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Anti-psychoticsAnti-psychotics
Mainstay of pharmacological treatment for Mainstay of pharmacological treatment for schizophrenia and related disordersschizophrenia and related disorders
Diminish positive symptoms such as Diminish positive symptoms such as hallucinations, delusions, thought disorderhallucinations, delusions, thought disorder
Some impact on negative symptoms such Some impact on negative symptoms such as lack of motivation, blunted affect, as lack of motivation, blunted affect, cognitive impairmentcognitive impairment
Important as a part of relapse preventionImportant as a part of relapse prevention
Anti-psychoticsAnti-psychotics
Antagonise dopamine receptors, Antagonise dopamine receptors, resulting in anti-psychotic effectsresulting in anti-psychotic effects
Indications-schizophrenia, acute Indications-schizophrenia, acute mania, psychotic depression,mania, psychotic depression,
Conventional and atypicalConventional and atypical Both of equivalent efficacy when taken Both of equivalent efficacy when taken
at recommended dosagesat recommended dosages Atypicals have lower incidence of EPSEAtypicals have lower incidence of EPSE
Dopamine TheoryDopamine Theory The dopamine hypothesis The dopamine hypothesis
of psychosis – overactivity of psychosis – overactivity of dopamine neurons in of dopamine neurons in the the mesolimbicmesolimbic pathway of pathway of the brain may mediate the the brain may mediate the positive symptoms of positive symptoms of psychosispsychosis
Mesolimbic pathway Mesolimbic pathway responsible for pleasure, responsible for pleasure, effects of drugs and effects of drugs and alcohol and hallucinations alcohol and hallucinations and delusionsand delusions
Blockade Of D2 Receptors?Blockade Of D2 Receptors?
D2ANTAGONIST
Mesolimbic pathway dramatic therapeutic action on positive psychotic symptoms
Tuberoinfundibular pathway
hyperprolactinemia (lactation,
infertility, sexual dysfunction)
Nigrostriatal pathway extrapyramidal side effects (EPS) and tardive dyskinesiaMesocortical pathway
enhanced negative and cognitive
psychotic symptoms
Dopamine ReceptorsDopamine Receptors
Five subtypes – D2 most important in Five subtypes – D2 most important in terms of psychosisterms of psychosis
Blockade of mesolimbic receptors Blockade of mesolimbic receptors leads to reduced psychotic leads to reduced psychotic symptomssymptoms
Blockade of the mesocortical Blockade of the mesocortical pathway leads to increased negative pathway leads to increased negative symptoms symptoms
Dopamine ReceptorsDopamine Receptors
Dopamine and acetylcholine have a Dopamine and acetylcholine have a reciprocal relationship-reciprocal relationship-• Blockade of dopamine receptors increases Blockade of dopamine receptors increases
the activity of acetylcholinethe activity of acetylcholine• Over activity of acetylcholine causes EPSEOver activity of acetylcholine causes EPSE• Blockade of dopamine causes movement Blockade of dopamine causes movement
disorders in the nigostriatal pathwaydisorders in the nigostriatal pathway• Long tem blockade causes “upregulation” Long tem blockade causes “upregulation”
and leads to Tardive Dyskinesiaand leads to Tardive Dyskinesia
Conventional or typical Conventional or typical AntipsychoticsAntipsychotics
Have four actions – Have four actions – blockade of:blockade of:• Dopamine 2Dopamine 2• Muscarinic/Muscarinic/
cholinergccholinergc• Alpha adrenergicAlpha adrenergic• HistamineHistamine
Serotonin and Dopamine Serotonin and Dopamine InteractionsInteractions
The Dopamine Receptor The Dopamine Receptor Antagonist Hypothesis of Antagonist Hypothesis of Antipsychotic drug ActionAntipsychotic drug Action
Blockade of post Blockade of post synaptic dopamine synaptic dopamine receptors in the receptors in the mesolimbic mesolimbic pathway is thought pathway is thought to mediate the to mediate the efficacy of the drug efficacy of the drug and its ability to and its ability to diminish positive diminish positive symptomssymptoms
Receptor AffinityReceptor Affinity
Low Affinity (loosely bound)Low Affinity (loosely bound)
- Quetiapine, Olanzapine, Amisulpride, - Quetiapine, Olanzapine, Amisulpride, ClozapineClozapine
High Affinity (tightly bound)High Affinity (tightly bound)
- Chlorpromazine, Haloperidol, - Chlorpromazine, Haloperidol, Flupenthixol, FluphenazineFlupenthixol, Fluphenazine
Tightly bound drugs lead to increased Tightly bound drugs lead to increased sensitivity to dopamine blockade so sensitivity to dopamine blockade so more likely to cause EPSEmore likely to cause EPSE
Atypical AntipsychoticsAtypical Antipsychotics
Pharmacologic Pharmacologic Properties Properties • 5HT2A and D2 5HT2A and D2
