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browri

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About browri

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  • Birthday 05/14/1991

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  1. Definitely second going slow. My pdoc started me at 0.5mg, which I did for 2 weeks and it was just too much to start on. We were originally going after mood stabilizing effects, but my pdoc and I generally agree that while Rexulti seems initially to be on-par with Zyprexa, Seroquel, and Abilify for depressive symptoms; it's actual anti-manic effect isn't until the higher doses if at all, and titrating up on Rexulti that fast would cause you to go a bit koo-koo. After 2 weeks at 0.5mg, I dropped down to 0.25mg. Major side effects from 0.5mg were serious sedation, orthostatic hypotension. One night my blood pressure just plummeted and I just passed out and fell face-first on my living room floor and broke the glass I was carrying in my hand. Amazing I didn't cut myself or whack my head on something and my partner was there to make sure I was okay. After about 4 weeks at 0.25mg and 6 weeks in total, I bumped back up to 0.5mg. This time it felt TOTALLY different. More soothing feelings but barely activating at all. After another 4 weeks, we bumped up to 0.75mg for 2-3 days and then 1mg, which I've been on now for a few months. I do find 1mg to be somewhat activating, but not enough to take it in the morning. There's a good possibility I may have to go up in the coming months because of my usual winter depression, in which case I may try switching it to the morning. Definitely on side effects being dose-dependent but also time-dependent. A good example of another drug that causes orthostatic hypotension is prazosin. It's use as an antihypertensive (second line) and it's sometimes used for PTSD because of its potent anti-adrenergic effects, something that Rexulti and prazosin share. They do emphasize with prazosin that initially, blood pressure decreases too much and the heart pumps harder (effectively meaning the condition is worse), but over time it restores to a healthier blood pressure. Since adjusting to Rexulti at 1mg. The anti-adrenergic effects aren't as bothersome anymore. Only thing that still happens to me as a persistent side effect that would be considered anti-adrenergic is if I'm sitting at my desk with my legs crossed at work, both of my legs will actually fall asleep completely and quite easily. So I actually have to take a few seconds to uncross my legs and let the blood flow and then stand up slowly so I don't collapse. For some reason though, it doesn't bother me. I just try to cross my legs less. I do agree that Rexulti is not very well understood. It was originally portrayed as an Abilify patent-extender, but anyone who has taken both knows that an Abilify clone, Rexulti is not. (sorry about the Yoda) Its intrinsic activity at the dopamine receptors is more like 40-45% to Abilify's 60-65%. Abilify is definitely the more activating of the two. And this is one of the reasons why it has a higher propensity for akathisia than Rexulti. Abilify post-hoc meta-analysis comparison showed that Rexulti in fact has half the rate of akathisia that Abilify has. However, Rexulti does cause more weight gain. Otsuka was at least up-front about it this time because there are definitely people who have gained weight on Abilify. There is one thing that makes Rexulti stand out too, and Dr. Stahl's categories are important here: "-pines" - have many more actions at serotonin receptors with higher affinity than dopamine receptors "-dones" - have several actions at serotonin receptors with higher affinity than dopamine receptors, but less than "-pines" (exception being lurasidone, which only acts at 5HT7 receptors more potently than dopamine) "two pips and a rip" - few if any actions at serotonin receptors with a higher affinity than dopamine receptors So Abilify fits into the mold because it has only one receptor that it certainly has a much higher affinity, and that is the 5HT2B receptor where it is an inverse agonist. Rexulti on the other hand has its primary serotonergic activity at the 5HT1A receptor, where it not only binds with higher affinity than dopamine receptors but also a higher affinity compared to Abilify. We know this receptor is important to anti-depressant effect, and we also know that it leads to downstream dopamine release which can ameliorate movement-related side effects in addition to its antidepressant action. Not only does Rexulti have a higher