Lecture 3

Key Outline:

1. Aripiprazole (Abilify):

• Partial agonist at D2 and D3 receptors; 5-HT1A agonist; 5-HT2A antagonist

• Unique for being a dopamine system stabilizer—activates dopamine under low tone, blocks under high tone

• Used in MDD as adjunct (2–5 mg/day); higher doses (>10–15 mg/day) for schizophrenia/bipolar disorder

• D2 partial agonism makes it less likely to cause EPS or hyperprolactinemia

2. Brexpiprazole (Rexulti):

• Similar to aripiprazole with higher affinity for serotonin receptors; 5-HT1A partial agonist and 5-HT2A antagonist

• Also has norepinephrine activity via alpha-1B and alpha-2C antagonism

• Used in MDD adjunct (1–3 mg/day); crosses into antagonism at ~3 mg

• Less akathisia than aripiprazole but not favored for bipolar due to increased noradrenergic activity

3. Cariprazine (Vraylar):

• High D3 > D2 receptor partial agonist; 5-HT1A agonist; 5-HT2B and 5-HT2A antagonist

• D3 preference may enhance pro-cognitive and antidepressant effects

• Bipolar depression dose typically 1.5–3 mg/day; mania/schizophrenia 3–6 mg/day

• Prodrug effect leads to active metabolite (DCAR) with long half-life (~1–3 weeks)

4. Ziprasidone (Geodon):

• D2, 5-HT2A antagonist; 5-HT1A agonist; inhibits serotonin and norepinephrine reuptake

• Must be taken with food (500 kcal) for adequate absorption

• Dosed BID due to short half-life; therapeutic range 40–160 mg/day (in divided doses)

• Caution: QTc prolongation risk

5. Risperidone vs. Paliperidone (Invega):

• Paliperidone is 9-OH metabolite of risperidone; available as long-acting injectables

• Risperidone more potent; lower dose required (e.g., 0.5 mg risperidone ≈ 3 mg paliperidone)

• Both are potent D2 and 5-HT2A antagonists; hyperprolactinemia common

• Paliperidone preferred when avoiding hepatic metabolism or using injectable formulations

6. Clozapine (Clozaril):

• Weak D2 antagonist, strong 5-HT2A antagonist; also binds M1, H1, alpha-1, and D4

• Unique for efficacy in treatment-resistant schizophrenia

• Virtually no EPS/TD; risk of agranulocytosis requires REMS monitoring

• High anticholinergic burden: sedation, constipation, sialorrhea

• Risk for myocarditis, seizures at higher doses

7. Loxapine (Adasuve, Loxitane):

• First-generation structure with atypical profile; D2 and 5-HT2A antagonist

• Inhaled form (Adasuve) for acute agitation

• Oral version shows strong alpha-adrenergic antagonism → hypotension

8. Olanzapine (Zyprexa):

• Potent D2 and 5-HT2A antagonist; also blocks H1, M1, alpha-1

• High risk for weight gain, sedation, metabolic syndrome

• Cognitive blunting likely due to muscarinic antagonism

• Strong efficacy in acute mania and maintenance in bipolar disorder

9. Quetiapine (Seroquel):

• Weak D2 antagonist, strong 5-HT2A antagonist, H1, alpha-1 blocker

• Active metabolite (norquetiapine) inhibits norepinephrine reuptake

• Doses <300 mg mostly sedative (H1); 300–600 mg for bipolar depression; >600 mg for schizophrenia

• Less EPS but high sedation and orthostasis

10. Olanzapine + Samidorphan (Lybalvi):

• Combines olanzapine with mu-opioid antagonist (samidorphan) to counteract weight gain

• Samidorphan mechanism mimics naltrexone; opioid use contraindicated

• Same antipsychotic profile as olanzapine, with improved metabolic tolerance in some patients

11. Asenapine (Saphris):

• Sublingual or transdermal delivery; bypasses first-pass metabolism

• D2/D3, 5-HT2A/2C, alpha-adrenergic antagonist

• High rates of oral side effects: dysgeusia, oral hypoesthesia, oral thrush

• Used in acute mania; limited tolerability in some patients

12. Lumateperone (Caplyta):

• Novel mechanism: serotonin 5-HT2A antagonist, D2 presynaptic partial agonist/postsynaptic antagonist

• Also modulates glutamate via D1 receptor pathways; minimal muscarinic, histaminic, or adrenergic activity

• FDA-approved for schizophrenia and bipolar depression (42 mg once daily)

• Low risk of metabolic effects, EPS, or sedation

• May improve sleep and cognition via indirect glutamatergic modulation

General Conceptual Themes:

• Partial agonists can have dual effects—stimulate or block based on receptor tone and dose

• Serotonin antagonism mitigates EPS and contributes to atypicality

• Understanding receptor affinities (D2, D3, 5-HT2A, M1, H1, etc.) guides clinical choice

• Many side effects stem from non-dopaminergic activity: H1 (weight), M1 (cognitive), alpha-1 (orthostasis)

Conclusion: Atypical antipsychotics offer diverse mechanisms and must be matched to patient profile and phase of illness. Personalizing antipsychotic use requires deep understanding of pharmacodynamics, titration thresholds, and receptor interactions.