Journal Club: A New Wave In Positive Psychiatry With Four Landmark Journal Articles

We launch a 'Psychiatry Journal Club' series built to get us reading again and to translate major psychiatry papers into practical, humane care. 

We walk through four landmark studies that reshape how we think about schizophrenia treatment, suicidal crisis care, metabolic health, and relapse prevention through a Positive Psychiatry lens. 

• why dopamine-first antipsychotics often miss negative symptoms and cognition while harming metabolic health 
• how xanomeline plus trospium (KarXT/Cobenfy) targets M1 and M4 muscarinic receptors without direct D2 binding 

• what the Emergent 3 phase 3 trial shows on PANSS change, onset by week two, and a cleaner metabolic and EPS profile 

• why preserving reward circuitry and reducing dysphoria can change adherence conversations in schizophrenia 

• the clinical gap between acute suicidality and multi-week SSRI and SNRI latency 

• how intranasal esketamine rapidly affects glutamate circuits, AMPA signaling, mTORC1, and BDNF-driven synaptogenesis 

• Aspire 2 outcomes at four hours and 24 hours, plus monitoring for dissociation and blood pressure changes 

• how GLP-1 receptor agonists can reverse antipsychotic-induced weight gain and improve BMI, waist circumference, glucose, and lipids 
• brain-gut-reward and neuroinflammation pathways that connect GLP-1s to neuropsychiatry 

• why early long-acting injectables reduce relapse risk, hospitalizations, and functional decline in early schizophrenia 

• how relapse biology and oral medication level swings support a neuroprotection argument for LAIs 

Let’s together keep reading. We must read more, folks. 

www.JainUplift.com

Transcript

Welcome And Why Journal Club

Rakesh Jain, MD, MPH 0:06

Hello everyone and welcome to a new series on this podcast, The Positive Psychiatry with Rakesh Jen podcast. And this one is going to focus on a journal club. I have been aware for a considerable length of time that while we do a lot of things well in mental health, what we really stop doing is reading journal articles, discussing them, and learning straight from it. And I can understand why. Things are hectic nowadays. They really are. We are just so busy. So from now on, what I'm going to do is find some major articles, the ones that I enjoy reading, and I'll just share them with you. Hope that works for you as well. And that benefits you as well. So today I brought for you four separate articles, four separate articles that I think are complete game changers. And let's have a journal club about them. Okay? So here's the first article.

The Muscarinic Shift In Schizophrenia

Rakesh Jain, MD, MPH 1:22

I'm going to call this The Muscaronic Revolution in Schizophrenia. The article I'll be reviewing is by Call, K-A-U-L, and colleagues. The title is Efficacy and Safety of Xonomaline and Trospium Chloride Car XD and Schizophrenia, a five-week randomized double-blind placebo-controlled phase three trial, also known as Emergent 3, that was published in a journal no less important than the Lancet in 2024. What an important article this is. I would say a landmark article. So here we go. Well, folks, we know the atypical revolution that we've had for perhaps, oh, let's see, 30, 35 years, added serotonin 5 HD2-A receptor antagonism to our D2 antagonism, which has undeniably helped mitigate EPS and many other things, including improving efficacy. But let's look at our patients quite honestly, the ones who are on atypicals. Are many of them truly thriving? Or for a vast, vast number of these individuals, the answer we have to give is not really. Not really. Our current D2, 5HD2 antagonists, I think do a reasonable job at dampening down the loud, intrusive positive symptoms like hallucinations and delusions. But they are notoriously ineffective against negative symptoms, against cognitive symptoms, against evolution, against elogia, against, you got it, social withdrawal. And of course, worse of all, they frequently worsen or even cause the devastating increase in cognitive deficits. And of course, the damage they cause to the metabolic health of a person is profound. So I think we trade our patient's psychosis for significant weight gain and hypolipidemia and type 2 diabetes and accelerated cardiovascular mortality. So is this the best we can do? No. And that's where this article from CAL, K-A-U-L and Colleagues, is so important. I'll make sure a link to this article is in the show notes so that you can read it for yourself. Because this paper, this journal club discussion, it represents a clean break. And when I say clean break, I am not exaggerating. It is a clean break from the dopamine D2 receptor modulation hypothesis. And what this paper showed that Xenobline and Trospium CARXT, which today we call Cobenphi, what it showed is through a completely novel mechanism of action, which is selective M1 and M4 muscarinic receptor agonism. So no direct binding to the dopamine D2 receptor. Folks, let that sink in. For the very first time in modern psychiatry, we have a highly effective antipsychotic that leaves the D2 receptor completely untouched. So now we're going to zoom into the neurobiology of this paper to better understand how this works. And then let's see why this medication is a masterclass in elegant drug design. So let's

