Positive Psychiatry and Two Forgotten Antidepressants

Your patient tells you, “The darkness is gone… but the color is gone too.” That line captures a problem many of us recognize: symptom scores can look great while real life still feels flat. From Texas, I walk through the positive psychiatry question that keeps nagging at clinicians and patients alike: are we only stopping the storm, or are we helping people experience the full spectrum of their lives again? 

We get specific about the “SSRI blight” and why emotional blunting, apathy, and cognitive fog can linger even when PHQ-9 and GAD-7 say “remission.” I argue for expanding our outcomes beyond symptom reduction to measures that reflect functioning and flourishing: focus, executive function, relationships, hobbies, resilience, and joy. That’s where the “forgotten antidepressants” come back into view. 

We shine a spotlight on vortioxetine (Trintellix) as a multimodal antidepressant with receptor activity that may support cognitive clarity and executive functioning for the right patient, and we break down vilazodone (Viibryd) as a SPARI with a more calibrated serotonergic signal that can be a strong fit for anxious depression and rumination. We also talk honestly about the GI side effects that scare people off, and how practical steps like slower titration, patient education, and taking vilazodone with a substantial meal can make a real difference. 

Clinicians and patients are both motivated to find the tools that move us from “better” to truly “well.”

www.JainUplift.com

Transcript

Welcome And The Sunset Question

SPEAKER_00 0:04

Hello friends and welcome to another episode of Positive Psychiatry with Rakesh Jan. And today's episode is, I think, pretty intriguingly titled as The Forgotten Antidepressants, Ortioxetine, Velazodone, and the Era of Positive Psychiatry. Intriguing, isn't it? My name is Rakesh Jan, and I'm very grateful that you have chosen to spend this time with me today. And I don't know if you're listening to it while sitting in your office or on your commute or perhaps out on a walk, perhaps even in the gym. I sometimes listen to podcasts when I'm working out. We are in this together, aren't we? And I'm recording this from my base here in Texas. And as I look out of the window today, I'm reminded of why we do what we do. Well, we do it to help people experience the full spectrum of their lives, not just to reduce their symptoms, but to experience the full spectrum of their lives. So perhaps to open our discussion today, I thought I might share a thought from a really great poet from India. His name was Rabindranath Tagore, T-A-G-O-R-E. And he wrote, Clouds come floating into my life no longer to carry rain or usher storm, but to add color to my sunset sky. I want you to hold on to that imagery for a moment. So clouds that are no longer carrying a storm, but exist simply to add color to the sky. So in the field of psychiatry, we are incredibly skilled at stopping the storm. We're masters of the crisis. We know how to take a patient who is drowning in the torrential rain of a major depressive episode, or perhaps even suffocating in the hurricane of a panic disorder, and we know how to pull them indoors. We know how to stop the rain. But I gotta ask you folks this. Are we adding color to the sunset sky? The color of wellness and functionality and cognitive health? Or are we simply leaving them in the gray, overcast, weatherless room that we call remission in modern-day psychiatry? Well, that's the central question of positive psychiatry. That are we just talking about improvement in symptoms? Or are we talking about the flourishing of the human being? So today we're going to embark on a deep, comprehensive exploration of the two pharmacological agents that I mentioned earlier that I think are unfairly forgotten by modern-day psychiatry. They are, they've become second line, third line, or sometimes zero-line. Why? Well, well, I guess they're older and we completely forgot about them. And these two agents are vortioxetine, which is also known as trintelix, and velazidone, also known as vibrid. They have been forgotten, but before we appreciate why they've been forgotten, we really ought to, in a few minutes, dive into the profound neurobiology of these specific agents and see could they serve, could they serve extra roles beyond then, beyond just being antidepressants? Could they in fact help our patients in ways that our traditional first-line therapies like SSRIs and perhaps even SNRIs don't.

