Schizophrenia Flashcards
What are the principle neurotransmitter defects in schizophrenia?
Increased DA in mesolimbic pathway: positive symptoms –> hallucinations (mediated by D2Rs)
Reduced DA in mesocortical pathway: negative symptoms –> affective flattening (mediated by D1Rs)
How are drugs targeting the dopaminergic system utilised in treatment of schizophrenia?
- Chlorpromazine: possible D2R antagonist
- Haloperidol: potent D2R antagonist
- Clozapine: 5-HT2A R antagonist
- Risperidone: 5-HT2A R + D2R antagonist
- Quetiapine: H1R antagonist
- Aripiprazole: partial D2R + 5-HT1A agonist
Which symptoms do anti-psychotics treat?
- Only positive symptoms
- Bc they are D2 antagonists correcting over activity of dopamine in mesolimbic system and striatum but have no effect on the forebrain dopamine deficits where negative symptoms are produced
What are the side effects of chlorpromazine?
- Anti-cholinergic: sedation (common)
- Extra-pyramidal (less common)
What are the symptoms of schizophrenia?
Positive:
- Delusions - paranoia
- Hallucinations (auditory + visual)
- Thought disorder - denial about oneself
Negative:
- Avolition/apathy - loss of motivation
- Alogia - lack of speech
- Affective flattening - lack of emotion
What cause the negative symptoms of schizophrenia?
Decreased mesocortical dopaminergic activity
What are the 1st generation anti-psychotics and how do they work?
- Chlorpromazine - possibly D2R antagonism
2. Haloperidol - potent D2R antagonism
Is chlorpromazine or haloperidol more potent?
Haloperidol is a 50x more potent D2R antagonist
What are the 2nd generation anti-psychotics and how do they work?
- Clozapine - potent 5-HT2A R antagonist
- Risperidone - potent 5-HT2AR + D2R antagonist
- Quetiapine - potent H1R antagonist
- Aripiprazole - partial D2R + 5-HT1A R agonist
Which symptoms does clozapine treat?
Positive symptoms (like most anti-psychotics) Some negative symptoms - only drug that does this
Which is the most effective anti-psychotic?
Clozapine
Treats positive and SOME NEGATIVE symptoms
What are the side effects of clozapine?
- Potentially fatal neutropenia, agranulocytosis, myocarditis
- Weight gain
- Tf only given in drug-resistant schizophrenia
What are the side effects of risperidone?
- Weight gain
- EPS
- Hyperprolactinaemia
What are the side effects of quetiapine?
- EPS (but lower incidence than other anti-psychotics)
What are the side effects of aripiprazole?
- Weight gain
- Hyperprolactinaeima
- But both less than other anti-psychotics
How does aripiprazole work?
Partial agonist of D2 + 5-HT1A Rs
- Brings down too much activity (mesolimbic)
- Brings up too little activity (mesocortical)
Why do some anti-psychotics cause extra-pyramidal symptoms?
Blockade of dopamine receptors in the nigrostriatal system can induce “Parkinson” like side effects
What are the general side effects of anti-psychotics?
- Anti-emetic effects
- Anti-histamine effects
- Extra pyramidal motor disturbances: acute dyskinesias, tardive dyskinesias (20-30%)
- Endocrine effects: hyperprolactinaemia
- Anti-muscarinic effects
When do acute dyskinesias develop? How can they be reversed and controlled?
- At the onset of treatment
- Reversible with drug withdrawal
- Controlled by anticholinergics or muscle relaxants e.g. diazepam
What exacerbates tardive dykinesias? How are they overcome? When do they occur?
- Worsened by drug withdrawal and anti-cholinergics
- Irreversible
- Overcome by increasing dose of anti-psychotic
- Occur after several months or years of treatment
What causes the endocrine effects associated with anti-psychotic treatment?
Blockade of dopamine receptors in the tuberofundibular pathway (from hypothalamus to median eminence + pituitary gland)
What might cause tardive dykinesias?
- Proliferation of dopamine receptors (pre-synaptic) in the striatum
- Toxicity of anti-psychotics
What are the typical anti-muscarinic side effects?
Blurring of vision, increased intra-ocular pressure, dry mouth, constipation, urinary retention
