ORIG I NALRESEARCH

PAPER

Hyperphagia and self-mutilation inPrader-Willi syndrome:Psychopharmacological issues

J.A. Yaryura-Tobias, M.S. Grunes, M.E. Bayles, and F. NezirogluDepartment of Biopsychosocial Research Institute for Biobehavioral Therapy and Research, Great Neck,NY, USA

ABSTRACT. This study focused in the treatment of two major Prader-Willi symptoms: hyperphagia and self-injurious behavior (SIB). Four patients participated in a four-year study withmonthly follow-ups. Patients lived in a behaviorally structured environment, and were treatedwith selective serotonin reuptake blockers and phenothiazines. Psychopharmacological intervention improved SIB symptoms, but was ineffective to control appetite satiation.(Eating Weight Disord. 3, 163-167, 1998). ©1998, Editrice Kurtis

INTRODUCTION

Prader-Willi syndrome (PWS) is a rare con-genital disorder (1, 2) affecting approximately1 in 10,000 newborns.

It is characterized by an array of physicaland mental symptoms. The most importantsymptoms are infantile hypotonia, shortstature, hypogonadism, chromosomalabnormalities, mental deficiency, and aninsatiable hunger drive or hyperphagiaresulting in extreme obesity (3). The chroso-mal aberration is characterized by an inter-stitial deletion of chromosome 15q11-13 inone half of patients.

PWS may present several interesting neuropsychiatric features: hyperphagia,food hoarding, self-injurious behavior(SIB), seizures, anxiety, psychosis, tempertantrums, severe aggressive behavior,obsessiveness, compulsiveness, and rigidbehavior (4). Due to the assortment of men-tal symptoms and behaviors (5), and vari-able cognitive strength (6), a psychiatricclassification for Prader-Willi Symptoms(PWS) was suggested (7).

This is a four-year study, focusing in thetreatment of two major symptoms: hyper-phagia and severe SIB. For this purposepartial or selective serotonin reuptakeinhibitors (SSRIs) were used. The use ofSSRIs is justified by their role in eating dis-orders, hyperphagia, impulse control,obsessionality, compulsiveness, skin pick-ing, and SIB (8-13).

METHODS

There were 4 patients, two females (ages 38and 28), and two males (ages 43 and 45who met ICD-9 diagnostic criteria for PWS.

Patients exhibited PWS symptoms including hyperphagia, obesity, short staturehypotonia, sexual immaturity, mental retardation (N=3), and SIB. All patients residedin a structured living environment staffedby personnel trained in caring for patientswith PWS. In addition to direct care staffthe residents were followed by psychologists, psychiatrists, and other medical doctors on a regular basis. All patients were onspecial low caloric diets, and behavior plansto control hyperphagia and impulsivebehaviors, notably, SIB. Food was locked incupboards, and monitored closely.

These clinical observations are presentedin a case review format, after four years omonthly follow-up.

Case 1A is a 38 year-old female who has been diagnosed with PWS and mild mental retardation. A was first diagnosed with PWS at theage of 27, although the physical manifestations of the syndrome were present sinceearly childhood. Past developmental historyreveals that A was the product of an uncomplicated pregnancy, but with a difficult delivery that caused cyanosis and almost deathShe remained in the hospital for one weekand received oxygen. A’s neonatal period

Key words: Prader-Willi, self-injuriousbehavior, SSRIs,neuroleptics.Correspondence: Dr. J.A. Yaryura-Tobias,Department ofBiopsychosocial ResearchInstitute for BiobehavioralTherapy and Research, Suite#102, 935 NorthernBoulevard, Great Neck, NY,11021 USA

163

PWS psychopharmacology

was compounded by poor feeding with aweak suckling reflex. Neurodevelopmentalmilestones were reached within normal limits.Her medical history showed a series ofproblems including borderline diabetes,underactive thyroid, cellulitis, edema andobesity. Past and current behavioral obser-vations revealed an obsession with food,hyperphagia, and the emergence of aggres-sive or defiant behaviors in order to obtainfood. Another behavioral symptom wassevere compulsive self-mutilation character-ized by deep skin picking, causing facial andlimbs sores and ulcerations.

