[Music] last week the FDA approved the first oral medication for postpartum depression and today I'll bring you 10 things you need to know about zeren alone welcome to the carlat Psychiatry podcast I'm Chris Aken the editor and chief of the carlot Psychiatry report and our co-host Kelly Nome is out today on vacation the FDA approved zerena loan brand named zuru for postpartum depression last week the approval was a peric victory for sage Therapeutics the company that developed the drug to replace its predecessor brexanolone the cumbersome IV drug that was approved for postpartum depression in 2019 as Zoro bre sen alone Zoro was a scientific breakthrough but not a financial success Sage had to lay off half its Workforce shortly after the Drug's release the drug worked well but it was hard to deliver requiring an overnight Ivy infusion oxygen checks because bolone is so sedating that it can knock people unconscious think back to 2020 when bre senone was first hitting the pharmacy shelves and covid precautions were in full swing were you in any position to open an overnight IV Clinic then probably not even hospitals didn't rise to the occasion most of us were trying to figure out how to deliver care with as little contact as possible back then only about 1,000 women have received bre calone and the minuscule Market has not helped its pricing a single treatment costs $34,000 for the drug alone and more for the overnight mon monitoring so Sage was hoping to break out of this morass with an oral version that women could take at home and that is where zoren alone comes in zoren alone is sedating but so far no one has lost Consciousness on it it comes with a simple warning though not to drive for 12 hours after taking it just dose it all at night and do take that warning seriously because there is evidence of driving impairment within those 12 hours and zenone has the bioavailability that bre senone lacked so it can be taken orally although it does need a fatty meal to grease the wheels of absorption in the gut last week I posted the fda's announcement on The Daily psych my feed on LinkedIn Twitter threads and Facebook if you want to follow the conversation join in at Chris Aken MD we got a lot of thoughtful questions in the comments on that post and I'm going to answer as many of them as I can here but first a preview of the CME quiz for this [Music] podcast you can earn CME credits through the link in the show notes zoren alone is a synthetic analog of which hormone a pregnant one b prazone c estrogen D Alor pregnanolone [Music] and here's the first question we got does zalone treat major depressive disorder the non-postpartum type that one is a big Maybe Sage originally developed the renal loone for treatment resistant depression but it failed there so they moved on to try it in a more responsive group of just regular major depression the first two trials were encouraging but as the trials got larger the benefits got smaller and in the latest trials zoren alone's anti-depressant effects were nothing more than a flash in the pan fizzling out within a week and leaving no trace of the initial separation from Placebo after reviewing those five trials in major depression none of them postpartum the FDA decided not to give it a go they told Sage that they needed more data before they would consider the drug in major depression but on the same day the FDA approved Zen alone in postpartum depression and here's where the story gets interesting because its mechanism might explain why [Music] by and that brings me to question two how does zenone work zenone and brexanolone have the same mechanism these are not really drugs in the traditional sense they are synthetic analoges of a naturally occurring hormone Alo pregnanolone one that rises during pregnancy and takes a sharp fall after delivery Alo pregnanolone modulates the Gaba a receptor that is involved in anxiety mood and cognition the same one that benzodiazapine is attached to so you can imagine the postpartum period is almost like a massive benzo aspine withdrawal well not exactly we're going to get to that but what's interesting here is that this treatment was designed to fit fit with the pathopysiology of postpartum depression and it works mood improves as the falling levels of Alo pregnanolone are replaced with its synthetic analog [Music] zenone question three with its gabaergic mechanism is zenone just a benzodiazapine masquerading as a neurosteroid no it works on the same receptor as the benzo aspenes Gaba a but benzo bind to a different part of that receptor zoren alone's unique binding there allows it to have broader effects across the gabaergic circuits that are prominent throughout the brain the details get a little complex but for our neuros psychopharmacology di hards zoren alone affects both phasic C aptic and tonic that's extra synaptic Gaba currents while the benzos affect only the phasic synaptic ones for the rest of us a more meaningful difference is this one over the long term benzodiazapines downregulate Gaba a receptors while zenone upregulates them at least that's what I read in an industry sponsored poster and I expect that we're all going to hear this fact repeated as it implies that zenone does not cause tolerance or addiction like the benzos do but think twice if you hear that benzos don't actually downregulate the Gaba a receptor except it's super high doses That You Don't See in