Novel case of Parkinson’s disease and schizophrenia: challenges in the management

Abstract

Coexistence of idiopathic Parkinson’s disease (iPD) and schizophrenia can pose great diagnostic and therapeutic challenges because of their pathophysiology. Our case highlights such challenges in management. We present a case of 73-year-old man who had parkinsonism for last several years and was also diagnosed with schizophrenia. Due to lack of collateral information about the onset of symptoms and clinical course, it was difficult to distinguish iPD from neuroleptic-induced parkinsonism. Even though, certain clinical findings may help to differentiate between the two conditions, single positron emission computerized tomography/DatScan was used to confirm the diagnosis of iPD. Treatment of coexisting iPD and schizophrenia can be challenging, and a delicate pharmacologic balance must be maintained to ensure adequate symptomatic control. Current evidence suggests that clozapine is a better choice for managing psychosis in these patients due to its unique receptor profile and better safety data.

Background

Idiopathic Parkinson’s disease (iPD) and schizophrenia are a rare co-occurrence, which can cause great diagnostic and therapeutic challenges for the clinicians because of their unique pathophysiology. iPD is a complex neurodegenerative disorder characterised by motor and non-motor symptoms. Clinical diagnosis requires the presence of bradykinesia and one other motor symptom, including rest tremor, rigidity and gait impairment.¹ It has been increasingly recognised that individuals with iPD may experience host of non-motor symptoms. Neuropsychiatric manifestations are frequently reported in iPD. These features include depression, dysthymia, anxiety, apathy, psychosis, impulse control disorders, dopamine dysregulation syndrome, sleep disorders and cognitive deficits.² Although the use of antidepressants, atypical antipsychotics and cholinesterase inhibitors may have a positive effect on the neuropsychiatric symptoms, therapeutic responses are frequently suboptimal. This remains a major area of unmet therapeutic need.

Schizophrenia is a chronic psychotic disorder characterised by the presence of delusional beliefs, hallucinations and disturbances in thought, perception and behaviour. Traditionally, symptoms have been divided into two main categories: positive symptoms such as hallucinations, delusions and formal thought disorders, and negative symptoms such as anhedonia, poverty of speech and lack of motivation. A third cognitive domain is also increasingly recognised to include deficits in attention and executive function. The diagnosis of schizophrenia is clinical, made exclusively after obtaining a full psychiatric history and excluding other causes of psychosis. Several studies postulate that the development of schizophrenia results from abnormalities in multiple neurotransmitters, such as dopaminergic, serotonergic and alpha-adrenergic hyperactivity or glutaminergic and Gamma aminobutyric acid hypoactivity.³

Available literature is limited to only a handful of case reports with the coexistence of both these conditions.^4–11 It poses a great diagnostic and therapeutic challenge for both psychiatrists and neurologists when dealing with such cases. The following case report will highlight the diagnostic and treatment challenges in a patient with iPD and schizophrenia.

Case presentation

We present a case of 73-year-old Caucasian man with past diagnosis of paranoid schizophrenia versus schizoaffective disorder and iPD (diagnosed by a private neurologist in 2008).

Presenting complaints

He was admitted involuntarily to the inpatient psychiatric facility in January 2019 due to paranoid belief that the staff at his assisted living facility were trying to kill him. He was also noted to have significant worsening of his PD symptoms and admitted to non-compliance with all medications prior to admission. Interestingly, he had a fixed delusion that one of his ex-colleagues, from a job he had decades ago, had the power to control and monitor his motor function and thus make it look like he had iPD. He was convinced that he did not have either PD or any psychiatric illness, hence believed that he did not require medications for either. Given this clear lack of insight into his illnesses, next of kin, patient’s son (power of attorney), was involved with decision-making throughout his admission.

Examination

Mental status: Montreal Cognitive Assessment revealed score of 23/30 with loss of points for delayed recall and visuospatial/executive function.

He appeared to be a white male of thin stature, dressed appropriately, with masked face, flat affect, tangential thought process with persecutory delusions, poor insight and no active auditory and visual hallucinations. He had persistent left hand, resting, pill-rolling tremor, with cog wheel rigidity, generalised bradykinesia, gait instability and freezing.

