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CME / ABIM MOC / CE

Does the Mechanism Matter? Breaking Down Novel Pharmacology in Bipolar Depression and Schizophrenia

  • Authors: Deanna L. Kelly, PharmD, BCPP; Christoph U. Correll, MD; Joseph F. Goldberg, MD
  • CME / ABIM MOC / CE Released: 10/20/2022
  • Valid for credit through: 10/20/2023
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Target Audience and Goal Statement

This activity is intended for psychiatrists, primary care physicians, neurologists, nurse practitioners (NPs), physician assistants (PAs), and other healthcare providers who provide care to patients with schizophrenia and bipolar disorder.

The goal of this activity is for learners to be better able to understand the pharmacologic mechanisms of emerging and novel treatments for bipolar depression and schizophrenia.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Mechanism of action of emerging and novel treatments for bipolar depression and schizophrenia
    • Tailoring of treatment decisions for bipolar depression and schizophrenia based on drug pharmacology
  • Have greater competence related to
    • Adjusting pharmacologic treatments in bipolar depression and schizophrenia


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Moderator

  • Deanna L. Kelly, PharmD, BCPP

    MPower Professor of Psychiatry 
    State of Maryland Strategic Partnership: MPowering the State 
    Acting Director, Maryland Psychiatric Research Center 
    University of Maryland School of Medicine 
    Baltimore, Maryland 

    Disclosures

    Deanna L. Kelly, PharmD, BCPP, has the following relevant financial relationships:
    Consultant or advisor for: Alkermes; Janssen; Sunovion
    Research funding from: Saladax Biomedical Inc.

Faculty

  • Christoph U. Correll, MD

    Professor of Psychiatry and Molecular Medicine
    Zucker School of Medicine at Hofstra
    Northwell, New York

     

    Disclosures

    Christoph U. Correll, MD, has the following relevant financial relationships:
    Consultant or advisor for: AbbVie; Acadia; Alkermes; Allergan; Angelini Pharma; Aristo Pharma; Boehringer Ingelheim; Cardio Diagnostics; Cerevel Therapeutics; CNX Therapeutics; Compass Pathways; Damitsa; Gedeon Richter; Hikma; Holmusk; Intra-Cellular Therapies; Janssen; Johnson & Johnson; Karuna Therapeutics; LB Pharma; Lundbeck; MedAvante-ProPhase; MedinCell; Merck; Mindpax; Mitsubishi Tanabe Pharma; Mylan; Neurocrine Biosciences; Noven; Otsuka; Pharmabrain; Recordati; Relmada Therapeutics; Reviva Pharmaceuticals; ROVI Pharmaceutical; Seqirus; Servier; SK Life Science; Sunovion; Sun Pharma; Supernus Pharmaceuticals; Takeda; Teva Pharmaceuticals; Viatris
    Speaker or member of speakers bureau for: AbbVie; Angelini Pharma; Aristo Pharma; Damitsa; Gedeon Richter; Hikma; Intra-Cellular Therapies; Janssen; Johnson & Johnson; Lundbeck; Mitsubishi Tanabe Pharma; Mylan; Otsuka; Recordati; Seqirus; Sunovion; Takeda; Viatris
    Research funding from: Janssen; Takeda
    Contracted researcher for: Janssen
    Stock options from: Cardio Diagnostics; LB Pharma; Mindpax

  • Joseph F. Goldberg, MD

    Clinical Professor of Psychiatry
    Icahn School of Medicine at Mount Sinai
    New York, New York

     

    Disclosures

    Joseph F. Goldberg, MD, has the following relevant financial relationships:
    Consultant or advisor for: BioXcel Therapeutics; Jazz Pharmaceuticals; Lundbeck; Otsuka; Sage Therapeutics; Sunovion; Supernus Pharmaceuticals
    Speaker or member of speakers bureau for: AbbVie; Alkermes; Intra-Cellular Therapies; Sunovion

Editor

  • Frances McFarland, PhD, MA

    Associate Medical Education Director, Medscape, LLC

    Disclosures

    Frances McFarland, PhD, MA, has no relevant financial relationships.

