zotepine
DESCRIPTION
zotepine an atypical antipsychotic by anant kumar rathiTRANSCRIPT
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ZOTEPINE IN PSYCHIATRIC DISORDERS
PRESENTOR
DR. ANANT KUMAR RATHI
1st YEAR RESIDENT
GUIDE
DR. D. K. SHARMA
PROF. & HEAD, DEPTT. OF PSYCHIATRY
GOVT. MEDICAL COLLEGE & M.B.S. HOSPITAL, KOTA
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CLASSIFICATION OF ANTIPSYCHOTICS
TYPICAL OR FIRST GENERATION ANTIPSYCHOTICS (FGA)
Phenothiazines:- Chlorpromazine Thioridazine Trifluperazine Fluphenazine
Butyrophenones:- Haloperidol Droperidol
Thioxanthines:- Flupenthixol Zuclopenthixol
Dibenzoxazepine:- Loxapine
Diphenylbutylpiperidine:- Pimozide
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CLASSIFICATION OF ANTIPSYCHOTICS
ATYPICAL OR SECOND GENERATION ANTIPSYCHOTICS (SGA)
Dibenzodiazepine:- Clozapine Thienobenzodiazepine:- Olanzapine Dibenzothiazepine:- Quetiapine Benzisoxazole:- Resperidone Benzisothiazolyl:- Ziprasidone Aripiperidylindole:- Aripiprazole Benzamide:- Amisulpride Levosulpride Dibenzothiepine:- Zotepine
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4
Fig.8Click for larger picture
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NEUROPHYSIOLOGY OF PSYCHOTIC SYMPTOMS
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Comparison between FGAs & SGAs
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MECHANISM OF ACTION OF ATYPICAL ANTIPSYCHOTICS
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SCHIZOPHRENIA
IMPAIRMENTSWORK
RELATIONSHIPSELF CARE
NEGATIVEFEW FEELINGS
LOSS OF
MOTIVATION & INTEREST
EMOTIONAL WITHDRAWL
POSITIVEHALLUCINATION
SDELUSIONSAGITATION
DISORGANISATION
AFFECTIVEDEPRESSION
HOPELESSNESSANXIETY
COGNITIVEIMPAIRED
LEARNING MEMORYFLUENCY
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SCHIZOPHRENIA - lMPACT
A major psychotic disorder Currently conceptualized as a broad
syndrome Functionally and socially debilitating
chronic illness Constant 1% worldwide life time
incidence 10% suicide rate Strong genetic component
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Abnormality of brain neurochemistry neuroanatomy and development
Mesolimbic overactivity of dopamine produce positive symptoms
Mesocortical underactivity of dopamine and serotonin produce negative and cognitive symptoms
Hypofrontality related to serotonin transmission is associated with negative symptoms
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Treatment options for schizophrenia
1st Generation Antipsychotics
Post synaptic
D2 blockade
in Mesolimbic
area
D2 blockade in
Tuberoinfundibular
pathway
Alleviates positive
symptoms
Results in adverse
effects as hyper
prolactinemia,
galactorrheaMenstrual
disturbances
D2 blockade
in
Nigrostriatal
pathway
Results in adverse
effects as EPS
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2nd Generation Antipsychotics
Bind to serotonin 5HT-2A
receptor,Less
affinity to D2
receptor
Alleviates positive negative cognitive
symptoms
Less affinity to
D2 receptor in
Tuberoinfundibular pathway
Lower propensit
y to cause
hyperprolactinemi
a
Less affinity to
D2 receptor in Mesocortic
al pathway
Lower propensit
y to cause EPS
Less affinity to
D2 receptor in
Nigrostriat
al pathway
Lower propensity to cause negative
and cognitive deficits
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ZOTEPINE PHARMACOLOGY
An atypical antipsychotic
Tricyclic substituted Dibenzothiepine drug
Developed by Astellas pharma in Japan 1982
Chemically similar to clozapine and quetiapine
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Pharmacokinetics
Only oral formulation available
Well absorbed in GI Tract Bioavailability is 7 to 13% due
to extensive first pass hepatic biotransformation
Peak plasma conc. within 1 to 4 hrs.
