ORIGINAL ARTICLE Seasonal Variation in Human Brain Serotonin Transporter Binding Nicole Praschak-Rieder, MD; Matthaeus Willeit, MD; Alan A. Wilson, PhD; Sylvain Houle, MD, PhD; Jeffrey H. Meyer, MD, PhD Context: It is a common experience in temperate zones that Intervention: Carbon 11–labeled 3-amino-4- individuals feel happier and more energetic on bright and (2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile sunny days and many experience a decline in mood and en- positron emission tomography. ergy during the dark winter season. Brain serotonin is in- volved in the regulation of physiologic functions, such as Main Outcome Measure: Regional serotonin trans- mating, feeding, energy balance, and sleep. Although these porter binding potential values. behaviors and serotonin-related conditions show a clear sea- sonal pattern in humans, the molecular background of sea- Results: Serotonin transporter binding potential values were sonal changes in serotonin function is entirely unknown. significantly higher in all investigated brain regions in in- The serotonin transporter is a key element in regulating in- dividuals investigated in the fall and winter compared with tensity and spread of the serotonin signal. those investigated in the spring and summer (P=.01 to .001). Moreover, binding potential values showed negative corre- Objectives: To detect seasonal variations in serotonin lations with average duration of daily sunshine in all brain transporter binding in the living human brain and to de- regions(␳=−0.21to−0.39;P=.05toϽ.001),suchthathigher tect correlations between serotonin transporter binding and duration of daily sunshine. values occurred at times of lesser light. Conclusions Design: Regional serotonin transporter binding poten- : Serotonin transporter binding potential val- tial values, an index of serotonin transporter density, were ues vary throughout the year with the seasons. Since assessed from December 1, 1999, to December 9, 2003, higher serotonin transporter density is associated with in a consecutive sample of healthy volunteers. Binding lower synaptic serotonin levels, regulation of serotonin potential values were related to meteorologic data. transporter density by season is a previously unde- scribed physiologic mechanism that has the potential to Setting: Tertiary care psychiatric hospital. explain seasonal changes in normal and pathologic behaviors. Participants: Volunteer sample of 88 drug-naı¨ve healthy individuals. Arch Gen Psychiatry. 2008;65(9):1072-1078 NDOLAMINES (TRYPTOPHAN, SERO- suggests that sunlight alters serotonin turn- Author Affiliations: Vivian M. tonin, melatonin, and related over in the human brain. Rakoff PET Imaging Centre (Drs Praschak-Rieder, Willeit, compounds) have transduced The serotonin transporter clears the Wilson, Houle, and Meyer) and light signals and information on synaptic cleft from serotonin and, there- Mood and Anxiety Disorders photoperiod into organisms and fore, has an important role in the regula- Division (Dr Meyer), Clarke cells since early in evolution,1 and their role tion of serotonergic neurotransmis- I 17 Division, Centre for Addiction in signaling change of seasons is pre- sion. Given the role of the serotonin and Mental Health, and served in humans.2 Serotonin is involved transporter, the seasonal variation in sero- Department of Psychiatry, in the regulation of many physiologic and tonin-related behaviors,3-12 and the sea- University of Toronto pathologic behaviors that vary with sea- sonal variation in brain serotonin concen- (Drs Praschak-Rieder, Willeit, son in clinical and nonclinical popula- trations and other serotonin markers,12-16 Wilson, Houle, and Meyer), tions.3-12 Seasonal variations in periph- we hypothesized that there is a seasonal Toronto, Ontario, Canada; and eral serotonergic markers have been variation in regional serotonin trans- Department of Biological 12-14 Psychiatry, Medical University demonstrated in several studies. A post- porter binding potential values in the liv- 15 of Vienna, Vienna, Austria mortem study shows seasonal differ- ing human brain. As a secondary hypoth- (Drs Praschak-Rieder and ences in serotonin concentration in the hu- esis, we expected to find a correlation Willeit). man hypothalamus; another study16 between serotonin transporter binding po- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 9), SEP 2008 WWW.ARCHGENPSYCHIATRY.COM 1072 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 tential values and the duration of sunshine throughout pants underwent a single [11C]DASB PET scan in a medication- the year. The serotonin transporter binding potential free state. The same protocols for participant preparation, PET 18 acquisition, image reconstruction, and tracer