Original Paper 81

Reduction of Parkinsonism and Psychosis with Mirtazapine: A Case Report

J. A. Godschalx-Dekker1, H. P. Siegers2 1

Affiliations

2

Key words ▶ psychosis ● ▶ hallucinations ● ▶ mirtazapine ● ▶ SSRI ● ▶ Parkinson’s disease ● ▶ Lewy bodies ●

received revised accepted

07.07.2013 06.01.2014 07.01.2014

Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1367014 Published online ahead of print: 9 February 2014 Pharmacopsychiatry 2014; 47: 81–83 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0176-3679 Correspondence J. A. Godschalx-Dekker, MD Department of Psychiatry University Medical Center Utrecht Postbus 85500 3508 GA Utrecht The Netherlands Judith_Anna_Dekker@hotmail. com

Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands Department of Neurology, St. Antonius Hospital, Nieuwegein, The Netherlands

Abstract



Introduction: Psychosis in Parkinson disease is a therapeutic challenge. Regular strategies of treatment are aimed at reducing dopamine medication, and if necessary addition of clozapine. Methods: We describe the case of a patient with persistent psychosis. Nocturnal visual hallucinations persisted in spite of reduced dopaminergic medication and sequential treatment with atypical antipsychotic medication (quetiapine and clozapine) in combination with an acetylcholinesterase inhibitor (rivastigmine). After dispensing a dopamine enhancing antidepressant (mirtazapine), prescribed to improve sleeping, the psychotic symptoms almost immediately disappeared while Parkinsons symptoms declined.

Results: One other case about a positive effect of mirtazapine on (auditory) hallucinations in Parkinson has been published. The reason for the reduction of psychosis in Parkinson-related disease could have been the effect of antagonism of serotonin (5HT)-2 A and/or antagonism of 5HT2C leading to dopamine release. Discussion: Therapeutic effects of medication with strong antagonism for 5HT-2 A and 5HT-2C, like mirtazapine, mianserine, trazodone and nefazodone, in Parkinson-related diseases should be subject for further research. Serotonin might be associated with psychosis in Parkinson-related disease.

Introduction

Case Report

Psychotic symptoms might be present in Parkinson’s disease (PD). Delusions and hallucinations in PD could be caused by the Parkinson medication. Other possibilities are psychosis by the disease itself or a delirium as a result of somatic illness. Psychosis is normally treated with typical antidopamine antipsychotic medication like haloperidol, but preferably not in cases of PD or Lewy body disease (LBD). Drugs of choice in treating psychosis in PD are atypical antidopamine antipsychotics and acetylcholinesterase inhibitors. In the case presented in this report, the authors observed a patient who experienced the disappearance of psychiatric symptoms and reduction of PD symptoms with mirtazapine, an antidepressant with dopamine acceleration and specific serotonin (5HT) receptor blockade.

A 67-year-old man had an 18-year history of PD. Sequentially he was treated in those years with amantadine 200 mg, eldepryl 10 mg, pergolide 0.75 mg, madopar 250 mg, ropinirol 9 mg, levodopa/carbidopa/entacapon 100 mg. After 15 years he gradually developed visual hallucinations, mainly during the night, and sometimes during the day. He saw unfamiliar people in a meadow that other people did not perceive, but he was not bothered by what he saw. The symptoms were acceptable for him and his family, and small changes in the medication did not influence the frequency and intensity of the hallucinations. After 2 years the visual hallucinations intensified, and were continually present during day and night, which resulted in severe sleep deprivation. He saw unfamiliar people with weapons, and wild animals around his house. Signs of illusion or pareidolia were not present. He described a man haunting him with a firearm and accused





Godschalx-Dekker J. A. Siegers HP. Reduction of Parkinsonism and … Pharmacopsychiatry 2014; 47: 81–83

