Antipsychotics

Mnemonic

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

Characteristic	High-Potency FGAs	Low-Potency FGAs	SGAs (Atypicals)
Examples	Haloperidol, Fluphenazine	Chlorpromazine	Risperidone, 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 Note	Best 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” SE	Tardive Dyskinesia (TD)	Sedation, Orthostatic Hypotension	Metabolic Syndrome Agranulocytosis (Clozapine) Hyperprolactinemia (Risperidone)

Drug Class	Primary Receptor Dynamic	Resulting Clinical Profile
High-Potency FGA	Tight D2 binding (Specific)	High EPS; minimal off-target effects.
Low-Potency FGA	Loose D2 binding + High Dose (Non-specific)	High Anti-HAM side effects (Histamine/Alpha/Muscarinic); Low EPS (due to intrinsic anticholinergic activity).
SGA (Atypical)	5-HT2A Antagonism > D2 Antagonism	Low EPS (5-HT blockade boosts Dopamine in striatum); Metabolic Syndrome (due to H1/5-HT2C effects).

• 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)
        • FDA Black Box Warning: Antipsychotic use in elderly patients with dementia-related psychosis is associated with increased all-cause mortality, primarily driven by cardiovascular events and infectious complications (specifically aspiration pneumonia). c2
      • Anti-alpha-1 (orthostatic hypotension)
• Second-generation antipsychotics (also called atypical antipsychotics)
  • Mechanism: Block D2 and Serotonin (5-HT2A) receptors. t
    • 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

• Hyperprolactinemia
  • Dopamine inhibits the release of prolactin via the D2 receptor in the tuberoinfundibular pathway. Therefore, dopamine antagonists increase the effects of prolactin.
• Extrapyramidal symptoms most common in high-potency FGAs
• Prolonged QT interval
• Neuroleptic malignant syndrome

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
  • Sedation due to histamine receptor blockade, see Antihistamines

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)

Antipsychotic (SGA)	Weight Gain / Metabolic Syndrome	Extrapyramidal Symptoms (EPS)	Prolonged QTc
Aripiprazole	Low	Low	Low
Clozapine	Very high	Low	Medium
Lurasidone	Low	Medium	Low
Olanzapine	Very high	Low	Medium
Quetiapine	High	Low	Medium
Risperidone	High	High	Medium
Ziprasidone	Low	Low	High

Clozapine

• Most effective antipsychotic c
• Indications
  • Treatment-resistant schizophrenia
  • Schizophrenia associated with suicidality
• Clozapine can cause agranulocytosis and lowers the seizure threshold c

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 c2

Mnemonic

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

Risperidone

• Less sedation, good for elderly patients
• Most “FGA-like” SGA: Highest rate of hyperprolactinemia and EPS among atypicals at higher doses

Mnemonic

Rise and shine

Quetiapine

• Low affinity for striatal $D_2$ receptors $\to$ Lowest risk of EPS.
• Drug of choice for psychosis in Parkinson disease or Dementia with Lewy Bodies (alternative: Pimavanserin - $5{\text{-HT}}_{2A}$ inverse agonist). c2
• High sedation, orthostatic hypotension.

Mnemonic

Quietiapine

Aripiprazole

• Partial $D_2$ agonist $\to$ weight neutral, low metabolic risk, non-sedating.
• Highest propensity among SGAs to cause Akathisia.

Ziprasidone

• High risk of QTc prolongation (contraindicated in patients with baseline prolonged QTc, recent MI, or uncompensated HF).
• Must be taken with meals (> 500 kcal) to optimize bioavailability.

Adverse effects

Summary

• Extrapyramidal side effects:
  • Acute dystonic reaction: Sudden, sustained contraction of the neck, mouth, tongue & eye muscles
  • 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)