A is observed rigid and unyielding in herdaily schedule, especially during the timesshe has to eat. She demands excessive reas-surance, and has difficulty acceptingchanges in her daily schedule, that is shehas difficulties to shift tasks (a commonobsessive-compulsive symptom).

A trial of thioridazine 20 mg/po/per day,and fluoxetine 40 mg/po/per day, wereadministered. Following a period of 2months of therapy, aggressive, iterative andnon compliant behavior improved withsome decrease in SIB. However, within 5months, anger, uncooperative behavior, andSIB recurred. Consequently, fluoxetine wasdiscontinued and a trial of clomipramine 100mg/po/per day was initiated in conjunctionwith thioridazine 60 mg/po/per day in divid-ed dose. After the presence of seizures dueto clomipramine adverse effect, the samewas replaced by fluvoxamine 50 mg/po/perday. Nonetheless, fluvoxamine causeddrowsiness that impaired patient’s ability tofunction, and had to be discontinued. A wasstabilized on thioridazine 60 mg/po/per dayin divided dose. On this present regimen Ais doing well with intermittent relapses ofaggressive behavior, and sporadic skin picking.

Case 2B is a 28-year old female with PWS. B’s pastdevelopmental history indicates that herumbilical cord was wrapped around herneck at birth, and this may have resulted insome minimal brain injury. The diagnosis ofPWS was made at the age of three. HerIntellectual Quotient is average.

B exhibits an insatiable craving for foodincluding a history of stealing food fromothers or rummaging through garbage cansin order to obtain food. If she is preventedfrom searching food, she would display

aggressive acting out to emphasize her needfor food. She engages in excessive skin pick-ing and scratching of the forehead, chin,arms and legs which causes open sores. Inaddition, B has been picking and digging foryears at a deep unhealed appendectomyscar. Also, she repeatedly does rectal dig-ging to remove feces; an act that became amajor problem. Other compulsive behaviorsinclude verborrhagia, and repetitive ques-tions to the staff and peers pertaining thecontents of her obsessions and compulsions.B describes herself as anxious, and she hasbeen known to speak, at a high pitch, con-tinuously for as much as 40 minutes at atime. This symptom seems to represent asevere anxious profile. Considerable distressoccurs with any change in her routine, andshe puts demands on the staff, reiteratinghow things ought to be arranged for her.Like in case A, she does not admit shifting,when performing a task.

After five months of fluoxetine 40mg/po/day, obsessions decreased, rectal dig-ging was completely eliminated, althoughSIB remained uncontrollable. Medicationside-effects included migraines.

Following an increase in facial picking,clomipramine 25 mg/od was added to theregimen, but discontinued three monthslater due to lack of efficacy. Presently, a trialof thioridazine 25 mg/po/day, and fluoxetine20 mg/po/day, resulted in an improvementof her behavior, albeit SIB and agitationwere still reported. Recently, cognitive andbehavioral therapy were added to her med-ication. This combination helped substan-tially to reduce her picking behavior.Recently, a 7-month trial of naltraxone 50mg/po/per day, in addition to thioridazineand fluoxetine, failed to further improve hersymptoms.

Case 3C, a 43 year-old male, weighed 6.4 ounces atbirth, and his neonatal period was complicat-ed by a poor suckling and feeding reflex. Atage 2, C was diagnosed mentally retarded.At age 6 he was diagnosed with PWS.Medical history indicates sleep apnea,bronchial asthma, hypothyroidism andessential arterial hypertension.

C exhibits an obsession with food, and inthe past he has reportedly panhandled formoney in order to obtain food.

Other symptoms presented are visual andauditory hallucinations, aggression, hyper-

164

J.A. Yaryura-Tobias, M.S. Grunes, M.E. Bayles, et al.

phagia, and compulsive behavior such asconstantly rearranging furniture. Someperseveration of verbal responses is alsoreported.

He engages in SIB such as chewing on hisfingernails until they are partially bitten off.His left nostril is missing due to repeatedSIB. On the American Association onMental Deficiency (AAMD) adaptive behav-ior scale, C scored at the 60th percentile ona measure of unacceptable or eccentrichabits, at the 70th percentile on a measureof stereotyped and odd behavior, and at the80th percentile on a measure of SIB.

