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@Jean 5892 wrote:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237392/pdf/dhps-3-069.pdf
Here is the abstract:
Monoamine depletion by reuptake inhibitors.
Hinz M, Stein A, Uncini T.
Drug Healthc Patient Saf. 2011;3:69-77. Epub 2011 Oct 20.Abstract
BACKGROUND:
Disagreement exists regarding the etiology of cessation of the observed clinical results with administration of reuptake inhibitors. Traditionally, when drug effects wane, it is known as tachyphylaxis. With reuptake inhibitors, the placebo effect is significantly greater than the drug effect in the treatment of depression and attention deficit hyperactivity disorder, leading some to assert that waning of drug effects is placebo relapse, not tachyphylaxis.METHODS:
Two groups were retrospectively evaluated. Group 1 was composed of subjects with depression and Group 2 was composed of bariatric subjects treated with reuptake inhibitors for appetite suppression.RESULTS:
In Group 1, 200 subjects with depression were treated with citalopram 20 mg per day. A total of 46.5% (n = 93) achieved relief of symptoms (Hamilton-D rating score ≤ 7), 37 (39.8%) of whom experienced recurrence of depression symptoms, at which point an amino acid precursor formula was started. Within 1-5 days, 97.3% (n = 36) experienced relief of depression symptoms. In Group 2, 220 subjects were treated with phentermine 30 mg in the morning and citalopram 20 mg at 4 pm. In this group, 90.0% (n = 198) achieved adequate appetite suppression. The appetite suppression ceased in all 198 subjects within 4-48 days. Administration of an amino acid precursor formula restored appetite suppression in 98.5% (n = 195) of subjects within 1-5 days.CONCLUSION:
Reuptake inhibitors do not increase the total number of monoamine molecules in the central nervous system. Their mechanism of action facilitates redistribution of monoamines from one place to another. In the process, conditions are induced that facilitate depletion of monoamines. The “reuptake inhibitor monoamine depletion theory” of this paper offers a novel and unified explanation for the waning of response seen after a reuptake inhibitor is started, independent of a drug or placebo etiology.PMID: 22171164 [PubMed] PMCID: PMC3237392
In reading the article, they argue that the use of monoamine reuptake inhibitors – such as serotonin-reuptake inhibitor Citalopram – in the treatment of depression can result in the progressive loss of monoamines by exposing them to monoamine oxidase. With Citalopram treatment, this then results in a greater need for serotonin precursors in the diet (i.e. tryptophan). Otherwise, if tryptophan is not in adequate amounts in the diet, the patient may experience recurrence of depression after an initial response to the medication. They believe that the usual diet does not provide an adequate mount of tryptophan, that even more is necessary when using a serotonin-reuptake inhibitor.
I think nutritional deficiencies are a major component to address in treating depression. Certainly a tryptophan deficiency (such as may occur with a vegetarian diet) may predispose a person to depression and may make serotonergic medications such as Citalopram less effective.
I am not convinced, however, that a greater need for monoamine precursors is the only reason a reuptake-inhibitors stop working. I think it is a minor factor if at all once nutritional deficiencies are addressed in treatment.
The article, for example, doesn’t adequately explain why 60% of study’s patients who had remission on Citalopram DID NOT have recurrence of depression. No lab tests were done to see if their nutrition already had adequate tryptophan or if there was no monoamine depletion in the first place.
Depression, from my perspective, has multiple simultaneous underlying causes (pathophysiologies), most important is excessive pro-inflammatory signaling. Serotonin reuptake inhibitors only address one pathophysiology. Recurrence of depression generally is more easily explained as an incomplete treatment of the pathophysiologies of depression, or a worsening of the unaddressed pathologies over time (some even have seasonal variation).
GROUP 1 ANALYSIS:GROUP 1:
93 subjects who had remission on Citalopram 20 mg
56 of them did not have recurrence of depression
37 of them had recurrence of depression
These 37 received amino-acid supplements
37 had restoration of remission of depression within 1-5 days.WEAKNESSES:
1. there were no control subjects – given placebo instead of amino-acid supplement
2. there was no double-blind, placebo-controlled study – the placebo effect may explain the restoration of remission of depression.
3. subjects had mild depression (avg Hamiltaon Depression Score = 10). They would be ineligible for FDA studies, any treatment may have worked including placebo
4. amino-acid supplement had 5-HTP not Tryptophan. 5-HTP is not naturally found in foods in significant quantities. 5-HTP at 300 mg a day is a therapeutic dose for depression.
5. The supplement – itself – may have antidepressant effects independent of supplementing serotonin and dopamine precursors. For example, it had dopamine precursors – which are not expected to be depleted when using a serotonin reuptake inhibitor.
6. Vitamin C at 1000 mg has antidepressant effects
7. Vitamin B6 at 75 mg is 57 times the RDA – is thus a medicinal dose.
8. Selenium may address Thyroid hormone activation problems as a contributing factor in depression, has antioxidant effect which contributes to anti-depressant effect, separate from serotonin and dopamine depletion
9. Folic acid has antidepressant effects independent of sulfur amino acid synthesis, is involved production of dopamine, serotonin, norepinephrine, DNA, protein synthesis, and has antinflammatory effects.
10. No measure of tryptophan, 5-HTP, blood serotonin, platelet serotonin or metabolites of serotonin and dopamine measured to see if the targetted biochemical effect – depletion and restoration of serotonin and dopamine level and their nutrient precursors actually occurred.
