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Rottraut Ille Æ Ju¨rgen Spona Æ Michaela Zickl Æ Peter Hofmann Æ Theresa LahousenNina Dittrich Æ Go¨tz Bertha Æ Karin Hasiba Æ Franz Alfons Mahnert Æ Hans-Peter Kapfhammer ‘‘Add-On’’-therapy with an individualized preparation consistingof free amino acids for patients with a major depression The efficacy of a deficit oriented add-on therapy with free amino acids in depressive patientstreated with the antidepressant RemeronÒ was eval- Life time prevalence for a major depression amounts uated. About 40 in-patients were investigated by a 12–17%, with women being affected two times more randomised double-blind placebo-controlled study than men [A newer epidemiological study from during 4 weeks. Plasma levels of 20 amino acids and the USA shows a 12-months prevalence of 10–12% measures of depression, suicidal behaviour and ]. Pharmacologic therapy with antidepressants aggression were surveyed on admission and after a improving neurotransmitter deficiency is the most 4 weeks’ therapy with RemeronÒ plus an individu- accepted treatment for all forms of moderate to severe alized amino acid mixture or placebo. The prepara- depressions independent of their genesis. The anti- tion of the amino acid mixture was based on an depressant therapy has a variety of undesirable side- aminogram and consisted of essential amino acids effects such as sedation, decrease of blood pressure, plus vitamins and trace elements as co-factors for the increase of weight, indigestion or sexual dysfunction.
amino acid metabolism. Patients of the experimental This often results in patients’ poor compliance group showed a significantly better improvement of resulting in a break-up of medication with recurrence depression and a higher responder rate than those of of depressive symptoms and increased suicidal risk the placebo group. The results suggest that oral , Previous investigations have shown that re- application of a deficit oriented amino acid mixture duced plasma concentrations of amino acids, such as can improve the therapeutic outcome of an antide- the serotonin precursors tryptophan and tyrosine are pressant. Furthermore, lacking side effects of the a good indicator for an insufficient availability of this amino acids resulting also in a better patient com- pliance may improve the benefit/risk ratio.
major depression showed lower absolute plasmaconcentrations of tryptophan and tryptophan/big neutral amino acid ratio in comparison to healthy aminogram Æ individualized amino acid preparation persons [The results of Gronier et al. ]suggest a defect of transport of L-tryptophan withinthe platelets of depressive patients. An experimentally This study was supported by the Ludwig Boltzmann Gesellschaft induced reduction (‘‘depletion’’) of the tryptophan and the ‘‘Amt der Steierma¨rkischen Landesregierung’’.
plasma levels to 70–90% of the basis concentration by Dr. R. Ille Æ Prof. Dr. J. Spona Æ Dr. M. Zickl application of an amino acid mixture without tryp- Ludwig Boltzmann Institute for Experimental EndocrinologyVienna, Austria tophan led to a decrease of central availability ofserotonin. In addition patients with major depression Prof. Dr. P. Hofmann Æ Dr. T. Lahousen Æ Dr. N. Dittrich exhibited a stronger mood decrease than healthy Prof. Dr. G. Bertha Æ Dr. K. Hasiba Æ Dr. F. A. MahnertProf. Dr. H.-P. Kapfhammer Æ Dr. R. Ille (&) received a balanced amino acid mixture showed no change of mood [Based on these results attempts were made to replace or supplement antidepressant therapy by a therapeutic increase of the tryptophan 711 levels primarily by means of an oral application of L- Table 1 Sociodemographic characters of subjects A backlash of such approaches occurred in 1989 when contaminations in tryptophan preparationscaused an epidemic outbreak of the eosinophilie- myalgie syndrome in the USA and tryptophan was Recent investigations could corroborate earlier re- sults and showed that tryptophan enhance the mood of depressive patients compared to placebo [ Levitan et al. ] found that the mood of depressive patients after a 1-week therapy by fluoxetine plus 2– 4 g tryptophan/d was enhanced superior than by a therapy with fluoxetine plus placebo. In spite of this,such approaches could not be established in psychi- % = percentage, M = mean, SD = standard deviation atric therapy schemes. One reason for this is the factthat the efficacy for moderate and severe depressionswas not sufficient [This also was true for the drug may be avoided by application of an acid preparation ‘‘Kalma’’ which has been registered since 1988. It is containing all essential amino acids based on indi- synthesized from L-tryptophan and used only in mild depressions and as ‘‘add-on’’ therapy on subjects on This study was aimed at examining the effects of an an antidepressant. Only high dosages of tryptophan were reported to increase mood and to improve improvement of symptoms of depression in patients insomnia but simultaneously increasing the rate of undesirable side effects such as eosinophilia myagliasyndrome, liver damage or development of a cataract.
