Psicosis y Tratamiento

Question 1

QUESTION ONE
A 24-year-old male initially presents with acute auditory hallucinations
and is treated with medication. Four days later he arrives
at your office for evaluation. You observe that he is neatly dressed,
avoids eye contact, and gives very short answers to your initial
questions. Which of the following questions would be most beneficial
for determining his degree of negative symptoms?

A. How often have you visited with friends in the past week?

B. Have the voices you’ve heard persisted or returned?

C. Have you ever thought about hurting yourself or someone else?

D. In the past week have you had difficulty concentrating?

Answer 1

A – Correct. How often have you visited with friends in the past week?
This is a useful question when assessing for negative symptoms, as
an important component of negative symptoms is reduced social
drive.

B – Incorrect. Have the voices you’ve heard persisted or returned?
Although this question is useful for determining the presence of
positive symptoms, it is not applicable to assessment of negative
symptoms.

C – Incorrect. Have you ever thought about hurting yourself or someone
else? This question can help assess for risk of suicide as well as
any possible aggression risk, but these are not part of the negative
symptom domain.

D – Incorrect. In the past week have you had difficulty concentrating?
This question is applicable to assessment for cognitive symptoms,
but not for negative symptoms.

Question 2

QUESTION TWO
A 21-year-old man who has just been diagnosed with schizophrenia
presents with his parents. He speaks with a reserved and simple language-
processing style; he is able to understand and relate to simple
questions but seems to get lost when the pace of the conversation
between the clinician and parents accelerates. When reviewing
the patient’s history, what pattern of cognitive functioning prior to
psychosis onset would you be most likely to find?

A. Normal cognitive functioning during premorbid and prodromal
phases

B. Impaired cognitive functioning that is stable across premorbid
and prodromal phases

C. Impaired cognitive functioning premorbidly with further decline
during the prodromal phase

D. Progressive decline of cognitive functioning premorbidly,
which stabilizes in the prodromal phase

Answer 2

Individuals who ultimately develop schizophrenia typically exhibit a
deficit in cognitive and social functioning that begins in childhood,
with a notable decline in cognitive and social functioning that occurs
during adolescence and precedes the onset of psychosis. This decline in
cognitive functioning coincides with the neurodevelopmental period
known as competitive elimination, during which extensive brain
restructuring and synaptic pruning takes place.

A – Incorrect. Individuals with schizophrenia typically exhibit a history
of cognitive impairment prior to psychosis onset.

B – Incorrect. Individuals with schizophrenia typically experience a
decline in functioning during the prodromal phase.

C – Correct. Individuals with schizophrenia typically exhibit impaired
cognitive functioning premorbidly with a notable decline during
the prodromal phase.

D – Incorrect. Individuals with schizophrenia generally show stable
cognitive functioning premorbidly, with decline not occurring
until the prodromal phase.

Question 3

QUESTION THREE
A 24-year-old woman is hospitalized after an altercation in which
she screamed at and attacked her neighbor when he knocked on
her door. Her mother reports that she has been increasingly erratic
recently, with emotional outbursts and impulsive behavior. Which
of the following brain regions is most likely associated with these
symptoms?

A. Dorsolateral prefrontal cortex

B. Nucleus accumbens

C. Orbital frontal cortex

D. Substantia nigra

Answer 3

A – Incorrect. Dorsolateral prefrontal cortex: this brain region is hypothetically
associated with cognition and executive functioning, not
with aggression.

B – Incorrect. Nucleus accumbens: this brain region is hypothetically
associated with positive symptoms such as delusions and hallucinations.
Although aggressive symptoms, such as those exhibited by
this patient, often occur in conjunction with positive symptoms,
they may not be localized to the nucleus accumbens.

C – Correct. Orbital frontal cortex: aggressive symptoms such as those
exhibited by this patient are hypothetically associated with impairment
in impulse control, which is largely regulated by the orbital
frontal cortex.

D – Incorrect. Substantia nigra: this region in the brainstem houses
dopaminergic cell bodies that project to the striatum. The substantia
nigra is not particularly linked to aggression.

