Antipsychotic drugs

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Antipsychotic drugs
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CNS drugs

• Functionally, the CNS is the most complex part of
  the body, and understanding drug effects is
  difficult
• Understanding the effects of drugs on individual
  neurons does not predict the effect on the whole
  organ
• In part this is due to complex interactions
  mediated by different neurotransmitters

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Dopamine

• Important neurotransmitter
• Present mainly in the nigrostriatal, mesolimbic
  and tubero-infundibular pathways
• Originally there were only thought to be two main
  groups of dopamine receptor D1 and D2 . These
  stimulate and inhibit adenylate cyclase
  respectively
• Subsequently D3 (related to D1) and D4 (related
  to D2 ) receptors were discovered
• D2 receptors are mainly responsible for the
  actions of anti-psychotic drugs

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Dopamine functions

• Motor control - nigrostriatal system
• Deficiency results in rigidity, tremor and
  difficulty initiating movement
• Behavioural effects - mesolimbic system
• Overactivity in rats leads to abnormal behavior
• Endocrine control - tubero-infundibular system
• Dopamine and dopamine agonists suppress prolactin
  release, dopamine antagonists may stimulate it

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Schizophrenia - dopamine

• Amphetamine (which releases dopamine) can produce
  a syndrome similar to the positive features of
  schizophrenia
• Levodopa may aggravate the condition
• Apomorphine and bromocriptine (D2 agonists)
  produce behavioral abnormalities in animals
• D2 receptor antagonists are effective in
  controlling the positive features of the disorder
• ? Increased D2 receptor binding in the brains of
  schizophrenic subjects. Evidence of genetic
  variation in the D4 receptor to which some
  anti-psychotic drugs have high affinity

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Schizophrenia - serotonin

• LSD which has mixed agonist/antagonist
  serotonergic actions produces hallucinations and
  behavioral disturbance
• Some antipsychotic drugs also act at 5-HT
  receptors (antagonists of 5HT2)
• 5-HT has a modulatory effect on dopaminergic
  neurones

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Modes of action

• All anti-psychotic drugs have inhibitory effects
  on the D2 receptor
• Some have actions against the D4 receptor
• All have other effects - to varying degrees
• Serotonin 5HT2 blockade (may improve negative
  symptoms)
• Histamine H1 blockade (drowsiness)
• Alpha adrenoceptor blockade (postural hypotension)

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How do we know they work?

• Mostly by accident for early drugs
• designing drugs to reduce anxiety in surgical
  patients
• Clinical experience
• Clinical trials
• especially more recent drugs
• PET scanning showing blockade of central D2
  receptors

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Clinical effects

• Control the positive features of the disease,
  but little effect on the negative features
• clozapine may be superior in this regard
• The main side-effects are on the extrapyramidal
  motor system
• Akathisia (hours)
• Dystonias (hours to days)
• Parkinsonism (weeks to months)
• rigidity, tremor, and loss of mobility
• Tardive dyskinesia (months to years)
• Repetitive abnormal movements of face and upper
  limbs
• Thought to be due to proliferation of D2
  receptors in the striatum

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Clinical effects

• Newer atypical anti-psychotic drugs are less
  inclined to produce these effects - possible due
  to their greater affinity for the mesolimbic over
  the striatal areas of the brain

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Other effects

• Some are effective anti-emetics
• Anti-muscarinic effects lead to dry mouth,
  blurred vision, difficulty with micturition
• a antagonist effects lead to postural hypotension
• Antihistamine effects (H1 receptor) lead to
  drowsiness
• Prolactin stimulation may lead to breast
  development
• Agranulocytosis is fairly common with an
  atypical drug clozapine which can also cause
  a myocarditis
• Neuroleptic malignant syndrome is a rare but
  serious effect leading to extrapyramidal
  rigidity, autonomic instability and hyperthermia

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Other effects
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Traditional Antipsychotics

