Jump to content
CrazyBoards.org
Skeletor

Why do strong SRIs induce apathy, indifference and laziness?

Recommended Posts

Posted (edited)

Why do strong SRIs (serotonin reuptake inhibitors) often cause / induce apathy, indifference and laziness? Maybe not in everyone, but it's one of the most common complaints. I regularly read about it on the internet. I myself was affected by it.

My questions would be:
1.) What causes it?
2.) Were you affected?
3.) Did you successfully get rid of these specific side effects? If so, how so?
4.) Further comments regarding that "phenomenon"?

Edited by Skeletor
SSRI apathy
  • Thanks 1

Share this post


Link to post
Share on other sites
Posted (edited)

This is the billion-dollar question I have also. A huge reason why I (and many others) have such a tough time staying on them for years. I often question if they should be taken for life in many cases. For me, SSRIs will prevent / stop an acute episode, they smooth everything out, the lability, triggers stop. The apathy effect doesn't hit right away. Yet usually (within like 9-12 months) it sets in.  I can't stand the  "I don't give a sh*t about anything/anyone, I'll just lay here & watch paint dry..." It's really not a healthy state to be in, it's still depression, just in a different (muted) form.

I'm trying to get down to the lowest possible dose that will prevent a major nosedive and maybe not have this effect. Adding a stimulant helps to an extent also, until the tolerance starts increasing. I'm no pharmacologist, but maybe there's a decrease in dopamine that occurs with longterm SSRI use?...and we are left with this serotonin sloth syndrome?

Edited by Blahblah
  • Like 1

Share this post


Link to post
Share on other sites
20 hours ago, Blahblah said:

For me, SSRIs will prevent / stop an acute episode, they smooth everything out, the lability, triggers stop. The apathy effect doesn't hit right away. Yet usually (within like 9-12 months) it sets in.  I can't stand the  "I don't give a sh*t about anything/anyone, I'll just lay here & watch paint dry..." It's really not a healthy state to be in.

Hahaha... exactly.

  • Like 1

Share this post


Link to post
Share on other sites

I wasn't able to find much, but I too believe I suffer from this. I believe my antipsychotic also contributes to this as well.

As for the antidepressant (specifically SSRI) induced indifference, I found one single link from pubmed that seemed to be somewhat reputable. I recommend checking it out. I'll summarize a little of it below.

Quote

Etiology

May be due to...

  1. Serotonergic effects on the frontal lobe, and/or
  2. Serotonergic modulation of mid-brain dopaminergic systems, which project to the prefrontal cortex

Clinical management

  • Dosage reduction of SSRI, if clinically feasible
  • Addition of a second drug (usually bupropion)
  • Switch to another drug class, such as SNRIs (or TCAs, or MAOIs...)

 

Personally I have gotten rid of it by adding a moderately high dose of desipramine (100 mg) to my SSRI. That's a secondary amine TCA which works primarily on norepinephrine (actually is the most selective NRI on the market in the US). Atomoxetine (Strattera) would work too theoretically (I've tried it and it didn't work too terribly great for me). Fluoxetine and atomoxetine was a good combination until Strattera went generic (then all hell broke loose).

MAOIs are really great for depression that are treatment resistant (if you're able to find a psychiatrist who's willing to prescribe them). They're even more effective when prescribed with a stimulant, which is classically contraindicated, but can be done under the close supervision of an expert psychiatrist.

  • Like 1
  • Thanks 1

Share this post


Link to post
Share on other sites
Posted (edited)
11 hours ago, mikl_pls said:

I wasn't able to find much, but I too believe I suffer from this. I believe my antipsychotic also contributes to this as well.

As for the antidepressant (specifically SSRI) induced indifference, I found one single link from pubmed that seemed to be somewhat reputable. I recommend checking it out. I'll summarize a little of it below.

Etiology

May be due to...

  1. Serotonergic effects on the frontal lobe, and/or
  2. Serotonergic modulation of mid-brain dopaminergic systems, which project to the prefrontal cortex

Clinical management

  • Dosage reduction of SSRI, if clinically feasible
  • Addition of a second drug (usually bupropion)
  • Switch to another drug class, such as SNRIs (or TCAs, or MAOIs...)

Personally I have gotten rid of it by adding a moderately high dose of desipramine (100 mg) to my SSRI. That's a secondary amine TCA which works primarily on norepinephrine (actually is the most selective NRI on the market in the US). Atomoxetine (Strattera) would work too theoretically (I've tried it and it didn't work too terribly great for me). Fluoxetine and atomoxetine was a good combination until Strattera went generic (then all hell broke loose).

MAOIs are really great for depression that are treatment resistant (if you're able to find a psychiatrist who's willing to prescribe them). They're even more effective when prescribed with a stimulant, which is classically contraindicated, but can be done under the close supervision of an expert psychiatrist.

