Positive Psychiatry - with Rakesh Jain, MD

Positive Psychiatry and Glutamate: A Marriage Blessed by Neuroscience

• Rakesh Jain, MD

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Positive Psychiatry and Glutamate: A Marriage Made in Heaven and Blessed by Neuroscience

In this in-depth episode of Positive Psychiatry with Rakesh Jain, MD, Dr. Rakesh Jain examines a critical convergence in contemporary psychiatry: the alignment of Positive Psychiatry with advances in glutamatergic neuroscience.

Traditional psychiatric models have appropriately emphasized symptom reduction—targeting mood, anxiety, psychosis, and behavioral dysregulation. Yet growing clinical and neuroscientific evidence suggests that symptom remission alone does not fully capture mental health outcomes that matter most to patients, including meaning, purpose, resilience, cognitive flexibility, and post-traumatic growth.

Positive Psychiatry emerged to address this gap, grounding constructs such as optimism, gratitude, wisdom, and flourishing in measurable neurobiological systems. In parallel, neuroscience has undergone a major shift in its understanding of glutamate—the brain’s most abundant excitatory neurotransmitter—not merely as a mediator of excitotoxicity, but as the central regulator of synaptic plasticity, learning, and adaptive change.

In this episode, Dr. Jain integrates these two domains, arguing that Positive Psychiatry and glutamate are not complementary by coincidence, but by necessity.

Listeners will explore:

  • Why flourishing depends on intact neuroplasticity
  • How glutamatergic signaling governs learning, updating, and cognitive flexibility
  • The role of AMPA and NMDA receptor dynamics in experience-dependent change
  • Why chronic stress and trauma impair plasticity at synaptic and network levels
  • How depression can be conceptualized as a disorder of reduced adaptability rather than mood alone
  • Why monoaminergic treatments modulate experience but often fail to restore plasticity
  • How psychotherapy, meaning-making, and strengths-based interventions are biologically plasticity-dependent

Importantly, this episode reframes glutamate as a process rather than a molecule—one that determines whether experience is capable of altering brain structure and function. Positive Psychiatry, in turn, provides the directional framework that guides plasticity toward adaptive, meaningful outcomes.

This conversation is not centered on a single treatment or intervention, but on a unifying model of psychiatric care—one that integrates neurobiology, psychotherapy, and human flourishing.

For clinicians, researchers, and learners seeking a scientifically grounded yet forward-looking perspective on mental health, this episode offers a rigorous and hopeful re-examination of how change becomes possible in the human brain.

www.JainUplift.com

SPEAKER_00:

