Why new dopaminergic antidepressants are not developed?

[Dreynar]

I don't really get this. What I heard from my psychiatrist, is that Dopamine was not considered as an important neurotransmitter in depression, which seems completely stupid.
Dopamine is responsible for the feeling of pleasure and motivation. It realises your anxiety and fear (if properly stimulated) and therefore Depression.
Every drug that is addictive stimulates Dopamine either directly (Amphetamines/Cocaine) or indirectly (Opioids, Alcohol and others).
The best anti-depressants is Zoloft, which is the second most prescribed SSRI in psychiatrie and reason for that is simple: it's far from being selective, because it's 85% SRI and 15% Dopamine Reuptake Inhibitor.

The next antidepressant that get more popular with time because I see how much of a mood boost it gives to people is Bupropion, which is an NDRI.

You may argue that there is already Ritalin and Dextroamphetamine, but problem with those is that after about an hour - when they come up - many people start to feel anxiety because of overstimulation. As I understand it, the reason for is that the stimulation with those it to fast, therefore and not very pleasant for many people. In opposition to that is Meth which works slower, and therefore more pleasures. But it has horrible side effects.

Meth, Cocaine, and drugs that affect Dopamine indirectly are the mostly abused drugs almost since 100 years.

So my question is what's going on? Why new Dopaminergic antidepressants are not developed or so little energy is put in it?


It's seems to me like a drug like this could be a salvation for humanity and the company that would develope such an antidepressant would be the richest on Earth.

 

[AlphaMethylPhenyl]

tldr: Because they aren't actually effective antidepressants.

Most of the explicit literature on psych. meds and neurotransmitters is quite reductive. So I'm not that surprised that this thread was created. To really understand things, you would have to at least take a biopsychology course. The learning curve is tough.

Dopamine might be better characterized as provoking a feeling of novelty/anticipation.

Stimulants, opioids, and alcohol taken at recreational doses can very temporarily offer an escape from reality. Then one experiences a low for lack of this chemical crutch, and so the user increases dosage/frequency of dosing. They continuously increase the dose/frequency to the point that their brain has been taken over. At this point, they have lost control, and severely decreased the quality of every aspect of their life for the substance. This is one of the worst possible states of being. This isn't relief from depression.

Dopaminergics work as antidepressants if the dosage is continually increased. The probability of negative side effects, and negative events in one's life, continues to go up, but the user still takes a dose to just fight depression. For example, way back when, psychiatric theory was under the false belief that amphetamine is an anti-depressant. And so the patient would tell their doctor at most appointments that they need a higher dose. Before they know it, they're taking 150mg a day to relieve depression that had not too long ago required 25mg, six times fewer mgs. They're just getting relief from depression, but even so, their risk of psychosis went up each time they raised the dose, and is now a grave risk.

Zoloft has some of that, but not that much (unless you have a credible source), and doesn't have the reputation you ascribe to it. Generally, as I understand, antidepressants work largely because of the signal transcription and neurotrophic activity related to receptor/release down-regulation of serotonin in the dendate gyrus.

Bupropion is not well-understood. There are a few gaping holes in the theory of its mechanism. Most of its activity comes from norepinephrine.

Addictive drugs, those of which you speak, aren't sustainable mood-enhancers. In other terms: they don't work as antidepressants. They are (much more crude) euphoriants. The human brain is advanced enough to not continuously, at the same dose, let an exogenous chemical make one happy without any phenomenal rationale in one's environment.

The side effects from abusing dopaminergic drugs steadily increase, no matter the mood that the drug manifests, just want to make that absolutely clear.

There are lots of different reasons that one might experience anxiety from substances.

You are really quite naive about all of this, my friend.

 

[Cotcha Yankinov]

The depression relief that some may experience from dopaminergic drugs (and buproprion is not necessarily a dopaminergic) is not sustainable.

The issue is really sustainability. Real antidepressants can evoke long lasting changes in the brain that lead to remission even after the SSRIs are tapered.

 

[5HT2c]

Hi Dreynar, it's very tempting to get caught in the neuro-reasoning that has proven very poor results in the field. As Ho-Chi-Minh says to start realizing how complicated this field is you should take several courses understanding what is depression is not an easy task, as biologic, psychologic and social discourses converge.

In any case, my advice is to be reluctant to the neuro-discourse. Trying to say what dopamine does or what region of the brain is responsible for a specific process is a kind of mythologic discourse replacing gods and nature powers for sciencey terms.

If you want to read about antidepressants I would reccomend this paper, although I don't like the description of depression has a good and short summary of the evolution of antidepressants. Also, tries to make a similar claim that you, maybe.

