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  1. I just bought Stahl's Essential Psychopharmacology: 5th Edition from this past June 2021: https://smile.amazon.com/gp/product/1108971636/ref=ppx_yo_dt_b_asin_title_o01_s00?ie=UTF8&psc=1 It's complicated, but I've made it through Chapter 1 and 2, and I already have a better grasp some of the how-it-works of things. Always glad to share that understanding if I can. @Selkie glad we can provide some info. Let us know how things go with the Vyvanse.
  2. Sorry @Iceberg. Realized after the fact that you actually provided a solid explanation already, and I basically re-said everything 😅
  3. Bupropion is actually a substituted phenylethylamine, and therefore its chemical structure is very similar to other phenylethylamines like amphetamine. What that gives them in common is the ability to inhibit the norepinephrine and dopamine transporters, which are responsible for clearing norepinephrine and dopamine from the synapse, respectively. However, amphetamine is an agonist of the TAAR1 receptor and an inhibitor of VMAT2. These effects cause the sending neuron to expel norepinephrine and dopamine into the synapse. Combined with inhibition of the transporters that are meant to clear the synapse, this creates for broad stimulation of adrenergic and dopaminergic receptors and lends to amphetamine's euphoric effects. The other difference between the two is bupropion's very weak impact on dopamine relative to norepinephrine. Bupropion does inhibit the dopamine transporter, but its metabolites do not do this to a significant degree. Additionally, bupropion's half-life is much shorter than those of the various metabolites, and the metabolites circulate at far higher levels at steady state than bupropion. This makes bupropion, overall, more of a pure inhibitor of the norepinephrine transporter. Without a significant impact on dopamine, bupropion's pleasure-inducing effects are limited, and this tempers its abuse. That isn't to say that bupropion isn't abused on the street, because it certainly is. However, its lack of euphoria when insufflated, for example, combined with a very high seizure risk limit its abuse potential. It is worth noting that, in the pre-frontal cortex, the dopamine transporter is limited in supply; and the norepinephrine transporter does take over the role of transporting dopamine, to a certain extent. Therefore, bupropion does have the potential of increasing dopamine in the PFC by inhibiting the norepinephrine transporter, and this may be significant when considering how bupropion works to alleviate depression and particularly anhedonic symptoms. Generally speaking, both bupropion and amphetamine are stimulating in similar ways. However, amphetamine has the ability to stimulate you and simultaneously make you feel good, which chemically reinforces your behavior when stimulated. Said another way, amphetamine will give you task reward to chemically reinforce your increased activity when stimulated (increased productivity & cognitive function)
  4. If you were able to tolerate Wellbutrin, then Vyvanse will be a piece of cake. Try your hardest not to think about it. Amphetamines could possibly cause less anxiety than Wellbutrin. It's difficult to compare though. It's better to understand that a lot of Wellbutrin's anxiety properties have to do with its inhibition of the norepinephrine transporter. It reduces norepinephrine frequency of firing overall but increases baseline norepinephrine levels in the synapse, thus desensitizing. Amphetamines can have a similar effect on norepinephrine, but dextroamphetamine in particular is preferential for dopamine release. It'll have more central stimulation (in the brain) than peripheral stimulation (in the heart) compared to Wellbutrin or Adderall. Well I imagine you may have tried the Vyvanse already, but in case you haven't....10mg is a very very low dose. Usually they start adults at 30mg and work up from there as needed to a max of 70mg. Roughly speaking: Vyvanse 25 = Adderall 10 Vyvanse 51 = Adderall 20 Vyvanse 76 = Adderall 30 This is just to convey that Vyvanse 30, 50, and 70 are roughly equivalent to Adderall 10, 20, and 30. Although, truly Adderall 30 is closer to about 80mg of Vyvanse. In my personal experience, my Adderall XR dose was always 20mg, but when I switched to Vyvanse and when I'm also taking an antidepressant, my Vyvanse dose is usually more like 40mg. I've gone as low as 30mg when I was taking 20mg of Trintellix because of how stimulating that was overall. I can tell you from my own personal experience that Vyvanse doesn't cause me anxiety the way that Wellbutrin does. And your pdoc is right that with ADHD, some of your anxiety symptoms (separate from your OCD symptoms) could actually stem from your ADHD. Things like worry when you're having a hard time keeping track of things. When a stimulant helps to resolve the inattentiveness, the other symptoms like disorganization anxiety fall in line. When I was in college, I would take a friend's Adderall to study and get homework done. In hindsight, not a good idea taking someone else's meds and I was also incorrectly diagnosed as MDD at the time and not on a mood stabilizer, so.....anyway, I learned that things made more sense when I took stimulants, I was infinitely more productive. Flash-forward to today, and my pdoc rediagnosed me as bipolar 2, but once we stabilized the mood (anticonvulsant and AAP) and addressed the depression (antidepressant), I was still having lingering cognitive issues and problems with attention. So we added a stimulant, and things started to make sense again. I have to admit that in the beginning I may have had a little subsyndromal hypomania, but we addressed it, and after two weeks everything leveled out. It's worth at least a shot. ADHD is one of those things that, if you correct it, you may find it to be a huge difference in your day-to-day life. My journey hasn't been too bad actually. Looking at my last post I was just taking Depakote, Pristiq, and Vyvanse. We've since added a low dose of Risperdal (0.5mg) as an adjunct to the valproate for mood stabilization. It's helped tremendously. Quite calming without being forced or sedating. I just had a pdoc appt recently and he agreed that I seemed to have a good pace but that I seemed measured and controlled. Here and there, my instinct is to ask to continue increasing the Risperdal to 1mg or to add 0.25mg in the morning (I take the 0.5mg at bedtime). I'm going 8 weeks though until my next pdoc appt. So there probably won't be any changes til then (Nov 9th). What I am slightly concerned about is the coming Fall/Winter. I've definitely determined at this point that I meet the DSM-V qualifiers for bipolar 2 disorder, with seasonal features. My depressions do almost always come in the Fall/Winter much like seasonal affective disorder. I do worry that my current regimen may not be enough, but then I remember that I can't imagine what I would do or take instead. We'll see what happens I guess.
