Impulse Control Disorders in Parkinson's Disease: Building Physician, Patient Awareness

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Clinicians should ask about ICDs at all clinical visits, as they can occur years after initiating treatment.
Clinicians should ask about ICDs at all clinical visits, as they can occur years after initiating treatment.

Impulse control disorders (ICDs) are increasingly becoming an area of focus in the treatment of Parkinson's disease (PD), due to their emergence in many patients as the result of dopaminergic therapies including dopamine agonists (DAs) and less commonly, levodopa.

The most frequent types of ICDs include 4 behaviors: compulsive eating, excessive gambling, compulsive shopping, and compulsive sexual behavior. Other ICD-related behaviors seen less frequently include punding (stereotyped, repetitive, non-goal directed behaviors or excessive hobbyism) and dopamine dysregulation syndrome (DDS) (compulsive PD medication overuse).1,2

Epidemiologic research indicates that the main ICDs are most likely the result of chronic DA use, particularly at higher dosages, while DDS is more likely to be triggered by chronic use of shorter-acting, higher-potency dopaminergic medications including apomorphine and levodopa.1,3,4

Daniel Weintraub, MD, professor of psychiatry at the Perelman School of Medicine at the University of Pennsylvania, Parkinson's Disease and Mental Illness Research, Education and Clinical Centers (PADRECC and MIRECC) in Philadelphia, and co-investigator in the DOMINION study,5 told Neurology Advisor that the dopamine connection to the expression of ICDs is well established, given the strong association with dopaminergic therapy in the context of PD treatment and imaging studies of the dopamine system. “All short-acting dopamine agonists seem to have the same impact,” Dr Weintraub said, “and there is a suggestion, although not clearly established, that long-acting oral agents or patch formulations may be less likely to cause ICDs compared with short-acting agents.”

Prevalence

The reported occurrence of the primary ICDs associated with PD is extremely broad, with prevalence estimates ranging from 3.5% to 42.8%.6 The DOMINION trial4 found an estimated rate of 17% in patients with PD taking DAs, while a 2016 cross-sectional study by Vela, et al7 reported that DA treatment was associated with a 7-fold increased risk of developing an ICD in patients with early-onset PD.

The ICARUS (Impulse Control disorders And the association of neuRopsychiatric symptoms, cognition and qUality of life in ParkinSon disease) study, reported recently by Antonini, et al6 in the Journal of Neurology, Neurosurgery and Psychiatry, found the prevalence of all 4 ICD types remained stable across the 2-year study period.

ICARUS was a large-scale, prospective, multicenter observational study of the prevalence of individual ICD behaviors in a cohort of 1069 patients with PD who had been pharmacologically treated for a minimum of 6 months.5 The investigators also reported that while the prevalence of ICDs related to the use of DAs and levodopa were similar (26.7%, 64/240 vs 25%, 56/211), the combination of DAs and levodopa was associated with a higher rate of ICDs (30.1%, 179/594).6

Amygdalar Mechanisms

Impulse control disorders are thought to be related to impaired function of decisional impulsivity associated with rapid, disinhibited decision-making, rather than motor impulsivity.2  They may comprise a number of features including delay discounting (an attraction to small, immediate rewards over larger, delayed ones), reflection impulsivity (rapid decision-making), risk taking, reduced sensitivity to adverse outcomes, and response conflict.2

Jennifer Goldman, MD, MS, FAAN, of Rush Medical Center in Chicago, Illinois investigated the roots of neuropsychiatric issues in PD, including cognitive dysfunction and ICDs.7 One proposed mechanism she found was amygdalar dysfunction that could affect behavioral signals to trigger fear, anxiety, and compulsive behaviors.8,9 

Known as the pain-pleasure center, the amygdala generates rapid, unconscious emotional and cognitive responses to sensory input.8,9 One of the primary functions is fear modulation — evaluation of situations for the initiation of the fight-or-flight response. These subliminal fear signals are processed unconsciously using visual pathways that have been shown to overlap with emotional pathways that may heighten arousal to both real and imagined (dissociated) stimuli.8,9

