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Amisulpride Augmentation in Acute Catatonia

Arora, Manu MBBS, MD, DPM1; Banal, Rakesh MBBS, MD1; Praharaj, Samir K. MBBS, MD, DPM2,*; Mahajan, Vivek MBBS, MD3

doi: 10.1097/MJT.0000000000000311
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Benzodiazepines are the first-line treatment of catatonia, but a substantial number of patients do not respond to them. Amisulpride is one of the atypical antipsychotic that has been effective for negative symptoms of schizophrenia. We examined the effect of augmentation of oral low doses of amisulpride with lorazepam on resolution of catatonic symptoms. Fifteen patients with catatonia were treated with a combination of oral lorazepam (2–4 mg) with amisulpride (100 mg). Catatonic symptoms were rated using the Bush Francis Catatonia Rating Scale at the baseline and daily thereafter. There was complete resolution of catatonic symptoms on the third day in all patients. There was significant reduction of the total Bush Francis Catatonia Rating Scale score over time (F = 181.38, P < 0.001) with a strong effect size (partial η2 = 0.96). Augmentation of lorazepam with low-dose amisulpride can be a reliable strategy for management of catatonia.

1Department of Psychiatry, Government Medical College, Jammu, India;

2Department of Psychiatry, Kasturba Medical College, Manipal, India; and

3Department of Pharmacology, Government Medical College, Jammu, India.

Address for correspondence: Associate Professor, Department of Psychiatry, Kasturba Medical College, Manipal, India. E-mail: samirpsyche@yahoo.co.in

The authors have no conflicts of interest to declare.

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INTRODUCTION

Catatonia is a neuropsychiatric syndrome, which presents with mental, motor, vegetative, and behavioral signs. In an edition of Diagnostic and Statistical Manual of Mental Disorders published by the American Psychiatric Association,1 catatonia is not recognized as a separate disorder, but is associated with psychiatric conditions such as bipolar disorder, depression, schizophrenia, and drug abuse. It may be associated with many medical disorders such as infections, focal neurologic lesions (including strokes), metabolic disturbances, alcohol withdrawal,2 benzodiazepine withdrawal,3,4 and cerebral neoplasms.5

Catatonia is a psychiatric emergency, and most of the patients require in-patient treatment. They require regular monitoring of vital signs, and may occasionally need to be managed in a psychiatric intensive care unit, specifically if there is catatonic excitement. Furthermore, depending on the physical condition of the patient, especially in prolonged catatonia, patients may require intravenous fluids and parenteral nutrition.

The presence of catatonia is an evidence of frontal lobe disease or dysfunction, and this is proposed because of the dopaminergic imbalance in the frontal lobe–basal ganglia–brain stem system.6 Functional changes in frontal-subcortical neural circuitry have been suggested in this disorder.7 Neurotransmitter alterations in the frontal circuitry that controls motor, speech, behavior, and cognition seem to be the underlying mechanism of pathophysiology of catatonia. The favorable therapeutic response to gamma-aminobutyric acid (GABA) agonists such as benzodiazepines in catatonia suggest that the reduced central GABA-ergic tone plays a role in the development of the motor symptoms in catatonia.7,8 Central dopaminergic hypoactivity also appears to be important, as evidenced from the precipitation of catatonia and neuroleptic malignant syndrome with dopaminergic blockers such as antipsychotic medications.7,9

Catatonia mostly responds well to benzodiazepines.8 In a review of 72 episodes of catatonia treated with benzodiazepines, a response rate of almost 80% was found.10 Patients who are unresponsive, or insufficiently responsive, to benzodiazepines need electroconvulsive therapy (ECT). The benzodiazepines represent the first-line treatment in catatonia because they have a wide margin of safety, rapid response, and are easily administered. Low-dose lorazepam offers advantages over ECT, which include short latency, not having a cardiovascular challenge even at high doses, and not requiring anesthesia; also ECT is associated with a greater stigma and availability always remain an issue.

Therapies other than benzodiazepines include antiepileptics like carbamazepine.11 Combination of lithium and an antipsychotic was useful in a patient with treatment-resistant catatonic stupor.12 Mastain et al13 reported that zolpidem was effective in a patient with catatonia, who was resistant to benzodiazepines and ECT. There are reports of antiglutamatergic drugs, amantadine,14 and memantine15,16 being effective in catatonia. These are antagonists at the N-methyl-d-aspartate receptor, which in turn tilt the neurochemical balance in favor of GABA. Thus, both proGABA and antiglutamatergic drugs seem to be beneficial in catatonia.

