Antipsychotics

Antipsychotics

Psychosis= loss of touch with reality. Can be associated with a variety of disorders including depression but most usually SCHIZOPHRENIA
1. Schizophrenia characterised by mutiple symptoms divided into positive (additional to normal behaviour) & negative (lacking compared to normal)
  1. Affects up to 1% of popn. Typical age of onset is 23-28 for men & 28-32 for women often with an earlier phase of social isolation & withdrawal
    1. ~65% of sufferers have one or more episodes with either no inter-espisode impairment (~55%) or a constant level (10%, ~35% have multiple episodes with increasing levels of impairment, ~10% of sufferers commit suicide
    2. genetic component- in twin studies, 14 x increase in incidence for a dizygotic sibling & a 50% incidence for a monozygotic sibling
Positive symptoms
1. Hallucinations (auditory & visual)- perceptions in the absence of a real stimuli/ Delusions of persecution & loss of control of own thoughts and actions. Nature of delusions determned by social and historical factors/ Thought disorders- making speech hard to follow
  1. tend to be associated with acute episodes (suffer then recover)
Negative symptoms
1. Loss of empathy with others, inappropriate or blunted mood; repetitive activity, apathy, attentional impairment
2. More frequently with chronic schizophrenia
Treatment
1. Early
  1. Asylum- treatment for 'lunatics'- remained the case into the 20th century
  2. Typical antipsychotics
    1. cause extra-pyramidal side effecs
      1. Acute dystonia- involuntary movements, often similar to Parkinson's includes rigidity, tremor, inability to sit still, slowing of voluntary movements
      2. Tardive dyskinesias- occurs after long term treatment in 10-20% of patients. Causes large involuntary movements. Symptoms may worsen with reduces antipsychotic doses
    2. Act against positive but not negative symptoms
    3. have unselective binding to dopamine receptors
    4. 3 classes- phenothiazines (chloropromazine), thioxanthenes & butyrophenones (haloperidol)
    5. mixed pharmacology eg. chlorpromazine (antagonist at D1, D2, D3, D4, 5HT1, 5HT2, a1, a2, M1, M2), Haloperidol (D2>D4>D3>D1/5 antagonist)
2. Atypical antipsychotics
  1. Dibenzodiazepines: More recently developed, exemplified by clozapine
    1. Clozapine antagonist at D4>D3>D1>D2, 5-HT 2A/2C
    2. Risperidone antagonist at D2, 5HT2A
  2. fewer extra-pyramidal side effects
  3. efficacy against both positive & negative symptoms
  4. A different receptor selectivity profile
3. Newer drugs
  1. benzamides eg amisulpride-selective antagonist at D2 receptors
  2. quetiapine- similar binding profile to clozapine but with lower affinities
  3. even with the latest drugs, ~30% of patients dont respond to treatment. The difference between responders and non-responders is not known.
Receptor subtypes & subunits
1. molecular cloning has identified 5 DA receptor subunits (D1-D5)- grouped into subtypes: D1 (D1 & D5), D2 (D2, D3, D4).
2. Most antipsychotics are antagonists at the D2 subtype. Extrapyramidal side effects tend to result from the block of the D1 subunit. Many of the newer atypical antipsychotics are selective for D2 & D4
Schizophrenia causes
1. MRI scans reveal structural neuronal defects. In particular, schizophrenic patients have smaller cortices & larger ventricles (particularly in medial temporal lobe & left hemisphere)
  1. These changes are not progressive, indicating the cause is developmental, rather than degeneration
2. Dopamine theory
  1. Compounds that increase dopaminergic signalling acitivty (eg amphetamines) can induce psychosis. There is a correlation between D2 receptor antagonist affinity & clinical antipsychotic efficacy (i.e. schizophrenia can be treated by blocking D2 receptor activation)
  2. Structural deficits in the brain suggest a loss of control of dopaminergic function
3. Glutamate theory
  1. Dysfunction in glutaminergic neurotransmission has also been suggested as a cause of schizophrenia based on -psychotomimetic actions of NMDA receptor channel blockers e.g. phencyclidine, ketamine -reduced glutamate binding in post-mortem studies of schizophrenic patients
4. Serotoninergic system
  1. 5HT has been proposed to play a role with some atypical antipsychotics selectively blocking 5HT2A receptors. LSD also has psychotomimetic properties. Serotonin modulates DA actions, so this is not necessarily incompatible with the dopamine theory

Next up

Description

Resource summary

Similar

	Created by tanitia.dooley over 11 years ago