Well, welcome dear friends to another episode of Positive Psychiatry with Rakesh Jan. I am your host, Rakesh, and today's episode is titled Positive Psychiatry and Glutamate, a marriage made in heaven and blessed by neuroscience. Well, I know, I know the title sounds poetic, and it may even sound very bold, but I will promise you it's neither exaggerated nor symbolic. It's in fact descriptive. Positive psychiatry and glutamate indeed do have a marriage made in heaven, and as I will show you, clearly blessed by neuroscience. Because something remarkable is happening in psychiatry right now. Two ideas, both of them powerful in their own right, are finally finding each other. Idea one is the birth, the slow birth, but definitely a birth of positive psychiatry. And the other is equally slow but expanding and exploding in its knowledge base, which is glutamate. So when they come together, something extraordinary becomes possible. So for decades upon decades, psychiatry has focused just on one thing, which is illness. Illness, symptoms. Focus has been on what is broken, what is disordered, what must be reduced, what must be suppressed, what must be corrected. And I have to say, we become fairly good at it. The problem is a whole bunch of our patients are not doing well. They may be better, but they're not doing well. So inside each of us, I genuinely believe believe that there lives a quiet discomfort because symptom reduction is not the same thing as a life well lived. I'm sure you agree with that. So a patient can become less depressed, but still feel empty, become less anxious, but still feel lost. Become perhaps even more stable, but still find disconnection from meaning. So positive psychiatry has now emerged to answer a different question. No longer what disease does the person have, but to go beyond it, to not ignore the disease the patient has, but to ask, what kind of human being is trying to emerge here? That's a very radically different thought, is it not? I most certainly was not exposed to in my residency training or my fellowship trainings. So on paper, I'm actually a rather well-trained psychiatrist. But the truth is, I help my patients become the walking wounded, but not the flourishing. That's why it's so important that we appreciate the potential great benefits of adding positive psychiatry to what we do, not rejecting anything from traditional psychiatry, but absorbing the important neurobiological, humanistic ideas emerging from positive psychiatry. And neuroscience has begun to realize that we have underestimated the most abundant, most powerful neurotransmitter in the human brain. Is it serotonin? No. Is it dopamine? No, not even that. So what is it? It's glutamate. It's the molecule of learning, it's the molecule of adaptation, it's the molecule of change itself. And when one embraces glutamate, everything starts to make sense. That's why I'm devoting an entire episode of this podcast to only the topic of glutamate and positive psychiatry, because one cannot build meaning, resilience, wisdom, or hope in a brain, in a mind that has lost the ability to change. So we cannot talk about flourishing without talking about neuroplasticity. And by default, if you're going to talk about neuroplasticity, glutamate is front and center of this conversation. So this episode will be a story of how positive psychiatry gives direction to change and glutamate makes this change biologically possible. So please settle in, take a deep breath. There's a lot we're going to cover today, and let's begin. And perhaps the best place to begin with is my confession. As I've said before, I was trained, as many of you were, in a model of psychiatry that's fundamentally reactive. We wait for illnesses to develop, we name it, we turn to DSM III or 4 or 5, whatever the case might be. And we hope the disorder doesn't come back. And to be clear, that work was important, is important. It is traditional psychiatry trying to do its best to help our patients. But it is not complete. It's best to think of it as incomplete task. So positive psychiatry in no shape or form rejects anything. It doesn't. It just adds to it. So these are some of the things positive psychiatry practitioner would be asking their patient. What strengths does my patient already have? What capacities do they already possess that they have survived the illness so far? What gives this person's life meaning? What allows them to endure? What helps them grow, in fact, because of the suffering? And then, of course, what are some of their positive psychiatric traits that are weakened that you and I could help them improve? There are four classic traits that we have discussed before: happiness, enthusiasm, resilience, and optimism. The hero, H-E-R-O. There's of course more, but hero is a very good place to start. And these are not philosophical questions. These are in fact neurobiological questions because resilience lives in brain circuits. Meaning lives in brain circuits. Hope has a physiology, it lives in brain circuits. Which circuit? Not the depression circuit, but the wellness circuit. You and I in previous episodes have talked about the neurobiology of wellness, but let's continue talking about it today. So when we talk about optimism, we're talking about future-oriented prediction systems. And when we talk about gratitude, we're talking about salience and valuation networks. And then when we talk about purpose, we're talking about the prefrontal integration of long-term goals. So positive psychiatry is not merely positive thinking, it's actually applied neuroscience of flourishing. Let me say that again because that is such an important point. Positive psychiatry is in fact applied neuroscience of flourishing. And here's the key insight that often goes unspoken. Positive