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browri

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  1. 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.
  2. 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.
  3. 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?
  4. 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.
  5. 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
  6. 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).
  7. @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.
  8. 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".
  9. 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*
  10. 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.
  11. 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.
  12. https://ir.intracellulartherapies.com/news-releases/news-release-details/intra-cellular-therapies-announces-fda-acceptance-caplytar https://seekingalpha.com/article/4420996-intra-cellular-substantial-unlocked-value-in-caplyta-franchises I've been watching this one like a hawk. The indication that was filed was for Caplyta (lumateperone) either as monotherapy or as an adjunct to lithium or valproate to treat depressive episodes associated with bipolar I and bipolar II disorder. This is big for the bipolar depression space because: Seroquel (quetiapine) is approved for depressive episodes in both bipolar I and bipolar II, but only as monotherapy Symbyax (olanzapine/fluoxetine) and Vraylar (cariprazine) are each approved as monotherapy only, and only for depressive episodes in bipolar I Latuda (lurasidone) is approved as both a monotherapy and as an adjunct to lithium or valproate for depressive episodes, but only in bipolar I What's crazy about the list above is that Seroquel actually has the best safety profile. That may not be your first guess, but Symbyax is terrible for obvious olanzapine reasons (metabolic disturbance), Vraylar has the worst EPS/akathisia profile in the list, followed immediately by Latuda, which has shown little to no utility/potential in the management of mania to boot, making its monotherapy indication a bit of a joke. So now we're adding a new medication to that list that supposedly does everything the others cannot with the most common side effects being somnolence, dizziness, and nausea; yet, very few people dropped out due to these side effects. Furthermore, neither the rate of metabolic disturbance nor the rate of movement disorders like akathisia were significantly different between the active group and the placebo group. Given the supposedly impressive safety profile, I wonder how hard the FDA will be on Intra-Cellular Therapies to prove that they should be given such a broad indication.
  13. @Selkie So I had my pdoc appointment, and we decided to replace the Wellbutrin XL (bupropion) with Pristiq (desvenlafaxine). I brought up the low-grade irritability/anxiety from Wellbutrin again. His instinct was to shave off some of the irritability and anxiety with Risperdal (risperidone), which I was very open to, but I also pointed out to him that despite my improved motivation and drive on 300mg bupropion, that I still didn't feel in a very good mood, and even all the while I would be going about and doing the things I'm not motivated to do, my thoughts are just negative the whole time. I don't really feel that bupropion has really done a whole lot to address the WHOLE depression even with mirtazapine on-board. With that in mind, he was more open to switching the bupropion because this is my third trial of it, and it has largely been similar to the other trials despite the different med cocktail "background". I told him I was still open to risperidone after this if I was still finding my thoughts are still agitated.
  14. Prolongation of the QT interval was an issue with citalopram (Celexa), which is why the maximum dose of that was reduced from 60mg to 40mg per day. However, even at 20mg, escitalopram (Lexapro) doesn't come close to the QT prolongation of 60mg of racemic citalopram. Going to 30mg on escitalopram for treatment-resistant cases like OCD that require significant SERT occupancy actually pretty common because of escitalopram's positive safety profile.
