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