In this episode of Psychiatric News Special Report, host Dr. Sulman Aziz Mirza speaks with Dr. Alexander Niculescu about pain as more than a physical symptom alone. Their conversation explores the overlap between chronic pain and psychiatric conditions, the promise of precision psychiatry, and how biomarkers may help clinicians better assess risk, guide treatment, and rethink refractory pain. They also discuss the limitations of current approaches, the role of non-opioid interventions, and why psychiatrists are uniquely positioned to treat the whole person.

Read this special report here: https://psychiatryonline.org/doi/10.1176/appi.pn.2026.03.3.28

PsychNews Special Report is a production of Psychiatric News, a media platform dedicated to serving as the primary and most trusted source of information for APA members, other psychiatrists and physicians, health professionals, and the public about developments in the field of psychiatry and mental health that impact clinical care and professional practice. Learn more at psychiatryonline.org/journal/pn

Transcript

Dr. Sulman Aziz Mirza (00:12) All right, everybody, welcome back to the Psych News Special Report podcast. We are here in the month of March. We have a special report on pain as a dual diagnosis disorder. We're gonna break that down with the author of the article, Dr. Alexander Nikolescu. I'm your host, Dr. Salman Aziz-Mirza, triple board certified psychiatrist out of Northern Virginia, adult child adolescent. and addiction medicine. this is an interesting podcast for me, an interesting article. get to put on the addiction medicine hat a little bit and do some of that stuff. But we're going to be talking with Dr. Nicolescu, who is the expert on this. So Dr. Nicolescu, welcome to the Psych News Special Report podcast. How are you doing today?

Dr. Alexander Niculescu (01:03) Thank you, Dr. Mirza. Pleasure to be with you and look forward to going over some of the things that are described in the article and going off-piste if necessary.

Dr. Sulman Aziz Mirza (01:15) Yeah. Can you give us a little bit of a bio background, blah, blah about yourself?

Dr. Alexander Niculescu (01:22) Yeah, yeah, yeah. So I'm a psychiatrist, geneticist, ⁓ educator, physician, scientist. I'm currently a professor of psychiatry at the University of Arizona College of Medicine in Phoenix. Went to school, started my career in California and San Diego, then was for two decades in the Midwest in Indiana, Indiana University, where we did a lot of the seminal studies that led to the birth of the field of precision psychiatry. And then A year and a half ago, I moved to Phoenix to start the Center for Precision Psychiatry. And we're continuing the work over here. Very glad to see that precision psychiatry is becoming a thing, you know, that, you know, there are now other centers, departments, et cetera, who are naming things as this new subfield, promoting a more precise approach so that we can be you know, just like any other area of medicine. And in some ways we're going to be, you know, more interesting than other areas of medicine because we're dealing with things that are upstream, uh, from a lot of the medical disorders.

Dr. Sulman Aziz Mirza (02:32) Yeah. So before we jump into the article, I think you brought up something interesting. So precision psychiatry. You know, I did not come across that much during my residency training, you know, about a decade, decade and a half ago.

Dr. Alexander Niculescu (02:47) We had to create that.

Dr. Sulman Aziz Mirza (02:51) Yeah. so for us who may be unfamiliar with that is can you dive into what, what is precision psychiatry?

Dr. Alexander Niculescu (02:58) Precision psychiatry is meant to sort of focus attention on the fact that there are ⁓ emerging ⁓ blood tests, emerging electrophysiological measures, emerging imaging measures that can be used to assess people in a more objective quantitative way. So we don't have to rely just on what the patient is telling us and our pattern recognition skills. I'm a clinician also. I still see patients, I've seen a lot of patients in my career and I've always felt the need to have these additional laboratory tests and imaging tests and electrophysiological tests to guide what we do. So we fly with instruments as opposed to flying by looking out the window as still, you know, as sort of the general approach. my scientific training back in the day, my graduate work at Scripps was actually in cancer molecular genetics oncology, historically has developed, you know, biomarker ⁓ testing to guide, you know, subtyping of types of cancer matching to treatments and so on. So when I moved over to the brain and to psychiatry, I wanted to bring the same sort of level of precision, the same methodology in our field. And it's been a longer journey than anticipated to cast over two decades because I like for cancer where you can biopsy the tumor and look at the, you know, the blood correlates, the liquid biopsy in the brain. As you know, we cannot biopsy the brain in our patients and then, you know, develop peripheral too. So we had to take a very careful step-wise ⁓ approach to find markers, to prioritize them, to validate them, to test them and so on. So it's been a journey, but, ⁓ you know, the field has matured, ⁓ other People in the field have done tremendous work trying to move forward EEG type approaches ⁓ for clinical trials, soon in clinic imaging type approaches to subtype depression and other things. So ⁓ in many ways, you know, we're catching up ⁓ and hopefully we'll, you know, move ahead of some of the other disciplines. As I said, a lot of the things are that we do impact all the other health issues. for example, today's topic is one of those topics where pain, chronic pain, treatment refractory pain may benefit from taking a psychiatry angle.

