Response of Catatonia to Amisulpride and Lorazepam in an Adolescent with Schizophenia

Introduction

Catatonia is a severe syndrome of motor abnormalities accompanying psychiatric symptoms. Motor abnormalities in catatonia may involve stupor, excitement, catalepsy, negativism, waxy flexibility, and stereotypical movements, and psychiatric symptoms may consist of mutism, social withdrawal, mannerism, echolalia, verbigeration, and schizophasia (Benarous et al. 2017). Although catatonia was previously defined as a subtype of schizophrenia, it appears as a separate entry in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). DSM-5 includes a list of 12 catatonic symptoms, 3 or more of which are required for the diagnosis of catatonia (American Psychiatric Association 2013). Even though it is a potentially life-threatening condition associated with various psychiatric and medical disorders, it is often underdiagnosed and undertreated in children and adolescents (Benarous et al. 2017). In contrast to adult catatonia, limited studies about pediatric catatonia reported male predominance and higher rates of underlying psychotic disorders rather than mood disorders (Benarous et al. 2017). Regardless of the cause, the first-line treatment of catatonia is benzodiazepines, especially lorazepam. Electroconvulsive therapy is recommended in benzodiazepine-resistant catatonia. However, antipsychotics are generally not recommended during catatonia because they can worsen symptoms and can trigger others, including neuroleptic malignant syndrome (Benarous et al. 2017). There are case reports in the literature documenting a clinical response of pediatric catatonia to olanzapine (Delbello et al. 2000), aripiprazole (Roberto et al. 2014), and quetiapine medication (Ishitobi et al. 2014). Nevertheless, there is no evidence for amisulpride treatment in pediatric catatonia. In this report, we describe a male adolescent with early-onset schizophrenia who also had catatonia and was treated effectively with amisulpride and lorazepam.

Case

A 14-year-old male adolescent with a previous diagnosis of psychotic disorder—not otherwise specified (NOS)—was admitted to our department with symptoms of mutism, insomnia, slow movements, and anorexia. The patient was completely mute; therefore, his history was obtained from his mother. His symptoms started a year previously with social withdrawal and preoccupations with his body and appearance. For the past 3 months, he was reported as crying frequently, neglecting his grooming, being irritable, and having loss of concentration. His speech and movements were gradually reduced and for the past month he was mute and was in stupor. His sleep and appetite were reduced. No stressors that could explain the emergence of symptoms could be elicited. There was also no history of an episode of mood disorder preceding the onset of symptoms. Risperidon 0.5 mg/day was initiated and titrated to 2 mg/day in an outpatient clinic 3 months ago, but he did not benefit from treatment. After this period, he refused medication and opposed admission to a hospital. When the symptoms worsened, his parents forced him to see a psychiatrist. Premorbid and medical history were within normal limits. The family history revealed that his aunt was found as having a psychotic disorder for which she received treatment. A mental status examination demonstrated social withdrawal, mutism, negativism, stupor, and waxy flexibility. The history and mental status examination was judged to be compatible with catatonia accompanying psychotic disorder NOS and the patient was hospitalized.

Comprehensive laboratory, imaging tests, and a physical examination to exclude organicity were within normal limits. Risperidone was tapered while amisulpride 100 mg/day and lorazepam 0.25 mg/day were started and titrated gradually to 200 mg/b.i.d and 0.5 mg/b.i.d for a 1-week period. The patient recovered spontaneous speech at the first week of treatment, his movements were also increased and more fluid. The waxy flexibility disappeared, and his sleep and appetite were increased. With the resolution of catatonic symptoms, he started to divulge his delusions, including auditory and visual hallucinations, and paranoid delusions for the past 5 months, after which the diagnosis changed to early-onset schizophrenia in accordance with the DSM-5 criteria. The patient was discharged with no sign of catatonia and minimal changes of psychosis at the second week with a prescription of amisulpride 400 mg/day and lorazepam 1 mg/day, and was followed up monthly. During the 6-month follow-up, the amisulpride dosage was increased up to 1000 mg/day; he was in partial remission. Lorazepam was stopped in the second month and his catatonic symptoms did not recur.

Discussion

In this case, the patient had four of the catatonic symptoms as described in DSM-5, including mutism, negativism, stupor, and waxy flexibility, thus he was found as having catatonia. Catatonia was easily recognized due to waxy flexibility. Unfortunately, pediatric catatonia is often underdiagnosed because its symptoms overlap with psychiatric and medical disorders. Careful consideration of catatonia is advised if motor abnormalities are found in addition to clinical manifestations (Benarous et al. 2017).

We started lorazepam 1 mg/day and amisulpride 400 mg/day, and the catatonic symptoms resolved dramatically from the first hours. The recommended doses for lorazepam start with 1 to 3 mg and titration to higher doses for complete resolution of symptoms is often required (Benarous et al. 2017). In a naturalistic study, the mean daily dose of lorazepam was 5.35 ± 3.64 mg/day and the response rate for benzodiazepine was 65% (Raffin et al. 2015). The dosages of lorazepam were higher than 3 mg/day in case reports of adolescents with catatonia in which a response to a combination of lorazepam and atypical antipsychotics was reported (Delbello et al. 2000; Ishitobi et al. 2014; Roberto et al. 2014). The lorazepam dose we initiated was less than that in the other cases.

The psychopathology of catatonia is not fully elucidated, but GABAergic hypoactivity, glutamatergic hyperactivity, and dopamine hypoactivity at the D2 receptor in cortical regions have been implicated (Carroll 2000). Lorazepam, which is the first-line treatment for catatonia, has high affinity and agonism on GABA-A receptors. The effectiveness of this drug in rapidly reducing catatonic symptoms supports the hypothesis of GABAergic hypoactivity. Antipsychotics are not recommended during catatonia because they may worsen catatonic symptoms (Benarous et al. 2017). If antipsychotic's mechanism of action is thought to be dopamine 2 receptor antagonism, this may promote the dopamine hypoactivity hypothesis. Interestingly, amisulpride, which we started for psychosis, did not cause any worsening of catatonic symptoms.

Amisulpride is an atypical antipsychotic with a unique mechanism of action. It is used in many countries for the treatment of schizophrenia, but it is not approved for use in the United States of America. At low doses (50–300 mg/day), it enhances dopaminergic neurotransmission by preferentially blocking presynaptic dopamine D2/D3 autoreceptors and reduces negative symptoms. At higher doses (400–1200 mg/day), it antagonizes postsynaptic dopamine D2 and D3 receptors, preferentially in the limbic system rather than the striatum, thereby reducing dopaminergic transmission and alleviating positive symptoms in schizophrenia (Curran and Perry 2001). The dosage of 400 mg/day amisulpride initiated in our patient is a vedge dosage; by acting like a low dose, it may increase dopaminergic transmission and may have contributed to the resolution of catatonic symptoms.

Considering the use of combined therapy, we cannot clearly associate the resolution of catatonic symptoms with amisulpride alone. Nevertheless, we may speculate that amisulpride decreases the need of higher doses of lorazepam.

As a result, although antipsychotics are not recommended in the treatment of catatonia, a low-dose amisulpride and lorazepam combination may be useful for the resolution of catatonic symptoms.