2024; 22(2): 387-389  https://doi.org/10.9758/cpn.23.1103
Mirtazapine Monotherapy for Antipsychotics-refractory Psychosis in a Patient with Very-late-onset Schizophrenia-like Psychosis: A Case Report
Kanji Ueno1, Makoto Ishitobi2, Hirotaka Kosaka1, Kei Ichijo3, Yukihiro Nagase3
1Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
2Department of Psychiatry, Jinkei Hospital, Himeji, Japan
3Department of Psychiatry, Takatsuki Hospital, Hachiouji, Japan
Correspondence to: Makoto Ishitobi
Department of Psychiatry, Jinkei Hospital, 275 Nozato, Himeji, Hyogo 670-0811, Japan
E-mail: mak1977019@yahoo.co.jp
ORCID: https://orcid.org/0000-0001-6848-7044
Received: June 14, 2023; Revised: August 12, 2023; Accepted: September 4, 2023; Published online: September 25, 2023.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Very-late-onset schizophrenia-like psychosis (VLOSLP) is a condition in which psychotic symptoms emerge after the age of 60 years. Given its heterogeneous nature, VLOSLP remains a diagnostic and therapeutic dilemma. Here, we report a case of a 68-year-old patient with psychosis refractory to antipsychotics who was successfully treated with mirtazapine monotherapy. This case suggests that mirtazapine monotherapy may be effective for the treatment of patients with antipsychotic- refractory VLOSLP.
Keywords: Mirtazapine; Antipsychotics-refractory psychosis; Late-onset schizophrenia

Very-late-onset schizophrenia-like psychosis (VLOSLP) is defined as a condition with the onset of psychotic symptoms after 60 years of age [1]. Approximately 60% of psychotic disorders in later life arise due to a secondary condition [2]. Particularly, VLOSLP is also suggested to encompass the prodromal phase of neurodegenerative diseases such as Alzheimer’s disease [3], frontotemporal dementia (FTD) [4], or dementia with Lewy bodies (DLB) [5]. Considering its heterogeneous nature, VLOSLP remains a diagnostic and treatment dilemma. Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NASSA), has a unique mode of action [6]. Systematic reviews suggest that mirtazapine, when used as an adjunct to antipsychotics, might be effective for negative and extra-pyramidal symptoms in patients with schizophrenia [6]. We report a patient with antipsychotics-refractory VLOSLP who was treated successfully using mirtazapine monotherapy without the emergence of adverse effects. Per-mission was obtained from the patient to share anonymized clinical information along with written consent to publish this report.


A previously well 68-year-old male was admitted to our inpatient ward complaining of hallucinations and delusions for 2 years. He complained of interactive auditory hallucinations, chasing delusions, sense of being watched, and thought propagation. He also had loosening of association and thought blocking. Furthermore, he did not indicate any affective symptoms. Overall, he had maintained a satisfactory level of functioning until he was 66 years old. He had no other significant medical history and no family history of psychiatric or neurologic disorders. General physical and neurological examinations were also normal. His mini-mental scale examination (MMSE) score was 23. On the frontal assessment battery (FAB), he scored 14/18, higher than the cut-off value of 12. He drew a normal clock. An electroencephalogram did not reveal any abnormality. Cerebral computed tomography revealed mild atrophy of the frontal and temporal lobes. Blood examination revealed no abnormalities including in tests related to thyroid function, B vitamins, and infections. The patient did not consent to undergo neuroimaging studies, such as magnetic resonance imaging or positron emission tomography.

Risperidone 4 mg/day, olanzapine 20 mg/day, blonanserin 24 mg/day, brexpiprazole 2 mg/day, asenapine 20 mg/day, haloperidol 4 mg/day, and paliperidone 12 mg/day were administered sequentially for a total of approximately 1 year but were ineffective and discontinued due to oversedation and severe extrapyramidal symptoms. The patient received no long-acting injectable antipsychotic medications. Clozapine and electroconvulsive therapy were suggested; however, he refused these treatments.

