SECOND GENERATION ANTIPSYCHOTICS

CHAIR PERSONS: PROF.Dr.V.GEETHANJALI, M.D(PSY) DCH

ASST.PROF.DR.G.AMUDHA, M.D.(PSY) DCH

ATYPICAL ANTIPSYCHOTICS

Low EPS good for negative symptoms Serotonin-dopamine antagonist D2 antagonist with rapid dissociation. D2 Partial agonist Serotonin partial agonist at 5HT1A receptor

The Mesolimbic Dopamine Hypothesis of Positive Symptoms of Schizophrenia

Mesocortical Pathway to VMPFC

negative symptom s affective symptom s

The Mesocortical Dopamine Hypothesis of Cognitive, Negative, and Affective Symptoms of Schizophrenia

What makes an antipsychotic atypical?

D2 antagonism and anticholinergic agents

5HT1A autoreceptors

Atypical antipsychotics and prolactin

Dopamine receptor output

Histamine H1 Combined with Serotonin 2C Antagonism May Stimulate Appetite

CLASSIFICATION
Dibenzodiazepines

Clozapine

Substituted Benzamides Amisulpride

Sulpride

Benzisoxazoles Iloperidone

Paliperidone
Risiperidone

Benzisothiazolyl

ziprasidone

CLASSIFICATION
Thienobenzodiazepine

Olanzapine

Dibenzothiazepine

Quetiapine

Partial Agonists Aripiprazole

Bifeprunox

Dibenzothiepin Zotepine

Dibenzooxepinopyrrole Asenapine

RISPERIDONE

Benzisoxizole derivative Bio-availability 70% 9-hydroxy risperidone half life 3-20 hrs 5-HT 2A ,D2,-1, -2,H1 antagonism Weak affinity 5-HT 1C ,5-HT 1D Metabolised by CYP 2D6

Therapeutic Ind-R

Acute psychosis Maintenance treatment Sczh. Bipolar mania Autism PTST Treatment resistant depression Bor.PD Lesch-Nyhan syndrome

Therapeutic Ind-R

Treatment refractory OCD Tourettes syndrome Conduct disorder MR with beh.prob.(.01-.06 mg/kg/day) AIDS related dementia Drug induced psychosis (.25-3 mg/day) Huntingtons disease

DOSAGE-R

Starting dose 0.5-1mg b.d Increase by 0.5-2mg b.d on days 2 and 3,with
further dose increases thereafter by 0.5-1mg

Sczh. - adult 8mg/day, adolescents-3mg/day Bipolar mania adult-6mg/day , adolescents2.5mg/day

Autism- < 20kg -.25mg/day, >20kg-0.5mg/day

R-CYP 2D6

Fluoxetine,Paroxetine,Bupropion,Quinidine CBZ, Phenytoin, Phenobarbital, Valproate by 20%

RISPERIDONE SIDE EFFECTS

Elderly patient - risk CVA Neuroleptic Malignant Syndrome Tardive dyskinesia D2 blockade in basal ganglia 12% wt. gain Diabetes Mellitus Orthostatic hypertension and syncope sedation., somnolence Hyperprolactinemia Erectile dysfunction

R- SPL. GROUP
Pregnancy category C 3% congenital malformation 16% spontaneous abortion Perinatal syndrome tremor , EPS, irritability,
somnolence, feeding problems

Lactation 2-4% of maternal dose Infertility -sperm motility in adults Pituitary gland adenoma, mammary gland

adenocarcinoma , pancreas adenoma-prolactin

DOSE RANGE -R
2-8 mg/day max.16mg Available 1,2,3,4mg tablets
1mg/ml oral solution

Long acting risperidone microspheres-I.M. aqueous

suspension glycolic acid lactate polymer

Drug release commences 3 weeks after inj. No test dose required Available dose 25,37.5 ,50mg every 2 weeks
3,6,>6 mg oral dose

Not suitable for treatment refractory Sczh.

PALIPERIDONE

Major active metabolite of Risperidone Shares Risperidone receptor profile Pressure based osmotic release oral system Gradual release without peak Initiation without titration No significant hepatic metabolism Fewer drug interaction

P-PHARMACOLOGY

P-extended release t - 23 hrs CYP 2D6 ,CYP 3A4 P 450 isoenzyme -not an inhibitor or inducer

P-INDICATION

Schizophrenia acute and maintenance

treatment

sleep architecture -stage 2 ,REM,SEI

P-ADVERSE REACTION

QT prolongation 12 msecs 7 % wt. gain Elderly - risk CVA NMS, TD DM Prolactin

P-DOSAGE
Extended Release 3,6,9 mg tablets Starting dose 6mg/day Titration once in 2-3 days Maximum 12mg/day Paliperidone palmitate long acting inj.

plasma level within a day max.13 days

no oral supplementation
no test dose no cold storage

bioavailability- 28 %

P-DOSE AND ADMINISTRATION Day 1 150 mg i.m deltoid

Day 8

100mg i.m

deltoid

Every month 50-150mg i.m.

