Antipsychotic Drugs

Question 1

42 yo pt treated with antipsychotic medication to manage schizo. Which agent is associated with skeletal muscle rigidity, tremor at rest, flat facies, uncontrollable restlessness, and spastic toritcollis?
A. Haloperidol 
B. Clozapine
C. Olanzapine
D. Chlorpromazine
E. Ziprasidone
F. Quetiapine

Answer 1

A. Haloperidol

Question 2

36 yo F schizo for several years. Currently on fluphenazine and experiencing amenorrhea and galactorrhea. Which agent would be more appropriate with lowest risk of current adverse effects? Which second gen agent would not be appropriate and would have near-equal risk of current effects?
A. Aripiprazole
B. Haloperidol
C. Chlorpromazine
D. Risperidone
E. paliperidone

Answer 2

A. Aripiprazole

D. Risperidone

Question 3

35 yo homeless M taking chlorpromazine for many years to control his schizo. Experiencing blurred vision, dry mouth, mydriasis, nausea, urinary retention, and constipation. Effects caused by blockade of which receptor?
A. alpha adrenergic
B. Dopamine
C. Nicotinic
D. Serotonin
E. muscarinic

Answer 3

E. muscarinic

Question 4

Pt with history of schizo is transported to emergency department by ambulance after repeated episodes of fainting. May be attributed to severe drug-induced orthostatic hypotension associated with one of her meds and thought to be due to alpha adrenergic blockade. WHat med would be most likely cause?
A. Risperidone
B. Thioridazine
C. Aripiprazole
D. Haloperidol
E. Ziprasidone
F. Fluphenazine

Answer 4

B. Thioridazine

Question 5

22 yo M student BMI 49 diagnosed with schizo. Which second gen agent would be most appropriate as first line therapy and have lowest impact on BMI?
A. Quetiapine
B. Olanzapine
C. Clozapine
D. Chlorpromazine
E. Ziprasidone
F. Risperidone

Answer 5

E. Ziprasidone

Question 6

Name the first generation (conventional, typical) antipsychotic agents

Answer 6

Chlorpromazine
Fluphenazine
Haloperidol
Thioridazine
Thiothiexene

Question 7

Name the second generation (novel, atypical) antipsychotic agents

Answer 7

Aripiprazole
Clozapine
Olanzapine
Quetiapine
Risperidone
Ziprasidone

Question 8

What are the indications for antipsychotics?

Answer 8

Mental health conditions associated with psychosis (schizophrenia, schizoaffective disorder)
Major depressive disorder (unipolar)
Bipolar I disorder; mania or mixed
Bipolar II disorder; depression
Tourette’s disorder
Irritability with autism spectrum disorders
Recurrent suicidal behavior (clozapine)

Question 9

Describe the dopamine hypothesis

Answer 9

Direct/indirect DA-agonists (methamphetamine and cocaine) provoke psychotic reactions in non-schizophrenics and exacerbate symptoms in schizophrenics
Alterations in DA-mediated transmission in schizophrenics (increased DA occupancy of D2 receptor)

Question 10

Describe the mesolimbic pathway and positive symptoms of schizophrenia

Answer 10

Anatomy: projections from VTA to nucleus accumbens
Phys: motivation, emotions, reward, positive symptoms
Implications: D2 antagonists reduce positive symptoms

Positive symptoms: halluncinations, delusions, disorganized speech/thinking, agitation, abnormal motor behavior

Question 11

Describe mesocortical pathway: negative and cognitive symptoms

Answer 11

Anatomy: projections from VTA to cortex (PFC)
Phys: cognition and executive functions (DLPFC), emotions, and affect (VMPFC)
Implications: hypofunction of mesocortical pathway might be related to cognitive and negative symptoms

Negative symptoms: apathy, abolition, alogia, cognitive deficits (working memory), social withdrawal

Question 12

Describe nigrostriatal pathway and EPS

Answer 12

Anatomy: projections from substantia nigra (pars compacta) to striatum (caudate and putamen)
Phys: stimulation of purposeful movement
Implications: D2 antagonism induces extrapyradimal symptoms (pseudoparkinsonism)

Question 13

Describe the tuberoinfundibular pathway and prolactin release

Answer 13

Anatomy: hypothalamus (arcuate and periventricular nuclei) to infundibular region (median eminence)
Phys: DA is released into portal circulation connecting median eminence with anterior pituitary gland. DA tonically inhibits prolactin release.
Implications: D2 antagonism increases prolactin levels

