Parkinson's is a neurodegenerative disorder characterised by tremor, rigidity and slowness of movement (Imran et al, 2019), and is thought to affect just under 1% of the over-60s population. Parkinson's was originally thought of as a movement disorder only; however, it has now been found to affect a multitude of areas and can have non-motor symptoms such as anosmia, insomnia, depression, anxiety and constipation (Pajares et al, 2020). The average age of onset is 60 years old and only 5-10% of patients are diagnosed under the age of 50 (Parkinson's UK, 2023). Owing to the UK's ageing population cases are predicted to rise by a fifth by 2030. In comparison, schizophrenia and other schizophrenia spectrum disorders (SSDs), such as schizoaffective disorder, delusional disorder, or psychosis, have a usual age of onset of under 25 years for males and under 35 years for females (Gaughran and Pillinger, 2021). National prevalence varies according to individual diagnoses with 0.87% for schizophrenia (Gaughran and Pillinger, 2021) and rising as high as 3.06% for lifetime prevalence for all psychotic disorders (Perälä et al, 2007).
There are millions of people around the world who have one of these conditions, but there is a scarcity of research documenting the two together (de Jong et al, 2014). Where such research does exist it mainly consists of a few documented case studies (Grover et al, 2017). When these conditions coexist it can prove challenging for clinicians to treat owing to the severity of one condition being worsened by the treatment of the other, because of them being caused by opposite pathophysiology in the brain. However, emerging evidence would suggest that this comorbidity is not as rare as first thought (Kuusimäki et al, 2021) and therefore further studies into their comorbidity and how best to treat and support these individuals would be valuable.
There is a lot of literature available about antipsychotics causing Parkinsonian symptoms (Shin and Chung, 2012). Similarly, there is also a large amount of research into psychosis being induced by anti-Parkinson's medication, with prevalence rates ranging between 20% and 60% (Weintraub et al, 2011; Carpenter et al, 2015). In both cases these symptoms are often alleviated when the relevant medications are reduced or discontinued (Aarons et al, 2012). The research around the comorbidity of these two conditions is mostly limited to a small number of case studies (de Jong et al, 2014; Oh et al, 2017; Grover et al, 2017) with no larger research studies (de Jong et al, 2014). Winter et al (2006) commented that several case reports only confirm the diagnosis of Parkinson's post-mortem as the patient's symptoms were deemed to be medication side effects in life. It is also suggested that long-term exposure to neuroleptic medication can be a risk factor for Parkinson's, even when the medications have been stopped for several years. However, Jeong et al (2021) reviewed this theory and challenged it with an alternative view, suggesting that patients who later develop Parkinson's actually have an underlying Parkinson's pathology, and it is the use of dopamine-blocking medications that trigger the pathology to a clinical level, whereas it may not have manifested otherwise. On the rare occasion that these two disorders do exist together it would be challenging to stop the medication of either without a negative impact on the patient's health and, as a result, this can have huge implications for clinicians (see case study in Box 1).
