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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 125 to 149 of 317. Go back in thread:
Posted by sigismund on January 28, 2012, at 19:27:24
In reply to Re: Adding Parnate and prazosin. » Phillipa, posted by SLS on January 28, 2012, at 5:31:11
Scott, can you explain something for me?
The ADs you have taken have increased NE (so to speak) and the prazosin blocks it (or something like that).
It just seems back the front, if you see what I mean.
Posted by Phillipa on January 28, 2012, at 21:04:29
In reply to Re: Adding Parnate and prazosin. » SLS, posted by sigismund on January 28, 2012, at 19:27:24
Sigi are you saying that the combo of two are normalizing Scotts brain back to what it was before MDD? PJx
Posted by SLS on January 29, 2012, at 6:41:52
In reply to Re: Adding Parnate and prazosin. » SLS, posted by sigismund on January 28, 2012, at 19:27:24
> Scott, can you explain something for me?
Probably not, but I'll try.
> The ADs you have taken have increased NE (so to speak) and the prazosin blocks it (or something like that).
Yes. Prazosin blocks NE alpha-1 receptors.
> It just seems back the front, if you see what I mean.
Yes. That's why I don't pay too much attention to theories anymore when it comes to choosing drugs for treatment. Theories are sometimes valuable to include drugs for consideration, but not for their exclusion.
I offered my doctor one possible explanation in an email I sent him:
"It occurred to me that prazosin might quiet those neurons that are observed to be hyperactive in cingulate cortex (Brodmann areas 24, 25) in indviduals with MDD. If so, it would effectively mimic DBS."
This is really nothing more than a wild guess for which I have little evidence to support. However, NE alpha-1 receptors do exist in the regions I specified.
- Scott
Posted by SLS on January 29, 2012, at 14:03:49
In reply to Re: Adding Parnate and prazosin. » Phillipa, posted by SLS on January 28, 2012, at 5:31:11
> One thing nice - I was able to read two entire Scientific American articles and comprehend them. I haven't had that kind of mental focus in over ten years.
Actually, it has been over thirty years since I was last able to read unimpaired. By 1980, I had to drop out of college because I could no longer read, learn, or remember. I had a six-month reprieve in 1987 during which I was able to read. I read a good book on physics called "Dance of the Wu Li Masters". Then, in 1998, I experienced a few days of improved cognitive function. Of course, I wasted them by reading about pindolol augmentation of SSRIs in the American Journal of Psychiatry. I could have instead better spent the time reading the articles in Playboy.
While we are on the subject, I have experienced a noticeable decrease in my sex-drive. I am pretty sure that it is the prazosin that is responsible for this. It seems to be a common side effect of this drug. Remission is worth the trade-off, though. Even a 50% improvement is worth the trade-off.
It's always something.
- Scott
Posted by Phillipa on January 29, 2012, at 18:34:45
In reply to Re: Adding Parnate and prazosin., posted by SLS on January 29, 2012, at 14:03:49
Scott and to me to put into perspective more the what if thoughts say what if you had cancer of the prostrate and the treatment took away your ability to engage in sex. Would you die rather than get treated? Just my thoughts on the subject. Phillipa
Posted by SLS on January 31, 2012, at 0:31:09
In reply to Re: Adding Parnate and prazosin. » SLS, posted by Phillipa on January 29, 2012, at 18:34:45
After experiencing diminishing returns with treatment for the past two weeks, I have come to the conclusion that my discontinuation of Abilify is responsible for this diminution of response.
I would prefer to not take Abilify because it raises my triglycerides level to over 400 mg/dL and keeps me 50 pounds overweight. I might try Latuda first before returning to Abilify.
- Scott
Posted by Bob on January 31, 2012, at 0:34:46
In reply to Re: Adding Parnate and prazosin., posted by SLS on January 31, 2012, at 0:31:09
> After experiencing diminishing returns with treatment for the past two weeks, I have come to the conclusion that my discontinuation of Abilify is responsible for this diminution of response.
>
> I would prefer to not take Abilify because it raises my triglycerides level to over 400 mg/dL and keeps me 50 pounds overweight. I might try Latuda first before returning to Abilify.
>
>
> - Scott
I wonder if Abilify will prove to have just as much of a weight problem as Zyprexa in the long term. My sister is currently on a low dose and has gained over 20 lbs in about 2 months. She is very unhappy about it.
