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Decrease in Brain Serotonin 2 Receptor Binding In ORIGINAL ARTICLE Decrease in Brain Serotonin 2 Receptor Binding in Patients With Major Depression Following Desipramine Treatment A Positron Emission Tomography Study With Fluorine-18–Labeled Setoperone Lakshmi N. Yatham, MBBS, FRCPC; Peter F. Liddle, PhD, MBBS; Joelle Dennie, MSc; I-Shin Shiah, MD; Michael J. Adam, PhD; Carol J. Lane, MSc; Raymond W. Lam, MD; Thomas J. Ruth, PhD Background: The neuroreceptor changes involved in Results: Eight of the 10 patients responded to desipra- therapeutic efficacy of various antidepressants remain un- mine treatment as indicated by more than 50% decrease clear. Preclinical studies have shown that long-term ad- in Hamilton Depression Rating Scale scores. Depressed ministration of various antidepressants causes down- patients showed a significant decrease in 5-HT2 recep- regulation of brain serotonin 2 (5-HT2) receptors in rodents, tor binding as measured by setoperone binding in fron- but it is unknown if similar changes occur following anti- tal, temporal, parietal, and occipital cortical regions fol- depressant treatment in depressed patients. Our purpose, lowing desipramine treatment. The decrease in 5-HT2 therefore, was to assess the effects of treatment with desi- receptor binding was observed bilaterally and was par- pramine hydrochloride on brain 5-HT2 receptors in de- ticularly prominent in frontal cortex. pressed patients using positron emission tomography (PET) and fluorine-18 (18F)–labeled setoperone. Conclusions: Depressed patients showed a significant reduction in available 5-HT2 receptors in the brain fol- Methods: Eleven patients who met DSM-IV criteria for lowing desipramine treatment, but it is unknown if this major depression as determined by a structured clinical change in 5-HT2 receptors is due to clinical improve- interview for DSM-III-R diagnosis and suitable for treat- ment or an effect of desipramine that is unrelated to clini- ment with desipramine were recruited. Ten patients un- cal status. derwent a PET scan before and another after 3 to 4 weeks of treatment with desipramine. Arch Gen Psychiatry. 1999;56:705-711 HE MECHANISMS by which ceptors in rats. It is, however, unknown antidepressants exert their if antidepressant treatment would lead to therapeutic effects in ma- similar changes in 5-HT2 receptor den- jor depression have re- sity in depressed patients. mained elusive. Since there The purpose of our study was to as- Tis a time lag of about 2 to 4 weeks be- certain the effects of 3- to 4-week treat- tween initiating antidepressant treat- ment with an antidepressant on brain 5-HT2 ment and the clinical response, it has been receptors using positron emission tomog- suggested that alterations in neurotrans- raphy (PET) in patients with major depres- mitter receptors occurring within this time sion. Ligands such as carbon 11 (11C (R)- frame might be relevant to therapeutic ef- (+)-4-(1-hydroxy-1-[2,3-dimethoxy- fects of these drugs.1 Because 5-hydroxy- phenyl]methyl)-N-2-(4-fluorophenylethyl)- 20 11 From the Divisions of Mood tryptamine (serotonin [5-HT]) has been piperidine (MDL 100 907), C-N-meth- 2,3 21 18 22 18 Disorders (Drs Yatham, Shiah, implicated in depression, a number of ylspiperone, F-setoperone, and F- 4-15 23 and Lam and Ms Dennie) and animal studies have assessed the changes altanserin are available for imaging 5-HT2 Schizophrenia (Dr Liddle and in 5-HT receptors after 2 to 4 weeks of the receptors in human brain.24 We chose 18F- Ms Lane), Department of administration of antidepressants. Sero- setoperone because (1) it has a total-to- Psychiatry, and the TRIUMF tonin 2 receptors are the most widely stud- nonspecific binding ratio of greater than 2; Positron Emission Tomography ied,4-9,11-13,15 and these studies have shown (2) it was recommended by the European Program (Drs Adam and Ruth), that long-term administration of tricyclic Task Force as a suitable ligand for imag- The University of British antidepressants,4-6,8,9,11-13 monoamine oxi- ing 5-HT receptors24; and (3) it has been Columbia, Vancouver; and the 2 dase inhibitors,4,6,8,12 atypical antidepres- used successfully by other groups to ex- Department of Psychiatry, 4,6,12 Tri-Service General Hospital, sants such as iprindole and mian- plore 5-HT function in psychiatric disor- 7,8,13 25-28 National Defense Medical serin hydrochloride, and most but not ders. We chose to test the effects of the Center, Taipei, Taiwan all serotonin reuptake inhibitors4,9,12,16-19 de- antidepressant desipramine hydrochlo- (Dr Shiah). creases the density of cortical 5-HT2 re- ride on 5-HT2 receptors because this medi- ARCH GEN PSYCHIATRY/ VOL 56, AUG 1999 705 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 SUBJECTS AND METHODS TREATMENT Each patient started desipramine hydrochloride therapy, 50 SUBJECTS mg, and