Anti-psychotics

Question 1

Schizophrenia

Clinical Manifestations

Answer 1

Schizophrenia is a thought disorder

The symptoms are divided into two categories:

• Positive symptoms: delusions (distorted beliefs), hallucinations (abnormal perceptions), disorganized speech and catatonic behavior
• Negative symptoms: affective flattening (decrease in range of emotion), decrease in fluency of speech and avolition

Question 2

Dopamine Hypothesis

Answer 2

Schizophrenia is caused by ↑ dopamine transmission in the brain

Supported by:

• Potency of typical antipsychotics ∝ affinity for dopamine D2 receptor
• Amphetamines, cocaine, and apomorphine ⇒ ⊕ dopaminergic receptors in the CNS ⇒ sx similar to schizophrenia
• Hallucinations are an adverse effect of L-DOPA therapy in Parkinson’s disease
• 2x dopamine levels in subcortical areas of schizophrenic pts vs controls

Question 3

Dopamine Receptors

Answer 3

Question 4

Serotonin Hypothesis

Answer 4

• “Atypical antipsychotics” also ⊗ serotonin 5HT2 receptors
  
  • Challenges exclusive role of Dopamine in Schizophrenia
• Serotonin receptor blockade (5HT2A) may exert actions by altering dopaminergic transmission
• LSD stimulates 5HT2A receptors ⇒ hallucinations similar to schizophrenia

Question 5

CNS

Dopaminergic Pathways

Answer 5

Four dopaminergic pathways in the CNS:

1. Nigrostriatal dopamine pathway
   
   • Part of the extrapyramidal nervous system
   • Controls motor function and movement
2. Mesolimbic dopamine pathway
   
   • Midbrain ventral tegmental area → nucleus accumbens
   • Pleasurable sensations
   • Euphoria of drug abuse
   • Delusions and hallucinations of psychosis
   • Thought to be overactive in schizophrenia
3. Mesocortical dopamine pathway
   
   • Midbrain ventral tegmental area → cortex
   • Mediates cognitive and affective sx
   • Thought to be underactive in schizophrenia ⇒ apathy, withdrawal, lack of motivation and pleasure
4. Tuberoinfundibular dopamine pathway
   
   • Hypothalamus → anterior pituitary
   • Controls prolactin secretion

Question 6

Extrapyramidal Symptoms

Answer 6

Caused by ⊗ of Dopamine D2 Receptors

Leads to ACh excess

Question 7

Typical Antipsychotics

Overview

Answer 7

• Clinical properties that distinguish this class are:
  
  • High extrapyramidal sx compared to the atypicals
  • May enhance negative sx by blocking reward mechanisms in the mesolimbic pathway
• Pharmacological properties that distinguish this class are:
  
  • Ability to cause effective and long-lasting blockade of dopamine D2 receptors in all dopaminergic pathways
    
    • Leads to undesirable side effects
  • May ↑ negative sx by causing 100% blockade of D2 receptors in the mesolimbic system
• Drugs divided into high, medium, and low potency.
  
  • High
    
    • Haloperidol (Haldol)
    • Fluphenazine (Modecate)
  • Medium
    
    • Perphenazine (Trilafon)
  • Low
    
    • Chlorpromazine (Thorazine or Largactil)
    • Thioridizine (Mellaril or Melleri)

Question 8

Side Effects of Typicals

Early-onset and Reversible

Answer 8

• Acute dystonia
  
  • Involuntary contractions particularly of the face, neck, tongue, and extraocular muscles
  • Will respond to anticholinergics or diphenhydramine
  • Low potency antipsychotics w/ significant anticholinergic effects less likely to cause acute dystonia
    
    • Ex. Chlorpromazine, Thioridizine
• Parkinsonism
  
  • Akinesia, muscle rigidity, tremor, shuffling gate
  • Due to blockade of nigrostriatal dopaminergic pathway
  • May be treated w/ anticholinergics or amantadine
• Akathisia
  
  • Motor restlessness and the urge to move
  • Reduce dose, treat w/ propranolol
  • Maybe treated w/ benzodiazepines or anticholinergics

Question 9

Side Effects of Typicals

Late-onset and Sometimes Irreversible

Answer 9

Tardive dyskinesia

• Involuntary movements of the lips, face, tongue and limbs
• Occurs in pts exposed to antipsychotics for 3 months or longer
• May be due to supersensitivity of dopamine receptors in the caudate
• Pts w/ acute dystonia more likely to develop tardive dyskinesia
• Anticholinergics will worsen sx of tardive dyskinesia
• Treated by ↓ dose, discontinuing drug, or switching to an atypical
• Valbenazine ⇒ new drug specifically designed to tx this condition
  
  • ⊗ Vesicular monoamine transporter ⇒ depletion of dopamine

Question 10

Other Side Effects of Typicals

Answer 10

Other common side effects:

• ⊗ Alpha-adrenergic receptors ⇒ orthostatic hypotension, male sexual dysfunction
• ⊗ Muscarinic receptors ⇒ constipation, dry mouth, urinary retention, visual problems
• ⊗ Histamine and muscarinic receptors ⇒ sedation
• ⊗ Dopamine D2 receptors in the pituitary ⇒ ↑ in prolactin ⇒ galactorrhea and amenorrhea
• Weight gain
• ↓ Seizure threshold
• Thioridazine can cause retinal deposits and arrhythmias

Rare side effect:

Neuroleptic malignant syndrome

(similar to malignant hyperthermia)

