Guest: Dr. Lex Denysenko

View the recording from our Migraine Clinician Masterclass, developed in partnership with IVPN Neuropsychiatry. In this webinar, we hear from Dr. Lex Denysenko, who discusses treatment approaches for migraine and psychiatric comorbidities, specifically anxiety and depression. Please note that this video is intended for healthcare providers.

TRANSCRIPT

Dr. Lex Denysenko: Well thank you so much for having me. I’m Dr. Denysenko. Yes, I’m a psychiatrist, and for the past six years, I’ve been the embedded psychiatrist within the Jefferson Headache Center, in Philadelphia, where we have both outpatient as well as an inpatient unit.

We do infusions of things like ketamine and lidocaine to help abort status migrainosus. I think there’s only about 700 experts in headache, in the United States, and only 2 of them are certified in headache medicine who are also psychiatrists. So if you know of anybody else on this that’s also a psychiatrist in headache medicine, I’d love to get together because I feel like I’m very lonely.

My disclosures are here. Several years ago I had some speaker honoraria from Teva, and I was an investigator on a study for fremanezumab for major depression in patients with migraine that’s in publication. 

I’m going to be talking about migraine primarily during this talk and psychiatric disease, but I can’t focus on all of psychiatric disease and its treatments. I’ll be focusing mostly on mood disorders and anxiety. I’ll be talking about how they’re comorbid, how the relationship between migraine and psychiatric disease is bidirectional with both affecting each other. 

We’ll go over the core symptoms of some of the psychiatric diseases, mostly major depression, and bipolar disorder, and anxiety. And how in a patient with migraine you might be approaching treatment differently or in what ways you might be approaching it similarly to how you would with someone without migraine.

Psychiatric comorbidities in people with migraine it’s very common. The number one is probably major depression, perhaps anxiety. Major depression, in the general population, is about 20% and that’s about two to four times higher in patients with migraine.

Anxieties are very common in patients with migraine as well, generalized anxiety disorder is extremely common. Panic disorder, anticipatory anxiety, they’re very high as well. While bipolar disorder remains rather rare, it is fascinating that bipolar disorder in patients with migraine is actually quite common.

When you look at everybody with bipolar disorder, a third of them have migraine. And if you have a family history of bipolar disorder such as a parent, you have a four-fold higher chance of having migraine yourself. We’re not quite sure why, maybe it has something to do with similar genetic patterns, maybe it has something to do with similar derangements in sodium or calcium channels. We don’t know quite yet.

If we focus on migraine, depression, and anxiety, we can see how these three diseases can really affect each other. Anxiety, for example, the higher your anxiety level is, your migraine frequency will also increase. Migraine is also associated with a decreased chance of your depression actually responding and remitting.

Depression untreated is an indicator of poor response to migraine medications. You combine stress on top of affecting all of these by increasing inflammation and making it even more difficult to follow treatment plans and stay motivated in care and you really have a difficulty. 

But even when we look at the core symptoms of migraine, anxiety, behavior, and depression are actually part of the cycle. If we take away the actual migraine attack and we look at the prodromal symptoms that could occur 24 to 48 hours before a migraine attack, we see that some patients do have a change in their mood. They become more drowsy or fatigued. Some might get euphoric, irritable, restless, and hyperactive.

Talkativeness can be a symptom that some patients report. Concentration difficulties and yawning, a loss of interest in food, or they might develop food cravings such as cravings for chocolate. And there might be other GI symptoms as well.

Many of these can occur 24 to 48 hours before an attack. They’re hard to predict that an attack is going to happen. After the attack, a patient might feel relieved, but they also might feel dysphoric. They might have lost energy. And soon after they recover during the interictal period between attacks, there will be anxiety. Headache is a common feature during interictal periods of migraine. And so when a headache develops, it’s a 5 out of 10, the patient’s not going to have anxiety.

Is this 5 out of 10 the beginning of a new migraine? Should I start taking my abortives? Should I cancel my plans today? And that anticipatory anxiety can be a major driver for increased anxiety, avoiding certain situations. And then by avoiding those situations, you might have more depressive thoughts that all you do is stay in bed and you have no social or financial impact on your family. 

