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Lecture 45: Antipsychotics
Timothy Beer (Modified by Dave Reilly 2013)
When Antipsychotic Agents Are Used
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FDA approved indications for antipsychotics
o Schizophrenia
o Bipolar disorder
o Delirium
o Depression with psychotic features (e.g. aripiprazole, quetiapine)
o To augment regular depression drugs
Off-label indications for antipsychotics
o Chronic aggression
o Personality disorders
o Impulse control disorders
o Eating disorders
Classes of Antipsychotics
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Typical Antipsychotics (1st generation antipsychotics aka Neuroleptics)
o The original antipsychotics
o Even though these are older medications, they are sometimes the 1st line drugs (e.g. Haloperidol where
IV delivery is needed)
o DOPAMINE ANTAGONISTS
Atypical Antipsychotics (2nd generation antipsychotics)
o The newer antipsychotics
o DOPAMINE AND SEROTONIN ANTAGONISTS
o Have significantly reduced extrapyramidal side effects compared to typical antipsychotics
 This is because presence of 5-HT2A blockade
“Third generation” Antipsychotics- Partial agonists:
o Aripiprazole- When there’s too much DA = antagonist, and too little = agonist
Mechanisms of Action
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Dopaminergic Pathways in the Brain
o Key to understanding the “dopamine hypothesis,” which links the MOA of antipsychotics on
schizophrenia with the MOA on the body
o In the brain, we have the following four DOPAMINE pathways:
 1) Mesolimbic pathway: overactivity of this pathway is thought to be the underlying physiology of
positive symptoms of psychosis in schizophrenia
 Midbrain ventral tegmental area (VTA- vestibule to addiction)  nucleus accumbens
o Pathway that creates the delusions and hallucinations that can be present in
psychosis
o Pathway of all things pleasurable
o Pathway for drugs of abuse to create the “high” feeling
 2) Mesocortical pathway: underactivity in this area is thought be the underlying physiology of
negative symptoms in schizophrenia
 Midbrain ventral tegmental area  limbic cortex
o May have a role in mediating psychotic symptoms
o May have a role in the cognitive side effects of typical antipsychotics
 3) Nigrostriatal pathway
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Substantia nigra  basal ganglia
o Controls movement
o Relevant in Parkinson’s disease
 4) Tuberoinfundibular pathway
 Hypothalamus  anterior pituitary gland
o Controls prolactin secretion
o Dopamine and prolactin have an inversely proportionate relationship
o The problem is that medications have effects on ALL of these pathways**************
Dopamine Hypothesis
o Used to explain the symptoms present in schizophrenia
o Explains the biochemical and pharmacological basis of schizophrenia
o Proposes the co-existence of the following two things:
 Hyper-dopaminergic activity in the mesolimbic pathway  positive symptoms of schizophrenia
 Hypo-dopaminergic activity in mesocortical pathway  negative symptoms of schizophrenia
 Dopamine antagonists can actually make the negative symptoms WORSE!
Categories of Antipsychotics
 Typical Antipsychotics (include Chlorpromazine, Haloperidol, Thiothixene)
o “Potency” describes the drug’s ability to bind to dopamine receptor**
 High potency drugs: haloperidol, fluphenazine
 Low anti-cholinergic properties
 Low sedating properties
 Fewer cardiovascular abnormalities
 Higher incidence of extrapyramidal symptoms
 Low potency drugs: chlorpromazine, thioridazine
 High anti-cholinergic properties
 High sedating properties
 More cardiovascular abnormalities
 Higher incidence of extrapyramidal symptoms
o MOA
 Act by competitively blocking dopamine receptors (D2, D3, D4)
 These dopamine receptors are linked to adenylyl cyclase through G-protein, which inhibits
activation of adenylyl cyclase
 Blocking receptors improves positive symptoms of schizophrenia, which are mediated by
the mesolimbic system
 Typical antipsychotics bind to the D2-receptors much more avidly than the D3-receptors
(10-50x more avidly)
 D2 receptors are located in the limbic, extrapyramidal and endocrine structures
 D3 and D4 receptors are located primarily in limbic structures
 Atypical Antipsychotics
o Serotonin & Dopamine Antagonists (include Clozapine, Risperidone, Olanzapine)
 More selective for the mesolimbic dopamine pathway than the nigrostriatal
 Higher affinity for D4 and D3 in addition to D2
 Block 5-HT2A serotonin receptors more avidly than D2 dopamine receptors and have the following
effects:
 Improves negative symptoms – anti-serotonin effect/dopamine effect
 Improves positive symptoms – Anti-dopamine effect
 Less extrapyramidal side effects than typical antipsychotics- less risk of movement d/o
o “Third Generation” Dopamine Agonist/Antagonists (the only drug in this class is Aripiprazole)
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Block dopamine receptors in areas of high dopamine activity (mesolimbic pathway)
Agonize dopamine receptors in areas of low dopamine activity (frontal lobes, nigrostriatal
pathway)
Tends to have a lot of movement disorders.