Plasma protein binding is 97% Half life is 15 to 24 hrs Steady state conc. reach in 4
days
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Major metabolic route is N-demethylation by Cyt-p450 isozyme 3A2 to norzotepine
Norzotepine also has about 30-40% activity of parent compound
Eliminated in bile and faeces
Pharmacokinetics
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Pharmacodynamics
Zotepine blocks D1&D2 receptors Implication:- Antipsychotic activity Extra Pyramidal Symptoms Raise serum prolactin Zotepine blocks 5HT2a, 5HT2c, 5HT6, 5HT7 receptors Implication:- Improved cognition, reduced anxiety, Increased sleep & appetite, weight gain Zotepine blocks 5HT receptors more potently than DA
receptors Implication:- Explain its atypical behaviour
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Zotepine blocks H1 histaminic receptors Implication:- Increased sleep & appetite, weight
gain Zotepine blocks alpha adrenergic receptors Implication:- Postural hypotension, dizziness Zotepine blocks M1 cholinergic receptors weakly Implication:- Less anticholinergic adverse effect Zotepine inhibits nor epinephrine reuptake Implication:- Efficacy against depressive
negative & cognitive symptoms
Pharmacodynamics
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Unique pharmacological profile of Zotepine
At low doses (75-150mg/day) it increases dopaminergic transmission
Implication:- Improves negative and cognitive deficits
At high doses (150-300mg/day) it inhibits dopaminergic transmission
Implication:- Improves positive symptoms Inhibits nor epinephrine reuptake Implication:- Improves affective and cognitive
symptoms
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ZOTEPINE: EFFICACY
SCHIZOPHRENIA HIGH DOSE
Postsynaptic D2 Antagonist
POSITIVE. Excitement /hostility
LOW DOSE
Balance DA Level
NEGATIVE, Cognitive & Depressive
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EFFICACY
Positive symptoms of schizophrenia
Schizophrenia in acute exacerbation
Negative symptoms of schizophrenia
Refractory schizophrenia Efficacy against hostility Efficacy against cognitive
symptoms Relapse prevention
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SCREENING
Weight, Blood Pressure, Fasting blood sugar, Lipid profile
Get personal & family history of diabetes, hypertension, cardiovascular disease, smoking
Refer such pt. for nutrition, weight management and medical management
Whether taking agents that prolong QT Risk of electrolyte disturbances (on
diuretics)
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DOSING
For negative symptoms schizophrenia Started in 25 mg t.d.s doses Gradually can be increased up to total of 150 mg/day For positive symptoms schizophrenia Started in 50 mg t.d.s doses Gradually can be increased up to total of 300 mg/day For critically ill patient it can be used upto450 mg/day
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ADVERSE EFFECTS
Weight Gain is most common
Somnolence is troublesome Extra Pyramidal Symptoms Reduced salivation Hypotension Hyperprolactinemia Constipation Excessive salivation
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ECG changes:- QT prolongation, torsades de pointes (dose dependant)
Seizures:- Dose related proconvulsive effect Paralysis of intestine:- anorexia, nausea,
vomiting, severe constipation, abdominal fullness or flaccidity
Neuroleptic Malignant Syndrome:- Fever, muscular rigidity, akinetic mutism, autonomic hyperactivity
ADVERSE EFFECTS RARE BUT SERIOUS
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Drug interactions
Serious fall in blood pressure occur when co administered with adrenaline
Additive antihypertensive effect with antiHTNs Additive sedation with CNS depressants as
BZDs, barbiturates, anesthetics including alcohol
Additive anticholinergic action with anticholinergics, TCAs, antiparkinsons drugs
Antagonize the effect of dopaminergic agents Combined use of Phenothiazines may increase
risk of seizures Fluoxetine and Diazepam increase plasma
conc. Of zotepine.
