Transcript The Neuroscience of Psychiatry

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