Activity Transcript

Trisha Suppes, MD, PhD: Welcome to this Medscape Education program today. Myself and Joe Goldberg will be speaking about treatments for bipolar depression, both where we are and where we are going. I'm Trisha Suppes. I'm a professor of psychiatry and behavioral sciences at Stanford, and I also work in the Palo Alto VA. Joining me today is Joe Goldberg. He is a professor of psychiatry at the Icahn School of Medicine at Mount Sinai in New York, New York. Welcome.

Joseph F. Goldberg, MD: Thank you, Trish.

Dr Suppes: So for the next 30 minutes or so, we're going to talk primarily about acute bipolar depression treatment. We're going to talk about current treatments, and Joe has some great stuff to show us on the mechanism of action (MOA). We're going to talk a little bit as well about the risk benefit of the approved agents for bipolar depression. And as well, we're going to spend, in the latter part, talking just a bit about some of the emerging agents, both MOAs and clinical data.

All right. So under approved medications, this is for bipolar depression, these are actually for bipolar I depression with a couple them approved for bipolar II. So for bipolar I, we have cariprazine, lurasidone, quetiapine, olanzapine and fluoxetine, and lumateperone. Not FDA-approved for acute bipolar depression, we have aripiprazole, lamotrigine, lithium, ziprasidone, and antidepressants. I would mention there are 2 drugs approved for bipolar II, and that would be quetiapine and lumateperone.

So while antidepressants are particularly not recommended for bipolar I depression, I think there is still some debate going on with bipolar II depression. I'm not sure we'll be able to drill down to that today, but it's an important difference to make. Just because something does or doesn't work in bipolar I does not necessarily imply that it won't work or will work for bipolar I in terms of antidepressants.

As we know, the switch to mania in bipolar I, or just switch, is greater with tricyclics, which aren't in use too much, but we see them in the dual agents, the serotonin noradrenaline reuptake inhibitors (SNRIs). We also know that transitorily, in a transitional, transitory way, antidepressants can cause irritation, irritability, restlessness. That is not a switch per se. That could be almost a side effect that will remit quickly or could even pass.

Dr Goldberg: I would just add that we really stopped studying monoaminergic antidepressants about 20 years ago. And so, we don't have really any current information on some of the newer agents, which makes them all the more experimental. If you're a clinician, it means before I give a patient something like vilazodone or vortioxetine, I'd want to tell myself and my patient, "This hasn't been studied for your ailment before." And so, we really can't anticipate an outcome till it gets studied.

Dr Suppes: I think that's an important comment. Thanks, Joe. All right. So now we're going to take a few minutes to look at some of the MOAs, mechanism of action, for approved and emerging therapies, particularly approved therapies. So Dr Goldberg is going to discuss first dopamine receptors and serotonergic pathways.

Dr Goldberg: So I'm going to just start with a caveat. If you look in the package insert of any psychiatric drug, Section 12.1, mechanism of action, unknown, all drugs. We make inferences from preclinical studies about mechanism, so I don't mean this to be a disclaimer, but everything we're about to talk about really comes from preclinical studies and is meant to hopefully inform our thinking about how we envision some of our psychotropics to work and some of the newer strategies that are coming along beyond monoamines in the 1960s.

We just said too much catecholamines, mania, too little depressed. Now we know that that was a huge oversimplification. We nowadays think more about circuits than chemicals, or we think about specific receptors, so not just saying the dopamine system or the serotonin system as if your brain is a big bag full of these chemicals, but rather particular receptors and particular circuits that we can target.

So we've all known about the D2 receptor and its impact in psychosis, its impact in mania, the extent to which blocking D2 receptors may lead to outright depression, if not akinesia and apathy and inertia. It doesn't really help anybody's motivation or drive or initiative to hit D2.

So among the things that the newer generation and even the newer, newer generation second antipsychotics do is really sort of going for receptors other than D2. For instance, D1 receptors, postsynaptic binding at D1 receptors is actually thought to have a modulatory effect on glutamate transmission. There may be ways of getting it excitatory pathways by having a D1 antagonist, example being the drug lumateperone.

D3 receptors, similarly, are very densely innervated and found in the reward pathway in the ventral striatum. And so, when we think about arousal, motivation, drive, initiative, the capacity for positive affect. Agents that may be partial agonists at the D3 receptors, such as cariprazine, come to mind as getting to a specific type of dopamine receptor that might do much more than just a D2 blocking agent in terms of treating psychosis.

