Correspondence: Dr Kenji Tagai MD, Department of Psychiatry, Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan. Email: email@example.com
Psychotic symptoms often occur as a complication in Parkinson's disease patients, and a set of criteria for Parkinson's disease with psychosis (PDPsy) has been established. Among these criteria, hallucinations are one of the specific symptoms, with visual hallucinations being the most common. While atypical antipsychotic agents are often used for the treatment of PDPsy, adverse effects, including extrapyramidal symptoms, often hinder its continuation or tolerance. There have been some reports and reviews indicating that antidepressants may be effective for PDPsy and other forms of dementia with psychosis. In this report, we present a patient with PDPsy who was treated with one of the new-generation antidepressants, mirtazapine. Mirtazapine improved the patient's refractory psychotic symptoms, especially her visual hallucinations, without worsening her motor symptoms.
Psychotic symptoms often occur as a complication in Parkinson's disease (PD) patients, and a set of criteria for PD with psychosis (PDPsy) has been established. Among these criteria, hallucinations are one of the specific symptoms, with visual hallucinations (VH) being the most common.[2-5] While atypical antipsychotic agents are often used for the treatment of PDPsy, adverse effects, including extrapyramidal symptoms (EPS), often hinder its continuation or tolerance. There have been some reports and reviews indicating that antidepressants may be effective for PDPsy and other forms of dementia with psychosis.[8, 9] In this report, we present a patient with PDPsy who was treated with one of the new-generation antidepressants, mirtazapine. Mirtazapine improved the patient's refractory psychotic symptoms, especially her VH, without worsening her motor symptoms.
Herein, we report the case of an 83-year-old woman whose illness started when she was 72 years old. The initial symptom was an upper limb resting tremor, with the subsequent development of rigidity and bradykinesia. Her illness was diagnosed as PD, and antiparkinsonian agents were prescribed, although the details of her prescription are unknown.
When she was 82 years old, her husband died, and she became depressed and began to talk about water being the colour of blood. Five months later, she entered a nursing home and began to experience VH. Her VH sometimes varied, and included that a child was peering at her over a door and a man coming for an interview. The person in her VH was always the same person, and the hallucinations were accompanied by feelings of being monitored. Although a previous doctor had prescribed antipsychotic agents including aripiprazole and risperidone, the patient had also developed delusions of persecution by the time she visited our hospital.
When she visited our outpatient clinic, she was recognized as having mild parkinsonism (Yahr II; Unified Parkinson's Disease Rating Scale: total score 68), psychosis with VH, and depression. In particular, she was very agitated. Her prescription at that time was for trihexyphenidyl 6 mg/day. Unfortunately, we do not have detailsn regarding her former prescriptions. She was not being treated with levodopa at the time of her entrance to the nursing home. A Mini-Mental State Examination and a Frontal Assessment Battery were performed; her scores were 21 points and 8 points, respectively.11,12 She could not complete the clock-drawing test. Cranial magnetic resonance imaging, an electroencephalogram and routine serum laboratory tests were normal for her age. We decreased the dosage of trihexyphenidyl to 3 mg/day and prescribed quetiapine 50 mg/day. However, the patient began to insist that she had committed a serious crime, and she did not eat very much at mealtimes. Furthermore, the staff of the nursing home reported that her EPS had worsened. After two months, she attempted suicide; she was subsequently admitted to the psychiatric department of our hospital.
After admittance, a second cranial magnetic resonance imaging (Fig. 1), electroencephalogram and routine serum laboratory tests were performed, but no changes were noted. As a further examination, single-photon emission computed tomography imaging with technetium-99m-ethyl cysteinate dimer was performed. The results of the single-photon emission computed tomography were analyzed with the easy Z-score imaging system (Fig. 2), and a decrease in the regional cerebral blood flow was seen in bilateral prefrontal cortices.
We prescribed risperidone 2 mg/day and trazodone 50 mg/day. On day 9, EPS appeared, and the patient's depression and agitation worsened. We consequently started treatment with mirtazapine 15 mg/day for both symptoms and increased the dosage to 30 mg/day over 7 days. In addition, we tapered the risperidone dosage over 15 days. On day 29, the patient showed a decrease in her psychotic symptoms, which consisted mainly of VH (Behavioural Pathology in Alzheimer's Disease total scores: from 21 to 10 points; delusion scores: from 3 to 2 points, hallucination scores: from 3 to 0 points).13 There was no increased aggravation of her EPS. The patient's depression also improved slightly (21-item Hamilton Rating Scale for Depression : from 38 to 29 points).14 She continued taking mirtazapine for 70 days, but her depression did not improve any further. However, she did not experience further VH, and her scores improved on the Mini-Mental State Examination (from 21 to 28 points) and Frontal Assessment Battery (from 8 to 14 points). These results suggested that her cognitive impairment might have arisen from her psychiatric symptoms (Fig. 3).
