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Home , Amisulpride, Atypical antipsychotic

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Graylands Hospital Drug Bulletin 2002 Vol 10 No 2 July ISSN 1323-1251 Amisulpride (Solian) will become the latest addition to the range of atypical Absorption available in , Amisulpride is absorbed rapidly, within 3- though it has been available in parts of 4 hours of oral administration. Europe since the late 1980s. It belongs to the class and will be available Metabolism on the PBS for the treatment of Amisulpride undergoes minimal from 1st August 2002. metabolism to form two metabolites (both inactive). Hepatic metabolism plays a Pharmacology limited role in healthy patients. Although it shares clinical properties that characterise other atypical agents eg. decreased incidence of extrapyramidal Excretion is primarily via urine (mainly as symptoms (EPS), amisulpride is unusual in unchanged drug). The elimination half- that it lacks the combined antagonism of life is approximately 12 hours. is low, therefore drug 5HT2/D2 receptors which usually defines “atypicality”. interactions due to displacement are unlikely. At low doses, amisulpride enhances Efficacy by Recent reviews have concluded that preferentially blocking pre-synaptic D /D 2 3 amisulpride (400 to 1200mg/day) was as receptors. This may explain its effective as (5 to 40mg/day), efficacy in the treatment of negative flupenthixol (25mg/day) and symptoms in schizophrenia. (8mg/day) in patients with acute exacerbations of schizophrenia with At higher doses, amisulpride antagonises predominantly positive symptoms (1,2). post-synaptic D /D dopamine receptors, 2 3 Amisulpride was found to be more reducing dopaminergic transmission, effective than haloperidol but equally as which may explain its efficacy against the effective as risperidone in controlling positive symptoms of schizophrenia. negative symptoms. Amisulpride has little affinity for other In patients with predominantly persistent dopamine subtypes or other negative symptoms, low dosages of neurotransmitter receptors such as amisulpride (50 to 300mg/day) , α-, and significantly reduced negative symptoms muscarinic. It is selective for dopamine compared to placebo. receptors in the limbic system rather than Amisulpride has been shown to be the , which should reduce its efficacious in long-term studies where it tendency to produce EPS. has been used as maintenance in patients with chronic schizophrenia with Graylands Hospital Drug Bulletin 2002 Vol 10 No 2 July - 1 - mixed symptoms. Long-term use was also Mixed positive and negative symptoms: associated with improvements in measures adjust dose to obtain optimal control of of quality of life and social functioning. positive symptoms. Contraindications Amisulpride has been available in France to These include -dependant treat schizophrenia since 1986, where a group of clinicians have produced a dosage tumours, phaeochromocytoma and use in (3) combination with medications that may algorithm (see Figure 1 below). This induce torsade de pointes – see drug suggests management strategies according interactions. to symptoms and treatment setting. Due to its lack of properties, it may Precautions be appropriate in the initial stages to use a Amisulpride shares similar warnings with or sedative to other atypical antipsychotics regarding the help control the symptoms of a very rare events of neuroleptic malignant disturbed or aggressive patient. syndrome, and the need for No specific titration is required for initiation caution in the elderly and Parkinson’s of therapy; adjust dosage to individual disease. response. Where the dose is above or equal In renal impairment, use a decreased dose to 400mg, administer twice daily. and consider intermittent treatment in Preferably give the dose before meals. severe cases. Use with caution in patients with moderate Renal impairment Dosage reduction will be or severe hepatic impairment – limited required in this patient group. data. Hepatic impairment Dosage reduction should not be necessary as the drug is Pregnancy and Lactation Pregnancy Category B3 – Contraindicated. weakly metabolised. Figure 1: Amisulpride dosage algorithm Adverse effects (based on extensive use in France). Similarly to risperidone, amisulpride appears to be linked with dose-related EPS ACUTE EPISODES and hyperprolactinemia. Unlike other Severe & recurrent Mild-moderate First episode atypicals however, sedation and Treated patients Out-patients Untreated patients Initial dose 800mg/d Initial dose 400mg/d Initial dose 600mg/d do not prominently feature in (up to 1200mg/d ↑by 200mg/d steps its side-effect profile. for in-patients) Adequate dose : 800mg/d Other commonly reported adverse events in clinical trials included , , agitation and weight gain. Cases of QT prolongation have been reported (dose dependant) and very