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

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

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

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

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

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

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)

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

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

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

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

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)

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

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

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

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

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

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

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

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

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

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

“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

“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

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