This treatment did not offer an advantage compared to Only a few studies were done to examine plasma concentrations other than tryptophan. Kishimoto andHama ] reported that plasma levels of tyrosin were About 48 in-patients (36 women, 12 men) out of a pool of 233patients at the University Hospital of Psychiatry, Graz, Austria were significantly lower in depressed patients than in included to the study. All patients gave informed consent to the controls and increased after the period of depression.
study, which was approved by the institutional review board of the Plasma concentrations of taurine and lysine were General and University Hospital of Graz.
increased for patients with a major depression , Inclusion criteria were the diagnosis of major depression whereas Tachiki et al. ] showed decreased levels of according to the criteria of DSM IV; [and indication of Rem-eronÒ (agent mirtazapine), applied with agitation and sleep dis- taurine in depressed patients. Mathis et al. ] found turbances being in the front of the depressive pathology.
increased levels of valin, leucine and isoleucine in Mirtazapine is a potent antagonist of central a2-adrenergic auto- and heteroreceptors, is an antagonist of both 5-HT2 and 5-HT3 Goldberg could reduce the dose of ampheta- receptors possibly preventing side effects associated with nonse-lective 5-HT activation and contributing also to the anxiolytic and mines after an oral therapy with L-tyrosine for patients sleep-improving properties of mirtazapine. Mirtazapine has mini- with a deficiency of norepinephrine. Sabelli et al. mal effects on monoamine reuptake and it enhances noradrenalin reported a successful therapy with phenylalanine transmission. Blockade of presynaptic a2 noradrenergic autore- of depressed patients compared to healthy controls.
ceptors leads to increased norepinephrine release [ Most patients suffered from a recurrent depression (Table No differences in the therapeutic effects of the anti- with 2–5 episodes in their history. The duration of the current depressant imipramine and of DL-phenylalanine were episode was about 7–30 days before admission. For pretreated noted when using the scores of the HAM-D scale ].
patients (82.5%) the previous antidepressant was tapered within Improvement of current therapies is an important 4 days and patients were changed to RemeronÒ.
issue in health policy. Previous findings on a rela- Exclusion criteria were other psychotic disorders, pregnancy, cancer and all aminoacidopathies and an additional medication tionship between deficiencies and increased plasma with another antidepressant than RemeronÒ.
concentrations of some amino acids in depressed Seven patients dropped out early after a change of the antide- patients and on oral treatment with amino acids are pressant due to incompatibility, ineffectiveness or a strong increase very inconsistent. Furthermore, therapeutic use of a of weight, and one woman was excluded during the course of thestudy because of a later diagnosed co-morbidity of major depres- single amino acid may result in an imbalance of sion with a distinct panic disorder. Thus, 40 patients were entered amino acids within the body as corroborated by the into the study. Twenty of the patients (17 women, 3 men) received negative effects of the ‘‘depletion’’ experiments. Pre- RemeronÒ and a mixture of amino acids, another 20 patients (14 liminary investigations have shown that plasma con- women, 6 men) were allotted to the placebo group receivingRemeronÒ plus placebo preparation. As an influence of nutrition centrations of the essential amino acids are correlated on plasma concentration of several amino acids could be expected significantly. Therefore, an imbalance of amino acids patients were matched respective to their hospital diet.