affinity for 5HT1A than Abilify, but it also has a near 100% intrinsic activity (near full agonist), whereas Abilify's is more balanced (true partial agonist). Agree with you here. I can only imagine Rexulti being titrated rapidly like that in a controlled setting like inpatient or partial inpatient. It definitely is misunderstood because doctor's are treating it like an anti-manic when it's actually much better for the depressive side of things. I do believe it has mood stabilizing properties, but I don't think it could ever fill the gap where Depakote currently is for me. They are going to most likely release an immediate-acting injection form for use in the emergency use which will likely never get used, because they tend to use olanzapine, loxapine, chlorpromazine or haloperidol in the ER to calm agitation based on what guidelines I've been able to find for various hospital ERs on the interwebs. But they're also working on a long-acting inj. for Rexulti too. Looks like they're early on in the process according to Otsuka's pipeline which was updated at the end of this past June: Major depressive disorder / Oral | EU | Phase III | Asia | Phase III | US | Approved Schizophrenia / Oral | US, EU | Approved Agitation associated with dementia of the Alzheimer's type / Oral | US, EU | Phase III Bipolar I / Oral | US, EU | Phase III Posttraumatic stress disorder / Oral | US, EU | Phase II Schizophrenia / Depot injection | US | Phase I
  2. @Lee Anne it would seem you aren't the only person who's had this problem: It would also seem that phenytoin (Dilantin) can do this as well, but @jt07 is right, anti-convulsants generally cause hair loss, not crazy hair growth. What I would be curious to see is what your testosterone levels are, and not the free testosterone level but the globulin-bound testosterone. Free testosterone is exactly as it sounds, it's free-floating in the blood stream. However, a portion of sex hormones bind to globulin and a smaller portion to albumin. Enzyme-enducing anti-epileptic medications don't necessarily increase testosterone levels, but they can increase the binding of free testosterone to globulin. Globulin-bound testosterone is now understood to be more bioavailable in many ways than free testosterone. While, as a woman, you would have far less testosterone than a man, it is still present in small amounts, and as a woman, your body would be more sensitive to it. So increasing the amount of testosterone that binds to globulin can have androgenic effects like hair growth on the face or arms, maybe some acne, etc. So the two tests your doctor would want to write for to determine if that is the problem would be SHBG (Sex Hormone Binding Globulin, Serum) and TTBS (Testosterone, Total and Bioavailable, Serum). Also testing Testosterone, Free will give your doctor a better picture as to why this is occurring if testosterone is the root cause.
  3. Actually kinda sounds like the panicky feelings I would get for a few hours after taking Latuda. Became less of a problem in the higher doses because it was sedating at 60mg+.
  4. I've definitely heard of some people feeling sleepy on Vraylar, but some find it pretty activating. How long have you been taking it? Vraylar has the longest half-life of all of the AAPs as far as I'm aware. This means that it takes a very long time to build up in the blood stream. There's the main cariprazine component, which is in the pill that you're taking, and then your body also breaks that down into a metabolite, DMC (desmethylcariprazine). The parent compound can take 11-27 days to reach steady state, but the metabolite can take another 2 and a half to 4 months to reach steady state beyond that. When you're starting Vraylar, it is a long journey, and if you aren't really experiencing any side effects otherwise, it would be worth it to try and stick it out. Do you take it morning or evening? Are you also still taking Latuda as your signature indicates?
  5. The last time I took lamotrigine, it was activating in the beginning but the fatigue did set in after I adjusted. Over a fairly long period of time (in the order of several months) I either didn't notice it anymore or it went away. At that point, I decided to split the dose 100AM/100PM which did help the ebbs and flows a bit. I felt less tired in the morning because I wasn't getting it all at once in the evening. This time around, I'm taking lamotrigine with valproate, in which case you usually don't go over 100mg on lamotrigine. I'm only taking 50mg at this point, and I take it in the morning. Don't have any problems.