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Warnings and precautions
Avoid in patients with:- Coma and Circulatory collapse Encephalitis, Brain tumors, Head injury Hepatic & Hematological disorder
Exposed to high environmental temperature Engaged in activities requiring alertness
Terfenadine or Astemizole (QT Prolongation)
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PoisoningECG changesHistory of seizures or lobotomy
Gout and NephrolithiasisNarrow angle glaucoma
Urinary retention, chronic constipation
Obese personElectrolyte disturbances
Warnings and precautions
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USE IN SPECIAL POPULATION RENAL IMPAIRMENT:- Start 25 mg b.d, up
to max. of 75 mg b.d HEPATIC IMPAIRMENT:- Start 25 mg b.d,
up to max. of 75 mg b.d, monitor LFTs CARDIAC IMPAIRMENT:- Used cautiously
specially if on antiarrhythmics or drugs causing bradycardia, hypokalemia
Elderly:- Start 25 mg b.d, up to max. of 75 mg b.d
Children:- Not recommended under age of 18
Pregnancy & Breast feeding:- Not recommended
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Over dosage:
CNS Depression from somnolence to coma
Low BP EPS occurs Restlessness, agitation Convulsions Abnormal ECG, arrhythmia Management:- No specific antidote Symptomatic and
maintenance therapies recommended
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PREDICTION OF EFFICACY (Lin et al, J Clin Psychiatry 2007)
135 acutely ill DSM-IV schizophrenics in Taiwan.
Zotepine 150 mg/day for 4 weeks. 35 drop outs due to inefficacy, adverse
effects, or withdrawal of consent. Response rate was 78% in the 100
completers. Response defined as 20% decrease in
BPRS. Improvement in BPRS at weeks 1 and 2
each predicted 4-week response.
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ACUTE EXACERBATION OF SCHIZOPHRENIA: Efficacy outcomes
(Petit et al, Psychopharmacol Bull 1996)
8-week study in 13 French centers Zotepine (150-300 mg/day; n=63) HPL (10-20 mg/day; n=63) BPRS, CGI-I, CGI-S outcomes: no
differences between groups. SANS improvement: Zotepine > HPL. Improvement curves: Max during weeks 1-
2; more gradual, thereafter.
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ACUTE EXACERBATION OF SCHIZOPHRENIA: Adverse effects
(Petit et al, Psychopharmacol Bull 1996)
AIMS, Simpson-Angus scores decreased with zotepine, increased with HPL (significant for latter)
No akathisia with zotepine. Weight change: Zotepine, +2.3 kg; HPL, -
0.8 kg Pulse raised by 5 bmp with zotepine, nil
with HPL No changes in blood pressure Uric acid levels significantly decreased
with zotepine but not with HPL.
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OPEN-LABEL, 6-WEEK, 7-CENTER, INDIAN RCT
238 young adults with DSM-IV schizophrenia
Zotepine 25 mg tid vs HPL 5 mg bd
Zotepine vs HPL: PANSS +vs s/s improvement, 49% vs 45% PANSS –ve s/s improvement, 42% vs 41% Virtually identical improvement in CGI-S,
CGI-I
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ASIAN STUDY: POSITIVE SYMPTOM SCHIZOPHRENIA, Efficacy outcomes
(Hwang et al, J Formos Med Assoc 2001)
6-week study in 2 Taiwanese centers ICD-10 schizophrenia (n=70; mostly
chronic) 17 drop outs, similar between groups Zotepine 150 mg/day vs HPL 9 mg/day Efficacy on PANSS, BPRS, CGI:
Zotepine=HPL 20% and 30% response rates:
Zotepine=HPL
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(Hwang et al, J Formos Med Assoc 2001)
No dystonia with zotepine EPS: Zotepine < HPL Weight gain: Zotepine +2.6 kg; HPL +0.4
kg Heart rate increased with zotepine Zotepine adverse effects: Dizziness (38%),
sedation (32%), dry mouth (29%), constipation (20%), increased salivation (18%)
ASIAN STUDY: POSITIVE SYMPTOM SCHIZOPHRENIA, Adverse effects
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EFFICACY AGAINST HOSTILITY (Briken et al, Schiz Res 2002)
Open-label RCT in ICD-10 schizophrenia, schizoaffective disorder (n=69) Zotepine 50-275 (mean 150) mg/day Olanzapine 2.5-20 (mean, 12) mg/day Risperidone 1-8 (mean, 4) mg/day
Zotepine > risperidone on BPRS measures of hostility (olanzapine efficacy was in between).
Benefits persisted after controlling for sedation and improvement in positive symptoms.
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EFFICACY AGAINST NEGATIVE SYMPTOMS
(Fleischhacker et al, Pharmacopsychiatry 1987)
10 chronic schizophrenics with –ve symptoms
Zotepine 50-200 mg/day for 8 weeks Significant decrease in SANS No increase in positive symptoms 1 patient had +ve symptom relapse at 3
weeks 2 more patients relapsed during
maintenance treatment.
