EFFICACY AND TOLERABILITY OF RAPID INITIATION OF AMISULPRIDE IN ACUTE PSYCHOSIS

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1 ARTICOLE ORIGINALE EFFICACY AND TOLERABILITY OF RAPID INITIATION OF AMISULPRIDE IN ACUTE PSYCHOSIS Maria Ladea*, Mihaela-Ruxandra Dumitrescu** Rezumat: Context: Amisulpridul are o puternicã activitate antipsihoticã ºi este eficient la pacienþii cu exacerbãri acute ale schizofreniei. Rezultatele bune, obþinute în clinicã, sunt ilustrate de numeroase studii ºi sunt explicate de profilul farmacologic al amisulpridului. Existã un consens în literaturã, referitor la dozã ºi anume: 8 mg de amisulprid pe zi asigurã cel mai bun echilibru beneficiu/risc pentru majoritatea pacienþilor, în tratamentul psihozei acute, iar aceastã dozã poate fi iniþiatã încã din prima zi. Metodã: În aceastã lucrare prezentãm un studiu observaþional, necontrolat, cu o duratã de 4 sãptãmâni, care a inclus pacienþi internaþi, cu exacerbãri acute ale schizofreniei sau un prim episod psihotic (conform criteriilor DSM-IV). Pacienþii au primit douã scheme de tratament, dupã cum urmeazã: dozele au început cu 4 sau 6 mg de amisulprid pe zi ºi au fost crescute, în trei zile, la 1 ºi respectiv 12 mg pe zi. Eficienþa tratamentului a fost evaluatã cu ajutorul Scalei pentru simptome pozitive ºi negative (PANSS), a Subscalei suplimentare privind riscul de agresivitate, derivatã din PANSS, precum ºi a Scalei de impresie clinicã globalã (CGI). Modificãrile înregistrate în scorurile acestor scale au arãtat cã ambele scheme terapeutice au fost eficiente ºi bine tolerate, în tratamentul simptomelor psihozei acute. S-a demonstrat, de asemenea, instalarea rapidã a rezultatelor pozizive, în ambele grupe de tratament. Efectele adverse au fost monitorizate sãptãmânal. Simptomele extrapiramidale au fost evaluate cu ajutorul Scalei Simpson-Angus (SAS), Scalei de akatisie Barnes (BAS) ºi a Scalei de miºcãri involuntare anormale (AIMS). Tratamentul cu amisulprid a fost bine tolerat în ambele grupuri, iar efectele secundare au fost uºoare sau moderate. Concluzii : Acest studiu observaþional a demonstrat cã amisulpridul iniþiat rapid, în doze mari, este eficient ºi bine tolerat la pacienþii cu recãderi acute ale schzofreniei sau aflaþi la primul episod psihotic. Cuvinte cheie: Psihozã acutã, amisulprid, iniþiere rapidã. INTRODUCTION The goals of management in acute psychosis include immediate measures to stabilize the crisis, assessment of symptoms, evaluation of risk of selfharm and harm to others. The acute psychotic patient is usually admitted in emergency psychiatric units, which Abstract: Background: Amisulpride has a strong antipsychotic activity and it is efficient in patients with acute exacerbations of schizophrenia. These good clinical results, illustrated by numerous studies, are consistent with the pharmacological profile of amisulpride. There is a consensus in the literature that 8 mg/day of amisulpride provides the best risk-benefit ratio for the majority of patients in the treatment of acute psychosis and that this dose may be initiated from the first day. Method: We present an observational, uncontrolled, 4-week, inpatient study, which included patients with acute exacerbation of schizophrenia or first psychotic episode (DSM-IV-TR criteria). Patients received amisulpride in rapid initiation over three days, following two schemes: doses started at 4 or 6 mg/day up to 1 and 12 mg/day respectively. Treatment efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), PANSS Supplemental Aggression Risk subscale and the Clinical Global Impression (CGI) Scale. The changes registered in these scores indicated that both schemes of treatment were effective and safe in treating the symptoms of acute psychosis. Rapid onset of efficacy was also demonstrated in both treatment groups. Adverse events were monitored on a weekly basis. Extrapyramidal symptoms were evaluated with the Simpson-Angus Scale (SAS), the Barnes Akathisia Rating Scale (BAS) and the Abnormal Involuntary Movement Scale (AIMS). Amisulpride treatment was well tolerated in the two groups, with adverse events that were mild to moderate. Conclusions: This observational study, demonstrated that amisulpride in higher doses, with rapid initiation was both effective and well tolerated