Depresion Unipolar y su tratamiento

Question 1

QUESTION ONE
A 26-year-old woman began treatment for a major depressive episode
8 months ago. Two months into her treatment she began to
experience noticeable symptom improvement, and for the last 5
months she has been mostly symptom free, except for persistent
cognitive dysfunction. Which of the following statements regarding
cognitive dysfunction in depression is most accurate?

A. Cognitive dysfunction is one of the most common residual
symptoms following recovery

B. Cognitive dysfunction can be treated with serotonergic modulation
of glutamate transmission

C. Both A and B

Answer 1

A – Partially correct.

B – Partially correct.

C – Correct. Cognitive dysfunction is one of the most common residual
symptoms of major depressive disorder and can endure longer
than mood symptoms following recovery. Moreover, cognitive
dysfunction is strongly correlated with physical, mental, and functional
disability. Pharmacotherapies used to treat depression that
have action on glutamate signaling via serotonergic modulation
also show pro-cognitive effects. The prime example is vortioxetine,
which has agonist action at 5HT1A, weak partial agonist action at
5HT1B/D, and antagonist action at 5HT3, 5HT1D, 5HT7, and
the serotonin transporter. Antagonism of 5HT3 disinhibits glutamate
release, while antagonism of 5HT7 enhances release of
glutamate release in the prefrontal cortex. In addition, agonism
of 5HT1A (full) and 5HT1B (partial) may enhance or suppress
glutamate transmission based on neuronal localization.

Question 2

QUESTION TWO
Amir is a 19-year-old patient with depression. He requests treatment
with a serotonin norepinephrine reuptake inhibitor (SNRI)
because he heard they are more effective than selective serotonin
reuptake inhibitors (SSRIs). Theoretically, what is the therapeutic
advantage of an SNRI over an SSRI?

A. Increased norepinephrine via norepinephrine transporter
inhibition

B. Increased dopamine via norepinephrine transporter inhibition

C. Increased norepinephrine and dopamine via norepinephrine
transporter inhibition

Answer 2

A – Partially correct.

B – Partially correct.

C – Correct. In addition to boosting serotonin
like SSRIs (via inhibition
of serotonin reuptake by the serotonin transporter [SERT]),
SNRIs can boost norepinephrine by inhibiting reuptake by the
norepinephrine transporter (NET). Additionally, in the prefrontal
cortex, SNRIs can boost dopamine levels. In the prefrontal cortex,
SERTs and NETs are present in abundance on serotonin and
norepinephrine nerve terminals, respectively, but there are very
few dopamine transporters (DATs) on dopamine nerve terminals.
Therefore, dopamine action is terminated by either enzymatic
degradation or NET. If NET is inhibited by an SNRI then it
cannot terminate the action of dopamine and dopamine levels
increase in this brain region.

Question 3

QUESTION THREE
A 36-year-old man with major depressive disorder is having lab
work done to assess his levels of inflammatory markers. Based on
the current evidence regarding inflammation in depression, which
of the following results would you most likely suspect for this
patient?

A. Elevated levels of tumor necrosis factor-alpha (TNF-α)

B. Reduced levels of interleukin 6 (IL-6)

C. Reduced C-reactive protein (CRP)

D. Elevated interferon gamma (IFNγ)

Answer 3

A – Correct. There is growing evidence that inflammation may play
an important role in the pathophysiology of major depression.
Clinical studies have shown that depressed patients have significantly
higher concentrations of several inflammatory central and
peripheral markers, including the pro-inflammatory cytokines
TNF-α and IL-6. Patients with depression also have higher concentrations
of CRP, which is synthesized by the liver in response
to pro-inflammatory
cytokines, and reduced IFNγ, which is a pro-inflammatory
cytokine. Furthermore, both cytokines and cytokine
inducers can cause symptoms of depression. For example, as many
as 50% of patients receiving chronic therapy with the cytokine
interferon develop symptoms consistent with idiopathic depression.

B, C, and D – Incorrect.

Question 4

QUESTION FOUR
A 28-year-old man with moderate depression achieves remission
after 16 weeks on a therapeutic dose of an antidepressant. According
to the neurotrophic hypothesis of depression, which of the following
is most likely true of his brain-derived neurotrophic factor
(BDNF) expression before and after his successful treatment?

