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    of 25

    Antipsychotics

    Robert Sims HA209


    [email protected]
    Lecture structure

    • Psychosis and the biological basis of schizophrenia; involvement of


    dopamine

    • Receptors activated by antipsychotics – therapeutic and harmful

    • Individual antipsychotic drugs – 1 st and 2nd generation


    Psychosis
    • Different perception of reality from most people; chiefly observed by
    hallucinations, delusions, confused thoughts

    • Numerous causes: Schizophrenia


    Bipolar disorder
    Neurodegenerative diseases
    Severe depression
    Severe stress
    Sleep deprivation
    Alcohol & drug abuse

    • Antipsychotics also used for sedation of individuals with conditions such as


    agitation and delirium
    Schizophrenia

    • Affects ~1% of the population, mostly develops in adolescents and


    young adults

    • Chronic, can severely disrupt life

    • Evidence of biological disorder?

    • Often associated with other mental disorders: anxiety, guilt,


    depression, high risk of suicide.

    • Frequently associated with drug abuse


    Symptoms
    • “Positive”: Delusions (often paranoid)
    Hallucinations (often “hearing voices”)
    Thought disorder (e.g. rambling speech)
    Abnormal and disorganised behaviour
    Catatonia (immobility, purposeless movement)

    • “Negative”: Social withdrawal


    Low emotional responses
    Inability to experience pleasure
    Reluctance to perform tasks

    • Cognitive deficits: Poor memory, low attention span


    Causes of schizophrenia

    • About 10% heritable; if one monozygotic twin has schizophrenia,


    about 50% chance the other does.

    • Multiple genes implicated (~100?); cause susceptibility?

    • Environmental factors
    Birth complications
    Drug use (e.g. cannabis, cocaine)

    • Psychological?
    Dopamine theory of schizophrenia
    Proposed by Arvid Carlsson MESOLIMBIC PATHWAY
    Nobel prize Physiol / Med (2000) → Positive symptoms

    Dopamine overactive
    MESOCORTICAL PATHWAY D2 receptors predominate
    → Negative symptoms

    Dopamine underactive
    D1 receptors predominate

    Nucleus
    accumbens Other dopaminergic
    pathways (nigrostriatal,
    tubuloinfundibular) appear to
    Ventral tegmental area be normal in schizophrenia
    Substantia nigra
    Other theories

    • Neurochemical:
    Dysregulation of DA, 5-HT, Glu, other neurotransmitters
    Serotonergic influence on dopamine release notable; may have
    therapeutic benefit

    • Neurodevelopmental:
    Disruption of neural development, especially early age

    • Neuroimmunological
    Neuroinflammation; BBB dysfunction?
    Antipsychotics

    • a.k.a. (archaic): major tranquilisers, neuroleptics, antischizophrenics

    • “First generation” or “typical” antipsychotics

    • “Second generation” or “atypical” antipsychotics

    • No clear definition between typical and atypical, but relates to:


    Receptor profile
    Extrapyramidal side effects
    Efficacy in treatment-resistant patients
    Efficacy against negative symptoms
    Side effects & compliance

    • Some general side effects (dopamine)

    • Side effects can vary (very) widely by drug depending on other


    interactions (e.g. histamine, ACh & 5-HT receptors)

    • There are a lot of antipsychotics available in the UK (~40) – but few


    are heavily used and many barely used.

    • Compliance is a major problem with antipsychotics


    Multiple receptor effects

    Antagonists (/ inverse agonists / partial agonists) at:

    • Dopamine D2 > D1; (D2 = Gi GPCR)


    possible
    • 5-HT receptors (especially 5-HT2A; Gq) therapeutic benefit

    • Muscarinic AChRs (Gq / Gi GPCRs)


    no therapeutic
    • Histamine H1: Gq GPCRs benefit

    • a adrenoreceptors (especially a1;Gq GPCRs)


    Common side effects of antipsychotics
    • Extrapyramidal effects (EPS): Acute dystonia
    Tardive dyskinesias
    D2 / D1
    • Endocrine effects: ↑ prolactin; breast swelling, pain,
    lactation (also affects males)

    • Sedation (Histamine H1 receptors, mAChR, a1)


    • Weight gain (H1, 5-HT, mAChR)
    • Hypotension (a adrenoreceptors)
    • Anticholinergic effects e.g. dry mouth, blurred vision (mAChR)
    • Sexual dysfunction (all receptors)
    • Risk of arrhythmia
    Other considerations

