"Clomipramine, Tryptophan and Lithium in Combination for Resistant Endogenous Depression: Seven Case Studies" - August 1987 | A. S. Hale (a1), A. W. Procter (a2) and P. K. Bridges (a3)

[Skeletor]

https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/clomipramine-tryptophan-and-lithium-in-combination-for-resistant-endogenous-depression-seven-case-studies/F3A1B19433959744DCF32C36C7B4A28F#

Unquestionably an extreme combination, but it seems to exhibit powerful antidepressant effects. Clomipramine on its own is regarded by many as maybe the most powerful non-MAOI antidepressant, at least in clinical practice and inpatient care, although the side effects can be quite rough, but combined with Tryptophan and Lithium it seems to be further boosted in its effect size and response rate.

Maybe worth trying before hopping on ECT / MAOIs...

One has to be careful because it is a small sample case "study", but nonetheless quite interesting to read. I encourage all those who have a view or experience to share it with us, regarding the aforementioned medications and especially the combination. Greetings!

[crazyguy82]

I’ve taken Tryptophan and I couldn’t notice any difference. I did I thing for me.

[mikl_pls]

Clomipramine was by far one of the worst meds for me. It significantly worsened my depression and anxiety at all doses I took (50-225 mg/day).

[browri]

I can certainly see why this would be considered a robust treatment regimen. Clomipramine is generally regarded as having the highest affinity for the serotonin transporter of the antidepressants except perhaps maybe paroxetine. Depends on how and where the number is reported.

With increasing inhibition of the serotonin transporter and subsequent ramp-up in central 5HT1 activation, my expectation would be that monoaminergic neurons would behave the same way that catecholaminergic neurons do by inducing the metabolism of said endogenous ligand. For example, when taking amphetamine, activation/agonism of the trace-amine associated receptor type 1 (TAAR1) causes a release of neurotransmitters. Activation of central D1 receptors results in an increase in the production of catechol-O-methyltransferase, an enzyme responsible for breaking down catecholamines. It's a feedback loop. Brain detects higher levels. Compensates by trying to decrease them.

So my expectation is that with high dose treatment of clomipramine you would possibly experience an increase in levels of monoamine oxidase A (preferrable to serotonin) and monoamine oxidase B (preferrable to norepinephrine and dopamine). Metabolism of neurotransmitters has to occur INSIDE of cells. So with an inhibitor of the serotonin transporter on-board, all of that serotonin is floating around in the synapse or "extracellular" but there's tons more MAO-A and MAO-B floating around in the neurons waiting to break that all down when the transporter does eventually return it to the sending neuron.

To compensate for this increase in neurotransmitter oxidation, you supplement with tryptophan, which acts as a pre-cursor to serotonin, thus propping up the serotonin lifecycle. While clomipramine may increase serotonin's oxidation/breakdown, you're supplementing with a pre-cursor the body can use to synthesize replacement serotonin.

The lithium is trickier to explain though because we don't fully understand how it works, but we do know that it somehow modulates serotonin signaling. It does seem to modify 5HT1 receptors density and causes changes in levels of serotonin (both up and down) in certain areas of the brain. Perhaps the clomipramine/tryptophan combo is too toxic but the lithium provides the neuro-protective effect? Now I'm just grasping for straws at this point.