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Amygdala abnormalities in first-degree relatives of individuals with schizophrenia unmasked by benzodiazepine challenge

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Abstract

Rationale

Impaired emotion processing in schizophrenia predicts broader social dysfunction and has been related to negative symptom severity and amygdala dysfunction. Pharmacological modulation of emotion-processing deficits and related neural abnormalities may provide useful phenotypes for pathophysiological investigation.

Objectives

We used an acute benzodiazepine challenge to identify and modulate potential emotion-processing abnormalities in 20 unaffected first-degree relatives of individuals with schizophrenia, compared to 25 control subjects without a family history of psychosis.

Methods

An oral 1 mg dose of the short-acting anxiolytic benzodiazepine alprazolam was administered in a balanced crossover placebo-controlled double-blind design, preceding identical 3 T fMRI sessions approximately 1 week apart. Primary outcomes included fMRI activity in amygdala and related regions during two facial emotion-processing tasks: emotion identification and emotion memory.

Results

Family members exhibited abnormally strong alprazolam-induced reduction in amygdala and hippocampus activation during emotion identification, compared to equal reduction in both groups for the emotion memory task.

Conclusions

GABAergic modulation with alprazolam produced differential responses in family members vs. controls, perhaps by unmasking underlying amygdalar and/or GABAergic abnormalities. Such pharmacological fMRI paradigms could prove useful for developing drugs targeting specific neural circuits to treat or prevent schizophrenia.

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Acknowledgments

The authors thank the following individuals: Kosha Ruparel, Jeffrey Valdez, Mark Griffin for assistance with neuroimaging analysis; Ross Weisman for assistance with behavioral analysis; Warren Bilker and Colleen Brensinger for assistance with statistical analysis; Monica Calkins for assistance with symptom assessment; John Detre and JiongJiong Wang for assistance with perfusion methods; and Maxim Zaitsev (University Hospital of Freiburg) for his distortion correction pulse sequence.

Funding and disclosures

This study was funded by AstraZeneca Pharmaceuticals LP. DHW was also supported by NARSAD and the Sidney R. Baer, Jr. Foundation. TDS was supported by NIMH grant MH60490 and APIRE. The work was also supported by National Institute of Mental Health grants MH085096, MH060722, MH064045, and MH019112. Dr. Smith and Dr. Dent are employees of AstraZeneca Pharmaceuticals LP, the study sponsor. Dr. Loughead is the recipient of funding from AstraZeneca and Merck. Drs. Gur report research funding from AstraZeneca and Pfizer. The other authors report no disclosures.

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Authors and Affiliations

  1. Department of Psychiatry, University of Pennsylvania, 10th Floor Gates Bldg., 3400 Spruce St., Philadelphia, PA, 19104, USA

    Daniel H. Wolf, Theodore D. Satterthwaite, James Loughead, Eve Overton, Ruben C. Gur & Raquel E. Gur

  2. Department of Radiology, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Mark A. Elliott, Ruben C. Gur & Raquel E. Gur

  3. Philadelphia Veterans Administration Medical Center, Philadelphia, PA, 19104, USA

    Ruben C. Gur

  4. AstraZeneca Pharmaceuticals LP, Wilmington, DE, 19850, USA

    Gersham W. Dent & Mark A. Smith

  5. Department of Psychology, Southern Methodist University, Dallas, TX, 75275, USA

    Amy Pinkham

Authors
  1. Daniel H. Wolf
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  2. Theodore D. Satterthwaite
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  3. James Loughead
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  4. Amy Pinkham
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  5. Eve Overton
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  6. Mark A. Elliott
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  7. Gersham W. Dent
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  8. Mark A. Smith
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  9. Ruben C. Gur
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  10. Raquel E. Gur
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Corresponding author

Correspondence to Daniel H. Wolf.

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Wolf, D.H., Satterthwaite, T.D., Loughead, J. et al. Amygdala abnormalities in first-degree relatives of individuals with schizophrenia unmasked by benzodiazepine challenge. Psychopharmacology 218, 503–512 (2011). https://doi.org/10.1007/s00213-011-2348-7

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  • DOI: https://doi.org/10.1007/s00213-011-2348-7

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