This makes sense. I initially was given Buproprion to counter the indifference, but that did nothing, seems a weak DRI (or maybe if you lack Dopamine in general, there's too little there for re-uptake?) This is the reason why pdoc added ritalin (a miracle at first, and now, not so much)...

Sadly, SNRIs like Effexor still have this apathy effect longterm (unless you ratchet up the dose to like 300mg, a withdrawal nightmare, should you ever need to taper off it!)

I often wonder if I ditched the SSRI, and switched to a TCA or MAOI (instead of the SSRI + Ritalin combo) that would be a more effective, longterm maintenance solution? Boosting Serotonin, Dopamine and Norepinephrine simultaneously?  That would be ideal, but pdocs don't like TCAs or MAOIs

Edited by Blahblah
  • Like 1

Share this post


Link to post
Share on other sites
5 minutes ago, Blahblah said:

This makes sense. I initially was given Buproprion to counter the indifference, but that did nothing, seems a weak DRI (or maybe if you lack Dopamine in general, there's little to there to re-uptake?) This is the reason why pdoc added ritalin (a miracle at first, and now, not so much)...and sadly, SNRIs like Effexor still have this apathy effect longterm.

That's what makes me wonder if an amphetamine would be better for you over a methylphenidate-based because with methylphenidate and bupropion I believe you have to already have dopamine and norepinephrine there to inhibit the reuptake of. If there's a deficiency of them, then you won't be able to get any benefit from them. Amphetamines forces the release of those catecholamines. You could get some benefit out of taking amino acids like DL-phenylalanine or L-tyrosine, but there haven't been any proven benefit from taking them (they metabolize into dopamine and norepinephrine supposedly).

As for the SNRIs, you've tried Effexor and Cymbalta to no avail... What about Pristiq or Fetzima?

29 minutes ago, Blahblah said:

I often wonder if I ditched the SSRI, and switched to a TCA or MAOI (instead of the SSRI + Ritalin combo) that would be a more effective solution? Boosting Serotonin, Dopamine and Norepinephrine simultaneously?  That would be ideal, but pdocs don't like TCAs or MAOIs

Honestly I think that would be a fantastic idea. The tertiary TCAs are pretty potent SRIs in lower doses, but as the dose increases, the become very potent SNRIs because the active metabolites (secondary amines which work on norepinephrine) increase in your system. Tertiary amine TCAs in the US include amitriptyline (which produces nortriptyline), imipramine (which produces desipramine), clomipramine (which produces desmethylclomipramine), doxepin (which produces nordoxepin), and trimipramine (which produces desmethyltrimipramine). Trimipramine is considered a second generation or "atypical" TCA because it does not produce any significant reuptake inhibition of any neurotransmitters. Instead, it possesses antipsychotic properties similar to clozapine (without the bad side effects). It has 5-HT2A antagonism and D2 antagonism, but preferentially antagonizes the presynaptic D2 autoreceptors in lower doses which leads to disinhibition of dopamine release. It's also a potent antihistamine and an anticholinergic. Clomipramine is regarded as the "golden standard" SNRI. Personally, I had a horrible experience with it, but be my guest and try it. It's supposed to work wonders for people. It just wan't my cup of tea. What I like are the secondary amine TCAs. Nortriptyline, desipramine, and protriptyline. They work primarily on norepinephrine, have less side effects, rather than being sedating are actually stimulating, especially protriptyline (which is taken during the day instead of night). (Desipramine can be taken during the day too.) These really help me with alertness, vigilance, and energy along with the SSRI that I take (Zoloft). I find that taking a secondary amine TCA with a SSRI (to create a customizable SNRI) is best for me. If I need more or less of one, all my pdoc has to do is tweak one or the other. It's super simple.

As for MAOIs, I personally loved Parnate (tranylcypromine), but it caused me so much weight gain which is very paradoxical. It's supposed to cause weight loss. But it along with the combo of Adderall had me out of my existential depression and I was so happy to be alive I could've burst into confetti. Literally. Emsam wasn't all that great, but it was better than the other one that I tried, Marplan. Marplan was kinda crappy and didn't work well, and it cost way too much for me. I never touched Nardil because of the menacing weight gain threat it has. That and it is supposedly sedating or stimulating—it can go either way. Also it can cause liver failure and vitamin B6 depletion which if left untreated can cause neuropathy. Emsam and Nardil are the safest, Marplan is the least researched and understood, and Parnate is most likely to cause both orthostatic hypotension and hypertensive crisis, paradoxically. (The orthostatic hypotension is how you know it's working.) Don't be afraid of MAOIs though. The dietary restrictions aren't that bad or super restrictive. Just watch fermented and pickled foods and you should be okay. That and aged cheese and certain alcoholic beverages. (Really you shouldn't be drinking alcoholic beverages on psych meds anyway, but.........)

