No Change in Serotonin Type 1A Receptor Binding in Patients With Posttraumatic Stress Disorder

Twelve unmedicated outpatients with PTSD (10 women and two men; mean age=44 years, SD=9) and a matched group of 11 never traumatized, healthy comparison subjects (10 women and one man; mean age=43, SD=8) participated in the study. PTSD status and severity were determined with the Clinician-Administered PTSD Scale. A minimal Clinician-Administered PTSD Scale score of 50 was required for inclusion (mean score=79, SD=19.4). Five PTSD subjects had suffered prepubertal sexual abuse, three had suffered childhood physical/emotional abuse, two had suffered sexual assault as adults, and two had experienced other severe traumatic events as adults. The Structured Clinical Interview for DSM-IV (8) evaluated the presence of concurrent and lifetime DSM-IV axis I disorders. Patients with current or past comorbid diagnoses of anxiety or major depressive disorder were included, provided that diagnosis of PTSD preceded the comorbid condition. Other DSM-IV axis I disorders precluded participation. Two patients suffered from concurrent major depressive disorder, one had generalized anxiety, and another had specific phobia. Three patients previously suffered from major depressive disorder. Two had been previously treated with antidepressants, and four had received benzodiazepines. Depression and anxiety symptoms were assessed with the Montgomery-Åsberg Depression Rating Scale (9) (mean=16.2, SD=8.3) and the Hamilton Anxiety Rating Scale (10) (mean=10.3, SD=3.7).

All participants were free of medical illness or major head trauma and had not been treated with psychotropic drugs in the 3 weeks preceding scanning. Subjects provided written informed consent, as approved by the NIMH Institutional Review Board.

A 120-minute PET study of 5HT1AR binding was acquired by using a GE Advance PET scanner in three-dimensional mode (35 contiguous slices, 4.25 mm plane separation; reconstructed resolution=7 mm full width at half maximum in all planes), bolus intravenous injection of 8 mCi of high specific activity [¹⁸F]FCWAY, and arterial blood sampling. Magnetic resonance images, obtained for each subject using a 3.0-T GE Signa Scanner and a three-dimensional MPRAGE sequence (TE=2.982 msec, TR=7.5 msec, inversion time=725 msec, voxel size=0.9×0.9×1.2 mm), were coregistered to the PET images to provide an anatomical framework for analysis and to perform partial volume correction of the PET images. Regional 5HT1AR binding was measured in regions of interest defined a priori and transferred to the coregistered PET images using MEDx software (Sensor Systems, Sterling, Va.). The regions of interest were localized to brain structures that contain abundant 5HT1AR concentrations: anterior cingulate cortex, posterior cingulate cortex, anterior insula, mesiotemporal cortex (hippocampus plus amygdala), anterior temporopolar cortex, and midbrain raphe. To correct data for free and nonspecifically bound radiotracer, a reference tissue region of interest was defined in the cerebellum, which is devoid of 5HT1AR (for details of region of interest placement see Neumeister et al. [5]). The regional [¹⁸F]FCWAY distribution volume (ml plasma/ml brain), corrected for plasma protein binding, and K₁, the delivery rate of [¹⁸F]FCWAY from plasma to tissue (ml/min/min), were obtained by using quantitative tracer kinetic modeling. The mean distribution volume values were compared between groups by using unpaired t tests. The specificity for receptor-specific binding was assessed post hoc by comparing regional binding potentials as (DV_ROI/DV_cerebellum – 1) to factor out the influence of free and nonspecifically bound radiotracer.

As seen in Figure 1, no significant differences in 5HT1AR distribution volume (ml plasma/ml brain, corrected for protein binding) were observed between patients and healthy subjects in any region of interest (midbrain raphe: mean=32.7 [SD=9.2] and 34.2 [SD=7.0], respectively; anterior temporopolar cortex: mean=60.2 [SD=10.8] and 57.6 [SD=15.1]; posterior cingulate: mean=39.4 [SD=5.5] and 40.6 [SD=8.2]; anterior insula: mean=50.7 [SD=9.7] and 51.9 [SD=10.2]; anterior cingulate: mean=45.6 [SD=6.9] and 45.4 [SD=8.6]; mesiotemporal cortex: mean=67.1 [SD=18.4] and 68.7 [SD=21.4]). Mean binding potential and tracer delivery (K₁) did not differ between groups in any region. No difference in 5HT1AR distribution volume was observed between PTSD patients with or without current or past diagnosis of major depression.

The results of this investigation suggest that in PTSD, which frequently co-occurs with depression and panic disorder, 5HT1AR binding potential is unchanged. Preclinical investigations have shown changes in 5HT1AR binding after exposure to stress. However, the presence and valence of change vary, depending on the duration and nature of stress and brain region (1). Therefore, the diversity in type and duration of trauma in our patient cohort may obscure potential alterations in 5HT1AR binding in PTSD. Still, state-related changes in 5HT1AR binding in humans have not been shown. Reduced 5HT1AR binding in depressed patients was not affected by clinical state or treatment (7). Acute and chronic corticosteroid administration to mentally healthy subjects, and acute administration of corticosteroids to subjects remitted from depression, likewise had no effect on 5HT1AR binding (11, 12). 5HT1AR binding in PTSD in our cohort was not related to comorbidity with depression or anxiety. Future studies with patient groups homogenous for trauma characteristics and comorbidity are needed to determine whether an interaction between genetic vulnerability and environment affects 5HT1AR expression in PTSD.

Presented at the 42nd annual meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico, Dec. 7–11, 2003. Received Jan. 20, 2004; revisions received April 27 and May 10, 2004; accepted May 26, 2004. From the Section on Experimental Therapeutics and the Section on Neuroimaging in Mood and Anxiety Disorders, NIMH Mood and Anxiety Disorders Program; and the National Institutes of Health PET Imaging Center. Address correspondence and reprint requests to Dr. Bonne, National Institutes of Health, NIMH Mood and Anxiety Disorders Program, North Drive, Bldg. 15K, Room 200, Bethesda, MD 20892–2670; [email protected] (e-mail). Dr. Drevets and Dr. Charney contributed equally as senior authors to this work.