Atypical Antipsychotics

DR.MURUGAVEL.VJunior resident

Institute of Mental HealthChennai

’30s ’40s ’50s ’60s ’70s ’80s ‘90 s ’00s

ECT

Chlorpromazine

Haloperidol FluphenazineThioridazine

LoxapinePerphenazine

Second-generationantipsychotics

ClozapineRisperidone OlanzapineQuetiapineZiprasidone

Aripiprazole Next-generation

The history of antipsychotic drug development

The history of antipsychotic drug development

• Often based on chance findings that bear little relationship to the intellectual background driving observation.

• In 1891, Paul Ehrlich observed the antimalarial effects of methylene blue, a phenothiazine derivative.

• Later, the phenothiazines were developed for their antihistaminergic properties.

• In 1951, Laborit and Huguenard administered the aliphatic phenothiazine, chlorpromazine, to patients for its potential anesthetic effects during surgery.

• thereafter, Hamon et al. and Delay et al. extended the use of this treatment in psychiatric patients and serendipitously uncovered its antipsychotic activity.

The history of antipsychotic drug development

• Between 1954 and 1975, about 15 antipsychotic drugs were introduced in the United States and about 40 throughout the world.

• Thereafter, there was a hiatus in the development of antipsychotics until the introduction of clozapine treatment in the United States in 1990 opened the era of "atypical" antipsychotic drugs.

Classic and commonly used terms

Proposed terms by WPA

Neuroleptics or Typical antipsychotics

First generation antipsychotics

Atypical antipsychotics (serotonin – dopamine antagonists)

Second generation antipsychotics

Dopamine partial agonists ( aripiprazole )

Third generation antipsychotics

WHY THEY ARE ‘ATYPICAL’ ?

LOWER RISK OF EPS

SPECTRUM OF ACTION Higher ratio of serotonin : dopamine receptor blockade Appear more specific for mesolimbic than striatal dopamine

system

DIFFERENT SIDE EFFECT PROFILE

characteristics

• Low D2 receptor blocking effects• Reduced risk of extrapyramidal side effects.HaloperidolHaloperidol ClozapineClozapine RisperidoneRisperidone OlanzapineOlanzapine

QuetiapineQuetiapine ZiprasidoneZiprasidone

5HT2A D2 D1 Alpha 1 Musc H1 5HT1A (agonist)

Casey 1994Casey 1994

Atypical Antipsychotics In Vivo Binding Affinities

RECEPTOR OCCUPANCY RECEPTOR AFFINITY

Differences among Antipsychotic Drugs

• Clozapine – binds more to D4, 5-HT2, α1, and histamine H1 receptors

than to either D2 or D1 receptors• Risperidone

– about equally potent in blocking D2 and 5-HT2 receptors• Olanzapine

– more potent as an antagonist of 5-HT2 receptors– lesser potency at D1, D2, and α1 receptors

• Quetiapine– lower-potency compound with relatively similar

antagonism of 5-HT2, D2, α1, and α2 receptors

Differences among Antipsychotic Drugs

• Clozapine, olanzapine and quetiapine– potent inhibitors of H1 histamine receptors– consistent with their sedative properties

• Aripiprazole– partial agonist effects at D2 and 5-HT1A receptors

Classification

MARTA (multi acting receptor targeted agents)• clozapine, olanzapine, quetiapine

SDA (serotonin-dopamine antagonists)• risperidone, ziprasidone, sertindole

Selective D2/D3 antagonists• sulpiride, amisulpiride

Available drugs (only 10 are FDA Approved)

Amisulpride Aripiprazole Asenapine Blonanserin Clotiapine Clozapine Iloperidone Lurasidone Mosapramine

Olanzapine Paliperidone Perospirone Quetiapine Remoxipride Risperidone Sertindole Sulpiride Ziprasidone Zotepine