  5. thanks @DogMan! This is kind of what I was fishing for. Someone on a similar cocktail that was faring well with it. The ruminating / "broken record" thought process is definitely something I'm familiar with. And that pretty accurately describes what I'm after. Issues with rumination. Antipsychotics always do really well for handling those obsessive thought processes, at least for me. We did find out that my TSH was high and my T4 was low recently as well, but we increased the Vyvanse a few months ago. It's possible we did this prematurely and we actually needed to increase the levothyroxine because my T4 was low. So we increased the levothyroxine from 75mcg to 88mcg at the beginning of June and it's possible I just need to go back to my original steady Vyvanse dose of 40mg. Then from there work on the risperidone and divalproex doses if necessary.
  6. The risperidone is for a variety of things. I find valproate to be the key mood stabilizer because to me it feels like it turns down the "overall volume" in the brain. Clear hypomania feels good in the beginning, but as it drags on and you finally get to a point that you want to slow down and relax but the volume is too "turned up". It almost feels like you're standing next to a waterfall or having the TV tuned to white noise with the volume turned up. Nails on a chalkboard. With valproate that all kind of evens out a lot, but there's usually breakthrough stuff. I do still have issues sleeping: falling asleep, waking up and not being able to fall back asleep, and my body waking me up too early and being wide awake from the second I open my eyes. That's usually coupled with some snappiness, irritability, agitation, etc. But it's all at a significantly lower level with a solid dose of valproate to keep that under wraps. I also tend to experience a lot of mixed anxious distress a well. Depressed symptoms are more pronounced but coincide with rapid thought process, agitation, anxiety, etc. This is why I'm on valproate in the first place and also why we think, based on my treatment history, that I've done better on an anticonvulsant+antipsychotic combo than either alone. When I first started taking valproate, I was taking 1000mg of Depakote ER at bedtime. Worked my way up to 1250mg sometime last year, because, as you can see in 2019 and beginning of 2020, my blood levels were quite low and dose escalation on valproate can be slowly escalating like that as your body gets use to the valproic acid on-board. Fast-forward and I'm now taking 1500mg Depakote ER at bedtime as of that blood level on 6/2 (which coincidentally was a 62ug/mL). That brief blip on 1/12 to 79 is semi-unexplained at this point. I had just recently increased from 1250mg to 1500mg around that time, so perhaps valproate accumulates a little before your liver picks up the pace. Honestly, I never thought I'd be willing to take risperidone either, but my husband is taking 1mg of it as his primary mood stabilizer and doesn't have significant side effects from it other than orthostatic hypotension. I don't plan on switching from valproate to risperidone. Rather I hope to be able to use both of them in more modest doses. This is to your point, but to answer a question you probably have: when taking the ER 24-hour formulation of divalproex at bedtime, you generally dose to the point that the blood level taken the following morning (12-hour post-dose) is 80-125ug/mL (50-100 for the regular DR, 12-hour formulation). Clearly mine is not that, but my pdoc doses to tolerability and response. Particularly because of the risks of liver damage over time with valproate, he wants to maintain on a minimum dose possible and would prefer "shaving" off these symptoms with an AAP. His choice of risperidone was because he expected it to cause the least weight gain relative to other generic AAPs, and that was a concern due to the valproate on-board having a weight-positive potential. Risperidone also is less sedating than olanzapine, quetiapine, or ziprasidone for this purpose. Generally, his statements have proven correct. I don't feel sedated at all during the day. If anything I feel slightly more upbeat. I also haven't put on much, if any, weight. Like I said, I'm currently taking 1500mg divalproex ER and 0.5mg risperidone, but I hope to eventually chip away the divalproex down to 1250mg or 1000mg to instead go up on risperidone to maybe 1mg based on how I feel right now. At least that feels like the general trajectory. Not surprised at all that risperidone as monotherapy didn't have an antidepressant effect, but taken at this low dose and also with an antidepressant on-board, I think I do notice a little bit more pep during the day. Positive emotional responsiveness. My husband has also said that in the time now that I've been taking it he does think I've been less snappy and reactive, a bit more cool and collected. So I appreciate it when it's a difference that he really notices. Yes that was basically the issue with Rexulti. As an adjunct to Depakote and an antidepressant, I didn't feel that Rexulti added much in the way of mood-stabilizing capabilities. I really liked it as an antidepressant, and in retrospect the one thing I didn't try was Depakote+Rexulti dual therapy for the bipolar disorder (w/o an antidepressant) and Vyvanse for the ADHD. However, Rexulti didn't seem to have significant