Box 1.Case studyJohn Adams (not his real name), a 52-year-old white male, was admitted to a mental health hospital because of concerns about his mental state. He had been diagnosed with Parkinson's 8 months earlier and was immediately started on anti-Parkinsonian medication after reporting an increasingly worse limp and unilateral difficulty with swinging his arm during the past year. He had also previously been diagnosed with paranoid schizophrenia and had developed strong, delusional ideas over a period of 10 months prior to his admission.Mr Adams was also thought to have an autism spectrum disorder. He first presented to mental health services at the age of 43, with anxiety and paranoid delusions. He was given a short course of venlafaxine, olanzapine and diazepam. He stopped taking the medications a few months later but was again started on fluoxetine and trifluoperazine the following year, having developed paranoid thoughts about people trying to break into his house. He had been off medication for several years, until the year of hospital admission when he was again started on olanzapine and citalopram and later promethazine. Mr Adams had tried to kill himself twice following the diagnosis of Parkinson's.On admission, Mr Adams was taking Sinemet (containing levodopa and carbidopa) for Parkinson's, aripiprazole for schizophrenia and citalopram for depression. He continued to report a lot of functional difficulties such as falling when trying to get into bed, struggling to do up his buttons/zips when getting dressed and spilling his food when feeding himself. He exhibited difficulty with walking in which he struggled to initiate movement and would then break into a shuffling run and subsequently struggle to stop. Mr Adams had a marked unilateral tremor and struggled to control his movements in his left arm. He also continued to have very marked delusional persecutory ideas, delusions of being controlled by others and pressured speech. He remained moderately depressed and was highly anxious.His psychiatric medical team felt that the first priority should be to treat the symptoms of depression and delusions more aggressively by increasing his medications, despite the risk to Mr Adams' functional and motor skills. At his next neurology review, the neurology team stated that his psychiatric medication needed to be drastically decreased and Sinemet increased in order to combat the motor symptoms he was experiencing.The two teams were unable to reach a decision that would best suit Mr Adams' needs and his medication continued to yo-yo between the two extremes for the initial treatment period. He was also offered physiotherapy and occupational therapy in an attempt to help daily functioning.The neurology team continued to express concerns about the adverse impact of antipsychotics on Mr Adams' Parkinson's symptoms and approximately 18 months after admission he was changed onto clozapine. There was a marked improvement in motor symptoms following this change. Unfortunately, this did not last and over the next 12 months there was a significant deterioration in Mr Adams' Parkinson's symptoms. This included the introduction of lip smacking, a constant shuffling gait, stiffness of upper and lower limbs sometimes requiring the use of a wheelchair, and involuntary neck and head movements that made eating very difficult.Mr Adams moved to a new ward at this point and was transferred to a new psychiatric consultant. In a relatively short period of time he was also put under a new neurologist. The anti-Parkinsonian medications were increased and Mr Adams was able to regain his mobility to not need the wheelchair, although he still walked with a stick. Unfortunately, with the increase of his Parkinson's medication he had a return of paranoid delusions, which had previously dissipated with the introduction of clozapine. As a result, clozapine was increased. He then began to develop involuntary movements of his right arm and it was agreed that this could be a tardive effect of the clozapine or being dyskinetic secondary to co-careldopa. His team worked together and adjusted different medications gradually to find the best balance for his care and establish the best quality of life possible. The two leading doctors also worked closely with occupational therapy, physiotherapy and nursing to provide a holistic care plan.The original treating team found it incredibly difficult to treat both of these conditions as any increase in medication for one disorder would greatly worsen the other. There was a lack of integrated working between the psychiatric medical team and the neurology team, with each specialty considering their own diagnosis to be the treating priority. However, when these opposing teams worked together, Mr Adams had a great improvement in his overall health.Unfortunately, due to the degenerative nature of Parkinson's it is likely that Mr Adams's health will deteriorate again, but if his clinicians continue to work together they should be able to maintain the best quality of life as possible for him.
Marsh et al (2004) found that 22% of patients with Parkinson's had psychotic features such as hallucinations or delusions, 56% of those also had a further psychiatric comorbidity such as depression or anxiety. This was a small study, but they were able to establish that those with psychotic features had significantly greater motor, functional and cognitive deficits than those without psychotic features. Imran et al (2019) carried out a similar study on a much larger cohort and found similar results. They concluded that Parkinson's patients with psychiatric comorbidities are more likely to have an impaired quality of life and a more severe Parkinson's progression. However, neither of these studies differentiated whether these were drug-induced symptoms; therefore, it's impossible to know if these outcomes can be generalised to comorbid patient cohorts.