Therapeutic indicationsSchizophrenia and schizoaffective disorder – acute and chronic psychoses- first line treatment all SGA’s except clozapineMood disorders acute mania- all SGA’s except clozapine acute bipolar depression- quetiapine,fluoxetine

combination Maintanence therapy-

aripiprazole,olanzapine,quetiapine Adjunctive therapy in treatment depression-

olanzapine,fluoxetine combination

Other indications: Exhibits outwardly aggressive and violent behaviour Autistic spectrum disorder Tourettes syndrome Huntington’s disease Lesch Nyhan Syndrome Along with methylphenidate/dextroamphetamine in

children with ADHD. Psychosis secondary to head trauma, dementia,

treatment resistant Decreases the risk of suicide and water intoxication in

patients with schizophrenia

Common Side Effects• Extra pyramidal symptoms• Orthostatic hypotension• Sedation• Weight gain• Metabolic syndrome• QT prolongation• Anti cholinergic side effects• Hyper prolactinemia• Sexual dysfunction• Increased risk of Pneumonia

Extra pyramidal side effects (EPS):

Risperidone > Olanzapine = Ziprasidone > Quetiapine > Aripiprazole = Clozapine

Orthostatic hypotensionDefinition fall in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg when a person assumes a standing position.

Treatment changing the dose of the medication or stopping it entirely.

Clozapine > > Quetiapine, Risperidone > Ziprasidone, Olanzapine, Aripiprazole

SEDATIONDue to histaminergic receptor (H1) blockade in CNSClozapine > > Olanzapine, Quetiapine > Risperidone, Ziprasidone, Aripiprazole

WEIGHT GAIN

Clozapine = Olanzapine > Quetiapine, Risperidone > Ziprasidone, Aripiprazole

Suggested mechanisms were • 5 HT 2C antagonism, • H 1 blockade• Hyperprolactinemia

and • Increased serum

leptin.

Metabolic effectsWeight gain over 1 year (kg)

aripiprazole 1

amisulpride 1.5

quetiapine 2 – 3

risperidone 2 – 3

olanzapine > 6

clozapine > 6

METABOLIC SYNDROME

DIABETES MELLITUSHow they cause?? 5 HT 2A/2C antagonism Increased plasma lipids Weight gain Leptin resistance

Most sensitive test to detect isOral Glucose tolerance test.

High Risk withCLOZAPINE>OLANZAPINE>>RISPERIDONE>QUETIAPINELow risk withARIPIPRAZOLE,AMISULPIRIDE

METABOLIC SYNDROME (contd)DYSLIPIDEMIARaise in triglycerides levels are more common than serum cholesterol.Treated with Fibrates Statin Dietary & life style modificationHYPERTENSIONPosibly due to alpha 2 antagonismSlow,steady rise over a period of time clozapine

Insulin resistance• Prediabetes (impaired fasting glycaemia) has

~ 10% chance / year of converting to Type 2 diabetes

• Prediabetes plus olanzapine has a 6-fold increased risk of conversion

• If olanzapine is stopped 70% will revert back to prediabetes

Stroke in the elderly• Risperidone and olanzapine associated with

increased risk of stroke when used for behavioural control in dementia

• Risperidone 3.3% vs 1.2% for placebo• Olanzapine 1.3% vs 0.4% for placebo• However, large observational database studies

– Show no increased risk of stroke compared with typical antipsychotics or untreated dementia patients

QT PROLONGATIONBlockade of potassium channelsCausing torsades des pointes and sudden cardiac deathHigh effect• Any intravenous antipsychotic• Haloperidol• Sertindole• Amisulpride• Chlorpromazine• Quetiapine• ZiprasidoneNo effect on QT interval• Aripiprazole• SSRI’s• Carbamazepine • Valproate• BZD’s

Clozapine > Olanzapine > others

HYPER PROLACTINEMIA

Risperidone,amisulpirideNormal values:Male 0-20 ng/dlFemale 0-25 ng/dl

Level around 30-50 ng/dl• Reduced libido• infertilityLevel around >100 ng/dl• Galactorrhea• Amenorrhea Rule out a prolactinoma if levels >118 ng/dl

HYPER PROLACTINEMIA

Non prolactin elevating antipsychoticsAripiprazoleZiprasidoneOlanzapineClozapineQuetiapine

SEXUAL DYSFUNCTIONresult from decreased dopaminergic activity centrally and alpha adrenergic blockade peripherally.Risperidone>olanzapine>quetiapine>aripiprazole