antagonism (as antagonism (as opposed to opposed to conventional drugs conventional drugs which are D2 which are D2 without 5HT2A without 5HT2A antagonism)antagonism)
• Atypicals – blockade Atypicals – blockade of D2 and 5HT2Aof D2 and 5HT2A
Dopamine and Serotonin Dopamine and Serotonin ReceptorsReceptors
Dopamine and Dopamine and serotonin have a serotonin have a reciprocal reciprocal relationshiprelationship
Serotonin opposes Serotonin opposes the release of the release of dopamine in the dopamine in the nigrostriatal and nigrostriatal and tuberofundibular tuberofundibular pathwayspathways
Dopamine and Serotonin Dopamine and Serotonin ReceptorsReceptors
Action of atypicals – firstly binds to the Action of atypicals – firstly binds to the D2 receptorD2 receptor
Secondly, binds to the 5HT2A receptorSecondly, binds to the 5HT2A receptor The second action reverses the first – The second action reverses the first –
reverses the blockade of D2reverses the blockade of D2 Blocking 5HT2A disinhibits the Blocking 5HT2A disinhibits the
dopamine neuron causing dopamine dopamine neuron causing dopamine to pour outto pour out
Dopamine and Serotonin Dopamine and Serotonin ReceptorsReceptors
The dopamine and serotonin then The dopamine and serotonin then compete with the drug for the D2 compete with the drug for the D2 receptorreceptor
Increased dopamine in the Increased dopamine in the mesocortical pathwaymesocortical pathway
Reduction in movement Reduction in movement disorders/EPSE for atypical disorders/EPSE for atypical antipsychoticsantipsychotics
AtypicalsAtypicals
In reality – not simple In reality – not simple serotonin-dopamine serotonin-dopamine antagonistsantagonists
Most complex Most complex pharmacological pharmacological propertiesproperties
Act on multiple Act on multiple serotonin and serotonin and dopamine receptors, dopamine receptors, histamine, alpha histamine, alpha adrenergic & adrenergic & cholinergiccholinergic
Atypicals versus conventionalAtypicals versus conventional
All equal efficacy (except Clozapine)All equal efficacy (except Clozapine) Consideration for:Consideration for:
• Merits of high versus low affinity drugsMerits of high versus low affinity drugs• Cerebral selectivity of the drugsCerebral selectivity of the drugs• Adverse effect profileAdverse effect profile• Dose necessary to achieve optimal D2 Dose necessary to achieve optimal D2
blockadeblockade• Patient tolerability, preference, responsePatient tolerability, preference, response
Anti-psychoticsAnti-psychotics
Conventional – eg chlorpromazine, Conventional – eg chlorpromazine, haloperidol, stelazine, depots such as haloperidol, stelazine, depots such as flupenthixol, zuclopenthixol, flupenthixol, zuclopenthixol, fluphenazinefluphenazine
Atypical – eg olanzapine, risperidone, Atypical – eg olanzapine, risperidone, quetiapine, amisulpride, clozapine, quetiapine, amisulpride, clozapine, risperdal consta intramuscular injection, risperdal consta intramuscular injection, aripiprazole, paliperidone, ziprasidonearipiprazole, paliperidone, ziprasidone
Also have effects on acetylcholine, Also have effects on acetylcholine, histamine,serotonin receptors – varying histamine,serotonin receptors – varying adverse effectsadverse effects
Atypical antipsychoticsAtypical antipsychotics
The ‘newer” antipsychoticsThe ‘newer” antipsychotics Effectively treat psychotic symptomsEffectively treat psychotic symptoms Lower incidence of extra pyramidal Lower incidence of extra pyramidal
side effects than conventional agentsside effects than conventional agents Have effects on dopamine, serotonin, Have effects on dopamine, serotonin,
histamine and muscarinic receptorshistamine and muscarinic receptors
Atypical antipsychoticsAtypical antipsychotics
Current atypicals in use in Australia are:Current atypicals in use in Australia are: AmisulprideAmisulpride AripiprazoleAripiprazole QuetiapineQuetiapine OlanzapineOlanzapine RisperidoneRisperidone ClozapineClozapine ZiprasidoneZiprasidone PaliperidonePaliperidone
Therapeutic effects on Therapeutic effects on symptomssymptoms
Agitation, sleep and appetite often Agitation, sleep and appetite often respond in the first 1-2 weeksrespond in the first 1-2 weeks
Personal hygiene and basic interpersonal Personal hygiene and basic interpersonal socialisation may take 2-3 weeks and socialisation may take 2-3 weeks and psychotic symptoms can gradually psychotic symptoms can gradually decrease over 2-6 weeksdecrease over 2-6 weeks
An effective trial should be at least 6-8 An effective trial should be at least 6-8 weeks at doses that are within the weeks at doses that are within the prescribed rangeprescribed range
How long should antipsychotics be How long should antipsychotics be taken for?taken for?
