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browri

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About browri

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  1. Rexulti has an average time to peak plasma levels of 4 hours post-dose. This is why 7PM/8PM works, because I'm halfway into it by the time I'm getting ready for bed and getting towards peak right around when I'm falling asleep. I may consider taking in the morning if I go any higher than 1mg. I think the higher doses are more stimulating from what I understand. Yeah Rexulti may be structurally similar to Abilify, but it's definitely not comparing apples to apples.
  2. I would recommend taking no later than 9PM to be honest. That will ensure that you want to go to sleep sometime between 10PM and midnight. That may be the adrenergic blocking side effects of olanzapine. They would be most noticeable in the morning when olanzapine plasma levels are highest. They should go away with time as you adjust. Effectiveness against paranoia or social anxiety may take some time to be fully realized. But one thing olanzapine does do quickly is calm you down. Much less reactive and not as rapid. How long have you been off aripiprazole and do you take any other medications besides olanzapine, like an antidepressant?
  3. I remember 2.5mg of olanzapine. 30-60 minutes before bedtime should definitely be good enough.
  4. Keep in mind that the idea of adding atypical antipsychotics to antidepressants in non-psychotic individuals with major depressive disorder is a relatively new phenomenon. It didn't start until after the usefulness of the older atypicals had expired (i.e. their marketing exclusivity / "brand only"). Therefore, these pharmaceutical companies didn't take the time to go back and get approvals for this indication for their original atypicals like risperidone because it wouldn't have made them any more money. Nevertheless, risperidone has still found usefulness for this indication, even though the FDA didn't give its stamp of approval. Risperidone does show antidepressant action in lower doses because that is where it is a more potent at blocking serotonin receptors, and its antagonism/blocking effect at dopamine receptors favors pre-synaptic autoreceptors at lower doses which actually causes dopamine release and activation of post-synaptic receptors. This, combined with inverse agonism of the 5HT2 receptors which would cause release of norepinephrine and dopamine throughout the brain. One thing that risperidone and Rexulti have in common is their potent antagonism of alpha-2C adrenergic receptors. The alpha-2 adrenergic receptor family acts as auto-receptors for adrenaline and noradrenaline/norepinephrine. Blocking them increases release of norepinephrine and adrenaline, activating does the opposite. But they are also hetero-receptors for serotonin, because blocking them increases serotonin release and thus indirectly activates the 5HT1 receptor family. Serotonin release is further enhanced by risperidone through its inverse agonism of 5HT7 receptors. Risperidone also blocks alpha-1 adrenergic receptors to calm some of the physical effects of adrenaline and norepinephrine such as increased heart rate. This is how the fight or flight response is reduced. However, the antidepressant effects of risperidone do still depend on its ability to activate post-synaptic dopamine receptors through both direct and indirect mechanisms. Doses much higher than 1mg per day introduce a dopamine receptor occupancy that blocks too many post-synaptic receptors and thus the antidepressant effect is lost. Rexulti has many of the same pharmacological effects as risperidone, and some are subtly different. @mikl_pls was so wonderful to sort them by affinity: 5-HT1A (0.12 nM, intrinsic activity = 60%) α1B (0.17 nM) D2L (0.3 nM, intrinsic activity = 43%) 5-HT2A (0.47 nM) α2C (0.59 nM) D3 (1.1 nM) (intrinsic activity = 15%) α1D (2.6 nM) 5-HT7 (3.7 nM) α1A (3.8 nM) 5-HT2C (12-34 nM) α2A (15 nM) α2B (17 nM) H1 (19 nM) 5-HT6 (58 nM) alpha-2 adrenergic receptor antagonism increases serotonin output and alpha-1 antagonism calms both central and peripheral adrenergic symptoms of anxiety. The increased serotonin output combined with 5HT1A agonism (which has actually been reported closer to 90%) causes downstream dopamine release in concert with the 5HT2A antagonism. What makes Rexulti different though? Where risperidone is actually a VERY low affinity blocker of the 5HT1A receptor (meaning that it binds, has null effect, and prevents other compounds from binding and activating the receptor), Rexulti is a partial (near-full) agonist. Partial agonist means it only has a portion of the activating effects of the receptor's endogenous ligand. In this case, that ligand is serotonin. Normally, serotonin would bind to its receptors and would have a 100% intrinsic activity effect making it an agonist. Anything that binds but does not activate 100% is considered a partial agonist. Keep in mind that for some receptors, activating them can reduce release of that neurotransmitter and blocking them can increase output. Rexulti has an intrinsic activity at the D2 receptors just under 50% making it a partial agonist, but still more blocker than activator (i.e. if you're a 45% partial agonist, that means you're 55% antagonist). It also ensures that dopamine or serotonin cannot displace it at 5HT1A and D2 receptors so that it can maintain that stabilization. Additionally, it's important to maintain activity at the dopamine receptors to address depressive symptoms, which pure dopamine antagonists have difficulty with in their normal dosing ranges. This is why Abilify was the first AAP to get approval for MDD adjunct. Seroquel got it, but it's also a intermediate