Increased susceptiblity to pneumonia

60% more risk in elderly populationHighest in the first week of treatmentSeen only with SGA’s

Possible mechanisms:• Sedation• Drymouth• Effects on immune response

Type Manifestations Mechanism

Autonomic nervous system

Loss of accommodation, dry mouth, difficulty urinating, constipation Muscarinic cholinoceptor blockade

Orthostatic hypotension, impotence, failure to ejaculate Alpha adrenoceptor blockade

Central nervous system

Parkinson's syndrome, akathisia, dystonias Dopamine receptor blockade

Tardive dyskinesia Supersensitivity of dopamine receptors

Toxic-confusional state Muscarinic blockade

Endocrine system

Amenorrhea-galactorrhea, infertility, impotence

Dopamine receptor blockade resulting in hyperprolactinemia

Other Weight gain Possibly combined H1 and 5-HT2 blockade

RISPERIDONE Benzisoxazole Undergoes first pass metabolism Peak plasma level levels – 1 hr (parent compound) ,

3 hrs for metabolite Combined half life 20 hrs (once daily dosing) Antagonist of serotonin 5HT2A, dopamine D2, α1, α2

adrenergic histamine H1 receptors.

Side effects

Weight gain Anxiety Nausea Dizziness, hyperkinesias, somnolence, Vomiting Rhinitis Erectile dysfunction

Dosages – Initially 1-2 mg/day , raised to 4 mg/ day

Only SDA available in depot formation IM injection every 2 weeks (25mg,50mg or 75 mg)

Drug interactions – Paroxetine and Fluoxetine (blocks the formation of RISPERIDONE’S

active metabolite) RISPERIDONE + SSRI – significant

elevation of prolactin - galactorrohea and breast enlargement

OLANZAPINE 85% absorbed from the GI tract 40% is inactivated by first pass metabolism Peak concentration - 5hrs Half life - 31 hrs 5HT2A ,D1, D4, α1 ,5HT1A , muscarinic M1 through M5

and H1 receptors

SIDE EFFECTS

Weight gain Somnolence Dry mouth Dizziness Constipation Dyspepsia Increased appetite Akathisia tremor

Periodic assessment of “blood sugar” and “transaminase”.

Increased stroke among patients with dementia DOSAGES – initial dose for treatment of psychosis –

5-10 mg , acute mania- 10-15 mg. Start 5-10 mg , raise to 10 mg per day 30-40 mg in treatment resistant cases.

• Drug interactions– FLUVOXAMINE and CIMETIDINE – increases– CARBAMAZEPINE and PHENYTOIN - decreases

QUETIAPINE

DIBENZOTHIAZEPINE Rapidly absorbed from GI tracts Peak plasma concentration – 1-2 hrs Steady half life – 7 hrs (2- 3 dosing per day) lower-potency compound with relatively similar

antagonism of 5-HT2, D2, α1, and α2 receptors .

Side effects somnolence, postural hypotension and dizziness –

most common side effect. Least likely to cause extra pyramidal side effects. –

used in Parkinsonism who develop DOPAMINE AGONIST induced psychosis.

Moderate weight gain Small rise in heart rate , constipation and transient

rise in liver transaminases can occur.

• DOSAGES – available in 25, 50 and 200 mg.• Schizophrenia – target of 400 mg/ day• Mania & BPD – 800 & 300 mg respectively• Insomnia – 25- 300 mg at night

ZIPRASIDONE BENZOTHIAZOLYL PIPERAZINE Peak plasma concentration- 2-6 hrs Terminal half life at steady state – 5-10 hrs Bioavailability doubles when taken along with food. Blocks 5HT2A and D2 receptors , antagonist 5HT1D,

5HT2C, D3,D4,α1 and H1 receptors.

Agonist activity at 5HT1A receptorSerotonin reuptake inhibitorNor epinephrine reuptake inhibitor

SIDE EFFECTS: somnolence, headache, dizziness , nausea , light

headedness, prolongation of QTc interval. avoided in patients with cardiac arrythmias.

