Antipsychotics & Mood Stabilizers

Question 1

“Classical” Antipsychotics

Answer 1

• “Neuroleptics”
• Block DA D2 receptors
• Target the mesolimbic system
• Alleviate the positive symptoms

Chlorpromazine (Thorazine®)
Haloperidol (Haldol®)

Question 2

“Atypical” Antipsychotics

Answer 2

• Block 5-HT2A and DA receptors
• Target the mesocortical (and mesolimbic) system
• Alleviate both negative and positive symptoms

Clozapine (Clozaril®)
Olanzapine (Zyprexa®)
Risperidone (Risperdal®)
Ziprasidone (Geodon®)
Quetiapine (Seroquel®)
Aripiprazole (Abilify®)
Lurasidone (Latuda®)

Question 3

Distribution of DA Receptors in CNS

Answer 3

 DA D2 receptors predominate the mesolimbic region

 DA D4 receptors distributed in mesocortical region

Question 4

Antipsychotic Drug Interactions

Answer 4

 Anticholinergics: more side effects (dry mouth,
urinary retention, constipation, etc)
 Sedative-hypnotics: will increase sedation
 TCAs - seizures and cardiac effects
 Drugs that induce CYP450s (carbamazepine;
cimetidine)
 Smoking – induces CYP450s
 Unpredictable w/ antihypertensives (alpha-blockade)

Question 5

Antipsychotic Side Effects

Answer 5

 Very common; generally not pleasant and
compliance is poor
 Decreased seizure threshold
 Endocrine-weight gain, increased prolactin secretion
 Autonomic
• Anticholinergic - dry mouth, blurred vision,
tachycardia, constipation
• α-adrenergic - postural hypotension
• Histamine - sedation
 Dental – xerostomia and bruxism

• Extrapyramidal Symptoms (EPS)
• Tardive Dyskinesia
• Neuroleptic Malignant Syndrome

Question 6

Neuroleptic Malignant Syndrome

Answer 6

• Life threatening
   Muscle rigidity, hyperpyrexia, changes in BP and
  heart rate
   Block of DA D2 receptors in the striatum and
  hypothalamus
   Treated with dantrolene (Dantrium®)
   DA agonists (bromocriptine) used to stimulate DA
  receptors

Question 7

Tardive Dyskinesia

Answer 7

 Choreiform; uncontrollable, jerky movements of face
and limbs
 Occurs late in disease following long-term treatment
 Difficult to treat, often irreversible - Discontinue drug
 Clozapine and olanzapine least likely to cause TD

Question 8

Extrapyramidal Symptoms (EPS)

Answer 8

 DA receptor antagonists also block DA receptors in
the nigrostriatal pathway
 Parkinson’s like - tremor, rigidity, dyskinesias, rocking
(akathisia), pacing, restlessness, anxiety, dystonia
 Imbalance of striatal DA and ACh
 Treat with anticholinergics such as benztropine
(Cogentin) to restore ACh/DA balance
 Degree of EPS is based on the anticholinergic
activity of the drug (chlorpromazine vs. haloperidol)
 Classical antipsychotics tend to cause more EPS
than atypicals

Question 9

Classical Antipsychotics - MoA

Answer 9

 Block DA D2receptors

 Requires ~60% receptor occupancy

Question 10

Classical Antipsychotics - Pharmacokinetics

Answer 10

 Readily absorbed from gut following oral
administration
 Most have high first pass metabolism
 Half lives range from 20 to 35 hours
 Effects persist for weeks after last administration
 Metabolized by CYP450s (2D6 and 3A4)

Question 11

Chlorpromazine (Thorazine®) - Uses

Answer 11

Psychosis associated with mania and drugs of abuse

Antiemetic (Prochlorperazine)

Pre-anesthetic

Question 12

Chlorpromazine (Thorazine®) - MoA

Answer 12

Blocks DA D2 receptors; also has alpha-adrenergic actions

Question 13

Chlorpromazine (Thorazine®) - Side Effects

Answer 13

 TD, and neuroleptic malignant syndrome may occur  High anticholinergic effects thus low incidence of
EPS
 Sedation, postural hypotension, blurred vision,
constipation, decreased GI motility, inhibition of
ejaculation, jaundice, decreases seizure threshold
 May cause retinal deposits; “browning of vision”

