Extrapyramidal side effects with low doses of amisulpride.

Amisulpride, the newly introduced antipsychotic in India, is claimed to be effective in both positive and negative symptom schizophrenia and related disorders, though it has little or no action on serotonergic receptors. Limbic selectivity and lower striatal dopaminergic receptor binding capacity causes very low incidence of EPS. But, in clinical practice, we are getting EPS with this drug even at lower doses. We have reported three cases of akathisia, acute dystonia, and drug-induced Parkinsonism with low doses of amisulpride. So, we should keep this side effect in mind when using amisulpride. In fact, more studies are required in our country to find out the incidence of EPS and other associated mechanism.

INTRODUCTION

The introduction of clozapine, risperidone, olanzapine, and quetiapine represents an important step forward in the treatment of schizophrenia. The “atypical” profile of these drugs has been linked to a combined antagonism of central serotonin type 2 (5-HT2) and dopamine type 2 (D2) receptors. Their main advantage is a lower risk of extrapyramidal side effects.

Amisulpride – a substituted benzamide that has been used as an antipsychotic in France for more than ten years[1] has come into the Indian market few years back. Amisulpride appears to be an effective agent in treating schizophrenia for what are characterized as positive and negative symptoms. Although this antipsychotic does not block serotonin receptors at all, it is a high-affinity and highly selective D3/D2 receptor antagonist, it is said to have atypical properties as well.[2] It is believed that its selective affinity for dopamine receptors in the limbic structures, but not in the striatum, leads to a low risk of extrapyramidal side effects.[3] Animal studies have shown that at low doses it preferentially blocks presynaptic dopamine autoreceptors; this blockage facilitates dopaminergic transmission and thus might make amisulpride effective for negative symptoms.[4]

All available reports suggest that chances of EPS is very less and mostly associated with doses >400 mg/day. But, we have seen EPS and drug-induced dystonia even in low doses of Amisulpride in Burdwan Medical College, Burdwan. We have highlighted three such cases here.

CASE REPORTS

Case 1

A 37-year-old female patient was suffering from schizophrenia. She has predominantly negative symptoms. She was on olanzapine 15 mg/d for more than two months without much improvement and became overweight. So, amisulpride was instituted with a starting dose of 50 mg/d gradually increased up to 200 mg/d within seven days, olanzapine was stopped within four days of starting amisulpride. Patient came after 14 days for follow up when she developed parkinsonian syndrome with slowed gait, mild rigidity, tremor of tongue and hands. Anti-parkinsonian drug was given to manage the side effect.

Case 2

A 28-year-old male patient was suffering from schizophrenia for last four years. He was treated with various antipsychotic when he came to our hospital. We gave trifluoperazine and olanzapine respectively with sufficient dose and duration without much improvement. Before going into clozapine trial, we had given amisulpride after a drug-free period of one week. We started with 100 mg/d and increased to 200 mg/d on day three. Patient returned back on seventh day with akathisia. We managed it with propranolol 40 mg/d and lorazepam 4 mg/d and stopping amisulpride.

Case 3

A 19-year-old male patient of schizoaffective depressive type was prescribed amisulpride 200 mg/d in two divided doses from first day along with clonazepam 0.5 mg/d. On 5th day, patient developed acute dystonic reaction with oculogyric crisis, spasm of neck, and hand muscles. He was treated with I.M promethazine 50 mg, which resolves dystonia, immediately amisulpride was stopped to start other antipsychotic.

DISCUSSION

Since the discovery that clozapine induces fewer extrapyramidal side effects and is more effective than conventional antipsychotics for the treatment of schizophrenia, psychopharmacological research has focused on the development of drugs that block central 5-HT2 receptors more than D2 receptors. Combined 5-HT2/D2 receptor antagonism is the most current explanation for the so-called “atypical” profile of some antipsychotic.[5] Although this concept is difficult to define and might be better understood as a continuum, the most frequent requirements for atypicality are a low risk of extrapyramidal side effects and greater efficacy for negative symptoms.

Proposed mechanism of action of amisulpride:

Amisulpride binds selectively to dopamine D2, D3 receptors in the limbic system, and has no affinity for D1, D4, and D5 receptor subtypes

Low doses of amisulpride block presynaptic D2, D3 auto receptors, thereby enhancing dopaminergic transmission

At higher doses, blocks postsynaptic receptors, thus inhibiting dopaminergic hyperactivity

In comparison to clozapine, amisulpride shows no affinity to other dopaminergic receptors as well as to central serotonergic, adrenergic, histaminic, or cholinergic receptors

Amisulpride has greater specificity for the limbic system and thus has low incidence of EPS

Amisulpride is clinically effective on the negative symptoms of acute schizophrenia at low doses, 50-300 mg/d

Amisulpride binds more loosely than dopamine to the dopamine D2 receptor and is rapidly dissociated from the dopamine D2 receptor. This keeps prolactin levels normal, spares cognitions, and obviates EPS. This explains clinical atypicality of amisulpride.

According to Christian la Fougère et al. 2005,[6] low-dose therapy with the atypical antipsychotic agent amisulpride is associated with a significantly lower blockade of striatal dopamine D2 receptors than is seen during high-dose treatment. However, a significant striatal D2 blockade was demonstrated at therapeutically effective dose ranges. Furthermore, their study showed a good relationship between the degree of striatal dopamine D2 receptor occupancy and the amisulpride plasma concentration or the administered dose.

Martinot et al.[7] reported a low postsynaptic D2 occupancy in the striatum at low doses of amisulpride (50-100 mg/d). The authors also suggested that extrastriatal binding could mediate the effect on negative symptom.

If we can remember, when risperidone came into the Indian market, researchers claimed that EPS would occur at doses >6 mg/d. But, we have seen EPS at lower doses even at 2 mg/d. It may be the same case for amisulpride also.

So, the probable causes of EPS with low doses of amisulpride are:

In low doses, it blocks postsynaptic D2 receptors significantly in striatum without much effect in mesolimbic pathway.[8] Therefore, it selectively acts on mesocortical and nigrostriatal pathways in low doses. Much more studies are required to establish its selectivity.

In general, blacks are slow metabolizers. Low body weight and slow metabolism may increase the plasma concentration of drugs causing side effects. Which is low for whites is not low for Indians.

Dissociation of amisulpride from D2 receptors is not as rapid as it is thought.

CONCLUSION

Amisulpride came into the Indian market few years back. Most of the available studies are from western countries. Its effectiveness, both for positive and negative symptom schizophrenia with lower chances of metabolic syndrome, will help psychiatrists to treat schizophrenic and related disorders more effectively. The most serious matter is that we have just started prescribing the drug in our hospital among which initial few patients developed EPS in lower doses. In our opinion, the lower incidence of EPS which is claimed by western researchers as well as many pharmaceutical companies should be studied well in our Indian context. We should at least keep in mind this side effect when starting or increasing the doses.