If your pdoc doesn't seem to be progressing with you or helping you, I would advocate as strongly as you can for a TCA or MAOI. MAOIs, believe it or not, have less side effects than SSRIs (if you take them right, watch food and drug interactions, etc.) and definitely less than TCAs.

  • Like 1
  • Thanks 1

Share this post


Link to post
Share on other sites
10 hours ago, Blahblah said:

Sadly, SNRIs like Effexor still have this apathy effect longterm (unless you ratchet up the dose to like 300mg, a withdrawal nightmare, should you ever need to taper off it!)

That's because Venlafaxine works predominantly on Serotonin. Its SNRI-label is more marketing than pharmacologically justified.

Relative to other SNRIs, levomilnacipran, as well as milnacipran, differ in that they are much more balanced reuptake inhibitors of serotonin and norepinephrine.[8][9][10] To demonstrate, the serotonin:norepinephrine ratios of SNRIs are as follows: venlafaxine = 30:1, duloxetine = 10:1, desvenlafaxine = 14:1, milnacipran = 1.6:1, and levomilnacipran = 1:2.[8] The clinical implications of more balanced elevations of serotonin and norepinephrine are unclear,[8] but may include improved effectiveness, though also increased side effects.[9][10][11] - source: https://en.wikipedia.org/wiki/Levomilnacipran#Pharmacodynamics

The strongest and most balanced SNRI is Clomipramine: https://en.wikipedia.org/wiki/Clomipramine
It probably is the most effective non-MAOI antidepressant.

  • Like 1

Share this post


Link to post
Share on other sites
13 hours ago, Skeletor said:

That's because Venlafaxine works predominantly on Serotonin. Its SNRI-label is more marketing than pharmacologically justified.

Relative to other SNRIs, levomilnacipran, as well as milnacipran, differ in that they are much more balanced reuptake inhibitors of serotonin and norepinephrine.[8][9][10] To demonstrate, the serotonin:norepinephrine ratios of SNRIs are as follows: venlafaxine = 30:1, duloxetine = 10:1, desvenlafaxine = 14:1, milnacipran = 1.6:1, and levomilnacipran = 1:2.[8] The clinical implications of more balanced elevations of serotonin and norepinephrine are unclear,[8] but may include improved effectiveness, though also increased side effects.[9][10][11] - source: https://en.wikipedia.org/wiki/Levomilnacipran#Pharmacodynamics

The strongest and most balanced SNRI is Clomipramine: https://en.wikipedia.org/wiki/Clomipramine
It probably is the most effective non-MAOI antidepressant.

Interesting thanks for the info. I had assumed that Fetzima would be nearly identical to Effexor, but appears that it isn't. I've never heard of milnacipran...

Isn't Clomipramine (Anafril) a TCA? Yeah, pdocs always told me the side effects are much more pronounced with TCAs. Worth a shot though.

  • Like 1

Share this post


Link to post
Share on other sites
11 hours ago, Blahblah said:

Interesting thanks for the info. I had assumed that Fetzima would be nearly identical to Effexor, but appears that it isn't. I've never heard of milnacipran...

Isn't Clomipramine (Anafril) a TCA? Yeah, pdocs always told me the side effects are much more pronounced with TCAs. Worth a shot though.

It has a tricyclic structure (btw: Sertraline also has a tricyclic structure)

https://psychotropical.com/tca-intro/

Share this post


Link to post
Share on other sites
On 4/3/2020 at 5:31 PM, Skeletor said:

The strongest and most balanced SNRI is Clomipramine:

Only when the clomipramine doses get high enough for the levels of its active metabolite, N-desmethylclomipramine, to get high enough to work on norepinephrine sufficiently. (N-desmethylclomipramine is a secondary amine TCA, meaning it acts mainly on norepinephrine.) At low doses of clomipramine, it primarily occupies the SERT (quite potently), and NET occupancy isn't very high at low doses due to the low levels of N-desmethylclomipramine.

For me, personally though, it worsened my depression and anxiety a lot... But everyone is subject to their own experience with any medicine.

14 hours ago, Blahblah said:

I had assumed that Fetzima would be nearly identical to Effexor, but appears that it isn't. I've never heard of milnacipran...

Nope, as @Skeletor said, Fetzima actually works more on norepinephrine than serotonin, which is unique amongst the SNRI class of medications. Milnacipran, marketed as Savella in the US specifically for Fibromyalgia (and not for depression, but is marketed for depression in other countries in the world), is the racemic version of Fetzima (levomilnacipran, which is the levorotatory enantiomer of milnacipran, or the left-hand side of the molecule). I forget where you reside, @Blahblah, but check it out, milnacipran may be available where you live. Some common brand names are Ixel, Dalcipran, and Toledomin (other than Savella). There may be other trade names that I don't know about...

