APRIL 2008 DELHI PSYCHIATRY JOURNAL Vol. 11 No.1. Harish Arora, Rajdeep Kaur Department of Psychiatry, G.G.S. Medical College, Faridkot, Punjab

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1 APRIL 2008 DELHI PSYCHIATRY JOURNAL Vol. 11 No.1 Original Article An Open Label Study on Amisulpride in Augmentation with Atypical Antipsychotics in Treatment Resistant Patients of Schizophrenia and Schizoaffective Disorders Harish Arora, Rajdeep Kaur Department of Psychiatry, G.G.S. Medical College, Faridkot, Punjab Abstract Objective: The authors report an open label study in treatment resistant patients of schizophrenia and schizoaffective disorders. The patients who were earlier being treated with atypical antipsychotics were put on combination of amisulpride and atypical antipsychotics and efficacy as well as safety of the combination was assessed. Method: A study of 6 weeks duration was conducted on 30 patients (9 women, 21 men).the mean dose of amisulpride used was from mg/day SAPS, SANS, CGI-S scales were applied. 4 patients dropped out of study. 26 patients completed 6 weeks duration. Results: There was significant improvement in negative symptoms, positive symptoms, cognition especially in old chronic schizophrenics.only two patients developed extrapyramidal symptoms.improvement in all symptoms was remarkable. Conclusion: The combination of amisulpride with atypical antipsychotics is a promising option in patients who are resistant to treatment. Keywords : Amisulpride augmentation, Schizophrenia, Schizoaffective disorders. Introduction Despite the various treatment options for schizophrenia, about 30% of patients have partial or no response to pharmacotherapy 1. Clozapine is generally drug of choice in patients who are treatment resistant, but 40-70% of patients may show an adequate response or slow clinical improvement. 2 This problem of treatment resistance is a big problem. Clinicians have considered various approaches to solve this problem. Usual approaches include switching treatment resistant patients from a classic neuroleptic dr ug to an atypical antipsychotic or to any alternative typical agent, the use of electroconvulsive therapy, adding another psychotropic drug such as a benzodiazepine, lithium, an anticonvulsant or combining high and low potency medications. 3 Antidepressants combinations as a treatment of resistant depression is widely used and effective, 4-7 but regarding resistant schizophrenia, polypharmacy is still controversial. Since the development and intr oduction of atypical antipsychotics into routine clinical management, the use of antipsychotic drug combinations to treat schizophrenia has appeared to gain new impetus. The newer atypical antipsychotics exhibit more novel neuroreceptor profiles, which lead to the assumption that combination with either typical or atypical antipsychotic medications would provide a more efficacious profile. But despite of combination to overcome treatment resistance in patients of schizophrenia, 8,9 polypharmacy is still recommended to be avoided and clinical trials are conducted in patients taking only one antipsychotic 83

2 DELHI PSYCHIATRY JOURNAL Vol. 11 No.1 APRIL 2008 drug. However, in daily clinical practice upto a quarter of patients are taking two drugs. 10 We cannot predict beforehand which medication regimen or drug combination will be effective. Every antipsychotic has its own affinities for different receptors. For example clozapine has high affinities for 5-HT 2a, 5-HT 2c, 5-HT 6, 5HT 7, M 1 -M 5, alfa 1 and alfa 2 adrenergic, muscarinic, histaminic H 1 receptors and dopamine D 1, D 2 (relatively weak), and D 4 receptors. 11 Risperidone affinity is related mainly to 5HT 2, dopamine D 2, norepinephrine alfa Olanzapine affinity is very close to that of clozapine-high affinity for 5HT 2a, 5HT 6, M 1 -M 5, H 1 receptors. 13 In contrast, amisulpride another atypical antipsychotic, possesses a unique pharmacological profile and is characterized by a selective interaction with dopamine D 2 /D 3 receptors Moreover, amisulpride is supposed to ameliorate negative symptoms even at low dose. This drug does not lead to weight gain and is associated with fewer extrapyramidal side effects than conventional neuroleptics Furthermore, several recent studies demonstrated that a combination of amisulpride and olanzapine or clozapine may be useful in treatment resistant schizophrenic patients The aim of present study was to investigate whether amisulpride was effective as add on treatment with other atypical antipsychotics in management of treatment resistant patients of schizophrenia and schizoaffective disorders. Methods In this open label study, we examined the clinical records of resistant patients suffering from schizophrenia, schizoaffective disorders. These patients had persisting positive, negative symptoms and they were already on treatment with atypical antipsychotics (clozapine,olanzapine,risperidone) as monotherapy or polypharmacy. Total 30 patients were included for trial (9 women, 21 men). Age group ranged from years.patients suffering from organic mental disease, epilepsy, pregnant females, lactating mothers, patients having history of substance abuse were excluded from trial. 