Psycho-Babble Medication Thread 1121100

Shown: posts 1 to 16 of 16. This is the beginning of the thread.

 

Tolerance is just so low!!

Posted by linkadge on November 20, 2022, at 14:55:58

I am having so much difficulty tolerating ANY venlafaxine. Even 1/4 of 37.5mg is giving me chest tightness. My tolerance of bupropion is much higher.

Trying to restart the venlafaxine is proving difficult.

Linkadge

 

Re: Tolerance is just so low!! linkadge

Posted by SLS on November 20, 2022, at 17:06:29

In reply to Tolerance is just so low!!, posted by linkadge on November 20, 2022, at 14:55:58

> I am having so much difficulty tolerating ANY venlafaxine. Even 1/4 of 37.5mg is giving me chest tightness. My tolerance of bupropion is much higher.
>
> Trying to restart the venlafaxine is proving difficult.
>
> Linkadge


1. You might need to take a drug-holiday from serotonin reuptake inhibitors before returning to them.

2. Consider switching to Pristiq right now.

3. Discontinue Effexor and add nortriptyline to the bupropion.

4. If you think that there might be bipoloarity involved in your mood disorder, you might consider focusing closer on MAOIs. A recent report suggests that MAOIs are more effective to treat bipolar depression than unipolar depression.


----------------------------------------------------------


"Effectiveness and safety of monoamine oxidase inhibitor treatment for bipolar depression versus unipolar depression"

https://onlinelibrary.wiley.com/doi/epdf/10.1111/acps.13518


* Take note that the original findings during the early 1980s were affirmed. Atypical depression responds better to MAOIs than melanancholic depression does.


- Scott

 

Re: Tolerance is just so low!! linkadge

Posted by jay2112 on November 20, 2022, at 19:21:45

In reply to Tolerance is just so low!!, posted by linkadge on November 20, 2022, at 14:55:58

> I am having so much difficulty tolerating ANY venlafaxine. Even 1/4 of 37.5mg is giving me chest tightness. My tolerance of bupropion is much higher.
>
> Trying to restart the venlafaxine is proving difficult.
>
> Linkadge

Try just taking the 37.5 and you should feel a bit better within a week or two. Do you have access to any benzo's, clonidine, or propranolol? Those will crumple the norepinephrine uptake. Propranolo, in particular, has made me actually tolerate and do not bad on Effexor. It won't work until you boost the Effexor so it can down-regulate the norepinephrine on it's own. It's like taking a horrible tasting cough medicine, and then you get used of it.

Jay

 

Re: Tolerance is just so low!!

Posted by SLS on November 21, 2022, at 7:10:32

In reply to Re: Tolerance is just so low!! linkadge, posted by jay2112 on November 20, 2022, at 19:21:45

> > I am having so much difficulty tolerating ANY venlafaxine. Even 1/4 of 37.5mg is giving me chest tightness. My tolerance of bupropion is much higher.
> >
> > Trying to restart the venlafaxine is proving difficult.
> >
> > Linkadge
>
> Try just taking the 37.5 and you should feel a bit better within a week or two. Do you have access to any benzo's, clonidine, or propranolol? Those will crumple the norepinephrine uptake. Propranolo, in particular, has made me actually tolerate and do not bad on Effexor. It won't work until you boost the Effexor so it can down-regulate the norepinephrine on it's own.

These are excellent ideas - except, perhaps. for the clonidine. I have seen clonidine be robustly depressogenic. Of course, this might not be true when added to Effexor when psychiatric side effects emerge.

> It's like taking a horrible tasting cough medicine, and then you get used of it.

...and maybe even like it.

What are your beliefs regarding Effexor and NE receptor downregulation?

