L8 Clinical Pharmacology Antipsychotics

Overview

This lecture covers schizophrenia and its drug treatment. It moves from basic dopamine neurobiology (dopaminergic brain regions, pathways, and the difference between tonic and phasic dopamine firing) to the clinical picture of schizophrenia (epidemiology, prognosis, positive and negative symptoms), then to the neurochemical theories of its cause (the dopamine hypothesis, altered salience, and historical evidence implicating acetylcholine, glutamate, and serotonin). It finishes with the pharmacology of treatment: dopamine D2 receptor structure and signalling, typical antipsychotics (haloperidol), atypical antipsychotics (clozapine), comparative efficacy, the hypoglutamate hypothesis, and the newer muscarinic-agonist approach (xanomeline–trospium), closing with a summary of which drug classes target positive versus negative symptoms.

Dopaminergic Brain Regions and Pathways

Dopaminergic neurons (neurons that release dopamine) are concentrated in two brainstem regions, each associated with distinct pathways and functions:

• Substantia nigra — movement and sensing (gives rise to the nigrostriatal pathway)
• Ventral tegmental area (VTA) — cognition, memory, learning (via projections to the prefrontal cortex) and pleasure/reward (via projections to the nucleus accumbens)

Three dopaminergic pathways are shown, running from these brainstem regions to cortical/limbic targets:

• Mesocortical pathway — VTA to prefrontal cortex
• Nigrostriatal pathway — substantia nigra to striatum
• Mesolimbic pathway — VTA to Nucleus accumbens

Dopamine Neuron Firing: Tonic vs Phasic

• Tonic firing: caused by baseline depolarisation; less depolarisation and dopamine release (1–8 Hz); neurons are tonic about 95% of the time.
• Phasic firing: caused by rapid depolarisation; more depolarisation and dopamine release (15–30 Hz); the dopaminergic system is activated/stimulated; neurons are phasic about 5% of the time.
• Phasic dopamine firing promotes movement in the striatum and causes euphoria in the nucleus accumbens.

Dopamine in the reward pathway: VTA activity (dopamine release into the nucleus accumbens) increases with the presence of an unexpected reward. This was shown across three firing-rate conditions:

1. No conditioned stimulus — firing increases sharply at the time of reward.
2. Conditioned stimulus, then reward — firing increases sharply at the conditioned stimulus, with little further increase at reward.
3. Conditioned stimulus, no reward — firing increases at the conditioned stimulus but then drops below baseline in the window where reward would have occurred.

Phasic dopamine signalling tracks reward expectation, not just reward itself — firing shifts from the reward itself to the cue that predicts it, and drops below baseline when an expected reward is withheld.

Schizophrenia: Epidemiology, Course, and Prognosis

Schizophrenia is a neurological disorder with abnormal social behaviour and difficulty understanding reality (delusions and hallucinations). Its cause is unknown, but is associated with:

• Genetic predisposition (64–81% heritability)
• Early life stress
• A strong correlational link to cannabis

Epidemiology and course:

• Affects 1% of the population
• Affects young people; typical age of onset in men is ~20 years old
• Chronic condition with no cure
• Minor, sporadic, or non-distressing delusions occur in 5.2–7.2% of the general population — distinct from schizophrenia
• Incidence peaks sharply in men around age 20–24 (~29 per 10,000 person-years) then declines; in women it peaks more gently around age 25–29 (~13 per 10,000 person-years) and declines more gradually, remaining above the men’s incidence rate at older ages

Prognosis:

• Life expectancy reduced by 13–15 years
• High rates of smoking (90%): may reduce cognitive symptoms of the disease and may reduce some antipsychotic side effects
• Unhealthy habits: poor diet, sedentary lifestyle
• More common in men
• Increased suicide risk: 5% of patients die by suicide
• ~33% completely recover; ~33% improve and maintain relative independence

Symptoms of Schizophrenia

“First class” symptoms are diagnostic in 75–95% of cases:

• Auditory hallucinations referring to the patient in the third person
• Subjective changes in the ownership of thinking: thought insertion, thought withdrawal, and thought broadcasting
• Passivity — the experience that one’s actions, bodily sensations, or emotions are controlled by outside forces

Reduced cognition also occurs, affecting executive function, long-term memory, and sustained attention.

