E10 - Potentially Potent Side Effects of the SSRIs

In this episode of The Y in Psychiatry, Dr. Amayo and Dr. Handratta explore the potentially potent side effects of SSRIs (selective serotonin reuptake inhibitors). They discuss the risks of switching to mania, the role of mood stabilizers, the increased risk of suicidality in younger patients, and the common side effects of nausea and vomiting. Tune in as they delve into the intricacies of psychiatric medication and its impact on the human experience.

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Transcript

Thanh: 0:01

Welcome to the Y in Psychiatry!

Dr. Amayo: 0:03

Hi, this is Dr. Amayo C/L fellow.

Thanh: 0:06

Where we delve into the intricate nuances of psychiatric topics.

Dr. Handratta: 0:09

My name is Dr. Handratta attending psychiatrist. I did my residency from University of Connecticut and then I did my fellowship from Georgetown University in consultation and liaison.

Thanh: 0:19

Each episode features interview style discussions that explore the intersection of the mind medicine and the human experience. Together we'll uncover the hidden why and the groundbreaking discovery shaping the psychiatric landscape. So grab a seat, warm beverage, tune in, and let's embark on this journey to unlock the mysteries of the human psyche. Only on The Y in Psychiatry.

Dr. Amayo: 0:46

Welcome to the Y in psychiatry. Today we will be talking about why we get the side effects from SSRIs. As usual, it's your host, Dr. Amayo, and I am here with Dr. Handratta

Dr. Handratta: 1:01

Hello guys. How are you guys doing?

Dr. Amayo: 1:03

I've found myself explaining to patients the side effects and one of the big things that I tell them is, they're gonna have some GI symptoms, some nausea. Then another thing I, I ask them, I tell them is, the risk of switching to mania. So that's a big warning. And another big black box warning is the increase in suicidality. So, Sir, I was wondering if we can start with why does SSRI increases your chance of mania? how does that work?

Dr. Handratta: 1:28

How does antidepressants actually switch a person into manic episode? So whenever we prescribe antidepressants, we always want to make sure, or whenever we evaluate any psychiatric patient we basically need to make sure that we rule out bipolar disorder. The best way to rule out bipolar disorder is by using scales like mood disorder questionnaire. Or rapid mood screening, which will screen a patient. If they are positive, then that means that there's a high probability that the patient might have bipolar disorder. Then you have to actually go for a detailed history taking. So you guys know exactly where I'm heading towards. So if a patient has bipolar disorder, then we stay away from conventional antidepressants because we know that they can switch a patient into mania

Dr. Amayo: 2:07

I have a question. Does SSRI cause someone to have manic episode or cause them to have bipolar, or does it just increases their, so are they already like bipolar and SSRI just increases their chances of them switching?

Dr. Handratta: 2:21

So SSRIs without a mood stabilizer in a patient who has bipolar disorder, increases the risk or switch into a manic or a hypomanic episode

Dr. Amayo: 2:31

Yes. And if the patient never has bipolar disorder or doesn't have a risk of bipolar disorder, would an SSRI increase that risk? I guess that was, that's my question.

Dr. Handratta: 2:40

No, it will not.

Dr. Amayo: 2:40

So if the baseline are not likely to have bipolar disorder, the SSRI would not.

Dr. Handratta: 2:45

No. Okay. It will not increase the patient doesn't have bipolar disorder at all and doesn't have any family history of bipolar disorder. Okay. Now, You have to be a little careful when you introduce an SSRI because patients can have side effects like increased agitation Irritability and restlessness for the first one to two weeks. That is, especially because of serotonin hypersensitivity it does not mean that the patient is switching But I think the screening will be extremely helpful because if you look at the bipolar data, about 70% of the patients are actually not diagnosed when they come during the initial visit 35% of the patients with bipolar will not be diagnosed for 10 years And they would've gone through almost three and a half diagnosis or through four different physicians before they get diagnosed with bipolar. So you need to be careful. And in the primary care clinic, out of every five patients that they diagnosed with the depression there'll be one patient who will have bipolar disorder. So always a good idea to screen the patient. Now what are the risks? We see in our practice that a lot of providers will use conventional antidepressants with mood stabilizer. So what's the data available When you use a mood stabilizer and use SSRI with a mood stabilizer, the risk of switch is less than placebo.