A. BDNF expression was abnormally low while he was depressed,
and increased during antidepressant treatment

B. BDNF expression was abnormally high while he was depressed,
and decreased during antidepressant treatment

C. BDNF expression was normal while he was depressed, and was
unaffected during antidepressant treatment

Answer 4

A – Correct. The neurotrophic hypothesis of depression posits that
depression results from decreased neurotrophic support, leading
to neuronal atrophy, decreased hippocampal neurogenesis, and that
antidepressant treatment blocks or reverses this deficit, thereby
reversing atrophy and cell loss. Several meta-analyses have reported
deficient BDNF levels in patients with major depressive disorder
and an elevation in BDNF following antidepressant treatment.

B – Incorrect.

C – Incorrect.

Question 5

QUESTION FIVE
Margaret is a 42-year-old patient with untreated depression. She is
reluctant to begin antidepressant treatment due to concerns about
treatment-induced weight gain. Which of the following antidepressant
treatments is associated with the greatest risk of weight gain?

A. Escitalopram

B. Fluoxetine

C. Mirtazapine

D. Vilazodone

Answer 5

A – Incorrect. Although weight gain may occur, it is not commonly
reported with escitalopram, and a meta-analysis suggests that the
risk of both short- and long-term weight gain with escitalopram is
low.
B – Incorrect. Although weight gain may occur, it is not commonly
reported with fluoxetine and a meta-analysis did not find significant
increase in weight over the short or long term. Some patients
actually experience short-term weight loss with fluoxetine.
C – Correct. Meta-analysis has shown that mirtazapine, an alpha 2
antagonist, may cause both short- and long-term weight gain. This
is consistent with its secondary pharmacological properties: mirtazapine
is an antagonist at both serotonin 2C and histamine 1
receptors, the combination of which has been proposed to cause
weight gain. However, it should be noted that average weight gain
with any antidepressant is small, and rather than a widespread
effect it may instead be that a small number of individuals experience
significant weight gain due to their genetic predispositions
and other factors.
D – Incorrect. Although weight gain may occur, studies with vilazodone
have suggested a lower risk for weight gain compared to
many other antidepressants that block serotonin reuptake; however,
head-to-head studies have not been conducted.

Question 6

QUESTION SIX
A 52-year-old man presents to the emergency room with symptoms
of hypertensive crisis after an evening dining out with friends.
He is currently taking a monoamine oxidase inhibitor (MAOI).
Which of the following foods must be avoided by patients taking
MAOIs?

A. Fresh fish

B. Aged cheese

C. Bananas

D. Bottled beer

Answer 6

A – Incorrect. Fresh fish does not have a high tyramine content and
can therefore be safely consumed when one is taking an MAOI.

B – Correct. Aged cheeses in general have high tyramine content and
must be avoided when a patient is taking an MAOI.

C – Incorrect. Bananas that are not overripe do not have a high
tyramine content and can therefore be safely consumed when one
is taking an MAOI. However, banana peels and bananas that are
overripe should be avoided.

D – Incorrect. Bottled beer does not have a high tyramine content and
can therefore be safely consumed when one is taking an MAOI.

Foods to AVOID* Foods ALLOWED
Dried, aged, smoked,
fermented, spoiled, or
improperly stored meat, poultry,
and fish
Fresh or processed meat,
poultry, and fish
Broad bean pods All other vegetables
Aged cheeses Processed cheese slices, cottage
cheese, ricotta cheese, cream
cheese, yogurt
Tap and unpasteurized beer Bottled or canned beer and
alcohol
Marmite Brewer’s and baker’s yeast
Soy products/tofu Peanuts
Banana peel Bananas, avocados,
raspberries
Sauerkraut, kimchee
Tyramine-containing nutritional
supplements

Question 7

QUESTION SEVEN
A 48-year-old woman with a history of treatment-resistant depression
is currently taking duloxetine 60 mg/day with partial response
as well as trazodone 50 mg/day for insomnia. Despite reporting
strict adherence to her medication dosages, she states that she feels
empty and useless, and she admits to having thoughts of death.
She states that she does not have plans to kill herself because it
would harm her family and pets. Her clinician decides to try tranylcypromine,
a monoamine oxidase inhibitor (MAOI) and one
of the few agents that she has not yet tried. Which of the patient’s
current medications MUST you discontinue BEFORE initiating
tranylcypromine?

A. Duloxetine

B. Trazodone

C. Both duloxetine and trazodone

D. Neither duloxetine nor trazodone

Answer 7

A – Correct. Duloxetine is a serotonin norepinephrine reuptake inhibitor.
Inhibition of the serotonin transporter leads to increased synaptic
availability of serotonin. Similarly, inhibition of MAO leads to
increased serotonin levels. In combination, these two mechanisms
can cause excessive stimulation of postsynaptic serotonin receptors,
which has the potential to cause a fatal “serotonin syndrome” or
“serotonin toxicity.” Because of the risk of serotonin toxicity, complete
washout of duloxetine is necessary before starting an MAOI.
Duloxetine must be down-titrated as tolerated, after which one
must wait five half-lives of duloxetine (at least 3–4 days) before
initiating the MAOI.

