03. Treatment of Psychiatric Disturbances in Hypokinetic Movement Disorders

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Let’s look at hypokinetic movement disorders, particularly Parkinson’s and dementia with Lewy bodies. According to a new review from the Expert Review of Neurotherapeutics, this category also includes multiple system atrophy, progressive supranuclear palsy, and corticobasal syndrome. However, the main problem is depression in Parkinson’s and psychotic symptoms in Lewy body dementia. Isn’t it interesting that if Lewy bodies turn up mostly in the brainstem, it is regarded as a neurologic or motor problem? On the other hand, if Lewy bodies are more widespread, leading to symptoms of psychosis, is it more “psychiatric”? From a practical point of view, let’s think of depression as a part of Parkinson’s. The hypodopaminergic state is part of most, not of all, these hypokinetic illnesses. So, is this hypodopaminergia the cause of depression? In other words, does depression respond to dopamine agonists?

Well, Dr. Berardelli and her colleagues reviewed several randomized trials of pramipexole, a dopamine agonist, in which it outperformed placebo. The dosages in these studies that were reviewed by Dr. Berardelli ranged widely from 0.125 mg t.i.d. to 1 mg t.i.d. Interestingly, the authors did not mention levodopa-carbidopa despite being another dopamine agonist.

Antidepressants have also been studied in Parkinson’s with several trials showing efficacy greater than placebo. There have also been several negative trials, somewhat like what we see in trials of major depression when the unpublished trials are also included. No particular antidepressant is better than another, having been trials of SSRIs, SNRIs, tricyclics, and MAOIs. Therefore, which is better—pramipexole or an antidepressant?

There is 1 head-to-head trial where both of them worked. Interestingly, the patients on sertraline had more side effects. One might think it is the other way around, even though the dosing of pramipexole in that study was quite aggressive, 1.5 mg to 4.5 mg per day. Also, one might think that psychotherapy would be ineffective if the mechanism of depression is a neuronal loss, but several small trials have shown benefit. In a randomized trial, add-on CBT vs treatment as usual, the remission in the CBT group was 56% vs 6% for routine clinical management. Based on that study and the support of the results of several smaller open trials, the authors of this review conclude that psychotherapy is a “useful adjunct.”

Likewise, the authors also reviewed a remarkable number of studies on physical activity effects on depression in Parkinson’s. There is a reason for physical activity programs in Parkinson’s. However, looking at the effects on depression, the trials are small and open, and the conclusion is open-ended. Exercise and physical therapy appear to be able to improve depression, but it is still unclear which interventions should be recommended.

Then finally, psychotic symptoms. Dopamine antagonists can worsen motor symptoms. So, numerous studies have examined clozapine and quetiapine for its lighter touch on the dopamine system. In 1 head-to-head study, clozapine was more effective than quetiapine, even at low clozapine doses, though we have to cope with blood dyscrasia. When looking at quetiapine, several studies found it ineffective vs placebo, again looking at psychotic symptoms in Lewy body dementia. Two other studies used up to 400 mg and saw benefits with no worsening of the motor symptoms.

Finally, there is pimavanserin. We will come back to this in subsequent Quick Takes because, to my surprise, after reviewing the randomized trials, the Italian specialists conclude “whether new drugs, such as serotonin inverse agonists, and other approaches may have an impact on this disabling condition needs to be confirmed.” In other words, they do not appear overwhelmed by the efficacy data for a drug that costs in the United States at least $3,000 a month.

In summary, in Parkinson-associated depression, do not forget psychotherapies, including physical therapies and pramipexole, perhaps before antidepressants. For psychotic symptoms, think not just of quetiapine, where you might have to push the dose, but also think of low-dose clozapine and, of course, the fancy new $3,000 pimavanserin.

Abstract

Treatment of Psychiatric Disturbances in Hypokinetic Movement Disorders

Isabella Berardelli, Daniele Belvisi, Massimo Pasquini, Andrea Fabbrini, Federica Petrini, Giovanni Fabbrini

Introduction: We reviewed studies that assessed the treatment of psychiatric disturbances in Parkinson’s disease and atypical parkinsonisms. Neuropsychiatric disturbances in these conditions are frequent and have a profound impact on quality of life of patients and of their caregivers. It is therefore important to be familiar with the appropriate pharmacological and non-pharmacological interventions for treating these disorders.

Areas covered: The authors searched for papers in English in Pubmed using the following keywords: Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, depression, apathy, anxiety, fatigue, sleep disorders, obsessive compulsive disorders, psychosis, hallucinations, delusions, impulse control disorders.

Expert opinion: In Parkinson’s disease, depression may benefit from the optimization of dopaminergic therapy, from the use of antidepressants acting on both the serotoninergic and noradrenergic pathways and from cognitive behavioral therapy. Psychosis in Parkinson’s disease may improve with the use of clozapine; the serotonin inverse agonist pimavanserin has been shown to be effective. Treatment of impulse control disorders is primarily based on the removal of dopamine agonists. No controlled studies have investigated the treatment of neuropsychiatric disorders in multiple system atrophy, progressive supranuclear palsy or corticobasal degeneration. Acethylcholinesterase inhibitors may be used to treat hallucinations in Lewy body dementia.

Reference

Berardelli, I., Belvisi, D., Pasquini, M., Fabbrini, A., Petrini, F., & Fabbrini, G. (2019). Treatment of psychiatric disturbances in hypokinetic movement disorders. Expert Review of Neurotherapeutics, 19(10), 965-981.