Dr. Sulman Aziz Mirza (05:28) Yeah. And just as like a quick review, I guess, for us in clinicians, we're like, what's a biomarker? It's been so long since we've taken like our step threes and stuff. We're like, what's a biomarker?

Dr. Alexander Niculescu (05:43) Yeah, I know. So let's do biomarker for dummies. in that category, I include myself. I have a very small hard drive, so things have to be explained in a very simple way for me to understand. And then the corollary of that is that when I explain something, it's also hopefully not simple. So biomarkers are exactly what the name says, biological markers. That's sort of the real definition. These are biological markers. It's been expanded a bit. you know, electrophysiological markers are also called biomarkers. Imaging changes are called biomarkers. But in essence, it's biological markers that are associated with a disease, with risk for a disease that can be used to monitor response to treatment, can be used to match people to medications. So Just to demystify things, we all are familiar with biomarkers that are used day in and day out, maybe on ourselves or on friends, relatives, family members. ⁓ Glucose is a biomarker. Hemoglobin A1c is a biomarker. Those are used all the time to monitor if you have something is emerging in terms of diabetes. responding to lifestyle changes to treatments and so on. So glucose is a state biomarker. Hemoglobin A1c is more of a trait biomarkers, more long-termists. So we've done the same for mental health. We came up with biomarkers, some of them that reflect state objectively, and some of them that reflect trait future risk of chronicization and so on. The markers that my teams have developed over the years are messenger RNAs. These are the product of genes being expressed. ⁓ we've looked in the blood because, that's the place where, you know, it's easily accessible clinically. ⁓ as, as I said, you know, ⁓ we can't really Bob see the brain. Right. ⁓ patients are not super enthused about getting spinal taps. So we didn't try a sort of, ⁓ an approach that relies on, on that. And, ⁓ you know, when we started this 25 years ago, it wasn't like really obvious that it would work. We just.

Dr. Sulman Aziz Mirza (07:47) Yeah.

Dr. Alexander Niculescu (07:58) tried to see if there's a signal there that will be solid, reproducible, et cetera. And fortunately it worked because it's very easy clinically to get another blood tube at the lab visit and then look at the markers. Markers are gene expression markers, mRNA markers. So it's based on... sequencing technology where you sequence the RNA from whole blood from white blood cells and there are specific panels of markers that can be assessed in terms of expression measure, their expression level, compute the score for state risk for future risk and so on. And we've done that for several mental health indications and more recently for pain.

Dr. Sulman Aziz Mirza (08:40) Yeah. I know there's discussion with DSM 6 being, you know, on the horizon and some of the planning committees are talking about introducing biomarkers as something that's going to be in there to help guide. So I know that's one of the trending kind of ⁓ buzzwords and something that we're seeing a lot more kind of moving away from, again, like the subjectivity, some of the criticisms of the field in regards to, it's just this made up thing where we go off of what the patient says. It's like, no, there's definitely some objective markers of these diagnoses that we're using. So, great.

Dr. Alexander Niculescu (09:22) Yeah. I mean, you know, in defense of phenomenology, all of medicine started as phenomenology, like superfluitions hundreds of years ago could diagnose people just by, you know, looking at them, palpating them, percussion, auscultation, all sorts of things. So, phenomenology is not something to be discarded. But even phenomenology nowadays could be done in a more quantitative analytical fashion, empirical and so on, as opposed to being decided by committee. So that's, think, one of the directions that ESM is taking where, you know, let's look up fresh, is there emerging data about what's really core to, you what are the dimensions and so on. Very exciting. It's a very exciting time in our field. Hopefully we'll simplify the number of you know, from 300 to maybe 30 diagnosis, looking at dimensions using biological markers, who knows, but I think we should all have an open mind and ⁓ adopt new things, but not throw the baby with the bat, you know, with the bat water. A lot of the intuitions about the big domains, know, anxiety disorders, mood disorder, cognitive disorders are correct. And they do map to, you know, neurobiology and so on. you know, Rather than completely disrupt things, think sort of reinforcing and building things is the proper approach. But what do know? I'm of a certain generation. All these new innovators, they all say, we're going to disrupt the system. And I told them, look, the system is already disrupted. It's already broken. Help the system.