in patients with acute relapse of schizophrenia or first psychotic episode. Key words: Acute psychosis, amisulpride, rapid initiation. is the case in the present study. In this state, patients are most often agitated, potentially aggressive toward themselves or others, uncooperative, with a high level of distress (1). In acutely psychotic agitated patients immediate pharmacotherapy is required, with adequate, usually high doses, besides providing a secure environ- * MD, PhD, Clinical Psychiatric Hospital Prof. Dr. Al. Obregia, Bucharest; Lecturer, University of Medicine and Pharmacy Carol Davila, Bucharest. ** MD, Resident in psychiatry, Clinical Psychiatric Hospital Prof. Dr. Al. Obregia, Bucharest. 184

2 Revista Românã de Psihiatrie, seria a III-a, vol. IX, nr. 4, 27 ment (2). The correct therapeutic approach will relieve distress and reduce florid psychiatric symptoms. The development of atypical antipsychotics represented a significant advance in the treatment of schizophrenia, as some of them may have a more pronounced antipsychotic effect than classical ones (3, 4, 5). All atypical antipsychotics have a lower incidence of extrapyramidal side effects for a similar level of symptom control compared with conventional drugs (3, 5, 6). Since the occurrence of such side effects is a major determinant of compliance to antipsychotic treatment, the use of the newer atypical drugs is associated with less treatment discontinuation (7) and thus more consistent long term control and a better outcome and quality of life. However, these new medications differ from each other regarding their pharmacological profile, actions on different symptoms of schizophrenia and especially side effects. The literature emphasizes the fact that atypical antipsychotics are not a homogenous group of drugs (5, 8, 9). Considering the heterogeneity of atypical antipsychotics the clinicians have many options but also a difficult task of choosing the right treatment for a specific patient. Differences in side-effect profiles appear to be the main factor in the therapeutic decision as well as the compliance of the patients. Among the recent antipsychotic drugs, amisulpride has a different pharmacological profile in comparison with other agents (1, 11, 12). Amisulpride is a substituted benzamide with a unique binding and clinical profile, due to the high affinity for dopamine D2 and D3 receptors and the preferential activity in the limbic region of the brain, rather than the striatal one (13, 14, 15). This seems to explain the efficacy in controlling the acute positive symptoms of schizophrenia on one side and the low incidence of extrapyramidal symptoms on the other side. Amisulpride has a dual dopamine blockade effect: at high doses it blocks postsynaptic D2/D3 receptors and at low doses it selectively blocks presynaptic receptors, enhancing dopaminergic transmission (15). Therefore, amisulpride is efficient in two types of patients: those with acute psychotic episodes and those with chronic schizophrenia. Another important issue is that amisulpride has no affinity for adrenergic, serotonergic or histaminergic receptor systems, which are at the origin of numerous side effects. Amisulpride has also no affinity for dopamine D1, D4 and D5 receptors. In this paper we will discuss the usefulness of amisulpride as an important therapeutic option in first psychotic episode or in acute exacerbation of schizophrenia. The efficacy of amisulpride in patients with acute psychosis has been demonstrated in many clinical trials (3, 5, 6, 16, 17, 18). The trials have demonstrated superior global efficacy to that of conventional antipsychotics (16, 19, 2, 21, 22, 23, 24), although not necessarily statistically significant, and similar efficacy to risperidone (25, 26, 27) and olanzapine (28, 29). The main factors influencing the choice of medication are the spectrum of efficacy, the tolerability, the rapid onset of action, and the dosage regimen. We will discuss the tolerability of amisulpride later. Antipsychotic drugs differ in their secondary psychotropic effects, some being sedative and some having a more activating effect. This heterogeneity is due to the relative pharmacological specificity of antipsychotic drugs for different receptors (3, 31). In agitated