anti-manic effects for me. It was positive for my sleep at lower doses, but increasing the dose to achieve additional mood stability didn't gain me anything. As for Abilify, I will jokingly call it the devil's drug, which it isn't of course, but that's how I was feeling after my 10-day trial of it. I found it to be EXTREMELY stimulating. Like <uncomfortably> stimulating. Akathisia out the wazoo. Then again, that was a point in my treatment when antipsychotics were the primary mood stabilizer. This has changed a bit, but my ability to tolerate dopamine partial agonists has not. I had a 3-month experience with Vraylar at 1.5mg back in 2019, which I aborted for similar reasons. Although admittedly, I was able to obviously tolerate that much longer than Abilify, but the issue was fundamentally the same. Too stimulating. By contrast, I found Rexulti to be quite tolerable and enjoyable compared to Abilify or Vraylar. I actually took Rexulti at night a few hours before bed, and it would help me sleep pretty well. So it may be a dopamine partial agonist, but it is clearly different from the other two. I was taking Trintellix from 2017 until the end of last year. However, I did find over time that it contributed to irritability. I was fairly compatible with it as a medication, but due to the irritability issues and the fact that it didn't do much for my anxiety, when we later decided to resume an antidepressant in my medication regimen, we decided against going back to Trintellix and instead go for something else I had tried in the past and been compatible with. The only other two antidepressants I've been compatible the way I was with Trintellix were Pristiq and Cymbalta. Only reason I discontinued Pristiq in the past was because my insurance wouldn't cover it anymore (it was new, brand-only at the time). And the only reason we discontinued Cymbalta was because I was rediagnosed as bipolar 2 and was in a bit of a hypomanic state having taken an antidepressant as monotherapy my whole life. Potentially, yes. I've taken both for extended periods of time historically, but only separately. This will be the first time I've experienced them together, and it is pretty stimulating. So I'm also considering actually backing down on Vyvanse as well. This was a similar experience for me with Vyvanse and Trintellix. When taking those two together, 40mg was my steady Vyvanse dose, but we would decrease it to as low as 30mg if my Trintellix dose was up to 15mg or 20mg. No dose adjustments for Pristiq really. I started at 50mg, and I happen to do well on it from a depression/anxiety perspective. So I don't see the need to increase it at all. So there is a possibility I may need to decrease the Vyvanse from 50mg back down to 40mg. Well, I'm 5'11" and 215lbs. 1500mg of Depakote ER to a blood level of only 62ug/mL with 0.5mg of risperidone for someone like me is actually bordering on pediatric treatment. It isn't really heavy mood stabilization at all to be honest. I did talk to my pdoc about this though, because you are right that if you have a basic understanding of the logic behind what dopamine antagonists do and what amphetamines do, then one would think that they effectively neutralize each other, but they really don't. My pdoc pointed out that bipolar disorder and ADHD actually co-occur quite frequently, and determining a dual diagnosis takes a long time, because the mood disorder needs to be addressed primarily before addressing the attention issue. It's too difficult to determine if you can't focus because you can't focus or if you can't focus because you aren't interested in something. We like to think that as patients we can tell the difference, but it's really tricky and takes a lot of introspection to arrive at that conclusion. So when my pdoc encounters this, he treats the bipolar disorder to euthymia (or slightly dysthymic, because he says that can sometimes be "par for the course" with bipolar disorder), then he adds the stimulant. And as a matter of course, he usually includes an antipsychotic in the cocktail as a safety measure and he will balance/counter-balance the dopamine antagonist against the stimulant, using the lowest dose of each until the patient reports that they are no longer having concentration issues but they simultaneously are not reporting feeling over-stimulated. Because amphetamines work upstream at the TAAR1 receptor as an agonist and inhibit VMAT2 to cause expulsion of neurotransmitters into the extraneuronal space, their mechanism is uniquely separate from the dopamine receptor system and that system's feedback loop. A dopamine antagonist actually won't nullify the nerve impulse/potential from TAAR1 agonism and VMAT2 inhibition. However, if you were taking a partial agonist with high intrinsic activity like Abilify (60% agonist at D2 receptors), or if you were taking bupropion with your amphetamines, those medications will actually directly inhibit dopamine release. Agonism of pre-synaptic D2-short receptors by Abilify reduces dopamine release, and Abilify more recently has been found to act more as a partial agonist at pre-synaptic receptors while being an antagonist at post-synaptic receptors for a double-suppression. Bupropion via its NET and DAT inhibition would act as an indirect dopamine agonist similarly, and would have the same suppressing effect on dopamine firing. This