Friday, January 24, 2014

Tryptophan Depletion studies

The best review of tryptophan-depletion studies is by Moore et al. (2000).

 I think it is an accepted part of clinical psychiatric theory that serotonin obviously is related to mood, and the more serotonin there is, the better mood must be, and the less serotonin there is, the worse mood must be!  

With tryptophan-depletion, subjects are given a drink which results in a radical reduction in serotonin synthesis within hours.  It is strongly believed, though not rigorously proven, due to technical limitations, that such depletion results in a reduction of serotonin release by serotonergic neurons in the brain. 

The main consistent finding of these studies is that depressed patients who are treated with a serotonergic antidepressant, such as an SSRI, but who have not yet recovered fully from their depressive episode, are very sensitive to a sudden worsening in their depressive symptoms immediately after tryptophan-depletion. 

But, fully remitted patients tend not to have any depressive relapse following tryptophan depletion!

And depressed patients who have not yet received any antidepressant tend not to have worsening depressive symptoms following tryptophan depletion! 

And depressed patients treated with non-serotonergic antidepressants (such as desipramine) do not have worsened depressive symptoms following tryptophan depletion! 

There is little evidence that tryptophan depletion consistently affects panic or OCD symptoms. 

One study quoted in this review, by Delgado (1991), showed that in a group of untreated depressed patients given tryptophan-depletion, 37% actually improved following depletion, compared to 23% who got worse (by 10 points on the HDRS). 

It is obvious that momentary tryptophan depletion, and the resulting drop in serotonin synthesis, does not have consistent effects on psychiatric symptoms.  The effect is only reliable in partially treated patients taking SSRI's.  It may be that in these patients, it is a sudden induction of a withdrawal-like state which causes the sudden symptom change.  Or, it could be that in these patients in an early state of recovery, there is a temporary dependence on serotonin levels, which are working to "push"the patients towards recovery.  The tryptophan depletion suddenly removes the source of this "push", causing sudden relapse.  But serotonin clearly must not be the only possible way to "push"towards recovery, because depleting serotonin only has a negative effect on patients beginning SSRI treatment. 


Anonymous said...

Hi! Great blog!

I think it is important to remember that tryptophan also effects cognition, memory, and motor function. In the elderly it actually showed no effect on mood in elderly. (see below)

I wonder if SSRIs are actually working to increase BDNF therefore increasing LTP (Long term potentiation) in the hippocampus. I would like to think of SSRIS are priming the brain to make new connections. It is kind of like giving parts of the brain more resources/ strength to have a choice. A choice to interpret information differently, to feel a different feeling, to focus on different items.

The effects of acute tryptophan depletion on neuropsychological function, mood and movement in the healthy elderly
Janet L Mace1
Richard J Porter2,3⇓
John C Dalrymple-Alford3,4,5
Keith A Wesnes6
Tim J Anderson3,5


Few studies have investigated the function of the serotonin (5-HT) system in the elderly. Previous studies have shown effects of reducing serotonin function, by acute tryptophan depletion (ATD), on neuropsychological function in healthy subjects but this technique has not previously been employed over a wide age range in the elderly. This study compared the effects of ATD on mood, cognitive function and motor function in two groups of healthy volunteers, one group aged 50–69 and the other aged 70–89. The effects of ATD were investigated in a double-blind, placebo-controlled, counterbalanced, crossover, randomized design. The effects of ATD were not significantly different between age groups, suggesting that there is relatively little functional change across these age ranges. Compared with studies in much younger age groups there was, however, more evidence of an adverse effect of ATD on psychomotor function and working memory. There was no effect of ATD on mood despite inclusion of subjects with a family history of depression.

Unknown said...

Getting a little bit off topic here, but as someone who has had had depression and GAD for 30+ years and has researched new treatments somewhat extensively, I have wondered how much of a role excess Acetylcholine plays in depression. I once tried supplementing with Choline and within days experienced a dramatic worsening of depression and anxiety, even a level of suicidality that was previously non-existent. In research I've come across many others who've experienced the same. I was able to eliminate this head space by taking benadryl, an anticholinergic.

Interestingly some of the best and gold standard antidepressants are the tryclics which are anticholinergic in action also.

It has been postulated that perhaps an increase in serotonin through SSRI's and subsequent antidepressant effects are not due to serotonin itself but it's increase causing a displacement and reduction of acetylcholine. Many anticholinergic drugs are seen as "dirty" in their side effect profiles, but perhaps developing cleaner ones may be the ticket. I know some developed for alzheimers are said to be cleaner and more specific.

Here's an interesting I've come across which may support this possible theory: