J Neural Transm DOI 10.1007/s00702-015-1400-x

NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE

Psychosis in Parkinson’s disease: identification, prevention and treatment Johannes Levin1 • Alkomiet Hasan2 • Gu¨nter U. Ho¨glinger3,4

Received: 11 February 2015 / Accepted: 7 April 2015  Springer-Verlag Wien 2015

Abstract Psychosis in Parkinson’s disease (PD) is a frequent condition affecting [20 % of all PD patients. It is characterized by vivid dreams, nightmares, illusions, delusions and mostly visual hallucinations. Typically psychosis occurs in the late stage of PD, affecting up to 70 % of the patients following a disease duration of 20 years or more, and can severely interfere with the care of the patients, especially if the patients develop delusions. Psychosis is the principal cause of admission to a nursing home for PD patients. Hence, preemptive identification of risk factors, and avoidance and elimination of triggers are most important measures against psychosis in PD patients. Secondarily, pharmaceutical measures are being undertaken successively, including simplification of medication regimes, discontinuation of non-essential CNS-active drugs, ordered reduction of antiparkinsonian drugs, addition of cholesterinase inhibitors in cognitively impaired patients, and finally addition of antipsychotic medication with limited parkinsonian side effects. As psychosis in PD is a frequent and important problem, we set out to write a

& Gu¨nter U. Ho¨glinger [email protected] Johannes Levin [email protected] 1

Department of Neurology, Ludwig-Maximilians-Universita¨t, Munich, Germany

2

Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universita¨t, Munich, Germany

3

Department of Neurology, Technische Universita¨t Mu¨nchen, Munich, Germany

4

Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE) Munich, Feodor-Lynen Str. 17, 81677 Munich, Germany

state-of-the-art treatment.

guideline

for

its

identification

and

Keywords Parkinson’s disease
Psychosis
Hallucination
Dopamine

Introduction Psychosis in Parkinson’s disease (PD) is frequent, places a significant burden on patients and caregivers, and can severely interfere with the quality of life and care of the patients (Carod-Artal et al. 2013; Goldman and Holden 2014). More than 20 % of all PD patients are affected by psychosis (Lee and Weintraub 2012; Bizzarri et al. 2015). Typically psychosis occurs in the late stage of PD, affecting up to 70 % of the patients after disease duration of 20 years or more. Psychosis is the most frequent cause of admission to a nursing home in PD, especially if delusions represent the main psychopathological symptom (Goetz and Stebbins 1993; Hassan et al. 2013). The most common symptoms in PD-related psychosis are visual hallucinations, which have been reported in up to 65 % of affected patients (Lee and Weintraub 2012). Hallucinations are observed in 50 % of PD patients after 15 years, and in 70 % after 20 years. The pathogenesis of PD psychosis is not resolved so far. Dopaminergic medication and disease duration seem to play a role. According to the dopamine hypothesis, increased sensitivity in mesolimbic and mesocortical areas is involved in the generation of psychosis (Wolters 1999). In schizophrenia, the dopamine hypothesis discusses the regional specificity of the dopaminergic imbalance (subcortical hyperdopaminergia with prefrontal hypodopaminergia) to explain different symptom dimensions in the range of positive, negative and cognitive

123

J. Levin et al.

symptoms (Howes and Kapur 2009). In PD psychosis, it is also hypothesized that the serotonergic and the acetylcholinergic systems play a role by means of an imbalance in the serotonin/dopamine equilibrium (Perry et al. 1990) or a cholinergic deficit (Whitehouse 1987).

Symptomatology The development of psychosis in PD usually follows a gradual course (Table 1). The prodromal phase includes, in most cases, vivid dreams and nightmares (Gama et al. 2015; Connolly and Lang 2014). This phase can be followed by the development of illusions (e.g., person in a curtain), a false sense of presence (mostly of other persons in the room). Next, patients typically develop hallucinations with preserved insight. The content of these predominantly visual hallucinations is typically recurrent. Finally, patients can develop hallucinations without insight and/or delusion. The symptoms of psychosis can occur in the presence or absence of dementia, and with either spontaneous or druginduced occurrence (Fernandez et al. 2008).

Diagnosis The diagnostic criteria of psychosis in PD are summarized in Table 1. The typical symptoms of both psychosis and PD need to be present. Diagnosis of PD is based on the UK brain bank criteria. Furthermore, the diagnosis of psychosis in PD requires an onset of psychosis after the onset of PD symptoms. A symptom duration of more than 1 month and exclusion of other conditions, such as dementia with Lewy bodies, schizophrenia or schizoaffective disorder, are also required (Fernandez et al. 2008).

