Zotepine

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

CLASSIFICATION OF ANTIPSYCHOTICS

TYPICAL OR FIRST GENERATION ANTIPSYCHOTICS (FGA)

Phenothiazines:- Chlorpromazine Thioridazine Trifluperazine Fluphenazine

Butyrophenones:- Haloperidol Droperidol

Thioxanthines:- Flupenthixol Zuclopenthixol

Dibenzoxazepine:- Loxapine

Diphenylbutylpiperidine:- Pimozide

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.8Click for larger picture

NEUROPHYSIOLOGY OF PSYCHOTIC SYMPTOMS

Comparison between FGAs & SGAs

MECHANISM OF ACTION OF ATYPICAL ANTIPSYCHOTICS

SCHIZOPHRENIA

IMPAIRMENTSWORK

RELATIONSHIPSELF CARE

NEGATIVEFEW FEELINGS

LOSS OF

MOTIVATION & INTEREST

EMOTIONAL WITHDRAWL

POSITIVEHALLUCINATION

SDELUSIONSAGITATION

DISORGANISATION

AFFECTIVEDEPRESSION

HOPELESSNESSANXIETY

COGNITIVEIMPAIRED

LEARNING MEMORYFLUENCY

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

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

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

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

ZOTEPINE PHARMACOLOGY

An atypical antipsychotic

Tricyclic substituted Dibenzothiepine drug

Developed by Astellas pharma in Japan 1982

Chemically similar to clozapine and quetiapine

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

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

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

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

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

ZOTEPINE: EFFICACY

SCHIZOPHRENIA HIGH DOSE

Postsynaptic D2 Antagonist

POSITIVE. Excitement /hostility

LOW DOSE

Balance DA Level

NEGATIVE, Cognitive & Depressive

EFFICACY

Positive symptoms of schizophrenia

Schizophrenia in acute exacerbation

Negative symptoms of schizophrenia

Refractory schizophrenia Efficacy against hostility Efficacy against cognitive

symptoms Relapse prevention

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)

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

ADVERSE EFFECTS

Weight Gain is most common

Somnolence is troublesome Extra Pyramidal Symptoms Reduced salivation Hypotension Hyperprolactinemia Constipation Excessive salivation

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

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.

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)

PoisoningECG changesHistory of seizures or lobotomy

Gout and NephrolithiasisNarrow angle glaucoma

Urinary retention, chronic constipation

Obese personElectrolyte disturbances

Warnings and precautions

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

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

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.

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.

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.

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

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

(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

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.

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.

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.

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

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)

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).

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

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

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

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

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

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

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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