MDS Evidence-Based Medicine Review: Non-Motor Symptoms of PD (2011)

This is a condensed summary of the 2011 International Parkinson and Movement Disorder Society Evidence-Based Medicine Review (Seppi et al.), updating the 2002 review with 54 new Level I studies through December 2010. This was the first MDS EBM review dedicated to non-motor symptoms. Interventions are classified by efficacy (efficacious, likely efficacious, unlikely efficacious, nonefficacious, insufficient evidence) and clinical practice implication (clinically useful, possibly useful, investigational, not useful).

1. Depression and Depressive Symptoms

Thirteen new studies were published, with varying definitions of depression (DSM-IV major depressive episode, minor depression/dysthymia, or rating scale thresholds). All recommendations are for short-term treatment (≤3 months).

Dopamine Agonists

• Pramipexole: Efficacious — clinically useful (3 studies; Barone 2010: 296 patients, 12-week RCT showed BDI improvement P = .01; path analysis confirmed 80% of antidepressant effect was direct, not mediated by motor improvement; Barone 2006: higher remission rate vs sertraline [61% vs 27%, P = .006]; Rektorova 2003: superior to pergolide on MADRS)
• Pergolide: Insufficient evidence (no placebo arm) — not useful (safety: cardiac fibrosis risk)

Tricyclic Antidepressants

• Nortriptyline: Likely efficacious — possibly useful (Menza 2009: superior to placebo on HDRS-17 [P = .002, effect size 1.20] and to paroxetine on response rate [53% vs 11%])
• Desipramine: Likely efficacious — possibly useful (Devos 2008: significant MADRS improvement vs placebo [P = .002]; AEs twice as common as citalopram/placebo)
• Amitriptyline: Insufficient evidence (no placebo arm) — investigational

SSRIs

• Citalopram: Insufficient evidence (2 small studies with divergent results) — investigational
• Sertraline: Insufficient evidence (positive in 2 studies but no placebo arm) — investigational
• Paroxetine: Insufficient evidence (1 negative small study) — investigational
• Fluoxetine: Insufficient evidence (2 studies without placebo arm) — investigational

Other Antidepressants

• Atomoxetine (NRI): Insufficient evidence (negative primary outcomes, but improved cognition [MMSE P = .003] and daytime sleepiness [ESS P = .001]) — investigational
• Nefazodone (SARI): Insufficient evidence — not useful (unacceptable hepatotoxicity risk; withdrawn in several countries)
• Omega-3 fatty acids: Insufficient evidence (1 small positive study) — investigational
• rTMS: Insufficient evidence (2 studies with methodological concerns) — investigational

2. Fatigue

Not previously reviewed. Two agents studied; neither exceeded 8 weeks.

• Methylphenidate: Insufficient evidence (positive trends on FSS and MFI but no direct between-group comparison; multiple testing concerns) — investigational (also insufficient safety evidence; controlled substance with abuse potential)
• Modafinil: Insufficient evidence (2 small studies, no improvement on MFI) — investigational

3. Impulse Control Disorders

Not previously reviewed. Only pathological gambling had qualifying RCT data.

• Amantadine: Insufficient evidence for pathological gambling (Thomas 2010: crossover study, n=17; dramatic 80% reduction in G-SAS on amantadine vs no change on placebo [P < .001], but small sample and low quality) — investigational
• No RCTs met criteria for other ICDs (hypersexuality, compulsive buying, punding)

4. Dementia

Not previously reviewed in the original 2002 review. Eight RCTs evaluated acetylcholinesterase inhibitors and memantine; none exceeded 24 weeks.

Acetylcholinesterase Inhibitors

• Rivastigmine: Efficacious — clinically useful (Emre 2004: large RCT, n=541; ADAS-Cog improvement of 2.1 points [vs 0.7 worsening on placebo]; ADCS-CGIC clinically meaningful improvement in 19.8% vs 14.5%; all secondary endpoints positive; nausea/vomiting most common AEs; tremor reported more often [10.2% vs 3.9%] but UPDRS-III not significantly different)
• Donepezil: Insufficient evidence (3 small studies with conflicting results; 2 showed some positive signals [MMSE, CIBIC+] but failed primary endpoints in others) — investigational
• Galantamine: Insufficient evidence (1 open-label low-quality study) — investigational

NMDA Receptor Antagonist

• Memantine: Insufficient evidence (3 studies with conflicting results; Aarsland 2009 showed CGI-C benefit [P = .03] with more pronounced response in PDD than DLB, but most secondary outcomes negative; Emre 2010 showed benefit at 12 weeks but not at 24 weeks) — investigational