Question 4

QUESTION FOUR
A major current hypothesis for the cause of schizophrenia proposes
that N-methyl-d-aspartate (NMDA) receptors may be:

A. Hypofunctional

B. Hyperfunctional

Answer 4

A – Correct. A major current hypothesis for the cause of schizophrenia
proposes that glutamate activity at NMDA receptors is hypofunctional
due to abnormalities in the formation of glutamatergic
NMDA synapses during neurodevelopment.
Normally, when glutamate synapses are active, their NMDA receptors
trigger an electrical phenomenon known as long-term potentiation,
or LTP. LTP leads to structural and functional changes of
the synapse that make neurotransmission more efficient, sometimes
called “strengthening” of synapses. During pubescence and adolescence,
a period known as competitive elimination occurs, with
extensive synaptic pruning and restructuring. Frequently used synaptic
connections with efficient NMDA neurotransmission survive,
whereas infrequently used synaptic connections with less active
NMDA receptors may be targets for elimination. This shaping of
the brain’s circuits normally allows the most critical synapses to
survive, while inefficient and rarely utilized synapses are eliminated.
Abnormalities in the NMDA receptor may jeopardize this essential
process and increase risk for neurodevelopmental disorders such as
schizophrenia.

B – Incorrect. NMDA receptors are not hypothesized to be hyperfunctional
in schizophrenia.

Question 5

QUESTION FIVE
According to the dopamine hypothesis of schizophrenia, which
underlying neurobiological mechanisms are associated with positive
symptoms?

A. Hyperactive mesocortical dopamine pathway to the dorsolateral
prefrontal cortex (DLPFC) and ventromedial prefrontal
cortex (VMPFC)

B. Hyperactive mesolimbic pathway

C. Hypoactive mesocortical dopamine pathway to the DLPFC
and VMPFC

D. Hypoactive mesolimbic pathway

Answer 5

A – Incorrect. In untreated schizophrenia, the mesocortical dopamine
pathways to the DLPFC and to the VMPFC are hypothesized to
be hypoactive. This hypoactivity is related to cognitive symptoms
(in the DLPFC), negative symptoms (in the DLPFC and VMPFC),
and affective symptoms of schizophrenia (in the VMPFC). These
pathways are not associated with positive symptoms.

B – Correct. In untreated schizophrenia, the mesolimbic pathway is
hypothesized to be hyperactive, resulting in excess dopamine at the
synapse, which leads to positive symptoms such as delusions and
hallucinations.

C – Incorrect.

D – Incorrect.

Question 6

QUESTION SIX
Tim is a 17-year-old patient with first-onset schizophrenia. He is
currently taking the antipsychotic fluphenazine but is not experiencing
any relief from his positive symptoms. Lab testing reveals
that Tim’s fluphenazine plasma levels are low; thus, there may not
be sufficient blockade of dopamine D2 receptors. In order for an
antipsychotic to exert therapeutic effects, what is the minimum
hypothetical threshold of D2 receptor occupancy?

A. >20%

B. >40%

C. >60%

D. >90%

Answer 6

A – Incorrect. With only 20% D2 receptor occupancy, it is unlikely
that a pharmacological agent will have any therapeutic effects.

B – Incorrect. With only 40% D2 receptor occupancy, it is unlikely
that a pharmacological agent will have any therapeutic effects.

C – Correct. Data indicate that 60% D2 receptor occupancy is the
minimum threshold for antipsychotic efficacy.

D – Incorrect. D2 receptor occupancy of 90% is well above the hypothetical
minimum threshold for antipsychotic effects and is also
above the hypothetical threshold for inducing drug-induced
parkinsonism.

Question 7

QUESTION SEVEN
Based on thorough evaluation of a patient and his history, his care
provider intends to begin treatment with a conventional antipsychotic
but has not selected a particular agent yet. Which of the
following is most true about conventional antipsychotics?

A. They are very similar in therapeutic profile but differ in side
effect profile

B. They are very similar in both therapeutic and side effect profile

C. They differ in therapeutic profile but are similar in side effect
profile

D. They differ in both therapeutic and side effect profile

Answer 7

A – Correct. Although individual effects may vary from patient to
patient, in general conventional antipsychotics share the same
primary mechanism of action and do not differ much in their
therapeutic profiles. There are, however, differences in secondary
properties, such as degree of muscarinic, histaminergic, and/or
alpha-adrenergic receptor antagonism, which can lead to different
side effect profiles.

B, C, and D – Incorrect.

