Anti-psychotics

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Anti-psychotics

• Mainstay of pharmacological treatment for
  schizophrenia and related disorders
• Diminish positive symptoms such as
  hallucinations, delusions, thought disorder
• Some impact on negative symptoms such as lack of
  motivation, blunted affect, cognitive impairment
• Important as a part of relapse prevention

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Anti-psychotics

• Antagonise dopamine receptors, resulting in
  anti-psychotic effects
• Indications-schizophrenia, acute mania, psychotic
  depression,
• Conventional and atypical
• Both of equivalent efficacy when taken at
  recommended dosages
• Atypicals have lower incidence of EPSE

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Dopamine Theory

• The dopamine hypothesis of psychosis
  overactivity of dopamine neurons in the
  mesolimbic pathway of the brain may mediate the
  positive symptoms of psychosis
• Mesolimbic pathway responsible for pleasure,
  effects of drugs and alcohol and hallucinations
  and delusions

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Blockade Of D2 Receptors?
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Dopamine Receptors

• Five subtypes D2 most important in terms of
  psychosis
• Blockade of mesolimbic receptors leads to reduced
  psychotic symptoms
• Blockade of the mesocortical pathway leads to
  increased negative symptoms

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Dopamine Receptors

• Dopamine and acetylcholine have a reciprocal
  relationship-
• Blockade of dopamine receptors increases the
  activity of acetylcholine
• Over activity of acetylcholine causes EPSE
• Blockade of dopamine causes movement disorders in
  the nigostriatal pathway
• Long tem blockade causes upregulation and leads
  to Tardive Dyskinesia

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Conventional or typical Antipsychotics

• Have four actions blockade of
• Dopamine 2
• Muscarinic/cholinergc
• Alpha adrenergic
• Histamine

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Serotonin and Dopamine Interactions
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The Dopamine Receptor Antagonist Hypothesis of
Antipsychotic drug Action

• Blockade of post synaptic dopamine receptors in
  the mesolimbic pathway is thought to mediate the
  efficacy of the drug and its ability to diminish
  positive symptoms

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Receptor Affinity

• Low Affinity (loosely bound)
• - Quetiapine, Olanzapine, Amisulpride,
  Clozapine
• High Affinity (tightly bound)
• - Chlorpromazine, Haloperidol, Flupenthixol,
  Fluphenazine
• Tightly bound drugs lead to increased sensitivity
  to dopamine blockade so more likely to cause EPSE

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Atypical Antipsychotics

• Pharmacologic Properties
• 5HT2A and D2 antagonism (as opposed to
  conventional drugs which are D2 without 5HT2A
  antagonism)
• Atypicals blockade of D2 and 5HT2A

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Dopamine and Serotonin Receptors

• Dopamine and serotonin have a reciprocal
  relationship
• Serotonin opposes the release of dopamine in the
  nigrostriatal and tuberofundibular pathways

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Dopamine and Serotonin Receptors

• Action of atypicals firstly binds to the D2
  receptor
• Secondly, binds to the 5HT2A receptor
• The second action reverses the first reverses
  the blockade of D2
• Blocking 5HT2A disinhibits the dopamine neuron
  causing dopamine to pour out

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Dopamine and Serotonin Receptors

• The dopamine and serotonin then compete with the
  drug for the D2 receptor
• Increased dopamine in the mesocortical pathway
• Reduction in movement disorders/EPSE for atypical
  antipsychotics

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Atypicals

• In reality not simple serotonin-dopamine
  antagonists
• Most complex pharmacological properties
• Act on multiple serotonin and dopamine receptors,
  histamine, alpha adrenergic cholinergic

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Atypicals versus conventional

• All equal efficacy (except Clozapine)
• Consideration for
• Merits of high versus low affinity drugs
• Cerebral selectivity of the drugs
• Adverse effect profile
• Dose necessary to achieve optimal D2 blockade
• Patient tolerability, preference, response

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Anti-psychotics

• Conventional eg chlorpromazine, haloperidol,
  stelazine, depots such as flupenthixol,
  zuclopenthixol, fluphenazine
• Atypical eg olanzapine, risperidone,
  quetiapine, amisulpride, clozapine, risperdal
  consta intramuscular injection, aripiprazole,
  paliperidone, ziprasidone
• Also have effects on acetylcholine,
  histamine,serotonin receptors varying adverse
  effects

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Atypical antipsychotics

• The newer antipsychotics
• Effectively treat psychotic symptoms
• Lower incidence of extra pyramidal side effects
  than conventional agents
• Have effects on dopamine, serotonin, histamine
  and muscarinic receptors

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Atypical antipsychotics

• Current atypicals in use in Australia are
• Amisulpride
• Aripiprazole
• Quetiapine
• Olanzapine
• Risperidone
• Clozapine
• Ziprasidone
• Paliperidone

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Therapeutic effects on symptoms

• Agitation, sleep and appetite often respond in
  the first 1-2 weeks
• Personal hygiene and basic interpersonal
  socialisation may take 2-3 weeks and psychotic
  symptoms can gradually decrease over 2-6 weeks
• An effective trial should be at least 6-8 weeks
  at doses that are within the prescribed range

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How long should antipsychotics be taken for?

• At least 6 months after an acute episode reduces
  relapse rates
• If the person experiences another episode they
  may need antipsychotic medication for 2-5 years
  before ceasing use
• For those with multiple episodes, they may need
  medication for much of their life

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Adverse Effects

• Sedation
• Postural hypotension
• Anticholinergic effects dry mouth, blurred
  vision, constipation, urinary hesitancy
• Weight gain-clozapine, olanzapine
• Metabolic effects-increased serum lipids,
  impaired glucose tolerance-clozapine, olanzapine,
  quetiapine

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Adverse Effects

• Hyperprolactinaemia-leads to
  galactorrhoea, amenorrhoea, decreased libido
• Sexual dysfunction
• QTc prolongation-leads to cardiac arrhythmias
• EPSE-extrapyramidal side effects
• Acute dystonias -laryngeal spasm, oculogyric
  crises
• Akathisia-severe sense of agitation, inner
  restlessness in the limbs, especially the legs

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Adverse Effects

• Akathesia a severe sense of psychomotor
  agitation
• Parkinsonism -poverty of movement, tremor,
  rigidity, drooling, hypersalivation
• Tardive dyskinesia-involuntary hyperkinetic
  movements, affects the mouth, lips, tongue, jaws
  with smacking, tongue writhing, sucking,chewing
  and tic like movements,limbs and trunk can be
  affected

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Adverse Effects

• Irreversible in some patients
• Neuroleptic malignant syndrome-rare but
  potentially fatal high temp, muscle rigidity,
  altered consciousness, raised creatinine kinase
  cease medication
• Can happen at anytime during treatment
• 30 patients will develop syndrome again on
  rechallenge

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Depot Anti-psychotics

• Used when concerns around compliance
• Conventional-zuclopenthixol(useful for
  agitated,aggressive,disturbed behaviour)
  flupenthixol (may have mood elevating effects)
  fluphenazine -EPSE common
• Typical-Risperdal Consta onset of action 3
  weeks, need oral Risperidone to supplement until
  peak plasma reached

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Comparative Information for Anti-Psychotics
Chlorpromazine, Pericyazine Most sedating, most potent anticholinergic effects, least likely to cause EPSE, most likely to cause orthostatic hypotension. Low potency antipsychotics
Trifluperazine, Fluphenazine Moderately sedating, intermediate propensity to cause EPSE, some potential to cause orthostatic hypotension
Haloperidol, Droperidol, Thiothixene, Pimozide Least sedating, almost no anticholinergic effects, most likely to cause EPSE, least likely to cause orthostatic hypotension, sometimes referred to as high potency antipsychotics
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Atypical antipsychotics
Amisulpride Less potential for weight gain and sedation
Aripiprazole May cause insomnia, less potential for hyperprolactinaemia
Clozapine Effective treatment-resistant patients but has serious side-effects (blood dyscrasias, seizures, cardiomyopathy, myocarditis, orthostatic hypotension, sedation, weight gain).
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Atypical antipsychotics
Olanzapine Related to Clozapine may cause sedation, weight gain, peripheral oedema increased risk of stroke and related mortality in elderly dementia patients
Quetiapine Sedating and vasoactive, less potential for hyperprolactinaemia
Risperidone, Paliperidone Orthostatic hypotension and hyperprolactinaemia, may be a problem increased risk of stroke and related mortality in elderly dementia patients
Ziprasidone Less potential for weight gain
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Drug Interactions

• Cytochrome P450 isoenzymes are significant in
  psychotropic drug interactions
• Inducers or inhibitors of this pathway may
  produce clinically important drug interactions
• May lead to increase or decrease of medications
  due to interactions

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Cytochrome P450

• Examples
• Fluvoxamine inhibits olanzapine and clozapine
  metabolism
• Smoking induces Olanzapine metabolism
• SSRIs inhibit most antipsychotics and therefore
  increase serum concentrations
• Phenytoin reduces serum concentration of
  Quetiapine
• Others grapefruit juice, Antibiotics,

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Clozapine

• Used when previously unresponsive to other
  antipsychotics
• Serious adverse effect profile
• Strict guidelines relating to commencement and
  monitoring
• Significant risk of agranulocytosis
• Trial at least 2 different standard
  antipsychotics at an adequate dose and for an
  adequate duration prior to commencing Clozapine

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Use of antipsychotics with older persons

• Various disorders treated with antipsychotics in
  the elderly psychosis, bipolar affective
  disorder, delirium dementia
• Use extreme caution because of side effect
  profile
• Start low go slow (Malone et al 2007)
  titrate over longer periods of time to reach the
  required dose
• Avoid polypharmacy wherever possible

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Pregnancy lactation

• Avoid antipsychotics if possible
• Use the lowest effective dose
• Neonatal adverse effects observed include
  generalised hypertonicity and dystonic reactions

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Pregnancy lactation

• The safety of atypical agents is yet to be
  established but preliminary reports there to be
  no deleterious effects to the foetus
• Isolated cases of congenital abnormalities with
  the use of Clozapine

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Pregnancy Lactation

• No increased risk has emerged with the use of
  Olanzapine
• The conventional agents are generally preferred
• Supervised dose reduction and cessation 7-10 days
  prior to delivery should be considered

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What other treatments are available?

• Remember that antidepressant medication is only
  part of the
• treatment for antenatal depression and anxiety.
  Also consider
• Psychological therapies
• Exclude organic illness as a cause of mental
  health symptoms
• Address any alcohol and/or illicit substance
  abuse
• Assess the social situation
• General lifestyle measures adequate rest/sleep,
  balanced diet, exercise
• The decision to treat should be made on an
  individual case basis
•  

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Conclusion

• Conventional and atypical antipsychotics are used
  as the foundation for pharmacological management
  of schizophrenia and related psychosis
• All have equal efficacy, exception Clozapine
• Atypicals generally better tolerated have less
  EPSE
• Atypicals first line treatment
• Start lowest effective possible dose titrate
  upwards
• Ongoing monitoring management of adverse
  effects
• Caution numerous drug interaction potential for
  neuroleptic malignant syndrome

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Resources

• Therapeutic Guidelines Psychotropic Version 5
• www.tg.com.au 9329 1566
• Australian Medicines Handbook
• www.amh.net.au 08 8303 6977
• MIMS online
• http//www.ppmis.org.au Perinatal Psychotropic
  Medicine Information Service