The DSM-5 criteria for major depression is not much different than previous iterations. It asks for two weeks of either persistent depressed mood or anhedonia, which is a decreased interest in hobbies that you enjoy almost every day. And you need to have additional symptoms present. Appetite, sleep, you’re either pacing or you’re not moving much at all, low energy, feelings of worthlessness or burden on others, concentration difficulties, and of course suicidal thoughts.

Unfortunately, when you look at patients with migraine, so many of these symptoms can be characterized as things that occur in migraine, which makes it extremely difficult to determine whether or not someone has depression separate of migraine symptoms. Some people use the mnemonic SIGECAPS to better remember all the possible symptoms in migraine. I ask that the G in guilt, you’ll see why that might not be a good word to describe burden on other people.

When you’re interviewing someone with migraine – and other people who might not have migraine – asking if you’re depressed might not resonate well on a patient with migraine. And other questions, like I said before, with symptoms, they might find that to be pan positive because of their migraine. So I try to use a more open-ended and indirect approach.

I know it’s very difficult for you to be with migraine. But have you noticed that even when your migraines might be doing well, that you still have a poor mood, poor motivation, low energy, and a feeling of hopelessness? Rather than asking, do you feel guilty? Because if you do that, most patients will say, I’m not guilty of anything. You really do want to say, do you feel that you’re a burden on your family? Do you want them not to worry about how you’re actually feeling, so you don’t really tell them? 

And this goes for both migraine as well as depression. Both of these disorders have high stigma, and people might not understand what depression is. People might not understand what migraine really is. So this can be also a very good kind of approach to help really determine if they have good social support among their family. Do they need more education in the family about what their migraine actually is like, and what their depression might be? 

I think that migraine patients don’t like to be told that this is all in their head, and it’s a very Victorian concept that women with migraine are just bad mothers, or they just don’t know how to handle stress, or a man with migraine is either just working too hard or has some kind of effeminate qualities to them. So we really have to avoid those kinds of stigmas. 

It’s true that depression can make migraine worse, and migraine can make depression worse. But I often encounter people, even in my psychiatric profession, that they really wonder is all their migraine just a symptom of their depression? And so rather than saying that, I sometimes might ask, just imagine if we could magically remove your migraine disorder, what are your chances that you would actually feel better? 

And sometimes people say, oh absolutely, if it was gone, I wouldn’t have any depression, I never did before. Others might say, I don’t know, actually realistic, I think it would be better, but I still think there’s a 50-50 chance I might still have depressive and anxiety symptoms. While that’s not particularly diagnostic of anything, that might help you really feel more encouraged to consider an intervention for depression and anxiety. 

Suicidal thoughts are something that a patient with migraine might not want to answer. Because in my experience, I feel that a lot of patients, particularly in the first year where episodic migraine might transform to chronic, that they do feel life is not worth living. When they see all of their friends graduating college, getting married, having jobs, and they’re still at home, this can have a lot of suicidal thoughts.

I try to open it up by saying, look, sometimes some patients when their migraines are really bad, they feel like going to sleep and not waking up, or life is not worth even…or even maybe even taking their own life. I’m not sure if that’s the case with you, but has that ever happened for you? And when the headache gets better, do those thoughts go away? How fleeting are those thoughts? How do you make them go away? Do you talk to people about it? And that can really kind of open up to more universalize how these symptoms might be for them. 

Have you ever had a diagnosis of bipolar disorder? This is a case where I might ask this question flat-out. Bipolar disorder, as I’m going to talk about actually for a lot of this talk, is often underdiagnosed or misdiagnosed as unipolar depression. Bipolar affective disorder, I’m not going to go into the detailed criteria, but the DSM describes three, type 1, type 2, and other, as well as all kinds of subtypes. Type 1 bipolar affective disorder is the one that has mania that typically lasts for days. The criteria wants at least a week. Patients with bipolar type 1 are often hospitalized psychiatrically for their mania. It’s a very severe illness.

Type 2 I’ve always found fascinating. The diagnosis seems to be what it is not, as opposed to what it is. It’s not type 1. The manic symptoms are less than a week, or the symptoms are kind of mania, but they’re not as severe, and we’ll call them hypomania. But even if they’re hypomania, they might last longer than a week. Patients with bipolar disorder type 2 might have hypomanic episodes so short they don’t even get hospitalized for them. And that’s important. I’ll discuss in a little bit more how it pertains to migraine.