M1 And M4 Neurobiology Explained

Rakesh Jain, MD, MPH 5:09

do this. Let's dive into the deep neurobiology of muscarinic agonism versus peripheral blockade. And to understand why this paper is such a big deal, we do have to understand the architecture of the cholinergic system. The human brain contains five distinct muscarinic receptors. We call them M1, M2, M3, M4, and M5. And decades of postmortem tissue studies and animal models have revealed that M1 and M4 receptors are heavily localized in the part of the central nervous system responsible for pathology that we call schizophrenia. So the M4 receptor acts primarily as a powerful inhibitor, as an autoreceptor, and a heteroreceptor within the ventral striatum. Why does this matter? Because this now becomes a direct regulator of dopamine release in the mesolimbic pathway. Aha, that's the magic of this mechanism of action. Just think about how beautiful that is. So instead of slapping a heavy blunt padlock on the postsynaptic D2 receptor, which of course can cause hyperprolactinemia, Parkinsonism, dysphoria, we're turning down the volume knob on the hyperactive dopamine release at the source, upstream, via the M4 receptor. And at the very same time, the M1 receptor is richly concentrated in the prefrontal cortex and hippogampus. And in schizophrenia, prefrontal cholinergic transmission is profoundly deficit. And this contributes directly to the negative and cognitive symptom clusters that we see as part of schizophrenia. Are you folks with me? We're going after both the positive, the negative, the cognitive sets of symptoms of schizophrenia through M1 and M4. So by selectively agonizing, acting as an agonist on the M1 receptor, CORXT, it's driving down glutamate release, and that improves long-term potentiation. So that's all terrific, is it not? But xenomalene, which we've had around for a long time, was actually tested a long time ago, but it caused a lot of nausea. It did because it's cholinergic. It's cholinergic. So what do we do? Well, now enters the brilliant dual drug strategy that is CARXD or Cobenphi. That's what was evaluated in this landmark paper. So this combination is interesting because trospium, which is part of CARXD, it's a potent non-selective muscarinic receptor antagonist, but it doesn't cross into the blood-brain barrier. It stays in the body. So what this paper teaches us is what happens when a patient takes CARXD, is both medications enter the bloodstream, but in the brain. The only thing that really has entry is xenomalin. The tropospium stays in the periphery and does its best to block xenomaline's procholinergic side effects. Wow, this is a true pharmacological Trojan horse.

Trial Results And Side Effects

Rakesh Jain, MD, MPH 8:57

Now, because this is a journal club, we're going to turn our attention to talking about trial design, data dissection, and then clinical endpoints. What do we know? Well, it's a multi-center, randomized, double-blind, placebo-controlled five-week study. It's a phase three study. In other words, its goal is to present its data to the FDA for approval of the medication. And they use the PANS, the positive and negative syndrome scale, as their primary outcome tool. And the primary endpoint of the study was change from baseline in the PANs at week five compared to placebo. Pretty standard stuff, right? But as we examine the data, something very interesting emerges. Well, this CAR XD combination, Cobenfi, was highly statistically significant. That's actually quite robust drops in the PAN score compared to placebo. 10 point greater than placebo arm, rapid onset of action, and becoming statistically significant pretty early at week two. But what made us clinicians really lean forward was the breakdown of the subscales. The drop in the positive symptoms was clear and decisive, pretty much matching or exceeding what we expect from high potency D2 blockers. But when we look at the negative symptom subscale, it achieved a highly significant reduction in negative symptoms compared to placebo. This is a big deal, folks. So now that we have a sense of the efficacy, I think we ought to be talking about, well, the side effects too, don't you think? Let's look at the metabolic profile. And over the course of the trials, there was actually no significant weight gain, no adverse shifts in fasting glucose, no elevation in total cholesterol, and no worsening of triglycerides. No EPS, no acute acesthesia, no drug-induced Parkinsonism, no elevation in serum prolactin. Yep, all of these are in fact incredibly important. So now that we've looked at the actual journal article, let me offer you some clinical takeaways and let's see how this integrates into positive psychiatry.

