The Teeter-Totter Effect Dopamine and Acetylcholine http://www.toonvectors.com/clip-art/cartoon-business-teeter-totter/11037

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

- Delusions - Bizarre behavior Increased DA in the mesolimbic dopamine tract = positive symptoms associated with schizophrenia including: - Delusions - Bizarre behavior - Hallucinations - Disorganized thinking http://www.medscape.org/viewarticle/585155

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

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”

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 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

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

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

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

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: http://0- www.accesspharmacy.com.libcat.ferris.edu/content.aspx?aID=7987911 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. DynaMed [Internet]. Ipswich (MA): EBSCO Publishing. 1995 –   .[cited 2013 Jan 16]. Available from http://www.ebscohost.com/DynaMed/. 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 Buchanan RW, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010 Jan;36(1):71-93.