Psychiatric history

Patient denied history of taking any psychotropic medications and any history of suicide attempts. He reported a prior psychiatric hospitalisation approximately 40 years prior to current admission for ‘insomnia’ and ‘curiosity’ but claimed he was not given any formal diagnosis. He described events leading to that distant admission, including being chased by a group of people and belief that someone had placed birth control in his drink. Further details of his history were unavailable as he was estranged from his family until his son reconnected with him as an adult a few years prior to current admission and arranged his accommodation at an assisted living facility. Son confirmed long-standing history of unaddressed psychiatric issues, that led to losing a job, homelessness and problems maintaining social contacts in the past. Son reported not knowing psychiatric diagnoses as he was a toddler when parents divorced, and he became estranged from his father.

Records from our hospital revealed one prior inpatient psychiatric admission at our facility in 2015 when he was brought in by a friend after being found trespassing at a bank and refusing to return to his assisted living facility. Patient was discharged on low-dose quetiapine at the time. MRI of the brain performed during that admission was reported as showing no acute process and ‘ventricles and sulci normal in size and configuration’. Labs and urine drug screen from that admission were also unremarkable. Patient was then followed by both outpatient neurology and psychiatry clinics and maintained on quetiapine and carbidopa/levodopa. Low-dose valproic acid was added at one point due to concerns about ongoing verbal agitation in context of paranoia at assisted living facility. Due to ongoing paranoia described by both staff at assisted living facility and by son, quetiapine dosage was also up titrated. After examination, review of records and additional history from both patient and collateral, psychiatric diagnosis was changed to schizophrenia in 2017.

Medical history

Patient had no other medical history, including no prior history of strokes, seizures, alcohol or drug abuse. He has never smoked. There was no known history of any occupational exposure or head injury.

Family history

There were no reports of progressive neurological disorder, including iPD in the family. Patient’s son suspected that patient’s brother had a mental illness.

Social history

Patient was raised by biological parents with no history of childhood abuse, graduated from high school and completed 3 years of college. He had been married once for brief period decades earlier but estranged from his ex-wife and children until his son contacted him as an adult. He denied any legal history. He was living alone in a mobile home when initially diagnosed with PD in 2008.

Clinical course

During current hospitalisation, collateral history was obtained from assisted living facility, which revealed that patient had indeed refused all his medication for last couple of weeks prior to admission. Due to lack of therapeutic effect of valproate on paranoia and no prior history of labile mood, it was decided to wean him off valproate. Quetiapine 300 mg two times per day and carbidopa/levodopa 25/250 three times per day were continued. Patient did not require any rescue medications during stay and was never aggressive. Once clinically stable, he agreed to medication compliance. Patient was, therefore, discharged back to the same assisted living facility. However, patient was quickly re-admitted a few days later in February 2019, this time voluntarily, due to worsening psychosis. On re-admission, patient continued with the delusion that others could somehow control his movements and nervous system. Patient gave the example that his roommate at the assisted living facility could control his movements by reading certain words from his book. Patient again allowed contact with his son for collateral and safe discharge planning.

Investigations

Laboratory investigations were unremarkable (table 1). The diagnosis of iPD was questioned, due to lack of reports about the mode of onset and clinical progression of both PD and schizophrenia. He underwent ioflupane-labelled single positron emission CT (SPECT/DatScan) to differentiate between neuroleptic-induced parkinsonism (NIP) versus idiopathic parkinsonism (iPD). The images showed no significant uptake of iodine tracer in bilateral putamen and asymmetrically decreased uptake in the left caudate that was consistent with iPD (figure 1).

Table 1.

