Intro to Psychopharmacology Caitlin Stork, MD. Besides dopamine blockade... ReceptorEffect of...
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Transcript of 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.