Table 2 Normal ranges of plasma concentrations (lmol/l) and mean plasma concentrations of the 20 amino acids in the experimental and the control group at theterm of admission (T1) and after a 4-week therapy (T2) M = mean, SD = standard deviation* CAA: sum from plasma concentrations of tyr, phe, val, ile, leu Sociodemographic characters of patients are reported in widely used observer-rating scale used for the evaluation of drug trials in depression [], and by a self-report using the ‘‘BeckDepression Inventory’’ (BDI; []) on the day of admission andafter 4 weeks of treatment. According to DSM IV one of the characteristics of a major depression episode is suicidal behaviourbeing an additional risk of this affective disorder. Therefore we A randomized double-blind placebo-controlled design was used in additionally recorded the value at the scale ‘‘auto-aggression’’ of the present study meaning that neither the patients nor the the ‘‘Fragebogen zur Erfassung der Aggressivita¨tsfaktoren’’ (FAF; attending physicians or the nursing staff knew if the verum or the []) being a reliable indicator for suicidal behaviour The placebo was given. Fasting blood samples were taken the day after benefit/risk ratio of the medicinal treatment was estimated by the admission and after 4 weeks of therapy. Analyses of the plasma ‘‘Clinical Global Impression-Test’’ (CGI; ]). Patients were levels of 20 amino acids (aspartic acid, glutamic acid, asparagine, treated by 30–60 mg/d RemeronÒ (mean dosage 34 mg ± 12.3) serine, glutamine, histidine, glycine, threonine, citrulline, tyrosine, depending on individual requirement and either an amino acid valine, methionine, tryptophan, phenylalanine, isoleucine, leucine, preparation or placebo. Subjects of the experimental group were ornithin, lysine, taurine, arginine) were performed by HPCL (high administered a free form amino acid mixture formulated pressure liquid chromatography) using a Hewlett Packard Series according to measured plasma levels. This consisted of a base 1100 HPLC and a pre-column derivatisation [Eight of these formulation containing the Recommended Daily Allowance (RDA) amino acids are essential (isoleucine, leucine, lysine, methionine, doses of 8 essential and 2 semi-essential amino acids (arginine phenylalanine, threonine, tryptophan und valine), they cannot be and histidine) in pharmaceutical grade and free form. Additional produced by the human body and must be provided by nutrition.
amounts of specific amino acids were added to this mixture if the Data were standardized to internal and external norms. Internal amino acid was below an optimized reference range as described norms were used for correcting potential losses during analysis and external norms for determination of calibration factors as not In addition, the amino acid preparation contained the vitamins all amino acids show similar signal strength at similar concen- ß-carotine, C, E, B1, B2, B6, B12, folic acid, pantothenic acid, nic- otinamide, biotine and additionally zinc, magnesium and selenium.
As controls of most previous studies are based on very small These vitamins and trace elements were dosed according to their samples amino acid plasma concentrations of the patients were RDAs and are obligatory as co-factors for the metabolism of the compared to normal ranges of amino acids published by Pangborn amino acids. The amino acids used were of herbal origin pre- ] previously. In this study healthy persons were characterized by dominantly. The mixture was prepared and administered to the nitrogen balance showing no defects of enzymes necessary for patients 5 ± 2 days after the aminogram has been figured. Patients amino acid metabolism. This normal range was used by Bralley [] of the experimental group got a dose of 5 g of the amino acid in a similar study (Table recently. Our experiences have shown mixture three times/day 15 min before the principal meals as a that also patients being within the low 20% of normal range fre- water soluble powder. Patients of the control got the same portion quently report different disturbances of health, therefore we in- of a placebo mixture, which was comparable to the verum as to cluded these values for group comparison.
Severity of depression was measured by external rating using After 4 weeks of therapy amino acid plasma concentrations and the ‘‘Hamilton Depression Scale’’ (HAM-D; []) being the most psychometric measures were analysed once more.
Table 3 Mean values of the psychometric tests for the experimental and the control group at the term of admission (T1) and after a 4-week therapy (T2) M = mean, SD = standard deviation* Age- and gender-related norm values (stanines) [] (Table No dosage dependent effect of RemeronÒcould be observed.
For comparison of groups, two-factor between subject ANOVAs,mixed factorial ANOVAs, independent means t-tests, Wilcoxon Patients after therapy also showed lower scores for signed-rank tests, McNemar tests and Friedman tests were calcu- auto-aggression (F = 6.33, p = 0.016) but there was lated, and chi-square tests for testing frequency distributions. Al- no difference between groups. Patients with suicidal pha level significance was set at 0.05 for all statistical tests. For behaviour showed higher values of auto-aggression correction of multiple testing a bonferroni correction was done.
than those without suicidal behaviour even aftertherapy (6.4 ± 1.2 vs. 4.2 ± 2.2, t = )4.00, p = 0.000).