Chen, Z., & Skolnick, P. (2007). Triple uptake inhibitors: therapeutic potential in depression and beyond. Expert Opinion on Investigational Drugs, 16(9), 1365–1377. http://doi.org/10.1517/13543784.16.9.1365

 

[Dreynar]

So the conclusion is that you will always build up tolerance? But will it be tolerance for the drug or for the feeling of Euphoria? Bacause if first would be the case, than when you have a couple of those drugs you can cycle them. But if we are talking about tolerance to Euphoria - are you sure about this?
I take Ritalin almost everyday for my ADHD I always get high every time I take it - the problem is that the high last only for 40-60 min. and after that it turns into agitation and it's easy to get paranoid about something. It doesn't work for Anhedonia almost at all. Although I feel good when I work and do something intence, like fast physical work. But when I want to sit and chill and enjoy life I don't really can.

So couldn't they develope a drug that would work like Methylphenidate but less intense so it would not produce this agitation (and anxiety)? Or some lighter drug that would cancer my restlessness and Anhedonia (and Social Anxiety)?


But even if dopaminergic drugs would be too addictive and tolerance is inevitable, so can't they at least think about some alternative to Bupropion, which could also work mostly for norepinephrine and partialy for Dopamine? I take Bupropion since two days and it's the only thing that really relaxes me.

There's also a russian nootropic/drug called Bromantane which works also in that direction. One guy said it completely killed his social anxiety.
I have to also try this one. Maybe do some combo. Russians actually invest some energy in those nootropic-like drugs.


I just came up with some wierd idea: Is it possible to create something like Desoxy-Methylphenidate?
Desoxy-Amphetamin is Methamphetamin and in 1970' there was an an ADHD med called Pipradril, which for unknown reason was removed from the market (only thing they say it has high abuse potential) and someone made Desoxypipradril, which also is an euphriant but it's not rally stimulative. It compeletely kills Anhedonia, everything is fun on it, even stying in a line. It also helps you concentrate and ofcourse with motivation. So it seems like doing desoxy versions of some stimulants may have a greate effect.

 

[DementiaSavantPlus]

My impression of "releasers" and some reuptake inhibitors is that specific ratios of increased S, N, and D levels cause euphoria in addition to a plethora of short/long-term effects. Even slight differences in these ratios can cause vastly different effects.

Simply aiming to isolate dopamine activity via a drug does not result in the subjective antidepressant effects of anticipation-of-reward that we associate with dopamine. A glance at the surface of literature may mislead us to believe that dopamine = pleasure.

An SSRI changes serotonin, and then changes dopamine as a reaction to this new serotonin. Amphetamine is not actually an antidepressant in that it ultimately does not enhance the functionality of one's steady mood and focus. It is an acute performance enhancer. It's antideppressant effects last about two weeks and then you often experience the inverse of these effects suddenly. Also this is not to say that SSRIs and their cousins are perfect at all. They are a generally mild and effective alternative to amp, and the older MAOIs and TCAs.

Having stated the above, Zoloft does share characteristics with the "feel" of amphetamine in a vague way.

 

[Limpet_Chicken]

I wonder a lot about the potential of things with modes of action like BPAP and PPAP, as antidepressants, things that don't cause a tonic, but rather phasic enhancement of monoamine release. Causing more monoamine to be released per stimulation of the presynaptic neuron, but without themselves directly inducing either release/reuptake inhibition. PPAP would IMO for tox reasons be favourable over BPAP given benzofuranyl groups aren't always easy on the liver. Basically the result is when neuronal firing of action potentials is already, naturally going to take place, the action is to increase the amplitude of transmitter release.

 

[WSH]

I just came up with some wierd idea: Is it possible to create something like Desoxy-Methylphenidate?
Desoxy-Amphetamin is Methamphetamin and in 1970' there was an an ADHD med called Pipradril, which for unknown reason was removed from the market (only thing they say it has high abuse potential) and someone made Desoxypipradril, which also is an euphriant but it's not rally stimulativet.

Nope, Desoxy-Amphetamin is not Methamphetamin, Desoxy-Amphetamine would be amhphetamine reduced by exactly one oxygen , and amphetamine doesn't actually even have any oxygens (at least non-pre-metabolization and i highly doubt that methamphetamine causes fewer hydroxy-metabolites than amphetamine, and even if that was the case, the term Desoxy-Amphetamine would STILL be technically incorrect).

Now on to Desoxypipradril, which actually does exist, does have a much longer half-life than both ritalin and pipradrol, so it won't get redosed as often, which is the reason why it isn't considered to be as "abusable" as both ritalin and pipradrol, as the effects are generally highest during binge use.