Deltoid or gluteal

ILOPERIDONE

SDA antagonist 1 antagonism hypotension Treatment of schz.,PCP induced psychosis Oral dose 20 -24 mg/day

CLOZAPINE

Dibenzodiazepine Only oral preparation Absorption peak plasma level 2hrs t - 12hrs Bioavailabilty 27-47% - 1st pass metab. N-desmethyl clozapine metabolite M 1 agonist ( cognition)

Clozapine

CLOZAPINE

Stronger 5-HT2 blockade, D1,D3,D4, 1 Less D2 antagonist (40- 50 % occupancy)

fast dissociation

Plasma conc. 10-20 ml/mg/kg

C-INDICATION
Treatment resistant Schiz. Suicidal behaviour,hostile,aggresion Severe TD ( spares striatal D2 receptors) Schiz. + substance abuse Treatment resistant Mania Severe psychotic depression Huntingtons disease, Idiopathic Parkinsons
disease

Treatment resistant autism, OCD Polydipsia hyponatremia syndrome

C- SIDE EFFECTS
Most common sedation HR (vagolytic property of drug)
>25 beats /min >300mg /day dose

QT interval
Reversible non specific ST,T wave flatting or inversion

Idiopathic myocarditis (first 6 weeks), ventricular

arrythmias

Blurring, dry mouth, constipation (Muscarinic

Antagonist)

C- SIDE EFFECTS

Sialorrhea Clonidine 0.1-0.2mg Amitriptyline useful Wt. gain 4kg Seizures > 600mg dose
4 % risk Add Sodium valproate/opiramate/Gabapentin No CBZ - precipitate neutropenia

C- SIDE EFFECTS
Agranulocytosis 0.7 % First 3 months
Before therapy WBC > 3500

6months weekly monitoring 6-12 months every 2weeks monitoring Then every 4 weeks monitoring If Pt.s WBC < 3000, Neutro < 1500 stop CLZ. Total Eosinophils > 4000 discontinue CLZ.

C-C.I.

WBC < 3500 cells/cu.mm BM disorder Previous h/o agranulocytosis with CLZ
treatment

CBZ co-drug Pregnancy Cat.B drug Excreted in breast milk should not feed Discontinuing CLZ
Cholinergic rebound taper 2-4 weeks

C-DRUG INTERACTION

CYP 1A2, 2D6, 3A4 CLOZAPINE

Fluoxetine Fluvoxamine Dupropion, TCA Caffeine Erythromycin Ciprofloxacin

C-DRUG INTERACTION

Clozapine

Lithium ppt. seizure,NMS Paroxetine - neutropenia

Nicotine CBZ Phenytoin Rifampicin

C-DOSE

Available 25,100mg Initial dose -12.5mg twice daily once 2-3 days max. 300mg Maintenance 150- 450 mg/day Titration
2nd day -50mg Daily 25-50mg till 300-450mg Then twice weekly

Max. dose 900 mg/day

OLANZAPINE

Thienobenzodiazepine Thieno ring substituted for clozapine,

carbonyl ring

Peak level 6hrs t -31 hrs I.M. onset within 45 mins. 5HT2A/2C antagonist 5HT6,5HT3,D1D4 ,1, H1,M1

64-84% D2 occupancy

OLANZAPINE
Metabolie CYP 1A2 Olanz.

Fluvoxamine Ciprofloxacin Ethanaol

Olanz.
Nicotine CBZ

Modafinil
Omeprazole

Bld. Conc. >23ng/ml -favourable

O-INDICATIONS

Acute Schz.- calming effect Maintenance treatment in Schz. Monotherapy Mania & mixed Agitation in Bipolar Mania & Schz. Adju.SSRI for PTSD Tourettes syndrome Dementia & Psychosis Anorexia Nervosa, Autism

O-DOSAGE

Available 2.5,5,7.5,10,15,20 mg tablets 5,10,15 mg orally disintegrating tablets Starting dose 5-10mg/day Maintenance -10-20 mg/day Titration
5mg once a day At intervals of once in 5 days

Max. dose 30mg/day I.M. 2.5 - 10 mg repeat every 2 hrs till

agitation settle down

O-SIDE EFFECTS

Wt. gain - > 7% TGL > 500mg/dl Hyperglycemia,DM,Insulin resistance

within 6 months

SGOT > 3 times Dry mouth,dizziness,somnolence,constipation EPS & dose related

O-HIGH RISK

Pregnancy
Cat. C drug LBW Gestational DM

Lactation 1% maternal dose

QUETIAPINE

Dibenzothiazepine Peak 1-2 hrs t - 6hrs ,steady state level 48hrs Potent 5-HT2 blocker(72%), H1, 1, 2 Low affinity for D1,D2(44%),D4,M1 Fast dissociation

Q-INDICATIONS

Schz. acute and maintenance Bipolar I &II Depressive episode

(acute & continued treatment)

Bipolar l Manic- acute treatment Psychosis in Parkinsons disease

Insomnia
Sleep induction H1 blockade Sleep maintenance 5HT2A antagonist

Q-ADVERSE EFFECTS

Orthostatic hypertension Cataract Fluctuation in T4 level -20% SGOT Sedation,Somnolence,Suicidal ideation Wt. gain, Hypertriglyceridemia Less EPS