• Phenothiazines
• chlorpromazine (Chlorpromazine Mixture,
  Chlorpromazine Mixture Forte, Largactil)
• fluphenazine (Anatensol, Modecate)
• flupenthixol (Fluanxol)
• pericyazine (Neulactil)
• pimozide (Orap)
• thioridazine (Aldazine)
• trifluoperazine (Stelazine)
• zuclopenthixol (Clopixol)
• Butyrophenones
• droperidol (Droleptan Injection)
• haloperidol (Haldol, Serenace)

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Newer Antipsychotics

• Atypical agents
• aripiprazole (Abilify)
• clozapine (CloSyn, Clopine, Clozaril)
• risperidone (Risperdal)
• quetiapine (Seroquel)
• amisulpride (Solian)
• olanzapine (Zyprexa)

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Antipsychotics
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Differences among Antipsychotic Drugs

• Chlorpromazine a1 5-HT2 gt D2 gt D1
• Haloperidol D2 gt D1 D4 gt a1 gt 5-HT2
• Clozapine D4 a1 gt 5-HT2 gt D2 D1

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Atypical antipsychotics

• Claims
• lower doses
• reduced side effects
• more effective (especially negative symptoms)
• better compliance
• Evidence?
• trials have been quite small and involved
  patients previously heavily treated and somewhat
  resistant
• trials have tended to show equivalent efficacy
  and better side effect profiles with newer drugs
• head to head trials claimed superiority of
  olanzapine over risperidone (but company
  sponsored and controversial) some parallel
  publications
• Costs
• Much higher with new drugs (10-40 times higher)

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Metabolic effects
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Insulin resistance

• Prediabetes (impaired fasting glycaemia) has
  10 chance / year of converting to Type 2
  diabetes
• Prediabetes plus olanzapine has a 6-fold
  increased risk of conversion
• If olanzapine is stopped 70 will revert back to
  prediabetes

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Stroke in the elderly

• Risperidone and olanzapine associated with
  increased risk of stroke when used for
  behavioural control in dementia
• Risperidone 3.3 vs 1.2 for placebo
• Olanzapine 1.3 vs 0.4 for placebo
• However, large observational database studies
• Show no increased risk of stroke compared with
  typical antipsychotics or untreated dementia
  patients

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Conclusions

• Atypical antipsychotics have serotonin blocking
  effects as well as dopamine blockade
• As a group have less chance of extrapyramidal
  side effects
• Most have weight gain and insulin resistance as a
  side effect (except perhaps aripiprazole and
  maybe amisulpride)
• May be associated with stroke when used for
  behavioural control in dementia
• Many have idiosyncratic toxicities

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Differences among Antipsychotic Drugs

• All effective antipsychotic drugs block D2
  receptors
• Chlorpromazine and thioridazine
• block a1 adrenoceptors more potently than D2
  receptors
• block serotonin 5-HT2 receptors relatively
  strongly
• affinity for D1 receptors is relatively weak
• Haloperidol
• acts mainly on D2 receptors
• some effect on 5-HT2 and a1 receptors
• negligible effects on D1 receptors
• Pimozide and amisulpride
• act almost exclusively on D2 receptors

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Differences among Antipsychotic Drugs

• Clozapine
• binds more to D4, 5-HT2, a1, and histamine H1
  receptors than to either D2 or D1 receptors
• Risperidone
• about equally potent in blocking D2 and 5-HT2
  receptors
• Olanzapine
• more potent as an antagonist of 5-HT2 receptors
• lesser potency at D1, D2, and a1 receptors
• Quetiapine
• lower-potency compound with relatively similar
  antagonism of 5-HT2, D2, a1, and a2 receptors

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Differences among Antipsychotic Drugs

• Clozapine, olanzapine and quetiapine
• potent inhibitors of H1 histamine receptors
• consistent with their sedative properties
• Aripiprazole
• partial agonist effects at D2 and 5-HT1A receptors