In the early 1980s, it was considered putative that NE reuptake inhibitors downregulated NE *beta* receptors. At the time, this was believed to be the mechanism of action of tricyclic antidepressants. If this beta downregulation property of NE reuptake inhibitors is still advocated by neuroscientists, a beta-blocker like propranolol might make the most sense to ease into establishing higher dosages of Effexor. I like pindolol as an alternative. Aside from being a NE beta-blocker, it also blocks serotonin 5-HT1a axo-dentritic receptors. Pindolol has been found to accelerate an antidepressant response, and perhaps potentiate it.

https://sci-hub.se/https://doi.org/10.1016/S0165-6147(00)01682-5

I get the impression that 150 mg/day is the lowest effective dosage of Effexor. Infequently, 75 mg/day. For me, Effexor does not produce its maximum antidepressant effect until I get to 300 mg/day, although the improvement was only partial. I found this dosage to be easily tolerable once established, despite having side effects after the very first dose of 25 mg. The side effects were of an uncomfortable stimulation. I had a sort of "warmth" and tingling in my head during my de novo treatment with Effexor. None of my subsequent trials of Effexor produced this effect. Also, I never experienced these side effects with Pristiq. Of course, this could have been an artifact of being treated with Effexor previously.

Speaking of side effects - and perhaps the receptivity to treatment - drug reactions are often changed by pre-treatment with another compound. Effexor was always helpful until I switched to it immediately after a trial of vortioxetine (Trintellix). It is a well-known and often-used experimental strategy to elucidate the mechanisms behind neuronal functions in normal versus manipulated biological states. This most often involves assaying receptor states to reveal how they control regional and global brain functions.


- Scott

 

Re: Tolerance is just so low!!

Posted by SLS on November 21, 2022, at 7:39:17

In reply to Re: Tolerance is just so low!!, posted by SLS on November 21, 2022, at 7:10:32

I forgot to mention that I have personally experienced a clonidine-induced exacerbation of depression.

Most salient, though, is that clonidine is capable of producing significant depression in people who have no history of depression.

1. Clonidine = (norepinephrine) NE alpha-2 presynaptic autoreceptor agonist (stimulatior).

2. NE alpha-2 receptors control the manufacture and release of NE via a negative feedback loop.

3. When NE presynaptic autoreceptors are antagonized (blocked), the presynaptic neuron increases the manufacture and release of NE. This is because the presynaptic neuron "sees" less synaptic NE than there actually is by blocking its "eyes" (autoreceptors) from accurately measuring synaptic NE levels. It sees less than there really is. The neuron is thus fooled into manufacturing and releasing more NE.

4. When NE autoreceptors are agonized (stimulated), the presynaptic neuron "sees" more synaptic NE than there really is. The presynaptic neuron thus reduces its manufacture and release of NE to compensate.

5. Clonidine thus reduces the synaptic concentration of NE by stimulating presynaptic autoreceptors.

6. Reduced synaptic concentrations of NE are associated with depression.


* I hope I got that right.


- Scott

 

Re: Tolerance is just so low!! SLS

Posted by jay2112 on November 21, 2022, at 17:45:32

In reply to Re: Tolerance is just so low!!, posted by SLS on November 21, 2022, at 7:10:32

> > > I am having so much difficulty tolerating ANY venlafaxine. Even 1/4 of 37.5mg is giving me chest tightness. My tolerance of bupropion is much higher.
> > >
> > > Trying to restart the venlafaxine is proving difficult.
> > >
> > > Linkadge
> >
> > Try just taking the 37.5 and you should feel a bit better within a week or two. Do you have access to any benzo's, clonidine, or propranolol? Those will crumple the norepinephrine uptake. Propranolol, in particular, has made me actually tolerate and do not bad on Effexor. It won't work until you boost the Effexor so it can down-regulate the norepinephrine on it's own.
>
> These are excellent ideas - except, perhaps. for the clonidine. I have seen clonidine be robustly depressogenic. Of course, this might not be true when added to Effexor when psychiatric side effects emerge.

Thanks, Scott! I often figure that if I get acute effects, there has *got* to be another med to antagonize. I do hear you, moreso now, on the depressing effect of clonidine. It is the strength in which it lowers blood pressure, which we absolutely don't want to get too low...putting our lives in danger. I used to eat it like candy, on 300mg of Effexor, and I felt so blahhh. Mind you, 300mg of Effexor, and I have been up to 450mg's, just turned me into this weird catatonic state. I would sit there and stare at walls.