patients the clinician have the choice of a sedative antipsychotic or a combination of a non-sedative antipsychotic and an anxiolytic drug, such as diazepam, lorazepam etc. The potential disadvantage of choosing to use a sedative drug to manage both psychosis and agitation in the same time is that the sedative effect may persist during the maintenance phase of therapy and become an undesired side effect with impact on the patient performances. Dose reduction to attenuate sedation may also be associated with loss of control over psychotic symptoms. The second option is a more flexible alternative, because the anxiolytic medication can be stopped when the patient is no longer agitated, without compromising the control of psychosis. Benzodiazepines are the treatment of choice for the short-term management of agitation and anxiety in patients with schizophrenia (32). Drugs such as alprazolam, lorazepam, and diazepam have been proved to ensure a good control of agitation in acute psychotic episodes (33, 34, 35). Intramuscular administration of benzodiazepines are useful in the emergency situations when patients are highly agitated an uncooperative. The long term use of benzodiazepines should be avoided to prevent the development of dependence and the rebound anxiety when treatment is discontinued. In a study showing the short-term control of agitation in patients treated by amisulpride and olanzapine, the use of benzodiazepines was of 48% in amisulpride group and 51% in the olanzapine group (28). The results regarding the control of agitation were similar in the two groups. The choice of the right dose to obtain an optimal response in acute psychotic patients is also a very important issue. The recommended dose of amisulpride for the treatment of acute psychosis is around 8 mg/day (19, 2, 21, 36, 37). The results of the studies indicated that the dose of 8 mg/day provides the best risk-benefit ratio for the majority of patients in the treatment of acute psychosis. In one study where the starting dose of amisulpride was above 8 mg/day (21) the dose was reduced in 5% of patients. In another study (19) the dose was initiated at 8 mg/day and was decreased in only 17% of patients. The dose of 8 mg/day is also sustained by neuroimaging studies (38). The rapid onset of antipsychotic effect is important to control symptoms, especially in acute psychotic patients and to optimize compliance. The antipsychotics that can be given immediately at the optimal dose, such as amisulpride, have advantages in this 185

3 M. Ladea, M.R. Dumitrescu: Efficacy and tolerability of rapid initiation of Amisulpride in acute psychosis respect over drugs that need titration. A comparison between amisulpride and haloperidol (39) showed a significant difference in treatment response. Thus, more patients responded to amisulpride at 7 and 14 days, than to haloperidol. Amisulpride has also another advantage, in the control of acute psychosis, due to the possibility of rapid initiation. For amisulpride there is no need of dose titration, so the optimal dose of 8 mg/day can be used from the first day (19). This is related to the pharmacokinetics of amisulpride (4). No dose titration is required for switching to amisulpride due, in part, to its low pharmacokinetic interaction with other drugs (41). In two drug utilization observation studies on patients with schizophrenia the authors (42, 43) concluded that a substantial group of patients benefited from switching either from conventional antipsychotics or atypical ones (olanzapine and risperidone) to amisulpride and consequently show an improvement in their clinical status. The decision to switch was completely based on medical needs of the individual patient and the main reasons for changing the treatment were the side effects, such as extrapyramidal symptoms for risperidone, weight gain for olanzapine. The first amisulpride dosage after switching was above 3 mg/day. Whenever possible, for the treatment of acute psychotic patients, the antipsychotic medication is recommended in oral administration. Nowadays the psychiatrist has a wide choice of oral antipsychotic medications, amisulpride being one of them. Intramuscular formulations are reserved for highly uncooperative patients, especially because certain