psychiatry can only happen when a person's brain has adequate neuroplasticity. So one cannot cultivate wisdom or post-traumatic growth or adaptive meaning or even possess a narrative coherence about the life's story unless they have neuroplasticity. You got it. You got it. This is why this conversation about glutamate is so important. Because if a brain is rigid and frozen or stuck in threat, a brain that's locked in a survival mode simply cannot flourish. So this brings us inevitably to glutamate, because glutamate is not just a neurotransmitter. It is in fact the currency of neuroplasticity. So we continue our conversation and we need to expand on this a great deal because if positive psychiatry asks what kind of life is possible, then glutamate asks the following question: whether change is biologically allowed. To understand why this matters so deeply, we need to slow down and really meet glutamate, not as a molecule on a slide, not even as a buzzword that we throw around casually just to appear important and have people be impressed, but because it is the central organizing force of the human brain. Because you see, glutamate is not simply another neurotransmitter. In many ways, it is the neurotransmitter. It is. If you're thinking that's a bit of a hyperbole, make note of the following things I'm going to share with you. Did you know 80% of all synapses in the cerebral cortex are glutamaturgic? 80%, four out of five. Every perception we have ever had, every memory we have ever formed, every skill we have ever learned, every meaning we have ever constructed, all of this has to pass through glutamate. No glutamate, none of this. No perception, no memory, no skill, no meaning. So if weather, if serotonin is the weather of the mind and dopamine is the drive of the mind, then we may want to think about glutamate as the architect of the mind. It's what builds everything that you and I hold dear to ourselves. Because it determines what experiences leave a trace. What do we learn? Which kind of learning did we possess? And of course, in psychotherapy too, glutamate really helps. Because you see, glutamate decides whether the brain remains open to change, neuroplasticity. But the truth be told, glutamate has made clinicians very uncomfortable in the past, including yours truly. Until I learned about glutamate maybe a couple of decades ago, I was mostly avoidant of it. I'm like, I got this. It's serotonin, it's norepinephrine, it is dopamine. I got my three. Please don't give me one more neurotransmitter to think about. But the truth is, all three of those neurotransmitters are beholden to glutamate. We learned early on also, glutamate, if it is in excess, can be profoundly neurotoxic. Therefore, overactivation of glutamate is not our goal. We do know that seizures, psychosis, brain degeneration all are in fact caused by an excess of glutamate. So we must be cautious. We must not make mistakes here. What we want to be aware of is dysregulated glutamate is in fact a signature of, if not all, almost all psychiatric disorders. So glutamate in itself is not dangerous. In fact, without glutamate, there is no life. Without glutamate, there is no brain. Without glutamate, there is no learning, there's no mood. Without glutamate, there is no neuroplasticity. So the human brain has evolved to be exquisitely good at regulating it. Therefore, you may want to think about glutamate modulation not in terms of intensity, but about precision. Let's transition a bit. Let's think about glutamate as a process and not simply as a chemical. Why do we want to do that? Well, because every moment our brain is flooded with information, the brain has to make a choice. What do I hold on to? What don't I hold on to? And thank goodness, majority of what happens to us, we simply don't remember. And psychiatric disorders often develop because we mislearn it. In other words, it's neuroplasticity gone wild. It's gone in the wrong direction. So I think now, as we have talked about glutamate, we really ought to have a deeper conversation about glutamatergic synapses. We need to figure out if it's important to learn about the glutamatergic receptors. Are they important? Are they meaningful? Are they worth our time? Let's talk about the two superstars in the world of psychiatry and in particular positive psychiatry. The two superstars from the glutamatergic family are the two inotropic receptors known as NMDA receptors and AMPA receptors. Look, folks, we do need to get to know these receptors well because this is where the world is going. So think of AMPireceptors as speed. They transmit information rapidly. They allow neurons to talk to each other now. On the other hand, NMDA receptors are more about permission. They are what we call coincidence detectors. They ask, is the timing of the signal right? Is the signal strength strong enough? Is this experience worth rewiring the brain? As you can see, clearly both are important. They do slightly different things. But when they work in tandem, important things happen. When AMPA and NMDA receptors are dysfunctional, I'm afraid poor things happen to the brain and to a patient's both traditional psychiatric symptoms as well as positive psychiatric symptoms. And the truth is when glutamate is suboptimum, the brain is literally stuck from a neurobiological perspective. And patients will report that. They will say, I know I have a good life, yet all I see is darkness. I know I should be grateful, but I can't change the way I think. That's it. That in a nutshell is impaired neuroplasticity. So there is a new emergent hypothesis in depression, major depression, which is not thinking of it just as a disorder of sadness, but to think of it as a disorder of collapsed neuroplasticity. The brain literally becomes rigid. I don't mean