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  • Lisa Simani, APRN, MS, ACNP

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Lisa Simani, APRN, MS, ACNP, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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CME / ABIM MOC / CE

Does the Mechanism Matter? Breaking Down Novel Pharmacology in Bipolar Depression and Schizophrenia

Authors: Deanna L. Kelly, PharmD, BCPP; Christoph U. Correll, MD; Joseph F. Goldberg, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 10/20/2022

Valid for credit through: 10/20/2023

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Activity Transcript

Deanna Kelly, PharmD, BCPP: Hello, I'm Deanna Kelly, MPower professor of Psychiatry in the state of Maryland Strategic Partnership Empowering the State and acting director at the Maryland Psychiatric Research Center at the University of Maryland School of Medicine. Welcome to this program titled ''Does the Mechanism Matter? Breaking Down Novel Pharmacology in Bipolar Depression and Schizophrenia.''

Joining me today are Dr Christoph Correll, who is professor of Psychiatry and Molecular Medicine at the Zucker School of Medicine in Hofstra, and Dr Joseph Goldberg, who is clinical professor of psychiatry at Icahn School of Medicine at Mount Sinai. Welcome.

Today, we will be discussing recent pharmacologic developments in schizophrenia and bipolar depression. We will be discussing the pharmacology of novel and emerging agents, and then we'll have a discussion around selecting treatments including reasons and methods for switching agents.

Let's start with how we think overall about treating psychiatric disorders. We no longer think of it in terms of correcting chemical imbalances. Joe, will you comment here?

Joseph F. Goldberg, MD: Yes. Thanks, Deanna. In the 1960s and 70s, life was very simple, and we thought about chemical imbalances as the driving force in mood disorders, to an extent in schizophrenia as well. Too much, too little, too much you have positive symptoms. Too little, you have negative symptoms. Too much, you have mania. Too little, you have depression. And nowadays, you don't really think about the neurotransmitters as being the problems so much as the circuits on which the neurotransmitters move and communicate.

So, our treatments nowadays and as we look forward to the future, are really geared more toward trying to fix broken circuitry or to protect nerve cells from damage to increase synaptic plasticity and really strengthen connections between nerve cells. So, when we talk about the chemicals that are involved in transmitting across neural circuits, we're not so much trying to change the chemicals as much as to affect the receptors that can tweak these circuits and try to make them function more efficiently.

Dr Kelly: Thank you so much. Christoph, what do we know about the mechanisms underlying schizophrenia?

Christoph Correll, MD: Well, as Joe said, we really have to think in terms of circuits. The term schizophrenia means a neural network disorder, this schism between different areas of human functioning – drive, behavior, affect, cognition. And underlying these basic functions of human behavior are different areas of the brain as we understand it right now, which are often subserved by dopamine. The basal ganglia, thalamocortical network loops control information from the cerebral cortex to the striatum pallidum and thalamus and then back to the cortex. And when that works in an orchestrated way, it's great, but when there are disruptions, then we have a problem. And people with schizophrenia seem to have that problem because there might be over pruning and there's less of an integration in the brain. We know also from resting states imaging that when the circuits are well or better connected, patients will also respond better to antipsychotics.

Now, dopaminergic projections are relevant. But the dopamine system is not just very simple. There are 5 major circuits that we need to think about. There's the mesocortical one, which has to do with cognition, maybe also with depression, and there may be too little dopamine. Then there is the mesolimbic pathway, that in the past we thought subserve psychosis. We now think this ventral striatum, which is part of the limbic system, actually has more to do with negative symptoms and it's the associative striatum, which is part of the nigrostriatal pathway that gives rise to positive symptoms. And then we have the nigrostriatal pathway that we know of. That's like extrapyramidal side effects when you block the dopamine system too much and we have the tuberoinfundibular system, and if you block dopamine there, then you have prolactin elevation. And so, we would like to have a stereotactically smart drug that only blocks dopamine in certain areas and actually increases dopamine in other areas. And it's very hard to find that.

