On October 6 PMD Alliance hosted a webinar on Anxiety and Behavioral Disturbances in PD. The speaker, psychiatrist Greg Pontone, MD, explained the cause of anxiety in people with PD may be dysfunction of the autonomic nervous system, which controls your fight or flight response. If your fight or flight response overreacts to everyday stressors, no amount of anti-anxiety medication will help because it is not targeting the source of the problem.
Dr. Pontone also shared a study that showed the fear of falling changes behavior in ways that increase freezing and turning hesitation, slow gait, and worsen postural impairment, resulting in decreased quality of life. BUT, with treatment to resolve the fear of falling, people were able to reduce those motor symptoms and regain quality of life.
There’s more good information in this webinar, including the most effective treatment options for anxiety and fear of falling, as well as explanations and treatment options for three behavior disorders seen in PD: impulse control disorder (ICD), punding, and dopamine dysregulation syndrome.
The webinar recording can be viewed here.
See these Stanford Parkinson’s Community Outreach Program webpages for more information about anxiety and PD and more information about fall prevention.
To determine if anxiety in PD is associated with the wearing off of levodopa, try using one of these symptom trackers. Symptom trackers are available electronically as websites or apps, but also as printable PDFs.
Hospitals and senior centers around the United States host fall prevention programs. See this Stanford Parkinson’s Community Outreach Program webpage for a list of fall prevention programs in Northern California. If you don’t see a fall prevention program near you, contact a local hospital or senior center.
And now, on with my notes…
– Denise
“Anxiety and Behavioral Disturbances in PD” – Webinar notes
Speaker: Greg Pontone, MD, MHS, Johns Hopkins Medicine
Webinar Host: PMD Alliance
Webinar Date: October 6, 2022
Summary by: Denise Dagan, Stanford Parkinson’s Community Outreach Program
Objectives
- Become familiar with the presentation of anxiety and behavioral disturbances in PD, including impulse control disorder (ICD) and punding
- Discuss how the physical/biological aspects of PD may be associated with anxiety and behavioral disturbances
- Review the best evidence treatments for anxiety and behavioral disturbances in PD
Overview of Anxiety in Parkinson’s Disease
Prevalence of Anxiety and Anxiety Disorders in PD
- Up to 55% have clinically significant anxiety symptoms
- 31% have an anxiety disorder, sometimes before motor symptoms
- anxiety disorder is more than just worry
- additional symptoms may also include muscle tension, stomach butterflies, heart palpitations, etc.
- 42% rank anxiety as a top 3 unmet need in PD
- Anxiety (and depression) have a greater negative impact on quality of life (QoL) than motor symptoms
Anxiety Disorders in PD
- Most common anxiety disorders in PD:
- Generalized anxiety disorder 14.1%
- also common in the general population
- perpetual, keyed up state of apprehension, worry, and tension, for no particular reason
- can interfere with sleep or concentration
- Social phobia 13.8%
- fear of talking or speaking in the company of others
- can be fear of eating or using the bathroom in the presence of others
- leads to social isolation and negative health outcomes
- Panic disorder
- brief episodes of extreme anxiety (10-20 mins)
- can’t think or function. May feel like you’re dying. Common to visit the ER.
- common to develop fear of having another panic attack, which can lead to social isolation.
- Anxiety disorder Not Otherwise Specified (NOS) 13.3%
- anxiety unique to Parkinson’s because they may be caused by the biology of PD
- fluctuating anxiety episodes caused by the wearing off of PD medications
- Anticipatory anxiety – worry or ruminate about even mundane events, like shopping or routine medical appointments,
- Generalized anxiety disorder 14.1%
- A third have 2+ anxiety disorders!
- For example: panic attacks and social phobia
Anxiety Disorders Can Occur at any Stage of PD (chart)
- People with anxiety disorders are at a two-fold, or more, increased risk of PD, possibly because changes in the brain cause increased anxiety prior to manifesting motor symptoms
First Anxiety Disorder Onset Relative to PD Onset (chart)
- 2/3 of people with motor symptoms have anxiety, even panic over the wearing off of medications and increase of PD symptoms. This type of anxiety is unique to people with PD.