Rapid cycling is not a kind of bipolar. It’s actually a transitory period that a patient with bipolar might enter into or might get out of. It’s described as 4 episodes within a 12-month period. So that could be a combination of either manic episodes or depressive episodes. Most people with bipolar have about one or two episodes per year. So four would be a significant increase.

And while that’s a very serious cycle, it’s more common in bipolar 2 than bipolar type 1. And here’s the interesting part. People with bipolar and migraine are more likely to have rapid cycling. So we really have to take care in patients who might have this.

A big myth that I often have students feel that they’ve believed is that antidepressants flip you into mania. A flip is something that sounds very quick and obvious. It’s not quick and obvious. If antidepressants flipped you into mania, there’d be somebody out there proposing that we use antidepressants as a litmus test in patients where we have diagnostic questions if they’re bipolar or not. But it often does not happen that way. More often, it’s an indolent course, a subacute course that could take weeks to develop.

And it doesn’t turn into a frank mania. It oftentimes is irritable, angry. You’re picking fights with people. It might also cause rapid cycling to develop, or it could make rapid cycling worse. And if it’s something that takes that long, and then you ask the patient, have you started anything new, they might not consider the medicine that they just started 12 weeks ago as a new medicine.

So it really requires a lot more history gathering. Just because an antidepressant or any medicine, for that matter, makes a mood exacerbation occur, our current DSM criteria allows us to call that bipolar disorder, or it could allow us to call that medication-induced mania. It’s really up to the clinician to decide whether or not it’s indicative of a bipolarity or not.

Risk factors for antidepressant-induced mood exacerbation are abundant. But the most probable risk factors are tricyclic antidepressants and antidepressant monotherapy, meaning no mood stabilizer is being used, such as lithium, an atypical antipsychotic, lamotrigine, or valproic acid. And possible risk factors may be bipolar 1, rapid cycling, some suggest yes, some suggest no.

Substance use disorder there have been some studies said yes, others only showed it to be more prevalent in alcohol use disorder. But substance use disorders and alcohol use disorders have so many factors involved. There’s so much chaos in those disorders. It’s really hard to really determine how much is influencing bipolarity and antidepressant-induced mood exacerbation. And anxiety is also such a broad term. 

We can’t ask a patient with bipolar disorder if they’ve ever been manic, for many reasons. One, like this prospective study where they looked at thousands of patients over an average of 14 years, the amount of weeks that are spent in either a hypomanic or manic state are very, very small. And most people with bipolar disorder are either in a depressive state or a euthymic state. So asking someone to remember that time many years ago when this occurred, they might not have any recall.

And they might not have any insight. Bipolarity really suffers from insight. A patient could be manic and hospitalized, and you ask them a year later, they said that was just a misunderstanding. I was feeling great. The problem was somebody else called police to the door. So insight can be a real issue here.

So what do we do? Well, we still need to rule out bipolarity in patients with migraine before we start a medication that might actually cause their symptoms to get worse. And we love to use tricyclic antidepressants and serotonin reuptake inhibitors, norepinephrine and serotonin reuptake inhibitors in migraine because they might have preventive benefits. 

Some of this I mentioned already before, but patients who have bipolar and migraine are more likely to have an earlier onset of bipolar disorder, greater psychosocial impairment, that’s probably a given, higher rates of suicide, almost as much as you might think in cluster, and more severe and more frequent mood episodes.

Mania has a lot of symptoms and signs in it. Often it is described in the mnemonic DIG FAST. They might have distractibility, a decreased need for sleep. You have to make sure that it’s a decreased need for sleep because a lot of patients might have poor sleep because of pain or anxiety, but they’re still very tired. A patient with mania doesn’t feel tired. 

Grandiosity, racing thoughts and flight of ideas, those racing thoughts, they have lots of big ideas. It’s not that they have racing thoughts about anxiety things. Speech might be so pressured, you can’t even get a word in edgewise. And they might have more risk-taking behavior, sexual activity, excessive spending. And now in today’s day of age, social media presence increases. 