intramuscular formulations are poorly tolerated, which may compromise the adherence to therapy (44, 45). Another important issue in the uncooperative patients is the possibility to give medication requiring a single daily intake, such as amisulpride. In conclusion amisulpride is an appropriate firstline treatment in the management of acute psychosis (46). Concerning the tolerability of antipsychotics, extrapyramidal effects, endocrine effects and weight gain are of particular relevance. Amisulpride has lower risk of extrapyramidal symptoms as compared to classical antipsychotics as a result of the preferential binding in the limbic system. Studies demonstrated that amisulpride has a more favorable tolerability profile in the treatment of acute psychosis, compared with conventional antipsychotic drugs. An analysis of numerous clinical trials (47) showed that the incidence of extrapyramidal effects, in general, and of dyskinesia and hypertonia, in particular, was significantly lower in patients treated with amisulpride compared with those receiving conventional antipsychotics. A meta-analysis of the clinical trials comparing amisulpride with conventional antipsychotics demonstrates that use of antiparkinsonian medication was 25% lower in patients receiving amisulpride (17). In the studies comparing amisulpride with risperidone or olanzapine it has been demonstrated that the extent of extrapyramidal symptoms and recourse to anticholinergic medication were very similar (26, 27, 29). With regard to endocrine effects amisulpride use is associated with elevated serum prolactin, effect which is dose dependent (11, 47). Impotence and delayed ejaculation were reported less frequently in patients treated with amisulpride than in those treated with risperidone. Amenorrhea was encountered in the amisulpride group when compared with risperidone or olanzapine (29, 47). Weight gain is less frequent and lower in patients receiving amisulpride than in patients treated with risperidone or olanzapine (25, 27, 28, 29, 48). One recent study showed that at doses that provide comparable control of psychosis, treatment with olanzapine was associated with greater increase of body weight and blood glucose compared with amisulpride (49). Effects on QT interval are considered to be an important measure of cardiac safety and thus the prolongation of more than 5 ms is considered to be clinically significant. There have been no such observations with amisulpride (47). Even if no particular monitoring procedures are required when using amisulpride in acute psychotic patients, the drug should be used with care in patients with cardiac rhythm disorders. These patients should be monitored regularly by electrocardiogram. Amisulpride is contraindicated or should be used with caution in patients taking drugs affecting cardiac rhythm. Concerning other cardiovascular effects, such as hypotension, tachycardia, and dizziness amisulpride was shown to be safer than risperidone (25). During treatment with amisulpride, no clinically relevant effects upon haematological or biochemical variables have been found (47). In concordance with its particular pharmacological profile, amisulpride has a low incidence of hypotension, anticholinergic and sedative effects, and cognitive impairment (21, 22), due to the lack of interaction with adrenergic, cholinergic and histaminergic receptors. No clinically relevant effects on renal function have been found (11), but since amisulpride is eliminated in the urine, in patients with impaired renal function, the dose should be reduced in line with creatinine clearance. Amisulpride is weakly metabolised by hepatic enzymes (4) so there is no adverse influence on liver function tests to be expected and it can be used at the standard doses in patients with hepatic impairment. Medications that have important pharmacokinetic or pharmacodynamic interactions with other drugs the patients are taking should be used with caution. Amisulpride has limited drug interactions, due to weak protein binding and limited capacity for drug interactions with cytocrome P45 drug-metabolizing enzymes (5). Therefore amisulpride can be safely used in com- 186