Anxiety as a ‘premotor’ Symptom of PD
Researchers have repeatedly found that anxiety is a prodromal symptom of PD up to 20 years before the onset of motor symptoms, regardless of the type of anxiety (panic disorder, phobia, or general anxiety/neurosis).
Potential Mechanisms or ‘Phenocopies’ of Anxiety in PD
Phenocopies are things that can be experienced as anxiety but are actually a biological phenomenon that cause you to feel as though you are anxious. Here are four examples unique to those with PD:
1. Dysfunction of the Autonomic Nervous System
Everybody has a fight or flight response. You get a dump of adrenaline when you see a bear or something bad happens. It is a cascade of chemicals and hormones that get you keyed up for action. The fight or flight response is mediated, in part, by your autonomic nervous system.
Parkinson’s Disease causes dysfunction of the autonomic nervous system by the progression, which results in triggering of the fight or flight response to some degree in nearly 70% of people with the disorder.
Autonomic dysfunction can cause excessive sweating, difficulty regulating your body temperature, changes in blood pressure (usually a drop in BP, but sometimes an increase), hyperventilation, and trembling (rhythmic oscillation of the musculature).
You’re used to experiencing the fight or flight response when you are startled, threatened, etc. When there is no obvious reason to feel that way, you experience it as a panic attack.
A couple of small studies verified this theory. (Rutten S. et al, 2015; Berrios GE et al, 1995)
What this means is that no amount of anti-anxiety medication will lessen your anxiety if the cause is dysregulation of the autonomic nervous system because the medication is targeting the wrong thing.
When you have PD, it is crucial to explain to your doctor precisely how you experience anxiety. Do you have physical symptoms? Are you tense, sweating, lightheaded, hyperventilating, etc. The more clues you can provide, the better your doctor can be at prescribing the most effective treatment.
2. Anticipatory Anxiety and Cognitive Impairment in PD
Anticipatory anxiety occurs in anticipation of an upcoming event. People with generalized anxiety who don’t have PD experience anticipatory anxiety as well, but it is very conspicuous in those with PD.
Dr. Pontone sees anticipatory anxiety in at least 1/3 of his patients with PD.
People with anticipatory anxiety cannot calm their nerves by thinking things through rationally. Instead, they catastrophize and wind themselves up even more.
Executive functioning is our ability to sequence, organize, and plan. Anticipatory anxiety could be associated with impairment to executive functioning ability commonly seen in the middle stages of PD.
It can help to have a family member or caregiver talk the person with anticipatory anxiety through the sequence of events to allay any specific fears. For example, if they worry that they will need the rest room, the care partner can explain when there are breaks in the schedule to do that and share where rest rooms can be found.
Dissanayaka et.al. 2017, found that people with PD and mild cognitive impairment (MCI) are 3x more likely to have anticipatory anxiety than those who are not anxious. This study demonstrates that anticipatory anxiety is associated with cognition/executive functioning impairment.
Again, no amount of anti-anxiety medication will be helpful because it is not targeting the cognitive change, which is the cause of anticipatory anxiety.
3. Anxiety Due to Wearing off of PD Medications (ON/OFF periods)
People with PD experience anxiety when their Parkinson’s medications wear off. They feel the dopamine leaving their body at the end of each dose and they start to feel their symptoms reemerge. Their tremors return, they become stiff and tense, and they slow down, maybe even freeze.
They begin to associate the return of symptoms and loss of dopamine, (which is also an import chemical for feeling good) with distress and anxiety.
Therefore, it is crucial to keep a medication & symptom diary. By showing your doctor the timing of your medications and the timing of your anxiety, you can demonstrate whether the two are corelated. If they are, your doctor can make medication adjustments to minimize wearing off of medications and the resulting anxiety.
Proof that anxiety fluctuates with levodopa was demonstrated in a study where people with PD were given a dopamine infusion. When the dopamine infusion was started, anxiety was relieved. When the dopamine infusion was stopped, anxiety increased.
Dr. Pontone knows some people who remain calm when their medications wear off. This leads him to believe people in general can be taught to control their emotional response and minimize their experience of anxiety due to wearing off of medications.
