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ANTIPSYCHOTICS

Complete MBBS Learning Note

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SECTION 1: BIG PICTURE OVERVIEW

What Problem Does This Drug Class Solve?

What is the disease?

• Hallucinations: Perceiving things that are not there (most commonly voices)
• Delusions: Fixed, false beliefs that cannot be changed by logic (e.g., "The government is spying on me through my teeth")
• Disorganized thinking: Speech and thoughts that jump around without logical connection

What goes wrong in the brain?

What does the drug achieve?

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SECTION 2: BUILD THE FOUNDATION

2A: Background Neuroscience - Dopamine and Its Pathways

What is dopamine?

The Four Dopamine Pathways - The Key to Understanding Everything

THE FOUR DOPAMINE PATHWAYS

1. MESOLIMBIC PATHWAY
   Ventral tegmental area (VTA) → Nucleus accumbens (limbic system)
   Function: Reward, pleasure, motivation, emotion
   In schizophrenia: OVERACTIVE → causes positive symptoms
   Drug effect: BLOCK this → reduces hallucinations & delusions ✓ (THERAPEUTIC)

2. MESOCORTICAL PATHWAY
   Ventral tegmental area (VTA) → Prefrontal cortex
   Function: Working memory, executive function, attention, social behavior
   In schizophrenia: UNDERACTIVE → causes negative symptoms & cognitive symptoms
   Drug effect: BLOCK this → worsens negative symptoms ✗ (UNWANTED)

3. NIGROSTRIATAL PATHWAY
   Substantia nigra → Striatum (caudate + putamen)
   Function: Control of voluntary movement
   In Parkinson's disease: this pathway degenerates
   Drug effect: BLOCK this → causes Parkinson-like movement side effects ✗
   (Extrapyramidal Side Effects / EPS)

4. TUBEROINFUNDIBULAR PATHWAY
   Hypothalamus → Pituitary gland (anterior)
   Function: Dopamine normally INHIBITS prolactin release
   Drug effect: BLOCK this → prolactin levels rise ✗
   (Hyperprolactinemia → gynecomastia, galactorrhea, amenorrhea)

The Dopamine Receptors

• D2 receptors are the most important for antipsychotic drug action
• D2 receptors are present in all four pathways
• All currently effective antipsychotics either block D2 receptors or act as partial agonists at D2 receptors
• This is known as the "D2 receptor hypothesis" of antipsychotic action

2B: The Dopamine Hypothesis of Schizophrenia

1. All effective antipsychotics block D2 receptors - the clinical potency of a drug correlates directly with its affinity for D2 receptors
2. Drugs that increase dopamine worsen psychosis - amphetamines, cocaine, levodopa, and bromocriptine can all trigger or worsen psychotic symptoms
3. Postmortem studies in unmedicated schizophrenics show increased D2 receptor density in the nucleus accumbens and striatum
4. PET imaging shows increased striatal dopamine synthesis and release, and greater baseline D2 receptor occupancy by endogenous dopamine in schizophrenic patients
5. The dopamine-releasing effect of amphetamine is exaggerated in schizophrenic patients compared to normal controls

• Negative symptoms (emotional blunting, social withdrawal, loss of motivation)
• Cognitive symptoms (memory problems, poor executive function)
• Why some patients respond poorly to dopamine-blocking drugs

2C: The Serotonin Hypothesis and Why It Matters

WHY ATYPICAL ANTIPSYCHOTICS CAUSE FEWER MOVEMENT SIDE EFFECTS:

Serotonin INHIBITS dopamine release in the nigrostriatal pathway.
↓
Block 5-HT2A receptors → remove serotonin's inhibitory effect
↓
More dopamine released in nigrostriatal pathway
↓
Partially offsets the D2-blocking effect there
↓
Result: Less parkinsonism / EPS