Positive Psychiatry Takeaways For Adherence

Rakesh Jain, MD, MPH 11:35

Let's step back for a moment. Let's not just look at the raw numbers, but look at it from the lens of positive psychiatry. Why does a non-dopaminergic, metabolically neutral antipsychotic make any difference to us? Well, first and foremost, it entirely changes the conversational dynamics around treatment adherence. Why do our patients stop taking traditional antipsychotics? Well, for lots of reasons. But a large component is they stop because they hate how they feel. D2 blockade in the mesolimbic reward pathway doesn't just stop hallucinations. It can in fact induce a state of profound emotional flattening, anhedonia, and overall sense of being a chemical zombie. So when we couple that psychological dysphoria with 20, 30, or 40 pounds of rapid weight gain, are you really surprised? Am I really surprised that adherence rates in schizophrenia are low, some of the lowest recorded in modern medicine with any disorder? So could this muscarinic agonist, could that in fact preserve the brain's reward architecture? To those of us who are interested in positive psychiatry, that's a big deal. We are protecting the patient's capacity to experience joy and motivation and positive reinforcement. This, my dear friends, is positive psychiatry at its purest, most practical formulation. We are managing the active psychosis. We need to do that. But at the same time, we are preserving the infrastructure required for well-being. So, yeah, this is a major article. I really encourage you to read it for yourself and view it from the lens of positive psychiatry. It is really important to remember we are not just interested in blunting the dopaminergic pathways willy-nilly. We do need to be circuit specific. And CAR XD, as the paper shows, not only shows clinical improvement, but clearly has a scientific basis for us to consider it as a significant development in the last 50 years if one is interested in positive psychiatry. So this ends my journal club review of this particular article. Let's now review another article in our journal club.

Esketamine For Suicidality Crisis Care

Rakesh Jain, MD, MPH 14:20

And this one is regarding glutamaturgic breakthroughs and suicidality control. The paper that I will be reviewing now for our mutual discussion is written by CUNUSCO, C-A-N-U-S-C-O, and colleagues. It is titled Eschetamine Nasal Spray for the Rapid Reduction of Symptoms in Major Depressive Disorder and Suicidal Ideation in Patients at imminent risk of suicide. Results of a double-blind randomized placebo-controlled study. The study is titled Aspire 2. It was published in the famous American Journal of Psychiatry in 2021. All right, folks, it's really important we appreciate that the crisis of acute suicidality and the latency of monoaminergically based treatments. Real problem, isn't it? And we need to be completely honest with one another about the daily realities in our clinical practice. When a patient presents to our clinics or in the emergency department in the grip of severe acute suicidal crisis, we sadly encounter a terrifying therapeutic void. Our traditional monoaminergic antidepressants, our, well, you know, very popular SSRIs, SNRIs, are excellent tools. But they are excellent tools for some, not for all. And they do have a major problem. They suffer from a dangerous multi-week therapeutic latency. It can take as long as four, six, eight weeks for these agents to fully, fully exert their antidepressant effects. And during these critical first few weeks, our patients remain in a state of profound vulnerability. Historically, our only resource has been psychiatric hospitalization, intensive, constant observation, and sometimes we have to sadly deploy sedative medications to blunt the acute distress. We have not had rapidly acting antidepressants that could work within hours. So this brings us to this landmark article, which is the focus of our journal club discussion, the landmark aspire 2 clinical trial that was published, as I said before, by CANUSCO and colleagues in the journal, American Journal of Psychiatry. So, what was this? This was a highly rigorous, multi-center, double-blind, randomized, placebo-controlled trial. It evaluated the efficacy and safety of intranasal eschetamine for the rapid reduction of suicidal ideations in patients who had major depression. This is a monumental study, because as you well know, in most studies we exclude patients with suicidal ideations. Here, it actively is looking for such patients to see if this glutamate-based intervention could help. I think we need to now lift the hood of the brain and look at the extraordinary neurobiology of glutamate signaling and synaptogenesis and how this could potentially lead to rapid dissolution of suicidal despair. Let's do that, shall we? Let's dive into its neurobiology because to understand this paper requires us to understand science and neurobiology.