rigid as in structurally, I mean rigid from functionality perspective. Its predictive models become pessimistic. New experiences simply fail to revise old beliefs, and hope stops feeling plausible as a possibility. And none of this is because the patient lacks insight. In fact, most patients with depression have exquisitely well-developed insight, but what they're not able to do is able to take advantage of it. They're not able to often appreciate that, oh my goodness, oh my goodness, it's not so much that I'm depressed as much my brain is frozen. That's what they would say. You and I would say their default mode network, which is a circuit heavily driven by glutamate and GABA, is stuck. Patient is excessively in it. And the clinical manifestations are both a combination of negative symptoms like sadness and anhedonia, as well as positive symptoms such as joy, happiness, enthusiasm, optimism, those profoundly positive feelings that we have from positive psychiatry that give our life meaning and purpose and joy often are stolen exactly for those reasons. So chronic stress is not just psychological exhaustion, it's biological exhaustion. It's biologically toxic in terms of impaired neuroplasticity, glutamate release becomes highly chaotic, receptors are downregulated, synapses literally retract, and the prefrontal cortex, the boss of the brain, the control center of the brain, literally leaves its post. And when the prefrontal cortex leaves its post, you can imagine the limbic system is allowed to go wild. And a limbic system, sadly, has a task, is to make us afraid, make us hyper-vigilant, look at the negatives, because a default setting of most human brains is not necessarily positive. So instead of just working on controlling the limbic system, wouldn't it be nice if we thought about improving this neuroplasticity? Right? Now you see why a conversation about positive psychiatry without glutamate is impossible. It's simply impossible. So let's continue our conversation because positive psychiatry believes that we want to not just help an individual control their DSM symptoms of their suffering, but they also have one more suffering, which is the absence of positive symptoms such as meaning, wisdom, gratitude. Literally growth. And none of this can happen unless they have brain plasticity. All right, now I think it's time for us to have a deeper conversation, now that we've covered the basics, about how do we improve plasticity? How does therapy that previously hasn't worked start working all of a sudden? How do insights arrive? What happens? And here we actually have an example. We have an example because for the last 25 years, we have through serendipity discovered a glutamatergic interventions benefits in psychiatry, an NMDA receptor antagonist, which is the off-label use of, you got it, ketamine. Think of it as a proof of principle. Think of it as the dramatic throwing open of a door of possibilities because ketamine is so much more than a rapidly acting antidepressant. It is in fact a major source of improving. Yeah, positive psychiatry. It really is. So let's see. Let's keep having this conversation about how exactly does this marriage between glutamate and between positive psychiatry come to be. So far, what have we covered? First, we have better understood what is positive psychiatry, what is glutamate, how do they interact at a network level achievement, and how we should be helping our patients achieve meaning, meaningful lives in networks, not just in molecules. That is the way to go. And we also rapidly covered the three major networks of the human brain, are by the way, all driven by glutamate. That being, if I may remind you one more time, the default mode network, also quite famously now known as the DMN. The second network is the salience network. This is the one that gets to decide. Are things important? Are things boring? Can I tune out? Can I pay attention? Should I pay attention? Should I tune out? That's the salience network. It's a very different network in the human brain. And then finally, we have the central executive network, C E N. Please get to know all three of these networks because they have very different tasks. But the truth of the matter is they all share the same currency, which is glutamate. So the default mode network helps us reflect, remember, to imagine our future. And the question, who am I, is answered by the default mode network because it holds our narrative identity. It holds personal meaning for us. It also holds our autobiographical memory. You can see how this is a profoundly important network in actually life. It's not a psychiatry issue, positive or traditional, in life. On the other hand, salience networks' main job is to be the decider. Is this important? Is this safe? Is this worth responding to? And sadly, the brain that is low in positive psychiatry traits doesn't do very good shunting. It almost always decides it's not worth it and they give up. But our job is to really truly wake up the central executive network, the one that we talked about before, because that gives us long-term values. We create meaningful goals and purpose over impulse. This is what we call the grit network, the toughness network, the doing it despite pain network. So it gives us agency and responsibility. And you got it. It helps us develop wisdom. Oh gosh, in psychiatry, we have simply not talked about wisdom the way we need to, but that's for another time. Today, let's just establish all three of these networks cannot function properly if the glutamate is a challenge for the human brain. So that's the convergence. Glutamate doesn't just strengthen synapses, it strengthens network functioning. The default mode network seems to soften, the salience priorities rebalance, and the executive control