2D: The Glutamate Hypothesis

2E: Symptoms of Schizophrenia - What Needs to Be Treated

POSITIVE SYMPTOMS                    NEGATIVE SYMPTOMS
("extra" abnormal things added)      ("loss" of normal things)
──────────────────────────────────   ──────────────────────────────
• Hallucinations (auditory most      • Affective flattening (flat face,
  common - "hearing voices")           monotone voice)
• Delusions (paranoid, grandiose,    • Alogia (poverty of speech)
  referential, somatic)              • Avolition (lack of motivation)
• Disorganized speech                • Anhedonia (inability to feel
• Disorganized or catatonic            pleasure)
  behavior                           • Social withdrawal/isolation
                                     • Decreased self-care
──────────────────────────────────   ──────────────────────────────
Caused by: Mesolimbic              Caused by: Mesocortical
HYPERDOPAMINERGIA                  HYPODOPAMINERGIA
                                   (and NMDA hypofunction)
──────────────────────────────────   ──────────────────────────────
Respond WELL to all                Respond POORLY to typical drugs;
antipsychotics                     BETTER with atypicals

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SECTION 3: DRUG CLASS FRAMEWORK

3A: Classification of Antipsychotics

By Generation (Most Important Classification)

FIRST-GENERATION ANTIPSYCHOTICS (FGA) / "TYPICAL" ANTIPSYCHOTICS
─────────────────────────────────────────────────────────────────
Also called: Conventional antipsychotics, neuroleptics
Mechanism: Primarily D2 receptor blockade
Problem: High rate of Extrapyramidal Side Effects (EPS)
Key feature: Clinical potency correlates directly with D2 affinity

SECOND-GENERATION ANTIPSYCHOTICS (SGA) / "ATYPICAL" ANTIPSYCHOTICS
─────────────────────────────────────────────────────────────────
Also called: Novel antipsychotics
Mechanism: D2 blockade + 5-HT2A blockade (and more)
Advantage: Fewer EPS, better for negative symptoms
Problem: More metabolic side effects (weight gain, diabetes risk)

By Chemical Structure (For Identification in Exams)

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3B: FIRST-GENERATION (TYPICAL) ANTIPSYCHOTICS

Mechanism of Action

1. Normally, dopamine is released from a presynaptic neuron
2. It crosses the synapse and binds to D2 receptors on the postsynaptic neuron
3. This binding activates the neuron and continues the dopamine signal
4. The FGA drug has a similar shape to dopamine
5. It sits in the D2 receptor "parking spot" and blocks dopamine from parking there
6. The neuron no longer receives the dopamine signal
7. The overactive mesolimbic dopamine pathway is calmed
8. Positive symptoms (hallucinations, delusions) are reduced

• Histamine H1 - causes sedation and weight gain
• Alpha-1 adrenergic - causes orthostatic hypotension (dizziness when standing up)
• Muscarinic (M1) - causes anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision)

High vs. Low Potency Typical Antipsychotics

HIGH POTENCY FGAs                    LOW POTENCY FGAs
(e.g., Haloperidol, Fluphenazine)    (e.g., Chlorpromazine, Thioridazine)
──────────────────────────────────   ──────────────────────────────────
Strong D2 blockade                   Moderate D2 blockade
Smaller dose needed                  Larger dose needed
MORE EPS                             LESS EPS
LESS sedation                        MORE sedation
LESS anticholinergic effects         MORE anticholinergic effects
LESS hypotension                     MORE hypotension

Spectrum of Activity

Key Individual FGAs

• Prototype high-potency FGA
• Dose: 5-20 mg/day oral; available as IM injection (especially decanoate form for depot)
• Most commonly used FGA in clinical practice today
• High EPS risk; low sedation; low anticholinergic effects
• Available as Haloperidol Decanoate (long-acting injection every 4 weeks) - excellent for non-compliant patients

• First antipsychotic ever discovered (1952)
• Low-potency prototype
• More sedating, more anticholinergic, more hypotensive
• Historical significance: Its discovery transformed psychiatry and ended the era of permanent institutionalization
• Also used as anti-emetic and for intractable hiccups

• High-potency; available as decanoate (long-acting depot injection)
• High EPS risk

• Low potency; notable for causing pigmentary retinopathy (eye damage)
• Rarely used now; associated with fatal arrhythmias (QTc prolongation)

Clinical Uses of FGAs

1. Acute and chronic schizophrenia
2. Acute mania (haloperidol commonly used)
3. Agitation and psychosis in delirium (haloperidol)
4. Tourette syndrome (haloperidol, pimozide)
5. Huntington disease (to suppress chorea)
6. Anti-emesis (prochlorperazine, a phenothiazine)
7. Intractable hiccups (chlorpromazine)
8. Severe behavioral disturbance

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3C: SECOND-GENERATION (ATYPICAL) ANTIPSYCHOTICS

What Makes a Drug "Atypical"?