B – Incorrect. Although trazodone does have serotonin reuptake
inhibition at antidepressant doses (150 mg or higher), this property
is not clinically relevant at the low doses used for insomnia. In fact,
because there is a required gap in antidepressant treatment when
switching to or from an MAOI, low-dose trazodone can be useful
as a bridging agent when switching.

C and D – Incorrect

Question 8

QUESTION EIGHT
A 56-year-old male patient with major depression is brought to
the emergency room with cardiac arrhythmia and possible cardiac
arrest. While at the hospital, he suffers a seizure. His wife states
that he may have ingested an increased dose of his medication.
Which of the following is most likely responsible for this apparent
overdose
reaction?

A. Atomoxetine

B. Clomipramine

C. Fluvoxamine

D. Venlafaxine

Answer 8

A – Incorrect. Atomoxetine, a norepinephrine reuptake inhibitor, does
not block voltage-sensitive sodium channels (VSSCs) and is not
noted to have severe cardiac impairments upon overdose; rather
sedation, agitation, hyperactivity, abnormal behavior, and gastrointestinal
symptoms are most commonly reported.

B – Correct. Clomipramine, a tricyclic antidepressant (TCA), may be
most likely to cause these effects in overdose. TCAs block VSSCs
in both the brain and the heart. This action is weak at therapeutic
doses, but in overdose may lead to coma, seizures, and cardiac
arrhythmia, and may even prove fatal.

C – Incorrect. Fluvoxamine, a selective serotonin reuptake inhibitor
(SSRI), also does not block VSSCs and does not generally cause
severe cardiac impairment in overdose.

D – Incorrect. Venlafaxine is a serotonin norepinephrine reuptake
inhibitor (SNRI). Although some data have suggested that SNRIs
can affect heart function in overdose and also may carry increased
risk of death in overdose compared to SSRIs, their toxicity in
overdose is less than that for TCAs.

Question 9

QUESTION NINE
A 65-year-old patient on theophylline for chronic obstructive pulmonary
disease (COPD) and fluvoxamine for recurring depressive
episodes required a decreased dose of theophylline due to increased
blood levels of the drug. Which of the following pharmacokinetic
properties may be responsible for this?

A. Inhibition of CYP450 1A2 by fluvoxamine

B. Inhibition of CYP450 2D6 by fluvoxamine

C. Inhibition of CYP450 3A4 by fluvoxamine

Answer 9

A – Correct. Fluvoxamine is a strong inhibitor of CYP450 1A2. Theophylline
is metabolized in part by CYP450 1A2, and thus strong
inhibition of this enzyme by fluvoxamine may require a dose
reduction of theophylline if the two are given concomitantly, so as
to avoid increased blood levels of the drug.

B – Incorrect. Of all selective serotonin reuptake inhibitors (SSRIs),
fluvoxamine shows the least interaction with CYP450 2D6.

C – Incorrect. Fluvoxamine is also a moderate inhibitor of CYP450
3A4, but since theophylline is neither a substrate nor an inhibitor
of 3A4, this should not affect theophylline blood levels.

Question 10

QUESTION TEN
Mike, a 31-year-old patient with major depressive disorder (MDD),
has experienced some response with the serotonin norepinephrine
reuptake inhibitor (SNRI) venlafaxine XR (150 mg/day). However,
the patient acknowledges that he and his wife have been having
relationship problems because of his poor libido. The patient
experienced this problem prior to being diagnosed and treated for
MDD, but he has found that the venlafaxine has worsened this
troubling symptom despite the fact that his mood has improved. He
asks if there is a way to both prevent worsening of his mood and
avoid this side effect. Which of the following treatment strategies
would you recommend for this patient?

A. Decrease venlafaxine dose

B. Switch to a norepinephrine and dopamine reuptake inhibitor
(NDRI)

C. Switch to a selective serotonin reuptake inhibitor (SSRI)

D. Augment current venlafaxine dose with a phosphodiesterase-5
inhibitor (e.g., sildenafil)

Answer 10

The prevalence of sexual dysfunction, including diminished libido,
impaired arousal, and lack of orgasm, is high among patients with MDD,
and sexual dysfunction may worsen with antidepressant treatment (particularly
treatment with a serotonin reuptake inhibitor). Serotonin plays
an inhibitory role in the human sexual response, both for desire and
for orgasm. Exacerbation of sexual dysfunction by antidepressant treatment
is one of the most common factors reported to cause treatment
nonadherence or discontinuation.

