Harvey's Garden

Antipsychotics

5 min read

Mnemonic

Antipsychotics are thought to work by blocking the D2 receptor. Psychotic patients sometimes take a DetouR from reality.

CharacteristicHigh-Potency FGAsLow-Potency FGAsSGAs (Atypicals)
ExamplesHaloperidol, FluphenazineChlorpromazineRisperidone, Olanzapine, Clozapine
EPS Risk↑↑↑ (High)↓ (Low)↓↓↓ (Lowest)
Metabolic Risk
(Wt Gain, DM)		↓ (Low)↓ (Low)↑↑↑ (High)
Other SEs
(Anticholinergic, Sedation, Hypotension)		↓ (Low)↑↑↑ (High)Variable
Key Clinical NoteBest for acute agitation, but high risk of EPS.High side effect burden limits use.First-line for schizophrenia due to lower EPS risk & efficacy for negative Sx.
”Must-Know” SETardive Dyskinesia (TD)Sedation, Orthostatic HypotensionMetabolic Syndrome
Agranulocytosis (Clozapine)
Hyperprolactinemia (Risperidone)
  • First-generation antipsychotics (also called typical antipsychotics)
    • Mechanism: Potent D2 receptor antagonists.
    • Clinical Use: Primarily treat positive symptoms of schizophrenia (hallucinations, delusions).
    • Side Effects: High risk of Extrapyramidal Symptoms (EPS) and hyperprolactinemia.
    • High-Potency FGAs
      • Drugs: Haloperidol, Fluphenazine (“Try to Fly High”).
      • Side Effects: High risk of EPS. Lower risk of anticholinergic, antihistaminic, and anti-alpha-1 side effects.
    • Low-Potency FGAs
      • Low potency means they bind weakly to D2 receptors. You need a much larger dose to get the same antipsychotic effect. So they also happen to block other receptors.
      • Drugs: Chlorpromazine, Thioridazine (“Cheating Thieves are Low”).
      • Side Effects: Low risk of EPS. High risk of:
        • Anticholinergic (dry mouth, constipation)
        • Antihistaminic (sedation)
        • Anti-alpha-1 (orthostatic hypotension)
  • Second-generation antipsychotics (also called atypical antipsychotics)
    • Mechanism: Block D2 and Serotonin (5-HT2A) receptors.
      • Serotonin antagonism can help modulate dopamine, reducing its EPS side effect.
    • Clinical Use: First-line for schizophrenia; treat both positive and negative symptoms.
    • Side Effects: Lower risk of EPS and tardive dyskinesia compared to FGAs. Major side effects are metabolic.

Tip

Antipsychotics block dopamine receptor, instead of inhibiting dopamine reuptake, as seen in antidepressants.

  • Dopamine Pathways & Effects of Blockade:
    • Mesolimbic: Therapeutic effect (reduces positive symptoms).
    • Nigrostriatal: Causes Extrapyramidal Symptoms (EPS).
    • Tuberoinfundibular: Causes hyperprolactinemia (e.g., gynecomastia, galactorrhea, amenorrhea).

First-generation antipsychotics (FGAs)

High-potency

Haloperidol

  • Brand name: Haldol
  • High-potency antipsychotics
    • Dopamine-specific antagonism (D2 receptor)
  • Extrapyramidal symptoms most common in high-potency FGAs
    • HOLD-ol

Adverse effects

Low-potency

Chlorpromazine

  • Low-potency antipsychotics
    • Dopamine antagonism
    • Anticholinergic
    • Antihistaminergic
  • First discovered, wide range of indications
  • Corneal deposits

Mnemonic

氯丙嗪，治精神；阻断多巴Ma不灵。止吐冬眠和降温，就是不治晕动病。不良反应帕金森，张口伸舌坐不能。口干好似阿托品，乳汁分泌羞死人。

Mnemonic

Chlor-neal deposits

Adverse effects

  • Anticholinergic effects, sympatholytic effects, metabolic effects, and sedation dominate

Difference of Adverse Effects

Low-potency antipsychotics require higher doses to achieve the desired effect, which leads to more prominent blockage of other receptors except D2.

Second-generation antipsychotics (SGAs)

Clozapine

  • Most effective antipsychotic
  • Indications
  • Clozapine can cause agranulocytosis and lowers the seizure threshold

Mnemonic

You must watch clozapine clozely to monitor for agranulocytosis!

