Amisulpride Amisulpride versusversus

Olanzapine Olanzapine in treatment of schizophrenia in in treatment of schizophrenia in Indian patients-A Randomized Controlled TrialIndian patients-A Randomized Controlled Trial

Amisulpride Amisulpride versusversus

Olanzapine Olanzapine in treatment of schizophrenia in in treatment of schizophrenia in Indian patients-A Randomized Controlled TrialIndian patients-A Randomized Controlled Trial

Dr Subhrojyoti BhowmickDr Subhrojyoti Bhowmick11

Dr Avijit HazraDr Avijit Hazra11 & Prof Malati Ghosh & Prof Malati Ghosh22

Dr Subhrojyoti BhowmickDr Subhrojyoti Bhowmick11

Dr Avijit HazraDr Avijit Hazra11 & Prof Malati Ghosh & Prof Malati Ghosh22

Department of PharmacologyDepartment of Pharmacology11

Institute of Postgraduate Medical Education & Research, Institute of Postgraduate Medical Education & Research, Kolkata – 700020Kolkata – 700020

Department of PsychiatryDepartment of Psychiatry22

Bangur Institute of Neuroscience & Psychiatry,Bangur Institute of Neuroscience & Psychiatry,Kolkata-700025Kolkata-700025

Department of PharmacologyDepartment of Pharmacology11

Institute of Postgraduate Medical Education & Research, Institute of Postgraduate Medical Education & Research, Kolkata – 700020Kolkata – 700020

Department of PsychiatryDepartment of Psychiatry22

Bangur Institute of Neuroscience & Psychiatry,Bangur Institute of Neuroscience & Psychiatry,Kolkata-700025Kolkata-700025

Amisulpride,Amisulpride,a dopamine a dopamine antagonistantagonist, approved for , approved for marketing in India on marketing in India on 01/08/200601/08/2006 for use in schizophrenia.for use in schizophrenia.

Clinical trials regarding its Clinical trials regarding its effectiveness reported from effectiveness reported from western countries.western countries.

No Indian trial reportedNo Indian trial reported till date. till date.

A single-blind randomized A single-blind randomized controlled trial comparing controlled trial comparing Amisulpride to Olanzapine Amisulpride to Olanzapine conducted in conducted in Indian Indian schizophrenic patients schizophrenic patients attending attending Psychiatry OPD of a Psychiatry OPD of a tertiary care tertiary care hospital in Kolkatahospital in Kolkata from from June June 2007-September 20082007-September 2008..

Amisulpride,Amisulpride,a dopamine a dopamine antagonistantagonist, approved for , approved for marketing in India on marketing in India on 01/08/200601/08/2006 for use in schizophrenia.for use in schizophrenia.

Clinical trials regarding its Clinical trials regarding its effectiveness reported from effectiveness reported from western countries.western countries.

No Indian trial reportedNo Indian trial reported till date. till date.

A single-blind randomized A single-blind randomized controlled trial comparing controlled trial comparing Amisulpride to Olanzapine Amisulpride to Olanzapine conducted in conducted in Indian Indian schizophrenic patients schizophrenic patients attending attending Psychiatry OPD of a Psychiatry OPD of a tertiary care tertiary care hospital in Kolkatahospital in Kolkata from from June June 2007-September 20082007-September 2008..

 

AmisulpridAmisulpridee

IntroductionIntroductionIntroductionIntroduction

To evaluate, in a To evaluate, in a randomized single-randomized single-blind parallel group blind parallel group study, thestudy, the

- Effectiveness- Effectiveness

- Safety- Safety

of Amisulpride in of Amisulpride in comparison to comparison to Olanzapine in Indian Olanzapine in Indian schizophrenic patients.schizophrenic patients.

To evaluate, in a To evaluate, in a randomized single-randomized single-blind parallel group blind parallel group study, thestudy, the

- Effectiveness- Effectiveness

- Safety- Safety

of Amisulpride in of Amisulpride in comparison to comparison to Olanzapine in Indian Olanzapine in Indian schizophrenic patients.schizophrenic patients.

ObjectiveObjectiveObjectiveObjective

Randomized, prospective, single-blind, Randomized, prospective, single-blind, parallel-group, phase IV trial.parallel-group, phase IV trial.

Study protocol approved by Ethics Study protocol approved by Ethics Committee, IPGME&R, Kolkata.Committee, IPGME&R, Kolkata.

Target sample size – Target sample size – 4040 analyzable patients analyzable patients per arm.per arm.