A – Incorrect. With regards to the diagnostic criteria for depression,
this patient has experienced some improvement with his current
dose of venlafaxine. Although lowering the dose of venlafaxine
may improve this patient’s sexual function, a dose reduction may
also increase his depressive symptoms.

B – Correct. Pharmacological agents that increase dopaminergic
neurotransmission and/or decrease serotonergic neurotransmission
(e.g., serotonin 1A agonists or serotonin 2 antagonists) are
often effective in ameliorating sexual dysfunction. Switching to an
NDRI such as bupropion would be expected to increase dopaminergic
neurotransmission and improve sexual function. Given
that the patient experienced libido problems prior to treatment
with the SNRI, and that the problem has worsened on treatment
with the SNRI, it makes sense to switch to bupropion. Augmentation
with bupropion to address sexual dysfunction, although
commonly done in clinical practice, is not actually supported by
randomized controlled studies.

C – Incorrect. Of the available antidepressant treatments, SSRIs are
associated with the greatest risk of worsening sexual function, so
switching from venlafaxine to an SSRI would not be expected to
improve sexual functioning.

D – Incorrect. Although it is usually best to try another antidepressant
monotherapy before resorting to augmentation strategies for the
treatment of side effects, for a patient such as this who is otherwise
responding well it might be reasonable to augment. However,
phosphodiesterase-5 inhibitors do not increase desire and thus
would not be a good option to treat this patient’s specific problems
with sexual function.

Question 11

QUESTION ELEVEN
In addition to treating depressed mood, preclinical data indicate
that serotonin 5HT3 receptor antagonists may have clinical utility
as adjunct treatment for which symptoms?

A. Cognitive symptoms

B. Irritability

C. Psychomotor retardation

D. Sleep problems

Answer 11

A – Correct. Serotonergic neurons synapse with noradrenergic
neurons, cholinergic neurons, and GABAergic interneurons, all
of which contain serotonin 5HT3 receptors. When serotonin
is released, it binds to 5HT3 receptors on GABAergic neurons,
which release gamma-aminobutyric acid (GABA) onto noradrenergic,
glutamatergic, and cholinergic neurons, thus reducing
release of norepinephrine, glutamate, and acetylcholine, respectively.
In addition, serotonin may bind to 5HT3 receptors on
noradrenergic and cholinergic neurons, further reducing release
of those neurotransmitters. This may theoretically contribute to
symptoms of depressed mood and impaired cognition. Therefore,
treatment with 5HT3 receptor antagonists improves depressed
mood and cognitive problems.

B, C, and D – Incorrect. Irritability, psychomotor retardation, and sleep
problems are not associated with antagonism at 5HT3
receptors.

Question 12

QUESTION TWELVE
A 36-year-old patient has only partially responded to his second
monotherapy with a first-line antidepressant. Which of the following
has the best evidence of efficacy for augmenting antidepressants
in patients with inadequate response?

A. Adding an atypical antipsychotic

B. Adding buspirone

C. Adding a stimulant

Answer 12

A – Correct. Atypical antipsychotics have been studied as adjuncts
to selective serotonin reuptake inhibitors (SSRIs) and serotonin
norepinephrine reuptake inhibitors (SNRIs), with approvals for
aripiprazole, brexpiprazole, quetiapine XR, and olanzapine (in
combination with fluoxetine). Overall, most studies of atypical
antipsychotics show a benefit of combination treatment over monotherapy,
although effect sizes have been modest. Although atypical
antipsychotics have the best evidence of efficacy for augmenting
antidepressants in patients with inadequate response, their adverse
event profiles may still put them later in the treatment algorithm.

B – Incorrect. Although adding buspirone, a serotonin 1A partial agonist,
to a first-line antidepressant makes sense mechanistically, the
limited data that exist are mixed/weak.

C – Incorrect. The limited controlled data for stimulant augmentation
in depression show a trend of benefit; however, this strategy is not
as well documented as is augmentation with atypical antipsychotics.

Question 13

QUESTION THIRTEEN
Miryam is a 24-year-old woman with a major depressive episode
that is only partially responding to treatment with a selective serotonin
reuptake inhibitor. In particular, she continues to display
reduced positive affect. She is prescribed adjunctive bupropion to
manage this symptom. Through which mechanism(s) does bupropion
theoretically ameliorate reduced positive affect?

A. Inhibition of the serotonin transporter

B. Inhibition of the dopamine transporter

C. Inhibition of the norepinephrine transporter

D. A and B

E. A and C

F. B and C

Answer 13

A – Incorrect. Bupropion does not appear to have pharmacological
action on the serotonin transporter.

