0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Rapid Tryptophan Depletion, Sleep Electroencephalogram, and Mood in Men With Remitted Depression on Serotonin Reuptake Inhibitors FREE

Polly Moore, BA; J. Christian Gillin, MD; Tahir Bhatti, MD; Anna DeModena, BA; Erich Seifritz, MD; Camellia Clark, MD; Stephen Stahl, MD, PhD; Mark Rapaport, MD; John Kelsoe, MD
[+] Author Affiliations

From the Department of Psychiatry, University of California, San Diego Mental Health Clinical Research Center, VA San Diego Health Care System (Mss Moore and DeModena and Drs Gillin, Bhatti, Seifritz, Clark, Stahl, Rapaport, and Kelsoe); and the National Multi-Site Training Program in Basic Sleep Research, University of California, Los Angeles (UCLA) Neuroscience Interdepartmental Graduate Program, UCLA Brain Research Institute (Ms Moore).


Arch Gen Psychiatry. 1998;55(6):534-539. doi:10.1001/archpsyc.55.6.534.
Text Size: A A A
Published online

Background  In previous studies, depletion of brain serotonin by administration of a tryptophan-free amino acid drink (TFD) (1) temporarily reversed the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) in euthymic patients who had a history of major depression, and (2) enhanced rapid eye movement (REM) sleep in normal volunteers. In this study, we hypothesized that the TFD would not only increase depressive symptoms but also the propensity for REM sleep in euthymic patients treated with SSRIs.

Methods  Ten fully remitted, medicated male patients who had a history of major depressive episode ingested a 100-g TFD (the experimental dose) or a 25-g TFD (designed to be the control drink) in double-blind, random order on separate days. The effects were assessed with mood ratings, plasma tryptophan concentrations, and an all-night sleep electroencephalogram.

Results  The TFDs produced a dose-dependent reduction in plasma tryptophan concentrations, sleep latency, and REM latency, as well as increased REM percentage, REM minutes, REM density, and total sleep time. Neither strength of TFD altered mood to a clinically significant degree.

Conclusions  Although the TFD affected plasma tryptophan concentrations and various sleep measures, our study did not confirm previous reports that TFD temporarily reversed the antidepressant effects of SSRIs in euthymic patients. Our patients, however, had been treated for a longer period with SSRIs and were more fully remitted at the time of the study. Our results suggest that TFD-induced relapse in SSRI-treated patients in remission decreases as a function of treatment duration, degree of remission, or both.

SEROTONIN (5-hydroxytryptamine, 5-HT) has been implicated in the pathophysiology of depression, in the mechanism of action of some types of antidepressants, and in sleep and neuroendocrine abnormalities associated with depression.1

Rapid reduction of plasma tryptophan by a tryptophan-free amino acid drink (TFD) seems to deplete central serotonin concentrations in humans2 and in animals.36 Delgado et al7 reported that a TFD temporarily reversed antidepressant-induced clinical remission in euthymic patients treated with selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs), but not in patients treated with tricyclic antidepressants. Transient mood-lowering effects of the TFD have been seen in healthy male subjects as well.8

In terms of sleep, serotonergic neurotransmission apparently inhibits rapid eye movement (REM) sleep in humans and animals. Administration of a TFD reduces REM latency (RL) (elapsed time between sleep onset and the first REM period) and increases REM percentage in normal male volunteers.9 Consistent with the serotonergic depletion hypothesis for depression, patients with moderate to severe depression often display short RL, increased REM percentage, and increased ocular activity during REM sleep (increased REM density [RD]) compared with normal controls. Furthermore, administration of SSRIs increases RL and reduces REM percentage in healthy controls9 and in depressed patients.10,11 In addition, "activation," insomnia, reduced total sleep time (TST), and sleep efficiency (SE) are common side effects seen in depressed patients treated with SSRIs.12,13

