Future Development Of New Psychopharmacological Treatments Of Depression

[nabollocks]

The major lesson to be learned from the history of modern sychopharmacology is that medicinal chemists and pharmacologists can synthesize and test new chemicals once a new therapeutic lead becomes available, sufficient to motivate a pharmaceutical company to make the financial investment to develop a patentable drug. Molecular manipulation to obtain a me-too drug can produce new therapeutic leads once the agent is introduced into human medicine. It is the task of the astute clinician to observe carefully the response of the patient, especially when given a new therapeutic agent. Chance identification of the unique therapeutic properties of a new drug may lead to important breakthroughs such as those obtained with chlorpromazine, imipramine, and fluoxetine as modifications of an antihistamine. Variations on any theory of the biochemical abnormality of a given disease are crucial. Although the norepinephrine reuptake theory of the action of tricyclic antidepressants was dominant years ago, because both clinical and pharmacological evidence suggested a role for serotonin eventually led to the development of SSRI, again by molecular modification of an antihistamine. Currently, the role of various neurotransmitters in mood disorders such as norepinephrine (59), dopamine (60), serotonin (61), and acetylcholine (62), as well as neuroendocrinology (63), neuropeptides (64), psychoneuroimmunology (65), biological rhythms (66), and the reproductive cycle (67) is discussed widely. The data indicate that brain, body, and mind relationships are extremely complex in dealing with mood disorders, as is true of most psychiatric disorders. Current knowledge of the biology of mood disorders (68) is ample evidence of mind-body complexities.

The original article can be found here

At present (2008), the Serotonin model for depression still dominates the medical world.

I want to know some of the areas that people think may be targeted in the coming years?

Or have we run out of ideas?

Is the drug industry now rigged in such a way that we can no longer find alternate solutions?

Discuss.

 

[nabollocks]

Well then, let me kick this one off.

I think we may see a return to basics.

I think we may be nearing the end of the antidepressant era as we know it.

Maybe a return to HGH type hormones?

 

[Sturnam]

i think we'll see a ketamine-esk antidepressant. from the few studies i've read of it used on treatment-resistant depression, it works amazingly well. so probably some non-psychoactive NMDA mixed agonists/antagonists. either that or we'll figure out it doesn't work, and find other routes for ketamine's antidepressant action.

that, and i'm hoping SSRE's will become bigger in the US, and maybe more will be developed. from what i've read of tianeptine, it sounds at least a little better and more tolerated than the SSRI's.

 

[Ham-milton]

I think we're gonna see ketamine be the next big antidepressant, too. I only see it being used in psychiatrists office at sub-aneasthetic doses, though- not a take home deal, of course!!

 

[negrogesic]

I certainly agree that NMDA will become more of a target. Also, neurosteroids and sigma agonists could become potential anti-d's. However, I am not sure about ketamine being using in psychiatrists offices, as psychiatrists have become a bit too lazy to do actual "work".

I am particularly curious about what psychiatry will look like in 20-30 years.

 

[nabollocks]

I am particularly curious about what psychiatry will look like in 20-30 years.

This is what I am also interested in.

It seems as though our symptom based treatment approach is coming to an end.

Maybe we will be looking at preventative medicine? Any suggestions here?

If doctors were more prevalent, I could see a return to physical activity and a promotion of self esteem as being a route to pursue. This is where I thought the Human Growth Hormone type drugs would play a big part?

Tianeptine sounds promising, but is more of the same old, just doing it a little better...

I want to hear about new system to target. I think the current model of depression is lacking in so many ways.

 

[negrogesic]

Also, in my opinion, they need to come up with something better than the "forced swim test" when determining the efficacy of antidepressants...

 

[serotonin-system]

^ Tail suspension test?

 

[Sturnam]

maybe we'll figure out more of why DBS works so well. i'm really really interested in that, and the promises it holds for all types of mental disorders. it also seems to open up a completely new area for the treatment of depression, as it seem to only synchronize the firings of neurons, and perhaps by doing that it regulates overactive or underactive (or both) excitement.

maybe depression for each person is slightly different combinations of overactive or underactive firings of neurons of various parts of the brain, and this is why any one antidepressant doesn't work well. thus, the DBS works because it brings both to a even playing field.

 

[nabollocks]

^That is what I am talking about!

We all know how to "supercharge" our brains now... but we still have not worked out what normal is.

Just as a side note: I was talking to a colleague this weekend past about the psychiatric hospital that she works at. She said after a while, the only difference between you and 'them' is that you go home at night. Food for thought.

 

[Sturnam]

hmmmm, that's not a comforting thought. i'd like to believe there's a little more difference between me and a paranoid schizophrenic then a padded wall on our rooms.

preventative medicine for depression? sounds sorta like a drug rep pitch to me....
as it is we already have million of people on antidepressants (in the US) that don't need to be on them. i agree with the exercise routine. that would do wonders for the depression and weight problem (again, US).

i suppose tianeptine is sorta the same old boring, but much less so than another SSRI or SNRI. to me it holds a little more interest because it does the exact opposite of traditional antidepressants, but still works the same or better. but i suppose most of that interest would be because it's challenging our current knowledge of depression, which the whole NMDA thing already does because of it's very quick improvement time. instead of waiting a couple weeks for the lifting depression, one only has to wait a couple hours.

