Dopamine Agonists and Impulse Control Disorders in Parkinson’s

“Whenever you are immersed in compulsive thinking, you are avoiding what is. You don’t want to be where you are. Here, Now.” Eckhart Tolle

“Somewhere between obsession and compulsion is impulse.” Alexander Pushkin

Introduction: In the latest issue of Neurology (June, 2018), Dr. Corvol and collaborators in Paris, France, present the results of a long-term study (5 years) on impulse control disorders (ICDs) in Parkinson’s.  The results of this longitudinal study (which is defined as research that involves repeated observations of the same variables or measurements over a set time period) imply that movement disorder physicians may be underestimating the influence of dopamine agonists (DAs) on ICDs.  Their results show the occurrence of ICDs approached 50% in the study of 411 people-with-Parkinson’s (PwP), which is significantly higher than the report of >3,000 PwP (ICDs of 14-17%) by Dr. Weintraub et al. in Arch. Neurol. from 2010.  Aspects of the Corvol et al. ICD study will be summarized below; however, we begin with an overview of the biologic action of dopamine/DAs with dopamine receptors, and some general features of ICDs, respectively.

“I have a little obsessive-compulsive personality. You can tell because I played online games for eight hours a day.” Felicia Day

Dopamine and Dopamine Receptors: Dopamine in the brain is a neurotransmitter, which is a substance released by neurons (nerve cells) to send signals to other nerve cells.   Dopamine works by binding to and interacting with (activating) dopamine receptors on cell surfaces.  We have 5 sub-types of dopamine receptors, named D1 to D5; they all work by a second messenger system (G protein-coupled receptors) (see figure below).   In studying these dopamine receptors on neurons in the nervous systems, it was shown that D1 receptors are the most numerous, then D2 receptors are second most common, with D3, D4, and D5 receptors found in significantly lower amounts. The dopamine receptors are divided into 2 families: ‘D1-like’ (including D1 and D5) and ‘D2-like’ (including D2, D3, and D4).  When presented with either of 5 locks (D1-D5), the key (dopamine) opens each lock (in signaling terms, dopamine binds to the dopamine receptor, it is activated and signal transduction pathways initiated) For further information about dopamine and dopamine receptors, see the previous post entitled “Purple Haze of Parkinson’s: How Dopamine Works” (click here).

“You cannot beat a roulette table unless you steal money from it.” Albert Einstein

Dopamine Agonists: Dopamine agonists (DAs) are compounds that mimic dopamine; they also bind to and activate dopamine receptors (primarily D2 and  D3) (see Figure above).  In Parkinson’s, DAs historically have been used either as initial therapy or in combination with levodopa/carbidopa.  In the USA, there are 3 approved DAs, Ropinirole (Requip), Pramipexole (Mirapex, Mirapexin, Sifrol), and Rotigotine (chemical structures of each compared to dopamine are given below). Also, shown in the Table below are the relative binding interactions of dopamine and the DAs for dopamine receptors.

“Gambling: The sure way of getting nothing for something.” Wilson Mizner

Location and Activity of Dopamine Receptors: Dopamine receptors share similar structures; however, both their location in the brain and physiological function differ along two-main routes (motor circuit and reward circuit). Only D1, D2, and D3 will be briefly described.  Locomotor activity is primarily controlled by D1, D2, and D3 dopamine receptors.  Additionally, D3 dopamine receptors have a role in reward and reinforcement mechanisms (including addictive drugs). In the brain, D1 dopamine receptors are expressed at a high level in the nigrostriatal, mesolimbic, striatum, and substantia nigra just to mention a few sites in many regions of the brain. Likewise,  D2 dopamine receptors are somewhat widely expressed in the brain, and they are found in the striatum, nucleus accumbens, olfactory tubercle, substantia nigra, and ventral tegmental area to mention a number of sites.  In contrast to the D1 and D2 dopamine receptors, D3 is not as widely distributed and is in a lesser amount, D3 is found in the limbic areas, the striatum,  substantia nigra pars compacta, the ventral tegmental area, and in various cortical areas. See the figures below (click on each image to enlarge). Also, see past reports: “Dopamine Agonist Withdrawal Syndrome (DAWS) in Parkinson’s” (click here); “”Go the Distance” With MAO-B Inhibitors: Potential Long-term Benefits in Parkinson’s” (click here); and “Dopamine: A Symbol of Hope” (click here).