Olanzapine

  • Second effective antipsychotic, without risk of agranulocytosis
  • Metabolic effects (usually weight gain, hyperglycemia, new-onset diabetes mellitus, dyslipidemia) most prominent

Mnemonic

Olanzapine can make patients gain weight, so it’s the pharmacological choice for Anorexia nervosa

Risperidone

  • Less sedation, good for elderly patients

Mnemonic

Rise and shine

Quetiapine

  • More sedation

Mnemonic

Quietiapine

Adverse effects

Summary

  • Extrapyramidal side effects:
    • Acute dystonic reaction: sudden-onset, sustained muscle contractions
    • Akathisia: subjective restlessness with inability to sit still
    • Drug-induced parkinsonism: tremor, rigidity, bradykinesia, masked facies
  • Tardive dyskinesia:
    • Involuntary movements after chronic use (e.g., lip smacking, choreoathetoid movements)
  • Neuroleptic malignant syndrome:
    • Fever, rigidity, mental status changes, autonomic instability
  • First-generation antipsychotics (FGAs)
    • High-potency (eg, haloperidol)
      • Extrapyramidal symptoms (acute dystonia, akathisia, parkinsonism), tardive dyskinesia
    • Low-potency (eg, chlorpromazine)
      • Sedation, cholinergic blockade, orthostatic hypotension, weight gain
  • Second-generation antipsychotics (SGAs)
    • Metabolic syndrome, weight gain
    • Extrapyramidal symptoms (less common than FGAs)

Hyperprolactinemia

  • Elevated prolactin levels: Dopamine inhibits the release of prolactin via the D2 receptor in the tuberoinfundibular pathway. Therefore, dopamine antagonists increase the effects of prolactin.
  • ↑ Prolactin → suppression of GnRH → ↓ LH, ↓ FSH → ↓ estrogen, ↓ testosterone → hypogonadotropic hypogonadism
  • Most common in risperidone, amisulpride
  • In men: gynecomastia, galactorrhea, hypogonadotropic hypogonadism (erectile dysfunction, reduced libido, infertility)
  • In women: galactorrhea, oligomenorrhea, hypogonadotropic hypogonadism (amenorrhea, reduced libido, infertility)

Mnemonic

RISE-PAIR-idone gives RISE to a PAIR

Extrapyramidal symptoms (EPS)

  • Pathophysiology: Inhibition of the nigrostriatal dopaminergic pathways results in EPS.
    • First-generation high-potency antipsychotics: D2 antagonism → EPS
    • Second-generation antipsychotics: weaker D2 antagonism → fewer EPS
  • Clinical features similar to Parkinson disease: Muscle, rustle, and hustle
    • Acute dystonia
      • Onset: Hours to days
      • Painful and lasting muscle spasms and stiffness predominantly affecting the head, neck, and tongue
      • Facial grimacing, torticollis
      • Tongue protrusion or twisting
      • Oculogyric crisis (upward deviation of the eyes)
      • In severe cases: laryngospasm, opisthotonus of the back
    • Pseudoparkinsonism
      • Onset: ∼ 1–4 weeks
    • Akathisia
    • Tardive dyskinesia
      • Months to years
      • Repetitive chewing and lip smacking
      • Choreic movements
      • Can be irreversible if drug is not discontinued
  • Treatment
    • Decrease or discontinue offending medication
    • Anticholinergics (trihexyphenidyl, benztropine)

Mnemonic

Chewing Tardive

Neuroleptic malignant syndrome

Epidemiology

Etiology

Pathophysiology

Clinical features

  • Mental status changes (encephalopathy)
    • Delirium (e.g., reduced vigilance)
    • Confusion
    • Stupor
    • Catatonia
  • Parkinsonism
  • Hyperthermia: High-grade fever is common.
    • Because muscles working overtime
  • Autonomic instability
    • Tachycardia, dysrhythmias, labile blood pressure
    • Tachypnea
    • Diaphoresis

Diagnostics

Clinical features similar to Serotonin syndrome

Neuroleptic malignant syndromeSerotonin syndrome
PrecipitantDopamine antagonistSerotonergic agent
Onset1-3 days<1 day
Altered mental statusYesYes
Sympathetic hyperactivityYesYes
Diffuse rigidity”Lead-pipe” rigidityNo
ClonusNoYes
ReflexesHyporeflexiaHyperreflexia

Tip

  • Neurotransmitter Specificity:
    • Dopamine Blockade in NMS: - Dopamine is crucial for inhibiting overactivity in muscle movements. Its blockade removes this inhibition, causing muscles to become rigid. - The lack of dopamine dampens reflex arcs, leading to hyporeflexia.
    • Serotonin Excess in Serotonin Syndrome: - Serotonin enhances excitatory signals in the nervous system. - Increased serotonin amplifies reflex pathways, resulting in hyperreflexia and clonus.
  • Neuromuscular Impact:
    • The balance between inhibitory and excitatory neurotransmitters is essential for normal muscle function.
    • NMS tips the scale towards inhibition loss (due to dopamine blockade), causing rigidity.
    • Serotonin syndrome tips the scale towards excess excitation, leading to clonus and hyperactive reflexes.

Treatment

  • Discontinue suspected causative agent (e.g., antipsychotics).
  • Pharmacotherapy
    • Skeletal muscle relaxant: Dantrolene (See Treatment)
    • Dopamine agonists, e.g., bromocriptine, amantadine, or apomorphine
    • Benzodiazepines, e.g., lorazepam: can be used to treat mild symptoms of NMS and/or psychomotor agitation
    • Calcium-channel blockers: for hypertension
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