Transcript Psychopharmacology: Antipsychotics

What do I need to know?
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Conventional / Atypical
Psychopharmacology:
Dopamine (+pathways)
Antipsychotics
Receptors
Individual
drugs, esp. Clozapine
21st May 2013
Dr Simon
Mitchell
Some
Ethnopsychopharmacology
Syllabus
• The principal CNS pharmacology of antipsychotics with
particular attention to their postulated modes of action in
achieving therapeutic affect: at both molecular/synaptic and
systems levels.
• The relationship of culture, race and ethnicity to
pharmacodynamics.
Resources
…plus NICE CG82 Schizophrenia
Overview
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Dimensions of Schizophrenia
Dopamine D2
Importance of Dopamine pathways
Conventional / Atypical
Pharmacokinetics
Psychosis
• Delusions & Hallucinations
• Grossly disorganized
• Speech
• Behaviour
• Reality testing
Psychosis
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as defining feature...
Schizophrenia
Substance-induced psychotic disorders
Schizophreniform disorder
Schizoaffective disorder
Delusional disorder
Brief psychotic disorder
Psychotic disorder due to a general medical condition
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as associated feature...
Mania
Depression
Cognitive Disorders
Schizophrenia
• Positive Symptoms
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Hallucinations, delusions
Distortions or exaggerations in language and communication
Disorganised speech and behaviour
Catatonia
Agitation
Schizophrenia
• Negative Symptoms
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Affective blunting
Alogia
Avolition
Anhedonia
Asociality
Symptom dimensions
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Positive
Negative
Affective
Aggressive
Cognitive
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Representing and maintaining goals
Attention
Learning
Verbal fluency
Malfunctioning circuits
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Positive – mesolimbic (DA, 5HT, GABA, glu)
Negative - mesocortical
Affective- ventromedial prefrontal cortex
Aggressive – orbitofrontal cortex and amygdala
Cognitive – dorsolateral prefrontal cortex
• Unfortunately (!) there is overlap...
• But understanding these circuits and neurotransmitters helps
with prescribing
Dopamine Hypothesis
• Amphetamine, cocaine increase levels of dopamine in the
brain
• Psychotic symptoms
– particularly after large doses or prolonged use
• May be almost identical to positive symptoms of
schizophrenia
• Other factors important too
• Genetic, structural, neurobiological, etc
Mechanism
• 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
• 5HT2A blockade (may improve negative symptoms)
• Histamine H1 blockade (drowsiness)
• Alpha adrenoceptor blockade (postural hypotension)
Chlorpromazine prevents D2
receptor activation
…by blocking
D2 receptor
Cocaine and
amphetamines
prevent reuptake
of dopamine and
thus increase D2
receptor
activation
Dopamine Blockade
• Therapeutic action of conventional antipsychotics results from
blockage of D2
– mesolimbic pathway
• But also causes most of side-effects because D2 receptors are
blocked throughout the brain
– Mesocortical
– Nigrostriatal
– Tuberoinfundibular
Dopamine Blockade
• Mesolimbic
– Secondary negative symptoms due to blockade of reward pathways
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Apathy, anhedonia, etc.
VTN to limbic system
N. Accumbens
Amygdala
Hippocampus
Dopamine Blockade
• Mesocortical
– Can cause or worsen negative and cognitive symptoms
• VTN to cortex
Dopamine Blockade
• Nigrostriatal
– Extrapyramidal nervous system
– EPS / drug-induced parkinsonism
– If blocked chronically
• Tardive Dyskinesia
• Facial and tongue movements (e.g. Lip-smacking,
grimacing)
• limb movements (e.g. Chorea)
Tardive Dyskinesia
• 5% of patients on conventional APDs per year (NNH=4 in 5
years)
• Higher risk in elderly
• Sometimes irreversible
• But if not by 15yrs, then unlikely
• Likely due to receptor upregulation
• Genetic factors influence susceptibility
– CYP 2D6 poor metabolisers
Dopamine Blockade
• Tuberoinfundibular – (normally these neurons are
active and inhibit prolactin release)
– Hyperprolactinaemia
• Galactorrhoea
• Amenorrhoea
• Bone demineralisation (esp. In postmenopausal
women)
• Sexual dysfunction & Weight gain (role unclear)
Reduced BMD
Other Effects of Conventional APDs
• Muscarinic cholinergic blockade
– Dry mouth, blurred vision, constipation, cognitive blunting
– Exacerbation of narrow angle glaucoma
– Impacts on EPS by mitigating the effect of D2 blockade in
nigrostriatal DA pathway
– Thus the use of anticholinergics for EPS (e.g. Procyclidine)
Other Effects of Conventional APDs
• Histaminergic blockade
– H1
– Weight gain, drowsiness
• Alpha-1 adrenergic blockade
– Orthostatic hypotension
– Dizziness
– Drowsiness
Typical Antipsychotics
• Phenothiazines
• Aliphatic side chain - chlorpromazine, triflupromazine
• Piperazine side chain – fluphenazine, trifluoperazine
• Piperidine side chain - thioridazine
• Thioxanthenes - flupenthixol
• Butyrophenones - haloperidol, trifloperidol, penfluridol
• Other heterocyclic: pimozide, loxapine
Differences among Typicals
• All effective antipsychotic drugs block D2 receptors
• Low potency: Chlorpromazine
– fewer EPS but more H1, α1, and muscarinic blocking effects
• High potency: haloperidol, fluphenazine
– more EPS and less histaminic(e.g. sedation), alpha adrenergic (e.g.
