Lecture on Dopamine Pathways and Antipsychotic Side Effects

Overview

• Discusses dopamine pathways, especially in untreated schizophrenia and effects of treatment.
• Focus on side effects of treating schizophrenia, particularly from blocking dopamine 2 (D2) receptors.
• Emphasis on motor side effects due to D2 antagonists.

Nigrostriatal Dopamine Pathway

• Originates in the substantia nigra and projects to the basal ganglia (striatum).
• Part of the extrapyramidal nervous system.
• Regulates movements via thalamus and cortex connections (CSTC loops).
  • Too little dopamine: Parkinsonism (tremor, rigidity, bradykinesia).
  • Too much dopamine: Hyperkinetic movements (ticks, dyskinesias).
• Pathway functions normally in untreated schizophrenia.

Dopamine and Motor Movements

• Direct pathway: Dopamine 1 receptors, excitatory, stimulates movement ("Go" pathway).
• Indirect pathway: Dopamine 2 receptors, inhibitory, blocks movement ("Stop" pathway).
• Synchronization of these pathways leads to smooth motor movements.

GABA Neurons in Movement Activation

• Direct Pathway: GABA neuron activation leads to glutamate release, stimulating movement.
• Indirect Pathway: GABA neuron activation inhibits movement by blocking glutamate.

Motor Side Effects of Antipsychotics

• D2 antagonists can cause "drug-induced parkinsonism" due to D2 blockade in the nigrostriatal pathway.
• Symptoms include tremor, rigidity, and bradykinesia.
• Precise terms for side effects: drug-induced parkinsonism, akathisia, dystonia, tardive dyskinesia.

Types of Motor Disorders

• Acute Dystonia: Muscle contractions, treated with anticholinergics like benztropine or Benadryl.
• Drug-induced Parkinsonism: Treated with anticholinergics to restore dopamine-acetylcholine balance.
• Akathisia: Inner restlessness, treated with beta blockers, benzodiazepines, or serotonin antagonists.
• Tardive Dyskinesia: Late-onset, potentially irreversible, treatable with VMAT2 inhibitors.

VMAT2 Inhibitors

• Tetrabenazine: Treats Huntington's Chorea, may be used off-label for tardive dyskinesia.
• Deuteration Process: Extends drug half-life; example is dutetrabenazine (Austedo).
• Valbenazine (Ingreza): FDA approved for tardive dyskinesia, longer half-life, no suicide warning.

Tuberoinfundibular Pathway and Prolactin

• Dopamine neurons here inhibit prolactin release.
• D2 blockers can increase prolactin levels leading to various symptoms (galactorrhea, gynecomastia).
• Guidelines suggest monitoring prolactin levels only if symptomatic.

Managing Elevated Prolactin

• Options: watch and wait, reduce or discontinue antipsychotic, switch to prolactin-sparing antipsychotic.
• Possible treatments: add Abilify, cautiously use dopamine receptor agonists, herbal supplements.

Conclusion

• Monitoring and addressing side effects of antipsychotic medications is crucial, especially in managing both motor symptoms and prolactin levels.