Neuropharmacology of Antipsychotic Drugs

These flashcards cover key terms and concepts related to the neuropharmacology of antipsychotic drugs, focusing on dopamine pathways, receptor types, associated disorders, and specifics of different drug classes.

Dopamine (DA)

A neurotransmitter that plays a key role in the brain's reward system and is implicated in psychosis and schizophrenia.

Dopamine Receptors

Five types of receptors (D1-D5) that mediate dopamine's effects in the brain, with varying structures and drug sensitivities.

D2 Receptor

A type of dopamine receptor that, when blocked by antipsychotic drugs, is primarily responsible for their antipsychotic effects.

Mesolimbic Pathway

A dopamine pathway associated with pleasure and reward; hyperactivity here is linked to positive symptoms of schizophrenia.

Mesocortical Pathway

A dopamine pathway responsible for cognition and emotion; hypoactivity here may exacerbate negative symptoms of schizophrenia.

Nigrostriatal Pathway

A dopamine pathway crucial for movement; its blockade can lead to extrapyramidal side effects (EPSEs) like dystonia.

Tardive Dyskinesia

A movement disorder resulting from prolonged D2 receptor blockade, characterized by involuntary facial and limb movements.

Extrapyramidal Side Effects (EPSEs)

Movement disorders occurring as a result of blocking dopamine pathways, often associated with first-generation antipsychotics.

Hyperprolactinemia

A side effect of antipsychotics that can lead to increased prolactin levels, resulting in symptoms like galactorrhea and amenorrhea.

Atypical Antipsychotics

Second-generation antipsychotics that generally have a lower risk of extrapyramidal side effects and act on both dopamine and serotonin receptors.

Risperidone

An atypical antipsychotic effective in treating schizophrenia with strong binding to serotonin and dopamine receptors.

Olanzapine

An atypical antipsychotic notable for its high affinity for serotonin receptors, used to treat various psychotic disorders.

Aripiprazole

Considered a third-generation antipsychotic; it acts as a partial agonist at dopamine D2 and D3 receptors.

Clozapine

An atypical antipsychotic reserved for treatment-resistant schizophrenia, noted for its unique receptor activity profile.

5HT2A Receptors

Serotonin receptors that atypical antipsychotics often target, playing a role in the efficacy and side effects of these medications.

Dopamine Hypothesis of Schizophrenia

A theory proposing that dysregulated dopamine function is a central factor in the pathophysiology of schizophrenia.

What’s the fundamental theory behind antipsychotic action in psychosis?

Dopamine dysregulation—excess mesolimbic D2 signalling + mesocortical hypoactivity.

Which dopamine receptor family is most central to antipsychotic efficacy?

D2 receptor antagonism/partial agonism.

Typical clinical D2 receptor occupancy needed for antipsychotic effect?

~65–80% D2 occupancy.

Which dopamine receptors are “excitatory” vs “inhibitory”?

D1-like (D1 D5) vs D2-like (D2 D3 D4).

What is a presynaptic autoreceptor?

A receptor on the releasing neuron (e.g. D2) that inhibits further dopamine release.

What’s the “fast-off” D2 hypothesis?

SGAs like clozapine/quetiapine bind D2 then dissociate quickly → fewer EPS.

How do many SGAs interact with 5-HT2A?

They antagonise/inverse-agonise 5-HT2A → modulate dopamine + lower EPS.

Why is the “messages in a bottle” synapse analogy helpful?

Monoamines diffuse; effects depend on release/reuptake/vesicles/auto-receptors.

Mesolimbic pathway role?

Reward/salience; hyperactivity → positive symptoms.

Mesocortical pathway role?

Cognition/affect; hypoactivity → negative/cognitive symptoms.

Nigrostriatal pathway role?

Motor control; D2 block → EPS and tardive dyskinesia.

Tuberoinfundibular pathway role?

Dopamine inhibits prolactin; D2 block → ↑prolactin.

Pharmacologic hallmark of FGAs?

Strong D2 antagonism → EPS/prolactin.

Pharmacologic hallmark of SGAs?

D2 block + strong 5-HT2A activity → fewer EPS.

Why are SGAs used despite metabolic risks?

Lower EPS burden and better functioning.

Major anticholinergic (M1) effects?

Dry mouth blurred vision constipation cognitive fog.

Life-threatening antipsychotic side effect to watch?

Anticholinergic constipation → obstruction/perforation.

Chronic D2 block risk?

Tardive dyskinesia.

Hyperprolactinemia symptoms?

Galactorrhea low libido sexual dysfunction osteoporosis risk.

How to fix hyperprolactinemia without switching drug?

Add low-dose aripiprazole.

SGA metabolic issues?

Weight gain ↑glucose ↑lipids (worst: clozapine/olanzapine).

