Background
A growing literature describes the behavioral phenotypes of people with neurodevelopmental disorders, but not all neurodevelopmental disorders receive equal research attention. Down syndrome, for example, is understudied both in relation to rare, clinically severe disorders and to more prevalent conditions such as autism spectrum disorders, or attention deficit hyperactivity disorder [
1]. Not surprisingly then, research gaps are increasingly identified in the Down syndrome literature [
2,
3].
One salient research gap concerns co-occurring mental health disorders in Down syndrome and how these are manifested in different age groups [
2]. Older adults with Down syndrome, for example, are relatively well studied because of their increased risks of Alzheimer’s disease, attributed to the third copy and overexpression of the amyloid precursor protein gene on chromosome 21 (for a review, see Zigman [
4]). Depressive symptoms in this older age group have also been described, and careful evaluations are necessary to differentiate a depressive disorder from the early clinical signs of dementia [
5]. On the other end of the developmental spectrum, young children with Down syndrome appear to have lower overall rates of disruptive behaviors as well as distinctive social, motivational, and attention profiles [
6-
8]. In contrast to older adults or children, remarkably little is known about the behavioral or emotional disorders of adolescents or young adults with Down syndrome [
2,
3].
This research gap is an important one to fill as young adults with intellectual disabilities, including Down syndrome, are transitioning out of educational settings and entering adult service systems that are often more fragmented and less readily available [
9]. These young adults also leave pediatric care, and problems transitioning to adult medicine are associated with persistent health care disparities in the intellectual disability population [
10]. People with intellectual disability (ID) and psychiatric problems may be more sensitive or negatively impacted by life events [
11], further justifying the need for studies in the adolescent to young adult transitional period.
This study identified psychiatric diagnoses in 13- to 29-year-old adolescent and young adult patients with Down syndrome and other intellectual disabilities, but with an eye toward also addressing two inconsistencies in the Down syndrome literature. First, consistent with higher risks of psychopathology in the ID versus general population, early studies found that adults with Down syndrome were especially prone to depressive or anxiety disorders [
12-
15]. In contrast, recent reports suggest that while some adolescents or young adults may become more withdrawn or quiet over time [
16,
17], rates of depressive disorders are no higher in Down syndrome than others with intellectual disabilities [
18].
A second and related research discrepancy relates to the severity of problems as reflected in community versus clinic samples. Relative to others with intellectual disabilities, much lower rates of behavior or emotional problems are consistently found in non-referred, community samples of individuals with Down syndrome [
5,
18,
19]. Such studies find that impulsivity, aggressive, and disruptive behaviors are particularly low in Down syndrome and lessen over time [
16,
19,
20].
Studies of clinic or hospitalized patients with Down syndrome paint a different picture involving more severe or unusual psychiatric concerns. Prasher [
21], for example, identified ‘young adult disintegrative syndrome’ characterized by depression, withdrawal, and significant regression in cognitive, language, or motor functioning in an unspecified number of young patients with Down syndrome. Similarly, Devenny and Mathews [
22] conducted a medical chart review of 197 patients with Down syndrome and identified 14 adolescents with regressions in cognitive and adaptive skills, as well as with depression, aggression, compulsivity, and withdrawal. Finally, Charlot
et al. [
23] identified what they called ‘obsessional slowness’ in performing routine daily living skills in 11 young adult patients with Down syndrome. Motoric freezing and tics were also observed in these patients, who did not appear to lose skills but to perform them at a markedly slower pace, features strongly suggestive of catatonia.
These clinic observations warrant further study as they fall outside the scope of the usual Down syndrome phenotype and may provide new insights into the range of phenotypic expression in this syndrome. This preliminary study compares the types and correlates of psychiatric disorders in adolescent and young adult clinic patients with Down syndrome versus intellectual disabilities.
Discussion
This preliminary, descriptive study is the first to address a long-standing research gap on psychiatric disorders in adolescents and young adults with Down syndrome and other intellectual disabilities. Although not applicable to the population of those with ID or Down syndrome, the young patients in this study had high rates of such severe psychiatric conditions as psychosis, bipolar, mood, and impulse control disorders. Findings offer important insights into atypical aspects of the Down syndrome phenotype, with group and gender differences that encourage new avenues of future research.