4 patients dropped out of study and 26 completed the 6 weeks duration. Out of these patients, many 84 patients had marked deterioration during course of illness and completely dependent for fiancial support on others. The following data were extracted from the medical records: age, gender, ICD-10 diagnosis, time of onset of illness, previous treatment history, rationale for combination therapy and side effects. Before conduction of clinical trial, informed written consent was taken from patients and relatives of patients. Thorough clinical and psychiatric examination of all patients was conducted before inclusion in clinical study. Summarised data are provided in Table 1. As there was no significant improvement in persisting positive and negative symptoms with treatment which was already going on, it was decided to switch the ongoing treatment to amisulpride. Amisupride was added to ongoing treatment with a starting dose of mg/day (depending on predominance of negative and positive symptoms) and its dose was increased by mg/day every week if clinical state was not improved. After an improvement of symptoms, there was a trial to reduce the dosage of previous medication. Maximum dose of amisulpride reached was upto 400mg/day only. Study was conducted for total duration of 6 weeks. Patients were followed up every week. Clinical improvement was evaluated with scale for assessment for positive symptoms (SAPS), scale for assessment of negative symptoms (SANS), clinical global impressions severity of illness scale (CGI-S). Results Total 26 patients completed the 6 weeks duration of study. Among them were 19 males, 7 female patients. Mean age was years ranging between 18 and 65 years. Following the ICD-10 classification, 21 patients were suffering from schizophrenia (F20.0), 5 were having schizoaffective disorder (F25.0). Patients were treated with the combination of amisulpride (dose mg/day, mean dose mg ), and clozapine (mean dose 300 mg, 6 patients), olanzapine (mean dose mg, 10 patients) and risperidone (mean dose 5.6 mg,10 patients). Only two patients developed side effects. 1 developed parkinsonism and another developed trismus. Mean baseline score on SAPS scale was which reduced to endpoint mean score of

3 APRIL 2008 DELHI PSYCHIATRY JOURNAL Vol. 11 No.1 Table-1: Sociodemographic and Clinical Characteristics of Patients Treated with Combined Antipsychotic Treatment No. ICD-10 Age in Sex First drug Adjuvant SAPS SAPS SANS SANS CGI-S CGI-S Side Diag- years and dose amisulpride Baseline Endpoint Baseline Endpoint before After Effects nosis mg/day dose mg/day Scores Scores Scores Scores Treatment Treatment 1 F Female Olanzapine 30 mg 300 mg Moderately ill Mildly ill No 2 F Male Olanzapine 20 mg 400 mg Markedly ill Normal No 3 F Male Clozapine 400 mg 400 mg Markedly ill Moderately ill No 4 F Male Olanzapine 30 mg 400 mg Moderately ill Borderline ill No 5 F Male Clozapine 300 mg 300 mg Moderately ill Mildly ill No 6 F Male Clozapine 200 mg 200 mg Moderately ill Moderately ill No 7 F Female Clozapine 200 mg 400 mg Markedly ill Mildly ill No 8 F Male Olanzapine 15 mg 200 mg Markedly ill Moderately ill Trismus 9 F Male Clozapine 300 mg 200 mg Moderately ill Borderline ill No 10 F Male Risperidone 6 mg 300 mg Markedly ill Moderately ill No 11 F Male Clozapine 400 mg 200 mg Markedly ill Moderately ill No 12 F Male Risperidone 6 mg 250 mg Moderately ill Borderline ill No 13 F Female Olanzapine 22.5 mg 100 mg Markedly ill Normal No 14 F Female Risperidone 6 mg 200 mg Markedly ill Normal Par-kinsonism 15 F Male Olanzapine 20 mg 200 mg Severely ill Borderline ill No 16 F Male Olanzapine 20 mg 100 mg Markedly ill Normal No 17 F Male Risperidone 6 mg 400 mg Markedly ill Borderline ill No 18 F Female Risperidone 6 mg 200 mg Moderately ill Borderline ill No 19 F Male Olanzapine 15 mg 150 mg Moderately ill Borderline ill No 20 F Female Risperidone 6 mg 300 mg Markedly ill Mildly ill No 21 F Male Risperidone 4 mg 200 mg Markedly ill Normal No 22 F Male Risperidone 6 mg 200 mg Moderately ill Normal No 23 F Female Olanzapine 30 mg 200 mg Moderately ill Normal No 24 F Male Risperidone 6 mg 200 mg Markedly ill Moderately ill No 25 F Male Olanzapine 20 mg 300 mg Markedly ill Moderately ill No 26 F Male Risperidone 4 mg 200 mg Markedly ill Moderately ill No 85