Laboratory data on admission (January 2019)

Hb	153g/L	Normal
WBC	6.4×109/L	Normal
Platelet count	217×109/L	Normal
Sodium	138 mmol/L	Normal
Potassium	4.2 mmol/L	Normal
Blood Urea Nitrogen	23 mg/dL	High
Creatinine	1.10 mg/dL	Normal
Calcium	9.4 mg/dL	Normal
Magnesium	2.0 mg/dL	Normal
Bicarbonate	24 mmol/L	Normal
Total bilirubin	0.5 ng/dL	Normal
Albumin	3.5 g/dL	Normal
Alkaline phosphatase	116 IU/L	Normal
Alanine aminotransferase	<5 IU/L	Low
Aspartate aminotransferase	21 IU/L	Normal
Thyroid stimulating hormine	1.48 μIU/ml	Normal
Serum valproic acid	17.4 μg/mL	Low
Serum ethanol	<10 mg/dL	Low
Rapid plasma reagin	Non-reactive	–
Hemoglobin A1c	5.7%	Normal
Vitamin B12	650 pg/mL	Normal
Folate	231 ng/mL	Normal
25-hydroxy vitamin D	32 ng/mL	Normal
Urinalysis	Normal	–
Fasting lipid profile	Normal	Normal
Benzodiazepines	Negative	–
Barbiturates	Negative	–
Cocaine	Negative	–
Amphetamines	Negative	–
Cannabis	Negative	–
Opiates	Negative	–

CT scan of the head without contrast did not show any acute abnormalities.

Hb, haemoglobin; WBC, white blood cells.

Figure 1.

DatScan: no significant tracer uptake in bilateral putamen, asymmetrically decreased radiotracer uptake in left caudate with preserved uptake in right caudate consistent with idiopathic Parkinson’s disease.

Differential diagnosis

NIP versus iPD were the main considerations. Asymmetry in parkinsonian signs, favourable response to levodopa intake and development of motor fluctuations hinted more in favour of iPD. Additionally, patient was not on any psychotropic agents when he was first diagnosed with iPD in 2008 and indeed per the son, had refused psychiatric evaluation prior to his hospital admission in 2015. Drug toxicity was ruled out via history and later urine drug screen. Another main consideration in the differential was PD psychosis (PDPsy). History of long-standing psychiatric issues leading to difficulty maintaining job, housing and relationships along with a past psychiatric hospitalisation decades earlier for what sounded consistent with psychotic symptoms was more consistent with a primary psychotic disorder. In addition, the type and severity of delusions hinted in favour of schizophrenia.

Treatment

Due to severe and refractory psychosis despite being on quetiapine for adequate length of time, alternative agents were considered, including pimavanserin and clozapine. Due to lack of definitive evidence for role of pimavanserin in management of primary psychotic disorder, clozapine was started and up titrated with improvement in acute worsening of psychosis. Clozapine levels were obtained during up titration and when on final dosage. Serum clozapine level on discharge dosage was low at 128 with serum norclozapine level of 118.

Due to worsening of motor symptoms and development of wearing off phenomenon, dose of carbidopa/levodopa was increased to 25/250 1 tab every 3 hours, five times per day. This did not lead to worsening of baseline delusions and favourable motor response was noted. Patient was discharged to a different assisted living facility on 100 mg of clozapine twice a day and carbidopa/levodopa 25/250, every 2 hours, with a plan for regular outpatient lab checks.

Outcome and follow-up

He has been stable since then (2 years) in terms of his delusions and parkinsonism and is closely being followed in psychiatry and neurology movement disorders clinic.

Discussion

Two important obstacles faced by the treating psychiatrists and neurologists in cases of comorbid schizophrenia and parkinsonism are to differentiate NIP from iPD and to maintain a pharmacologic balance while treating them so that both the conditions remain under adequate control.

NIP is the second most common aetiology of parkinsonism in elderly patients after iPD.¹² There are certain clinical features and neuroimaging findings that can help in differentiating the two conditions. Asymmetry and rest tremor are the two important clinical findings of iPD as opposed to NIP. In addition to that, whole body involvement is a feature of iPD, whereas NIP mainly involves upper torso.^{12 13} On the other hand, Lorberboym et al reported that NIP is clinically indistinguishable from iPD and brain imaging with a SPECT scan helps to determine whether parkinsonism is drug induced or idiopathic.¹⁴ Studies using single-photon emission CT with dopamine transporter (DAT) tracer suggest significant bilateral decrease of striatal DAT uptake in patients with iPD as compared with NIP.^{4 5 15}