rarely (<0.01%) SHORT-TERM FOLLOW-UP (3 months) torsade de pointes. According to symptom evolution No reference is made in the product Reduce dose Continue treatment Increase dose information to possible disturbances in by 200mg/d steps at same dose by 200mg/d steps glucose metabolism. During the period January 1997 to January 2002, the manufacturers received only 3 reports of this nature worldwide (Personal MAINTENANCE communication, -Synthelabo). Modulation according to symptoms No positive symptoms Dosage and administration Patient stable The recommended dose varies according Dose reduced by 100-200mg/d every 2-3 months to which symptoms predominate. Usual maintenance dose: 400mg/d Acute positive symptoms: 400-800mg/day (two divided doses). May be increased to 1200mg/day in individual cases (no If +ve symptoms reappear If -ve symptoms present superior efficacy proven). Increase dose to previous Decrease dose to 100-300mg/d stabilising level for Usual dose 100mg/d Predominantly negative symptoms: 50- several months before 300mg/day given once daily. renewed dose reduction Adapted from Reference 3 Graylands Hospital Drug Bulletin 2002 Vol 10 No 2 July - 2 - Switching to amisulpride be enhanced by amisulpride. Concomitant Taper down existing antipsychotic and during use with levodopa is not recommended due this period, begin amisulpride at the to reciprocal antagonism of effects. therapeutic dose required; no titration is necessary. Overlapping periods of 1-4 weeks Conclusion – place in therapy have been described depending on the Amisulpride appears to offer no significant patient’s clinical state. benefit over the existing atypical agents. It may be associated with the least weight Drug Interactions gain of the atypicals (4) and has less Interactions via the CYP450 system are potential for interaction with other drugs, unlikely as amisulpride is not significantly due to its lack of hepatic metabolism. metabolised by the . Further trials are needed comparing it with the other atypical agents. Comparative The potential for increased risk of ventricular data with should be available arrhythmias must be borne in mind. Use with later this year. Class IA and III antiarrhythmic agents eg. flecainide and amiodarone respectively, is Presentation contraindicated. Caution is required in the Manufacturer: Sanofi-Synthelabo concomitant use of drugs that may induce Brand name: Solian or hypokalemia or other drugs Available in following tablet strengths: known to prolong the QT interval, such as 100mg, 200mg and 400mg (all breakable). and . References Caution is advised when used with other 1. Curran MP and Perry CM. Amisulpride – A Review of its Use in the Management of Schizophrenia. Drugs renally cleared drugs eg. , which may 2001;61(14):2123-2150. interfere with clearance of amisulpride. 2. Leucht S, Pitschel-Walz G, Engel RR, Kissling W. However, a study of the concomitant use of Amisulpride, an Unusual “Atypical” Antipsychotic: a (500mg twice daily) with Meta-Analysis of Randomised Controlled Trials. Am J Psychiatry 2002;159:180-190. low dose amisulpride (100mg twice daily) in 3. Lecrubier Y, Azorin M, Bottai T, Dalery J, Garreau G, healthy young males, showed no effect of Lemperiere T et al. Consensus on the Practical Use of amisulpride on the pharmacokinetics of Amisulpride, an , in the Treatment lithium. of Schizophrenia. Neuropsychobiology 2001;44:41-46. 4. Taylor DM and McAskill R. Atypical Antipsychotics and Weight Gain – a Systematic Review. Acta Psychiatr The effects of CNS eg. Scand. 2000;101(6):416-32. , narcotics and may

Serotonin syndrome – recognising the signs

Serotonin syndrome (SS) is a condition ! concomitant use of agents that caused by drug-induced serotonin promote the release of serotonin from hyperstimulation. It is difficult to diagnose, presynaptic neurons eg. usually mild and as a result may go largely ! pharmacokinetic interactions eg. unreported. SS may occur with co- CYP2D6 inhibition of administration of drugs or lack of adequate (TCA) metabolism by washout period when switching drugs. This agents such as , , increases synaptic serotonin concentration leading to increased TCA plasma levels causing hyperstimulation of mainly 5HT1A ! inhibition of serotonin metabolism eg. receptors (other serotonin receptors may be cocaine involved). See Table 1 for examples of drugs that may contribute to the development of this ! stimulation of postsynaptic serotonin syndrome. receptors eg. lithium Less often, SS results from the use or Possible causes of serotonin syndrome overdose of a single agent. ! inhibition of serotonin re-uptake eg. .Many patients can take two, possibly even (particularly the SSRIs), more, serotonergic drugs together without and related agents, , problems while a very small number of some MAOIs cases can be severe and result in death. This suggests other factors not yet identified may play a role.