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NEGATIVE SYMPTOMS, NEGATIVE STUDY
(Moller et al, Pharmacopsychiatry 2004)
80 schizophrenic with stable negative symptoms
Zotepine 25-225 mg/day (mean, 130) vs placebo
8-week study Zotepine not significantly superior to
placebo on PANSS (positive, negative, general psychopathology subscales), CGI, MADRS, EPS measures.
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RELAPSE PREVENTION(Cooper et al, Psychopharmacol Berl 2000)
119 patients with chronic, DSM-IIIR schizophrenia
Zotepine 150-300 mg/day vs placebo for 26 weeks
Drop out due to adverse events, 26% vs 7%
Estimated 26-week relapse rate, 9% vs 53% (HR, 0.16; 95% CI, 0.05-0.48)
SANS scores did not improve, placebo-level EPS
Uric acid levels decreased by 43% with zotepine (unchanged with placebo)
Weight change, zotepine +3.9 kg; placebo -0.7 kg
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REFRACTORY SCHIZOPHRENIA
45 patients with treatment-resistant schizophrenia
Zotepine 137-299 mg/day in monotherapy or as add-on therapy (maintenance dose, 231 mg/day)
BPRS decreased from week 2 to week 12 in 29 of 35 evaluable patients.
Better outcomes in younger and catatonic patients, and in those with acute exacerbation and shorter illness duration
Harada et al (Fortschr Neurol Psychiatr 1991)
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EFFICACY: OTHER INDICATIONS
Zotepine (12.5-150 mg/day) was effective against Behavioral and Psychological Symptoms of Dementia (BPSD) in a open study of 24 patients (Rainer et al, CNS Drugs 2004)
Zotepine is effective against Mania as monotherapy (Amann et al, Bipolar Disord 2005) or in combination with a mood stabilizer (Chan et al, Psychiatry Clin Neurosci 2010).
Zotepine reduced Chorea in one patient with Huntington’s disease (Bonelli et al, Human Psychopharmacol 2003).
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Side Effect Week 1 Week 2
Week 3
Week 4
Difficulty in concentration 7 11 7 7
Asthenia 7 14 14 25
Sleepiness 36 29 29 29
Falling memory 7 4 4 7
Tension 4 7 7 11
Dystonia 4 7 4 4
Rigidity 0 4 11 18
Hypokinesia 7 14 14 29
Tremor 7 14 18 18
ADVERSE EFFECTS (UKU scale) (Kondo et al, Ther Drug Monitor 1994)
Akathisia 7 25 29 25
Incidence % of adverse effect of Zotepine in 28 patients
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ADVERSE EFFECTS (UKU scale) (Kondo et al, Ther Drug Monitor 1994)
Incidence % of adverse effect of Zotepine in 28 patients
Side Effect Week 1
Week 2 Week 3 Week 4
Accommodation disturbance
0 4 0 0
Increase salivation 4 14 4 7
Reduced salivation 43 32 29 29
Constipation 29 43 46 39
Orthostatic dizziness
21 7 4 4
Headache 7 0 4 4
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ADVERSE EFFECTS: ZOTEPINE vs HPL(Riedel et al, Expert Opin Drug Saf 2010)
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What constitute an ideal Antipsychotic
Ideal
Antipsychotic
Mood-stabilizingproperties
Low EPS, TD
Weight Neutral
No adverseLong-term healthConsequences
Affordable
Efficacious for Positive & negativesymptoms
Cognitive benefits
Improved Function andQuality of life
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TO SUMMARISE
1st discovered in Japan Initially studied in Asian countries Only few studies available Tricyclic Dibenzothiepine molecule Receptor profile:- Dopaminergic blockade(D2&D3 >
D1&D4) Serotonergic
Blockade( 5HT2A&5HT2C) Inhibit reuptake of norepinephrine All leading to improvement in positive,
negative as well as cognitive symptoms and less
EPS
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TO SUMMARISE
As per studies available, it is effective in Acute exacerbation of schizophrenia
Refractory schizophrenia Relapse prevention
Side Effects:- Weight gain, sedation, dry mouth, EPS, Constipation, hyperprolactinemia
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PROS & CONS
POTENTIAL ADVANTAGES:- Controlling positive, negative, affective as well as cognitive symptoms
POTENTIAL DISADVANTAGES:- lack of studies Not FDA approved
Frequent dosing Seizure potential Slow onset of action
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