The administration of clomipramine 200mg/po/per day was prescribed over thecourse of his illness. Initially, symptomsdecreased only slightly, but gradually hispsychotic symptoms and self-harm ren-dered improvement.

Case 4D, a 45-year old man, was diagnosed withPWS with mild to moderate mental retar-dation at the age of 10. He is the product ofa full term pregnancy. Developmental mile-stones were delayed, whereas the neonatalperiod was complicated by poor coordina-tion and inability to grasp objects or sit-up.

D is grossly obese due to an insatiableappetite and inability to control his compul-sion to eat. He tends to lose his temper andengage in aggressive acts, especially inrelation to diet control and daily hygiene.He has been hospitalized for psychoticepisodes in which he was self-abusive andunresponsive to staff redirection. D has anurge to bite and scratched himself to thepoint of injury. He has been observed asecholalic, engaging in frequent doublechecking, and suffering from bed wettingand encopresis. Compulsive behavior andunsteady gait were reported, to the pointthat he uses a cane. Frequent falling withloss of consciousness, mood swings, anxi-ety and aggressive behavior were alsoreported. Although an electroencephalo-gram failed to show a seizure disorder pat-tern, he was placed on an anticonvulsantmedication.

A trial of paroxetine 20 mg/po/per day,carbamazepine 1000 mg/po/in four divideddoses and hydroxyzine 100 mg/po/per daywas ineffective. Discontinuation of thesemedications was followed by a trial ofclomipramine 25 mg/po/per day, combinedwith sertraline 100 mg/po/per day.

Clomipramine was replaced by fluoxetine.For the past year D has been maintained onfluoxetine 40 mg/po/per day, in addition tovalproate 50 mg/po/per day to substitute forcarbamazepine. Although D reportedfatigue, improvement in behavior resulted.Overall, behavior in general and compul-siveness in particular have improved. Gait ismore steady and self-mutilation decreased.

DISCUSSION

Treatment results indicate that SSRI’s,namely fluoxetine, can be, in moderation,an effective measure to treat SIB andaggressive behavior, although for otherauthors fluoxetine usually is very good tocontrol skin picking and behavioral prob-lems (14). The therapeutic action of fluoxe-tine, and SSRIs in general, relies on ahypothesis proposing that low serotonin (5-HT) levels is associated with impulsive,aggressive and SIB behavior, whereasthese substances increase 5-HT availability(10). However, SIB treatment for PWS islimited to anecdotal reports from severalauthors. A systematic, larger and rigorousstudy has yet to be done.

Patients AC and D showed improvementwith pharmacological approaches alone.Patient D failed to improve on carba-mazepine, although there is a report indi-cating otherwise (15). Patient D improvedon valproate.

Patient B showed improvement after cog-nitive and behavioral therapy were addedto pharmacotherapy. However, this patientfailed to improve SIB, following the com-bined administration of Naltrexone and flu-oxetine, although there is an early reportshowing marked improvement in weightcontrol, picking, and behavior (5).

Nonetheless, SSRIs were ineffective inreducing hyperphagia in any of the cases.

Several variables should be analyzed try-ing to explain the difficulties encounteredto treat these patients: 1) symptom com-plexities, 2) etiological factors, 3) age at thetime of treatment, and 4) psychopharmaco-genetics.

Patients displayed a complex symptoma-tology due to the expected extensive bodilyinvolvement in PWS. Our work was gearedto treat two major symptoms present in ourpatients: an uncontrollable urge to eat andsevere self-harm. Within this symptom

165

PWS psychopharmacology

mosaic, hyperphagia, SIB, hypogonadism,and short stature may suggest a combinedhypothalamic, pituitary, and amygdala par-ticipation, cerebral locations related to thesymptoms listed above.

Inside this hypothalamic-pituitary axis,hyperphagia may be bound to an obsessivephenomenon associated to an eating disor-der. Of course, to say so, one puts PWSbinging phenomenon in a wider context (16).For example, binging reminds us of severaleating disorders observed in patients withOCD as a comorbid process (4), in theCompulsive-obsessive-mutilative syndrome,in primary anorexia nervosa and dysmenor-rhea as a major component (17), and in Gillesde la Tourette syndrome with anorexia ner-vosa (18).