leads into a valid point that activation of dopamine receptors to a high degree can be similarly stabilizing to dopamine antagonists. You can either give someone a dopamine antagonist to throttle the flow of dopamine and restrict how stimulated the receptors can become, or you can give them a dopamine partial agonist to actually desensitize receptors to a certain level of dopamine signaling. Similarly this partial agonist not only binds and activates (60% for Abilify) but also prevents endogenous dopamine (98-100%) from supplanting them. Truly though, bupropion has been regarded as having a significant stabilizing effect in some people with bipolar disorder. Desensitizing the dopamine receptor system reduces dopamine bursting, thus decreasing the risk of precipitating any mood episode as well. And I actually saw a psychologist for a while who did a lot of research into the stabilizing effects of stimulants on those with bipolar disorder, particularly with comorbid ADHD. Haha a question that's hard to answer directly. When I was taking Depakote with only Vyvanse, it was usually fairly able to manage hypomania. However, I just generally tended towards the depressive side of things, and I felt better when we reintroduced an antidepressant. Thus we've ended up here with Depakote+Vyvanse+Pristiq, but now instead of being euthymic or sub-dysthymic, I tend towards euthymic or above. Just general snappiness and irritability that are really misplaced. Like to the point that afterwards I'm confused and asking myself why I lashed out. It really isn't terrible because it doesn't happen super frequently, but that's coupled with a general feeling of being on-edge and tense even though a lot of my mental thought processes surrounding anxiety have resolved. And I also obviously don't like the impact I have on other people when I'm like that even if I am apologetic later. At 0.25mg of Risperdal, I really didn't find it to be too terribly helpful, but 0.5mg for a few weeks and I'm starting to notice a bit of a difference that I like. I feel more settled without feeling all that blunted, and in some ways I feel like I'm more able to take things in stride than I was before. Like the Pristiq did help with general anxiety, but the Risperdal has settled my thoughts even just the slightest bit and I like what I'm seeing. I think of my brain like one of those sound mixers with all the knobs for the various volumes. Imagine each of the littles ones is a neuron or area of the brain. But there's always a Master volume knob that's bigger than the others. If I had to describe the way I felt in an analogy, taking Depakote is like turning down the overall volume with the Master knob, but you can still have a bunch of little knobs after that that are still turned up too high and might drown out others, so the AAP helps to "smooth" that out.
  7. Hello everyone! So, this is more exploratory than anything. I accept that, as someone with bipolar disorder, taking an antipsychotic might be a necessary part of my maintenance treatment, and lately that has become more evident. I had been taking Rexulti (brexpiprazole) in varying doses since 2017 when I started it with Depakote ER (divalproex, 24-hour) and Trintellix (vortioxetine). Still taking the Depakote (now up to 1500mg), but Trintellix and Rexulti have worked their way out of the equation, as of late. My medication regimen has taken a more classical turn due to a breakthrough hypomanic episode in Dec./Jan., and I am currently taking a combo of Depakote ER at night along with 0.5mg of Risperdal (risperidone). Because of persistent issues with depression and anxiety, I am also now taking 50mg of Pristiq (desvenlafaxine) each morning along with 50mg of Vyvanse (lisdexamfetamine) for ADHD that I have been taking for some time. This combo seems to be working fairly well for me. When I started the Risperdal at 0.25mg/day at bedtime, I didn't really notice much difference at all during the day, but I suppose it was nice as a sleep aid. I increased to 0.5mg on Day 4 and I've parked here to try it out for a bit before deciding to increase further. The Risperdal is really to deal with those breakthrough hypomanic/mixed symptoms such as irritability and agitation, which have always been tough for me. In the beginning of my treatment (2014), antipsychotics were used as monotherapy for mood stabilization, but I could never tolerate the doses necessary to calm those symptoms, because I was easily susceptible to EPS like akathisia. Fast-forward a few years, and we've found that using an anticonvulsant as the primary mood stabilizer with the antipsychotic as a secondary has generally served me well without too much incidence of akathisia. I started Risperdal on June 8th and increased to 0.5mg a few days afterward. So it's been almost 3 weeks at this dose. My experience so far tells me to keep increasing. I'm curious to know people's experiences on Risperdal, particularly in combination with another established mood stabilizing agent like lithium or valproate. I recognize that I take Depakote and that a combo of lithium+Risperdal may not be the same, but the mood stabilizing effects of lithium and valproate are generally regarded with equal respect in most literature for the time being. Any thoughts on lower dose Risperdal?....particularly in concert with another mood stabilizer?