But DIG FAST is not a screen for bipolar disorder. My students will say, well, he doesn’t have bipolar, he was DIG FAST negative. That’s not a thing. What else can we do to try to determine bipolar? There is a Mood Disorders Questionnaire, which is validated for identifying patients with bipolar disorder, but it’s mostly helpful in bipolar type 1. It is harder to detect bipolar type 2 and has a positive predictive value of only 15%.

I do try to look at these risk factors for bipolar disorder to help us determine a family history of bipolarity in either children or parents is helpful or siblings. Depression with additional features. Depression is so severe that it has psychotic symptoms. A history of medication-induced mood exacerbation. And I try to have the patient try to expand their horizon that this is not just psychiatric medications. 

What about antibiotics? What about birth control pills? Did any of that kind of stuff make you suicidal? Steroids might be the one exception, since so many people with steroid-induced psychosis or steroid-induced agitation, I don’t think that by itself would be very helpful.

Postpartum psychosis, which is different than postpartum depression, because postpartum psychosis involves real paranoid fears that someone is going to harm the baby, or you have intrusive thoughts that you might self-want to harm the baby. That has also been shown to increase the chance that you might have bipolar disorder. And as I said before, potentially history of migraine is something we should also be looking at.

Dr. Hagop Akiskal, who recently passed away, was, I believe, from Stanford. He was a big proponent of the bipolar spectrum. Patients who don’t meet criteria for bipolar 1, not quite sure if they meet bipolar 2, but they have other signs and symptoms suggesting bipolarity in the way that they respond or don’t respond to antidepressants.

In his prospective work, he found other soft signs of bipolarity. So for a patient who comes to you that has had a lot of depression all their life, some of these questions might help push you over the edge to consider a bipolarity, such as a strong family history, many failed antidepressants. A history of a lot of anxiety disorders or personality disorders, impulse control disorders, three substances of use. The number three was very big for him. 

People in the family that held imminence in certain kinds of fields. For example, if a person who’s not just a lawyer but also started his own business and also does acetylene torch welding, that might be interesting. Someone who’s held multiple jobs at the same time or has had sexual relationships with multiple people, dating people at the same time, a predilection or favoritism for bright colors, particularly red. 

In the United States where proficiency in more than one language is very rare, he found proficiency in three languages to be significant. So none of this means anything that you’re bipolar, but he hopes that this kind of history gathering might make you want to ask more questions and not be so quick to turning to an antidepressant.

If you do suspect bipolar disorder and you are not a psychiatrist, refer to psychiatry for additional diagnostic evaluation. Consider a mood stabilizer first. We use valproate for migraine, although it’s difficult to tolerate for a lot of patients. Lurasidone and quetiapine have the highest evidence and best tolerability in patients with bipolar depression, and they do not seem to cause migraine to get worse. 

Lithium does not appear to have any effect on migraine – it might help with cluster – but lithium is very helpful as an antimanic agent and as a mood stabilizer. While lamotrigine has controversial evidence of whether or not it’s helpful in migraine, perhaps maybe there’s some emerging evidence it could help in people with vertiginous migraine, it is more helpful in reducing the episodes of bipolar depression.

I would avoid antidepressant monotherapy and probably avoid tricyclic antidepressants if I can help it. There’s also some suggestion that the SNRI, venlafaxine, might also be associated with more chances of mood exacerbation with antidepressant monotherapy in bipolar disorder. 

But if you have ruled out bipolar disorder, then you should definitely start an antidepressant if they have major depression. And this treatment will work better when taken together with psychotherapy. I’m not going to be able to have time to talk about psychotherapy here. But psychotherapy of any kind of modality – whether it’s CBT, traditional supportive psychotherapy, acceptance and commitment therapy, or dialectic behavioral therapy – having that help will make the medicine work better. 

So what antidepressant do you choose? These are kind of our four top classes. The serotonin reuptake inhibitors are our gold standard for anxiety. It’s where we generally turn to for depression because they’re better tolerated than most other agents except for perhaps bupropion. But they won’t help migraine.

