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Focus on Amisulpride
Ben Green MB, ChB, MRCPsych
University of Liverpool, UK.
Introduction
Amisulpride is manufactured by Lorex-Synthelabo under the trade name Solian. Tablets are available in 50 mg or 200 mg formats. The recommended doses are between 400 mg/day and 800 mg/day. Amisulpride appears to be effective against negative symptoms at low doses e.g. 100 mg daily.
Summary
Amisulpride is a second generation
antipsychotic, a substituted benzamide. Amisulpride appears to be an effective
agent in treating schizophrenia for what are characterised as positive and negative
symptoms. The recommended doses are between 400 mg/day and 800 mg/day. Amisulpride
demonstrates a good global safety profile, particularly when compared with first
generation antipsychotics, such as haloperidol. There are interesting studies
that point towards amisulpride's antidepressant effect in dysthymia and one
could speculate on possible roles in affective psychoses and chronic fatigue
syndrome.
Indications
Primarily recommended by the manufacturer for the positive and negative symptoms of acute and chronic schizophrenia in adults.
As ever though there are prescriptions of the drug outside licensed indications and there are reports of the drug's unofficial use for other conditions, even such apparently unrelated conditions as dysthymia, (Boyer et al, 1999 and Smeraldi, 1998).
Prescription for children and adolescents has been reported in the literature, (Toren et al, 1998)
Pharmacology
Amisulpride has 'dual dopamine blockade' and a unique therapeutic profile being antipsychotic, at high doses, and disinhibitory, at low doses (Schoemaker et al, 1997) - at low doses (< or = 10 mg/kg) amisulpride preferentially blocks presynaptic dopamine autoreceptors that control dopamine synthesis and release in the rat, whereas at higher doses (40-80 mg/kg) postsynaptic dopamine D2 receptor occupancy and antagonism is apparent. It binds selectively with a high affinity for human dopaminergic D2 (Ki = 2.8 nM) and D3 (Ki = 3.2 nM) receptors and is devoid of affinity for D1, D4 and D5 receptor subtypes. It has no affinity for serotonergic alpha-adrenergic, H1 histaminergic or cholinergic receptors. Amisulpride acts preferentially on presynaptic receptors increasing dopaminergic transmission at low doses (Boyer et al, 1999)
There are two absorption peaks - one hour post-dose and a second 3-4 hours after taking the tablet. The elimination half-life is 12 hours.
Absolute bioavailability is 48%.
Amisulpride is weakly metabolised by the liver. There are two inactive metabolites. The drug is mainly eliminated unchanged by the kidney. 50% of an iv dose is eliminated by the kidney - of which 90% is eliminated in the first 24 hours.
Structure
Amisulpride is a substituted benzamide.
Figure One: Chemical Structure of Amisulpride
Efficacy
A four week double blind randomised study of 319 schizophrenia sufferers compared amisulpride with 16 mg haloperidol daily and found the efficacy was best at 400mg to 800 mg daily (measured according to the Brief Psychiatric Rating Scale (BPRS) and the PANSS) (Peuch et al).
Positive symptoms in schizophrenia
Wetzel et al (1998) compared amisulpride with flupenthixol a conventional antipsychotic (a thioxanthene). The study ran for 6 weeks and involved 132 patients suffering from acute schizophrenia (DSM-III-R) with predominant positive symptomatology. Doses were initially fixed (amisulpride: 1000 mg/day; flupenthixol: 25 mg/day) but could be reduced by 40% in case of side effects (mean daily doses: amisulpride: 956 mg; flupenthixol: 22.6 mg). Intention-to-treat evaluation demonstrated significant improvement under both medications. ANCOVA analysis showed that reductions of BPRS scores were more pronounced under amisulpride. Due to adverse events, significantly fewer amisulpride patients (6%) were withdrawn from the study (flupenthixol: 18%). Extrapyramidal tolerability was better in the amisulpride group.Negative Symptoms in schizophrenia
Amisulpride's efficacy against negative symptoms was investigated by Boyer et al (Boyer et al, 1995). In this parallel group, double blind, placebo controlled trial patients had to have high negative symptoms scores on the Scale for the Assessment of Negative Symptom (SANS) to be included. The authors said these were 'pure negative forms of schizophrenia'. 104 inpatients received amisulpride 100 mg daily, 300 mg daily or placebo. Amisulpride doses were significantly more effective on negative symptoms than placebo (p<0.02). Interestingly enough the differences between the 100 mg daily and 300mg daily groups were 'minimal' according to the authors. Withdrawal symptoms from previous antipsychotics were controlled by a 6 or 12 week washout period.