Question 8

QUESTION EIGHT
A 34-year-old man is initiated on an atypical antipsychotic for the
treatment of schizophrenia. The majority of atypical antipsychotics:

A. Have higher affinity for dopamine 2 receptors than for serotonin
2A receptors

B. Have higher affinity for serotonin 2A receptors than for dopamine
2 receptors

C. Don’t have affinity for dopamine 2 receptors or serotonin 2A
receptors

Answer 8

A – Incorrect. Nearly all atypical antipsychotics have an affinity for
blocking serotonin 2A receptors that is equal to or greater than
their affinity for blocking dopamine 2 receptors.

B – Correct. Serotonin neurons originate in the raphe nucleus of the
brainstem and project throughout the brain, including to the cortex.
They synapse there with glutamatergic pyramidal neurons,
which project to the substantia nigra in the brainstem. The substantia
nigra is the origin of dopaminergic neurons that project to
the striatum. All serotonin 2A receptors are postsynaptic. When
they are located on cortical pyramidal neurons, they are excitatory.
Thus, when serotonin is released in the cortex and binds to
serotonin 2A receptors on glutamatergic pyramidal neurons, this
stimulates them to release glutamate in the brainstem, which in
turn stimulates gamma-aminobutyric acid (GABA) release. GABA
binds to dopaminergic neurons projecting from the substantia
nigra to the striatum, inhibiting dopamine release.
Nearly all atypical antipsychotics have an affinity for blocking serotonin
2A receptors that is equal to or greater than their affinity
for blocking dopamine 2 receptors. The “pines” – clozapine,
olanzapine, quetiapine, asenapine, and zotepine – all bind much
more potently to the serotonin 2A receptor than they do to the
dopamine 2 receptor. The “dones” and “rone” – risperidone, paliperidone,
ziprasidone, iloperidone, lurasidone, and lumateperone –
also bind more potently to the serotonin 2A receptor than to the
dopamine 2 receptor or show similar potency at both receptors.
Aripiprazole and cariprazine bind more potently to the dopamine
2 receptor than to the serotonin 2A receptor; however, they are
also partial agonists at dopamine 2 receptors. Brexpiprazole (also a
dopamine 2 partial agonist) has comparable binding affinity to the
dopamine 2 and serotonin 2A receptors.

C – Incorrect.

Question 9

QUESTION NINE
A 34-year-old male recently began experiencing breast secretions
while receiving perphenazine. After switching to quetiapine,
the secretions ceased. Which of the following is the most likely
pharmacological explanation for the resolution of this side effect?

A. Dopamine 2 antagonism

B. Serotonin 2A antagonism

C. Serotonin 2C antagonism

D. Histamine 1 antagonism

Answer 9

A – Incorrect. Stimulation of dopamine 2 receptors inhibits prolactin
release; thus, a dopamine 2 antagonist such as perphenazine could
increase prolactin release and potentially lead to breast secretions.

B – Correct. Stimulation of serotonin 2A receptors stimulates prolactin
release. Since they have opposing effects on prolactin, adding
serotonin 2A antagonism to dopamine 2 antagonism results in a
neutral effect on prolactin and may relieve breast secretions caused
by dopamine 2 antagonism alone.

C and D – Incorrect. Although quetiapine is an antagonist at serotonin
2C and histamine 1 receptors, both of which are associated
with some side effects, neither receptor type has an established
role in prolactin elevation.

Question 10

QUESTION TEN
Compared to aripiprazole, where do brexpiprazole and cariprazine
fall on the dopamine agonist spectrum?

A. Brexpiprazole and cariprazine have less intrinsic activity/are
more antagonistic than aripiprazole

B. Brexpiprazole and cariprazine have more intrinsic activity/are
more of an agonist than aripiprazole

C. Brexpiprazole and cariprazine have about the same intrinsic
activity/are equally antagonistic compared to aripiprazole

Answer 10

A – Correct. Brexpiprazole and cariprazine, like aripiprazole, are partial
agonists at the dopamine 2 receptor. Pharmacologically, brexpiprazole
has less intrinsic activity (i.e., is less of a partial agonist and
more of an antagonist) at dopamine 2 receptors than aripiprazole.
Similarly, cariprazine also has less intrinsic activity at dopamine
2 receptors than aripiprazole; its activity is very similar to brexpiprazole.
Cariprazine and brexpiprazole differ from each other in
terms of their secondary pharmacological properties.

B – Incorrect.

C – Incorrect.

