Psychosis in Parkinson’s disease

1. Psychiatric Clinic - University of Trieste Psychosis in Parkinson’s disease Eugenio Aguglia Summer School Neuroscience - Luglio – 2007 Parkinson’s Disease Multiple Domains

2. Contrary to James Parkinson’s claim in his original description of the “ Shaking palsy” in 1817, that intellect was preserved, it now seems clear that cognitive and psychiatric disorders are the most frequent and disabling “non-motor” complication of Parkinson’s disease (PD)

3. Psychotic symptoms, autonomic and sensory disturbances are extremely important for these reasons: • Psychosis is associated with reduced patient quality of life (Schrag et al., 2000) and increased caregiver distress (Aarsland et al., 2001) • Psychosis is a major risk factor for nursing home placement and subsequently increased mortality • High prevalence of disorder: studies suggest that they may affect over half of patients with PD at some point during the course of their disease. Hence these symptoms have serious consequences in both social and health economics terms (Williams-Gray et al., 2006).

4. Epidemiology (I) Most studies have used hospital-based series, which are likely to overstimate the true prevalence of psychosis because of referral bias, with more severe symptoms or management issues being referred to hospital specialists: 1) Inzelberg et al.,1998: in 121 patients with PD followed up at a movement disorder clinic, 37% reported experiences of hallucinations in the previous 2 years 2) Fenelon et al., 2000: study of 217 consecutive PD outpatients detected the occurrence of hallucinations during the previous 3 months in 40% Other studies ( Tanner et al.,2001) found somewhat lower prevalences of around 30%

5. Epidemiology (II) • There are few systematic population-based studies on the incidence and prevalence of psychotic symptoms in PD. • Aarsland et al.,1999: 245 patients with an average duration of PD of 9.1 (+ 5.8) years, investigated using the UPDRS (Unified Parkinson’s Disease Rating Scale) - 10% hallucinations with insight retained - 6% more severe hallucinations or delusions • Barnes et David, 2001: prevalence of hallucinations, in 182 patients, of 17%

6. Reported prevalence of hallucinations in Parkinson’s disease (prospective studies)

7. Epidemiology (III) • Epidemiological studies have also identified a significant association between cognitive deficit and psychotic sympyoms in PD • Aarsland et al.1999: 25 of 37 patients with hallucinations or delusions were also diagnosed with dementia (according to DSM-III-R criteria in addiction to performance on specific cognitive rating scale) • Fenelon et al., 2000: overall prevalence of visual hallucinations of 39.8% of 217 patients; the prevalence rose to 70% in those patients with dementia • Holroyd et al., 2001: in a hospital-based study of 102 patients with PD, significantly lower cognitive score in patients with visual hallucinations compared with those without hallucinations

8. Fènelon et al., Brain. 2000;123:733-45.

9. Psychosis is defined as a disturbance of perception and thought, and encompasses a spectrum of symptoms, including hallucinations, delusions, paranoid beliefs and agitation. The ‘continuum hypothesis’ (Moskowitz, 1978) assumes that psychosis in Parkinson’s disease develops progressively from vivid dreams to hallucinations, then to delusions and finally to florid psychosis. This idea forms the basis of the thought disorder subscale of the UPDRS.

10. However, some studies have demonstrated that hallucinations and delusions in Parkinson’s disease are stable over prolonged periods, from 18 months to 5 years, arguing against a “progressive psychosis” (Goetz et al. 2001) Psychosis in Parkinson’s disease may, in fact, be heterogeneous, with different patterns of symptoms in different patients

11. PHENOMENOLOGY OF PSYCHOSIS IN PD 1. • Visual hallucinations are the most prevalent manifestation of psychosis in Parkinson’s disease. • These can range from: • simple flashes of light or colour, • vague feelings of the presence or passage of an animal or human, • complex formed visions of people, animals or objects. • When occurring in patients who do not have dementia, insight is usually retained and the visions are non threatening. • Auditory hallucinations have also been reported in up to 10% of patients with Parkinson’s disease, again usually with preserved insight and consisting of nonfrightening voices or sounds associated with concurrent visual hallucinations.