Risk factors and triggers Characteristic risk factors predispose PD patients for development of psychosis (Table 2). They include mild cognitive impairment or dementia, depression, old age, duration and severity of PD, and significant psychiatric or medical comorbidity. Other important risk factors are sensory deprivation due to reduced vision or reduced hearing and pharmacological risks such as complex medication regimes (Sawada et al. 2013). Well-defined medical conditions can trigger the onset of psychosis or increase the severity of symptoms (Table 3). They include medical conditions, such as dehydration, infections and diverse metabolic causes, and psychosocial factors such as impaired sleep, irregular nutrition and psychological stress such as hospital admissions. Another frequent trigger for psychosis are specific drugs such as amantadine, anticholinergic drugs, dopaminergic drugs and beta-blockers (Sawada et al. 2013). Benzodiazepines may induce a paradoxical reaction, including agitation, euphoria, excitation, restlessness, and sleeplessness, but rarely psychosis in PD patients. It is important to take all these factors into consideration to prevent and treat psychosis in PD.

Documentation Several scales have been developed to (1) assess the risk of developing PD psychosis (Chaudhuri et al. 2007) or (2) to confirm the presence of the condition or (3) to grade its severity. Some of these scales are integrated as sub-scores into more general PD scales, such as the MDS-UPDRS (Goetz et al. 2007), while others, such as the Parkinson

Table 1 Diagnostic criteria for PD-associated psychosis A

Characteristic symptoms of psychosis (at least one of the following) Illusions False sense of presence Hallucinations Delusions

B C

Characteristic symptoms of PD (UK brain bank criteria) Chronology: symptom(s) in A occur(s) after the onset of PD

D

Duration: symptom(s) in A is/are recurrent or continuous for 1 month

E

No other causes: symptom(s) in 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

F

Associated features (specify) With/without insight With/without dementia With/without treatment for PD

Reference: Fernandez et al. (2008)

123

Psychosis in Parkinson’s disease… Table 2 Risk factors for psychosis in PD Higher age

then using scales that focus on severity, such as SAPS (Fernandez et al. 2008).

Higher PD severity Mild cognitive impairment/dementia

Treatment

Depression Impaired vision/hearing High medical comorbidity Polypharmacy, particularly psychoactive drugs Reference: Sawada et al. (2013)

Psychosis Questionnaire (PPQ) (Sawada and Oeda 2013), the Scale for Assessment of Positive Symptoms (SAPS) (Voss et al. 2013), or the scale for evaluation of neuropsychiatric disorders in PD (SEND-PD) (Rodrı´guez-Violante et al. 2014) have been developed to focus exclusively on psychosis in PD. A recommended selection of the available scales is summarized in Table 4. Each scale has its particular strengths. While it might be practical to have a psychiatric subscale integrated into a broader evaluation of the patients, in other cases it might be helpful to focus specifically on the neuropsychiatric symptoms using, e.g., the SEND-PD, which has been shown to correlate very well with the MDS-UPDRS (Rodrı´guez-Violante et al. 2014), or the SAPS score, which also takes the impact of psychosis on well-being and care of the patient into account. A task force of the Movement Disorders Society has proposed first using scales that focus on the diagnosis of psychosis, such as MDS-UPDRS, and

To optimize treatment, it is ideal to combine distinct strategies that are summarized in Table 5. General measures should be initiated immediately in the treatment of all PD patients as most of these can be applied independently of the cause or severity of psychosis. These measures include re-establishment of circadian rhythms, re-establishment of normal-level sensory inputs, for example, by applying hearing and vision aids or simply by having sufficient light in the rooms in which the patient lives, and finally re-establishment of a familial environment, if possible. If specific triggers are identified, such as infections, dehydration or imbalance of electrolytes, these factors should be treated as soon as possible as a matter of urgency. Also elimination of non-essential medication, particularly anticholinergic, antiglutamatergic or sedating drugs should be pursued early on. As an essential prerequisite before diagnosis PD psychosis to exclude a delirium as there is a significant overlap in symptoms and as PD patients are highly at risk to develop a delirium. The re-evaluation of the medication should also be extended to the anti-Parkinson medication. The anti-