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Authors

his wife of adultery. His wife was not able to sleep, while her husband felt anxious and screamed at night. The Parkinson medication was reduced to madopar 125 mg. The patient was sequentially treated with quetiapine 400 mg and clozapine 75 mg in a combination with rivastigmine 14.1 mg, but his psychotic symptoms did not reduce. To sedate the patient at night, 1 mg of clonazepam was prescribed. The visual hallucinations persisted; he became unstable and needed a wheelchair. The patient slept almost the whole afternoon. Classified according to the Hoehn and Yahr staging of PD [1], the patient was in stage 4; masked face, lips parted some of the time, dysarthric and occasional choking of food. He was rigid, showed signs of bradykinesia, required assistance with walking, washing, dressing and cutting food. The differential diagnosis was reconsidered because of the lack of an antipsychotic effect. Lewy body dementia was unlikely because of the sequence of illness (for example, asymmetric symptoms in the beginning, good improvement on L-dopa for the first 5 years and the loss of uptake of 123U-Ioflupanein the putamen of the DAT scan). There were no signs of depression; neither a decreased mood nor anhedonia was present. A delirium was unlikely because he lacked cognitive disturbances and there were no signs of disorientation. Moreover, there were no signs of additional somatic illness in his laboratorial results. As the hallucinations were extremely inconvenient during the night, mirtazapine 30 mg was given as a substitute for clonazepam to restore the sleep cycle. Mirtazapine was selected because of its effects on variables related to sleep continuity: it increases sleep efficiency, while decreasing the number of awakenings and their duration [2]. 2 days after starting mirtazapine the patient slept during the nights and had only sporadic hallucinations. Surprisingly, without changing the dopaminergic medication, the Parkinson symptoms also reduced after 2 weeks and were even better than 2 years before. The patient became less rigid, could walk without assistance, his speech became comprehensible and he needed less help with eating, washing and dressing.

Discussion



This case suggests that mirtazapine (an antidepressant with indirect dopamine enhancing properties) is able to decrease psychosis in a patient with PD. This is a remarkable finding of coincidence, because the general application of treating psychosis is reducing the mesolimbic pharmacological effects of dopamine. The effect of mirtazapine could be explained by the alteration of the serotonin-dopamine balance. Mirtazapine is a strong anti-histamine (anti-H1) receptor antagonist, a strong serotonin receptor antagonist (anti-5HT-2 A, anti-5HT2-C, anti5HT-3), and an alpha 2 antagonist. Its effect on sleeping is probably due to its receptor H1 antagonism, its alpha 2 antagonism, and its 5TH-2 A antagonism. Our hypothesis is that mirtazapine improved the psychotic symptoms through its anti-5HT-2C and, its anti-5HT-2 A. We knew that 5HT(2 A) receptors are increased in ventral visual pathways in PD patients with visual hallucinations [3]. Di Matteo and others reported in 2002 that the disinhibition of the mesocorticolimbic function caused by 5HT2C receptors antagonism could influence psychotic symptoms in PD [4]. To the best of our knowledge one other case report about the positive effects of mirtazapine on auditory hallucinations in PD has been published [5]. In contrast, there is another case report

in which mirtazapine triggers psychosis during levo-dopa therapy [6]. If mirtazapine reduced the psychotic symptoms in PD due to its anti-5HT-2 A and anti-5HT-2C action, other drugs with strong 5HT-2 A and 5HT-2C receptor antagonisms should also reduce psychotic symptoms in PD. For example, clozapine is an atypical antipsychotic that inhibits dopamine, but is also the strongest 5HT-2 A and 5HT-2C receptor antagonist of all atypical antipsychotic medications. Only clozapine has level A evidence to support its use in PD patients with psychosis [7]. Like mirtazapine, the antidepressants mianserine, trazodone, and nefazodone are strong anti-5HT-2 A and anti-5HT-2C agents, without inhibiting dopamine. Mianserine has most indications for antipsychotic effects in PD. Fujimoto (2009) suggested mianserine as the first step in treating hallucinations and mild delusions that often manifest at night in PD [8]. Ikeguci and Kuroda (1995) treated 12 patients with PD, with psychosis or pure visual hallucinations with mianserine [9]. Complete relief or marked improvement in psychotic symptoms was noted in 8 patients, moderate improvement in 2 patients, and no effect in 2 patients. Trazodone had a positive effect on psychotic symptoms in Alzheimer’s disease, mixed type dementia, or fronto-temporal dementia [10] and Lewy body dementia [11, 12]. No publications were found about the effect of nefazodone on psychotic symptoms in PD. The positive effect of mirtazapine on Parkinsonism might be via several routes of dopamine release. Mirtazapine disinhibits serotonin release by alpha 2 antagonism, however, mirtazapine simultaneously blocks the actions of serotonin at 5HT-2 A, 5HT2C, and 5HT3 receptors, leaving net stimulation of only 5HT1A receptors. This results in an elevated dopamine release due to dopamine acceleration [13]. Some studies report that mirtazapine given in doses of 30 mg or 45 mg a day had a positive effect on Parkinson symptoms like resting tremor, essential tremor and levo-dopa-induced diskynesias [14–17]. There were some clues that other dopamine releasing antidepressants (i. e., mianserin or nefazodone), were also effective against tremor and dyskinesia. For example, the Parkinsonian disability decreased slightly in 8 of 12 patients treated with mianserin [9]. When fluoxetine (a 5HT-2C antagonist without effect on 5HT-2 A) was compared with nefazodone (both 5HT-2C antagonist and 5HT-2 A antagonist) in 16 patients with PD and depression, patients on nefazodone showed a significant reduction of Parkinson symptoms, but those on fluoxetine did not [18].