How Glutamate Rebuilds Synapses Fast

Rakesh Jain, MD, MPH 18:10

So here we go. While under states of acute or chronic severe stress, and in the states of major depression, a process called synaptic atrophy occurs in the prefrontal cortex. So we have high unregulated levels of cortisol, neuroinflammation that lead to dramatic loss of dendritic spines. What is that? Those are the connections between neurons, the dendrites that allow neurons to talk to each other. And there is, in fact, a pretty significant loss of synapses in the brain circuits that regulate mood and cognitive flexibility and executive control. So the brain literally loses its structural connectivity. So the brain doesn't die. It's just, you know, it's lost its cell signal in many ways, if I can use that analogy. So the patient becomes cognitively locked into rigid, agonizing loops of hopelessness and psychic pain and suicidal ideations. They cannot see alternatives to their suffering. That's the challenge for them. So now we have eschetamine, which acts through a complex multi-stage mechanism, but it all starts with the blockade or antagonism of the NMDA receptor, which is a member, you got it, of the glutamate family. It's a primal member of the glutamate family. And these NMDA receptors are widely distributed in the human brain, but they're also located on the GABA inhibitory interneurons in the prefrontal cortex. So let's trace this circuit carefully. By blocking the NMDA receptor on these interneurons, we are turning off the brakes on the glutamaturgic system. You got it? By blocking NMDA receptors on these interneurons, whose main job in life is to tell glutamate to not fire, by taking them out of the loop, guess what happens? You got it? We have more firing. We have immediate but transient surge in glutamate release into the synaptic cleft. Now this burst of glutamate leads to activation of another member of the glutamate family we call AMPA. AMPA, when that's triggered, folks, leads to a massive improvement in intracellular signaling cascade. Very important. This then targets, those of us who are geeky would know this, MTORC1, MTURC1 pathway. Well, what that does is it immediately kicks off increased production of key synaptic proteins and BDNF, brain-derived neurotrophic factor. We could think of BDNF as like the ultimate fertilizer of the human brain because BDNF, once it's elevated, it binds to its own receptor that's called tropomyosin receptor kinase B. Tropomyosin receptor kinase B, also known as trec B receptors. Once that's activated, folks, this promotes rapid growth and maturation and stabilization of these new dendrites that were lost in depression, and this happens rapidly. How rapidly are we talking about? Hours, not days, hours. We talk about 12 hours, we talk about 18 hours, we're talking about 24 hours, we are talking about not metaphorical, but literal physical improvement in synaptogenesis that occurs at a breathtaking pace. So by rapidly rebuilding these prefrontal connections, restoring the connection between the limbic system and the prefrontal cortex, the thinking is the suicidality break that the brain has been under is unlocked, it's released, cognitive flexibility returns, and the intense psychic pain de-escalates, and the hope is the patient gets. We now turn our attention to the journal club dissection of the article.

Aspire 2 Outcomes And Safety Profile

Rakesh Jain, MD, MPH 22:47

So this is a highly structured clinical trial design from our CONUSCO and colleagues article that we're reviewing. It's a complex cohort. These are adult patients who are hospitalized with severe major depression, but they had active, imminent suicidal ideations with intent. Oh my gosh, the one population that we need the greatest help with. So these participants were randomized to receive either the intranasal esketamine, we call that spravato, plus standard optimized oral antidepressant care, or they received placebo along with the standardized optimized oral antidepressant care. So no patient in this particular trial ever not received treatment. They did receive treatment. It's just that they got standard of care plus placebo, or they got standard of care plus plus spravato plus eschetamine intranasally. And the primary efficacy endpoint was using the scale that's now becoming the gold standard called the madras. And of course, suicidality was also examined. Now let's look closely at the outcome data because it's quite impressive at just four hours. Yep, yep, yep. You heard me correctly. Four hours later, after the first administration, the group that received S-ketamine demonstrated a dramatic and statistically superior reduction in the madras scores and the suicidality compared to placebo group. Four hours later. Now you see why the glutamaturgic mechanism, which is ionotropic, meaning it's fast, is so important. You can perhaps understand why I picked this paper as, you know, a landmark paper. Over 50% of the active treatment group achieved a complete resolution of their active suicidal ideations within the first 24 hours. Think about that. That's a paradigm shift. A single intervention. Remember, in the 24 hours, they had only had one single intervention of eschetamine that reversed in that many people a life-threatening psychiatric crisis. This is a landmark paper, folks. Now let's review the safety, tolerability, and side effect profile of this particular paper. What did we see? Well, dissociation and depersonalization was observed, peaking at about 40 minutes post-dose and completely resolving in most people by 90 minutes. There was in fact transient mild to moderate elevation of systolic and diastolic blood pressure. That was the case. And mild sedation and nausea was reported, but that also, you know, resolved pretty rapidly. So crucially, this paper tracked the long-term safety data, confirming that when deploying this intervention within a structure medically supervised protocol, there was no signal of developing substance dependence or cognitive decline or persistent dissociative states. Now let me offer you my takeaways and how this how this fits into the positive psychiatry pattern. So let's do that together. I think this reveals the great importance of rapid acting glutamaturgic interventions in our patients with major depression. I think it strongly advises us to consider this as a potential. So do I think this is revolutionary data? Yes, I do. And I am inviting you to read the paper for yourself so you can determine how this how this changes the paradigm of treatment for you. Now, how does this fit into our positive psychiatry lens? Well, I can think of so many different ways, but think about it in the following manner. If the goal of treatment of depression, particularly depression the severe, is not just a reversal of their symptoms, but also hopefully to not induce side effects that we often cause with SSRIs and SNRIs, then eschetamine definitely fits the bill. If the goal of positive psychiatry is rapid, rapid improvement without worsening of underlying challenges, then eschetamine, one more time, quite admirably fits our model of positive psychiatry and positive psychiatry interventions. Okay, folks, I think this is a major article, one that I am very much encouraging you to read as part of this journal club. Okay, folks, now it's our time to turn to the third landmark article, journal club review.