  8. So I did a "hard" switch from Wellbutrin 150mg to Pristiq 50mg. Started it on 5/4 with the Wellbutrin and the next day 5/5 stopped taking the Wellbutrin. Because of the Remeron on-board and switching from Wellbutrin to Pristiq I started experiencing some visual disturbances. Nothing too serious, but enough that I wanted to discontinue the Remeron, which I did on 5/10, and I pretty much just discontinued it right at 30mg. Didn't even bother titrating. I was having issues with attention/focus with work and everything. So we needed to act quickly but the visual disturbances weren't significant enough to warrant anything like hospitalization. By half-life, Wellbutrin probably cleared my system around 5/13 and Remeron around 5/20. However it probably wasn't until sometime this past week that I really started to feel better I think from the Pristiq. It's been since January that I've taken a serotonin reuptake inhibitor, and I'm now starting to realize what I lost by discontinuing an SSRI or SNRI. So now I'm just taking Depakote ER, Pristiq, and Vyvanse. However, I do believe I'm going to take my pdoc up on his offer of low-dose Risperdal to help with sleep and deal with some break-through mixed stuff that I don't really like. Still, I had forgotten just how much I love Pristiq. We're very compatible. I've taken 50mg before and I've also taken 150mg Effexor XR when I had to switch off Pristiq due to an insurance change (this was back in 2013). Generally speaking, 150mg venlafaxine hydrochloride will yield steady state plasma concentrations of O-desmethylvenlafaxine equivalent to those produced by 50mg of desvenlafaxine succinate. So they are supposedly "equivalent" doses. However, that isn't always the case for everyone. At 150mg=50mg they are generally equivalent in efficacy where desvenlafaxine is more tolerable. Desvenlafaxine can be dosed up to 400mg, but in trials, when the effect size was averaged out across all people in the study, doses greater than 50mg generally didn't make much of a difference and caused more side effects. So that means that while 150mg venlafaxine = 50mg desvenlafaxine, 300mg venlafaxine does not generally equal 100mg desvenlafaxine. 300mg of venlafaxine may produce O-desmethylvenlafaxine levels equivalent to 100mg desvenlafaxine, but while tolerability gets worse for both, efficacy is generally only better for venlafaxine at 300mg and equivalent efficacy is not seen from 100mg desvenlafaxine, even though they produce similar levels of O-desmethylvenlafaxine at steady state. In essence, if 150mg of Effexor XR is sufficient for your depression but you have issues with side effects, Pristiq 50mg may definitely be for you. And if you switch and find that Pristiq 50mg is not quite enough oomph, you can try the 100mg, but you might have just been better off going to 225mg or 300mg on the Effexor at that rate because they'll be just as intolerable but far more effective. Although, again, not everyone is the same, and this assumes you even have to go higher then 50mg on Pristiq. Currently and historically, I've personally found 50mg of Pristiq to be enough.
  9. As a continuation and an aside to that, while the "-pines" are known for their intermediate binding, other AAPs accomplish increased dopamine signaling via other ways. For example, risperidone has a tight binding profile at dopamine receptors unlike clozapine. However, its affinity for the pre-synaptic short form of the dopamine receptors (D2S) is slightly greater than its affinity for the post-synaptic long form (D2L). At the usual antipsychotic doses >2mg/day, this doesn't matter because high levels of receptor occupancy occur regardless of receptor locus. However, in very small doses, this can be significant because risperidone has the potential to preferentially antagonize pre-synaptic receptors over post-synaptic ones. This means net positive dopamine signaling. So something like 0.25mg to 0.5mg at night added to an antidepressant can even be useful in major depressive disorder for some people. Despite low doses of risperidone rarely showing signs of EPS, pdocs still shy away from it sometimes because it still carries a fairly high rate of EPS overall for an AAP despite its significant 5HT2A antagonism, which is apparently insufficient to offset those movement-related side effects. Lurasidone carries a similar rate of EPS and akathisia to risperidone, but for bipolar depression it is used at lower doses 20mg-60mg/day. You can go >60mg/day, but clinical trials showed on average that the higher doses didn't make a difference in depression. In lurasidone's case, it similarly has a greater affinity for pre-synaptic dopamine receptors than post-synaptic, like risperidone, and a somewhat intermediate binding profile at post-synaptic receptors as long as you keep the dose low, similar to the "-pines". Higher doses seem to block all dopamine receptors indiscriminately though, making it more like its "-done" siblings. So if you keep the dose between 20mg-40mg, you can actually cause a net increase in dopamine signaling with a dopamine antagonist. There is something to be said, however, for lurasidone's unparalleled antagonism of the 5HT7 receptors, which act as auto-receptors in a similar way to the D2S form dopamine receptors. Particularly this causes increased serotonin signaling in the hippocampus and some other brain regions. So it is suspected that some of lurasidone's antidepressant effect also comes from this 5HT7 antagonism. Wow. Got off on a tangent. Hope some of this is useful to ya lol
