Intro to Psychopharmacology Caitlin Stork, MD

Besides dopamine blockade... ReceptorEffect of Blockade Acetylcholine (muscarinic; M1) Anticholinergic effects: Central (memory impairment, confusion), cardiac (sinus tachycardia, other arrythmia), and peripheral (blurred vision, dry mouth, constipation) BENEFIT: Reduced EPS Histamine (H1)Sedation, weight gain Alpha-1 Adrenergic (α1) Orthostatic hypotension WHY?

Muscarinic Cholinergic Blockade 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.

Atypical Antipsychotics How are atypicals different from typical 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

Receptor Binding Profiles: Atypicals

5-HT 2A /DA Antagonism Theory  Atypicals antagonize 5HT 2A receptors  inhibit the inhibitor, thus increasing DA release  Normally, activate 5HT 2A receptors  inhibit DA release  Increased DA can then compete with D2 blocking action, balancing the unmitigated D2 blockade of typical antipsychotics  Nigrostriatal  reduced EPS?

5-HT 2A /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):

“Fast Off” Theory

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

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

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

CATIE Trial: Hypotheses 1.There are overall differences in discontinuation rates among antipsychotic medications (olanzapine, quetiapine, risperidone, ziprasidone, and perphenazine). 2.The first-generation antipsychotic perphenazine is less effective than second-generation antipsychotic medications (olanzapine, quetiapine, risperidone, and ziprasidone), as measured by discontinuation rates. 3.There are differences among second-generation antipsychotic medications in discontinuation rates for reasons of both efficacy and safety (olanzapine, quetiapine, risperidone, and ziprasidone).

Discontinuation Rates, CATIE Phase I 64%

Reasons for Discontinuation

Most Intolerable Side Effects

CATIE Trial: Take Homes 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

Modern-Day Antidepressants

Noradrenergic and Specific- Serotonin Antagonist: Mirtazapine

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

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

Pharmacology of Antidepressants:

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

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.

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.

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.