GLP-1s For Antipsychotic Weight Gain

Rakesh Jain, MD, MPH 28:34

And this time we're going to talk about incretin mimetics, which pretty much means GLP1 type medications, and this armamentarium and what role it may play in neuropsychiatry. So the journal club article we're going to review together today is by Ishii ISHI and colleagues. The title of this paper is Glucagon Like Peptide 1 Receptor Agonists for Antipsychotic Induced Weight Gain and Metabolic Abnormalities, a systemic review and meta-analysis of randomized controlled trials. This was published in the very prestigious Progress in Neuropsychopharmacology and Biological Psychiatry, and this was published in 2024. I'll be giving you a link to this article so you can review it for yourself. Well, we need to confront a deeply uncomfortable reality that plagues our specialty of psychiatry, and it's plagued it for generations. So individuals living with severe mental illness, that includes, you know, major depression, bipolar disorder, schizophrenia, they really do suffer from a staggering reduction in life expectancy. They die on average 15 to 20 years earlier than the, well, someone without these disorders. And here's the tragedy. They're not just dying from their primary psychiatric diagnosis. They are dying from premature accelerated cardiovascular disease. Now, why do they have this high level of cardiovascular disease? Well, the answer is multilayered, pretty challenging. First, the disease state itself. The disease state itself is characterized by profound shifts in autonomic regulation, elevated systemic inflammation, lifestyle disruptions that impaired sleep and exercise and nutritional quality. But on top of that, our potent psychopharmacological tools, particularly our atypical antipsychotics, and certain mood stabilizers directly drive severe metabolic dysfunction. You and I have seen this a million times, haven't we? These medications often alter the hypothalamic feeding centers and they trigger intense carbohydrate cravings. They can induce insulin resistance and cause rapid, massive weight gain that the patient cannot lose. So for decades, we as psychiatric professionals have watched in frustration as the medications that stabilize our patients' moods and minds, well, they continue to damage their bodies. Now we've tried metformin, we've tried to pyramate, we've tried lifestyle interventions. They all hold promise, but the benefits are modest. They are completely outmatched by the sheer force of antipsychotic-induced metabolic syndrome, right? But this paper heralds the arrival of a new way of doing things. It's a revolution. The medical world has been transformed by GLP1 medications, right? Semaglutide, terzepatide. These are now household names, Ozempek, Monjaro. Well, these were originally engineered, as we know, for type 2 diabetes and obesity. But guess what? They're coming to psychiatry. So a landmark article review is a definitive, high-impact systematic review and meta-analysis that, as I said before, was published by Ishi and colleagues. And this pulled the global randomized control trial data and explored how these medications, when used as adjunctive therapies for patients who are experiencing atypical medication-induced weight gain, how might it help? But before we go any further, just like before, we just have to understand the deep neurobiology connecting the brain-gut immune axis and how GLP1s really play a role.