Loo et al (1997) performed a multi-centre, randomised parallel group, double blind study looking again at fairly low doses (100 mg daily) compared with placebo. 141 patients received either amisulpride or placebo (69 receiving the drug). The study used SANS and Scale for the Assessment of Positive Symptoms (SAPS) on DSM-III criteria patients. All efficacy assessments were in favour of amisulpride.
Danion et al (1999) performed a placebo-controlled study of amisulpride on primary negative symptoms. After completion of a 4-week washout period, schizophrenic patients with primary negative symptoms participated in a 12-week, multicentre double-blind trial of placebo (N = 83), amisulpride, 50 mg/day (N = 84), or amisulpride, 100 mg/day (N = 75). They were evaluated with the SANS, the SAPS, the BPRS, and the Montgomery-Asberg Depression Rating Scale (MADRS). Both amisulpride treatment groups showed significantly greater improvement in negative symptoms than the placebo group. The improvement in negative symptoms was independent of any improvement in positive symptoms.
Dysthymia
Smeraldi (1998) reported a multicentre, double blind, parallel group study in which 281 patients with DSM III-R diagnosis of dysthymia or a single episode of major depression in partial remission were randomised and given either 3 months of treatment with amisulpride 50 mg/day or fluoxetine 20 mg/day. The baseline MADRS total score was reduced by at least 50% in 74.1% of patients (103/139) with amisulpride and 67.4% (87/129) with fluoxetine (P =0.230). No significant differences between treatment groups were found in the reductions in mean total score with the MADRS, Widlöcher psychomotor retardation scale, Sheehan disability scale, and CGI. Anxiety measured by HAM-A total mean score decreased significantly more with amisulpride (63%) than with fluoxetine (54%; P = 0.021). There were 13 dropouts due to adverse events with amisulpride and ten with fluoxetine. The number of patients reporting at least one adverse event was similar in the two groups (amisulpride 47.5%; fluoxetine 40.9%). As expected, in the amisulpride group endocrine-like adverse events in female patients were the most common, while nausea, dyspepsia, anorexia and insomnia occurred more frequently with fluoxetine.
Lecrubier et al (1997) compared amisulpride (50 mg/daily) to imipramine (100 mg/daily) in the treatment of patients with DSM-III-R criteria for primary dysthymia, dysthymia with major depression or major depression in partial remission. A total of 219 patients were included. Both analyses (intention-to-treat and "per protocol' analysis) detected significant differences between groups (active treatment vs. placebo) on all main rating scales (CGI, MADRS, ERD, and SANS). The number of patients reporting at least one adverse event was higher in the imipramine group than in the two other, mainly due to anticholinergic effects.
Further work from this French group compared amisulpride and amineptine with placebo, (Boyer et al, 1999). During this 3-month study of 323 patients, amisulpride (50 mg/day) was compared to amineptine (200 mg/day) in the treatment of primary dysthymia. Both amisulpride and amineptine were found to be statistically superior to placebo on the Clinical Global Impression (item 2), Montgomery-Asberg Depression Rating Scale and the Scale for the Assessment of Negative Symptoms.
This observed antidepressant activity was enthusiastically followed up by work such as that of Papp and Wieronska (2000) who used two animal behavioural models: the forced swim test (FST) and the chronic mild stress (CMS) model. The duration of immobility time in FST was reduced by administration of imipramine (10 mg/kg) and amisulpride (1 and 3 mg/kg), although the effect of imipramine was more potent. In CMS, the stress-induced decrease in the consumption of 1% sucrose solution was gradually reversed by chronic treatment with imipramine (10 mg/kg) and amisulpride (5 and 10 mg/kg). The dosing appeared to be critical in that lower (1 or 3 mg/kg) or higher (30 mg/kg) doses of amisulpride were inactive. Amisulpride's onset of action was faster; at the most active dose of 10 mg/kg, amisulpride significantly increased the sucrose intake in stressed animals within 2 weeks of treatment while imipramine required 4 weeks before first effects on the stress-induced deficit in sucrose consumption could be observed.
These results provided further support for clinical observations that amisulpride
may possess potent and rapid antidepressant activity.
Cautions and contra-indications
In the elderly amisulpride can cause hypotension and sedation. There are no systematic published data on efficacy in children less than 15.
Renal impairment significantly reduces the clearance and prolongs the elimination half-life of amisulpride and risperidone (Caccia, 2000). If there is renal insufficiency there should be a reduction in the dose of amisulpride. The dose should be halved if the creatinine clearance is between 30-60 ml/min and reduced to a third for clearances between 10-30 ml/min.
