Original Investigation

Psychopharmacology

, Volume 218, Issue 3, pp 503-512

First online:

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

  • Daniel H. WolfAffiliated withDepartment of Psychiatry, University of Pennsylvania Email author 
  • , Theodore D. SatterthwaiteAffiliated withDepartment of Psychiatry, University of Pennsylvania
  • , James LougheadAffiliated withDepartment of Psychiatry, University of Pennsylvania
  • , Amy PinkhamAffiliated withDepartment of Psychology, Southern Methodist University
  • , Eve OvertonAffiliated withDepartment of Psychiatry, University of Pennsylvania
  • , Mark A. ElliottAffiliated withDepartment of Radiology, University of Pennsylvania
  • , Gersham W. DentAffiliated withAstraZeneca Pharmaceuticals LP
  • , Mark A. SmithAffiliated withAstraZeneca Pharmaceuticals LP
  • , Ruben C. GurAffiliated withDepartment of Psychiatry, University of PennsylvaniaDepartment of Radiology, University of PennsylvaniaPhiladelphia Veterans Administration Medical Center
    • , Raquel E. GurAffiliated withDepartment of Psychiatry, University of PennsylvaniaDepartment of Radiology, University of Pennsylvania

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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.

Keywords

Pharmacological fMRI Benzodiazepine Endophenotype Amygdala Facial emotion GABA Schizophrenia