Brain Gut Reward And Inflammation Links

Rakesh Jain, MD, MPH 33:16

I think to understand GLP1 receptors, we need to discard the old notion that GLP1 is merely a peripheral metabolic hormone. That is not true because glucagon-like peptide is a powerful neuropeptide that's directly synthesized in the brain. In the brainstem, there's a part of the brain that we call the nucleus tractus solitaris. Ooh, that's that's a mouthful, is it not? Let's call it the NTS for short. It is present in the brain stem, and that has extensive receptor expression throughout the human brain. So when we administer a long-acting GLP-1 receptor agonist, like the medications I just mentioned, the Ozempics, the Monjaros of the world, the Wigovis of the world, they cross the blood-bane barrier, directly bind to GLP-1 receptors that are located in key neural networks in the human brain, particularly another part of the brain called the arcuate nucleus of the hypothalamus, the ventral tegmental area, and the nucleus accumbens. Now, those of us who are on the geeky side, and that includes me, folks, these three names that I just articulated, the arcuate nucleus of the hypothalamus, the ventral tegmental area, and the nuclear accumbus immediately, immediately grab our attention because these areas are involved in mood regulation. They're involved in the generation of even positive emotions. They are involved in craving and satisfaction. See how positive psychiatry and GLP1s overlap? So now what we ought to do is to understand how this mechanism of action can in fact lead to suppression of appetite and rapidly improve satiety. So by acting on these areas, particularly the ventral tegmental area and the nucleus accumbens, these receptor agonists, these GLP ones, modulate the mesodopaminagic reward circuit. The mesodopaminagic reward circuit. What does that do? Well, that downregulates the intense, compulsive food-seeking behavior and the increased drive to eat carbohydrates, that food noise we know about. The food noise that atypical antipsychotics can turn up to high, deafening volumes. And the patient could potentially be liberated from the constant distressing biological drive to eat. But I have even better news for you. The neurobiology of these GLP1 medications gets even more exciting. So beyond the control of appetite, recent data shows us that these medications also reduce neuroinflammation, which we know is a big part of major depression and bipolar depression, even dementing illnesses, and most certainly psychotic illnesses as well. We should truly appreciate that GLP1 receptors are also highly expressed on microglia cells. Microglia, that are the primary immune cells of the human brain, of the cortex. When our patients are in a state of severe depression or chronic psychosis, their microglia are frequently locked into a pro-inflammatory, neurotoxic M1 phenotype. That's what we call it. When a microglia is ready for battle, it becomes, it transforms itself into an M1 phenotype. It pumps out damaging cytokines like TNF alpha, interleukin 1 beta, and interleukin 6. So what happens is when we have GLP1 medications on board, these agents shift the microglia into the M2 phenotype, which is in fact protective, anti-inflammatory. This downregulates the neuroinflammatory cascade and suppresses oxidative stress and actively promotes neuroplasticity and cellular survival within, in particular, the hippocampus. So what does this mean? That when we prescribe a GLP1 receptor agonist, we might be helping our patient not just lose weight, we might directly be deploying a highly potent, multi-targeted anti-inflammatory neuroprotective agent that might as well address the foundational pathophysiology of mood and psychotic disorder. Wow, is your mind as blown as mine is? So now we turn our attention to looking at the paper because this is, after all, a journal club.

Meta-Analysis Results And Tolerability

Rakesh Jain, MD, MPH 38:57

So let's look at the clinical data. And this paper aggregates data from multiple rigorous randomized controlled trials. And these are vulnerable patients. These are psychiatrically ill patients who are on atypical antipsychotics. Big, big, big challenge. So let's look at the data trends that emerged. And here they are. So across the pooled clinical data, the group that received GLP1 receptor agonists demonstrated a pretty significant reduction in body weight and BMI as compared to the placebo group. And they, in fact, many of them completely reversed a significant portion of the weight gain caused by their antipsychotic medication. Also, waist circumference dropped significantly. That's a big deal. Because the fat that we accumulate in our bellies that we call visceral fat is a real problem because visceral fat is highly metabolically active in a negative way. Also, glycemic control, so blood sugars and insulin sensitivity, also reversed to a significant degree. And finally, lipids that includes total cholesterol and triglycerides, these also showed favorable downward trajectories in the people who received this treatment. Now let's look at tolerability in this paper. There were gastrointestinal adverse events, but the good news is most of the occurred were mild to moderate nausea, occasional vomiting, and dose-dependent constipation. These are not to be taken lightly. These can be significant. So we need to be quite mindful about these side effects as we start prescribing these medications. And that's what this paper reminds us to do. But it's really important to note these medications did not worsen depressive symptoms. They did not trigger suicidal ideations, and they did not have a negative adverse impact on the stability of the primary psychiatric condition. So let me offer you my own takeaways from this particular journal club article review and how it fits the positive psychiatry worldview. So I think this is a big, big deal article, because it's a paradigm-shifting data. Because now I can view my patients through a more expansive lens of positive psychiatry. We no longer have to separate the mind and the body. We can think of them as a singular, integrated biological continuum. I can now see clearly that my medications that are offered patients, if they do damage, I can think about potential reversal of them. So when we deploy a GLP-1 receptor agonist like the ones I mentioned before, we are in fact executing positive psychiatry at the highest possible level. We really are going to dismantle the metabolic barriers. We are going to interestingly also improve insulin resistance. We are going to have an impact on central neuroinflammation. You can imagine how all of this is going to positively impact our practices. Now we are waiting for further trials, and there'll be many further papers that we'll be reviewing looking at interventional trials with medications in this class. But this meta-analysis that we just reviewed, this paper that we just reviewed, really tells us we no longer have to passively wait for our patients' bodies to be damaged by our psychotropic medications. We don't. We can intervene directly, and this paper is strong proof that these interventions are both effective and they very nicely fit the paradigm of positive psychiatry.

