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Bupropion augment for anxiety?


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On 1/28/2021 at 12:41 PM, Selkie said:

As ever if @browri or @mikl_pls has the time and energy to chime in I'd love to hear about the pharmacology of these 3 options! But also no pressure if not, of course!!!

Hey @Selkie! The past few weeks have been interesting for me, and for whatever reason I felt the need to write a thesis for a response. By the time I realized it was insanely long, I was like screw it I can't let this go to waste. So I posted it anyway. Sorry in advance :wtf:

Actually, until recently I was taking a combination of Vyvanse 50 in the morning with Trintellix 20 / Rexulti 2 / Depakote 1250 at night. Due to recent events, a change was required. So now I'm on a combo of Wellbutrin XL 150 / Vyvanse 50 in the morning and Depakote 1500 / Remeron 15 in the evening. We'll go through your pdoc's suggestions and others in the thread. But I'll also try and give my own experience too.

Much of the anxiety caused by Wellbutrin has to do with increased adrenergic tone due to the fact that bupropion and its various metabolites are all very potent norepinephrine reuptake inhibitors. This really ramps up the fight-or-flight system in a serious way. And for those who are already a little flighty, this can be overwhelming in some scenarios. Tempering that adrenergic effect or modulating it is key to also mentally feeling less anxious.

Buspar

I've spoken with my pdoc about Buspar (buspirone) in the past, and he said he's never had much luck with it. While it is indicated for anxiety disorders, its mechanism of action isn't necessarily entirely complementary to Wellbutrin. It's a 5HT1A partial agonist with high intrinsic activity. Intrinsic activity is a measure in percent form of the activating effect that a compound/ligand has for a receptor relative to the native neurotransmitter. So if serotonin is the native neurotransmitter binding to the receptor, activating the receptor to 100%, a full agonist, then a partial agonist would be anything that binds to the receptor and has an effect greater than 0% (0% effect would mean it binds and blocks the native neurotransmitter, which would make it an antagonist) but less than 100% of serotonin. Buspirone is considered a functional partial agonist because its activating effect at the 5HT1A receptor is >50% measuring in most studies between 60-80%. This specific subtype of serotonin receptor is present as a heteroreceptor in some areas, where it controls downstream dopamine release. In other areas, it is more commonly known as a pre-synaptic auto-receptor where it acts as negative feedback to reduce the release of additional serotonin. This has the potential to reduce activation of serotonin type 2 receptors (5HT2A/B/C), which would indirectly increase norepinephrine and dopamine release on top of the dopamine release already occurring from buspirone's direct 5HT1A receptor stimulation. In this way, perhaps buspirone may be able to augment bupropion. It's hard to say whether the net effect would be less anxiety though, particularly if buspirone had little effect for you in the past.

Lamictal

Lamictal (lamotrigine) may have potential. In regards to your pdoc's statement that you aren't bipolar and therefore you don't need lamotrigine, not sure that's totally aligned, but perhaps a bigger point they were trying to make was that other things should be tried before thinking outside the box like this. Lamotrigine is generally regarded as a glutamate reducing agent. Glutamate acts as the chief excitatory neurotransmitter in the brain, and GABA is its opposite. Medications like benzodiazepines work directly on the GABA-A receptors to mediate their sedation by making those receptors more sensitive to GABA than they normally would be. Alternatively, reducing glutamate release by using something like lamotrigine or topiramate (Topamax), more glutamate is retained inside of neurons instead of released into the synapse. Inside of neurons, glutamate can go through the normal metabolic lifecycle and be broken down by enzymes produced in our body and/or converted into its chemical opposite, GABA. So theoretically, if glutamate and GABA were on a see-saw, lamotrigine would make glutamate "lighter" by reducing its release, thus making GABA relatively "heavier". In my experience, lamotrigine is pretty mild, even at 200mg. I describe it this way, and I've had other people who've taken it agree that lamotrigine makes things kind of "roll off your shoulders" both ups and downs. It just generally takes more to get worked up about something. But it's all very general speaking honestly, and I don't know if it would or would not be good to neutralize any anxiety from Wellbutrin. I don't believe I've ever taken them together. What I will say though is you are likely to feel quite different if you SWITCH from Wellbutrin to Lamictal. If you choose to add Lamictal to the Wellbutrin, it can possibly have some neutralizing impact on Wellbutrin's adrenergic effects. There is also a feedback loop for Wellbutrin much like I described for the 5HT1A receptors and Buspar. When Wellbutrin increases norepinephrine and dopamine levels in the synapse and leads to increased activation of those receptors, the brain compensates by releasing glutamate because the brain is excited. When glutamate binds to NMDA receptors, among others, it then REDUCES norepinephrine and dopamine release, thus negative feedback. With Lamictal in place and reduced glutamate signaling, there is the potential for increased efficacy of Wellbutrin's antidepressant effects because the brake line for norepinephrine and dopamine will be "cut" or "leaky" in a sense, but the reduced glutamate may lend to less excitation of the brain and this may lead to less anxiety. Again, this is only a theory of HOW it MIGHT work IF it DOES work.