Q-HIGH RISK GROUPS

Pregnancy Cat. C drug LBW Safe to use in pregnancy Lactation 0.09% of maternal dose

Q-DOSAGE

Starting dose 25mg twice a day Maintenance 200-800mg/day Max. 800mg/day Titration
25 mg b.d D1 100 mg D2 400 mg D4 Further increase of 50mg b.d. every 2 days

Q-DOSAGE
Mania
D1-100 D8- 800 mg/day

Depression
D1- 50mg D2- 100mg D3- 200mg D4- 300mg

Quetiapine extended release

Once daily at bed time initial 300mg

Q-INTERACTION

CYP 3A4 Quetiapine

Nefazodone Erythromycin Ketoconazole Protease inhibitor

Quetiapine
CBZ Phenytoin modafenil

Q-INTERACTION

No dose adjustment
Lithium Lorazepam Fluoxetine Risperidone Haloperidol Imipramine

ZIPRASIDONE

Benzisothiazolyl piperazine Peak plasma level 6-8hrs t - 5-10 hrs After I.M. inj.
Peak 1hr t - 2-5 hrs

Z-MECH.OF ACTION

5 HT 2 A : D 2 Antagonist
(11 : 1)

D1,D3,D4 Antagonist Agonist 5HT1A, antagonist 5HT2C, 5HT1D Affects NE, Serotonin uptake sites

Z-INDICATIONS

Schz. 1. Acute episodes 2. Preventing relapses 3. Acute agitation

Z- ADVERSE REACTIONS

QT prolongation
(4.7-1.4 msec in 120 mg/day)

Dont

administer in Pts. Taking

CPZ Thioridazine Gatifloxacin, Moxifloxacin Guinidine Tacrolimus

Z- DRUG INTERACTION

CYP 3A4 Ziprasidone

Ketoconazole Erythromycin Protease inhibitor

Ziprasidone
CBZ Phenytoin Modafinil

Z-DOSAGE
Available 20,40,60,80 mg capsules I.M. Inj. 20 mg/ ml vial Starting dose 20mg twice a day with food Maintenance 20-80 mg B.D Titration once in 2 days Maximum 80 mg B.D. I.M. inj.

Titration

10 mg once in 2 hrs 20 mg once in 4 hrs

Max. 40 mg/day for 3 days

ZOTEPINE

SDA antagonist 5HT2C,H1 antagonist wt. gain

1 antagonist sedation
5HT2C,NRI efficacy for mood symptoms Perospirone,sertindole - STA antagonist - QTc prolongation

Loxapine atypical at low doses

- metabolite Amoxapine (NARI) effective as antidepressant

ASENAPINE

Antipsychotic with antidepressant action
Serotonin,Dopamine antagonist 5HT1A partial agonist 5HT2C antagonist release DA,NE in prefrontal cortex - antidepressant effect Half life 24 hrs Dose 5mg S/L twice daily Max. dose 10mg twice daily

ARIPIPRAZOLE

Quinoline derivative Peak plasma conc. 3-5hrs t - 75 hrs Metabolite dehydroaripiprazole t 1/2 Bioavailability 87% Steady state plasma conc. 14 days Metabolised by CYP 3A4, 2B6

96 hrs

ARIPIPRAZOLE

Partial agonist D2 receptor 5HT1A partial agonist 5HT2A/2C ,D3,H1 antagonist

A-DOSAGE

Starting dose 10 -15 mg OD

Maintenance dose 10-30 mg/day

Titration- should not be made before 2
weeks

Max . Dose 30mg/day

A- DRUG INTERACTION

CYP 2D6, 3A4 Arpiprazole

Quinidine SSRI Erythromycin Protease inhibitor

Arpiprazole
CBZ Phenytoin

A-INDICATIONS

Schizophrenia acute & maintenance

treatment

Adolescents started at 2mg max.10mg Bipolar disorder Adjunctive treatment for depression I.M. dose for agitation

A-DOSAGE

Available - 5,10,15,20,30 mg tabs. I.M. 9.75 mg effective in 45 mins.

A-ADVERSE EFFECTS

Akathisia like-activation Insomnia seizures

AMISULPRIDE

Substituted Benzamide Partial agonist at D2 receptor High affinity for presynaptic D2,D3 receptor

AMISULPRIDE -ADVANTAGES
Lacks affinity for D1 negative symptoms
improvement

No affinity for 5HT2A/1A- low EPS Function as D partial agonist at low doses D2 antagonist at high doses

AMISULPRIDE -DISADVANTAGES

QTc prolongation Prolactin Wt. gain

AMISULPRIDE - DOSE

Available dose 50,100,200 mg tabs. Dose range 200-1000 mg/day Maintenance 400mg/day

SULPRIDE

At low dose function as atypical antipsychotic At high dose function as typical antipsychotic

BIFEPRUNOX

DPA + SPA agonist Full agonist than Aripiprazole- nausea & vomiting Efficacy - +ve symptoms of Schz., Mania