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Brief Report   |    
Low Dopamine D2 Receptor Binding Potential in Social Phobia
Franklin R. Schneier, M.D.; Michael R. Liebowitz, M.D.; Anissa Abi-Dargham, M.D.; Yolanda Zea-Ponce, Ph.D.; Shu-Hsing Lin, Ph.D.; Marc Laruelle, M.D.
Am J Psychiatry 2000;157:457-459. doi:10.1176/appi.ajp.157.3.457

Abstract

OBJECTIVE: This study compared dopamine D2 receptor binding potential in patients with social phobia and healthy comparison subjects. METHOD: Dopamine D2 receptor binding potential was assessed in 10 unmedicated subjects with generalized social phobia and no significant lifetime psychiatric comorbidity and 10 healthy comparison subjects matched for age and sex. Binding potential was measured in the striatum by using single photon emission computerized tomography and constant infusion of the D2 receptor radiotracer [123I]iodobenzamide ([123I]IBZM). RESULTS: Mean D2 receptor binding potential was significantly lower in the subjects with social phobia than in the comparison subjects. Within the social phobia group, there was a nonsignificant correlation of binding potential with the Liebowitz Social Anxiety Scale score. CONCLUSIONS: Generalized social phobia may be associated with low binding of [123I]IBZM to D2 receptors in the striatum.

Abstract Teaser
Figures in this Article

The generalized subtype of social phobia, characterized by fear and/or avoidance of most social situations, is chronic (1), is heritable (2), and may share behavioral features with subordinate social status in animals (3), yet the biology of social phobia has been little studied. Evidence for an association of social phobia with subnormal transmission in the dopamine system includes treatment efficacy for monoamine oxidase inhibitors but not tricyclic antidepressants (4), low dopamine transporter density in generalized social phobia (5), low CSF levels of homovanillic acid among panic disorder patients with comorbid social phobia (6), a high rate of social phobia among patients with Parkinson’s disease (7), and increased social phobia symptoms during haloperidol treatment of patients with Tourette’s syndrome (8).

In this study we compared dopamine D2 receptor binding potential in patients with generalized social phobia and healthy comparison subjects.

Ten subjects with social phobia were recruited by advertisement and clinical referrals; their mean age was 32.5 years (SD=10.4), and the group comprised five men and five women. All subjects were physically healthy as determined by complete medical evaluation, with no current or lifetime psychosis, organic mental disorders, major depression, bipolar disorder, panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, eating disorders, attention deficit hyperactivity disorder, substance abuse or dependence, schizotypal or borderline personality disorder, or family history of schizophrenia. Ten healthy comparison subjects, matched by age and sex and with no current or past mental disorders, were recruited by advertisement. Diagnoses were confirmed by using the Structured Clinical Interview for DSM-IV Axis I Disorders (9).

All subjects had been free of psychotropic medication for at least a year, and a drug screen was performed before scanning. After complete description of the study to the subjects, written informed consent was obtained.

The Liebowitz Social Anxiety Scale (10) was used to measure the severity of social phobia. D2 receptor binding potential was measured by using the radiotracer [123I]iodobenzamide ([123I]IBZM) with single photon emission computerized tomography, by means of the bolus plus constant infusion method, as previously described (11). A standard region-of-interest profile of constant size and shape was used to analyze the studies. Right and left striatal regions and occipital regions were positioned on summed images. Specific binding was calculated as the difference between striatal activity and occipital activity at equilibrium. [123I]IBZM binding potential (in ml/g), corresponding to the product of the free receptor density (Bmax, in nM or picomoles per gram of brain tissue) and affinity (1/KD, in 1/nM or milliliters of plasma per picomole of [123I]IBZM), was calculated as the ratio of striatal specific binding (in microcuries per gram of brain tissue) to steady-state free unmetabolized plasma tracer concentration (in microcuries per milliliter of plasma) (12).

The group comparisons used two-tailed unpaired t tests with an alpha of 0.05. Binding potential was related to clinical severity by means of rank-transformed data (Spearman rank correlation).

There were no significant group differences in age, sex, race, education, marital status, or handedness.

There was a significant difference in [123I]IBZM binding potential between groups (t=2.6, df=18, p=0.02), with lower binding potential in the patients with generalized social phobia (mean=93.6 ml/g, SD=29.8) than in the comparison subjects (mean=133.5 ml/g, SD=38.2) (F1). Within the social phobia group, there was a nonsignificant negative correlation of binding potential with the total score on the Liebowitz Social Anxiety Scale (rs=–0.59, N=10, p=0.07).

These findings suggest that generalized social phobia may be associated with low D2 receptor binding potential in the striatum. Low D2 receptor binding potential would be consistent with the findings of low dopamine system activity in social phobia.

This study is limited by the small number of subjects. Also, because only one high-specific-activity experiment was performed with each subject, D2 receptor density and affinity could not be measured.

The findings appear to parallel those from animal studies of subordinate social status, which has been suggested to share behavioral features with human social phobia (3). For example, a recent positron emission tomography study of female cynomolgus monkeys (13) showed lower striatal D2 binding in subordinates, similar to our finding in generalized social phobia. Animals of subordinate social status may be a useful model for understanding the brain function underlying human social phobia.