Smith et al (2013) and Gabilondo et al (2017) both found that people with schizophrenia have a higher likelihood of having a physical health comorbidity including Parkinson's. However, neither of these studies accounted for the occurrence of drug-induced parkinsonism and therefore their results cannot be considered an accurate reflection of the comorbidity of idiopathic Parkinson's. Kuusimäki et al (2021) used national registers to establish the co-existence of Parkinson's and SSD after excluding any drug-induced cases, although this did include some cases with historical medication use. They found that having a diagnosis of SSD actually increases the chances of developing Parkinson's. This ties in with Winter et al (2006) who suggested that a lot of comorbid cases are dismissed as side effects and as a result are not treated adequately or appropriately.
Kuusimäki et al (2021) hypothesised that the increased likelihood of Parkinson's in those with SSD could be due to antipsychotic drugs causing long-term hypodopaminergic neural states by blocking the dopamine receptors and causing cell degeneration.
The neurotransmitter dopamine plays a very important role in both SSDs and Parkinson's, although the two conditions are linked to the impact of dopamine in two different brain pathways (Sharma and Aggarwal, 2019). It was originally thought that dopamine changes were the only cause of both these conditions but research has demonstrated that this is not the case and the development of these illnesses is multifactorial.
The majority of SSDs are hypothesised to be caused due to an increase in dopamine, conversely Parkinson's is thought to be caused by the decrease of dopamine (Sharma and Aggarwal, 2019). This causes an inverse relationship of dopamine between the two conditions and, as a result, leads to the worsening of one condition when the other is treated.
In people with Parkinson's it has been found that dopamine-producing cells may be reduced by up to 80%. This drastic reduction of dopamine can result in the motor symptoms such as bradykinesia, akathisia, rigidity and dystonia (Gupta et al, 2017).
Parkinson's is a progressive degenerative condition where symptoms increase over time (Splittgerber, 2019) although the exact cause of this degeneration is unknown (Sonne et al, 2020). Research into theories that may explain why this might be happening has been undertaken and include inflammation (Pajares et al, 2020), oxidative stress (Trist et al, 2019), and environmental toxins (Jo et al, 2021). There is also thought to be a genetic component; however, this is rare and only accounts for 3-5% of cases (Klein and Westenberger, 2012; Parkinson's UK, 2019).
The dopamine hypothesis of schizophrenia focuses on the mesolimbic pathway of the brain (Gould, 2014). The dopamine hypothesis was originally suggested in the 1960s, but it has been adapted and updated over the 60 years since then (Brisch et al, 2014). The theory suggests that the increase in dopamine in the mesolimbic pathway results in what are known as positive symptoms of schizophrenia, these include delusions and hallucinations.
Research has shown that up to a third of people with schizophrenia do not respond to most antipsychotics, suggesting their symptoms are either unrelated to dopamine or are multifactorial (Brisch et al, 2014). This group of patients are known as ‘treatment resistant’ and are often commenced on clozapine, which not only blocks dopamine receptors but also targets serotonin, noradrenaline, acetylcholine and histamine (Stahl, 2013). Although dopamine is still considered to be the main factor in schizophrenia, research has shown that there are other chemical imbalances such as in serotonin and glutamate (Eggers, 2013; Uno and Coyle, 2019) as well as neuroanatomical differences such as a reduction in brain volume (Gaughran and Pillinger, 2021).
Medications used to treat Parkinson's act by increasing dopamine in the nigrostriatal pathway of the brain; however, it has an inadvertent effect in other pathways as well and this could subsequently cause schizophrenia-type symptoms such as psychosis or hallucinations, and can worsen the presentation for people with a comorbid schizophrenic disorder (Gupta et al, 2017). The medications used to treat schizophrenia aim to lower dopamine levels, and can therefore produce Parkinsonian symptoms in patients without Parkinson's or worsen symptoms in those with Parkinson's. It is therefore vital to be careful when treating these conditions in tandem to try to maintain a balance between the two and alleviate the person's condition without also worsening it (Gupta et al, 2017) (see Box 1).