4. Fear of Falling
Complications from injury due to falls play a significant role in shortening the life of those with PD. This makes fear of falling (FOF) a very rational fear, especially after suffering injury from a fall.
At least 22 studies have looked at the fear of falling and how it changes behavior. 51.5% of more than 1000 study participants experienced FOF and resulting changes of behavior.
People with FOF experienced more frequent freezing, turning hesitation, slower gait speed, and greater postural impairment (balance issues).
Resolving FOF reduced the experience of these motor symptoms and increased quality of life.
Best Evidence Treatment of Anxiety in Parkinson’s
Pharmacologic treatment of anxiety in PD
- Movement Disorder Society Task Force on Evidence Based Medicine and the American Academy of Neurology found that “the evidence to support or refute specific treatments for anxiety in PD is insufficient.” This means more research is needed.
- Evidence that does exist is usually secondary outcomes from randomly controlled trials.
- Example: A drug study to treat depression in PD may have asked participants a few questions about anxiety. Participant responses on anxiety are a secondary outcome. It is only partial information, but it is the best information available.
- Dr Pontone’s information about anxiety is based on these secondary outcomes because direct studies on treatments for anxiety in PD are needed.
- Optimizing motor function and addressing ON/OFF motor fluctuations is likely important for controlling anxiety in PD. This is because we know that wearing-off of medications, dose values, and fear of falling can all trigger anxiety – another PD symptom that impacts quality of life and should be treated.
Buspirone for Anxiety in PD
One randomized, placebo-controlled study of a medication to treat anxiety in PD was a very small, proof of concept study to demonstrate the effectiveness of Buspirone.
Of 21 people enrolled, every 4th participant was given the medication. The rest were given a placebo. The median dose was 7.5mg, three times daily.
Even though participants receiving the medication reported a decrease in anxiety symptoms, the mean improvement was not statistically significant.
Tolerability was an issue. 53% related worsened motor function. 41% failed to complete the study because side effects were intolerable.
Nabilone Phase II for Non-motor Symptoms in PD
Nabilone is a synthetic cannabinoid (a tetrahydrocannabinol analogue). In a phase II trial to determine safety, tolerability, and dose-finding all participants were initially assigned to take the drug. This is called open label titration.
After four weeks participants were randomized to either continue taking Nabilone, or switch to a placebo.
77% experienced side-effects during open label titration, but side effects were similar in double blind phase, none were serious and were usually tolerable.
Although this is an early phase trial, the final determination is that Nabilone may lower anxiety and help sleep. There is still a long way to go, probably years and many hurdles before it is determined whether this drug is suitable for treatment of anxiety in PD.
Non-pharmacologic Treatments of Anxiety in PD
- Cognitive Behavioral Therapy (CBT)
- Shown to be the most effective treatment for anxiety in PD, regardless of the cause or type of anxiety
- Very structured type of therapy, requiring 10-20 sessions to be helpful
- Can be done alone or in conjunction with medication
- No risk (excepting time and $)
- Mindfulness based therapies
- Emerging evidence that mindfulness can be very helpful for anxiety.
- Similar to CBT, teaches you to separate your emotional response from your thoughts and behaviors
- Can be combined with yoga or meditation
- Exercise based therapies
- Diffuses physical tension experienced during stress
- Helps movement, cognition, anxiety, and depression
- Neuromodulation is an emerging option
- Can be invasive (surgical) or non-invasive (non-surgical)
- Examples: Repetitive Transcranial Magnetic Stimulation (rTMS), Transcranial Direct-Current Stimulation (tDCS), and DBS
- All evidence thus far that these therapies may be effective in treating anxiety in PD is all from secondary outcomes.
Cognitive Behavioral Therapy (CBT) for Anxiety in PD
In a study with 48 participants over 10 weekly sessions, half were given CBT while the other half were interviewed about how they are feeling.
Researchers used the Hamilton Anxiety Rating Scale (HAMA) and the Parkinson Anxiety Rating Scale (PAS).
Not only was CBT effective during the study, but participants also reported significant sustained improvement (lower anxiety) at 3 and 6 month follow ups.
