Brain Imaging in Depression
Condition: Depression; Bipolar Disorder
MeSH terms: Depression; Depressive Disorder; Bipolar Disorder
Study type: Observational

Summary: 
      The purpose of this study is to use brain imaging technology to examine the role of certain
      brain receptors and the nervous system chemical acetylcholine in major depression.

      The cholinergic system involves the regulation of neurotransmitters and the brain receptors
      to which they bind. Evidence suggests that the cholinergic system may play a role in the
      development of depression. Acetylcholine is a neurotransmitter that binds to certain brain
      receptors called muscarinic cholinergic receptors. Cholinomimetic drugs (drugs that stimulate
      the cholinergic system) often exacerbate depressive symptoms in people with mood disorders
      and in healthy individuals. This increase in depressive symptoms may be caused by stimulation
      of muscarinic acetylcholine receptors (mAChRs), but further study is needed to confirm this.
      This study will use positron emission tomography (PET) and magnetic resonance imaging (MRI)
      to study the function of mAChRs in individuals with depression.

      Participants in this study will undergo a physical examination, psychiatric interviews,
      neuropsychological tests, PET and MRI scans, and rating scales of depression, anxiety, and
      negative thinking symptoms. Questions about behavior and functioning will be asked and blood
      samples will be collected for genetic analysis.
    

Detailed description: 
      Several paths of evidence converge in implicating a role for the cholinergic system in the
      pathophysiology of affective illness. In both unipolar depressed and euthymic bipolar
      subjects, cholinomimetic drugs (i.e., muscarinic agonists, acetylcholinesterase inhibitors)
      exacerbate depressive signs and symptoms such as dysphoria, psychomotor retardation,
      impairment of attention and memory, hypothalamic pituitary adrenal axis hyperactivity and
      sleep EEG abnormalities. In healthy subjects, the acetylcholinesterase inhibitor
      physostigmine elicits a range of depressive symptoms including dysphoria, anergia,
      psychomotor slowing, emotional lability, sleep disturbances, memory and concentration
      impairment, and with higher doses, tearfulness and depression. These effects have been shown
      to reflect stimulation of muscarinic receptors. Cholinomimetics also exacerbate behavioral
      despair in putative animal models of depression. Conversely, the anticholinergic agent
      biperidine improved symptoms of depression in a placebo controlled study. Moreover,
      muscarinic cholinomimetics and a choline rich nutrient, lecithin (phosphatidylcholine) exert
      antimanic effects in bipolar subjects.

      Potentially consistent with these observations, depressed subjects exhibit hypersensitivity
      to cholinomimetic agents. Administration of muscarinic cholinergic agonists, ACh releasing
      agents or acetylcholinesterase inhibitors induce exaggerated effects on REM density and
      latency in depressed subjects than in healthy controls. In addition, both manic and depressed
      bipolar subjects show increased pupillary sensitivity to the muscarinic cholinergic agonist
      pilocarpine relative to controls.

      Despite the data implicating the mAChR receptor system in mood disorders, no direct in vivo
      investigations of the central mAChR have been performed in depressed subjects. A novel PET
      radioligand, [(18)F]FP-TZTP was recently developed by Eckelman as a selective agonist of M(2)
      receptors. Because the M(2) receptor functions predominately as a presynaptic
      release-controlling autoreceptor, decreased distribution volume (V) of this receptor could
      conceivably give rise to increased postsynaptic muscarinic receptor sensitivity.

      This application proposes a pilot PET study of M(2) receptor distribution volume in currently
      depressed subjects with major depressive disorder (n=30), currently depressed subjects with
      bipolar disorder (n=30), and psychiatrically healthy controls (n=30). The proposed pilot
      study will test the central hypothesis that M(2) receptor V is decreased in regions where
      they are primarily located presynaptically in depressed subjects relative to healthy
      controls. The proposed study will advance knowledge regarding the pathophysiology of
      depression.
    

Keywords: PET; [18F]FP-TZTP; Bipolar Disorder; Major Depressive Disorder; Muscarinic 2 Receptors