Antipsychotics

Describe the role of Dopamin in these pathways:

• Mesolimbic pathway

• Mesocortical pathway

• Nigrostriatal pathway

• Tuberoinfundibular pathway

cDopaminergic Pathways:

• Mesolimbic pathway

  • ↑ Dopamine linked to positive symptoms

  • Antipsychotic D2 blockade helps here

• Mesocortical pathway

  • ↓ Dopamine linked to negative and cognitive symptoms

  • D2 blockade = worsen 

• Nigrostriatal pathway

  • Dopamine helps regulate movement

  • D2 blockade → EPS: dystonia, parkinsonism, akathisia, tardive dyskinesia

• Tuberoinfundibular pathway

  • Dopamine normally inhibits prolactin

Describe these hypothesis for schizophrenia:

• Dopamine

• Glutame

• Serotonin

DOPAMINE HYPOTHESIS for Schizophrenia:

• ↑ subcortical D2 dopamine signaling = (positive symptoms)

• ↓ cortical dopaminergic tone = (negative/cognitive symptoms)

• Clinical Relevance:

  • D2-blocking antipsychotics alleviate schizophrenia & psychosis

  • Dopamine-enhancing drugs (e.g., amphetamines) can worsen schizophrenia & induce psychosis

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GLUTAME HYPOTHESIS

• NMDA hypofunction (cortical GABA interneurons) → ↓ inhibition → cortical disinhibition/network dysfunction → DA imbalance → psychosis + cognitive deficits.

• ↓ GABA tone → ↑ glutamate → ↑ AMPA/kainate excitation → impaired cortical processing

• Phencyclidine (PCP)/ketamine (NMDA antagonists) → worsen psychosis + cognitive impairment

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SEROTONIN HYPOTHESIS

• ↑ 5-HT2A signaling → altered cortical processing/perception → psychosis-like symptoms

• 5-HT2A antagonism (atypicals) + D2 blockade → ↓ positive symptoms with fewer extrapyramidal symptoms and possible benefit for negative/cognitive symptoms

Compare A/Typical

• Blockade of?

• Clinical Usage?

• EPS?

Typical (1st generation)

• Strong D2 blockade

• Best for positive symptoms

• Higher risk of EPS, dystonia, parkinsonism, akathisia, tardive dyskinesia

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Atypical (2nd generation)

• 5-HT2A + D2 blockade

• Treat positive (+ mood/negative) symptoms

• Lower EPS risk, higher metabolic risk

Describe the LOW POTENCY 1st-GEN

• Members

• AE

• Benefits

LOW POTENCY 1st-GEN

• Members:

  • Chlorpromazine, Thioridazine

• AE:

  • More:

    • sedation, 

    • anticholinergic effects,

    • orthostatic hypotension

• Benefits:

  • Less EPS than high-potency FGAs

Describe the HIGH POTENCY 1st-GEN

• Members

• Effects

• AE

HIGH POTENCY 1st-GEN

• Members:

  • Fluphenazine, 

  • haloperidol, 

  • loxapine,

  • molindone, 

  • perphenazine, 

  • pimozide,

  • prochlorperazine, 

  • thiothixene,

  • trifluoperazine

• Effects:

  • Less

    • sedation, 

    • anticholinergic effect, 

    • orthostatic hypotension

• AE:

  • More EPS & ↑ prolactin release

Describe the Atypical antipsychotics

• Members

• Clinical Usage

• Important Risk

Atypical antipsychotics

• Members:

  • Risperidone, 

  • olanzapine, 

  • quetiapine,

  • ziprasidone, 

  • clozapine, 

  • lurasidone

• Clinical Usage:

  • schizophrenia 

  • bipolar

• Important Risk:

  • metabolic toxicity

Describe Third-generation:

• Members

• MOA

• Benefits

• AE

THIRD-GENERATION

• Members:

  • Aripiprazole, 

  • brexpiprazole, 

  • cariprazine

• MOA:

  • Partial D2 agonists

  • Act as dopamine stabilizers

• Benefits:

  • Lower prolactin rise than many D2 blockers

  • Lesser EPS/metabolic burden 

• AE:

  • akathisia

What is the main issue of D2 Blockade:

• Core Issue?