    • As a very general rule, atypical antipsychotics have fewer motor side


    effects, but worse other side effects

    • In practice, all antipsychotics vary considerably; low EPS side effects


    favoured with chronic use

    • Antipsychotic overdose: sedation if mild


    cardiotoxicity and seizure risk if severe
    Extrapyramidal system
    Extrapyramidal symptoms (EPS):

    Basal ganglia Acute dystonia 1-5 days

    Thalamus Parkinsonism 1-4 weeks

    Cerebellum Akathisia 1-2 months


    Red nucleus

    Neuroleptic malignant Months


    Extrapyramidal pathways do not syndrome
    pass through the medullary
    pyramids. Mostly trunk movement, Months –
    balance, reflexes
    Tardive dyskinesia years
    Acute dystonia & other early onset

    • Involuntary movements, muscle twitching

    • Can be ameliorated by antimuscarinics and 5-HT 1A receptor


    antagonists

    • Reversible upon cessation of treatment

    • Later development of Parkinsonian symptoms, and then akathisia

    • Neuroleptic malignant syndrome: hyperthermia, confusion,


    tachycardia – medical emergency
    Tardive dyskinesia

    • Upregulation & sensitisation of D2 receptors

    • Involuntary movements of face, trunk & limbs; potentially disabling.


    Affects 20-40% of patients.

    • Develop after months to years of treatment, especially with first


    generation drugs.

    • May get worse after treatment cessation

    • Often irreversible
    Antipsychotics & arrhythmias

    • All antipsychotics have cautions with cardiac dysfunction

    • Risk of sudden death

    • Mixed evidence of whether 1st gen worse than 2nd

    • Inhibition of some cardiac K+ channels: torsade de points


    History; first generation antipsychotics

    • Psychoactive effects discovered 1952

    • 1st antipsychotic – originally developed as anaesthetic

    • “Pharmacological lobotomy” (!)

    • 1st generation antipsychotics mostly 50s-70s

    • 2nd generation antipsychotics mostly since 1990s


    1st gen drugs
    • Chlorpromazine: Most commonly used 1st gen. Notable side effect
    of jaundice, lower EPS than many other 1 st
    gen antipsychotics. Also nausea & vomiting.

    • Haloperidol: Rarely prescribed for long-term use (high


    EPS) Usually for treatment of acute delirium
    (IV), also nausea.

    • Zuclopenthixol: Non-selective D1 / D2 antagonist. Available as


    depot preparation

    Many, many others…


    Second generation (“atypical”) antipsychotics

    • Much more a mixed bag of effects

    • Usually less likely to cause extrapyramidal symptoms

    • Clozapine highly recommended* with treatment resistance

    • Only some thought to be more clinically effective

    * But…
    2nd gen drugs
    • Quetiapine & Most prescribed. Olanzapine more efficacious
    Olanzapine: than quetiapine, but worse motor side effects.

    • Risperidone: available as depot preparation; medium EPS. First line


    choice to reduce agitation in patients with dementia

    • Aripiprazole: partial agonist at D2; lower DAergic side effects


    moderate efficacy, relatively well tolerated

    • Amisulpiride: Good efficacy; mild anticholinergic effects, moderate


    EPS, hyperprolactinaemia

    Many, many, others.


    Clozapine
    First “2nd generation” antipsychotic, although discovered early (1958)

    • Often effective in otherwise treatment-resistant patients

    • Now rarely prescribed; serious side effect of agranulocytosis; sudden


    death (often myocarditis)

    • Lack of EPS = useful for Parkinson’s Disease psychosis


    Antipsychotic receptor affinities:
    Receptor affinity
    D1 D2 a1 H1 mACh 5-HT2A
    Approx. # of prescriptions (UK, 2016)

    Quetiapine + + +++ +++ + +


    4 most prescribed

    Olanzapine +++ +++ + + ++ +++


    Risperidone + +++ ++ ++ +++
    Aripiprazole + +++* ++ ++ +++ *D2 partial agonist

    Chlorpromazine ++ ++ +++ +++ ++ +++


    Haloperidol ++
    Amisulpiride +++ +++ +++ + +++
    Zuclopenthixol ++ +++ ++ + ++
    Clozapine + + +++ +++ ++ +++
    Note: there are other antipsychotics not included here that are more prescribed than some of the bottom 4
    Summary
    • Schizophrenia likely to be underpinned by biological disorder

    • First line treatment 2nd generation antipsychotics; less adverse effect

    • Second line treatment 1st generation antipsychotics, chiefly


    chlorpromazine and related compounds

    • Antagonism at dopamine D2 (& 5-HT2A?) receptors critical to


    therapeutic use

    • Antagonism of other receptors major determinant of side effects


    Further reading

    Rang & Dale’s Pharmacology, 8th Ed. Chapter 46.

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