However, hyperphagia, one importantvariable common amongst all 4 patientswith obsessive and compulsive features, didnot improve with SSRIs, that is with phar-macological agents known for its action onOCD. This observation speaks of hyperpha-gia and patient’s insatiability as a regulatorydeficit of the hypothalamic eating mecha-nism, rather than an OCD comorbid mecha-nism. Furthermore, one may explain thefast weight increase as a consequence ofhyperphagia, by accepting PWS as a meta-bolic disorder (15), or as a failure to regu-late satiation. Lack of reaction to controlhyperphagia may be explained in terms ofinconsistent therapeutic outcome to SSRIsin patients with PWS. Similar results arepartially seen in patients responses to SIBtreatment.

We did not find a specific drug as a thera-peutic common denominator, but ratherdrugs which acted on an individual basis. Inaddition, the administration of antipsychot-ic medication alone or combined (e.g., thior-idazine) could modify or neutralize SSRIsaction when given combined. However inpatients A and B, the addition of thiori-dazine improved symptoms as previouslyreported (19-21). Within this context, thereis some evidence indicating the inadvisabili-ty of using neuroleptics as an appetite sup-pressant drug in PWS (15). Our uneventherapeutic findings are partially corrobo-rated by the current literature.

In recent years, there have been severalreports specifying that psychopharmacologi-cal interventions may be helpful for PWSsymptoms (13). Stein et al (13) surveyedtreatment approaches and outcome of 347

patients with PWS. They found that 11.5% ofthe patients were administered an SSRI,6.9% were administered an antipsychotic,and 4.6% were given anticonvulsant. Ofthose given SSRI’s 17.5% improved withtheir hyperphagia, and 12.5% with skin pick-ing. On antipsychotics the percent improve-ment in hyperphagia and skin picking wereboth found to be at 20.8%. For anticonvul-sants 6.3% improved with their hyperphagia,and 12.5% with skin picking.

Anecdotal reports indicated that patientswith PWS responded favorably to SSRI, andspecifically, with fluoxetine, for severe behav-ior problems including hoarding and explo-sive outbursts (14). Bodfish and Madison (22)also found preliminary data in support of theefficacy of fluoxetine in the treatment of indi-viduals with mental retardation.

One may appraise the psychological pro-file of these patients that changes with thepassage of time, that causes symptom irre-versibility if the process is of long stand-ing. Therefore, our patient’s age (X=38.5)may indicate symptom chronicity, andthereby posing difficulties to a favorabletreatment outcome. It has been stated thatin PWS rapid changes in behavior increas-es with age and after puberty (9).Therefore, our expectations were perhapstoo optimistic.

Finally, an other aspect to consider is PWSpharmacological treatment from a psycho-genetic view point, that includes genes,drugs, and behavior (23), an approach wedid not consider.

We assume the vast mosaic of non-psychiatric and neuropsychiatric symptomsin PWS constitutes a caveat. This situationcauses the therapeutic design to fail, mostlydue to undesirable drug interactions.

Overall, we were pleased with the resultsof controlling self-harm, while we wereunable to considerably decrease hyperpha-gia. Much research still needs to be done inorder to determine the effectiveness ofdrug therapy for hyperphagia and SIB inpatients with PWS.

REFERENCES

1. Pettigrew A.L., Gollin S.M., Greenberg F.,Riccardi V.M., Ledbetter D.H.: Duplicationof proximal 15q as a cause of Prader-Willisyndrome. Am. J. Med. Genet., 28, 791-802,1987.

166

J.A. Yaryura-Tobias, M.S. Grunes, M.E. Bayles, et al.

2. Ledbetter H., Greenberg F., Holm V.A.,Cassidy S.B.: Conference report: second an -nual Prader-Willi syndrome scientific confer-ence. Am. J. Med. Genet., 28, 779-790, 1987.

3. Holm V.A.: The diagnosis of Prader-Willisyndrome. In: Holm V.A., Sulzbacher S.J.,Pipes P. (Eds.), Prader Willi Syndrome.Baltimore, University Park Press, 1981, pp.27-44.