12. PHENOMENOLOGY OF PSYCHOSIS IN PD 2. • A proportion of patients, however, experience paranoid hallucinations associated with anxiety and fright, frequently in the setting of clouded consciousness. • These hallucinations often have a combination of visual, tactile and auditory components. Paranoid beliefs or delusions are reported at lower frequency than hallucinations in Parkinson’s disease. Examples include beliefs of a spouse’s infidelity or persecution. • Patients can even develop a Capgras syndrome in which they recognise a close relative or familiar object but believe them to have been replaced by an exact alien or ‘double’. • Delusions can occur in the absence of visual hallucinations, both in patients with a clear consciousness and those with a clouded consciousness.

13. Prodromics signs and symptoms in early psychosis in PD Juncos JL, J Clin Psychiatry. 1999;60 Suppl 8:42-53

14. Course of Psychotic Symptoms in PD Marsh et al., Curr Psychiatry Rep. 2003 May;5(1):68-76

15. Diagnostic Criteria for Psychosis in Parkinson’s Disease: Report of an NINDS, NIMH Work Group Duration The symptom(s) in Criterion A are recurrent or continuous for 1 month Exclusion of other causes The symptoms in Criterion A are not better accounted for by another cause of Parkinsonism such as dementia with Lewy bodies, psychiatric disorders such as schizophrenia, schizoaffective disorder, delusional disorder, or mood disorder with psychotic features, or a general medical condition including delirium Associated features: (specify if associated) With/without insight With/without dementia With/without treatment for PD (specify drug, surgical, other) Characteristic symptoms Presence of at least one of the following symptoms (specify which of the symptoms fulfill the criteria): Illusions False sense of presence Hallucinations Delusions Primary diagnosis UK brain bank criteria for PD Chronology of the onset of symptoms of psychosis The symptoms in Criterion A occur after the onset of PD Movement Disorders, Vol. 22, No. 8, 2007

16. Characteristics of Apathy in Parkinson’s Disease Apathy Profiles (LARS) Component Action initiation p<0.001 Emotion Intellectual curiosity p<0.001-p<0.024 Self-awareness p<0.001 Dujardin et al., 2007

17. Characteristics of Apathy in Parkinson’s Disease Regression Analyses • The MADRS dysphoric apathy subscore was a statistically significant predictor: • The Intellectual Curiosity (F(1,154)=39.1, P<0.01); • Action Initiation (F(1,154)=7.7, P<0.01); • Emotion (F(1,154)=15.9, P<0.01). • The self-awareness subscore was explained only by the Mattis DRS predictor (F(1,154)=28.7; P<0.01). • Mattis Dementia Rating Scale DRS score was a statistically significant predictor of the action initiation (F(1,154)=19.3; P<0.01) and intellectual curiosity (F(1,154)=6.7; P<0.02) dimensions. Linear regression analysis revealed that the apathy level was mainly determined by cognitive impairment, and only associated with the apathy subcomponent of the Montgomery and Asberg Depression Rating Scale. Dujardin et al., 2007

18. CLINICO-PATHOLOGICAL CORRELATION BETWEEN LEWY BODIES AND VISUAL HALLUCINATION LB DENSITIES amygdala temporal cingulate parahippo Both the DLB and PDD groups have greater LB densities than the PD-only group, although the PDD group was only significantly greater than the PD-only group in the parahippocampus and amygdala. The DLB group differed from the PDD group in the total sum of LB and in the LB density in the inferior temporal cortex. Harding Et Al., 2002

19. cingulate parahippo amygdala temporal Harding Et Al., 2002

20. Cingulate Parahippo Amygdala Temporal Harding Et Al., 2002

21. Altered cortical visual processing in PD with hallucinations: an fMRI study. PD patients with chronic visual hallucinations respond to visual stimuli with greater frontal and subcortical activation and less visual cortical activation than non-hallucinating PD subjects. Shifting visual circuitry from posterior to anterior regions associated primarily with attention processes suggests altered network organization may play a role in the pathophysiology of visual hallucinations in PD.” Stebbins GT Neurology. 2004 Oct 26;63(8):1409-16.

22. … Among hallucinating subjects, we found that visual stimuli, especially kinematic, did not activate regions of posterior cortex (occipital, temporal, parietal) involved in the perception of visual stimuli or the perception of apparent movement to the same extent as seen in non-hallucinating patients.