There was some initial suggestion that maybe fluoxetine would be helpful, but there’s other studies that show that fluoxetine was not helpful for migraine. Maybe fluoxetine is helpful for tension-type headache. 

Bupropion has very few side effects. It might also help with some attentional components like augmentation agent and attention deficit disorder. It might also help with anxiety, particularly if the anxiety is related to depression. But 27% of people report headache on bupropion. And in our practice, it’s really hit or miss. I’ve had patients with migraine who say bupropion is something they’ve taken, it has not made their migraine worse.

And I’ve had other patients that say, oh no, I can’t take bupropion, it made my migraine worse. So it’s not the first thing I might turn to. But there are many patients who do find benefit on it.

Mirtazapine, which has its own mechanism of action – it’s a bit different from the others on this list – it has side effects of sedation. It might help nausea, because it has mild antagonism at serotonin 3, similar to ondansetron. And it might help with chronic tension-type headache. But it’s not something I generally turn to. 

So then the question is, do we try an SNRI or tricyclic, since these might also help with migraine. And as you can see, that is a good option, though they might have a little bit more side effects than a serotonin reuptake inhibitor. SSRIs, serotonin reuptake inhibitors, are first-line agents for many depression disorders, including major depression, and also anxiety disorders, including panic and generalized anxiety. 

Buspirone, which is not an antidepressant, it’s an agonist to the serotonin 1A receptor, has been approved for decades for generalized anxiety disorder. Mostly it’s probably helpful as an augmentation agent for someone who’s already on an antidepressant, since the serotonin 1A receptor is really the one that’s most implicated in anxiety and depression. And it is usually very devoid of side effects. Even though headache is listed as a side effect, in most of my patients, they tolerate it very well.

Its problems of use is that you have to take it twice a day or three times a day, and you have to really increase the dose from 5 mg twice daily to probably 15 or 20 mg twice daily before it starts having effectiveness. Only one small study showed that it might have decreased migraine frequency, and I haven’t really noticed that in patients. 

Tricyclic antidepressants for migraine are dosed much lower than the dose for depression. And of all the tricyclics, amitriptyline has the most evidence and is probably the most effective. And when you take it to doses of 100 to 150 mg – where at that point you also want to do blood tests to make sure you’re within the therapeutic window – it appears to be the most efficacious of all antidepressants. But it also has the highest problems with tolerability. 

The reason why you have to do levels when you get amitriptyline to that dose is that it affects sodium channels, which affects electrical conduction in the heart that can cause a lethal arrhythmia. In fact, amitriptyline and other tricyclics can be lethal in overdose. If you simply took perhaps one to two weeks’ worth of a tricyclic in an intentional suicide, that can be very deadly. That is not the case with other antidepressants.

Other tricyclics have been used for other indications. Clomipramine, on the bottom of the list, is the most serotonergic. It’s our gold standard for obsessive compulsive disorder, which needs a high level of serotonin. It does not appear to be much help for migraine. Nortriptyline, which is the active metabolite of amitriptyline, might be a little bit better tolerable than amitriptyline, it’s more activating. And it’s probably effective in migraine prevention. Some patients that did find amitriptyline or nortriptyline helpful for migraine but still too sedating, my colleagues might turn to desipramine or protriptyline, which are the most noradrenergic of the tricyclics. They might be helpful, but there’s low evidence for them. 

Tricyclics and SNRIs both are reuptake inhibitors of serotonin and norepinephrine, but tricyclics are dirtier with more anticholinergic, more antihistamine, and more sodium channel blocking properties, which makes them more difficult and more intolerable. SNRIs might have more GI upset and nausea and more problems with insomnia. About 10 to 15% might have insomnia. And sexual dysfunction is something they share in common with SSRIs.

Some people think that SNRIs are more helpful for depression, that they’re stronger. But actually, they’re not that much better than an SSRI for depression. And they seem to have the same efficacy for anxiety compared to SSRIs, even though we consider SSRIs the gold standard, probably because we worry that an SNRI might make some people with anxiety too jittery.