Psychotic features are common in iPD, particularly as the disease progresses to dementia. PDPsy is defined with psychotic features occurring only after onset of iPD.¹⁶ Therefore, timing of psychosis onset is often enough to determine aetiology. However, when history is unclear or unavailable, distinguishing characteristics and the form of psychosis can provide clues. Visual hallucinations are by far the most common form of psychosis experienced in PDPsy,¹⁷ whereas patients with schizophrenia and other primary psychotic disorders often do not experience this phenomenon, and almost never experience visual hallucinations alone without other psychotic features. In contrast, bizarre, grandiose and systematised delusions are rarely, if ever, seen in iPD but are a common feature of schizophrenia spectrum disorders. Delusions themselves occur in 90% of patients with schizophrenia versus only 5% in iPD cases.¹⁷

There is limited data available on the management of cases with comorbid schizophrenia and iPD,^4–11 due to their rare coexistence. Dopamine replacement therapy in iPD patients can cause psychotic side effects or exacerbate existing psychosis, similarly neuroleptics used in schizophrenia can cause extrapyramidal side effects, including acute parkinsonism or may worsen chronic parkinsonism. Hence, treating such patients is always a dilemma. Our patient was able to tolerate carbidopa/levodopa with improvement in his PD symptoms for a long time, indicating that PD medications can be used effectively for management of PD in patients with primary psychotic disorder. Choice of antipsychotic medication in a patient with PD had been challenging. Weintraub et al reported predominant use of quetiapine in PD-related psychosis with rare use of clozapine.¹⁸ In 2016, FDA approved use of pimavanserin in PD-related psychosis and since then it is labelled as a safe alternative to quetiapine and clozapine. Pimavanserin is a selective serotonin 5-hydroxytryptamine_2A inverse agonist, which is proven to be effective for management of PDPsy with no significant worsening of motor functions.¹⁹ Use of pimavanserin in primary psychotic disorders is not indicated or approved yet. Most of the case reports on coexisting PD and schizophrenia reported successful use of clozapine,^{4 6–10} due to its unique and broad receptor profile, that is, weak D2 and D1 antagonism, with very mild or no extrapyramidal side effects.²⁰ Several open-label and randomised controlled trials also establish the efficacy of clozapine in the treatment of dopaminergic drug-induced psychosis in iPD.^{21 22} Furthermore, use of clozapine in patients with iPD and psychosis has also been reported to improve dyskinesias,^{6 23} and it is also considered as a second-line treatment for levodopa-resistant late-stage PD tremors in two small double-blind studies.^{21 24}

Agranulocytosis (neutrophil count: 500/mm³) is an important, potentially dangerous, side effect of clozapine that has led to mandatory blood counts monitoring. The estimated risk of agranulocytosis in schizophrenic patients treated with clozapine is approximately 1%. The time of greatest risk is within the first 3 months of treatment. Agranulocytosis is an idiosyncratic reaction and not dose related.²¹ The most commonly reported adverse effects (≥5%) associated with clozapine intake are central nervous system reactions (sedation, dizziness/vertigo, headache and tremor), cardiovascular reactions (tachycardia, hypotension and syncope), autonomic nervous system reactions (hypersalivation, weight gain, drooling, sweating, dry mouth and visual disturbances) and gastrointestinal reactions (constipation and nausea).²⁵

Some literature also demonstrated the use of electroconvulsive therapy in treatment-resistant cases with comorbid schizophrenia and iPD resulting in significant improvement in both psychosis and parkinsonian symptoms.^26–28

Learning points.

• Whenever a patient who has been treated with antipsychotics presents with Parkinsonian symptoms, one should not only consider neuroleptic-induced parkinsonism but also consider idiopathic Parkinson’s disease as a possible diagnosis.

• Efforts must be made to differentiate between the two based on the clinical features and if required using functional neuroimaging.

• Elderly individuals with both the disorders should be treated with more caution to improve the quality of life.

• A delicate pharmacologic balance must be maintained so that symptoms of both disorders remain under control.

• Parkinson’s disease medications should be titrated carefully while selecting appropriate antipsychotic medication, of which clozapine seems a better choice due to its unique receptor profile, better safety data and known efficacy in the management of psychotic disorders.

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