23. Risk factors • Age • Disease duration and severity • Cognitive impairment • Depression • Sleep disorder • Visual sensory dysfunction

24. AGE Age-related influences on the clinical characteristics of new-onset hallucinations in Parkinson's disease patients. At the time of first onset of hallucinations, patients whose hallucinations were nonvisual or mixed were significantly older than those with purely visual hallucinations (mean age, 69.8+/-8.3 vs. 61.9+/-10.6; P=0.031). Age-related disinhibition may facilitate wider cortical activation in PD and potentiate aberrant signaling that invokes other types of hallucinations besides the classic visual forms. Goetz CG Mov Disord. 2006 Feb;21(2):267-70.

25. DISEASE DURATION AND SEVERITY Positive associations between the presence of hallucinations and disease severity as measured by UPDRS scores have also been described in some hospital-based series. Halroyd S. et al. Neurol Neurosurg Psychiatry 2001;70:734–738. Positive correlation between higher thought disorder scores in the UPDRS part I in patients with more severe parkinsonian impairment on the UPDRS activities of daily living subscale. Aarsland D. et al. Arch Neurol 1999;56:595–601

26. COGNITIVE IMPAIRMENT • Studies using cognitive scores have consistently found associations of psychosis and specifically hallucinations with poorer scores on a variety of screening tests for cognitive dysfunction. • Inzelberg R. J Neurol Neurosurg Psychiatry 1998;64: 533–535 • Caroline H. Williams-Gray et al. CNS Drugs 2006; 20 (6): 477-505 Spontaneous visual hallucinations are one of the cardinal features of dementia with Lewy bodies (DLB). Up to 80% of patients with this parkinsonian variant have prominent degrees of psychosis, specifically visual hallucinations and delusions. Semin Clin Neuropsychiatry 1998;3:51–60

27. On clinical grounds, Parkinson’s disease with dementia and DLB appear to be the same disease and the high incidence of psychosis in DLB studies underlines the importance of dementia as a risk factor for parkinsonian psychosis. Richard H Mov Disord. 2002 Nov;17(6):1161-5. Parkinson’s disease is likely to form part of a spectrum of a-synucleinopathies in which the development of dementia reflects a shift towards the pattern of Lewy body pathology seen in dementia with Lewy bodies. Williams-Gray et al. CNS Drugs 2006; 20 (6)

28. DEPRESSION Holroyd and coll. found associations between hallucinations and higher scores on the Geriatric Depression Scale (GDS). J Neurol Neurosurg Psychiatry 2001;70:734–738 Mania and major depression are significant risk factors for the onset of psychosis in parkinsonism. Recognizing and treating depression early may prevent more advanced psychiatric symptoms from developing,including psychosis.

29. Affective symtoms Depression Anxiety/panic Transient “off” period anxiety Sustained Transient “off” period depression Sustained Manage motor fluctuations Manage motor fluctuations Counselling and support group Counselling and support group Anxiolytics Antidepressants/ Mood stabilizers Antidepressant ECT Atypical antipsychotic J.L. Juncos, 1999

30. SLEEP DISORDERS Pappert and coll. found that 82% of Parkinson’s disease patients with hallucinations had some form of sleep disorder, which is not significantly different from the overall prevalence of sleep disorders in PD. However, these authors reported a close association between hallucinations and altered dream phenomen. Mov Disord 1998;13(Suppl.):90.

31. Hallucinations and sleep disorders in PD Six-year prospective longitudinal study Hallucinations and global sleep disorders follow different patterns of progression in Parkinson disease and are separate behavioral abnormalities. Sleep alterations are not necessarily harbingers of hallucinations. Christopher G. Goetz NEUROLOGY 2005;64:81–86

32. VISUAL SENSORY DYSFUNCTION Relationship Between Hallucinations, Delusions, and Rapid Eye Movement Sleep Behavior Disorder in Parkinson’s Disease. The presence of RBD was associated with an increased risk of manifesting hallucinations and delusions (odds ratio [OR], 2.73). Other independent clinical factors found to have an effect on psychotic disorders were cognitive impairment (OR, 3.92), disease duration (OR, 2.46), advanced age (OR, 2.34), and severity of motor symptoms (OR, 2.06). These results suggest that RBD is widely associated with psychosis in PD. Movement Disorders Vol. 20, No. 11, 2005, pp. 1439–1448