General Mechanism: The "Serotonin-Dopamine Antagonism" Model

ATYPICAL ANTIPSYCHOTIC EFFECTS AT FOUR PATHWAYS:

MESOLIMBIC (positive symptoms):
D2 blockade >> 5-HT2A blockade → Net D2 block → Reduces hallucinations ✓

MESOCORTICAL (negative/cognitive symptoms):
5-HT2A blockade >> D2 blockade → Net dopamine increase → Improves
negative symptoms ✓ (partial improvement)

NIGROSTRIATAL (EPS):
5-HT2A blockade >> D2 blockade → Net dopamine increase → LESS EPS ✓

TUBEROINFUNDIBULAR (prolactin):
5-HT2A blockade >> D2 blockade → Less prolactin elevation ✓
(BUT risperidone still raises prolactin significantly - exception!)

Key Individual SGAs

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CLOZAPINE - The Gold Standard for Treatment-Resistant Schizophrenia

• Blocks D2, D1, D4 dopamine receptors (but with LOWER D2 affinity than FGAs - "loose binding" or "fast off" hypothesis)
• Strong 5-HT2A, 5-HT2C, 5-HT3 antagonism
• Strong H1 antagonism → sedation, weight gain
• Strong muscarinic antagonism → anticholinergic side effects (notably sialorrhea is paradoxical despite anticholinergic effects - due to M4 agonism)
• Alpha-1 adrenergic blockade → hypotension

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RISPERIDONE

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OLANZAPINE

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QUETIAPINE

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ZIPRASIDONE

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ARIPIPRAZOLE

• Where dopamine is TOO HIGH (mesolimbic - positive symptoms): aripiprazole competes with dopamine, reducing activity → treats positive symptoms
• Where dopamine is TOO LOW (mesocortical - negative symptoms): aripiprazole provides some dopamine activity → helps negative symptoms

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LURASIDONE

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CARIPRAZINE

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3D: LONG-ACTING INJECTABLE (LAI) ANTIPSYCHOTICS

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SECTION 4: TEACH USING ANALOGIES

The Four Analogy Arsenal

Analogy 1: D2 Receptor Blockade (Typical Antipsychotics)

"The dopamine pathway in schizophrenia is like a flooded river with no banks. The hallucinations and delusions are the flood damage. Typical antipsychotics are like a dam - they block the flow. Effective, but the dam blocks ALL the water, including the water needed for normal movement (causing Parkinson-like side effects) and normal function of other areas."

Analogy 2: Why Atypical Antipsychotics Are Better

"Typical antipsychotics are like a bulldozer trying to control traffic - they flatten everything. Atypical antipsychotics are more like a smart traffic management system - they use two controls (D2 and 5-HT2A) to redirect traffic selectively. They calm the flooded road (mesolimbic pathway) while keeping the other roads running normally."

Analogy 3: Aripiprazole as a Partial Agonist

"Imagine a car's accelerator pedal. Full dopamine agonism = pedal floored = psychosis. Full antagonism (haloperidol) = pedal completely removed = too little dopamine = EPS. Aripiprazole = pedal stuck at 30% = just enough to keep the engine running smoothly. It stabilizes dopamine activity rather than eliminating it."

Analogy 4: Clozapine's "Fast Off" Binding

"Most antipsychotics are like a key that goes into the D2 receptor's lock and gets stuck there. Clozapine is like a key that goes in, does the job, and pops back out quickly. This lets normal dopamine briefly access the receptor when needed, which prevents the motor side effects and allows function in pathways that need some dopamine activity."

Analogy 5: The Prolactin Story

"Dopamine is the brake pedal for prolactin release from the pituitary. As long as dopamine is pressing the brake, prolactin stays low. Block dopamine (with antipsychotics) = remove the brake = prolactin floods out. This causes breast milk in men and women who are not pregnant (galactorrhea), breast enlargement (gynecomastia), and absent periods (amenorrhea)."

Analogy 6: Why EPS Happens

"The nigrostriatal pathway is the brain's motor control highway. Dopamine on this highway normally keeps movements smooth. Typical antipsychotics are colorblind - they block dopamine on this highway as collateral damage. Without dopamine on the motor highway: movements become rigid, slow, and tremulous (drug-induced Parkinsonism). It's like disabling the power steering in a car - every movement becomes stiff and effortful."