Posted by SLS on January 31, 2012, at 1:04:07
In reply to Re: Adding Parnate and prazosin. » SLS, posted by Bob on January 31, 2012, at 0:34:46
> > After experiencing diminishing returns with treatment for the past two weeks, I have come to the conclusion that my discontinuation of Abilify is responsible for this diminution of response.
> >
> > I would prefer to not take Abilify because it raises my triglycerides level to over 400 mg/dL and keeps me 50 pounds overweight. I might try Latuda first before returning to Abilify.
> >
> >
> > - Scott
>
>
> I wonder if Abilify will prove to have just as much of a weight problem as Zyprexa in the long term. My sister is currently on a low dose and has gained over 20 lbs in about 2 months. She is very unhappy about it.
My observations with Abilify are that the onset of weight gain is latent and insidious. There doesn't seem to be a plateau of effect, one just keeps gaining. Weight gain was not observed with clinical trials of Abilify because the subjects were not followed for long enough. The same thing happened with Prozac.Portion control helps.
- Scott
Posted by SLS on February 5, 2012, at 9:55:02
In reply to Re: Adding Parnate and prazosin. » Bob, posted by SLS on January 31, 2012, at 1:04:07
> > > After experiencing diminishing returns with treatment for the past two weeks, I have come to the conclusion that my discontinuation of Abilify is responsible for this diminution of response.
> > >
> > > I would prefer to not take Abilify because it raises my triglycerides level to over 400 mg/dL and keeps me 50 pounds overweight. I might try Latuda first before returning to Abilify.Well, Latuda did not produce acceptable results. At 40 mg, it did not produce a satisfactory antidepressant response, and it left me feeling cognitively numb and in a "brain-fog". Still, I believe that Latuda will help some people with depression. Researchers are looking closely at 5-HT7 receptor antagonism and its antidepressant effects. Latuda does this. Some people may not need the D2/D3 partial agonism of Abilify, in which case, Latuda might be a good choice for its lack of metabolic side effects.
I restarted Abilify at 10 mg few days ago, and I am beginning to recapture an antidepressant response.
Currently:
Parnate 80 mg
nortriptyline 150 mg
Lamictal 200 mg
Abilify 10 mg
lithium 300 mg
prazosin 6 mgIt pisses me off that I need to take so many drugs, but beggars can't be choosers.
- Scott
Posted by ed_uk2010 on February 5, 2012, at 13:31:00
In reply to Re: Adding Parnate and prazosin., posted by SLS on February 5, 2012, at 9:55:02
>Latuda did not produce acceptable results.
I'm sorry to hear that. It's good that you tried it though. Have you tried asenapine Scott? I don't recall.
Posted by SLS on February 5, 2012, at 15:18:19
In reply to Re: Adding Parnate and prazosin. » SLS, posted by ed_uk2010 on February 5, 2012, at 13:31:00
> >Latuda did not produce acceptable results.
>
> I'm sorry to hear that. It's good that you tried it though. Have you tried asenapine Scott? I don't recall.Yes, I tried asenapine. It didn't help, but it seemed like a rather benign drug, otherwise. I remained on Abilify while taking it, though. I can't be sure that asenapine would not have been an effective substitute for Abilify. I wasn't looking for a substitute back then, though. If I had responded amazingly well to asenapine, I would then have attempted to discontinue Abilify.
I am pretty sure that it is the dopamine D2/D3 receptor partial agonist properties of Abilify that is responsible for its beneficial effects on me. Abilify is unique in this regard, so I guess I'm stuck with it. There is a compound, OPC-34712, currently under investigation as an antidepressant that is a D2 receptor partial agonist. However, it is without effect on D3 receptors. I think partial agonism at both receptors is important to produce an antidepressant effect. I hope not, though. It would be great if OPC-34712 turned out to be an effective substitute for Abilify without increasing my triglyceride and producing weight gain.
- Scott
Posted by papillon2 on February 5, 2012, at 16:49:07
In reply to Re: Adding Parnate and prazosin. » ed_uk2010, posted by SLS on February 5, 2012, at 15:18:19
Sorry to hear it didn't have a better outcome.
Posted by ed_uk2010 on February 5, 2012, at 17:57:45
In reply to Re: Adding Parnate and prazosin. » ed_uk2010, posted by SLS on February 5, 2012, at 15:18:19
>I think partial agonism at both receptors is important to produce an antidepressant effect.
What is the role of D3 receptors in depression?
Also, does Fanapt have a role in mood disorders? I'm not very familiar with this drug at all.