The inhibitory mechanisms in the amygdala involve mostly gamma-aminobutyric acid (GABA) neurons, which are largely regulated by dopamine. “Physiological dopaminergic modulation of the amygdala's response to emotional processing follows an inverted U-shaped curve,” Dr. Goldman wrote.8,9 Affective behaviors including ICDs are then triggered in stressful situations as a result of dopaminergic disinhibition.10,11 In healthy individuals, this response was shown on magnetic resonance imaging (MRI) to be initiated in the amygdala by levodopa.12

Impulse control disorders are among the positive or “plus” symptoms of amygdalar dysfunction, believed to be triggered by D2/D3 dopaminergic overstimulation in predisposed individuals.8 An interesting physiological finding by Biundo, et al13 pointed to a potential cause of a plus dopaminergic response when they discovered significant increases in gray matter (GM) volume on MRI in the left amygdala of patients with PD exhibiting ICDs.13 These patients also demonstrated cortical thinning of the frontostriatal circuitry, along with reduced volume of the corpus collosum and nucleus accumbens.12 The investigators hypothesized that preserved amygdalar function in these individuals might put them at higher risk of ICDs when they are treated with levodopa or dopamine agonist therapies.13

Treatment of ICDs

The main treatment for ICDs is stopping drug therapy or dose reduction, Dr. Weintraub suggested. “Deep brain stimulation (DBS) — which can lead to dose reduction — psychopharmacology (antidepressants, naltrexone), and psychotherapy (cognitive behavioral therapy), may all be beneficial,” he said.

The majority of patients with PD who take DAs or levodopa do not go on to develop ICDs, and the dopaminergic effects may not appear immediately in patients who do, so monitoring is an important part of PD therapeutic management. The potential for ICDs is generally not discussed early in the course of PD, Dr Weintraub explained, but usually comes up later, after treatment is initiated. “A patient really should be notified of the possibility of developing an ICD before initiating any dopaminergic treatment for PD, particularly dopamine agonists,” he said. “And then it should be asked about at all clinical visits, as ICDs can have their onset years after initiating treatment.”

References

  1. Weintraub D, David AS, Evans AH, et al. Clinical spectrum of impulse control disorders in Parkinson's disease. Mov Disord. 2015;30:121-127.
  2. Voon V, Napier TC, Frank MJ, et al. Impulse control disorders and levodopa-induced dyskinesias in Parkinson's disease: an update. Lancet Neurol. 2017;16:238-250.
  3. Zhang G, Zhang Z, Liu L, et al. Impulsive and compulsive behaviors in Parkinson's disease. Front Aging Neurosci. 2014;6:318.
  4. Weintraub D, Nirenberg MJ. Impulse control and related disorders in Parkinson's disease. Neurodegener Dis. 2013;11:63-71.
  5. Weintraub D, Koester J, Potenza MN, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol. 2010; 67: 589–95.
  6. Antonini A, Barone P, Bonuccelli U, et al. ICARUS study: prevalence and clinical features of impulse control disorders in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2017;88:317-324.
  7. Vela L, Martinez Castrillo JC, Garcia Ruiz P, et al. The high prevalence of impulse control behaviors in patients with early-onset Parkinson's disease: A cross-sectional multicenter study. J Neurol Sci. 2016;368:150-154.
  8. Goldman JG. Neuropsychiatric issues in Parkinson disease. Continuum. 2016;22:1086-1103.
  9. Diederich NJ, Goldman JG, Stebbins GT, et al. Failing as doorman and disc jockey at the same time; amygdala dysfunction in parkinson's disease.  Mov Disord. 2016;3:11-22.
  10. Janek PH, Tye KM. From circuits to behavior in the amygdala. Nature. 2015:517:284-292.
  11. Pape HC, GABAergic neurons; gate masters of the amygdala, mastered by dopamine. Neuron. 2005;48:877-879.
  12. Delaveau P, Salgado-Pineda P, Micallef-Roll J, et al. Amygdala activation, modulated by levodopa during emotional recognition processing in healthy volunteers: a double-blind, placebo-controlled study. J Clin Psychopharmacol. 2007;27:692-697.
  13. Biundo R, Weis L, Facchini S, Formento-Dojot P, et al. Patterns of cortical thickness associated with impulse control disorders in Parkinson's disease. Mov Disord. 2015;30:688-695.
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