Risperidone pros?

Many forms depot option strong efficacy not very sedating.

Risperidone limiting AEs?

EPS + hyperprolactinemia.

Paliperidone advantage?

Active metabolite of risperidone with steadier PK + depot forms.

Olanzapine pros?

High efficacy in schizophrenia + mania.

Olanzapine downsides?

Major metabolic burden + strong sedation (H1).

Quetiapine role by dose?

Low = sedative; mid = antidepressant; high = antipsychotic.

Quetiapine AE pattern?

Sedation anticholinergic effects weight gain low EPS.

Amisulpride low-dose effect?

Blocks presynaptic D2/D3 → ↑dopamine → may help negatives.

Amisulpride hallmark AE?

Very high prolactin.

Aripiprazole mechanism?

D2 partial agonist (~30% activity).

Aripiprazole AEs?

Akathisia minimal weight gain.

Cariprazine niche?

D3-preferring partial agonist → motivation/negative symptoms.

Lurasidone appeal?

Good efficacy lower metabolic burden low sedation.

When is clozapine indicated?

Treatment-resistant schizophrenia (after ≥2 SGAs).

Clozapine pros?

Best for refractory positives; very low EPS; no prolactin rise.

Clozapine must-know risks?

Agranulocytosis seizures constipation metabolic load sedation.

Why choose depots beyond adherence?

Steady levels convenience fewer relapses.

Dose titration trade-off?

Lower side effects vs maintaining positive symptom control.

Positive vs negative symptom targets?

Positive = ↓mesolimbic DA; Negative = ↑mesocortical DA.

EPS mechanism?

Nigrostriatal D2 blockade.

Why SGAs preferred?

Less EPS even if metabolic risk high.

Cause of antipsychotic-induced lactation?

D2 block in tuberoinfundibular pathway.

Managing olanzapine-induced weight gain?

Lifestyle ± metformin or switch to low-metabolic drug.

Emergency with clozapine + no stool?

Possible ileus → urgent treatment.

Lowest-weight-gain agents?

Aripiprazole lurasidone.

Highest-weight-gain agents?

Clozapine olanzapine.

Strongest prolactin raisers?

Risperidone paliperidone amisulpride.

Most sedating antipsychotics?

Clozapine olanzapine quetiapine.

Ideal “unicorn” antipsychotic?

↓Mesolimbic DA ↑Mesocortical DA but spares nigrostriatal/tuberoinfundibular.

Why smoking common in psychosis?

Nicotine transiently boosts dopamine and counters side effects.

Why warn older adults about anticholinergics?

High delirium + constipation risk.

Depot olanzapine requirement?

2-hour post-injection monitoring.

Who gets tardive dyskinesia?

Long-term D2 blockade risk grows with duration/dose.

VTA?

Origin of mesolimbic/mesocortical DA.

SNc?

Origin of nigrostriatal DA.

NAcc?

Reward/salience hub.

PFC/dlPFC/vmPFC?

Executive function emotion regulation.

EPS definition?

Motor symptoms from D2 block.

TD definition?

Late-onset involuntary movements.

NMS definition?

Life-threatening rigidity hyperthermia autonomic instability.

FGA/SGA?

Typical vs atypical antipsychotics.

LAI?

Long-acting injectable.

5-HT2A role in SGAs?

Target of inverse agonism lowering EPS.

H1/M1/α1 roles?

Sedation; anticholinergic; orthostasis.

DAT/SERT/NET?

Monoamine transporters for DA/5-HT/NE.

VMAT2?

Loads monoamines into vesicles.

MAO/COMT?

Enzymes that break down monoamines.

QTc?

ECG measure prolonged by some antipsychotics.

ANC?

Absolute neutrophil count for clozapine safety.

AIMS?

Scale for tardive dyskinesia.

EBM?

Evidence-based medicine guideline trends.

Mesolimbic DA normal role?

Salience/wanting/motivation.

Mesolimbic hyperactivity causes?

Positive symptoms.

Mesolimbic D2 blockade risk?

Emotional blunting.

Mesocortical DA normal role?

Executive function motivation affect.

Mesocortical hypoactivity?

Negative + cognitive symptoms.

Ideal mesocortical antipsychotic effect?

Increase dopamine tone here.

Nigrostriatal DA role?

Motor selection; blockade → EPS.

Tuberoinfundibular DA role?

Inhibits prolactin.

D2 autoreceptor function?

Feedback brake reducing dopamine release.

Low-dose amisulpride effect?

Blocks autoreceptors → ↑dopamine → improves negatives.

Fast-off binding clinical meaning?

Short D2 occupancy → fewer EPS (clozapine/quetiapine).

D3 receptor importance?

Limbic-focused; cariprazine effects.