Question 14

Haloperidol (Haldol®)

Answer 14

 “Vitamin H”
 Potent blocker of DA D2 receptors
 Also has affinity for DA D1, 5-HT2, and H1 receptors
 Used frequently in acute situations
 May be injected 
 Long half life
 No anticholinergic activity
 Extrapyramidal symptoms; especially when used 
    chronically

Question 15

Fluphenazine (Prolixin®)

Answer 15

similar to chlorpromazine; selective for DA D2 receptors; less anticholinergic activity and more EPS

Question 16

Atypical Antipsychotics - MoA

Answer 16

 Block 5-HT2A receptors but also block DA D2 (and
D4) receptors
 Alleviate both the “negative” and “positive”
symptoms

Question 17

Clozapine (Clozaril®)

Answer 17

 Blocks 5-HT2A and DA D4 receptors; some affinity
for DA D2
 EPS and tardive dyskinesia are very rare
 Side effects – Hypersalivation, sedation, dizziness,
postural hypotension, tachycardia,
weight gain
 Decreased seizure threshold
 Rapid relapse if discontinued abruptly
 Drug of last choice due to agranulocytosis
 Blood must be monitored

Question 18

Olanzapine (Zyprexa®)

Answer 18

Similar to clozapine but no agranulocytosis
 Improves “positive” and “negative” symptoms
 Blocks 5-HT2A receptors; also blocks DA D4 and D2
receptors
 Some anticholinergic activity
 Extrapyramidal symptoms rare
 Side effects - sedation, orthostatic hypotension,
weight gain
• Hyperglycemia, type II diabetes (“Zyprexia
diabetes”)
 Also used for bipolar disorder

Question 19

Risperidone (Risperdal®)

Answer 19

 “First-line drug” for psychosis
 Blocks and 5-HT2A and DA D2 receptors
 Improves both positive and negative symptoms
 No significant effect on DA neuro-transmission in
nigrostriatal pathway
 Extrapyramidal symptoms and tardive dyskinesia are
rare
 Side effects - hypotension, weight gain, insomnia,
anxiety, some cardiac effects (lengthens QT interval)

Question 20

Ziprasidone (Geodon®)

Answer 20

 Blocks DA D2 and 5-HT2A receptors
 Some antidepressant activity (5-HT1A receptor agonist, inhibition of 5-HT reuptake)
 Uses: Tourette’s syndrome; acute mania
 Given orally or injected IM; Metabolized by CYP3A4
 Side Effects
• Prolongs QT interval
• Causes sedation, impairs cognitive and motor skills
• May cause hyperprolactinemia
• Used with caution in patients with history of seizure
disorders or with drugs that decrease seizure
threshold

Question 21

Quetiapine (Seroquel®)

Answer 21

 Similar to clozapine
 No agranulocytosis
 Blocks 5-HT2A and DA D2 receptors
 Used to promote sleep onset and maintenance
 Few extrapyramidal symptoms
 Side effects - very sedating, dizziness, constipation,
xerostomia, orthostatic hypotension, weight gain
 Does not elevate prolactin

Question 22

Aripiprazole (Abilify®)

Answer 22

“Dopamine system stabilizer”
• Dopaminergic tone is low– DA receptors are activated
• Dopaminergic tone is high– DA receptors are blocked
 Partial agonist for DA D2 and 5-HT1A; Antagonist for
5-HT2A
 Low incidence of EPS
 Metabolized by CYP3A4 and 2D6
 Also blocks α1 and histamine receptors
 No increase in prolactin; Does not lengthen QT
interval
 Side effects - hyperglycemia, seizures, sedation,
increased glucose, orthostatic hypotension,
decreases esophageal motility

Question 23

Lurasidone (Latuda®)

Answer 23

 Blocks D2 and 5-HT2A receptors
 Partial agonist at 5-HT1A
 No antihistamine or antimuscarinic effect
 Used in treatment of depression associated with
bipolar disorder
 Some incidence of agranulocytosis and neutropenia,
blood counts should be monitored.
 Side effects similar to other atypical antipsychotics

Question 24

Bipolar Disorder Treatment

Answer 24

• Lithium (Eskalith)
• Anticonvulsants

 Patients with bipolar disorder are often treated with
combinations of these drugs and antipsychotics such
as olanzapine (Zyprexa®).