Question 14

Describe the MOA of first gen antipsychotics

Answer 14

FGAs primarily block dopamine type2 (D2) postsynaptic receptors (D2»5HT2)

Also block one or more other receptors (primarily inducing SEs)
Muscarinic receptors
Histamine receptors (H1)
Alpha-adrenergic receptors (a1)
D2 receptors in nigrostriatal (movements) and tuberoinfundibular (prolactin) pathways

Question 15

Describe the muscarinic, alpha-adrenergic, histamine, and other effects of FGA’s

Answer 15

Muscarinic (anti-cholinergic): dry mouth, constipation, urinary retention, blurred vision, sedation
Alpha-adrenergic: orthostatic hypotension, dizziness/syncope
Histamine: sedation
Other: risk of QTc prolongation and seizure activity

Question 16

Describe the dopamine effects of FGAs

Answer 16

Hyperprolactinemia (tuberoinfundibular pathway): amenorrhea/galactorrhea/gynecomastia/decreased libido

Extrapyramidal symptoms (EPS)/Tardive dyskineisia (TD) (nigrostriatal pathway)
Acute dystonia/akathisia/dyskinesia/Parkinsonism-like
**Treatments
-anticholinergic agents: diphenhydramine, benztropine, trihexyphenidyl
-non-anticholinergic: amantadine (antiviral)
-propranolol/clonazepam for akathisia

Question 17

Describe low potency vs high potency agents based on D2 potency/receptor occupancy of FGAs

Answer 17

Low potency:
More sedation, hypotension, and seizure-threshold reduction
Agents: chlorpromazine, thioridazine

High potency:
More movement (EPS) and endocrine effects (prolactin)
Agents: fluphenazine, haloperidol, thiothixene

Question 18

What are limits to dopamine hypothesis?

Answer 18

Does not account for all cognitive deficits/negative symptoms associated with schizophrenia (related to decreased DA signaling in prefrontal cortex)
Does not fully explain role of 5HT2 (LSD, 5HT agonist)
Does not fully explain role of NMDA/glutamate (PCP/ketamine, antagonist)

Question 19

Describe MOA of second generation antipsychotics (SGAs)

Answer 19

Block dopamine type2 (D2) postsynaptic receptors and 5HT2A

Stronger 5HT2a blocker&raquo_space; D2

Question 20

Describe the SGA dual 5HT2a/D2 theory

Answer 20

5HT2a antagonism increases DA transmission in nigrostriatal pathway
May contribute to improved negative and cognitive symptoms via increased DA release in PFC
Reduced EP SE’s

SGAs may rapidly dissociate more from D2 receptors (reduced EP SE’s)
Some SGAs are D2 partial agonists (aripiprazole)
Some SGAs are 5HT1A full agonist (ziprasidone) or partial agonists (aripiprazole and clozapine)
Some also block one or more other DA receptor and have greater propensity to be agonist/antagonist on one or more other 5HT receptors

Question 21

Describe side effects of SGAs

Answer 21

Common:
Weight gain
Metabolic effects (hyperglycemia/insulin resistance, hyperlipidemia)

Rare:
QTc prolongation/ECG changes: negative inotropic actions (greater risk for women, elderly, and those on antiarrhtymics)
Stroke: greater risk in elderly with dementia (increase all-cause mortality with all antipsychotics (class warning))

Question 22

Which FGAs and SGAs have the most and least risk for weight gain and diabetes?

Answer 22

SGAs higher risk > FGAs

FGA:
Most: chlorpromazine (most), thioridazine, thiothixene
Least: fluphenazine, haloperidol

SGA:
Most: Olanzapine
Least: Aripiprazole, ziprasidone

Question 23

Which FGAs and SGAs have the most and least risk for hypercholesterolemia?

Answer 23

SGAs higher risk > FGAs

FGAs:
Most: chlorpromazine
Least: fluphenazine, haloperidol

SGAs:
Most: Olanzapine (most), quetiapine
Least: aripiprazole, ziprasidone

Question 24

Which FGAs and SGAs have the most and least risk for EPS/tardive dyskinesia?