Table 3 Trigger of psychosis in PD Infection

e.g., of lower urinary tract, respiratory tract, fever

Dehydration Sleep deprivation Irregular nutrition Psychosocial stress

e.g., hospitalization

Deprivation of or overload with sensory inputs

e.g., loss of glasses or hearing aid, single-room housing

Operation/narcosis Metabolic alterations

Hypo-/hyperglycemia Electrolyte alterations Anemia Uremia Hepatic encephalopathy Hyper-/hypothyreosis Hyper-/hypoparathyroidism Hypovitaminosis (thiamine, folate, niacin, vitamin B12), …

Drugs

e.g., amantadine, anticholinergics, benzodiazepines, beta-blockers, corticosteroids, digoxin/digitoxin, dopaminergics, gyrase inhibitors, ketamine, lithium, metronidazole, opioids, penicillin, theophylline, and others

Reference: Sawada et al. (2013)

123

J. Levin et al. Table 4 Recommended scales to assess psychosis in PD Scale

Objective

References

PD Non-Motor Symptom Scale

Risk of developing psychosis

Chaudhuri et al. (2007)

MDS-UPDRS I, item 1.2

Presence and severity of psychosis

Goetz et al. (2007)

Parkinson Psychosis Questionnaire (PPQ)

Presence and severity of psychosis

Scale for Evaluation of Neuropsychiatric Disorders in Parkinson’s disease (SEND-PD)

Presence, severity of psychosis and other neuropsychiatric symptoms

Sawada and Oeda (2013) Rodrı´guez-Violante et al. (2014)

Scale for Assessment of Positive Symptoms (SAPS)

Presence, severity, and impact of psychosis

Voss et al. (2013)

Table 5 Therapy of psychosis in PD Step

Action

I

General measures

Re-establishment of circadian rhythms Re-establishment of normal-level sensory inputs Hearing and vision aids Re-establishment of familial environment

II

Treatment of specific triggers

Treatment of infection, dehydration Balancing electrolytes, glucose, vitamins, hormones Treatment of heart insufficiency

III

Elimination of non-essential medication

Particularly anticholinergic, antiglutamatergic, sedating drugs

IV

Reduction of anti-Parkinson medication

Anticholinergics [ amantadine [ MAO-B-inhibitors [ dopamine agonists [ COMTinhibitors [ L-dopa retard [ L-dopa non-retarded

V

Cholinesterase inhibitors in cognitively impaired patients

e.g., Rivastigmine 6–12 mg/d 2–3/d, or donepezil 5–10 mg/d 1/d (off-label), or galantamine 4–32 mg/d 2–3/d (off-label)

VI

Antipsychotic medication

Clozapine 12.5–62.5 mg/d (firs-line), or quetiapine 12.5–75 mg/d (off-label)

Reference: Seppi et al. (2011) and Connolly and Lang (2014)

Parkinson drugs may be reduced as much as tolerated with regard to the movement disorder. The regimen should be changed to a simplified strategy, avoiding first anticholinergic drugs and then reducing amantadine, MAO-B-inhibitors or dopamine agonists in this order. Then, it may furthermore be helpful to avoid COMT-inhibitors and retard preparations of the dopaminergic medication. As next step, it can be helpful to add cholinesterase inhibitors in patients with cognitive impairment. Finally, if the measures described above fail to treat psychosis efficiently, antipsychotic medication should be considered. Typical dopamine-receptor-blocking antipsychotics can worsen parkinsonian motor features and have been associated with increased morbidity and mortality (Goldman and Holden 2014). The first-line recommendation is the antipsychotic clozapine. Typically, comparatively low doses, e.g., 12.5–62.5 mg/d of clozapine are needed. However, possible severe side effects of clozapine, such as agranulocytosis, myocarditis, hypotension, sedation, seizures and anticholinergic effects, have to be monitored and may limit its use. However, one should note that agranulocytosis and myocarditis are rare complications and

123

the FDA allowed in schizophrenia patients a reduction of the blood-monitoring schedules during continuous treatment. Hypotension and sedation have a great impact on the outcome and well-being of PD patients. On the other hand, there is no data regarding other cardiovascular parameters (e.g., QTc time) for clozapine. While more than 60 % of patients in a single-center trial showed complete or partial remission of psychosis on clozapine medication, it was discontinued in more than 40 % of these cases, mainly because of the necessity of frequent blood tests because of side effects such as leukopenia (Hack et al. 2014). It was suggested that therapeutic monitoring of clozapine serum levels might be helpful (Lutz et al. 2014). From another perspective, a clear blood-level efficacy relationship has been described in treatment-resistant schizophrenia (Hasan et al. 2012). In clinical practice, quetiapine is also frequently used. This use is also suggested by retrospective studies (Weintraub et al. 2011). Data with regard to efficacy of quetiapine are inconsistent. While open label trials indicate an effect on PD psychosis, in placebo-controlled double-blind trials quetiapine failed to show an effect (Friedman 2011). Furthermore its use to treat psychosis in

