Psychosis in Parkinson's Disease

Muhammad Hasnain Haider, MBBS (1), Adeel A. Memon (2)
1 - Allama Iqbal Medical College, Lahore, Pakistan
2 - University of Alabama at Birmingham


Introduction

  • Parkinson disease psychosis (PDP) manifests as visual and auditory hallucinations, delusions, and illusions (1)
  • Increases emergency department visits
  • Has high morbidity and mortality rates, impacts quality of life adversely, and commonly requires admission in a nursing home (2)
  • Burdens healthcare system significantly (2)

Epidemiology

  • The prevalence of psychosis among Parkinson's disease patients varies from 20% to 60% (3,4,5,6)

Pathophysiology

  • Pathophysiology of PDP is not yet fully understood (8)
  • Pathophysiological mechanisms of PDP can be categorized into intrinsic and extrinsic processes (7)
  • Intrinsic mechanisms revolve around neurodegeneration causing imbalance between endogenous neurotransmitters e.g. Dopamine, Serotonin and Acetylcholine, in subcortical, limbic and cortical neuronal pathways (7)
  • Extrinsic influences primarily involve overtreatment with dopaminergic drugs or undertreatment with cholinergic medications (8)

Risk Factors

  • Associated risk factors are mentioned below (7)
    • Dopamine agonists
    • Anticholinergic drugs (8)
    • Advanced age
    • Late-onset disease
    • Advanced disease
    • Concurrent cognitive impairment
    • Concurrent depression
    • Diurnal somnolence
    • REM sleep behavior disorder
    • Visual disturbances
    • Predominant axial impairment
    • Autonomic dysfunction
    • Psychoactive drugs
    • Other comorbidities

Diagnostic Criteria (10)

🧠
Diagnostic criteria for Parkinson Disease Psychosis according to the NINDS, NIMH Work Group
Criteria A:
  • Patient exhibits one, or more than one, of the following symptoms
    • Hallucinations
    • False sense of presence
    • Illusions
    • Delusions
Criteria B:
  • U.K. Brain Bank criteria for diagnosis of Parkinson's Disease is fulfilled
Criteria C:
  • Parkinson's symptoms are evident before criteria A symptoms
Criteria D: Duration
  • Criteria A symptoms recur or last for at least 1 month
Criteria E: Exclusion of other causes
  • Other medical causes for psychosis, e.g., dementia with Lewy bodies (DLB), primary psychotic disorders (schizophrenia, schizoaffective disorder, delusional disorder, mood disorder with psychotic features), and delirium have been either ruled out or are highly unlikely
Source: Gordon, P. C., Kauark, R. B. G., Costa, C. D. M., de Oliveira, M. O., Godinho, F. L. F., & Rocha, M. S. G. (2016). Clinical implications of the National Institute of Neurological Disorders and Stroke criteria for diagnosing psychosis in Parkinson’s disease. The Journal of neuropsychiatry and clinical neurosciences28(1), 26-31.

Clinical Presentation

  • Psychosis, initially, presents as hallucinations and illusions that mainly affect visual sensory system (12)
  • Individuals may experience sleep disorders (especially, REM sleep disorder) and vivid dreams weeks or months prior to exhibiting any signs of visual hallucinations (8)
  • Visual hallucinations can be described as simple or complex (1)
  • Formed visual hallucinations, involving people, animals or objects as altered figures with distorted colors, are the most common symptom of PDP (11)
  • Minor symptoms that may accompany visual hallucinations, are presence and passage hallucinations, and visual illusions (11)
  • Hallucinations are short-lived (seconds to minutes), happen multiple times a day, and are more frequent towards the end of the day or at night (12)
  • Other manifestations that may also be observed along with visual hallucinations, are isolated diplopia (single object or figure, rather than the whole scene, is doubled), freezing (hesitancy to walk through slim passages), and spatial misjudgment (inability to anticipate the relative distance between objects and self while walking) (12)
  • Initially, cognition and insight i.e. the ability to differentiate hallucinations from reality, is intact and deteriorates gradually at later stages of disease (12)
  • As the disease progresses to later stages, cognition and judgement deteriorates gradually
  • Hallucinations and delusions are experienced in other sensory systems as well, especially older patients (11,12)
  • Auditory hallucinations occur as unintelligible voices, animal sounds or others, that can compromise the auditory sense (12)
  • Tactile hallucinations revolve around sensations of insects or small animals (11)
  • Symptoms are exacerbated by sensory deprivation e.g. alone in a silent, dark room (12)
  • Associated delusions are persecutory, erotomanic and jealous in nature (1)

