Category: Winter 2017/2018 Issue

People with Parkinson disease (PD) have low dopamine stores, and many of the drugs used to treat PD are aimed at either replacing or simulating dopamine.  Carbidopa/levodopa (Sinemet) provides levodopa to the brain, which is then converted to dopamine.  There is also a class of dopamine simulating drugs, the dopamine agonists (DA).  DA are synthetic drugs that are meant to stimulate the basal ganglia (BG) in a way similar to dopamine.

The BG is the part of the brain that uses dopamine to normalize movement and eliminate tremor.  The BG is, in a way, the quality control center for movement, is linked to several other parts of the brain, and is involved in various functions.  For our purposes here, it regulates learned movements such as typing, playing the piano, handwriting, walking, dancing, or riding a bike.  When walking, the BG helps determine how much muscle tone you should use, how far your foot should go when you step, and where it should land.  Those functions may fail to some degree when a person has PD (think of shuffling gait, for example).  If dopamine is replaced or simulated, the functions may improve.  That is the goal in giving these medications.

The reason dopamine replacement helps is because the cells of the BG have structures called dopamine receptors.  Dopamine binds to the receptors and the cell is then activated to do something, such as change muscle tone.  There are many different cell types and many different effects.  DA bind to the same receptors, but there are some differences between dopamine and DA.

One big issue is that after one takes a carbidopa/levodopa pill to replace dopamine, levodopa only spends about 90 minutes in the blood at a reasonable concentration.  During that time, it washes through the brain’s blood supply and is absorbed by and stored in the BG. When that happens, the BG can convert levodopa to dopamine, and more or less distribute dopamine appropriately to the cells that need it, as they need it.  It is sort of like filling a gas tank.  The problem is that the brain’s ability to store dopamine decreases over time in PD, as if the gas tank keeps shrinking.  People with PD generally have to take doses of levodopa more frequently over the course of disease because of this decrease.

DA are not stored in the brain, and instead circulate in the blood for several hours after taking a dose.

This means that the entire brain is washed with DA for those several hours, during which time the receptors can be stimulated and symptoms reduced.   The effect is weaker than pure dopamine, but often the duration of the drug is longer.   This might become a problem, however, because there are other dopamine receptors in the brain that are not involved in movement and yet may be stimulated by the constantly available drug.

A part of the brain that is sometimes affected is the limbic system.  The limbic system is involved in craving, lust, emotion, risk-taking, and addiction.   Let’s think about risk-taking for a moment. You are with a friend, we’ll say his initials are E.K., and he is a motorcycle stunt artist.   He has a really fast Harley Davidson and he likes to pop wheelies and jump over things.  It is fun to watch him perform, and he seems fearless.  One day E.K. asks if you would like to jump over the fountains at a hotel in Las Vegas with him.  For a split second it sounds exciting, and you think, “cool.”  Your brain swings into action to deal with this situation.

Let’s talk brain anatomy.  There is a part of your brain that analyzes risk.  It is called the dorsolateral prefrontal cortex (DLPFC).   This is the part of the brain that tries to peer into the future and consider possible outcomes:  if X happens, then Y will be the result.  It is purely logical (to the extent that you are logical).  Its risk assessment says “if you jump the fountains on that motorcycle, you will probably crash:  bad idea.”  Among other neurotransmitters, the DLPFC is connected to the limbic system with a steady flow of dopamine, and for our purposes, we will focus only on dopamine.

Dopamine generally makes the limbic system feel good, and that seems to be the default.

So, there should be some trickle of dopamine flowing at all times. When you like an idea or the risk is low, dopamine is steady or even increased.   When your DLPFC says you should not do something, dopamine flow to the limbic system is decreased.  That gives us a negative emotional feeling about the risk and then the logical and emotional parts of the brain can be in agreement.  “No thanks E.K., I don’t want to break any bones or die today.”  But what if the limbic system is stimulated by DA washing the brain?  Does it become harder to follow the instructions of the DLPFC?

For a minority of people, the answer is yes.   These people may develop what is called impulse control disorder (ICD).

ICD was defined by the American Psychiatric Association as a group of psychiatric disorders characterized by a failure to resist an impulse, drive or temptation to perform an act that is harmful to the individual or to others (1). 