More recently, there has also been more of a focus not only on dopamine but also glutamate. Remember, glutamate is the gas pedal in the brain. It's basically the stimulator. And then we have GABA, which is the brake in the brain, but they interact. So, if there's too little of the gas pedal –NMDA receptors, glutamate -- that go to the brake -- the GABA receptors, the interneurons -- you might actually then have a disinhibition. And that can happen when it underlies positive symptoms. But there might also be an area in the brain in the frontal lobe where there's just too little glutamatergic functioning and that can lead to cognitive dysfunction, negative symptoms and maybe also to depression.

So, the current model, we have a combination of genetic risk, environmental load, maybe also some pre-synaptic dopamine dysregulation, which then turns into psychosis in people who are susceptible. Now, the question then is how do our treatments target these different mechanisms? And well, you all know the conventional antipsychotics, they're mainly selective dopamine blockers, and that's not too bad for psychosis, but it's so hard to titrate this. And we have had a lot of problems with extrapyramidal side effects, prolactin elevation, secondary negative and cognitive symptoms. And then some of these typical antipsychotics also block muscarinic and histaminergic receptors, which can be calming but also cause secondary negative and cognitive side effects.

Now, the atypical antipsychotics on the other hand are serotonin, dopamine antagonists. And so, the serotonin blockade was thought initially to maybe enhance the antipsychotic efficacy. But what it also does is, when you block serotonin 5-HT2A receptors, you're releasing a little bit of dopamine in certain areas which may then lead to less negative symptoms and less extrapyramidal side effects. Some of these atypical agents have also other serotonergic action. So, for example, partial agonism on 5-HT1A, which might help to release dopamine release, it might help anxiety and depression. But all these drugs as we currently know them, that block postsynaptic dopamine receptors can have, dose dependently extrapyramidal side effects, prolactin elevation and problems with secondary negative cognitive symptoms. Now, the newer agents also have weight gain and metabolic dysregulation. To some degree, not all of these agents are created equally.

In addition to the dopaminergic and the glutamatergic system, we also have the cholinergic system, and that's relevant for some of the newer agents that we'll be talking about. And the muscarinic system is relevant because it's related to the dopaminergic system. So, for example, M1 and M4 receptor density was found to be reduced in postmortem examinations of patients with schizophrenia. And when you stimulate M1 receptors in the frontal cortex, you can actually improve cognition. And when you stimulate M4 receptors, you decrease in cholinergic tone, you can then reduce dopamine. So that's a convergence on the dopamine system.

And then finally, another receptor system that may be novel to some and is related to agents under development is the TAAR system. What's a TAAR? It's a trace amine-associated receptor. These are cool receptors. They're both intracellularly and extracellularly. They are stimulated by trace amines, as the name says, and when they're stimulated, they can go to the postsynaptic dopamine receptor and hug it and then internalize it. That means without blocking postsynaptic receptors, you are making less of them available. And at the same time, stimulating TAAR1 receptors reduces presynaptic dopamine firing. So, we might actually carve schizophrenia at its joint. We think there's much more of a problem with a presynaptic output that is too much in schizophrenia, rather than the postsynaptic system.

Dr Kelly: Christoph, this was a great summary. Thank you so much. Let's turn to bipolar depression. Joe, what do we know about the mechanisms here?

Dr Goldberg: Right. Well, I wish things were as simple and straightforward in the world of bipolar depression as they seem to be in schizophrenia. But we have a number of challenges when it comes to bipolar depression. First how is it different from unipolar depression? If you think about depression in the brain, is there something identifiably unique about the circuitry or the neurotransmitter systems in people who have highs and lows compared to people that have never had highs but only lows? Plus, the phenomenology of depression in bipolar disorder as we'll talk about a little later, is rather indistinguishable from the phenomenology of unipolar major depression. That is, the symptoms of sadness and anhedonia and sleep-wake cycle and so on tend to be fairly similar unless there's an overlay of mixed features.

