Schizophrenia Learning Objectives

1. Positive vs. Negative Symptoms

Positive symptoms = “add-ons” (extra things not normally present)

• Hallucinations 👂👁

• Delusions (fixed false beliefs)

• Disorganized speech/thinking

• Disorganized or catatonic behavior

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Negative symptoms = “take-aways” (loss of normal functions)

• Alogia (poverty of speech)

• Avolition (lack of motivation)

• Anhedonia (lack of pleasure)

• Asociality (social withdrawal)

• Affective flattening (reduced emotional expression)

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👉 Hint: Think P for Positive = Plus/add symptoms, N for Negative = Not there (missing normal things).

2. Dopamine Pathways

There are 4 dopamine pathways, each linked to specific symptoms/side effects:

1. Mesolimbic: Too much DA → positive symptoms.

2. Mesocortical: Too little DA → negative symptoms.

3. Nigrostriatal: Blockade here → movement side effects (EPS, Parkinsonism).

4. Tuberoinfundibular: Blockade here → ↑ prolactin (galactorrhea, amenorrhea, sexual dysfunction)

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👉 Hint:

• “Limbic = Loud hallucinations”

• “Cortical = Cold, flat emotions”

• “Striatal = Stiff”

• “Infundibular = Infertility”

In a normal brain

• All 4 dopamine pathways are balanced.

• Mesolimbic = normal DA (no psychosis).

• Mesocortical = normal DA (normal motivation/emotion).

• Nigrostriatal = normal DA (smooth movement).

• Tuberoinfundibular = normal DA (prolactin kept in check).

In schizophrenia (untreated)

• Mesolimbic = too much DA → positive symptoms (hallucinations, delusions).

• Mesocortical = too little DA → negative symptoms (flat affect, avolition).

• Nigrostriatal & Tuberoinfundibular = usually normal at baseline.

When you give a D2-blocking antipsychotic

• It fixes the mesolimbic overactivity → positive symptoms improve 👍.

• But it doesn’t discriminate — it also blocks DA in the other pathways, which were already normal or even underactive.

  • Mesocortical: makes low DA even lower → can worsen negative symptoms.

  • Nigrostriatal: blockade = EPS, Parkinsonism.

  • Tuberoinfundibular: blockade = ↑ prolactin (sexual dysfunction, galactorrhea, amenorrhea).

Why SGAs/TGAs are special

They bring in serotonin (5-HT2A) antagonism and/or partial agonism at D2:

• In nigrostriatal & mesocortical pathways, blocking 5-HT2A actually releases dopamine → this helps offset EPS and may improve negative symptoms

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• In tuberoinfundibular, the same serotonin effect can help prevent prolactin rise.

• TGAs (like aripiprazole) act like “dopamine stabilizers” — lowering DA when it’s too high (mesolimbic) but giving a little boost when it’s too low (mesocortical).

👉 So to answer your Q simply:
Yes — in a normal brain, all pathways are balanced. In schizophrenia, only mesolimbic is too high and mesocortical too low. When we give broad D2 blockers, they “fix” mesolimbic but accidentally disrupt the other pathways (causing side effects or worsening negatives). That’s why SGAs/TGAs were developed — to be smarter about which pathways they help vs. harm.

3. Dopamine Hypothesis of Schizophrenia

• Classic idea: Too much dopamine in mesolimbic → positive symptoms.

• But… too little dopamine in mesocortical → negative/cognitive symptoms.

• Supported because:

  • Drugs that ↑ dopamine (amphetamine, cocaine) → psychosis.

  • Drugs that block D2 → reduce psychosis

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👉 Hint: “High in the limbic, low in the cortex” = schizophrenia imbalance.

4. Antipsychotics (Generations)

First-Generation (FGAs, “typical”)

• Strong D2 antagonists.

• Great for positive symptoms.

• High EPS, tardive dyskinesia, ↑ prolactin.

• Examples: haloperidol, chlorpromazine

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Second-Generation (SGAs, “atypical”)

• D2 antagonism + 5-HT2A antagonism.

• Treat positive and some negative symptoms.

• Less EPS, but metabolic side effects (weight gain, diabetes, lipids).

• Examples: risperidone, olanzapine, quetiapine, clozapine

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Third-Generation (TGAs)

• D2 partial agonists (balance dopamine rather than fully blocking).

• Lower risk of EPS/prolactin issues.

• Can improve negative symptoms.

• Examples: aripiprazole, brexpiprazole, cariprazine

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👉 Hint:

• FGA = “First = Full block”

• SGA = “Second = Serotonin helps”

• TGA = “Third = Tweaks DA” (partial agonists balance instead of block).

5. Pharmacodynamics & Clinical Differences

• D2 antagonism → antipsychotic effect (mesolimbic) but also EPS/prolactin issues (nigrostriatal, tuberoinfundibular).

