This review concerns the topic of evidence based pharmacological treatment of apathy in PD. Although several studies are done, it is hard to draw strict conclusions about the best evidence-based pharmacological treatment. Overall, there was a substantial heterogeneity with respect to study design, analysis, domain, interventions, and outcome measures in the selected studies. We tried to neutralize this by strictly defining the in- and exclusion criteria for the selection of the articles. Nevertheless, in some studies, standard oral anti-parkinsonian medication was the comparative treatment and in other studies, the intervention treatment was given as an add-on to the standard oral anti-parkinsonian medication.
Based on the findings in this review, one could say with caution that rivastigmine(26), pramipexole(24), istradefylline(20), and selegiline combined with levodopa(27) are better in the treatment of apathy in PD than monotherapy with levodopa, DA or placebo (Table 3). These studies show significant outcomes in favor of the intervention treatment. Other treatment like apomorphine(21, 22), rasagiline(25, 27), and levodopa (7, 28) have contradictive results and therefore inconclusive.
Table 3
Favorable treatment | Unfavorable treatment | P-value | Author |
Istradefylline | None | p = 0.005 | Nagayama 2019 (20) |
Apomorphine | Standard care | p = 0.02 | Auffret 2017 (22) |
Pramipexole | Levodopa | p = 0.02 | Perez-Perez 2015 (24) |
Rivastigmine | Placebo | p = 0.034 | Devos 2014 (26) |
Rasagiline/ selegiline & Levodopa | Levodopa or DA | p = 0.032 | Krishna 2014 (27) |
Levodopa (OFF-first) | 12 hours without levodopa before levodopa | p < 0.0001 | Czernecki 2002 (28) |
Trend to favorable treatment | Trend to unfavorable treatment | | |
Pramipexole | Ropinirole | p = 0.06 | Perez-Perez 2015 (24) |
Levodopa (ON-first) | 12 hours without levodopa after levodopa | p = 0.068 | Czernecki 2002 (28) |
Comparative treatment | Comparative treatment | | |
Apomorphine | None | p = 0.27 | Houvenaghel 2018 (21) |
Apomorphine | Standard care | p = 0.72 | Auffret 2017 (22) |
Rotigotine low dose | Placebo | p = 0.977 | Hauser 2016 (23) |
Rotigotine high dose | Placebo | p = 0.859 | Hauser 2016 (23) |
Ropinirole | Levodopa | p = 0.45 | Perez-Perez 2015 (24) |
Rasagiline | Placebo | No significant difference | Barone 2015 (25) |
DA, levodopa or both | None | No significant difference | Spalletta 2014 (7) |
By using the Cochrane Collaboration’s Risk of Bias evaluation tool, we found that most studies had a high risk of bias because of selection bias based on the type of study, like cohort studies and observational studies. Due to these biases the findings may be difficult to generalise to a regular population of PD patients with apathy. The studies with the lowest risk of bias were the multicentre RCT’s which investigated rivastigmine(26), rasagiline(25), and rotigotine(23), yet these studies were funded by the pharmaceutic industry or did have small sample sizes. Combining the results of the studies with a focus on favorable significant outcomes and the risk of bias, we would advise rivastigmine as a treatment of apathy in patients with PD.
Based on the comorbidity of each patient, one should tailor the treatment for apathy to that unique patient. Rivastigmine can cause gastro-intestinal side effects like nausea and vomiting(29), although it can have beneficial effects on dementia and cognition (30). Istradefylline is a relatively new treatment for PD symptoms and not yet approved in Europe. A proven side effect of istradefylline on short term is aggravation of dyskinesia, however more studies should be performed on the long term side effects in PD(31). Pramipexole can cause side effects like sleep attacks, somnolence, visual and auditory hallucinations, and impulse control disorders. On the other hand it is mentioned as a good option for treating a depression in PD (32), so those patients with both apathy and depression may benefit from pramipexole. Selegiline is mainly prescribed in the early stages of PD (33). It can cause side effects like nausea, vomiting, sleeplessness, dry mouth, orthostatic hypotension, dyskinesia(34), and hallucinations(35).