The SSRI Blight And Emotional Blunting

SPEAKER_00 4:18

So now is the moment, I think, my dear colleagues, that we need to confront pervasive phenomena in our daily clinical work. Why don't we just call it the SSRI blight? Because we got to be brutally honest with ourselves as clinicians, because we've seen this before. We've seen this every week. A patient comes into our clinic. Let me give you an example. Let's call this patient Sarah. And she's a 42-year-old lady, a mother of two. She's the marketing director at a medium-sized business. Six months ago, she came to us weeping, unable to go out, get out of bed, paralyzed by a deep melancholic depression. What we prescribe an appropriate medicine, right? An SSRI. But here she is, six months later. And her PhQ9? It's only four. Wow. GAD 7, 3. Based on that, she's in remission. So she is in remission. The numbers look great, don't they? The depression is on paper very well managed. But then you look up from the paperwork and you look into her eyes, and what do we see? We often, as much as a third of the time, we do not see the spark of engagement. We do not see the vibrancy of a life fully lived. We see a muted, grayed out sky of a person, washed out version of the woman that she used to be. We ask her how is she doing? And she says something that should break our hearts as healers. She says, Dr. Jane, the darkness is gone. I no longer cry every day. But the color is gone too. I don't feel sad. I just don't feel joy. I am just here. So you know what this is, right? She is experiencing emotional blunting. She's experiencing cognitive fog. She's experiencing a sense of being shackled by her treatment rather than unleashed by it. So the storm is gone, but she has no sunset sky. And as a profession, we have become absolute masters of symptom suppression. But we've become novices at symptom replacement with vitality. We often settle for better and we forget to aim for well. And this is why this framework of positive psychiatry is so important.

From Symptom Reduction To HERO Traits

SPEAKER_00 7:12

It's not a rejection of traditional psychiatry, not in the slightest bit. But it does demand we look above and beyond just the basics. So positive psychiatry is not about ignoring illness. It's not about toxic positivity. It is rigorous, evidence-based. Pursuit of human flourishing. So in our field, we often get stuck in what I would call symptom reduction rut. We focus entirely on what is wrong. We try to subtract this negative out of our patients' lives. But subtracting a negative does not automatically equal a positive. Removing sadness does not automatically create happiness or enthusiasm or resilience or optimism. These are the hero traits, H E R O, happiness, enthusiasm, resilience, optimism. So how often are our traditional pharmacological tools, our first-line treatment tools fostering these hero traits, or are they simply putting a heavy lead blanket over the entire nervous system? When we rely exclusively on standard SSRIs, SNRIs, we are flooding the synapses with serotonin and perhaps some norepinephrine. We are downregulating receptors across the board, though. I hope you heard that last comment I made. By doing that, we are downregulating receptors across the board. The ones that we want to and need to, but alas also the ones we don't want to, thereby creating a numbing effect. Now there's nothing wrong with a numbing effect when a patient is in acute crisis. I do not want to diminish the historical importance of the SSRIs. I firmly believe they have saved millions of lives. But they're often tourniquetes, they're not the physical therapy that restores the full range of motion emotionally. We must move beyond applying this tourniquet. So when a patient like Miss Sarah sits in front of us, suffering from cognitive fog, executive function, emotional blunting, while on our standard first-line therapy, what is a typical clinical reflex? Well, often the inertia for training kicks in. We say, well, the depression is somewhat better. But she's still struggling, so let's increase the dose of the SSRI. Guess what happens? She gets worse. Or we might say, hmm, I've identified a side effect. Let me decrease the dose. But adjusting the dose of a single mechanism of action drug is very limiting. Just imagine your master mechanic trying to fix a highly sophisticated, multi-layered, beautiful complex engine. You and I wouldn't try and fix the entire engine by turning one single screw tighter or looser, would we? No. We would look at the entirety of this engine, this complex engine, and then determine what we tighten, what we loosen. And of course I'm using that as a metaphor. So when we stick to the classic SSRI path, we're essentially trying to play a symphony by only plucking at one string. That's not going to work. It's like saying, I have an excellent piano, but I'm only going to play one key. So when we simply increase the dose of a standard re-eptic inhibitor, we often make the patient more blunted. We make the apathy worse. We deepen this brain drain. And this is why thinking about psychopharmacology in a broader sense is both a clinical, but I think it's also a moral imperative. We must seek out agents that do not just blindly flood the system with neurotransmitters, but in fact actively and intelligently modulate the receptor landscape. We need to look at the excitation and inhibition balance in the brain. We need to look at the glutametergic signal. We need to look at different serotinergic signaling. We need to look at different receptors in the dopamine, norepinephrine family. We must demand more from our molecules. And that is precisely why we are shining a massive spotlight on voltooxetine, also known as trintelex to very many, and velazidone, known as vibrid, to very many. Now there are a whole lot of relatively new clinical practitioners in psychiatry. They could be MDs or DOs or NPs or PAs or even prescribing psychologists. And it's quite possible they have not had exposure to these medications. So let's dive into it. Now please note, both of these two medications don't think of them as just another antidepressants, because they really, in many ways, are not Me Too drugs, and they represent a fundamental shift in pharmacological philosophy. Well, think about this. Atypicals are a major development in mood disorders. They were and are a fundamental shift in pharmacological philosophy. Primarily glutamaturgic drugs like dextromethorphin and buproprion combination, known as ovality, also a major fundamental shift in pharmacological philosophy, and so is eschetamine, known as spravato and ketamine, glutamaturgically important medications, a fundamental shift in pharmacological philosophy. They've all helped, but should we really forget about these two V medications? Vortioxine, velazdone, I don't think we ought