The key word here is “harmful.”  Not all behaviors are harmful, and it is important to keep in mind that not everyone agrees on what is considered bad behavior.  ICD in PD has been called “hedonistic homeostatic dysregulation” (2) and “dopamine dysregulation syndrome” (3).  It should also be noted that ICDs have been reported with all anti-parkinsonian drugs, though it is most often seen with DA.

ICD behaviors can include compulsions for shopping, spending, traveling, eating, sex/libido, reckless driving, and pathological gambling.  Patients with ICD may also exhibit obsessive-compulsive disorder (OCD) features such as repetitive behaviors, checking (light switches or locks, for example), religious obsession, sexual obsession, symmetry and ordering, washing, cleaning, and punding.  Punding is intense fascination with some action such as writing, repetitive handling, examining, sorting, arranging, craft-making, collecting, hoarding, repairing, or gardening.  There is a range of severity from excess interest in hobbies to prolonged stereotyped activity that interferes with normal activities of daily living.  If your other interests fail so that you can keep repetitively perform some function, you may be punding.

Patients with ICD often abuse dopaminergic drugs in a way that resembles addiction.

These people tend to take very high doses of drugs and sometimes surpass the upper limits of doses approved by the FDA.  Needless to say, they are often not following the advice of a doctor (4), though ICD does sometimes occur at prescribed doses.

ICD is often present when a person with PD has a history of other psychiatric or neurologic disorders such as substance use disorder, antisocial personality disorder, major mood disorder, or anxiety (5-9), though it may occur without these features as well.  ICD may be more common in people with young-onset PD.  Combining high doses of DA with high dose levodopa is also a risk factor (10).

What can we do about ICDs?

Always follow your doctor’s instructions.  Do not change doses on your own.  Reducing or stopping the offending medication with your doctor is usually effective.  Sometimes a switch to a different DA is helpful.  Failing these interventions, caretakers may need to limit access to money or credit cards.  Sometimes appointing a financial guardian is needed.  One may need to cut off internet access or firewall away gambling sites.  PD support groups may be helpful.  It is not clear whether other groups such as Gamblers Anonymous are helpful for PD patients.  Other medications have been tried, such as opioid antagonists, antipsychotics, selective serotonin reuptake inhibitors, and amantadine.

The person with the ICD is typically quite aware the behavior is unusual and is too embarrassed to admit to it.  However, knowing this may be related to medications should give you some idea that it is not unheard of, and can be helped.  Telling your physician is a good first step.

REFERENCES

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder, 4th ed, Text Revision. Washington DC: American Psychiatric Association; 2000.
2. Giovannoni et al. Hedonistic homeostatic dysregulation in patients with Parkinson’s disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry. 2000;68:423–428.
3. Evans et al.  Impulsive and Compulsive Behaviors in Parkinson’s Disease.  Movement Disorders 2009;24(11): 1561–1570.
4. Stamey W, Jankovic J. Impulse control disorders and pathological gambling in patients with Parkinson’s disease.  The Neurologist 2008:14(2);89-99.
5. Black DW, Moyer T. Clinical features and psychiatric comorbidity of subjects with pathological gambling behavior. Psychiatr Serv. 1998; 49:1434 –9.
6. Crockford DN, Goodyear B, Edwards J, et al. Cue-induced brain activity in pathological gamblers. Biol Psychiatry. 2005;58:787–795.
7. Potenza MN, Fiellin DA, Heninger GR, et al. Gambling: an addictive behavior with health and primary care implications. J Gen Intern Med. 2002;17:721–32.
8. Petry NM, Stinson FS, Grant BF. Comorbidity of DSM-IV pathological gambling and other psychiatric disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2005;66:564 –74.
9. Petry NM. Comorbidity of disordered gambling and other psychiatric disorders. In: Petry NM, ed. Pathological Gambling. Etiology, Comorbidity,and Treatment. Washington, DC: American Psychological Association;2005:85–115.
10. Evans et al., Impulsive and Compulsive Behaviors in Parkinson’s Disease. Movement Disorders Vol. 24, No. 11, 2009, pp. 1561–1570.