Tricyclics

Tricyclic antidepressants are still regarded as quite effective in some difficult scenarios. However, as you've pointed out, they've certainly fallen out of fashion as front-line agents, and that's for a variety of reasons. In a sense, the strength of tricyclic antidepressants is also their weakness. They're broad spectrum in the number of targets they hit, but that also means that many times they are off-target in what they actually hit. Said another way, most tricyclics inhibit reuptake of both serotonin and norepinephrine, which is likely the primary effect. Some, like protriptyline for example, are also modest dopamine reuptake inhibitors. Many also bind to and block some serotonin and alpha-adrenergic receptors as well, which we now know does contribute to antidepressant effect.

However, tricyclics are also oftentimes very strong antihistamines, which leads to sedation, an overall sedentary lifestyle if you aren't careful, and subsequently weight gain. Combine this with the blocking of subtype 1 adrenergic receptors, which will lead to reduced cardiac activity and add to the sedation. However, this sedating effect can be very useful for sleep and anxiety. An example of this would be amitriptyline which is often used in low doses at night to help with sleep and also provides a modest mood improvement. So a pdoc has to pit the risk of weight increases against the need for sedation and whether or not an antihistamine is more appropriate than a long-acting benzo like Klonopin (clonazepam), etc.

Another problem with some tricyclics is that many are anticholinergics. Off the top of my head, acetylcholine is important for two things. First, many people know that acetylcholine has to do with cognition and memory. It's often compromised in those with dementia, particularly Alzheimer's disease. In fact, medications for Alzheimer's like donepezil (Aricept) actually work by inhibiting the breakdown of acetylcholine. The theory of course is that with more acetylcholine available, cognition will improve. However, increased acetylcholine activity can also mean more irritability, which may be why smoking cessation drugs that bind to and partially activate acetylcholine receptors like varenicline (Chantix) can actually lead to irritable or aggressive behavior. Secondly, acetylcholine (in concert with dopamine) is responsible for smooth muscle control (gut, bladder, others). Ever hear from a smoker that a cigarette in the morning "gets their gut moving" yeah, that's because nicotine is structurally very similar to acetylcholine and binds to some of those receptors.

So knowing all that, what would happen if you blocked acetylcholine receptors? Well, potentially constipation by slowing down the gut. Urinary retention due to reduction of bladder contractions (useful for some, not for others). Issues with cognition or "feeling foggy". In tandem with that brain fog might be some sedation as well. Personally when I took Cogentin (benztropine) for akathisia for a few days, I couldn't even do basic arithmetic. Acetylcholine receptors are also found on the pancreas where they can control insulin production and release. Blocking those receptors can in the long term actually lead to type 2 diabetes (e.g. Zyprexa [olanzapine]).