Conclusion



This case report supports the notion that the possible pharmacological mechanism of mirtazapine in the improvement of psychosis in Parkinson-related disease could be the antagonism of 5HT-2 A and/or antagonism of 5HT-2C receptors. In conjunction with this hypothesis, the disrupted serotonin/dopamine balance acting on the 5HT-2 receptors may be responsible for psychosis in Parkinson-related disease. Therefore, the therapeutic effects of dopamine releasing antidepressants like mirtazapine, mianserine, trazodone and nefazodone, should be subject to further research in treating Parkinson psychosis.

Godschalx-Dekker J. A. Siegers HP. Reduction of Parkinsonism and … Pharmacopsychiatry 2014; 47: 81–83

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

82 Original Paper

Probably a section of patients with PD already use mirtazapine for depression or sleep improvement. A retrospective cohort study might answer some questions about the effects of mirtazapine on psychosis and movement problems in PD.

Conflict of Interest



The authors report no conflicts of interest in this work.

References 1 Hoehn NM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967; 17: 427–442 2 Aslan S, Isik E, Cosar B. The effects of mirtazapine on sleep: a placebo controlled, double-blind study in young healthy volunteers. Sleep 2002; 25: 677–679 3 Huot P, Johnston TH, Visanji NP et al. Increased levels of 5-HT1A receptor binding in ventral visual pathways in Parkinson’s disease. Mov Disord 2012; 27: 735–742 4 Matteo V, di Cacchio M, Di Giulio C et al. Role of serotonin (2C) receptors in the control of brain dopaminergic function. Pharmacol Biochem Behav 2002; 71: 727–734 5 Nagata T, Shinagawa S, Tagai K et al. A case in which mirtazapine reduced auditory hallucinations in a patient with Parkinson disease. Int Psychogeriatr 2012; 30: 1–3 6 Normann C, Hesslinger B, Frauenknecht S et al. Psychosis during chronic levodopa therapy triggered by the new antidepressive drug mirtazapine. Pharmacopsychiatry 1997; 30: 263–265

7 Friedman JH. Parkinson disease psychosis: Update. Behav Neurol 2013; 27: 469–477 8 Fujimoto K. Management of non-motor complications in Parkinson’s disease. J Neurol 2009; 256: (Suppl 3): 299–305 9 Ikeguchi K, Kuroda A. Mianserin treatment of patients with psychosis induced by antiparkinsonian drugs. Eur Arch Psychiatry Clin Neurosci 1995; 244: 320–324 10 Lebert F. Serotonin reuptake inhibitors in depression of ’Alzheimer’s disease and other dementias. [Article in French] Presse Med 2003; 32: 1181–1186 11 Rojas-Fernandez CH, MacKnight C. Dementia with Lewy bodies: review and pharmacotherapeutic implications. Pharmacotherapy 1999; 19: 795–803 12 Geroldi C, Frisoni GB, Bianchetti A et al. Drug treatment in Lewy body dementia. Dement Geriatr Cogn Disord 1997; 8: 188–197 13 Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. Cambridge University Press; 2011 14 Gordon PH, Pullman SL, Louis ED et al. Mirtazapine in Parkinsonian tremor. Parkinsonism Relat Disord 2002; 9: 125–126 15 Pahwa R, Lyons KE. Mirtazapine in essential tremor: a double-blind, placebo-controlled pilot study. Mov Disord 2003; 18: 584–587 16 Uccellini D, Grampa G, Spina I et al. Mirtazapine in the treatment of essential tremor: an open-label, observer-blind study. Neuropsychiatric Disease and Treatment 2006; 95–100 17 Pact V, Giduz T. Mirtazapine treats resting tremor, essential tremor, and levodopa-induced dyskinesias. Neurology 1999; 53: 1154 18 Avila A, Cardona X, Martin-Baranera M et al. Does nefazodone improve both depression and Parkinson disease? A pilot randomized trial. J Clin Psychopharmacol 2003; 23: 509–513

Godschalx-Dekker J. A. Siegers HP. Reduction of Parkinsonism and … Pharmacopsychiatry 2014; 47: 81–83

This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Original Paper 83

Copyright of Pharmacopsychiatry is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.

Reduction of parkinsonism and psychosis with mirtazapine: a case report.

Psychosis in Parkinson disease is a therapeutic challenge. Regular strategies of treatment are aimed at reducing dopamine medication, and if necessary...
159KB Sizes 0 Downloads 0 Views