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Schizophrenia
Dr. Irfan Ahmad Khan discusses the management of schizophrenia. Some key points: - Schizophrenia is a mental disorder characterized by breakdown of thought processes and poor emotional responsiveness. It typically begins in early adulthood. - Symptoms include positive symptoms like hallucinations and delusions, as well as negative symptoms like affective flattening and anhedonia. - The dopamine hypothesis suggests dopamine excess in the mesolimbic pathway contributes to symptoms. Current antipsychotics target dopamine and serotonin receptors. - Treatment involves antipsychotic drugs, including classical antipsychotics that mainly target D2 receptors, and atypical antipsychotics that have multi-receptor profiles and cause
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Introduces schizophrenia, its characteristics, prevalence (1.1%), risk factors, and genetic and environmental etiology.
Covers positive symptoms (hallucinations, delusions), negative symptoms (affective flattening, apathy), and cognitive symptoms.
Discusses dopamine hypothesis, dopamine pathways' role, and other neurotransmitters involved in schizophrenia's etiology.
Focuses on antipsychotic medications—classical vs. atypical—administration guidelines, and effects on symptoms.
Details adverse reactions of classical antipsychotics including muscle dystonia, neuroleptic syndrome, and other side effects.
Outlines modes of action, uses, and adverse effects of various atypical antipsychotics, including clozapine and olanzapine.
Explores novel antipsychotic strategies involving dopamine stabilizers and other receptor modulators for treatment.
Concludes the presentation.
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Schizophrenia
- 1. Dr. Irfan AhmadKhan Management of Schizophrenia
- 2. Introduction Schizophrenia ismental disorder characterized by breakdown of thought processes and by poor emotional responsiveness. Major psychiatric illness that makes difficult to: Tell the difference between real and unreal experiences, Think logically, Have normal emotional responses, Behave normally in social situations,
- 3. Introduction Prevalence Ratefor schizophrenia is approximately 1.1% of the population over the age of 18. Onset: typically begins in early adulthood; between the ages of 15 and 25. When there is schizophrenic patient in a family, the chance for a sibling to be diagnosed with schizophrenia is 7-9%. If a parent has schizophrenia, the chance for a child to have the disorder is 10-15%
- 4. Introduction Etiology : result of a genetic predisposition combined with environmental stresses during pregnancy or childhood . Key genes altered imposing risk for schizophrenia. DISC1, Dysbindin, Neuregulin and G72 genes.
- 5. Symptoms Positive Symptoms: Hallucinations : auditory, visual Delusions: delusion of persecution, paranoid behavior , delusion of thought broadcasting, thought insertion Bizarre behavior: agitation, repetitive behavior Thought disorder manifested by failure of organization of speech Catatonia: difficult moving Negative symptoms: Affective flattening: unchanging facial expression with lack of communication, thought expression Alogia:poverty of speech Anhedonia: inability to derive pleasure from any activity Apathy: lack of energy, motivation to work •Cognitive symptoms include deficits in working memory and cognitive
- 6. Pathogenesis Dopamine hypothesisof schizophrenia : Various evidence suggest that dopamine excess in mesolimbic : Many antipsychotic drugs block post-synaptic D2 receptors in meso-limbic area Drug that increase dopamine as levodopa (precursor) ; apomorphine (agonist) & amphetamine (releaser): aggravate schizophrenia or produce de novo psychosis D2 receptors density increased in brains of schizophrenic (postmortem finding & PET scanning in live patients) not treated with drugs Successful treatment has reported to change amount of homovanillic acid (metabolite of dopamine) in CSF, urine & plasma
- 7. Dopamine pathwaysin brain: Meso limbic:-substantia nigra to limbic area, prefrontal cortex behavior, thought Nigrostriatal:- substantia nigra to caudate & putamen coordination of voluntary movements Tubuloinfundibular:- arcuate nuclei to hypothalamus & pituitary dopamine inhibits prolactin secretion
- 8. Pathogenesis But theclassical drugs are partially effective in patients: this led to surge of research in finding of other neurotransmitters involved in causation of Schizophrenia: Atypical antipsychotics which Serotonin : 5HT2a receptor antagonism mainly, less antagonism of D2 receptor Other neurotransmitters GABA, acetylcholine, endocannabinoids , Glutamate.