Why Vortioxetine And Vilazodone Vanished

SPEAKER_00 13:46

to. So why have they been forgotten? I think they arrived at a time in psychiatry when perhaps the psychiatric community was experiencing a bit of fatigue. The market was crowded, the options were very many, the generics were plentiful, good enough, and I put that in quotes, had become the standard of care. And because they're not traditional SSRIs, they require a bit more thought. They require a deeper understanding of receptor binding profiles. And unfortunately, in the rush of modern 15-minute medication management appointments, well, this nuance is often the first casualty. So in many ways, these rather brilliant, nuanced, multimodal tools were pushed to the side. They became, yes, the forgotten antidepressants. But from the lens of positive psychiatry, we cannot afford to forget them. We really can't. And you will see that in the next few minutes of the podcast, why we can't. Because when we care about cognitive clarity, when we care about a patient's ability to focus, to read a novel, or to be truly present at the dinner table with their children, we need pharmacology that supports executive function. When we care about emotional range, when we want our patients to be able to carry out and to enjoy a beautiful piece of music or laugh at a joke or just enjoy a quiet sunset, we need pharmacology that does not blunt their affect. When we care about functional flourishing, we need agents of restoration, not just masking. So as we prepare to continue this conversation, I want to challenge you, if I may, to perhaps redefine your outcome measures. I know we should use the PHQ 9 and the GAT 7, and I'm all for it. But they are incomplete. I would recommend you add a new set of questions. When your patient sits across from you, ask, how is your life satisfaction? How is your engagement with your hobbies? How are your relationships? How is your resilience? Because you know, medications are not magic pills, they're not chemical bandages that magically cure the human condition. Medications are scaffoldings. So think about a building that is undergoing a massive, beautiful renovation. Well, we cannot rebuild the facade or strengthen the foundation without putting up the right kind of scaffolding first. So the scaffolding itself does not build the house. So in the case of depression, using that as a metaphor, the patient restores themselves. They do the work, they go to therapy, they engage in life, they find ways to eat better, sleep better, socialize more. But the scaffolding does provide the structural stability that allows the patient to pick up the task and move forward. So if we use a medication that causes sedation or weight gain, well, we're building scaffolding out of wet cardboard, right? It'll collapse under the weight of the patient's efforts. But if we are using a medication that causes emotional blunting, no matter how severe it is, we are building a scaffolding that is innately problematic. The patient will struggle to recreate, rebuild the broken house of depression. So let's now start thinking about vorteoxetine and velazidone. Let's think of them as differently engineered scaffoldings, and we're going to dive into each differently, separately.

