Intro to Psychopharmacology

1. Intro to Psychopharmacology Caitlin Stork, MD

2. Besides dopamine blockade . . . WHY?

3. In nigrostriatal pathway . . . • DA and ACh have a reciprocal relationship • Complex modulation of DA system by ACh neurons • Anticholinergic action mitigates D2 blockade specifically in nigrostriatal pathway • Leading to fewer movement-related side effects • Consequently, neuroleptics with significant anticholinergic effects (generally low-potency) will have fewer movement-related side effects. Muscarinic Cholinergic Blockade

4. How are atypicals different from typical antipsychotics? Atypical Antipsychotics • Pharmacologically, more heterogenous receptor antagonism • Clinically, thought to have fewer movement-related side effects and possibly more effective for negative symptoms. • But why? • Serotonin-Dopamine antagonism theory – 5-HT2 receptor blockade • “Fast Off” Theory – Rapid dissociation from D2

5. Receptor Binding Profiles: Atypicals

6. Normally, activate 5HT2A receptors inhibit DA release 5-HT2A/DA Antagonism Theory • Atypicals antagonize 5HT2A receptors  inhibit the inhibitor, thus increasing DA release • Increased DA can then compete with D2 blocking action, balancing the unmitigated D2 blockade of typical antipsychotics • Nigrostriatal  reduced EPS?

7. 5-HT2A/DA Antagonism Theory – Refuted? • Newer research indicates EPS a matter of D2 receptor occupancy, regardless of 5-HT2 effects • 65% D2 receptor occupancy  antipsychotic effect • 80% D2 receptor occupancy  EPS Am J Psychiatry. 2001;158(3):360-369

8. “Fast Off” Theory

9. D2 Rapid Dissociation Theory • Atypical antipsychotics more “loosely” bound to D2 receptors. • Allows for some endogenous dopamine to bathe receptors, perhaps mitigating EPS

10. Joint H1 and 5HT 2C antagonism? Why the Metabolic Syndrome? • H1 blockade  weight gain and drowsiness • 5HT2C blockade  may play a role in obesity, mood • Synergistic effect  Metabolic Syndrome associated with Atypicals? Newcomer, 2004

11. Clinical Antipsychotics Trial of Intervention Effectiveness Phase 1: Double-blind, random Olanzapine Quetiapine Risperidone Ziprasidone Perphenazine Phase 3: Choice of path (open-label) Aripiprazole Clozapine Fluphenazinedec. Olanzapine Perphenazine Quetiapine Risperidone Ziprasidone Any 2 of above Phase 2: Choice of path Clozapine(open-label) Olanzapine, Quetiapine, or Risperidone Ziprasidone Olanzapine, Quetiapine, or Risperdione The CATIE Trial: R • 1460 pts with schizophrenia • Comorbidities • Other meds R Stroup, 2003

12. There are overall differences in discontinuation rates among antipsychotic medications (olanzapine, quetiapine, risperidone, ziprasidone, and perphenazine). The first-generation antipsychotic perphenazine is less effective than second-generation antipsychotic medications (olanzapine, quetiapine, risperidone, and ziprasidone), as measured by discontinuation rates. There are differences among second-generation antipsychotic medications in discontinuation rates for reasons of both efficacy and safety (olanzapine, quetiapine, risperidone, and ziprasidone). CATIE Trial: Hypotheses

13. Discontinuation Rates, CATIE Phase I 64%

14. Reasons for Discontinuation

15. Most Intolerable Side Effects

16. All of the antipsychotics decreased psychotic symptoms and improved functioning • No one drug was significantly better tolerated than another; overall rates of discontinuation were high for all medications studied • Olanzapine was highly efficacious but associated with significantly more metabolic side effects • Perphenazine, the only typical antipsychotic studied, was as efficacious and as well tolerated as the atypical antipsychotics CATIE Trial: Take Homes

17. Modern-Day Antidepressants

18. Noradrenergic and Specific-Serotonin Antagonist: Mirtazapine

19. Pharmacology of Antidepressants: High = ++++, Moderate = +++, Low = ++, Very Low +, None = -

20. Pharmacology of Antidepressants: High = ++++, Moderate = +++, Low = ++, Very Low +, None = -

21. Pharmacology of Antidepressants: High = ++++, Moderate = +++, Low = ++, Very Low +, None = -

22. Phase One: Everyone on Citalopram Phase Two: Switch vs. Augment (bupropion, venlafaxine, sertraline, CT) (bupropion, buspirone, CT) STAR*D Phase Four: Switch to MAO-I or venlafaxine+mirtazapine Phase Three: Switch to non-SSRI vs. Augment weirder (TCA, mirtazapine) (lithium, T3)

23. The STAR*D Trial • Phase 1: Citalopram • 28-33% experienced remission after 8-12 weeks; additional 10-15% experienced at least some relief of sx. • In total, antidepressants helped about 50% of pts.

24. Phase 2: Switch vs. Augment • Intolerance to/inefficacy of an SSRI does not predict a lack of efficacy or intolerance of another SSRI. Any one of the medications in the study provided a reasonable second step option; 25% of those who switched to another antidepressant achieved remission. • Adding a second antidepressant medication can help achieve symptom remission: 30% of those who chose to add a medication got better.

25. The STAR*D Trial • Phase 3 results: • Use of successive antidepressant therapies resulted in only a modest remission rate (<20%) of symptoms for those with treatment resistant depression — even if varied greatly in their pharmacological properties.