A Report of Rabbit Syndrome Who Benefited from Sigma 1 Agonist Fluvoxamine.

Rabbit Syndrome is an uncommon side effect of antipsychotic treatment. Although it is usually associated with typical antipsychotics, it can also be related to atypical antipsychotics. Anticholinergics are the most accepted treatment approach in treating Rabbit Syndrome. Fluvoxamine is a member of selective serotonin reuptake inhibitors and it is a potent agonist of sigma 1 receptors. In this article, we report a Rabbit Syndrome case who has benefited from fluvoxamine, in terms of both depressive disorder and Rabbit Syndrome; and present the data on the effects of sigma 1 agonist fluvoxamine on numerous movement disorders.

INTRODUCTION

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) which is used for the treatment of depressive disorder and obsessive compulsive disorder.1,2) Besides its effect on the serotonergic system, it was well established that fluvoxamine is a potent sigma 1 chaperone receptor agonist.3) The data on the effects of sigma 1 agonism on neuropsychiatric diseases is limited. Sigma receptor agonism has various effects on the central nervous system, as well as on other systems of body via Ca signaling, protein kinase translocation or activation, ion channel firing, neurotransmitter release, cellular differentiation, neuronal survival, and synaptogenesis.4–9) Several therapeutic drugs, which have been used on humans, and some neurosteroids such as dehydroepiandrosterone have high to moderate sigma-1 receptor affinity. Cumulative data suggest benefits of sigma 1 agonism on neuropsychiatric diseases, however there still has not been any exact explanation which can highlight the action of mechanism.10) Although all SSRIs share the same mechanism of action by means of the serotonergic system, their effects on sigma 1 receptors vary. Among these drugs, fluvoxamine exerts the most potent agonistic activity on sigma 1 receptors.3,11) There have been experimental studies which demonstrated the effects of fluvoxamine as a potent sigma 1 receptor agonist. Furthermore, there have been clinical studies and case reports which reported the beneficial effects of fluvoxamine, by means of sigma 1 receptor agonistic activity, on numerous neuropsychiatric diseases.10)

Rabbit syndrome is a drug induced movement disorder that is particularly associated with antipsychotics.12) It is relatively uncommon and is characterized by rhythmic movements of perioral muscles, which seems as the appearance of a chewing rabbit. It has been reported to commonly be associated with typical antipsychotics13); however, it can also be associated with atypical antipsychotics.12,14) Here, we report a case, who developed Rabbit syndrome after long acting risperidone treatment, and benefited from fluvoxamine in terms of both depressive symptoms and symptoms of Rabbit syndrome.

CASE

A 62-year-old man admitted to outpatient clinic with symptoms of depressive mood, anhedonia, insomnia, decreased appetite, difficulty in concentration, ideas of hopelessness, psychomotor agitation, and abnormal movements of the lips. In his history, his complaints began four months ago as; being followed by strangers, hearing voices that commented and humiliated him, being unable to leave his home, a decrease of self hygiene, increase in irritability, and having some homicidal attempts to family members. The patient had been taken to a psychiatrist without his will and he had been assured to be examined by a psychiatrist.

At initial assessment, the patient was assessed with routine laboratory and toxicology examinations, brain magnetic resonance imaging, and electroencephalogram. Both physical and laboratory examination had been resulted unremarkable, thus organic etiology had been excluded. Moreover, he had scored a 26 in the mini mental status examination. The patient had been diagnosed with “brief psychotic disorder” according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5)15) by a psychiatrist working in another center. After his psychiatric and physical assessment, the patient had been given a treatment of olanzapine 10 mg/day. During his first outpatient control on the fifteenth day of treatment, it had been noticed that the patient was non adherent to oral treatment and his symptoms persisted. The patient had been given 25 mg of long acting risperidone treatment bimonthly, due to lack of adherence to oral treatment. After the fourth injection of risperidone (at the second month), the psychotic symptoms were reported to be remitted; however, abnormal movements of lips developed. Because of the remission of his initial symptoms and development of abnormal movements, the treatment of 25 mg of long acting risperidone had been stopped. The abnormal movements of the lips were consulted with the neurology department, and the patient’s neurological examination had been reported to be unremarkable. The patient had been treated with biperiden 6 mg/day for 3 weeks, and diazepam 5 mg/day had been added to his treatment for 5 weeks due to lack of response to biperiden treatment in terms of abnormal movements of his lips.

After these interventions, the patient admitted to our outpatient clinic at the fourth month of his treatment. In his psychiatric and physical examination, abnormal movements of lips in a vertical axis, being fine, rapid, and rhythmic, were noted additional to depressive symptoms. Routine laboratory examination, brain magnetic resonance imaging, and other neurological assessments were unremarkable. The patient was diagnosed as major depressive disorder and medication induced movement disorder (Rabbit syndrome) according to DSM-5. Fluvoxamine 100 mg/day was prescribed as his current treatment; whereas, biperiden and diazepam treatments were stopped. The patient was recommended to be followed up bimonthly in our outpatient clinic. In his first assessment, there was a significant improvement in symptoms of Rabbit syndrome and a moderate amelioration in depressive symptoms. The dose of fluvoxamine was increased to 200 mg/day. After the second assessment, the patient was asymptomatic in terms of Rabbit syndrome, and there was significant improvement in depressive symptoms. During the follow-up outpatient visits, the patient was noted to be asymptomatic in terms of both Rabbit syndrome and depressive disorder.