Symptoms are further divided into two categories:

Positive symptoms (additions to consciousness) — associated with increased tonic dopamine release in the nucleus accumbens:

• Reality distortion (delusions and hallucinations, including auditory hallucinations)
• Wild trains of thought
• Irrational conclusions
• Disorganised behaviour

Negative symptoms (decrease in functionality):

• Thought disorder
• Poor social functioning
• Flattening of emotional responses
• Decreased cognitive function

A slide included a video clip presented as an example/testimonial illustrating a delusional belief (a person describing a "neuroradio" implanted in their brain). It is supporting/illustrative content rather than lecture data, and is flagged here as such rather than treated as a clinical fact.

The Dopamine Hypothesis and Salience

The lecture maps the dopamine pathways onto schizophrenia’s symptom domains:

1. Mesolimbic pathway — in schizophrenia, increased dopamine causes positive symptoms.
2. Mesocortical pathway — in schizophrenia, dopamine hypoactivity causes negative, cognitive, and affective symptoms.
3. Nigrostriatal pathway — not part of the disease mechanism itself, but the site where antipsychotic drugs produce extrapyramidal side effects (EPS) and tardive dyskinesia (TD), producing Parkinson’s-like symptoms.

Salience and schizophrenia: in neuroscience, salience means the detection of important stimuli (“top-down” perception). The salience network modifies sensory information so that attention is directed to survival-relevant stimuli — meaning much of what is perceived isn’t strictly “raw” sensory reality. People with schizophrenia can recognise the hollow mask illusion (where healthy people are fooled into seeing a concave mask as convex), which the lecture frames as suggesting people with schizophrenia may in this respect be interpreting reality more literally/correctly. Excessive tonic dopamine signalling is proposed to reduce activity of the salience network.

Historical Evidence for Other Neurotransmitters

The lecture notes that clinical trials of dubious ethics historically informed which signalling pathways are involved in schizophrenia, implicating several neurotransmitter systems beyond dopamine:

• Acetylcholine (muscarinic receptors): a case report described acute-onset psychosis with complex neurobehavioural symptoms following intramuscular hyoscine butylbromide injection. Historically, “flying ointment” (16th century) was believed to contain hyoscine and other muscarinic acetylcholine receptor (AChR) antagonists derived from mandrake.
• Glutamate (NMDA receptors): PCP (“Sernyl”) was studied as a “schizophrenomimetic” drug, producing body-image disturbances, loss of “ego boundaries,” impaired ability to distinguish self from non-self stimuli, depersonalisation, a sense of unreality, and disorganisation of thought (blocking, neologisms, word salad).
• Serotonin (5-HT2A receptors) and dopamine were also implicated [slide does not elaborate on the specific historical evidence for these two beyond naming the receptor targets].
• LSD given to normal volunteers produced disturbances of thought and speech, intellect, and perception (auditory and visual).
• Amphetamine reproduced amphetamine psychosis in 12 of 14 amphetamine-dependent patients given a large intravenous dose, with paranoia as a constant feature.
• Overall: amphetamine seemed to mimic the positive symptoms of schizophrenia, while hyoscine and PCP seemed to approximate both positive and negative symptoms.

Dopamine Receptor Pharmacology

Clinical potency and D2 affinity: across antipsychotic drugs, high clinical potency corresponds to high affinity for the D2 receptor (because lower drug concentrations are needed to inhibit dopamine binding, i.e. low IC50). Low clinical potency corresponds to low D2 affinity. On a log(IC50) vs log(average clinical dose) plot, drugs fall along a roughly linear trend:

• High-potency/low-dose end: spiroperidol, benperidol, trifluperidol, pimozide, fluphenazine, droperidol, haloperidol
• Middle: thiothixene, trifluperazine, moperone, molindone
• Low-potency/high-dose end: prochlorperazine, thioridazine, clozapine, chlorpromazine, trazodone, promazine

Dopamine receptor families:

• D1 family (D1, D5): increase cAMP production; K+ channel inhibition and Ca2+ channel activation or inhibition, depending on subtype; enhancement of NMDA receptor responses. D1 is expressed in striatum and neocortex; D5 in hippocampus and striatum.
• D2 family (D2, D3, D4): decrease cAMP production; decreased excitability via K+ channels; increased presynaptic inhibition via Ca2+ channels. D2 is expressed in striatum, hippocampus, and cortex; D3 in striatum, hippocampus, and nucleus accumbens; D4 in cortex, striatum, and hippocampus.