Values on the CGI were slightly lower after treatment than on admission (F = 5.03, p = 0.031) suggestingan improvement of the disease but there was no dif- Frequency distributions of the demographic parame- ters did not differ between groups (Table On Mean baseline plasma levels of aspartic acid and admission patients of the experimental group showed glutamine were below the normal range for both higher values of depression (HAM-D: t = )3.87, groups, additionally valine within the experimental p = 0.000) than patients of the placebo group (Ta- group and asparagine within the placebo group (Ta- ble Patients with suicidal behaviour (ideations or ble Histidine, valine and glutamic acid were below earlier suicide attempts) scored higher for auto- the normal range especially frequent for patients of the experimental group, serine, asparagine and aspartic acid and glutamine for patients of the placebo The average plasma levels of the 20 amino acids group and glutamine for patients of both groups but and proportion of patients with levels in the range of the two groups did not differ respective to frequencies the lower 20% and below the normal range did not of low-level amino acids (Table ). After therapy differ between groups at the term of admission (Ta- mean concentration of asparagine in the experimental bles ). Average dosage of RemeronÒ (Table did group and of aspartic acid in the placebo group were not differ between groups (p < 0.10). Controlling for below normal range, besides plasma level of serine for the dosage of RemeronÒ we could find a significant both groups (Table Glycine and asparagine were effect of therapy as a decrease of scores on the HAM- below the normal range for most patients of the D-scale (F = 11.39, p = 0.002) and a significant experimental group, aspartic acid for patients of the interaction between therapy and group allocation placebo group, and serine and glutamine for patients (F = 18.28, p = 0.000). After therapy the patients of of both groups (Table Additionally, a high pro- the experimental group showed lower depression portion of patients of both groups showed levels of scores than those in the placebo group (Table The most amino acids being in the lower 20% of the mean difference between depression values before normal range at both measuring times. Also after and after therapy (experimental group: 19.0, placebo therapy the two groups did not differ respective to group: 8.6) was higher in the amino acid group than frequencies of low-level amino acids, and no changes in the placebo group (t = )4.31, p = 0.000) indicating could be demonstrated between baseline and mea- a greater therapy effect in patients of the experimental surement after therapy. Only for taurine more pa- group. Proportion of responders (reduction in the tients of the experimental group had levels within the HAM-D Rating Scale >50%) differed between groups norm range (v2 = 12.00, p = 0.001) (Table Plasma (experimental group: 66.7%, placebo group: 33.3%; levels of serine were lower after therapy than before v2 = 9.23, p = 0.002) but proportion of remitters (F = 9.04, p = 0.005). There was an interaction be- (score on HAM-D-scale after therapy <7) was not tween therapy and group allocation for taurine different (experimental group: 64.7%, placebo group: (F = 9.13, p < 0.05). After therapy plasma levels of 35.3%; v2 = 2.56, p = 0.110). A significant therapy · taurine were higher in patients of the experimental group interaction (F = 6.14, p = 0.018) could also be group than in these of the placebo group. For all the shown for the self-reported depression on the BDI other amino acids no changes and no differences Table 4 Proportion of patients with deficient amino acid plasma concentrations at the term of admission and after a 4-week therapy )1: in the range of the lower 20% of the normal range depending on group allocation were found after risk sufficiently. A therapeutic effect of the amino therapy. Baseline values of ‘‘auto-aggression’’ showed acids could be shown on the basis of both depression a weak correlation to the levels of valine (r = )0.29, scales. Patients, which had received the amino acid p = 0.074) and methionine (r = )0.28, p = 0.079).