Dr. Sulman Aziz Mirza (10:58) We need to put the system back together a little bit.

Dr. Alexander Niculescu (11:00) Yeah, put it back.

Dr. Sulman Aziz Mirza (11:03) Okay, let's talk about pain. Pain is one of those things that is similar in a way because there are some subjective measures. It's hard to kind of put an objectivity on it. It's a point of discussion and controversy in regards to people saying the whole movement of pain is the fifth vital sign led to things like the opioid crisis and the mess that we're in with all of that and et cetera, et cetera. Pain is something I think we all see as clinicians, psychiatric clinicians, and when we're working patients and they're saying, my pain is really bad and my depression is really bad and they're connected and I wonder why these things are there. So let's talk about that to help us dive into that as a intro.

Dr. Alexander Niculescu (11:52) That's a very good insight, a very good question. so pain probably evolutionarily is like a body reaction to a hostile environment that's damaging, directly damaging or, you know, the perception is that there's damage from the environment. And so it's a sort of a physical corollary of stress disorders, have pain disorders and so on. So it's this, you know, body response to a traumatic, actually trauma, physical trauma.

Dr. Sulman Aziz Mirza (12:22) you

Dr. Alexander Niculescu (12:22) Yeah. And so on. The organism also responds to hostile traumatic environment with brain adaptations, know, increased anxiety, increased depression, sometimes dissociation, things like that. So they're all part of this sort of response to external trauma, whether physical trauma, psychological trauma, and so on. That's one way to look at it evolutionarily. ⁓ The other way is pragmatic, which is ⁓ it's right in our wheelhouse in psychiatry because it's something subjective is being treated in medicine. But really it's almost like a psychiatric condition because rely on what the patient is telling you and on your pattern recognition skill, especially for a lot of these chronic cases of pain where the primary lesion has healed and there's a discrepancy between what the patient is reporting in terms of subjective distress and the actual physical findings or imaging findings that are gone are very minimal at that point. So we had the platform, the tools to look at blood biomarkers. We had the measures collected in our patients. had pain measures, ⁓ functional impairment measures, and so on. So we decided to go after this ⁓ almost a decade ago. And it took us years to get our first study and then recently, and of last year, had a much larger study that confirmed and expand that in a definitive way, some of our initial biomarker findings and so on. I'll talk about that a bit. Yeah. A recent study, but, ⁓ you know, it's, it's, something that, ⁓ is very much akin to the other sort of mental health conditions. And because of this sort of commonality of, ⁓ you know, being part of a response to traumatic or hostile environment because of the fact that, know, it's, like the other conditions, we went after it before going after it. I talked to some colleagues who were experts in pain, anesthesia and so on, Stanford, other places. And we said, look, you know, we have this approach. We would like to find biomarkers for pain. Should we go after it? And I said, no, it's not going to work. Don't do it. So, so then I went to my team. said, look, you know, I talked to that guy, very big guy, you know, he's, know, ⁓ expert in pain, he's on all these societies and he said, it's not gonna work. And I said, let's do it. So we went after it. We used that as Phil's motivation. It took us a while, but to his credit, ⁓ that colleague ⁓ ended up, we learned later being a reviewer on our first paper, gave it a very good review and he was very sort of fair and supportive of the work after it developed. So.

Dr. Sulman Aziz Mirza (14:51) Yeah.

Dr. Alexander Niculescu (15:10) Sometimes you have to go for things even if it's uncertain that they would work, you just have to do the work you never know in advance and then see what happens. So that's the genesis of our work on pain. There are three main findings from this study that are described in the special report. One is that there is an overlap between genes involved in pain and genes involved in different major psychiatric disorders. ⁓ Second is that this overlap can be measured at the gene expression level in the blood. So we have biomarkers for pain that also are ⁓ biomarkers, overlap with biomarkers for other psychiatric conditions that we've studied in the past, like stress, like depression, like cognitive disorders. And then thirdly, that because of this overlap, ⁓ it behooves us to treat in a dual diagnosis way these conditions as a way of getting complete resolution. And you can do that empirically without precision medicine, just as a good doctor, you say, look, this patient has a chronic pain condition. I'll treat that, but let me see what else is going on in terms of mental health, because if I also treat that well, and maybe I find medications that work for both, then we would get complete resolution as opposed to this sort of treatment refractory pain conditions where you try opioids, you try everything and they still persist. You have to treat the comorbidity. So that's sort of the empirical approach. The other approach which is now becoming available is to use precision medicine approaches to do this biomarker tests in your patients and get reports on them. What's the score for these different conditions, including pain and what are the medications that overall will treat the comorbidities. And then, you you have a higher rate of success, a higher rate of resolving something. The matches that our biomarker studies show, fortunately, are with non-opioid medications, which is great news because, as you mentioned initially and rightly so, we've had a lot of problems in the field with addictions created by... ⁓ sort of the broad use of opioids. It doesn't mean that they don't work, but to our surprise, they were ranked lower for matching than some of the, you know, psychiatric medications and so on. And lastly, you know, with these types of study, also can sort of tiptoe a little into new therapeutics. So we identified some off-label medications that could be used, you know, current psychiatric medication that could be used more proactively, empirically for pain. And then we identified some to drug repurposing using biomarker signatures, some non-psychiatric medications that could be used for, studied and used for as new pain therapeutics. So ⁓ there is this opportunity to improve clinical care and to have better, more innocuous treatments.