kinetic model- (which is also referred to as 5-HTT BPND ) is an index ϫ ing were applied for each participant. of serotonin transporter levels and is defined as fND Bavail/ 11 K , where f is the free fraction of radioligand in the non- Synthesis of [ C]DASB measurement of serotonin trans- d ND porter binding potential with [11C]DASB PET scanner and meth- displaceable compartment; Bavail, the concentration of avail- ods reported in this study are the same as those used in previ- able transporter; and Kd, the dissociation constant. ous studies.26,30-35 The ROIs were delineated using an automated 19,20 Previous investigations of regional serotonin trans- software program,32 as described previously. The posterior half porter binding and season in humans have not led to a clear of the cerebellar cortex under exclusion of vermis and cerebel- understanding of the relationship between these 2 mea- lar white matter served as the reference region. We also kept sures. The techniques applied were not optimally sensi- at least 1 full width at half maximum (5.5 mm) from the ve- tive, and the results were in opposite directions. A study21 nous sinuses and occipital cortex. At a distance of 1 full width using the nonspecific monoamine transporter ligand at half maximum, spillover from the occipital cortex (which iodine 123–labeled 2-␤-carboxymethoxy-3-␤-(4- has specific binding) or the venous sinuses is negligible. iodophenyl)-tropane and single-photon emission com- Serotonin transporter binding potential values were deter- mined using the Logan noninvasive method36 implemented puted tomography reported increased serotonin trans- within computer software (PMOD; PMOD Technologies Ltd, porter binding during summer in healthy women. A Zurich, Switzerland). This analysis method provides valid and 11 subsequent carbon 11–labeled McN5652 ([ C]McN5652) reproducible [11C]DASB PET measurements of serotonin trans- positron emission tomography (PET) study22 reported no porter binding potential values with low between-subject vari- seasonal change in serotonin transporter binding in the ance in serotonin transporter binding potential for most brain thalamus and, in a subset of analyses, a seasonal change regions.32-35 An additional analysis was performed using the in serotonin transporter binding in the mesencephalon such modified simplified reference tissue method (SRTM-227,37)in that serotonin transporter binding was lower in spring and a data subset. Analysis of intraclass correlation coefficients summer. The authors of the second study22 reported that showed good agreement for the 2 analysis methods (prefron- no other brain regions were assessable. Limitations of tal cortex, 0.98; cingulate cortex, 0.98; caudate, 0.87; puta- 11 men, 0.91; and thalamus, 0.94). Between-subject variability of [ C]McN5652 PET include a modest ratio of specific bind- mesencephalon serotonin transporter binding potential deter- ing relative to free and nonspecific binding and slow phar- mined with the SRTM-2 model was overly elevated in this data 23 macokinetics, which may reduce the ability of this method set, so only the Logan method was applied to determine sero- to detect significant effects.19 tonin transporter binding potential in the mesencephalon. The highly selective PET serotonin transporter li- gand carbon 11–labeled 3-amino-4-(2-dimethylamino- methyl-phenylsulfanyl)-benzonitrile ([11C]DASB24) al- STATISTICAL ANALYSIS lows valid and reliable in vivo measurement of serotonin transporter binding potential values in cortical and sub- Individual scans were grouped according to season of scan with cortical brain regions25-27 and is the optimal method for the equinoxes as the cutoff between the fall and winter season quantification of serotonin transporter binding poten- and the spring and summer season: for fall and winter, the scan tial values in humans.20,25,28 To definitively address the dates were September 23 to March 20 (n=38), and for spring and summer, the scan dates were March 21 to September 22 question of whether brain serotonin transporter bind- (n=50). In the initial step, age, sex, and season of scan (fall and ing relates to season, we conducted a retrospective study winter vs spring and summer) were entered into a logistic re- in a large sample of healthy control subjects (N=88) liv- gression model separately for all 6 ROIs because some stud- ing in the greater Toronto area, measuring serotonin trans- ies32,38 have suggested an influence of age and sex on brain sero- porter binding in multiple regions of interest (ROIs), many tonin transporter binding. Because sex had no effect in the of which have dense serotonergic innervation (antero- regression model in any of the ROIs even at most liberal prob- medial prefrontal