Unexpectedly, psychosis NOS was seen in 35% of the 49 patients with Down syndrome, significantly higher than the 13% with psychosis in the ID group. An additional 8% of patients with Down syndrome had depression with psychotic features. Although the rate of psychosis in the ID group is consistent with previous clinical studies [
28,
29], psychosis is not generally reported in population-based or community samples of people with Down syndrome [
18]. Psychotic symptoms have, however, been reported in hospitalized or clinic adult patients with Down syndrome and in older adults with dementia. For example, auditory hallucinations were reported in 45% of 22 adult patients with Down syndrome and depression [
30], and Urv
et al. [
5] identified delusions or hallucinations in up to 79% of older adults over the age of 50 with possible or definite dementia. The present study, however, identified psychotic symptoms in a much younger cohort.
Two cautionary notes are in order about psychotic symptoms in people with Down syndrome or other IDs. First, some cognitive processes in people with intellectual impairments could easily be confused with delusions or hallucinations, but are instead consistent with mental age expectations and pre-operational levels of cognitive development [
31]. These processes include a blurring of what is real versus pretend, having fantasies or imaginary friends, and engaging in overly concrete or magical thinking. Second, persons with Down syndrome often talk or mumble to themselves. Glenn and Cunningham [
32] found that 91% of a sample of 77 young adults with Down syndrome either talked to themselves now or had done so in the past. Self-talk was often used to guide problem solving or revisit previous conversations and activities, and it was not related to social or behavioral problems. Both cognitive development and benign self-talk thus need to be taken into account when evaluating possible delusions or hallucinations in people with Down syndrome or ID.
Unexpectedly, females comprised a full 81% of Down syndrome patients with psychosis. Gender differences in psychosis are not found in the general population [
27], nor were they seen in our ID group. As such, the preponderance of psychosis in young women with Down syndrome may simply be a function of chance. On the other hand, we examined the 22 cases of major depression in adults with Down syndrome reported by Meyers and Pueschel [
15] and discovered that females comprised 70% of those with hallucinations.
Women with Down syndrome may be more susceptible to early aging, as well as premature menopause and reduced levels of estrogen [
33,
34]. Schupf
et al. [
35] found that women with Down syndrome and specific polymorphisms in the estrogen receptor gene 1 were three times more likely than women without these polymorphisms to develop Alzheimer’s disease. Although speculative, alterations in estrogen receptors and reduced estradiol availability may play a role in aberrant cognitive or emotional functioning in younger women with Down syndrome.
Relative to patients with ID, those with Down syndrome did not show higher rates of anxiety or depressive disorders. A well-controlled study of adults with Down syndrome who averaged 43 years of age also found rates of depression that were similar to others with ID [
18]. However, high rates of depression or depressive symptomatology have previously been reported in older adults with Down syndrome [
12-
15], including withdrawal, irritability, mutism, and urinary incontinence [
5,
18]. These symptoms require careful evaluation as they may also signal the beginning stages of dementia. Advancing age may thus be a risk factor for depression in Down syndrome, yet the course of depressive symptoms from young to older adulthood is largely unknown.
Prominent slowing was observed in 17% of the Down syndrome group, and only in those with psychosis, anxiety, or depression. It was common for these individuals to take hours to complete otherwise routine grooming or feeding activities, to passively refuse to engage in activities they previously enjoyed, and to have pronounced delays (up to 20 min) in responding to simple queries that they had previously mastered (for example, ‘What is your name?’, ‘What color are your socks?’). Charlot and colleagues [
23] attributed such ‘obsessional slowness’ in their patients to an extreme form of obsessive-compulsive disorder (OCD) and possible dopaminergic dysfunction.
However, none of the patients with marked slowing in our sample met criteria for OCD and instead bear a striking resemblance to two case reports of Down syndrome and catatonia reported by Jeb and Ghaziuddin [
36]. These adolescent females had withdrawal, hallucinations, blunted affect, posturing, and psychomotor slowing, and they responded well to conventional treatment for catatonia. On an intriguing historical note, in 1946, Rollins [
37] described ‘catatonic psychosis’ in 29% of 73 institutionalized adolescents and young adults with Down syndrome characterized by regression in speech, toileting and feeding skills, docility, inertia, apathy and withdrawal, motor rigidity, and unpredictable bouts of excitation. Although the diagnosis of catatonia may be underrecognized in contemporary psychiatric practice [
38], it is much more common in those with versus without intellectual disabilities [
39]. Future studies are needed that probe neurological, motor and physiological functioning in individuals with Down syndrome, and apparent catatonia.
