Wednesday, February 6, 2013

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

Tuesday, February 5, 2013

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

Monday, February 4, 2013

Oxytocin and Grandparent Attachment

I a previous post I summarized a review of the emerging research field of oxytocin and human attachment.

This research supports a key role for oxytocin in reproduction and parental infant bonding.   The above mentioned review emphasized the important role of gender, genetic and early environment in the effect individual human variation in oxytocin response.

One additionally related important research topic relates to the effect of ageing on oxytocin-related systems.  Huffmeijer and colleagues from Leidenand Eramus University recently published a review on this topic in the journal Gerontology.

The authors of this review note the importance of oxytocin in parent-infant bonding and argue by extension this system is probably important in grandparent-grandchild bonding.

However, the review notes there is a paucity of research focusing on the age-related effects on the human oxytocin system.  There is extensive data linking oxytocin with prosocial maternal and paternal behavior towards infants.  There is no research examining the role of the oxytocin system in grandparents.

The limited study of the animal human oxytocin system and ageing points to a few key findings:
  • Animal studies support a decreased level of oxytonergic activity with age--the results in humans on this area have been mixed
  • Older animals with reduced oxytocin activity still have a prosocial response to exogenously administered oxytocin
  • The brain amygdala-limbic system has rich neural connections with oxytocin-related neurons but  amygdala volumes decline with age (this effect is more pronounced in Alzheimer's disease)
  • With ageing, amygdala connectivity increases with frontal regions but decreases with posterior brain regions
  • Age-related amygdala changes may contribute to the decline in emotional recognition with age seen in humans

The authors conclude that the effect of oxytocin in older humans cannot simply be assumed to be the same as in younger adults.   Due to the effects of ageing, oxytocin response (and adverse effects) may be quite different in elderly humans.

Oxytocin research needs to include a focus on the elderly including grandparent-grandchild bonding.  Many children are primarily raised by their grandparents.  Understanding the dynamics of the oxytocin system in the elderly has practical implications for many families.

Readers with more interest in this topic are directed to the free full text manuscript that can be accessed by the PMID

Photo of reddish egret from the author's files.

Huffmeijer R, van Ijzendoorn MH, & Bakermans-Kranenburg MJ (2013). Ageing and oxytocin: a call for extending human oxytocin research to ageing populations - a mini-review. Gerontology, 59 (1), 32-9 PMID: 22922544

Friday, February 1, 2013

Oxytocin and Human Attachment

In a previous post, I summarized a recent review on the neuroscience of human attachment

This review highlighted research related to the human bonding and social interactions.  Attachment ability shows significant variability in humans with insecure attachment styles contributing to risk for some mental disorders.     

The neuroanatomical framework for social processing is being investigated with brain imaging techniques.

Hormonal factors including the role of oxytocin also play a key role in social processing.  

Kai MacDonald recently published a review of the prosocial role of oxytocin in attachment.  This review highlighted individual factors that influence variability in oxytocin response.

Molecular Model of Oxytocin
Oxytocin is a central nervous system nine amino acid peptide that has both central and peripheral effects.   Oxytocin can be administered through intranasal mist administration.

The biological effects of oxytocin are complex and include stimulation of uterine contraction during labor, stimulation of breast milk letdown during nursing and modulation of sexual arousal and response.

The effects of oxytocin in social interactions include:
  • increases in strength of human bonding
  • decreases in anxiety in social situations
  • increases in the trust in others 
  • increases in calmness and contentment in the presence of a mate

MacDonald notes that individuality in response to oxytocin can be separated into three categories.

Gender: Women appear to be more responsive to the effects of oxytocin.  This may be due to the role of estrogen.  The presence of estrogen upregulates oxytocin and oxytocin receptor production.  Oxytocin response in women is dependent on female hormonal phase with more response during periods of higher estrogen levels.  Administration of intranasal oxytocin has a stronger effect on increasing prosocial behavior in women compared to men. 

Genetic Variation in Oxytocin Receptor Gene and CD38: Genetic variability in the oxytocin receptor gene modulate response to oxytocin with some alleles linked to stronger and weaker responses.  Additionally, genetic variation in the ectoenzyme CD38 have similar effects.  CD38 contributes to the biologic process of oxytocin secretion.  Specific combinations of oxytocin receptor and CD38 genes may contribute to clinical deficits in attachment, stress response and anxiety.

Early Childhood Attachment Environment: Early traumatic experiences appear to impair the development of the oxytocin system.  This may be due to more general adverse effects on neuroplasticity.  Parents with a personal history of childhood abuse are less responsive to the prosocial effects of intranasal oxytocin.  Early traumatic experience may unfortunately contribute to lifelong attachment impairment through this epigenetic effect.

Future research in the role of oxytocin and the oxytocin receptor in a variety of mental disorders will be important.  Intranasal oxytocin clinical trials will be coming in anxiety disorders, stress disorders and disorders of social interaction such as autism and schizophrenia.  Understanding the factors associated with variability in oxytocin response will be key in interpreting the results of future research.

Readers with more interest in this topic can access the free full-text manuscript by clicking the PMID link below. 

Photo of blue heron from the author's files.

Molecular model from the Wikipedia Commons File authored by MindZiper.

Macdonald KS (2012). Sex, receptors, and attachment: a review of individual factors influencing response to oxytocin. Frontiers in neuroscience, 6 PMID: 23335876