However, the response in catatonia to benzodiazepines is less than satisfactory in a sizeable number of patients. It has been estimated that one-fifth of the patients with catatonia do not respond to lorazepam,10,17 and many of those who respond have a partial reduction of the symptoms. In those patients where catatonia is associated with psychosis, the use of antipsychotics, specifically typical antipsychotics, is limited, as there is a risk of worsening of catatonia. Amisulpride, a substituted benzamide derivative, which is an atypical antipsychotic, has been found to be useful for the treatment of negative and deficit symptoms of schizophrenia at doses varying from 50 to 300 mg. At these doses, it enhances dopaminergic neurotransmission in the frontal cortex by preferentially blocking presynaptic dopamine D2/D3 autoreceptors thereby alleviating negative symptoms and deficit syndrome. At higher doses, amisulpride antagonizes postsynaptic dopamine D2 receptors, predominantly in the limbic system rather than the striatum, thereby reducing dopaminergic transmission, and consequently improves positive symptoms in schizophrenia.18,19 There are reports of catatonia showing dramatic improvement with amisulpride. French and Eastwood20 reported successful use of amisulpride in resolving the resistant catatonic symptoms in a patient of chronic schizophrenia, which was previously unresponsive to multiple antipsychotics, ECT, and benzodiazepine and lorazepam. In another case, catatonia associated with an autoactivation deficit that occurred with methadone overdose, had shown partial response to lorazepam, and the addition of low-dose amisulpride resulted in complete resolution of catatonia.21 Based on these reports, we studied whether augmentation with low-dose amisulpride of lorazepam in catatonia results in faster symptom resolution.

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MATERIALS AND METHODS

Participants

This was a hospital-based open-label study conducted at Psychiatric Diseases Hospital, Government Medical College, Jammu, in northern India. The study was approved by institutional ethics committee. The study sample consisted of 15 patients with catatonia at presentation. Of these, 8 patients were diagnosed with acute psychosis, 6 had undifferentiated schizophrenia, and 1 had depression, according to American Psychiatric Association.1 None of the 15 subjects had any serious medical condition, which was ruled out by detailed physical and neurological examination, biochemical investigations, and brain computerized tomography, wherever indicated. One patient had an incidental posterior fossa archanoid cyst on computerized tomography scan, which was otherwise asymptomatic. There was no history of significant alcohol or other substance abuse in our sample. Written informed consent was taken from the relatives of the patients.

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Assessment

All patients were rated on the clinician-administered 23-item Bush–Francis Catatonia Rating Scale (BFCRS).22 It is the most widely used instrument for rating the severity of catatonia. Each item is scored from 0 to 3. The reliability and validity of the BFCRS is well established.22 The patients were rated on the BFCRS at the baseline, and then daily until catatonia symptoms resolved.

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Treatment

All 15 patients were treated with oral lorazepam, with a daily dosage ranging from 2 to 4 mg in 3 divided doses. All patients also received amisulpride tablet 50 mg twice daily (100 mg/d) along with lorazepam.

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Statistical analysis

The data obtained were analyzed using SPSS 16.0 for Windows. Descriptive statistics was used to summarize the data. Repeated measures ANOVA was used to examine the changes of BFCRS scores over time. Effect sizes were reported as partial η2. The significance level was set at 0.05 (2 tailed).

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RESULTS

Sample characteristics are summarized in Table 1. The mean age of the patients was 26.13 (SD 7.15) years. Among them 7 (46.7%) were male. The duration of illness varied from 1 to 2 weeks in cases with acute psychosis, 3 months to 5 years in those with undifferentiated schizophrenia and 2 months in depression. Duration of catatonic symptoms varied from 2 to 14 days. The patients in our study had a predominantly retarded type of catatonia. All patients displayed the combination of immobility, mutism, staring, posturing, rigidity, and withdrawal. Grimacing and mannerisms were present in 25%–30%, whereas waxy flexibility, stereotypy, ambitendency, and verbigeration were seen in less than 10% of the patients. Grimacing, mannerism, and ambitendency were apparent mostly among the patients with undifferentiated schizophrenia and, 1 case of acute psychosis presented features of Automatic obedience. None of the symptoms, other than as described above, were seen in any of the patient.

