Okay, guys outrageously how your question here -- it's extremely important for the board so buckle down with me and let's do this one.
A 28 year old woman is brought to the emergency department by her friends,
she is naked except for a blanket and speaking rapidly and incoherently.
Her friend say that she was found watering her garden naked and refuse to put on any clothes when they tried to make her do so.
Saying that she has accepted how beautiful she is inside and out.
She also has purchased a new car that she cannot afford.
They are concerned about her and they have never seen her behave this way before.
For the past week, she has not shown up to work and has been acting strangely.
She was observed to have a new approached to life that is out of sync with her previous personality.
She was extremely excited and has been calling them at odd hours of the night to tell them about her future plans.
The physician gives her an antipsychotic to calm her down.
Which of the following drug mechanism will help the long term management of these symptoms.
Answer choice A: Inhibit the reuptake of norepinephrine and serotonin from the presynaptic cleft.
Answer choice B: Inhibition of inositol monophosphatase and inositol polyphosphate 1-phosphatase.
Answer choice C: Increase the concentration of dopamine and norepinephrine at the synaptic cleft.
Answer choice D: Modulate the activity of gamma aminobutyric acid receptors, or
Answer choice E: Acts as an antagonist at the dopamine, serotonin and adrenergic receptors.
Now take a moment to come to the answer by yourself before we go through them together.
Okay, like I was saying guys, this is an extremely important question
and you will see some variant of this question on your exam, it's that common.
Now let's go the question characteristics.
Now this is a psychiatry question.
We have a 28 year old woman coming in, behaving very abnormally, being given antipsychotics.
So this is psychiatry.
Now, this is a three step question, the modern world of USMLE has full of three step questions.
We have to first determine the diagnosis of what this patient has and then figure out the long term pharmacological treatment
for these conditions and then the mechanism of action of these treatments.
And of course the stem is required because we have to pull the diagnosis from the complex description of the patient’s story.
Now, first let's determine the diagnosis, now we have a young female patient presenting and she's brought in by her friends.
The chief complaint is abnormal inappropriate behavior and her reported symptoms are inappropriate nudity,
extensive talkativeness, inflated self-esteem and increase goal-directed activity.
Now, the symptoms are severe enough to cause marked impairment because she has stopped going to work.
And there was no report of drug or substance consumption, so we can't say that its substance induced.
Now the clinical presentation here is consistent with what's called a manic episode
and this is different from a hypomanic episode because a hypomanic episode is not severe enough to cause impairment
and in this case she's not going to work so we recall this manic.
Now, the diagnosis of a manic episode is consistent in part of -- bipolar disorder type 1.
So the diagnosis here is bipolar disorder type 1.
Now, there is bipolar disorder type 2 which is the less severe form because it only includes
hypomanic episodes and not manic episodes.
So now that we know the diagnosis is bipolar disorder type 1.
We have to determine the long term pharmacological treatment for this condition.
And to do so you need to give the patient what's called a mood stabilizer and the treatment of choice for bipolar disorder is lithium.
Now, lithium is the long-term management choice and his psychotics or what you can give in acute episodes, that's a distinction.
If you look at the question they said, what is the helpful long term management strategy, not acute, so that's why we're picking lithium.
Next, is the third step of coming to our solution, we have to know the mechanics of action of lithium.
Now, the mechanism of action is the inhibition of inositol monophosphatase and inositol polyphosphate 1-phosphatase.
So the correct answer is answer choice B.
Now, let's go through the other answer choices and see why they're wrong.
Now, answer choice A is how tricyclic anti-depressants work.
Answer choice C is how the atypical anti-depressant Bupropion works
and answer choice D refers to how benzodiazepine work and answer choice E refers to anti-psychotics or what are also called neuroleptics.
So again the answer here is answer choice B. But let's go through these and a little bit more detail
because this is an outrageously important question and all the answer choices really have a lot to learn
from them so let's go through them more carefully.
Now, like we said, this patient is showing up with symptoms of mania and likely a suffering from bipolar disorder type 1.
And the best way to treat these patients in a long term is with the mood stabilizer and our first line treatment of choice is lithium.
Now, there are several potential mechanism of action associated with lithium, it's not just one.
Now classically what you need to know for boards is that it inhibits inositol monophosphatase
and inositol polyphosephate 1-phosphatase.
But it also blocks the effects of various hormones and secondary messengers and inhibits receptor upregulation
Now, bipolar type 1 is a mood disorder and it's recognized by the symptoms of having mania
and depression and the diagnosis of type 1 again requires a frank manic episode.
But of course this differs from bipolar disorder type 2 in which you have hypomania and depressive features.
Now, during the true manic episode, the patient can have feelings of grandiosity, what's called flight of ideas,
increase optimism, insomnia and also participation in practical schemes.
They appear more excitable and aggressive.
They may also have symptoms of psychosis.
Now patients when they have what's called hypomania -
it's just say less pronounce form of these and don't interfere with their daily lives.
Now in addition to this mania, you have to have major depression which is also one of the features of bipolar disorder
and the disturbances for depression, you need to have five at least of the following symptoms
and we're going to reference our good mnemonic SIGECAPS.
So, S is for sleep, I is for interest, G is for guild, E is for energy, C is for concentration, A is for appetite,
P is for psychomotor, retardation or agitation and S is for suicidality.
Now, these symptoms of at least five of the SIGECAPS have to be present for at least over two weeks to call it major depressive disorder.
Now lithium is the first line treatment for bipolar disorder, types 1 and type 2.
