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

Donepezil Improves Dementia With Lewy Bodies

Dementia with Lewy bodies (DLB) is a type of dementia less common than Alzheimer's disease.  However, Lewy bodies (brain neuron deposits of the proteins alpha-synuclean and ubiquitin) are found in up to 10 to 15% of individuals dying of dementia.

DLB is known to deplete brain acetylcholine and dopamine neurotransmitter levels in the brain.  This leads to a clinical syndrome characterized by both cognitive decline and motor symptoms similar to Parkinson's disease.

DLB may be difficult to distinguish from Alzheimer's disease but typically exhibits fluctuations in cognitive function, visual hallucinations, visuoperceptual impairment and concurrent motor symptoms.

Few clinical trials have targeted DLB due to it's relative infrequency and diagnostic classification.  A Japanese study of 148 subjects with DLB recent found support for the effectiveness of the Alzheimer's drug donepezil.

Mori and colleagues conducted a randomized clinical trial with the following key elements in the research design:

• Subjects: Met probable DLB diagnosis using structured criteria, no Parkinson's disease diagnosis more than one year before onset of dementia, no evidence of focal vascular disease on CT or MRI
• Drug administration: Double-blind randomization of donepezil 3 mg, 5 mg, 10 mg or placebo for 12 weeks
• Outcome measures: Minimental state exam (MMSE) scores, attention, executive function and visuoperceptual cognitive function from the Wechsler Memory Scale-Revised (WMS-R), tests for verbal fluency and agnosia.  Ten behavioral domains were also assessed.  Clinicians blind to treatment rated global clinical status.  Caregivers rated burden of care.  Motor symptoms were assessed using the Unified Parkinson's Disease Rating Scale.
• Statistical analysis: Last observation carried forward analysis on all subjects with at least one valid post-treatment measurement

This trial found significant therapeutic effects for donepezil across a variety of DLB disease domains (doses statistically associated with improvement compared to placebo)

• Minimental status exam: 5 and 10 mg
• Clinician global improvement scores: 3, 5 and 10 mg
• Behavioral scores for hallucinations, cognitive fluctuation, delusions, apathy and depression: 5 and 10 mg
• Caregiver burden scores: 10 mg

Photo of two brain Lewy Bodies 

Donepezil was fairly well tolerated in this study sample with 3 to 8% of the active drug groups discontinued due to adverse effects.  This rate was not different than placebo withdrawals.

The authors conclude that their study provides support for the effectiveness of donepezil across a variety of clinical domains.  They note the study supports using a 10 mg dose if tolerated.  

Recruiting clinical sample sizes sufficient to study treatment options in DLB is not easy.  This makes the current study an important one.  Additional clinical trials have also found support for rivastigmine, galantamine and memantine for DLB.  However, there is likely to be a paucity of clinical trials for DLB in the future relative to the number of trials in Alzheimer's dementia. 

Individuals with additional interest in this clinical trial can access the free full-text of the study by clicking on the PMID link below.

Photo of cinnamon teal duck is from the author's files.

Photo of Lewy bodies from the Wikipedia Commons file authored by Dr. Andreas Becker

Mori E, Ikeda M, Kosaka K, & Donepezil-DLB Study Investigators (2012). Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial. Annals of neurology, 72 (1), 41-52 PMID: 22829268

Top Ten Brain Post 2012: #7 Tinnitus and Depression

The number seven highest viewed Brain Post blog from 2012 was a review of research related to tinnitus and depression.

In this study, a survey of adults in Sweden examined a series of medical and psychological problems over a period of time.

Individuals with rating of severe tinnitus also endorsed high levels of depression.  Increased depression severity tended to be associated with increased ratings of tinnitus severity.

The authors noted depression and tinnitus appear to "share core symptomatology or stem from a common etiolog

Because depression is a treatable problem, clinicians would be wise to screen for depression in tinnitus clinical populations.  

Photo of manger scene from the author's files.