So generally speaking, tricyclics have fallen out of fashion because pdocs expect the broad spectrum of activity of those agents to lead to more side effects overall than SSRIs or SNRIs. They try you on an SSRI or two first, then move to the SNRIs, then try augmenting either of those with medications like buspirone, bupropion, or mirtazapine before they introduce the tricyclics. If there's one thing that the STAR*D study did teach psychiatry, it's that when initiating monotherapy with an antidepressant, the chances of responding to the next one are lower and lower and lower with each additional antidepressant tried, but these statistics don't necessarily hold true in the case of combination therapies, which have been shown in some combinations to be more robust than others. To this point, psychiatry has more recently started to look favorably on using combination therapy of newer, complementary agents (e.g. Effexor+Remeron aka "California Rocket fuel") as second-line treatment; and in some cases, they more readily use combination therapy as first-line in patients demonstrating a need for a faster response than is typically expected from antidepressants, which in most cases take at least 2 weeks to start working and sometimes up to 8 weeks for full effect.

So with a propensity for greater side effect burden than newer agents, combining tricyclics with other agents should probably be tried after combining newer agents. Additionally, monotherapy with a tricyclic may be worth trying first before combining a tricyclic with something else, as tricyclics do have a myriad of effects that may negate the need for augmentation.

Gabapentinoids

I have no personal experience with gabapentin or pregabalin, but both are certainly worth a try. Neither work directly on GABA receptors the way that benzodiazepines do. However, at least pregabalin (and maybe gabapentin) increases levels of the enzyme L-glutamic acid decarboxylase. L-glutamic acid acts as a precursor to both glutamate (via glutamine) and GABA. However, the decarboxylating enzyme is responsible for synthesizing GABA specifically. This would therefore increase the GABA supply in the brain and reduce the amount of L-glutamic acid that would be available for conversion into glutamine > glutamate. Going back to my "seesaw" analogy earlier, this would lead to a brain that is "lighter" in glutamate and "heavier" in GABA. This should be generally calming and therefore reduce anxiety. Even though they aren't approved for anxiety, I've seen people swear by gabapentinoids like Neurontin and Lyrica. So I imagine there's gotta be something to that.

Remeron: Part 1 (Pharmacodynamics and Augmentation Strategies)

Finally to address a combination of Remeron (mirtazapine) and Wellbutrin (bupropion hydrochloride). I referenced a study earlier in this post called STAR*D. I would encourage those with the patience to read through studies to dig this one up and take a peek when you can: https://www.nimh.nih.gov/funding/clinical-research/practical/stard/allmedicationlevels.shtml

It was in this study that certain switching and augmentation strategies were investigated. These modes of attack are ones commonly used in clinical practice, and the purpose was to determine if there was merit to these practices. However, the study was also guided by the tolerability of the patient. From the NIH's site:

Quote

The design of the STAR*D study reflects what is done in clinical practice because it allowed study participants to choose certain treatment strategies most acceptable to them and limited the randomization of each participant only to his/her range of acceptable treatment strategies.

Here is also a 6-week, double-blind, placebo-controlled trial with four groups including the placebo group. One group was given fluoxetine+placebo, one was given fluoxetine+mirtazapine, one was given venlafaxine+mirtazapine, and one was given bupropion+mirtazapine:

https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2009.09121768

  • fluoxetine+mirtazapine did indeed do better than fluoxetine+placebo. There were fewer nonresponders in the combination group (32%) than in the placebo group (46%). Far more people achieved remission in the combination group (52%) than in the placebo group (25%).
  • HOWEVER, one of the active control groups, venlafaxine+mirtazapine, performed better than all other groups with a remission rate of 58% and a non-response rate of 27%.
  • This would actually put the venlafaxine+mirtazapine combination in first place, fluoxetine+mirtazapine in second, and bupropion+mirtazapine in third, with fluoxetine monotherapy coming in dead last.

