intro to psychopharmacology caitlin stork, md. besides dopamine blockade... receptoreffect of...

Intro to Psychopharmacology

Caitlin Stork, MD

Besides dopamine blockade . . .

Receptor Effect 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-HT2A/DA Antagonism Theory

Atypicals antagonize 5HT2A receptors inhibit the inhibitor, thus increasing DA release

Normally, activate 5HT2A 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-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

“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 5HT2C 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

R

R

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

Olanzapine Quetiapine Risperidone Perphenazine Ziprasidone0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Percent Discontinuation at 18 Months82%

74% 75%

79%

64%

Olanzapine Quetiapine Risperidone Perphenazine Ziprasidone0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Pt PreferenceIntolerabilityLack of Efficacy

Reasons for Discontinuation

Most Intolerable Side Effects

Olanzapine Quetiapine Risperidone Perphenazine Ziprasidone0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

OtherSedationEPSWeight/Metabolic

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:

Reuptake Inhibition Receptor Antagonism

Antidepressant NE 5-HT DA 5-HT3 5-HT2 2 H1 ACh

TCAs : tertiary amines

doxepin + + - ? ++ - ++++ ++++

amitriptyline ++ +++ - ? ++ - ++++ ++++

imipramine +++ +++ - ? + - ++ ++++

clomipramine ++ ++++ - ? ? ? ? ++++

TCAs: secondary amines

nortriptyline +++ + - ? ++ - ++ ++

desipramine ++++ +/- - ? - - + ++

High = ++++, Moderate = +++, Low = ++, Very Low +, None = -

Reuptake Inhibition Receptor Antagonism

Antidepressant NE 5-HT DA 5-HT3 5-HT2 2 H1 ACh

SSRIs

citalopram - ++++ - ? - - - -

escitalopram - ++++ - ? - - - -

fluoxetine - ++++ - ? - - - -

fluvoxamine - ++++ - ? - - - -

paroxetine - ++++ +/- ? - - - +

sertraline - ++++ + ? - - - -

Pharmacology of Antidepressants:

High = ++++, Moderate = +++, Low = ++, Very Low +, None = -

High = ++++, Moderate = +++, Low = ++, Very Low +, None = -

Pharmacology of Antidepressants:

Reuptake Inhibition Receptor Antagonism

Antidepressant NE 5-HT DA 5-HT3 5-HT2 2 H1 ACh

Other Agents

bupropion + - - ? - - - -

duloxetine +++ +++ - ? - - - -

mirtazapine - - - ++ ++ ++ ++++ ++

nefazodone - + - ? ++ - - -

trazodone - + - ? ++ +/- +++ -/+

venlafaxine ++ +++ - ? - - - -

STAR*D

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.