SL32112-Lecture 31 - Psychosis & Schizophrenia

Define: Psychosis

A state defined by hallucinations (sensory) and delusions (beliefs), often with confused thoughts and a lack of insight that these experiences aren't real.

Symptoms

•Hallucinations

•Sight, sound, smell, touch, taste

•Delusions

•Eg. persecutory, grandiose

•Confused and disturbed thoughts

•Eg. rapid and constant speech, disturbed speech, loss of train of thought

•Lack of insight and self-awareness

•Unaware that the delusions or hallucinations aren’t real

Define: Schizophrenia (Etymology & Clinical)

Means 'split mind' ('skhizein' + 'phrēn'), referring to a split between internal thought and external reality, not multiple personalities. It's a chronic illness considered after a second psychotic episode.

diagnosed if 2 episodes of psychosis 

Three Main Symptom Categories of Schizophrenia

Positive symptoms, negative symptoms, and cognitive symptoms.

Positive Symptoms of Schizophrenia (Definition & Examples)

The increase or presence of abnormal active behaviours. Examples include hallucinations, delusions, disordered thoughts, and disturbed speech.

Negative Symptoms of Schizophrenia (Definition & Examples)

The absence or loss of normal active behaviours. Examples include affective blunting (flat emotion), avolition (no motivation), anhedonia (no pleasure), and social withdrawal.

Cognitive Symptoms of Schizophrenia

A disturbance of normal thought processes. Examples include poor executive function, poor decision-making, memory problems, and attention deficits.

Genetic Aetiology of Schizophrenia

It is strongly inherited, with a ~50% (48-50%) concordance rate in monozygotic twins. It is polygenic, with >100 'susceptibility genes' implicated rather than one specific gene.

Environmental Aetiology of Schizophrenia

There is no single specific factor, but risk is associated with

pregnancy/delivery complications,

prenatal virus infection,

urban birth/residence

psychosocial stress.

Structural Brain Abnormalities in Schizophrenia

Neurological defects→ functional → structural abnormalities 

Progressive loss of neuronal (grey) matter (e.g., in STG and DLPFC) and corresponding enlargement of the ventricles (fluid-filled spaces).

Evidence for the 'Dopamine Theory'

1. Psychostimulants (cocaine, amphetamine) increase dopamine and can cause psychosis.

2. All antipsychotic drugs are D2 receptor antagonists.

3. D2 receptor gene polymorphism is a risk factor.

Mesolimbic Pathway in Schizophrenia

A dopamine pathway from the Ventral Tegmental Area (VTA) to the Nucleus Accumbens. Hyperactivity in this D2 receptor-rich pathway is associated with positive symptoms.

Increase/overactivation of D2 receptors

Mesocortical Pathway in Schizophrenia

A dopamine pathway from the Ventral Tegmental Area (VTA) to the Frontal Lobe. Hypoactivity in this D1 receptor-rich pathway is associated with negative and cognitive symptoms.

Underactivation/ Decreased D1 receptors negative and cognitive symptoms

Typical (1st Gen) Antipsychotics: Mechanism & Efficacy

MOA: High affinity D2 receptor antagonists

Examples: Chlorpromazine, Haloperidol. Mechanism: High-affinity D2 receptor antagonists.

Efficacy: Effective ONLY against positive symptoms.

Cause of Motor (Extrapyramidal) Side Effects from Typical Antipsychotics

Blockade of D2 receptors in the Nigrostriatal pathway (involved in motor control) leads to Parkinson's-like symptoms (acute dystonias) and Huntington's-like symptoms (tardive dyskinesia).

Taken systemically, bind to receptors all round

Cause of Hormonal (Prolactin) Side Effects from Typical Antipsychotics

Blockade of D2 receptors in the Tuberoinfundibular pathway (which normally inhibits prolactin) leads to increased prolactin release, causing galactorrhea.

Extra non-DA related side effects

•Non-DA related (most antipsychotics are also antagonists at other GPCRs)

–Sedation (histamine H1 / muscarinic)

–Hypotension (a-adrenergic)

–Peripheral autonomic – blurred vision, dry mouth, constipation (muscarinic)

–Sexual dysfunction (muscarinic, a-adrenergic, dopamine)

Atypical (2nd Gen) Antipsychotics: Mechanism & Efficacy

Examples: Clozapine, Risperidone. Efficacy: Effective against BOTH positive and negative symptoms.

Mechanism: Low-affinity D2 antagonists and high-affinity 5HT2A antagonists.

High ratio 5HT2:DA block is desirable and causes less side effects

Atypical (2nd Gen) Antipsychotics: Side Effects

Fewer motor side effects than typicals

but

cause significant weight gain (H1, 5HT2C block), diabetes, and a risk of agranulocytosis (low white blood cells), especially with clozapine.

Role of 5HT2A Receptors in Psychosis

5HT2A receptor agonists, like LSD, can cause psychosis.

Therefore, 5HT2A receptor antagonists are beneficial, which is a key property of atypical antipsychotics.

Hypothesized 5HT2A-D2 Interaction for Atypical Drugs

5HT neurons (via 5HT2A-R) act as a 'brake' on dopamine neurons.

Atypicals block 5HT2A-R, 'removing the brake' and increasing DA release. T

This DA competes with the drug's low-affinity D2 block, resulting in a balanced, partial D2 blockade and fewer motor side effects.

In the nucleus accumbens there are no 5HT neurones so it just blocks the DA

Clozapine: Clinical Use & Major Risk

Clozapine can be effective in patients who are resistant to other antipsychotics, but it is only given if >2 other drugs are ineffective due to its significant side effect of

agranulocytosis (leukopenia).

The 'Glutamate Theory' of Schizophrenia

Supported by evidence that NMDA receptor antagonists (e.g., ketamine, phencyclidine) can induce psychosis. Patients also show loss of cortical glutamate receptors and abnormal glutamate circuits.

Link between Smoking and Schizophrenia

A high proportion of people with schizophrenia smoke. This may be self-medication, as nicotine enhances attention/memory ('sensory gating'). However, smoke induces CYP1A2, which metabolizes drugs like clozapine.

Antipsychotic Efficacy vs. D2 Binding Affinity

There is a strong correlation between the average clinical dose of an antipsychotic and its binding affinity for the D2 receptor. An ~80% blockade of D2 receptors is required for the antipsychotic effect.

Non-Dopaminergic Side Effects of Typical Antipsychotics

Many are 'dirty drugs' (antagonists at other GPCRs). This causes sedation (H1/muscarinic block), hypotension ($\alpha$-adrenergic block), and dry mouth/blurred vision/constipation (muscarinic block).

New Drug: Cobenfy (FDA Approved Sept 2024)

A combination of xanomeline (M1/M4 agonist) and trospium (peripheral muscarinic antagonist). It is effective against positive and cognitive symptoms by modulating glutamate and dopamine release via presynaptic M4 receptors.