“Efficiency for me is an obsession..It not only helps me get stronger but makes things simpler.” Georges St. Pierre

Impulse Control Disorders (ICDs) in Parkinson’s: Humans have the ability to control their urges and impulses.  People that have an impulse control disorder (ICD) have difficulty resisting their urges and may do harm to either themselves or others.  At the least, ICDs are a troublesome burden; at the worst, ICDs could lead to significant and serious financial, legal or psychosocial complications.  Thus, ICDs are behavioral disorders that arise by an inability to resist an impulse, whereby one is not able to control specific behaviors.  Unfortunately, ICDs occur in Parkinson’s, and several reports have shown the use of dopamine agonists (DAs) increase the frequency of ICDs. The approved DAs preferentially bind to D2-D3 dopamine receptors when compared to dopamine; thus, it is speculated that DA activation of D3 receptors in the limbic system contributes to the development of these ICDs.

The most common ICDs in Parkinson’s include pathological gambling, compulsive shopping, compulsive eating, and hypersexism; they also include punding (An intense fascination with complex, excessive, repetitive, non–goal-oriented behaviors. The behaviors include less complex acts, such as shuffling papers, reordering bricks, or sorting handbags, shoes, clothes, etc.) or more intense acts like hobbyism (painting, gardening, writing) or compulsive internet browsing, and hypercreativity.

“Obsession with self is the motif of our time.” Charles Krauthammer

Clinical Description of Compulsive Dopaminergic Medication Use (also termed Dopamine Dysregulation Syndrome): In 2007, Dr. McKeon and associates provided a detailed description of compulsive behavior for 7 of their patients (6 with Parkinson’s and 1 with Multiple System Atrophy) taking DAs (6 patients) and carbidopa/levodopa (1 patient).  Publication citation:  McKeon, A., Josephs, K. A., Klos, K. J., Hecksel, K., Bower, J. H., Michael Bostwick, J., & Eric Ahlskog, J. (2007). “Unusual compulsive behaviors primarily related to dopamine agonist therapy in Parkinson’s disease and multiple system atrophy.” Parkinsonism and Related Disorders, 13(8), 516-519. The verbatim details for these patients are given below:

• Patient 1: “A 65-year-old female with PD for 9 years developed compulsive eating, and also felt compelled to repetitively weigh herself at frequent intervals during the day and at night. She found her behavior both purposeless and repetitive. Obsessive thoughts were also a feature, as the patient ‘had to’ weigh herself three times each occasion she used the weighing scales”.
• Patient 2: “A 67-year-old female with PD for 8 years played computer games and solitaire card games for hours on end, often continuing to do so through the night. She did not enjoy the experience and found it purposeless, but did so as she felt she had ‘to be doing something’. She also developed compulsive eating and gambling”.
• Patient 3: “A 48-year-old male with PD for 5 years, with little prior interest, developed an intense interest and fascination with fishing. His wife was concerned that he fished incessantly for days on end, and his interest did not abate despite never catching anything. This patient also developed compulsive shopping, spending large amounts of time and money in thrift stores”.
• Patient 4: “A 53-year-old male with PD for 13 years became intensely interested in lawn care. He would use a machine to blow leaves for 6h without rest, finding it difficult to disengage from the activity, as he found the repetitive behavior soothing. He also developed compulsive gambling”.
• Patient 5: “The wife of a 52-year-old male with an 11-year history of PD complained that her husband now spent all of his time on his hobbies, to the detriment of their marriage. The patient made small stained glass windows, day and night. In addition, he would frequently stay awake arranging rocks into piles in their yard, intending to build a wall, but never doing so. He would start multiple projects but complete nothing. He was also noted to have become hypersexual, demanding sexual intercourse from his wife several times daily”.
• Patient 6: “This 60-year-old male, with a history of alcohol abuse and ultimately diagnosed with MSA, relentlessly watched the clock, locked and unlocked doors and continually arranged and lined up small objects on his desk. He also became hyperphagic and hypersexual, developing an intense fascination with pornographic films”.
• Patient 7: “The wife of a 59-year-old male with PD for 1 year described how her husband dressed and undressed several times daily. On one occasion, while guests were at their house for dinner, he spent most of his time in his bedroom repeatedly changing from one pair of trousers into another. This behavior deteriorated considerably on increasing levodopa dose to 1100mg/day, and on a subsequent occasion after reducing quetiapine from 100 to 75 mg/day”.

Besides the vivid description given for each patient, it is apparent that each compulsive behavior is both repetitive and unwanted. The authors importantly remark on these findings as follows: “The temporal association between medication initiation and the onset of these behaviors led to our suspicion that medications were causative. In the aggregate, these patients illustrate that the behaviors provoked by drug therapy in parkinsonism cover a broad spectrum, ranging from purposeless and repetitive to complex, reward-oriented behaviors.”