At least 6 months after an acute At least 6 months after an acute episode reduces relapse ratesepisode reduces relapse rates
If the person experiences another If the person experiences another episode they may need antipsychotic episode they may need antipsychotic medication for 2-5 years before medication for 2-5 years before ceasing useceasing use
For those with multiple episodes, For those with multiple episodes, they may need medication for much they may need medication for much of their lifeof their life
Adverse EffectsAdverse Effects
SedationSedation Postural hypotensionPostural hypotension Anticholinergic effects – dry mouth, Anticholinergic effects – dry mouth,
blurred vision, constipation, urinary blurred vision, constipation, urinary hesitancyhesitancy
Weight gain-clozapine, olanzapineWeight gain-clozapine, olanzapine Metabolic effects-increased serum Metabolic effects-increased serum
lipids, impaired glucose tolerance-lipids, impaired glucose tolerance-clozapine, olanzapine, quetiapineclozapine, olanzapine, quetiapine
Adverse EffectsAdverse Effects Hyperprolactinaemia-leads to Hyperprolactinaemia-leads to
galactorrhoea, amenorrhoea, decreased galactorrhoea, amenorrhoea, decreased libidolibido
Sexual dysfunctionSexual dysfunction QTc prolongation-leads to cardiac QTc prolongation-leads to cardiac
arrhythmiasarrhythmias EPSE-extrapyramidal side effectsEPSE-extrapyramidal side effects
• Acute dystonias -laryngeal spasm, Acute dystonias -laryngeal spasm, oculogyric crisesoculogyric crises
• Akathisia-severe sense of agitation, inner Akathisia-severe sense of agitation, inner restlessness in the limbs, especially the restlessness in the limbs, especially the legslegs
Adverse EffectsAdverse Effects
Akathesia – a severe sense of Akathesia – a severe sense of psychomotor agitationpsychomotor agitation
Parkinsonism -poverty of movement, Parkinsonism -poverty of movement, tremor, rigidity, drooling, hypersalivationtremor, rigidity, drooling, hypersalivation
Tardive dyskinesia-involuntary Tardive dyskinesia-involuntary hyperkinetic movements, affects the hyperkinetic movements, affects the mouth, lips, tongue, jaws with smacking, mouth, lips, tongue, jaws with smacking, tongue writhing, sucking,chewing and tic tongue writhing, sucking,chewing and tic like movements,limbs and trunk can be like movements,limbs and trunk can be affectedaffected
Adverse EffectsAdverse Effects
Irreversible in some patientsIrreversible in some patients Neuroleptic malignant syndrome-rare Neuroleptic malignant syndrome-rare
but potentially fatal – high temp, but potentially fatal – high temp, muscle rigidity, altered consciousness, muscle rigidity, altered consciousness, raised creatinine kinase –cease raised creatinine kinase –cease medicationmedication
Can happen at anytime during Can happen at anytime during treatmenttreatment
30% patients will develop syndrome 30% patients will develop syndrome again on rechallengeagain on rechallenge
Depot Anti-psychoticsDepot Anti-psychotics
Used when concerns around complianceUsed when concerns around compliance Conventional-zuclopenthixol(useful for Conventional-zuclopenthixol(useful for
agitated,aggressive,disturbed behaviour) agitated,aggressive,disturbed behaviour) flupenthixol (may have mood elevating flupenthixol (may have mood elevating effects) fluphenazine -EPSE commoneffects) fluphenazine -EPSE common
Typical-Risperdal Consta – onset of action Typical-Risperdal Consta – onset of action 3 weeks, need oral Risperidone to 3 weeks, need oral Risperidone to supplement until peak plasma reachedsupplement until peak plasma reached
Comparative Information for Comparative Information for Anti-PsychoticsAnti-Psychotics
Chlorpromazine, PericyazineChlorpromazine, Pericyazine Most sedating, most potent Most sedating, most potent anticholinergic effects, least anticholinergic effects, least likely to cause EPSE, most likely likely to cause EPSE, most likely to cause orthostatic to cause orthostatic hypotension. Low potency hypotension. Low potency antipsychoticsantipsychotics
