zotepine an atypical antipsychotic by anant kumar rathi

1. 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

2. CLASSIFICATION OF
ANTIPSYCHOTICS
TYPICAL OR FIRST GENERATION
ANTIPSYCHOTICS (FGA)
Phenothiazines:- Chlorpromazine
Thioridazine
Trifluperazine
Fluphenazine
Butyrophenones:- Haloperidol
Droperidol
Thioxanthines:- Flupenthixol
Zuclopenthixol
Dibenzoxazepine:- Loxapine
Diphenylbutylpiperidine:- Pimozide

3. 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

4. Fig.8
Click for larger picture
4

5. NEUROPHYSIOLOGY OF PSYCHOTIC
SYMPTOMS

6. Comparison between FGAs &
SGAs

7. MECHANISM OF ACTION OF ATYPICAL ANTIPSYCHOTICS

8. SCHIZOPHRENIA
POSITIVE NEGATIVE
HALLUCINATION FEW FEELINGS
S LOSS OF
DELUSIONS MOTIVATION &
AGITATION INTEREST
DISORGANISATI EMOTIONAL
ON WITHDRAWL
IMPAIRMENTS
WORK
RELATIONSHIP
SELF CARE
COGNITIVE AFFECTIVE
IMPAIRED DEPRESSION
LEARNING HOPELESSNESS
MEMORY ANXIETY
FLUENCY

9. 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

10.  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

11. Treatment options for
schizophrenia
1st Generation Antipsychotics
Post synaptic D2 blockade
D2 blockade
D2 blockade in in
in
Nigrostriatal Tuberoinfundi
Mesolimbic
bular pathway
area pathway
Results in
adverse effects
Results in as
Alleviates
adverse hyper
positive
effects as prolactinemia,
symptoms galactorrhea
EPS
Menstrual

12. 2nd Generation Antipsychotics
Bind to
serotonin Less affinity
5HT-2A Less affinity Less affinity
to D2
to D2 to D2
receptor, receptor in
receptor in receptor in
Less Tuberoinfun
Mesocortica Nigrostriatal
affinity to dibular
l pathway pathway
D2 pathway
receptor
Lower
Alleviates propensity Lower
Lower
positive to cause propensity
propensity
negative negative to cause
cognitive to cause
and hyperprola
symptoms EPS
cognitive ctinemia

13. ZOTEPINE PHARMACOLOGY
 An atypical
antipsychotic
 Tricyclic substituted
Dibenzothiepine
drug
 Developed by
Astellas pharma in
Japan 1982
 Chemically similar to
clozapine and
quetiapine

14. 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

15. Pharmacokinetics
 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

16. 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

17. Pharmacodynamics
 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

19. 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

20. ZOTEPINE: EFFICACY
Postsynaptic D2
Antagonist
POSITIVE. Excitement
/hostility
LOW
DOS SCHIZOPHRENIA HIGH
DOS
E E
NEGATIVE, Cognitive &
Depressive
Balance DA
Level

21. EFFICACY
 Positive symptoms of
schizophrenia
 Schizophrenia in acute
exacerbation
 Negative symptoms of
schizophrenia
 Refractory schizophrenia
 Efficacy against hostility
 Efficacy against cognitive
symptoms
 Relapse prevention

22. 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)

23. 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

24. ADVERSE EFFECTS
 Weight Gain is most
common
 Somnolence is troublesome
 Extra Pyramidal Symptoms
 Reduced salivation
 Hypotension
 Hyperprolactinemia
 Constipation
 Excessive salivation

25. ADVERSE EFFECTS RARE BUT
SERIOUS
 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

26. 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.

27. 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)

28. Warnings and precautions
Poisoning
ECG changes
History of seizures or lobotomy
Gout and Nephrolithiasis
Narrow angle glaucoma
Urinary retention, chronic constipation
Obese person
Electrolyte disturbances

29. 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

30. 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

31. 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.

32. 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.

33. 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.

34. 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

35. 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

36. ASIAN STUDY: POSITIVE SYMPTOM
SCHIZOPHRENIA, Adverse effects
 (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%)

37. 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.

38. 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.

39. 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.

40. 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)

41. 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)

42. 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).

43. 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
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
Akathisia 7 25 29 25

44. 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 0 4 0 0
disturbance
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

45. ADVERSE EFFECTS: ZOTEPINE vs HPL
(Riedel et al, Expert Opin Drug Saf 2010)

46. What constitute an ideal
Antipsychotic
Mood-stabilizing
Efficacious for properties
Positive & negative Low EPS, TD
symptoms
Cognitive benefits Ideal Weight Neutral
Antipsychotic
Improved No adverse
Function and Long-term health
Quality of life Consequences
Affordable

47. 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

48. 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

49. 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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