Dr. Amayo: 3:55

And this is for patients that already have confirmed bipolar disorder?

Dr. Handratta: 3:58

Exactly. So and the, the, basically the reason when you use SSRI for a long period of time, it decreases the sensitivity of the beta adrenergic receptors. So under stressful situation, when the norepinephrine level goes up, you do not have the beta adrenergic receptors to attach to. So that is one of the theory behind why SSRIs is when used with mood stabilizer risk of switching to mania is equivalent to placebo.

Dr. Amayo: 4:19

That's the SSRIs, yes. Yes. But it doesn't do that when it's given alone.

Dr. Handratta: 4:23

So when it's given alone, you don't have a mood stabilizer on board. If you don't have a mood stabilizer on board, then the risk actually increases. But I would advise with a mood stabilizer try to use an FDA recommended medication for bipolar depression rather than conventional antidepressant. Unless they've failed everything. Now, what's the data on mood stabilizers with Bupropion? The data actually shows that when you use mood stabilizer with bupropion for bipolar depression, the risk of switch is less than placebo. One of the hypothesis is that Bupropion is not a very potent norepinephrine and dopamine reuptake inhibitor. Plus, it does not act on the postsynaptic receptors like other antidepressants. The risk actually with a mood stabilizer plus an SNRI like or with the TCA tricyclic antidepressant, the risk of switching is more than placebo. So I would advise, don't even touch SNRI or TCA with a mood stabilizing bipolar patient.

Dr. Amayo: 5:10

Is there a reason? Do we have any theories as to why?

Dr. Handratta: 5:13

So there are, so again, everything is in hypothesis. We do not know for sure. There's a lot of research data floating around. But one of the most possible explanation is that when you use tricyclic antidepressant is that it is the anticholinergic effect that causes the switch to mania. That ability to block the M2 and M4 muscarinic receptor. As well as a N-acetylcholine receptor. That switches them into a manic episode. With an SNRI, when you use SNRI at a higher dose, they also increase the dopamine. Oh, For example, venlafaxine. When you use 225 and above, it actually will hit the dopamine, and with des venlafaxine, when you go actually close to a hundred or more, it will increase the dopamine.

Dr. Amayo: 5:48

So sir, I guess the next question would be, So just without the mood stabilizer. Why does antidepressants increases the risk of switching to mania?

Dr. Handratta: 5:59

So now we heard about like why we don't use conventional antidepressants with the mood stabilizer. So the research data that you actually see says that when you use conventional antidepressant, there are different reasons why your patient switches into mania. One reason actually is that when you use antidepressant over a long period of time, it causes decreased sensitivity of the pre-synaptic dopamine D2 receptors. And we know that pre-synaptic D2 receptors are auto receptors, okay? So when you decrease the sensitivity of the auto receptor, you increase the release of dopamine from the presynaptic. The second is it also increases the sensitivity of the postsynaptic dopamine receptor, especially the D2 receptor. So it's acting in both. So it's first is increasing the D two and second is making the postsynaptic receptor more sensitive to the D two. Which increases your risk of a manic episode. The next theory is as we talked about, the anticholinergic effects of tricyclic antidepressants.

Dr. Amayo: 6:53

And so sir to, to summarize so why there's an increased risk of switching dominion in just regular normal, everyday anti-depressant is there's an reduced sensitivity in the auto receptors. And that leads to an increase in dopamine from the presynaptic neuro, and there's double whammy with an increased sensitivity in the postsynaptic neuron to D two receptors. And so that we increase our chances of Of switching to mania and also, again, possibly the anticholinergic effect, which we see more with the TCAs and possibly paroxetine which has a anticholinergic effect. So I guess next question is the suicidality. Why, and especially again, it's been an increased risk in the younger population.