Psychosis in Parkinson’s disease…

PD patients is off-label. An advantage of quetiapine of clozapine has been discussed in its favorable side effect profile. However, recent meta-analysis from schizophrenia studies conducted on more than 43.000 patients indicates that the antipsychotic efficacy of quetiapine is lower than of clozapine, amisulpride, risperidone or olanzapine and that quetiapine is associated with significant sedation and weight gain (Leucht et al. 2013). On the other hand, quetiapine has together with olanzapine the best profile regarding motor side effects apart from clozapine (Leucht et al. 2013). In this context, study drugs expressed as chlorpromazine equivalents used in PD psychosis clinical trials differ significantly. This could be one possible explanation of inter-trial differences. However, a part from olanzapine and quetiapine only the second-line drug sertindole which is characterized by an unfavorable risk profile for severe cardiac complications (torsades-depoints, sudden cardiac death) has a comparable tolerability regarding motor side effects.

Outlook Since the antidopaminergic treatment of psychosis bears the intrinsic risk to worsen the motor function in PD patients; alternative approaches have been explored. A recent randomized, placebo-controlled phase 3 trial studied pimavanserin, a selective inverse serotonin receptor agonist, acting mainly at 5HT2A receptors, for patients with Parkinson’s disease psychosis (Cummings et al. 2014). The study met all pre-determined endpoints, specifically on the scale for assessment of positive symptoms in Parkinson’s disease (SAPS-PD), the clinical global impression of change. The intervention improved nighttime sleep without daytime somnolence, and the caregiver burden, relative to placebo. It is particularly noteworthy that motor symptoms did not worsen in the verum arm. From the pharmacological view on modern antipsychotics, the 5HT2-receptor antagonism has been discussed to explain in parts the reduced motor side effects of these drugs (Meltzer and Huang 2008), but it remains controversial whether this antagonism is directly associated with the antipsychotic efficacy of these drugs (Kapur and Seeman 2001). One randomized trial in schizophrenia patients indicates that the add-on of pimavanserin to sub-effective dosage of risperidone shows an equal efficacy compared to a standard dose of risperidone, but has a better tolerability (Meltzer et al. 2012). It is discussed that, analogous to so-called atypical antipsychotics with a 5HT2/D2 antagonism, pimavanserin reduced dopamine release in the nucleus accumbens in preclinical experiments (Li et al. 2005) possibly providing a pathway to explain antipsychotic properties. Future trials will have to address the long-term

benefits of pimavanserin and the relative efficacy and safety of pimavanserin compared to clozapine or other antipsychotics with a 5HT2 antagonism. In this context, it is unlikely that established antipsychotics other than for PD psychosis will have a sufficient risk–benefit profile. Thus, different strategies for the treatment of PD psychosis need to be explored. As case reports indicate a potential of effect of mirtazapine on PD psychosis (Godschalx-Dekker and Siegers 2014) and current discussion grade the risk to induce psychosis with antidepressants to be low, future studies may use antidepressants as possible treatments for Parkinson psychosis. Finally, evidence is available that electro-convulsive therapy is effective in the treatment of PD psychosis with a concomitant improvement in motor functions (Ueda et al. 2010; Usui et al. 2011). Acknowledgments G. Ho¨glinger is funded by the Deutsche Forschungsgemeinschaft (DFG, HO2402/6-2). We wish to thank Katie Ogston for editing the manuscript. Conflict of interest Ho¨glinger GU received speaker honoraria and travel support from Abbvie, Roche, and UCB; and compensation for scientific advisory board activity for Bristol-Myers Squibb, Roche, Sellas, and UCB. Hasan A has been invited to scientific meetings by Lundbeck, Janssen-Cilag, and Pfizer, and he received paid speakership by Desitin, Otsuka and BAK. He was member of the Roche Advisory Board.