  6. Well they're called that because they follow the crossover/comorbidity of physical and mental illness. But I suppose this is a more suitable paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674976/ I'm sure you already know that some receptors cause dopamine release when activated like 5HT1A. However, the article linked above postulates that a good portion of the suppression of dopamine signaling can be overcome by a 5HT2C antagonist. It only focused on that one receptor of course because escitalopram is known to interact with that receptor and introducing a 5HT2C antagonist reduced escitalopram's negative impact on dopamine signaling. Another good example would be this one: https://academic.oup.com/ijnp/article/20/12/1036/3901225 In a nutshell, antidepressants most likely cause anhedonia through suppression of dopamine signaling after chronic administration. If you consider that movement-related disorders from antipsychotic treatment such as restlessness could be related to a syndrome like restless legs, then perhaps the pathologies of akathisia vs RLS are not that dissimilar. Another potential problem to consider is how these neurotransmitters are metabolized. If a patient has an over-expressed COMT gene, this could prove problematic with SSRI use. If dopamine signaling is reduced then that would mean most of the dopamine is intracellular which is where a good portion of monoamine and catecholamine metabolism occurs. If they're a fast metabolizer of catecholamines and their catecholamines are predominantly intracellular due to suppression of dopamine release, then you might have a problem. In that case, encouraging dopamine release with 5HT1A agonists or 5HT2A antagonists could be a good thing. But then again, who am I. I just like to read too much.
  7. @notloki @Catwoman has regularly reported restless leg syndrome with many SSRIs she has taken. This isn't necessarily because of dopamine depletion, but is quite possibly the result of reduced dopamine signaling due to higher serotonergic activity: https://www.psychosomaticsjournal.com/article/S0033-3182(98)71370-2/abstract
  8. Another good way of looking at it is just in percents to make it clearer. Usually SSRIs need to be dosed to a point where they inhibit the serotonin transporter 60-85%. So let's say Drug A inhibits the transporter to 65% at 50mg and Drug B inhibits 60% at 25mg. If you take those two medications together at those doses, it doesn't equate to 125% inhibition, it might just come out to 75%. Just random numbers I'm throwing out, but it shows that taking two medications of the same class MIGHT be synergistic but not enough to make the side effects worthwhile. Risks outweigh the benefits.
  9. @Sync actually your combo is all the more intriguing. Sertraline at doses 150-200mg actually inhibits dopamine reuptake along with serotonin. Bupropion is stronger at inhibiting norepinephrine reuptake than dopamine reuptake (doesn't touch serotonin at all). Sertraline (as a so-called SSRI) is obviously far more potent at inhibiting serotonin reuptake than dopamine reuptake. However, the two of them together, while modest inhibitors of dopamine reuptake on their own could theoretically be quite synergistic when combined. If you combine two strong reuptake inhibitors and max out the transporter that performs reuptake, there isn't much added benefit. Imagine thousands of people all trying to carry rocks from one little pile to another little pile. No matter how many people you have to carry those rocks, only so many people can clamor around a small pile to get a rock and then only so many of those people can get close enough to the second pile to drop off the rock. Yeah that rock pile is going to still get moved pretty quickly, but more doesn't always mean you'll get more in the nervous system. Imagine instead that just 1 or 2 people are moving the rocks from one pile to another. If 1-3 more come, then that will certainly pick up the pace, but there comes a point when adding people doesn't actually make it any faster. I know it's kind of a rough analogy so I welcome criticism, but that's just how it made sense in my brain. EDIT: Will add that I only understand this to be the case for reuptake inhibitors but I can imagine the concept can be applied, at least in part, to other neurological functions.
  10. @argh you are correct. Sertraline is a moderate inhibitor of CYP2B6, which metabolizes bupropion. Therefore, sertraline would increase bupropion's blood levels. However, there is a bit more to it. Sertraline also inhibits CYP2D6, which is responsible for sertraline's metabolism. So in fact, sertraline actually inhibits its own metabolism similarly to fluoxetine and paroxetine. Taking it even a step further, bupropion ALSO inhibits CYP2D6. So sertraline increases its own blood levels as well as bupropion's, and bupropion increases sertraline's levels, which would theoretically increase bupropion's levels even further, because typically the impact on metabolic enzymes is dose dependent or falls in line with increasing blood levels, simply meaning that as you go to higher doses or reach higher blood levels, the metabolic inhibition increases. Therefore, it may not be the best idea in a pdoc's toolbox to do like 200mg of sertraline and 300mg of bupropion, just as an example. Typically, you would see a combo like this of 50mg sertraline and 150mg bupropion XL, because taking them together makes the lower doses go much further. One thing I cannot stress more is to not freak out and think its a major interaction or that you're experiencing overdose symptoms. Combining SSRIs with bupropion is a strategy that has been in use for quite some time now. Pretty much all of the SSRIs and many of the tricyclic antidepressants are metabolized by CYP2D6, so the impact that bupropion has on that enzyme is actually a positive treatment mechanism to be explored as long as it's done carefully. A more heroic example would be combining clomipramine and fluvoxamine for treatment-resistant OCD. It has to be dosed VERY carefully because fluvoxamine very dramatically inhibits clomipramine's metabolism, but in low doses of each, the summation is generally greater than its parts.