If there is apathy and cognitive impairments as comorbidity in PD, a first step in the treatment is to stop anti-cholinergic medication as this may worsen cognitive impairment(36). Also DA and MAO-B inhibitors could worse the cognition in patients. Other causes of cognitive disturbance in PD, such as delirium, should be investigated and treated. However, if apathy and cognitive disturbances or dementia are comorbid in PD then the findings of this review support rivastigmine as an add-on treatment. Because there is limited experience in using rivastigmine for the indication of apathy in PD, one should refer to a movement disorder specialist.
In patients with apathy and possible depression it is important to distinguish and diagnose a comorbid depression as this is a treatable disorder in PD. Depressive patients have a depressed mood, sad and negative feelings, feelings of guilt, suicidal thoughts, negative thoughts, are pessimistic, and have a lot of self-criticism. These symptoms are not present in patients with only apathy(2). First line treatment would be to start antidepressant medication, however pramipexole as add-on could be considered in patients with both apathy and (persisting) depression(24, 32).
Treating PD with more than just monotherapy might result in better improvement of PD and concurrent neuropsychiatric symptoms such as apathy. The findings of this review indeed support the use of “add-on medication” in the treatment of apathy(22, 26, 27). Current data suggest that improving the underlying PD might be the most effective way to treat apathy in PD. This is also seen in other non-motor symptoms of PD, such as pain, hallucinations, anxiety and depression, which show improvement with better treatment of PD. In case of apathy in PD, one should tailor the non-pharmacological interventions, like establishments of daily schedules to keep the patient engaged (37), psychotherapy, and occupational therapy (38). One should keep in mind that not only medical treatment, but probably the combination with non-pharmacological options is the best way to treat apathy in PD.
Strengths and limitations
Although research is sparse on evidence-based pharmacological treatment of apathy in PD we tried to give an extensive and complete update of the research done in this field. The latest update known in the literature was done until December 2016 and published recently (39), therefore missing publications after 2016. We performed an extensive search until November 2019, therefore adding to the existing literature. We searched for studies that assessed apathy as both as a primary outcome measurement. By doing so we included as many studies as possible about evidence-based pharmacological treatment for apathy in PD in order to get a complete overview of the existing data. Therefore, also negative findings were included in this review in order to preclude a publication bias. Another strength of this review is that we assessed the risk of bias. This showed that almost all studies had some high risk of bias, as based on their type of study, pharmaceutical influence, and small sample sizes.
An important limitation is that the studies show a broad heterogeneity. This may possibly be the cause why results of different studies are in conflict with each other and conclusions are not easily to drawn. Furthermore, we notice that apathy is a neuropsychiatric symptom that can be easily missed, or not be the focus of trials.
Implications for further research
Apathy in PD is a challenging problem, however by good treatment it can improve the prognosis and quality of life of patients and their caregivers. Further research needs to be done in this field. The first, and most important, step for further research is that apathy should get more attention in guidelines (40, 41) and in research. Not only more research needs to be done, but research with good methodological strategy, like RCT’s, needs to be performed to prevent high risk of bias. Data out of these RCT’s should be collected to come to “big data” meta-analyses. This will lead to better protocol and guidelines in the medical treatment of apathy in patients with PD. If apathy is treated in patients with PD, there will be likely more adherence to treatment for other symptoms of PD in the individual patient.
Implications for practice
It seems very important to achieve better clinical recognition of apathy in PD. This is especially the case when the patient does not improve as expected on the prescribed pharmacological treatment, or when caregivers complain on the adherence of treatment in patients. There are non-pharmacological options in the treatment of apathy in PD, like psychotherapy, and occupational therapy (38), but medical treatment could also play an important role in the treatment of apathy in PD. Few conclusions can be drawn from this review, but we suggest with caution that rivastigmine, pramipexole, istradefylline, and selegiline combined with levodopa is better in the treatment of apathy in PD than monotherapy with levodopa, DA or placebo. Combining the results of the studies with a focus on favourable significant outcomes and the risk of bias, we would advise rivastigmine as a treatment of apathy in patients with PD. One should keep in mind that every patient has different comorbidity and experience different side effects, so we should tailor the treatment of apathy in PD to every unique patient.