Within the class of SNRI, the ratio of binding affinity to serotonin and norepinephrine is quite different. Venlafaxine and duloxetine and desvenlafaxine are more serotonergic than noradrenergic, and these three share in common the sexual side effects and weight gain of other SSRIs. Venlafaxine does not have a dose-response relationship, meaning the low doses are mostly serotonergic, the higher doses are noradrenergic, and the really high doses can have dopamine reuptake inhibition. While duloxetine and probably desvenlafaxine appear to affect serotonin and norepinephrine regardless of the dose.

But then when you look at these newer agents milnacipran and levomilnacipran, which both in the United States are still brand name, they have a lot more noradrenergic potential. That causes them to have a different side effect profile, such as more insomnia, jitteriness, maybe hypertension, but no weight gain and sexual side effects. They’re also metabolized in a different way, which might be more helpful or favorable for someone who might be a poor metabolizer of certain enzymes.

Differences between venlafaxine and duloxetine – venlafaxine turns into desvenlafaxine through 2D6 metabolism. And in a patient who’s a poor metabolizer of this enzyme, it might not be a favorable agent. And while we do try to use venlafaxine, it might be harder to taper off because of its short half-life.

While duloxetine is generally better tolerated, it does have a higher incidence of nausea. It might inhibit 2D6 metabolism of other medications, though not a significant amount, it’s still moderate. For depression, we don’t go higher than 60. But in our headache center, we might go up to 120 mg for a couple of months to see if it actually improves migraine frequency and severity. 

Desvenlafaxine is the metabolite of venlafaxine. I haven’t been very happy with this medicine, which is marketed as Pristiq, because it doesn’t seem to work as well for depression compared to venlafaxine. Because both venlafaxine and desvenlafaxine have antidepressant properties, maybe that’s why just having the metabolite is not as good. But the studies have also panned out. It seems to be really hard to prove that a higher dose of desvenlafaxine is any better than a lower dose for depression.

It seems to be better tolerated, but higher medicine milligrams means higher chance of side effects. When we look at the blood level of desvenlafaxine in someone who takes 75 mg of venlafaxine, the equivalent blood level of someone taking desvenlafaxine would be 50. If you use that to extrapolate dose, it’s possible that if we’re going to 225 or 300 with venlafaxine for headache, maybe we could go up to 150 or 300 with desvenlafaxine. And I have no evidence to support this, but some of my patients have reported that desvenlafaxine has helped their migraine at higher doses. 

I’ve had similar success with milnacipran and levomilnacipran. Some patients do report these to be more helpful for migraine. But only so far, we have a small open-label study of a couple dozen patients that showed that in a typical dose that we would use for depression, milnacipran had a reduction in headache days and migraine frequency. The population was mostly episodic and minority were chronic migraine. Levomilnacipran, which has some benefits of its own, being more noradrenergic and once daily dosing, up to this point has still no published reports. 

A lot of patients will think do antidepressants cause headache? And it’s actually true that it’s listed as a side effect on the bottle of almost every antidepressant medicine. I joke with patients and say, look, the kids that were in college that took this medicine as part of a drug study to make some extra money really have no idea what a headache is. And a headache does not necessarily mean more migraine. A really good meta-analysis really uncovered that only bupropion and escitalopram appeared to be statistically significant in their increased risk of headache.

Trazodone and vilazodone had large effect sizes, but they crossed the confidence interval. I think there’s something special about trazodone and vilazodone that I’ll mention, and that is that trazodone, nefazodone, and vilazodone are metabolized to mCPP. This is a chemical that we feed to mice to give them migraine.

Approximately 150 mg of trazodone would give you the same blood level of mCPP. And that appears to cause migraine symptoms in patients who already have migraine and doesn’t seem to cause that much of a problem in people who do not have migraine. When they actually gave mCPP to patients with migraine compared to healthy controls, the frequency of migraine after mCPP was significantly higher compared to placebo among the migraine subjects. I have patients who might be taking trazodone for years.

I’ve noticed that some of them describe waking up three to four hours after taking trazodone, and sometimes that’s with headache. Sometimes they might have false positive urine drug screens for amphetamines, which can happen at high doses of trazodone. And while I have no real good evidence for this, it’s for those patients that I think maybe you don’t metabolize trazodone well, maybe it’s too strong, maybe it’s contributing to some of your migraine burden, and can we find something else that would be helpful for your insomnia? 