Dr. Sulman Aziz Mirza (18:20) Yeah. When I was reading this, was getting reminded or getting the thing that was popping into my mind was these pharmacogenetic tests, things like genome mind, gene site. Am I correct to be thinking that?

Dr. Alexander Niculescu (18:36) ⁓ Those tests look at DNA. ⁓ We look at RNA. So DNA is, you know, doesn't change. So you do those tests once you have the information. Moreover, those specific tests that you mentioned that we've all used in the field of clinicians, look primarily at cytochrome P450 mutations and tell you really the only thing that they tell you for sure is whether the patient is a slow or fast metabolizer for a certain medication that you would like to use. So those pharmacogenetic tests have their use, more sort of ⁓ at the final decision point. Like once you know what a patient has and what medication you want to use, what dose should you be using? So if you have the test information, can, I start lower, I start higher, or you can just do it empirically. Start low and go slow. So that's all they do. Very different than our functional biomarker test with mRNA where these are dynamic markers, they change over time with disease severity or response to treatment. And they really ⁓ target more the biology rather than the metabolism, the pharmacokinetic part, the pharmacodynamic marker. So they can tell you about the intensity of the disease, the future risk, ⁓ and you can use the signature to match people on to medications that may be a good fit. They don't tell you about, you know, those use a high dose or low dose, but they fulfill the first two steps. What does a person have? What should they be on? And then you can use those pharmacogenetic tests to see, know, should I use a high dose or a low dose? That would be the ideal scenario to use everything.

Dr. Sulman Aziz Mirza (20:18) Yeah. Yeah. Cause like, like you said, like, think we've all clinicians have all come across those. And again, kind of controversial issue in regards to like, are those worth anything? Do they help at all? Do they not help at all? ⁓

Dr. Alexander Niculescu (20:32) Don't get me started. All right, I'll start. Yeah. No, no. mean, ⁓ use properly. They're very useful. So I use them in my patients, but I think when they were marketed or, even when some of the clinical utility studies were done, was this fudging of the barrier between you can tell, you know, whether it's slow or fast metabolizer, you can tell which medication you should use. They don't really tell you which medication you should use. But they tell you whether you should use a low dose or high dose. So because of that, the outcomes were not great in their clinical utility studies and in clinical practice because there was this confusion about you can use them to choose a medication, which, so it doesn't matter if you give the right dose of the wrong medication to the wrong patient, right? So you have to start first with what the patient has, what the medication should be, and then the dose. So because of that, it backfired, unfortunately, for ⁓ the credibility of those tests for their use in the field. Had they been more modest and said, look, these tests are great. So, you know, whether to be aggressive or not with your dosing of medications, they would have been, you know, become part of the mainstream. And in fact, at VA hospitals, they're generic. They're part of the workflow at VA hospitals. You know, you just can, ⁓ you know, request the pharmacogenetic testing for cytochrome P450 and it's in the chart. And then, you know, you know, with your, what dose you should use. So they should be part of the regular workflow. just that the marketing got ahead of itself.

Dr. Sulman Aziz Mirza (22:04) Yeah. And I think I have to kind of like remind my patients all the time. I was like, it's the marketing is wrong. The marketing is wrong. It's not going to tell us what is the right medicine for you. so, so that's, that's a great kind of, you know, things for clarifying that there's, there's a distinction of that. Cause I think a lot of us clinicians, again, have that kind of, hear things like biomarkers, we think of something like, like in one of these tests and we're like, I don't know if this is something that's worth it doing or not, but I got things.

