Download Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore

Rajiv Gandhi University of Health Sciences, Karnataka,
Bangalore
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1
Name of the Candidate
and Address
(in block letters)
2
Name of the Institution
3
Course of study and subject
DR. LAKSHMIPATHI B. S.
POST GRADUATE STUDENT IN M.D.,
PHARMACOLOGY
VIMS, BELLARY- 583104
Vijayanagara Institute of Medical Sciences,
Bellary.
M.D. Pharmacology
4
Date of admission to course
23-06-2011
5
Title of the Topic
A comparative study of efficacy, tolerability and
safety profile of Asenapine with Olanzapine in
patients with schizophrenia in a tertiary care
hospital.
6
6.1
NEED FOR THE STUDY:
Schizophrenia is a clinical syndrome of variable, but profoundly disruptive,
psychopathology that involves cognition, emotion, perception and other aspects of
behavior1.Median lifetime prevalence of schizophrenia is about 0.7%–1.0%2.It
causes recurring and progressive episodes of positive and negative symptoms,
disturbed cognitive function and other abnormalities. This disorder is associated
with an increased risk of mortality3, 4and imposes a huge financial burden on
society,5 although with striking differences in the annual cost of care per patient
between and within different countries.6Optimal treatment of the disease could
lessen this burden but it is still challenging to develop effective and safe
antipsychotic drugs7. Although many antipsychotics are currently available, the
response to treatment varies widely.
The lack of efficacy and intolerance in patients with schizophrenia for the older,
conventional antipsychotics, commonly defined as “first-generation”
antipsychotics8, resulted in the introduction of second generation drugs with the
archetype Clozapine. These are now the mainstay of treatment in several countries.
Even after the introduction of second generation antipsychotics, some drugs are
likely to produce certain untoward effects like weight gain, hyperglycemia and
dyslipidemia; drug-related cardiac changes (QTc prolongation) have also been
reported9.
In this direction efforts have been made to find out some drugs which can
have more efficacy and better safety profile. Agents promising in second generation
antipsychotics are being tried. Hence the present study has been planned to
compare the efficacy, tolerability and safety profile of Asenapine, a novel,
sublingual, atypical antipsychotic with Olanzapine, a Thienobenzodiazepine
atypical antipsychotic.
6. 2
REVIEW OF THE LITERATURE:
The immediate goals of acute antipsychotic treatment are the reduction of
agitated, disorganized or hostile behavior, decreasing the impact of hallucinations,
the improvement of organization of thought process and the reduction of social
withdrawl10. Since schizophrenia requires long term treatment, antipsychotic agents
with greater metabolic liabilities especially weight gain should be avoided as first
line therapies 10. Existing typical and atypical antipsychotic medications are
relatively equally effective in treating what are known as the positive symptoms of
schizophrenia, as evidenced by the interpretation of the findings of the governmentfunded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)
study11. Thus, current treatment guidelines do not favour one class of antipsychotic
over the other, rather suggest that “the choice of an antipsychotic medication and its
dose, and subsequent decisions about changes in treatment, require careful initial
consideration and ongoing, shared decision making between the patient and
clinician”12.
Asenapine was initially approved by the US Food and Drug Administration
(FDA) in 2009 for the treatment of acute schizophrenia. Sublingual administration
of Asenapine results in a rapid absorption with peak plasma concentrations within
0.5–1.5 hours and moderate (35%) bioavailability. Oral dosing of Asenapine results
in low bioavailability (<2%) due to first pass metabolism in the gut and the liver13.
Consistent with other atypical antipsychotics, Asenapine exhibits a higher binding
affinity for the 5HT2A receptor compared to D2 receptors. Moreover, Asenapine
exhibits a broad range of effects on other neurotransmitter systems including 5HT2C, 5-HT7, 5-HT2B, 5-HT6, α2B, D3, H1, D4, α1A, α2A, α2C, D2L, D1, D2S,
5-HT1A, 5-HT1B, and H2 receptors14. One major difference between Asenapine
and most other atypical antipsychotics (except Risperidone, Ziprasidone, and
Aripiprazole) is that it exhibits little muscarinic receptor antagonist effects15, which
may produce a less cognitively deleterious profile16, given that D2 receptor
occupancy has been deemed as vital for antipsychotic efficacy 17.