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SECTION 5: STEP-BY-STEP CLINICAL REASONING

Clinical Scenario 1: First Presentation of Psychosis (Likely Schizophrenia)

Step-by-step thinking:

• Duration > 6 months with prodrome? (required for schizophrenia diagnosis)
• Positive symptoms: Auditory hallucinations (command/commentary type), thought broadcasting (delusion)
• Negative symptoms: social withdrawal, avolition, poor self-care
• Ruling out: substance-induced psychosis, bipolar with psychosis, schizoaffective disorder, medical causes (brain tumor, thyroid, epilepsy)

• First episode schizophrenia: SGA preferred (lower EPS risk, better tolerability → better adherence)
• Do NOT start with clozapine (reserved for treatment resistance)

• Side effect profile (metabolic risk? patient already overweight? family history of diabetes?)
• Adherence concerns (LAI immediately? Or oral first, switch later if adherence poor?)
• Comorbidities (bipolar features? depression? sleep problems?)
• For first episode: often start with risperidone (2-4 mg/day), aripiprazole, or olanzapine (10 mg/day)

• First-episode patients are MORE sensitive to antipsychotics → start low
• Most antipsychotic response seen by Week 2 (this is an exam fact)
• If no response by 2 weeks: reassess adherence, check plasma levels before increasing dose
• Continue treatment for minimum 1-2 years after first episode

• Metabolic monitoring: weight, fasting glucose, lipids at baseline, 12 weeks, then annually
• EPS monitoring: AIMS scale for tardive dyskinesia; SAS for parkinsonism
• Prolactin (if on risperidone/paliperidone especially)
• ECG if using ziprasidone, haloperidol, or thioridazine (QTc)

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Clinical Scenario 2: Treatment-Resistant Schizophrenia

• Has she truly been adherent? (Check plasma levels - if low, LAI before switching)
• Have doses been adequate and given for sufficient duration?
• Has comorbid substance use been addressed?

• Response rate 40-60% in treatment-resistant schizophrenia vs <5% for other agents
• This is the only approved drug for treatment-resistant schizophrenia

• Baseline ANC (absolute neutrophil count) - must be > 1500/μL
• Baseline ECG, troponin, echocardiogram (myocarditis risk)
• Metabolic panel, BMI

• ANC: Weekly × 6 months → biweekly × 6 months → monthly thereafter
• Stop clozapine if ANC falls below 1000/μL (agranulocytosis)

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Clinical Scenario 3: Acute Agitation in the Emergency Department

1. Rule out medical causes of acute agitation first (hypoglycemia, head injury, intoxication)
2. If psychotic agitation: IM haloperidol 5-10 mg (can combine with IM lorazepam for synergy)
3. Alternative: IM olanzapine 10 mg (do NOT combine IM olanzapine + IM benzodiazepine - cardiovascular risk)
4. Alternative: IM ziprasidone 10-20 mg
5. Alternative: IM aripiprazole 9.75 mg

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SECTION 6: MEMORY TOOLS

6A: Mnemonics

Mnemonic 1: Four Dopamine Pathways - "MINT"

• Mesolimbic - Madness (psychosis, positive symptoms)
• Infundibular (Tuberoinfundibular) - Increase in prolactin
• Nigrostriatal - No movement (EPS, parkinsonism)
• Theory: Thinking, cognition (Mesocortical - negative/cognitive symptoms)

Mnemonic 2: Clozapine's UNIQUE side effects - "CLOZAPINE SEAS"

• Seizures
• EOS (eosinophilia)
• Agranulocytosis (life-threatening!)
• Sialorrhea (drooling - paradoxical anticholinergic)

Mnemonic 3: Low-Potency vs High-Potency FGAs - "ASHES" for Low Potency

Mnemonic 4: Adverse Effects of Antipsychotics - "SWEAT CAMP"

• Sedation
• Weight gain (metabolic)
• EPS (Extrapyramidal Side Effects)
• Agranulocytosis (clozapine)
• Tardive dyskinesia
• Cardiac effects (QTc prolongation)
• Anticholinergic
• Metabolic syndrome
• Prolactin elevation (hyperprolactinemia)

Mnemonic 5: EPS Types and Timing - "ADAPT"