> > It's like taking a horrible tasting cough medicine, and then you get used of it.
>
> ...and maybe even like it.
>
> What are your beliefs regarding Effexor and NE receptor downregulation?
>
> In the early 1980s, it was considered putative that NE reuptake inhibitors downregulated NE *beta* receptors. At the time, this was believed to be the mechanism of action of tricyclic antidepressants. If this beta downregulation property of NE reuptake inhibitors is still advocated by neuroscientists, a beta-blocker like propranolol might make the most sense to ease into establishing higher dosages of Effexor. I like pindolol as an alternative. Aside from being a NE beta-blocker, it also blocks serotonin 5-HT1a axo-dentritic receptors. Pindolol has been found to accelerate an antidepressant response, and perhaps potentiate it.

I am certainly no expert in this area. My doctor once thought of Pindolol, but at the time, I was doing awesome on Serzone, with 75mg's of Effexor, and added 5ht2 blockade with a small dose of Risperidone. I have never really found my way back, as nefadozone has been taken off the market in Canada.I am on the spectrum, high functioning when medicated properly. One little supplement I find helpful during an "overload/meltdown", is Lecithin, which has choline in it, and is a mild but slightly helpful treatment.

> https://sci-hub.se/https://doi.org/10.1016/S0165-6147(00)01682-5
>
> I get the impression that 150 mg/day is the lowest effective dosage of Effexor. Infequently, 75 mg/day. For me, Effexor does not produce its maximum antidepressant effect until I get to 300 mg/day, although the improvement was only partial. I found this dosage to be easily tolerable once established, despite having side effects after the very first dose of 25 mg. The side effects were of an uncomfortable stimulation. I had a sort of "warmth" and tingling in my head during my de novo treatment with Effexor. None of my subsequent trials of Effexor produced this effect. Also, I never experienced these side effects with Pristiq. Of course, this could have been an artifact of being treated with Effexor previously.

25 mg's of Effexor? Are you talking about the original, immediate release? OMG, I remember taking a 25mg tab, and having the hugest panic attack I *ever* had!! I remember the place...I was just going into a restaurant with a friend. And the *burning, seething* anger!! Yikes!!

> Speaking of side effects - and perhaps the receptivity to treatment - drug reactions are often changed by pre-treatment with another compound. Effexor was always helpful until I switched to it immediately after a trial of vortioxetine (Trintellix). It is a well-known and often-used experimental strategy to elucidate the mechanisms behind neuronal functions in normal versus manipulated biological states. This most often involves assaying receptor states to reveal how they control regional and global brain functions.
>
Yeah, I honestly have found dropping the dose after a fw weeks, then increasing a few weeks latter, then dropping, to be the only way I can really tolerate Effexor. I know...strange as F*&^$....but whatever gets us through the night, right?

> - Scott

Jay

 

Re: Tolerance is just so low!!

Posted by jay2112 on November 21, 2022, at 18:33:28

In reply to Re: Tolerance is just so low!!, posted by SLS on November 21, 2022, at 7:39:17

> I forgot to mention that I have personally experienced a clonidine-induced exacerbation of depression.
>
> Most salient, though, is that clonidine is capable of producing significant depression in people who have no history of depression.
>
> 1. Clonidine = (norepinephrine) NE alpha-2 presynaptic autoreceptor agonist (stimulatior).
>
> 2. NE alpha-2 receptors control the manufacture and release of NE via a negative feedback loop.
>
> 3. When NE presynaptic autoreceptors are antagonized (blocked), the presynaptic neuron increases the manufacture and release of NE. This is because the presynaptic neuron "sees" less synaptic NE than there actually is by blocking its "eyes" (autoreceptors) from accurately measuring synaptic NE levels. It sees less than there really is. The neuron is thus fooled into manufacturing and releasing more NE.
>
> 4. When NE autoreceptors are agonized (stimulated), the presynaptic neuron "sees" more synaptic NE than there really is. The presynaptic neuron thus reduces its manufacture and release of NE to compensate.
>
> 5. Clonidine thus reduces the synaptic concentration of NE by stimulating presynaptic autoreceptors.
>
> 6. Reduced synaptic concentrations of NE are associated with depression.
>
>
> * I hope I got that right.
>
>
> - Scott

I am sure your mechanisms are right, Scott...but the bottom line, clonidine is a very powerful drug, given 0.1mg's lower almost anyone's blood pressure. Clonidine was used quite a bit in the 70's and 80's to help many rock stars and celebrities kick heroin. I have had that experience of sub-low blood pressure, and it is not a nice feeling.