Dr. Alexander Niculescu (22:33) Yeah, yeah, we should think more. should look at our colleagues in oncology. You know, this is new and seems sort of exotic in psychiatry, but it's done day in and day out in oncology. And if you have colleagues or God forbid, if you went through that process with a family member or something, you know, it's just part of the workflow where you get the liquid biopsy or you get the molecular sampling of your tumor and, you know, see which subtype was the prognosis, which ⁓ therapeutics should be used and so on, monitoring the response to treatment. we should just look at oncology and it's just exactly the same workflow. And in fact, that's what we're doing where, ⁓ you know, we're just following in the footsteps of oncology with our liquid biopsy approach that my teams have developed.

Dr. Sulman Aziz Mirza (23:19) Yeah. What were some of the surprises that came out? think you were surprised by some of the treatment options that were showing up as potentially effective.

Dr. Alexander Niculescu (23:30) Yeah. So ⁓ lithium came on top in terms of some of the existing medications where we use bioformatics to match, you know, which medications have the most impact on the top biomarkers for pain. ⁓ If you think about it more deeply, lithium, you know, is a neuronal function optimizer. It reduces neuronal overexcitability. ⁓ signaling, that's how it works in bipolar and depression can, you know, it's, it's, it's the greatest medication probably that we have in psychiatry, I would say. ⁓ and, ⁓ I use it a lot, ⁓ over, know, having seen some of these results over the years, how lithium is a good match for biomarkers for pain or mood disorders, for other things that we studied. So it's an interesting thing to consider, ⁓ low dose lithium. so you don't go into toxicity range, but useful to try it. And, ⁓ You know, it's also neurotrophic. you know, if some of these chronic pain conditions, like neuropathic pain where the nerves start to be damaged, if you have lithium that actually keeps those neurons alive and reduces the firing, the overexcitability, I think, you know, that's a good thing. There's all this recent evidence about how lithium keeps neurons alive might be useful for Alzheimer prevention, things like that. So microdose lithium, low dose lithium. can be a game changer if used more broadly for pain and for other conditions more broadly beyond the primary indications. It's the only thing approved for suicide prevention and suicide is always lurking in severe mental health and severe chronic pain conditions. So why not? get multiple benefits. So that was a surprise that it's so prominent. ⁓ When we did drug repurposing, one of the top findings, besides some things like adrenergic blockers, sort of the parallel with PTSD. So you have post-traumatic stress disorder here, you have post-traumatic pain disorder, perhaps. So that energy blockade that might lead to pain, that combats that pain chronicization. But one of the surprises was quetiapine, know, an old versatile antipsychotic that again, you know, score pretty high in terms of drug repurposing for pain. And, you know, ⁓ Then when you dig more deeply, it's not that surprising, right? So there are these three types of pain. ⁓ just to remind ourselves, there is a nocioceptive pain, which is primarily the sensory part from, from the physical trauma. Then there is neuropathic pain where the nerves actually are damaged. And then the last and the most pernicious and refractory type of pain, in my opinion, is nocioplastic pain, where there's some centralization of of pain, almost like a persistent hallucination or delusion in the central nervous system. And that persists even after the peripheral lesions have healed. And that may be, you know, one of the, you know, primary reasons of these sort of treat so-called treatment refractory pain conditions, ⁓ like complex regional pain syndrome and so on this central pain, osteoplastic pain. Well, if it's like you know, like a hallucination or delusion with circuitry that's modified, then a neuroleptic and antipsychotic like what type in maybe just the ticket and the empirical evidence supports that. So I've started to use it more, more broadly in my practice as well. Those are some of the, you know, big surprises. ⁓ Ketamine was a high scoring compound. It's interesting. It's obviously being used more broadly nowadays for psychiatric conditions, for pain. Again, it might help with those ⁓ central nocioplastic pain where you have things stuck and you get this dissociation from ketamine and resetting of the circuitry. ⁓ There are a lot of nutraceuticals that could be tried like omega-3 fatty acids, ⁓ fish oil capsules, inoculants, very high sort of matching. We sometimes forget that they're also highly anti-inflammatory that 25 % of our ⁓ Synapses, fatty acids are actually omega-3 fatty acids. so those are some of the things that are sort of directly applicable. You know, first do no harm like when we take our Hippocratic oath, but these are things that are, you know, have strong clinical biological rationale and now this emerging precision ⁓ medicine evidence. So those are things that could be directly tried and useful.

Dr. Sulman Aziz Mirza (28:14) Yeah, I had a um, survival patients. So the intranasal is ketamine. And I remember when he first started, was, there's a guy with chronic pain. Um, you know, he said the, you know, then the, and the quote unquote, trim and resistant depression for insurance purposes, but there's oppression. Um, and that was his first, after his first session, you know, I always kind of check and make sure, Hey, how, was it right? And he said, he's like, the first thing he's like, felt a wave of pain disappearing from me when I, when I, you know, inhaled the, ⁓ the spravato and I was like, huh, interesting. So, you know, to see the ketamine popping up on here was like, surprise, not a surprise, right? There it is. Right.

