Can we discuss pharmacology here??

Under_Graduate

Well.

Can we??

I'd like to discuss to potential effect dopamine agonism exerted by parkinsons agents on depressive symptoms, as well their counter effect to hyperprolactima.

Am I in the right spot??

Speedwell

I hope so, because I for one would love to be in the spectator's gallery. No, seriously, this is one of the things I'm tangentially interested in.

SOL

Well, that depends really, it could definitely be classified as medicinal chemistry and I would definitely encourage discussion.

On the other hand, may of the dopamine agonist/reuptake inverse agonists are controlled substances and it could definitely stray into areas which would not be suitable for discussion - discussing the synthesis of controlled substances is not acceptable. Also, you should watch out for the possibility of your discussion being interpreted as medical (or legal) advice. But provided you can avoid these problems I would welcome a discussion, I would also be interested in contributing.

Under_Graduate

No no, from what I understand, there is ongoing research regarding the use of cabergoline, pramipexole and bromocriptine, parkinsons agents, as a means to counter sexual dysfunction or improve sexual function generally, due to their dopaminergic activity.
I understand there are subclasses of dopamine, D1 to D5.

Pramipexole apparently having the greatest affinity for D3 agonism, and carrying less cardiotoxicity side effect.

I believe I am right in saying that none of them are controlled substances - as may be the case with the likes of methylphenidate and amphetamines - but their mode of action, I'm not certain of.
Dopaminergic or what?

In terms of side stepping the medical advice obstacle - from my point of view, this is discussion of pharmacological effects of various dopaminergic based drugs, and their implications, and I began looking at it specifically due to their licencing as parkinsons agents, but ongoing research into their potential anti-depressant properties also.
So - take from that what you will, but for me, it's an area of interest.


I was initially drawn to this class, upon understanding that some anti-depressant drugs that induce sexual dysfunction at lower doses, can have this side effect reversed at higher doses, once the dosage range is increased to the point of also affecting the dopamine receptor, in addition to serotonine.
Dopamine agonism acting to alleviate the dysfunction side effect.

The dysfunction may be brought on my the increased prolactin activity in the pituitary, as a result of the anti-depressant drug.
However, somewhat counter intuitively, increasing the dose, for the aforementioned reason, can alleviate this as, dopamine acts to suppress excessive prolactin levels - thus a counter to hyperprolactima.

....

Under_Graduate

The initial drug type that was brought to my attention as a dopamine agonist that had apparently shown AD induced sexual dysfunction relief in clinical trials, was buproprion, marketed in this country as Zyban - a smoking cessation agent, but the active ingredient being the same as Welbutrin, marketed as one of the most popular anti-depressants in the US.

Anyways, often co-prescribed to alleviate induced dysfunction, due to it's activity on dopamine.

Now, despite this claim, there has been speculation that bupropion actually has negligible impact on dopamine, and acts more so on noradrenaline.
I don't know the details.

But the point being, this brought to my attention the fact that dopamine can serve this direct purpose.

Controlled drugs such as Ritalin or methylphenidate are reputed to ameliorate this side effect - again I mentioned, I don't know their mode of action, dopamine or what?

But I was specifically curious about this information, given the fact that the parkinsons agent, Levodopa, L-dopa, acts directly as a dopamine agonist.
Intuitively, wouldn't that also carry an anti-depressant property?

Well, looking into the matter more so, L-dopa was not mentioned, but the aforementioned dopamine agonists, which are licensed as parkinsons agents, were.

Cabergoline - is apparently a first line treatment for hypoprolactima, the reputed cause of SSRI/SNRI induced sexual dysfunction, acting as a repressor to this hormone.


But, having spoken to many pharmacists and doctors etc - they don't seem to know sh1t about this.
Despite the fact that there are a multitude of papers published on this topic.


At higher doses, there is the potential for cardiotoxicity, apparently.

But to treat the sexual dysfunction side effect, starting at the lowest dose, and titrating upwards....


Any thoughts?

Speedwell

I'm very much a layman and can only weakly cite "my case for example", but my therapist in the US was intrigued by the fact that my mother had narcolepsy that responded well to methylphenidate and modafinil (at different times), my brother was diagnosed with ADHD in childhood, and I have Asperger's. All three are characterised by problems with dopamine regulation. When I'm having an "attack" of unmanageable anxiety and depression, I find that a combination of L-theanine, loratadine, magnesium chelate, and folate will relieve the worst of it in about an hour. I'm not crazy; I take all of those things within the recommended over-the-counter dosages, and only once or at most twice to "break" the bad mood. But it's interesting that all of them have some effect on dopamine. None, to the best of my knowledge, are cardiotoxic, even loratadine (uniquely among similar antihistamines). I've been told the first two are often recommended to help with sexual side effects from antidepressants; I see several mentions of loratadine in particular being looked at for treatment of SSRI-induced sexual dysfunction (I don't know the mechanism of action).