14 hours ago, Blahblah said:

Isn't Clomipramine (Anafril) a TCA?

Yes, it is.

14 hours ago, Blahblah said:

Yeah, pdocs always told me the side effects are much more pronounced with TCAs. Worth a shot though.

Side effects are more pronounced in the tertiary amine TCAs definitely, but in the secondary amine TCAs, not so much. I know I already listed them, but I'll list them again.

Tertiary amine TCAs in the US include: (more side effects, more serotonin except in higher doses which act include more norepinephrine)

  • amitriptyline (Elavil)
  • doxepin (Sinequan) (basically a glorified antihistamine, not that effective for depression)
  • imipramine (Tofranil, Tofranil-PM)
  • clomipramine (Anafranil)
  • trimipramine (Surmontil) (this one does not cause any reuptake inhibition of any neurotransmitters; rather, it has atypical antipsychotic properties similar to clozapine)

Secondary amine TCAs in the US include: (less side effects, more norepinephrine and indirectly dopamine, higher doses include serotonin too)

  • nortriptyline (Pamelor)
  • desipramine (Norpramin)
  • protriptyline (Vivactil)

Don't forget about the tetracyclic antidepressants! (TeCAs)

  • amoxapine (Asendin)
    • This is the active matabolite of the first-generation (sometimes debated as an atypical) antipsychotic loxapine (Loxitane).
    • It is a potent norepinephrine reuptake inhibitor and a weak serotonin reuptake inhibitor.
    • It has "built-in" atypical antipsychotic properties, with D2 antagonism and potent 5-HT2A, 5-HT2C, and 5-HT6 antagonism.
    • It, too, has some active metabolites that have D2 antagonism. One active metabolite has more potent serotonin reuptake inhibition, balancing out its monoamine reuptake inhibition profile.
  • maprotiline (Ludiomil)
    • A potent norepinephrine reuptake inhibitor, 5-HT7 antagonist, and H1 antagonist (antihistamine).
    • This medication has a narrow therapeutic index due to its propensity to causing seizures.
    • It's not very commonly used anymore, and is very hard to find nowadays.
  • mirtazapine (Remeron)
    • Considered a tetracyclic antipsychotic, though its mechanism of action differs vastly from the other two, which more closely resemble those of the tricyclics (sometimes they're even referred to as secondary amine TCAs).
    • Causes no reuptake inhibition.
    • Potent 5-HT2A and 5-HT2C inhibition, leading to disinhibition of dopamine and norepinephrine release.
    • Potent 5-HT3 antagonism, resulting in antiemetic effects, as well as release of acetylcholine and other neurotransmitters.
    • Potent presynaptic α2A and α2C antagonism, leading to disinhibition and enhancement of norepinephrine an serotonin release (leading to indirect increased 5-HT1A stimulation, presynaptically causing downregulation of the autoreceptors in time which disinhibits serotonin release and postsynaptically causing downstream dopamine release)
    • Potent H1 antagonism, leading to increased appetite and weight gain (especially when combined with the potent 5-HT2C antagonism that this medicine has)
    • This medicine is commonly paired with SNRIs to get a more potent response for treatment-resistant depression (prototypically Effexor XR), called "California Rocket Fuel" by Dr. Stephen Stahl, a psychopharmacologist.
    • It is typically more sedating in lower doses (7.5-15 mg), and less sedating and maybe even stimulating to some in higher doses (30-45 mg). (This, however, was not the case for me at all...) Some people need supratherapeutic doses of 60-90 mg.
4 hours ago, Skeletor said:

btw: Sertraline also has a tricyclic structure

I'm sorry, but I have never heard of this. Looking at the molecule, it does not have the prototypical tricyclic structure. Can you please provide a source for this?

Share this post


Link to post
Share on other sites

@mikl_pls thanks again...I'm at a loss as to what will be most helpful for me. I'm not sure if NE if super helpful, because it increases the "flight or flight" vigilance response. Which can easily make someone more restless and agitated it seems. Cymbalta sort of did that to me, after awhile I ended up very paranoid on edge on it.  I know you are well versed in switching meds around quite often, but I am terrified of switching when I'm "stable" and have something trigger a major episode. So I just remain stuck and sort of resigned to settle. I've been told to give meds a long time before deciding to switch, and I never know when to make the move.

Share this post


Link to post
Share on other sites
17 hours ago, mikl_pls said:

Only when the clomipramine doses get high enough for the levels of its active metabolite, N-desmethylclomipramine, to get high enough to work on norepinephrine sufficiently. (N-desmethylclomipramine is a secondary amine TCA, meaning it acts mainly on norepinephrine.) At low doses of clomipramine, it primarily occupies the SERT (quite potently), and NET occupancy isn't very high at low doses due to the low levels of N-desmethylclomipramine.