Question 11

QUESTION ELEVEN
Frank is a 24-year-old patient recently diagnosed with schizophrenia.
He is currently taking an antipsychotic, and his psychosis
symptoms are reasonably well resolved. At a follow-up visit, you
notice that Frank does not seem to be able to sit still; he is constantly
pacing the examining room, and when he does sit down, he
rocks back and forth, fidgets, and repetitively crosses and uncrosses
his legs. Drug-induced akathisia is caused by:

A. Dopaminergic hypoactivity

B. Dopaminergic hyperactivity

C. Unknown pathophysiology

Answer 11

Akathisia is a distressing side effect characterized by a subjective feeling
of inner restlessness that prompts a need to move. It is often extraordinarily
difficult for the patient to describe, in part because there are few
subjective states to which it can be compared.

A – Incorrect. Dopaminergic hypoactivity has been proposed as an
underlying cause of akathisia because most antipsychotics are
potent antagonists at the dopamine 2 receptor, it occurs in Parkinson’s
disease, and similar disorders (restless legs syndrome and periodic
limb movement disorder) are treated with dopamine agonists.
However, there is no established direct link between parkinsonism
and akathisia, and agents that cause the least drug-induced parkinsonism
can still cause akathisia. In addition, other agents can also
cause akathisia, including notably the selective serotonin reuptake
inhibitors (SSRIs).

B – Incorrect. Akathisia has not been linked to dopamine hyperactivity.

C – Correct. The pathophysiology of akathisia is not known

Question 12

QUESTION TWELVE
A 44-year-old woman with schizophrenia has developed tardive
dyskinesia after taking haloperidol 15 mg/day for 2 years. Which
of the following would be the most appropriate pharmacological
mechanism to manage her tardive dyskinesia?

A. Antagonism at serotonin 2A receptors

B. Antagonism of beta-adrenergic receptors

C. Inhibition of vesicular monoamine transporter 2

D. Antagonism of muscarinic acetylcholine receptors

Answer 12

A – Incorrect. Although dopamine 2 antagonists with the additional
property of serotonin 2A antagonism were initially thought to
carry less risk of tardive dyskinesia, it is now known that tardive
dyskinesia continues to be a potential side effect of these agents,
and that any possibly reduced risk does not necessarily seem to
correlate with the degree of serotonin 2A antagonism.

B – Incorrect. Beta-blockers (e.g., propranolol) do not show evidence
of efficacy in the treatment of tardive dyskinesia.

C – Correct. The best evidenced (including approved) medications to
treat tardive dyskinesia are selective inhibitors of vesicular monoamine
transporter 2 (VMAT2), which packages monoamines,
including dopamine, into synaptic vesicles of presynaptic neurons
in the central nervous system.

D – Incorrect. Central anticholinergic medication can improve
drug-induced parkinsonism but exacerbate or unmask tardive dyskinesia.
This effect may be reversible if the anticholinergic medication
is discontinued.

Question 13

QUESTION THIRTEEN
A patient who has been taking an atypical antipsychotic for 6
months has experienced a 22-pound weight gain since baseline.
Which of the following pharmacological properties most likely
underlies this patient’s metabolic changes?

A. Dopamine 2 antagonism

B. Serotonin 2A antagonism

C. Serotonin 2C antagonism

D. Alpha 1 adrenergic antagonism

Answer 13

A – Incorrect. Antagonism of dopamine 2 receptors is associated with
both therapeutic and side effects but is not linked to weight gain.

B – Incorrect. Similarly, antagonism of serotonin 2A receptors has not
been linked to risk for weight gain.

C – Correct. Antagonism of serotonin 2C receptors is associated with
increased risk for weight gain, perhaps in part due to stimulation
of appetite regulated by the hypothalamus, and especially in combination
with histamine 1 antagonism.

D – Incorrect. Antagonism of alpha 1 adrenergic receptors is associated
with side effects but is not linked to weight gain

Question 14

QUESTION FOURTEEN
A 34-year-old woman with schizophrenia has been taking a therapeutic
dose of olanzapine (20 mg/day) for 6 weeks. She has shown
no response but also exhibits no side effects. The ideal course of
action at this point would be to:

A. Obtain a plasma level of olanzapine

B. Raise the dose of olanzapine

C. Switch to a different antipsychotic

D. Add a mood-stabilizing anticonvulsant

Answer 14

A – Correct. Obtaining antipsychotic plasma levels in patients who
have had poor response despite a trial with an adequate dose/
duration of medication can be helpful in order to rule out poor
adherence, identify rapid elimination, or confirm true treatment
resistance. Although not all antipsychotics have well-established
therapeutic plasma levels, olanzapine is among those agents that do.