  15. O-desmethylvenlafaxine has been regarded as venlafaxine's chief metabolite because the metabolite has a greater affinity for inhibition of the serotonin transporter than venlafaxine does (~40nM for desvenlafaxine and ~80nM for venlafaxine). Because psychiatry has clung to the serotonin hypothesis, this made sense. Desvenlafaxine also seemed to have a somewhat higher affinity for the norepinephrine transporter than venlafaxine, but less of an ability to inhibit norepinephrine's reuptake. Couple this with the fact that desvenlafaxine is taken in smaller concentrations because of its higher affinity for the serotonin transporter. This kind of leads into your next question. It's lost on me now to find an actual article that backs this up, but equivalency of the two is based solely on blood concentration at steady state. If someone is taking Effexor XR, it takes 3 days to ready steady state. After chronic administration of 150mg venlafaxine hydrochloride ER, the steady state concentrations of the metabolite, O-desmethylvenlafaxine, are equivalent to those seen at steady state after chronic administration of 50mg desvenlafaxine succinate. Equivalent dose in this case is not synonymous with equivalent efficacy. O-desmethylvenlafaxine may be regarded as venlafaxine's active metabolite due to its greater potency relative to venlafaxine. However, venlafaxine is dosed much higher and accumulates to great levels, which makes up for its marginally weaker affinities for the serotonin and norepinephrine transporters. In other words, Effexor is not a medication whose effect is mediated solely via the metabolite. On the contrary, venlafaxine plays a significant role in the therapeutic effect of Effexor, and this is hypothesized to be the reason for Pristiq's somewhat lackluster presentation. Desvenlafaxine lacks the parent compound and therefore is kind of looked at as Effexor-lite. Additionally, while desvenlafaxine does have slightly greater affinities for the SERT and NET, it does not appreciably inhibit the dopamine transporter (DAT) the way that venlafaxine can at high doses. There is some minimal inhibition of the DAT by desvenlafaxine at doses of 400mg per day. But at that point, most psychiatrists would have long given up on Pristiq because they know that they can get more oomph out of 225mg-300mg of Effexor than they can out of 400mg of Pristiq.
  16. To your first question about aripiprazole and weight, in order to understand whether or not it will make a difference, it's important to understand the why of it. For most people, aripiprazole, unlike other antipsychotics, doesn't have a significant direct impact on metabolic parameters like fasting blood glucose, lipids, prolactin, etc. Most of those side effects from other antipsychotics occur via dopaminergic antagonism, and in the case of olanzapine and clozapine particularly, cholinergic antagonism. However aripiprazole is a dopamine partial agonist with an intrinsic activity at these receptors greater than 50%. Oftentimes >60%. And aripiprazole's occupancy of dopamine receptors is significant. More dopamine activation than blockade may be why aripiprazole is unlikely to cause these symptoms via that system and also having little interaction with the cholinergic systems to begin with. However, just because there is no metabolic dysfunction, doesn't mean that the patient can't gain weight. The hunger drive is controlled through a variety of hormones (e.g. glucagon, ghrelin), and serotonin acts as part of a feedback system to regulate our hunger drive. Broad activation of serotonin receptors by a simple SSRI can often lead to reduced appetite, nausea, vomiting, all negative gastrointestinal side effects but only due to the impact that increased serotonin levels have on feeling less hungry along with the fact that 80% or so of the body's serotonin supply is located in the gut. The 5HT2C receptor has been identified as an important receptor in that feedback loop. Activation makes you feel full. That's the science that lorcaserin is built on. Block that receptor and people describe inexplicably being unable to feel full and notably crave carbohydrates and sweets, in particular. Aripiprazole has a fairly high affinity for the 5HT2C receptor, and it acts as a partial agonist at about 40-60%. So in the absence of significant levels of serotonin, it will act more as an agonist. However, when aripiprazole is administered with an SRI, baseline intrasynaptic serotonin levels are higher, making aripiprazole behave more as an antagonist. So with an SRI, you might actually feel more hungry on aripiprazole than if you took aripiprazole by itself. At least that's the theory behind the weight differences in trials. As for the difference between mood stabilizers and antipsychotics, there are lots of opinions on how things should be named like neuroscience-based nomenclature that says we should do away with terms like mood stabilizer for lithium and antipsychotic for aripiprazole and start calling them by what they do. So aripiprazole might instead be called a serotonin-dopamine activity modulator (SDAM). However, the classic, general rule is that the mood stabilizer category contains only one drug and that's lithium. Drugs like valproate, lamotrigine, carbamazepine are ultimately called anticonvulsants. One might call valproate an anti-manic agent, yet despite more emerging evidence that valproate might have ability to prevent bipolar depressive episodes there's still hesitation to actually call it a mood stabilizer because most medications don't have the sheer volume of evidence that lithium has. Antipsychotic is almost invariably a term reserved for dopamine antagonists, whether they do or do not have serotonergic activity. However these are commonly used as mood stabilizers nowadays, and pdocs will often refer to them as mood stabilizers to try and move them away from the stigma associated with the word psychosis. There's also something to be said for the fact that if something is effective against more things than psychosis, then calling it an antipsychotic is kind of a narrow way of conceptualizing something. Past few days have been okay. Agree with you that a 100mg XL would probably have a good market.