Why Early LAIs Prevent Relapse

Rakesh Jain, MD, MPH 43:23

We now move on to review another article in our journal club series, and this one is on long-acting injectables, LAIs, and their use in the care of patients with schizophrenia. The article that I'll be reviewing with you is published by Christoph Carell, C-O-R-R-E-L-L. This one is titled Acknowledging and Overcoming Barriers to the Use of Long Acting Injectable Antipsychotics in the Early Course of Schizophrenia. This was published in therapeutic advances in psychopharmacology. This was published in 2023. And I will, of course, be providing you with links to this paper so that you can review it for yourself. Okay, why do I think this is a big deal paper and completely worthy of our discussion in this journal club? Well, do I need to remind us what a devastating illness schizophrenia is? No. As we sit here, I think we're reminded of the painful, undeniable reality that when we see a young person in the very beginning phases, their first or second episode of psychosis, our heart breaks, our heart sinks. We of course start an excellent oral atypical antipsychotic in most cases. The positive symptoms often clear. Their insight improves and we celebrate their recovery. But you know what classically happens? The predictable tragedy unfolds. The patient goes home, they feel better, they experience a side effect, or they simply forget and they stop taking their oral medication. And within weeks or months, the psychosis returns with a vengeance. And that leads to a traumatic relapse, and the cycle begins all over again. An emergency room visit, a rehospitalization, and of course, an ongoing, ongoing profound loss of structural brain volume. The patient sinks further and further and further into that disorder. And the data tells us that about 75% of patients has three out of four with schizophrenia. They struggle with significant non-adherence within the first two years of a hospital discharge. Yes, my dear friends, you heard me correctly. This one disorder in psychiatry that desperately needs medications. 75% of patients within two years are not taking their medication. And this is our clinical blind spot. And I must be hard on us as a specialty. This is our clinical blind spot. We in the mental health field are notoriously terrible at predicting which patients are adherent or not. Simply asking our patients, are you taking your pills? is simply not working out. Because we sadly accept their answers. And then guess what? Actual adherence rates are very low. And there's consequences to this. You know they are. So historically, our field has reserved LAIs, long-acting injectables, as a treatment of last resort. We wait until a patient has relapsed five, ten, fifteen, or more times, the cognitive reserves are depleted before we say, okay, fine, let's switch to an LAI. Wow, what a profound clinical error we make. And in this landmark paper, a major international consensus led by Dr. Christophe Correl, that, as I said before, published in the therapeutic advances in psychopharmacology, this completely flips this old, useless, damaging paradigm on its head. This paper does establish that the early first-line deployment of long-acting injectables in the early phase of schizophrenia is in fact a powerful form of preemptive neuroprotection. Yes, neuroprotection. So now let's take a small detour away from this journal review and take a deeper look at the neurobiology of relapse in schizophrenia, why is it dangerous, and what are the extraordinary benefits of continuous stable plasma concentration of an antipsychotic?

Relapse As Brain Injury Biology

Rakesh Jain, MD, MPH 48:21

So here we go. To fully comprehend this particular argument that this paper makes, we really do have to understand what happens to the human brain during a psychotic relapse. Because a psychotic relapse is not just a temporary psychological setback, not at all. It's a direct, pretty neurotoxic event. We may have to stop thinking of these as relapses. We gotta literally think of them as brain fractures. So during an acute phase of unmedicated psychosis, the brain in fact experiences a profound unregulated surge of this dopamine release. It's subcortical. But what it leads to is massive glutamaturgic excited toxicity all over the context. So this hyperdopaminergic, hyperglutamaturgic storm triggers a pretty massive tsunami wave of oxidative stress and microglia activation and neuroinflammation, and you know what the results are. Just think of a tsunami wave. What are the results? Everything in its way is washed away. And post mortem and neuroimaging studies showed that every single episode of psychosis leads to an often permanent and irreversible loss of gray matter volume, particularly in areas of the brain that really matter, like the superior temporal gyrus, the prefrontal cortex, and of course, even the prized hippocampus. So with every relapse, the patient's cognitive performance is dropping. The treatment resistance rises, and their response to future antipsychotic interventions becomes weaker and weaker and weaker. We are without meaning to, as clinicians, converting our patients into treatment resistance. How terrible. It's not that we are cruel or mean, we are not. It's just that we're not thinking this carefully. Oral antipsychotic medications, even if they're taken with reasonable consistency, they do bring about a dangerous liability, which is massive pharmacokinetic volatility. You know, every time a patient takes an oral pill, the plasma levels spike rapidly and then they drop. So this is problematic. Why? Well, the high peaks often lead to EPS, acesthesia, hyperprolactinemia. But the low troughs with the D2 binding dropping to 60% or lower, well, you know what? Create brief windows of vulnerability where the subcortical dopamine can break through and trigger microrelapses, which then leads to lower adherence. See the dramatic challenge we have. So these long-acting injectables completely eliminate this volatility. Yep, they do. During their time of effectiveness, they have consistent, continuous presence of dopamine receptor regulation. So by utilizing these advanced technologies, LAI slowly and continuously release the active antipsychotic medication and the systemic circulation, which is very helpful because it's relatively flat and remarkably stable pharmacokinetic profile hour upon hour upon hour. This is important. This is highly important to the brain that has the capacity to have surges of dopamine as part of the pathology of their disorder. Let's do this. Let's now look at the study again, the paper.

