1. The Teeter-Totter Effect Dopamine and Acetylcholine

2. In the treatment of psychiatric conditions like schizophrenia, there is a delicate balance between the neurotransmitters in the central nervous system
Including: dopamine (DA), acetylcholine (ACh), and serotonin (5-HT)
When there is ↑DA or ↓ ACh in the brain, patients may show signs of psychosis or delirium

3. - Delusions - Bizarre behavior
Increased DA in the mesolimbic dopamine tract = positive symptoms associated with schizophrenia including:
- Delusions - Bizarre behavior
- Hallucinations - Disorganized thinking

4. Normal = Balance between ACh and DA in the central nervous system
Increased DA in the mesolimbic
dopamine tract = positive symptoms of schizoprenia
Treatment goal with antipsychotics = restore the balance of dopamine

5. However, an unwanted consequence of potent D2 antagonism in the nigrostriatal dopamine tract = pseudo-parkinsonism
As DA decreases, this causes an increase in ACh DA
ACh
Mild extrapyradimal side effects (EPS) such as pseudo-parkinsonism can actually be treated with anticholinergics such as:
benztropine, diphenhydramine, or trihexyphenidyl
ACh DA
HOWEVER: excess blockade of ACh (ie: using several anticholinergics) can shift the ACh/DA balance. This may lead to confusion, delirium, hallucinations, and agitation otherwise known as
“mad as a hatter”

6. Therefore: anticholinergic medications (especially in combination) May Increase the Risk of Psychosis
Antihistamines
Diphenhydramine
Tricyclic antidepressants
Antispasmodics
Oxybutynin
Benztropine
Trihexyphendiyl
Amantadine
Metoclopramide
Antiemetics
Prochlorperzine
Promethazine
Scopolamine

7. Antipsychotics First generation antipsychotics
D2 receptor antagonists
Examples: haloperidol, chlorpromazine, fluphenazine, perphenazine, thiothixene
Second generation antipsychotic
D2 antagonist + 5-HT2 antagonist
Examples: ziprasidone, olanzapine, aripirazole, quetiapine, risperidone

8. Risk of EPS With Antipsychotics (proportional to D2 blockade)
High risk
Fluphenazine
Haloperidol
Perphenazine
Thiothixene
Moderately high
Chlorpromazine
Thioridazine
Moderate risk
Asenapine
Olanzapine
Paliperidone
Risperidone
Ziprasidone
Low
Aripiprazole
Clozapine
Quetiapine
**If pseudo-parkinsonism occurs with a second generation antipsychotic (atypical antipsychotic), consider switching to quetiapine, aripiprazole, or clozapine**

9. Antipsychotics: adverse effects due to multi-receptor antagonism
Dopamine
EPS, increased prolactin, sexual dysfunction
Muscarinic
Anticholinergic effects
Histamine
Sedation, weight gain
Alpha-1
Orthostatic hypotension, dizziness
Each antipsychotic agent differs in its affinity for
each of these receptors

10. The degree of adverse effects are different for each antipsychotic depending on receptor affinity…Here are some examples

11. Adverse Effects of Typical (1st Generation) Antipsychotics
High Potentcy
(ie: haloperidol)
Low potency
(ie: chlorpromazine)
Sedation +
+++
EPS
++++ ++
Anticholinergic
Weight gain
Prolactin increase
Orthostasis
QT prolongation
(only Thioridazine)
Unique Bonus
Voted most likely to cause Parkinson's
Corneal deposits
Cholestatis
Too many to list!
+4 to 0 = highest risk to lowest risk

12. Adverse Effects of Atypical (2nd Generation) Antipsychotics
Clozapine
Risperidone
Olanzapine
Sedation
+++ + ++
EPS
(esp. at higher doses)
Anticholinergic
+ to ++
Weight gain
++++
Prolactin increase
Orthostasis
QT prolongation
(possibly dose-dependent)
Unique Bonus
Agranulocytosis, seizures
Got milk?
Diabetes anyone?
+4 to 0 = highest risk to lowest risk

13. Adverse Effects of Atypical (2nd Generation) Antipsychotics
Quetiapine
Ziprasidone
Aripirazole
Sedation
+++ ++
EPS
+/- +
Insufficient data to compare
Anticholinergic
0 to +
Weight gain
Prolactin increase
Orthostasis
+ to ++
QT prolongation
Unique Bonus
HTN
EPS is probably low risk except - Akathisia
+4 to 0 = highest risk to lowest risk
Tardive dyskinesia
1st Gen Typicals> 2nd Gen Atypicals > Clozapine

14. What about the other symptoms associated with schizophrenia?
Negative symptoms = decreased DA in the mesocorticol dopamine tract
Negative symptoms include:
- Poverty of speech
- Blunted affect
- Withdrawal
- Apathy

15. Hey ! If negative symptoms are associated with less dopamine how do antispychotics (DA antagonists) help??
Atypical Antipsychotics also block 5-HT2A receptors
May increase DA in the mesocortical tract
Without eliminating the antipsychotic effect in the mesolimbic tract
In the nigrostriatal tract (remember pseudo- parkinsonism?), it is thought to reverse enough D2 antagonism to reduce EPS

16. And THAT my friends…….

17. Is the Teeter-Totter Effect of Dopamine and Acetylcholine

18. References
Crismon ML, Argo TR, Buckly PF. “Chapter 76. Schizophrenia” (Chapter). DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 8e. Retrieved January 16, 2013 from:
Josephson SA, Miller BL. “Chapter 25. Confusion and Delirium” (Chapter). In Fauci AS, Kasper DL, Jameson JL, Longo DL, Hauser SL, eds. Harrison’s Principles of Internal Medicine, 18e. Retrieved January 16, 2013 from
DynaMed [Internet]. Ipswich (MA): EBSCO Publishing –   .[cited 2013 Jan 16]. Available from
Kopala LC, Meltzer HY, Meyer JM, Stahl SM. Are all atypical antipsychotics equal for the treatment of cognition and affect in schizophrenia? Medscape, LLC Accessed Jan 16. Available from:
Buchanan RW, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull Jan;36(1):71-93.