References Bizzarri JV, Giupponi G, Maniscalco I, Schroffenegger P, Conca A, Kapfhammer HP (2015) Parkinson’s disease and psychoses. Neuropsychiatr. (Epub ahead of print) Carod-Artal FJ, Mesquita HM, Ziomkowski S, Martinez-Martin P (2013) Burden and health-related quality of life among caregivers of Brazilian Parkinson’s disease patients. Parkinsonism Relat Disord 19:943–948. doi:10.1016/j.parkreldis.2013.06.005 Chaudhuri KR, Martinez-Martin P, Brown RG, Sethi K, Stocchi F, Odin P, Ondo W, Abe K, Macphee G, Macmahon D, Barone P, Rabey M, Forbes A, Breen K, Tluk S, Naidu Y, Olanow W, Williams AJ, Thomas S, Rye D, Tsuboi Y, Hand A, Schapira AH (2007) The metric properties of a novel non-motor symptoms scale for Parkinson’s disease: results from an international pilot study. Mov Disord 22:1901–1911 Connolly BS, Lang AE (2014) Pharmacological treatment of Parkinson disease: a review. JAMA 311:1670–1683. doi:10.1001/jama. 2014.3654 Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, Dhall R, Ballard C (2014) Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet 383:533–540. doi:10.1016/S01406736(13)62106-6 Fernandez HH, Aarsland D, Fe´nelon G, Friedman JH, Marsh L, Tro¨ster AI, Poewe W, Rascol O, Sampaio C, Stebbins GT, Goetz CG (2008) Scales to assess psychosis in Parkinson’s disease: critique and recommendations. Mov Disord 23:484–500. doi:10. 1002/mds.21875 Friedman JH (2011) Atypical antipsychotic drugs in the treatment of Parkinson’s disease. J Pharm Pract 24:534–540. doi:10.1177/ 0897190011426556

123

J. Levin et al. Gama RL, de Bruin VM, de Bruin PF, Ta´vora DG, Lopes EM, Jorge IF, Bittencourt LR, Tufik S (2015) Risk factors for visual hallucinations in patients with Parkinson’s disease. Neurol Res 37:112–116. doi:10.1179/1743132814Y.0000000418 Godschalx-Dekker JA, Siegers HP (2014) Reduction of parkinsonism and psychosis with mirtazapine: a case report. Pharmacopsychiatry 47:81–83. doi:10.1055/s-0034-1367014 Goetz CG, Stebbins GT (1993) Risk factors for nursing home placement in advanced Parkinson’s disease. Neurology 43:2227–2229 Goetz CG, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stebbins GT, Stern MB, Tilley BC, Dodel R, Dubois B, Holloway R, Jankovic J, Kulisevsky J, Lang AE, Lees A, Leurgans S, LeWitt PA, Nyenhuis D, Olanow CW, Rascol O, Schrag A, Teresi JA, Van Hilten JJ, LaPelle N (2007) Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): process, format, and clinimetric testing plan. Mov Disord 22:41–47 Goldman JG, Holden S (2014) Treatment of psychosis and dementia in Parkinson’s disease. Curr Treat Options Neurol 16:281. doi:10.1007/s11940-013-0281-2 Hack N, Fayad SM, Monari EH, Akbar U, Hardwick A, Rodriguez RL, Malaty IA, Romrell J, Shukla AA, McFarland N, Ward HE, Okun MS (2014) An eight-year clinic experience with clozapine use in a Parkinson’s disease clinic setting. PLoS ONE 9(3):e91545. doi:10.1371/journal.pone.0091545 Hasan A, Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Thibaut F, Mo¨ller HJ, World Federation of Societies of Biological Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia (2012) World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry 13:318–378 Hassan A, Wu SS, Schmidt P, Dai Y, Simuni T, Giladi N, Bloem BR, Malaty IA, Okun MS, Investigators NPF-QII (2013) High rates and the risk factors for emergency room visits and hospitalization in Parkinson’s disease. Parkinsonism Relat Disord 19:949–954. doi:10.1016/j.parkreldis.2013.06.006 Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull 35(3):549–562. doi:10.1093/schbul/sbp006 Kapur S, Seeman P (2001) Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: a new hypothesis. Am J Psychiatry 158:360–369 Lee AH, Weintraub D (2012) Psychosis in Parkinson’s disease without dementia: common and comorbid with other non-motor symptoms. Mov Disord 27:858–863. doi:10.1002/mds.25003 Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, La¨ssig B, Salanti G, Davis JM (2013) Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382:951–962. doi:10. 1016/S0140-6736(13)60733-3 Li Z, Ichikawa J, Huang M, Prus AJ, Dai J, Meltzer HY (2005) ACP103, a 5-HT2A/2C inverse agonist, potentiates haloperidolinduced dopamine release in rat medial prefrontal cortex and nucleus accumbens. Psychopharmacology 183:144–153 Lutz UC, Sirfy A, Wiatr G, Altpass D, Farger G, Gasser T, Karle KN, Batra A (2014) Clozapine serum concentrations in dopamimetic psychosis in Parkinson’s disease and related disorders. Eur J Clin Pharmacol 70:1471–1476. doi:10.1007/s00228-014-1772-0

