Comparison of at risk individuals who carry the HD mutation with those who do not revealed no significant differences in terms of lifetime prevalence of psychiatric disorder. However, gene carriers did report a higher current prevalence of affective disturbance at the time of interview compared with non‐carriers, and both the prevalence and severity of these affective symptoms appeared to be related to proximity to clinical onset of HD.
Contrary to the present findings, previous studies have found low rates of current psychiatric disorder in individuals at risk from HD.10,13
A number of factors may explain these contrasting findings. Whereas previous studies have often excluded people with soft motor signs,10,12,13
we chose to include such individuals allowing us to investigate psychiatric symptoms across the whole preclinical period. We found prevalence rates most marked in individuals who were closest to clinical onset of HD. Moreover, inclusion of more broadly defined psychiatric criteria enabled us to identify increased prevalence of subthreshold disturbances in gene carriers that would otherwise have remained undetected by more formal diagnostic classifications.
Our findings allow us to comment on the temporal evolution of affective symptoms in HD. High rates of affective disorder were observed in people who were 6–10 years from onset, increasing in severity in those who were 1–5 years from onset, with a further marked increase in those who were closest to clinical onset. However, only individuals who were less than 1 year from clinical onset reported a significantly higher rate compared with non‐carriers. This clustering of affective symptoms around the time of motor onset is in keeping with some earlier reports. In a retrospective review of affected HD individuals, Shiwach7
found that the onset of all cases of major depression occurred in the 8 years preceding or following motor onset, with 33% of depression cases occurring (on average 4 years) before neurological onset. Watt and Seller11
also reported a clustering of minor depressive symptoms around the time of onset of motor chorea (using rather different criteria to our study), but attributed them to the stress of receiving a clinical diagnosis of HD. The present study extends these findings by demonstrating that depression remains highly prevalent even when knowledge of genetic status is not disclosed.
The nature of the observed affective changes deserves comment. In addition to depression, a large proportion of affective symptoms were recorded under the diagnostic entity of mania. However, these symptoms consisted principally of periods of increased irritability. Elevated mood, a core symptom of mania, was never reported, and associated manic symptoms were rarely observed. Moreover, unlike depression, irritability symptoms remained stable in relation to motor onset, both in terms of prevalence and severity, and did not converge to bipolar disorder. Although reports of mania have been described in HD, the precise nature is not clear, and given the present findings it is possible that what is being described is an increase in irritability. Irritability was present to some extent also in non‐carriers, suggesting that concerns of being at risk and life stressors may contribute to the occurrence of this symptom. However, the data suggest that this may not be a sufficient explanation. There was a non‐significant trend (p
0.06) for a higher frequency of irritability in gene carriers. The increase in irritability appearing up to 10 years before onset raises the intriguing possibility that this might reflect a prodromal change occurring even earlier than major affective disorder and extending for a substantial period of time before motor onset.
The present study sheds light on the aetiological mechanisms underlying psychiatric disorder in preclinical HD. It has been suggested that preclinical psychiatric symptoms arise from early expression of the HD gene.2,8
The finding that lifetime psychiatric symptoms were reported as frequently in individuals without the HD mutation as those with, contests this interpretation. Both gene carrier and non‐carrier groups reported high rates of major affective disorder compared with lifetime estimates of 8%,22
suggesting that higher rates of adverse life events or early social deprivation associated with a family history of HD may predispose some at risk individuals to develop depression. However, this observation should be interpreted with a degree of caution. A recent epidemiological study using an updated version of the CIDI found that the rate of affective disorder in a European population (14%) was similar to that observed in non‐carriers in the present study (15%).23
Although the present study was carried out in the same time period and used the same diagnostic classification (DSM‐III) as the American study,22
our participants may share more cultural characteristics with the population sampled in the European study.
In addition to the possibility of increased lifetime prevalence of psychiatric disorders, the present study shows that mood disorder is a salient characteristic of the prodromal stage of HD. The clear temporal relationship between symptoms of depression and the onset of neurological signs offers two interpretations. One possibility is that the high rate of depression observed close to clinical onset reflects an emotional response to increasing awareness of emerging motor impairment. Indeed, although cases of definite HD were excluded from the study, several participants displayed soft neurological signs on examination and could arguably have been aware of them. However, it is well recognised that, even in the early stages, HD patients lack subjective awareness of their movement disorder and that this denial of symptoms is likely to have a physiological, rather than a psychological, basis.24
The fact that subjects in our study requested a presymptomatic genetic test rather than a diagnostic test and, furthermore, that they all denied motor symptoms on interview, indicates that, at least on a conscious level, they were not aware of emerging motor deficits. Moreover, the finding that high rates of depression were also observed in patients who were further from clinical onset and had a normal neurological presentation argues against an explanation in purely reactive terms and suggests a common neural substrate for depression and motor impairment. The observation that affective symptoms may anticipate clinical motor onset by several years suggests that depression is an early manifestation of neuronal dysfunction. That subtle neuropathological changes can occur before any detectable motor impairment is supported by evidence from structural25,26
imaging studies as well as neuropathological investigations28
showing early changes in the striatum in presymptomatic HD gene carriers. Moreover, studies have linked depressive symptoms in HD to dysfunction of frontal‐striatal pathways29,30
implicated in reward mediated behaviours.31
The present findings also mirror our data showing that mild cognitive change represents an early feature of striatal dysfunction in preclinical HD.32
To our knowledge, this is the largest study to investigate psychiatric disorder in preclinical HD. The double blind design allowed direct comparison of gene carriers and non‐carriers, controlling for social factors and investigator bias. Subsequent follow‐up of gene carriers allowed us to document the evolution of psychiatric disorder across the preclinical period. The present study indicates that affective disorder is a salient characteristic of the prodromal stages of HD and highlights the strong temporal relationship between depression and onset of clinical motor symptoms. Longitudinal studies will be essential to further characterise the evolution of affective disorder as the disease progresses.