Methylphenidate actually does have oxygens, however their cleavage via Carboxylesterase_1, which is fast, but not as fast as with cocaine (which is why methylphenidate isn't as abusable as cocaine, but it's it's still abused) and removing these oxygens (either "desoxy" or, in my example, "didesoxy") would most likely dramatically reduce the potency, so that you would have to take A MUCH HIGHER DOSE or (more likely) actually no effects at all even with insane doses

But now let's talk about drugs that actually are like Desoxypipradril:

Dasotraline for example. It has a

a mean apparent half-life of 47h

which means that

results of this study support the concept that symptoms of ADHD may be improved by providing constant, steady-state inhibition of DA and NE reuptake. This pharmacologic profile suggests the potential for sustained treatment effects throughout the 24 h dosing interval, and contrasts with the peak and trough pattern of effects within the dosing interval induced by current ADHD medications, attributable to either their faster pharmacodynamics (methylphenidate medications) or their facilitated release of dopamine (amphetamine-based medications).

because

Currently available treatments for ADHD tend to produce high rates of adverse CNS and cardiovascular and gastrointestinal effects, with abuse liability a risk for the stimulant class of medications. Therefore, there is a need for additional treatment options that may offer reduced abuse liability and a different tolerability profile. [...] the pharmacokinetic and pharmacodynamic characteristics of dasotraline suggest that it may have a favorable pharmacologic profile for the treatment of ADHD, including sustained treatment effects throughout a once-per-day 24 h dosing interval, and a reduced risk for abuse and diversion,

However, since this thread is about antidepressants, I have to mention that that dasotraline has been discontinued for the treatment of antidepression :

Highest Development Phases

Phase III: Attention-deficit hyperactivity disorder; Eating disorders
Discontinued: Major depressive disordor

like the following long list of SDNRIS:

Failed clinical trials

Bicifadine (DOV-220,075) (1981)[56][57]
BMS-866,949
Brasofensine (NS-2214, BMS-204,756) (1995)[58]
Diclofensine (Ro 8-4650) (1982)[59][60]
DOV-216,303 (2004)[61][62]
EXP-561 (1965)[63]
Liafensine (BMS-820,836)
NS-2359 (GSK-372,475)[64]
RG-7166 (2009–2012)
SEP-227,162
SEP-228,425
SEP-228,432

 

[ungelesene_bettlek]

Bupropion caused me very disturbing effects of what seemed to me as an amphetamine psychosis. Sertraline (Zoloft (R)) at 100 mgs dayly has no real effect to me.

EDIT: I can feel the effecs of Sertraline right now, but probably I was just having a good day. Nevertheless I decided together with my Psychiatrists today (welll, actually yesterday) to increase the dose to 200 mg daly.

 

[asecin]

hi ungelesene, zoloft and prozac are similar in that regard, i have heard people adding bupropion to them as adjunct against their sexual dysfunction effect, not sure if you have had that issue, but were you ever mixing them to notice difference in various factors?
how would you describe this amphetamine psychosis you experienced and if combining with SSRI med did you see if it eases the anxiety? well, in general, amphetamine psychosis is treated with benzodiazepines, maybe those would have come in handy

 

[ungelesene_bettlek]

The best anti-depressants is Zoloft [Sertraline], which is the second most prescribed SSRI in psychiatrie and reason for that is simple: it's far from being selective, because it's 85% SRI and 15% Dopamine Reuptake Inhibitor.

Is that truely the case? I increased my Sertraline dosage from 100 mg to 200 mg today and was just asked if I was sober.

zoloft and prozac are similar in that regard

first of all, I very much prefer handling international nonproprietary name instead of copyrighted marketing names, so we should rather talk about Fluoxetine and Sertraline. Of course I know that they are both SSRIs and therefore very similar. But can someone give scientific claums on the claim Dreynar gave? This would be quite important to me, because I increased my Sertraline dosage from 100 mg to 200 today and was just asked if I was sober.

i have heard people adding bupropion to them as adjunct against their sexual dysfunction effect, not sure if you have had that issue

I'm an Asperger's Autist and I heavenly agree with the quote from Aldous Huxley: "An intellectual is a person who's found one thing that's more interesting than sex.". IMHO is bupropion just a dirty cathinone derivate and it is a shame that it is marketed as antidepressant.

how would you describe this amphetamine psychosis you experienced and if combining with SSRI med did you see if it eases the anxiety?

I think I started with S-Citalopram and bupropion came in later. It caused weird thought and made me more depressed. More on that probably later, I just got an important task to do for a close friend.

well, in general, amphetamine psychosis is treated with benzodiazepines, maybe those would have come in handy

I will try to limit my benzodiazepine dosage as much as usual, as I have learned that they are neurotoxic recently.

 

[xbandit07x]

I disagree that Dextroamphetamine, Benzodiazapines, and tryptophan supplements, and even cannabis when cycled properly at the right times of the day/week develop any tolerance and are significantly more helpful for depression/anhedonia/generalized anxiety/social anxiety, than anything else.

The only Dopergenic or euphoriant that I think has a straight up Chase the high/tolerance to it is Opiods, because the High of opium being a new record
type feeling is almost required for it to work.

Combinations of Adhd medication, anxiety meds, and Serotonin stuff usually works wonders, its just that usually only using one thing isnt convenient.


Amphetamines and methylphenidates dont have a tolerance to their ability to make you Content with things in life but if you arent sleeping itl appear they are sucking and benzos only have a tolerance if you literally eat them everyday at a medium-large dosage.