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Anti-psychotics Mainstay of pharmacological treatment for schizophrenia and related disorders Mainstay of pharmacological treatment for schizophrenia and.

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Presentation on theme: "Anti-psychotics Mainstay of pharmacological treatment for schizophrenia and related disorders Mainstay of pharmacological treatment for schizophrenia and."— Presentation transcript:

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

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

3 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 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 Mesolimbic pathway responsible for pleasure, effects of drugs and alcohol and hallucinations and delusions

4 Blockade Of D2 Receptors? D2 ANTAGONIST Mesolimbic pathway dramatic therapeutic action on positive psychotic symptoms Tuberoinfundibular pathway hyperprolactinemia (lactation, infertility, sexual dysfunction) Nigrostriatal pathway extrapyramidal side effects (EPS) and tardive dyskinesia Mesocortical pathway enhanced negative and cognitive psychotic symptoms

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

6 Dopamine Receptors Dopamine and acetylcholine have a reciprocal relationship- Dopamine and acetylcholine have a reciprocal relationship- Blockade of dopamine receptors increases the activity of acetylcholineBlockade of dopamine receptors increases the activity of acetylcholine Over activity of acetylcholine causes EPSEOver activity of acetylcholine causes EPSE Blockade of dopamine causes movement disorders in the nigostriatal pathwayBlockade of dopamine causes movement disorders in the nigostriatal pathway Long tem blockade causes “upregulation” and leads to Tardive DyskinesiaLong tem blockade causes “upregulation” and leads to Tardive Dyskinesia

7 Conventional or typical Antipsychotics Have four actions – blockade of: Have four actions – blockade of: Dopamine 2Dopamine 2 Muscarinic/choliner gcMuscarinic/choliner gc Alpha adrenergicAlpha adrenergic HistamineHistamine

8 Serotonin and Dopamine Interactions

9 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 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

10 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

11 Atypical Antipsychotics Pharmacologic Properties Pharmacologic Properties 5HT2A and D2 antagonism (as opposed to conventional drugs which are D2 without 5HT2A antagonism)5HT2A and D2 antagonism (as opposed to conventional drugs which are D2 without 5HT2A antagonism) Atypicals – blockade of D2 and 5HT2AAtypicals – blockade of D2 and 5HT2A

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

13 Dopamine and Serotonin Receptors Action of atypicals – firstly binds to the D2 receptor Action of atypicals – firstly binds to the D2 receptor Secondly, binds to the 5HT2A receptor Secondly, binds to the 5HT2A receptor The second action reverses the first – reverses the blockade of D2 The second action reverses the first – reverses the blockade of D2 Blocking 5HT2A disinhibits the dopamine neuron causing dopamine to pour out Blocking 5HT2A disinhibits the dopamine neuron causing dopamine to pour out

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

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

16 Atypicals 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 blockadeDose necessary to achieve optimal D2 blockade Patient tolerability, preference, responsePatient tolerability, preference, response

17 Anti-psychotics Conventional – eg chlorpromazine, haloperidol, stelazine, depots such as flupenthixol, zuclopenthixol, fluphenazine 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 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 Also have effects on acetylcholine, histamine,serotonin receptors – varying adverse effects

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

19 Atypical antipsychotics Current atypicals in use in Australia are: Current atypicals in use in Australia are: Amisulpride Amisulpride Aripiprazole Aripiprazole Quetiapine Quetiapine Olanzapine Olanzapine Risperidone Risperidone Clozapine Clozapine Ziprasidone Ziprasidone Paliperidone Paliperidone

20 Therapeutic effects on symptoms Agitation, sleep and appetite often respond in the first 1-2 weeks 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 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 An effective trial should be at least 6-8 weeks at doses that are within the prescribed range

21 How long should antipsychotics be taken for? At least 6 months after an acute episode reduces relapse rates 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 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 For those with multiple episodes, they may need medication for much of their life

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

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

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25 Adverse Effects Akathesia – a severe sense of psychomotor agitation Akathesia – a severe sense of psychomotor agitation Parkinsonism -poverty of movement, tremor, rigidity, drooling, hypersalivation Parkinsonism -poverty of movement, tremor, rigidity, drooling, hypersalivation Parkinsonism tremor Parkinsonism tremor 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 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 tongue writhing tongue writhing

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

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

28 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

29 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).

30 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

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

32 Cytochrome P450 Examples Examples Fluvoxamine inhibits olanzapine and clozapine metabolismFluvoxamine inhibits olanzapine and clozapine metabolism Smoking induces Olanzapine metabolismSmoking induces Olanzapine metabolism SSRIs inhibit most antipsychotics and therefore increase serum concentrationsSSRIs inhibit most antipsychotics and therefore increase serum concentrations Phenytoin reduces serum concentration of QuetiapinePhenytoin reduces serum concentration of Quetiapine Others – grapefruit juice, Antibiotics,Others – grapefruit juice, Antibiotics,

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

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

35 Pregnancy & lactation Avoid antipsychotics if possible Avoid antipsychotics if possible Use the lowest effective dose Use the lowest effective dose Neonatal adverse effects observed include generalised hypertonicity and dystonic reactions Neonatal adverse effects observed include generalised hypertonicity and dystonic reactions

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

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

38 What other treatments are 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: 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 abuse Address any alcohol and/or illicit substance abuse Assess the social situation Assess the social situation General lifestyle measures: adequate rest/sleep, balanced diet, exercise General lifestyle measures: adequate rest/sleep, balanced diet, exercise The decision to treat should be made on an individual case basis The decision to treat should be made on an individual case basis

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

40 Resources Therapeutic Guidelines – Psychotropic Version 5 Therapeutic Guidelines – Psychotropic Version Australian Medicines Handbook Australian Medicines Handbook MIMS online MIMS online Perinatal Psychotropic Medicine Information Service Perinatal Psychotropic Medicine Information Service


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