Posted by SLS on February 5, 2012, at 21:53:01
In reply to Re: Adding Parnate and prazosin. » SLS, posted by ed_uk2010 on February 5, 2012, at 17:57:45
> >I think partial agonism at both receptors is important to produce an antidepressant effect.
>
> What is the role of D3 receptors in depression?D3 receptors occur in limbic structures such as the nucleus accumbens, a region that mediates reward, pleasure, and drive. Dysfunction here is thought to be responsible for anhedonia.
"and a D2/D3 dopamine receptor agonist exhibits antidepressant-like effects in numerous depression models including learned helplessness paradigm and chronic mild stress model [104]. Moreover, it has been reported that stimulation of D2/3 dopamine receptors, but not of the D4 dopamine receptor, exhibits an antidepressant-like effect in the forced swimming test [12]"
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475798/
DBS in the nucleus accumbens reduces depression.
"We demonstrate antidepressant and antianhedonic effects of DBS to NAcc in patients suffering from TRD."
http://www.ncbi.nlm.nih.gov/pubmed/19914605
> Also, does Fanapt have a role in mood disorders? I'm not very familiar with this drug at all.
I tried Fanapt (iloperidone), but I didn't like it for some reason. I don't remember why. Looking at its binding profile, I see that Fanapt acts like prazosin at the NE alpha-1 receptor. Interesting.
http://www.ncbi.nlm.nih.gov/pubmed/11750183
- Scott
Posted by g_g_g_unit on February 6, 2012, at 4:44:29
In reply to Re: Adding Parnate and prazosin. » ed_uk2010, posted by SLS on February 5, 2012, at 21:53:01
> > >I think partial agonism at both receptors is important to produce an antidepressant effect.
> >
> > What is the role of D3 receptors in depression?
>
> D3 receptors occur in limbic structures such as the nucleus accumbens, a region that mediates reward, pleasure, and drive. Dysfunction here is thought to be responsible for anhedonia.
>Are you aware whether most standard anti-depressants will agonize D3 receptors? Is this something MAOIs are capable of?
Posted by SLS on February 6, 2012, at 6:20:33
In reply to Re: Adding Parnate and prazosin. » SLS, posted by g_g_g_unit on February 6, 2012, at 4:44:29
> > > >I think partial agonism at both receptors is important to produce an antidepressant effect.
> > >
> > > What is the role of D3 receptors in depression?
> >
> > D3 receptors occur in limbic structures such as the nucleus accumbens, a region that mediates reward, pleasure, and drive. Dysfunction here is thought to be responsible for anhedonia.
> >
>
> Are you aware whether most standard anti-depressants will agonize D3 receptors? Is this something MAOIs are capable of?An MAOI might act to help neurons release more dopamine and thus stimulate more D3 receptors.
Two antiparkinson drugs are full agonists at both D2 and D3 receptors. They are pramipexole (Mirapex) and ropinerole (Requip). They are used for depression, but I question their usefulness. They help with restless legs as well.
There is only one drug that acts as a partial agonist at D2 and D3 receptors. This is aripiprazole (Abilify). Partial agonism, compared to full agonism, probably produces a more balanced stimulation of postsynaptic dopamine neurons. I think full agonists tend to poop-out and are liable to produce sedation or "sleep-attacks". Abilify has proven itself out in the field. In my opinion, the full agonists have not.
My depression is remitting little by little. I have not yet reached the same degree of improvement that I had before attempting to discontinue Abilify. I have lost 3-4 weeks as a setback for the time I did not take Abilify. I need to recover the lost ground. I have tried every one of the AAPs with the exception of clozapine (Clozaril). Abilify is the only one that produces a persistent antidepressant effect. I even tried Latuda before returning to Abilify. It was unsatisfactory. Abilify, with its unique D2/D3 partial agonism, is thus a necessary component to my successful treatment. (It is still early in treatment, and success is far from guaranteed, but I tend to be an optimist). The good news is that a new drug, OPC-34712, is a novel D2/D3 receptor partial agonist under investigation for depression. I hope it comes to market. I think it is currently in Phase II. Perhaps this drug won't raise my triglycerides to the extreme levels that Abilify does.
- Scott
Posted by ed_uk2010 on February 6, 2012, at 6:31:13
In reply to Re: Adding Parnate and prazosin. » ed_uk2010, posted by SLS on February 5, 2012, at 21:53:01
Thanks for the information Scott.
