Abstract
Dopamine supersensitivity is an important consideration for assessing treatment-resistant schizophrenia. The emergence of dopamine supersensitivity might be related to upregulation of dopamine D2 receptor, which engenders tolerance to antipsychotics, rebound psychosis, and tardive dyskinesia (TD). A 24-year-old man with a history of treatment-resistant schizophrenia was hospitalized for treatment of bone fracture sustained during a suicide attempt. After the operation, his clinical symptoms implied malignant catatonia. The patient discontinued antipsychotics without rebound psychosis under clonazepam treatment. His psychotic symptoms were controlled further with 24 mg/day aripiprazole without relapse or worsening. Clonazepam might be an effective option for the management of dopamine supersensitivity psychosis (DSP).
Introduction
Dopamine supersensitivity is an important consideration for assessing treatment-resistant schizophrenia. Although the emergence of dopamine supersensitivity might be related to the upregulation of dopamine D2 receptor, which engenders tolerance to antipsychotics [Chouinard, 1991], no established treatment exists for this condition except for the use of clozapine [Kane et al. 1988].
This report describes a case of a treatment-resistant schizophrenia for which dopamine supersensitivity was ameliorated by clonazepam treatment.
Case report
During the 2 years before recent admission to our hospital, Mr O, a 24-year-old man with a 5-year history of schizophrenia, had been hospitalized for refractory auditory hallucinations and disorganized behaviors. After admission following his first psychotic episode at age 19, his psychotic symptom was controlled by aripiprazole 30 mg for 2 years. However, at age 21, he was hospitalized again for relapse that had resulted from his self-discontinuation of oral medication. Symptoms were resolved with olanzapine 20 mg and haloperidol long-acting injection (LAI) 50 mg. Thereafter, his psychotic symptom remained stable for about 1 year.
During a regular visit, he reported increased body weight and somnolence. Olanzapine might have caused these symptoms. Therefore, it was gradually switched to paliperidone. During the reduction of olanzapine, negative symptoms including loss of motivation, social withdrawal, and diminished affective responsiveness emerged. His psychotic symptoms remained stable under paliperidone 12 mg/day for several months. However, after the reduction of paliperidone for extrapyramidal symptoms, he began to experience auditory hallucinations and persecutory delusion together with severe agitation and hostility. Consequently, he was hospitalized. The paliperidone dosage was increased to 12 mg/day. Although his hallucinations had improved 1 week later, agitation and hostility were refractory. Irrespective of the remaining symptoms, neither he nor his family accepted clozapine treatment. Therefore, he was transferred to a community hospital for long-term admission. Then, haloperidol LAI 100 mg/4 weeks was initiated. Because of repeated relapse, risperidone 8 mg and zotepine 200 mg were added. Nevertheless, only slight improvement was observed. He received high doses of antipsychotic drugs for the subsequent 2 years, without full remission.
After femoral fracture resulting from a suicide attempt by leaping, he was admitted to our emergency ward. He was drowsy and displayed severe psychomotor retardation. He spoke with an indistinct voice with increased latency. He exhibited formal thought disorder. His mood was depressed. On the day after the operation for fracture, he began to exhibit clinical features that were consistent with catatonia including catalepsy, stupor, waxy flexibility, mutism, negativism, stereotypy, and posturing. Because these symptoms accompanied abnormalities in vital signs, which included elevated blood pressure, tachycardia and diaphoresis, a diagnosis of malignant catatonia was made. All antipsychotics were discontinued. Two hours after the administration of oral clonazepam 2 mg, his mobility was improved slightly. Marked reduction in motor signs of catatonia was apparent a day later. Then he started eating and drinking. Surprisingly, long-standing refractory psychotic symptoms disappeared completely as well. Thereafter, he spent 2 months undergoing rehabilitation and reading magazines under 2 mg clonazepam. Aripiprazole was added later because of gradual exacerbation of psychotic symptoms including agitation and auditory hallucinations. Psychotic symptoms improved with no relapse of catatonic symptoms. Therefore, he was discharged home with a prescription of 24 mg/day aripiprazole. During 7 months following his discharge, his symptoms were controlled completely using the same dosage of aripiprazole.
Discussion
Dopamine supersensitivity psychosis (DSP) is characterized by rebound psychosis, drug tolerance, and tardive dyskinesia (TD). Because DSP might be difficult to differentiate from the relapse of original psychiatric disorder, the diagnostic criteria have been established (Table 1). In this case, catatonic symptoms appeared immediately after the reduction of antipsychotics. From a pharmacokinetic perspective [Hubbard et al. 1987; Cohen et al. 1988], this onset time is not typical for a relapse caused by diminished drug dosage. Moreover, the high-dose treatment duration was sufficiently long to develop D2 receptor upregulation [Hess et al. 1988; Schroder et al. 1998].