4 DELHI PSYCHIATRY JOURNAL Vol. 11 No.1 APRIL at completion of 6 weeks. Whereas on SANS scale, baseline mean score was which decreased to endpoint score of at 6 weeks. Disappearance or persistence of only few psychotic symptoms with full resocialisation (+++) was considered as major improvement; partial improvement of some psychotic and negative symptoms (++) was defined as marked improvement; clinically marginal changes were considered as minor improvement (+); no change (0), or deterioration of mental state (-). The mental state of 25 patients treated with combination had improved. (10 patients, 38.46%) of them had marked improvement and (1 patient, 3.8%) had mild improvement. Only one patient (3.8%) showed no change in his mental state. In 14 patients, (53.84%) there was an amelioration of positive and negative symptoms including improvement of daily functioning. No patient demonstrated worsening of mental symptoms. Discussion Resistance or nonresponsiveness to antipsychotic treatment is a significant problem in management of schizophrenic patients. Failure of atleast 2 antipsychotic trials of adequate dose and duration of treatment is generally required to consider a patient treatment refractory 23,24, although some researchers believe that the length of an adequate drug trial is difficult to define. 25 Ideally, combination of psychotropic drugs should be implemented in only those cases in whom monotherapy with different classes of typical antipsychotics or atypical antipsychotics was ineffective. 26 In clinical practice, different combinations of psychotropic drugs are used only for a relatively small group of patients who failed with conventional methods of psychopharmacotherapy and were r esistant to atypical antipsychotics. For example, Munro et al treated 33 schizophrenic patients resistant to clozapine with combination of clozapine and amisulpride in an open label nonrandomized study. The authors concluded that coadministration of amisulpride in patients partially or nonresponsive to clozapine may lead to a substantial improvement in positive and negative symptoms without side effects. 20 The mechanisms underlying the combined action of antipsychotics remain unclear. Amisulpride is considered a highly selective dopamine D 2 /D 3 receptor antagonist that binds preferentially to receptors in mesolimbic system, 15 probably supplements the relatively broad receptors interactions of other antipsychotics, resuting in highly synergistic therapeutic potency without increasing the side effects. Bergemann et al reported about the elevation effect of amisulpride as a result of combination with clozapine. 19 In our study, it has been concluded that majority of patients were either very much or much improved as a result of combined treatment. Tolerability was good; only two patients developed extrapyramidal symptoms. There was improvement in both positive, negative symptoms along with improvement in overall cognitive status of patient. 2 of male patients 86

5 APRIL 2008 DELHI PSYCHIATRY JOURNAL Vol. 11 No.1 have started earning money to support their family members. In these patients, improvement is remarakable. Others patients are also able to look after themselves. only one patient has not shown any improvement. Out of side effects with this combination observed are trismus in one patient and parkinsonism in another patient. Except for these no other side effect was noticed. Our study demonstrates that adjunction of amisulpride to previous antipsychotic medicine may benefit a subgroup of chronic schizophrenic patients nonresponsive to typical antipsychotics and/or partially responsive to clozapine or other atypical antipsychotics. Our results coincide with data of previous publications regarding coadministration of amisulpride with olanzapine and clozapine. 21,22 Furthermore our findings show that the combination of amisulpride with other antipsychotics is also beneficial and safe. However, there is limitation of study also due to small number of patients. One more commonly cited problem in discussions about polypharmacy is the cost of such treatment. Of course, the combination of 2 atypical antipsychotics is expensive, but prolongation of hospitalization is also expensive. The opportunity to reduce the length of stay by this combination therapeutic approach may reduce total cost of whole treatment significantly. 