• 5-HT2A antagonism → increases DA release → ↓ EPS, may improve negative symptoms

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• 5-HT1A partial agonism → reduces EPS, improves mood.

• D3 partial agonism (esp. cariprazine) → good for negative symptoms

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👉 Clinical translation:

• FGAs = more EPS/prolactin.

• SGAs = more metabolic issues.

• TGAs = less EPS/prolactin, possible akathisia instead.

6. Treatment Guidelines

1. First episode: start with SGA or TGA. Monitor early — if no 20% improvement by 2 weeks, unlikely to respond

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2. If no response → switch to another SGA/TGA.

3. If multiple failures → clozapine (gold standard for treatment-resistant schizophrenia).

4. Partial response on clozapine → consider augmentation (aripiprazole, mood stabilizer, antidepressant, or ECT)

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7. Long-Acting Injectables (LAIs)

• Improve adherence → ↓ relapse, ↓ rehospitalization.

• Examples: risperidone LAI, paliperidone (1M/3M), aripiprazole LAI

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• Special dosing schedules (loading, overlap with oral meds).

• Good option for patients with adherence issues or frequent relapse.

👉 Hint: Think of LAIs as “safety nets” — they catch patients who forget or refuse oral pills.

8. Treatment-Resistant Schizophrenia

• Definition: Failure of ≥2 adequate trials of antipsychotics.

• Gold standard: Clozapine.

• Requires careful titration and monitoring (CBC for agranulocytosis, metabolic labs).

• Augmentation strategies if clozapine fails

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9. Monitoring Guidelines

• CBC: esp. for clozapine (weekly → q2wk → monthly).

• Weight/BMI/waist circumference: baseline, 1mo, 3mo, annually.

• Lipids, glucose/HbA1c: baseline, 3–6mo, annually.

• Prolactin: if symptomatic.

• ECG: for QT prolongation risk (ziprasidone, haloperidol, etc.)

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👉 Hint: Remember the “metabolic 3”: Weight, Sugar, Cholesterol.

10. Antipsychotic Side Effects & Treatments

EPS (nigrostriatal D2 block)

• Akathisia, dystonia, Parkinsonism, tardive dyskinesia.

• Tx: anticholinergics (benztropine), beta-blockers (akathisia), VMAT2 inhibitors (TD).

Prolactin elevation (tuberoinfundibular block)

• Galactorrhea, amenorrhea, infertility.

• Tx: switch to TGA (aripiprazole).

Metabolic syndrome (esp. clozapine, olanzapine)

• Weight gain, diabetes, dyslipidemia.

• Tx: lifestyle, metformin, switch antipsychotic.

Anticholinergic (M1 block)

• Dry mouth, constipation, urinary retention.

• Tx: symptomatic relief (laxatives, fluids).

Sedation/weight gain (H1 block).

👉 Hint: Use receptor profiles to predict side effects:

• H1 = Hungry & Heavy

• M1 = Mouth dry, Memory down

• α1 = “1 step and you fall” (orthostatic hypotension)

• D2 = Dyskinesia, DA problems

1) The four dopamine pathways (what they normally do)

Mesolimbic (VTA → nucleus accumbens): reward/salience tagging (“what matters”).
Mesocortical (VTA → prefrontal cortex): cognition, motivation, executive function.
Nigrostriatal (substantia nigra → dorsal striatum): smooth movement.
Tuberoinfundibular (hypothalamus → pituitary): keeps prolactin down (DA inhibits prolactin release).

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💡 Why this matters: Exam stems love “match the pathway to the effect.” If you know the baseline jobs, you can predict both therapeutic effects and side effects when DA is pushed up or down.

🧠 Hint: Limbic = Loud (salience/psychosis), Cortical = Cognition, Striatal = Steps (movement), Infundibular = Inhibits prolactin.

2) Schizophrenia pathophysiology (simple but exam-powerful)

• Mesolimbic DA is too high → positive symptoms (hallucinations, delusions, disorganized thought/behavior).

• Mesocortical DA is too low → negative/cognitive symptoms (alogia, avolition, anhedonia, affective flattening, asociality).

• The idea was “reverse-engineered”: drugs that raise DA (e.g., amphetamines) can cause psychosis, while D2 blockers reduce it; yet the pure DA hypothesis doesn’t fully explain PFC DA deficiency (that’s why serotonin & glutamate matter too).

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💡 Why this matters: Just knowing “limbic high / cortical low” lets you predict why a pure D2 blocker helps positives but may worsen negatives.

🧠 Hint: “High in the limbic, low in the cortex.”

3) What D2-blocking antipsychotics actually do (occupancy thresholds = exam gold)

Antipsychotic effect & side effects depend on where and how much D2 you block:

• Mesolimbic: ~65–75% D2 occupancy → antipsychotic efficacy (positives improve).