Subsequently, paliperidone was tapered off, and mirtazapine monotherapy was initiated at a dosage of 15 mg/day and titrated to 45 mg/day. His psychotic symptoms, such as interactive auditory hallucinations, chasing delusions, sense of being watched, thought propagation, loosening of association, and thought blocking, improved dramatically after two weeks on mirtazapine, with decreased brief psychiatric rating scale scores from 45 to 27. In contrast, the patient’s MMSE score remained unchanged at 23/30, and the score of FAB declined progressively to 9/18 despite dramatic symptomatic improvement. There was no relapse of psychotic symptoms and no emergence of symptoms that would have suggested dementia clearly during more than 1 year of follow-up with no adverse event, although there was a slight decrease in the FAB scores.


This is the first report of a patient having VLOSLP with antipsychotics-refractory psychosis who improved dramatically with mirtazapine monotherapy.

Specifying the etiology of VLOSLP was challenging because of the limited clinical information. In addition to mild cognitive impairment (MMSE 23/30), a progressive decline of executive function was observed despite symptomatic improvement. Thus, neurodegenerative diseases such as DLB or FTD, which initially present as psychosis before signs of executive dysfunction [4,7], are important differentials. On the other hand, the symptoms of these neurodegenerative diseases that cause secondary psychosis overlap with those of schizophrenia [8]. Long-term follow-up with a detailed clinical evaluation of the behavioral features and neuroimaging might assist in the differentiation between neurodegenerative diseases and primary psychotic disorders. In addition to genetic and cerebrospinal fluid testing, more detailed neuropsychological evaluations, including aphasia testing, could have helped us better understand his pathophysiology. Naturally, severe major depressive disorder with psychotic features could be considered in the differential, as the mirtazapine monotherapy was markedly effective. However, he had no core symptoms of depression, such as depressed mood or loss of interest/pleasure in activities (anhedonia), and no problems with sleep or appetite. Thus, his psychotic symptoms were not considered to be associated with depression.

Only one study has reported that adjunctive mirtazapine improved positive symptoms of schizophrenia [9]. On the other hand, several studies have reported that NASSAs, including mirtazapine, are effective for patients with Parkinson’s disease (PD) with psychosis and other forms of dementia with psychosis [10,11]. NASSAs work by altering the serotonin-dopamine balance through a strong serotonin receptor antagonism (i.e., anti-5HT2A, anti-5HT2C, and anti-5HT3) [12]. Pimavanserin, a selective 5HT2A inverse agonist/antagonist, was approved in the US for psychosis associated with PD and has a favorable treatment effect on psychotic symptoms of other neurodegenerative disorders [7]. These suggest that dysregulation of serotonin in the mesolimbic and mesocortical systems might be associated with the occurrence of psychotic symptoms in these disorders. Considering the dramatic improvement with mirtazapine monotherapy and progressive cognitive decline in our patient, prevailing psychotic symptoms might be the initial presentation of a neurodegenerative disorder before the development of obvious neurological symptoms. It is necessary to follow-up to examine whether mirtazapine continues to be effective over the long term because the pathophysiology may change over time including progressive cognitive decline if his psychosis is considered an early manifestation of neurodegenerative disorders.

In conclusion, our case suggests that mirtazapine monotherapy may be effective for treating antipsychotics-refractory psychosis in a patient with VLOSLP. The use of mirtazapine for late-onset psychosis should be further assessed in controlled studies.



Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Author Contributions

Conceptualization: Kanji Ueno, Makoto Ishitobi. Data acquisition: Kei Ichijo, Yukihiro Nagase. Supervision: Makoto Ishitobi, Hirotaka Kosaka. Writing−original draft: Kanji Ueno. Writing−review & editing: Makoto Ishitobi, Hirotaka Kosaka, Kei Ichijo, Yukihiro Nagase.

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