dissociation dopamine antagonist which means it dissociates rapidly enough from dopamine receptors to allow for normal dopamine signaling. Same goes for olanzapine with the fluoxetine/olanzapine "Symbyax" combination. Now Rexulti has approval, and Vraylar likely will get the approval as well, being another dopamine partial agonist like Abilify and Rexulti. So we've established that the main differences between risperidone and Rexulti are that Rexulti activates 5HT1A where risperidone lightly blocks it, and Rexulti is a partial agonist at dopamine receptors and risperidone only blocks. It's better to compare Rexulti to Abilify seeing as it's the most similar in chemical structure even if the pharmacology is quite different. Abilify was also a 5HT1A partial agonist like Rexulti but with much lower intrinsic activity. Rexulti may be closer to 80 or 90% but Abilify was closer to 50 or 60% or even lower in some reports. Abilify had almost 20% greater intrinsic activity at dopamine receptors (totaling 60-70%), making it the more stimulating of the two and a higher propensity for akathisia and restlessness than Rexulti. Abilify also did not as potently block the alpha adrenergic receptors the way Rexulti does, which may underlie Rexulti's lower risk for movement related side effects than Abilify. The short of it is, if you theoretically would have responded well to Abilify but you just couldn't tolerate it, chances are you should try Rexulti and will likely be pleasantly surprised to find it is nothing like Abilify even if the chemical names sound similar and they're made by the same company. This is not a case of Celexa -> Lexapro or Effexor -> Pristiq. Sure, tolerability may improve, but actual effect is quite different, coming from someone who has taken both. So really, risperidone's usefulness in depression doesn't extend that far beyond 1mg/day. Rexulti has a wider useful dose range for depressive disorders (seeing as there is 0.25mg, 0.5mg, 1mg, and 2mg tablets) up to 2mg and relatively stronger affinity at all receptors than risperidone. There's also the option of pushing Rexulti further to 3mg for some patients that need more oomph, but it isn't usually needed.
  5. Actually the reason that olanzapine causes type 2 diabetes is the reason why it has very little movement related side effects. It's a potent muscarinic acetylcholine blocker of many receptor subtypes. But specifically, its antagonism of M3 muscarinic receptors (which are predominantly located on pancreatic cells) fundamentally alters your body's insulin production and resistance. Antagonism of other muscarinic receptors reduces movement related side effects much like Cogentin does when it's given for akathisia. Cogentin and other anticholinergics also carry this risk for type 2 diabetes.
  6. I take it a few hours before bedtime (~7-8PM). Helps calm rumination so I don't lay in bed before an hour or two before I fall asleep. Helps my sleep to be restful, and I wake up in the morning ready to go. I get what you mean though about Rexulti not making you tired but just making you really calm. I've taken it mid-day before and that was pretty much my experience as well.
  7. You could talk to your pdoc about dialing back the Depakote. What is it about Depakote that you don't like? (i.e. side effects)
  8. I mean I see what she's trying to do. There's a lot of evidence that many people do get by on 10mg after being on it for several weeks, but 20mg still statistically results in better outcomes. My pdoc did the same thing with Trintellix. 5mg for like 6-8 weeks before increasing to 10mg, and I think I was on that for at least 2 months if not 3 before he was willing to increase it to 15mg. Maybe because it's such a tight dose range, they want to be extra sure. Generally speaking though, Trintellix is faster acting than its cohorts like Prozac. Easy does it is smart. See where Trintellix takes you and then decide later whether you even need to swap the Risperdal for Rexulti. Ideally you would be able to get off the Lexapro though.
  9. Not too much of a surprise. When I first started Trintellix, I felt some activation at 5mg but not much else. Then maybe a little more activation when we increased to 10mg, but it wasn't until I got to 15mg that I really started to feel like it might be doing something for me, and 20mg was even better, but again a dose I relegate to just deep winter. Trintellix is weird in that it can make you more stimulated initially as you increase the dose, but then it starts to calm you down at the same time while still stimulating you. Only other medication that was like that was probably Viibryd (vilazodone). Definitely should try 15mg and 20mg before you throw in the towel. I have my appt today and I'm going to talk to my pdoc about increasing my Rexulti and Trintellix because I know where my mood is headed (downhill). All the tell tale signs like oversleeping even though you've had plenty of hours of sleep, not really ever hungry for anything. Momentary dissociative blues during the day. So if you switched the Risperdal for Rexulti, would you continue on the Trintellix? I ask because I have found the combo of Trintellix and Rexulti to be stellar for my depression and my anxiety. Comparing therapeutic effect and intensity/potency, 20mg of Trintellix should theoretically go further than 30mg of Lexapro. and 1-2mg of Rexulti should go much further than 2mg of Risperdal.
  10. Yeah so you really should be able to see at this stage what 10mg is or isn't going to do for you. It only takes 2 weeks to reach steady state and there's maybe an additional 1-2 weeks needed for additional receptor sensitivity changes. I do think you'll find it hard getting much higher than 15mg though without reducing your escitalopram.