I'm not recommending anyone else try this; I spoke of it to my doctor in the US and he saw nothing wrong with it, but that was taking into account my particular health history and status.

Labarbapostiza

Under_Graduate wrote: »

Controlled drugs such as Ritalin or methylphenidate are reputed to ameliorate this side effect - again I mentioned, I don't know their mode of action, dopamine or what?

But I was specifically curious about this information, given the fact that the parkinsons agent, Levodopa, L-dopa, acts directly as a dopamine agonist.
Intuitively, wouldn't that also carry an anti-depressant property?

Well, looking into the matter more so, L-dopa was not mentioned, but the aforementioned dopamine agonists, which are licensed as parkinsons agents, were.

If you've never seen the film Awakenings it's worth seeing. It's based on the true story of Dr Oliver Sachs, who on attending a conference on the use of L-dopa for treating parkinsons suffers, applies it to a ward of patients suffering from encephalitis lethargica (sleeping sickness).

It worked. The patients awoke....but after a while it began to stop working. The patients first developed amphetamine psychosis (the effects of prolonged dopaminergic ), and fell back into their slumber.

And that's where the film ends.

But it's not the end of the story. A cure was found for these patients. Instead of giving them speed, they tried giving them a sleeping pill, and paradoxically they awoke. There is a reason this works, and why the speed initially worked. And it was due to the specific parts of their brain that had been damaged. The speed was ramping the damaged area up performing with the undamaged. But the Ambien worked by suppressing activity on the undamaged functions bringing them into line with the damaged area. For a more technical reference, you might be able to find a lecture online on the specific case. It's an interesting story.

The dopaminergic drugs are generally not prescribed for depression in Ireland due to their abuse potential, and that they can make people psychotic. Cocaine is the original dopaminergic drug used for the treatment of depression. Sigmund Freud took it all his life, and wrote a treatise On Cocaine. It has its' down sides; try reading Freud; he writes like a babbling coke fiend.

Cabergoline - is apparently a first line treatment for hypoprolactima, the reputed cause of SSRI/SNRI induced sexual dysfunction, acting as a repressor to this hormone.


But, having spoken to many pharmacists and doctors etc - they don't seem to know sh1t about this.
Despite the fact that there are a multitude of papers published on this topic.


At higher doses, there is the potential for cardiotoxicity, apparently.

But to treat the sexual dysfunction side effect, starting at the lowest dose, and titrating upwards....


Any thoughts?

That sounds like an interesting drug. In Ireland the medical profession are very conservative in the prescription of treatments that are rated as experimental (they use an English standard I can remember the name of). A Parkinsons specialist or someone in geriatric medicine might know what it is.

Under_Graduate

There is a reason this works, and why the speed initially worked. And it was due to the specific parts of their brain that had been damaged. The speed was ramping the damaged area up performing with the undamaged. But the Ambien worked by suppressing activity on the undamaged functions bringing them into line with the damaged area. For a more technical reference, you might be able to find a lecture online on the specific case. It's an interesting story.

Find a lecture?
Any idea where I'd go looking, a relevant google key word?

That sounds like an interesting drug. In Ireland the medical profession are very conservative in the prescription of treatments that are rated as experimental (they use an English standard I can remember the name of). A Parkinsons specialist or someone in geriatric medicine might know what it is.

Yes, apparently so, but it's first line treatment in US for hyperprolactima, SNRI induced hyper levels of prolactin giving rise to sexual dysfunction.

Not widely prescribed here, which makes it more difficult to get a script for.

Pramipexole however, is used to treat restless leg syndrome.
This has also shown potent anti-depressant properties, being a dopaminergic.

Labarbapostiza

Under_Graduate wrote: »

Find a lecture?
Any idea where I'd go looking, a relevant google key word?

I can't think of one of the top of my head, but I've heard the story given several different talks. You should be able to find some version of the story somewhere. If you read up on the treatment of encephalitis lethargica with Ambien, the sleeping pill, you should be able to find the details.

Yes, apparently so, but it's first line treatment in US for hyperprolactima, SNRI induced hyper levels of prolactin giving rise to sexual dysfunction.

Not widely prescribed here, which makes it more difficult to get a script for.