So, part of the challenge in understanding the mechanisms that underlie the pathophysiology and potentially the treatment is not just what goes on in depression and classical neurotransmitters systems in mood-regulating areas as we think about in major depression. But rather above and beyond that, what happens in the switch process? That is, how does one go from the lethargy, inertia, amotivation, apathy, anhedonia of depression to the psychomotor acceleration state or the mixture of both. So just phenomenologically, that's one limitation in understanding bipolar depression.

Now that said, we certainly can talk about classical catecholamine-indolamine theories. There's certainly evidence that noradrenergic tone, serotoninergic tone in those brain circuits that are involved in mood play a role in both unipolar and bipolar depression. But here comes a challenge when we think about classical antidepressants, that is agents that might tweak these circuits. Antidepressants, monoaminergic antidepressants, have not been shown to be as efficacious in bipolar depression as in unipolar depression. There's got to be more than just these classical mechanisms of monoaminergic antidepressants.

The drugs that have been shown to treat depression and bipolar disorder probably have more to do with different regions, different circuits. For example, 5-HT2A antagonism, as is the case with atypical antipsychotics, 5-HT7 antagonism, as is the case with some second-generation antipsychotics, the glutamatergic system, as Christoph just described very elegantly in schizophrenia, may very well also play a role in understanding depression of both polarities, unipolar and bipolar disorder. And then lastly, when we think about mood stabilizers like lamotrigine as having antidepressant properties, that really moves us far beyond catecholamines and indoleamines. It brings us more into ion channels, voltage-gated sodium channels, and the effects on second messengers.

So, this is an extensive way of saying that from a pathophysiologic standpoint, there may be different underlying manifestations in bipolar patients compared to unipolar patients. So, there are at best loose analogies between catecholamine malfunction, catecholamine receptor effects on neural circuits that translate from unipolar to bipolar depression. We know a lot more about unipolar depression and its mechanisms than I think we do about bipolar depression.

So, I said a few moments ago, depression, the syndrome, for the most part looks identical in unipolar and bipolar disorder. Those 9 DSM features that remind us, depression as a syndrome is not just sadness, it's diminished capacity to feel pleasure. So those core elements are fundamentally indistinguishable in unipolar and bipolar disorder with some arguable exceptions. There's some research to suggest that in bipolar depression, atypical features are somewhat more common. So instead of loss of appetite and insomnia with fatigue, you may see overeating and oversleeping, reverse vegetative signs as it's known. There's a somewhat greater likely to seeing psychosis in bipolar disorder than unipolar disorder. The duration of episodes is also shorter in bipolar depression. So, we think of unipolar patients oftentimes having persistent depression, where symptoms can last for up to 2 years, and bipolar disorder brief episodes, usually 3 to 5 months is about the timeframe that we'd expect to see.

So, this is another important point when we think about mechanisms is the timeframe. And a pearl I always like to share is always ask a patient when this episode began. You're interested in their natural cycle length in terms of the duration of the episode. So, we're not just interested in tweaking neurotransmitters around depression. The whole notion of mood stabilization is really to try to achieve and sustain euthymia without triggering the next phase of illness.

Now, this can bring us to the notion of mood stabilizers as antidepressants. Lamotrigine probably stands as the best example. The one most clinicians think of. It's an off-label use acutely for bipolar depression. Lamotrigine's on-label efficacy is for prevention of recurrences, but the collective database shows a much stronger preventative effect against depressive episodes than against manic episodes. And some people think that may have to do with the combined mechanisms of lamotrigine around voltage-gated sodium channels, as well as the effects on glutamate.

Last thing I wanted to say about mood stabilizer mechanisms, is lithium and its mechanisms, which we don't fully understand. The current thinking is that lithium has multiple targets that are involved in its effects. It seems to importantly play a role in second messenger signal transduction. So, if someone asks me, "Well, what do you think the mechanism of lithium is?" Aside from saying, "We don't really know," we'd say, "It involves intracellular signaling and second messenger pathways in cells to try to enhance neuroplasticity.”