Depends highly on how you metabolize it. You could rapidly metabolize Clomipramine into Desmethylclomipramine, and then desmethylclomipramine gets metabolized slowly ^^

Share this post


Link to post
Share on other sites

I too had this problem on every SSRI I took and I tried a HEAP of them before finally getting into the mental health service (rather than just first-line GP) and was able to try other types. It's such a frustrating problem. I always found them emotionally dulling (which everyone complains about, but I actually liked having a more flat and even mood, just less reactive I guess) and I wonder if it's just the fact that they smooth out your emotions which makes you care about less things and therefore are less motivated. I dunno. I took venlafaxine (effexor) for a while and I don't recall if I was tired or not, I wasn't on it long... the norepinephrine I guess helps it be more activating. Has anyone experienced the tiredness and lethargy from venlafaxine? Aside from @Blahblah :) I just really can't recall.

The only things so far that have helped with lethargy are getting completely off SSRIs and trying bupropion and now moclobemide. Bupropion was too activating and my anxiety shot through the roof, but man I was productive and I just didn't need naps anymore. Now on moclobemide I do have more normal energy levels so I do nap sometimes but it's usually only for 20/30 mins max (as opposed to 3 hours when I was on SSRIs!). I can get through a day now and not feel like I have bricks attached to my feet and hands and a cloud in my head. 

Share this post


Link to post
Share on other sites

@Skeletor So the first part is how increasing serotonin signaling causes a downstream increase in dopamine signaling and then the brain becomes desensitized over time and the patient enters anhedonia.

Antidepressant-naive individuals often report starting antidepressants like SSRIs and feeling initial activation, agitation, anxiety, insomnia, irritability. "Things get worse before they get better." This is because serotonin reuptake inhibitors start working almost immediately even though we don't feel better for a few weeks. Upon initially inhibiting the serotonin transporter, serotonin will begin collecting in the synapses between neurons. This will increase activation, particularly, of 5HT1A receptors, which is how serotonin reuptake inhibitors are believed to ultimately mediate their effect (central 5HT1 activation, which causes downstream dopamine release).

The brain responds fairly quickly by reducing serotonin output into the synapse, to reduce the rate at which serotonin collects there. Despite this compensatory mechanism to offset the impact an SRI has on the synapse, activation of 5HT1 receptors continues both pre- and post-synaptically. After a few weeks, the brain becomes desensitized to the activity at pre-synaptic receptors and these neurons begin releasing serotonin again. When this happens, this is when an antidepressant is believed to start working.

The second part to this is the downstream release of dopamine that occurs upon 5HT1 activation. Dopamine receptors will respond to this in the same way. With increasing amounts of dopamine in the synapse, the brain will compensate by reducing dopamine output, DESPITE the 5HT1 activation. The net result after several weeks of administration of a serotonin reuptake inhibitor is much, much higher serotonin signaling along with a spike in dopamine signaling that then bottoms out and results, ultimately, in a net DECREASE in dopamine signaling. This is the chemical state of the brain in anhedonia.

Doctors fight part 2 of the above process by swapping out the SSRI for an SNRI or by adding bupropion. Switching to the SNRI will inhibit norepinephrine reuptake, which will also further increase dopamine because the brain inter-converts these two neurotransmitters between each other and also because in the PFC, dopamine is largely transported between neurons by the norepinephrine transporter (NET) because this region of the brain possesses very limited quantities of the dopamine transporter (DAT).

If you instead add bupropion to the SSRI, you do the same thing as switching to an SNRI with the added effect of DIRECT dopamine reuptake inhibition. Doctors will also take advantage of compounds that are antagonists of alpha-2 adrenergic receptors because these are auto-receptors that slow down the release of norepinephrine and serotonin. By blocking those receptors, serotonin and adrenergic activation is increased. A good example of this combo strategy is mirtazapine (Remeron).

  • Like 1

Share this post


Link to post
Share on other sites
19 hours ago, browri said:

@Skeletor So the first part is how increasing serotonin signaling causes a downstream increase in dopamine signaling and then the brain becomes desensitized over time and the patient enters anhedonia.

Antidepressant-naive individuals often report starting antidepressants like SSRIs and feeling initial activation, agitation, anxiety, insomnia, irritability. "Things get worse before they get better." This is because serotonin reuptake inhibitors start working almost immediately even though we don't feel better for a few weeks. Upon initially inhibiting the serotonin transporter, serotonin will begin collecting in the synapses between neurons. This will increase activation, particularly, of 5HT1A receptors, which is how serotonin reuptake inhibitors are believed to ultimately mediate their effect (central 5HT1 activation, which causes downstream dopamine release).