mixture scored lower on these scales than patients of After therapy we only found significant correlations the placebo group despite starting with significant between psychic parameters and amino acid plasma higher depression scores. This more unfavourable concentrations within the placebo group: Values on start data of patients of the experimental group was a the BDI were correlated to levels of isoleucine consequence of the randomised classification of pa- (r = 0.65, p = 0.002), leucine (r = 0.70, p = 0.001) tients for the two groups. The proportion of variance and glutamine (r = 0.60, p = 0.005), values of HAM-D defined by the interaction between therapy and group were slightly correlated to levels of leucine (r = 0.45, allocation was 33.1% (HAM-D). The difference be- p = 0.048), and values on the CGI were correlated to tween the depression scores of patients of the two levels of isoleucine (r = 0.61, p = 0.004) and leucine groups after therapy was 4.5 points, which means a (r = 0.70, p = 0.001). No therapy or group effect medium effect size of 0.63 []. The effect size for the could be shown for relation between tryptophan and self-rating scale (BDI) was 14.2% (2.8 points of dif- the big neutral amino acids (tyrosine, phenylalanine, ference) showing that patients themselves observed a smaller therapeutic effect than the attending psychi-atrists. Patients of the experimental group also morefrequently responded to the therapy showing a high response rate of 67%. As RemeronÒ is a very efficientantidepressant an additional effect of the amino acid Therapy with the antidepressant RemeronÒ and application means a therapeutic benefit.
additional application of amino acids or placebo re- Analyses of amino acid plasma levels showed eight duced depression scores of the ‘‘Hamilton Depression amino acids being most frequently deficient on Scale’’ and of the scale ‘‘auto-aggressions’’ and slightly admission as follows phenylalanine, aspartic acid, decreased the values of the ‘‘Clinical Global Impres- asparagine, tryptophan, histidine, valine, serine and sion-test’’ which should give a global impression of glutamine whereas phenylalanine, histidine and valine patients’ health. Patients who had reported suicidal are essential amino acids. Histidine and valine are behaviour (ideations and/or attempted suicides) indicators for an increased demand of amino acids in scored higher on the scale ‘‘auto-aggression’’ indi- cating that this therapy could not decrease suicidal exceeds protein synthesis under such unfavourable conditions. As amino acids cannot be stored in the effect and a stabilization of the amino acid levels may body a continuous supply by diet is necessary. If be expected after 4–5 weeks at the earliest. Further- deficiencies occur during increased stress or diseases more, it was reported previously that amino acid availability of amino acids is not sufficient for mus- serum levels rise after amino acid supplementation cles, neurotransmitters in brain and hormone syn- but decline rapidly due to their metabolism [ thesis [To prevent such deficiencies in the Taurine was the only amino acid with an increase course of the depressive episode the additional supply after therapy in patients of the experimental group.
of amino acids is the basis of our therapeutic ap- This may be due to the better resorption of taurine proach. Depressions are connected with a deficiency compared to the other amino acids. The serine levels of the neurotransmitters serotonin and norepineph- were even lower for both groups after therapy than at rine in particular. Phenylalanine, which was lowered baseline. A possible explanation is that serine is a very in 90% of the patients at least serves as source for reactive amino acid with high concentrations in all norepinephrine. Tryptophan being lowered in 90% of cell membranes. The supply of amino acids could the patients, too, is the precursor for the neuro- result in an increase of metabolism with an increased transmitter serotonin, which is not available in suffi- consumption of amino acids. As the additionally cient amounts in depressed subjects showing the supplied amino acids will be reabsorbed and metab- typical symptoms like depressed mood and sleep- olised very rapidly a relative deficiency of serine can lessness. Decreased levels of tryptophan also may be observed As certain amino acids are starting result in increased aggressiveness [This is substances of other amino acids their concentrations important for therapy of depressed patients as high are not independent. Our data show movements of values of auto-aggression are an indicator for suicidal concentrations between certain amino acids between risk A comparison of the levels of tryptophan the two times of measurement. Therefore, in addition and the neutral amino acids with control groups of to a deficiency of amino acid plasma concentrations a other studies , ] showed that levels of our loss of balance may be important for the development patients were significantly lower but were in accor- of a depressive episode. The importance of balance is dance with the values of the corresponding experi- also indicated by the ‘‘depletion studies’’ with tryp- mental groups (patients with a major depression tophan whereas amino acid mixtures without tryp- respectively women before delivery). This also con- tophan resulted in a depressive mood [, ]. Also cerned the ratio of total tryptophan to neutral amino the technical information of the manufacturer firm of acids, confirming the results of Cowen et al. [We ‘‘Kalma’’ with the agent L-tryptophan includes the could show a positive relation between values of passage to avoid nutrition poor of proteins when depression and the plasma levels of leucine and iso- taking this drug for preventing an imbalance of amino leucine, two of these neutral amino acids. They are transported to the brain by the same transport system We found no correlation between severity of than tryptophan and therefore compete for the same depression and amino acid plasma concentrations carrier proteins Hence, this relation represents before or after therapy. This is according to the results also a better indicator for availability of serotonin of Altamura et al. [Whereas Moller et al. ] than the absolute plasma concentration of tryptophan showed positive correlations between levels of tryp- tophan, tyrosine and the neutral amino acids ratio Therapeutic effect of RemeronÒ and the optimized and the values on the HAM-D after therapy with cit- amino acid preparation or placebo were not related to a change of amino acid plasma levels or a decrease of Our results show an improvement of the antide- proportion of patients with lowered plasma levels.