  17. So two weeks later, I'm not feeling too hopeful. I still feel "keyed up" a good portion of the time with low-grade anxiety and irritability. But no panic or rage/explosiveness. So everything is smoothed over but still above level. I've been at 30mg of mirtazapine for 4 weeks and on 300mg of bupropion for 8 weeks. The low level tension doesn't seem to be getting better and I'm (literally) chewing my lips to hell. So I called into the pdoc, and I'm going to drop back down to 150mg of bupropion for the next two weeks until my appointment. Then decide if 150mg is both effective enough and tolerable enough, or if we need to swap it out for desvenlafaxine or duloxetine.
  18. Thanks, @Iceberg! Appt went well this morning. Talking to him about the low-grade anxiety and irritability that has stuck around, his suggestion was to back the bupropion down to 150mg. But after some discussion, we decided to keep everything as it is for another month before we make any more changes. Here's to patience...
  19. Yeah I usually have to remind myself to be patient. But I'm at least noticing enough of a difference at this point that it feels worth waiting patiently for, which is promising at a minimum.
  20. So it's been 12 weeks now on mirtazapine at escalating doses and 30mg for the past 2 weeks (since 3/23). The first week of 30mg was interesting, but by the middle of last week I was starting to notice some light mood differences that are more noticeable now. Some of the issues I was having with bupropion 300 + mirtazapine 15 were that I didn't feel very nice (like I didn't feel nice to be around, not very social or friendly), my baseline anxiety and irritability are higher (expected from bupropion) even though I am generally less explosive/reactive overall, and I would sometimes get lost in depressive rumination. Upping the mirtazapine to 30mg has made some differences in mood, and I feel perhaps slightly less standoffish than I was before (which is odd for me at all because I'm not a very standoffish kind of person). I perhaps ruminate a bit less. I can feel a bit of that serotonin aspect now to mirtazapine that I don't think I was really getting out of it before in a meaningful way. My irritability and anxiety haven't improved as much as I had hoped though. I have an appt with my pdoc tomorrow to review the last two weeks. I'm likely going to continue on this for another 4 weeks to really kick the tires. It's enough of an improvement so far that I really have to give it enough time and see the full potential. I did talk to my pdoc about time to effect with mirtazapine, pointing out that it reaches steady state quickly and some patients notice improvements by the beginning of Week 2, and he said that in his experience the real improvements on mood and anxiety even for mirtazapine are delayed. Not like fluoxetine, but there are long term changes that go along with it. I also have to remind myself that I'm on bupropion 300 / mirtazapine 30, which is a VERY different cocktail from vortioxetine 20 / brexpiprazole 2. What I can say so far is that I definitely like the mirtazapine, and increasing it to 30mg was definitely a good decision, but I'm still not totally sold on bupropion as the 2nd in that pair. I still feel like either venlafaxine (or desvenlafaxine) or duloxetine would do better in its place, but time will tell over the next month.