 

[negrogesic]

Tail suspension test, nice...

 

[Hammilton]

looking at that makes me sad.

 

[morphiquet]

Also, in my opinion, they need to come up with something better than the "forced swim test" when determining the efficacy of antidepressants...

agreed, this test is more than ridiculous. i also don't understand why they don't have better ones for evaluating anti-depressant effects, they've got really nice and meaningful ones for anti-anxiety in contrast (like the open-field-test)

regarding new targets for anti-depressants, there are countless.

the most recent one i've read of is activation of the neuropeptide-S-receptor (NPS), supporting motivating and concomitantly anti-anxiety effects, which sounds promising, but as it is a typical g-protein-coupled receptor, it will soon turn out that the effects are short-termed due to receptor endocytosis and tolerance.

on the other side, the former aspect might qualify this receptor as a target for new recreational or mind-boosting substances.

 

[morphiquet]

isn't paris hilton currently propagating cannabidiol market entry? btw, cannabidiol does not act via the cannabinoid-sytem in the brain.

 

[morphiquet]

oh well, nice to be teached the truth by you, obviously i was not up-to-date at this topic

 

[MurphyClox]

maybe depression for each person is slightly different combinations of overactive or underactive firings of neurons of various parts of the brain, and this is why any one antidepressant doesn't work well. thus, the DBS works because it brings both to a even playing field.

I think we're gonna get more specific in the coming years. SSRIs.. MAOIs.. SNRIs.. DNRIs, NRIs, etc., etc., are big time overkill. We don't need to fuck with everything, we just need to stimulate the specific receptors where the problem is present. If we do that we can eliminate the vast majority of side effects from drugs like SSRIs and treat the problem better than they ever could.

I'm convinced that both posters do not understand the complexity of depression in humans (on a molecular level!). Don't get me wrong: This is in no way meant be be offensive!
But: The fact that some antidepressants work with certain depressive people while they fail in others shows us that the differences between the causes of these depressions must be definitively much more complicated.
And FOR SURE it's not just one specific type of receptor that has to be modulated (either turned on or off). If it would be this easy, a cure to most kinds of depression would be at hand for long.

We should not forget that the very complicated origin of such a disease prevented a satisfying cure until now. It's more like doctors just acted "ummm....now lets try this one" and if it fails they switch to another one, and then to another.
I admit, a lot of people get their help but still a huge number has to walk through hell until some amelioration happens. And some even fail before this event and commit suicide.

Therefore, the answer can not be such a simple one as proposed but definitively includes various, by far more complicated means.

Peace! Murphy

 

[nabollocks]

^ This is why we need to be thinking about new ways of treating depression.

You have made a great point about rocknroll714's post and I agree totally.

The problem is that we are fed information, and we believe it. You have to understand that we are only fed the information that people want us to know...

We must start to think outside the square. Afterall, if you had the time to read the article mentioned in the original post, antidepressants were accidentally found whilst trying to make better antihistamines.

 

[Sturnam]

Murphy: i was saying that in reference to the amazing success of DBS in depression, as well as other mental conditions. maybe i'm thinking of it too simply though. would there be more complex downstream effects from synchronizing neuronal firings?
because IIRC the researchers had a little switch to change the DBS off or on, and patients could tell them almost exactly when they turned it off or on. an almost instant improvement. so at least this seems to be closer to the core of what depression is compared to the lag with SSRI's or even the several hours with ketamine.

maybe someone more versed in this could share their theory of the root of depression. or do we think that eventually we'll discover that defining the cause of depression is impossible, and depends entirely on the patients own individual neural/neurochemical characteristics?

 

[serotonin-system]

I think we're gonna get more specific in the coming years. SSRIs.. MAOIs.. SNRIs.. DNRIs, NRIs, etc., etc., are big time overkill. We don't need to fuck with everything, we just need to stimulate the specific receptors where the problem is present. If we do that we can eliminate the vast majority of side effects from drugs like SSRIs and treat the problem better than they ever could.

For example, specifically agonizing the 5-HT1A receptor for treating depression and anxiety is an interesting idea. It's hypothesized that MDMA agonizes this receptor through the roof and that's why it's so empathogenic and anxiolytic.

We could also create dopamine/norepinephrine receptors that only improve concentration and the ability to focus, while not affecting the reward pathways. That could be a future ADD medication for example.

Oh, and SSRIs are the main type of drug used to treat OCD. We just recently found out that OCD is caused by a deficit in only the 5-HT2C receptor. We'll probably see specific 5-HT2C receptor agonists as OCD medications come out very soon. And as evidenced by drugs like psilocin and LSD (5-HT2C agonists), these drugs will probably completely cure OCD.QUOTE]

I agree with a lot of this. In terms of the 5-HT system, I think we're gonna see more of blocking 5-HT receptors which are not conducive to an AD effect, while giving an SSRI. ie SSRI combined with 5-HT2C/5-HT1A antagonists. These receptors are involved in mediating negative feedback on the 5-HT system for one, and activation of the 5-HT2C induces anxiogenic behavior. Also we might see specific activation of 5-HT receptors with selective agonists. The 5-HT4 has recently been shown to mediate positive feedback on the 5-HT system.