the dose was increased to 100 mg on day 4. Patients underwent assessment weekly with a clinical interview and Eleven patients who met DSM-IV criteria for major depres- a 21-item HAM-D. If there was no improvement in symp- sive disorder29 and who were suitable for treatment with toms by the second week, the dose of desipramine hydro- desipramine were recruited from the University of British chloride was increased to 150 mg; a further increase in dose Columbia Hospital, Vancouver. The study was approved was made if no improvement was seen by the third week. No by the University Ethics Committee, and subjects gave writ- other psychotropic medication was allowed except loraze- ten informed consent. The diagnosis of major depression pam or oxazepam as required for night sedation. Subjects had was made using the Structured Clinical Interview for DSM- a second PET scan 3 to 4 weeks after the commencement of III-R.30 None had other Axis I diagnoses or current or past desipramine therapy, 12 to 20 hours after the last dose. alcohol or substance abuse. All subjects were physically healthy as determined by history and results of physical ex- DATA ANALYSIS amination. The severity of depression was quantified us- ing the 21-item Hamilton Depression Rating Scale (HAM- Using the multipurpose imaging (MPI) tool33 to define D).31 All study subjects were free of psychotropic drugs for regions in frontal, temporal, and parietal cortex and cer- at least 2 weeks (5 weeks in the case of fluoxetine hydro- ebellum, we confirmed previous observations34 that corti- chloride) before baseline PET scan, and none had ever re- cal- to-cerebellar ratio is constant, indicating pseudoequi- ceived electroconvulsive therapy. librium, between 70 to 110 minutes after injection of 18F-setoperone in depressed patients. PET PROCEDURE Statistical parametric mapping (SPM96) software35,36 was used to align PET images in the 70- to 110-minute pe- Radiosynthesis of 18F-setoperone was accomplished by a riod, to coregister them to magnetic resonance images, and modified method of Crouzel and colleagues,22 as to transform the magnetic resonance images (and PET im- described by Adam et al.32 Radioactivity in brain tissue ages) into the standard coordinate frame used for tem- was measured with a PET system (ECAT 953B/31; CTI/ plates in SPM96. Images were smoothed by applying a Siemens, Knoxville, Tenn). The spatial resolution of 12-mm (full width at half maximum) isotropic Gaussian images is 6 mm (full width at half maximum). Subjects filter to improve the signal-to-noise ratio. were supine with the head slightly tilted to obtain brain For trace doses of setoperone at equilibrium, the slices parallel to the canthomeatal line. Each subject had a amount of setoperone bound to receptors is proportional 10-minute transmission scan for correcting PET images to the binding potential, Bmax/Kd, where Bmax is the total num- for attenuation. Following this, subjects were given 148 to ber of receptors and Kd is the equilibrium-binding con- 259 MBq of 18F-setoperone intravenously, and a 15-frame stant. To determine the binding potential from the mea- scan was performed. The numbers and durations of sured concentration of setoperone in cerebral tissue, it is frames were as follows: 5 frames for 2 minutes each, 4 necessary to allow for variation in the amount of setoper- frames for 5 minutes each, 4 frames for 10 minutes each, one in plasma. This can be performed by comparing the and 2 frames for 20 minutes each (total duration, 110 setoperone concentration in the region of interest with minutes). that in a reference region. Provided the capacity for cation consistently has been shown to decrease the den- score of 27.0 ± 5.6, and the mean HAM-D score de- sity of 5-HT2 receptors in rat studies. creased to 7.0 ± 7.8 following treatment. Eight of 10 pa- tients improved (defined as $50% reduction in 21-item RESULTS HAM-D score) with treatment by second PET scan. Depressed patients showed a significant reduction in One patient could not tolerate the side effects of desi- setoperone binding in several cortical areas, including fron- pramine and dropped out on day 4. The other 10 pa- tal, temporal, parietal, and occipital regions, following de- tients completed the study, and the data analysis is pre- sipramine treatment. Analysis using SPM96 demon- sented for these 10. strated an extensive cluster of voxels in which there was The subjects had a mean age of 40.6 ± 9.2 years. Three a significant decrease in setoperone binding following treat- patients had no previous depressive episodes, and 2 had ment with desipramine (Table 2, Figure 1, and 1 previous episode. The other 5 patients had from 3 to 12 Figure 2). This cluster was highly significant after cor- previous episodes of depression (Table 1). The dura- recting for multiple comparisons (P,.001).
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