Treatment of psychosis

TREATMENT OF PSYCHOSIS

1. DRUG TREATMENT OF PSYCHOSIS

2. Dopa receptors DA receptor 5 Types D1,2,3,4,5 D 1 -D 5  cAMP  PIP 2 Gs D1 encoded by chrosome -5, located in Nigrostraital pathway ( Extra Pyramidal Side eff ) D5 Chro 4, hypothalamus, Hippocampus Role not yet clear

3. D2,D3,D4  cAMP , Blcok Ca +2 , Open K + Gi D2 Chro 11, Substantia nigra and pituitary Behaviour , Voluntary movements, prolactin D3 Chro 11, Midbrain, Hypothalamus, D4 frontal cortex, medulla, midbrain, mesocortical pathway

4. Psychiatric illness Psychosis Neurosis OCD Phobia Anxiety PTSD Schizophrenia Mania Depression Bipolar Psychosis: Pt is not aware of illness and refers to treatment Neurosis: Less serious and insight present (Obsessive compulsive disorder, Post traumatic stress disorder)

5. Psychosis Psychosis is a thought disorder characterized by : Disturbances of reality and perception Impaired cognitive functioning Inappropriate or diminished affect (mood) Psychosis denotes many mental disorders. Schizophrenia is a type of functional psychosis in which severe personality changes and thought disorders

6. Earlier: termed as major tranquilizers USA: Antipsychotics Europe: Neuroleptics (both antipsyo + EPS)

7. Schizophrenia Pathogenesis is unknown. Onset of schizophrenia is in the late teens early twenties. Genetic predisposition -- Familial incidence. Multiple genes are involved. Afflicts 1% of the population worldwide. May or may not be present with anatomical changes.

8. Schizophrenia It is a thought disorder. The disorder is characterized by a divorcement from reality in the mind of the person (psychosis). Symptoms positive or negative. Positive: visual and auditory hallucinations Delusions Thought disorders Irrational conclusions Control by external forces (paranoia),

9. Negative Poor socialization Emotional blunting Introvert behaviour Lack of motivation Congnitive deficits (lack of attention and loss of memory)

10. Psychosis Producing Drugs Levodopa CNS stimulants Cocaine Amphetamines Khat , cathinone , methcathinone Apomorphine Phencyclidine

11. Role of DA in psychosis Positron emission tomographic (PES)  DA receptor density Postmortem  DA density Inc DA by L Dopa , Amphetamine, Apomorphin  precipitate the symptoms Most antipsychotic drugs blocking D2 in CNS  Mesolimbic , frontal Inc Homovalinic acid (HVA) Drug should absolutely  rather then partially, ineffective

12. Central Dopaminergic pathway Ultra short  Periglomular cells in olfactory bulb Intermediate  Ventral hypothalamus  role in prolactin release, Hypothalamic- hypophyseal functions Long : most IMP. Cover SN, Ventral Tegmental areas to Limbic system, amygdala , Caudate, Putamen

13. Parkinson’s  dec . DA in basal ganglia Scizopherenia  Over activity of DA in Mesolimbic Mesocortical Mesofrontal There are four major pathways for the dopaminergic system in the brain: The Nigro-Stiatal Pathway: Voluntary movements The Mesolimbic Pathway.: Behaviour The Mesocortical Pathway: Behaviour The Tuberoinfundibular Pathway: Prolactin release

14. 5HT2  agonist visual hallucinations and sensory disturbance , which are similar to psychosis 5HT has a modulator role on DA pathway After has fall off because 5HT Visual Schizo  Auditory predominate

15. Glutamate Glutamate exerts excitatory, while DA exerts inhibitory role over GABA ergic striatal neurons which projects to thalamus and serves as sensory gate. Inc Glu , or Dec DA disturbed the Gate t allow uninhibited sensory inputs to cortex. Hallucination and thought disorders.