Dr. Alexander Niculescu (29:01) Yeah. So that's probably he had nocioplastic pain. had the surgery imprinted and the esketamine led to the dissociation that sort of was therapeutic for him. I think, you know, more broadly, just always looking at the pain patient as a dual diagnosis patient. Yeah. And the corollary of that when we treat our psychiatric patients, we should always ask them about pain because a lot of them have pain there that if it's not treated, they're more, we label them a somatic, psychosomatic, et cetera. But a lot of the, you know, that persisting pain is driving their misery and their, you know, their chronicization of their mental health condition. So we should always address both empirically or with precision medicine approaches as is emerging, you know, do these liquid biopsies, see what they have, see what the matches are, and so on. And ⁓ I think, you know, this would be sort of high impact societal type of that, you know, improvements that we will do. mean, we'll help our psychiatric patients, we'll help the chronic pain patients. And that's, you one in four people basically in the US have either a mental health or a chronic pain condition. So these are, you know, areas in which we can do a lot of good and move the needle basically.

Dr. Sulman Aziz Mirza (30:19) You had mentioned that you were doing, or that this was some of your patients use this maybe potentially like change treatment or modify treatment or yeah. What have you kind of seen with your patients? Yeah.

Dr. Alexander Niculescu (30:31) Well, so I have experience in two ways. know, I've always disclosed I'm a co-founder of a company that has developed these, has developed practical versions of these tests that are being used by early adopting doctors and patients. So we have some experience there where we've done over 200 complex treatment refractory patients. And we've seen the impact of providing these reports to doctors. We don't diagnose people. The doctors get their reports. They know. the patient's history, their family history, their comorbidities and so on. And it helps them with their diagnosis and it helps them choose a treatment from the list. And the results are ⁓ amazing, actually. So that sort of keeps us going. And then in my own sort of academic clinical practice with my own patients, ⁓ even without using the blood testing, because it's not yet insurance reimbursed, et cetera. you know, it's one of the things that we're working on. to get Medicare insurance reimbursement over the company. even using these principles of like looking more often at adding lithium, looking at things in a dual diagnosis way, pain and mental health conditions and so on have been transformative as well in clinical care. And when I mentioned adding lithium and you know, it's like 150 milligrams at bedtime, maximum 300. So way below the the doses that we used to use back in the day, you know, in manic patients, in patients and so on up to thousand five hundred and so on. Right. And the interesting things is with this low dosage, it works. But I always get calls from the lab or pharmacy, look, they're subtherapeutic. I said, OK, because the therapeutic levels for lithium were determined back in the day again, for those high doses, for those sort of acutely manic patients where you needed something to whack them to stabilize things. But this off label or sort of broader label indication, very low doses, which creates zero side effects can be used more broadly. at this point, you know, I'm probably one of the biggest proponents of using lithium at low dose more broadly. And that came directly out of this whole biomarker work and the effects that we've seen in patients. Everybody in my clinical practice, academic clinical practice, or at the VA where I'm also affiliated, is on omega-3 fatty acids, unless they have a bleeding disorder, that's it by default if you're on them. So things like that. it's fun and it's rewarding after all the hard work to be able to translate to practice some of the things that the teams have discovered and then, you know, educate the next generation of residents, younger colleagues about carrying the torch and applying and practice some of these things.

Dr. Sulman Aziz Mirza (33:04) Yeah. Yeah. I take my Omega threes every day as well, just cause it's good for you.

Dr. Alexander Niculescu (33:29) You look very fit, yeah.

Dr. Sulman Aziz Mirza (33:31) I try, try every once in a while, but if we're conceptualizing pain, right, as a dual diagnosis condition, does this expand or redefine the scope of the average psychiatrist?

