Mood Activation as a Complication of Gonadal Steroid Therapy in Prader-Willi Syndrome

Glenn B. Berall1, Janice L. Forster2, Linda M. Gourash2

Prader Willi Syndrome Service, North York General Hospital, Toronto ON¹; Pittsburgh Partnership: Specialists in Prader Willi Syndrome, Pittsburgh PA²

Introduction: The antidepressant effect of estrogen in neurotypical individuals is well documented, especially in the peri-menopausal period. The authors note that the combination of hormone replacement therapy (HRT) and medication in the selective serotonin reuptake inhibitor (SSRI) class may function as a stimulus to mood activation in PWS. Mood activation presents with mood elevation, lability, irritability, impulsivity, and/or increased goal directed behavior. Although mood activation can be an early manifestation of Bipolar Mood Disorder, it has also been associated with the use of antidepressants and stimulant medications. Unlike Bipolar Mood Disorder that requires management with mood-stabilizing agents together with environmental interventions, mood activation is preferentially treated by withdrawing the agent producing the iatrogenic effects. The identification of the root cause for mood activation is the first step toward effective management.

Results: The authors present case reports exemplifying the finding of mood activation resulting from the concurrent administration of HRT and SSRI medication. Case 1 (GB) is a 21 year-old woman with PWS who had been receiving an SSRI (paroxetine). She was placed on a low dose birth control pill for HRT. After 3 weeks time, a pattern of changed behavior was noted with increased energy, alertness, distractibility, assertiveness and goal-directed activity (perseverative questioning, food seeking). She was not irritable or tearful. She consumed more time and effort from her mother with whom she lived. Case 2 (LG) is a 49 year old woman with PWS referred for consultation for severe behavior problems. She was taking fluoxetine. Her history revealed that on 2 separate occasions when HRT was started, her behavior deteriorated with severe agitation and aggression. Each time the HRT was discontinued, there was an improvement in her behavior.

Discussion: Gonadal hormone replacement has been recommended in PWS for management of osteoporosis. It has also been used to further the development of secondary sexual characteristics to improve self-esteem and social assimilation. SSRI medications are often selected for the management of symptoms of anger, impulsivity, moodiness and excessive/repetitive behaviors occurring among individuals with PWS.

Estrogen produces antidepressant effects by acting as a neuromodulator of serotonin. In the presence of progesterone, it enhances the expression of tryptophan hydroxylase, the rate-limiting step in the synthesis of serotonin. It also down-regulates the expression of the gene for the serotonin reuptake transporter (SERT). SERT is responsible for the re-uptake of serotonin from the synaptic cleft into the neuron, so less SERT means more available serotonin. The anti-depressant efficacy of SSRI medications has been attributed to their blockade of the serotonin transporter, also resulting in an increase in available serotonin in the synaptic cleft. Therefore, a combination of estrogen and SSRI medication results in the augmentation of the antidepressant effect through serotonin function. Further, studies in rat models suggest that the results of estrogen augmentation on behavior equivalents of mood occur more quickly than the antidepressant effects of the SSRI medications.

Although the precise mechanism of mood activation in PWS and other special populations has not been elucidated, the augmentative effects of SSRI medication and gonadal steroids provide another etiological pathway for consideration. The clinician must proceed cautiously when using SSRI medication or gonadal steroid replacement therapy in persons with PWS, and especially when using these agents in combination.