And then we come to the whole world of the atypical antipsychotics. And here things get even more interesting, because there's really not a known class effect with atypical antipsychotics when it comes to efficacy for bipolar depression. So, there are a handful of second-generation antipsychotics that have demonstrated efficacy and even FDA approval to treat the depressed phase of bipolar disorder. Quetiapine, lurasidone, olanzapine/fluoxetine combination, lumateperone, and then cariprazine are the examples. And there's differences among these agents apart from their effects on D2 antagonism and 5-HT2A antagonism. These agents differ at other receptor sites and the neural circuitry thereof. So lurasidone for example, has some 5-HT7 antagonizing effects and some 5-HT1A agonizing effects. Cariprazine has a very powerful effect on the D3 dopamine receptors. It becomes very intriguing to speculate about how a drug such as cariprazine that we think of as a D3 partial agonist, among other things, may have its antidepressant effect through the reward pathway. The drug lumateperone, recently FDA approved for bipolar depression, very potent 5-HT2A effects, as well as some D1 postsynaptic binding, which we think indirectly modulates glutamate. So many systems that are involved, [it’s] hard to classify them under 1 single unifying rubric.

Dr Kelly: Joe thanks so much. So, taking all this information, this leads us into looking at the novel and emerging treatments. So, you mentioned lurasidone, cariprazine, lumateperone, which are some of the approved agents that we're looking at with mechanisms beyond pure dopamine 2 antagonism. Another agent that is recently out is an olanzapine/samidorphan combination. Now, we know the mechanism of olanzapine. Samidorphan is added as a mu opioid receptor antagonist and some agonist capabilities at the kappa and delta opioid receptors. Really, it's for the attenuation of weight gain.

In terms of investigational medications, there are some very exciting things coming out. Ulotaront for example, has some interesting mechanisms. It's nothing within the dopamine system as primary, but this is where we're looking at the TAAR1 agonist properties of ulotaront. Also, the serotonin 1A agonism with that medication. Another exciting compound in the pipeline is xanomeline with trospium. So KarXT is the combination here, but it's primarily working on the muscarinic receptor. So M1 and M4 agonist activities. Also, pimavanserin is approved for Parkinson disease, but keep in mind, this is not a dopamine antagonist. This is an inverse agonist-antagonist at the serotonin 7 receptor.

Christoph, do you want to go ahead and talk a little bit of some of the data of these compounds of in schizophrenia?

Dr Correll: Sure. So, as you said, lumateperone recently approved, for schizophrenia, also for bipolar depression. It was tested in a phase III study, both the approved 42 milligrams and the lower dose, 28 milligrams. The 42 separated on total symptoms and on positive symptoms, as well as CGI, separating on total PANSS as early as we'd want. The 28 milligrams, interestingly, didn't separate on total symptoms but on positive symptoms and on clinical global impression. There's very few side effects. It's approved at 42 milligrams. Only when there's a liver dysfunction would you go to 28 and it's approved for its efficacy and safety.

Then we have ulotaront, which is currently under investigation, which is this TAAR1 agonist with 5-HT1A agonism separating in a 4-week study nicely for total symptoms as well as for CGI. Interestingly, we know that when positive symptoms improve, negative symptoms follow soon, that was shown here too. But there was also, even though patients were not selected for depression, a good signal on the matter as for depression and here placebo-like side effects similar to lumateperone.

And then there is KarXT. The xanomeline, which is an M1, M4 agonist as you mentioned, plus the peripheral trospium, it's an anticholinergic, so it's not centrally active. There's a little bit of nausea, very little vomiting. There's a little bit now also in terms of urinary hesitancy or having some constipation, but patients stayed in the study, there was no greater decrease and dropping out than with placebo as have been seen in other studies. And I think that's very exciting because we have a positive phase II study.

Dr Kelly: Thanks, Christoph. I agree this is exciting So let's switch gears here and look at some of the data for bipolar depression. We have data with lurasidone, cariprazine, lumateperone, and let's turn that over to Joe.

