Dopaminergic Pathways and Antipsychotics Lecture

Overview

• Topics Covered:
  • Dopaminergic pathways: mesolimbic, mesocortical, tubero-infundibular, nigrostriatal
  • First and second generation antipsychotics (typicals vs. atypicals)
  • Extrapyramidal symptoms (EPS) and Neuroleptic Malignant Syndrome (NMS)

Dopaminergic Pathways

Mesolimbic Pathway

• Originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens (NA)
• Associated with positive symptoms of schizophrenia (hallucinations, delusions)
• High dopamine causes overactivity leading to positive symptoms
• Antipsychotics decrease dopamine to reduce these symptoms

Mesocortical Pathway

• Also starts at the VTA but projects to the cortex
• Associated with negative symptoms of schizophrenia (anhedonia, flat affect)
• Low dopamine in this pathway causes negative symptoms
• Antipsychotic treatment can potentially worsen these symptoms

Nigrostriatal Pathway

• Originates in the substantia nigra and projects to the striatum (caudate and putamen)
• Responsible for the coordination of movement
• Dopamine reduction (from antipsychotics) can cause Parkinsonism

Tubero-infundibular Pathway

• Projects from the hypothalamus to the pituitary gland
• Dopamine inhibits prolactin secretion
• Antipsychotic-induced dopamine reduction can lead to hyperprolactinemia (galactorrhea, amenorrhea)

Antipsychotics

First Generation (Typical)

• Examples: Haloperidol, Fluphenazine, Chlorpromazine, Thioridazine
• Mechanism: D2 receptor inhibitors; anti-HAM1 effects (histamine, alpha, muscarinic)
• Side effects: High incidence of EPS (e.g., Parkinsonism), neuroleptic malignant syndrome (NMS)

Second Generation (Atypical)

• Examples: Risperidone, Olanzapine, Ziprasidone, Clozapine, Quetiapine, Aripiprazole, Lurasidone
• Mechanism: Block D2 and 5-HT2A receptors
• Side effects:
  • Metabolic syndrome (weight gain, diabetes)
  • Hyperprolactinemia (higher with Risperidone)
  • Agranulocytosis (with Clozapine)

Extrapyramidal Symptoms (EPS)

Types

1. Dystonia
   • Sustained muscle contractions, including oculogyric crisis and torticollis
2. Akathisia
   • Restlessness and inability to stay still
3. Parkinsonism
   • Symptoms similar to Parkinson's disease (e.g., cogwheel rigidity, mask-like face)
4. Tardive Dyskinesia
   • Repetitive, uncontrolled movements (e.g., lip-smacking, tongue movements)

Treatment

• Dystonia and Parkinsonism: Anticholinergics (e.g., Benztropine, Benadryl)
• Akathisia: Beta-blockers
• Tardive Dyskinesia: Discontinue antipsychotic, consider Clozapine

Neuroleptic Malignant Syndrome (NMS)

• Symptoms: Fever, tachycardia, muscular rigidity, confusion, rhabdomyolysis
• Lab findings: Increased CK, potassium, white blood cells
• Treatment: Discontinue antipsychotic, Dantrolene, Dopamine agonist (Bromocriptine)

Key Mnemonics

• Anti-HAM: Antipsychotic side effects (Histamine - weight gain, Alpha - orthostasis, Muscarinic - dry mouth)
• NMS Kidney Disease:
  • Increased K (potassium, CK, killer cells/white blood cells)
  • Three D's for treatment: Discontinue, Dantrolene, Dopamine agonist

Conclusion

• Know the different dopaminergic pathways and their clinical significance
• Understand the distinction between first and second generation antipsychotics
• Recognize and treat EPS and NMS appropriately