Total duration – Total duration – 12 weeks12 weeks..

Visits – Screening/baseline, two interim visits Visits – Screening/baseline, two interim visits at 4 & 8 weeks and end of study visit at 12 at 4 & 8 weeks and end of study visit at 12 weeks.weeks.

Randomized, prospective, single-blind, Randomized, prospective, single-blind, parallel-group, phase IV trial.parallel-group, phase IV trial.

Study protocol approved by Ethics Study protocol approved by Ethics Committee, IPGME&R, Kolkata.Committee, IPGME&R, Kolkata.

Target sample size – Target sample size – 4040 analyzable patients analyzable patients per arm.per arm.

Total duration – Total duration – 12 weeks12 weeks..

Visits – Screening/baseline, two interim visits Visits – Screening/baseline, two interim visits at 4 & 8 weeks and end of study visit at 12 at 4 & 8 weeks and end of study visit at 12 weeks.weeks.

Materials & Methods 1Materials & Methods 1Materials & Methods 1Materials & Methods 1

Drugs - Either Drugs - Either AmisulprideAmisulpride (100-800 mg) or (100-800 mg) or OlanzapineOlanzapine (10-20 mg) once daily orally at night. (10-20 mg) once daily orally at night.

Blood sampled for routine hematological Blood sampled for routine hematological investigations and LFT, and 12-lead ECG recorded, investigations and LFT, and 12-lead ECG recorded, at the beginning and end of study.at the beginning and end of study.

Compliance by traditional pill count method.Compliance by traditional pill count method.

Drugs - Either Drugs - Either AmisulprideAmisulpride (100-800 mg) or (100-800 mg) or OlanzapineOlanzapine (10-20 mg) once daily orally at night. (10-20 mg) once daily orally at night.

Blood sampled for routine hematological Blood sampled for routine hematological investigations and LFT, and 12-lead ECG recorded, investigations and LFT, and 12-lead ECG recorded, at the beginning and end of study.at the beginning and end of study.

Compliance by traditional pill count method.Compliance by traditional pill count method.

Materials & Methods 2Materials & Methods 2Materials & Methods 2Materials & Methods 2

EFFICACY VARIABLESEFFICACY VARIABLESEFFICACY VARIABLESEFFICACY VARIABLES

PrimaryPrimary Brief Psychiatric Rating Scale Brief Psychiatric Rating Scale

(BPRS)score(BPRS)score

PrimaryPrimary Brief Psychiatric Rating Scale Brief Psychiatric Rating Scale

(BPRS)score(BPRS)score

SecondarySecondary Scale for Assessment of Scale for Assessment of

NegativeNegative

symptoms (SANS) & Positive symptoms (SANS) & Positive Symptoms (SAPS) scoresSymptoms (SAPS) scores

Clinical Global Impression Clinical Global Impression (CGI) rating by physician(CGI) rating by physician

SecondarySecondary Scale for Assessment of Scale for Assessment of

NegativeNegative

symptoms (SANS) & Positive symptoms (SANS) & Positive Symptoms (SAPS) scoresSymptoms (SAPS) scores

Clinical Global Impression Clinical Global Impression (CGI) rating by physician(CGI) rating by physician

TolerabilityTolerability assessed by treatment emergent assessed by treatment emergent adverse events (AE). Abnormal laboratory adverse events (AE). Abnormal laboratory test values also recorded. test values also recorded.

Statistical analysisStatistical analysis of efficacy on modified of efficacy on modified intention-to-treat (subjects with at least 1 intention-to-treat (subjects with at least 1 post-baseline visit) basis.post-baseline visit) basis.

All subjects with single dose intake were All subjects with single dose intake were considered for tolerability analysis.considered for tolerability analysis.

Missing valuesMissing values dealt with by last observation dealt with by last observation carried forward method.carried forward method.

TolerabilityTolerability assessed by treatment emergent assessed by treatment emergent adverse events (AE). Abnormal laboratory adverse events (AE). Abnormal laboratory test values also recorded. test values also recorded.

Statistical analysisStatistical analysis of efficacy on modified of efficacy on modified intention-to-treat (subjects with at least 1 intention-to-treat (subjects with at least 1 post-baseline visit) basis.post-baseline visit) basis.

All subjects with single dose intake were All subjects with single dose intake were considered for tolerability analysis.considered for tolerability analysis.

Missing valuesMissing values dealt with by last observation dealt with by last observation carried forward method.carried forward method.