4. Yaryura-Tobias J.A., Neziroglu F.:Obsessive-compulsive disorder spectrum:Pathogenesis, diagnosis, and treatment.Washington, D.C, American PsychiatricPress, Inc., 1997.

5. Curfs L.M.G., Verhulst F.C., Fryns J.P.:Behavioral and emotional problems inyoungsters with Prader-Willi syndrome.Genet. Couns., 2, 33-41, 1990.

6. Gabel S., Tarter R.E., Gavaler J., Golden W.L.,Hegedus A.M., Maier B.: Neuropsychologicalcapacity of Prader-Willi children: General andspecific aspects of impairment. AppliedResearch in Mental Retardation, 7, 459-466,1986.

7. Bartolucci G., Younger J.: Tentative classifi-cation of neuropsychiatric disturbances inPrader-Willi syndrome. J. Intellect. Disabil.Res., 38, 621-629, 1994.

8. Benjamin E., Buot-Smith T.: Naltrexone andfluoxetine in Prader-Willi syndrome. J. Am.Acad. Child Adolesc. Psychiatry, 32, 870-873, 1993.

9. Borghgraef M., Fryns J.P., Van Den BergheH.: Psychological profile and behavioralcharacteristics in 12 patients with Prader-Willi syndrome. Genet. Couns., 38, 141-150,1990.

10. Eichelmann B.: Catecholamines and aggres-sive behavior. In: Usdin E. (Ed.), Neurore gu -lators and Psychiatric disorders. New York,Oxford, 1977.

11. Insel T.R., Zohar J., Benkelfat C: Serotoninin obsessions, compulsions, and the controlof aggressive impulses. In: Whitaker-Azmita P.M., Peroutka S.J. (Eds.), The neu-ropharmacology of serotonin, New York,New York Academy of Sciences, 1990, pp.574-586.

12. Jimersen D.C., Lesem M.D., Hegg A.P:Serotonin in human eating disorders. In:Whitaker-Azmita P.M., Peroutka S.J., (Eds.),The neuropharmacology of serotonin, NewYork, New York Academy of Sciences, 1990,pp. 532-544.

13. Stein D.J., Keatings J., Zar H., Hollander E.:A survey of the phenomenology and phar-macotherapy of compulsive and compulsive-aggressive symptoms in Prader-Willi syn-drome. J. Neuropsychiatry Clin. Neurosci.,6, 23-29,1994.

14. Hellings J.S., Warnock J.K. : Self-injuriousbehavior and serotonin Prader-Willi syndrome.Psychopharmacol. Bull., 30, 245-250, 1994.

15. Tu J.B., Hartridge C., Izawa J.: Psycho -pharma cogenetic aspects of Prader Willi syn-drome. J. Acad. Child Adolesc. Psychiatry,31, 1137-1140, 1992.

16. Ballard C.G., Mohan R.N., McGibben L.,Kurian M.: The phenomena of “bingeing”. Ir.J. Psychol. Med., 9, 61-62, 1992.

17. Yaryura-Tobias J.A., Neziroglu F., Kaplan S.:Self-mutilation, anorexia, and dysmenor-rhea in obsessive compulsive disorder. Int.J. Eating Disord., 10, 47-57, 1995.

18. Yaryura-Tobias J.A.: Gilles de la Tourettesyndrome: Interactions with other neu-ropsychiatric disorders. Acta Psychiatr.Scand. 59, 9-16, 1979.

19. Aman M.G., White A.J: Thioridazine doseeffects with reference to stereotypic behav-ior in mentally retarded residents. J. AutismDev. Disord., 18, 3, 1988.

20. Singh N.N., Millichamp C.J.: Pharma -cological treatment of self-injurious behav-ior in mentally retarded persons. J. AutismDev. Disord., 15, 257-267, 1985.

21. Singh N.N., Winton A.S.: Behavioral moni-toring of pharmacological interventions forself injury. Applied Research in MentalRetardation, 5, 161-170, 1984.

22. Bodfish J.W., Madison J.T.: Diagnosis andfluoxetine treatment of compulsive behaviordisorder of adults with mental retardation.Am. J. Ment. Retard., 98, 360-367, 1993.

23. Elftheriou B.E.: Psychopharmacogenetics.New York, Plenum Press, 1975, pp 1-10.

167