16. Dopamine Synapse DA L-DOPA Tyrosine Tyrosine

17. Antipsychotic treatments In 1940’s Phenothiazenes were isolated and were used as pre-anesthetic medication, but quickly were adopted by psychiatrists to calm down their mental patients. In 1955, chlorpromazine was developed as an antihistaminic agent by Rh o ne-Pauline Laboratories in France. In-patients at Mental Hospitals dropped by 1/3.

18. Antipsychotic/Neuroleptics Three major groups : Phenothiazines Thioxanthine Butyrophenones OLDER DRUGS

19. Antipsychotic/Neuroleptics Phenothiazines Chlorpromazine Thioridazine Fluphenazine Trifluopromazine Piperacetazine Perfenazine Mesoridazine Acetophenazine Carphenazine Prochlorperazine Trifluoperazine Aliphatic Piperidine Piperazine * * Most likely to cause extrapyramidal effects.

20. Antipsychotic/Neuroleptics 2) Thioxanthines Thiothixene Chlorprothixene Closely related to phenothiazines

21. Antipsychotic/Neuroleptics 3) Butyrophenones Haloperidol Droperidol * *Not marketed

22. Atypical Antipsychotic Pimozide Atypical A ntipsychoitcs Loxapine Clozapine Olanzapine Quetiapine Indolones Sertindole Ziprasidone Olindone Molindone Risperidone

23. Classification of antipsychotic drugs : Atypical Antipsychotic Drugs : Clozapine, Olanzapine, Risperidone , Ziprasidone Typical Antipsychotic Drugs: Phenothiazines : Chlorpromazine, Thioridazine , Trifluperazine , Fluphenazine . Butyrophenones : Haloperidol Benperidol . Thioxanthenes : Thiothixene Others : Pimozide Loxapine

24. Antipsychotics/Neuroleptics The affinities of most older “classical” “Typical” agents for the D 2 receptors correlate with their clinical potencies as antipsychotics dopamine receptor antagonist D 2

25. Typical 1 st generation Agitation, Acute mania More extrapyramidal symptom Less efficacy addicitive Difficulty to discontinue Slow excret Atypical 2 nd generation Depression, bipolar, mania Less extrapyramidal symptom Efficacy is more Less addicitive Easier discontinue Fast excret (relapse)

26. Antipsychotics/Neuroleptics Presynaptic Effects Blockade of D 2 receptors  Compensatory Effects Firing rate and activity of nigrostriatal and mesolimbic DA neurons. DA synthesis, DA metabolism, DA release. Postsynaptic Effects Depolarization Blockade Inactivation of nigrostriatal and mesolimbic DA neurons.  Receptor Supersensitivity The acute effects of antipsychotics do not explain why their therapeutic effects are not evident until 4-8 weeks of treatment.

27. Antipsychotic/Neuroleptics Chlorpromazine:  1 = 5-HT 2 = D 2 > D 1 > M >  2 Haloperidol: D 2 > D 1 = D 4 >  1 > 5-HT 2 > H 1 > M =  2 Clozapine : D 4 =  1 > 5-HT 2 = M > D 2 = D 1 =  2 ; H 1 Quetiapine : 5-HT 2 = D 2 =  1 =  2 ; H 1 Risperidone : 5-HT 2 >>  1 > H 1 > D 2 >  2 >> D 1 Sertindole : 5-HT 2 > D 2 =  1

28. Thioridazine Least incidence of EPS Low D2 blocking preset central anticholinergic activity Interferes male sexual by inhibiting ejaculation It can cause cardical arry . (Prolong QT interval) Retinal damage limits long term admnistration

29. Trifluperazine , fluphenazine , Haloperidol High potency drugs and have least α blocking, anticholinergic , sedative, Cause jaundice, Penfluridol : long acting anti psychotic Pimozidine : Selective D 2 , long duration, inc QT

30. A typical antipsychotics Unique receptor profile Effective against the negative as well as positive schizophrenia Lesser liability for inducing Extra pyramidal Effectiveness in patient refractoru to typical neuroleptics