We actually have very little data that combination therapy with a tricyclic and another antidepressant would be better for migraine and depression than either agent alone. There was this small study that showed no superiority of low-dose amitriptyline with generally okay doses of fluoxetine. And this one was a little bit larger, showed that combination therapy of both amitriptyline and a low dose of citalopram was better for both depression and migraine than either agent alone.

So, it could be that you could use amitriptyline or nortriptyline together with a serotonergic reuptake inhibitor, but we always do have to worry about serotonin syndrome. So what is the risk? You know, serotonin syndrome is something that is very, very rare, and most of our data is only in patients who deliberately overdosed on their serotonergic medicines. Those are very obvious.

Minutes to hours of taking a whole bottle, you could have agitation, a lot of behavioral symptoms, fever up to 106, dilated pupils, diarrhea, hyperreflexia. But what if someone is just taking the medicine as prescribed, and they’re a little anxious and have a little GI upset.

And you measure their reflexes, and they’re 3+, they’re brisk, but nothing really to write home about. Is that perhaps something on the spectrum of maybe you don’t call it serotonin syndrome, but maybe it is just too much medicine.

I’ve had patients that where reducing the serotonergic agent improved their anxiety and physical symptoms because they were on too much of it. Obviously, with severe cases of serotonin syndrome, it can be life-threatening. What causes it, we’re still not quite sure, and there’s actually quite a bit of myth and inaccurate research about serotonin syndrome. It appears that serotonin 2A receptors are the most severe cases, the ones that seem to cause a need for intensive care unit monitoring. While serotonin 1A receptors – which have a lot more affinity for the 2A, so they get binded to first – might have more of the jittery and hyperactive feelings. 

There might be other genetic factors or polymorphisms, but we still haven’t figured it out. There’s a theory that if you are on a serotonin blocker, such as an atypical antipsychotic, often used in augmentation of depression or bipolar disorder, it’ll shunt all the serotonin from the 2A receptor, which the atypical antipsychotic is blocking, to the colocalized 1A receptor, which could actually increase symptoms of serotonin syndrome.

There are other cases as well. And when you’re on an antipsychotic and an antidepressant, it does become hard to determine if someone’s severe symptoms are due to serotonin syndrome or neuroleptic malignant syndrome. So often someone just needs to be stopped on all their medicines and try to get them better first. But when we look at our agents that we might use the serotonin reuptake inhibitors they increase serotonin on all the receptor subtypes. The ergot derivatives that we might use in migraine also have high affinity for the receptor subtypes, but that’s 20-fold less for the 2A receptor, so I view this as a therapeutic window.

Yes, there are cases of convulsive ergotism, which may be a serotonic syndrome-like illness, but that’s typically at very toxic levels of ergots. We have had no difficulty in prescribing an as-needed ergot derivative on someone who’s already taking a serotonergic antidepressant. Triptans and lasmiditan are agents that only have agonism at receptors that have not been implicated for serotonin syndrome.

Nevertheless, these agents have been reported in case reports for causing serotonin syndrome. When we actually look at huge studies, it doesn’t seem to be that high of a risk. There’s probably hundreds of thousands of people taking a triptan right now while being on a high dose of a serotonergic antidepressant, and they’re not in bad shape.

We do have to worry about it. But I think if someone is only taking eight pills of triptans per month, you’re not going to develop any sort of autoreceptor upregulation of the serotonin that might increase risk of serotonin syndrome for most patients. Lasmiditan there’s been some postmarketing suggesting, again, very similarly, very low-level cases of serotonin syndrome that may or may not meet criteria. I tell patients about it. But when pharmacies call me and tell me they won’t fill this medicine, I often have to tell the pharmacist it’s okay.

I’m sorry I ran a little bit over, but these are the conclusions that I want to give from this short talk. Which is always keep in mind in your patient with migraine and depression, is this potentially bipolar disorder? And then you really have to decide do you want to treat it with a serotonin reuptake inhibitor that maybe won’t help with headache but could be better tolerated? Would you want to then maybe add the tricyclic to that? Or do you want to try killing two birds with one stone by using an SNRI to treat both the migraine and the depression and anxiety symptoms? I hope that you enjoyed this talk.