Treaments

Treaments

Antipsychotic Drugs and Dopamine
1. Chlorpromazine relieves positive symptoms of schizo for most patients
2. antipsychotic/neuroleptic drugs in 2 chemical families
  1. phenothiazines including chlorpromazine
  2. butyrophenones include haloperiodol
  3. behavioural benefits of these drugs develop gradually over month+
  4. symptoms generally return after cessation of treatment
  5. block dopamine synapses
    1. inspired dopamine hypothesis of schizophrenia
      1. holds schizo results from excess activity at dopamine synapses in certain brain areas
        concentration of dopamine in brain no higher than normal, turnover is elevated especially in basal ganglia
        KUMAKURA ET AL 2007
        neurons release dopamine at faster than average rate and synthesise more to replace molecules that they do not reabsorb
        elevated dopamine release also occurs in people showing first symptoms of schizo
        HOWS ET AL 2009
3. support for dopamine hypothesis comes from fact late, repeated use of amphetamine, methamphetamine
  1. or cocaine induces substance induced psychotic disorder
    1. characterised by hallucinations and delusions (positive symptoms)
  2. each drug increases prolongs activity at dopamine synapses
    1. LSD produced psychotic symptoms best known for effects on serotonin synapses but also stimulates dopamine synapses
4. researchers set out to measure number of dopamine receptors occupies given moment
  1. used radioactively labeled drug, IBZM that binds to dopamine type D2 receptors
    1. because IBZM binds only to receptors that dopamine didn't already bind, measuring radioactivity counts number of vacant dop receptors
      1. used second drug AMPT to block all synthesis of dopamine and again used IBZM to count number of vacant D2 receptors
        because AMPT had revenged production of dopamine, all D2 receptors should be vacant so researchers got a count of the total
        they subtracted first count of second count, yielding number of D2 receptors occupied by dopamine at first count
        first: IBZM binds to D3 receptors not already attached to dopamine
        second: IBZM binds to all D2 receptors because AMPT eliminated production of dopamine
        second count minus first equals number of D2 receptors bound to dopamine at first count
      2. researchers found people with schizo had twice as many D2 receptors occupied as normal
Role of Glutamate
1. glutamate hypothesis of schizo
  1. problem relates in part to deficient activity at glutamate synapses, especially in prefrontal cortex
  2. many brain areas dopamine inhibits glutamate release or glutamate stimulates neurons that inhibit dopamine release
    1. increased dopamine would produce same effects as decreased glutamate
    2. antipsychotic effects of drugs block dopamine compatible with either excess dopamine hypothesis or deficient glutamate hypothesis
2. schizo assoc with lower than normal release of glutamate and fewer than normal receptors in prefrontal cortex and hippo
  1. similar in those high at risk for developing schizo due to family background
3. support for glutamate hyp of schizoi from effects of phencyclidine (PCP)
  1. inhibits NMDA glutamate receptors
    1. low doses produces intoxication and slurred speech
    2. high doses produces both negative and positive symptoms of schizo including hallucination though disorder, loss of emotions and memory loss
  2. PCP and ketamine produce little if any psychotic response in preadolescents
    1. just as symptoms of schizo usually begin emerge well after puberty, so do psychotic effects of PCP and ket
  3. LSD, coke and amphetamine produce temp schizo symptoms in anyone and effects aren't much worse with this with history of schizo
    1. PCP produces severe effects for someone recoveringg form schizo
4. administer glutamate itself?
  1. strokes kill neurones by overstimulating glutamate synapses
  2. too risky
  3. drugs stimulating particular kinds of metabotropic glutamate receptors have shown promise in treating schizo
    1. PATIL ET AL 2007
New Drugs
1. brian had several dopamine pathways with diff functions
  1. drugs that block dopamine synapses produce benefits by acting on neurones in mesolimbocortical system
    1. set of neurons that project from midbrain tegmentum to the limbic system
    2. drug also blocks dopamine neurons in mesostriatal system projects to basal ganglia
      1. effect on basal ganglia produces tardive dyskinesia
        characterised by tremors and involuntary movement that develop gradually to varying degrees among different patients
        once tardive dyskinesia emerges, can last long after someone quits the drug
        KIRIAKAKIS ET AL 1998
2. second-generation antipsychotics alleviate schizo without producing movement problems
  1. most common is clozapine, risperidone, apripipazole
    1. more effective than older drugs at treating negative symptoms of schizo and now used more widely
      1. other side effects like weight game and impairment of immune system
3. don't improve quality of life much more than older drugs

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