Dr Goldberg: So, these drugs are multipurpose compounds. They were first studied in schizophrenia. So, for someone like Christoph, they are antipsychotics. So, some patients may wince at the notion, “You're giving me an antipsychotic drug, does that have some implication about psychosis?” But really, it's the mechanism that we're intrigued by. So, as we said a bit earlier, these are all compounds that have different molecular signatures and profiles. So, I think as clinicians, we want some language with which to impart this to patients just so that they have some sense of, this is because it's really trying to target receptors that we believe play a role in mood stability.

So let me quickly just talk about the data with each of these 3 compounds, which are all FDA-approved for bipolar depression, starting with lurasidone, either alone or in combination with lithium or valproate has its FDA indication. The original studies that were done looked at low-dose and high-dose ranges and interestingly found an identical effect in reducing depression symptoms at a low-dose range where the mean dose was about 32 milligrams a day or a higher dose range where the mean dose was about 82 milligrams a day. So that means one might very well start out at 20 milligrams a day, give it a couple of weeks. We like to see an inkling of improvement by 2 weeks. If you're not seeing improvement by that point, you are welcome to escalate the dose up. But bear in mind, once you get past 60 milligrams a day, the high-dose range didn't necessarily show a greater effect. We sometimes go higher if there may be mixed features or if there's psychosis or if we're trying to fine-tune a response for it, but don't assume you've got to push the dose, push the dose, push the dose. Christoph and I both were talking about cognition is one of the off targets that we look at in patients with both schizophrenia and bipolar disorder. And there actually was one randomized trial in euthymic bipolar patients demonstrating some improvement in global cognitive functioning with this molecule, different from some of the older more antihistaminergic antipsychotics.

Cariprazine dosed either at 1.5 or 3 milligrams a day, there were 3 randomized trials in bipolar depression. Across those studies, the 1.5 milligram dose uniformly separated from placebo, the 3 milligram dose separated in 1 study but not the other 2. So once again, we don't necessarily think if some is good, more is better. We may want to keep the dosing on the lower side, start at 1.5, potentially may go higher if there are mixed features if there's psychosis or to fine-tune a response. But don't assume the need to go higher necessarily.

And then but not least, lumateperone, which was FDA approved the end of last year. There was one dose 42 milligrams a day, recently 2 lower doses, the 21 and I think the 10.5 milligram dose strictly for people with moderate to severe hepatic disease. So that's not meant to give you wiggle room for the dosing. The data are compelling, particularly in bipolar 2 disorders. The size of the effect with lumateperone was even greater in bipolar 2 depression than bipolar 1 depression. Side effect profile, about a 13% incident rate of sedation. And then some nonspecific CNS side effects, dizziness, nausea, all less than 10%, relatively weight neutral in both short and long-term studies as are all of these compounds. So, these are really in advance, I think in many respects of above and beyond things that have been tried before and really stand is the first-line treatments for bipolar depression.

Dr Kelly: Joe, thank you for the information on the established treatments we have for bipolar depression. Could you comment a little on emerging treatments for bipolar depression?

Dr Goldberg: Yeah. So, what's exciting down the line, ketamine is now established as esketamine for unipolar major depression. There are, at last count, 3 randomized trials of racemic ketamine for bipolar depression, with a large effect size. It's an off-label use, but it's a very promising area, invites us more to think about the anti-glutamatergic effects, NMDA receptor effects, maybe even sigma-1 effects. So, watch for more data on ketamine.

And the other really interesting emerging area are the psychedelics. Psilocybin is getting a lot of attention, the initial studies done in unipolar disorder. There are now some ongoing multi-site trials of psilocybin for bipolar depression. And the thinking here is again about neurotrophic effects. So, it's not necessarily the psychedelic effect that you get from a 5-HT2A agonist. It's actually the neuroprotective effects. But these are 2 very promising compounds ahead.

Dr Kelly: Joe thanks, this is really helpful information. Let's have a discussion now that we know the pharmacology of these agents. What do we consider when we initiate a new treatment in a patient? Christoph, do you want to start?