• Dosages – 20,40, 60 ,80 mg.• IM comes single use daily 20mg/ml vial• Oral ziprasidone initiated at 40 mg a day.• Efficacy in the range of 80-160 mg/day.• High as much as 240 mg are being used.

Clozapine DIBENZODIAZEPINE Rapidly absorbed Plasma level – 2 hrs Steady state – less than one week if twice daily

dosing is used. Half life – 12 hrs Antagonist of 5HT2A , D1,D3,D4 and α receptors.

Conventional antipsychotic:90% of striatal D2 receptor

occupied

Clozapine occupies only 20-67% of D2 receptors

Relatively low potency as a D2 receptor antagonist.

• Special indications– patients with severe tardive dyskinesia.– Patients prone to develop EPS– Treatment resistant schizophrenia

– Severe treatment resistant mania– Severe psychotic depression– Idiopathic Parkinson’s disease– Huntington’s disease– Suicidal patients with schizophrenia and schizoaffective disorder.– Pervasive developmental disorder– Autism of childhood– OCD (rarely)

Side effects

– Sedation– Dizziness– Syncope– Tachycardia– Hypotension– ECG changes – Fatigue– Weight gain– constipation

– Anticholinergic effects

– SIALORROHEA– AGRANULOCYTOSIS– SEIZURES– MYOCARDITIS

Clozapine-associated seizures occur most often at doses greater than 600 mg /day.

AGRANULOCYTOSIS Leucocyte and differential blood count normal before

starting Monitor counts every week for 6 months, then at least

2 weeks once for 1 year At least Q 4 weeks after count stable for 1 year (for 4

more weeks after discontinuation) If leucocyte count < 3000/mm3, or if ANC <

1500/mm3, discontinue immediately and refer to hematologist

Patient should report immediately symptoms of infection, esp. flu-like illness (fever, sore throat)

Dosages– Initial dosage is 25 mg one or 2 times daily

although conservative initial dosage is 12,5 mg daily.

– Raised gradually to 25 mg a day for every 2-3 days to 300 mg divided doses

– 900 mg can be used.– Plasma conc greater than 350 ng/mL is likely hood

for better response.

Drug interactions

Clozapine + (carbamazepine, phenytoin, propulthiouracil, sulfonamides, captopril) causes bone marrow suppression.

Clozapine+ Lithium – increases the risk of seizures, confusion and movement disorders.

Clozapine+ Paroxetine – precipitate clozapine associated neutropenia.

Amisulpiride Half life 12 hours Bioavailablity 48 % Primarily a D2,D3 antagonist Antidepressant effect due to 5HT7 blockade Used in treating schizophrenia,bipolar disorder Also in dysthymia

Side effects Extrapyramidal side effects Insomnia Hypersalivation Nausea Headache Hyperactivity Anxiety Vomiting Hyperprolactinaemia

Very less chances of causing• sedation• Tardive dyskinesia• Blood dyscrasias

Amisulpride's use is contraindicated in Phaeochromocytoma Concomitant Prolactin dependent tumours e.g. Prolactinoma,

Breast cancer Movement disorders (e.g. Parkinson's disease and dementia with

lewy bodies) Lactation Children before the onset of puberty Amisulpride should not be used in conjunction with drugs that

prolong the QT interval and Torsades de Pointes is common in overdose.

TCAs are very dangerous Amisulpride is moderately dangerous SSRIs are modestly dangerous.

• (with the and

ARIPRIPAZOLE

QUINOLONE DERIVATIVE Well absorbed reaching peak levels of 3- 5

hrs Half life is about 75 hrs

Other SDA’s

• Bifeprunox - partial dopamine agonist.– Treatment of schizophrenia– GI side effects are most common.

• Paliperidone – major active metabolite of risperidone.– Recommended dose of 6mg per day with 3-12

mg/day.

SGA vs FGANO EVIDENCE OF

BENEFIT OF SGA’S OVER FGA’S IN

IMPROVEMENT OF NEGATIVE SYMPTOMS

CLOZAPINE HAS SHOWN CLEAR UTILITY IN

TREATMENT RESISTANT SCHIZOPHRENIA

Conclusion

Good clinical practice involves using both types of medication at different times, depending on the specific needs of the patient.

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