Likewise, in the serotonin systems, once again, there's particular receptors that are of interest, so by the wayside has gone to serotonin transporter. But we're really more interested in what's happening on the postsynaptic side, the extent to which we can modulate or even selectively bind to certain postsynaptic receptors. Some are good, some are not so good. So we'd like to avoid indiscriminate binding at postsynaptic receptors, such as the 5-HT2A receptor agonism there, potentially, at least in some situations, could lead to sexual dysfunction or agitation.

5-HT2A agonism may also be a new novel way to get it depression. 5-HT1A is often thought of as being a very desirable target for both depression and anxiety, and many of our atypical antipsychotics bind to the 5-HT1A receptor. We'd like to not bind to 5-HT3, that can cause nausea. We'd like to not bind to 5-HT2C, it can account for some of the metabolic and weight, adverse effects that occur.

And then agent binding sites like the 5-HT7 receptor are thought to be importantly involved in mood, learning, memory, cognition. So think beyond transmitters, think more along the lines of more specific targets.

Lurasidone, in part, is thought to exert its unique mechanism by virtue of its 5-HT7 effects. Also affects 5-HT1A. The postsynaptic 1A receptor may have an antidepressant effect, may have an anxiolytic effect, which by the way also raises the issue of treating anxiety in the context of bipolar depression and secondary analyses with all of the FDA-approved treatments for bipolar depression show efficacy in reducing anxiety as well as depression symptoms.

Trisha is now going to tell us about clinical efficacy with lurasidone and some of the other agents approved for bipolar depression.

Dr Suppes: Thanks, Joe. So we start with lurasidone, but we're also going to look at a few other agents. So a lot of folks like to look at need to treat, which is the estimate of, if you add one more person, are you likely to see a response? And as somebody said, anytime you're below 10. It's likely to be clinically significant.

So needed to treat and needed to harm is always tied to a specific measure. So in that sense, they're limited. They're not giving you an overall perspective of overall wellness or function. They're looking at a specific scale or a specific side effect. So number needed to treat (NNT) for lurasidone was very good, looking at the Montgomery-Åsberg Depression Rating Scale (MADRS) in bipolar depression. This is bipolar I depression. And it had an NNT of 5, which was almost a 20% separation from placebo, which is quite good.

It should be mentioned, all of the four agents I'm going to review. All have an NNT 10 or under. So all of them would be viewed as very good agents in terms of treatment.

And the remission rate was also separated for lurasidone by quite a bit, relative to placebo. And then when you look at the overall harm, there's that very nice sort of heat-sensitive diagram showing olanzapine/fluoxetine combination (OFC), quetiapine, lurasidone, and cariprazine, which I think we'll be showing. And you see that under lurasidone and cariprazine, there's much more green than yellow or red, whereas the older agents, olanzapine/fluoxetine and quetiapine, have more significant red and yellow.

So for example, and we'll get into a few more specifics, but the olanzapine/fluoxetine, as folks know, is weight gain; quetiapine, somnolence. Neither lurasidone or cariprazine seem to suffer from these quite at the same way. Though it should be noted, they have their own side effects, and as Joe has enumerated in the receptors panoply that that it's consistent. So there could be, for example, extrapyramidal symptoms (EPS) with lurasidone, you do see akathisia, you actually do see this also with cariprazine as well. Then Joe, why don't you talk a little bit about the mechanisms for one of our other newer agents, quetiapine, please?

Dr Goldberg: Yeah. So quetiapine, you could say, is not so new an agent. It's been around for a while. We often thought of it initially from the studies in, well, psychosis, and then in acute mania where it works. It is one of the few compounds, the only other one being cariprazine, that we might say has bimodal efficacy.

As I mentioned before, back to 5-HT1A partial agonism, there's actually a pre and a postsynaptic 5-HT1A receptor.

The presynaptic one is like a gatekeeper. Selective serotonin reuptake inhibitors (SSRIs) downregulate that over the first few weeks, and then we're interested in what's happening on the postsynaptic side. As I had said earlier, sucking serotonin quanta toward the postsynaptic 5-HT1A receptor is thought to be one way to get in an antidepressant and an anti-anxiety effect.

Additionally, as you may know, the active metabolite of quetiapine, norquetiapine, has an appreciable binding affinity at the norepinephrine transporter. Now, here's a sort of a conundrum in some ways, Trisha was saying before, we don't love tricyclics and we're leery of SNRIs because of their binding at the norepinephrine transporter, and the whole question of whether that could destabilize mood is still an open question. Here is a molecule whose active metabolite happens to be a norepinephrine transport reuptake inhibitor. There's no data to suggest that quetiapine induces mania or accelerate cycle accelerations.