B – Incorrect. Although raising the dose of olanzapine in a patient
who has neither a response nor side effects could be attempted,
plasma levels – not dose – are the best guide to the extent of
patient medication exposure and are the best predictors of antipsychotic
response. Thus, given that the olanzapine dose is at the
top of the typically recommended range, one would ideally obtain
plasma levels prior to any treatment adjustment.

C – Incorrect. Given that the patient has neither a response nor any
side effects, it is reasonable that her medication exposure is subtherapeutic
despite being dosed in the therapeutic range. Thus, it
would make sense to obtain antipsychotic plasma levels prior to
switching medications.

D – Incorrect. While an augmentation treatment strategy might help,
it is important to first obtain antipsychotic plasma levels to determine
whether the patient is actually treatment-resistant to the
medication, or the dose needs to be adjusted to achieve a therapeutic
response.

Question 15

QUESTION FIFTEEN
A 38-year-old man was diagnosed with schizophrenia 14 years ago,
and over the course of his illness has taken several different antipsychotics,
all with partial response and no severe side effects. He now
presents with acute exacerbation of hallucinations and delusions.
He recently had bowel resection due to a gastrointestinal disorder,
and blood levels reveal that he is not absorbing his medications
well. One option for this patient would be to prescribe heroic oral
doses of his antipsychotic. Aside from this approach, which of the
following antipsychotics have formulations that may be good longterm
options for bypassing his problem with absorption?

A. Asenapine, paliperidone, risperidone

B. Paliperidone, risperidone, quetiapine

C. Risperidone, quetiapine, ziprasidone

D. Quetiapine, ziprasidone, asenapine

Answer 15

A – Correct. For patients with difficulty absorbing medications, the
best options in order to reach therapeutic blood levels would be
to prescribe heroic oral doses or to use parenteral, sublingual, or
suppository administration. Asenapine has a sublingual formulation
and a transdermal patch, while several atypical antipsychotics
are available as long-acting injectable (LAI) antipsychotics: risperidone
microspheres (2-week formulation), paliperidone palmitate
(4-week and 12-week formulations), olanzapine pamoate
(4-week formulation), aripiprazole monohydrate (4-week formulation),
and aripiprazole lauroxil (4-, 6-, and 8-week formulations).
Additional antipsychotics with LAI formulations include
fluphenazine, haloperidol, flupenthixol, pipothiazine, and zuclopenthixol.
Clozapine, olanzapine, and risperidone have orally disintegrating
tablets; however, these medications are not absorbed
sublingually and must be swallowed in order to undergo absorption
in the gut. Chlorpromazine has a suppository formulation,
and other antipsychotics may also be able to be administered as
suppositories.

B – Incorrect. Paliperidone and risperidone are both viable options,
but quetiapine is only available as an oral tablet.

C – Incorrect. Risperidone is a viable option. However, quetiapine is
only available as an oral tablet. Ziprasidone is available in an intramuscular
formulation, which would bypass absorption issues, but
it is for acute agitation and is not to be administered long term.

D – Incorrect. Asenapine is a viable option, but neither quetiapine nor
ziprasidone would be (see above for explanation).

Question 16

QUESTION SIXTEEN
A 28-year-old man was recently diagnosed with schizophrenia. He
has a body mass index of 30, fasting triglycerides of 220 mg/dL,
and fasting glucose of 114 mg/dL. Which of the following is least
likely to worsen his metabolic profile?

A. Olanzapine

B. Quetiapine

C. Risperidone

D. Ziprasidone

Answer 16

A – Incorrect. Olanzapine is one of the antipsychotics most associated
with weight gain and metabolic risk and would not be a first-line
option for patients who have a primary concern about metabolic
issues. Clozapine also can cause problematic weight and metabolic
side effects.

B – Incorrect. Quetiapine can lead to weight gain and increased triglyceride
levels and may be a second-line option if a primary concern
is metabolic issues.

C – Incorrect. Risperidone can lead to weight gain and increased
triglyceride
levels and may be a second-line option if a primary
concern is metabolic issues. Paliperidone, which is the active
metabolite of risperidone, can also lead to weight gain and metabolic
changes. Iloperidone, asenapine, cariprazine, and brexpiprazole
may also cause weight gain.

