Okay, guys, we have a great case here; really pay attention -- let’s go into it.
A 29-year-old woman visits her physician with low mood and tearfulness on most days.
She goes on to tell her physician that over the past one month she has been struggling to cope with her life
and feels that everything that is going wrong in her life is her fault.
In the last three weeks she cannot recall a day when she felt interested to go out and participate in her daily activities.
She doesn’t seem to have much energy and also says that she has fatigue all day.
She has lost her appetite and feels that she is losing weight.
She also says that there are nights when she cries herself to sleep as the burden of the whole day is too overwhelming for her.
She also reports experiencing frequent and often unbearable migraine headaches.
Before starting her on any medication the physician specifically rules out any history of cardiac conditions.
The drug he wishes to prescribe is known to be cardiotoxic and may result in ECG changes.
Which of the following is the most likely mechanism of action of this drug?
Answer choice A: Blocks reuptake of serotonin, increasing its concentration in the presynaptic cleft;
Answer choice B: Non-selectively inhibits monoamine oxidase A and B;
Answer choice C: Stimulates release of norepinephrine and dopamine in the presynaptic cleft;
Answer choice D: Inhibits reuptake of serotonin and norepinephrine at the presynaptic cleft; or -
Answer choice E: Acts as an antagonist at dopamine and serotonin receptors.
Now take a moment to come to the answer by yourself before we go through it together.
Okay, guys, this is a great question and I have to say this is another beautiful question by Lecturio,
in which this is so like the USMLE, I feel like you’re gonna see this or an extremely similar question to it on your exam day.
Now, let’s go through the question characteristics.
Now here we have a psychiatry question.
A patient’s coming in with mood problems, lost of interest in activities, etc. -
this is psychiatry. Now this is a three step question, again, what we’re seeing on USMLE all the time.
The first thing you have to do on a three step is get the diagnosis,
then you have to think of the pharmacological treatment that we want to give,
and then we have to know the mechanism of action of it.
Now, of course the stem is required because there’s lots of detailed information in the stem
especially in psychiatry question to come to the correct answer so let’s walk through it.
The first thing to do is to determine the diagnosis.
Now, we have a young female patient who is presenting with a chief complaint of recent onset low mood and tearfulness.
Now for her reported symptoms -- she has feelings of sadness and hopelessness,
loss of interest and pleasure, feelings of guilt, decreased appetite, constant fatigue
and loss of energy, and she also has migraines.
Now the reported duration of her symptoms are three to four weeks, they occur all day and they seem to occur every day.
Now the differential diagnosis here is several.
The first one is mood disturbance due to underlying medical condition.
Now say if a patient has multiple sclerosis, stroke, or hypothyroidism -- these are conditions
that can actually lead someone to have a mood disorder due to the underlying medical condition as in the name.
Also on our differential is major depressive disorder which is a diagnosis that requires 5 out of the 9 diagnostic criteria
and it’s clinically significant distress that the patient has with no underlying medical condition
or substance use to explain the symptoms.
Another diagnosis on our differential is adjustment disorder with depressed mood and of course also normal sadness.
Now the clinical presentation here, there’s no evidence of an underlying mood disorder or a medical condition.
There’s no adjustment that we’re taking into account and this obviously sounds much more severe than normal sadness,
so really here the patient’s condition is consistent with the diagnosis of major depressive disorder,
but that catch is that she also has migraines so there are actually two diagnosis here -
welcome to modern day USMLE, you thought it was one but we got with two.
So correct major depressive disorder and migraine disorder and you’ll see momentarily why that’s important.
So because the patient has major depressive disorder, there are many different ways to treat major depressive disorder.
Of course, you can use medications, you can use psychotherapy, you can also do electroshock therapy in severe cases.
Now, with respect to pharmacological treatments for major depressive disorder
we have these selective serotonin reuptake inhibitors -
these are first line agents given the limited side effect profile.
We have tricyclic antidepressants such as amitriptyline or imipramine.
These are generally second line agents because they have more side effects than the SSRIs,
and as our next category we have what are called the atypical antidepressant such as mirtazapine, trazodone,
and these are third line agents because they have even more side effects.