pressant pharmacological therapy by application of Neither the antidepressant RemeronÒ nor the amino an amino acid mixture in addition to the antide- acid preparation led to verifiable increase of amino pressant RemeronÒ. The intake of RemeronÒ re- acid concentrations. This was contrary to our expec- sulted in an increase of appetite and weight for some tations but antidepressants may result in different patients with change of antidepressant and a dropout effects on changes and displacements of the amino of study. The amino acid mixtures showed no side acid plasma concentrations during course of medi- effects resulting in a better compliance and an in- cation. Thus, Mauri et al. [reported that a therapy crease in the benefit/risk ratio. A restriction of using with fluvoxamine had no effect on tryptophan con- amino acids concerns depressed patients treated with centrations. Whereas Bralley et al. [found an monoamino oxidase inhibitors, which may lead to an improvement of symptoms of the ‘‘chronic fatigue overload with tryptophan/serotonine.
syndrome’’ related to an increase of amino acid Decreased concentrations of amino acids being the plasma concentrations after a 3 months application of starting substances for neurotransmitters are only one reason for the development of a depression. Avail- In the present study amino acid application could ability of neurotransmitters in the brain are also re- only be performed over a period of 4 weeks because stricted by dysfunctions of their transfer between the of the time limit of the stay at the hospital. But an nerve cells, e.g. due to low density of receptors in the brain. Further influencing factors are the transfer of pramine or fluoxetine: implications for the role of serotonin in amino acids into the cell (cellular availability of the mechanism of antidepressant action. Biol Psychiat 46:212–220 amino acids) and the biosynthesis of final products 14. Demyttenaere K, Haddad P (2000) Compliance with antide- from the precursors. Therefore, it is not clear how pressant therapy and antidepressant discontinuation symp- much of the amino acids attain to the brain with macrobiotic supply. Furthermore, individual opti- 15. Dougherty DM, Moeller FG, Bjork JM, Marsh DM (1999) mum of amino acid concentrations within normal Plasma L-tryptophan depletion and aggression. Adv Exp MedBiol 467:57–65 range is unexplained. Indeed, this is a problem con- 16. Evans L, Golshan S, Kelsoe J, Rapaport M, Resovsky K, Sutton cerning all reference ranges in medicine. Limitations L, Gillin JC (2002) Effects of rapid tryptophan depletion on of our results are also conditioned by the fact that sleep electroencephalogram and mood in subjects with partially there may be an interaction of effects between Rem- remitted depression on bupropion. Neuropsychopharmacol27:1016–1026 eronÒ and the amino acids. Although placebo-con- 17. Farkas T, Dunner DL, Fieve RR (1976) L-Tryptophan in trolled trials with antidepressants are accepted to be essential [the effect of amino acids being expected 18. Fernstrom JD, Wurtman RJ (1972) Brain serotonin content: was not strong enough allowing a comparison without physiological regulation by plasma neutral amino acids. Science178:414–416 19. Goldberg I (1980) L-Tyrosine in depression. Lancet 16:364 Further studies are necessary to find out whether 20. Gronier B, Azorin JM, Dassa D, Jeanningros R (1993) Evidence for mild to moderate depressed patients a dosage for a defective platelet L-tryptophan transport in depressed reduction of antidepressant with add-on of amino patients. Int Clin Psychopharmacol 8:87–93 acids or even a mono-therapy with amino acids may 21. Hamilton M (1976) Hamilton depressions scale. In: Guy W (ed) ECDEU Assessment Manual for Psychopharmacology. Rev. Ed.
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