This study demonstrates that if you remember and practice techniques learned in CBT, you will continue to benefit from CBT. It is not uncommon to do refresher CBT.
Surprisingly, study participants who were merely interviewed about their anxiety also reported improved (lower) anxiety. This seems to demonstrate that there is some reassurance in checking in with patients more frequently.
Mindfulness Yoga vs Stretching and Resistance Training for Anxiety
In an 8-week study of 138 participants, half did yoga and mindfulness with a personal trainer and half did strength and resistance band training.
As expected, all participants’ movement improved, but yoga and mindfulness were superior to strength and resistance band training for anxiety and depressive symptoms.
Something about focusing your mind deliberately on something other than your stressed emotional state seems to lower anxiety and depression.
With mindfulness and CBT, you learn to find a place in your head where you’re less worried about your emotional responses. You are able to overcome automatic thoughts of catastrophe and reframe your thoughts in a more hopeful way.
PD Anxiety Treatment Algorithm (flowchart)
Dr. Pontone and Kelly Mills, MD, created a flowchart to guide doctors treating Parkinson’s patients with anxiety.
Regardless of the type of anxiety someone reports or if they have PD, the first line treatment is anti-depressants. There are a few drug categories to try, including SSRIs, SNRIs, Tricyclics (which are SSRI + SNRI + dopamine).
Treatment for anxiety should always include behavioral activation (reengaging in activities you once loved or finding new activities to engage with others socially).
You can try medication or CBT, mindfulness/yoga or relaxation therapy alone, but medications are always more effective with CBT, mindfulness/yoga, or relaxation therapy.
The flowchart shows the order in which to try single or combination therapies for generalized anxiety and anxiety due to non-motor fluctuations, fear of falling, cognitive impairment, and autonomic dysfunction.
Dr. Pontone wants listeners to know that doctors have many things to try so if you don’t find relief in your first attempt at treatment, don’t give up! It is worth going through the various treatment options until you find what works for you.
Impulse Control and Other Behavioral Disorders in PD
These behavioral disturbances in PD are often under recognized, partly because they are things everyone does. These behaviors become a problem when they are done excessively or in a way that leads to a bad outcome.
When caregivers notice any of these behaviors, they should notify the Parkinson’s patient’s neurologist immediately for a medication review and adjustment.
Impulse Control Disorders (ICDs) in PD
- About 20 behaviors which can be performed repetitively, excessively, and with a lack of self-control to an extent that interferes with life functioning. The examples below are the most common.
- In PD specifically, they are associated with dopamine agonist medications (see list below) and high doses of carbidopa/levodopa
- Pramipexole/Mirapex
- Ropinirole/Requip
- Neupro/Rotigotine patch (less likely to cause ICD)
- The estimate is that 15% of people experience ICDs while taking dopamine agonist medications
- Most common ICDs
- Pathological gambling
- more common in casual gamblers prior to PD
- occasionally someone who never gambled before
- Compulsive buying/shopping
- out of control shopping with no rational thought
- Hypersexual behaviors
- Most people with PD are over age 60 and their natural sexual appetite is low
- When driven by dopamine, even those over 60 can have the sex drive of a teenager
- Can disrupt relationships if not treated
- Binge eating
- Beyond hunger or emotional eating
- Sometimes to the point of vomiting
- Pathological gambling
Dopamine Dysregulation Syndrome
- When people are on high levels of dopamine they can experience euphoria.
- They may begin to take more and more dopamine until they are self-medicating in a drug addiction-like state
- More common in early onset PD and males, 3-4%
- Co-occurs with ICDs, psychosis, and panic attacks
Punding
- Repetitive, purposeless behaviors, characterized by an intense preoccupation with specific items or activities, like collecting, rearranging items, folding and unfolding, taking apart objects, or starting a task but repeating part over and over rather than completing the task.
- Higher level repetitive behaviors (e.g., excessive internet use, reading, artwork, work on projects, hobbyism)
- Can also be videogame use into early hours of the morning and can’t stop
- Similar behavior to someone on speed
- Directly related to higher dopamine levels so punding behavior diminishes as dopamine levels recede.