B, C, D, and E – Partially correct.

F – Correct. Bupropion has weak reuptake blocking properties
for dopamine (dopamine transporter [DAT] inhibition), and for
norepinephrine (norepinephrine transporter [NET] inhibition).
Human positron emission tomography scans suggest that as little as
10–15% and perhaps no more than 20–30% of striatal DATs may
be occupied at therapeutic doses of bupropion. NET occupancy
would be expected to be in this same range.

Question 14

QUESTION FOURTEEN
Wei is a 33-year-old patient with major depressive disorder beginning
at age 17; his current depressive episode has persisted for 10
months. His treatment history includes fluoxetine, nefazodone,
venlafaxine, mirtazapine, agomelatine, lithium augmentation, and
electroconvulsive therapy. Each of these treatments produced moderate
but transient response; therefore, he will begin ketamine infusions
to treat his treatment-resistant depression. Which of the following
statements about ketamine treatment is true?

A. The strongest evidence for the efficacy of ketamine is in bipolar
depression

B. Repeated dosing extends the duration of ketamine effects

C. High-frequency ketamine administration is recommended

D. A history of antidepressant treatment is not necessary to start
ketamine treatment

Answer 14

A – Incorrect. To date, the strongest evidence for ketamine’s clinical
benefit in psychiatric disorders is in the treatment of major depressive
episodes without psychotic features associated with major
depressive disorder.

B – Correct. Studies suggest that repeated dosing may extend the duration
of ketamine effects. Ketamine administration of 2–3 times
per week over 2–3 weeks, followed by a taper period and/or continued
treatments may be most effective.

C – Incorrect. High-frequency ketamine administration is not recommended.
Chronic high-frequency use of ketamine is associated
with cognitive impairment and cystitis.

D – Incorrect. A thorough history of antidepressant treatment should
be collected and documented to confirm previous adequate trials
of antidepressant treatments and confirm treatment resistance.

Question 15

QUESTION FIFTEEN
A patient with depression is prescribed mirtazapine as adjunctive
treatment to venlafaxine, a serotonin norepinephrine reuptake
inhibitor. Mirtazapine acts on alpha 2 receptors to produce what
effect?

A. Disinhibition of norepinephrine and serotonin release via alpha
2 agonism

B. Disinhibition of norepinephrine and dopamine release via
alpha 2 agonism

C. Disinhibition of norepinephrine and serotonin release via alpha
2 antagonism

D. Disinhibition of norepinephrine and dopamine release via
alpha 2 antagonism

Answer 15

A – Incorrect.

B – Incorrect.

C – Correct. Norepinephrine turns off its own release via alpha 2 presynaptic
receptors; therefore, alpha 2 antagonism with mirtazapine
facilitates disinhibition of norepinephrine. Furthermore, norepinephrine
migrating from a norepinephrine terminal can also turn
off serotonin release via alpha 2 presynaptic heteroreceptors on
serotonin neurons. Therefore, alpha 2 antagonists like mirtazapine
can have a dual effect on facilitating the release of both norepinephrine
and serotonin.

D – Incorrect.

Question 16

QUESTION SIXTEEN
A 34-year-old man with depression characterized by depressed
mood, sleep difficulties, and concentration problems has not
responded well to a selective serotonin reuptake inhibitor (SSRI)
or a serotonin norepinephrine reuptake inhibitor (SNRI). His clinician
elects to switch him to vortioxetine, which has prominent
serotonin 5HT7 receptor antagonism. What may be a primary
function of these receptors?

A. Regulation of serotonin–acetylcholine interactions

B. Regulation of serotonin–dopamine interactions

C. Regulation of serotonin–glutamate interactions

D. Regulation of serotonin–norepinephrine interactions

Answer 16

A – Incorrect.

B – Incorrect.