Real-World LAI Benefits And Barriers

Rakesh Jain, MD, MPH 52:28

We're going to look at how rigorous they were. They looked at real-world evidence, longitudinal data. Christoph and colleagues, Corell, Christoph Corell is a friend of mine who had just lapsed into calling him just by his first name. But a premier high-quality research group was very meticulous in compiling real-world evidence, and they looked at individuals within the first five years of the diagnosis. And the outcomes analyzed in the paper focus heavily on head-to-head architectural comparisons. They looked at transitioning to a long-acting injectable antipsychotic early in the treatment course versus those maintained on standard of care oral antipsychotic medications. The primary outcome measures were demanding, as they should be. So that we want to find out what was the psychiatric relapse, the total number of all-cost psychiatric hospitalizations over an extended period of time, and how well did they perform in terms of functional capacity and social performance. Now, as we lean into this journal article and look at the findings, there's a number of things here that really could make you and I shift our clinical practice. So over the long-term observation windows, the group of people who got long-acting injectables early on, they did have a significant reduction in relapse rates compared to those who got just oral medications. It's pretty significant. There's a 60 to 70% lower risk of relapse. Yes, that's a huge reduction. All cost psychiatric hospitalizations were also reduced, with the LAI group spending, if they got hospitalized, significantly fewer days in acute inpatient units. But really look at the functional scores. The patients who got early LAI treatment, they in fact had higher scores on functional scales, particularly in the domains of socially useful activities and in personal and social relationships and self-care. All of these are profoundly important goals. And just doing one thing, which is to use LAIs early, significantly helped. But what about side effects? What about a patient who's actually taking LAIs? Does that in fact increase side effects? Well, what did we see? We actually saw something interesting. The overall incidence of EPS and acute akesthesia was in fact lower in the LAI group. Sure, there were injection site reactions, but thank goodness they were mostly mild, transient pain, and were reported but rarely led to treatment discontinuation. So what's the big deal with this paper? Well, the paper summarizes that the data is showing that early deployment of LAIs leads to dramatic increase in overall treatment retention, improves the quality of life, fewer relapses, and is an important tool in breaking the revolving door cycle of non-adherence and subsequent relapses. Okay, now that we've reviewed the paper, let me offer you my clinical takeaways and how does this paper, in my opinion, fit the positive psychiatry paradigm. I think it fits in extremely well, right? The whole point of positive psychiatry is not just symptom reduction, but functionality in all manners. To not be hospitalized, that's really important. To be able to take better care of yourself, of your social relationships. All of these are big-time goals of positive psychiatry, no matter what your psychiatric disorder must be. And what this paper really compels us to reconsider is our current behavior of saving long-acting injectables for later. No, we should in fact, we should in fact, if we're believers in positive psychiatry, advocate for the early protective deployment of long-acting injectables. And this is not an act of coercion. We are in fact offering patients an act of clinical kindness, deep humanity, and true positive psychiatry. We're in fact liberating our patients and the families from the daily exhaustive cognitive burden of managing oral medications. We take the friction of pill taking completely off the kitchen table. But more importantly, we allow for the patient's brain biology to meet continuous coverage of their symptomatology with their antipsychotic medication. Oh yes, this paper very much, this article very much meets the standards of being a primo top-notch article that helps us understand how positive psychiatry can be a force for good for our patients.

Closing Thoughts And Keep Reading

Rakesh Jain, MD, MPH 58:10

Okay, folks, thanks so much for joining me on this particular inaugural podcast that reviewed, that reviewed four major articles in this series that I'll just call Journal Club with Rakesh Jayan. And let's together keep reading. We must read folks. The lifeblood of progress in psychiatry is research and conversation between colleagues, which are, well, really, journal club articles. This is Rakesh Jan, and it was my pleasure to converse with you, to offer you deeper insights into these four major landmark articles. And thank you again for joining me on this journal. Goodbye for now.