Interferon-induced Depression: Genetics

Photo of a pair of green wing teal

Interferon remains a key first line treatment for treatment of hepatitis C.  However, interferon has significant neuropsychiatric effects including risk for depression and even suicide in rare individuals.

Some individuals with hepatitis C are unable to complete a course of interferon because of induced depression.  This makes understanding this phenomenon important to develop prevention and treatment strategies.

Understanding how interferon induces depression in some individuals and not other may provide insight into some of the core mechanisms involved in mood disorders.

Joerg Schlaak and colleagues from Germany recently published an important manuscript on gene expression in interferon treated humans.  

The key elements of design in their study included:
Subject characteristics: 50 subjects with hepatitis C followed prospectively while receiving antiviral therapy (interferon alpha and ribavirin), 22 psychiatric patients hospitalized for severe depression and 11 controls without hepatitis C or depression
Gene expression analysis: Total RNA isolation, DNA microarray analysis, real time detection gene expression using PCR
Statistical analysis: group comparisons using T-test or Mann-Whitney U test

Eleven subjects (22%) in the prospective interferon/ribavirin hepatitis C trial developed significant depression.  Fifteen genes were identified in these interferon-induced depression subjects that were "hyper-responsive" to the interferon alpha compared to the response in subjects that did not develop depression.  Six genes identified in this study have previously been identified as important in depression and neuron development:

• DISC1: linked to schizophrenia, hippocampus, neuron migration
• DYNLT1: linked to hippocampus neuron development
• GCH1: linked to bipolar disorder, depression, dopamine metabolism
• TOR1B: linked to major depression, neurotransmitter regulation
• MEF2A: linked to neuronal and hippocampal development
• ST3GAL: linked to a form of epilepsy and hippocampal cell apoptosis

Cells from psychiatric patients with major depression were exposed to interferon alpha in vitro.  The authors were able to demonstrate a statistically higher induction rate for DISC1, DYNLT1, GCH1 and TOR1B in these cell lines.  MEF2A and ST3GAL5 showed a statistical trend for higher induction in psychiatric major depression subjects compared to controls.

Molecular Structure Interferon Alpha

Additionally, psychiatric inpatient depression in this study showed enhanced production of endogenous interferons.  

Interestingly, all eleven subjects developing depression during interferon alpha treatment responded to initiation of selective serotonin reuptake drug treatment (citalopram).

The authors conclude dysregulation of cytokine inflammatory pathways appear to be working in both interferon-induced depression and depression in psychiatric inpatients.  This dysregulation may be acting through the specific genes identified in this study. 

The link of interferon-induced depression with several genes related to the hippocampus is also intriguing.  The authors note hippocampus neuron loss is found in depression and that antidepressants and lithium stimulate neurogenesis.

Further study of interferon-induced depression is a promising strategy in understanding psychiatric depression.  This approach may yield development of novel drug treatments for the mood disorders.

Photo of green winged teal from the author's files.

Graphic of interferon alpha is from a Wikipedia Commons file authored by Nevit Dilmen. 

Schlaak JF, Trippler M, Hoyo-Becerra C, Erim Y, Kis B, Wang B, Scherbaum N, & Gerken G (2012). Selective hyper-responsiveness of the interferon system in major depressive disorders and depression induced by interferon therapy. PloS one, 7 (6) PMID: 22701688