>I see that Fanapt acts like prazosin at the NE alpha-1 receptor. Interesting.
A large number of psych meds are alpha-1 blockers, especially TCAs and many APs (both old and new). This can cause orthostatic hypotension, dizziness and fainting/syncope. Alpha-1 antagonism isn't often thought of as a positive feature of psych meds, but I suppose it could be in some cases.
Posted by SLS on February 6, 2012, at 7:40:25
In reply to Re: Adding Parnate and prazosin. » SLS, posted by ed_uk2010 on February 6, 2012, at 6:31:13
> Thanks for the information Scott.
>
> >I see that Fanapt acts like prazosin at the NE alpha-1 receptor. Interesting.
>
> A large number of psych meds are alpha-1 blockers, especially TCAs and many APs (both old and new). This can cause orthostatic hypotension, dizziness and fainting/syncope. Alpha-1 antagonism isn't often thought of as a positive feature of psych meds, but I suppose it could be in some cases.I think it depends on the subtype of NE alpha-1 receptor that occurs in the brain compared to peripherally. TCA probably does not hit the right receptors in the brain.
"More recently, three subtypes of the alpha1-receptor, the alpha1A, alpha1B and alpha1D have been isolated, cloned and characterized"
http://www.mc.uky.edu/pharmacology/instruction/pha824ar/pha824ar.html
"Prazosin antagonizes phenylephrine (alpha1 agonist)-induced contractions, in vitro, and binds with high affinity to the alpha1c adrenoceptor, which is thought to be the predominant functional type in the prostate."
* Note: The NE alpha-1c receptor has been renamed to NE alpha-1d.
* Note: Prazosin is non-selective and hits all NE alpha-1 receptor subtypes, albeit with differing binding affinities.
http://www.drugbank.ca/drugs/DB00457
For a review:
http://www.nature.com/mp/journal/v8/n7/full/4001351a.html
- Scott
Posted by Phillipa on February 6, 2012, at 18:36:46
In reply to Re: Adding Parnate and prazosin. » g_g_g_unit, posted by SLS on February 6, 2012, at 6:20:33
Scott in all sincerity an old poster from here now fully recovered but still taking low doses of meds recovered with his main med requip. Back to opening his law practice. Married with a child now also. So requip for him took is depression possibly bipolar and worked for him. I think he also takes a low dose of an AAP used to zyprexa. Think still is with a minute amount of desipramine. FYI only Phillipa
Posted by SLS on February 6, 2012, at 21:04:47
In reply to Re: Adding Parnate and prazosin. » SLS, posted by Phillipa on February 6, 2012, at 18:36:46
> Scott in all sincerity an old poster from here now fully recovered but still taking low doses of meds recovered with his main med requip. Back to opening his law practice. Married with a child now also. So requip for him took is depression possibly bipolar and worked for him. I think he also takes a low dose of an AAP used to zyprexa. Think still is with a minute amount of desipramine. FYI only Phillipa
Thanks for the information. It's nice to hear success stories.
- Scott
Posted by ed_uk2010 on February 7, 2012, at 10:24:22
In reply to Re: Adding Parnate and prazosin. » ed_uk2010, posted by SLS on February 6, 2012, at 7:40:25
>TCA probably does not hit the right receptors in the brain.
I'm not sure, I need to get my head around the different subtypes.
>Note: The NE alpha-1c receptor has been renamed to NE alpha-1d.
I'm a bit confused about this. I keep reading that the alpha-1a subtype was formerly classified as alpha-1c.
Posted by ed_uk2010 on February 7, 2012, at 11:08:07
In reply to Re: Adding Parnate and prazosin. » ed_uk2010, posted by SLS on February 6, 2012, at 7:40:25
I just had a look in one of my textbooks. It says 'The alpha-1c designation has been removed due to an unfortunate confusion in the literature'.
It seems that alpha-1a and alpha-1b receptors are both found in the brain, but have a different distribution. The alpha-1d is a novel receptor found in the rat aorta.
Alpha-1a is the major alpha receptor in the prostate, and partially selective antagonists such as tamsulosin are widely used for BPH. Lower affinity for alpha-1b apparently equals fewer hypotensive adverse effects.
I wasn't able to find anything about the subtype selectivity of TCAs at alpha receptors. They are generally described vaguely as alpha-1 antagonists. I suspect they are not very selective.