To really understand why the combination treatments in this study and the STAR*D study performed so much better than many monotherapies like SSRIs, it's important to understand what monotherapies like SSRIs lack, and what they do in the brain in the long term. For many patients who have a significant response to their first or second SSRI but don't achieve remission, many symptoms resolve, but anhedonia and motivation or interest issues still persist. The reported issues are often centered around pleasure, which would be a dopaminergic problem. By taking an SSRI, broad activation of the 5HT2 family of serotonin heteroreceptors actually results in a decrease in norepinephrine and dopamine output. This is a good thing for some people whose depression is at least partially a result of a low serotonin / high dopamine state in the brain. However despite the popularization of SSRIs, this is not the root issue for everyone, or there may be added complexity in certain patients due to dysfunctions in other, indirectly-related pathways. Being aware of these balancing mechanisms has led us to Wellbutrin augmentation, which is a popular addition to many SSRIs. As a releasing agent and reuptake inhibitor of both norepinephrine and dopamine, it restores some of their signaling that may have been lost due to the SSRI, an underlying genetic predisposition to low NE/DA signaling, or both at the same time. This makes Wellbutrin a good complementary agent to any SSRI. Monotherapy with SNRIs like venlafaxine, desvenlafaxine, or duloxetine is believed to possibly achieve this via norepinephrine reuptake inhibition. In the pre-frontal cortex, reuptake of dopamine is handled predominantly via the norepinephrine transporter. Inhibiting it should directly increase dopamine in the PFC.

Problem with Wellbutrin is that many find it to cause anxiety, and with SNRIs there may be lingering issues like sexual dysfunction. In these cases, pdocs may turn to Remeron. As a 5HT3 antagonist it can reduce nausea caused by SSRIs or SNRIs. As a broad antagonist of 5HT2 receptors, it blocks a negative feedback mechanism for norepinephrine and dopamine, therefore NE and DA output are increased. It blocks alpha-2 adrenergic receptors which are found as auto-receptors and control the release of norepinephrine (block = increase) and are also found in regions like the hippocampus as heteroreceptors and control the release of serotonin (block = increase again) and indirectly control activation of 5HT1 receptors. Increased release of norepinephrine also means increased alpha-1 activation which also increases serotonin release. So Remeron has no effect on reuptake of neurotransmitters, but it does control release of neurotransmitters by blocking specific receptors. Comparatively, it is also the most potent antihistamine of the tricyclic and tetracyclic antidepressants, which makes it quite the sedative at bedtime.

Okay, so Wellbutrin and Remeron are both great augmenting agents because they both restore norepinephrine and dopamine signaling that may have been lost due to inhibition of serotonin reuptake. Wellbutrin is better for those who have low energy/motivation and fatigue issues who don't have much anxiety, whereas Remeron is probably better if you're the anxious type and need to calm down.

Remeron: Part 2 (My experience)

I started on Remeron at 7.5mg a day for the first week while I was washing out from Trintellix and Rexulti. It was fairly sedating and made for a good sleeping pill. I was very calm during the day, and my husband even noted that my anxiety and overall "tension" appear to be nonexistent. And he was right. Remeron calmed me in a way no other medication had except for Zyprexa (olanzapine). It was actually kind of like a massage. Afterwards you feel so relaxed and you're amazed because you didn't even realize you were so tense to begin with.

In this regard, it was the middle of winter, but I felt "warm and cozy". I noticed an increase in my sex drive. I also noticed an increase in appetite, and once or twice I actually surprised myself while I was eating. Food tasted really good, but the whole satiety thing just wasn't functioning properly. It took a lot to feel satisfied. I also was having issues with energy and motivation. And this was all while only taking Depakote 1500mg and Vyvanse 50mg as my other meds. I did increase Remeron to 15mg at week 2 and did notice some mood and interest improvements during the day, but it definitely wasn't going to cut it. I was at a whole new baseline. And the combination of low energy/motivation with an increased appetite was a recipe for disaster (i.e. weight gain). So we actually added Wellbutrin XL 150mg to the mix to ramp things up. Our thinking was that Wellbutrin would help offset some of the energy/motivation and satiety issues of Remeron and would also inhibit Remeron's metabolism and increase its levels. So 15mg is perhaps maybe 20mg or 25mg. It's generally understood that Remeron's real antidepressant potential in most patients is at its 30mg or 45mg doses. So theoretically, pushing that Remeron 15mg up with Wellbutrin's pharmacokinetic interaction (CYP2D6 inhibition) combined with Wellbutrin's complementary effects on NE and DA would allow for lower doses of both Remeron and Wellbutrin to go further.