So perhaps its norepinephrine transport blocking effects in the context of its other many properties accounts for some of its antidepressant effects. And then we have these other serotonin targets such as the 5-HT2C receptor, the 5-HT7 receptor, which we talked about earlier with lurasidone, is also a target here.

Trish, you're going to tell us something about the efficacy with some of these other compounds?

Dr Suppes: Yeah. So quetiapine, if you do look at need to treat, responder rate also under 10, 6, very good, almost a 20% spread. Responder is defined by a 50% change in the depression scale, which sometimes can be meaningful, but you could actually still be depressed if you started 40 or 35. You're still depressed.

Whereas remitters, you're talking about more absolute remission, and that's usually a MADRS of 12 or less actually. So in terms of remission, again, it's under 10 for quetiapine. Remission rate is also separated by almost 20% between quetiapine and placebo. So under the side effects I mentioned briefly, but I think that quetiapine is one of the few drugs approved for treating both mania and depression. Cariprazine being the only other one that I'm aware of.

And it does have side effects. And I think the main use of it now is actually for either acute use or for helping sleep because it has such a good somnolence. But there are people who've done very well on it and not so good on anything else, so one should keep it in the armamentarium, and it should be noted the dose for depression is about 300, acute depression, bipolar I or II. Though in II, you might go a little lower because of side effects, sensitivity, and acute mania is about 600.

Now, what you use to treat someone acutely may not be the same thing you want to use when their symptoms are less. Often, you'll have to do a dose adjustment based on increased side effects when the acute state has passed. And now I think Joe is going to talk about the drug that led the whole thing off, olanzapine/fluoxetine.

Dr Goldberg: And now we can speculate mechanistically about serotonergic effects, 5-HT2C. I mentioned earlier 5-HT2C can have a bad reputation. Antagonism can cause weight gain, but it can also contribute to an antidepressant effect. Mirtazapine and nefazodone are examples of direct 5-HT2C antagonists where that's thought to have some antidepressant properties.

And then really interesting is the extent to which you might actually see increased catecholamine turnover in the prefrontal cortex, this is least in rats, when you give olanzapine with fluoxetine. And the way these studies were done seemed to suggest a unique value with that pairing. If you took a different atypical antipsychotic, you didn't see quite the same prefrontal cortical turnover of catecholamines. If you took a different SSRI, you also didn't see that. So for what it is worth, this was, I think, the first molecule that got the FDA's indication for bipolar depression and really set the stage.

Dr Suppes: So in terms of responder rates, again, responders 50% down. On a standard, whatever depression scale, remission is below an absolute number. And indeed, olanzapine/fluoxetine is only 4 in terms of responder rate with a more than 20% difference between placebo and the combination. And in terms of remission, also lowest in the need to treat of 5 with more than a 20% between placebo and the combination, so it is very effective.

But if you look at the side effects, it comes with a whole... A lot of them, as we know. I think in general, olanzapine is used more as a rescue medicine at this time for acute mania, might be used briefly, because the weight gain and metabolic impact is now very well-recognized. Having said that, there are some people where olanzapine or olanzapine/fluoxetine is the only thing that really works for them, it gets them better, and they cope with the side effects.

So we shouldn't just shy away because of a side effect. We really have to look at efficacy and what the patient is comfortable working with because they're the ones of course who have to live with the drugs and what the side effects they can live with relative, so it's the risk benefit for them. Anyway, so in terms of the combination, as we know, weight gain, you've got a lot of somnolence, which of course is why it's good for use in acute situations. Now, Joe is going to tell us about a newer agent, cariprazine.

Dr Goldberg: A real breakthrough came with the notion of partial agonism at D2 and D3 receptors, and the idea of a rheostat that is ambient dopamine tone can differ in different pathways. Again, it's the circuits, not the chemicals. So we have our mesocortical pathway, our mesolimbic pathway, our tuberoinfundibular, prolactin pathway, and then the dorsal striatum.

And you could talk about the idea of having selectivity. It'd be really nice if I could increase dopamine tone in prefrontal cortex, the reward pathway, arousal, drive, motivation, while downregulating dopamine in mesolimbic circuitry that might contribute to psychosis or mania, and potentially spare collateral damage in the dorsal striatum or in the tuberoinfundibular pathway.