Pramipexole however, is used to treat restless leg syndrome.
This has also shown potent anti-depressant properties, being a dopaminergic.

In the US they do things differently. The Irish health board follows Britain's NHS' standards. They don't prescribe what they consider to be experimental treatments.

In America the use of "off label" prescribing is more widespread and acceptable. Here, they can be more than a bit nervous about it.

Looking up the detail on Pramipexole, I would put its' antidepressant effectiveness down it being speedy. And the described side effects are pretty much dopamine dysregulation syndrome; tweaking. This is not a kind of drug the health board would like to prescribe. It's actually very hard for doctors to tell the difference between uni-polar depression and bi-polar. If you give this kind of drug to someone with bi-polar, there's a very good chance they'll become psychotic at some stage and do something really crazy. Which will get whoever prescribed them the drug into big trouble.

If you're depressed, and you take speed, you will feel better....for a while.

Under_Graduate

Actually - D2 agonism exerts more of a "slow" effect, and is quite sedating.

In terms of pharmacology - I'd be interested in learning and understanding the comparatives between SNRI's at high doses, and actual tri-cyclics.
Both influencing serotinine and noradrenaline.

Like prozac and zyban conceptualized into one pill.

But - they are reputed to carry significant differences in terms of efficacy.

Why is that?
Can anyone expound on their knowledge surrounding the matter?

Also - in terms of induced sexual dysfunction, is it as a result of the greater serotonine reuptake inhibition specifically, that gives rise to greater incidence of this in SNRI's as oppose to tri-cyclics??

Labarbapostiza

Under_Graduate wrote: »

Actually - D2 agonism exerts more of a "slow" effect, and is quite sedating.

In terms of pharmacology - I'd be interested in learning and understanding the comparatives between SNRI's at high doses, and actual tri-cyclics.
Both influencing serotinine and noradrenaline.

Like prozac and zyban conceptualized into one pill.

But - they are reputed to carry significant differences in terms of efficacy.

Why is that?
Can anyone expound on their knowledge surrounding the matter?

The simple answer is, it's just not that simple. Issues of mental health are quite complex. How people actually react to the drugs also varies on an individual basis. This leads to clinical trials where the efficacy of a drug may be deemed to be ineffective, when it may in fact be effective, but just among a limited population. It's hard for a medical professional to tell if someone is genuinely depressed, and then to distinguish mono-polar from bi-polar depression. If you give a powerful antidepressant to someone who is not depressed, they can have a bad reaction, a way they have of telling that a person is genuinely depressed is how they react to the medication. Bi-polars have a dysregulation of their brain chemistry. Antidepressants can make them worse exacerbating the manic phase. And then you have schizophrenia and personality disorders, of which depression can be a feature.

Also - in terms of induced sexual dysfunction, is it as a result of the greater serotonine reuptake inhibition specifically, that gives rise to greater incidence of this in SNRI's as oppose to tri-cyclics??

I believe the most common reason given by people for discontinuing a course of antidepressants, is sexual dysfunction. What is actually happening in the initial loading phase is very complicated. The experience can be profound and disturbing. That distraction in itself is likely to lead to sexual dysfunction. But, there's also another question here; if someone is able to have sex before taking an antidepressant, how depressed can they actually be. One of the symptoms of depression is a loss of interest in sex. I believe many people mistake stress and anguish they experience due life events as being depression. They're not.

Speedwell

Labarbapostiza wrote: »

The simple answer is, it's just not that simple. Issues of mental health are quite complex....

I believe the most common reason given by people for discontinuing a course of antidepressants, is sexual dysfunction. What is actually happening in the initial loading phase is very complicated. The experience can be profound and disturbing. That distraction in itself is likely to lead to sexual dysfunction. But, there's also another question here; if someone is able to have sex before taking an antidepressant, how depressed can they actually be. One of the symptoms of depression is a loss of interest in sex. I believe many people mistake stress and anguish they experience due life events as being depression. They're not.

It depends what kind of depression you have, how it manifests chemically in your body and brain. No, all genuinely depressed people do not lose interest in sex. Sometimes it's all that feels good in a world that doesn't feel good. Sometimes, even if you partially lose interest in sex, you have a non-depressed partner who still wants to keep that part of your relationship going because, you know, healthy people have a healthy interest in sex, and when they initiate, you have no particular objection.

Labarbapostiza

Speedwell wrote: »

It depends what kind of depression you have, how it manifests chemically in your body and brain. No, all genuinely depressed people do not lose interest in sex. Sometimes it's all that feels good in a world that doesn't feel good. Sometimes, even if you partially lose interest in sex, you have a non-depressed partner who still wants to keep that part of your relationship going because, you know, healthy people have a healthy interest in sex, and when they initiate, you have no particular objection.