C – Correct. Serotonin 5HT7 receptors are postsynaptic G-protein-
linked receptors. They are localized in the cortex, hippocampus,
hypothalamus, thalamus, and brainstem raphe nuclei, where
they regulate mood, circadian rhythms, sleep, learning, and memory.
A major function of these receptors may be to regulate serotonin–
glutamate interactions.
Serotonin can both activate and inhibit glutamate release from
cortical pyramidal neurons. Serotonin released from neurons in the
raphe nucleus can bind to 5HT2A receptors on pyramidal glutamate
neurons in the prefrontal cortex, activating glutamate release.
However, serotonin also binds to 5HT1A receptors on pyramidal
glutamate neurons, an action that inhibits glutamate release. Additionally,
serotonin binds to 5HT7 receptors on GABA interneurons
in the prefrontal cortex. This stimulates GABA release, which
in turn inhibits glutamate release.
Serotonin binding at 5HT7 receptors can also inhibit its own
release. That is, when serotonergic neurons in the raphe nucleus are
stimulated, they release serotonin throughout the brain, including
not only in the prefrontal cortex but also in the raphe itself. Serotonin
can then bind to 5HT7 receptors on GABA interneurons in
the raphe nucleus. This stimulates GABA release, which then turns
off serotonin release.
Serotonin binding at 5HT7 receptors in the raphe inhibits serotonin
release; therefore, an antagonist at this receptor would be
expected to enhance serotonin release. Specifically, by blocking
serotonin from binding to the 5HT7 receptor on GABA interneurons,
a 5HT7 antagonist would prevent the release of GABA onto serotonin neurons, thus allowing the continued release of serotonin
in the prefrontal cortex.

D – Incorrect.

Question 17

QUESTION SEVENTEEN
A 32-year-old woman with major depressive disorder has been
taking a selective serotonin reuptake inhibitor (SSRI) with good
response for months. She presents now with complaints that she
feels numb, and that even when she’s sad she can’t cry. Her clinician
is considering reducing the dose of her SSRI in an effort to
alleviate this problem. Is this a reasonable option?

A. Yes, data suggest that SSRI-induced indifference is dose-dependent
and can be alleviated by reducing the dose

B. No, although data suggest that SSRI-induced indifference is
dose-dependent, patients who develop this side effect generally
require switch to a different medication

C. No, SSRI-induced indifference is not dose-dependent and thus
cannot be alleviated by reducing the dose

Answer 17

A – Correct. Apathy and emotional blunting can be symptoms of
depression, but they are also side effects associated with SSRIs.
These symptoms – termed “SSRI-induced indifference” – are
under-recognized but can be very distressing for patients. They
are theoretically due to an increase in serotonin levels and a consequent
reduction of dopamine release. The first recommended
strategy for addressing SSRI-induced indifference is to lower the
SSRI dose, if feasible. Additional options include adding an augmenting
agent or switching to an antidepressant in another class.

B and C – Incorrect.

Question 18

QUESTION EIGHTEEN
A 31-year-old woman is diagnosed with severe postpartum depression
3 weeks after giving birth. Treatment with brexanolone, a
positive allosteric modulator of GABA at the GABA-A receptor,
ameliorated her symptoms. GABA has more recently been implicated
in the neurobiology of depression. Theoretically, individuals
with depression may display a lack of normal GABAergic tonic
inhibition via:

A. Postsynaptic benzodiazepine-sensitive GABA-A receptors

B. Extrasynaptic benzodiazepine-insensitive GABA-A receptor

C. Both A and B

Answer 18

A – Incorrect. Postsynaptic benzodiazepine-sensitive GABA-A receptors
are thought to mediate phasic inhibition.

B – Correct. Extrasynaptic benzodiazepine-insensitive GABA-A
receptor subtypes are thought to mediate tonic inhibition. Tonic
inhibition may be regulated by the ambient levels of extracellular
GABA molecules that have escaped presynaptic reuptake and
enzymatic destruction and persist between neurotransmissions
and is boosted by allosteric modulation at these sites. Thus, tonic
inhibition is thought to set the overall tone and excitability of the
postsynaptic neuron, and to be important for certain regulatory
events such as the frequency of neuronal discharge in response to
excitatory inputs. Since neuroactive steroids have antidepressant
properties, this has led to the proposal that some depressed patients
may have a lack of normal tonic inhibition, and thus too much
excitability in some brain circuits.
Indeed, in the case of postpartum depression, it may be potentially
explainable on the basis that pregnant women have high circulating
and presumably brain levels of neuroactive steroids. When they
deliver, there is a precipitous decline in circulating neuroactive
steroid levels, hypothetically triggering the sudden onset of a major
depressive episode when tonic inhibition is lost. Restoring neuroactive
steroid levels – and tonic inhibition – via brexanolone may
be enough for the patient to respond by reversing their depression
and then having some additional time to accommodate to the
lower levels of neuroactive steroids postpartum.

C – Incorrect.