Dr. Handratta: 7:33

So this is a good question, right? So we always deal with this. So in patients 24 years or less, there's a black box warning on the use of antidepressants. One reason is that one of the hypothesis that people actually say is that, did we miss bipolar disorder? So the patient is too young to be diagnosed with bipolar disorder has a of bipolar disorder has had like short episodes of depression, multiple episodes of depression before the age of 25 years So all So all these are risk factors for bipolar, right? But the patient has never exhibited a manic or hypomanic symptom. If uou introduce an SSRI or an antidepressant, did you switch the patient into a mixed state? Because the risk of suicide is higher in patients with bipolar mixed state. Now, there is no solid data, which shows that this is the reason why there's an increased risk of suicide, right? There's a different hypothesis. So in 2004, I think, so the FDA actually put the black box warning they updated in 2007 saying that depression itself can actually increase the risk of suicide But I think like the good, the best practice is actually to educate the patient 24 years or younger about the risk of switching to mania. And also to educate the family members, because when patients become manic, they have no insight. So it's always a good idea to involve the family member. Talk to them about the risk so that if the patient misses it, at least the family members can pick it up.

Dr. Amayo: 8:49

That's a good point with it being that younger of age, maybe there's more of a bipolar components to it, and that would make sense as to why it's specific for that age group that, that we see that risk as opposed to older. But then I wonder if, because women tend to develop, manic disorder later in life or what are, if they're risk for suicidality, Is a little bit more extended than males. I don't know.

Dr. Handratta: 9:14

We don't know that exactly. Because another hypothesis is that the patient who is depressed and is suicidal to begin with, and as the depression gets better, there are more energy actually now to actually complete this. So there are different hypothesis, but none of these hypothesis has been proven.

Dr. Amayo: 9:26

Yeah, sir. And then lastly Why do nausea and vomiting? I think that's the most common side effects with our regular antidepressants. How about that?

Dr. Handratta: 9:36

So why do we develop nausea? So the, so there are different types of serotonin receptors right? So there's one group of serotonin receptor called five HT three receptors, five HT three, which is basically an ionotropic receptors It's not a G-protein couple receptor. So these five HT three receptors are located in your gut. As well as it's present in the blood-brain barrier. So when you stimulate them, it usually stimulates nausea, vomiting, and headaches. That's the same reason when you are actually using chemotherapeutic agent for cancer. What the chemotherapeutic agent does is that it usually stimulates the antichromaffin cells in the duodenum to produce a huge amount of serotonin Which serotonin. Which will stimulate the five HT three receptor causing nausea in patients receiving chemotherapy. Oh, and that's why you have five HT three antagonists like ondansetron So these are actually used for nausea because they block the five HT three receptors.

Dr. Amayo: 10:21

And because of their inotropic. Is that why they work so fast as opposed to the, the typical two to three weeks before we see the desired effects we want from antidepressants.

Dr. Handratta: 10:30

Exactly. Ionotropic receptors are faster acting because they are iron controlled receptors rather than G protein, which basically uses a second messenger system.

Dr. Amayo: 10:39

And then I always comfort my patients telling them that that, the nausea and vomiting will get better after five to six days. So do, does this ionotropic five HT three receptors get desensitized to it?

Dr. Handratta: 10:52

So the theory behind actually, when you use antidepressant for a long period of time They'll desensitize these five HT three receptors. That's when nausea and vomiting disappears. After about a week or two weeks? Sometimes, actually, if it's really bad, I sometimes actually add a five H three antagonist to the antidepressants so they can tolerate it better, and after two weeks I slowly take them off it. But just make sure that when you're giving an antiemetic agent always makes sure to educate the patient about dystonia Especially of the jaw, actually, patient can tell a dystonic reaction, so it's a good idea to actually educate them. But they do develop tolerance to it.

Dr. Amayo: 11:24

Dystonia. I wasn't tracking that. Let's talk about it on the next episode. Okay. Thank you guys and we'll see you next time.

Katrina: 11:35

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