Objective: To identify and analyze psychiatric manifestations acting as early indicators in individuals carrying the HTT gene mutation during the premanifest stage, evaluating their prevalence and association with proximity to motor clinical diagnosis.

Background: Huntington’s disease (HD) is characterized by motor, cognitive, and psychiatric manifestations. Although diagnosis relies on motor signs, symptoms such as depression, apathy, and irritability may appear years earlier during the prodromal phase and may reflect early neurobiological changes.

Method: A systematic literature review was conducted to identify studies evaluating psychiatric manifestations in individuals with premanifest HD carrying the expanded CAG mutation. Searches were performed in PubMed, Scopus, and Google Scholar using terms related to Huntington disease, psychiatric symptoms, and prodromal or premanifest stages. Longitudinal, cohort, and cross-sectional studies including adult mutation carriers without motor diagnosis were considered eligible. Data on psychiatric manifestations and their association with proximity to motor onset were extracted and qualitatively analyzed. Ten studies met the inclusion criteria

Results:

The included studies comprised over 1,500 participants, primarily premanifest mutation carriers. Psychiatric manifestations were frequently reported before motor onset. The most common symptoms were depression, apathy, irritability, and anxiety, while obsessive-compulsive symptoms, aggression, and psychotic manifestations were less frequent. Several longitudinal studies showed that the prevalence and severity of psychiatric symptoms increase as individuals approach motor onset. Apathy and depressive symptoms were most consistently associated with cognitive decline and functional impairment.

Conclusion: Psychiatric manifestations are common in the premanifest stage of HD and may precede motor symptoms by several years. Apathy and depression appear to be the most consistent symptoms and may represent early clinical features of disease progression. Further longitudinal research is needed to determine their predictive value as early markers of disease progression.

References: Duff K, Paulsen JS, Beglinger LJ, Langbehn DR, Stout JC, Ross CA, et al. Psychiatric symptoms in Huntington’s disease before diagnosis: the PREDICT‑HD study. Biol Psychiatry. 2007;62(12):1341‑6.

Epping EA, Paulsen JS, Queller S, Long JD, Jiang H, Kaufer DI, et al. Characterization of depression in prodromal Huntington disease in the Neurobiological Predictors of HD (PREDICT‑HD) study. J Psychiatr Res. 2013;47(10):1313‑21.

Epping EA, Long JD, Paulsen JS, Carlozzi NE, Queller S, Guttman M, et al. Longitudinal psychiatric symptoms in prodromal Huntington’s disease: a decade of data. Am J Psychiatry. 2016;173(2):184‑92.

Martinez‑Horta S, Perez‑Pardo P, Gil JM, Pagonabarraga J, Pascual‑Sedano B, Campolongo A, et al. Neuropsychiatric symptoms are very common in premanifest and early stage Huntington’s disease. Parkinsonism Relat Disord. 2016;22:52‑8.

Fritz NE, McCarthy J, Poudel GR, Epping EA, Paulsen JS. Apathy predicts rate of cognitive decline over 24 months in premanifest Huntington’s disease. Psychol Med. 2021;51(9):1552‑60.

Carroll JB, van Duijn E, Bates GP, Tabrizi SJ, Scahill RI. A systematic review and meta‑analysis of depression and apathy frequency in adult‑onset Huntington’s disease. Neurosci Biobehav Rev. 2023;142:104857.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/psychiatric-manifestations-in-premanifest-huntingtons-disease-as-early-indicators-of-motor-onset-a-systematic-review/