The Teeter-Totter EffectDopamine and Acetylcholine

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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

http://www.medscape.org/viewarticle/585155

Increased DA in the mesolimbic dopamine tract = positive symptoms associated with schizophrenia including:

- Delusions - Bizarre behavior- Hallucinations - Disorganized thinking

Normal = Balance between ACh and DA in the central nervous system

Treatment goal with antipsychotics = restore the balance of dopamine

DAACh

Increased DA in the mesolimbic dopamine tract = positive symptoms of schizoprenia

ACh

DA

DAACh

However, an unwanted consequence of potent D2 antagonism in the nigrostriatal dopamine tract = pseudo-parkinsonismAs DA decreases, this causes an increase in ACh

Mild extrapyradimal side effects (EPS) such as pseudo-parkinsonism can actually be treated with anticholinergics such as:benztropine, diphenhydramine, or trihexyphenidyl ACh

DA

DA

ACh

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”

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

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

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**

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

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

Adverse Effects of Typical (1st Generation) Antipsychotics

High Potentcy(ie: haloperidol)

Low potency (ie: chlorpromazine)

Sedation + +++

EPS ++++ ++

Anticholinergic + +++

Weight gain 0 +++

Prolactin increase +++ +++

Orthostasis + +++

QT prolongation ++ ++++(only Thioridazine)

Unique Bonus Voted most likely to cause Parkinson's

Corneal depositsCholestatis

Too many to list!

+4 to 0 = highest risk to lowest risk

Adverse Effects of Atypical (2nd Generation) Antipsychotics

Clozapine Risperidone Olanzapine

Sedation +++ + ++EPS 0 +++

(esp. at higher doses)

+

Anticholinergic +++ 0 + 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

Adverse Effects of Atypical (2nd Generation) Antipsychotics

Quetiapine Ziprasidone Aripirazole

Sedation +++ ++ ++

EPS +/- + +/-Insufficient data to compare

Anticholinergic 0 to + + +

Weight gain ++ 0 0

Prolactin increase + ++ 0

Orthostasis ++ + to ++ + to ++

QT prolongation ++ +++ 0

Unique Bonus HTN EPS is probably low risk except - Akathisia

Tardive dyskinesia

1st Gen Typicals> 2nd Gen Atypicals > Clozapine

+4 to 0 = highest risk to lowest risk

What about the other symptoms associated with schizophrenia?

Negative symptoms = decreased DA in the mesocorticol dopamine tract

http://www.medscape.org/viewarticle/585155

Negative symptoms include:- Poverty of speech- Blunted affect- Withdrawal- Apathy

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

And THAT my friends…….

Is the Teeter-Totter Effect of Dopamine and Acetylcholine

http://www.toonvectors.com/clip-art/cartoon-business-teeter-totter/11037

References1. 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: http://0-www.accesspharmacy.com.libcat.ferris.edu/content.aspx?aID=7987911

2. 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 http://0-www.accesspharmacy.com.libcat.ferris.edu/content.aspx?aID=9096335.

3. DynaMed [Internet]. Ipswich (MA): EBSCO Publishing. 1995 –   .[cited 2013 Jan 16]. Available from http://www.ebscohost.com/DynaMed/.

4. Kopala LC, Meltzer HY, Meyer JM, Stahl SM. Are all atypical antipsychotics equal for the treatment of cognition and affect in schizophrenia? Medscape, LLC. 1994-2013. Accessed 2012 Jan 16. Available from: http://www.medscape.org/viewarticle/484929

5. Buchanan RW, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010 Jan;36(1):71-93.