Trifluperazine, FluphenazineTrifluperazine, Fluphenazine Moderately sedating, Moderately sedating, intermediate propensity to cause intermediate propensity to cause EPSE, some potential to cause EPSE, some potential to cause orthostatic hypotensionorthostatic hypotension
Haloperidol, Droperidol, Haloperidol, Droperidol, Thiothixene, PimozideThiothixene, Pimozide
Least sedating, almost no Least sedating, almost no anticholinergic effects, most anticholinergic effects, most likely to cause EPSE, least likely likely to cause EPSE, least likely to cause orthostatic to cause orthostatic hypotension, sometimes referred hypotension, sometimes referred to as ‘high potency’ to as ‘high potency’ antipsychoticsantipsychotics
Atypical antipsychoticsAtypical antipsychoticsAmisulprideAmisulpride Less potential for weight gain Less potential for weight gain
and sedationand sedation
AripiprazoleAripiprazole May cause insomnia, less May cause insomnia, less potential for potential for hyperprolactinaemiahyperprolactinaemia
ClozapineClozapine Effective treatment-resistant Effective treatment-resistant patients but has serious side-patients but has serious side-effects (blood dyscrasias, effects (blood dyscrasias, seizures, cardiomyopathy, seizures, cardiomyopathy, myocarditis, orthostatic myocarditis, orthostatic hypotension, sedation, hypotension, sedation, weight gain).weight gain).
Atypical antipsychoticsAtypical antipsychoticsOlanzapineOlanzapine Related to Clozapine may Related to Clozapine may
cause sedation, weight gain, cause sedation, weight gain, peripheral oedema; peripheral oedema; increased risk of stroke and increased risk of stroke and related mortality in elderly related mortality in elderly dementia patientsdementia patients
QuetiapineQuetiapine Sedating and vasoactive, less Sedating and vasoactive, less potential for potential for hyperprolactinaemiahyperprolactinaemia
Risperidone, PaliperidoneRisperidone, Paliperidone Orthostatic hypotension and Orthostatic hypotension and hyperprolactinaemia, may be hyperprolactinaemia, may be a problem; increased risk of a problem; increased risk of stroke and related mortality stroke and related mortality in elderly dementia patientsin elderly dementia patients
ZiprasidoneZiprasidone Less potential for weight gainLess potential for weight gain
Drug InteractionsDrug Interactions
Cytochrome P450 isoenzymes are Cytochrome P450 isoenzymes are significant in psychotropic drug significant in psychotropic drug interactionsinteractions
Inducers or inhibitors of this pathway Inducers or inhibitors of this pathway may produce clinically important may produce clinically important drug interactionsdrug interactions
May lead to increase or decrease of May lead to increase or decrease of medications due to interactionsmedications due to interactions
Cytochrome P450Cytochrome P450
ExamplesExamples• Fluvoxamine inhibits olanzapine and Fluvoxamine inhibits olanzapine and
clozapine metabolismclozapine metabolism• Smoking induces Olanzapine Smoking induces Olanzapine
metabolismmetabolism• SSRIs inhibit most antipsychotics and SSRIs inhibit most antipsychotics and
therefore increase serum concentrationstherefore increase serum concentrations• Phenytoin reduces serum concentration Phenytoin reduces serum concentration
of Quetiapineof Quetiapine• Others – grapefruit juice, Antibiotics, Others – grapefruit juice, Antibiotics,
ClozapineClozapine
Used when previously unresponsive to Used when previously unresponsive to other antipsychoticsother antipsychotics
Serious adverse effect profileSerious adverse effect profile Strict guidelines relating to Strict guidelines relating to
commencement and monitoringcommencement and monitoring Significant risk of agranulocytosisSignificant risk of agranulocytosis Trial at least 2 different standard Trial at least 2 different standard
antipsychotics at an adequate dose and antipsychotics at an adequate dose and for an adequate duration prior to for an adequate duration prior to commencing Clozapinecommencing Clozapine
Use of antipsychotics with older Use of antipsychotics with older personspersons