  21. Well last night was my 6th night at 30mg of mirtazapine. So far so good, and each day is a little bit better. A lot of the concerns I had previously have been mostly allayed since the increase. Time will tell though. That's probably a smart idea to not make a change like that amidst the pandemic. Just the same, if using clonazepam as a prn, it should be used as minimally as possible. It might be difficult, though, with the bupropion on-board. Another smart idea. Benzos are good for short term management, or for those with chronic anxiety, for breakthrough anxiety management. But the whole of anxiety is better maintained with an SSRI or SNRI. Oh yeah, this I understand. Sexual dysfunction is the absolute PITS. But your pdoc is right. Sexual dysfunction caused by serotonergic agents like SSRIs and SNRIs can usually be negated by bupropion. Serotonin reuptake inhibition leads to a higher baseline level of serotonin activity in the brain. However, increased serotonin activity leads to a certain level of desensitization of the serotonin receptors. This reduces their response to "bursting". During activities like sex and when you are approaching orgasm, bursting of neurotransmitters is critical to the cascade in the brain that leads to orgasm. By desensitizing serotonin receptors and reducing bursting, the ability to achieve orgasm is diminished. The other problem is that increased serotonin activity from a reuptake inhibitor would lead to broad activation of the 5HT2 and 5HT3 receptors, which act as heteroreceptors. Their activation reduces norepinephrine and dopamine activity. Blocking those receptors would disinhibit their release in various parts of the brain. With reduced norepinephrine/dopamine activity; there is reduced pleasure, libido, and drive. Activation of 5HT7 receptors also seems to be problematic, as those act as auto-receptors, reducing the release of serotonin in some parts of the brain when activated. So really, if the problem with SSRIs is that they reduce norepinephrine and dopamine signaling, then move to an SNRI, or an SSRI/SNRI+bupropion as this will restore some normal norepinephrine and dopamine signaling that are required for pleasure. Any psychiatrist would likely say that if your mom took aripiprazole (Abilify) and loved it, then that likely means you will too. And funny you bring this up because I was just reading some interesting articles the other day about the combination of bupropion+aripiprazole. It's certainly not common, but it's definitely not rare either. For one, as an antipsychotic, aripiprazole does carry a risk for extrapyramidal side effects (EPS). However, in trials of the combo, EPS-related events in the bupropion+aripiprazole group were lower than in the aripiprazole+placebo control group. As for weight gain, data would indicate that aripiprazole mediates its weight gain effects via the 5HT2C receptor. Much of what we know about this receptor is that it is responsible for satiety or "feeling full". Blocking this receptor cause a big increase in the release of norepinephrine and dopamine in the prefrontal cortex and has antidepressant effects. It can actually be quite stimulating. However, it also makes you hungry. Or rather, when this receptor is blocked it takes quite a bit to actually feel full. Now aripiprazole, is actually a partial agonist at this receptor of only maybe 40-50% intrinsic activity. So when serotonin levels are high, it blocks. When serotonin levels are low, it activates. At least in theory. So when aripiprazole is taken with an SSRI and SNRI and serotonin levels are always high, then it will basically always act as an antagonist, and thus make the patient hungry. In fact in trials of aripiprazole for bipolar disorder and schizophrenia, they saw little weight gain. Whereas, when they did trials for aripiprazole as an augment to an antidepressant for major depressive disorder, there was considerably higher weight gain when compared to bipolar or schizophrenic cohorts that weren't taking antidepressants. With Wellbutrin though, you aren't having direct impact on serotonin signaling and this would make aripiprazole more agonist than antagonist at the 5HT2C receptor. So you may not see the same weight gain your mom experienced on aripiprazole. It may be worth asking her if she was taking an antidepressant with it at the time and which one. Yeah it would be better to try other things first. if only haha Enjoying it!
  22. Had my pdoc appt yesterday morning and basically relayed everything to him from the quote above. Let him know that the bupropion may not be agreeing with me completely (increased baseline irritability and anxiety), but I wasn't totally sure. We talked about the options, his first suggestion being to increase mirtazapine to 30mg. I agreed it made sense to try current medications at regular doses before swapping out for different medications. Being that this is a game of chess, we did plan a few moves ahead by discussing SNRIs again during this appt like we did at the last appt. We went over my SNRI treatment history; having taken venlafaxine XR 150mg, desvenlafaxine 50mg, and duloxetine 60mg (screw levomilnacipran). He agreed that if increasing the mirtazapine to 30mg wasn't a complete fix that he would be open to swapping out the bupropion for an SNRI. Fast forward to this morning....last night was my first increased dose of mirtazapine at 30mg. After about 2-3 hours, I was out cold. Couldn't stay awake any longer. Yet, my alarm went off this morning at 7:30AM, and I was pretty much ready to get out of bed. I really didn't feel all that hung over or anything. So far, so good.