So we have 3 partial agonists, which in principle should raise dopamine where the pathway is too low and should lower dopamine in pathway where it's too high. Aripiprazole is the first of these. It has been shown to have efficacy as an add-on to monoaminergic antidepressants in unipolar disorder, although the studies of aripiprazole in bipolar depression turned out to be negative.

By contrast, cariprazine, a different D2/D3 partial agonist, has high efficacy with a low number needed to treat a significant effect for acute bipolar depression as well as mania. And one interesting point mechanistically is its binding affinity at the D3 dopamine receptor. As I mentioned earlier, very deep concentration of D3 receptors in the reward pathway, the ventral tegmental area, the nucleus accumbens, the region that we really don't want to shut down.

You could make someone very sort of apathetic and anhedonic, almost negative symptom-looking, by giving a tight D2 binder. But giving a partial agonist with a very good binding affinity at D3, at least in principle, might help with things like anhedonia, apathy, motivation, drive, arousal, initiative. Cariprazine has the strongest binding affinity of any of the D2/D3 partial agonists at the D3 receptor.

So that's one distinguishing point and other mechanisms in the serotonergic pathway, yet again, the 5-HT1A receptor partial agonism. And a subtype of 5-HT2A receptor is the 5-HT2B receptor, also seems to have antagonistic properties which may contribute at least in part to mood effects. So as you can see in this sort of cartoon description here, many receptors that are involved, and we're especially interested in the D3 effect and in reward.

Trisha will tell us about how the data play out for efficacy in bipolar depression.

Dr Suppes: Sure. And it's worth mentioning that cariprazine like quetiapine has approval for bipolar I mania and bipolar I depression. Cariprazine does not have approval for bipolar II depression. So looking again at the depression scales of interest, this one was 10, but it's still within that area where you would view it as having meaningful clinical outcome.

And usually, the depression dose is around 1.5 in bipolar depression, and mania might be higher. Again, these would be adjusted over time. Then the remission rate, again, the absolute number, also still very close to 10. It's 11 with a 10% difference between placebo and the drug. It's on the basis of these studies of course that cariprazine was approved. These are the FDA phase III, so it did separate.

So one thing is, we're talking about need to treat, need to harm, but you also have to look at the clinical significance of separation, and there was placebo separation as well in all of these compounds we're discussing. So if you look at the heat chart, as Les Citrome says, you can see that cariprazine is pretty well-tolerated with the one thing, the one notable side effect at higher doses would be akathisia.

So I think there's a potential at the higher doses, particularly for some motor impact, but generally well-tolerated. Because it's the newest kid on the block, it can be hard to get insurance and to cover it. But if possible, you've gotten the whole play in terms of the mania and depression for bipolar I, assuming it's tolerated, and there's not the same risk of weight gain. In fact, the number needed to harm for weight gain is 50 versus for olanzapine/fluoxetine at 6, just to give you a comparison of the risk effects. And now Joe is going to chat just for a few minutes about glutamatergic pathways. So Joe?

Dr Goldberg: Yeah. So as we sort of move beyond catecholamines and start to think about other mechanisms that are pertinent for depression, it was really the work with ketamine that I think ushered in an era in the 21st century of considering the ways in which this excitatory neurotransmitter can have synaptogenic effects, neuroplastic efficacy, neuroprotective effects as a novel mechanism. So we think when you give people ketamine, among other things that happen is you turn on neuroprotective genes by causing a burst of glutamate.

There has been a great deal of interest in looking for other ways of doing that in the glutamate system besides ketamine. There are three so-called ionotropic glutamate receptors, the N-methyl-D-aspartate (NMDA) receptor being one, and then these other two receptors called the kainate receptor and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor are others. If we could think of some way to cause this burst of glutamate that might cause downstream turning on of genes that protect nerve cells from oxidative stress.

So this is, in a sense, the essence of why are we interested in the glutamate system. It's excitatory, but bottom line, cortical glutamate neurons can regulate other circuits that ultimately will protect nerve cells from neuronal damage and have a neuroprotective effect, which may go hand in hand with an antidepressant response.

So one way to get at the glutamate system is through the back door postsynaptically. We have postsynaptic D1 receptors, which will regulate AMPA and kainate receptors. Those are the other types of ionotropic glutamate receptors that are thought to be involved in turning on genes that protect nerve cells against oxidative stress and damage.