  11. Well vortioxetine for anxiety and OCD can be a mixed bag. Like I said previously, some people find it makes their anxiety worse, and some say it improves their anxiety, kind of like bupropion. Vortioxetine doesn't just work on serotonin. It only DIRECTLY interacts with the serotonin transporter and the receptors, but it has so much more downstream activity because of its complex actions at serotonin receptors. It increases the release of glutamate, histamine, norepinephrine, and dopamine...something that not many antidepressants can boast. The histamine release is responsible for increased alertness. The glutamate release is activating and can be pro-cognitive. The dopamine release as well should help to combat SSRI-induced apathy/anhedonia. The problem is the increase in glutamate and dopamine release. For treatment-resistant OCD, the augmentation techniques to SSRIs are typically to reduce glutamate release or block dopamine receptors. Many SSRIs reduce dopamine activity initially, but some of that dopamine signaling function can return, which is why for OCD, treatment resistance can be common and much higher doses of SSRIs are required to more strongly suppress dopamine. Additionally, with dopamine suppressed, this should also suppress glutamate downstream. The alternatives would be to perform this directly by taking a dopamine antagonist like an atypical antipsychotic such as quetiapine or risperidone or a glutamate reducing agent like lamotrigine or topiramate. The fact that citalopram, sertraline, and lamotrigine worked for you makes a lot of sense. Citalopram and escitalopram are not regarded as the most potent SSRIs (that prize goes to paroxetine, which has the highest affinity for the serotonin transporter), but they do have the most selectivity, meaning they bind to the serotonin transporter and inhibit it, but they don't do much else. This effect being as pure as it is, should seriously suppress dopamine signaling, which falls in line with the apathy that a lot of people feel on citalopram and escitalopram. Sertraline on the other hand is actually a modest dopamine reuptake inhibitor, particularly in the higher doses >100mg. Fluoxetine is likely stronger at inhibiting the dopamine transporter While it would seem from some evidence that you would want to reduce dopamine activity to improve OCD symptoms, sertraline and fluoxetine actually can increase this activity. This isn't necessarily a bad thing though. Initially, there would be an increase in dopamine activity and thus more glutamate release downstream, but dopamine receptors would desensitize over time, dopamine release shoudl reduce and restore to a more stabilized function. Theoretically, the increased glutamate transmission should reduce after a time as well. So perhaps what would be good is a combo of medications that worked for you previously. I find lamotrigine to be kind of activating. Combine that with sertraline, and it should provide quite an "oomph". If you wanted to try something over-the-counter, you can try magnesium. It is a glutamate blocker at NMDA receptors, but this does increase and stabilize glutamate neurotransmission. Some people find relief with magnesium augmentation if they don't respond completely to an antidepressant. Lamotrigine actually reduces glutamate release from the sending neuron, whereas magnesium would be at the receiving neuron guarding the door. If you were to try magnesium, I would recommend the Neuro-Mag brand. It's a specific formulation called magnesium L-threonate. It's essentially magnesium that's been bonded to vitamin C because it enables the magnesium to cross the blood-brain barrier more efficiently. Initially, it can make people kind of foggy, but if you continue taking it, many people report increased cognition. Also consider that calcium is the mineral that causes the muscles to contract. Magnesium is the element that makes them relax. So it can have calming effects on anxiety as well, and even can help with cramps induced by "statin" cholesterol medications.