  10. Aww thanks, @Iceberg! @the maze runner the above quote describes what makes clozapine unique relative to other atypical antipsychotics. AAPs are all unique from typical antipsychotics because of their serotonergic antagonism, particularly 5HT2A. Of the atypicals, clozapine's ratio of antagonism at 5HT2A to D2 activity is the greatest. This action at 5HT2A receptors is known to promote norepinephrine and dopamine signaling. So the theory is that the more we promote dopamine relative to how much we're blocking dopamine receptors, we should be able to improve mood issues in tandem with treating psychosis. Combined with this is clozapine's binding profile at dopamine receptors. Quetiapine is known for some of the loosest binding in the atypicals. Olanzapine, loxapine, and clozapine share this intermediate binding profile with quetiapine, but they bind slightly more tightly to dopamine receptors. This binding potential to a degree is dose proportional. They will always release from dopamine receptors more readily than their typical AP cousins, and usually more than their atypical AP siblings. What's important though is the potential action this has. Dopamine receptors are present in the short-form (i.e. D2S), which is pre-synaptic and negatively controls dopamine outflow into the synapse. They are also present post-synaptic in the long-form (i.e. D2L). The post-synaptic receptors are where dopamine would mediate its effects in psychosis but also its ability to ease anhedonia in depression. By binding to both forms for a period of time and disassociating, dopamine signaling is promoted but modulated. By blocking the pre-synaptic receptors, dopamine is released from neurons into the synapse. Blocking post-synaptic receptors dulls some of this increased dopamine activity, but after a time, the antagonist disassociates and "normal" physiological dopamine signaling can proceed. I say "normal" because while the receptors are no longer blocked, by blocking the pre-synaptic receptors, the synapse now has an increased baseline level of dopamine, hence the antidepressant effect. Certain areas of the brain like the pre-frontal cortex don't contain any native dopamine transporter and rely upon the norepinephrine transporter to clear both norepinephrine and dopamine. Because blockade happens more so at night and receptors are less antagonized during the day, normal (but now slightly increased) dopamine signaling during the day, particularly in the pre-frontal cortex, should theoretically reduce things like akathisia and other kinds of EPS while also having an antidepressant effect. This may be why quetiapine and olanzapine in particular are known for their antidepressant utility. And clozapine's 5HT2A/D2 ratio being greater than any other AAP may underlie why it works where other things just don't for one reason or another. Disclaimer: Caplyta (lumateperone) was just approved by the FDA last year as a new atypical antipsychotic. It is the first AAP to best clozapine's 5HT2A/D2 ratio. In addition to its extremely significant 5HT2A antagonism, it only seems to occupy dopamine receptors to about 30-40% at its standard dose of 42mg. Additionally, its dopamine receptor affinity matches its affinity for inhibition of the serotonin transporter (SERT).
  11. @OCDme have you talked to your pdoc about boosting the Pristiq with something? Until recently, I had been taking a combo of 300mg Wellbutrin XL and 30mg of Remeron for depression, but I was having issues with this constant low-grade anxiety and irritability from the Wellbutrin, so we recently switched it to Pristiq 50mg. I've taken Pristiq as monotherapy for depression before I was rediagnosed as bipolar 2. But taking it now with Depakote as a mood stabilizer and also being able to take Vyvanse for my ADHD, I appreciate it so much more, and the Remeron is a really nice pair in my experience so far. Effexor+Remeron is the combo called "California Rocket Fuel" coined by psychiatrist, Stephen Stahl. So named because it's a cocktail that first became popular among psychiatrists in California and the surrounding states. The pharmacology behind the combo could theoretically be exploited with Remeron combined with any of the SNRIs (i.e. Effexor, Pristiq, Cymbalta, and MAYBE Fetzima). 5HT2A/5HT2C - Remeron blocks these receptors, which increases norepinephrine and dopamine release. Normally, Pristiq would inhibit serotonin reuptake and cause excessive activation of these receptors which would inhibit the release of norepinephrine and dopamine. This is problematic because the inhibition of norepinephrine release can hinder Pristiq's efficacy as a norepinephrine reuptake inhibitor. And inhibition of dopamine release can lead to anhedonia. So by blocking these receptors, Remeron actually promotes/amplifies Pristiq's norepinephrine reuptake inhibition. Additionally, it is via these receptors that Remeron is able to calm some of the SRI initiation effects of agitation, insomnia, anxiety, etc. 5HT3 - These are located on GABA interneurons and they kind of control the seesaw in the brain between GABA and glutamate. Therefore they act to inhibit or disinhibit the release of various neurotransmitters including serotonin, norepinephrine, dopamine, acetylcholine, and histamine. Overall, antagonism of these receptors actually increases glutamate signaling and the release of all the previously mentioned neurotransmitters. This would further promote Pristiq's effects. Additionally, it's through this receptor that Remeron can calm some of the nausea associated with SRIs. 5HT7 - major auto-receptor for serotonin. Blocking it will disinhibit the release of serotonin in key areas of the brain like the hippocampus. This further lends to Pristiq's SRI capabilities. alpha-1 and alpha-2 adrenergic receptors - These would be the receptors that norepinephrine would activate. The type 2 receptors are located throughout the brain where they act as auto-receptors for norepinephrine. Activating them reduces the release of