Introduction
Psychotic symptoms are often present as a complication of Parkinson disease (PD) and are defined as PD with psychosis (PDPsy) (Ravina et al., Reference Ravina2007). Among psychotic symptoms, visual hallucinations are a comparatively common symptom, but auditory hallucinations (AHs) are relatively rare (Inzelberg et al., Reference Inzelberg, Kipervasser and Korczyn1998; Ravina et al., Reference Ravina2007). While atypical antipsychotic (AAP) agents are often used for the treatment of PDPsy, severe adverse effects including extrapyramidal symptoms (EPS) can hinder treatment continuation or tolerance (Zahodne and Fernandez, Reference Zahodne and Fernandez2008). Previous studies have reported that antidepressants are effective for patients with PDPsy as well as other forms of dementia with psychosis (Meco and Bernardi, Reference Meco and Bernardi2007; Seitz et al., Reference Seitz, Adunuri, Gill, Gruneir, Herrmann and Rochon2011). Moreover, we recently experienced a case in which mirtazapine (MRZ) was effective against refractory psychosis in a patient with PD (Tagai et al., in press). Herein, we report a patient with PD who suffered from refractory AHs and was treated with MRZ, which has an alpha (α) 2-adrenergic serotonin 2 and 3 receptor-antagonizing action, without the development of any extrapyramidal adverse effects. MRZ has not been previously reported to be effective against AHs that are refractory to AAPs in patients with PD.
To maintain patient privacy, all personal information has been altered in this case report; the patient's written informed consent was obtained.
Case report
A 41-year-old woman complained of a right upper limb resting tremor and clumsiness as her initial symptoms, which were treated effectively with antiparkinsonian agents. She had not experienced any significant problems with growth, development, medication, substance abuse, or sleep disturbances. No significant family medical history was present. Based on these findings, she was diagnosed as having PD. At the age of 47 years, with the aggravation of parkinsonism, she began to say that she could hear the voices of strangers when she was actually alone. Gradually, this symptom worsened, and she began to talk to herself and say, “A stranger came here again” and “Go way!” on a daily basis. The dose of her antiparkinsonian agent (ropinirole) had been reduced by a previous doctor, but her AHs did not disappear. Thus, she visited our clinic for the first time at the age of 48 years.
When she visited our outpatient clinic, she was taking levodopa (250 mg/d), pramipexole (0.75 mg/d), and trihexyphenidyl (3 mg/d). She had moderate parkinsonism (Hoehn &Yahr stage: II-III; Unified Parkinson Disease Rating Scale (UPDRS), version 3.0, part I: 27–66 points) and clinical fluctuations (UPDRS part III: 3 points) and complained of discomfort because of vivid AHs and movement disability in the morning. Her consciousness was intact, and her other neurological findings were normal. Brain magnetic resonance imaging and routine serum laboratory tests were within the normal ranges. After a neurologist tapered her doses of pramipexole and trihexyphenidyl, we added quetiapine (25 mg/d) or the Asian herbal medicine Yokukansan (7.5 g/d) for about two months. However, her parkinsonism worsened without any improvement in her psychotic symptoms. Severe EPS appeared (UPDRS part I: 70–90), and she complained of anxiety, sleeplessness, and a depressive mood. Thus, her dose of quetiapine was tapered. To lessen her anxiety and depressive mood (Hamilton Rating Scale for Depression (HAM-D): 20 points), we started to treat her with MRZ at a dose of 7.5 mg/d and then titrated this dose up to 15 mg/d for a month without levodopa dose reduction (250 mg/d). On day 28 after the start of MRZ treatment, because the degree of her AHs and subsequent depressive symptoms had decreased to about half of the previous severity (HAM-D: 11 points) without any aggravation in her EPS (UPDRS part I: 21–53 points), we prescribed a dose of 15 mg/d. On day 56 after the start of MRZ therapy, her AHs and subsequent symptoms had completely disappeared. She continued to take MRZ for about 180 days, and her AHs did not recur nor did her motor symptoms worsen.