D2 receptor signalling (Gi pathway):

1. D2 receptor is coupled to a Gi subunit.
2. Gi deactivates adenylyl cyclase.
3. This decreases cAMP.
4. Gβγ activates potassium ion channels (GIRK).
5. Gβγ closes calcium ion channels.

By contrast, D1 receptors couple to Gs/olf, stimulating adenylyl cyclase (opposite direction to D2).

Drug Classes for Schizophrenia

Three mechanistic classes are introduced:

• Dopamine antagonists → typical antipsychotics (e.g. haloperidol)
• 5-HT2A antagonists → atypical antipsychotics (e.g. clozapine)
• Muscarinic agonists → e.g. xanomeline

Typical Antipsychotics: Haloperidol

• First generation (classical) antipsychotics.
• Act as antagonists at dopamine D2 receptors.
• Useful for severe psychosis and behavioural problems, and used when second-generation antipsychotics are ineffective.
• Example drug: haloperidol.
• Large side effect profile: extrapyramidal side effects, Parkinson’s-like symptoms, anhedonia (lack of pleasure).

Side effects of typical antipsychotics:

• Inhibition of dopamine receptors in the striatum can cause Parkinson’s-like effects.
• Inhibition of dopamine receptors in the prefrontal cortex can cause negative symptoms of schizophrenia.
• Weight gain.
• Cholinergic side effects (from muscarinic acetylcholine receptor antagonism): reduced parasympathetic modulation, producing pupil dilation, reduced secretions, and reduced GI motility.

Atypical Antipsychotics: Clozapine

• Second generation antipsychotics.
• Act as antagonists at some or all of D2, D1, D4, and/or 5-HT2A receptors.
• Clozapine specifically is an antagonist at serotonin 5-HT2A and D4 receptors.
• Clozapine can improve negative symptoms of schizophrenia.
• Lower risk of Parkinson’s-like symptoms than typical antipsychotics; clozapine does not cause Parkinson’s symptoms.
• At high doses, atypical antipsychotics can have side effects similar to typical antipsychotics.

Clozapine side effects and status

• Typically not a first-line treatment because of its side-effect profile.
• High efficacy: standardised mean difference (SMD) = 0.89, odds ratio 2–3.
• 3.8% risk of neutropaenia and agranulocytosis, fatal in ~0.01% of cases.
• α1 antagonism → decrease in blood pressure.
• Weight gain, constipation, sedation.

Comparative Efficacy of Antipsychotics

Clozapine has the highest efficacy of the antipsychotic drugs compared. Forest plots (Hedges’ g effect size) comparing second-generation antipsychotics (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine) against typical (first-generation) antipsychotics across overall, positive, and negative symptom domains show:

• Clozapine has the largest favourable (negative) effect size in all three domains (roughly −0.5 to −0.9 for overall symptoms) — i.e. clozapine performs best.
• Quetiapine shows a significantly worse result than typical antipsychotics specifically in the positive symptoms panel.

The Hypoglutamate Hypothesis

• Glutamate antagonists (ketamine, PCP) can produce both positive and negative symptoms of schizophrenia.
• Frequent ketamine users have been found to exhibit deficits in spatial memory and schizotypal symptoms.
• Drugs targeting the glutamatergic pathway have so far been unsuccessful in humans [slide does not elaborate further on why].