Side Effects of Antipsychotics
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Side Effects Due to Effects on Multiple Receptor Systems In Addition To D2 and 5-HT2 (e.g. H1, a1, M1)
o Anti-cholinergic effects
 Dry mouth
 Mydriasis
 Urinary retention
 Constipation
o Anti-histaminergic effects
 Weight gain (can be significant)
 Sedation
o Anti-α-Adrenergic effects
 Orthostatic hypotension
 Sedation
o Anti-dopaminergic effects
 Extrapyramidal side effects
5 major Extrapyramidal Side Effects – result from the blockade of multiple dopaminergic pathways, especially
those in the basal ganglia
o 1) Parkinsonian syndrome: results from inhibition of nigrostriatal pathways by competitive blockade of
D2 receptors in the striatum
 Muscle rigidity
 Slowed movement (bradykinesia)
 Shuffling gait
 Resting tremor
 Mask-like facial expression
 Cogwheel rigidity
o 2) Acute dystonia
 Prolonged muscle spasms of the neck, eyelids, pharynx, eyes, jaw, tongue or whole body
 Treated with benztropine or diphenhydramine (IM)
o 3) Tardive dyskinesia: prolonged blockade of D2 receptors in hypothalamus and striatum 
compensatory upregulation of D2 receptors
 Abnormal writhing movement of the tongue, face, limbs or trunk of the body
 Treated by:
 Slowly weaning patient OFF of the antipsychotic drug – 50% chance it will resolve… shitty
 Discontinuation of any other drugs with central anti-cholinergic actions (e.g. tricyclic
antidepressants)
 If symptoms are acute, administer diazepam parenterally to enhance GABAergic activity
o 4) Neuroleptic malignant syndrome: results from blockade of the D2 receptors in the hypothalamus and
striatum
 Potentially life-threatening illness seen more commonly in med and must be recognized and
treated quickly
 Symptoms include hyperthermia, hypertension, tachycardia, tremor, seizures, dyskinesia
 Treated by:
 Discontinuation of antipsychotics
 Supportive measures (addressing individual symptoms)
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 +/- dantrolene +/- bromocriptine
o 5) Akathisia
 Extremely uncomfortable subjective feeling of motor restlessness (patients will be unable to
remain still)
 Treated by diphenhydramine, propranolol or a benzodiazepine
Cardiovascular Effects
o Prolonged QT (not that big of a deal)
o Orthostatic hypotension (secondary to α1-adrenergic blockade)
Endocrine Side Effects: result from blockade of D2 receptors in the hypothalamus and/or anterior pituitary
o Increased prolactin secretion
 In females, this can cause galactorrhea (lactation)
 In males, this can cause gynecomastia (also partially due to increased estrogen-to-testosterone
ratio)
o Decreased gonadotropin secretion
 In females, this can cause amenorrhea
o Decreased growth hormone
o Decreased LH
o Decreased ACTH
Metabolic Syndrome
o Weight gain
o Increased lipids
o Glucose intolerance
o Insulin resistance
****Clozapine, specifically, is associated with the important side effect agranulocytosis, neutropenia,
myocarditis and seizures at very high doses
o Sedation, weight gain, orthostatic hypotension.
o This is a GREAT drug but you must first fail two other drugs before you can be started on this because of
serious side effect risks.
Other Therapeutic Effects of Antipsychotics
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Anti-emetic effects
o Decreases sensitivity of the “chemoreceptor trigger zone” by blocking D2-receptors
o Prochlorperazine and promethazine are two agents that may be used for this indication (but can have
side effects such as akathisia)
Anti-histaminergic effects
o Phenothiazine is a drug in this class which has little anti-psychotic activity, but is an effective H1 histamine
receptor blocker
Delivery Systems
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Traditional pills and capsules
Immediately dissolving oral tablets
o Atypicals
 Risperidone (m-tab risperdal)
 Olanzapine (zydus zyprexa)
Short-acting IM preparations
o Typicals
 Haloperidol
 Chlorpromazine
 Droperidol
o Atypicals
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 Olanzapine
 Ziprasidone
Long-acting IM preparations
o Typicals
 Haloperidol
 Fluphenazine
o Atypicals
 Risperidone (risperdal consta)
Challenges with Medication Compliance
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With rare exception, patients can NOT be forced to take medications
You should always ask your patient if they are having undesirable side effects
If your patients are not able to tolerate the side effects, you should discuss other medication and treatment
options with them