Adding Wellbutrin to the Remeron was an interesting experience. I imagine that coming off Trintellix and Rexulti and simultaneously titrating up on Remeron was a pretty big shift for my mood from one space to another. So starting on Wellbutrin reintroduced some of that simulation fairly rapidly and it was an interesting experience to say the least. I imagine that being stable on Wellbutrin first and adding Remeron would probably be a different experience. Regardless, in the past few days I have actually started to feel pretty good. I still have my appetite but I'm more in control of it like I was before starting Remeron. But I also find that Remeron does indeed calm most of the anxiety and irritability/snappiness from Wellbutrin. I've taken Wellbutrin two times before. The first time in college as an adjunct to Celexa but that was before my bipolar diagnosis and without a mood stabilizer. Needless to say, that didn't go well. Second time, I was controlled with a mood stabilizer and was taking Wellbutrin as my sole antidepressant. This trial went much better, but I had the same issues many had like anxiety or irritability. Remeron has made this feel quite different. When I noticed this, I actually went and just did a hunt on the web for data regarding the combination. Aside from the study above that showed it performed better than fluoxetine monotherapy, I also found various posts from other people who have taken the combination and reported similar success for the same reasons. Wellbutrin tempered Remeron's appetite issues and Remeron tempered Wellbutrin's anxiety/agitation/irritability issues. So it may be worth a shot.

 

Okay, I'm done :) 

Edited by browri
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27 minutes ago, Iceberg said:

Hey @browri, thorough as always. Just from my own memory the primary endpoint measured was depression but did they actually assess anxiety scores as a Main variable? I’m not trying to discount your input just asking  

I'm not sure whether anxiety was an endpoint at all in the trial, but if it was, I'm inclined to think it wasn't a primary endpoint. Statistically significant changes may have been noted, but the study wouldn't have been dependent on those measures because the focus was depression.

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Followed up on that and confirmed from the NIH's website:

Quote

In most clinical trials of treatment for depression, the measure of success (outcome) is called “response” to treatment, which means that the person’s symptoms have decreased to at least half of what they were at the start of the trial. In STAR*D, the outcome measure was a “remission” of depressive symptoms—becoming symptom-free. This outcome was selected because people who reach this goal generally function better socially and at work, and have a better chance of staying well than do people who only achieve a response but not a remission.

 

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On 2/12/2021 at 10:14 AM, Selkie said:

@browri OMG thank you, I missed this alert, going to have a thorough read now - I appreciate this so much! 

Glad I could provide some info and hopefully your eyes don't hurt too much after reading that.

When is your next pdoc appointment to discuss next move?

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@browri - I am still waiting for my next appointment. I live in Canada, and it's very difficult to actually get to see a psychiatrist, I have to talk to my family doctor and then she talks to the pdoc, but I requested a direct consult with him since I haven't had one in over a year, and my symptoms have changed drastically during the pandemic. 

 

In the meantime I've actually gone off wellbutrin because my anxiety was getting so bad.... but now my motivation and energy are totally shot. I really wish this wasn't the tradeoff, I love the way wellbutrin gives me focus, energy, patience, positive outlook etc. But I was finding I was getting even some pure O OCD symptoms which I haven't really had in many years (like, since childhood....so that's weird). 

I feel like your remeron/bupropion combo sounds really promising - how are you feeling on it now that it's settled in again? 