  12. Well yeah but a good doctor should also know that you have to titrate these or you'll make the patient miserable especially one that has a long half-life like vortioxetine that doesn't slow down the metabolism of other drugs. This is why pdocs like to use low dose fluoxetine to help patients get off antidepressants because it replaces the existing antidepressant but it slows down the metabolism of most SSRIs so it helps the old drug persist for a bit and makes it decrease more slowly so you don't have to break tablets up and titrate yourself. Trintellix doesn't have the inhibition on metabolism though and with a long half-life it does take 2 weeks to reach steady blood levels and even more time beyond that for it to really really work. It definitely does have immediate effects, but the complete effect on your mood does still take several weeks like many other ADs. With Trintellix, my recommendation would normally be to take it slow, but in this case, even if it takes 2 weeks to reach steady state it should take less time for it to kick in beyond that because you're already taking an antidepressant. In this case it would make sense in my mind for your pdoc to follow the manufacturer dosing guidelines and drop you down pretty quickly on sertraline if it isn't doing that much for you. Each person is different though. Listen to your body.
  13. Yep. In fact, extensive study of PMDD is how there's enough data to correlate changes in hormones to changes in neurotransmitter levels, BUT..... ....there is likely less data that specifically correlates hormone changes to changes in actual gene expression which ultimately lead to those changes in neurotransmitter levels. As for how I know so much about it......a lot of reading. An obsessive number of hours doing so. In fact, the research has been a bit therapeutic when combined with talk therapy. What I've found is that for few studies that correlate specific genes to certain neurological functions, there's a smaller few more that directly contradict those findings. It's difficult reading the papers sometimes, because over time, you clearly see the bias that comes from certain people's work, especially when the papers were of clinical trials that were funded by pharmaceutical companies. It's good to look at that data, but in psychiatry, pharmaceutical companies rarely want to compare their new product to "incumbent" therapies to which medical professionals have grown accustomed. But a lot of my research has shown me just how "in-absolute" your genes are. For example, they've found a correlation between inflammation and many different mental disorders. A large genome analysis study found that of all the mental health disorders from autism to schizophrenia to bipolar disorder, they all share crossover on CD genes or rather, the genes that encode your white blood cells. An overactive immune system where your white blood cells are constantly releasing toxins that are intended to destroy foreign bodies like bacteria and viruses end up inadvertently impacting the brain and other bodily systems. This would effectively make some mental conditions auto-immune disorders....if by a bit of a stretch. But this is also why there are some studies that show omega-3 from fish oil can reduce inflammation and a few that say it also is a good supplement for depression. I think there might be a small handful that show it can modestly improve the efficacy of antidepressants. I recently did a study with 23andMe. They signed up 10,000 people I believe with either bipolar disorder or major depressive disorder. They allowed us to do the full 23andMe test for free and then had us take questionnaires about our mood and cognitive tests once a month for 9 months. I don't believe that the results of the study have been published yet. They partnered with another foundation and the pharmaceutical company. Lundbeck. for the study. I don't believe this was for Lundbeck's research. I believe they actually supplied the cognitive test. Because the same test I took for 9 months was ultimately used to add labeling to the Trintellix label showing that it improves cognitive function in those with depression. Bit of a coincidence? I think not. Once your sample has been analyzed you can export the raw data and then use other online tools to analyze it SNP by SNP (single nucleotide polymorphism). There are some decent free tools, but I personally use SelfDecode. It is a recurring annual cost, but I use it enough that it's worth it to me. The nice thing about SelfDecode is that for each gene, it explains its general function, provides a list of SNPs for that gene in your DNA sample (if they were analyzed), and then also show you which substances alter the expression or reaction of those different genes. Then for each of your own SNPs on that gene, it will provide studies that analyzed the function of that specific SNP. I have A LOT of SNPs that say I'm at a higher risk for schizophrenia, but I'm bipolar, again lending to that lack of absolute effect that your genes have on who you are as a person. I actually just finished reading an interesting study that correlated a specific variant of a SNP on the COMT gene matching mine that showed when taken with