TREATMENT OF PSYCHOSIS

1. DRUG TREATMENT OF
PSYCHOSIS

2. 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)

3. 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

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

5. 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.

6. 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),

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

8. Psychosis Producing Drugs
1) Levodopa
2) CNS stimulants
a) Cocaine
b) Amphetamines
c) Khat, cathinone, methcathinone
3) Apomorphine
4) Phencyclidine

9. 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

10. 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

11. 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:
I. The Nigro-Stiatal Pathway: Voluntary movements
II. The Mesolimbic Pathway.: Behaviour
III. The Mesocortical Pathway: Behaviour
IV. The Tuberoinfundibular Pathway: Prolactin release

13. • 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

14. 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.

15. Dopamine Synapse
DA
L-DOPA
Tyrosine
Tyrosine

16. 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 Rhone-Pauline Laboratories
in France.
 In-patients at Mental Hospitals dropped by 1/3.

17. Antipsychotic/Neuroleptics
Three major groups :
1. Phenothiazines
2. Thioxanthine
3. Butyrophenones
OLDER DRUGS

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

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

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

21. Atypical Antipsychotic
Pimozide
Atypical Antipsychoitcs
Loxapine
Clozapine
Olanzapine
Quetiapine
Indolones
Sertindole
Ziprasidone
Olindone
Molindone
Risperidone

22. 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

23. Antipsychotics/Neuroleptics
• The affinities of
most older
“classical” “Typical”
agents for the D2
receptors correlate
with their clinical
potencies as
antipsychotics
Dopamine Synapse
DA
L-DOPA
Tyrosine
Tyrosine
dopamine
receptor
antagonist
D2

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

25. Antipsychotics/Neuroleptics
Presynaptic Effects
Blockade of D2 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.

26. Antipsychotic/Neuroleptics
Chlorpromazine: 1 = 5-HT2 = D2 > D1 > M > 2
Haloperidol: D2 > D1 = D4 > 1 > 5-HT2 >H1>M = 2
Clozapine: D4 = 1 > 5-HT2 = M > D2 = D1 = 2 ; H1
Quetiapine: 5-HT2 = D2 = 1 = 2 ; H1
Risperidone: 5-HT2 >> 1 > H1 > D2 > 2 >> D1
Sertindole: 5-HT2 > D2 = 1

27. 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

28. Trifluperazine, fluphenazine, Haloperidol
• High potency drugs and have least α blocking,
anticholinergic , sedative, Cause jaundice,
• Penfluridol: long acting anti psychotic
• Pimozidine : Selective D2, long duration, inc QT

29. 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

30. • 5HT2, and D4 high affinity
• Besides α1, M1, H1, D2
• No singal receptor action best predict
Clozapine 5-HT2 >H1=M1= 1 =D4>D2=D1
olanzapine 5-HT2 >H1=M1=D4> 1 =D2=D1
Risperidone 5-HT2 > 1 = D2>D4>H1>D1
Quetiapine 1 =H1>D2=5-HT2 =M1>D1

31. 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,

32. 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

33. 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

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

35. Antipsychotic/Neuroleptics
Clinical Problems with antipsychotic drugs
include:
1) Failure to control negative effect
2) Significant toxicity
a) Neurological effects
b) Autonomic effects
c) Endocrine effects
d) Cardiac effects
3) Poor Concentration

36. Neurological effects
• Acute dystonia- Spasms 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

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

38. ADR/Anticholinergic
 Some antipsychotics have effects at
muscarinic acetylcholine receptors:
• Dry mouth
• Blurred vision
• Urinary retention
• Constipation
Clozapine
Chlorpromazine
Thioridazine

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

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

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

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

43. 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

44. • 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 )

45. THANK Q

48. Etiology of Schizophrenia
Idiopathic
Biological Correlates
1) Genetic Factors
2) Neurodevelopmental abnormalities.
3) Environmental stressors.