Opinions - the serotonin reuptake theory of treating depression is obsolete?

[Sloop]

We may of all been taken for a ride with the popular model that you just needed to add more serotonin into the synaptic cleft to have an antidepressant effect.

If this is the case then serotonin reuptake inhibitors like prozac or zoloft etc would demonstrate some therapeutic effect from the first dose (like ritalin does with dopamine, NE and concentration). The model that they only worked once you slowly built up enough residual serotonin through constant reuptake inhibition over weeks may be erroneus. Downstream and upstream changes in neurotransmitter and receptor behaviour (not just serotonin) as a result of an SSRI antidepressant therapy and structural adaption and change or stimulation of neuroplasticity caused by an antidepressant may be the reasons why the therapeutic effect is often delayed.

The significant antidepressant effectiveness of Tianeptine, a serotonin reuptake enhancer has thrown a spanner in the works. Research aimed at discovering why and how tianeptine with a opposite mode of action in the synaptic cleft can be just as, if not more effective than many SSRI's (effectiveness that matches TCA's without the side-effects Servier claims) on depression has led to a whole new look by some researchers as to how and why our antidepressants work.

They have looked downstream and upstream of the synaptic cleft and found previously unoticed or ignored positive neuroplastic responses. Many drugs including SSRI's TCA's MAOI's and even some of the powerful hallucinogens like DMT, Ibogaine, Psilycibon(?spelling) Mescaline ketamine etc have demonstrated effects on enhancing neuroplasticity.

Both Tianeptine and Prozac had some actions in common in promoting valuable dendrite growth and branching in various parts of the brain.

It is way above my head to explain or properly grasp but I think this may eventually lead to a very interesting stage of development into drugs and other therapies that encourage and focus on neuroplasticity and we can drop this SSRI model, which although may of been initially useful it has for some time been very limiting.

It may be that depression fundamentally means we have a brain with a stuck structure or pattern of function and something needs to get new life and new growth happening in new directions, to break out of these rigid brain morphilogical patterns that basically mean you are rigidly hard-wired to responses and behaviors that dont work well in a changed and ever changing world.

Perhaps going home from work a new way every so often, learning a new language or music or dancing skill is useful after all. Or eating some magic mushrooms or cactus at the right time as well.

This may make sense of why many lift out of depression without drugs when forced to adapt to new situations or learn new skills to survive, even though the situation may be absolutely terrible such as a war.

Any thoughts out there on this? I dont have time to cite these statements, but a bit of a search around the web using Tianeptine as a key yields interesting stuff I am finding.

This change will probably take a while though for many professors and drug companies have built their careers/profits on the SSRI model and may probably feel threatened at some stage as it is revealed they were barking up the wrong tree. I guess none of us like being made to look ignorant.

regrads sloop

Reputation Comments on this post:

great ideas and well backed up; the ssri model is way overrated, but didn't know the exact opposite would works as antid...

[rocknroll714]

I don't really know about serotonergic neuroplasticity, but as far as I'm concerned it all has to do with serotonin autoreceptors.

Take a look at this article I wrote the other day:

Serotonergic drugs and serotonin autoreceptors.

Kobie J. Whetstone (rocknroll714@gmail.com)
April 21st, 2009

Article

The administration of a serotonin reuptake inhibitor (SRI) or monoamine oxidase inhibitor (MAOI) leads to elevated extracellular levels of serotonin and an increase in the stimulation of post-synaptic serotonin receptors. A few serotonin receptors are located pre-synaptically and are known as "autoreceptors". Activation of serotonin autoreceptors has an inhibitory effect on serotonin synthesis and release. Due to the stimulation of these autoreceptors by SRIs and MAOIs, at first serotonin activity in certain areas is lower than usual. Over time the autoreceptors desensitize via downregulation, thereby returning to normal. Unfortunately they do not downregulate to a state of activity any lower than normal however, therefore serotonergic synapses containing autoreceptors will never be overstimulated by an SRI or MAOI under any circumstance.