norepinephrine. They are also located in the hippocampus where they act to control the release of serotonin to central 5HT1 receptors. Activation of alpha-1 receptors by norepinephrine will actually lead to direct release of serotonin. Remeron is a strong antagonist at all alpha-2 receptors. This causes dramatic increases in the release of serotonin in the hippocampus leading to indirect activation of 5HT1 receptors. It also dramatically increases norepinephrine throughout the brain. The increased norepinephrine release does lead to activation of alpha-1 receptors, which further increases serotonin release. All of this contributes to the increases in serotonin and norepinephrine signaling that Pristiq would do on its own. But if Pristiq inhibits serotonin reuptake, it will rampantly activate the 5HT2A/5HT2C, 5HT3, and 5HT7 receptors along with the alpha-2 adrenergic receptors and thus work against itself due simply to the normal negative feedback mechanisms in the brain to try to keep things in balance. But we know that some brains don't know how to keep themselves in balance, which is why serotonin antagonists like the atypical antipsychotics have become so popular as boosters to antidepressants for treatment-resistant depression, anxiety, or OCD.
  12. I was curious about this too. Apparently the studies that included risperidone did not include it as an active comparator but rather an active control similar to placebo in order to validate assay sensitivity (i.e. they needed to make sure that the PANSS test itself actually worked for both a known proven drug as well as the study drug). As I indicated in a previous post, there was a switch study where patients with an acute exacerbation of schizophrenia who went inpatient were given risperidone to stabilize them. Then after a period of stabilization, the patients were split into groups. One stayed on risperidone, one switched to Caplyta 42mg, and one switched to placebo. There was no significant change in the symptoms or relapse rate for the Caplyta group relative to the group that stayed on risperidone, and as expected the placebo group had a high rate of relapse due to that fact that their standard-of-care antipsychotic was discontinued. However, the study on the website was a different study altogether. This one, new inpatients were randomized to initially receive risperidone 4mg, Caplyta 42mg, Caplyta 84mg, or placebo 1:1:1:1. The measure was change in PANSS score from treatment initiation to Day 28. Caplyta 42mg was generally non-inferior to risperidone 4mg in the treatment of schizophrenia. Risperidone 4mg resulted in a reduction of 13.4 points at Day 28. Caplyta 42mg resulted in a reduction of 13.2 points. The difference .2 is far too negligible to consider Caplyta inferior to risperidone 4mg. They don't mention any specifics about the 84mg dose on the website, but I seem to recall from previous reading that while the 84mg dose did confer some additional benefit for some people, the improvement from 42mg to 84mg was largely incremental and the outsized increase in side effects was disproportionate to the modest increase in efficacy. On the other hand, 28mg I believe was more tolerable for many but they needed to do more studies to prove its efficacy at that dose due to efficacy that I believe was described as "less robust".
  13. You make a fair point. It might be on the formulary, but it's a non-preferred brand that they'll only pay for after you've tried several other things, and even then you can't use it off-label. And even if you are using it for its FDA-approved indication, some plans make the copay for a non-preferred brand completely unaffordable month-by-month. I guess the hope is that if they get a broad approval like the one they've submitted, that it will be one less hurdle for the patient. By default, the drug reaches more populations by removing one of the insurance company's excuses not to pay. I suppose they can always come up with another one though. And a whole other layer to that is the non-preferred vs preferred aspect. If a pharmacy benefit manager (PBM) is coming up with a formulary and there are 2 brand name medications that can treat a specific illness, they're going to meet with both drug manufacturers and offer to put the manufacturer's drug on the preferred brand tier for a better wholesale price of the drug. And some pharmaceutical companies demand as well that their brand name medication be the ONLY preferred brand medication, to stifle any competition. And so because the PBM can't milk other manufacturers for similar deals, they require an even lower wholesale price from the manufacturer to sweeten the deal further. And so the vicious cycle of price heckling goes back and forth. All the while, manufacturers increase the retail price of their medication year over year so that when they go to the bargaining table, they start the bargaining at a higher number than the year before. And so the vicious cycle is perpetuated. And yes, it's sick to do this to people with chronic conditions, but what's even sadder is that they also do it to patients with terminal conditions like cancer, and oncology is a space with about as much a rate of success as psychiatry; I mean, yeah, sure it's getting better, but it certainly leaves <a lot> to be desired. So add a layer to that: if Caplyta really does have the better side effect profile, particularly from a metabolic perspective where cardiovascular disease is the majority comorbidity in schizophrenia and bipolar disorder, would encouraging patients and their doctors to switch to Caplyta be in the insurance companies' best interest simply by lives saved and overall cost of care being reduced? I mean that not only means less money out of the insurance companies' pockets but also out of the patient's pocket, thus they're able to live a more normal life not burdened by type 2 diabetes and/or obesity, and thus lending to overall improved outcomes, which again leads to additional reduced cost. It's actually a viciously positive cycle and the insurance companies somehow avoid it. *shrug*