Low D2 receptor binding seems at least partially specific to social phobia, rather than representing a nonspecific correlate of stress or mental disorder. D2 binding has not been found to be low in schizophrenia (14) or major depression (15). It has been reported to be low in substance abuse disorders (16), which may often be comorbid with social phobia (17).

These data suggest that low D2 receptor binding potential might be associated with social phobia. Combined with results from other centers, these data add to the growing evidence that D2 receptor function modulates social behavior in humans.

Received Feb. 23, 1999; revisions received July 13 and Aug. 27, 1999; accepted Sept. 2, 1999. From the Anxiety Disorders Clinic and the Brain Imaging Division, New York State Psychiatric Institute; and the Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York. No reprints are available. Address correspondence to Dr. Schneier, Anxiety Disorders Clinic, Unit 69, New York State Psychiatric Institute, 1051 Riverside Dr., New York, NY 10032; frs1@columbia.edu (e-mail). Supported by grants from the Sycamore Foundation and from Solvay Pharmaceuticals and by NIMH Independent Scientist Award MH-01603 to Dr. Laruelle. The authors thank Kathy Rivera, Tami Edwards, Janine Rodenhiser, Ph.D., Suehee Chung, Mali Pratap, Ted Pozniakoff, Richard Weiss, Dan Schneider, and Analea Arevalo for technical assistance.

 
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FIGURE 1.

Dopamine D2 Receptor Binding Potential in Patients With Generalized Social Phobia and Healthy Comparison Subjects

Chartier MJ, Hazen AL, Stein MB: Lifetime patterns of social phobia: a retrospective study of the course of social phobia in a nonclinical population. Depress Anxiety  1998; 7:113–121
[PubMed]
[CrossRef]
 
Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ: The genetic epidemiology of phobias in women: the interrelations of agoraphobia, social phobia, situational phobia, and simple phobia. Arch Gen Psychiatry  1992; 49:273–281
[PubMed]
 
Ohman A: Face the beast and fear the face: animal and social fears as prototypes for evolutionary analyses of emotion. Psychophysiol  1986; 23:123–145
[CrossRef]
 
Liebowitz MR, Campeas R, Hollander E: Possible dopamine dysregulation in social phobia and atypical depression. Psychiatry Res  1987; 22:89–90
[PubMed]
[CrossRef]
 
Tiihonen J, Kuikka J, Bergstr�, Lepola U, Koponen H, Leinonen E: Dopamine reuptake site densities in patients with social phobia. Am J Psychiatry  1997; 154:239–242
[PubMed]
 
Johnson MR, Lydiard RB, Zealberg JJ, Fossey MD, Ballenger JC: Plasma and CSF levels in panic patients with comorbid social phobia. Biol Psychiatry  1994; 36:426–427
 
Stein MB, Heuser IJ, Juncos JL, Uhde TW: Anxiety disorders in patients with Parkinson’s disease. Am J Psychiatry  1990; 147:217–220
[PubMed]
 
Mikkelsen EJ, Detlor J, Cohen DJ: School avoidance and social phobia triggered by haloperidol in patients with Tourette’s disorder. Am J Psychiatry 1981; 138:1572–  1576
 
First MB, Spitzer RL, Gibbon M, Williams JBW: Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition (SCID-P), version 2. New York, New York State Psychiatric Institute, Biometrics Research, 1994
 
Heimberg RG, Horner KJ, Juster HR, Safren SA, Brown EJ, Schneier FR, Liebowitz MR: Psychometric properties of the Liebowitz Social Anxiety Scale. Psychol Med  1999; 29:199–212
[PubMed]
[CrossRef]
 
Laruelle M, Abi-Dargham A, van Dyck CH, Rosenblatt W, Zea-Ponce Y, Zoghbi SS, Baldwin RM, Charney DS, Hoffer PB, Kung HF, Innis RB: SPECT imaging of dopamine release after amphetamine challenge. J Nucl Med 1995; 36:1182–  1190
 
Laruelle M, Abi-Dargham A, Al-Tikriti MS, Baldwin RM, Zea-Ponce Y, Zoghbi SS, Charney DS, Hoffer PB, Innis RB: SPECT quantification of [123I]iomazenil binding to benzodiazepine receptors in nonhuman primates, II: equilibrium analysis of constant infusion experiments and correlation with in vitro parameters. J Cereb Blood Flow Metab  1994; 14:453–465
[PubMed]
[CrossRef]
 
Grant KA, Shively CA, Nader MA, Ehrenkaufer RL, Line SW, Morton TE, Gage HD, Mach RH: Effect of social status on striatal DA D2 receptor binding characteristics in cynomolgus monkeys assessed with positron emission tomography. Synapse  1998; 29:80–83
[PubMed]
[CrossRef]
 
Laruelle M: Imaging dopamine transmission in schizophrenia: a review and meta-analysis. Q J Nucl Med  1998; 42:211–221
[PubMed]
 