So, I think, tiny amounts are the key. I don't think, for psychiatric use, there is any need to go above 0.1mg b.i.d. Your body does adjust, once on a regular schedule. It was *magic* for my PTSD nightmares. But, I tried raising the dose. Not good for mental health.

Jay

 

Re: Tolerance is just so low!! jay2112

Posted by SLS on November 21, 2022, at 21:10:14

In reply to Re: Tolerance is just so low!!, posted by jay2112 on November 21, 2022, at 18:33:28

> I am sure your mechanisms are right, Scott...but the bottom line, clonidine is a very powerful drug, given 0.1mg's lower almost anyone's blood pressure. Clonidine was used quite a bit in the 70's and 80's to help many rock stars and celebrities kick heroin. I have had that experience of sub-low blood pressure, and it is not a nice feeling.
>
> So, I think, tiny amounts are the key. I don't think, for psychiatric use, there is any need to go above 0.1mg b.i.d. Your body does adjust, once on a regular schedule. It was *magic* for my PTSD nightmares. But, I tried raising the dose. Not good for mental health.
>
> Jay

If you take a look in the literature, depression caused by clonidine is common. I have not found any articles describing clonidine as being capable of improving depression. However, it does help ADHD, anxiety, and schizophrenia. As you indicate, clonidine might act very differently at micro-doses compared to using traditional therapeutic dosages. I guess it's possible that, whereas clonidine monotherapy causes depression, it might act very differently when used as an adjunct to other agents.

I'm sure someone knows the answers to these propositions. I don't. It would make a good research project.

Interesting: Compare clonidine to yohimbine.


- Scott

 

Re: Tolerance is just so low!! SLS

Posted by jay2112 on November 22, 2022, at 21:44:03

In reply to Re: Tolerance is just so low!! jay2112, posted by SLS on November 21, 2022, at 21:10:14

> > I am sure your mechanisms are right, Scott...but the bottom line, clonidine is a very powerful drug, given 0.1mg's lower almost anyone's blood pressure. Clonidine was used quite a bit in the 70's and 80's to help many rock stars and celebrities kick heroin. I have had that experience of sub-low blood pressure, and it is not a nice feeling.
> >
> > So, I think, tiny amounts are the key. I don't think, for psychiatric use, there is any need to go above 0.1mg b.i.d. Your body does adjust, once on a regular schedule. It was *magic* for my PTSD nightmares. But, I tried raising the dose. Not good for mental health.
> >
> > Jay
>
> If you take a look in the literature, depression caused by clonidine is common. I have not found any articles describing clonidine as being capable of improving depression. However, it does help ADHD, anxiety, and schizophrenia. As you indicate, clonidine might act very differently at micro-doses compared to using traditional therapeutic dosages. I guess it's possible that, whereas clonidine monotherapy causes depression, it might act very differently when used as an adjunct to other agents.
>
> I'm sure someone knows the answers to these propositions. I don't. It would make a good research project.
>
> Interesting: Compare clonidine to yohimbine.
>
>
> - Scott

Guanfacine, similar in action to clonidine, seems effective, without the deadening low-blood pressure clonidine causes. I honestly don't think clonidine has much efficacy in treating depression, but Guanfacine..possibly, by reducing the stressor effect of norepinephrine. However, vegetative types of depression, I don't think, would respond to either.

Yohimbine is an interesting treatment, as it promotes norepinephrine release, but is also an alpha-2-adrenergic blocker. I actually have had some late interest in trying it for sexual dysfunction. (which it is said to treat.) I did try it, from a health food store, about 25-30 years ago, but with little response.

Jay

 

Re: Tolerance is just so low!!

