Psychopharmacology: Anti-psychotic Medications
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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
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