11. No discussion of the other effects Citalopram has – including Alpha-2 Adrenergic receptor blockade, anti-cholinergic effect, insulin resistance, reduction in dopamine production, etc. these may have contribute to recurrence of depression
12. 56 of the 93 subjects on Citalopram did not have recurrence of depression. The article doesn’t discuss why this is so. This fact does not support their thesis that serotonin reuptake inhibition depletes serotonin and its nutritional precursors.
13. Depression generally has multiple underlying causes – this article assumes only one – serotonin deficiency. The unaddressed causes can be the actual factors resulting in recurrence of depression.
GROUP 2 ANALYSIS:GROUP 2:
198 subjects had appetite suppression on Phentermine 30 mg in AM, Citalopram 20 mg
198 had recurrence of appetite within 4-48 days
These 198 received amino acid precursor supplement
198 had restoration of appetite suppression within 1-5 daysWEAKNESSES:
1. there were no control subjects – given a placebo instead of animo acid supplement
2. there was no double-blind, placebo controlled study – the placebo effect may account for the restoration of appetite suppression.
3. The discussed mechanisms of action for Phentermine is highly inaccurate.Phentermine as an amphetamine does more than just dopamine-reuptake inhibition, it:
- reverses the vesicular monoamine transporter-2 (VMAT-2) – depleting vesicular dopamine content, increasing intracellular dopamine
- reverses Dopamine Transporter (DAT) – increasing extracellular dopamine
- blocks Dopamine Transporter (DAT) competitively – increasing extracellular dopamine
- inhibits Monoamine Oxidase competitively – increasing extracellular dopamine
4. Phentermine alone can increase inflammatory signaling, which impairs gluconeogenesis, which then increases appetite. This alternative explanation is not discussed.
5. Citalopram at 20 mg also is known to cause weight gain or prevent weight loss. It increases risk of insulin resistance, which can then increase appetite. This alternative explanation is not discussed.
6. amino-acid supplement had 5-HTP not Tryptophan. 5-HTP is not naturally found in foods in significant quantities. 5-HTP at 300 mg a day is a therapeutic dose for depression
7. Vitamin C at 1000 mg has antidepressant effects
8. Vitamin B6 at 75 mg is 57 times the RDA – is thus a medicinal dose.
9. Selenium may address Thyroid hormone activation problems as a contributing factor in depression, has antioxidant effect which contributes to anti-depressant effect, separate from serotonin and dopamine depletion
0. Folic acid has antidepressant effects independent of sulfur amino acid synthesis, is involved production of dopamine, serotonin, norepinephrine, DNA, protein synthesis, and has antinflammatory effects.
10. No measure of tryptophan, 5-HTP, blood serotonin, platelet serotonin or metabolites of serotonin and dopamine measured to see if the targetted biochemical effect – depletion and restoration of serotonin and dopamine level and their nutrient precursors actually occurred.
AMINO-ACID PRECURSOR SUPPLEMENT USED:L-Tyrosine 3000 mg – dopamine precursor
5-Hydroxytryptophan 300 mg – serotonin precursor
Vitamin B6 75 mg – cofactor for serotonin/dopamine synthesis
Vitamin C 1000 mg – cofactor for serotonin/dopamine synthesis (Inaccurate statement in article. This is also a cofactor for norepinephrine synthesis, NMDA receptor antagonist, has anti-oxidant/antinflammatory effects)
Calcium Citrate 220 mg (46 mg Calcium) – cofactor for serotonin/dopamine synthesisL-Cysteine 4500 mg – sulfur amino acid – since L-tyrosine can deplete sulfur amino acids
Vitamin B9 (Folic Acid) 400 mcg – cofactor for dopamine synthesis, support for sulfur amino acid synthesis
Selenium 400 mcg – to reduce methylmercury toxicity from L-Cysteine
L-Lysine 500 mg – for hair lossCOMPARISON TO MUSCLE MILK 70 GRAMS (2 scoops):
L-Tyrosine 1540 mg – dopamine precursor
L-Phenylalanine 1520 mg – dopamine precursor
L-Tryptophan 455 mg – serotonin precursor
Vitamin B6 0.5 mg – cofactor for serotonin/dopamine synthesis
Vitamin C 32 mg – cofactor for serotonin/dopamine synthesis? cofactor for norepinephrine synthesis, NMDA receptor antagonist
Calcium 1000 mg – cofactor for serotonin/dopamine synthesisL-Cysteine 310 mg – sulfur amino acid
L-Methionine 820 mg – sulfur amino acidVitamin B9 (Folic Acid) – cofactor for dopamine synthesis, support for sulfur amino acid synthesis
Selenium none.
L-Lysine 2495 mg
Thanks you for this good analysis, many publications have financial interest and have some biased answer. I like the answer of 2 scoops of milk protein powder. 🙂
@Jean 6742 wrote:
Thanks you for this good analysis, many publications have financial interest and have some biased answer. I like the answer of 2 scoops of milk protein powder. 🙂
I emphasize optimizing nutritional status as an important part of treatment.
The authors of the article primarily focus on specific amino acid precursors and other cofactors as part of treatment. These provide the foundation for neurotransmitter production.
They suggest using these with reuptake inhibitors such as SSRI antidepressants since they theorize the major reason these medications stop working is because of an accelerated depletion of the precursors for neurotransmitters from the use of the medication itself.
The data they provide for this theory is very weak. And I think there are numerous more important other reasons – such as non-addressed underlying causes of depression – that cause recurrence despite treatment.
But I don’t disagree with the practice of supplementing these amino acids and cofactors. The ones they suggest have independent actions themselves on improving mood and mental function – particularly at the doses used.
For years, in complementary medicine, the use of specific amino acids and cofactors have been an alternative to antidepressant and other psychiatric medical treatment.
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