Various disorders treated with Various disorders treated with antipsychotics in the elderly – psychosis, antipsychotics in the elderly – psychosis, bipolar affective disorder, delirium & bipolar affective disorder, delirium & dementiadementia
Use extreme caution because of side Use extreme caution because of side effect profileeffect profile
‘‘Start low & go slow’ (Malone et al 2007) Start low & go slow’ (Malone et al 2007) & titrate over longer periods of time to & titrate over longer periods of time to reach the required dosereach the required dose
Avoid polypharmacy wherever possibleAvoid polypharmacy wherever possible
Pregnancy & lactationPregnancy & lactation
Avoid antipsychotics if possibleAvoid antipsychotics if possible Use the lowest effective dose Use the lowest effective dose Neonatal adverse effects observed Neonatal adverse effects observed
include generalised hypertonicity and include generalised hypertonicity and dystonic reactionsdystonic reactions
Pregnancy & lactationPregnancy & lactation
The safety of atypical agents is yet to The safety of atypical agents is yet to be established but preliminary be established but preliminary reports there to be no deleterious reports there to be no deleterious effects to the foetuseffects to the foetus
Isolated cases of congenital Isolated cases of congenital abnormalities with the use of abnormalities with the use of ClozapineClozapine
Pregnancy & LactationPregnancy & Lactation
No increased risk has emerged with No increased risk has emerged with the use of Olanzapinethe use of Olanzapine
The conventional agents are The conventional agents are generally preferredgenerally preferred
Supervised dose reduction and Supervised dose reduction and cessation 7-10 days prior to delivery cessation 7-10 days prior to delivery should be consideredshould be considered
What other treatments are What other treatments are available?available?
Remember that antidepressant medication is only part of the Remember that antidepressant medication is only part of the treatment for antenatal depression and anxiety. Also consider:treatment for antenatal depression and anxiety. Also consider:
Psychological therapies Psychological therapies
Exclude organic illness as a cause of mental health symptoms Exclude organic illness as a cause of mental health symptoms
Address any alcohol and/or illicit substance abuseAddress any alcohol and/or illicit substance abuse
Assess the social situation Assess the social situation
General lifestyle measures: adequate rest/sleep, balanced diet, General lifestyle measures: adequate rest/sleep, balanced diet, exerciseexercise
The decision to treat should be made on an individual case basisThe decision to treat should be made on an individual case basis
ConclusionConclusion Conventional and atypical antipsychotics are used as Conventional and atypical antipsychotics are used as
the foundation for pharmacological management of the foundation for pharmacological management of schizophrenia and related psychosisschizophrenia and related psychosis
All have equal efficacy, exception ClozapineAll have equal efficacy, exception Clozapine Atypicals generally better tolerated & have less EPSEAtypicals generally better tolerated & have less EPSE Atypicals first line treatmentAtypicals first line treatment Start lowest effective possible dose & titrate upwardsStart lowest effective possible dose & titrate upwards Ongoing monitoring & management of adverse Ongoing monitoring & management of adverse
effectseffects Caution numerous drug interaction & potential for Caution numerous drug interaction & potential for
neuroleptic malignant syndrome neuroleptic malignant syndrome
ResourcesResources
Therapeutic Guidelines – Psychotropic Therapeutic Guidelines – Psychotropic Version 5 Version 5
www.tg.com.auwww.tg.com.au 9329 1566 9329 1566 Australian Medicines HandbookAustralian Medicines Handbook www.amh.net.au 08 8303 6977www.amh.net.au 08 8303 6977 MIMS onlineMIMS online http://www.ppmis.org.au http://www.ppmis.org.au Perinatal Perinatal
Psychotropic Medicine Information Psychotropic Medicine Information ServiceService