Discussion
In the present patient with PD and chronic AHs, treatment with MRZ improved the patient's AHs, depressive mood, and anxiety. Some risk factors or causes of PDPsy are known. From a pharmacological aspect, the introduction or dose increment of a novel antiparkinsonian agent can often generate PDPsy (Fénelon, Reference Fénelon2008; Zahodne and Fernandez, Reference Zahodne and Fernandez2008). A previous study and review stated that motor fluctuations (especially during the off period) might be related to the appearance of AHs (Inzelberg et al., Reference Inzelberg, Kipervasser and Korczyn1998; Ravina et al., Reference Ravina2007; Fénelon, Reference Fénelon2008). In the present case, the doses of the dopamine agonists and anticholinergics were tapered off without levodopa dose reduction, but the patient's AHs did not change. Depressive symptoms had not been observed before EPS was worsened by low dose of quetiapine. Patient's AHs synchronized with off-movement period in the morning, thus those motor disabilities might be disease-related factors in the present case. However, the possibility of levodopa-induced psychosis or depressive symptoms associated with psychotic symptoms could not be completely excluded as a causative mechanism in the present case.
MRZ was prescribed in the present case because the patient had anxiety, a depressive mood, and sleeplessness; thus, an antidepressant with a sedative action was needed (Meco and Bernardi, Reference Meco and Bernardi2007). Moreover, we gradually increased the dose beginning with a low dose of MRZ; sedative antidepressants include those with an antagonistic action for histamine 1 and serotonin 2, rather than a selective serotonin reuptake inhibitor or cholinesterase inhibitors, such as rivastigmine for AHs and depressive symptoms (Zahodne and Fernandez, Reference Zahodne and Fernandez2008; Seitz et al., Reference Seitz, Adunuri, Gill, Gruneir, Herrmann and Rochon2011). The reason for the gradual increment from a low dose of MRZ (7.5 mg/d) was to avoid any worsening of psychosis or delirium manifestations as a result of rapid titration (Padala et al., Reference Padala, Padala, Malloy and Burke2010). Among AAP agents, clozapine or quetiapine has comparatively lower affinities for dopamine receptors, suggesting their effectiveness without a worsening of motor symptoms (Zahodne and Fernandez, Reference Zahodne and Fernandez2008). In the present case, we first treated the AHs using low-dose quetiapine; however, her EPS gradually worsened. We could not use clozapine, which had not been officially adopted at our hospital, because of its severe side effects, such as agranulocytosis (Zahodne and Fernandez, Reference Zahodne and Fernandez2008).
From the viewpoint of the psychopharmacological pathogenesis of psychotic symptoms, not only the dopaminergic but also the serotonergic and cholinergic systems may be involved in the effects on several neurotransmitters (Fénelon, Reference Fénelon2008). The contributions of serotonergic modulators to psychosis and agitation in dementia or PD have been suggested in some case reports or meta-analyses (Meco and Bernardi, Reference Meco and Bernardi2007; Seitz et al., Reference Seitz, Adunuri, Gill, Gruneir, Herrmann and Rochon2011). Also, because the dysregulation of serotonin in the mesolimbic and mesocortical systems might be linked to the occurrence of hallucinations, ondansetron, a specific serotonin 3 receptor antagonist, has been reported to be successful for improving PDPsy without causing any worsening of the motor symptoms (Zoldan et al., Reference Zoldan, Friedberg, Livneh and Melamed1995; Inzelberg et al., Reference Inzelberg, Kipervasser and Korczyn1998). Thus, MRZ, which has a serotonin 3 receptor antagonist action, might alleviate AHs in patients with PD without any extrapyramidal adverse effects. However, some previous reports have shown contradictory results; therefore, further careful discussion of the effectiveness of MRZ for psychosis is needed in the future (Normann et al., Reference Normann1997; Padala et al., Reference Padala, Padala, Malloy and Burke2010).
In conclusion, our case report suggests the effectiveness of MRZ, which could be clinically useful for the treatment of refractory AHs in patients with PD without any worsening of motor symptoms. A future prospective study involving more patients is needed to clarify the effectiveness of MRZ.
Conflict of interest
None.
Description of authors’ roles
Nagata wrote the paper. Shinagawa and Tagai provided advice regarding the treatment methods. Nakayama reviewed the case.