Vortioxetine And Cognitive Clarity

SPEAKER_00 18:07

So first, let's go to vorteoxetine, trintelics. Think of it as a multimodal maestro. We will explore how antagonizing the 5HD3 and 5HD7 receptors of the serotonin family that this medication does so uniquely opens up pathways for executive function and cognitive clarity. After that, we will explore velazedone, who I tend to think of as the precision engineer. In fact, it's so different. There's a brand new name for it. It's called the SPARI, SPARI, the serotonin partial agonist and reuptake inhibitor, a very different mechanism of action. So let's do this, folks. It's time for us to move on to a much deeper conversation with the full appreciation that SSRI blight, this SSRI-related structural scaffolding problems are very real. They affect a large number of individuals who otherwise are defined as in quote remission, end quote, but they are only in remission with their symptoms, not with their wellness. So it's time to talk about phortioxetine, the multimodal maestro. Now, most of us, certainly those of us who trained in the 1990s, grew up with the belief that more serotonin means better. So if a little bit is good, a whole lot is better for you. But as we look at voteoxidine, that is absolutely not the case. When we look at its pharmacodynamics, we will see three critical components that distinguish it from the standard class. What are those components? The first one that we must address is serotonin 5HD3 receptor antagonism. And this is absolutely key to this particular forgotten medication's utility. Because by antagonizing the 5HD3 receptor, we're doing something quite brilliant. We are in fact going to downstream effect two neurotransmitters that we typically do not modulate acetylcholine and glutamate. Now we turn our attention to looking at 5HD7 receptor because you know this medication, volteoxetine, in fact has significant antagonism at 5HD7 receptor. This receptor, in fact, is pretty well known in psychiatry and is often jokingly called the cognitive receptor. So for patients who have memory difficulties, executive function difficulties, which is, the truth be told, between 70 and 90 percent of individuals, this is quite helpful. And then finally, the third thing we should talk about is the glutamaturgic link. It's indirect, it doesn't directly act on the NMD or MPI receptor, but there is a glutamaturgic link because vorteoxetine trintelix does have effects on 5HT3 and 5HD1. And what that does, it in fact becomes a Glutamaturgic intervention worthy of note. So all of this comes together to give this multimodal maestro. Actually, that's not a bad way to describe it, a pretty significant separation from other members of the cast of characters of antidepressants. Now, let's do this. Let's ground all this science in the story. And I had a patient, let's just call him David, who was a software architect, a brilliant man, 52 years old, very creative. His work was so complex when he would try and describe it to me. My head would spin after the first 30 seconds. Well, he had been on high dose SSRIs for years, and his mood was stable. His PhQ9 was low, but he came to me and said, not depressed, not suicidal. But you know what? I am no longer David. That's what he said. I'm no longer David. I don't really see me anymore. Oh, I work. I take care of my family. But I don't see me anymore. I'm not in touch with myself, my emotional life. But also, I'm not making decisions as rapidly as I used to. And I need to. With my work, I need that. So this is the blunting I was talking about. This is the executive dysfunction I was talking about. So we need to appreciate that these symptoms for David were genuinely problematic. So he's one of those patients where thank God I was listening to him and I brought in positive psychiatry. And I'm happy to tell you he was able to take full advantage of the shifting landscape he and I created in his psychopharmacology. But all that happened only because he and I were thinking deeper and broader and keeping his positive mental health front and center of our decision-making process. If you get a chance to look at the package insert for vortioxetine, I think you're in for a whole bunch of surprises. This is one of those rare antidepressants where even on label, the FDA has said there is a clear advantage in terms of executive functioning. Yes, in terms of cognitive abilities. Is that important? It really can be hugely important for the right patient. And because this is an important issue, I would encourage you when we're engaging with our patients, particularly at follow-up visits, to ask them questions like, How is your focus? Do you feel like your thoughts are sharp or are they hazy? Do you feel like you're able to plan your day or you're just surviving the day? These are all important things to ask. Because these cognitive symptoms are a really strong predictor of long-term functional impairment. And if we ignore cognitive symptoms, you guessed it correctly, the patient will struggle to return to the original self, to the family life, to the community. So this multimodal receptor activity is important.

