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Psychopharmacology: Anti-psychotic Medications Brian Ladds, M.D.

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Presentation on theme: "Psychopharmacology: Anti-psychotic Medications Brian Ladds, M.D."— Presentation transcript:

1 Psychopharmacology: Anti-psychotic Medications Brian Ladds, M.D.

2 Outline Role of dopamine in psychosis Dopamine pathways Dopamine receptors Anti-psychotic medication –Mechanism of action –Classification –Side effects

3 Schizophrenia: The Dopamine Hypothesis Chance discovery: –Chlorpromazine (Thorazine) reduced psychosis –It was found to block the effects of dopamine The “dopamine hypothesis” posits that the development of schizophrenia involves an overactive dopamine system in the brain

4 Dopamine One of the key neurotransmitters in the brain, together with: –other ‘monoamine’ neurotransmitters: norepinephrine, serotonin, acetylcholine –and the commonest neurotransmitters: glutamate, GABA Dopamine is released by a relatively small number of neurons, but serves important regulatory functions

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6 Dopamine Pathways Several different dopamine pathways –all originate in the mid-brain 2 of the main clusters of nuclei are: –Ventral Tegmental Area (VTA) meso-limbic/meso-cortical pathway –Substantia nigra nigro-striatal pathway

7 Dopamine Pathways VTA (ventral tegmental area): Mesolimbic & mesocortical pathways –projects to limbic system and to the pre-frontal cortex primary path for production of psychosis target for anti-psychotic medications »blockade of the post-synaptic dopamine receptors

8 Dopamine Pathways Substantia nigra: Nigro-striatal pathway –projects to the striatum (caudate and putamen) –anti-psychotic medications block the post- synaptic dopamine receptor in the striatum causing motoric side effects (e.g., rigidity and tremors)

9 Dopamine Pathways Arcuate and peri-ventricular nuclei: Tubero-infindibular pathway –project to the pituitary inhibits prolactin release some anti-psychotic medications cause increased prolactin release (by blocking dopamine) and cause galactorrhea

10 Dopamine Receptors D-2 receptors –main site of action for the anti-psychotic effect of many medications –clinical potency for many of the older conventional anti-psychotic medications correlates with their affinity for the post- synaptic D-2 receptor

11 Dopamine Receptors D-3 and D4 receptors –May also be involved in the actions of some of the newer “atypical” anti-psychotic medications –These receptors are present more in limbic areas than in striatum Therefore there are less motoric side effects with the newer “atypical” medications

12 Anti-psychotic Medication: Mechanism of Action Anti-psychotic medications all involve blockade of the post-synaptic D-2 dopamine receptor The therapeutic actions of the newer “atypical” anti-psychotic medications: –May also involve blockade of other types of dopamine receptors, and, –blockade of certain post-synaptic serotonin receptors

13 Anti-psychotic Medication: Classification Conventional (typical) medications –vs. “atypical” anti-psychotic medications Affinity for the D-2 receptor is related to clinical potency (especially for the conventional meds) –high affinity -> low dose e.g., haloperidol (Haldol), fluphenazine (Prolixen) –low affinity -> high dose e.g., chlorpromazine (Thorazine), thioridazine (Mellaril)

14 Side Effects Low potency anti-psychotic medication (e.g., chlorpromazine) cause more of the non-motoric side effects –sedation (H-1 blockade) –hypotension (alpha-adrenergic blockade) –anti-cholinergic

15 Anti-cholinergic Side Effects Blurred vision Urinary retention Constipation Dry mouth (Confusion)

16 Side Effects High potency anti-psychotic medication (e.g., haloperidol) cause more of the neurological and motoric side effects –EPS –TD –NMS

17 Extra-pyramidal Symptoms Parkinsonian-like symptoms –“Parkinson’s Disease” = too little dopamine »due to degeneration of dopaminergic neurons bradykinesia rigidity –shuffling gait tremor

18 EPS cont.’ Dystonia: sudden spasms of head/neck muscles Akathisia: restlessness –subjective and/or objective

19 EPS: Causes and Treatment Nigro-striatal pathway finely regulates initiation and coordination of movements –DA inhibits acetycholine release in the striatum –Anti-psychotic medications block DA in striatum causing too much Ach there and thus EPS

20 EPS: Treatment Treatment with anti-cholinergic medication decreases EPS benztropine (Cogentin) diphenhydramine (Benadryl)

21 Tardive Dyskinesia Involuntary choreo-athetoid movements of mouth, tongue, and other muscles –generally irreversible –after chronic use (> 3 months) of anti-psychotic –10-20% of patients on conventional AP after 1 year get TD –usually mild, but can be severe –elderly and women at highest risk –etiology: upregulation of striatal D-2 receptor

22 Neuroleptic Malignant Syndrome NMS –fever –muscular rigidity –autonomic instability tachycardia increased blood pressure fluctuating levels of consciousness Rare, but has 20% mortality Males and younger people are at higher risk

23 “Atypical” Anti-psychotic Meds Clozapine (Clozaril) Risperidone (Risperidal) Olanzapine (Zyprexa) Quetiapine (Seroquel) Ziprasidone (Geodon)

24 “Atypical” Anti-psychotic Meds Efficacy: –Generally comparable to conventional meds –May have some superior effects Clozapine helps where conventional meds fail They may help more with “negative symptoms” Side effect profile: –Superior to conventional meds Little EPS, less TD, less sedation, less anti-cholinergic Some may cause EKG changes, weight gain, or increase in serum glucose

25 “Atypical” Anti-psychotic Meds May have different mechanism of action –? more DA blockade in mesolimbic pathway including more D-3 and D-4 ? –? weak D-2 antagonists, esp. in striatum Minimal EPS –?? Increases DA in frontal cortex ?? ? Improves negative symptoms

26 Clozapine –agranulocytosis 1% weekly cbc tests approved only for treatment-refractory schizophrenia seizure risk 3-5%, dose-dependant


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