Materials & Methods 3Materials & Methods 3Materials & Methods 3Materials & Methods 3

Study groups Study groups were were comparable at baselinecomparable at baseline with respect to age, sex, with respect to age, sex, baseline BPRS, SANS & baseline BPRS, SANS & SAPS scores.SAPS scores.

Study groups Study groups were were comparable at baselinecomparable at baseline with respect to age, sex, with respect to age, sex, baseline BPRS, SANS & baseline BPRS, SANS & SAPS scores.SAPS scores.

ResultsResultsResultsResultsInclusion criteriaInclusion criteria• Schizophrenia diagnosed Schizophrenia diagnosed

by DSM –IV TR criteriaby DSM –IV TR criteria• 18-65 years18-65 years• LAR willing to give LAR willing to give

written informed consentwritten informed consent

Exclusion criteriaExclusion criteria• Pregnant & lactating Pregnant & lactating

femalesfemales• Patients with liver, Patients with liver,

kidney, pituitary diseasekidney, pituitary disease• No caregivers at homeNo caregivers at home

Inclusion criteriaInclusion criteria• Schizophrenia diagnosed Schizophrenia diagnosed

by DSM –IV TR criteriaby DSM –IV TR criteria• 18-65 years18-65 years• LAR willing to give LAR willing to give

written informed consentwritten informed consent

Exclusion criteriaExclusion criteria• Pregnant & lactating Pregnant & lactating

femalesfemales• Patients with liver, Patients with liver,

kidney, pituitary diseasekidney, pituitary disease• No caregivers at homeNo caregivers at home

Changes in the BPRS scores during study

Changes in the BPRS scores during study

Time point

Amisulpride (n= 39)

Olanzapine (n=38) p value

Baseline 62.66 ± 5.16 61.21 ± 5.13 NS

At 4 w 56.79 ± 6.07 53.07 ± 6.57 0.012

At 8 w 47.74 ± 6.25 43.57 ± 7.03 0.007

At 12 w 37.65 ± 9.67 33.18 ± 9.44 0.044

Values are as Mean Values are as Mean Standard deviation Standard deviation

Results-EfficacyResults-EfficacyResults-EfficacyResults-Efficacy

SANS Score SAPS ScoreSANS Score SAPS Score

Changes in SANS & SAPS scoresChanges in SANS & SAPS scoresChanges in SANS & SAPS scoresChanges in SANS & SAPS scores

AmisulprideAmisulpride OlanzapineOlanzapine

Overall 76 AEs recorded from 46 subjects - 43 from 27 subjects in Amisulpride arm and 33 from 19 in Olanzapine arm.

Vital signs & laboratory parameters remained in the normal range throughout.

Increased mean body weight in both arms – 3.53 kg with Amisulpride and 4.74 kg with Olanzapine (statistically significant difference).

Other common AEs were tremor (47.5%) & akathisia (17.5%) with Amisulpride and sedation (25%) with Olanzapine.

No Serious Adverse Events reported & no subject withdrew due to AE.

Compliance was excellent in majority (92%).

Overall 76 AEs recorded from 46 subjects - 43 from 27 subjects in Amisulpride arm and 33 from 19 in Olanzapine arm.

Vital signs & laboratory parameters remained in the normal range throughout.

Increased mean body weight in both arms – 3.53 kg with Amisulpride and 4.74 kg with Olanzapine (statistically significant difference).

Other common AEs were tremor (47.5%) & akathisia (17.5%) with Amisulpride and sedation (25%) with Olanzapine.

No Serious Adverse Events reported & no subject withdrew due to AE.

Compliance was excellent in majority (92%).

Results - Adverse events Results - Adverse events Results - Adverse events Results - Adverse events

Both drugs effective in combating the symptoms of disease

Final BPRS score at 12 weeks significantly less for olanzapine than for Amisulpride.

Both SANS and SAPS scores decreased & remained comparable between groups throughout study period.

CGI scale (Physician) scores also remained comparable in both groups throughout

Both treatments well tolerated as evident clinically as well as through laboratory parameters.

Adverse events encountered in 67.5% and 47.5% patients on Amisulpride and Olanzapine respectively

Most mild-moderate and not requiring discontinuation.

Both drugs effective in combating the symptoms of disease

Final BPRS score at 12 weeks significantly less for olanzapine than for Amisulpride.

Both SANS and SAPS scores decreased & remained comparable between groups throughout study period.

CGI scale (Physician) scores also remained comparable in both groups throughout

Both treatments well tolerated as evident clinically as well as through laboratory parameters.

