Antipsychotic drugs

1. Antipsychotic drugs

2. CNS drugs • Functionally, the CNS is the most complex part of the body, and understanding drug effects is difficult • Understanding the effects of drugs on individual neurons does not predict the effect on the whole organ • In part this is due to complex interactions mediated by different neurotransmitters

3. Dopamine • Important neurotransmitter • Present mainly in the nigrostriatal, mesolimbic and tubero-infundibular pathways • Originally there were only thought to be two main groups of dopamine receptor: D1 and D2 . These stimulate and inhibit adenylate cyclase respectively • Subsequently D3 (related to D1) and D4 (related to D2 ) receptors were discovered • D2 receptors are mainly responsible for the actions of anti-psychotic drugs

5. Dopamine functions • Motor control - nigrostriatal system • Deficiency results in rigidity, tremor and difficulty initiating movement • Behavioural effects - mesolimbic system • Overactivity in rats leads to abnormal behavior • Endocrine control - tubero-infundibular system • Dopamine and dopamine agonists suppress prolactin release, dopamine antagonists may stimulate it

6. Schizophrenia - dopamine • Amphetamine (which releases dopamine) can produce a syndrome similar to the ‘positive’ features of schizophrenia • Levodopa may aggravate the condition • Apomorphine and bromocriptine (D2 agonists) produce behavioral abnormalities in animals • D2 receptor antagonists are effective in controlling the positive features of the disorder • ? Increased D2 receptor binding in the brains of schizophrenic subjects. Evidence of genetic variation in the D4 receptor to which some anti-psychotic drugs have high affinity

7. Schizophrenia - serotonin • LSD which has mixed agonist/antagonist serotonergic actions produces hallucinations and behavioral disturbance • Some antipsychotic drugs also act at 5-HT receptors (antagonists of 5HT2) • 5-HT has a modulatory effect on dopaminergic neurones

8. Modes of action • All anti-psychotic drugs have inhibitory effects on the D2 receptor • Some have actions against the D4 receptor • All have other effects - to varying degrees • Serotonin 5HT2 blockade (may improve negative symptoms) • Histamine H1 blockade (drowsiness) • Alpha adrenoceptor blockade (postural hypotension)

9. How do we know they work? • Mostly “ by accident” for early drugs • designing drugs to reduce anxiety in surgical patients • Clinical experience • Clinical trials • especially more recent drugs • PET scanning showing blockade of central D2 receptors

10. Clinical effects • Control the ‘positive’ features of the disease, but little effect on the ‘negative’ features • clozapine may be superior in this regard • The main side-effects are on the extrapyramidal motor system • Akathisia (hours) • Dystonias (hours to days) • Parkinsonism (weeks to months) • rigidity, tremor, and loss of mobility • Tardive dyskinesia (months to years) • Repetitive abnormal movements of face and upper limbs • Thought to be due to proliferation of D2 receptors in the striatum

11. Clinical effects • Newer ‘atypical’ anti-psychotic drugs are less inclined to produce these effects - possible due to their greater affinity for the mesolimbic over the striatal areas of the brain

12. Other effects • Some are effective anti-emetics • Anti-muscarinic effects lead to dry mouth, blurred vision, difficulty with micturition • a antagonist effects lead to postural hypotension • Antihistamine effects (H1 receptor) lead to drowsiness • Prolactin stimulation may lead to breast development • Agranulocytosis is fairly common with an ‘atypical’ drug – clozapine which can also cause a myocarditis • ‘Neuroleptic malignant syndrome’ is a rare but serious effect leading to extrapyramidal rigidity, autonomic instability and hyperthermia

13. Other effects

15. Traditional Antipsychotics • Phenothiazines • chlorpromazine (Chlorpromazine Mixture, Chlorpromazine Mixture Forte, Largactil) • fluphenazine (Anatensol, Modecate) • flupenthixol (Fluanxol) • pericyazine (Neulactil) • pimozide (Orap) • thioridazine (Aldazine) • trifluoperazine (Stelazine) • zuclopenthixol (Clopixol) • Butyrophenones • droperidol (Droleptan Injection) • haloperidol (Haldol, Serenace)

17. Newer Antipsychotics • Atypical agents • aripiprazole (Abilify) • clozapine (CloSyn, Clopine, Clozaril) • risperidone (Risperdal) • quetiapine (Seroquel) • amisulpride (Solian) • olanzapine (Zyprexa)

18. Antipsychotics

19. Differences among Antipsychotic Drugs • Chlorpromazine: α1 = 5-HT2 > D2 > D1 • Haloperidol: D2 > D1 = D4 > α1 > 5-HT2 • Clozapine: D4 = α1 > 5-HT2 > D2 = D1

20. Atypical antipsychotics • Claims • lower doses • reduced side effects • more effective (especially negative symptoms) • better compliance • Evidence? • trials have been quite small and involved patients previously heavily treated and somewhat ‘resistant’ • trials have tended to show equivalent efficacy and better side effect profiles with newer drugs • head to head trials claimed superiority of olanzapine over risperidone (but company sponsored and controversial); some “parallel publications” • Costs • Much higher with new drugs (10-40 times higher)

21. Metabolic effects

22. 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

23. 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

24. Conclusions • Atypical antipsychotics have serotonin blocking effects as well as dopamine blockade • As a group have less chance of extrapyramidal side effects • Most have weight gain and insulin resistance as a side effect (except perhaps aripiprazole and maybe amisulpride) • May be associated with stroke when used for behavioural control in dementia • Many have idiosyncratic toxicities

28. Differences among Antipsychotic Drugs • All effective antipsychotic drugs block D2 receptors • Chlorpromazine and thioridazine • block α1 adrenoceptors more potently than D2 receptors • block serotonin 5-HT2 receptors relatively strongly • affinity for D1 receptors is relatively weak • Haloperidol • acts mainly on D2 receptors • some effect on 5-HT2 and α1 receptors • negligible effects on D1 receptors • Pimozide and amisulpride† • act almost exclusively on D2 receptors

29. 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

30. 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