• Core Pathophysiology (DA-ACh Imbalance):
  • D2 blockade in nigrostriatal tract relieves dopamine’s normal inhibitory tone on striatal cholinergic interneurons $\to$ relative acetylcholine (ACh) excess over dopamine (DA).
  • Tardive Dyskinesia is opposite: Chronic, long-term D2 antagonism induces compensatory D2 receptor upregulation and supersensitivity in the striatum $\to$ Even normal or low amounts of DA now produce an exaggerated, hyperactive motor response c
• Clinical features similar to Parkinson disease: Muscle, rustle, and hustle
• Acute Dystonia (Onset: Hours to days):
  • Presentation: Sudden muscle contractions (torticollis, oculogyric crisis, trismus, laryngospasm).
  • Management: Benztropine (IV/IM) or Diphenhydramine (IV/IM).
• Akathisia (Onset: Days to weeks):
  • Presentation: Subjective inner restlessness + motor agitation (pacing, inability to sit still). c
    • Akathisia is frequently misdiagnosed as worsening psychotic agitation, leading to inappropriate antipsychotic dose escalation, which exacerbates the condition.
  • Management: Dose reduction, Propranolol (1st-line), Lorazepam, or Benztropine.
• Drug-Induced Parkinsonism (Onset: Weeks to months):
  • Presentation: Bradykinesia, resting tremor, cogwheel rigidity, masked facies.
    • See Restless legs syndrome
  • Management: Benztropine or Amantadine (preferred in elderly); switch to Quetiapine or Clozapine.
• Tardive Dyskinesia (Onset: Months to years):
  • Presentation: Involuntary choreoathetoid movements (orofacial dyskinesia, lip-smacking, tongue protrusion, chorea).
  • Management: Switch to Clozapine, initiate VMAT2 inhibitors (Valbenazine, Deutetrabenazine).
  • Key Exam Trap: Do NOT give benztropine (anticholinergics worsen TD). c

Mnemonic

Chewing Tardive

Neuroleptic malignant syndrome

Tip

Malignant Hyperthermia and Neuroleptic Malignant Syndrome (NMS) have almost same symptoms. The only differentiating factor is c

• Malignant Hyperthermia is triggered by inhaled anesthetics (e.g., halothane) or succinylcholine
• NMS is triggered by antipsychotics

Epidemiology

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Etiology

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• High-potency first-generation antipsychotics (most common association)
• Second-generation antipsychotics
• Other dopamine antagonists, e.g., metoclopramide, promethazine

Pathophysiology

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• Central D2 receptor blockade in the nigrostriatal pathway and hypothalamus, resulting in movement disorders and impaired thermoregulation

Clinical features

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

Diagnostics

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Clinical features similar to Serotonin syndrome

	Neuroleptic malignant syndrome	Serotonin syndrome
Precipitant	Dopamine antagonist	Serotonergic agent
Onset	1-3 days	<1 day
Altered mental status	Yes	Yes
Sympathetic hyperactivity	Yes	Yes
Diffuse rigidity	”Lead-pipe” rigidity	No
Clonus	No	Yes
Reflexes	Hyporeflexia	Hyperreflexia

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

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• Immediate First-Line:
  1. Stop causative neuroleptic agent immediately (or immediately restart stopped dopamine agonists in Parkinson pts).
  2. ICU Admission & Supportive Care:
     • Aggressive IV hydration with isotonic crystalloids (prevents renal heme-pigment cast precipitation from rhabdomyolysis).
     • Active cooling: Ice packs (axilla/groin), cooling blankets, cold IV fluids.
     • Airway & Circulation: Intubation for severe AMS, respiratory failure, or hypoventilation due to chest-wall rigidity.
• Second-Line / Medical Therapy (Moderate-to-severe cases refractory to supportive care):
  • Dantrolene: Direct-acting skeletal muscle relaxant (ryanodine receptor antagonist); reduces hyperthermia and rigidity.
  • Bromocriptine or Amantadine: Dopamine receptor agonists; restores central dopaminergic tone. c
  • Benzodiazepines (e.g., IV Lorazepam): For agitation, catatonia, and mild rigidity.
  • Anticholinergics are CONTRAINDICATED: Anticholinergics cause anhidrosis → Heat cannot dissipate → rapid, catastrophic acceleration of core temperature c
• Refractory:
  • Electroconvulsive Therapy (ECT): Indicated if unresponsive to medical therapy within 48–72 hours.
• Long-Term / Re-challenge:
  • Avoid neuroleptics for at least 2 weeks post-resolution.
  • Rechallenge: Low dose, low-potency agent or second-generation atypical agent with slow titration.

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