 

It's super interesting to read about the way the drugs are and are not complementary - I feel like my main doctor (GP) is just like "buspar is for anxiety so it will lessen the anxiety of wellbutrin", but it seems like that's not really accurate. Honestly you have more knowledge and care than any doctor I've ever talked to! 

 

When you say if I switched from wellbutrin to lamictal I'd feel quite different...what do you mean by that? Or like...how I'd feel different? 

 

 

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On 2/18/2021 at 12:32 PM, Selkie said:

@browri - I am still waiting for my next appointment. I live in Canada, and it's very difficult to actually get to see a psychiatrist, I have to talk to my family doctor and then she talks to the pdoc, but I requested a direct consult with him since I haven't had one in over a year, and my symptoms have changed drastically during the pandemic. 

Yeah a direct consult is probably good to re-assess, if it's been a while. The pandemic has really been making a lot of work for mental healthcare workers like psychiatrists. It's introduced whole new variables to which people aren't normally subjected. That's complicated things for them. But at least they aren't out of a job like so money, on the other hand.

On 2/18/2021 at 12:32 PM, Selkie said:

In the meantime I've actually gone off wellbutrin because my anxiety was getting so bad.... but now my motivation and energy are totally shot. I really wish this wasn't the tradeoff, I love the way wellbutrin gives me focus, energy, patience, positive outlook etc. But I was finding I was getting even some pure O OCD symptoms which I haven't really had in many years (like, since childhood....so that's weird). 

I feel like your remeron/bupropion combo sounds really promising - how are you feeling on it now that it's settled in again? 

Yeah starting from Remeron only and then adding Wellbutrin, there's definitely a settling period. Each day has been a little bit better than the last. But I do think I need increases. I am only on 15mg of Remeron and 150mg of Wellbutrin XL at this point.

That being said I feel a lot less anxious than I normally felt in the past on Wellbutrin, and a lot of the sedation of Remeron has really eased up at this point. If I take it at 7PM early enough, it really doesn't affect me much in the morning at all. My appetite is more normal now too.

On 2/18/2021 at 12:32 PM, Selkie said:

It's super interesting to read about the way the drugs are and are not complementary - I feel like my main doctor (GP) is just like "buspar is for anxiety so it will lessen the anxiety of wellbutrin", but it seems like that's not really accurate. Honestly you have more knowledge and care than any doctor I've ever talked to! 

Buspar is for anxiety, but there are so many people whose anxiety doesn't respond to Buspar. So you have to imagine then that anxiety can occur via different pathways in the brain and not just the pathway that Buspar manages (5HT1A). And therefore you could suppose that maybe Buspar may temper Wellbutrin anxiety for some people and not others.

As for my knowledge, I will gladly admit that my understanding of this stuff is like Swiss cheese, riddled with gaps. I'm no psychopharmacologist, but when there are manic and obsessive qualities, this can drive a person to read......a lot. So I may absorb a lot of information, but I don't always understand the why and how of it.

On 2/18/2021 at 12:32 PM, Selkie said:

When you say if I switched from wellbutrin to lamictal I'd feel quite different...what do you mean by that? Or like...how I'd feel different? 

Well my experience with Wellbutrin is that it's activating and revs you up a bit, whereas Lamictal can be activating in the beginning but that really isn't its chief quality. It isn't really stimulating or sedating either way once you've adjusted to it. I can't tell you that Lamictal will help with energy or motivation all that much, but by reducing some negative thought processes, it may perhaps indirectly improve your focus because your mind isn't stewing over something (rumination), and by all that it may lend to a more positive outlook. It won't improve your focus in the way that a stimulant does though.

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On 1/29/2021 at 2:16 PM, Gearhead said:

Just a heads-up if you do decide to try lamictal: the titration period can be rough. It can be very activating, which would be a real treat to deal with on top of Wellbutrin anxiety.