27 Polypharmacy for bipolar disorders is considered as an acceptable and modern approach. 28 The use of the antipsychotic combinations for the management of treatment resistant patients may prove to be equally optimal. 27 The results of our study show that there are treatment resistant schizophrenic patients, who may be successfully managed with a combination of amisulpride and other antipsychotic medications without serious side effects. However, Further prospective, systematic, controlled, randomized and double blind clinical studies including only nonresponding schizophrenic patients are needed. References 1. Kane JM. The current status of neuroleptic therapy. J Clin Psychiatry 1989; 50 : Kane J, Honigfeld G, Singer J, et al. Clozapine for treatment resistant schizophrenic. A double blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45 : Zarate CA Jr, Daniel DG, Kinon BJ, et al. Algorithms for the treatment of schizophrenia. Psychopharmacol Bull 1995; 31 : Fava M. Augmentation and combination strategies in treatment resistant depression. J Clin Psychiatry 2001; 62 (Suppl 18) : Alao AO, Malhotra K, Pies R, et al. Pharmacological strategies in treatment resistant depression. West Afr J Med 2003; 22 : Shelton RC. The use of antidepressants in novel combination therapies. J Clin Psychiatry 2003; 64 (Suppl 2) : Trivedi MH. Treatment-resistant depression: new therapies on the horizon. Ann Clin Psychiatry 2003; 15 : Pantelis C, Barnes TR. Drug strategies and treatment-resistant schizophrenia. Aust N Z J Psychiatry 1996; 30 : Koshino Y. Algorithm for treatment-refractory schizophrenia. Psychiatry Clin Neurosci 1999; 53 (Suppl) : Stahl SM. Selecting an atypical antipsychotic by combining clinical experience with guidelines from clinical trials. J Clin Psychiatry 1999; 60 (Suppl 10) : Meltzer HY, McGurk SR. The effects of clozapine, risperidone and olanzapine on cognitive functions in schizophrenia. Schizophr Bull 1999; 25 : Nyberg S, Eriksson B, Oxenstierna G, et al. Suggested minimal effective dose of risperidone based on PET-measured D 2 and 5HT2a receptor occupancy in schizophrenic patients. Am J Psychiatry 1999; 156 : Schmidt AW, Lebel LA, Howard HR Jr, et al. Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile. Eur J Pharmacol 2001; 425 : Scatton B, Claustre Y, Cuddenec A, et al. Amisulpride: from animal pharmacology to therapeutic action. Int Clin Psychopharmacol 1997; 12 (suppl 2) : Leucht S. Amisulpride a selective dopamine antagonist and atypical antipsychotic: results of a meta-analysis of randomized controlled trials. Int J Neuropsychopharmacol 2004; 7 (Suppl 1) : Rein W, Turzanski S. Clinical update on amisulpride in deficit schizophrenia. Int Clin 87

6 DELHI PSYCHIATRY JOURNAL Vol. 11 No.1 APRIL 2008 Psychopharmacol 1997; 12 (Suppl 2) : Lecrubier Y, Azorin M, Bottai T, et al. Consensus on practical use of amisulpride, an atypical antipsychotic, in the treatment of schizophrenia. Neuropsychobiology 2001; 44 : Agelink MW, Kavuk J, AK I. Clozapine with amisulpride for refractory schizophrenia. Am J Psychiatry 2004; 161 : Bergemann N, Kopitz J, Kress KR, et al. Plasma amisulpride levels in schizophrenia or schizoaffective disorders. Eur Neuropsychopharmacol 2004; 14 : Munro J, Matthiasson P, Osborne S, et al. Amisulpride augmentation of clozapine: an open non-randomised study in patients of schizophrenia partially responsive to clozapine. Acta Psychiatr Scand 2004; 110 : Zink M, Henn FA, Thome J. Combination of amisulpride and olanzapine in treatment resistant schizophr enic psychosis. Eur Psychiatry 2004; 19 : Zink M, Knopf U, Henn FA, et al. Combination of clozapine and amisulpride in treatment resistant schizophrenia-case reports and review of literature. Pharmacopsychiatry 2004; 37 : Bondolfi G, Baumann P, Dufour H. Treatment resistant schizophrenia: Clinical experience with new antipsychotics. Eur Neuropsychopharmacol 1996; 6 (Suppl 2) : Kane JM. Management strategies for the treatment of schizophrenia. J Clin Psychiatry 1999; 60 (Suppl 12) : Marder SR. Management of treatment resistant patients with schizophrenia. J Clin Psychiatry 1996; 57 (Suppl 11) : Freudenreich O, Goff DC. Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatr Scand 2002; 106 : McCue RE, Waheed R, Ureuyo L. Polypharmacy in patients with schizophrenia. J Clin Psychiatry 2003; 64 : Freeman MP, Stoll AL. Mood stabilizer combinations: a review of safety and efficacy. Am J Psychiatry 1998; 155 : ANNUAL SUBSCRIPTION RATE Members : Free of Cost Non-Members : Rs. 500/- (Cost includes that of CD and postage) Indian Institutions : Rs. 1000/- (Cost includes that of CD and postage) Foreign Individual : US$ 25 Institutions : US$