valproate, dextromethorphan significantly reduced the symptoms of bipolar depression in individuals that were otherwise stabilized. Dextromethorphan of course is the cough suppressant in all kinds of over-the-counter cold medicine, but of course you've heard of people going on "Robo-trips" and dextromethorphan is what causes the high. In moderate doses though it has shown a pretty robust antidepressant effect all its own. Only problem is that it doesn't last all day. So there's actually a company that's working on a combo of Wellbutrin+dextromethorphan for depression because Wellbutrin will increase dextromethorphan's blood levels. Point of bringing up dextromethorphan though is that one of its most potent effects is its ability to block glutamate receptors in the brain. Glutamate is important for cognition and neuronal activation, but in high levels can be quite toxic. With low COMT and increased dopamine activity, this may have a downstream effect of increased release of glutamate to "excite" the brain and reinforce the "feel goods" that dopamine gives you. dextromethorphan blocks a specific type of glutamate receptors called NMDA receptors to cancel out some of the depressive effects that glutamate can have in excitotoxic levels. The brain is a proxy war. Enemy A and Enemy B fight on Enemy C's turf. Like a game of whack-a-mole or trying to plug a leaky boat. Great, that antidepressant increased your serotonin, but now your dopamine activity is low, which may explain why you can't feel any pleasure and you can't have an orgasm. Add Wellbutrin to deal with the anhedonia and sexual dysfunction, now that increased norepinephrine and dopamine ramps up cortisol and glutamate which for bipolar disorder probably would lead to bipolar depression. Ketamine is being heavily researched right now for its antidepressant effects and it is a glutamate blocker at NMDA receptors like dextromethorphan. Another more natural over-the-counter example is your basic magnesium Lots going on in this post, I know. But the point is, you can take the time to do all this research and find that all the things your doctor has been telling you to do to make you feel better are actually legitimate. Aspartame is an artificial sweetener quite frequently used. In the body, it can be converted to a compound that can bind to and activate NMDA receptors like glutamate. NMDA does stand for N-methyl-D-aspartate after all. Glutamate and gluten also sound similar for a reason. What do you think your body does with all that gluten? I'm not saying eliminate it, but a super high carb diet might just give you a sugar rush and ultimately make you more depressed. As I indicated in a previous post, if I eat healthy, quit smoking, and start exercising, it'll increase my testosterone, subsequently my COMT, and I'll probably feel a lot better. Genes have also helped me target medications. Ultimately I have an under-expressed serotonin transporter, which MIGHT mean I can't tolerate antidepressants but historically I've never known them to be an issue. Nevertheless, my pdoc and I try to operate without them. I have an under-expressed MAO-A and COMT gene, which is likely why Depakote is my dream drug. It increases MAO-A and while it doesn't increase COMT, it does seem to prevent dopamine synthesis. If you can't help get rid of it, just keep the brain from making it in the first place. Lol. Also, it increases the conversion of glutamate to GABA and prevents it from being converted back or broken down into unusable compounds. Anyway, back to work. Enjoy!
  14. Generally pdocs don't combine antidepressants so you wouldn't be kept on a sertraline 50mg + vortioxetine 10mg for very long but if you did that combo for 2 weeks you should start noticing a difference by then. It won't have totally kicked in by that point but you'll know if it's doing anything. I just didn't feel like it was really doing anything for my depression until I hit 15mg. Then I started to notice a difference but 20mg was a game changer. 2 weeks in to 20mg and I knew I wanted to keep it. And if I ever become depressed again, you better believe I will be going back to Trintellix. I think I have at least 3 months if not 6 each of the 5mg, 10mg, and 20mg tablets. So that would be a no brainer lol
  15. This is why the combination of fluovaxamine+clomipramine may be better. Fluvoxamine will prevent clomipramine from being broken down into desmethylclomipramine (DMC) which is responsible for most of the noradrenergic effects. The muscle twitchiness might be the antagonism of 5HT2A leading to dopamine release when you aren't on a high enough dose of clomipramine to block dopamine receptors to compensate. You would need to get to therapeutic doses of 100-200mg/day before this happens. But looking at receptor affinities, you likely would need fluvoxamine for this to happen because DMC has a much lower affinity for the dopamine receptors than clomipramine and has twice the circulating concentrations in the blood than clomipramine when at steady state. Likely you just need more time to adjust. I would continue working with your pdoc to try and get to the 100mg before you ask yourself how you're feeling.
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