Also, somewhat complicating and anxiety provoking, both medications can cause rashes/allergic responses. The Wellbutrin one, while not the most comfortable to deal with, you can take a daily non-drowsy antihistamine like Zyrtec to manage it. It happened to me and I still take Wellbutrin XL. The other, unless the psychiatrist is well, well versed in rashes and has balls of steel, will likely immediately tell you to stop taking it, regardless of how far along in the titration you are or how helpful it is, because the cons far outweigh the pros of they were wrong if you ended up in the ER and/or ICU. 

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Also, apologies if this was already brought up / addressed, but ... minus the side effects, do you think the Wellbutrin could be worthwhile to try again, but this time either titrating up more slowly and/temporarily managing the start up agitation/anxiety/whatever with a benzo like clonazepam (Klonopin)?

Because I personally found it to be a worthwhile medicine in spite of the week or so of increased agitation and anxiety. I'm still on it now and the agitation/anxiety never came back. 

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@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.

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On 3/11/2021 at 10:23 AM, browri said:

@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.

I've never taken mirtazapine personally, but through work both anecdotally and observationally, I've heard and seen doses > 15mg to be less sedating and more activating, likely due to greater noradrenergic simulation and so possibly triggering more agitation, anxiety, hypomania/mania, etc. 

That being said, if you feel like the Bupropion is actually helping, I'd be more likely to reduce the mirtazapine than cross-taper to desvenlafaxine, as they're just different meds and not likely to generate the same results.

I don't know how your psychiatrist feels about it, but specifically with the XL formulation of bupropion, you can go up to a max dose of 450mg (which I'm personally on and find helpful). 

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On 3/17/2021 at 10:13 PM, psychwardjesus said:

I've never taken mirtazapine personally, but through work both anecdotally and observationally, I've heard and seen doses > 15mg to be less sedating and more activating, likely due to greater noradrenergic simulation and so possibly triggering more agitation, anxiety, hypomania/mania, etc. 

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.

Quote

That being said, if you feel like the Bupropion is actually helping, I'd be more likely to reduce the mirtazapine than cross-taper to desvenlafaxine, as they're just different meds and not likely to generate the same results.

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.

Quote

I don't know how your psychiatrist feels about it, but specifically with the XL formulation of bupropion, you can go up to a max dose of 450mg (which I'm personally on and find helpful). 

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.

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On 3/18/2021 at 10:29 AM, browri said:

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. ... 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.

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.

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@browri thank you so much for the update! I don't check this site too often, but I'd be curious to hear what you landed on! 

Right now I'm still just on bupropion xl 150, and clonazepam prn for anxiety, which I'm taking at least once and often twice a day. Long term goal for both me and more so for my doctors is to get the clonazepam to be closer to a couple times a week, but at least my doctors are understanding that maybe the pandemic isn't the best time to make such a change. 

I had a consult with the pdoc who works with my doctor on Thursday... He thinks I should stay on the bupropion more consistently (I tend to start and stop taking it more often than is really advisable), and find a good, tolerable augment for anxiety. 

His main suggestions were just adding a classic SSRI - I've been very very anti SSRI/SNRI for myself since they all seem to cause what I consider intolerable sexual side effects. I think also because I started taking them when I was a teenager (paxil around 14 I think, effexor 16-20 or so), and I didn't know about SSE, I just thought I was "broken". But he said that since I've never tried an SSRI *with* bupropion, it's worth seeing if it would counteract these. I'm still nervous, especially because I have a new girlfriend, lol, but he's right that if it would just cut the anxiety and the bupropion would do its thing for SSE, that would be great. 

His second line recc was abilify, which I know my mom took and loved the effects of but had very significant and rapid weight gain. Seems common. However, the wellbutrin might counteract that too. I just have heard really mixed things about this drug. 

Lamictal he didn't seem to keen on for anxiety, but I think they'd let me try it if I was really adamant. 

A big problem for me is that I'm very anxious to start new meds, I often go fill the prescription and then never take even one pill, so my doctor said she wants me to wait until I'm ready to actually give something a try...oof. I might need to bring that up with my therapist and work on a plan to get me to actually try a new drug 😕 ....is there a med that you can take to make you not scared to take new meds, lol. 