network reasserts its rightful position in controlling how the brain works. So when the glutamatergic signaling is healthy, the narratives we have about our life change. You've seen this clinically. You've seen patients who've been acutely traumatized or chronically traumatized who over time literally find a way to change their narrative, their story. They can shift from a victimization story to a heroic story. That, my dear friends, is a great example of a network reconfiguring itself. That is positive psychiatry. Now you and I can facilitate that with medications, but quite prominently with psychotherapy. But psychotherapy perhaps not just focused on clinical symptoms, but psychotherapy also focused on giving the patient elements of positive psychiatry that we have been discussing. These are the breakthrough moments we see. Every one of us has been in situations where someone has been quote unquote stuck for a long time, and then all of a sudden something clicks, as a patient might say, something clicked. And then you can see a pretty significant long-term shift in their thinking. Well, let's make sure we thank glutamate for this gift to our patients. Because if not for glutamate, we end up with inflexible networks. But with glutamate, we end up with not just flexible, but resilient networks that create a better narrative reconstruction for our patients. Folks, this is why the marriage between positive psychiatry and glutamate, I think, is so important. And I'm just simply delighted you gave me the opportunity to talk about it. So let's continue this conversation and remind ourselves this plasticity, this neuroplasticity, is not a brain that's larger or smaller. That's not how plasticity works. It's reshaping. Glutamate opens that door, and positive psychiatry and those of us who are practitioners in that skill set decide where to walk in, when to walk in, and what to do with it. So, yeah, they are mutually dependent with each other. I like that. Glutamate without meaning is just noise. And positive psychiatry without plasticity is just aspirational. Let me say that again because these are such important concepts. Changing glutamate without helping an individual have better meaning, better psychological traits is just noise. But by the same token, positive psychiatry without neuroplasticity is just a hope and a dream. But what if you combine them? Well, when you combine them, what we have is human growth, human flourishing, but it is deeply grounded in biology. Now, this is why I'm calling it a marriage, a marriage between positive psychiatry and glutamate. I'm not trying to be poetic. I'm in fact trying to be precise. So now as we move towards the latter part of our conversation, I think what we ought to do is to shift our attention just a little bit. We ought to think about if we believe glutamate is this important in an individual's growth, particularly if we are firm believers in positive psychiatry, what can we do? Is it all about medications? Is it about non-medication techniques? What is it? And here's where the conversation becomes very interesting, because the answer is both. Why don't I first talk about medication interventions that can improve glutamate that have now clearly demonstrated, believably demonstrated, that positive psychiatry traits are enhanced. So we're talking about, well, ketamine has by far the greatest data set right now, but there are two other glutamaturgic interventions that are available to us. One of them is called S-ketamine, that's a nasal spray, also known as sprovato in America. It does have data showing that it's not just reduction in negative symptoms that occurs, but also positive symptoms occur. And then we have another medication. It is a combination of two things, dextromethorphan and buproprion. And that one's called avality. So all three of these, two are on label, one is off label. These are all glutamaturgic interventions that work their way through the NMDA receptor modulation. But by now we have established, haven't we? While it may be an NMDA receptor antagonist, when these medications work, and they work in a lot of people, they literally change brain networks. And these brain networks may be the reason why these patients don't just experience improvement in negative affect, as I said before, depression and anhedonia and hopelessness, even suicidality, but in positive traits, a desire to socialize, a wanting to be engaged in life, an inner sense of competence and resilience and happiness and optimism and joy. All words I was taught to kind of look the other way because you know they aren't really science, is what I was taught 40 years ago. Wrong, wrong, wrong, wrong, wrong. These are very much part of positive psychiatry. So, yes, medications can absolutely help. They improve neuroplasticity. That much is now believed to be the very much the case as to how these medications work. But I do think we should not stop this conversation about glutamate and positive psychiatry by only talking about medications, because some of the more powerful ways to change glutamate are in fact non-pharmacological techniques. So let's talk about some of them. Well, the first is sleep. Sleep. Oh yeah. People who have trouble with sleep, which we would call insomnia, have very clear glutamaturgic abnormalities. They literally have surges of excess glutamate. They have a disequilibrium. They have an imbalance not just of glutamate, but the networks driven by it. And correction of sleep through whatever means one hopes through non-pharmacological means can and does lead to improvement in glutamate. The same thing has been noted with physical exercise. Physical exercise, both acute and chronic, meaning someone who does it on a regular basis, they can get really significant changes, positive