TCPR: I think that a lot of psychiatrists, myself included, could use a refresher course on Parkinson disease and how to distinguish its symptoms from those induced by antipsychotics (parkinsonism). What exactly is parkinsonism?
Dr. Kaufman: Parkinsonism is a clinical syndrome comprised primarily of rigidity, tremor, and bradykinesia (slowed movements). The most common cause of parkinsonism is Parkinson disease, but parkinsonism also can occur from the use of any medication that blocks the D2 (dopamine type 2) receptor. Those include antipsychotics but can also include non-psychiatric medicines, particularly metoclopramide (Reglan), an anti-nausea medicine. So, we see parkinsonism in people who are being treated for nausea and vomiting associated with prolonged migraines, chemotherapy, and pregnancies. In addition, vesicular monoamine transporter 2 (VMAT2) inhibitors such as deutetrabenazine (Austedo), tetrabenazine (Xenazine), and valbenazine (Ingrezza)—medications that reduce tardive dyskinesia, chorea in Huntington disease, or both—have recently been reported to induce parkinsonism as an adverse effect.

TCPR: What other disorders might cause parkinsonism?
Dr. Kaufman: In addition to parkinsonism being related to antipsychotics and other medications, psychiatrists need to consider the ­possibility that parkinsonism can be a manifestation of neurologic illnesses, including Lewy body dementia, Wilson disease, drug abuse, or Huntington disease, at least its juvenile form. These particular illnesses are especially important because they cause mood and thought disorders, as well as parkinsonism, and thus a patient developing one of them may see a psychiatrist before any other specialist.

TCPR: Can you tell us more about how we determine diagnostically whether parkinsonism is due to the use of antipsychotics or Parkinson disease? Could it be both?
Dr. Kaufman: It could be both, especially in older adults. If older patients have been receiving antipsychotics and develop parkinsonism, a psychiatrist might consider that these patients may have been developing idiopathic Parkinson disease and that the psychiatric symptoms may have been related. It is not always easy to tell the difference between the disease and its adverse effects. The first thing to do, if possible, is to stop the antipsychotic agent and wait 3 weeks to 3 months to see if the symptoms resolve. If the psychiatrist cannot discontinue the antipsychotic, the next strategies would be to reduce the dose, switch to a second-generation antipsychotic, or use clozapine. In equivocal cases, or when there is urgency, there is a new nuclear medicine test called a dopamine transporter scan (DaT) that usually can reliably distinguish between Parkinson disease and medication-induced parkinsonism (Bhattacharjee S, Ng KL, Indian J Nucl Med 2016;31(4):320–321).

TCPR: How should we examine a patient who appears to have parkinsonism?
Dr. Kaufman: To start, observe whether the patient has reduced facial and limb expressions and gestures. For example, there may be decreased smiling and decreased affect. The patient will not make any hand gestures. There will also be characteristically fewer eye blinks and a tendency to stare, which neurologists call a ­“reptilian stare.” In most cases, a patient with parkinsonism will have a tremor of one or both hands. If it is unilateral or asymmetric, a resting tremor suggests idiopathic Parkinson disease, but if it is symmetric, we really cannot say whether it is idiopathic or medication-induced.

TCPR: After we make those observations, what should we do next?
Dr. Kaufman: Neurologists rotate the hand around the wrist and see if there is cogwheel resistance. Both wrists need to be tested. In individuals who have a tremor on one side, that wrist ought to have rigidity, and the other one will not. Another maneuver is the so-called “pull test.” With the patient standing, the physician stands behind the patient, hands on the patient’s shoulders, and says, “At the count of 3, I’m going to pull you back a little.” During this, a normal healthy patient will take a step back or bend the shoulders backwards to maintain balance. In contrast, someone with Parkinson disease will either take many steps backwards (“retropulsion”) or just topple over like a statue (“falling en bloc”). Another simple thing we do is watch people walk to see if they have normal arm swing. A lack of normal swinging on one or both sides is consistent with ­parkinsonism.

TCPR: Interesting. How do you suggest we evaluate tremors in these patients? And can you clarify the difference between intention tremors and resting tremors?
Dr. Kaufman: Parkinson disease is usually associated with a resting tremor. That is, a tremor of 4–6 Hertz (Hz, cycles per second) in one or both hands, in which the fingers and the hand repeatedly flex. Although this tremor is present at rest, patients actually can suppress it for several seconds to several minutes. We ask patients, “Please stop the shaking as I count to 10.” Patients will also have a diminished tremor when we ask them, “Take your finger and move it from your nose to my finger, then go back and forth.” And, when a patient is holding the hands in fixed positions against gravity—say, straight out—the tremor will be reduced compared to when the patient holds the hands at rest.

TCPR: So, in parkinsonism we would see a resting tremor. When would we see an intention tremor?
Dr. Kaufman: A common intention tremor is “essential tremor,” which is more frequent, develops in younger individuals, and frequently has developed in a patient’s family members. This tremor is a more rapid tremor and is not present when patients have their hands in their lap, but is present when the arms are held in fixed positions against gravity—for example, when the patient sticks out both hands for 10 seconds.

TCPR: Are there any clues during the exam that might make you think that what you are seeing is more likely drug-induced parkinsonism?
Dr. Kaufman: Well, if it’s asymmetric or unilateral, it is more likely to be idiopathic Parkinson disease. But otherwise—putting aside the history, of course—it is hard to tell the two apart.