Dr Correll: Yeah, so I think there are multiple domains. Ideally, where we would like to head to is that we have biomarkers and we know a certain patient will respond to a certain medication. We don't have that yet, but there are pointers. So, people who are in the first episode or early phase will respond to most agents except for a small group in schizophrenia that is predominant or primary treatment resistant, maybe 20%, but 80% will respond. And so here you should give really agents that have very few side effects as much as possible because patients respond better but have more side effects.

Then there is another dimension. earlier phase patients that have not yet learned about the illness are more likely to stop, and treatment nonadherence will come about many times during the treatment course. So, thinking about a long-acting injectable. We talk about positive symptoms, sure, but what about negative and cognitive symptoms? We don't want strong dopamine blockers or sedating agents that can make cognition and negative symptoms worse.

And then let's not forget about depression and schizophrenia. That often happens especially early on in the illness when also suicidality happens. So here some of the newer agents that have antidepressant capacity and are approved in mood disorders might be our go-to drugs early on.

And then finally, anybody I think should be protected against the weight gain and metabolic abnormalities that can happen with many of these agents and with the illness itself. So, selecting drugs that don't have that and then also sparing sexual side effects and extrapyramidal side effects so that they can live a healthier life, but also, more functional life.

Dr Kelly: Yeah, Christoph, I think it's going to be really important. It's going to be interesting to see how this plays out, but with the new agents not having the dopamine 2 antagonism and the side effects that go with it, we have the opportunity now as we move forward in the future to have people starting potentially on agents where they wouldn't have had the initial EPS, those prolactin side effects, the sexual dysfunction, gynecomastia, galactorrhea, all these things I've spent some time studying.

A few things also is once in a while we pay attention also to the pharmacokinetics or the drug interactions. I know that the lumateperone for example has a lower dose now, but if we do have a strong CYP3A4 inhibitor on board for example, we might start a little bit lower. So, we pay attention to that a little bit.

Joe, what are some of the things in bipolar depression that you consider in initiating treatments?

Dr Goldberg: So just as I was saying earlier, antipsychotic connotes antipsychotic effects, although we're not interested in that so much as their antidepressant properties. We have to explain to patients and sometimes colleagues that the drugs we call antidepressants aren’t necessarily beneficial in bipolar depression. They still remain the most widely prescribed class of medicines. One meta-analysis found the number needed to treat to get a benefit with an antidepressant is 29. That's a lot, right? You got to treat 29 people with an SSRI or an SNRI before you're going to see a benefit. We often think that antidepressants mainly have the risk of switching into mania, which is a relatively lesser risk. The biggest risk is they’re not going to work. So, step 1 is what has your prior treatment been? If you are the rare bird for whom a monoaminergic antidepressant has worked, that is evidence in your favor. But if not, let's not do the same thing over and over again. Of the 5 FDA approved treatments for bipolar depression, let's start with 1 of them.

Side effects and tolerabilities nowadays are nonstarters for many patients and colleagues who will say, "I'm not going to use this drug if there's a certain side effect." And yet the morbidity and mortality from depression and bipolar disorder remains substantial. So, we want to pick things that work and preferably things that are metabolically neutral. We've got now 3 molecules that fit that bill. We might from among them, think of certain nuances like, "Is this bipolar 2 depression?" If so, lumateperone happens to have the strongest data. Is this someone for whom cognitive functioning is particularly an issue? Lurasidone may have some edge there, perhaps by virtue of the 5-HT7 effect. Is there something around motivation and reward? For some people, it's been said 70% of people with depression have an impaired capacity to feel pleasure. So maybe a D3 partial agonist such as cariprazine might have value there.

So first and foremost, make a clear diagnosis. Decide if someone is in that small minority for whom monoaminergic antidepressants may be of value, like no mixed features, bipolar 2, not bipolar 1, no recent mania, no psychosis, prior good response. It's a small subset, and then focus on the FDA-approved, evidence-based treatments. And then we can think from among the nuances among them as we tell patients that we've got options now that we didn't have just a few years ago.

Dr Kelly: Yeah. That's a great point. Christoph, do you want to make any comments about when you think about switching and how you do that?