And it’s been used to treat both acute and over the long term but the real question and real option here is long term management.
You wanna use anti-psychotics for the short term treatment choice.
Now the mechanism of action like we said is not completely understood but our understanding is,
that it blocks the effects as we have mentioned of hormones and secondary messengers and inhibits receptor upregulation
Now if you look at our image here, what we have the proposed mechanism of action of lithium.
We see that it also inhibits the enzyme, inositol monophasphatase and inositol polyphosphate 1-phosphatase.
And this as you see in the diagram, causes a deficiency of free inositol
and ultimately a depletion of these secondary messenger PIP2 and also IP3 and DAG.
Now very important to understand, lithium has a low therapeutic index and has multiple side effects
including hypothyroidism, nephrogenic diabetes insipidus, renal failure, edema, heart block
and it also access to teratogen when taken by pregnant patients.
Now, medication levels because it has a low therapeutic index and creatinine
because of the renal excreted must be carefully monitored
because some patients could beyond diuretics or take thyroid medications which can modify the dose.
Now, valproic acid and carbamazepine are also useful in rapid cycling bipolar disorder.
Now, anti-psychotics have been used in acute manic episodes but we can also use outside of medication psychotherapy
such as cognitive behavioral therapy and psychodynamic therapy has been also been shown to show us some benefit
and patients and that's always going to be on the boards.
They don’t want you to think just meds, they want you to think of what they call,
cognitive behavioral therapy, the biggest buzz word for psyche questions.
As almost never wrong.
Now, anti-depressants though are not, not, not, did I said not you better right it down,
not used in these cases because if you give an anti-depressant to someone who is manic or hypomanic.
You can actually precipitate this mania or hypomania.
So we do not, did I mention not -- you bet I did, write this down.
You don't give anti-depressants to your patient with bipolar disorder even though they have depression
because that can induce or precipitate mania or hypomania, that's a classic board question
because if you imagine, patient comes in and they're sad, they give anti-depressant
and they had bipolar and you induced the mania spell, that's horrible.
Now, of course hospitalization maybe necessary sometimes for a patients with bipolar disorder if they're becoming violent or suicidal.
Now, let's go through some of the other answer choices. Now, answer choice A, tricyclic antidepressants.
Now these work by inhibiting the uptake of both serotonin and norepinephrine at the presynaptic cleft.
In addition, TCA is remember, block histaminic, alpha adrenergic and muscarinic receptors and that's why you got the side effect profile of TCAs.
Now TCA therapy is used for unresponsive depression and they are also used for treating neuropathy
such as diabetic neuropathy and also migraine.
Now TCA have a strong anticholinergic side effect and should be prescribed very carefully in adults,
excuse me in the elderly because you can induced delirium.
Now, other side effects include blurred vision, urinary tension, constipation, nausea and drowsiness
as common side effects including convulsions, arrhythmia and even coma, a serious side effects.
Now there's another cause of medications called SNRIs and venlafaxine and duloxetine
are what are called serotonin norepinephrine reuptake inhibitors.
And these inhibit the uptake of both norepinephrine and serotonin.
Now the primary indications for using SNRIs are in major depressive disorder, phobias,
general anxiety disorder, neuropathic pain and obsessive compulsive disorders.
Now SNRIs are pretty well tolerated but they had been associated
with something called anti-depressant discontinuation syndrome
and that has flu like syndromes and sleep disturbances.
Now, looking at answer choice C, here we have Bupropion a unique medication
which induces the release of norepinephrine and dopamine for the presynaptic cleft.
It also inhibits though the reuptake of these neurotransmitters and it's been used for the treatment of depression
in addition to giving a patient an SSRI or SNRI and also very important has a separate mechanics for this drug use.
It decreases cravings and withdraw symptoms for patients who are trying to quit smoking.
So if you have a patient who wants to quit smoking, you can also give them Bupropion.
Now it's not useful as a first line therapy for treating atypical depression though.
Now, side effects of Bupropion include dry mouth, sweating, nervousness and tremors and at high doses, they can even cause seizures.
Now answer choice D, here we have the action of benzodiazepine which are class of drugs that work on the gamma receptor.
Now, these are used in the management of general anxiety and seizures
but they've also been used as hypnotic drugs and muscle relaxant.
Now, adverse effects here of benzodiazepine includes, drowsiness, hypotension, decreases alertness,
sexual dysfunction and a lack of coordination
and I remember these side effects by thinking that alcohol and benzodiazepines work on the same receptor.
So you get a lot of similar symptoms.
Now, answer choice E, here you have antipsychotics especially the atypical antipsychotics
which act as an antagonist at the serotonin, dopamine, and adrenergic receptors.
Now, let's review some high-yield facts for lithium.
Now, lithium is a chemical element but we use the compound form as a psychiatric medication for stabilization of mood
and we use it for major depressive disorder and first line for bipolar disorder and the exact mechanism of lithium is clearly unknown
but there is a current hypotheses and that is, it works by inhibition of inositol monophosphate
as we can we see again in our diagram, below that we referred to before.
Now, we know that inositol disruptions have been associated mood disorders
and that's where these hypotheses partly comes from and we know that depletion of inositol is available for PIP2 formation.
Now there are multiple side effects for taking lithium. This includes increase urination, shaking hand or tremor, increase thirst,
hypothyroid and even lithium toxicity can lead to coma and death in severe cases
and that's because lithium has a very narrow therapeutic margin or index
and of course ongoing treatment monitoring is required to make sure that lithium is one working and the blood level is therapeutic.