In this case, treatment with mirtazapine improved VH rather than depression in a patient with PD with chronic episodes for more than 10 years. PDPsy typically occurs in advanced PD patients 10 or more years after the initial PD diagnosis. Some triggers or risk factors are known. Among pharmacological factors, the introduction or dose increment of antiparkinsonian agents often triggers PDPsy.[15, 16] Among disease-related factors, cognitive impairment is strongly associated with PDPsy. In particular, an association has been found among visuoperceptual, executive, reality monitoring, and memory tasks. Psychiatric disorders, especially depressive disorders, are also strongly associated with PDPsy. In our case, the VH may have been induced by the trihexyphenidyl. However, the VH did not improve by when the dosage of trihexyphenidyl was reduced, and instead, her psychotic symptoms worsened somewhat.
PDPsy increases the caregiver's burden and the patient's risk of mortality.[18, 19] Therefore, this symptom must be managed. Several approaches to treatment exist. First, stopping or reducing the antiparkinsonian agents can be effective, though motor function may worsen.[6, 16] Second, atypical antipsychotic agents can be effective.[6, 15, 20, 21] Several double-blind placebo-controlled trials have been performed, and some reviews report that clozapine can be effective and does not appear to worsen EPS. Quetiapine appears to be less effective than clozapine but may not worsen EPS, but other agents such as risperidone, olanzapine or aripiprazole may worsen such signs.[6, 15, 20, 21] Third, some studies have reported that cholinesterase inhibitors also can be mildly effective for the treatment of Parkinson's disease with dementia or dementia with Lewy bodies with hallucinations.[22-24] A few reports have also indicated that antidepressants may be effective.[7, 8] In these reports, antidepressants, such as clomipramine and citalopram, may actually improve psychotic symptoms, especially in patients with concurrent depression. In contrast, some previous studies have shown that antidepressants, including mirtazapine, caused or exacerbated psychotic symptoms.[25, 26] In these studies, the patients received dopamine-replacement therapy. In the absence of dopamine-replacement therapy in our case, mirtazapine might have improved the patient's VH, rather than her depression.
The neural mechanisms underlying psychotic symptoms remain unclear. Of the brain's neurotransmitters, not only dopamine but also serotonin and acetylcholine may also play a role in the emergence of psychotic symptoms. In particular, serotonin's contribution to PDPsy has been suggested by some treatment experiences.[15, 16] Atypical antipsychotic agents are dopamine receptor antagonists as well as serotonin 2A and 2C receptor antagonists. Also, ondansetron, a serotonin 3 receptor antagonist, has been found to be successful in improving PDPsy,[27, 28] and a positron emission tomography study found increased serotonin 2A receptor binding in the ventral visual pathway of PD patients with VH. Mirtazapine acts by antagonizing alpha2-adenoreceptors as well as serotonin type 2 and type 3 receptors. In our case, this action of antagonizing serotonin type 2 and type 3 receptors may have helped to decrease her psychotic symptoms, especially her VH. However, her depression did not improve significantly. As far as we know, there have been no published papers indicating that mirtazapine improves depression in PD. In addition, the chronically cyclic deficiency of dopamine in PD may influence fluctuations in motor activity linked to psychogenic symptoms (e.g. depressive mood) or cognitive function. Therefore, dopaminergic agonists, such as pramipexole and pergolide, also improve depression in PD. In our case, the dosage of antiparkinsonian agents had been reduced to mitigate the distress of the VH, and the treatment of the patient's motor symptoms may have been insufficient. Such deficiencies of dopamine might have caused the insufficient efficacy for depression and prevented the exacerbation of the VH.
Our report has some limitations. We could not perform 123I-metaiodobenzylguanidine cardiac scintigraphy or single-photon emission computed tomography imaging with technetium-99 m-ethyl cysteinate dimer after treatment. Furthermore, no details were available regarding the patient's clinical course prior to her visit to our outpatient clinic. Thus, other parkinsonian syndromes cannot be ruled out.
Regardless of these limitations as a treatment for psychosis in PD patients with VH and depression in PD, we were able to alleviate her distress and prevent its recurrence without any remarkable adverse effects. In conclusion, our case report highlights the effectiveness of mirtazapine and indicates that mirtazapine may be useful for clinicians treating patients with PD with refractory VH.