So as we begin to talk about the molecule lumateperone, let me just say few things about the D1 receptor. Again, it's a way of modulating glutamate postsynaptically. Partial agonism at that receptor increases phosphorylation of NMDA glutamatergic N2B receptors in the mesolimbic brain region that increases glutamatergic neurotransmission in AMPA and NMDA channels that can result in potent and rapid antidepressant effects.

As all antipsychotics, it binds to D2 that we know. Although interestingly, it's got a much, much greater binding affinity at the 5-HT2A receptor than the D2 receptor. About a 60-fold difference. One of the definitions of atypicality is that ratio of 5-HT2A to D2 binding, and greater than one is one definition of an atypical antipsychotic. This is 60 times greater.

But here, it gets interesting. So we have the D1 effects with this molecule, we have effects at 5-HT2A, as I mentioned, much more potent than just about all the other atypical antipsychotics relative to D2. It happens to have a serotonin transport blocking effect as well, and may actually be a novel approach to get at psychotropic effects, not just through the dopamine system, but through the glutamate system by virtue of the D1 effect. We have efficacy data in bipolar I and bipolar II depression, and Trish is going to tell us about those efficacy data now.

Dr Suppes: Okay. So first, the bottom line in the story is it was efficacious in both bipolar I and II. We saw a 15% difference in responders. Again, that's 50% less of baseline, and there was about a 7% spread for remitters. It should be noticed actually, the bipolar II effect size was bigger than the bipolar I, which is a little bit unusual.

Again, as we noted before, the side effects for lumateperone, actually it wasn't on our heat map, but in this study, the side effects were somnolence and a little nausea. And in this study, switch... are the limitation of treatment-resistant and suicidality. And I think now we're going to begin to talk about some newer agents that aren't yet approved. So I think, Joe, do you want to start talking with the classic hallucinogens as potential antidepressants?

Dr Goldberg: Yeah. Again, moving beyond traditional monoamines, classical hallucinogens have been of interest and study going back to the 1950s and 1960s.

So why are traditional hallucinogens such as psilocybin or LSD thought to be important? The presumed mechanism has to do with the 5-HT2A receptor, and this is again a very complex receptor.

We think of some drugs having antidepressant value by blocking that receptor. That's what the atypical antipsychotics by and large do. It is what some monoaminergic antidepressants do, such as mirtazapine or nefazodone. And yet, there are widespread projections from these receptors into the cortical glutamatergic circuitry that may allow 5-HT2A agonism as a way of tweaking glutamate, as we talked about before, and promoting synaptogenesis.

So think about this: It's not necessarily the hallucinogenic effect that we're looking for. Much the same way with ketamine, we're not so much interested in the dissociative effect in order to judge a subsequent antidepressant effect that's almost a separate component. It's the impact of binding at the 5-HT2A receptor as an agonist that then sends projections up to cortical layer 5, deeper cortical layers, and the brainstem that in turn, will lead to increased glutamate release and potential increased neuroplasticity.

So we have some very preliminary studies that have just come along with classical hallucinogens in major depressive disorder. We don't yet have completed data, I think, to speak of in bipolar depression, but that's become a very active area of interest. Preceding this has really been the studies with ketamine. I alluded to them briefly.

Dr Suppes: Can I just say one thing about the psychedelics, which is what... We're not talking about it, but I think it's worth mentioning that we're not talking about it, and that is MDMA, which in some... Some people lump it with the classic psychedelics. It's really not. And they're starting their second phase III, but it's for PTSD. And the overall kind of huge, I don't know, media enthusiasm, the public, and so on, all of the psychedelics, particularly psilocybin and MDMA, are now being tested in anything you can think of.

Dr Goldberg: Ranging from substance use disorders to PTSD, to mood disorders and anxiety disorders. So enthusiasm may in part be outpacing the data and the science, but it's another novel strategy and way of getting at neural plasticity and synaptogenesis in a way sort of coming from the land of ketamine, which we talked about mechanistically before. While the intranasal enantiomer of esketamine is FDA-approved for unipolar depression, there are data with bipolar depression off-label. Trisha, do you want to tell us about those studies?

Dr Suppes: Well, and that's an example of where people want to generalize from major depressive disorder (MDD) to bipolar, and maybe that'll work, but I don't think we know yet. As Joe mentioned on a side conversation we had, one thing about ketamine, there doesn't appear to be triggering of mania, which you do worry about, for example, with psilocybin or MDMA, so I don't think bipolar I would be trial subjects for those compounds, but bipolar II might.

So in these studies which were done quite a while ago now, led to an entire field study in ketamine and a new J&J esketamine approval. But the approvals at MDD, whereas now, other people are now beginning to look more at bipolar. I think not much more to say than that right now.