Adverse events encountered in 67.5% and 47.5% patients on Amisulpride and Olanzapine respectively

Most mild-moderate and not requiring discontinuation.

Discussion 1Discussion 1Discussion 1Discussion 1

Results in conformity with 3 Results in conformity with 3 large randomized control trialslarge randomized control trials in Western countries comparing in Western countries comparing Amisulpride and Olanzapine in Amisulpride and Olanzapine in schizophrenia till dateschizophrenia till date

Mortimer A, et al for the SOLIANOL Mortimer A, et al for the SOLIANOL Study Group. A double-blind, Study Group. A double-blind, randomized comparative trial of randomized comparative trial of amisulpride versus olanzapine for 6 amisulpride versus olanzapine for 6 months in the treatment of months in the treatment of schizophrenia. Int Clin schizophrenia. Int Clin Psychopharmacol 2004; 19: 63-9.Psychopharmacol 2004; 19: 63-9.

Haro JM, et al. The SOHO Haro JM, et al. The SOHO (Schizophrenia Outpatient Health (Schizophrenia Outpatient Health Outcome) study: implications for the Outcome) study: implications for the treatment of schizophrenia. CNS Drugs treatment of schizophrenia. CNS Drugs 2006; 20: 293-301.2006; 20: 293-301.

Lecrubier Y, et al. Olanzapine versus Lecrubier Y, et al. Olanzapine versus amisulpride and placebo in the amisulpride and placebo in the treatment of negative symptoms and treatment of negative symptoms and deficit states of chronic schizophrenia. deficit states of chronic schizophrenia. Eur Neuropsychopharmacol 1999; 9: Eur Neuropsychopharmacol 1999; 9: 288-90.288-90.

Results in conformity with 3 Results in conformity with 3 large randomized control trialslarge randomized control trials in Western countries comparing in Western countries comparing Amisulpride and Olanzapine in Amisulpride and Olanzapine in schizophrenia till dateschizophrenia till date

Mortimer A, et al for the SOLIANOL Mortimer A, et al for the SOLIANOL Study Group. A double-blind, Study Group. A double-blind, randomized comparative trial of randomized comparative trial of amisulpride versus olanzapine for 6 amisulpride versus olanzapine for 6 months in the treatment of months in the treatment of schizophrenia. Int Clin schizophrenia. Int Clin Psychopharmacol 2004; 19: 63-9.Psychopharmacol 2004; 19: 63-9.

Haro JM, et al. The SOHO Haro JM, et al. The SOHO (Schizophrenia Outpatient Health (Schizophrenia Outpatient Health Outcome) study: implications for the Outcome) study: implications for the treatment of schizophrenia. CNS Drugs treatment of schizophrenia. CNS Drugs 2006; 20: 293-301.2006; 20: 293-301.

Lecrubier Y, et al. Olanzapine versus Lecrubier Y, et al. Olanzapine versus amisulpride and placebo in the amisulpride and placebo in the treatment of negative symptoms and treatment of negative symptoms and deficit states of chronic schizophrenia. deficit states of chronic schizophrenia. Eur Neuropsychopharmacol 1999; 9: Eur Neuropsychopharmacol 1999; 9: 288-90.288-90.

Discussion 2Discussion 2Discussion 2Discussion 2

Single-blindSingle-blind Relatively short Relatively short

duration (3 m)duration (3 m) Relapse rates not Relapse rates not

assessed.assessed. Serum prolactin Serum prolactin

not measured.not measured.

Single-blindSingle-blind Relatively short Relatively short

duration (3 m)duration (3 m) Relapse rates not Relapse rates not

assessed.assessed. Serum prolactin Serum prolactin

not measured.not measured.

Study limitations Study limitations

Amisulpride comparable to Amisulpride comparable to Olanzapine in Olanzapine in SANS & SAPS SANS & SAPS score reduction & score reduction & tolerability tolerability

Amisulpride comparable to Amisulpride comparable to Olanzapine in Olanzapine in SANS & SAPS SANS & SAPS score reduction & score reduction & tolerability tolerability

ConclusionConclusionConclusionConclusion

Improvement more with Improvement more with Olanzapine inOlanzapine in BPRSBPRS score score reductionreduction

Amisulpride to be a Amisulpride to be a secondary secondary choice in limited extent, choice in limited extent, such as such as to avoid problems like weight to avoid problems like weight gain or excessive sedationgain or excessive sedation