Now, you could pick any of those three to purely treat major depressive disorder,
but here’s the kicker -- the patients has major depressive disorder and has migraine disorder.
Now you have to think what medication is my double agent?
What can treat both major depressive disorder and migraine disorder?
And the answer is tricyclic antidepressant. So the recommended treatment we want to give is a TCA.
Now, we have to go through and think, okay, what's the mechanism of action of TCAs?
Well, we diagnose major depressive disorder with migraines so looking at our answer choices,
if we don’t know right away how this works, we can eliminate the answers,
that’s what you’re gonna do in USMLE. You're not always gonna know the answer, to be frank,
you may commonly not know the answer -- elimination is the name of the game.
So let’s look at our answer choices.
Well, we can get rid of answer choice E because this is really an antipsychotic medication and we’re dealing with depression.
Now looking at answer choice A, this can be excluded because it refers to SSRI’s
and it doesn’t help with migraines. Answer choice B can also be eliminated because that’s a monoamine oxidase inhibitor,
that’s not going to help us, that’s a type of atypical antidepressant.
Now, the mechanism of action of tricyclic antidepressants -- these inhibit uptake of serotonin
and norepinephrine at the presynaptic cleft.
Now, tricyclic antidepressants, very important to know, have a risk of cardiotoxicity.
In addition to serotonin and the norepinephrine receptors, here’s why TCAs also act
on what’s called L-type calcium channels which are found in the heart.
Now, if we look at another answer choice, Answer choice C is also there
which refers to the mechanism of action of a specific medication called bupropion,
one of the atypical antidepressants which, again, we could use for depression but not for migraine.
So the correct answer choice here is Answer choice D, inhibition of uptake of serotonin and norepinephrine
at the presynaptic cleft which is the mechanism of action of tricyclic antidepressants.
Now, that may have sounded like a very difficult question but it’s important that you can think this way,
because really, now that you’re kind of familiar with this two-step thinking or let me rephrase that, three-step thinking
but two diagnosis management with one medication, now you’re kind of aware of it,
you’ll think about it in other questions.
If you see it on exam day you’ll think, oh, yeah, they told me about that at Lecturio, I remember.
So let’s go through the answers in a little bit more detail to reinforce these points.
Answer choice D is the correct answer as we have noted.
The physician here really wants to give a tricyclic antidepressant
because not only does it treat major depressive disorder it also treats migraine disorder.
But, tricyclic antidepressants can cause QT prolongation with toxic doses as one of the adverse effects linked to TCAs.
Now, if you look at the image here which shows the mechanism of action of tricyclic antidepressants,
you can see they work by inhibiting the uptake of both serotonin and norepinephrine at the presynaptic cleft.
Now this helps improve the symptoms of major depressive disorder
and what’s interesting is that TCAs are also used to treat phobias, generalized anxiety disorder,
neuropathic pain and even obsessive-compulsive disorder.
Now, there are different medications within the category of tricyclic antidepressant.
You have a medication called imipramine. Now, this is routinely used to treat enuresis.
We have another medication, this one is very important to know called amitriptyline
and this is actually used as a prophylactic agent for migraine disorder.
Now, TCAs also block the uptake of histaminic, adrenergic, and also muscarinic receptors
and this unfortunately is where we hit our bad side effect profile that’s associated with TCAs.
Now when you take TCAs what ends up happening is that they elevate the mood,
they improve participation in physical activity and even increase mental awareness.
Now it also has been seen to reduce the preoccupation that is commonly observed in depressed patients.
Now patients are started on small doses as TCAs have a narrow therapeutic index,
then the dose is adjusted at symptoms once they are resolved.
Now there are some side effects here you should be aware of such as blurred vision,
urinary retention, constipation, nausea, and drowsiness are common reported side effects.
More serious side effects but less common are tachycardia, an arrhythmia, and even coma.
Now what’s very important and high yield is that you understand that TCAs
should be used in caution in patients with bipolar disorder.
Also MAO inhibitors, ethanol, and other CNS depressants can interact with TCAs.
Now, let’s look at some of our other answer choices.