D – Correct. Ziprasidone in general seems to be weight neutral and has
been shown to lower triglyceride levels. It is therefore a recommended
choice for individuals for whom metabolic issues are a
primary concern. Other newer antipsychotics that may be less
likely to cause weight gain or metabolic side effects include aripiprazole
(although data suggest that weight gain may occur more
in children and adolescents), lurasidone, and lumateperone.

Question 17

QUESTION SEVENTEEN
A 37-year-old woman with schizophrenia has failed to respond
to two sequential adequate trials of antipsychotic monotherapy
(first olanzapine, then aripiprazole). Which of the following are
evidence-based treatment strategies for a patient in this situation?

A. High dose of her current monotherapy (aripiprazole)

B. Augmentation of her current monotherapy with another atypical
antipsychotic

C. Switch to clozapine

D. A and C

E. A, B, and C

Answer 17

A – Incorrect. Controlled studies for high doses of antipsychotics are
quite limited. In particular, the limited data that exist for aripiprazole
suggest that it is not usually more effective at doses above
the usual recommended range (i.e., 15–30 mg/day for psychosis).
Before resorting to high-dose monotherapy, evidence-based strategies
for treatment resistance should be exhausted, including the
use of clozapine.

B – Incorrect. There is limited evidence to support the superior efficacy
of combining antipsychotics vs. switching to clozapine or
another monotherapy. Controlled studies are limited and review
of the evidence that does exist (clinical trials and case reports) has
not led to recommendations for antipsychotic polypharmacy in
routine clinical practice.

C – Correct. After failure of two sequential adequate trials of antipsychotic
monotherapy, the recommended and evidence-based
treatment strategy is to switch to clozapine.

D and E – Incorrect.

Question 18

QUESTION EIGHTEEN
Carol is a 47-year-old patient with schizophrenia. She was taking a
conventional antipsychotic but decided to stop taking it when she
developed parkinsonian symptoms. Secondary to stopping her conventional
antipsychotic, Carol’s auditory hallucinations and paranoia
returned, and she was rehospitalized. You recommend that she
be started on an atypical antipsychotic. Which of the following has
the lowest risk of drug-induced parkinsonism associated with it?

A. Asenapine

B. Iloperidone

C. Olanzapine

D. Paliperidone

Answer 18

As a class, atypical antipsychotics tend to have a decreased risk of movement
disorders relative to conventional antipsychotics; however, the
risk differs with each individual agent.

A, C, and D – Incorrect.

B – Correct. Of the agents listed here (asenapine, iloperidone, olanzapine,
paliperidone), iloperidone has a relatively lower risk of
drug-induced parkinsonism. Other agents with a relatively lower
risk of drug-induced parkinsonism include clozapine, lumateperone,
and quetiapine.

Question 19

QUESTION NINETEEN
Ryan is a 26-year-old white male with treatment-resistant schizoaffective
disorder, depressive type, and frequent suicidal ideation and
behavior. After adequate but unsuccessful trials with several mood
stabilizers and atypical antipsychotics (both as monotherapy and
in various combinations), you are considering a trial of clozapine.
Which of the following testing should you order prior to initiating
clozapine?

A. White blood cell count (WBC)

B. Absolute neutrophil count (ANC)

C. A and B

D. Neither A nor B

Answer 19

A – Incorrect. Total WBC is no longer used when deciding whether to
initiate or continue clozapine.

B – Correct. Before initiating clozapine treatment, it is necessary to
obtain ANC. The lower ANC threshold for starting clozapine is at
least 1500/μL in the general population and at least 1000/μL in
individuals with benign ethnic neutropenia (BEN). BEN is a condition
observed in certain ethnic groups (most commonly those
of African descent, some Middle Eastern ethnic groups, and other
non-Caucasian ethnic groups with darker skin). Patients with
BEN have normal hematopoietic stem cell numbers and myeloid
maturation, are healthy, do not suffer from repeated or severe
infections, and are not at an increased risk for developing clozapine-
induced neutropenia.

C – Incorrect. ANC, but not WBC, is required
prior to initiating clozapine.

D – Incorrect. ANC is required prior to initiating clozapine.

Question 20

QUESTION TWENTY
A 38-year-old woman was diagnosed with schizophrenia approximately
2 years ago, and after multiple trials of atypical and typical
antipsychotic medications she has been maintained on haloperidol
for the last several months with good response. Two weeks ago, she
began exhibiting mild motor symptoms of drug-induced parkinsonism.
Which of the following would be the most appropriate
adjunct medication for this patient?