Shah PJ, Ogilvie AD, Goodwin GM, Ebmeier KP: Clinical and psychometric correlates of dopamine D2 binding in depression. Psychol Med 1997; 27:1247–  1256
 
Hietala J, West C, Syvalahti E, Nagren K, Lehikoinen P, Sonninen P, Ruotsalainen U: Striatal D2 dopamine receptor binding characteristics in vivo in patients with alcohol dependence. Psychopharmacology (Berl)  1994; 116:285–290
[PubMed]
[CrossRef]
 
Schneier FR, Martin LY, Liebowitz MR, Gorman JM, Klein DF, Fyer AJ: Alcohol abuse and social phobia. J Anxiety Disord  1989; 3:15–23
[CrossRef]
 

FIGURE 1.

Dopamine D2 Receptor Binding Potential in Patients With Generalized Social Phobia and Healthy Comparison Subjects

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References

Chartier MJ, Hazen AL, Stein MB: Lifetime patterns of social phobia: a retrospective study of the course of social phobia in a nonclinical population. Depress Anxiety  1998; 7:113–121
[PubMed]
[CrossRef]
 
Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ: The genetic epidemiology of phobias in women: the interrelations of agoraphobia, social phobia, situational phobia, and simple phobia. Arch Gen Psychiatry  1992; 49:273–281
[PubMed]
 
Ohman A: Face the beast and fear the face: animal and social fears as prototypes for evolutionary analyses of emotion. Psychophysiol  1986; 23:123–145
[CrossRef]
 
Liebowitz MR, Campeas R, Hollander E: Possible dopamine dysregulation in social phobia and atypical depression. Psychiatry Res  1987; 22:89–90
[PubMed]
[CrossRef]
 
Tiihonen J, Kuikka J, Bergstr�, Lepola U, Koponen H, Leinonen E: Dopamine reuptake site densities in patients with social phobia. Am J Psychiatry  1997; 154:239–242
[PubMed]
 
Johnson MR, Lydiard RB, Zealberg JJ, Fossey MD, Ballenger JC: Plasma and CSF levels in panic patients with comorbid social phobia. Biol Psychiatry  1994; 36:426–427
 
Stein MB, Heuser IJ, Juncos JL, Uhde TW: Anxiety disorders in patients with Parkinson’s disease. Am J Psychiatry  1990; 147:217–220
[PubMed]
 
Mikkelsen EJ, Detlor J, Cohen DJ: School avoidance and social phobia triggered by haloperidol in patients with Tourette’s disorder. Am J Psychiatry 1981; 138:1572–  1576
 
First MB, Spitzer RL, Gibbon M, Williams JBW: Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition (SCID-P), version 2. New York, New York State Psychiatric Institute, Biometrics Research, 1994
 
Heimberg RG, Horner KJ, Juster HR, Safren SA, Brown EJ, Schneier FR, Liebowitz MR: Psychometric properties of the Liebowitz Social Anxiety Scale. Psychol Med  1999; 29:199–212
[PubMed]
[CrossRef]
 
Laruelle M, Abi-Dargham A, van Dyck CH, Rosenblatt W, Zea-Ponce Y, Zoghbi SS, Baldwin RM, Charney DS, Hoffer PB, Kung HF, Innis RB: SPECT imaging of dopamine release after amphetamine challenge. J Nucl Med 1995; 36:1182–  1190
 
Laruelle M, Abi-Dargham A, Al-Tikriti MS, Baldwin RM, Zea-Ponce Y, Zoghbi SS, Charney DS, Hoffer PB, Innis RB: SPECT quantification of [123I]iomazenil binding to benzodiazepine receptors in nonhuman primates, II: equilibrium analysis of constant infusion experiments and correlation with in vitro parameters. J Cereb Blood Flow Metab  1994; 14:453–465
[PubMed]
[CrossRef]
 
Grant KA, Shively CA, Nader MA, Ehrenkaufer RL, Line SW, Morton TE, Gage HD, Mach RH: Effect of social status on striatal DA D2 receptor binding characteristics in cynomolgus monkeys assessed with positron emission tomography. Synapse  1998; 29:80–83
[PubMed]
[CrossRef]
 
Laruelle M: Imaging dopamine transmission in schizophrenia: a review and meta-analysis. Q J Nucl Med  1998; 42:211–221
[PubMed]
 
Shah PJ, Ogilvie AD, Goodwin GM, Ebmeier KP: Clinical and psychometric correlates of dopamine D2 binding in depression. Psychol Med 1997; 27:1247–  1256
 
Hietala J, West C, Syvalahti E, Nagren K, Lehikoinen P, Sonninen P, Ruotsalainen U: Striatal D2 dopamine receptor binding characteristics in vivo in patients with alcohol dependence. Psychopharmacology (Berl)  1994; 116:285–290
[PubMed]
[CrossRef]
 
Schneier FR, Martin LY, Liebowitz MR, Gorman JM, Klein DF, Fyer AJ: Alcohol abuse and social phobia. J Anxiety Disord  1989; 3:15–23
[CrossRef]
 
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