Depressive symptoms were strikingly prevalent among study participants. Given the degree of morbidity associated with depression in the general population and the demonstrated efficacy of treatment12
, it seems reasonable that all adolescents and adults with XXY should be routinely screened for depressive symptoms and appropriately referred for evaluation and treatment. According to the United States Preventative Services Task Force, the specific screening tool utilized may be less important than making the effort to screen individuals12
. Even a simple 2-question tool assessing for depressed mood and anhedonia had 96% sensitivity and 57% specificity, which was similar to several other tools32
. Such screening could logically be suggested as part of the evaluation during any clinical encounter. Providers who tend to see individuals with XXY on a recurring basis (e.g. Internists, Family Practitioners, and Endocrinologists) are more likely to have established good rapport and thus be able to elicit important symptoms. On the other hand, specialists seeing a patient for the first time may be better positioned to notice important signs and symptoms that developed gradually over time and thus were missed by clinicians who have an established relationship with the patient. Simple screening tools could even be administered by community-based health outreach providers and/or self-administered, as long as opportunities for formal medical evaluation and management are readily available.
The considerable proportion of study participants indicating a clinically significant level of depressive symptoms makes us question whether depressive symptoms are a primary component of XXY, or secondary due to consequences of living with XXY, or both. A study by van Rijn et al. found that men with XXY experience difficulty with social-emotional cues, experience increased emotional arousal in response to emotion-inducing events, but have problems identifying and verbalizing these emotions, in comparison to the general population33
. These can be considered possible risk factors for depressive symptoms or other psychiatric problems, and may help to explain the prevalence of depressive symptoms among this study’s participants. Research aimed at understanding the causes of social cognitive processing and emotion regulation problems found in individuals with XXY have attributed these problems to structural brain differences2,34
and over-expression of genes on the X chromosome that may be involved in social cognition and susceptibility to psychiatric disorders4,35,36
Moreover, an association between hypogonadism and depression has been suggested, although study results are inconsistent. One population-based study reported a hazard ratio of 4.2 for depression among hypogonadal men37
. Similarly, another population-based study found that depressed men were 1.55–2.71 times more likely than those without depression to have low testosterone levels38
. However, a follow-up of the Massachusetts Male Aging Study found that serum testosterone levels alone were not significantly associated with depressive symptoms, except among men with shorter CAG repeat lengths in the androgen receptor gene39
. Results of randomized, controlled intervention trials are also mixed, with some studies of testosterone replacement in hypogonadal men showing improved mood40,41
, while at least one study found no significant difference in mood after testosterone replacement42
Although the association between hypogonadism and depression may not be fully understood, it can be challenging to distinguish between depressed mood and hypogonadism in light of their shared symptoms. The CES-D captures symptoms specific to depression, including feelings of guilt, hopelessness, helplessness, and psychomotor agitation, but these symptoms may not be entirely distinct from symptoms of low mood that have been, inconsistently, found in hypogonadal men. This study was not designed to distinguish between hypogonadism and depression. While we are not able to identify the underlying cause of reported symptoms, our data show a high level of self-reported symptoms that are clinically consistent with one or both diagnoses.
In addition, we were able to identify several psychosocial factors that were significantly associated with higher levels of depressive symptoms. The relationship between emotion-focused coping strategies and depressive symptoms is consistent with the findings of the initial studies of the WCC-R24,25
. Among the three study populations included in the validation study (medical students, spouses of individuals with Alzheimer’s disease, and psychiatric outpatients), the investigators found a significant positive correlation between wishful thinking and depression, and a significant negative relationship between problem-focused coping and depression. Moreover, wishful thinking accounted for the greatest variance in depression (14–21%)24
. In this study, wishful thinking accounted for only 9% of the variance in depressive symptoms. Instead, problem-focused coping, followed by self-blame accounted for 27% and 23% of the variance in depressive symptoms, respectively. Other studies of individuals with chronic illnesses43
and genetic conditions44
have also suggested that greater use of emotion-focused coping strategies, particularly wishful thinking and avoidance, is associated with increased self-reported depressive symptoms.
