Jonas O'Gara Hannestad, MD, PhD

Assistant Professor (Adjunct) of Psychiatry; Chief, Inpatient Division, Clinical Neuroscience Research Unit

Research Interests

Depressive Disorder; Psychiatry and Psychology

Research Organizations

Addictions, Division of

Research Summary

We all know the feeling colloquially called “coming down with something,” the early signs of infectious illness. All of a sudden you feel a slight ache in your body, you feel tired, and it is difficult to concentrate. Ideally, you would go home, lie down, do nothing and talk to nobody. This phenomenon, called sickness behavior, shares certain features with depression. Sickness behavior occurs when inflammatory cytokines produced by the innate immune system signal to the brain. Usually, the innate immune system produces these cytokines when faced with a pathogen. In depression, however, some patients have elevated blood levels of inflammatory cytokines such as TNF and IL-6 in the absence of an infection. It is not known whether these immune abnormalities play a pathogenic role in depression, or if they are merely epiphenomena. The impetus behind my research is to determine how cytokines can have such profound effects on the brain, leading to changes in behavior, motivation, cognition, and mood. I believe that inflammation may be pathogenic, not just in depression, but in a variety of neuropsychiatric disorders. I approach this question by combining experimental immune system activation with PET imaging to determine which brain regions and which neurotransmitter systems are affected by cytokines.

Extensive Research Description

A large body of evidence has demonstrated that increased inflammation can produce depression. In subjects without depression, inflammatory cytokines are associated with negative mood, and in patients with depression, plasma levels of inflammatory cytokines are elevated. Certain anti-inflammatory medications, such as cyclooxygenase-2 inhibitors and TNF antagonists, can ameliorate depressive symptoms. A variety of inflammatory stimuli can cause depressive symptoms. In patients treated with interferon-alpha (IFN-a), 20-45% develop depression. IFN-a causes increases in plasma levels of TNF and IL-6, cytokines commonly elevated in patients with idiopathic depression. Certain vaccines can cause transient depressed mood, and so can stimulation of the innate immune system with low doses of endotoxin. Endotoxin, a cell wall component of gram negative bacteria, is a potent stimulus of the innate immune system. When administrated to humans, endotoxin at doses of 2-4 ng/kg causes flu-like symptoms such as fever, chills, muscle aches and headaches, whereas lower doses (<1 _ng2f_kg29_="" cause="" milder="" symptoms="" that="" are="" more="" similar="" to="" what="" occurs="" in="" _depression2c_="" including="" _fatigue2c_="" _anhedonia2c_="" depressed="" _mood2c_="" and="" impaired="" cognition.="" because="" endotoxin-induced="" sickness="" behavior="" shares="" many="" features="" with="" we="" using="" it="" is="" an="" experimental="" paradigm="" study="" the="" potential="" role="" of="" inflammatory="" cytokines="" depression.="" studies="" rodents="" have="" demonstrated="" endotoxin="" or="" tnf="" administered="" peripherally="" causes="" expression="" mediators="" brain="" parenchyma.="" _likewise2c_="" monkeys="" peripheral="" administration="" il-1="" led="" increased="" levels="" il-6="" cerebrospinal="" fluid="" _28_csf29_2c_="" patients="" receiving="" ifn-a="" _treatment2c_="" csf="" also="" increased.="" these="" demonstrate="" both="" _primates2c_="" when="" _increase2c_="" pathways="" can="" be="" activated.="" neuroinflammation="" could="" contribute="" depression="" other="" neuropsychiatric="" syndromes="" through="" interactions="" _monoamines2c_="" glutamate="" neuroplasticity.="" trying="" develop="" imaging="" method="" reliably="" measure="" vivo.="" a="" protein="" called="" translocator="" 18="" kda="" _28_tspo29_2c_="" located="" on="" outer="" membrane="" _mitochondria2c_="" present="" at="" very="" low="" healthy="" tissue.="" tspo="" upregulated="" wide="" variety="" neuroinflammatory="" neurodegenerative="" disorders.="" _rodents2c_="" induce="" brain.="" current="" pet="" spect="" tracers="" poor="" signal-to-noise="" _ratio2c_="" there="" several="" ongoing="" efforts="" better="" for="" imaging.="" testing="" various="" immune="" system="" activation="">PET imaging of the glutamate metabotropic receptor type 5 in patients with hepatitis C treated with interferon-alpha.
This project will measure the density of the mGluR5 receptor, which is decreased in idiopathic depression, in patients with hepatitis C before and after IFN treatment, to determine whether IFN-induced depression is also associated with reduced mGluR5 density.

PET imaging of endotoxin-induced changes in the brain
This proposal, funded by the Yale Center for Clinical Investigation, uses endotoxin to induce depressive-like symptoms in human subjects and PET imaging to determine the brain regions involved in such symptoms.

Neuroinflammation and depression during interferon-alpha treatment of hepatitis C
This proposal, funded by the Society for Nuclear Medicine, aims at using SPECT imaging to assess whether neuroinflammation occurs during treatment of hepatitis C with interferon-alpha, and to measure whether neuroinflammation correlates with depressive symptoms.

Validation of the SPECT ligand CLINDE as a marker of microglial activation in baboons
This proposal, funded by the Department of Defense, aims to develop a reliable method of microglial imaging for use in human traumatic brain injury by imaging endotoxin-induced microglial activation in baboons.

The effect of citalopram on inflammation-induced depressive symptoms This double-blind, placebo-controlled, cross-over study, funded by NARSAD, aims to determine whether citalopram pretreatment can block depressive symptoms induced by endotoxin-induced inflammation in humans.

Selected Publications

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Contact Info

Jonas O'Gara Hannestad, MD, PhD
Mailing Address
Psychiatry Ribicoff ResearchPO BOX 208068
New Haven, CT 06520-8068

Curriculum Vitae