  23. I have considered that. Most worrisome is that 30mg of mirtazapine may make for far more irritability than I have now. Like I said in my previous post, where previously my irritability would settle around 0 with bursts up to a 5 or so, with bupropion+mirtazapine, I'm pretty much always at either a 2 or a 3, and I never really have sudden bursts of irritability. Like yesterday and today I have been super irritable and frustrated about 60-70% of the time, but it's all very controlled and maintained, and I haven't exploded once. So even without increasing mirtazapine, it's something I'm already having a problem with. I think the bupropion is definitely helping in that it is motivating me and helping with the task reward aspect, but it isn't really doing much of anything good for my mood overall. Like with SSRIs or SNRIs, they oftentimes can correct your mood, but they don't usually do a good job correcting issues with pleasure or enjoyment in activities (i.e. anhedonia). This feels like the opposite, fixing anhedonia and nothing else. I don't feel very socially engaged. I haven't really been all that nice to my partner lately. He says that he has seen some improvement but that every once in a while he watches me staring off into space with a certain look on my face, and he wonders if something is wrong under the surface. And that's really kinda how I feel. Like most of the time I'm okay, but then I will still have periods of time when I can get kinda lost in a depressed thought process. I would like to at least give the mirtazapine a solid shot at 30mg, because that really could increase serotonergic effect. At 7.5mg, mirtazapine is mostly just an H1 antagonist. Increasing to 15mg starts to introduce 5HT2A/5HT2C antagonism. Increasing further to 30mg would move into considerable alpha-2 antagonism. So at 15mg, the 5HT2 antagonism could contribute to downstream norepinephrine-dopamine disinhibition in the pre-frontal cortex. But at 30mg, the alpha-2 antagonism is going to cause a much more direct and systemic increase in the release of serotonin and norepinephrine in the brain. So while increasing mirtazapine to 30mg MIGHT make me more irritable, it also has the potential to continue reducing my anxiety in a big way because of the different effect it will have. But this is a game of a chess after all, and you need to plan 2-3 steps ahead. ....which leads to the desvenlafaxine. If increasing mirtazapine to 30mg helps my mood and my anxiety but makes my irritability worse, I would just as soon have my pdoc reduce the bupropion to 150mg to see if that resolves things. If it doesn't, then just proceed to desvenlafaxine. It will maintain the noradrenergic effect of bupropion while reintroducing serotonin reuptake inhibition. I've already taken it before and know at least that on its own it didn't cause irritability for me. I'm also taking 1500mg of divalproex on the other end of that, which should theoretically be a good enough safety net. I've never actually had a conversation with my pdoc about the 450mg dose for two different reasons. Firstly, based on my current level of stimulation, I don't think I could handle 450mg, and my pdoc even had me wait two more weeks before he would be willing to increase the mirtazapine to 30mg because he was concerned I would find it too stimulating with 50mg of lisdexamfetamine and 300mg of bupropion. Secondly, there is a history of epilepsy in my extended but close family. Grandmother has been taking phenytoin since she had her first seizure in her 50s. Then her son (my uncle) developed epilepsy in his 40s or so and has been taking a combo of phenytoin and levetiracetam. His daughters both have epilepsy as well. One takes levetiracetam and is controlled. The other isn't taking medication right now. And my other cousin on that side of the family used to take 450mg of bupropion and actually had a seizure. She switched to desvenlafaxine and never looked back. I actually trialed desvenlafaxine in the past because it worked well for her, and it ended up being very compatible for me too. Only reason I stopped taking it was because it was brand-only at the time, my insurance changed, and the new insurance wouldn't cover it. Such is life. I have a pdoc appt this Tuesday 3/23. We'll see how I'm feeling then and what we decide to do.