Muscarinic Agonists: Xanomeline–Trospium

• Muscarinic antagonists such as hyoscine can cause psychotic-like effects (see Historical Evidence section above).
• Xanomeline, a muscarinic M1 and M4 partial agonist, has been found effective at treating schizophrenia, but has many undesirable systemic effects.
• It is delivered together with trospium, a muscarinic antagonist that does not cross the blood-brain barrier, to counter those peripheral effects — a codrug strategy compared in the lecture to L-dopa and carbidopa in Parkinson’s disease treatment.
• The xanomeline–trospium combination was FDA approved in 2024: the first approved antipsychotic acting at a new biological target in 60 years. Effect size 0.65 (Cohen’s d, Positive and Negative Syndrome Scale).

Proposed mechanism:

1. Schizophrenia is proposed to be caused by too much dopamine release in the VTA.
2. M4 receptors are inhibitory Gi-coupled GPCRs that inhibit dopaminergic neurons from firing.
3. M4 receptor activation also prevents the release of acetylcholine.
4. This causes less activation of nicotinic receptors.
5. Which causes less depolarisation of dopaminergic neurons in the VTA.
6. Which decreases schizophrenia symptoms.
7. Separately, M1 receptor activation in the prefrontal cortex is believed to improve cognition and treat negative symptoms.

Treatment Summary and Symptom Targeting

• Positive symptoms are treated by: haloperidol, clozapine, xanomeline.
• Negative symptoms are treated by: clozapine, xanomeline (notably not haloperidol).

Lecture summary points:

• Schizophrenia is a severe condition, but treatment options are effective in most patients.
• Tonic dopamine levels that are too high in the nucleus accumbens and too low in the prefrontal cortex are proposed to cause schizophrenia.
• Effective treatments include D2 antagonists, 5-HT2A antagonists, and muscarinic agonists.
• Clozapine has high efficacy but significant side effects.
• Muscarinic agonists may offer a new breakthrough drug class for schizophrenia.

Self-test

1. Name the two brainstem dopaminergic regions covered and state the main function associated with each.
2. Name the three dopaminergic pathways described and the brain regions each connects.
3. Distinguish tonic from phasic dopamine firing in terms of firing rate and proportion of time active.
4. Describe what phasic dopamine firing does functionally in the striatum and in the nucleus accumbens.
5. Explain what the three-panel VTA firing experiment (no CS/reward, CS then reward, CS with no reward) demonstrates about dopamine signalling and reward.
6. List the factors associated with the cause of schizophrenia, with the heritability range given.
7. What proportion of the population is affected by schizophrenia, and what is the typical age of onset in men?
8. Describe how life expectancy, smoking rates, and suicide risk are affected in schizophrenia, and state the approximate recovery/improvement rates.
9. List the three “first class” symptoms of schizophrenia and the proportion of cases in which they are diagnostic.
10. Distinguish positive from negative symptoms of schizophrenia, listing at least three examples of each.
11. Explain how the mesolimbic and mesocortical pathways are each thought to be dysregulated in schizophrenia, and what symptom domain each produces.
12. Why does the nigrostriatal pathway matter for antipsychotic treatment even though it is not implicated in causing schizophrenia?
13. Define salience as used in this lecture, and explain how excessive tonic dopamine signalling is proposed to affect the salience network.
14. A patient with schizophrenia can readily perceive the hollow mask illusion as concave (unlike most healthy people). What point does the lecture make about this observation?
15. List the three non-dopamine neurotransmitter systems implicated in schizophrenia through historical (and ethically dubious) experiments, with the receptor and one experimental drug/finding for each.
16. Distinguish the symptom profile produced experimentally by amphetamine from that produced by hyoscine and PCP.
17. Describe the relationship shown between a drug’s clinical potency and its D2 receptor affinity, including which measurement (IC50 or dose) is used for each axis.
18. Distinguish the D1 and D2 dopamine receptor families in terms of their subtypes, effect on cAMP, and principal brain locations.
19. Describe the intracellular signalling steps triggered by D2 receptor activation, starting from the Gi subunit.
20. List the three drug classes for schizophrenia given in the lecture, with one example drug for each.
21. Explain why haloperidol is described as a “typical” antipsychotic, including its receptor target and main side effect categories.
22. Explain, using the striatum and prefrontal cortex specifically, why typical antipsychotics can cause both Parkinson’s-like effects and negative symptoms.
23. Describe clozapine’s receptor-binding profile and how it differs from haloperidol’s.
24. A patient started on clozapine needs regular blood monitoring. Explain why, citing the relevant risk figures from the lecture.
25. Explain why clozapine is not used as a first-line antipsychotic despite having the highest efficacy of the drugs compared.
26. Describe the evidence from the hypoglutamate hypothesis linking glutamate antagonism to schizophrenia symptoms.
27. Describe the proposed mechanism by which M4 receptor agonism in the VTA reduces schizophrenia symptoms, as an ordered sequence of steps.
28. Why is xanomeline co-administered with trospium, and what earlier drug combination is this strategy compared to?
29. Integrative: using the mesolimbic/mesocortical dopamine model, explain why haloperidol treats positive but not negative symptoms, while clozapine and xanomeline treat both.