31. 5HT2, and D4 high affinity Besides α 1, M1, H1, D2 No singal receptor action best predict Clozapine 5-HT 2 >H1=M1=  1 =D4>D2=D1 olanzapine 5-HT 2 >H1=M1=D4>  1 =D2=D1 Risperidone 5-HT 2 >  1 = D2>D4>H1>D1 Quetiapine  1 =H1>D2= 5-HT 2 =M1>D1

32. Clozapine : weak D2 blocking action 5HT2, α , D4 Positive and negative schizophrenia Dyskinesia rare Reserve drug, (Risk of precipitation of seizures and agranulocytosis ) Risk of EPS Risks of intestinal dysfunction, weight gain, uncontrol BP, hyperlipidemia ,

33. Risperidone : 5HT2, α , D2 EPS at high dose , less precipitation of seizures Olanzapine : 5HT2, α , D2, M more action Anti cholinergic side effects Can cause seizures, weight gain, Mania, bipolar disorder Ziprasidone : Inc QT, arrhythmias Quetiapine : Cataract formation , short half life Aripiprazole : partial agonist 5HT1a, D2, antagonist at 5HT2a/. DA, 5HT stabilizer

34. PK Oral BV vary largely IM inj 10 fold inc BV IM Oil depot longer acting Highly lipophilic Highly protein binding Metab cyto p-450

35. Non psychotics Uses Antiemetics:D2 block in CTZ Preanaesthetic ( Promethazine ) Anti H, Anti Choli , Antiemetic Huntington’s disease (Haloperidol)

36. Antipsychotic/Neuroleptics Clinical Problems with antipsychotic drugs include: Failure to control negative effect Significant toxicity Neurological effects Autonomic effects Endocrine effects Cardiac effects 3) Poor Concentration

37. Neurological effects Acute dystonia- S pasms of muscles of tongue, neck and face ( ACh ) IM anticholinergic Akasthisia – Uncontrolled motor restlessness Parkinsonism Neuroleptic Mallignant Syndrome  dantrolene , Diazepam Rabbit syndrome ( perioral tremors)  Anti choliner Tardive dyskinesia Piperazines Butyrophenones

38. Tardive Dyskinesia (TD) Repetitive involuntary movements, lips, jaw, and tongue Choreiform quick movements of the extremities As with P arkinson’s, movements stop during sleep May get worse when medications discontinued, No effective treatment

39. ADR/ Anticholinergic Some antipsychotics have effects at muscarinic acetylcholine receptors: D ry mouth B lurred vision Urinary retention C onstipation Clozapine Chlorpromazine Thioridazine

40. ADR/CVS Some antipsychotics have effects at a- adrenergic receptors: Chlorpromazine Thioridazine Postural hypotension, Palpitation, Inhibition of ejaculations, Q-T prolongation ( Tiori ) Excess cardiovascular mortality Phenothiazine

41. ADR/CNS Drowsiness, Lethargy, confusion (typical) Other side effects are increased appetite Sedation (RAS) Weight gain Aggravation of seizures

42. ADR/ Endocrinal Blockade of D2 receptors in lactotrophs in breast increase prolactin concentration Galactorrhea in females Males Gynaeocmastia Dec FSH, LH  amenorrhoea Riseridone

43. ADR/ Metabolic Elevation of blood sugar (insulin resistance) Triglyceride levels Low potency drug high risk

44. Antipsychotics/Neuroleptics Antipsychotics produce catalepsy (reduce motor activity). BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA. Antipsychotics reverse hyperkinetic behaviors (increased locomotion and stereotyped behaviour ). BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS. Antipsychotics prevent the dopamine inhibition of prolactin release from pituitary. BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.  hyperprolactinemia

45. Postural hypotension ( α blocking) Weight again ( except haloperidol) Retinal damage ( Thioridazine ) Agranulocytosis ( Clozapine ) Cataract formation ( Quetiapine ) Cholestatic jaundice ( Chlorpormazine ) Dryness mouth, blurred vision( max thioridazine )

46. THANK Q

47. Etiology of Schizophrenia Idiopathic Biological Correlates Genetic Factors Neurodevelopmental abnormalities. Environmental stressors.