“Thought changes structure… I saw people rewire their brains with their thoughts, to cure previously incurable obsessions and trauma.” Norman Doidge

Longitudinal analysis of impulse control disorders in Parkinson disease by Corvol et al., Neurology (2018, in press): 

• Goal- To investigate the longitudinal dose-effect relationship between dopamine replacement therapy and impulse control disorders (ICDs) in Parkinson disease (PD);
• They studied patients with PD <5 years from a multicenter longitudinal cohort of patients followed up annually up to 5 years. ICDs were evaluated during face-to-face with movement disorder specialists;
• ICDs studied here include compulsive gambling, compulsive shopping, compulsive eating, hypersexism, hobbyism, and hypercreativity;
• Results- Untreated patients with Parkinson’s do not have increased ICDs compared to the general population;
• They found that the incidence of ICDs approached 50% in the 5-year study, which indicates that the occurrence of ICDs are more common than reported previously;
• DA use was strongly associated with ICDs, with a dose-effect relationship for both increasing duration and dose;
• After discontinuation of DAs, ICDs progressively resolved, with 50% of patients without ICDs 1 year after DA discontinuation;
• ICDs were most strongly associated with the use of DAs compared with levodopa;
• Due to the younger age of patients studied, may have inflated their values for the general PD population; however, younger patients are at higher risk for ICDs and they are generally started on DAs and not levodopa (traditional medical teaching);
• A strength of this study is the 5-year length and longitudinal aspect of repeating the study questions/evaluation process. They convincingly report the association of ICDs with the use of DAs, not levodopa and other treatments;
• The authors conclude: “Given the high cumulative incidence of ICDs in patients with PD, these adverse effects should be carefully monitored in patients ever treated with DA. There is a need to develop tools for screening these disorders and identifying patients at high risk. Further studies are needed to understand the mechanisms involved in the relation between DAs and ICDs, in particular, the role of apathy, anxiety, and depression.”

“It’s extraordinary these obsessions. You conquer one but then you move onto another.” Marco Pierre White

Risky Business: Dopamine Agonists and Impulse Control Disorders in Parkinson’s: You have enough on your plate just having Parkinson’s and managing life day-by-day.   Like the wisdom and advice given by Gandalf to Frodo (J.R.R. Tolkien, The Lord of the Rings), “It’s a dangerous business, Frodo, going out your door. You step onto the road, and if you don’t keep your feet, there’s no knowing where you might be swept off to.”  The ultimate goal of this blog post is to help introduce this disheartening and potential side effect of DAs that are linked to ICDs in Parkinson’s. 

Since 2006 or so there has been growing accumulation of clinical reports linking the use of DAs and ICDs in Parkinson’s. Please remember I’m neither a Neurologist nor a Psychiatrist, but from reading many reviews/primary publications, ICDs in Parkinson’s may ultimately be due to some combination of DAs either magnifying an underlying compulsive tendency or the dysfunction from the imbalance of ‘loss and gain’ of dopamine in the brain resulting from Parkinson’s and medical treatment/replacement. It is important to remind you that the specificity of most approved DAs is toward the “D2-type” dopamine receptors (D2, D3, and D4). D3 dopamine receptors are involved in reward and motivated behaviors, which possibly explains why DAs may promote ICDs.

This is clearly both an awkward and a difficult patient-movement disorder specialist conversation. One topic my Neurologist asks me about every 6 months is related to pathological gambling and spending money (i.e., like totally-depleting your annuities). Realizing the potential existence of the ICD is clearly important because it’s not your fault.  The studies cited here suggest replacing the DA with levodopa slowly over time will reduce ICD symptoms (remember- this is not meant to be medical advice, this is the decision to be made by you, your family, and your Neurologist). The vast majority of PwP can use such a strategy, please see the following post for PwP who have difficulties replacing a DA with levodopa [“Dopamine Agonist Withdrawal Syndrome (DAWS) in Parkinson’s” (click here)]. Also, if they are present, ICDs can be managed by expert Psychiatric care in concert with your Neurologist.  This can be achieved by patient and caregiver education combined with behavioral work/therapy. One example can be reviewed in this post [“Treatment of Parkinson’s Psychosis with Nuplazid” (click here)].

Besides the papers cited here, for detailed medical/scientific overviews of impulse control behavior disorders, please read these two outstanding reviews (they will provide the framework you need to really understand DAs, ICDs, and Parkinson’s):

“I have been driven many times upon my knees by the overwhelming conviction that I had nowhere else to go. My own wisdom and that of all about me seemed insufficient for that day.” Abraham Lincoln

Cover Credit Photo: outdoor-photos.com/photo/79303.html