Dr. Alexander Niculescu (33:49) Yes, I think so. I think we should be doctors first and psychiatrists second. ⁓ And, you know, we have a medical degree. ⁓ A lot of my patients, you know, it takes me two, three sessions to fix the psychiatric part. That's easy for me after all these years and having seen, know, so many patients over the years, but then I become their family doctor. So when they, you know, I look over all their other medication or blood pressure diabetes, because I always treat the whole person. asked them about their nutrition, about their exercise, et cetera. ⁓ and you know, we should, we should not be afraid to, to sort of be family doctors in addition to being specialist psychiatrist and treat the whole person and help them improve their lifestyle. Cause sometimes we have the opportunity where to do that. ⁓ whereas when they're seen in primary care and frequently and so on, a 15 minute block. You know, we have the opportunity to integrate things in a, in a very beneficial way for patients. And it's, it's more fun. see sort of a better effect when you, when you take care of not just of their mental health, but their, you know, physical health as well. It's all one thing. And so, so I think, you know, we shouldn't be shy about treating pain disorders, not at all. And we shouldn't be shy about maybe, you know, going a bit beyond what we're treating and helping people just be healthier in general, whether it's with, you know, taking care of their addictions, their appetite issues, their, you know, having a healthier lifestyle and so on. So I always say I'm a family doc who knows a little bit more about psychiatry.

Dr. Sulman Aziz Mirza (35:27) Yeah, we're the doctors first. when we, you you talked about like right now it's not insurance covered. How, what's the pipeline or what does that look like in regards to more acceptance and feasibility?

Dr. Alexander Niculescu (35:43) Yeah. So, so three things. First of all, we were academics. So the company was started by academics, co-founded by me, by the academics, along with some business people. So everything has to first be rigorously studied, published in peer reviewed international journals, and only then moved to clinical ⁓ settings. ⁓ So everything has to have, you know, it's research and publications first before anything is launched, which is very different. to a lot of other sort of things that you see in the consumer space and so on. These are prescription tests. A doctor has to be involved to get the information. A clinician has to be involved with information, et cetera. So it's not sort of ⁓ marketing-driven consumer approach. It's a science-driven clinical approach. So we always have tried to have the highest standards in everything in privacy, conservative statements, et cetera. ⁓ So that's always going to be the case. The second thing is that ⁓ as we accumulate real-world evidence, we will continue to publish that so more colleagues, doctors in the field see that and start using, trying them in their ⁓ practice and so on. And then thirdly, we want this to be affordable, not just by people who pay out of pocket, but by everybody more broadly. And there we're looking at how cancer tests were developed and then sort of went to the regulatory process to be able to be reimbursed and so on. So there is a clear path forward to do those things to demonstrate the evidence necessary for them and so on. So we'll take that path as well so that more people can afford them. mean, if you look at these tests, even with a small company like Mindex Sciences, they are marketed deliberately at the price that's lower than cancer tests, ⁓ that barely sort of covers costs and so on, because we want people to have access to them. And that price is lower than a day of hospitalization. And I think you're somebody who, you know, ends up in the hospital for a few days or a week, even your copay is going to, you know, the bill will be high. You go to the ER for repeated episodes and so on. So In many ways, ⁓ we think that at the societal level, precision medicine approaches, while there is some cost upfront, will reduce reduction in health care costs, because you're going to prevent a lot of the expensive hospitalization, ER visits, so on. And more importantly, you're going to prevent, you know, lost time in people's lives, you know, the misery and the drifting and the downward spiral that occurs in in some of our patients who don't get the right treatment right off the bat and so on. So that's what drives us.

Dr. Sulman Aziz Mirza (38:38) Yeah, mean, the pain is, you know, for chronic pain patients, like it's debilitating. ⁓

Dr. Alexander Niculescu (38:44) terrible. Yeah, it's all these patients. Yeah, I mean, you've had patients, I've had patients who have this complex regional pain syndrome is stunning, like there you can see sort of the color changes, the physiological that you can't touch them like that they sort of overreact, they react to it and so on. So imagine living day in day out with that misery and not being taken seriously, let's say, well, you know, ⁓ same thing with the and even more broadly with fibromyalgia and women. So a lot of women have fibromyalgia, which is, you know, definite biological disorder. can study the biomarkers for it now and everything. And they go for months or years saying, well, you know, you're just, you know, it's in your head. Yeah, it is in your head, but you're over it, you know, without getting the proper treatment and so on. So there are all these areas where I think, you know, we worry a lot about, you know, with opioids, about people overstating their pain to get opioids. But I think the broader issue is like people not getting the adequate treatment for their pain because the physical lesion has healed, but the internal thing has not been properly assessed. So, you know, I think a lot of progress will be made there in the next few years and we should be part of that vanguard of driving the process as a psychiatrist because we really sort of care deeply about patients. We have a deep connection with them and we can address this sort of dual diagnosis aspect.

Dr. Sulman Aziz Mirza (40:11) Good, yeah. Anything else that you feel like we're not talking about that you want to have our listeners take away from the article or from the research and work that you're doing?

