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Dr. Bob is Robert Hsiung, MD,
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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.
----------------------------------------------------------------------
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?
Posted by SLS on February 7, 2012, at 15:20:01
In reply to Re: Adding Parnate and prazosin. » SLS, posted by sigismund on February 7, 2012, at 13:45:12
> Scott, what was it that made you think of trying prozasin?
It was a stroke of brilliance on the part of my doctor. I would not have thought of it myself.
- Scott
Posted by SLS on February 7, 2012, at 16:04:56
In reply to Re: Adding Parnate and prazosin., posted by SLS on February 7, 2012, at 13:14:14
PTSD and the amygdala:
http://www.ptsd.va.gov/professional/pages/pharmacological-treatment-acute-stress.asp
"In PTSD, the normal checks and balances on amygdala activation have been impaired, so that the restraining influence on the amygdala of the medial prefrontal cortex (PFC, especially the anterior cingulate gyrus and orbitofrontal cortex) is severely disrupted (2,3). Disinhibition of the amygdala produces a vicious spiral of recurrent fear conditioning, in which ambiguous stimuli are more likely to be appraised as threatening; mechanisms for extinguishing such responses are nullified; and key limbic nuclei are sensitized, thereby lowering the threshold for fearful reactivity (2, 4-6)"
Perhaps prazosin would compensate for the PTSD-induced sensitization and thereby reduce anxiety.
- Scott
Posted by sigismund on February 7, 2012, at 17:33:15
In reply to Re: Adding Parnate and prazosin., posted by SLS on February 7, 2012, at 16:04:56
>Disinhibition of the amygdala produces a vicious spiral of recurrent fear conditioning
Right. That could be me.
Years ago Firebreather appeared on the alternative board talking about the benefits of eating pure capsaican for this reason.
There have been a few surprises lately. Hearing that Baclofen was as good as Nardil was a surprise.
Posted by ed_uk2010 on February 8, 2012, at 6:44:30
In reply to Re: Adding Parnate and prazosin. » ed_uk2010, posted by SLS on February 7, 2012, at 13:01:27
>TCA = Potent NE alpha-1a; NE alpha-1d
>TCA = Weak NE alpha-1b
>
> My 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.If 1b receptors are known to be impaired in depression, would blocking them be a good thing? Perhaps 1b antagonists are useful in PTSD but not depressive illness? In clinical trials, prazosin often causes a lack of energy and weakness, and less commonly depressive symptoms and nervousness.
Posted by ed_uk2010 on February 8, 2012, at 7:59:45
In reply to Re: Adding Parnate and prazosin. » SLS, posted by sigismund on February 7, 2012, at 17:33:15
>There have been a few surprises lately. Hearing that baclofen was as good as Nardil was a surprise.
As good for what Sigi? Baclofen is mainly used for muscle spasticity, especially in MS, for all the good it does.
Posted by SLS on February 8, 2012, at 10:20:34
In reply to Re: Adding Parnate and prazosin. » SLS, posted by ed_uk2010 on February 8, 2012, at 6:44:30
> >TCA = Potent NE alpha-1a; NE alpha-1d
> >TCA = Weak NE alpha-1b
> >
> > My 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.> If 1b receptors are known to be impaired in depression, would blocking them be a good thing?
I don't know.
It would probably depend upon the function of the circuits that the NE alpha-1b receptor-innervated neurons modulate.
> Perhaps 1b antagonists are useful in PTSD but not depressive illness?
I have depression (probably bipolar). For me, prazosin is making a significant improvement in depression. It "feels" like a potent and clean antidepressant rather than an anxiolytic. It might depend on what were the psychosocial inducers of the depression. If abuse or neglect were conditions extant during childhood, prazosin might work specifically for the type of depression that results. Who knows? Maybe its antidepressant effects are more generalized. That would be nice. The question is: What are the antidepressants that prazosin best augments.
> In clinical trials, prazosin often causes a lack of energy and weakness,
Yup. These are well known side effects seen in general usage. They generally dissipate over time. I experienced these side effects during the first two or three weeks. They have disappeared completely. Unfortunately, prazosin can also reduce sex-drive, although it is now returning to some degree.
- Scott
Posted by SLS on February 8, 2012, at 10:29:34
In reply to Re: Adding Parnate and prazosin. » sigismund, posted by ed_uk2010 on February 8, 2012, at 7:59:45
> > There have been a few surprises lately. Hearing that baclofen was as good as Nardil was a surprise.
> As good for what Sigi? Baclofen is mainly used for muscle spasticity, especially in MS, for all the good it does.
Baclofen is another drug that is being investigated for the treatment of PTSD as well as panic disorder. With PTSD, baclofen relieves attendant anxiety and depression.
- Scott
Posted by sigismund on February 8, 2012, at 13:38:33
In reply to Re: Adding Parnate and prazosin. » sigismund, posted by ed_uk2010 on February 8, 2012, at 7:59:45
>As good for what Sigi?
Whoever it was didn't say. I assumed social anxiety or depression. Recently.
Posted by ed_uk2010 on February 8, 2012, at 13:39:02
In reply to Re: Adding Parnate and prazosin. » ed_uk2010, posted by SLS on February 8, 2012, at 10:20:34
>It "feels" like a potent and clean antidepressant
That's great. Are you going to try a higher dose?
Posted by ed_uk2010 on February 8, 2012, at 13:40:20
In reply to Re: Adding Parnate and prazosin. » ed_uk2010, posted by SLS on February 8, 2012, at 10:29:34
>Baclofen is another drug that is being investigated for the treatment of PTSD as well as panic disorder. With PTSD, baclofen relieves attendant anxiety and depression.
I've heard of it being used in alcohol dependence, but it's not popular.
Posted by SLS on February 8, 2012, at 13:52:33
In reply to Re: Adding Parnate and prazosin. » SLS, posted by ed_uk2010 on February 8, 2012, at 13:39:02
> >It "feels" like a potent and clean antidepressant
>
> That's great. Are you going to try a higher dose?
You know, I hadn't even thought to do that. Duh. I was so preoccupied with the Abilify thing. My main concern would be dizziness, which I am experiencing now. It is tolerable for the most part. Considering that I am on both Parnate and prazosin, that's not too bad.I see my doctor in two weeks. I'll discuss my prazosin dosage then.
Thank you for your input, Ed. You have a talent for making objective observations and drawing logical conclusions.
- Scott
Posted by ed_uk2010 on February 8, 2012, at 13:57:31
In reply to Re: Adding Parnate and prazosin. » ed_uk2010, posted by SLS on February 8, 2012, at 13:52:33
>My main concern would be dizziness, which I am experiencing now. It is tolerable for the most part. Considering that I am on both Parnate and prazosin, that's not too bad.
How much prazosin are you taking now? If your BP drops when you stand up, it might be useful to increase your salt/fluid intake.
>You have a talent for making objective observations and drawing logical conclusions.
Thanks! You have a talent for neuroscience, and eloquent writing :)
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