- 9. Drug therapy Mainstayof treatment is antipsychotic drugs Two types: Classical or atypical antipsychotics Early treatment soon after diagnosis is made : better response to treatment Start with lowest dose, increased to maximum tolerated dose
- 10. Antipyschotic drugs Classical Atypical Phenothiazines: Aliphatic chain: chlorpromazine Piperidine chain: thioridazine Piperazine chain: trifluroperazine , prochlorperazine, fluphenazine Butyrophenones: haloperidol Substituted benzamide: sulpiride Thioxanthines: flupentixol Clozapine Olanzapine Quetiapine Risperidone Ziprasidone Aripiprazole
- 11. Classical Atypical Modeof action: D2 antagonism in mesolimbic area Thioridazine also has anticholinergic effect (sometimes classified as atypical) ADRs: extra pyramidal symptoms and hyperprolactinemia Mainly effective against positive symptoms Mode of action: act on other receptor neurotransmitters than D2 antagonism 5HT2/D2 antagonism ratio high D4 receptor antagonism Partial agonism of D2 Adrenergic α2 antagonism Muscaranic receptor antagonism ADRs: better tolerated- less chances of EPS Metabolic syndrome, stroke Agranulocytosis (clozapine) Greater efficacy against positive and negative symptoms also More effective against resistant
- 12. Classical Antipsychotic drugs Action : D2 antagonism in brain Other effects: Adrenergic α blocking: hypotension Anti-histaminic H1 Lower seizure threshold Increase prolactin release: galactorrhoea, gynecomastia, infertility Thioridazine: marked anticholinergic action- least chances of EPS among classical Trifluperazine, fluphenazine: minimum autonomic effects, less significant hypotensive, sedation & lowering seizure potential; less jaundice & hypersensitivity Haloperidol: preferred drug for acute psychosis, huntington diseases
- 13. Classical Antipsychotic drug:ADRs Reaction Presentation Time of maximal effect Proposed mechanism Treatment Acute muscle dystonia •Spasm of muscles of tongue, face, neck, back; may mimic seizures •More common in children ( esp girls), •2% incidence 1-3 days Unknown Central anticholinergic drugs Akathisia Motor restlessness 20% incidence 5-60 days Unknown Central anticholinergic or propranolol Parkinsonis m Bradykinesia, rigidity, variable tremor, mask facies, shuffling gait 5 to 30 days Antagonism of D2 receptors in nigrostriatal pathway Central anticholinergic s
- 14. Classical Antipsychotic drug:ADRs Reaction Presentation Time of maximal effect Proposed mechanis m Treatment Neuroleptic malignant syndrome High doses of potent agents Catatonia, stupor, fever, unstable blood pressure, myoglobinemia; can be fatal Weeks; can persist for days after stopping neurolept ic Antagonis m of dopamine may contribute Stop neuroleptic immediately; dantrolene or bromocriptin e may help Perioral tremor ("rabbit syndrome") Perioral tremor (a late variant of parkinsonism) After months or years of treatment Unknown Anticholinerg ic Tardive dyskinesia Oral-facial dyskinesia; widespread choreoathetosis or dystonia After months or years of treatment Increased Dopamine sensitivity of receptors High doses of antipsychotic drugs may be required
- 15. Classical antipsychotics OtherADRs of classical antipsychotics: Cholestatic jaundice: phenothiazines Hypersensitivity, photosensitivity: CPZ Thioridazine : Blue pigmentation on exposed skin, corenal & lenticular opacities, retinal degeneration, cardiac arrhythmias Male sexual dysfunction
- 16. Atypical antipsychotics Modeof action: High 5HT2/D2 receptor antagonism ratio Antagonism of adrenergic α2: respiridone, clozapine, olanzapine D4 receptor antagonism: clozapine Partial D2 receptor agonist: aripiprazole Also have anticholinergic & antihistaminic activity
- 17. Drug Comment Clozapine •NoEPS, tardive dyskinesia rare, prolactin level do not rise •Anticholinergic action but cause: hypersalivation •Effective in correcting negative symptom schizophrenia & resistant schizophrenia •ADR: agranulocytosis (0.8% incidence), myocarditis •Reserve drug for resistant schizophrenia . Regular monitoring of TLC Resperidon e • potent D2 blockade as compared to other atypical •EPS are less only at low doses (<6 mg/d) •Hyperprolactinemia may occur esp at high doses •Other ADRs: metabolic syndrome, stroke Olanzapine •Most commonly prescribed drug: effective in positive or negative symptoms of schizophrenia, mood stabilizer in mania •Anticholinergic action: cause dry mouth & constipation •Less D2 blockade- less EPS risk or less rise of prolactin •ADRs: weight gain, worsening diabetes, stroke risk
- 18. Drug Comments Quetiapine •short acting (t1/2= 6 hrs); BD-QID dosing •Less potent D2 block: less EPS & less hyperprolactinemia •Less propensity to cause weight gain & rise in blood sugar •Common side effect: sedation •Useful as mood stabilizer in mania/ bipolar disease Ziprasidone •5HT1D antagonism/ 5HT1a agonism / reuptake inhibitor of noradrenaline : antidepressant & anxiolytic activity •Useful in schizophrenic patient with depression , also as mood stabilizer •Causes QT prolongation- precipitate cardiac arrhythmias : issued black box warning Aripirazole •Partial agonist of D2 receptor – acts as D2 antagonist in meso limbic area (excess dopaminergic activity), but may act as partial agonist at nigrostriatal area • less tendency to cause weight gain, diabetes , stroke
- 19. Novel approaches asantipsychotic action Dopamine stabilizers : partial agonist bifeprunox, CI- 1007, DAB-452, roxindole NMDA agonism: Stimulating the glycine modulatory site of the NMDA receptor (e.g., L-glycine, serine, D-cycloserine, S-18841). 5-HT6 -receptor antagonists (SB-271046, SB-742457), and 5-HT7-receptor antagonists (SB-269970) α4β2 nicotinic receptor agonists (e.g., S1B-1553A), Cannabinoid CB1 antagonist (SR141716), Neurokinin-3 antagonists (SB-223412, SR-142801),
- 20.