Asenapine appears to have relatively higher potency at serotonin receptors
than at dopamine receptors, including the serotonin HT7 receptor, which has been
studied regarding object discrimination in rats, and may be a therapeutic target for
achieving antidepressant and memory-enhancing actions18.
Olanzapine is a thienobenzodiazepine atypical antipsychotic. And it has
affinity for serotonin, muscarinic, histamine (H1), and adrenergic (α1) receptors as
well as various dopamine receptors. The most frequent adverse effects with
Olanzapine are somnolence and weight gain. Hyperprolactinaemia is also common,
but usually asymptomatic. The antimuscarinic effects of Olanzapine contra-indicate
its use in patients with angle-closure glaucoma; caution is also advised in those
with conditions such as benign prostatic hyperplasia or paralytic ileus19.
.
Different second-generation antipsychotics are associated with differing
effects on glucose and lipid metabolism. While Asenapine has a favourable effect
on glucose and lipid metabolism, studies offer generally consistent evidence that
Olanzapine treatment is associated with an increased risk of diabetes mellitus and
dyslipidaemia20.
6. 3
OBJECTIVES OF THE STUDY:
1. To compare the efficacy of Asenapine with that of Olanzapine.
2. To compare the tolerability and safety profile of Asenapine with those of
Olanzapine.
3. To note the adverse effects of Asenapine if any.
7
MATERIALS & METHODS:
1. Source of data: Patients diagnosed with schizophrenia, according to ICD-10,
attending the outpatient Department of Psychiatry, Vijayanagar Institute of Medical
Sciences, Bellary form the material for our study.
2.
Method of collection: The present study is a prospective, randomized, open
label study. A detailed history of all registered patients will be recorded. A
thorough clinical examination will be done by the qualified psychiatrist for all
patients and so will be the required laboratory investigations. A written/ informed
consent will be taken from all patients before subjecting them to the study. Data
collected will be entered into a specially designed proforma (CRF) for the study.
Efficacy will be measured by Positive And Negative Symptom Scale (PANSS).
Tolerability and safety will be assessed by measuring the incidence and severity of
adverse effects that will be compared with the adverse effect check list prepared for
both the drugs separately. The data collected will be subjected to statistical analysis
using Normal Distribution Test for proportions.
3. Sampling size: The present study will be conducted during the period from
January 2012 to March 2013.One hundred (100) patients will be selected applying
inclusion –exclusion criteria. These patients will be divided randomly into two
groups. One group will be given Tab Asenapine (4-8mg/day) & another group will
be given Tab Olanzapine (2.5-5mg/day). The patients will be given treatment for 6
weeks and will be followed once every two weeks. Periodic psychiatric assessment
will be done at every visit.
4. a)
Inclusion Criteria:
All patients diagnosed with schizophrenia according to ICD-10, in the age
group of 19-60 years (both males and females) will be included in the study.
b) Exclusion Criteria:
1. Patients falling in the age category <19 years and >60 years.
2. Pregnant and lactating mothers.
3. Patients with history of severe cardiac, hepatic and renal diseases.
4. Patients diagnosed with dyslipidemia.
5. Patients with comorbid illnesses like glaucoma, BPH and cancer.
6. Known cases of Pulmonary Tuberculosis, HIV – AIDS, Leprosy.
7. Patients with comorbid major psychiatric illness including intellectual
difficulties and mental retardation.
8. Patients with late onset(onset after 40 yrs age) schizophrenia
9. Treatment resistant schizophrenia
10. Drop out cases will be excluded. [Patients who do not complete 6
weeks of treatment are considered as drop out cases]
Investigations: All the patients included in the study are subjected to the following
investigations.
1.
Baseline / At O week: PANSS(for assessing the efficacy),
Complete blood count, blood glucose levels, serum cholesterol
levels, liver function tests, blood urea & serum creatinine & ECG.
2.
PANSS, Complete blood count, liver enzymes will be repeated at
2nd, 4th & 6th weeks.
3.
Blood glucose levels, serum cholesterol levels & ECG will be
repeated at the end of the study (6th week).
8.