Question 25

Lithium (Li) - MoA

Answer 25

Suppress 2nd messengers (IP3) | • May increase ACh, NE, and DA

Question 26

Lithium (Li) - Uses

Answer 26

 Calming effect in manic patients

Question 27

Lithium Absorption

Answer 27

 Lithium is reabsorbed by the proximal tubule in the kidney  Competes with sodium (Na+) for re-absorption • Na+ decreases -> Li absorption increases -> Toxicity • Na+ increases -> Li absorption decreases; excretion increases • Li increases -> Na+absorption decreases -> hyponatremia

Question 28

Lithium Side Effects and Toxicity

Answer 28

Small therapeutic window - (Optimal plasma concentrations range from 0.6-1.2 mEq/L) • Plasma levels > 2 mEq/L - Nausea, diarrhea, anorexia, muscle weakness, headache, tremor, confusion, memory impairment • Plasma levels > 2.5 mEq/L - Confusion, slurred speech, sedation, nystagmus, seizures, renal failure, cardiac arrhythmias, coma, death  Thyroid function reduced (Hypothyroidism)  Diabetes insipidus • Li inhibits ADH; collecting tubule cannot conserve water • Increased thirst and urine output • Treat with amiloride (blocks entry of Li into collecting duct)  Not recommended in pregnancy

Question 29

Lithium Drug Interactions

Answer 29

 Antidepressants: mania may increase  Benzodiazepines & antipsychotics: safe  Diuretics (alter sodium excretion) can alter Li clearance  NSAIDS • Increase Li toxicity - decrease clearance, increase Li uptake  Sodium • Reduces Li concentration • Li may lead to decreased Na+ re-absorption and hyponatremia

Question 30

Anticonvulsants: Alternative to Lithium

Answer 30

Valproic Acid (Depakene®) Gabapentin (Neurontin®) Lamotrigine (Lamictal®) Carbamazepine (Tegretol®)

Question 31

Valproic Acid (Depakene®)

Answer 31

 Rapid cycling manic/depressive phases  Effective in some patients who do not respond to lithium  Efficacy is equal to or greater than lithium; rapid onset of action  Mechanism: Unknown (inhibition of ion channels, increased GABA)  Side Effects: GI upset, sedation, liver enzyme induction, weight gain, surgical bleeding (dental)  Teratogenic - Anticonvulsants are generally not safe in pregnancy

Question 32

Gabapentin (Neurontin®)

Answer 32

used for rapid cycling

Question 33

Carbamazepine (Tegretol®)

Answer 33

 Refractory bipolar disorder; used in combination with lithium  Side Effects - GI upset, sedation, CNS toxicity, hypersensitivity, rashes, hematologic reactions  Drug interactions - competes for metabolism with cimetidine, isoniazid, fluoxetine, erythromycin; increases toxicity  Stevens Johnson Syndrome • Toxic epidermal necrolysis • Testing for the human antigen is now required

Question 34

Lamotrigine (Lamictal®)

Answer 34

Approved for: - Prevention of relapse - Depressive state following mania - Acute mania

Question 35

“Positive” symptoms

Answer 35

• Hallucinations (auditory and visual) & delusions • Catatonic behavior, disorganized speech & thinking • Over-active dopamine pathways in limbic system (Mesolimbic)

Question 36

“Negative” symptoms

Answer 36

• Affective behavior, apathetic, withdrawn, anti-social, lack of motivation, depressed • Under-active dopamine pathways in frontal cortex (Mesocortical)