4 Revista Românã de Psihiatrie, seria a III-a, vol. IX, nr. 4, 27 bination with benzodiazepines, whenever such a strategy is needed, at the beginning of the treatment to control agitation and anxiety. A pharmacodymanic interaction study (51) of amisulpride and lorazepam revealed no interaction between the two drugs. Overall, the clinical experience with amisulpride shows it is a safe drug and no concern with respect to hematology, hepatic and cardiovascular function or weight gain have arisen (11). METHODOLOGY Inclusion and exclusion criteria We included in the study patients 18 to 65 years old, with acute exacerbation of schizophrenia or first psychotic episode (DSM-IV-TR criteria). Exclusion criteria included serious concomitant illnesses or acute and unstable medical conditions. Study design This was an observational, uncontrolled, 4-week, inpatient study, conducted at Ward 3, Clinical Hospital of Psychiatry Prof. Dr. Al. Obregia, Bucharest. We included in the study patients that suited the criteria, admitted between November 26 and June 27. Patients received amisulpride orally for 4 weeks. Patients were divided in two groups, following the two treatment schemes that were used: I. 32 patients received amisulpride 4 mg, once daily, in Day 1, then 8 mg once or twice daily, in Day 2 and 1 mg, twice daily from Day 3. II. 28 patients received amisulpride 6 mg, once daily, in Day 1, then 1 mg, twice daily, in Day 2 and 12 mg from Day 3. The decision to include each patient in one group or another was done for clinical reasons, and especially the degree of agitation, aggressivity and hostility. Stahl, in his Prescriber s Guide, recommend that daily doses above 4 mg should be divided in 2 (52). Initiation of amisulpride was made immediate at the admission or after discontinuation of current antipsychotic therapy. Discontinuation of previous treatment was done for individual clinical reasons and not because of the study. Dosages remained fixed throughout the study. Patients were hospitalized for the entire duration of the trial. After the observation period of 4 weeks, the doses of amisulpride were adjusted if necessary, always downward. Efficacy assessments Treatment efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS). Assessments included the PANSS total score (3 items) at baseline and at the end of Weeks 1, 2 and 4. The evaluations of PANSS Supplemental Aggression Risk subscale were performed at Day 1, Day 2, Day 3, Day 5, Day 7 and Day 14. PANSS Supplemental Aggression Risk subscale score is the sum of 3 standard PANSS items Excitement, Hostility and Depression and 3 supplemental PANSS items related to anger Anger, Difficulty in Delaying Gratification and Affective Lability. The Clinical Global Impression (CGI) Scale was used to assess efficacy and consists of two 7-point subscales: the Severity of Illness Scale (CGI-S) and the Global Improvement Scale (CGI-I). The CGI-S was performed at baseline and at the end of Weeks 1, 2 and 4. CGI-I assessments were conducted at the end of Weeks 1, 2 and 4. Safety assessments Adverse events were monitored at baseline and thereafter weekly. Potential EPS-related side effects (parkinsonism, dyskinesia and akathisia) were evaluated using three standardized rating instruments: the Simpson-Angus Scale (SAS), the Barnes Akathisia Rating Scale (BAS) and the Abnormal Involuntary Movement Scale (AIMS). These scales were completed at baseline and at the end of Week 4. Vital signs (blood pressure and heart rate) were measured at baseline and thereafter weekly. Twelvelead ECG and physical examinations were performed at baseline. Also, serum chemical parameters and urinalysis were obtained. Concomitant medication Benzodiazepines were allowed in doses up to 8 mg/day lorazepam equivalent, such as up to 4 mg diazepam/day. Benztropine treatment was allowed for EPS, if necessary. RESULTS AND DISCUSSIONS A total number of 6 patients participated at this trial. All of them were male, due to the organization of the ward. Overall mean age for patients in the first group was 41.7 and 39.7 for the second group. From the total number of patients, 46 were diagnosed with schizophrenia and 14 were diagnosed with a first psychotic episode (Table 1). Tabel 1. Baseline Demographic Characteristics ant Efficacy Parameters CHARACTERISTIC GROUP I GROUP II No. patients Age (y), mean Diagnosis Schizophrenia 26 2 First psychotic episode 6 8 Mean Baseline PANSS score Total Supplemental Aggression Risk CGI-S score