Prescription should be avoided if there is proven hypersensitivity to the drug, a prolactin dependent tumour, phaeochromocytoma, pregnancy or lactation.
Side Effects
Insomnia, anxiety, agitation are common side effects (occurring in 5-10%). Somnolence, constipation, nausea, vomiting and dry mouth may occur in up to 2% of patients. Other side effects include weight gain, acute dystonia, extrapyramidal side effects, tardive dyskinesia, hypotension, bradycardia and QT prolongation.
Amisulpride can cause hyperprolactinaemia and thus may lead to galactorrhoea, gynaecomastia, breast pain and amenorroea. Amisulpride's endocrine effects are remarked on throughout the relevant literature. Grunder et al (1999) compared the endocrine actions of amisulpride and flupenthixol, (a mixed D1/D2-like antagonist also blocking serotonin, H1, and D1 receptors) -on anterior pituitary hormone secretion in schizophrenic patients. Blood was withdrawn at 15-min intervals to assess basal secretion of prolactin, growth hormone (GH), and thyroid-stimulating hormone (TSH). Four hundred micrograms of thyrotropin-releasing hormone (TRH) was injected i.v. to investigate drug effects on TRH-stimulated secretion of prolactin, TSH, and GH. Prolactin plasma levels were markedly elevated in both treatment groups. This elevation was significantly more pronounced in females(but not males) with amisulpride than with flupenthixol. The prolactin response to TRH was significantly blunted by amisulpride only in male subjects. Interestingly enough, low basal prolactin levels predicted improvement of negative symptoms in patients treated with amisulpride.
Amisulpride may reduce reaction time in those using machinery. Seizure threshold reduction. May exacerbate Parkinson's disease. Neuroleptic malignant syndrome is a rare though possible side effect.
The drug has been given to healthy volunteers and compared to haloperidol (Raemarkers, 1999). Amisulpride 400 mg daily had some mild adverse effects on psychomotor and cognitive performance, but no significant extrapyramidal disturbances in the group as a whole. On clinical rating scales or during a structured psychiatric interview it produced no signs of mental disturbances. Haloperidol ubiquitously impaired psychomotor and cognitive performance in a similar fashion after the first and the final doses and produced extrapyramidal disturbances in nearly every subject, the most common being akathisia and the most severe, in the case of one individual, being acute dystonia. Haloperidol produced a number of mental disturbances, the most noteworthy being negative symptoms.
Looking at the results from 11 studies Coulouvrat and Donddey-Novel (1999) concluded that in these studies of a total of 1933 patients amisulpride demonstrated a satisfactory global safety profile. There was an absence of cardiovascular events. Extrapyramidal side effects were fewer than with haloperidol, endocrine events were similar to risperidone. Haematological and liver function problems were absent on laboratory tests. Their conclusion was that from a safety perspective amisulpride was superior to reference compounds.
Long term safety data (Colonna et al, 2000) looked at 370 patients receiving amisulpride over 12 months compared to 118 patients on haloperidol. The overall incidence of endocrine events was comparable between groups (4% for amisulpride, 3% for haloperidol), but extrapyramidal events were predictably fewer in the amisulpride group. Maintenance of efficacy was comparable in both treatment groups
Interactions
Co-administered ethanol increased the AUC by over 10%. There are no apparent interactions with benzodiazepines.
Comparison with other antipsychotics
Peuskens et al (1999) compared
amisulpride with risperidone and found a marginal superiority for amisulpride.
Their study was double-blind and involved 228 patients allocated, after a short
wash-out period, to amisulpride 800 mg (n = 115) or risperidone 8 mg (n = 113)
for 8 weeks. Decreases in mean BPRS total score were 17.7 +/- 14.9 for amisulpride
and 15.2 +/- 13.9 for risperidone. All the individual factors on the BPRS showed
a numerically greater improvement in the amisulpride group There was a trend
towards greater improvement in negative symptoms patients receiving amisulpride.
Patients receiving risperidone experienced an increase in body weight, which
was significantly greater than for amisulpride (P = 0.026).
Compared to the previous gold standard antipsychotic haloperidol amisulpride
has a superiority in treating schizophrenia in terms of positive and negative
symptoms and a more acceptable side effect profile, (Collona et al, 2000). Carriere
et al (2000) found that compared to haloperidol amisulpride had a beneficial
effect on the quality of life measured by the Quality of Life Scale (QLS) and
the Functional Status Questionnaire (FSQ).