Despite this noted correlation, emotion-focused coping is not considered to be inferior to problem-focused coping. Rather, coping effectiveness is often based on whether a chosen coping strategy matches an individual’s appraisal of the stressor28
. More specifically, when a person appraises the stressor as alterable or controllable, problem-focused coping is most often effective. When a “good fit” between a person’s appraisal and chosen coping strategy is achieved, individuals are expected to experience fewer psychological symptoms than when there is lack of a good fit28,45
. Our finding of a positive correlation between emotion-focused coping and depressive symptoms raises concern that these strategies are not associated with effective coping, perhaps because emotion-focused coping strategies are not best aligned with the types of stressors encountered by study participants. This highlights a potential opportunity for health care providers to intervene.
Coping Effectiveness Training (CET) is one intervention that teaches individuals how to choose a coping strategy according to the extent to which a stressor can be changed45
. This principle may be extended to the use of social support to enhance coping efforts. For example, individuals are asked to create a list of their support persons according to the type of support provided. By identifying individuals who generally provide problem-focused support, such as advice-giving, as well as individuals who provide emotion-focused support, such as listening, individuals are better equipped to choose a support person according to the type of support sought. CET has been shown to effectively increase individuals’ coping efficacy and to reduce depression and anxiety45,46
The relationship between perceived negative consequences and depressive symptoms is also supported by other studies that have shown that negative illness appraisals are associated with depressive symptoms47
. Illness appraisals may serve as another potent target for interventions aimed at decreasing depressive symptoms, facilitating adaptation, and enhancing quality of life. Brief interventions aiming to challenge unhelpful beliefs and to enhance feelings of control among individuals with chronic medical conditions have been shown to lower concern and anxiety among study participants when compared to controls who received no intervention 48,49
. Challenging perceptions of negative consequences and teaching individuals to distinguish between aspects of their life that are associated with XXY or not associated with XXY are cognitive-behavioral based strategies that health care providers can use to intervene. For example, an individual could be asked to create a list categorizing aspects of his life that are associated with XXY or not associated with XXY. This list can be used to challenge an individual’s perceptions about the implications of his condition and to increase awareness of those aspects of his life that are not entirely associated with his diagnosis, and, therefore, are within his control and amenable to change. Other interventions aimed at improving control include helping individuals to take more active roles in medical decision-making, facilitating disclosure decision-making, and helping individuals to develop positive responses to stressful situations so that they feel better prepared for, and more in control of, future interactions.
The positive relationship between perceived stigma and depressive symptoms found in this study is consistent with what has been reported in other studies of individuals living with genetic conditions44,50
. Common strategies used to cope with stigma include secrecy, avoidance, withdrawal (three emotion-focused coping strategies), and education of others (a problem-focused coping strategy)44,50
. Emotion-focused coping strategies may “fit” appraisals of stigma considering that individuals are unable to control the way other people perceive them. However, the use of secrecy and/or withdrawal has been associated with depressive symptoms44
, whereas education of others has been shown to be an effective coping strategy in studies of individuals with achondroplasia51
, Marfan syndrome44
, and craniofacial abnormalities52
. Interventions aimed at facilitating effective coping with stigma for individuals with XXY, such as through problem-focused coping strategies like education of others, may impact self-reported levels of depressive symptoms. That said, language-based learning disabilities may limit the effectiveness of educating others as a potential coping strategy for this population.
Finally, the correlation between greater importance of having children and greater self-reported depressive symptoms was not surprising given that infertility poses a major threat to accomplishing this life goal. Studies of men with infertility have found that these men experience considerable emotional distress53
. Although advances in artificial reproductive techniques are offering hope and options to individuals with XXY, the strong emotional responses that accompany infertility must not be ignored. Health care providers should be aware that individuals with XXY who are of reproductive age may be at greater risk for depressive symptoms.
A limitation of this study was that clinical data was not collected. Karyotype, medications, and symptoms were not confirmed by medical record review. Participants were not asked, and did not report any history of psychiatric diagnosis or use of psychiatric medications or testosterone replacement therapy. In addition, the cross-sectional study design allows conclusions to be drawn regarding correlations between variables, rather than to temporal relationships and causal pathways. We were unable to calculate a response rate because we do not know how many potential participants saw the study advertisements. It is possible that individuals who participate in support groups differ from those who do not. Self-selection introduces a potential bias to our findings but there is conflicting thought about whether those who respond are more likely in need of support or doing sufficiently well to have the interest to participate in a study. The results of this study are not generalizable to the entire population of adolescents and adults with XXY. Although the study population was largely non-Hispanic Caucasian, our large sample size, range of ages, and international participation increase the external validity of our findings.