Posted by SLS on February 7, 2012, at 13:01:27
In reply to Re: Adding Parnate and prazosin. » SLS, posted by ed_uk2010 on February 7, 2012, at 10:24:22
Research on the NE alpha-1 receptor subtypes is limited.
However...
NE alpha-1b: Brain cortex (including frontal), hippocampus, and amygdala
TCA = Potent NE alpha-1a; NE alpha-1d
TCA = Weak NE alpha-1bMy guess is that TCA does not effectively antagonize enough brain NE alpha-1b receptors to modulate brain monoaminergic neurotransmission. It just doesn't hit the right spots. NE alpha-1b receptors are known to be impaired in depression.
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http://www.ncbi.nlm.nih.gov/pubmed/20363235
"Amitriptyline, nortriptyline and imipramine are much weaker antagonists of rat and human alpha(1B)-adrenoceptors than of alpha(1A)- and alpha(1D)-adrenoceptors. The differential affinities for these receptors indicate that the alpha(1)-adrenoceptor subtype which activation is most increased by the augmented noradrenaline availability resultant from the blockade of neuronal reuptake is the alpha(1B)-adrenoceptor. This may be important for the behavioural effects of these drugs."
----------------------------------------------------------------------
http://www.nature.com/npp/journal/v28/n8/full/1300222a.html
"Currently, most basic and clinical research on depression is focused on either central serotonergic, noradrenergic, or dopaminergic neurotransmission as affected by various etiological and predisposing factors. Recent evidence suggests that there is another system that consists of a subset of brain alpha1B-adrenoceptors innervated primarily by brain epinephrine (EPI) that potentially modulates the above three monoamine systems in parallel and plays a critical role in depression."
"Binding affinities were obtained from the literature by computing the average of all published values (311 studies) for these antagonists at cloned alpha1A-, alpha1B-, and alpha1D-receptors. The results showed a high and significant correlation for alpha1B (0.89), with none for either the alpha1A- (0.27) or alpha1D-receptors (0.13). This finding agreed with a previous study that showed that agonists of alpha1B-receptors, but not of alpha1A or alpha1D were effective in the reversal of cataplexy in narcoleptic dogs (Nishino et al, 1993)."
"New behavioral and neuropharmacological evidence has implicated a subgroup of brain alpha1B-adrenoceptors as a key factor in positively motivated behavioral activity. Most of these 'motoric' alpha1-receptors are located in or close to monoamine-containing neuron cell bodies (NE and 5HT) or their terminal targets (nucleus accumbensDA) and appear to receive EPI as their neurotransmitter. It is speculated that this 'EPI-innervated-alpha1-system' activates behavior by producing a coordinated excitation of the major monoaminergic systems of the brain. There is evidence that this system is impaired or inhibited in depressive illness from the findings of low levels of EPI in the CSF and of altered responsiveness of brain alpha1-receptors in depressed patients. There is also evidence that its impairment may facilitate CNS brain atrophic effects in depression as it is linked to growth factor induction and MAPK activation. As a number of antidepressant agents are capable of restoring or enhancing its function, the EPI-alpha1-system would appear to represent a new target for this illness."
----------------------------------------------------------------------
I still haven't figured out how prazosin modulates monoamine tracts via NE alpha-1b receptors. However, it is a wild guess of mine that prazosin might reduce the activity of NE neurons along the brain subgenual cingulate cortex (Brodmann Area 25), a region known to be hyperactive in depression. If so, then prazosin might mimic the action of DBS in that area.
Of course, I would love to have prazosin be a wonder drug for more people with depression, but I am not ready to recommend it generally. I hope a few people read this stuff and decide to try prazosin. It would be interesting to see a few more guinea pigs get well with it.
I wonder if the anti-PTSD properties of prazosin are due to its blocking the NE alpha-1b receptors in the amygdala. Maybe I should look into that.
- Scott
Posted by SLS on February 7, 2012, at 13:14:14
In reply to Re: Adding Parnate and prazosin. » ed_uk2010, posted by SLS on February 7, 2012, at 13:01:27
> NE alpha-1b: Brain cortex (including frontal), hippocampus, and amygdala
Important: I forgot to list the nucleus accumbens.
How silly of me.
- Scott
Posted by sigismund on February 7, 2012, at 13:45:12
In reply to Re: Adding Parnate and prazosin. » ed_uk2010, posted by SLS on February 7, 2012, at 13:01:27
Scott, what was it that made you think of trying prozasin?
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Dr. Bob is Robert Hsiung, MD,
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