Depression in the Early Stages of Huntington Disease

Epping, Eric A.; Paulsen, Jane S.

doi:10.2217/nmt.11.45

Cited by 83 publications

(64 citation statements)

References 43 publications

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“…Some emotional changes, such as depression and lack of interest, seem to emerge in stage 2 of HD (i.e. after the onset of motor impairments), suggesting that these symptoms are a side effect of the diagnosis or neurological symptoms of HD, but not caused by the disease itself (Epping & Paulsen, 2011). Alternatively, irritability, anger/aggression, and anxiety are present prior to motor symptom onset, indicating that these emotional changes are key features of the disease (Dewhurst, Oliver & Trick, 1969; Berrios et al, 2002; Kirkwood et al, 2002; Duff et al, 2007; Marshall et al, 2007; Vassos et al, 2007; Bouwens, et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Increased irritability, anxiety, and immune reactivity in transgenic Huntington’s disease monkeys

Raper

Bosinger²,

Johnson³

et al. 2016

Brain, Behavior, and Immunity

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Although the most notable clinical symptoms of Huntington’s disease (HD) are motor disturbances and brain atrophy, other symptoms include cognitive dysfunction, emotional and hormonal dysregulation. Emotional dysregulation (irritability, anger/aggression, and anxiety) and increased inflammation are early emerging symptoms which can be detected decades before the onset of motor symptoms in HD patients. Despite the advances in understanding the genetic causes of HD there is still no cure or preventative treatment. Thus, to better understand the pathogenesis of HD and develop effective treatments, a holistic understanding of HD is needed, as well as animal models that replicate the full spectrum of HD symptoms. The current study examined the emotional, hormonal, and gene expression responses to an acute stressor of adult male transgenic HD rhesus monkeys (HD, n=2) as compared to wild-type controls (n=2). Results revealed that HD monkeys expressed increased anxiety and irritability/aggression as compared to controls. Reactive cortisol response to the stressor was similar between groups. However, HD monkeys exhibited increased pro-inflammatory cytokines and higher induction of immune pathway genes as compared to controls. Overall, results reveal that HD monkeys exhibit these early emerging symptoms of HD and may be an effective animal model to facilitate the development of new therapeutics for HD patients.

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Section: Discussionmentioning

confidence: 99%

Increased irritability, anxiety, and immune reactivity in transgenic Huntington’s disease monkeys

Raper

Bosinger²,

Johnson³

et al. 2016

Brain, Behavior, and Immunity

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“…Depression is the most common mood disorder in HD and has an early onset in about 50% of symptomatic patients [298, 299]. In fact, suicide among HD patients is 4 to 6 fold higher than in the general population [10, 300].…”

Section: Dopamine Modulationmentioning

confidence: 99%

“…Neuroimaging studies of HD patients have implicated the PFC in these same psychiatric symptoms [298]. It already is clear from work on the R6/2 mouse model that information processing in the PFC is altered in HD mice [57].…”

Section: Dopamine Modulationmentioning

confidence: 99%

Dysregulation of Corticostriatal Connectivity in Huntington’s Disease: A Role for Dopamine Modulation

Rangel‐Barajas

Rebec

2016

JHD

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Aberrant communication between striatum, the main information processing unit of the basal ganglia, and cerebral cortex plays a critical role in the emergence of Huntington’s disease (HD), a fatal monogenetic condition that typically strikes in the prime of life. Although both striatum and cortex undergo substantial cell loss over the course of HD, corticostriatal circuits become dysfunctional long before neurons die. Understanding the dysfunction is key to developing effective strategies for treating a progressively worsening triad of motor, cognitive, and psychiatric symptoms. Cortical output neurons drive striatal activity through the release of glutamate, an excitatory amino acid. Striatal outputs, in turn, release γ-amino butyric acid (GABA) and exert inhibitory control over downstream basal ganglia targets. Ample evidence from transgenic rodent models points to dysregulation of corticostriatal glutamate transmission along with corresponding changes in striatal GABA release as underlying factors in the HD behavioral phenotype. Another contributor is dysregulation of dopamine (DA), a modulator of both glutamate and GABA transmission. In fact, pharmacological manipulation of DA is the only currently available treatment for HD symptoms. Here, we review data from animal models and human patients to evaluate the role of DA in HD, including DA interactions with glutamate and GABA within the context of dysfunctional corticostriatal circuitry.

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“…The mechanisms by which biological and social factors result in depression remain poorly understood. While standard treatments for depression are recommended for depressed HD gene carriers (Epping et al 2011), empirical support is limited (Rosenblatt 2007; Phillips et al 2008; Holl et al 2010). Greater understanding of depression in this population promises to improve identification and treatment, and ultimately may reduce the prevalence of depression in gene carriers and its negative impact.…”

Section: Introductionmentioning

confidence: 99%

Characterization of depression in prodromal Huntington disease in the neurobiological predictors of HD (PREDICT-HD) study

Epping

Mills

Beglinger

et al. 2013

Journal of Psychiatric Research

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Depression causes significant morbidity and mortality, and this also occurs in Huntington Disease (HD), an inherited neurodegenerative illness with motor, cognitive, and psychiatric symptoms. The presentation of depression in this population remains poorly understood, particularly in the prodromal period before development of significant motor symptoms. In this study, we assessed depressive symptoms in a sample of 803 individuals with the HD mutation in the prodromal stage and 223 mutation-negative participants at the time of entry in the Neurobiological Predictors of HD (PREDICT-HD) study. Clinical and biological HD variables potentially related to severity of depression were analyzed. A factor analysis was conducted to characterize the symptom domains of depression in a subset (n=168) with clinically significant depressive symptoms. Depressive symptoms were found to be more prevalent in HD mutation carriers but did not increase with proximity to HD diagnosis and were not associated with length of the HD mutation. Increased depressive symptoms were significantly associated with female gender, self-report of past history of depression, and a slight decrease in functioning, but not with time since genetic testing. The factor analysis identified symptom domains similar to prior studies in other populations. These results show that individuals with the HD mutation are at increased risk to develop depressive symptoms at any time during the HD prodrome. The clinical presentation appears to be similar to other populations. Severity and progression are not related to the HD mutation.

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Depression in the Early Stages of Huntington Disease

Cited by 83 publications

References 43 publications

Increased irritability, anxiety, and immune reactivity in transgenic Huntington’s disease monkeys

Increased irritability, anxiety, and immune reactivity in transgenic Huntington’s disease monkeys

Dysregulation of Corticostriatal Connectivity in Huntington’s Disease: A Role for Dopamine Modulation

Characterization of depression in prodromal Huntington disease in the neurobiological predictors of HD (PREDICT-HD) study

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