  11. Makes sense. Definitely spend at least 2 weeks at each dose to really adjust. It may be tougher because you're on 30mg of escitalopram as well. If you do have tolerability issues with 15-20mg, reducing escitalopram may help some of those effects. How many days would you say you've been on 10mg of Trintellix at this point?
  12. @MuddlingThru do you have a copy of the results of your GeneSight test? Usually what you truly need to pay attention to is the list of drugs that are in the "red" list. The yellow list means they could be bad matches but the science isn't totally certain, and the greens mean you don't have any pharmacogenomic interactions but that doesn't necessarily mean they won't work for you, just that they should be "tolerable" Without the test results I could make a few suggestions.....or rather....I would simply +1 what has previously been said. If you do have pain issues, you will find that the SNRI class will be helpful with your pain. There's a reason for this. When you are in a fight or flight situation, your body releases adrenaline, which does increase your body's pain tolerance / reduces its sensitivity to pain. SNRIs work by increasing the adrenergic baseline in the nervous system thus increasing your pain tolerance baseline as well. With this in mind I would second the use of Cymbalta (duloxetine) or Pristiq (desvenlafaxine) in lieu of Fetzima (levomilnacipran). Going back to the question about the GeneSight results, I would be curious to know why the test said Pristiq was fine but Effexor XR was not. This could be a CYP2D6 genetic interaction that would be critical to knowing which drugs would be preferable to your system. That being said, you did indicate that you and SSRIs don't mix. Fetzima is a norepinephrine-heavy SNRI and that may be the only reason you are tolerating it if you can't handle SSRIs or more serotonin-heavy SNRIs. Cymbalta will be 1:1 in its affinity for the serotonin and norepinephrine transporters, Pristiq will be more serotonin-heavy. However, Effexor has been shown to have more positive impact on pain than Pristiq despite the fact that Pristiq is simply Effexor's chief metabolite. Effexor has a wider array of interactions in the body than Pristiq which could have a positive impact for you where Pristiq did not. If you do decide to go the TCA route, I would probably direct you towards nortriptyline first being that it's more norepinephrine-heavy. Another option would be desipramine. Either of these TCAs can be combined synergistically with a low dose of good ole fluoxetine (Prozac) to augment them. At that rate though, I would say to ditch the bupropion (Wellbutrin).
  13. @CrazyRedhead I see that you are currently on 30mg of escitalopram as well. Would the goal be to discontinue escitalopram eventually? I imagine you may be able to if you went to 20mg on vortioxetine (Trintellix).
  14. I can see why the choice of the combination of valproate+bupropion then. Valproate is good for stabilizing any sort of rapid cycling like you're describing, and bupropion is pretty much the only antidepressant with the least likelihood to trigger mania or make it worse. In fact I've known a pdoc or two to even go as far to say that for some of their patients bupropion in and of itself can actually be stabilizing even though it's primarily activating. The side effects you describe seem to be mostly related to bupropion. Specifically the tremor and tinnitus. I believe valproate could potentially cause tremor at higher doses but not at the dose you are taking, tremor is more of a lithium thing......unless of course you don't weigh much and 750mg actually yields a blood level in the range of 50-100mcg/mL. That being said, I find with valproate that when I'm not cycling and am more depressive, I usually back down to 500mg and move back up to 1000mg when the situation calls for it (i.e. tougher mood swings like in the spring/summer) For me, generic bupropion caused a certain level of anxiety that I couldn't really tolerate. Personally, I wouldn't recommend the generic versions of Wellbutrin XL and would stay on the SR generics myself. The only way I can really tolerate a 24-hour "XL" formulation of bupropion is when I take the Aplenzin brand which is actually bupropion hydrobromide instead of bupropion hydrochloride. Not all insurance companies will cover it, but if they do, you typically only have to try generic bupropion for the step therapy requirement. And if your insurance covers it and you get the savings card, it's actually pretty cheap anyway. In the DSM definition of bipolar disorder, you would be correct. It sounds like your mood swings don't last long enough to meet the definition of "basic" bipolar disorder. However, with the rapid-cycling diagnostic modifier available to clinicians, patients that experience mood switches inside of a 24-hour period can still qualify as bipolar. The fact that your condition easily reacts to external stimuli may indicate that your depression is "atypical" but not necessarily untreatable or any less than what it actually is.
  15. I think with Viibryd, you don't ever go to the doses that would be necessary to produce any meaningful of inhibition of DAT. That being said, they are finding that for some people, doses higher than 40mg are useful, and it's possible that at those doses, you could achieve a level of DAT inhibition that may be significant......possibly, but even then it's kind of a stretch. It's very much the same though with Zoloft in the 150mg-200mg range. For some people like @HydroCat, there are noticeable energizing effects at those doses that are kind of hard to just write off as "initial serotonergic activation/agitation". Many people get by just fine though on 25-50mg of Zoloft, and those patients likely aren't experiencing any sort of DAT inhibition. For what it's worth I don't think Viibryd's bioavilability is all that great to begin with so that could be problematic.
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