orthostatic hypotension) and anticholinergic effects (e.g. dry mouth)
Dilemma
• How to decrease dopamine in mesolimbic pathway to treat
positive symptoms
• How to increase dopamine in mesocortical pathway to treat
negative and cognitive symptoms
• How to avoid interfering with dopamine in nigrostriatal and
tuberoinfubdibular pathways to avoid side-effects
‘Atypical’ APDs
• ‘Low EPS’
• ‘Good for negative symptoms’
• Serotonin Dopamine antagonists
• D2 antagonists with rapid dissociation (‘hit and run’)
– Less receptor occupancy
– Less likely to cause side effects
• D2 partial agonists
• Serotonin partial agonists
Atypical 5HT2A antagonism
• 5HT2A antagonists stimulate DA release in the
striatum
– thus reducing EPS
• 5HT2a antagonism stimulates DA release in
mesocortical pathway
– Fewer negative symptoms
Atypical 5HT2A antagonism
• Can also reduce positive symptoms
– By inhibiting glutamate release
• Reduced hyperprolactinaemia
– By mitigating the effect of D2 blockade
Atypical APDs
• D2 partial agonists
• Aripiprazole
– ?amisulpride / sulpiride
• Fewer side effects
• ?effective
Atypical APDs
• Serotonin partial agonists
– 5HT1A agonism has similar net effects to 5HT2A
antagonism
– Reduced EPS and –ve symptoms
– Aripiprazole, Clozapine, Quetiapine, Zisprasidone
Cardiometabolic Risk
• Increased appetite
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Weight gain
Dyslipidaemia
Diabetes
Genetic contribution of mental illness
Other risks
• The ‘metabolic highway’
* = not good
Premature
Death by 20 years*
Cardiometabolic Risk
• Weight gain: H1, 5HT2C
– Clozapine, Olanzapine more than
– Risperidone, Quetiapine more than
– Aripiprazole
– Insulin resistance
Sedation
• Antagonism: D2, M1, H1, alpha-1 adrenergic
– Can be useful in the short term
– In long term may be intolerable
• CATIE
• Weight gain, EPS
Pharmacokinetics
• How the body acts on these drugs
• Cytochrome P450 system
– Gut wall / liver
– Black and minority ethnic groups have variants of these
isoenzymes with different, often slower, activity.
• 1A2
– Clozapine, olanzapine, zotepine
– Induced by smoking, carbamazepine,brassicas
– Inhibited by fluvoxamine, verapamil, grapefruit
CYP450
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Risperidone, clozapine, olanzapine, aripiprazole
Inhibited by several SSRI’s
5% to 10%caucasians poor metabolisers by this route
0% to 2% of Asians are classified poor metabolisers
Poor metabolisers have an increased risk of EPS as
measured by rating scales or the need for antiparkinson
medication.
CYP450
• 3A4
– Clozapine, quetiapine, aripiprazole, sertindole
– Inhibited by fluvoxamine, norfluoxetine, erythromycin,
grapefruit
– Induced by carbamazepine, phenytoin, rifampicin, SJW
CYP450
• Determining CYP450 polymorphisms is prohibitively expensive
• Usually only possible within a clinical trial.
• Differences in treatment of psychotic patients (admission,
detention and seclusion rates)
• UK prescribing of antipsychotics appears overall to be broadly
equitable in minority ethnic groups. Not the case in USA
• Black patients more likely to have depot and at a higher dose
• Trials done on Caucasians subjects
Newer Atypical Antipsychotics
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aripiprazole
clozapine
risperidone
quetiapine
olanzapine
Differences among Antipsychotic
Drugs
• Clozapine binds more to D4, 5-HT2, α 1, and histamine
H1 receptors than to either D2 or D1 receptors
• Risperidone about equally potent in blocking D2 and 5HT2 receptors
• Olanzapine more potent as an antagonist of 5-HT2
receptors lesser potency at D1, D2, and α 1 receptors
• Quetiapine lower-potency compound with relatively
similar antagonism of 5-HT2, D2, α 1, and α 2 receptors
Atypicals’ Side-Effects
• EPS
– Risperidone > Olanzapine = Ziprasidone > Quetiapine >
Aripiprazole ?=? Clozapine
• Anticholinergic
– Clozapine > Olanzapine > others
• Hypotension
– Clozapine > > Quetiapine, Risperidone > Ziprasidone,
Olanzapine, Aripiprazole
Atypicals Side-Effects
• Sedation
– Clozapine > > Olanzapine, Quetiapine > Risperidone, Ziprasidone,
Aripiprazole
• Agranulocytosis
– Clozapine
• Weight gain
– Clozapine = Olanzapine > Quetiapine, Risperidone > Ziprasidone,
Aripiprazole
• Prolactin elevation
– Risperidone > others
Atypical antipsychotics
• Claims
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lower doses
reduced side effects
more effective (especially negative symptoms)
better compliance
• Costs
– Much higher (10-40 times)
• Side-effects
• Most trials are industry-funded
• > $15 billion per year
CATIE & CUtLASS
• Two large, non-commercial, pragmatic clinical trials
comparing first- and second-generation antipsychotic drugs
for people with chronic schizophrenia in the US and UK
• Newer drugs were no more effective or better tolerated than
the older drugs.
• Clozapine outperformed other second-generation drugs.
• Results were surprising
What do I need to know?
•
•
•
•
•
Conventional / Atypical
Dopamine (+pathways)
Receptors
Individual drugs, esp. Clozapine
Some Ethnopsychopharmacology
How can I learn this?
• Resources
• Think of clinical examples
• Better to try and understand the mechanism rather than rote
learning
Questions??