The brain responds fairly quickly by reducing serotonin output into the synapse, to reduce the rate at which serotonin collects there. Despite this compensatory mechanism to offset the impact an SRI has on the synapse, activation of 5HT1 receptors continues both pre- and post-synaptically. After a few weeks, the brain becomes desensitized to the activity at pre-synaptic receptors and these neurons begin releasing serotonin again. When this happens, this is when an antidepressant is believed to start working.

The second part to this is the downstream release of dopamine that occurs upon 5HT1 activation. Dopamine receptors will respond to this in the same way. With increasing amounts of dopamine in the synapse, the brain will compensate by reducing dopamine output, DESPITE the 5HT1 activation. The net result after several weeks of administration of a serotonin reuptake inhibitor is much, much higher serotonin signaling along with a spike in dopamine signaling that then bottoms out and results, ultimately, in a net DECREASE in dopamine signaling. This is the chemical state of the brain in anhedonia.

Doctors fight part 2 of the above process by swapping out the SSRI for an SNRI or by adding bupropion. Switching to the SNRI will inhibit norepinephrine reuptake, which will also further increase dopamine because the brain inter-converts these two neurotransmitters between each other and also because in the PFC, dopamine is largely transported between neurons by the norepinephrine transporter (NET) because this region of the brain possesses very limited quantities of the dopamine transporter (DAT).

If you instead add bupropion to the SSRI, you do the same thing as switching to an SNRI with the added effect of DIRECT dopamine reuptake inhibition. Doctors will also take advantage of compounds that are antagonists of alpha-2 adrenergic receptors because these are auto-receptors that slow down the release of norepinephrine and serotonin. By blocking those receptors, serotonin and adrenergic activation is increased. A good example of this combo strategy is mirtazapine (Remeron).

What's your take on tricyclics?

Share this post


Link to post
Share on other sites
On 4/7/2020 at 8:06 AM, Skeletor said:

What's your take on tricyclics?

Well going along with what I've said above, the reason why tricyclics typically have more robust efficacy where SSRIs or SNRIs may fail is because every tricyclic AD is an SNRI (in varying ratios of SERT:NET inhibition, but still SNRIs statistically have far more robust treatment efficacy regardless of tolerability). However:

1. Tricyclics are also often 5HT2 antagonists, which further increases norepinephrine and dopamine release and is a key target for calming agitation in a variety of disorders.

2. They are also often antagonists of adrenergic receptors (both alpha and beta) which can have therapeutic effect and also contribute to side effects. For example, alpha-2 antagonism will increase norepinephrine and serotonin output and increase 5HT1 activation, but it can contribute to the subjective report of being "nervous" because it cuts the brake line (auto-receptor) on the adrenergic system (alpha-2 activation by norepinephrine SLOWS norepinephrine output). On the flip side, blocking beta receptors results in subjective improvements in anxiety ratings and can calm tremor that is a side effect of other medications like lithium.

3. Some tricyclics like desipramine are nearly entirely norepinephrine reuptake inhibitors and therefore do well as augmenting agents to other more selective serotonergic antidepressants like escitalopram or by complementing a more serotonergic agents weaker adrenergic/dopaminergic promoting effects. For example, a popular combination is fluoxetine/desipramine because fluoxetine is a 5HT2C antagonist, which promotes norepinephrine and dopamine output. Pair this with desipramine's NRI mechanism, and you have a combination that is far more stimulating than fluoxetine could ever be alone even if you went to 80mg, and even then it probably wouldn't be as tolerable as low doses of the combo. The same can be said for sertraline+desipramine. @mikl_pls can attest to this combo personally.

4. However, there are disadvantages like the propensity for these early-stage tricyclic compounds to also have anti-cholinergic side effects that contributed to cognitive effects or sedation (along with antihistamine effects). This is why they are less often used. However, there is a reason why tricyclics are generally regarded as being more likely to cause mania in people with bipolar disorder because they do in fact have far more robust responses due to the above-mentioned effects.

 

However, a tricyclic effect can truly be achieved by pairing an SNRI with an atypical antipsychotic (tricyclics sometimes have dopamine blockings effects e.g. clomipramine).

  • Like 2

Share this post


Link to post
Share on other sites
On 4/9/2020 at 12:29 AM, browri said:

4. However, there are disadvantages like the propensity for these early-stage tricyclic compounds to also have anti-cholinergic side effects that contributed to cognitive effects or sedation (along with antihistamine effects). This is why they are less often used. However, there is a reason why tricyclics are generally regarded as being more likely to cause mania in people with bipolar disorder because they do in fact have far more robust responses due to the above-mentioned effects.

 

Can those anti-cholinergic properties be of any usefullness?

Share this post


Link to post
Share on other sites
On 4/6/2020 at 6:28 PM, browri said:

@Skeletor So the first part is how increasing serotonin signaling causes a downstream increase in dopamine signaling and then the brain becomes desensitized over time and the patient enters anhedonia.