123

Meltzer HY, Huang M (2008) In vivo actions of atypical antipsychotic drug on serotonergic and dopaminergic systems. Prog Brain Res 172:177–197. doi:10.1016/S0079-6123(08)00909-6 Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, Hacksell U (2012) Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2 mg/day, but does not enhance efficacy of haloperidol, 2 mg/day: comparison with reference dose risperidone, 6 mg/day. Schizophr Res 141:144–152. doi:10.1016/j. schres.2012.07.029 Perry EK, Marshall E, Kerwin J, Smith CJ, Jabeen S, Cheng AV, Perry RH (1990) Evidence of a monoaminergic-cholinergic imbalance related to visual hallucinations in Lewy body dementia. J Neurochem 55(4):1454–1456 Rodrı´guez-Violante M, Cervantes-Arriaga A, Vela´zquez-Osuna S, Llorens-Arenas R, Caldero´n-Fajardo H, Pin˜a-Fuentes D, Martinez-Martin P (2014) Independent Validation of the SEND-PD and Correlation with the MDS-UPDRS Part IA. Parkinsons Dis 2014:260485. doi:10.1155/2014/260485 Sawada H, Oeda T (2013) Protocol for a randomised controlled trial: efficacy of donepezil against psychosis in Parkinson’s disease (EDAP). BMJ Open 3:e003533. doi:10.1136/bmjopen-2013003533 Sawada H, Oeda T, Yamamoto K, Umemura A, Tomita S, Hayashi R, Kohsaka M, Kawamura T (2013) Trigger medications and patient-related risk factors for Parkinson disease psychosis requiring anti-psychotic drugs: a retrospective cohort study. BMC Neurol 13:145. doi:10.1186/1471-2377-13-145 Seppi K, Weintraub D, Coelho M, Perez-Lloret S, Fox SH, Katzenschlager R, Hametner EM, Poewe W, Rascol O, Goetz CG, Sampaio C (2011) The Movement Disorder Society Evidence-Based Medicine Review Update: treatments for the non-motor symptoms of Parkinson’s disease. Mov Disord 26(Suppl 3):S42–S80. doi:10.1002/mds.23884 Ueda S, Koyama K, Okubo Y (2010) Marked improvement of psychotic symptoms after electroconvulsive therapy in Parkinson disease. J ECT 26:111–115. doi:10.1097/YCT.0b013e3181c 18a3d Usui C, Hatta K, Doi N, Kubo S, Kamigaichi R, Nakanishi A, Nakamura H, Hattori N, Arai H (2011) Improvements in both psychosis and motor signs in Parkinson’s disease, and changes in regional cerebral blood flow after electroconvulsive therapy. Prog Neuropsychopharmacol Biol Psychiatry 35:1704–1708. doi:10.1016/j.pnpbp.2011.05.003 Voss T, Bahr D, Cummings J, Mills R, Ravina B, Williams H (2013) Performance of a shortened Scale for Assessment of Positive Symptoms for Parkinson’s disease psychosis. Parkinsonism Relat Disord 19:295–299. doi:10.1016/j.parkreldis.2012.10.022 Weintraub D, Chen P, Ignacio RV, Mamikonyan E, Kales HC (2011) Patterns and trends in antipsychotic prescribing for Parkinson disease psychosis. Arch Neurol 68:899–904. doi:10.1001/arch neurol.2011.139 Whitehouse PJ (1987) Clinical and neurochemical consequences of neuronal loss in the nucleus basalis of Meynert in Parkinson’s disease and Alzheimer’s disease. Adv Neurol 45:393–397 Wolters EC (1999) Dopaminomimetic psychosis in Parkinson’s disease patients: diagnosis and treatment. Neurology 52(7 Suppl 3):S10–S13