Question 19

QUESTION NINETEEN
A 27-year-old patient who has been taking a selective serotonin
reuptake inhibitor (SSRI) for depression for the last 2 years has just
found out that she is 12 weeks pregnant. Cumulative data for SSRI
use in pregnancy have established a small but clinically significant
increase in absolute risk of:

A. Cardiovascular malformations

B. Persistent pulmonary hypertension

C. Autism spectrum disorder

D. All of the above
E. None of the above

Answer 19

A – Incorrect. The evidence for increased risk of first trimester major
malformations with antidepressants has been limited and inconsistent.
A recent large, population-based, case-control study did not
identify a substantial increase in risk of cardiac malformations with
SSRI use in early pregnancy after adjusting for maternal underlying
condition. Furthermore, a recent review of 22 meta-analyses
of observational studies concluded that there were no associations
between SSRI use during early (or anytime during) pregnancy and
neonatal outcomes that were supported by convincing evidence.
Only highly suggestive evidence supported an association between
SSRI use in the first trimester and the risk for cardiovascular malformations;
however, the studies included in the meta-analyses did
not account for maternal diagnosis or severity of illness. The results
of these studies suggest that any increase in the absolute risk of
cardiac malformations with SSRI use during early pregnancy is
small.

B – Incorrect. Meta-analysis and a recent large, population-based,
cohort study indicate that there is no significant association
between SSRI use in early pregnancy and risk of persistent pulmonary
hypertension in offspring. However, there is a positive
association between SSRI use in late pregnancy and risk of persistent
pulmonary hypertension in offspring; clinically the absolute
risk appears to be low.

C – Incorrect. After accounting for confounding factors (e.g., maternal
severe psychiatric problems), first trimester exposure to antidepressants,
including SSRIs (82%), compared with no exposure, was
not associated with an increased risk for autism spectrum disorder,
in a large retrospective cohort study. A recent meta-analysis of 14
studies that included maternal psychiatric disorders as covariates
also concluded that there is no significant association between maternal
SSRI use during any trimester of pregnancy and risk for
autism spectrum disorder.

D – Incorrect.

E – Correct. Large cohort and case-controlled studies, as well as
meta-analyses indicate there is no meaningful association between
SSRI use during early pregnancy and risk for cardiovascular malformation,
persistent pulmonary hypertension, or autism spectrum
disorder in offspring.

Question 20

QUESTION TWENTY
Sasha is a 58-year-old patient with a history of depression who has
been prescribed agomelatine. At present, she is relatively free of
depressive symptoms, likely due in part to binding of agomelatine
to what receptors in the suprachiasmatic nucleus?

A. Melatonin receptors

B. Serotonin 2C receptors

C. Melatonin and serotonin 2C receptors

Answer 20

A and B – Partially correct.

C – Correct. Agomelatine is both a melatonin M1 and M2 receptor
agonist and a serotonin 5HT2C receptor antagonist. This unique
receptor profile gives agomelatine the ability to address impairments
in neurotransmission as well as circadian rhythm dysfunction.
First, agomelatine can modulate circadian rhythms through its agonist
actions at melatonin receptors. Melatonin is normally released
from the pineal gland in response to environmental cues. It then
acts on the suprachiasmatic nucleus, the location of the master
clock, to reset circadian rhythms. Thus, as an agonist at melatonin
receptors, agomelatine likewise regulates the molecular clock and
can resynchronize circadian rhythms that are disturbed in depression.
Second, agomelatine affects neurotransmission by blocking
5HT2C receptors. Normally, serotonin excites GABA interneurons
by stimulating 5HT2C receptors, which increases the release
of the inhibitory neurotransmitter GABA. GABA can then bind to
GABA-A receptors on noradrenergic and dopaminergic neurons.
Since GABA is inhibitory, it will prevent these neurons from
releasing norepinephrine and dopamine in the prefrontal cortex.
As a 5HT2C receptor antagonist, agomelatine blocks serotonin
from binding to GABA interneurons. This leads to disinhibition of
monoaminergic neurons and increased norepinephrine and dopamine
in the prefrontal cortex, which could potentially improve
mood and cognition.

Question 21

QUESTION TWENTY-ONE
A patient presents to a new clinician with a major depressive episode.
In addition to taking the patient’s history, the two most useful
factors for determining if a current depressive episode is indicative
of unipolar or bipolar depression are:

A. Family history and input from someone close to the patient

B. Input from someone close to the patient and specific symptoms
of the current episode

C. Specific symptoms of the current episode and patient insight

D. Patient insight and family history

Answer 21

A – Correct. Family history of bipolar disorders is arguably the most
robust and reliable risk factor for bipolar disorder. Although most
patients with bipolar disorder do not have a family history of bipolar
disorder, individuals with a first-degree relative with bipolar
disorder are at an 8–10 times greater risk of developing bipolar
disorder compared to the general population. Obtaining additional
information from a close outside informant, such as a parent or
spouse, is also quite useful, as patients tend to under-report their
hypomanic symptoms. Under-reporting may be due to patients
not recalling important details of their history with enough accuracy
or not viewing (hypo)manic symptoms as being problematic.

