Augmenting amisulpride with clozapine had led to unmasking of akathisia.

Amisulpride is a newer antipsychotic, which is very effective on its own, as well as augmenting other antipsychotic clozapine, which is an effective molecule for treatment resistant schizophrenia. In most cases, amisulpride is added on, in partial responders to clozapine. Here a case is reported where clozapine was added on, in an amisulpride partial responder but this produced side effect and had to be discontinued. The case later responded to clozapine alone. It has been discussed about possible reasons of this finding. It has also been suggested if sequence of introduction of medication is critical regarding getting the desired effect of the augmentation strategy.

Amisulpride is an atypical antipsychotic of benzamide class. It blocks D2 and D3 receptors (presynaptic in low doses, postsynaptic in higher). Unlike other atypical or typical antipsychotic, it has low affinity for serotonin, α-adrenergic, histaminergic, muscarinic and sigma receptors including D1, D4, and D5 receptors. It can cause dose related extra pyramidal side-effects, which is significantly less than typical antipsychotics like haloperidol and comparable to risperidone.[1]

Clozapine was the first second generation antipsychotic invented and used. It has good effectiveness as an antipsychotic, while it lacks the extra pyramidal side-effects of typical ones, though it has a different array of side effects such as metabolic problems, sialorrhoea, neutropenia and a tendency of seizure disorder. It is efficacious in the treatment of resistant schizophrenia.

Akathisia is a subjective feeling of motor restlessness manifested by a compelling need to be in constant movement. It is an extra pyramidal adverse effect of antipsychotic medications. Second generations antipsychotic are less prone to induce this side effect, though they are not immune to this problem. Extra pyramidal syndrome, in general is least with Clozapine. Most studies of akathisia due to clozapine have dealt with chronic akathisia, which is sometimes difficult to distinguish from tardive dyskinesia.[2]

CASE REPORT

A 20-year-old man presented with akathisia with psychomotor agitation. He had a 5-year history of schizophrenia and was previously partially controlled on risperidone 6 mg with trihexyphenidyl 4 mg in two equally divided doses daily in the last 2 years. Then he was switched to amisulpride 200 mg twice daily, that initially controlled the akathisia and agitation symptoms. However, this dose of amisulpride (400 mg in two divided doses) for 2 months did not achieve full symptom remission although he was better than before with akathisia remitted and psychomotor agitation controlled but still had disorganized behavior, fleeting delusion and hallucination. In an attempt to achieve complete symptom remission the patient was switched to amisulpride 200 mg thrice daily (600 mg/day) for next 6 weeks. Unfortunately, the patient did not achieve any further symptom remission, but did not deteriorate either. At this juncture, clozapine was definitely a strong choice. However, as the patient has already partially responded to amisulpride without much side-effect and amisulpride augmentation of clozapine is a proven effective procedure,[3] to achieve further clinical improvement this augmentation strategy were thought of. Here reverse augmentation strategy i.e., to augment amisulpride with clozapine (25 mg to start with, which then escalated to 75 mg with 25 mg increments every 3 days) was tried, with an expectation of achieving symptom remission, as these two medicines may have synergistic effect. However, within 2 weeks this patient presented severe akathisia, restlessness, hypertonia along with sialorrhoea and tachycardia. These were managed with propranolol 120 mg and trihexyphenidyl 4 mg, but with modest success for 1 week. As clozapine was the medication last introduced, it was withdrawn and the patient continued the other medications, i.e., amisulpride 600 mg/day in three divided doses along with propranolol 120 mg and trihexyphenidyl 4 mg. Moderate improvement of akathisia and agitation symptoms was noted after 1 month, but it did not reach the base level, which were present before start of clozapine. Sialorrhoea was completely subsided on this regime. In order to achieve total side effect remission, amisulpride was completely withdrawn under the cover of lorazepam 6 mg and propranolol 120 mg. In another 2 weeks, akathisia symptoms drastically remitted but psychotic symptoms like aggressiveness, disorganized speech and behavior, use of abusive language severely increased.

It is known that clozapine has one of the least tendencies to cause akathisia symptoms on its own[2] and withdrawal of clozapine did not remit akathisia and agitation completely, led to a hypothesis that it may not be clozapine per se, but its interaction with amisulpride might be instrumental in generation of the akathisia symptoms. So it was decided to give clozapine as a mono therapy a try, as it is a proven effective agent in treatment resistant schizophrenia. Hence clozapine was reintroduced without amisulpride at 50 mg/day, which was increased to 150 mg/day with small increments of 25 mg weekly. This regime showed very significant symptom control without any akathisia, along with propranolol 120 mg and lorazepam 4 mg. Even after slow withdrawal of supportive medications like propranolol and lorazepam the patient maintained effective symptom control without any akathisia or other unwanted side effect.

DISCUSSION

Only one case report[4] and another case in a case series report[5] have reported positive results attempting clozapine augmentation of patients after non successful treatment of amisulpride. However, this case reported here have shown an occurrence of unwanted side effects in the form of akathisia, dystonia and sialorrhoea after addition of clozapine. Whereas, sialorrhoea can solely be due to clozapine, which was subsided after withdrawal of clozapine, akathisia, and dystonia is very unlikely to be caused by clozapine at a dose of 75 mg/day. It is rather more likely to be caused by amisulpride, especially after an escalation of dose. Here amisulpride dose was not escalated but side effects occurred, which was time related to addition of clozapine. Though amisulpride serum level could not be measured in this case, from clinical setting, it was very evident that most probably there may be increase in amisulpride serum level due to drug interaction with clozapine. It is known that amisulpride is only sparingly metabolized by liver enzymes and thus it is not known to participate in many drug interaction.[6] However, an article had already reported that there was increase of blood level of amisulpride on addition of clozapine.[6] This interaction might be a probable explanation for this case's adverse effect. As the symptoms persisted even after complete withdrawal of clozapine and administration of supportive medications in proper doses, it raises the possibility of delayed onset akathisia with amisulpride.[7] Furthermore, both these mechanisms may have some role in this clinical setting. It also raises the question, whether elevation of amisulpride blood level is instrumental in obtaining good result in augmentation strategy, as a study has already shown that amisulpride doesn’t seem to increase the blood level of clozapine.[8] Interestingly these two pharmacokinetic observations cannot fully explain the reason, why patients resistant to both the medication alone, can respond to their combination therapy.[4] There may be some pharmacodynamics factors involved also. But question may be raised whether sequence of introduction of medications may have some role in this augmentation strategy, as clearly it is safer to augment a partial responder with optimal dose of clozapine with amisulpride than the reverse, because there are more chances of producing side effects in the later schedule. Further systematic research is required to study, whether it is mere association or sequence of introduction of medications may have some role in augmentation strategies and also the exact nature of amisulpride, clozapine drug interaction and possible reasons behind it.