Differential Diagnosis

  • The differential diagnosis of Parkinson Disease Psychosis include (17)
  • Other neurodegenerative causes of dementia
    • Lewy body dementia
    • Alzheimer's disease
    • Vascular dementia
  • Primary psychiatric disorders
    • Schizophrenia
    • Schizoaffective disorder
    • Psychotic depression

Management

History

  • Assess for toxic-metabolic causes of acute psychosis (9)
    • Poor hydration or nutrition
    • Infections
    • Metabolic derangements
    • Sleep cycle disturbances
    • Stress
    • Hospital admissions
  • Drug history should be reviewed specifically to identify the use of following drugs that can trigger or worsen psychosis
    • Dopamine agonists and amantadine (9)
    • Anticholinergics (9)
    • Beta blockers (9)
    • Hypnotics and anxiolytics (13)
    • Narcotics (13)
    • Antidepressants (13)
  • Onset of psychosis in early course of Parkinson's disease or within 3 months of levodopa therapy initiation points to a diagnosis other than PDP (13)

Assessment

  • Presently, PDP is diagnosed clinically when the history of hallucinations, illusions, and delusions, is fulfilled according to established criteria (1)
  • No assessment scale is yet approved, either clinically or theoretically, for quantification of psychosis in Parkinson's disease (1)

Investigations

  • The essence of diagnostic work-up is to rule out other medical diseases that manifest with same phenomenology and symptomatology (13)
  • Following tests may be ordered to rule out delirium or underlying infection as the possible cause of psychosis (1)
    • Complete blood count
    • Metabolic work-up
      • check amphetamines, methamphetamines, protoporphyrin, and digoxin levels (7)
    • TSH level
    • Liver function tests
    • Serum ammonia level
    • Folate and vitamin B12 level
    • Urinalysis
    • RPR test
  • CT, MRI, and EEG for evaluation of intracranial disease processes (1)

Treatment

Acute psychosis

  • Intramuscular or oral benzodiazepine can be administered, if the patient is agitated
  • Treatment of triggering illnesses encompasses (7)
    • Elimination of underlying infection or dehydration
    • Correction of metabolic, hormonal, or electrolyte disturbances
    • Supplements in cases of nutritional deficiencies
    • Optimization of cardiac functioning
  • Additional drugs (e.g. anticholinergics, antiglutamatergics, hypnotics) should be stopped to reduce polypharmacy (7)
  • Anti-Parkinsonian therapy should be reviewed, if needed, in the following order (1)
    • Anticholinergics, selegiline and amantadine should be discontinued first
    • Second, dopamine agonists and COMT inhibitors should be revised
    • Decrease levodopa at the very last if above adjustments don't prove effective
    • Taper off dopamine agonists and amantadine slowly while monitoring for withdrawal symptoms
  • Cholinesterase inhibitors may be prescribed to treat associated decline in cognition (7)
    • Rivastigmine 6-12 mg/d 2-3/d
    • Donepezil 5-10 mg/d 1/d (off-label)
    • Galantamine 4-32 mg/d 2-3/d (off-label)
  • Antipsychotic medications should be used after excluding long QTc interval by EKG as all these drugs prolong it (7)
    • Pimavanserine 34mg daily
      • Causes peripheral edema, confused sensorium, and nausea (15)
    • Clozapine 6.25-75 mg daily (level B)
      • Causes sedation, confusion, dyslipidemia, orthostatic hypotension, and agranulocytosis (1%) (14)
      • Monitor WBC counts every week for first 6 months, every other week for next 6 months, and then monthly after that
    • Quetiapine 12.5-200 mg daily (level C)
      • Causes dyslipidemia and orthostatice hypotension (14)
    • Olanzapine 2.5-5 mg daily (level B)
      • Causes dyslipidemia (14)

Chronic psychosis

  • In chronic psychosis, first step in management is to reduce the anti-Parkinsonian medication to minimum dose required to treat motor symptoms (7)
  • Cholinesterase inhibitors and antipsychotics may be used in same dosing regimens as used for acute psychosis, if adjustments in anti-Parkinsonian medications don't help (7)
  • The role of electroconvulsive therapy in PDP treatment has not been thoroughly investigated yet (12)

Pimavanserin

  • Pimavanserin is the first and only medication that has ever been approved by FDA for treatment of PDP-associated hallucinations and delusions (15)
  • It is an atypical antipsychotic that acts as a serotonin antagonist/inverse agonist at the 5HT2A receptor (15)
  • It has no effect on dopaminergic systems, and hence, doesn't affect motor function (15)
  • It has demonstrated a marked reduction in frequency and severity of psychotic symptoms without any disabling repercussions (15)
  • It is efficacious, clinically useful, and doesn't require any monitoring (16)
  • It can be administered orally once daily and the recommended dose is 34mg (15)

