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The Teeter-Totter Effect Dopamine and Acetylcholine

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Presentation on theme: "The Teeter-Totter Effect Dopamine and Acetylcholine"— Presentation transcript:

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 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 Treatment goal with antipsychotics = restore the balance of dopamine DAACh Increased DA in the mesolimbic dopamine tract = positive symptoms of schizoprenia ACh DA ACh

5 However, an unwanted consequence of potent D 2 antagonism in the nigrostriatal dopamine tract = pseudo-parkinsonism  As 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 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”

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 ▫D 2 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 D 2 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 DopamineEPS, increased prolactin, sexual dysfunction MuscarinicAnticholinergic effects HistamineSedation, weight gain Alpha-1Orthostatic 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 (1 st Generation) Antipsychotics High Potentcy (ie: haloperidol) Low potency (ie: chlorpromazine) Sedation++++ EPS++++++ Anticholinergic++++ Weight gain0+++ 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 (2 nd Generation) Antipsychotics ClozapineRisperidoneOlanzapine Sedation ++++++ EPS 0+++ ( esp. at higher doses) + Anticholinergic +++0+ to ++ Weight gain ++++++++++ Prolactin increase +++++++ Orthostasis +++ ++ QT prolongation + (possibly dose-dependent) ++ Unique Bonus Agranulocytosis, seizuresGot milk?Diabetes anyone? +4 to 0 = highest risk to lowest risk

13 Adverse Effects of Atypical ( 2 nd Generation ) Antipsychotics QuetiapineZiprasidoneAripirazole Sedation +++++ EPS +/-+ Insufficient data to compare Anticholinergic 0 to +++ Weight gain ++00 Prolactin increase +++0 Orthostasis +++ to ++ QT prolongation +++++0 Unique Bonus HTNEPS is probably low risk except - Akathisia Tardive dyskinesia 1 st Gen Typicals > 2 nd Gen Atypicals > Clozapine +4 to 0 = highest risk to lowest risk

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-HT 2A 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 D 2 antagonism to reduce EPS

16 And THAT my friends…….

17 Is the Teeter-Totter Effect of Dopamine and Acetylcholine

18 References 1.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- 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- 3.DynaMed [Internet]. Ipswich (MA): EBSCO Publishing. 1995 –.[cited 2013 Jan 16]. Available from 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: 5.Buchanan RW, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010 Jan;36(1):71-93.

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