Dr Correll: Yeah. I mean, there are various reasons and junctures. One is certainly in the beginning of an acute episode. If you have someone on 2 weeks of a good dose and it's taken and you see nothing, absolutely nothing, that's a good predictor that you won't see much down the road. So then maybe switching the treatment might be helpful. Or in one study with lurasidone actually doubling the dose within the package insert dosing from 80 to 160 also was helpful.

And then we switch for intolerability or we switched for inefficacy and we switched for patient preference and we switch for problems with functionality and also at times, adherence. These are all reasons to switch. And then sometimes we're caught between a rock and a hard place when there is efficacy, but there are side effects. And how much do you risk the efficacy by going to a drug that has maybe less side effects?

Dr Kelly: Yeah, I agree. And I think it's also important when we're thinking about switching that we want to avoid relapse. So, we don't want to have a rebound of symptoms here. So, I traditionally take a slow cross taper too when we're switching agents so that we make sure that we're not just stopping an agent. There's lots of data that tells us it's probably better to do a cross and take it slow, so our patients do well.

Joe, do you want to add to the discussion?

Dr Goldberg: Yeah, I actually want to borrow, if not steal what Christoph just said in underscore this 20% issue. So, in the bipolar depression world, it's pretty well-established at this point that if you haven't seen at least a 20% improvement in the first 2 weeks, the probability of seeing response or remission in subsequent weeks is pretty low. And the flip side of this is you don't want to prematurely abort a clinical trial saying, "Well, you're not all better in 2 weeks. I guess move on to the next thing.” That's not an adequate trial. You need to use some metric. Measurement-based care I think is becoming standard of care. Whether it's a self-report, a PHQ-9, a QIDS, a MDRS, a Hamilton, a visual analog scale, are you better the same or worse? If you're still not seeing anything after having tweaked after 2 weeks, then it may well be time to move on. That may well be an adequate trial and that means picking something else.

So, this means going back to reviewing the same symptoms that began our initial decision-making.What's your sleep-wake cycle pattern like? What's mood like? What's anhedonia like? What's motivation? What's concentration like? We sometimes do augment. Polypharmacy is not a bad word, particularly if there's complementarity of mechanisms. My own recommendation to patients is we cycle through the evidence-based fare before moving on to the more experimental or off-label kinds of treatments or consider them as auxiliary treatments.

How do we switch partly depends on the half-life. And just watch carefully when you're doing the switch, because the drug you think isn't working may sometimes surprise you to discover that it actually was working imperfectly better than you thought. And if you take it away and you're auditioning the new drug, it may or may not be as efficacious.So, we want to meet with close enough eyes on the patient during that switch over period and also watch for the additive effects, especially EPS and sedation, to try to get people on whatever the next patient's going to be.

And lastly, we don't want to duplicate mechanisms. We probably make a switch there and if we're going to augment, just watch very carefully during those transition periods.

Dr Kelly: That's great. I think it's also important as we switch and we have medications on board for a little while as we switch over to also pay attention if the other medication wasn't working, we need to remember to sort of eventually taper that down and take them away. I see too often where we have so many medications on board, and we were switching and they just never got discontinued especially with many different people in the treatment paradigm. So, it's really important and I think you both--

Dr Goldberg: Deprescribing is the word, right?

Dr Kelly: Yeah. Exactly. Deprescribing. And it's critical, both of you really pointed out that early indication of treatment is really going to matter and there's 2 weeks to understand that, be looking for that.

So, let's summarize here today. So, the current thinking as both of you pointed out that behavioral symptoms, psychiatric disorders, they're associated with dysfunctional brain circuitry. So, in terms of treating disorder, we need to address circuits and not just neurotransmitter. There are overlapping symptoms that we talked about. Our new treatments are targeting some of these dysfunctions we're talking about. They're beyond dopamine 2 antagonism. And then these emerging treatments too that are very exciting.

Christoph and Joe, I thank you for this great discussion. I thank you, the audience for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has been edited for style and clarity.

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