TCPR: Moving on to idiopathic Parkinson disease, let’s talk about the complications or psychiatric conditions that could develop in patients. What is the timing of some of these psychiatric symptoms?
Dr. Kaufman: Initially, when people come to grips with the fact that they have developed a neurodegenerative disorder, they have to deal with the usual psychological problems of loss. People often must retire, curtail their social life, and cut back on their physical activities. These are losses that could be ameliorated by psychotherapy, vocational counseling, and physical therapy. With a regimen of Parkinson medications, such as carbidopa/levodopa and/or dopamine agonists, people usually maintain all their normal activities for five years.

TCPR: Switching to treatment for drug-induced parkinsonism, what’s your take on using anticholinergics?
Dr. Kaufman: The idea is that there is an imbalance in Parkinson disease between dopamine activity and cholinergic activity, and if you give an anticholinergic and reduce the cholinergic activity, you will counterbalance the deficit in dopamine activity. Although anticholinergics may reduce the tremor of Parkinson disease, their potential side effects are daunting. After all, we are dealing generally with an older population, and the doses that we need to suppress the tremor cause cognitive impairment and delirium.

TCPR: What are your thoughts on the dilemma of treating psychosis and Parkinson disease, where dopamine is already depleted and you’re prescribing dopamine blockers?
Dr. Kaufman: The psychosis in Parkinson disease tends to be worse at bedtime. Its hallmarks are paranoia and visual hallucinations. Of course, unnecessary medications, whether or not they cause psychosis, should be discontinued. Then, less potent Parkinson disease medications should be tapered if not discontinued. Typically, our go-to antipsychotics were—and still are, for many clinicians—the lower-potency antipsychotics, such as quetiapine and clozapine. Quetiapine’s effectiveness in this situation is still not established. Clozapine is effective for psychosis in Parkinson patients, but it is difficult to prescribe because of the white blood count monitoring requirement (see TCPR, “Clozapine: A Fresh Look,” March 2018). One medication that may reduce hallucinations in Parkinson disease patients is pimavanserin (Nuplazid). However, because recent reports have described excess mortality in Parkinson disease patients taking this medicine, it now carries a “black box warning.” Moreover, I haven’t seen any data comparing pimavanserin to quetiapine or clozapine.

TCPR: Moving on, I’d like to touch on another hot topic in neuropsychiatry—frontotemporal dementia vs Alzheimer dementia. How common is frontotemporal dementia, and how is it different clinically from Alzheimer dementia?
Dr. Kaufman: Frontotemporal dementia (FTD) is much more common in younger populations—meaning under the age of 65. Among this age group, FTD is about as prevalent as Alzheimer dementia (AD). However, among those older than 65, AD is much more common. Incidentally, what we call AD is often actually a combination of vascular dementia and AD.

TCPR: So, how would we know if somebody had frontotemporal dementia?
Dr. Kaufman: Patients with frontotemporal dementia typically present with changes in or loss of executive function, inhibition, or language function that are at least as prominent as cognitive impairment. They will often, on one hand, be uninhibited in their speech and their activities, but they may have marked apathy, reticence, and in some cases primary aphasia—a loss of language ability. In contrast, people with Alzheimer disease generally present with loss of memory and then loss of judgment. In neither case are there clear physical deficits. Neither group of patients will have paralysis or gait impairment; however, because of the frontal lobe degeneration, frontotemporal dementia patients often have pseudobulbar palsy. As far as confirmatory tests, frontotemporal dementia will show up differently on PET scans than Alzheimer disease, and amyloid imaging will be much clearer-cut in Alzheimer disease than in FTD.

TCPR: What kind of story would you hear from a patient’s family member that would make you think there’s a good chance the patient has frontotemporal dementia?
Dr. Kaufman: I might hear family members talk about the development of behavioral disturbances, such as manic or depressive symptoms, rather than simply memory impairment or poor judgment. In some patients with frontotemporal dementia, language impairment will be the primary symptom.

TCPR: Why is it important to distinguish between frontotemporal dementia and Alzheimer’s?
Dr. Kaufman: It is more important to distinguish frontotemporal dementia from psychiatric disturbances—bipolar disorder, primary depression, or personality disorder. So, the difference is not so much between frontotemporal dementia and Alzheimer disease as it is between frontotemporal dementia and midlife psychiatric illnesses. Because there is more of a familial tendency among frontotemporal dementia patients than there is among Alzheimer disease patients, it is good for the family to have information on this distinction.

TCPR: What are some of the treatment implications or differentials between the two conditions?
Dr. Kaufman: If the clinical diagnosis is clearly frontotemporal dementia and confirmatory tests, such as fluorodeoxyglucose (FDG)-positron emission tomography (PET), are unnecessary, therapy should be directed first toward disruptive behavior. Caregivers might make changes in the physical and psychologic environment, such as stopping driving and potential social confrontations. When language impairment is a major symptom, speech therapy may be helpful in preserving patients’ ability to communicate. Depending on the symptoms, some neurologists prescribe SSRIs or SNRIs (Rabinovici GD and Miller BL, CNS Drugs 2010;24(5):375–398). Antipsychotic agents’ risks may preclude their use in all but extreme cases of disruptive behavior. Unlike in treatment of Alzheimer disease, cholinesterase inhibitors and memantine may worsen symptoms in frontotemporal dementia (Kirshner HS, Neuropsychiatr Dis Treat 2014;10:1045–1055). Treatment of Alzheimer disease symptoms also initially rests on general support, adjusting cognitive expectations, and managing symptoms. Symptomatic treatment of depression and disruptive behaviors do not occur with such regularity, but the treatments would be similar. Here, cholinesterase inhibitors and memantine slow the progression of cognitive impairments. Unfortunately, no treatments reverse the pathology of either frontotemporal dementia or Alzheimer disease—but promising studies are underway.

TCPR: Thank you for your time, Dr. Kaufman.