changes in their brain glutamate. And this marriage between glutamate and positive psychiatry really comes into its own when you start thinking about physical exercise, sleep restoration, correction, socialization, those are really important. Mindfulness and meditation, those are often called lifestyle modifications. And I never have liked that because it almost sounds like we are, you know, paying lip service to these, like, yeah, yeah, yeah, let's do those lifestyle modifications, but I will give you bigger interventions. Not true. The things that we just talked about are highly responsive to these non-pharmacological techniques if one believes in the importance of glutamate and the fact that glutamate is the partner, is the designated married partner to positive psychiatry. We of course have to talk about psychotherapy. We do. All kinds of psychotherapies. In fact, there's evidence, really good evidence, neurobiological evidence, that even psychodynamic psychotherapy, the one that Freud offered, and there are of course multiple versions of it now, do in fact not just improve symptoms, but they change brain chemistry, glutamate being one of the brain chemicals that prominently are changed, but also changes brain circuits. In other words, brain neuroplasticity. So these insights in fact lead to a potential synaptic shift. This therefore leads to reframing in the networks. And of course, the individual, when psychotherapy works, not only learns new skills, literally has a different brain. Now you might say, but I didn't give you a glutamaturgic medication. And I would argue back and say, but you did. Psychotherapy is in fact a recalibration, a recorrection of glutamate, which leads to improved neuroplasticity, which of course is at the very core of what positive psychiatry means. So if you're a clinician listening to this or someone who's just a scientifically minded individual who's listening to this deep conversation, I would like to speak to you quite directly and ask you to perhaps consider a complete reframing of what is a successful human mental health life. What is it? Is it a life filled with no pain and no stress? Well, first, it's not possible. And because it is not possible, in many ways, our goal is to learn to live with it in a manner that is adaptive. So our goal really ought to be to diminish symptoms of stress, diminish symptoms of depression and anxiety and sleep difficulties. Absolutely worthy goals to have. But I would argue, in addition, we have one more goal, which is to learn from those adversities, is to get stronger because of those challenges. And that's not possible unless the human brain has neuroplasticity, has an ability to mold itself in a manner that ultimately is adaptive. That, if you really reconceptualize this, is exactly the definition of positive psychiatry, which is not the avoidance of difficulties entirely, it's growth from it. And that growth is what leads to a person having an experience of a completely fulfilling life. And perhaps this is why these questions matter so much. The questions of is our brain capable of learning right now? Well, if it is, it's because of glutamate. Is there neuroplasticity that I can employ? Can I enable growth? Those are all questions that invite us to really be hopeful, really to kind of think, what can I do to move someone who's feeling stuck? It's not because they're weak, it's because their brain is not protecting them. Their mind may not have direction. So the stuckness is not failure, it's a state of mind. And this state of mind can be changed. And I do believe, I believe this strongly, that positive psychiatry offers both the clinician and the patient a direction to go above and beyond the basics of what we do in everyday practice. Where we tend to ask, what is wrong with you? But what if we asked, in addition to that, what is wrong with you? What if we asked, what is possible for you? See how that conversation shifted? In other words, humans, our patients, us are not defined solely by symptoms, but by our strengths, values, and capacity for meaning. And neuroscience is now affirming this. The brain is just not an organ, it's not just a machine. It's in fact a great gift from nature to continuously adapt. And it does not appear that there is an upper limit to human wellness. There isn't. But psychiatry does have an obligation to embrace all the concepts of traditional psychiatry and to infuse it with the elements of positive psychiatry that we're talking about. So today's psychiatrist really ought to be thinking about neuroplasticity, meaning, resilience, even wisdom. And I think this can be done today because psychiatry without neuroscience becomes nothing but aspiration. And neuroscience without positive psychiatry is nothing like, it's just like a machinery. But together they become something far more powerful because they can become the medicine for the human spirit, grounded in biology, guided by meaning, and capable. Of real change. And it is glutamate that gives the brain permission to change. Positive psychiatry gives the change a direction worth taking. This, of course, is how I would have defined a good marriage. A good marriage made in heaven and most certainly blessed by neuroscience. Thank you so much for letting me speak to you from my heart about this very important topic of this marriage between glutamate and positive psychiatry. I certainly hope you found it interesting. And of course, my greatest hope is it gives you the neuroplasticity to be excited, to be enthusiastic about learning even more about both glutamate and positive psychiatry. This is Rakesh Jan, bidding you goodbye for the time being. Take care.

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Rakesh Jain, MD

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