5 M. Ladea, M.R. Dumitrescu: Efficacy and tolerability of rapid initiation of Amisulpride in acute psychosis Fifty-six patients completed the 4-week study period and 4 patients were discontinued due to lack of clinical response (Table 2). Table 2. Discontinuation Rates Group I Group II Total Completed study Discontinued Both amisulpride groups showed improvements in the PANSS total score at the end of the 4 weeks with minimal differences between the two groups. This is illustrated by a reduction in the mean PANSS total score of (Figure 1). frequent adverse events were akathisia (26 patients) and extrapyramidal syndrome (24 patients) (Table 3). Table 3. Adverse events Adverse event Number of patients Akathisia 26 Extrapyramidal 24 syndrome Tremor 14 Somnolence 11 Dry mouth 6 Headache 4 The scores on the Simpson Angus scale, Barnes Akathisia scale, and the AIMS increased slightly during the study (Figure 3). Mean Change in PANSS Total Score over 4 weeks Mean change from baseline Figure 1. Mean Change in PANSS Total Score From Baseline Over 4 Weeks of Treatment With Amisulpride During the one month period of clinical observation, PANSS Supplemental Aggression Risk Subscale scores improved as early as Day 1, the improvement increasing to Day 3, 5, 7, until Day 14. The improvement is illustrated by a reduction of 4.56 (Figure 2). Mean change from baseline Weeks Mean change from baseline in PANSS Supplemental Aggression Risk Subscale scores -.5 D1 D2 D3 D5 D7 D Days Group I Group II Total Group I Group II Figure 2. Mean Change in PANSS Supplemental Aggression Risk Subscale Score From Baseline Over 2 Weeks of Treatment With Amisulpride After 4 weeks of treatment, 46 patients registered an important improvement on CGI-I score as follows: very much improved or much improved. Overall, both dosages of amisulpride were well tolerated, with mild to moderate adverse events and there was no need for treatment adjustment. The most Total Mean Change for Simpson-Angus Scale, Barnes Akathisia Scale and AIMS.8 Simpson-Angus Scale Barnes Akathisia Scale AIMS Figure 3. Mean change over 4 weeks of treatment for Simpson-Angus Scale, Barnes Akathisia Scale and AIMS for all treatment groups There were no clinically significant changes in vital signs or laboratory results over the treatment period. CONCLUSIONS In acute psychotic patients, treatment needs to be continuously monitored and adjusted, to respond such emergency cases. The management of acute psychosis comprises the approach of agitation, aggressiveness, hostility and marked anxiety. Amisulpride is an appropriate first-line treatment, being both effective and well tolerated. Amisulpride is at least as effective as classical neuroleptic agents and new antipsychotic drugs in reducing acute psychotic symptoms. It has a rapid onset of action and there is no need for titration. Amisulpride has a good safety profile, being well tolerated by the patients. Haematological, biochemical and cardiovascular effects are negligible and the incidence of extrapyramidal symptoms is very low. For all these reasons amisulpride offers an important alternative in the antipsychotic pharmacotherapy. Numerous studies are indicating that the optimal dose is 8mg/day. When the agitation and anxiety are severe benzodiazepine therapy is needed

6 Revista Românã de Psihiatrie, seria a III-a, vol. IX, nr. 4, 27 In our observational study patients received amisulpride in rapid initiation, over three days, as follows: doses started at 4 or 6 mg/day up to 1 and 12 mg/day respectively. The changes registered in PANSS total score, from baseline to the end of the observation period, indicated that both schemes of treatment with amisulpride were effective in treating the symptoms of acute psychosis. Rapid onset of efficacy was also demonstrated in both treatment groups. One of the most important measures consisted in PANSS Supplemental Aggression Risk Subscale. The scores of this subscale improved as early as Day 1 until Day 14, with a reduction of 4.56 (Figure 2). Amisulpride treatment was well tolerated in the two groups, with adverse events that were mild to moderate. 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