A. Alpha 1 adrenergic agonist

B. Cholinesterase inhibitor

C. Histamine 1 antagonist

D. Muscarinic 1 antagonist

Answer 20

Drug-induced parkinsonism is associated with a relative deficiency of
dopamine and an excess of acetylcholine in the nigrostriatal pathway.
Dopamine normally suppresses acetylcholine activity; thus, blockade of
dopamine 2 receptors by antipsychotics enhances release of acetylcholine
and can lead to the production of parkinsonian symptoms. Increasing
availability of dopamine and/or decreasing acetylcholine would
therefore be expected to relieve drug-induced parkinsonism.

A – Incorrect. Haloperidol is an antagonist at the alpha 1 adrenergic
receptor and an agonist would therefore reverse its effects; however,
alpha 1 stimulation may actually decrease striatal dopamine
release and thus would not relieve parkinsonism.

B – Incorrect. A cholinesterase inhibitor would reduce metabolism of
acetylcholine and cause a further increase, rather than decrease, in
this neurotransmitter.

C – Incorrect. Similarly, the histamine system is not associated with
development of, or relief from, drug-induced parkinsonism. Some
antihistamines are muscarinic 1 antagonists but their histamine 1
antagonist properties do not regulate extrapyramidal side effects.

D – Correct. Antagonism of the muscarinic 1 receptor for acetylcholine
would prevent it from binding there and thus reduce its
effects, potentially relieving drug-induced parkinsonism.

Question 21

QUESTION TWENTY-ONE
With long-acting injectable (LAI) antipsychotics, the time to steady
state is a function of:

A. Elimination rate

B. Absorption rate

Answer 21

A – Incorrect. Typically, when an immediate-release medication is
administered orally, it is absorbed rapidly. How long it takes to
remove the medication from the body is therefore largely dependent
on the rate of elimination. This also means that the time to
steady state with repeated dosing is a function of elimination rate.
However, with LAI antipsychotics, the rate of absorption is much
slower than the rate of elimination, which leads to something
called “flip-flop” kinetics. That is, because the medication cannot
be eliminated until it is absorbed, the terminal slope is largely
dependent on the absorption rate. In this case, the time to steady
state is a function of absorption rate.
The long half-lives of LAI antipsychotics mean that, when converting
from oral formulations, one must either adequately load
the dose, if possible, or provide oral supplementation. A loading
dose is the dose required to immediately achieve a plasma concentration
that is equivalent to the steady-state concentration. The
failure to adequately load the dose or provide oral supplementation
can lead to subtherapeutic antipsychotic plasma levels for
weeks or months.

B – Correct. Time to steady state for LAI antipsychotics is a function
of absorption rate.

Question 21

QUESTION TWENTY-TWO
Reggie is a 30-year-old male patient with schizophrenia. He is currently
taking iloperidone 24 mg/day as well as aripiprazole 15 mg/
day but continues to experience visual hallucinations. To improve
this patient’s psychosis, it is likely necessary to further increase the
blockade of dopamine D2 receptors. Which treatment strategy is
likely the best course of action?

A. Increase iloperidone dose while keeping aripiprazole dose the
same

B. Increase iloperidone and aripiprazole doses

C. Increase aripiprazole dose while keeping iloperidone dose the
same

D. Maintain iloperidone dose and discontinue aripiprazole

Answer 21

Aripiprazole is a D2 partial agonist and is also one of the most potent
agents that bind to D2 receptors. Thus, when given concomitantly with
a D2 antagonist, such as iloperidone, it can actually reduce the level of
D2 blockade compared to D2 antagonist monotherapy, thus reducing
the antipsychotic efficacy.

A – Incorrect. Increasing the dose of iloperidone while maintaining
the aripiprazole dose would not likely lead to a relevant increase in
D2 blockade (and corresponding improvement of psychotic symptoms),
since aripiprazole has higher affinity for the D2 receptor.

B – Incorrect. Increasing doses of both iloperidone and aripiprazole
would not likely lead to improvement of psychotic symptoms,
since aripiprazole would continue to compete with iloperidone at
the D2 receptor.

C – Incorrect. Increasing the dose of aripiprazole may actually decrease
D2 blockade rather than increase it, since aripiprazole has higher
affinity for the D2 receptor than iloperidone.

