Dysfunctional attitudes and 5-HT2 receptors during depression and self-harm

Am J Psychiatry. 2003 Jan;160(1):90-9. doi: 10.1176/appi.ajp.160.1.90.


Objective: Dysfunctional attitudes are negatively biased assumptions and beliefs regarding oneself, the world, and the future. In healthy subjects, increasing serotonin (5-HT) agonism with a single dose of d-fenfluramine lowered dysfunctional attitudes. To investigate whether the converse, a low level of 5-HT agonism, could account for the higher levels of dysfunctional attitudes observed in patients with major depression or with self-injurious behavior, cortex 5-HT(2) receptor binding potential and dysfunctional attitudes were measured in patients with major depressive disorder, patients with a history of self-injurious behavior, and healthy comparison subjects (5-HT(2) receptor density increases during 5-HT depletion).

Method: Twenty-nine healthy subjects were recruited to evaluate the effect of d-fenfluramine or of clonidine (control condition) on dysfunctional attitudes. Dysfunctional attitudes were assessed with the Dysfunctional Attitude Scale 1 hour before and 1 hour after drug administration. In a second experiment, dysfunctional attitudes and 5-HT(2) binding potential were measured in 22 patients with a major depressive episode secondary to major depressive disorder, 18 patients with a history of self-injurious behavior occurring outside of a depressive episode, and another 29 age-matched healthy subjects. Cortex 5-HT(2) binding potential was measured with [(18)F]setoperone positron emission tomography.

Results: In the first experiment, dysfunctional attitudes decreased after administration of d-fenfluramine. In the second experiment, in the depressed group, dysfunctional attitudes were positively associated with cortex 5-HT(2) binding potential, especially in Brodmann's area 9 (after adjustment for age). Depressed subjects with extremely dysfunctional attitudes had higher 5-HT(2) binding potential, compared to healthy subjects, particularly in Brodmann's area 9.

Conclusions: Low levels of 5-HT agonism in the brain cortex may explain the severely pessimistic, dysfunctional attitudes associated with major depression.

Publication types

  • Clinical Trial
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Attitude*
  • Brain Mapping
  • Cerebral Cortex / diagnostic imaging
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / physiopathology*
  • Clonidine / pharmacology
  • Depressive Disorder, Major / diagnostic imaging
  • Depressive Disorder, Major / drug therapy
  • Depressive Disorder, Major / physiopathology*
  • Female
  • Fenfluramine / pharmacology
  • Humans
  • Male
  • Personality Inventory
  • Pyrimidinones
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / physiology*
  • Reference Values
  • Self-Injurious Behavior / diagnostic imaging
  • Self-Injurious Behavior / drug therapy
  • Self-Injurious Behavior / physiopathology*
  • Tomography, Emission-Computed


  • Pyrimidinones
  • Receptors, Serotonin
  • Fenfluramine
  • setoperone
  • Clonidine