8.
LIST OF REFERENCES:
1.
Kaplan and Sodocks Synopsis of psychiatry. Tenth edition, Page 467.
2.
Saha S, Chant D, Welham J, Mgrath J. A systematic review of
theprevalence of schizophrenia.PLoS Med. 2005;2(5):e141.
3.
Stahl SM. Symptoms and circuits, part 3: schizophrenia. J Clin Psychiatry.
2004;65:8–9.
4.
Seeman MV. Symptoms of schizophrenia: normal adaptations to inability.
Med Hypotheses. 2007;69:253–257.
5.
Wu EQ, Birnbaum HG, Shi L, et al. The economic burden of schizophrenia
in the United States in 2002. J Clin Psychiatry. 2005;66:1122–1129.
6.
Salize HJ, McCabe R, Bullenkamp J, et al. Cost of treatment of
schizophrenia in six European countries. Schizophr Res. 2009;1 11(1–
3):70–77.
7.
Rössler W, Salize HJ, van Os J, Riecher-Rössler A. Size of burden of
schizophrenia and psychotic disorders. EurNeuropsychopharmacol.
2005;15(4):399–409.
8.
Lieberman JA, Stroup TS, McEvoy JP, et al; Clinical Antipsychotic Trials
of Intervention Effectiveness (CATIE) Investigators. Effectiveness of
antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med.
2005;353:1209–1223.
9.
Luft B, Taylor D. A review of atypical antipsychotic drugs versus
conventional medication in schizophrenia. Expert OpinPharmacother.
2006;7(13):1739–1748.
10.
Goodman & Gillman’s, the pharmacological basis of therapeutics, 12th
edition, page 422.
11.
Carpenter WT, Buchanan RW. Lessons to take home
CATIE.PsychiatrServ 2008;59(5):523– 525. [PubMed: 18451009].
12.
Parks J, Radke A, Parker G, Foti ME, Eilers R, Diamond M, et al.
Principles of antipsychotic prescribing for policy makers, circa 2008.
Translating knowledge to promote individualized treatment. Schiz Bull
2009;35(5):931–936.
from
13.
Expert OpinPharmacother. 2010
doi:10.1517/14656566.2010.506188.
August;
11(12):
2107–2115.
14.
Cosi C, Koek W. Agonist, antagonist, and inverse agonist properties of
antipsychotics at human recombinant 5-HT(1A) receptors expressed in
HeLa cells. Eur J Pharmacol 2001;433(1):55–62. [PubMed: 11755134].
15.
Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage
AS, et al. Risperidone compared with new and reference antipsychotic
drugs: in vitro and in vivo receptor binding. Psychopharmacology
1996;124(1–2):57–73. [PubMed: 8935801].
16.
Bishara D, Taylor D. Upcoming agents for the treatment of schizophrenia:
mechanism of action, efficacy and tolerability. Drugs 2008;68(16):2269–
2292. [PubMed: 18973393].
17.
Swerdlow NR, Braff DL, Taaid N, Geyer MA. Assessing the validity of an
animal model of deficient sensorimotor gating in schizophrenic patients.
Arch Gen Psych 1994;51 (2):139–154.
18.
Ballaz SJ, Akil H, Watson SJ. The 5-HT7 receptor: Role in novel object
discrimination and relation to novelty-seeking behavior. Neuroscience.
2007;149(1):192–202. [PubMed].
19.
Martin dale, 36th edition, the complete drug reference page 1013.
20.
Newcomer JW.Department of Psychiatry, Washington University School of
Medicine, St. Louis, Missouri 63110, USA.CNS Drugs. 2005;19 Suppl 1:193.
9
Signature of candidate:
10
Remarks of the guide:
11
Name & Designation of
(in block letters)
DR. K. LAKSHMINARAYANA.
PROFESSOR OF PHARMACOLOGY,
VIJAYANAGAR INSTITUTE OF MEDICAL
SCIENCES, BELLARY.
11.1 Guide
11.2 Signature
DR. SRINIVAS. T. R.
11.3 Co-Guide (if any)
11.4 Signature
11.5 Head of Department
11.6 Signature
12
12.1 Remarks of the
Chairman & Principal
12.2 Signature