Consistent with previous studies, impulse control disorders were more common in the ID versus Down syndrome group; these were the most frequently occurring diagnosis in our ID sample. Poor impulse control and aggressive behaviors in people with ID remain the leading reasons for caregivers to seek specialized care [
40,
41]. As in previous work, impulse control problems in our Down sample were more common in males and in adolescents versus young adults [
15,
19,
20,
30].
Relative to those with Down syndrome, the ID group had significantly higher rates of bipolar disorder (4% versus 29%, respectively). Relatively high rates of bipolar disorder have also been identified in other specialized psychiatric clinics for persons with ID, ranging from 26.5% to 42% of 200 and 166 patients with ID, respectively [
41,
42]. In contrast, studies conducted abroad find much lower rates of bipolar in ID samples, from 1% to 3% [
28,
43,
44], raising the possibility that ID studies in the US mirror the increase in bipolar disorder diagnoses among children or youth in the general population. Debates continue about the extent to which chronic irritability, impulsivity, and explosiveness are valid indices of bipolar disorder in children or youth [
45], or are instead subsumed under a new DSM-5 diagnosis ‘disruptive mood dysregulation disorder.’ Future research on bipolar diagnoses in youth with ID stands to benefit from these ongoing debates.
This study had several limitations. The sample size was relatively small, primarily because of our restricted age range and focus on patients in specialized psychiatric clinics. Second, clinicians did not utilize standardized psychiatric interviews. Even though clinicians were well trained in ID and also used a team approach, they may have overlooked concerns that are required probes in standardized interviews. Third, we were not able to obtain systematic data on the types or dosages of prescribed medications. Psychotropic medications have, however, been studied in much larger samples of people with ID and consistently show high levels of anticonvulsant and antipsychotic drug use relative to antidepressants or anxiolytics, as well as high rates of polypharmacy [
29,
46,
47]. Future large-scale studies are needed that differentiate psychotropic medication use in specific etiologies, including Down syndrome.
The study did not formally measure relations between psychiatric symptoms and specific life events. Anecdotally, we noted that many young adults with Down syndrome had graduated from high school but were then left with little or nothing to do during the day. These informal observations warrant further study, as isolation and a lack of stimulating cognitive, physical, or recreational activities are risk factors for poorer outcomes in typical aging, as well as in depression and dementia [
48,
49]. A final limitation is that the clinics were not set up to conduct in-depth medical evaluations. Even so, clinicians ruled out medical conditions that are known to contribute to emotional or behavioral problems in the ID population, such as undetected or untreated pain, constipation, reflux, poor sleep, low thyroid, and untreated infections [
50,
51].
Conclusions
Although clinic samples are not representative of broader populations, this study nonetheless highlights an urgent need for further research on psychiatric problems in youth and young adults with ID and Down syndrome. Work is especially needed on the high rates of apparent bipolar disorder in youth with ID, including the extent to which they respond to conventional bipolar treatment, have positive family histories of bipolar illness, or could instead be diagnosed with other disorders, including the new DSM-5 disruptive mood dysregulation disorder.
Future research is also needed on the pronounced withdrawal, psychosis, and apparent catatonia in some patients with Down syndrome. This research needs to identify the onset and course of such symptoms and their associations to aberrant neurologic, hormonal and neuroendocrine functioning, altered gene expression, acute or chronic illnesses, stressful life events, and inadequate environmental stimulation. From 1946 to today, different terms have been used to describe subsets of individuals with Down syndrome and severe clinical presentations, including catatonic psychosis, young adult disintegrative syndrome, depression, psychosis, catatonia, regression, and obsessional slowing. Although not well understood, research on these severe psychiatric presentations in youth and young adults stand to inform treatment options and add new dimensions to our phenotypic understandings of Down syndrome.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
ED conceived the study and took the leading role in analyzing data and drafting the manuscript. BS was the lead clinician at one of the study sites who evaluated the patients, drafted the case vignette, and prepared preliminary observations regarding patients with Down syndrome. BD, TF, and JF were lead clinicians at the second study site; all evaluated the patients with ID or Down syndrome. TF additionally added literature to a preliminary draft of the manuscript. BD and CB helped tabulate the patient diagnoses, and CB and JF assisted with extracting symptom data from charts. All authors read and approved the final manuscript.