• Acute dystonia (1-3 days): neck twisting, eye rolling
• Drug-induced Parkinsonism (weeks): tremor, rigidity, bradykinesia
• Akathisia (days-weeks): restlessness, can't stay still
• Perioral tremor (months)
• Tardive dyskinesia (months-years): involuntary orofacial movements

6B: Key Comparison Tables

Table 1: Side Effect Profiles of Key Antipsychotics

Table 2: Clinical Indications Beyond Schizophrenia

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SECTION 7: EXAMINER'S CORNER

Most Tested Facts (High-Yield)

Absolute Must-Knows:

1. Clozapine causes agranulocytosis - requires ANC monitoring; used only for treatment-resistant schizophrenia; only antipsychotic that reduces suicidal behavior; does NOT cause TD or significant EPS
2. Tardive dyskinesia (TD):
   • Involuntary orofacial movements (lip smacking, tongue protrusion, chewing) after months-years of antipsychotic use
   • Caused by D2 receptor supersensitivity (upregulation) after prolonged blockade
   • Less common with SGAs but NOT absent
   • Treatment: Reduce/switch drug; add VMAT2 inhibitors (valbenazine, deutetrabenazine) - newly approved treatments
   • Do NOT mask with increasing dose (only temporarily suppresses)
3. Neuroleptic Malignant Syndrome (NMS):
   • Rare, life-threatening emergency
   • Tetrad: Hyperthermia, Rigidity (lead-pipe), Altered consciousness, Autonomic instability (↑BP, tachycardia, diaphoresis)
   • Elevated creatine kinase (CK) and WBC are lab markers
   • Can occur with ANY antipsychotic, any time
   • Treatment: STOP the antipsychotic immediately; dantrolene (muscle relaxant), bromocriptine (dopamine agonist); ICU care
   • Do NOT confuse with serotonin syndrome (see table below)
4. Acute Dystonia:
   • Sudden, sustained, painful muscle contraction (oculogyric crisis - eyes rolling back; torticollis - neck twisting; opisthotonus - arching of back)
   • Occurs within 1-3 days of starting drug
   • Treatment: IV/IM benztropine or diphenhydramine (anticholinergic drugs)
5. Akathisia:
   • Subjective feeling of inner restlessness; inability to sit still; constant movement
   • Very distressing; can be misdiagnosed as worsening psychosis (causing clinicians to wrongly INCREASE the dose)
   • Treatment: Reduce dose; propranolol (most effective); benzodiazepines; benztropine (less effective)
6. Drug-induced Parkinsonism:
   • Appears within weeks
   • Tremor (pill-rolling), rigidity (cogwheel), bradykinesia, mask-like face, shuffling gait
   • Treatment: Benztropine, trihexyphenidyl (anticholinergics); reduce dose; switch to low-EPS drug

NMS vs. Serotonin Syndrome - A Critical Differentiation Table:

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Most Likely Essay Questions

1. "Classify antipsychotic drugs. Describe the mechanism of action, therapeutic uses, and adverse effects of a second-generation antipsychotic drug."
2. "Discuss the pharmacology of clozapine. Why is monitoring required? What are its advantages over typical antipsychotics?"
3. "Describe the extrapyramidal side effects of antipsychotics. How are they classified, caused, and managed?"
4. "What is the dopamine hypothesis of schizophrenia? How do antipsychotic drugs support or challenge this hypothesis?"
5. "Compare and contrast typical and atypical antipsychotics in terms of mechanism, efficacy, and adverse effects."

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Most Likely Short Notes

1. Tardive dyskinesia (cause, features, management)
2. Neuroleptic Malignant Syndrome
3. Clozapine - advantages, disadvantages, monitoring
4. Dopamine pathways and their clinical relevance
5. Long-acting injectable antipsychotics
6. Aripiprazole - mechanism of action as a partial agonist

