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TREATMENT OF PSYCHOSIS
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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.