practice and downregulation of this receptor is not thought to be the pathway through which benzo aspenes cause tolerance so the word is still out on whether zalone will cause tolerance but the FDA is only approving it for 2 weeks and the FDA and DEA is likely to restrict zuranolone as a controlled substance the FDA papers cite a study where zenone had similar rewarding qualities as Al praisal Lam Xanax and was more rewarding than placebo [Music] next question zalone works but does it keep working zoren alone's main advantage is its rapid onset patients felt better within 3 days of taking it and the drug is meant to be taken shortterm as a two-e course but what happens after those two weeks are over the longest they've measured is 4 weeks after the last dose at that time there was a mild decline in its benefits the effect size went down from .5 to3 but it still surpassed Placebo at the 4-we Mark to put that in perspective those effect sizes it's like at the end of the two-e treatment zenone was as powerful as azod aspine in anxiety and a month later after the treatment was stopped it was about as powerful as an SSRI in anxiety judging by its effect size but when it comes to prevention the picture looked very different in the major depression trials and that's a big reason that zuranolone failed to gain approval there in major depression the effects were only notable for a few days and after that it fizzled out not exactly surprising or impressive that a sedative which improves sleep would bring some short-term relief in major depression this issue of prevention is important because most patients with postpartum depression have chronic mood disorders zenone will help them get back on their feet but they're probably going to need something else maybe Psychotherapy maybe exercise maybe anti-depressants or lithium to keep depression at Bay and a lot of postpartum episodes are due to bipolar disorder the link is strong enough that postpartum depression is considered a soft sign of bipolar that brings us to the next [Music] question how does zenone affect bipolar patients there are no studies of zenone or of brexanolone in bipolar disorder and no studies in depression with mixed features either so we just don't know but we can say that there was no sign of manic induction in these trials and while we have no reason to think that it's gabaergic mechanisms will trigger mania this is New Territory so let's all keep an open mind and stay [Music] tuned so if this med has gabaergic effects why is it being used for depression instead of anxiety the simple answer is that postpartum anxiety is not a disorder that they can get approval for now anxiety is a big part of the picture for a lot of women who go through postpartum depression and anxiety levels did improve with zenone as did sleep in the postpartum trials I don't think this is simply an anti-anxiety effect though that is making people less depressed the Gaba system is linked to depression but the link is is poorly understood one theory is that it involves Gaba A's regulatory effects on the hypothalamic pituitary adrenal axis question seven what else does zenone treat so far we've seen positive trials in Parkinson's Tremor and primary insomnia in animal models it has anti-convulsive effects which may make it helpful in epilepsy it is also under investigation for bipolar depression and we've heard talk about studies in post-traumatic stress disorder and premenstrual dysphoric disorder neurosteroids like Alo prenolone are involved in the pathophysiology of those conditions but we couldn't find anything published yet question eight when is the drug going to be available the FDA has some details to finish up over the next 3 months including what level of control to restrict it as so the earliest I expect to see it on the pharmacy shelves is late [Music] 2023 and can you breastfeed on zenone this one is an unknown so the FDA is recommending against breastfeeding while taking the drug which is how the study iies were done zenone does cause sedation for one in four women who take it so it may not be safe in breastfeeding where it could be sedative to the baby on the other hand Dr dagianis Who led the clinical trials told Time magazine that the levels that pass into breast milk are very low we couldn't find that data so assume it's unpublished for women who are breastfeeding I recommend continuing to pump during the two-e treatment so they don't lose their lactation ability for the mother zenone was well tolerated the main side effects were drowsiness dizziness and diarrhea nobody lost Consciousness as they did with the bre calone [Music] trials and last question 10 can you give zenone with other psychiatric drugs yes zenone can be taken with anti-depressants 15 to 20% of the women in the studies were taking anti-depressants but whether it's going to work with a gabaergic benzo or Z hypnotic is less clear patients were not allowed to take those drugs during the trials and we at least expect there'd be an additive sedative effect zenone is metabolized by Cy P3 A4 and the dose needs to be approximately doubled if paired with a strong cyp3a4 inducer like carbamazapine or maphil or the dose needs to be approximately cut in half if it's taken with a strong cyp3a4 inhibitor like grapefruit juice or fluvoxamine [Music] oh and one more bonus question number 11 why are there so many Z's in zenone brand named zuru medications