One of the most troubling features of PWS is the high risk of mental illness in adults with the syndrome. Although a considerable amount has been written on obsessive-compulsive traits, stubbornness and maladaptive behaviors associated with PWS, less is known about the incidence and course of mental illness.
In the past few years, a number of studies have suggested a high frequency of mental illness and psychosis in the adult PWS population, but, to date, most of these have studied just a relatively small number of individuals with PWS [Boer 2002], [Verhoeven 2003], [Vogels 2003]. A more comprehensive analysis is reported in the January issue of the Journal of Intellectual Disability Research, and provides a solid basis for beginning to understand and find effective treatments for mental illness in PWS.
The article, The course and outcome of psychiatric illness in people with Prader-Willi syndrome: implications for management and treatment Soni et al., includes more than 100 adults with confirmed PWS in the United Kingdom. The authors used a survey-based assessment of psychiatric illness, with follow-up in home visit and evaluation of participants who reported psychiatric problems. They followed patients over a period of up to 2.5 years.
Of 119 people with confirmed PWS surveyed (~ 69% deletion, 28% UPD, 3% imprinting mutation or translocation), 46 individuals (24 deletion, 22 UPD) were initially identified as potentially positive for mental illness (this did not include individuals with only behavioral problems such as obsessive-compulsive disorder, for example). Thus, approximately 28% of those with deletion and 65% of those with UPD reported some history of mental illness. This is consistent with earlier studies that also showed an increased frequency of mental illness in all PWS adults compared to the general population, and a particular susceptibility to affective psychotic illness in those with PWS by UPD.
In looking more closely at the type of mental illness, the authors followed up with patients who screened positive on the questionnaire to assess their psychiatric illness. Non-psychotic depressive illness and depressive psychosis represented the diagnoses most often found in those with PWS by deletion; each was diagnosed at a rate of slightly higher than 10% of all individuals with deletion. Individuals with UPD most often received a diagnosis of bipolar illness with psychotic symptoms. None of the individuals were diagnosed as having schizophrenia. Patients with a psychiatric diagnosis continued to be followed over the period of the study, and individuals with PWS by UPD were more prone to have recurrent episodes of mental illness.
The authors also went on to look at what medications were being taken. In general, psychotropic medication (drugs that alter brain function [mood, perception, emotion, consciousness, behavior]) worked fairly well. Most depressive illness was being treated with antidepressants (most often serotonin reuptake inhibitors, SSRIs, such as Prozac), and these seemed to work well. Those with psychotic symptoms were treated with antipsychotic drugs (different patients were taking different drugs). The downside of these were their side effects, 15-25% of individuals had undesirable side effects including weight gain, tremor, confusion and sedation. Nevertheless, the drugs appeared to be effective; individuals on antidepressants and antipsychotics were less likely to have a recurrence of disease than those who were not put on these drugs.
Unexpectedly, those individuals with bipolar disorder who were put on "mood stabilizing" drugs were more likely to than those who did not receive the drugs to have a recurrence. Whether there represents a true relationship is hard to determine; there were a very small number of patients (n=6) and some of these individuals had had several episodes of illness. Thus, the individuals put on those mood-stabilizers may represent the toughest cases - those most likely to recur regardless of what medication they are taking. This finding is very intriguing, however, and warrants further investigation to determine if mood stabilizers are beneficial in PWS. Based on the study, the authors suggest it may be worth investigating whether mood-stabilizing drugs that don't work on the GABAergic systems (such as lithium) might be more effective in PWS.
The authors also tried to determine what seemed to precipitate incidences of psychotic illness, and looked at number of potential contributors. The most important factor seemed to be the occurrence of a "life event" stressor in the life of the individual. Loss of a close family member (either permanently, through death, or having someone move away), and the possibility of losing a family member (life threatening illness) have been previously reported as precipitating events to psychosis in people with PWS. Interestingly, none of the patients in this study had undergone any formal psychotherapy. This is consistent with the (perhaps unfortunate) fact that individuals with intellectual disability are most often treated with medication only. Given the apparent susceptibility of this population to stressful life events, it would be of interest to determine if formal counseling/psychotherapy might assist them in coping with stress, thereby reducing the frequency and/or intensity of episodes of mental illness. It was also unclear how aggressively physical problems, which might have contributed to at least some cases of mental illness, were ruled out in the patients studied. The PWS population has high pain tolerance as well as susceptibility to a variety physical problems such as sleep apnea, hypothyroidism, etc. These features coupled with comparatively weak expressive language skills could conceivably mask underlying physiological contributions to mental illness. As the field moves forward, it will be important to continue to consider physiological factors that might contribute to mental illness in individuals with PWS.
One final note of caution, in two cases, abrupt withdrawal of anti-obesity drugs that work through the serotonin system (fenfluramine in one case, sibutramine in another) seemed to trigger psychotic illness.
One much needed area of investigation that arises from this and other studies of psychiatric illness in PWS is how duplication of the maternal PWS region as in UPD may make individuals more susceptible to bipolar disorder. There is some evidence that a gene on chromosome 15 near the PWS region (CHRNA7) may be involved, although at this point it's just a suggestion. Clearly, there's much to be done. Additional long term studies in other PWS populations are needed to confirm and extend these findings. Further, work to understand the underlying biology of these psychiatric problems is needed to direct the rational choice of drugs that are likely to be most effective.