Answers

Reveal answers

1. Substantia nigra — movement and sensing; ventral tegmental area (VTA) — cognition/memory/learning (via prefrontal cortex) and pleasure/reward (via nucleus accumbens).
2. Mesocortical pathway (VTA to prefrontal cortex), nigrostriatal pathway (substantia nigra to striatum), mesolimbic pathway (VTA to nucleus accumbens).
3. Tonic firing: 1–8 Hz, active ~95% of the time, driven by baseline depolarisation. Phasic firing: 15–30 Hz, active ~5% of the time, driven by rapid depolarisation.
4. In the striatum, phasic dopamine firing promotes movement; in the nucleus accumbens, it causes euphoria.
5. It shows dopamine firing tracks reward prediction rather than reward alone: firing rises at an unpredicted reward; once a cue reliably predicts reward, firing shifts to the cue itself; and if a predicted reward is withheld, firing drops below baseline at the time reward was expected.
6. Genetic predisposition (64–81% heritability), early life stress, and a strong correlational link to cannabis use.
7. Affects 1% of the population; typical age of onset in men is ~20 years old.
8. Life expectancy is reduced by 13–15 years; smoking rates are high (90%, and may reduce cognitive symptoms/some antipsychotic side effects); suicide risk is increased, with 5% of patients dying by suicide; ~33% completely recover and ~33% improve and maintain relative independence.
9. Auditory hallucinations referring to the patient in the third person; subjective changes in ownership of thinking (thought insertion, withdrawal, broadcasting); passivity (actions/sensations/emotions experienced as controlled by outside forces). Diagnostic in 75–95% of cases.
10. Positive symptoms (additions to consciousness): reality distortion/delusions/hallucinations, wild trains of thought, irrational conclusions, disorganised behaviour. Negative symptoms (decrease in functionality): thought disorder, poor social functioning, flattening of emotional responses, decreased cognitive function.
11. The mesolimbic pathway shows increased dopamine in schizophrenia, producing positive symptoms; the mesocortical pathway shows dopamine hypoactivity, producing negative, cognitive, and affective symptoms.
12. Because antipsychotic drugs act on dopamine receptors throughout the brain, including the nigrostriatal pathway, where blockade produces extrapyramidal side effects and tardive dyskinesia (Parkinson’s-like symptoms), even though this pathway isn’t part of the disease process itself.
13. Salience is the detection of important stimuli (“top-down” perception); the salience network normally filters sensory information toward survival-relevant stimuli. Excessive tonic dopamine signalling is proposed to reduce activity of this network.
14. It suggests that, in this specific respect, people with schizophrenia may be interpreting the raw visual reality more literally/“correctly” than people without schizophrenia, whose salience network is “fooled” into seeing the mask as convex.
15. Acetylcholine (muscarinic receptors) — hyoscine caused acute psychosis in a case report, and historically “flying ointment” contained muscarinic antagonists; Glutamate (NMDA receptors) — PCP (“Sernyl”) produced body-image disturbance, loss of ego boundaries, depersonalisation, and disorganised thought; Serotonin (5-HT2A receptors) — receptor named but supporting experimental detail not given on the slide.
16. Amphetamine reproduced mainly the positive symptoms of schizophrenia (paranoia was the constant feature); hyoscine and PCP approximated both positive and negative symptoms.