Posted by Christ_empowered on November 29, 2022, at 9:38:28

In reply to Tolerance is just so low!!, posted by linkadge on November 20, 2022, at 14:55:58

maybe...a non-antidepressant approach?

I've read here and there...some people become less and less tolerant of antidepressants over time. I don't even pretend to begin to know the underlying mechanisms, but...

antidepressants are clearly not for all of us, anyway.

I seem to recall reading...

a lot of the antidepressants function like the old school "goof balls." a lot of those pills involved an upper (usually an amphetamine, now and then ritalin) and a sedative (usually barbiturates, sometimes meprobamate)...

but a number of them used some flavor neuroleptic, and those pills, in particular...

have a lot of overlapping actions with today's antidepressants. so...

are you still taking ritalin? maybe see about a prescription for a low dose of gabapentin? Some doctors report good effects on mood using buspirone with uppers.


sorry this is happening.

 

Re: Tolerance is just so low!! Christ_empowered

Posted by SLS on November 29, 2022, at 15:58:27

In reply to Re: Tolerance is just so low!!, posted by Christ_empowered on November 29, 2022, at 9:38:28

> maybe...a non-antidepressant approach?

Whatever works. It would be an instructional exercise to have people list those drugs or other substances that worked best for them.

The growing magnitude of side effects to the same drug might be a result of a "sensitization" process - similar to how one becomes more responsive to cocaine with each subsequent exposure early in the course of its usage.

Are there any non-antidepressants that you consider particularly effective at producing a remission of depression? Unfortunately, it might be a process of desensitization that renders an antidepressant less effective with each subsequent exposure upon restarting treatment.


- Scott

 

Re: Tolerance is just so low!!

Posted by undopaminergic on December 8, 2022, at 7:15:35

In reply to Re: Tolerance is just so low!! Christ_empowered, posted by SLS on November 29, 2022, at 15:58:27

> > maybe...a non-antidepressant approach?
>
> Whatever works. It would be an instructional exercise to have people list those drugs or other substances that worked best for them.
>

I won't try to go through them all, but my best combination was buprenorphine + methylphenidate. I felt I was in the process of getting on my feet again when the drugs were taken away from me.

-undopaminergic

 

Re: Tolerance is just so low!! undopaminergic

Posted by SLS on December 28, 2022, at 14:18:41

In reply to Re: Tolerance is just so low!!, posted by undopaminergic on December 8, 2022, at 7:15:35

> > > maybe...a non-antidepressant approach?
> >
> > Whatever works. It would be an instructional exercise to have people list those drugs or other substances that worked best for them.
> >
>
> I won't try to go through them all, but my best combination was buprenorphine + methylphenidate. I felt I was in the process of getting on my feet again when the drugs were taken away from me.
>
> -undopaminergic


What property of buprenorphine do you think mitigated your depressive symptoms? What led you to combine the two drugs?

I found this:

"Major Depressive Disorder and Kappa Opioid Receptor Antagonists"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871611/

Buprenorphine is a partial agonist at the mu opioid receptor and an *antagonist* at the kappa receptor, which could explain the antidepressant properties of buprenorphine. Perhaps you can find another kappa receptor antagonist. I wouldn't know where to look.


- Scott

 

Re: Tolerance is just so low!! SLS

Posted by undopaminergic on December 28, 2022, at 16:40:08

In reply to Re: Tolerance is just so low!! undopaminergic, posted by SLS on December 28, 2022, at 14:18:41

> > > > maybe...a non-antidepressant approach?
> > >
> > > Whatever works. It would be an instructional exercise to have people list those drugs or other substances that worked best for them.
> > >
> >
> > I won't try to go through them all, but my best combination was buprenorphine + methylphenidate. I felt I was in the process of getting on my feet again when the drugs were taken away from me.
> >
> > -undopaminergic
>
>
> What property of buprenorphine do you think mitigated your depressive symptoms? What led you to combine the two drugs?
>
> I found this:
>
> "Major Depressive Disorder and Kappa Opioid Receptor Antagonists"
>
> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871611/
>
> Buprenorphine is a partial agonist at the mu opioid receptor and an *antagonist* at the kappa receptor, which could explain the antidepressant properties of buprenorphine. Perhaps you can find another kappa receptor antagonist. I wouldn't know where to look.
>
>
> - Scott

I was largely guided by neuroscience. I think kappa-antagonism was the main factor in my success. (I did enjoy the initial mu-agonism as well.)