DISCUSSION

In the present case, we reported the beneficial effect of sigma 1 agonist fluvoxamine on symptoms of Rabbit syndrome and depressive disorder. The etiology of Rabbit syndrome is unclear, and it is commonly confused with and misdiagnosed as tardive dyskinesia.12) Due to the fact that Rabbit syndrome is commonly seen after anti-psychotic treatment, the etiology has been considered to be associated with the dopaminergic system.16) Rabbit syndrome is generally known to occur due to long-term use of typical antipsychotics with a range between 1.5% and 4.4%.17) Quetiapine, clozapine, olanzapine, aripiprazole, paliperidone, amisulpride, and most commonly risperidone have been reported to be associated with the development of Rabbit syndrome.14) In terms of treatment, the most acceptable approach is using anticholinergic drugs, such as benzatropine, biperiden, trihexyphenidyl.12) In some case reports, haloperidol, olanzapine, sulpiride, and chlorpromazine were reported to be effective in the treatment of Rabbit syndrome.18) However, the present case is the first to demonstrate the beneficial effect of sigma 1 agonist fluvoxamine on Rabbit syndrome.

Sigma 1 receptors include 223 amino acids and as noted in the introduction section, they have been associated with many cellular functions, such as cellular redox, cellular survival, neurotransmitters release etc.4–9) It has been demonstrated that sigma 1 receptors act as a chaperone, and have the ability to fix and stabilize endoplasmic reticulum proteins. Both clinical and experimental studies reported various effects of sigma 1 receptors on various systems throughout the body, such as the cardiovascular system, immune reactions, pain, liver functions, cancer proliferation, and various neuropsychiatric disorders.6,9,19,20) Fluvoxamine has been reported to be the most potent sigma 1 receptor agonist among all SSRIs.3) Furthermore, in a positron emission tomography study, fluvoxamine was reported to bind to sigma 1 receptors in the living human body.21) Thus, some effects of SSRIs, particularly of fluvoxamine, are mediated with sigma 1 agonism.19,22–24)

In literature, there have been restricted numbers of papers that reported association between sigma 1 agonist fluvoxamine and movement disorders. Furuse and Hashimoto25,26) reported cases who developed akathisia after aripiprazole treatment and blonanserin monotherapy and whose akathisia resolved after switching to fluvoxamine monotherapy. They firstly concluded that the action mechanism of fluvoxamine for resolving akathisia might be associated with sigma 1 receptor agonism. We have also reported cases who benefited from fluvoxamine in terms of; hemiballism and depressive disorder27); tardive dyskinesia in patients with post-psychotic depressive disorder of schizophrenia28); duloxetine induced tardive dyskinesia29); tardive dyskinesia in two patients with schizophrenia30); tardive akathisia in a patient with schizophrenia30); and improvement of chorea.31) There are conflicting data on the activity of sigma 1 receptors on the dopaminergic system. Sigma 1 receptor agonists can either increase or decrease dopaminergic activity via the striatal pathway of dopamine.24) Furthermore, sigma 1 receptors are highly concentrated in the limbic and motor systems of the human brain. Sigma 1 receptors are highly existent in the putamen, septum, caudate, nucleus accumbens, and amygdala in rats and humans. Fluvoxamine can act as a dopamine regulator, particularly on the striatal pathway, in patients with movement disorder via sigma 1 agonism.32,33) Sigma receptor agonistic activity can act to prevent neurodegeneration and inhibit excitotoxic factors.34) Because the etiology of movement disorders such as, tardive dyskinesia, akathisia, chorea, and hemiballism are complex; it is difficult to say the exact mechanism of action of fluvoxamine. However, it can be suggested that the sigma 1 agonistic activity of fluvoxamine might mediate beneficial effects for the movement disorders mentioned above.

Anticholinergic agents such as, benzatropine, biperiden, trihexyphenidyl are accepted to be the most effective agents for the treatment of Rabbit syndrome12); however, besides treatment, these agents can affect various systems of the body regarding cholinergic distribution of cholinergic receptors.35) Although fluvoxamine has anticholinergic activities on the living body, it has been considered to lack specific and significant affinity on muscarinic receptors. Among antidepressants, fluvoxamine has been placed in the low anticholinergic effect class with antidepressants, such as bupropion, fluoxetine, mirtazapine, sertraline, and trazodone.35–37) Since the most acceptable approach in the treatment of Rabbit syndrome is the use of anticholinergics, in this case a question arises that the action of mechanism of fluvoxamine might be due to its low anticholinergic effects. However, our patient had been given the treatment of biperiden and he did not benefit from it in terms of Rabbit syndrome. Thus, it may be more plausible to consider the action of mechanism from potent sigma 1 receptor agonism, rather than anticholinergic effects. From this point, sigma 1 agonist fluvoxamine, can be considered to be an alternative treatment choice for movement disorders, without the serious and uncomfortable side effects.

In conclusion, we suggest that fluvoxamine, as well as other sigma 1 receptor agonists, may be good candidates for the treatment of movement disorders. Current data about the effect of sigma 1 receptor agonism on movement disorders is restricted with case studies. Further studies are needed to highlight the role of sigma 1 receptor agonists on the treatment of movement disorders.