As demonstrated, dopamine plays a huge role in the development of both Parkinson's and SSDs (Gupta et al, 2017). There is currently no single test to determine the diagnosis of Parkinson's (Kumar and Clark, 2017). Because of this, and the way that both conditions are medicated, it can be very difficult for clinicians to determine if these presentations are idiopathic disorders or medication-induced effects. The response to medication change is normally the key indicator to determine whether this is medication induced because effects normally alleviate when medications are reduced (Grover et al, 2017), although they can persist in up to 30% of cases (Jeong, et al, 2021). When Parkinsonian symptoms are induced by antipsychotics they usually present symmetrically and without resting tremors, whereas idiopathic Parkinson's normally start asymmetrically.
There is research into a new test for Parkinson's which analyses lipids within sebum, the oily substance on the surface of the skin. Initial tests have shown an 85% accuracy for diagnosis (Sinclair et al, 2021). The concept of a skin test is supported by Ezquerra et al (2019) who found that there are biological changes associated with Parkinson's not only in the brain, but also in peripheral autonomic nerves and non-neural tissues such as skin and blood.
This would be a huge step in diagnostic ability and potentially eliminate any doubt over comorbidity; it would then be easier to establish a treatment programme that catered for both disorders. It also highlights the need for an integrated approach to care, which has been found to be crucial in these cases (Gupta et al, 2017; Imran et al, 2019).
Anti-Parkinson's medication works by increasing the dopamine levels in the brain; however, as the disease develops, patients may experience a lack of responsiveness to the medication and experience ‘on and off’ episodes where the medication is or isn't working, so patients must also be reviewed regularly due to the likelihood of the medication's effect changing over time (Harrow and Jobe, 2013; Mizuno, 2019). According to Safarpour et al (2023), despite levodopa being considered the definitive medication for Parkinson's, other dopaminergic treatments should be trialled initially due to the increased risk of development of dyskinesia with levodopa. Levodopa can then be used when symptoms become more severe. Levodopa has been found to become less effective for Parkinson's over time, with up to 75% of patients experiencing what is known as ‘wearing off’ if it is used for more than 10 years (Mizuno, 2019) and 18% experience this within 5 years. Wearing off refers to the decreasing duration of effect of levodopa, resulting in periods of uncontrolled Parkinson's symptoms between doses (Kumar and Clark, 2017). In order to combat this effect clinicians have to give higher and higher doses of dopamine replacement. However, this is impossible in those with comorbid SSD because of the risk to the patient's mental health (de Jong et al, 2014). Although, in cases when comorbidity has not been established, this treatment approach may go ahead and subsequently exacerbate SSD. Research suggests that mental health symptoms of Parkinson's are often overlooked or ignored completely, with priority being given to stabilise motor symptoms only (Ghanemi, 2013).
There are several international published guidelines for best practice approaches to treating Parkinson's (American Academy of Neurology, 2015; National Institute for Health and Care Excellence (NICE), 2017; Safarpour et al, 2023) and schizophrenia (NICE, 2014; Keepers et al, 2020; Gaughran and Pillinger, 2021), although these do have their limitations. For example, the NICE guidelines for schizophrenia are 7 years old. Nevertheless, there is no formal guidance for the treatment of both conditions together (Grover et al, 2017).
Parkinson's guidelines offer advice on treatment for Parkinson's-induced psychosis and suggest that quetiapine, clozapine and pimavanserin are the best antipsychotics for Parkinson's as they do not worsen motor symptoms. Pimavanserin is the first antipsychotic drug approved by the US Food and Drug Administration for psychosis in Parkinson's (Dashtipour et al, 2021). However, there is limited availability in developing countries and as yet pimavanserin has not been extensively researched (Sharma and Aggarwal, 2019). It is also worth noting that it has been specifically approved for Parkinson's-induced psychosis, not for comorbidity of Parkinson's with SSD; in fact, it has been found to have low efficacy as an antipsychotic and identified as having skewed research that focused on motor safety only (Seppi et al, 2019). It was also found to have a high dropout rate in studies due to 14% of patients not seeing a benefit and 12% reporting unmanageable side effects (Sellers et al, 2019).