I know. The thing is "depression" is a word. It varies in severity. Some people lose the ability to do the most basic functions, like eating. And it's not always the same thing. But that's a kind of long discussion in itself.

Under_Graduate

Speedwell wrote: »

It depends what kind of depression you have, how it manifests chemically in your body and brain. No, all genuinely depressed people do not lose interest in sex. Sometimes it's all that feels good in a world that doesn't feel good. Sometimes, even if you partially lose interest in sex, you have a non-depressed partner who still wants to keep that part of your relationship going because, you know, healthy people have a healthy interest in sex, and when they initiate, you have no particular objection.

I'm gonna have to quote this for truth.

The previous assertion that this quote was a response to, contradicting the possible presence of depression based on the fact that one may continue their engaging in sexual activity - IMO - is woefully flawed and narrow minded.

The above bolded text, hits the nail, on the head.
Something I have seen in many people.

Sexual activity can be the sole form of pleasure and relief available to those who - can't eat, can't sleep, can't function etc.
Though - it definitely detracts from the quality of the activity, partners enjoyment etc - it's still a relief.
So no - continued participation in and enjoyment of sexual activity, is most certainly not indicative of a patient whose symptoms do not stem from depression.

Under_Graduate

Also - the use of SAMe with 5-HTP, whilst apparently not a widely used counter to low mood induced by receptor imbalance, is seemingly a very effective one according to material i've been going over recently.

Has anyone heard of this??

Speedwell

Under_Graduate wrote: »

Also - the use of SAMe with 5-HTP, whilst apparently not a widely used counter to low mood induced by receptor imbalance, is seemingly a very effective one according to material i've been going over recently.

Has anyone heard of this??

I did it. Gave myself a mild and temporary case of serotonin syndrome because, whatever is wrong with me, it is not a lack of serotonin.

I tried telling my escitalopram-happy ex-psychiatrist back in the US that, and asked for a different medication. You'd think I called his mother a whore. How dare I know more about my body than someone who met me less than an hour ago. I refused to take the medication and he refused to treat me, which is fine with me.

Labarbapostiza

Under_Graduate wrote: »

Also - the use of SAMe with 5-HTP, whilst apparently not a widely used counter to low mood induced by receptor imbalance, is seemingly a very effective one according to material i've been going over recently.

Has anyone heard of this??

I think the problem with 5-HTP is it metabolises too fast. Effective medicines generally require a kind of consistent level in the blood over a reasonable period. I can say anecdotally, that people use it to get relief when they're stepping down from an antidepressant, and they're having an uncomfortable reaction. But the effect is short lived.

On the issue of people having sex or not, if they're depressed. If they're not, when they do have the option, that's a strong sign of depression. If they are, it generally doesn't mean they are not depressed. But, this gets very complicated. Limiting the discussion to depression as a result of a chemical deficiency for the sake of discussion is worthwhile, as when depression is wrapped up in other complexities; a schizophrenic may be depressed because they have schizophrenia. A person with a personality disorder may have depression because their personality disorder is traumatising in itself.

It's also possible for people to be severely depressed without realising it.

Back to the chemistry.

There are known issue with both the serotoningenic and dopaminergic drugs. There is another interesting approach; Melatonergic drugs. Which works on the melatonin receptors. Agomelatine is one of these drugs, I don't know if any more are on the market.

Under_Graduate

It's also possible for people to be severely depressed without realising it.

Yeah tell me about it.
Strictly endogenous - completely baffling.

I've read conflicting reports regarding agomelatine - that it carries only weak AD properties, but it's good for sleep.
Then there's the issue of liver toxicity with it.

Comparing the likes of duloxotine with venlafaxine - they have similarly efficacy reports, though the ratio of nor-adrenaline reuptake inhibition is quite different, duloxotine being significantly stronger.

In terms of the use of 5-HTP, I was under the impression that was kind of like, used as an augmentation strategy whilst taking SAM-e.
Conflicting reports regarding the efficacy of this combination, but one acquaintance studying neuroscience, absolutely sweared by it's potency, in particular using methycobalamin, pryridoxal phosphate, and l 5 methylfolate , as well as N-Acetyl L-Tyrosine, dramatically increasing it's mood enhancing potential efficacy.

Under_Graduate

http://mentalhealthdaily.com/2014/08/18/tricyclic-antidepressants-list-tcas/#comment-125229

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