Graylands Hospital Drug Bulletin 2002 Vol 10 No 2 July - 3 - Table 1: Examples of drugs that may contribute to development of SS (i.e. serotonergic) All antidepressants Lithium Amphetamines Pentazocine Phentermine Cocaine Dextromethorphan (in OTC cough preps) St John’s Wort Diethylpropion Sumatriptan Ergot derivatives (in migraine preps) Tramadol Fentanyl Illicit drugs (eg. MDMA, LSD) Clinical features of serotonin syndrome discontinued. Most cases are mild and The clinical features of SS fall into three resolve quickly with supportive symptom main areas as follows; altered mental management. status, autonomic dysfunction and and have neuromuscular abnormalities. Typical been used successfully to treat SS. symptoms are shown below. Summary Mental state changes eg. confusion Antidepressant combinations are increasingly being used by clinicians to Agitation treat depression. This strategy is not Myoclonus recommended and should only be Hyperreflexia undertaken with extreme caution and when Sweating other treatment options have failed. Shivering The most common drug combinations thought to be the cause of SS are Diarrhoea MAOIs/SSRIs, MAOIs/TCAs and Lack of co-ordination MAOIs/. Although the incidence Fever of SS may be low, serotonergic drug combinations should be avoided where Sternbach’s criteria are most commonly possible due to rare reports of fatalities cited for diagnosis of SS. He suggested and severe complications such as that at least three of the above symptoms hyperthermia, and must be experienced in order for the /liver failure. reaction to be classified as SS. In contrast Caution should be used when starting to neuroleptic malignant syndrome serotonergic agents following cessation of (NMS), with which it shares many similar agents with long elimination half- features, SS peaks and later resolves over a lives, such as . period of hours rather than days. Symptoms include myoclonus and Swapping or cross-tapering of hyperreflexia in contrast to "lead-pipe" antidepressants should be undertaken with care. In general, antidepressants should rigidity seen in NMS. not be used in combination with MAOIs or Other potential causes, such as infection, within two weeks of stopping substance abuse or concurrent or . antipsychotic dose changes prior to References symptom onset, must be ruled out. Stockley IH. Pharmacodynamic interactions. In: Drug Interactions, 5th ed. : Pharmaceutical Onset of SS symptoms Press, 2001:11-12. Onset can occur as early as an hour after Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705-713. single or multiple drug overdose or the Bazire S. Serotonin syndrome. In: Psychotropic Drug addition of another serotonergic agent to Directory, United Kingdom: Mark Allen, 2001:123-124. Linden CH, Burns MJ. Serotonin syndrome [online] 2001 current therapy and as long as several days [cited 2002 July 1st]. Available from: after increasing the dose of one or more URL:http://www.harrisonsonline.com/ agents. Effects may last from 6 to 48 Acknowledgement hours, depending on severity. This article was prepared by Kate Smith and reviewed by the Pharmacy Department. Treatment Comments are welcome at the e-mail address: Drugs with serotonergic activity should be [email protected] Graylands Hospital Drug Bulletin 2002 Vol 10 No 2 July - 4 -