I had read abstracts suggesting that the dopamine elevation in the nucleus accumbens from buprenorphine (BUP) plus cocaine was superior to either of them alone, and, interestingly, BUP was as effective as morphine, despite the limited efficacy of BUP at the mu-opioid receptor. Of course, I substituted methylphenidate for cocaine.

I had also read that kappa-antagonism elevated dopamine release in the prefrontal cortex. Perhaps that is why the combination helped my ADHD.

> Perhaps you can find another kappa receptor antagonist. I wouldn't know where to look.
>

David Pearce (author of the Good Drug Guide) has been able to acquire and test JDTic, an orally and centrally active kappa-opioid antagonist. He implied that it did not do much for depression but did have nootropic effects.

Both kappa-agonists and kappa-antagonists reduce the amount of cocaine consumed by rodents. Kappa-antagonists are more effective. I propose that agonists reduce the experience of reward derived from cocaine, and that antagonists prevent the development of tolerance, allowing doses to remain low.

I had also read (or interpreted) that the use of stimulants (eg. cocaine) stimulated dynorphin (the endogenous kappa-agonist), and that dynorphin diminished (downregulated) the expression of direct (dopamine transporter) and indirect (dopamine D2-receptor) targets of the stimulants.

-undopaminergic

 

Re: Tolerance is just so low!! undopaminergic

Posted by SLS on December 28, 2022, at 21:20:47

In reply to Re: Tolerance is just so low!! SLS, posted by undopaminergic on December 28, 2022, at 16:40:08

You make my brain hurt.

What is your impression of zuranolone? Before I hit pay-dirt with my current drug regime, zuranolone was the drug I was most interested in. All I know about it pharmacologically is that it is described as a positive allosteric modulator of GABA-A receptors. Zuranolone works to potentiate GABA-mediated currents. I imagine you know more than me about proposed role of GABA in depression. From what I understand, zuranolone increases the reactivity of GABA-A receptors, thus potentiating GABA currents. How might the stimulation of GABA-A receptors manifest?

In clinical trials, zuranolone was reported by the manufacturer to be effective in treating Major Depressive Disorder, Bipolar Depression and Post-Partum depression. I don't know which indications(s) SAGE Pharmaceuticals will apply for.


- Scott

 

Re: Tolerance is just so low!! SLS

Posted by undopaminergic on December 29, 2022, at 10:34:05

In reply to Re: Tolerance is just so low!! undopaminergic, posted by SLS on December 28, 2022, at 21:20:47

> You make my brain hurt.
>

How so?

> What is your impression of zuranolone? Before I hit pay-dirt with my current drug regime, zuranolone was the drug I was most interested in. All I know about it pharmacologically is that it is described as a positive allosteric modulator of GABA-A receptors. Zuranolone works to potentiate GABA-mediated currents. I imagine you know more than me about proposed role of GABA in depression.
>

I'd say I probably don't. But I am aware that anxiety is often comorbid with depression, and it can "feed" the depression. Ie. the anxiety makes you feel lower. So treating the anxiety with GABAergic drugs (including zuranolone) can ameliorate (part of) the depression.

> From what I understand, zuranolone increases the reactivity of GABA-A receptors, thus potentiating GABA currents. How might the stimulation of GABA-A receptors manifest?
>

Maybe like benzodiazepines?

Benzodiazepines increase the frequency of GABA chloride channel opening, and barbiturates prolongs the opening. Do you know how zuranolone works?

> In clinical trials, zuranolone was reported by the manufacturer to be effective in treating Major Depressive Disorder, Bipolar Depression and Post-Partum depression. I don't know which indications(s) SAGE Pharmaceuticals will apply for.
>
>
> - Scott

I'd be interested in trying it but I'm not particularly excited about it.

-undopaminergic


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