Although there are no high-quality randomised controlled trials looking at the efficacy of quetiapine for the treatment of Parkinson's psychosis, it has been found to be equally as effective as clozapine in many small studies and case studies (Seppi et al, 2019). This is thought to be because quetiapine has a faster dopamine receptor dissociation and therefore does not block the receptors for as long as other antipsychotics (Sharma and Aggarwal, 2019).
Clozapine, on the other hand, is known to have poor dopamine selectivity (Sharma and Aggarwal, 2019) owing to it being a unique antipsychotic with a very complex binding profile. It can be very effective in people who have not had a response to other antipsychotics but due to the possibility of high-risk side effects its use is recommended only in those who have not responded to at least two other antipsychotics (Gaughran and Pillinger, 2021). Clozapine's side effects include constipation, neutropenia, agranulocytosis, cardiomyopathy and myocarditis (Gaughran and Pillinger, 2021).
Case studies of comorbid Parkinson's and SSD patients suggest that quetiapine and clozapine also work in practice for these conditions (Orr et al, 2001; Urban et al, 2003; Stoner et al, 2005; Winter et al, 2006; de Jong et al, 2014; Carpenter et al, 2015; Grover et al, 2017; Sharma and Aggarwal, 2019). There is also one case study that documents successful treatment with aripiprazole (Fujino et al, 2010) and another review that found positive effects from risperidone (Weintraub et al, 2011), although both of these medications have been dismissed in other research (de Jong et al, 2014) because of the therapeutic benefit to mental health not outweighing the increased motor effects seen (Simonet et al, 2020).
There is plenty of research that also looks into alternative treatment methods for Parkinson's other than dopaminergic medications. This includes a replenishment of endocannabinoids, or use of cannabidiol, which have been found to have good effects in reducing motor dysfunction in Parkinson's (Jamwal and Kumar, 2019). However, the use of cannabis has been found to greatly increase the chances of developing schizophrenia, increases the risk of relapse, and is also associated with a reduction in medication concordance, so would not be suitable for an SSD comorbidity (Gaughran and Pillinger, 2021).
Other non-pharmacological treatments have been found to have some positive benefit, including caffeine (Ren and Chen, 2020), deep brain stimulation (Safarpour et al, 2023), and surgical lesions (Hall, 2015), although this more extreme approach is currently limited to those patients who have not responded to other treatments (Splittgerber, 2019). Other treatment ideas such as bee venom or human fetal tissue transplantation have been shown not to be efficacious (Fox et al, 2018). Alternative treatment approaches might have great importance for those with Parkinson's and SSD comorbidity as they can be used to treat the Parkinson's symptoms without risk of worsening SSD; however, further research would be needed to confirm this.
As well as the difficulty for clinicians of finding the right combination of medication to treat both disorders, there are also other lifestyle factors that can worsen both conditions and are exacerbated by the comorbidity of having both conditions together. One such factor is stress; van der Heide et al (2021) found that patients with Parkinson's experienced more stress than control subjects. They found that the risk of stress is not only higher in Parkinson's but that when present it also significantly worsens both motor and non-motor symptoms and can quicken the progression of degeneration (Hiller et al, 2017), and can also be a trigger for the development of the disease itself (Djamshidian and Lees, 2014). The comorbidity of schizophrenia further compounds this issue because it has been found that in those with schizophrenia there is a disrupted stress response and an increased presence of dopamine in the striatum (Schifani et al, 2018). Stress has also been documented to be a triggering factor for schizophrenia (Gaughran and Pillinger, 2021). The effect of stress on comorbid Parkinson's and schizophrenia has not previously been studied, but it could be hypothesised that the combination of an increased risk of stress, and the resulting negative impact, could be a risk factor contributing to the development of either condition as a second comorbidity.
van der Heide (2021) found that the best ways to deal with stress in Parkinson's were non-pharmaceutical and reported that 83.1% of participants reported a reduction through physical exercise and 38.7% found improvement in both motor and non-motor symptoms when practising mindfulness skills.