Chouinard research diagnostic criteria for supersensitivity psychosis [Chouinard, 1991].
Regarding diagnostic criteria, he experienced repeated relapse during continuous treatment with neuroleptic drugs (Criteria A and B2). A higher dosage of antipsychotics was necessary to achieve the same therapeutic effect, perhaps because of cumulative tolerance to the antipsychotic effect (Criterion B3). We identified newly developed psychotic symptoms including negative symptoms and persecutory delusion after decreasing the antipsychotic drug dosage (Criterion B5), which is the exact characterization of rebound psychosis. Eventually, the increased neuroleptic drug dosage did not mask psychotic symptoms (Criterion B4). Then he was treated with higher doses of neuroleptic drugs on at least a bid regimen (Criterion B7). Finally, he progressed from the first acute phase of illness. His psychotic symptoms were responsive to neuroleptic drugs, at least in the incipient stage (Criterion D). Therefore, this patient exhibited typical DSP induced by antipsychotics. Dopamine sensitivity was resolved with discontinuation of antipsychotic drugs and administration of clonazepam.
Regarding the DSP mechanism, it has been suggested that oral high-dose administration might induce upregulation of D2 receptor density, thereby increasing the risk of fluctuation of psychotic symptoms and TD [Iyo et al. 2013]. In fact, some evidence suggests upregulation of striatal dopamine receptors following chronic antipsychotic drug exposure [Lee and Seeman, 1980]. This dopamine hypothesis explains the low tendency of clozapine to cause DSP because clozapine has less D2 blockade [Chakos et al. 2001].
However, the development of DSP might also involve changes in the gamma-aminobutyric acid (GABA) system. For example, TD, a relevant symptom of DSP, can result from a loss of striatal interneurons that use GABA as their neurotransmitter. Gunne and colleagues examined monkeys that had developed TD. Chronic antipsychotic treatment showed reduced GABA synthesis in several regions of the basal ganglia [Gunne et al. 1984]. Another report described a significant reduction in cerebrospinal fluid levels of GABA in schizophrenic patients with TD [Thaker et al. 1987]. A double-blind, randomized controlled trial conducted based on the GABA hypothesis for TD demonstrated that clonazepam, a potent agonist at benzodiazepine receptors, reduced dyskinesia scores more than a placebo did [Thaker et al. 1990].
The relevant literature includes no histopathologic data related to the GABA system in DSP. However, for schizophrenia, evidence for changes in GABAergic interneurons is clear in post-mortem studies [Lewis and Hashimoto, 2007]. Benzodiazepines are used as agents for the treatment of schizophrenia. Wolkowitz and Picknar reviewed double-blind trials [Wolkowitz and Pickar, 1991]. The authors concluded that the response is highly variable; about one-third to one-half of patients improved. In addition, some results of studies suggest a relation between GABA system and psychotic symptoms that is similar to that for neuroleptic drugs [Pickar et al. 1984]. Benzodiazepine-associated reductions in the plasma levels of a dopamine metabolite, homovanillic acid, were correlated with reductions in the ratings of both positive and negative schizophrenic symptoms [Wolkowitz et al. 1988].
These study results suggest that clonazepam contributed to the improvement of dopamine sensitivity. The patient examined for this study discontinued antipsychotics without rebound psychosis under clonazepam. Symptoms were controlled further with 24 mg/day aripiprazole without relapse or worsening. This clinical course suggests that clonazepam improved his psychotic symptoms via the GABA system rather than via the dopaminergic system. The D2 receptor density was downregulated during this phase. Gradual exacerbation of psychotic symptoms after clonazepam treatment might be attributable to the limited duration of therapeutic effects of clonazepam. In fact, a report of a previous study revealed that, in some patients, therapeutic effects of benzodiazepines on schizophrenia diminished after several weeks [Wolkowitz and Pickar, 1991]. We selected aripiprazole as a treatment for relapse because aripiprazole, known as a dopamine partial agonist, prevents the development of dopamine supersensitivity with stable striatal D2 receptor density [Tadokoro et al. 2012].
In conclusion, this report is the first describing the efficacy of clonazepam for DSP. Although the mechanism remains unclear, the GABA system might be associated with the pathophysiological change of DSP. Given that the DSP frequency is estimated as 75% among patients with treatment-resistant schizophrenia [Yamanaka et al. 2016], additional studies must be conducted to confirm the strategy for treatment of DSP.
The patient gave written informed consent for the publication of details of his case.
Contributions
Author Mina Fukai collected data and wrote the first draft of the manuscript. Authors Tetsu Hirosawa, Tetsuya Takahashi, Reizo Kaneda, Mitsuru Kikuchi, and Yoshio Minabe revised the manuscript critically for important intellectual content.
Footnotes
Acknowledgements
The authors thank the patient and his family.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors declare that there is no conflict of interest.