  14. Heard that as well. Additionally, in schizophrenia and bipolar disorder, one of the highest comorbidities is cardiovascular disease of some kind. Some of this is due to lifestyle but a lot of it is also due to the treatments for these conditions. They claim that Caplyta should allow clinicians to not compromise efficacy in order to achieve a better safety profile. Clinicians will prescribe it because it leads to similar outcomes to other standard-of-care antipsychotics while having a placebo-like safety profile. Insurance companies should pay for it because it's demonstrated utility in a wide range of indications and because the better safety profile should theoretically mean lower cost to the insurance company paying for said comorbidities (i.e. type 2 diabetes, dyslipidemia). They're also working on a deuterated form of lumateperone for a "Caplyta ODT" (sublingual tablet/film) as well as a long-acting injectable. During the presentation, they noted that Caplyta was effective against bipolar depression whether or not mixed features were present. If the presence of mixed features did not alter the outcome, this might indicate that Caplyta has some stabilizing effect. However, the premise of these studies was to investigate the improvements in negative symptoms that they noted from schizophrenia patients on preclinical trials. They figured that if schizophrenia patients reported subjectively feeling better, that may be of use in patients with bipolar disorder who typically respond favorably to atypical antipsychotics that do well in schizophrenia patients. It's just uncommon that an antipsychotic is so effective at improving negative symptoms. Few do this at typical antipsychotic doses except the dopamine partial agonists, Abilify, Rexulti, and Vraylar; along with Latuda, which was similarly found to be effective against bipolar depression. However, just because the focus is on bipolar depression doesn't necessarily mean Caplyta doesn't have anti-manic effects, only that perhaps they are either insufficient on their own, or not convincing enough for a monotherapy indication. So they may go after acute mania and bipolar maintenance indications for Caplyta only as an adjunct to lithium or valproate. They're having a similar problem with Rexulti. It quite clearly has benefit in bipolar depression on its own or in combination with lithium or valproate, and it does have some mood-stabilizing effects, but you probably wouldn't rely on it as monotherapy for bipolar maintenance. Likely if it gets a bipolar indication at all, it would only be for bipolar depression and/or maintenance and only as an adjunct to lithium or valproate. Hard to say how well it'll work for psychosis. At least they proved it was non-inferior to risperidone in a double-blind placebo-controlled switch study. They took schizophrenia patients stabilized on risperidone and divided them up into 3 groups. One group was abruptly switched to Caplyta, one was switched to placebo, and one remained on risperidone. Caplya was non-inferior on the PANSS against risperidone, and the metabolic disturbances seen in risperidone patients improved significantly in both the Caplya and placebo groups.
  15. For what it's worth, it would seem that the meal requirement might be in place for two reasons. The prescribing information definitely says to take it with food. Looking at the pharmacokinetics, its absolute bioavailability is 4.4% which is really low. Combined with a half-life of 18 hours. It takes 5 days of continuous dosing to reach steady-state. Taking Caplyta with food, increases the time to maximum concentration after oral administration from 1 hour to 2 hours, decreases the maximum concentration by 33% and stretches out the average area under the curve by about 9%. Taken together, that tells me that they need you to take it with food in order for it to be released more slowly over a longer period of time rather than have the pill dump it all at once. This makes it more extended release, but the 18 hour half-life should allow for missing a meal with it on occasion. Not sure though. You'd have to talk to your pdoc about it. The prescribing information says take with food, but they don't specifically say why it SHOULDN'T be taken WITHOUT food, which is weird. They usually state something like the bioavailability being dramatically altered in the presence of a meal versus fasting. I suppose another thing to consider is the salt form that they've chosen to use for Caplyta. They've manufactured lumateperone as a tosylate salt. Toluenesulfonic acid (i.e. 4-methylbenzenesulfonic acid) is an extremely strong acid and might explain some of the high incidence of nausea. The 18-hour half-life makes for a 5-day climb to steady state. But it wouldn't be, for example, like starting Vraylar at 3mg on Day 1 and going to like 6mg on Day 3 because there are definitely going to be effects that you experience several weeks to months out. I do agree though that the 28mg capsule they used on a few trials might be useful for some who need to start on a lower dose before going to the full 42mg dose. However, they don't really want you to use the 28mg dose because in trials, it wasn't as effective as the 42mg dose. I suppose an equivalent scenario might be Pristiq. They start you at 50mg and that's the target dose. They only made the 25mg dose as an after-thought to make it easier to discontinue if you wanted to.
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