Parkinson's and SSD also have overlaps with some of their associated side effects and medication-induced comorbidities. These includes the risk of constipation, which has been found in 60-80% of Parkinson's patients. This is thought to be due to damage to the nervous system, as well as decreased mobility and a lack of fibre and fluid intake associated with dysphagia (British Dietetic Association and Parkinson's UK, 2021). Constipation is also a known side effect of many antipsychotics and therefore frequently seen in those with SSD, but especially with those on clozapine (Gaughran and Pillinger, 2021). It is therefore important to regularly monitor patients for constipation and offer appropriate advice and treatment for this when necessary. There is also a much higher than average chance of developing diabetes in these populations, which has been found to be 36% in those with Parkinson's (Pajares et al, 2020) and 15% in those with schizophrenia (Annamalai et al, 2017) compared to only 9% in the general population (Saeedi et al, 2019).
As mentioned previously, there is a lack of guidance for best management for these two conditions when dealt with at the same time, and the scarce research that is available is primarily based on individual case studies. It has long been thought that individual case studies are the lowest level in the hierarchy of evidence due to their lack of generalisability (Murad et al, 2016). However, Tsang (2014) stated that case studies still hold some merit in terms of testing theories. It is not possible to establish if the treatment approaches that work for a handful of cases can work on a much wider scale and there will need to be further research carried out to determine that.
People with a serious mental illness (SMI) are known to die on average 15 to 20 years earlier than the general population (Public Health England, 2018). This could partly explain the lack of reported cases of comorbidity due to the average age of onset for Parkinson's being after the premature death of those with an SMI (Kuusimäki et al, 2021). Parity of esteem programmes are specifically targeting this gap and aiming to bring equality to those with SMI (Millard and Wessely 2014; Royal College of Nursing, 2019; British Medical Association, 2020). If those with an SSD start to have an increased lifespan this could result in a much higher number of cases of people who develop a Parkinson's comorbidity.
These patients can only achieve a good quality of life if both of their conditions are treated in unison and, as a result, would be best dealt with by an integrated service (Wilkinson et al, 2017). The NHS Long Term Plan set out a plan for an integrated care system (NHS England/NHS Improvement, 2019a), which would ensure that different health services are able to work collaboratively and join previously divided services such as physical and mental health. This will also enable more personalised care and provide more co-ordination, especially for those with long-term health conditions (NHS England/NHS Improvement, 2019b).
There is a need for further research into these two conditions as a comorbidity, not just into medication but also non-pharmacological treatments and supportive therapies. It would also be extremely beneficial to patients' quality of life if research was conducted into exacerbating lifestyle factors such as stress, and associated high-risk side effects in the context of this comorbidity. Once this research has been completed it will then be possible to establish best practice guidance and establish specific services aimed at this group of patients.
KEY POINTS
- Parkinson's and schizophrenia spectrum disorders can co-exist without being medication-induced
- Treatments for one condition can negatively impact the other
- Mental health conditions and neurodegenerative conditions are still not completely understood, with further research needed to understand how they co-exist and interact
- There is ongoing research into new and alternative treatment ideas which might revolutionise how these two conditions are managed
CPD reflective questions
- Have you ever been blinded by diagnostic overshadowing and dismissed new symptoms as side effects, instead of investigating for other causes?
- Do you think you could differentiate between Parkinson's-induced psychosis, or drug-induced Parkinsonisms, and true comorbid conditions?
- Has there been a time in your own practice when two different specialties have struggled to agree on a treatment plan?