The second part to this is the downstream release of dopamine that occurs upon 5HT1 activation. Dopamine receptors will respond to this in the same way. With increasing amounts of dopamine in the synapse, the brain will compensate by reducing dopamine output, DESPITE the 5HT1 activation. The net result after several weeks of administration of a serotonin reuptake inhibitor is much, much higher serotonin signaling along with a spike in dopamine signaling that then bottoms out and results, ultimately, in a net DECREASE in dopamine signaling. This is the chemical state of the brain in anhedonia.

Doctors fight part 2 of the above process by swapping out the SSRI for an SNRI or by adding bupropion. Switching to the SNRI will inhibit norepinephrine reuptake, which will also further increase dopamine because the brain inter-converts these two neurotransmitters between each other and also because in the PFC, dopamine is largely transported between neurons by the norepinephrine transporter (NET) because this region of the brain possesses very limited quantities of the dopamine transporter (DAT).

 

@browri Great info... Do you know how long it would take for this "desensitization" to go away (after the SSRI is removed?) Or is it difficult for this to be reversed?

Another thing: Maybe I'm a weird case, but SNRIs (Effexor and Cymbalta) both caused a similar anhedonia for me as well.....and Wellbutrin did not have an effect for me...

Share this post


Link to post
Share on other sites
Posted (edited)
13 hours ago, Adolf said:

Can those anti-cholinergic properties be of any usefullness?

Certainly. When you lower dopamine signaling and throw it out of balance with acetylcholine, it can cause restlessness. So the anti-cholinergic effects of of tricyclics on the one hand can caused blurred vision, urinary retention, cognitive issues, possibly contribute to combination by slowing down the GI, on the other hands it calms you down from a psycho-motor perspective.

4 hours ago, Blahblah said:

@browri Great info... Do you know how long it would take for this "desensitization" to go away (after the SSRI is removed?) Or is it difficult for this to be reversed?

Another thing: Maybe I'm a weird case, but SNRIs (Effexor and Cymbalta) both caused a similar anhedonia for me as well.....and Wellbutrin did not have an effect for me...

Sounds like a fringe case to me. I wonder if you should be taking like a combo of Deplin and EPA-only fish oil (like Vascepa) with probably Effexor because it's worked so well for you in the past. The fish oil reduces inflammation and is a natural way to augment an antidepressant and the Deplin (L-5-methylfolate) will increase the amount of neurotransmitters in the brain to hopefully assist with the anhedonia.

Reversal would likely be SIMILAR from person to person but each person would be different when it comes to subjective perception of anhedonia reversal. Meaning the time frame probably doesn't vary too terribly much but genetic variation from person to person would certainly make for slight variations in that time frame in the order of a few weeks maybe. That time would effectively begin from the point that the antidepressant has completely cleared your system (AD's half-life in hours multiplied by 5.5). However, a person could certainly will their subjective experience of perception longer than the time it would take for the brain to technically recover from the antidepressant, like the white elephant effect, trying to not think about something causes you to think about it. When you're trying to recover from symptoms like anhedonia you have to always play devil's advocate for your brain and tell yourself that it's not there. Err on the negative side as it were. Next thing you know if you keep telling yourself over and over that it's not happening as it slowly gets better all of the sudden it's gone and you didn't even miss it. lol.

Edited by browri
  • Like 1
  • Thanks 1

Share this post


Link to post
Share on other sites
Posted (edited)
21 hours ago, browri said:

Sounds like a fringe case to me. I wonder if you should be taking like a combo of Deplin and EPA-only fish oil (like Vascepa) with probably Effexor because it's worked so well for you in the past. The fish oil reduces inflammation and is a natural way to augment an antidepressant and the Deplin (L-5-methylfolate) will increase the amount of neurotransmitters in the brain to hopefully assist with the anhedonia.

Reversal would likely be SIMILAR from person to person but each person would be different when it comes to subjective perception of anhedonia reversal. Meaning the time frame probably doesn't vary too terribly much but genetic variation from person to person would certainly make for slight variations in that time frame in the order of a few weeks maybe. That time would effectively begin from the point that the antidepressant has completely cleared your system (AD's half-life in hours multiplied by 5.5). However, a person could certainly will their subjective experience of perception longer than the time it would take for the brain to technically recover from the antidepressant, like the white elephant effect, trying to not think about something causes you to think about it. When you're trying to recover from symptoms like anhedonia you have to always play devil's advocate for your brain and tell yourself that it's not there. Err on the negative side as it were. Next thing you know if you keep telling yourself over and over that it's not happening as it slowly gets better all of the sudden it's gone and you didn't even miss it. lol.

@browri  Crazy you mention this! I was doing MUCH better last year, (and I was taking a Multivitamin, NAC, Omegas, and this Supergreen powder supplement). I ran out of all of it, and then went on holiday December, and since January, I noticed the lethargy & apathy increasing...like my Ritalin wasn't working. I even took a Ritalin holiday all of December!

