A Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Safety and Efficacy of the 5-Hydroxytryptophan on REM Sleep Behavior Disorder, Levodopa-Induced Motor Complications and Neuropsychiatric Disorders in Idiopathic Parkinson's disease.

Background and purpose: Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by the motor symptoms of bradykinesia, tremor, rigidity and postural instability. However, non-motor symptoms such as depression, apathy and rapid eye movement sleep behavior disorder (RBD) are also frequent and play a significant role. Several studies have indicated that altered serotonergic neurotransmission may contribute to the motor and non-motor features commonly associated with PD such as levodopa-induced motor complications, sleep disorders, apathy and depression.The 5-Hydroxytryptophan (5-HTP) is the intermediate metabolite of L-tryptophan in the production of serotonin. Studies in other populations indicate that 5-HTP might be useful in the treatment of depression, chronic headache and sleep disturbances. Furthermore, a recent study demonstrated the antidyskinetic effect of 5-HTP in the rat model. To date, there has been inconsistent research on the use of 5-HTP in PD. The purpose of this study was to compare the effects of 5-HTP to placebo on RBD, depression, apathy and levodopa-induced motor complications in patients with PD. Materials and Methods: A single-center, randomized, double-blind placebo-controlled cross-over trial was employed; 36 subjects were subsequently enrolled into the study, 32 subjects completed the 16-week protocol. Patients received placebo and 50 mg of 5-HTP daily in a cross-over design over a period of 4 weeks. There were 4-weeks washouts between treatments. For the assessment of efficacy on the RBD, video-polysomnography (v-PSG) was performed at baseline, and home-based polysomnography was performed at weeks 4 and 12. For the assessment of efficacy on the overall functional status, depression, apathy and motor complications, the UPDRS (parts I, II, III), Beck Depression Inventory II (BDI-II), 21-item version of Hamilton Depression Rating Scale (HDRS21), Apathy Scale (AS), Unified Dyskinesia Rating Scale (UDyRS), UPDRS IV, Wearing-Off Questionnaire (WOQ-19) and the self-reported 24-hour home dyskinesia diaries were respectively obtained at baseline and weeks 4, 8, 12 and 16 (T-end). Primary efficacy outcomes were the effect of 5-HTP on the the percentage of REM Sleep without Atonia (RSWA) and other polysomnographic sleep measures compared to placebo as well as the comparison of 5-HTP to placebo in mean change from baseline to weeks 4, 8, 12 and 16 in total score on the AS, BDI-II, HDRS21, UDysRS, UPDRS IV and WOQ-19. Results: Repeated measures analysis revealed a significant improvement of levodopa-induced dyskinesias (LIDs) and depressive symptoms during the 50 mg 5-HTP treatment compared to placebo as assessed by the UDyRS, UPDRS-IV and HDRS21. Treatment with 5-HTP significantly reduced the percentage of time in stage N3 compared to placebo. Furthermore, the 5-HTP produced a marginal, non-significant reduction in arousal index, wake after sleep onset (WASO) as well as an increase in total percentage of REM sleep. There were no other significant effects of 5-HTP at dose 50 mg compared to placebo on nighttime sleep parameters evaluated in our study. Conclusions: This study provides preliminary evidence of clinical benefit with 5-HTP for treating LIDs and depressive symptoms in PD. Larger studies with a longer treatment duration need to corroborate these early findings.