• Extreme muscle rigidity, dystonia, akinesia, agitation, hyperthermia, and autonomic instability
• Lab findings include ↑ WBC count and ↑ creatinine phosphokinase
• Treat w/ dantrolene and dopamine agonists such as bromocriptine
  
  • Dantrolene - works inside skeletal muscle to uncouple actin and myoin

Question 11

Medication Adherence

Answer 11

Question 12

Atypical Antipsychotics

Overview

Answer 12

Clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole

• Clinical properties:
  
  • Fewer extrapyramidal sx compared to typicals
  • Effective for both positive and negative sx relative to the typicals (tx mostly positive sx)
• Pharmacological properties:
  
  • Serotonin antagonist at 5HT2A receptors
  • Dopamine D2 antagonists w/ rapid dissociation
  • Dopamine D2 partial agonists (only aripiprazole)

Atypical antipsychotics via multiple mechanisms have a theoretical superiority over the typicals

Enhance dopaminergic activity in some pathways and inhibit it in other

Each class has its own advantages and disadvantages

Question 13

Atypical Antipsychotics

Mechanisms of Action

Answer 13

1. Serotonin antagonist at 5HT2A receptors
   
   • Reduction in EPS
     
     • DA neurons and GABA interneurons have 5HT2A receptors
     • ⊕ 5HT2A receptors ⇒ ⊗ DA release
     • Atypicals: ⊗ 5HT2A receptors of nigrostriatal system ⇒ ↑ DA release
       
       • DA competes w/ atypicals @ D2 receptors ⇒ ↓ ⊗ of D2 receptors in the striatum ⇒ ↓ risk of EPS
     • ⊗ of D2 receptors in mesolimbic system attenuated but still substantial
   • Reduction of negative sx
     
     • ↓ DA activity in prefrontal cortex w/ Schizophrenia ⇒ negative sx
     • Atypicals: ⊗ 5HT2A receptors ⇒ ↑ DA release from mesocortical neurons (VTA → prefrontal cortex) ⇒ ↓ negative sx
     • Prefrontal cortex w/ low density of D2 receptors
       
       • ⊗ 5HT2A > ⊗ D2 ⇒ release effect predominates
   • Reduce positive sx
     
     • Cortical glutaminergic cells ⇒ ⊕ dopaminergic cells in mesolimbic pathway ⇒ positive sx
     • Atypicals: ⊗ 5HT2A receptors ⇒ ↓ excitatory input to mesolimbic pathway
       
       • Attenuates overactivity mesolimbic pathway
       • Minimizes side effects of DA blockade
   • Regulates prolactin release
     
     • Dopamine normally inhibits prolactin release
       
       • ⊗ D2 receptors ⇒ ↑ prolactin release
     • Serotonin via 5HT2A receptors normally stimulates prolactin release
       
       • Atypicals: ⊗ 5HT2A receptors ⇒ ↓ prolactin release
         
         • Mitigates effects of D2 blockade
     • Atypicals except for risperidone do not stimulate prolactin release
2. Dopamine D2 antagonists w/ rapid dissociation
   
   • Atypicals loosely bind to D2 receptors
     
     • Long enough for antipsychotic action
     • Not long enough to cause side effects such as EPS
3. Dopamine D2 partial agonist
   
   • Aripiprazole: right mix between agonism and antagonism ⇒ intermediate signal transduction
     
     • Attenuates signal transduction at D2 receptors in the mesolimbic system to tx Schizophrenia
     • Allows enough signal transduction in nigrostriatal system to avoid extrapyramidal sx

Question 14

Atypical Antipsychotics

Common Side Effects

Answer 14

• Comparatively low extrapyramidal and low anticholinergic sx compared to typicals
• Cardiometabolic risk
  
  • ⊗ histamine H1 and 5HT2C receptors in hypothalamus ⇒ ↑ appetite ⇒ ↑ weight ⇒ ↑ TAG, insulin resistance, DM and CV events
  • Monitor weight, waste circumference, glucose, lipids and triglycerides
• Sedation
  
  • Many including atypicals ⊗ muscarinic M1, histamine H1, and α-adrenergic receptors
  • Can cause sedation and somnolence ⇒ cognitive impairment ⇒ compromise functional outcomes

Question 15

CATIE Study

Answer 15

Moderate dose of medium-potency typical antipsychotic about equal to newer atypicals w/ relatively few side effects.

Therapeutic Considerations:

• Typicals may be considered as first line therapy
• Take a pt hx for previously used drugs and side effects of greatest concern
  
  • Pre-DM pt vs underweight pt and Olanzapine
  • Pt w/ sexual dysfunction ⇒ no drugs that ↑ prolactin
  • Pt w/ signs of tardive dyskinesia ⇒ newer atypicals like quetiapine
• Consider injectables to enhance pt compliance
  
  • Typicals: haloperidol and fluphenazine
  • Atypicals: risperidone and ziprasidone

Question 16

Antipsychotic Use

Management

Answer 16

Question 17

Antipsychotics

Other Uses

Answer 17

• Psychosis caused by other conditions such as Alzheimer’s and other dementias
• Atypicals are used as mood stabilizers for the manic, depressed and maintenance phases of bipolar disorder
• Atypicals are used “off label” for:
  
  • Augmentation of antidepressants in treatment of resistant depression
  • Augmentation of anxiolytics in treatment resistant anxiety disorders
• Autism (for control of aggressive behaviors)
• Gilles de la Tourette’s Syndrome – chronic tics
• Severe agitation in mentally retarded and in Alzheimer’s pts

Question 18

Antipsychotics

Drug Table

Answer 18