Nuance Matters Side Effects And Patience

SPEAKER_00 25:40

Now I think this is a time and a place to discuss a clinical nuance with you. That's always important, isn't it? Nuances always require. These multimodal agents require patients. I have to tell patients we are retuning their orchestra. We're not just turning up the volume up or down. We like adjusting the violence, the cellos, the percussion. Using that as a metaphor. So we need to appreciate that these are not one-day fixed medications, that's their weaknesses. But the advantages are they have clear cut data. Let's just turn our attention to vortioxidine on helping with cognitive dysfunction, but also with sexual dysfunction. It's been demonstrably better at causing less sexual dysfunction than SSRIs. On top of that, we should appreciate that these multimodal mechanisms of action medications can have side effects, particularly GI side effects, that cannot be underestimated. Nausea can be a significant challenge with both vortioxetine and velazodone. Yes, when we stimulate other receptors besides serotonin, there can be a price to pay. So any clinician who wants to use either one of these two medications would be well advised to educate their patients about these side effects and to arm these patients on how to deal with them. Because with both of these two medications, a large number of patients do improve with their difficulties with nausea. All right.

Vilazodone As A SPARI Dimmer

SPEAKER_00 27:45

Because very many patients could benefit from such an intervention. And now we shift our attention to an agent that represents a very different kind of clinical precision, and that is velazodone. This medication has been known in America for a long time as vibrid. So if vortioxidine is the conductor of a symphony, from a metaphoric perspective, you may want to think about velazedone as a precision engineer. And it is often dismissed because, well, it's different. Well, because of its gastrointestinal profile. But we look past the initial hurdles some patients have, by the way, most patients don't, we find that a unique mechanism that serves a specific vital patient population emerges. That's why I do think velazodone is a forgotten medication. And especially if you're interested in positive psychiatry, it is really important not to do so. So let's dive into velazodone. As I shared with you before, it's classified as a spARI, S-B-A-R-I. Is serotonin, partial agonist, and reuptake inhibitor. You got it? Brand new, right, for us? SPARI. Serotonin, partial agonist, and reuptake inhibitor. So I think in many people's clinical experiences, many patients struggle with traditional SSRIs because of the all-or-nothing nature of pure reuptake inhibitor and inhibition. SSRIs flood the system, which can sometimes lead to that profound emotional blunting we discussed earlier. There is something different with velazedone, and that is the partial agonism at the serotonin 5HD1A receptor that provides a breaking mechanism. So it does not flood the system, it provides a controlled calibrated signal. Think of it as a dimmer switch to the brain's neurotransmitter system rather than an on-off light toggle. Therefore, it allows for a more nuanced stabilization of the serotonergic system. And through it, interestingly, even the glutamatergic system. And this is essential for the patient who is sensitive to the side effects of standard antidepressants that we have already talked about. So for a moment, let's come back to the hero traits we had discussed previously. Remember those hero traits? Happiness, enthusiasm, resilience, and optimism. We often find that the biggest barriers to these are this challenge with anxiety-induced paralysis of the individual. So the patient is wired and tired at the same time. And they're not able to use this energy that they have in the right direction. So it converts into anxiety and rumination and flat out exhaustion. They don't sleep well. They want to exercise, but they can't muster the motivation. They're stuck in a feedback loop of worry and fear and yeah, literal paralysis. So Velastone is particularly effective for a whole bunch of individuals, but I think it may be particularly effective for the individual who has a combination of these ruminative worry loops that pull anxiety in. And because of this unique receptor interaction, it offers more of a gentle push rather than a sedative push into antidepressant and anxiolytic effects. It seems to be a molecule that in addition can offer resilience. And the data shows us that the onset of benefits with this medication in trial after trial has been quick, quicker than anticipated, and broader than anticipated, with carrying capabilities as an antidepressant. In fact, some years ago I published, I led to the I led a research project where I was the lead presenter, the lead published author on an article where we combined two different trial data to see if this medication could be of benefit to human beings. And yes, it was. It was broad effect, it was rapid effect, it was sustained effect. But it's interesting, even though that was a mere decade ago or so, psychiatry has a short-term memory and has forgotten in in large part because of lack of education on both of these two V medications. Now we talked about the GI hurdle, right? The gastrointestinal side effects.