• Nigrostriatal: >80% D2 occupancy → EPS (Parkinsonism, dystonia, akathisia, TD).

• Tuberoinfundibular: significant D2 blockade → ↑ prolactin.

• Mesocortical: lowering DA further can worsen negative/cognitive symptoms (secondary negatives / “neuroleptic-induced deficit”).

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💡 Why this matters: If you see EPS or galactorrhea/amenorrhea/sexual dysfunction, think too much D2 block in the wrong place. If a patient’s negatives worsen on a strong FGA, that’s pharmacology—not “the illness getting worse.”

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🧠 Hint: 65–75% = sweet spot (mesolimbic); >80% = stiff (nigrostriatal).

4) Why SGAs help (5-HT2A antagonism = the “release DA” trick)

Serotonin (5-HT) sitting on 5-HT2A receptors suppresses DA release in the nigrostriatal and mesocortical pathways. When SGAs block 5-HT2A, that disinhibits DA release in these two areas:

• In nigrostriatal, the DA “push-back” reduces EPS risk.

• In mesocortical, a DA nudge can help negative/cognitive symptoms.

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SGAs still block D2 (so they treat mesolimbic positives), but the 5-HT2A effect selectively softens the DA drop where you don’t want it (striatum, cortex). That’s the core “atypical” advantage.

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💡 Why this matters: This is the test-worthy mechanistic reason SGAs have less EPS and may help negatives compared with FGAs. (They often trade EPS for metabolic effects based on H1/5-HT2C/M1 profiles, but that’s a separate receptor story.)

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🧠 Hint: Block 5-HT2A → DA gets freed in cortex/striatum → fewer EPS, better motivation.

5) Why TGAs (aripiprazole, brexpiprazole, cariprazine) are “dopamine stabilizers”

These are D2 partial agonists:

• Where DA is too high (mesolimbic), they behave like functional antagonists (net downshift).

• Where DA is too low (mesocortical), they provide a gentle agonist signal (net upshift).

• On lactotrophs (pituitary), D2 agonism can reduce prolactin if it’s elevated.

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Some also hit D3 with high affinity (esp. cariprazine), which may support negative symptoms (mesocortical) while still treating positives (NAc).

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💡 Why this matters: If a case stem screams hyperprolactinemia on risperidone/paliperidone, aripiprazole (TGA) is a classic move because of that D2 partial agonism at the pituitary.

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🧠 Hint: TGAs “tune” DA, not just block it.

6) Tying receptor profiles → class differences (predict the side-effect pattern)

• D2 antagonism → treats psychosis; excess block = EPS, ↑ prolactin, can worsen negatives.

• 5-HT2A antagonism → releases DA in cortex/striatum → ↓ EPS, possible negative benefit.

• H1 antagonism → sedation, weight gain.

• 5-HT2C antagonism → appetite/weight gain.

• M1 antagonism → dry mouth, constipation, urinary retention, cognitive dulling.

• α1 antagonism → orthostasis, dizziness, reflex tachycardia.
  Armed with the receptor “barcode,” you can anticipate the clinical feel of each drug.

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💡 Why this matters: Many exam questions are just receptor profiles in disguise.

🧠 Hint:

• H1 = Hungry & Heavy

• 5-HT2C = Cravings/Calories

• M1 = Mouth dry, Memory down

• α1 = “1 step and you fall” (orthostasis)

7) Primary vs secondary negative symptoms (easy to miss on exams)

• Primary: due to disease (mesocortical DA deficit).

• Secondary: due to psychosis itself (e.g., withdrawal from paranoia), comorbidities (depression/OCD/PTSD), or medication side effects (EPS, sedation).

  • D2 block in the striatum (EPS) or heavy sedation can mimic/worsen negatives.

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💡 Why this matters: If negatives worsened after an FGA and the patient looks stiff/sedated, you may be looking at secondary negatives → fix the drug/receptor issue (e.g., lower dose, switch to SGA/TGA) rather than “the illness progressed.”

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8) So… to your original Q (with the full “why”):

9) Tiny add-ons that win points

• Early response rule-of-thumb: ~20% improvement by 2 weeks predicts you’re on a “keeper”; if not, consider dose optimize/switch (don’t let them languish).

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• Hyperprolactin case? Switch to/augment with aripiprazole (TGA). Mechanism: D2 partial agonism at lactotrophs.

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• EPS showing up? Likely >80% D2 block in striatum → consider dose reduction, switch to SGA/TGA, or treat EPS.

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10) Quick memory scaffold

• Pathways: Loud Limbic, Clever Cortex, Smooth Striatum, Prolactin Pituitary.

• Occupancy: 65–75 = treat; >80 = stiff.

• SGA superpower: Block 5-HT2A → free DA in cortex/striatum.

• TGA superpower: Partial D2 → stabilizes + lowers prolactin.