33. Management and Therapy

34. Antipsychotic Use in Older Adults With Parkinson’s Disease Kaplan–Meier curve of antipsychotic use over entire study window. The Kaplan–Meier estimate for the cumulative probability of requiring an antipsychotic at 7 years was 35%; 499 individuals (4.8%; 5.2/100 person–years) were prescribed an antipsychotic within 1 year of starting dopaminergic therapy. The proportion of initial antipsychotic prescriptions for typical antipsychotics decreased from 56% (42 of 75) in 1998 to 9% (8 of 88) in 2002. Marras et al., 2007

35. Double-Blind, Placebo-Controlled, Unforced Titration Parallel Trial of Quetiapine for Dopaminergic-Induced Hallucinations in Parkinson’s Disease The Baylor PD Hallucination Questionnaire showed a modest trend toward improvement compared to placebo but did not reach statistical significance. The demographics between subjects randomized to drug (n=21) vs. pl (n=10) were similar. The final dose of active drug was 200 (n=11), 150 (n=2), 100 (n=3), and 75 (n=1) mg per day. Ondo et al., 2005

36. Effect of Quetiapine in Psychotic Parkinson’s Disease Patients: A Double-Blind Labeled Study of 3 Months’ Duration Brief Psychiatric Rating Scale (BPRS) of parkinsonian patients treated with quetiapine and placebo (over time). BPRS did not change significantly after treatment in either group (QTP and placebo) in ITT patients and in patients who completed 12 weeks of treatment Rabey et al., 2007

37. Summary of primary and secondary outcome measures: Intent-to-treat results comparing quetiapine and placebo groups Kurlan et al., 2007 No significant differences in the primary or secondary outcome measures of efficacy were observed. An unexpectedly large placebo effect, inadequate dosage (mean 120 mg/day), and inadequate power may have contributed to lack of demonstrable benefit. Quetiapine was generally well-tolerated and did not worsen parkinsonism, but was associated with a trend toward a decline on a measure of daily functioning.

38. Open-Label Flexible-Dose Pilot Study to Evaluate the Safety and Tolerability of Aripiprazole in Patients With Psychosis Associated With Parkinson’s Disease Number of patients demonstrating changes in psychosis and Parkinson’s symptoms during acute phase of study Improvement in mean BPRS and positive BPRS subscales occurred with open-label aripiprazole. While some patients had a favorable response, aripiprazole was associated with an exacerbation of motor symptoms. Friedman et al., 2006

39. Parenteral ziprasidone: a new atypical antipsychotic for emergency treatment of psychosis in Parkinson’s disease? CASE REPORT- series BPRS sum scores before and 2 h after injection of ziprasidone All patients showed moderate to good effects on agitation and excitement 30–60 min after injection of 20 mg of ziprasidone. The BPRS sum scores showed a reduction in all patients 2 h after injection. Oechsner et al., 2005

40. Treating dopamimetic psychosis in Parkinson's disease: Structured review and meta-analysis Efficacy of clozapine and olanzapine. Clozapine vs. placebo Olanzapine vs. placebo Favours treatment Favours placebo Change of CGI severity scores in the 4-week trials comparing clozapine or olanzapine versus placebo. Only clozapine significantly improved psychotic symptoms. Frieling et al., 2007

41. Effect of clozapine and olanzapine on motor function Clozapine vs. placebo Olanzapine vs. placebo Favours treatment Favours placebo Change of UPDRS motor scores in the 4-week trials comparing clozapine or olanzapine versus placebo. While patients receiving clozapine showed improved motor functions, olanzapine treatment significantly worsened Parkinsonism. Frieling et al., 2007