Beating GI Hurdles With Strategy

SPEAKER_00 33:24

That is real. It's a valid concern. Both of these medications can produce GI side effects, and it's often a reason for discontinuation, but that is so not appropriate. It isn't. GI difficulties are temporary and highly manageable. You know what? Wake-in isn't, sexual dysfunction isn't, cognitive apathy isn't. So for very many patients, the extra effort that we need to put in to help some people, not all, but some people, get on vorteoxetine and velazidone is well worth it. So here are some tools, some clinical secrets, but they're not really secrets, are worthy of keeping in mind. The first one is titration. Titration is really important. These are medications that tend to do far more than just serotonin impact. As a result, we must give the body's receptors time to adapt. Therefore, starting at lower doses and adjusting it upwards based on the individual's own adaptation is really important. It's so important with the lazodone to instruct patients to take it with a substantial meal, ideally, something containing some protein and healthy fats, which significantly helps in absorption and tolerability. And of course, you have heard me talk many a time before about fiber-rich Mediterranean-style nutrition that, if a patient is willing to adopt, could really go a long way in helping deal with these side effects. As I said before, generally speaking, in most individuals, these side effects are temporary, and it would be a complete shame if a patient stops either one of these two medications too quickly. So maybe I can offer you some thoughts on who I think might be a vilazidone specific responding patient. It's hard to say, but I kind of think it's the anxious, depressed overthinker. And it could be the patient who has tried an SSRI and felt muted or foggy. Both of these two are really great treatment options. And here's the good news vortexine is not velazidone. Velazidone is not vorteoxetine. As a result, we end up with two options that when you look at our patients through the lens of positive psychiatry, these are two options worthy of keeping in the back of our mind. They could be used first line, they could be used second line, they could be used whenever it's appropriate. Just remember, what would not be appropriate is to ever completely forget about them. That's why the very title of this podcast is The Two Forgotten Medications, and that is such a shame for patient well-being.

A Practical Decision Matrix For Clinicians

SPEAKER_00 36:43

So let's synthesize everything we have discussed so far. We have built a clinical decision matrix that really helps us choose with confidence what to do, but also why, and also the shortcomings, the limitations of the way we have been practicing, which is it doesn't matter who you are, dear patient, it doesn't matter what you tried, what has worked, what hasn't worked, we will not change our behaviors, clinicians. That approach has not worked. And our goal ought to be to really fit the patient with the greatest chance of success with the medication's abilities. And if you believe cognitive and executive functioning are important, if you believe cognitive and executive functioning, if damaged by an antidepressant, something should be done, then by default, what you and our agreeing to is the following that both voltaine and velazdone are appropriate medications to keep in mind and are worthy members of our clinical decision toolbox. I think it is really important that we retread several points that we made. Remember, please, we should all remember and we should remind our patients that medications are only the scaffolding. They, in fact, are not what build the house of wellness. They just help the patient build their house brick by brick, wall by wall, easier, better. It is the patient with our guidance and our help who build the house that they're going to live in for the rest of their lives.

Meds As Scaffolding Plus Lifestyle

SPEAKER_00 38:43

That's why I think along with thoughtful psychopharmacology, we should be recommending lifestyle changes such as movement, right? Such as physical exercise, such as nutrition, such as sleep hygiene. All of those, along with things like increasing social connectedness, mindfulness, are profoundly important. As we get to the very end of our time together, my dear friends, it is important to remember that those of us who are practitioners in the fine art of psychopharmacology, we are practitioners of the long game. We don't prioritize the quick fix. We prioritize everything. The quick fix, the long fix. We prioritize durability, but most certainly, we also prioritize the fullness of the improvement. We don't want just symptom reduction. We want this patienthood, humanhood improvement. And as a result, we do not want to induce side effects that really do harm our patients. And that's why I wanted to talk to you about these two options that have been forgotten. And I do think they deserve to be one of the many medications available in our toolbox. And finally, because we're talking about positive psychiatry, we must talk about the great importance of the scaffolding approach, that medications are scaffolding, and that our patients should be reminded that the best way to build the beautiful mansion that is their mind, their brain, and the soul is to strongly consider psychotherapy and one less interventions. I have no doubt you will entirely agree with what I'm saying. Alright dear friends, very lovely to have spent time with you. I wish you folks the very best. Until next time, goodbye.