Answer 24

FGAs higher risk > SGAs

FGAs:
Most: fluphenazine, haloperidol, thiothixene
Least: chlorpromazine, thioridazine

Question 25

Which FGAs and SGAs have the most and least risk for prolactin secretion?

Answer 25

FGAs higher risk > SGAs

FGAs
Most: fluphenazine, haloperidol, thioridazine
Least: chlorpromazine, thiothixene

SGAs
Most: Risperidone
Least: aripiprazole(least), olanzapine, quetiapine, ziprasidone

Question 26

Which FGAs and SGAs have the most and least risk for sedation?

Answer 26

FGAs
Most: chlorpromazine, thioridazine
Least: fluphenazine, thiothixene

SGAs
Most: olanzapine, quetiapine
Least: aripiprazole, risperidone, ziprasodone

Question 27

Which FGAs and SGAs have the most and least risk for anticholinergic SEs?

Answer 27

FGAs more risk > SGAs

FGAs
More: thioridazine (most), chlorpromazine
Least: fluphenazine, haloperidol, thiothixene

SGAs
More: Olanzapine, quetiapine
Least: aripiprazole, ziprasidone, risperidone

Question 28

Which FGAs and SGAs have the most and least risk for orthostatic hypotension?

Answer 28

SGAs more > FGAs

FGAs
More: thioridazine (most), chlorpromazine
Least: fluphenazine, haloperidol, thiothixene

SGAs
More: quetiapine
Least; aripiprazole, olanzapine, risperidone, ziprasidone

Question 29

Which FGAs and SGAs have the most and least risk for QT prolongation?

Answer 29

FGAs
More: thioridazine
Least: chlorpromazine, haloperidol, thiothixene

SGAs
More: ziprasidone
Least: aripiprazole, olanzapine, quetiapine, risperidone

Question 30

Which SGA causes rare but sever SE of agranulocytosis?

Answer 30

Clozapine (1-2%)
Monitor WBC
REMS program

Question 31

What SGAs causes drug reaction with eosinophilia and systemic symptoms (DRESS)? Describe

Answer 31

Olanzapine
Very rare, potentially life threatening drug-induced hypersensitivity reaction
Includes skin eruption, hematologic abnormalities (eosinophilia, atypical lymphocytosis), lymphadenopathy, and internal organ involvement (liver, kidney, lung)
Long latency (2-8 weeks) between drug exposure and disease onset
Prolonged course with frequent relapses despite D/Cing culprit drug
Frequent association with reactivation of latent human herpes virus infection

Question 32

Describe neuroleptic malignant syndrome (NMS)

Answer 32

Rare but potentially fatal, severe Parkinson’s-like movement disorder with widespread muscle contraction
Mesocortical effects: altered mental status
Nigrostriatal effects: muscle rigidity, increased muscle metabolism, rhabdomyolysis
Hypothalamic effects: hyperthermia
Autonomic dysfunction: dehydration

Treatment: dantrolene (malignant hyperthermia)
Ryanodine receptor Ca2+ channel being open causes muscle contraction
Dantrolene occupies receptor, so it is closed. Peripheral muscle relaxation.

Question 33

For antipsychotic monitoring, what baseline items?

Answer 33

Serum glucose, lipids, BMI, BP, waist circumference, personal/family histories of metabolic and CV disease

Question 34

Which agents are more commonly recommended and used as first-line, initial therapy?

Answer 34

Atypical agents (SGAs)

Question 35

What are therapeutic pearls of treatment?

Answer 35

Favorable prognosis seen in shorter duration and less severe symptoms of disease prior to diagnosis/treatment. Strong, positive pre-illness functionality
**Adherence is critical! Non-adherence can be managed with long-acting injectable agents (LAIAs) (every 2-12 wks): haloperidol decanoate, fluphenazine decanoate, risperidone, olanzapine, aripiprazole lauroxil, paliperidone palmitate
Minimum 2-3 wks therapy necessary for response evaluation (remission may take months)
Acute high doses not universally beneficial in providing more rapid response
Adjunctive pharmacotherapies useful for multiple comorbidities
Non-pharmacotherapy adjunctive treatments beneficial
Combo antipsychotic not universally supported by literature but necessary clinically (combo for comorbidities: psychotic depression (olanzapine/fluoxetine), mania with psychotic features (lithium, anticonvulsant)
**Multidrug resistant disease: clozapine
**Psychotic with anti-suicidal thoughts/behaviors: clozapine