Further Reading

  • Samudra, N., Patel, N., Womack, K. B., Khemani, P., & Chitnis, S. (2016). Psychosis in Parkinson disease: a review of etiology, phenomenology, and management. Drugs & aging33(12), 855-863.
  • Jakel, R. J., & Stacy, M. (2014). Parkinson’s disease psychosis. Research and Reviews in Parkinsonism4, 41-51.
  • Creese, B., Politis, M., Chaudhuri, K. R., Weintraub, D., Ballard, C., & Aarsland, D. (2017). The psychosis spectrum in Parkinson disease. Nature Reviews Neurology13(2), 81-95.

Bibliography

  1. Samudra, N., Patel, N., Womack, K. B., Khemani, P., & Chitnis, S. (2016). Psychosis in Parkinson disease: a review of etiology, phenomenology, and management. Drugs & aging33(12), 855-863.
  1. Fredericks, D., Norton, J. C., Atchison, C., Schoenhaus, R., & Pill, M. W. (2017). Parkinson’s disease and Parkinson’s disease psychosis: a perspective on the challenges, treatments, and economic burden. Am J Manag Care23(5 Suppl), S83-S92.
  1. Forsaa, E. B., Larsen, J. P., Wentzel-Larsen, T., Goetz, C. G., Stebbins, G. T., Aarsland, D., & Alves, G. (2010). A 12-year population-based study of psychosis in Parkinson disease. Archives of Neurology67(8), 996-1001.
  1. Fénelon, G., Mahieux, F., Huon, R., & Ziégler, M. (2000). Hallucinations in Parkinson's disease: prevalence, phenomenology and risk factors. Brain123(4), 733-745.
  1. Graham, J. M., Grünewald, R. A., & Sagar, H. J. (1997). Hallucinosis in idiopathic Parkinson’s disease. Journal of Neurology, Neurosurgery & Psychiatry63(4), 434-440.
  1. Martinez-Ramirez, D., Okun, M. S., & Jaffee, M. S. (2016). Parkinson's disease psychosis: therapy tips and the importance of communication between neurologists and psychiatrists. Neurodegenerative disease management6(4), 319-330.
  1. Taddei, R. N., Cankaya, S., Dhaliwal, S., & Chaudhuri, K. (2017). Management of psychosis in Parkinson’s disease: emphasizing clinical subtypes and pathophysiological mechanisms of the condition. Parkinson’s Disease2017.
  1. Thanvi, B. R., Lo, T. C. N., & Harsh, D. P. (2005). Psychosis in Parkinson’s disease. Postgraduate medical journal81(960), 644-646.
  1. Levin, J., Hasan, A., & Höglinger, G. U. (2016). Psychosis in Parkinson’s disease: identification, prevention and treatment. Journal of Neural Transmission123(1), 45-50.
  1. Gordon, P. C., Kauark, R. B. G., Costa, C. D. M., de Oliveira, M. O., Godinho, F. L. F., & Rocha, M. S. G. (2016). Clinical implications of the National Institute of Neurological Disorders and Stroke criteria for diagnosing psychosis in Parkinson’s disease. The Journal of neuropsychiatry and clinical neurosciences28(1), 26-31.
  1. Schneider, R. B., Iourinets, J., & Richard, I. H. (2017). Parkinson's disease psychosis: presentation, diagnosis and management. Neurodegenerative disease management7(6), 365-376.
  1. Creese, B., Politis, M., Chaudhuri, K. R., Weintraub, D., Ballard, C., & Aarsland, D. (2017). The psychosis spectrum in Parkinson disease. Nature Reviews Neurology13(2), 81-95.
  1. Zahodne, L. B., & Fernandez, H. H. (2008). Pathophysiology and treatment of psychosis in Parkinson’s disease. Drugs & aging25(8), 665-682.
  1. Muench, J., & Hamer, A. M. (2010). Adverse effects of antipsychotic medications. American family physician81(5), 617-622.
  1. Cusick, E., & Gupta, V. (2021). Pimavanserin. StatPearls [Internet].
  1. Seppi, K., Ray Chaudhuri, K., Coelho, M., Fox, S. H., Katzenschlager, R., Perez Lloret, S., ... & Djamshidian‐Tehrani, A. (2019). Update on treatments for nonmotor symptoms of Parkinson's disease—an evidence‐based medicine review. Movement Disorders34(2), 180-198.
  1. Jakel, R. J., & Stacy, M. (2014). Parkinson’s disease psychosis. Research and Reviews in Parkinsonism4, 41-51.
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