Psychopharmacology: Anti-psychotic Medications

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Psychopharmacology Anti-psychotic Medications

• Brian Ladds, M.D.

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Outline

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

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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

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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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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

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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

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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)

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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

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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

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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

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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

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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 -gt low dose
• e.g., haloperidol (Haldol), fluphenazine
  (Prolixen)
• low affinity -gt high dose
• e.g., chlorpromazine (Thorazine), thioridazine
  (Mellaril)

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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

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Anti-cholinergic Side Effects

• Blurred vision
• Urinary retention
• Constipation
• Dry mouth
• (Confusion)

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Side Effects

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

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Extra-pyramidal Symptoms

• Parkinsonian-like symptoms
• Parkinsons Disease too little dopamine
• due to degeneration of dopaminergic neurons
• bradykinesia
• rigidity
• shuffling gait
• tremor

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EPS cont.

• Dystonia sudden spasms of head/neck muscles
• Akathisia restlessness
• subjective and/or objective

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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

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EPS Treatment

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

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Tardive Dyskinesia

• Involuntary choreo-athetoid movements of mouth,
  tongue, and other muscles
• generally irreversible
• after chronic use (gt 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

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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

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Atypical Anti-psychotic Meds

• Clozapine (Clozaril)
• Risperidone (Risperidal)
• Olanzapine (Zyprexa)
• Quetiapine (Seroquel)
• Ziprasidone (Geodon)

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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

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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

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Clozapine

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