treatment of psychosis

DRUG TREATMENT OF PSYCHOSIS

Psychiatric illness

Psychosis Neurosis

OCDPhobiaAnxiety

PTSD

Schizophrenia

Mania Depression Bipolar

Psychosis: Pt is not aware of illness and refers to treatmentNeurosis: Less serious and insight present

(Obsessive compulsive disorder, Post traumatic stress disorder)

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

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

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.

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),

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

Psychosis Producing Drugs

1) Levodopa2) CNS stimulants

a) Cocaine b) Amphetaminesc) Khat, cathinone, methcathinone

3) Apomorphine 4) Phencyclidine

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

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

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 movementsII. The Mesolimbic Pathway.: BehaviourIII. The Mesocortical Pathway: Behaviour IV. The Tuberoinfundibular Pathway: Prolactin release

• 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

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.

Dopamine Synapse

DA

L-DOPA

Tyrosine

Tyrosine

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.

Antipsychotic/Neuroleptics

Three major groups :1. Phenothiazines 2. Thioxanthine3. Butyrophenones

OLDER DRUGS

Antipsychotic/Neuroleptics

1) Phenothiazines

Chlorpromazine Thioridazine FluphenazineTrifluopromazine Piperacetazine Perfenazine

Mesoridazine Acetophenazine

Carphenazine

Prochlorperazine

Trifluoperazine

• Aliphatic Piperidine Piperazine*

* Most likely to cause extrapyramidal effects.

Antipsychotic/Neuroleptics

2) ThioxanthinesThiothixeneChlorprothixene

Closely related to phenothiazines

Antipsychotic/Neuroleptics

3) ButyrophenonesHaloperidolDroperidol*

*Not marketed

Atypical Antipsychotic

PimozideAtypical Antipsychoitcs

LoxapineClozapine

OlanzapineQuetiapine

IndolonesSertindole

ZiprasidoneOlindone

MolindoneRisperidone

Classification of antipsychotic drugs:

Atypical Antipsychotic Drugs:Clozapine,Olanzapine, Risperidone, Ziprasidone

Typical Antipsychotic Drugs:Phenothiazines:

Chlorpromazine, Thioridazine ,Trifluperazine, Fluphenazine.Butyrophenones:

Haloperidol Benperidol.Thioxanthenes:

ThiothixeneOthers:

Pimozide Loxapine

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

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)

Antipsychotics/Neuroleptics

Presynaptic EffectsBlockade of D2 receptors

Compensatory Effects

Ý Firing rate and activity of nigrostriatal and mesolimbic DA neurons.

Ý DA synthesis, DA metabolism, DA release.

Postsynaptic EffectsDepolarization 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.

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

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

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

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

• 5HT2, and D4 high affinity• Besides α1, M1, H1, D2• No singal receptor action best predict

Clozapine 5-HT2 >H1=M1= 1 =D4>D2=D1olanzapine 5-HT2 >H1=M1=D4> 1 =D2=D1Risperidone 5-HT2 > 1 = D2>D4>H1>D1Quetiapine 1 =H1>D2=5-HT2 =M1>D1

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,

Risperidone: 5HT2, α, D2• EPS at high dose , less precipitation of seizuresOlanzapine: 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

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

Non psychotics Uses

• Antiemetics:D2 block in CTZ• Preanaesthetic (Promethazine) Anti H, Anti

Choli, Antiemetic • Huntington’s disease (Haloperidol)

Antipsychotic/Neuroleptics

Clinical Problems with antipsychotic drugsinclude:

1) Failure to control negative effect2) Significant toxicity

a) Neurological effectsb) Autonomic effectsc) Endocrine effectsd) Cardiac effects

3) Poor Concentration

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

PiperazinesButyrophenones

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

ADR/Anticholinergic

Some antipsychotics have effects at muscarinic acetylcholine receptors:

• Dry mouth• Blurred vision• Urinary retention• Constipation

ClozapineChlorpromazine

Thioridazine

ADR/CVS

Some antipsychotics have effects at -aadrenergic receptors:

ChlorpromazineThioridazine

Postural hypotension, Palpitation, Inhibition of ejaculations, Q-T prolongation ( Tiori)Excess cardiovascular mortality Phenothiazine

ADR/CNS

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

ADR/ Endocrinal

Blockade of D2 receptors in lactotrophs in breast increase prolactin concentration

Galactorrhea in females Males Gynaeocmastia Dec FSH, LH amenorrhoea

Riseridone

ADR/ Metabolic

Elevation of blood sugar (insulin resistance) Triglyceride levels

Low potency drug high risk

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

• 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 )

THANK Q

Etiology of Schizophrenia

IdiopathicBiological Correlates1) Genetic Factors2) Neurodevelopmental abnormalities.3) Environmental stressors.