Serotonin release agents (SRAs) overpower the autoreceptors by directly bypassing their inhibition of serotonin release. This is why MDMA and other SRAs are so much more efficant against depression and anxiety than SRIs, and it is also why they kick in instantly. This is in stark contrast to SRIs and MAOIs, which can take anywhere from weeks to months to fully kick in. The same applies to certain serotonin agonists such as buspirone (Buspar). Additionally, acute, autoreceptor-mediated disinhibition of serotonin release may be the mechanism of action of tianeptine (Stablon).

Serotonin receptors verified to be located both pre-synaptically as autoreceptors and post-synaptically as regular receptors thus far include 5-HT1A, 5-HT1B, and 5-HT1D.

With some further research I think I'm gonna retract my tianeptine statement as it doesn't seem to hold true both logically and from studies. If tianeptine enhances reuptake and causes there to be less extracellular serotonin in the synapse, the lower activity of the autoreceptors will result in enhanced serotonin release, but that serotonin will once again hit the autoreceptors so it'll ultimately just be balanced out. Therefore it doesn't really work.

It seems that many serotonin receptors are dysphoric and depressive including the 5-HT2C, 5-HT6, and 5-HT7 receptors. Mirtazapine, mianserin, nefazodone, trazodone, and agomelatine all likely exert their antidepressant effects primarily via 5-HT2C antagonism in my opinion. 5-HT6 and 5-HT7 antagonists have shown positive results in rat models of antidepressant efficacy, but they have not yet been tested in humans. However many of the atypical antipsychotics such as olanzapine are 5-HT6/5-HT7 antagonists and they have been shown positive results antidepressant augmentation. If olanzapine was selective for the serotonin receptors I think it would be a fabulous antidepressant drug.

On the other hand, 5-HT1 and 5-HT3 receptors seem to be positive. 5-HT3 blockade blocks the positive effects of alcohol for example. The 5-HT1 receptors are the seat of positive effects for all SSRIs, SNRIs, the serotonergic TCAs and MAOIs, and finally MDMA and the other SRAs. Buspirone as well. The 5-HT2B receptors have also shown to be anxiolytic which appears to denote that they are also positive.

I think it all comes down to selectively and carefully targeting the 5-HT system in specific ways. Enhance the activity of the 5-HT1 receptors, and block the 5-HT2C receptors, without affecting the others, at least for now. We don't really want to enhance the activity of the 5-HT3 receptor because of nausea for example, and we don't have enough data (or ligands for that matter) to sufficiently utilize the 5-HT6 or 5-HT7 receptors in a way against depression.

I hope that they develop and market more selective ligands. I'd like to see a fully selective 5-HT1A full agonist and a fully selective 5-HT2C antagonist on the market. Agomelatine is good but it blocks the 5-HT2B receptor and agonizes the melatonin receptors as well. This could cause anxiogenesis and sleepiness. It's all about selectivity! I think a non-toxic selective SRA like MMAI or MDAI would be pretty sweet as well. Combination SRA with something like a mirtazapine without H1 antagonism would be absolutely excellent in my opinion.

rocknroll714 added 4 Minutes and 2 Seconds later...

Also note that I think dopamine is the true culprit in depression. In fact in these modern times I think it's pretty much verified. All drugs that "make you feel good" or even just "make you feel better", hit dopamine somewhere down the line. That includes alcohol, tobacco, marijuana, amphetamines, cocaine, ecstasy, opiates/opioids, benzos, dissociatives, and even psychedelics to a mild extent. The SSRIs work by enhancing and suppressing dopamine release in specific areas (hence emotional blunting - no good, no bad, just nothingness almost). I don't think triggering dopamine directly is the key though. Too many undesirable side effects like nausea, anxiety, and psychosis. Specific modulation via receptors like the 5-HT1A receptor and the mu-Opioid receptor subtypes appears to be a better way of going about it.