Neurology (SA, WP), Medical University of Vienna; Department of Statistics and Mathematics (KH), Vienna Uni- versity of Economics and Business Administration; and Department of Public Health (KZ-E), University of Veterinary Medicine, Vienna, Austria. Address correspondence to Werner Zitterl, M.D., Department of Psychiatry and Psychotherapy, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria; E-mail: werner.zitterl@meduniwien.ac.at. Received Mar 3, 2009; revised Jul 1, 2009; accepted Jul 14, 2009. BIOL PSYCHIATRY 2009;66:1115–1122 0006-3223/09/$36.00 doi:10.1016/j.biopsych.2009.07.009 © 2009 Society of Biological Psychiatry