B – Partially correct.

C – Incorrect. Other than a history of a prior (hypo)manic episode,
patients with unipolar depressive episodes are diagnosed using the
same symptom criteria as patients with bipolar depressive episodes;
thus, specific symptoms during the current episode may not help
differentiate between unipolar depression and bipolar disorder.
An exception would be a major depressive episode with mixed
features, which may indicate a bipolar disorder. Patient insight
may not be a reliable factor for differentiating between unipolar
or bipolar depression because patients may not recall important
details of their history with enough accuracy or may not view
previous (hypo)manic symptoms as being problematic.

D – Partially correct.

Question 22

QUESTION TWENTY-TWO
April is a 14-year-old patient recently diagnosed with moderate to
severe major depressive disorder (MDD). She endorses passive suicidal
ideation, but no specific plan or intention for suicide attempt.
She denies any suicidal ideation or attempts prior to her current
depressive episode. In addition to beginning cognitive behavioral
therapy (CBT), which pharmacotherapy option would be best
suited for treating her depressive episode?

A. Imipramine

B. Bupropion

C. Fluoxetine

D. No pharmacotherapy should be initiated

Answer 22

A – Incorrect. Randomized clinical trials suggest tricyclic antidepressants
(TCAs), including imipramine, are not useful for treating
depression in children and only marginally effective in adolescents.
TCAs are not recommended as first-line pharmacotherapy for the
treatment of pediatric MDD.

B – Incorrect. To date, there are no randomized clinical trials examining
safety or efficacy of bupropion in pediatric MDD.

C – Correct. Fluoxetine, a selective serotonin reuptake inhibitor
(SSRI), has a good evidence base for efficacy in treating pediatric
MDD and is one of only two antidepressants with US Food and
Drug Administration (FDA) approval for pediatric MDD. Escitalopram,
also an SSRI, is the second antidepressant approved for
treating pediatric MDD. There is no strong evidence to suggest
that any particular SSRI is more effective than any other for pediatric
MDD. However, both the National Institute for Health and
Care Excellence (NICE) and the American Academy of Child and
Adolescent Psychiatry (AACAP) recommend evidence-based psychotherapy,
such as CBT, and/or fluoxetine to treat moderate to
severe depression in adolescence.
D – Incorrect. Although there are several antidepressant clinical trials
reporting negative findings in pediatric MDD, specifically industry-
sponsored trials, these trials suffer from implementation challenges
(i.e., study design) and should be considered failed trials. By
contrast, trials funded by the National Institute of Mental Health,
which are characterized by methodological strengths and lower
placebo response rates, demonstrate good efficacy of SSRIs for
treating pediatric depression. Concerns regarding an increased risk
for suicide with SSRI use in pediatric MDD may not warrant
avoidance of pharmacotherapy. Adding fluoxetine to CBT appears
to eliminate fluoxetine-associated risk for suicidal events. Furthermore,
epidemiological data suggest that youth with depression
receiving antidepressants are at lower risk for death by suicide than
untreated youth.

Question 23

QUESTION TWENTY-THREE
The hypothesis that the therapeutic effects of antidepressants are
due to downstream changes in neuroplasticity is consistent with
the fact that clinical improvement with antidepressants is typically
delayed by several weeks. The downstream effects of monoamine
antidepressants include:

A. Decreased AMPA receptor expression, decreased NMDA
receptor expression, decreased glutamate

B. Increased AMPA receptor expression, decreased NMDA
receptor
expression, decreased glutamate

C. Decreased AMPA receptor expression, increased NMDA receptor
expression, decreased glutamate

D. Increased AMPA receptor expression, decreased NMDA
receptor
expression, increased glutamate

Answer 23

A – Incorrect. AMPA receptor expression is increased.

B – Correct. There is increasing evidence that the underlying mechanism
of antidepressant treatment may not be alterations in the
levels of monoamines themselves, but rather changes in the downstream
molecular events and neuroplasticity triggered by those
monoamines. Monoaminergic antidepressants likely exert their
therapeutic effects by influencing downstream signaling, such
as increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid, or AMPA, receptor expression, decreased N-methyl-d-aspartate,
or NMDA, receptor expression, and decreased glutamate,
suggesting agents with direct activity at these downstream targets
may lead to faster treatment response. Antidepressant treatments
may modify the AMPA:NMDA receptor ratio, resulting in downregulated
NMDA receptors, and increased AMPA receptors.

C – Incorrect. NMDA receptor expression is decreased.

D – Incorrect. Glutamate is decreased