5. Psychosis

Atypical Antipsychotics

• Clozapine: Efficacious — clinically useful (confirmed by 2 new comparator studies [Morgante 2004, Merims 2006] and open-label extensions of prior placebo-controlled RCTs; low doses effective [mean 13–26 mg/day]; safety: acceptable risk with specialized monitoring — agranulocytosis risk 0.38% requires regular blood count monitoring)
• Quetiapine: Insufficient evidence (6 studies; 4 placebo-controlled RCTs all negative; no significant improvement on any psychosis measure vs placebo across studies) — investigational (acceptable risk without specialized monitoring; sedation and occasional motor worsening reported)
• Olanzapine: Unlikely efficacious — not useful (3 RCTs: no improvement in psychosis measures + significant motor worsening on UPDRS-II and UPDRS-III vs placebo in all studies; unacceptable risk of motor deterioration; also carries risk of mortality and cerebrovascular events in elderly dementia patients)

6. Orthostatic Hypotension

• Fludrocortisone: Insufficient evidence (1 low-quality crossover study; n=13 completers; COMPASS-OD improved [P < .02] but not all patients had documented OH) — investigational
• Domperidone: Insufficient evidence (same study; COMPASS-OD improved [P < .04]) — investigational
• Midodrine, droxidopa, dihydroergotamine: Insufficient evidence (no qualifying RCTs in PD) — investigational

Nonpharmacological measures should be tried first: head-up bed tilt, meal fragmentation, physical counter-maneuvers, increased salt and water intake, compression stockings.

7. Sexual Dysfunction

• Sildenafil: Insufficient evidence (1 small crossover study, n=12 PD patients; significant improvement in ability to achieve/maintain erection but no between-group PD-specific statistics provided) — investigational (caution with autonomic dysfunction and OH; contraindicated with nitrates)

8. Gastrointestinal Dysfunction

Constipation

• Macrogol (polyethylene glycol): Likely efficacious — possibly useful (Zangaglia 2007: n=57; 80% responder rate vs 30% placebo [P < .001]; 8-week study)

Nausea/Vomiting (L-dopa Associated)

• Domperidone: Likely efficacious (unchanged from 2002) — possibly useful
• Metoclopramide: Insufficient evidence — not useful (unacceptable risk of motor worsening in PD)

9. Sialorrhea (Drooling)

Not previously reviewed. Four new RCTs.

Botulinum Toxin

• BTX-B (RimabotulinumtoxinB): Efficacious — clinically useful (2 RCTs: consistent large effect sizes on drooling rating scales [P < .05 to P < .0001]; 2500–8000 units injected into parotid and/or submandibular glands; AEs: mild dry mouth, transient swallowing difficulties)
• BTX-A (OnabotulinumtoxinA): Efficacious — clinically useful (Lagalla 2006: n=32; significant VAS improvement [P < .0001] and reduced objective saliva [P < .0001]; 50 units per parotid gland)
• Both require specialized monitoring (trained physicians for injection technique)

Anticholinergic Agents

• Glycopyrrolate (oral): Efficacious for 1-week treatment — possibly useful (Arbouw 2010: 95% quality score; 39% responded [≥30% improvement] vs 4% on placebo [P = .021]; BUT only 1-week treatment periods studied)
• Ipratropium bromide spray (sublingual): Insufficient evidence (no significant effect in 1 small study) — investigational

10. Sleep Disorders

Insomnia

• Levodopa/carbidopa CR at bedtime: Insufficient evidence (1 study; trend for increased sleep time [P = .07] but no improvement in sleep latency or awakenings) — investigational
• Pergolide: Insufficient evidence (actually worsened sleep efficiency by 7% vs 0.6% on placebo [P = .049]) — not useful (ergot safety issues)
• Eszopiclone: Insufficient evidence (negative primary TST outcome; some positive secondary endpoints) — investigational
• Melatonin (3–5 mg): Insufficient evidence (improved subjective sleep quality in 1 study but small effect on objective measures) — investigational (acceptable risk without monitoring)
• Melatonin (50 mg): Insufficient evidence (significant but minimal [10 min] increase in sleep time) — investigational (insufficient safety data at this dose)

Excessive Daytime Sleepiness

• Modafinil: Insufficient evidence (3 RCTs with conflicting ESS results; no consistent improvement on objective measures [MWT, MSLT]) — investigational (safety concerns: rare severe rash including SJS, psychiatric AEs)

REM Sleep Behavior Disorder

• No RCTs met inclusion criteria — no evidence-based recommendations possible
• Clonazepam and melatonin are widely used in clinical practice based on open-label data

Domains Without Qualifying RCTs

The following non-motor domains had no randomized controlled trials meeting inclusion criteria:

• Anxiety disorders
• Apathy
• Impulse control disorders other than pathological gambling
• REM sleep behavior disorder
• Sweating disorders
• Urinary dysfunction

Reference

Seppi K, Weintraub D, Coelho M, et al. The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the Non-Motor Symptoms of Parkinson's Disease. Mov Disord. 2011;26(Suppl 3):S42-S80. doi: 10.1002/mds.23884