43. General principles of management 1. • It is vital to exclude delirium in all patients who present with psychosis. This is important as the treatment of the precipitating illness can potentially ‘‘cure’’ psychosis. A thorough search should be undertaken to exclude an intercurrent physical illness, drug effect, electrolyte imbalance, and systemic infection. • A multidisciplinary team approach, involving patient, carer, physician, liaison psychiatrist, PD specialist nurse, and social worker is required for the effective management. Proper explanation of the nature and course of psychosis to the patient and carer helps them to cope with the situation. • Simple measures should be tried first, for example, improving sleep hygiene, avoiding excessively patterned furniture, and reducing sensory overload and sensory deprivation. Thanvi et al., 2005

44. General principles of management 2. • Psychiatric comorbidities of non-psychotic nature, for example, depression, anxiety, and apathy are common in PD patients with psychosis and may add to the functional impairment. Treatment of these conditions may reduce morbidity and distress to carers. • Vivid dreams alone usually do not warrant medical treatment. Similarly, occasional visual hallucinations with insight retained may not require any action beyond reassurance. • If simple measures fail, reduction in drug dose or elimination of one or more antiparkinsonian agents should be considered. The agent introduced most recently or one with the lowest antiparkinson efficacy (anticholinergics, amantadine, selegiline) should be stopped first. Next in order are dopamine agonists, catecholamine O-methyl transferase inhibitors, and L-dopa. It should be emphasised that dopamine agonists are much more likely to produce psychosis than L-dopa. One might have to accept worsening of parkinsonism. Thanvi et al., 2005

45. Drug treatment Thanvi et al., 2005

46. Atypical antipsychotics (AA): • Risperidone and olanzapine are associated with sedation and can cause considerable worsening of parkinsonism. • Additionally, olanzapine can worsen cognition and hyperglycaemia in patients with diabetes. • A recent CSM warning suggests an increased risk of strokes associated with the use of risperidone and olanzapine in old people. • Clozapine is probably the most effective agent and does not cause worsening of parkinsonism. However, it is associated with the risk of potentially fatal, idiosyncratic agranulocytosis necessitating regular white blood cell counts. • Quetiapine is favoured by many psychiatrists because of its better side effect profile. • Preliminary experience with the latest AA, aripiprazole, has not been very encouraging, as it caused worsening of PD symptoms.

47. AA should be started at very low doses with gradual increments if needed, as hypersensitivity to these agents can induce delirium or malignant neuroleptic syndrome. The doses required to treat psychosis are much lower than those used in schizophrenia. • All AA cause prolongation of QT interval on ECG, particularly in older patients. Therefore, baseline ECG and periodic ECG monitoring are advisable. • Optimal duration of treatment with AA in PD associated psychosis is not known. Stopping AA in patients in remission is fraught with the possibility of recurrences and even ‘‘rebounds’’ of psychosis. Fernandez et al. (2005) conducted a prospective study on PD patients receiving successful treatment with quetiapine and clozapine as these drugs were withdrawn. After the antipsychotic agent was stopped, psychosis recurred in five of six patients. In three patients the ‘‘rebound psychosis’’ was worse than the original psychotic episode requiring higher antipsychotic drug doses.

48. Acetylcholinesterase inihibitors (AChI): • These agents increase concentrations of acetylcholine in the brain and have been in use for treating Alzheimer dementia. • Their use in psychosis of PD has been advocated on the basis of reports of beneficial effects in dementia with Lewy bodies. • There is a significant loss of cholinergic neurons in PD and AChI may prove beneficial by increasing acetylcholine concentrations. • In an open label study (Bullok et al., 2002), rivastigmine led to improvement in cognitive and functional abilities, as well as the resolution of behavioural problems and visual hallucinations. • Donepezil, another commonly used AChI, has also shown some promise in open label studies (Bergman et al., 2002).

49. Cholinesterase inhibitors may prove an additional option in psychotic PD patients with dementia. Poewe, 2003

50. Ondansetron: It is a 5-HT3 antagonist widely used to treat vomiting attributable to anticancer agents. In an open label (Zoldan et al., 1995), short term (four to eight weeks) study, it was used to treat psychosis in PD at a dose of 12 to 24 mg daily. There was pronounced to moderate improvement in measures of visual hallucinations, paranoid delusions, confusion, and the associated global functional impairment. It did not cause worsening in PD symptoms and was well tolerated. However, there have not been any large sized, controlled studies using ondensetron in PD associated psychosis.