with the letter Z are perceived as more potent and elicit a strong placebo effect this one has three Z's while those that start with the letter t or S are perceived as being more tolerable [Music] and now for the study of the day a leaky umbrella has little value evidence clearly indicates the serotonin system is implicated in depression by Samir jhau and colleagues in molecular Psychiatry last year molecular Psychiatry published a review that garnered a lot of attention in the press and on social media because it concluded what many of us have suspected all along there is no consistent evidence linking serotonin to depression this month the same Journal published a sharply worded rebuke of the earlier review and while the new paper suggests that the issue is not as black and white as the old paper laid out it doesn't exactly connect the dots between ssris and depression which is what the fuss was all about to begin with written by 36 experts the new paper finds many flaws with the original review and they fall into three categories here they are one double counting data the review lumped together single studies with metaanalyses that contain those single studies two misinterpretations the original review made a few leaps of logic that don't hold true in the land of neurobiology for example when less serotonin is bound to the transporter it does not mean that there is more serotonin in the synapse the original review claims that there is no evidence linking reduced binding at the serotonin transporter to depression but actually there is good evidence for this link if we limit our Focus to specific brain regions number three tryptophan depletion one of the core supports for the serotonin theory of depression is a classic lab finding that depression can be induced in vulnerable people in the lab by depleting their diet of tryptophan which is a precursor of Serotonin I say in the lab because you have to carefully create a meal plan to cut out all tryptophan it doesn't happen in everyday life and the reverse by the way is not true adding tryptophan supplements to the diet like many patients do does not improve mood rather it just makes you feel tired like the way you'd feel after a tryptophan Rich turkey dinner the original review attempted to debunk the tryptophan hypothesis but they missed a few papers that indeed support it in the end this was all much to do about nothing no self-respecting psychiatric textbook has ever suggested that depression is due to a chemical imbalance or a single neurotransmitter but the media has and that's why the original review was so popular the new review reminds us where things stand first tryptophan depletion does cause depression in some people but we haven't really figured out why since the first tryptophan depletion studies came out in 1977 two two serotonin is involved in depression but that's about as meaningful as saying electricity is involved in your smartphone there are 15 serotonin receptors in the brain some of them have Pro depressive properties and some have anti-depressant properties increasing serotonin in the brain just causes problems like the kinds of side effects you see when people start an SSRI including suicidality much like turning up the electricity doesn't make my phone work better it just makes it heat up building on that analogy if you deplete your phone of electricity it'll stop playing this podcast just like if you deplete your diet of tryptophan you'll get depressed but that doesn't tell us how your phone started playing this podcast in the first place I wasn't surprised by either of these papers but the intensity of the public response did catch me off guard a bit and that is the real take-home Point here patients do not like the black box approach of evidence Bas medicine we use where we put random drugs in the animal model slot machines move the winners up to human trials and bring the ones that bring down a symptom rating scale to Market without ever understanding how they work and that is why the zalone story is so compelling because the drug was developed right out of the known pathophysiology of postpartum depression or at least a Slither of what is known falling Alor pregnanolone is not the only thing that depresses a new mother poverty domestic abuse isolation sleep disruption poor diet lack of exercise the gut microbiome low vitamin B6 and complications of pregnancy are all implicated in postpartum depression and let's get back to that vitamin B6 cuz it brings us full circle with serotonin vitamin B6 converts to tryptophan that precursor of Serotonin and we have some new evidence that B6 prevents postpartum depression in 2021 researchers gave a daily dose of B6 80 Mig late in the third trimester of pregnancy or a placebo to women who were at high risk of developing postpartum depression after delivery the ones who got the vitamin B6 had significantly less [Music] depression get daily research updates like these in the daily psych feed which is now on Facebook search for Chris Aken MD or follow me on Twitter threads or LinkedIn @ Chris s MD subscribe to our online carlat journal and get $30 off your first year subscription with the promo code podcast you'll find a new Journal there the carap Psychotherapy report edited by Mark Ruffalo [Music] thanks for watching hit subscribe if you enjoyed this content and to earn CMEs for listening head on over to the carlat report.com podcast