Problem is, quality supplements are expensive. I'm unemployed, my hub balks at me spending so much on supplements (he says they aren't really proven unless you are deficient, he's a scientist, go figure!)  I just ordered a new multivitamin and re-started NAC, I keep wondering if it's purely psychological placebo effect, but I did have more energy (mentally & physically) when I was taking these. It was subtle over time, but I think the supplements do make a difference.

Would Deplin help if I don't have the MTHR mutation? I really want to get a Fish Oil, but overwhelmed at the options (I know high EPA is ideal) but which brands, and where to order? I used to take Nordic Naturals and they are really quite expensive (plus I must pay shipping to Europe). If you have any other supplements/vitamins you recommend (and specific brands that are easy to get, or without a prescription) Please let me know!

Edited by Blahblah

Share this post


Link to post
Share on other sites

Join the conversation

You can post now and register later. If you have an account, sign in now to post with your account.

Guest
Reply to this topic...

×   Pasted as rich text.   Paste as plain text instead

  Only 75 emoji are allowed.

×   Your link has been automatically embedded.   Display as a link instead

×   Your previous content has been restored.   Clear editor

×   You cannot paste images directly. Upload or insert images from URL.


  • Similar Content

    • By Skeletor
      Both are second-generation SSRIs, both exhibit minimal drug interactions via Cytochrome P450, both are the most prescribed SSRIs and are considered first line antidepressants. Who's been taking both and what were your experiences? (How did they compare to each other?). I am looking forward to read your experiences...
      Which one did you like more?
    • By Blahblah
      Have a strong itch to drop Effexor...(I won't go cold turkey). It stopped my dysphoric crying spells, but now, 10 months later, I'm feeling increasingly flat, apathetic, numb, no motivation (even after dropping to 75mg). I hate how all A/Ds have this lobotomy effect on me longterm. It's initially fine in acute episodes, I'm not sad now, but I can't function properly, and I continue to score Moderate-Severe on the depression scale.
      I think it's counteracting my Ritalin (which I increased to 30-40mg)? I don't want to increase Effexor above 150mg, I'd never be able to go off.
      I'm trying dosing at night instead, will this make any difference @mikl_pls ? I skipped yesterday's morning dose (then came the intense nausea, over stimulation & brain slosh awfulness @10 hours later) and I took my dose with dinner.
      I'm seriously considering going on low-dose mild SSRI instead (Prozac?) I'm sensitive to meds & side effects, and I'm also VERY worried about withdrawals. Especially from Effexor, they are the WORST, and I just read study that Effexor withdrawal syndrome is not dose-dependent:
      https://www.researchgate.net/publication/7402189_Venlafaxine_and_Serious_Withdrawal_Symptoms_Warning_to_Drivers
      https://metro.co.uk/2018/01/24/woman-shares-coming-off-antidepressant-ruined-life-7255570/
       
       
    • By Blahblah
      Starting this thread because boredom, idleness, lack of stimulation is often a key trigger of depression and bad habits. When I get bored, I feel an emptiness, uselessness and physical/mental lethargy, cue ruminations, then I sleep excessively. This isn't always fatigue: It's an automatic (and very negative) avoidance behavior.
      This link lists 150 ideas (from high effort to minimal effort - from "fun" to mundane) in order to build healthier habits. I need to stop waiting to "feel good" before taking any action. Any thoughts?
      https://www.developgoodhabits.com/what-to-do-bored/
      Today, I:
      Journaled, Cleaned my desktop, Backed up computer, unsubscribed to some junk email, Did some stretching, called a relative, dealt with an admin issue, read some blogs about depression, provided some words of support/appreciation for someone.
    • By Blahblah
      Anyone find Zoloft more motivating than Effexor? Any weight gain? (it made me insomniac with psychosis 20 years ago). But meds often act differently over time. I've already done trials (some multiple times) of:
      Prozac (lethargic), Celexa (fatigue/apathy), Lexapro (similar to prozac), Cymbalta (vigilance/restlessness legs, but dissociative mind/feeling), Wellbutrin (no effect), Trintillex (no effect), Remeron (sedating/+appetite), Notryptaline (don't recall), Abilify (++appetite, RLS), ..Doc won't RX MAOIs and says that TCAs typically more sedating effects.
      Basically, I don't want to take more than 3 meds (keeping with Lamictal & Ritalin). I want to avoid A/Ps...I like the calming feeling of Prozac & Effexor, but it's as if I am in this fuzzy cloud and I can't move or do anything, comfortably numb. Totally apathetic, in addition to sexual dysfunction, maybe my dosage is wrong. I'm also considering Viibryd, but don't know if it works on Serotonin...?
×
×
  • Create New...