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Most Likely Viva Questions

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Most Likely MCQs

1. "A patient on haloperidol develops oculogyric crisis 2 days after starting the medication. The most appropriate treatment is..." Answer: Benztropine (anticholinergic)
2. "An antipsychotic drug that acts as a partial agonist at D2 receptors is..." Answer: Aripiprazole
3. "The only antipsychotic approved specifically for reducing suicidal behavior in schizophrenia is..." Answer: Clozapine
4. "A patient on clozapine develops fever, sore throat, and mouth ulcers. What must be done first?" Answer: Urgent ANC (absolute neutrophil count) - suspect agranulocytosis; stop clozapine if ANC < 1000/μL
5. "Which atypical antipsychotic is MOST likely to cause EPS?" Answer: Risperidone (dose-dependent)
6. "A patient on long-term chlorpromazine develops involuntary tongue movements, lip smacking, and grimacing. The diagnosis is..." Answer: Tardive dyskinesia
7. "Neuroleptic Malignant Syndrome is treated with..." Answer: Stopping the antipsychotic + dantrolene + bromocriptine
8. "Which antipsychotic has the highest risk of weight gain and metabolic syndrome?" Answer: Clozapine and olanzapine (tied for highest)
9. "The dopamine pathway responsible for positive symptoms of schizophrenia is..." Answer: Mesolimbic pathway
10. "First antipsychotic ever discovered was..." Answer: Chlorpromazine (1952)

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Common Student Traps

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SECTION 9: HIGH-YIELD REVISION SHEET

╔══════════════════════════════════════════════════════════════════════╗
║          ANTIPSYCHOTICS - HIGH-YIELD REVISION SHEET                 ║
╚══════════════════════════════════════════════════════════════════════╝

CLASSIFICATION:
  FGA (Typical): D2 blockers - high EPS, effective for positive symptoms
  SGA (Atypical): D2 + 5-HT2A blockers - less EPS, better negative symptoms

FOUR DOPAMINE PATHWAYS:
  1. Mesolimbic → Block → Treats positive symptoms ✓
  2. Mesocortical → Block → Worsens negative/cognitive symptoms ✗
  3. Nigrostriatal → Block → EPS (parkinsonism, TD) ✗
  4. Tuberoinfundibular → Block → Hyperprolactinemia ✗

KEY DRUGS TO KNOW:
  Haloperidol → High-potency FGA; high EPS, low sedation; IM/depot available
  Chlorpromazine → First antipsychotic; low-potency; high sedation, anticholinergic
  Clozapine → Treatment-resistant schizophrenia ONLY; agranulocytosis!
               ANC monitoring mandatory; no EPS, no TD, no prolactin↑
               Reduces suicidal behavior; seizures risk; myocarditis
  Risperidone → Most EPS among SGAs (dose-dependent); highest prolactin↑
  Olanzapine → Most metabolic risk (with clozapine); highly effective
  Quetiapine → Lowest EPS; bipolar depression; sedating
  Ziprasidone → Weight neutral; QTc prolongation risk; take with food
  Aripiprazole → D2 PARTIAL AGONIST (not full antagonist!); weight neutral;
                 akathisia; adjunct for MDD

EPS - TYPES AND TIMING (ADAPT):
  Acute Dystonia: 1-3 days → Tx: Benztropine (anticholinergic) IM/IV
  Drug-induced Parkinsonism: weeks → Tx: Benztropine, reduce dose
  Akathisia: days-weeks → Tx: Propranolol (most effective)
  Perioral tremor: months
  Tardive Dyskinesia: months-years → Tx: VMAT2 inhibitors; stop/reduce drug
                      Worsened by: anticholinergics
                      Mechanism: D2 receptor supersensitivity

NEUROLEPTIC MALIGNANT SYNDROME:
  Tetrad: Hyperthermia + Lead-pipe Rigidity + Altered consciousness + Autonomic instability
  Labs: ↑CK, ↑WBC
  Treatment: STOP antipsychotic + Dantrolene + Bromocriptine + ICU

HYPERPROLACTINEMIA:
  Caused by all FGAs and risperidone/paliperidone (mainly)
  Effects: Galactorrhea, gynecomastia, amenorrhea, sexual dysfunction, osteoporosis

CLOZAPINE MONITORING:
  ANC: Weekly × 6mo → Biweekly × 6mo → Monthly
  Stop if ANC < 1000/μL
  Also monitor: ECG, troponin, metabolic panel, weight

METABOLIC MONITORING (ALL ANTIPSYCHOTICS):
  Baseline: Weight, BMI, waist circumference, fasting glucose, lipids, BP
  At 12 weeks: Repeat all
  Then: Annually (or more frequently if abnormal)

MUST-KNOW CLINICAL USES:
  Treatment-resistant schizophrenia → CLOZAPINE only
  Suicidality in schizophrenia → CLOZAPINE only
  Bipolar depression → Quetiapine, lurasidone
  Parkinson's disease psychosis → Clozapine, pimavanserin
  MDD augmentation → Aripiprazole, quetiapine
  Tourette syndrome → Haloperidol, pimozide, aripiprazole
  Antiemetic → Prochlorperazine (phenothiazine)