  24. @Selkie just checking in and providing an update on my progress with the bupropion/mirtazapine combination. So timeline: --Started mirtazapine at 7.5mg on Jan 12th. Increased to 15mg on the 17th. Been on 15mg since then (almost 8 weeks now) --Started bupropion XL at 150mg on Jan 23rd. Increased to 300mg on Feb 22nd (going on 3 weeks now at 300mg) --I have a significantly clearer head now than I did when I first started this combo and was adjusting. Mirtazapine was making me a bit foggy, and bupropion kind of does that too on the startup because of the nicotinic acetylcholine receptor antagonism, but the net result is actually increased acetylcholine signaling I believe, which means the cognitive dysfunction does clear up for some people after the first few weeks. --Mirtazapine 15mg was calming but also made me hungry and really sleepy. Bupropion does seem to be a good complementary agent to negate some of those effects. Increasing the bupropion further seems to have had a boosting effect on the mirtazapine as well, which is kind of what I was hoping for. --It wasn't until the end of the week last week and beginning of this week that I really started to notice some differences in my day-to-day. I'm getting up in the morning when the alarm goes off, and I'm not continuously snoozing it. I am not as irritable or snappy as I was when I first started bupropion, and I think my baseline irritability is lower than before starting the bupropion. My husband says occasionally my irritability breaks through but it's nothing like it used to be, and it seems to improve as the days go on. --I would use the word "brightening" to actually describe my mood over the past week. I sit upstairs in my office in the mornings and open the windows and listen to the birds chirp and stuff will I sit at my computer and work. The fresh air feels good. It doesn't always feel like I'm looking at the world through a gray-colored lens. I did have an appointment with my pdoc on Tuesday. I asked to continue increasing the mirtazapine to 30mg because even though I am noticing some improvements, I do find that my anxiety is a bit high for my liking. He seemed open to the idea but also said that increasing the mirtazapine would almost certainly have a stimulating effect and he had concerns about that happening while I'm also taking 300mg of bupropion and a Vyvanse dose that's roughly equivalent to 15mg of dextroamphetamine. I do see where he's coming from. Looking at my cocktail the way it's currently tuned, we can rely on bupropion 300mg and lisdexamfetamine 50mg in the morning to stimulate and 1500mg of divalproex and 15mg of mirtazapine in the evening to sedate. The concern would be pushing the seesaw too far in the one direction. If we were to increase mirtazapine to 30mg, then we're basically relying on divalproex to handle the brunt of the mood stabilization. On the other hand, many pdocs do employ bupropion as a mood stabilizer, and mirtazapine can have a stabilizing effect on the mood as well. Hypomania is actually a potential discontinuation symptom of mirtazapine, making it unique among antidepressants. I have also met someone with schizophrenia who is actually incredibly well managed on 300mg of bupropion and a couple hundred mgs of quetiapine. We did also talk about what next steps would be if we did increase the mirtazapine and found it to be stimulating. Probably decrease bupropion back down to 150mg at that rate. But he and I agreed at that appt that we didn't want to lose the progress I made. I also told him I would be open to swapping the bupropion out for desvenlafaxine, which was brand-only Pristiq when I last took it and had to switch to generic Effexor XR when my insurance changed and the new insurer wouldn't cover it. He seemed open to it, but one step at a time. So we decided to just stay at the current doses of bupropion 300mg and mirtazapine 15mg for now and go 2 weeks to see if I notice any further improvement before we make an adjustment.
  25. I have hard that the Zydis form of Zyprexa MAY cause less weight gain. Perhaps less exposure in the digestive tract to olanzapine, which might change things metabolically to a certain degree. Hard to say. But like I said with @jarn, "If it ain't broke, don't fix it." Your cholesterol was normal last time you checked, and you're losing weight on the Zydis form. Plus the metformin. If there really was a problem, your pdoc would talk to you about it.
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