D – Correct. Because aripiprazole may be reducing the level of D2
blockade relative to iloperidone monotherapy, the best strategy for
increasing D2 blockade (and correspondingly improving psychotic
symptoms) may be to use monotherapy

Question 21

QUESTION TWENTY-THREE
Lumateperone has a unique mechanism of action that targets
three neurotransmitter pathways through modulation of dopamine
D1 and D2 receptors and glutamate (NMDA) receptor
subunit epsilon-2, also known as N-methyl-d-aspartate receptor
subtype 2B (GLuN2B), via downstream dopamine D1 receptors
and through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) currents via the mTOR protein pathway. It is also
a selective serotonin (5HT) 5HT2A receptor antagonist. Which
component hypothetically may contribute to improved cognition?

A. Dopamine phosphoprotein D2 modulator (DPPM)

B. 5HT2A receptor antagonist

C. Glutamatergic phosphoprotein modulator

D. Serotonin reuptake inhibitor

Answer 21

A – Incorrect. Lumateperone acts as a D2 presynaptic partial agonist
and a D2 postsynaptic antagonist selectively in the mesolimbic and
mesocortical areas. This mechanism is not posited to be related to
potential differential effects on cognition.

B – Incorrect. 5HT2A receptor antagonism is a property shared across
the atypical antipsychotic class. This property enhances antipsychotic
activity, reducing positive symptoms, while enhancing
antidepressant
activity. It may also be related to improved sleep
quality, reduced anxiety, and reduced agitation. It is not posited to
be related to improved cognition.

C – Correct. As a glutamatergic phosphoprotein modulator, lumateperone
increases phosphorylation of mesolimbic GluN2B subunits of
NMDA receptors resulting in indirect enhancement of glutamatergic
NMDA function, along with NMDA and AMPA receptor enhancement
via downstream D1 receptors. This may result in improved cognition
as well as a reduction in positive and negative symptoms. It
may also contribute to rapid-acting antidepressant activity.

D – Incorrect. Serotonin reuptake inhibition is not related to improved
cognition.

Question 22

QUESTION TWENTY-FOUR
A 33-year-old man who was recently diagnosed with schizophrenia
is taking 10 mg of sublingual asenapine twice a day. He reports a
marked reduction in positive symptoms, and no motor side effects.
Unfortunately, he also reports that he has noticed a numbness in his
mouth, a loss of taste, and there are blisters under his tongue. Which
treatment strategy is likely the best course of action?

A. Reduce the sublingual asenapine dose to 5 mg twice a day

B. Chew or swallow the medication in order to avoid the oral
adverse effects he is experiencing

C. Switch to the FDA-approved asenapine transdermal patch

D. Only administer the sublingual asenapine dose once a day

Answer 22

A – Incorrect. Reducing the dose may reduce the adverse oral side
effects he is experiencing, but it may also reduce the alleviation of
positive symptoms. The recommended therapeutic dose to alleviate
positive symptoms of schizophrenia is 10 mg twice a day for a
total of 20 mg per day.

B – Incorrect. Patients should be instructed to place the tablet under
the tongue and allow it to dissolve completely, which will occur
in seconds. The tablet should not be divided, crushed, chewed, or
swallowed. Asenapine is not absorbed after swallowing (less than
2% bioavailable orally) and thus must be administered sublingually
(35% bioavailable), as swallowing would render asenapine inactive.
Patients may not eat or drink for 10 minutes following sublingual
administration so that the drug in the oral cavity can be absorbed
locally and not washed into the stomach (where it would not be
absorbed).

C – Correct. The asenapine transdermal system is the only transdermal
medication approved for schizophrenia. Transdermal delivery systems
may have benefits over other formulations, such as the ability
to visually confirm medication adherence and possible improved
tolerability. Adverse oral events, such as the hypoesthesia and dysgeusia
associated with the sublingual asenapine, could be avoided
by utilizing the transdermal patch. Since this patient has benefited
from the effects of asenapine, a non-oral formulation of asenapine,
such as the transdermal patch, may be ideal to avoid the oral side
effects he has been experiencing.

D – Incorrect. Once daily use seems theoretically possible because
the half-life of asenapine is 13–39 hours, but this has not been extensively
studied and may be limited by the need to expose the
limited sublingual surface area to a limited amount of sublingual
drug dosage.