• Consequences in Women/Men

Core Issue:

• Blockade in tuberoinfundibular pathway -> Hyperprolactinemia

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Consequences:

• Women:

  • Galactorrhea, 

  • amenorrhea / oligomenorrhea,

  • infertility / anovulation, 

  • ↓ libido; 

  • Long-term bone loss 

• Men:

  • ↓ libido, 

  • erectile dysfunction, 

  • gynecomastia,

  • infertility; 

  • long-term bone loss 

Describe EPS:

• MOA

• Types

MOA:

• From nigrostriatal D2 blockade,

• more common with high-potency FGAs

---

Types:

• Acute Dystonia

• Akathisia

• Drug-Induced Parkinsonism

• Tardative Dyskinesia

List the Symptoms, Course, MOA, Tx for:

• Acute Dystonia

• Akathisia

• Drug-induced parkinsonism

• TD

ACUTE DYSTONIA

• Symptoms:

  • Muscle Spasms:

    • Neck, jaw, eyes 

      • (torticollis, trismus, oculogyric crisis)

• Course:

  • Often early after dopamine-blocking drugs

• MOA:

  • Due to ↓ dopamine, relative ↑ acetylcholine

• Tx:

  • Stop/reduce drug

  • benztropine or diphenhydramine

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AKATHISIA

• Symptom:

  • inner restlessness with urge to move

• Course:

  • Often soon after starting or increasing antipsychotics

• MOA:

  • dopamine blockade in motor pathways

• Tx:

  • Reduce dose/switch drug

  • Meds:

    • Propranolol = classic 

    • Benzodiazepines 

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DRUG-INDUCED PARKINSONISM

• Symptoms:

  •  bradykinesia, rigidity, tremor

• Course:

  • days to weeks after starting antipsychotics

• MOA:

  • dopamine blockade in the nigrostriatal pathway

    • More common with high-potency D2 blockers

• Tx:

  • Reduce dose/switch drug

  • Meds:

    • Benztropine: tremor and rigidity

    • Amantadine

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TARDIVE DYSKINESIA

• Symptoms:

  • delayed involuntary choreiform movements

    • lip smacking, tongue movements, grimacing

• Course:

  • chronic dopamine-blocking drug exposure

• MOA:

  • dopamine receptor supersensitivity

• Tx:

  • Reduce dose/switch drug

  • Meds

    • VMAT2 Inhibitors

    • Anticholinergics = Worsens 

1. List the effects of BLOCKADE OF M1, H1, α1 RECEPTORS

2. List the METABOLIC SYNDROME RISKS

   • Symptoms

   • Specific Drugs

3. Other AEs

4. Describe the Symptoms and Tx of NEUROLEPTIC MALIGNANT SYNDROME

BLOCKADE OF M1, H1, α1 RECEPTORS

• M1 blockade

  • Anticholinergic effects: 

    • dry mouth, blurred vision, constipation, urinary retention, confusion / cognitive dulling

• H1 blockade

  • Sedation, weight gain, increased appetite

• α1 blockade

  • Orthostatic hypotension, dizziness, reflex tachycardia, falls risk

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METABOLIC SYNDROME RISKS

• Symptoms:

  • Weight gain, hyperglycemia, dyslipidemia

• Specific Drugs:

  • Olanzapine, clozapine 

    • (atypical)

---

Other AE:

• QT / cardiac

  • QT prolongation, 

  • risk of arrhythmia

• Seizure risk

  • lower seizure threshold

• Sedation / autonomic burden

  • Sedation, orthostatic hypotension, anticholinergic effects

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NEUROLEPTIC MALIGNANT SYNDROME

• Symptoms:

  • Fever

  • Severe rigidity

  • Autonomic instability

  • ↑ CK

• Tx:

  • dantrolene

Describe CHLORPROMAZINE

• Class

• Benefits

• AE

• Class:

  • Low-potency first-gen

• Benefits:

  • Lower EPS risk 

• AE:

  • More sedation (H1)

  • More orthostatic hypotension (α1)

  • More anticholinergic effects (M1)

Describe HALOPERIDOL

• Class

• Clinical Usage

• AE

HALOPERIDOL

• Class:

  • High-potency first-gen

• Clinical Usage:

  • acute psychosis/agitation

• AE

  • High risk of EPS

  • ↑ prolactin

Describe CLOZAPINE

• Class

• Clinical Usage

• MOA

• Benefits

• AE

• CI

• PK

CLOZAPINE

• Class:

  • Atypical

• Clinical Usage:

  •  treatment-resistant schizophrenia

  • Reduces Suicidality in those disorders

• MOA:

  • Multi-receptor antagonist

    • blocks 5-HT2A > D2

• Benefits:

  • Very low EPS and lower prolactin rise

---

AE

• Agranulocytosis / neutropenia

  • Reactive metabolites -> trigger immune-mediated destruction 

  • Req. absolute neutrophil count (ANC) monitoring

• Seizures

• Myocarditis

• Weight gain / metabolic syndrome

• Sedation

• Sialorrhea

• Severe GI Hypomotility

• Orthostatic hypotension

---

CI:

• Serious clozapine hypersensitivity

• Avoid/Warning:

  • Dementia psychosis

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PHARMACOKINETICS

• Well-absorbed orally

• Hepatic CYP metabolism

  •  (notably CYP1A2; also 3A4/2D6)

• Changes in Level:

  • Smoking induces 1A2 → ↓ levels

  • Infection/inflammation → ↑ levels

• Req. Slow titratio

Describe ARIPIPRAZOLE

• Class

• Clinical Usage

• Benefits

• AE

ARIPIPRAZOLE

• Class:

  • 3rd gen

• Clinical Usage:

  •  schizophrenia and bipolar disorder

• Benefits:

  • Lower prolactin rise

  • Less EPS/metabolic burden

• AE:

  • akathisia

List the 3rd-GENERATION: ADVERSE EFFECTS

3rd-GENERATION: ADVERSE EFFECTS

• Akathisia = key 

• Can still cause EPS (though less likely)

• insomnia, 

• anxiety, 

• Agitation

• Nausea

• HA

• Dizziness

List the CI for Antipsychotics and why

ANTIPSYCHOTICS: CONTRAINDICATIONS

• Antihypertensive medications

  • Additive orthostatic hypotension 

    • (higher risk with low-potency FGAs) 

• Dopamine agonists

  • Oppose antipsychotic effect, 

  • worsen psychosis or reduce efficacy

• CNS depressants

  • Additive sedation and respiratory/CNS depression

• SSRIs

  • add QT or serotonergic/CNS adverse-effect burden 

• Pregnancy/lactation

  • neonatal or infant effects possible

Describe the effects of WEIGHT GAIN & INSULIN RESISTANCE

• Higher-risk agents

• MOA

WEIGHT GAIN & INSULIN RESISTANCE

• Higher-risk agents

  • Olanzapine, clozapine

  • Common with some atypical antipsychotics

• MOA:

  • H1 + 5-HT2C Blockade ↑ appetite / sedation

    • Promotes insulin resistance

    • May lead to hyperglycemia & type 2 diabetes

Describe LYBALVI

• What is it?

• Clinical usage

• AE

• CI

LYBALVI

• What is it?

  • Olanzapine (2nd gen) + samidorphan (Opioid antagonist)

    • samidorphan counters olanzapine-associated weight gain

• Clinical Usage:

  • schizophrenia and bipolar I disorder

• AE:

  • metabolic, sedation, & anticholinergic risks

• CI:

  • Do not use with opioids