17. High clinical potency corresponds to high D2 affinity (low IC50, since less drug is needed to inhibit dopamine binding); low clinical potency corresponds to low D2 affinity (high IC50). The plot uses log(IC50) on one axis against log(average clinical dose, mg/day) on the other, with drugs falling along a roughly linear trend.
18. D1 family (D1, D5): increases cAMP, inhibits K+ channels, activates/inhibits Ca2+ channels depending on subtype, enhances NMDA responses; D1 in striatum/neocortex, D5 in hippocampus/striatum. D2 family (D2, D3, D4): decreases cAMP, decreases excitability via K+ channels, increases presynaptic inhibition via Ca2+ channels; D2 in striatum/hippocampus/cortex, D3 in striatum/hippocampus/nucleus accumbens, D4 in cortex/striatum/hippocampus.
19. The Gi subunit deactivates adenylyl cyclase, decreasing cAMP; the Gβγ subunits activate potassium (GIRK) channels and close calcium channels.
20. Dopamine antagonists — typical antipsychotics, e.g. haloperidol; 5-HT2A antagonists — atypical antipsychotics, e.g. clozapine; muscarinic agonists, e.g. xanomeline.
21. Haloperidol is a first-generation/classical antipsychotic and D2 receptor antagonist, used for severe psychosis and behavioural problems; its main side effects are extrapyramidal effects, Parkinson’s-like symptoms, and anhedonia.
22. Blocking dopamine receptors in the striatum removes normal dopaminergic tone there, producing Parkinson’s-like motor effects, while blocking dopamine receptors in the prefrontal cortex (already dopamine-hypoactive in schizophrenia) worsens the negative symptoms associated with that hypoactivity.
23. Clozapine is an antagonist at serotonin 5-HT2A and D4 receptors (and, more generally, atypical antipsychotics act at some or all of D2, D1, D4 and/or 5-HT2A), whereas haloperidol is a D2-selective antagonist. Clozapine’s profile gives it a lower risk of Parkinson’s-like symptoms and the ability to improve negative symptoms.
24. Clozapine carries a 3.8% risk of neutropaenia and agranulocytosis, which is fatal in approximately 0.01% of cases, so blood counts must be monitored.
25. Because of its side-effect profile — including the neutropaenia/agranulocytosis risk, hypotension (α1 antagonism), weight gain, constipation, and sedation — despite having the highest efficacy (SMD 0.89, OR 2–3) of the antipsychotics compared.
26. Glutamate antagonists such as ketamine and PCP can produce both positive and negative symptoms of schizophrenia, and frequent ketamine users show deficits in spatial memory and schizotypal symptoms, supporting a role for reduced glutamatergic signalling.
27. (1) Schizophrenia is linked to too much dopamine release in the VTA; (2) M4 receptors are inhibitory Gi-coupled GPCRs on dopaminergic neurons; (3) M4 activation prevents acetylcholine release; (4) this causes less activation of nicotinic receptors; (5) which causes less depolarisation of VTA dopaminergic neurons; (6) which decreases schizophrenia symptoms.
28. Xanomeline has many undesirable systemic (peripheral) muscarinic effects; trospium is a muscarinic antagonist that does not cross the blood-brain barrier, so it blocks those peripheral effects while leaving xanomeline’s central action intact. This mirrors the L-dopa/carbidopa codrug strategy used in Parkinson’s disease.
29. Haloperidol only blocks D2 receptors, which addresses the excess mesolimbic dopamine driving positive symptoms but does nothing for the mesocortical dopamine hypoactivity driving negative symptoms (and can worsen it via prefrontal D2 blockade). Clozapine (5-HT2A/D4 antagonism) and xanomeline (M1/M4 agonism, reducing VTA dopamine release and improving prefrontal cognition) act through mechanisms capable of addressing both the mesolimbic excess and mesocortical deficit, so both are effective against positive and negative symptoms.