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The pathobiology of depression in Huntington’s disease: an unresolved puzzle

  • Neurology and Preclinical Neurological Studies - Review Article
  • Published:
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Abstract

Huntington’s disease (HD) is an autosomal-dominant progressive neurodegenerative disease that manifests with a triad of symptoms including motor dysfunctions, cognitive deficits, and prominent neuropsychiatric symptoms, the most common of which is depression, with a prevalence between 30 and 70%. Depressive symptoms occur in all stages of HD, beginning in presymptomatic HD gene carriers, and are strongly associated with suicidal ideation and suicidality, but their relationship with other clinical dimensions in HD is controversial and the underlying pathophysiology is poorly understood. Analysis of the available literature until November 2023 concerned the prevalence, clinical manifestations, neuroimaging, transgenic models, and treatment options of HD depression. While it was believed that depression in HD is due to psychosomatic factors in view of the fatal disease, studies in transgenic models of HD demonstrated molecular changes including neurotrophic and serotonergic dysregulation and disorders of the hypothalamic–pituitary–adrenal axis inducing depression-like changes. While relevant neuropathological data are missing, recent neuroimaging studies revealed correlations between depressive symptoms and dysfunctional connectivities in the default mode network, basal ganglia and prefrontal cortex, and changes in limbic and paralimbic structures related to the basic neurodegenerative process. The impact of response to antidepressants in HD patients is controversial; selective serotonin reuptake inhibitors are superior to serotonin-norepinephrine reuptake inhibitors, while electroconvulsive therapy may be effective for pharmacotherapy resistant cases. Since compared to major depressive disorder and depression in other neurodegenerative diseases, our knowledge of the molecular basis in HD depression is limited, further studies to elucidate the heterogeneous pathogenesis in this fatal disorder are warranted.

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Abbreviations

HD:

Huntington’s disease

polyQ:

Polyglutamine

CAG:

Cytosine–adenine–guanine

HTT:

Huntingtin protein

FA:

Fractional anisotropy

DMN:

Default mode network

tg:

Transgenic

HPA:

Hypothalamic–pituitary–adrenal

SERT:

Serotonin transporter

BDNF:

Brain-derived neurotrophic factor

SSRIs:

Selective serotonin reuptake inhibitors

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Acknowledgements

The author thanks Mr. E. Mitter-Ferstl for secretarial and editorial work.

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The study was funded by the Society for the Promotion of Research in Experimental Neurology, Vienna, Austria.

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  1. Institute of Clinical Neurobiology, Alberichgasse 5/13, 1150, Vienna, Austria

    Kurt A. Jellinger

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Jellinger, K.A. The pathobiology of depression in Huntington’s disease: an unresolved puzzle. J Neural Transm (2024). https://doi.org/10.1007/s00702-024-02750-w

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