Answer choice A -- now selective serotonin reuptake inhibitors only block the reuptake of serotonin at the presynaptic cleft
and this is actually one of the most effective and least toxic drugs in the category of antidepressants
and this actually makes them the drug of choice in the treatment of major depressive disorder.
They don’t block the histaminergic, the adrenergic, or the muscarinic receptors that are seen with TCAs
and that’s why they have a more favorable side effect profile.
Now, very important to know, it takes up to two weeks for these SSRI medications
to improve mood and physical activity, now that’s another board question you’ll see.
They’ll tell you, a patient comes in, they were depressed, a physician put them on an SSRI,
they come back a week later not happy because nothing’s changed.
Well, of course not. Give it two weeks, people, that’s its other hidden board question there.
Now, for SSRIs, you can have anxiety, sleep disturbances, sexual dysfunction and weight gain though as common side effects.
Now, looking at Answer choice B, we have the monoamine oxidase inhibitors.
Now these are nonselective and irreversible blockade of the action of monoamine oxidase.
Now phenelzine, tranylcypromine, and mocopamine are common drugs in this class of MAOI inhibitors.
Now they’re not useful for the first line treatment of major depressive disorder
but they’ve been actually shown to be beneficial in the treatment of atypical depression
and persistent depressive disorder, so really here, we're talking third line agents.
There are also know very high yield to metabolize tyramine and tyramine containing products
such as cheese and red wine which if people take when on an MAOI inhibitor,
they can have a hypertensive crisis and after ingestion of these foods.
Common side effects though for our MAOI inhibitors are headache, nausea, arrhythmia and seizures.
Now looking at Option C, bupropion, a very unique medication
actually induces the release of norepinephrine and dopamine from the presynaptic cleft.
It also inhibits the reuptake of these neurotransmitters
and it’s been used for the treatment of depression in addition to either SSRIs or SSRIs.
Now, it’s been known to decrease cravings and decrease withdrawal symptoms in patients who are trying to quit smoking,
so you can use bupropion for depression but also for smoking cessation.
Now, common side effects are going to be a dry mouth, sweating, nervousness
and tremors as common side effects and in high doses it can actually precipitate seizures.
Now looking at answer choice E, antipsychotics
and you know, well, actually, primarily act by antagonizing the actions at the serotonin and dopamine receptors in the brain.
Now this would be counter-productive in patients with depression
as increase stimulation is necessary to bring about improvement in their depressive symptoms.
Now, second generation antipsychotics block both serotonin and dopamine actions
and this helps to improve cognitive symptoms, impaired attention
and the blurred effect noticed with schizophrenia and other psychotic disorders.
Now let’s review some high-yield facts.
Major depressive disorder, now this is a mood disorder.
An episode of depressed mood and or loss of interest in pleasures are seen and these episodes last at least two weeks each.
Individual episodes sufficient for diagnosis but they can actually generally reoccur in patients.
Now, you have to assume here that there’s a combination of environmental factors
and also genetic predisposition as to how patients develop major depressive disorder.
In the DSM-5 there’s detailed diagnostic criteria.
There’s a higher prevalence in the age group of 15 to 29 years; there’s a higher prevalence in females
and the treatment really depends on the severity
but usually includes a combination of pharmacological treatment, psychotherapy.
You could even have electroshock therapy or luminotherapy.
Now let’s review some high-yields facts for tricyclic antidepressants
now this is a classic medication used to treat depression among other conditions
including migraine as we’ve learned in this question.
Now, this is grouped due to a shared chemical structure of having three rings of atoms
and this is, you know, if you have this structure, we’ll call you a TCA.
Now, this was discovered and developed in the 1950s, very old medication;
and the mechanism of action of depression, if you again look at our image here of the mechanism of action of tricyclic antidepressants,
we see that they have blocking of the serotonin transport or sort, blocking of the norepinephrine transport or net,
and then you’ll have higher levels of serotonin and norepi in the synaptic cleft and this is then increased neurotransmission.
And may well know side effects includes severe cardio and also neurotoxicities
because TCAs work on various receptors like we had mentioned histamine receptors,
muscarinic receptors to give you the side effect profile and even L-type calcium channels to give you cardiotoxicity.
And of course, TCAs have been largely superseded by newer and safer drugs mainly the SSRIs.