Dr Goldberg: Yeah. I mean, it'd be nice to have more than three studies with enrollees of 30 people or more. Yeah. A big question too, which, it's the expert consensus, people talk about is, "What do you do after a response? Do you continue ketamine?" I think is the real holy grail in looking for what will be efficacious, not just to prevent recurrence of bipolar depression, but to prevent mood episodes of any polarity, and that's a big unknown.

So back to the NMDA receptor. Another way to try to tweak glutamate is with the molecule D-cycloserine. There is a molecule under investigation right now I'd like you to know about. It's called NRX-101. It is the unique pairing of D-cycloserine and NMDA receptor antagonist, maybe another way to get glutamate doing its thing with neuroprotection, paired with lurasidone. Potentially a synergistic strategy.

Here is a proof-of-concept trial. Got 10 people in one group and 5 in the other, but notice, after a single infusion of ketamine, the question of, can you sustain the benefit we see in actually greater sustained improvement with this pairing of D-cycloserine and lurasidone as compared to just lurasidone alone over the course of a few weeks? So very preliminary data, but intriguing and interesting.

Then we can talk about another molecule that is just coming under investigation. A very recent published trial with a molecule called SEP-4199. So this is a non-racemic formulation of an old drug called amisulpride that's not available in the US, at least not in pill form for psychotropic uses. It's used in Europe as an antipsychotic. It's also used in dysthymic disorder. It's got some D1 and D2 effects, but what's interesting about this formulation is it's got a very strong binding affinity at the 5-HT7 receptor, that receptor we talked about earlier with some of the newer molecules such as lurasidone.

So there is a very preliminary study just recently published in the Journal of Affective Disorders comparing this molecule to placebo where it just failed to meet statistical significance, and there's some ongoing research to see if SEP-4199 might actually pan out as a novel strategy, again through the 5-HT7 system predominantly, and maybe some D1 and D2 effects secondarily for bipolar depression.

Want to turn your attention to the GABAergic system, and in particular, the notion of neurosteroids. So GABA-A receptors and GABA interneurons play a very important role in regulation of mood. There is a novel strategy for tweaking GABA-A receptors and potentially effecting an antidepressant effect through allosteric modulation of the GABA-A receptor.

You may know an earlier drug called brexanolone, which is a molecule that's FDA-approved to treat postpartum depression in intravenous form, and there's now an oral, similar form of that molecule that targets the GABA-A allosteric modulatory site called zuranolone. Zuranolone has had several clinical trials in unipolar major depression, and we now have some open-label phase 2 data in bipolar depression.

What's interesting about this, apart from it's a neurosteroid, so it's a different way of getting it at treating mood disorders, seems to be the case that you give a 2-week course of treatment, and then you look and see the effects. So this may not be so much the traditional perspective of ongoing open-ended treatment, so much as a 2-week period, where we might then look to see efficacy.

And while this is... In this slide, we see just open-label data in a sample of 35 patients over the course of just a few weeks. Fairly well-tolerated, little risk of induction of mania, a significant-from-baseline improvement in depression symptom scores. And so, we eagerly await more. Trish, you want to tell us about this study coming up with vortioxetine, one of the newer antidepressants?

Dr Suppes: Yeah. This is an exploration since 1999, right? It's one of the few looking at vortioxetine and bipolar depression adjunct. There's 2 randomized controlled trials (RCTs) going on right now in patients, so about 60, so it's not super small. Probably not enough to be a definitive trial. It's nice that it's 6 months. It is open-label, so it's an adjunct, so it's not a placebo control, so there's not a registration trial.

So far, they're seeing a response rate of quite a bit, 73%; remission, 50%. I think what's important here in an open-label, you're, at the end of the day, going to have a suggestion of what to do, but you don't actually know.

Dr Goldberg: With fingers crossed, we wonder if the 5-HT7 receptor again is accounting for this.

Dr Suppes: Yeah. I'd like to just hark back to what you said at the beginning, which is, we don't actually know how any of this works. We're making an effort. But I like how you're thinking about the different receptor action. There are little clues about things that may be true, but it has to be tested to see if it actually plays out with the patient. Thank you, Joe. It's been great having you, sharing-

Dr Goldberg: My pleasure.

Dr Suppes: Thank you for participating in this activity. Please though, do stay on. There's going to be some questions and an evaluation after. Thanks very much.

This is a verbatim transcript and has not been copyedited.