Table 1

Table 1

Table 2 summarizes the BFCRS scores at the baseline and over days 1 and 2. No catatonic symptom was present in any patient on day 2. There was a significant reduction of total BFCRS score over time (F = 181.38, P < 0.001) with strong effect size (partial η2 = 0.96). There was significant reduction in the stupor, mutism, staring, posturing, stereotypy, mannerism, rigidity, negativism, and withdrawal scores over time. None of the patients had any emergent adverse effects.

Table 2

Table 2

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DISCUSSION

Catatonia, being a life-threatening condition, requires early intervention. Response to benzodiazepines in acute catatonia is a much replicated finding. Among benzodiazepines, the effects of lorazepam is studied the most and found to be effective. Studies suggest that within hours of receiving lorazepam of 1–3 mg sublingually or intramuscularly, there is a dramatic recovery in patients with catatonia, who have been immobile, mute, withdrawn, and rigid for days23 or even years.24

There is some evidence that typical antipsychotics may aggravate malignant and nonmalignant catatonia. Atypical antipsychotics are less likely to cause exaggeration of catatonia than classical antipsychotics and hence are used in disorders associated with catatonia. Antipsychotics are generally not recommended during a catatonic phase, even if there is an underlying psychotic illness such as schizophrenia, as the risk of precipitating neuroleptic malignant syndrome is increased. However, there are studies that suggest that they may be effective in the treatment of treatment-resistant catatonia. Hesslinger et al25 reported a patient with catatonia unresponsive to benzodiazepines who showed rapid and persistent improvement on risperidone. In a review by Van Den Eede et al26 it was concluded that atypical antipsychotics may have a role in the treatment of nonmalignant forms of catatonia.

In the factor analytic study by Abrams et al27 on 55 patients, 2 factors emerged, which was suggestive of different catatonic syndromes: (1) first was akinetic catatonia or akinetic mutism, which was characterized by mutism, negativism, and stupor; and (2) the other was characterized by stereotypy, catalepsy, and automatic cooperation. In our study, all the patients presented in the retarded state of catatonia across diagnoses, with “food refusal” being the most common reason for the presentation.

Augmentation of lorazepam with low-dose amisulpride showed faster resolution of catatonic signs with complete disappearance by the second day in all the patients. Most of the patients had a dramatic recovery within few hours of the first dose of lorazepam and amisulpride; they started talking, accepted food, and could be discharged from the hospital. The rapid response was noted across diagnoses, which was unlike the previous observation by Ungvari et al28 who found a rapid response only with mood disorders, but not in schizophrenia.

The dose of lorazepam used was much less compared to the one in previous studies and none required parenteral administration. The dose was 2 mg in 13 of the 15 patients. It is possible that the combination of amisulpride might have reduced the need for higher doses of lorazepam, which would be an advantage in elderly patients who are sensitive to benzodiazepines.

In view of the dopaminergic agonist action of low-dose amisulpride, we decided to offer the patients treatment with amisulpride; the response of amisulpride in retarded depression, negative symptoms of schizophrenia, deficit syndrome, and catatonia lends to the hypothesis that this may be a continuation of the severity of hypodopaminergic states. Amisulpride is not marketed in the United States, although it is widely available across several Asian and European countries. It is considered as an atypical antipsychotic with a unique mechanism of action that underlies its efficacy not only for positive symptoms, but also for negative and affective symptoms, particularly at lower doses.29 Furthermore, the lack of extrapyramidal adverse effects is an edge over typical antipsychotics, whereas avoidance of weight gain confers advantages over other atypical antipsychotic medications, making it a superior choice in a wide range of clinical conditions.29

Our study findings suggest that augmentation with low-dose amisulpride of lorazepam in the treatment of catatonia is well tolerated and may lead to faster resolution of symptoms. However, our study findings are limited by the small sample size and a lack of comparison group. Further studies using a randomized controlled design will be required to study the efficacy of combination therapy of low-dose amisulpride and lorazepam in the treatment of catatonia.

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Keywords:

catatonia; amisulpride; lorazepam

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