Dr. Alexander Niculescu (40:23) I would say that always look at the data and the literature when you know, in terms of new approaches that are being promoted, but don't be afraid to try certain things in your practice, ⁓ gain experience and see how sort of things are evolving. And, and all of us in the real world can contribute to this revolution in psychiatry, whether it's, you know, contributing at the phenomenon. logical level to the new iterations of the DSM, which are likely going to be dimensional, getting involved in collecting experience from using precision tools in patients and so on. And the FDA is moving in that direction where they are actually much more open to using real world data, which is the best data to know which treatments work, which interventions and so on, as opposed to the very artificial research that, you know, clinical trials that were done before that. you know, ⁓ where, you know, where ⁓ they're not always spanning out in the population in the real world, because they had all the exclusion criteria and so on. And lastly, hopefully, you know, pharma companies that work on developing psychiatric drug will embrace these approaches more like in like they're doing oncology so that we have more options, more tools, you know, in our hands, new medications being developed, we haven't had that many new medications in psychiatry over the last 10, 20 years. We're still sort of coasting on some of the old successes. mean, if lithium is one of the best drugs, if clozapine is an amazing drug, those are things that have been developed, you know, 60 years ago, 40 years ago, et cetera. So we need to develop new things because people are diverse and not, you know, one size does not fit all. So hopefully pharma will get in the game and use some of these precision approaches for more successful drugs.

Dr. Sulman Aziz Mirza (42:17) Awesome. And then I always try to ask people when they come on here, just cause you know, as a parting wing, what are some things that you do for yourself or self care and taking care of yourself? Yeah.

Dr. Alexander Niculescu (42:30) Well, so that's a very good question. We should practice what we preach. Otherwise we don't have credibility with our patients. Right. ⁓ so like you, take ⁓ omega three fatty acids. take social every day. ⁓ I meditate most mornings, just like I teach my patients to take some time to meditate in the morning before all hell breaks loose before you have to fall, you know, meditate. I exercise daily, nothing. you know, stunning. I'm not, you know, like Patrick Mahone or something. I'm to exercise every day. And I tried to eat, you know, proteins, vegetables, fruits, things like that. Because in the end, you know, we are bio socio psychological creatures, but you have to start with the biology, you have to take care of your biology, then curate your social environment, and then have a positive mentality. So those are some of the things that I try and I'm not perfect. I don't always sort of manage to do them daily, but I tried to do them as a way of being a more energetic and effective person in my interactions with my family, friends, patients, colleagues, and also I teach them to my patients. I'm not shy about teaching patients to meditate, to eat well. have them all have a Fitbit or something when they come to appointment, they show me their steps, their sleep, all these things. So, you know, fitness is the best shield against illness and we should practice that and teach our patients to do that.

Dr. Sulman Aziz Mirza (43:56) Absolutely. I'm a big, big believer in food, sleep, exercise, connection. As I get those things covered and that will take care of, you know, 90 % of it or so, hopefully.

Dr. Alexander Niculescu (44:08) Yeah, so prehabbing, preemption and a lot of the biomarker studies that we do, there are markers there that are modifiable by exercise, by diet. There are markers that were shown to change in studies of meditation and so on. So those are not fringe things, they should be mainstream things used in our life and our clinical practice and they're as effective as medications.

Dr. Sulman Aziz Mirza (44:29) And a lot of times more effective, right? Less side effects hopefully, right?

Dr. Alexander Niculescu (44:34) Exactly, exactly. Yeah, especially since we have this tradition of having used medications at high doses because they were not necessarily the best fit and so on. So we have some history that we need to redeem ourselves as a field and sort of become more, you know, more holistic and maybe use less, you lower doses of things that actually help the patient and so on, as opposed to mandating, you know, everybody should get SSRI or the less latest generation and type psychotic or something. Let's be open minded and it's okay if it's an old cheap medication if it works, it's okay.

Dr. Sulman Aziz Mirza (45:12) Old is gold, good. Awesome. Well, Dr. Nicholas, thank you so much.

Dr. Alexander Niculescu (45:17) Thank you, Mendoza. It's been a pleasure spending time with you and pleasure sharing some of our work with colleagues in the field. So thank you very much.

Dr. Sulman Aziz Mirza (45:25) Yeah, I think it's super exciting. So I'm very excited to kind of see what keeps coming on coming on out. All right, everybody. Thank you for joining the psych news special report. Make sure to check out the article in the March edition of psychiatric news. If you're listening to the podcast on here, make sure to give us a like, a subscribe, give us some ratings, maybe drop a comment on there on iTunes. always a good thing to hear what you want to see, what you want to hear from, then hopefully we can cover some of those things in future episodes. until next month, we will talk to them.

Dr. Alexander Niculescu (46:06) you