FIRST-LINE APPROACH:
  First-episode psychosis → SGA (not clozapine)
  Treatment resistance (failed 2 drugs) → CLOZAPINE
  Non-adherence → Long-acting injectable (LAI)

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SECTION 10: SELF-ASSESSMENT

10 Short-Answer Questions with Explanations

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1. Review whether the antipsychotic is still necessary
2. Reduce dose if possible (worsening on dose reduction = "unmasking" - temporary)
3. Switch to a lower-EPS antipsychotic (quetiapine or clozapine)
4. VMAT2 inhibitors: valbenazine or deutetrabenazine (these reduce dopamine release presynaptically, treating TD)
5. Do NOT use anticholinergics - they worsen TD
6. Clozapine is the most effective antipsychotic for patients who still need treatment

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1. Obtain urgent ANC (Absolute Neutrophil Count) and CBC with differential immediately
2. If ANC < 1000/μL: STOP clozapine immediately and do not rechallenge
3. If ANC < 500/μL: Treat as agranulocytosis - isolate patient, start broad-spectrum antibiotics, consider G-CSF (filgrastim) to stimulate granulocyte production
4. Refer to hematology

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• Hyperthermia (>38°C, often >40°C)
• Muscular rigidity (lead-pipe rigidity - severe)
• Altered consciousness (ranging from confusion to coma)
• Autonomic instability (fluctuating BP, tachycardia, diaphoresis, tachypnea)

1. IMMEDIATE: Stop all antipsychotic drugs and other dopamine blockers
2. Supportive care: ICU admission, cooling measures for hyperthermia, IV fluids
3. Dantrolene (sodium dantrolene): A direct-acting muscle relaxant that reduces rigidity and hyperthermia by inhibiting calcium release from sarcoplasmic reticulum in muscle
4. Bromocriptine or amantadine: Dopamine agonists that restore dopaminergic activity
5. If also on lithium or SSRIs: Stop those too (to exclude serotonin syndrome)
6. Once resolved: If antipsychotic is still needed, restart cautiously with a lower-EPS drug (e.g., quetiapine) after several weeks

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• Galactorrhea: Prolactin stimulates milk production regardless of pregnancy
• Amenorrhea: High prolactin suppresses GnRH → LH and FSH fall → no ovulation → no menstrual cycle
• Sexual dysfunction: Low estrogen/testosterone
• Long-term: Osteoporosis (due to low estrogen)

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• Potent H1 histamine blockade → increased appetite, sedation (reduces physical activity)
• 5-HT2C antagonism → disinhibits appetite and promotes fat storage
• Direct effect on glucose metabolism (insulin resistance) - mechanism not fully understood

• Weak H1 affinity
• Partial agonism at 5-HT2C rather than blockade

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1. Clozapine transiently occupies D2 receptors enough to reduce mesolimbic hyperactivity (treating psychosis)
2. But it releases quickly enough to allow endogenous dopamine brief, normal access to the receptor in the nigrostriatal pathway
3. This transient normal signaling prevents the development of EPS

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• He needs an antipsychotic for psychosis
• But conventional antipsychotics (which all block D2 receptors to some degree) will WORSEN his Parkinson's disease by further depleting the already deficient nigrostriatal dopamine activity

1. Clozapine (low dose): Best evidence for Parkinson's disease psychosis. Its low D2 affinity, fast-off kinetics, and multimodal receptor action allow antipsychotic effect with minimal worsening of motor symptoms. Requires ANC monitoring.
2. Quetiapine: Low D2 affinity; low EPS profile; commonly used in clinical practice for Parkinson's disease psychosis, though evidence is less robust than clozapine.
3. Pimavanserin (not widely available everywhere): A selective 5-HT2A inverse agonist/antagonist that does NOT block D2 receptors at all. FDA-approved specifically for Parkinson's disease psychosis. No EPS, no worsening of motor function. Does not appear in older pharmacology textbooks but is increasingly important.
4. Drugs to AVOID: All high-potency FGAs (haloperidol, fluphenazine), risperidone, olanzapine - these have significant D2 blocking activity that will markedly worsen the motor symptoms of Parkinson's disease.

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