Anyway thanks so much for your support, this is nice to be able to talk about. I'm in some facebook groups for meds, but no one is going into nearly this much depth. 

I hope you're finding something that works for you! ❤️ 

Oh oops I saw your last post was just on Wed! I guess you're still checking out the 30mg mirtazapine... I hope it's still feeling good! 

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On 3/27/2021 at 7:54 AM, Selkie said:

@browri thank you so much for the update! I don't check this site too often, but I'd be curious to hear what you landed on! 

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.

On 3/27/2021 at 7:54 AM, Selkie said:

Right now I'm still just on bupropion xl 150, and clonazepam prn for anxiety, which I'm taking at least once and often twice a day. Long term goal for both me and more so for my doctors is to get the clonazepam to be closer to a couple times a week, but at least my doctors are understanding that maybe the pandemic isn't the best time to make such a change. 

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.

On 3/27/2021 at 7:54 AM, Selkie said:

I had a consult with the pdoc who works with my doctor on Thursday... He thinks I should stay on the bupropion more consistently (I tend to start and stop taking it more often than is really advisable), and find a good, tolerable augment for anxiety. 

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.

On 3/27/2021 at 7:54 AM, Selkie said:

His main suggestions were just adding a classic SSRI - I've been very very anti SSRI/SNRI for myself since they all seem to cause what I consider intolerable sexual side effects. I think also because I started taking them when I was a teenager (paxil around 14 I think, effexor 16-20 or so), and I didn't know about SSE, I just thought I was "broken". But he said that since I've never tried an SSRI *with* bupropion, it's worth seeing if it would counteract these. I'm still nervous, especially because I have a new girlfriend, lol, but he's right that if it would just cut the anxiety and the bupropion would do its thing for SSE, that would be great. 

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. 

On 3/27/2021 at 7:54 AM, Selkie said:

His second line recc was abilify, which I know my mom took and loved the effects of but had very significant and rapid weight gain. Seems common. However, the wellbutrin might counteract that too. I just have heard really mixed things about this drug. 

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.

On 3/27/2021 at 7:54 AM, Selkie said:

Lamictal he didn't seem to keen on for anxiety, but I think they'd let me try it if I was really adamant. 

Yeah it would be better to try other things first.

On 3/27/2021 at 7:54 AM, Selkie said:

A big problem for me is that I'm very anxious to start new meds, I often go fill the prescription and then never take even one pill, so my doctor said she wants me to wait until I'm ready to actually give something a try...oof. I might need to bring that up with my therapist and work on a plan to get me to actually try a new drug 😕 ....is there a med that you can take to make you not scared to take new meds, lol. 

if only haha

On 3/27/2021 at 7:54 AM, Selkie said:

Anyway thanks so much for your support, this is nice to be able to talk about. I'm in some facebook groups for meds, but no one is going into nearly this much depth. 

I hope you're finding something that works for you! ❤️ 

Oh oops I saw your last post was just on Wed! I guess you're still checking out the 30mg mirtazapine... I hope it's still feeling good! 

Enjoying it!

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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.

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@browri for what it’s worth, I had two docs use mirtazapine on me and both told me that the faster full response only happens for a lucky few. I read this really cool article lately discussing why some serotonin-affecting antidepressants have effect times that lag behind their steady state due to the way down regulation works at 5HT receptors. Maybe I will try to refind it 

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2 hours ago, Iceberg said:

@browri for what it’s worth, I had two docs use mirtazapine on me and both told me that the faster full response only happens for a lucky few. I read this really cool article lately discussing why some serotonin-affecting antidepressants have effect times that lag behind their steady state due to the way down regulation works at 5HT receptors. Maybe I will try to refind it 

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.

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1 hour ago, browri said:

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.

I have always thought that summoning the required patience is one of the hardest parts of mental illness. Good luck with future improvement!

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