Conclusions
Amisulpride appears to be an effective agent in treating schizophrenia for what are characterised as positive and negative symptoms (negative symptoms particularly at low doses e.g. 100 mg daily). Quality of life and function appears to be better on amisulpride than haloperidol. Further more it appears to initially have a good global safety profile. There are interesting studies that point towards its antidepressant effect in dysthymia and one might speculate on possible roles in affective psychoses and chronic fatigue syndrome.
References
Boyer, P, Lecrubier, A J, Peuch, J et al. (1995) Treatment of negative symptoms in schizophrenia with amisulpride. British Journal of Psychiatry, 166, 68-72.
Boyer P, Lecrubier Y, Stalla Bourdillon A, Fleurot O. (1999) Amisulpride versus amineptine and placebo for the treatment of dysthymia. Neuropsychobiology, 39:1, 25-32.
Carriere P. Bonhomme D. Lemperiere T. Amisulpride has a superior benefit/risk profile to haloperidol in schizophrenia: results of a multicentre, double-blind study (the Amisulpride Study Group).European Psychiatry: the Journal of the Association of European Psychiatrists. 15(5):321-9, 2000 Aug.
Caccia S. Biotransformation of post-clozapine antipsychotics: pharmacological implications. [Review] [191 refs]Clinical Pharmacokinetics. 38(5):393-414, 2000 May.
Colonna L. Saleem P. Dondey-Nouvel L. Rein W. Long-term safety and efficacy of amisulpride in subchronic or chronic schizophrenia. Amisulpride Study Group.International Clinical Psychopharmacology. 15(1):13-22, 2000 Jan.
Coulouvrat C. Dondey-Nouvel L. (1999) Safety of amisulpride (Solian): a review of 11 clinical studies. International Clinical Psychopharmacology. 14(4):209-18, 1999 Jul.
Danion JM, Rein W, Fleurot O. (1999) Improvement of schizophrenic patients with primary negative symptoms treated with amisulpride. Amisulpride Study Group. Am J Psychiatry, 156:4, 610-6.
Gründer G; Wetzel H; Schlösser R (1999) Neuroendocrine response to antipsychotics: effects of drug type and gender. Biol Psychiatry, 45:1, 89-97.
Lecrubier Y, Boyer P, Turjanski S, Rein W (1997) Amisulpride versus imipramine and placebo in dysthymia and major depression. Amisulpride Study Group.J Affect Disord, 43:2, 95-103.
Loo, H, Poirier-Littre, MF, Theron, M (1997) Amisulpride versus placebo in the medium-term treatment of the negative symptoms of schizophrenia. British Journal of Psychiatry. 170, 18-22.
Papp M. Wieronska J. (2000) Antidepressant-like activity of amisulpride in two animal models of depression. Journal of Psychopharmacology. 14(1):46-52, 2000 Mar.
Peuch, A, Fleurot, O, Rein, W et al. (1998) Amisulpride, an atypical antipsychotic in the treatment of acute episodes of schizophrenia: a dose ranging study vs. haloperidol. Acta Psychiatrica Scandinavica, 98:65-72.
Peuskens J. Bech P. Moller HJ. Bale R. Fleurot O. Rein W. (1999) Amisulpride vs. risperidone in the treatment of acute exacerbations of schizophrenia. Amisulpride study group.Psychiatry Research. 88(2):107-17, 1999 Nov 8.
Ramaekers J G, Louwerens J W, Muntjewerff N D; et al (1999) Psychomotor, Cognitive, extrapyramidal, and affective functions of healthy volunteers during treatment with an atypical (amisulpride) and a classic (haloperidol) antipsychotic.J Clin Psychopharmacol, 19:3, 209-21
Schoemaker H, Claustre Y, Fage D et al. (1997) Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. J Pharmacol Exp Ther, 280:1, 83-97
Smeraldi E (1998) Amisulpride versus fluoxetine in patients with dysthymia or major depression in partial remission: a double-blind, comparative study. J Affect Disord, 48:1, 47-56.
Toren P, Laor N, Weizman A (1998) Use of atypical neuroleptics in child and adolescent psychiatry. J Clin Psychiatry, 59:12, 644-56.
Wetzel H, Gründer G, Hillert A (1998) Amisulpride versus flupenthixol in
schizophrenia with predominantly positive symptomatology -- a double-blind controlled
study comparing a selective D2-like antagonist to a mixed D1-/D2-like antagonist.
The Amisulpride Study Group.Psychopharmacology (Berl), 1998 Jun, 137:3, 223-32
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