- Punding can occur any time but is most likely to occur later in the day, when people are tired, or in the late evening after dose stacking (buildup of dopamine doses).
Treatment of ICDs in PD
- Withdrawal or reduction of Dopamine Agonist (DA) is the first treatment option for ICDs, dopamine dysregulation syndrome, and punding.
- Since levodopa is less likely to cause these behaviors, you can usually replace the DA with an equivalent amount of levodopa. This helps about 1/3 of the time.
- Dopamine agonist withdrawal syndrome requires monitoring of worsening motor function while weaning off DAs
- There have been very few trials for drugs to treat ICDs.
- Amantadine, usually used to treat dyskinesias
- Naltrexone, sometimes used to treat opioid abuse
- Neither is clearly efficacious
- Cognitive behavioral therapy my help ICD according to one small study(Okai, et al.). Also helps with anxiety and depression
- Addition model – 12-step groups, involve caregiver and family, which is important because people with ICD often have limited perspective of their own behavior or embarrassment.
- Johns Hopkins encourages patients with ICD gambling and hypersexual disorder join these groups.
When a person with cognitive impairment is agitated, ‘acting out,’ or is in distress, it is because they are experiencing anxiety, depression, or can’t articulate their needs. Rather than reaching for a sedating medication, caregivers and family members should seek the cause of their behavior and try to meet their needs.
Nonpharmacological Intervention for Anxiety in Dementia
- CBT and mindfulness may not be appropriate in PD dementia because they cannot fully participate
- Music therapy or other environment modifications to reduce stimulation that may contribute to anxiety
- Activity therapy – providing a structured activity can create a distraction from emotional distress
Question and Answer:
Question: Multitasking is an anxiety trigger for a webinar attendee. Can you hypothesize as to why this happens?
Answer: The model for anticipatory anxiety is that it is caused by executive dysfunction. When you multitask, the demand on the speed of your central processing is greater than you can accommodate with PD, which slows processing. People who focus on one task at a time tend to have less anxiety and function better.
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Question: Stress causes a listener to burn through carbidopa levodopa faster and they “run out of gas.”
Answer: When you are directing your body to do something, but it is distracted by emotions like fear, anxiety, or worry, it drains the amount of energy you can put toward the task. It’s like multitasking. You’re trying to pay attention to the fear and anxiety while doing something and it’s exhausting. You are running energy through two channels instead of one. When you turn down the anxiety your energy is better directed toward the task at hand.
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Question: A webinar attendee participated in a study on ketamine. When they were getting infusions they felt really good, and a lot of their physical issues disappeared. Is this study applicable to anxiety and PD?
Answer: Most ketamine studies have been done on non-PD populations. Ketamine is not only efficacious for anxiety and depression, but it works rapidly, within hours or days. This is because there are receptors in the brain that ketamine binds to very tightly. It takes 4-8 weeks for antidepressants to bind to the same receptor. There is no reason to believe ketamine will not be as effective in people with PD.
Ketamine must be used under close supervision. Ketamine is a dissociative anesthetic and has been primarily used in pediatric burns during wound debriding. It allows the child to disassociate from the intense pain of debriding and minimize trauma. This dissociative nature of ketamine could be a problem for people with Parkinson’s, because it can cause confusion and increased risk of falls.
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Question: What are your thoughts on THC or CBD (cannabinoids)?
Answer: Michael Pollen writes about plant-based and psychedelic therapies. Johns Hopkins, where Dr. Pontone works, has a long history of studying these compounds.
The brain has a ton of cannabinoid receptors for both synthetic or natural sources. There isn’t enough research to know how much or for how long to administer these compounds, but studies are ongoing.
Remember, cannabinoids can cause confusion and increase your risk of falling.
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Question: What type of medication works better for depression and anxiety, SSRIs or SNRIs?
Answer: In non-PD populations, where these drugs have been tested, SSRIs seem to work better for anxiety. There are a bunch of them, including Zoloft/Sertraline, Prozac/Fluoxetine, Lexapro/Escitalopram, Celexa/Citalopram, and Paxil or Pexeva/Paroxetine.