This study examined the effect of acute tryptophan depletion on mood measures and sleep in euthymic depressed patients currently treated with SSRIs. Based on the studies of Delgado et al,7 we expected that the TFD—a 100-g mixture of amino acids—would significantly increase depressive symptoms. Furthermore, based on preclinical studies in animals and on our sleep studies in normal volunteers, we predicted the following: (1) that REM measures would be suppressed at baseline compared with a group of matched never-depressed comparison subjects and (2) that the TFD would shorten RL, increase REM percentage, and increase RD in these patients. When we designed this study, the Food and Drug Administration did not permit the administration of tryptophan because of the eosinophilia-myalgia syndrome that had been associated with synthetically made tryptophan. We chose a one quarter–strength dose of the TFD (25 g of amino acids) as our control drink based on both personal communication (Pedro Delgado, MD, and Norman Rosenthal, MD, oral communication) and previous publications indicating that the quarter-strength TFD did not affect plamsa concentrations of tryptophan.

Ten euthymic white male patients (mean [±SD] age, 42.5 ± 12.1 years) who had a history of a major depressive episode completed this study (Table 1). Patients were recruited from outpatient clinics at the San Diego Veterans Affairs Medical Center, San Diego, Calif, and by public announcements on radio and television, and in the newspapers. They were paid for their participation, and gave written informed consent to participate in the study.

Table Graphic Jump LocationTable 1. Demographic, Diagnostic, and Baseline Mood Variables of the Subjects

Inclusion criteria were the following: (1) a history of a major depressive episode in full remission for at least 2 months by the clinical judgment of the patient and a psychiatrist, (2) on-going treatment with only an SSRI and no other major psychotropic medications, (3) a score below 7 on the 17-item Hamilton Rating Scale for Depression (HRSD),14 and (4) no other recent or current major comorbid medical, psychiatric, or substance abuse disorders. All subjects underwent a full medical and psychiatric diagnostic interview, physical examination, screening medical laboratory tests (chemistry panel, complete blood cell count, urinalysis, electrocardiogram, human immunodeficiency virus screen, and drug screen), a formal structured diagnostic psychiatric interview (Structured Clinical Interview for DSM-III-R [SCID]), and ratings of symptoms with the HRSD and Profile of Mood States (POMS).15 Diagnostic interviewers and raters were trained and tested for reliability by the Diagnostic and Rating Core of the University of California, San Diego (UCSD) Mental Health Clinical Research Center (MHCRC).

As given in Table 1, patients were virtually euthymic. This was the first depressive episode for 3 patients; the second for 3 patients; the third for 2 patients; and the fourth and fifth depressive episode for the remaining 2 patients. Two of the 10 patients had prior psychiatric hospitalization. For 5 patients, this was the first trial with antidepressants; for 2 patients it was the second, and for 3 patients it was the third.

We excluded female patients because of increased vomiting compared with men with the 100% TFD (ie, 4/4 women, 2/20 men).

Patients received their usual dose of antidepressant throughout the protocol, including the day of the TFD challenge.

Patients ate a low-tryptophan diet starting at dinner the night before administration of the TFDs. The diet contained 9623 kJ/d (2300 kcal/d) and 48 g/d of protein, but only 160 mg/d of tryptophan. The TFD contains 15 amino acids in the same proportion as human milk, except that tryptophan, aspartic acid, and glutamic acid are omitted.16 The 100%-strength TFD mixture weighed a total of 102.5 g, the 25-g or 25%-strength TFD was one quarter strength. Both TFDs were served with chocolate-flavored syrup in a 300-mL "slurry" with crushed ice. Methionine, cysteine, and arginine were given in blinded pill form (21 pills per TFD challenge) because of the bitterness and unpalatability they added to the drink. The blood samples for tryptophan were collected with EDTA, centrifuged, and frozen (−80oC) until analysis. Free plasma tryptophan and total plasma tryptophan concentrations were determined using a modified fluorometric method.17

Current mood was assessed by blinded raters (κ= 0.82), using a modified 19-item version of the HRSD, based on the 24-item HRSD excluding items 4 through 6 (pertaining to insomnia/sleep), 16 (weight change), and 18 (diurnal variation). Patients also completed the POMS and a side effects symptom checklist was also administered.

At 2:30 PM, mood ratings and 10 mL of blood for tryptophan levels were obtained. At 3 PM, either the 25% TFD or the 100% TFD was given, in double-blind, randomized, cross-over fashion. At 11 PM, mood ratings, a side effects scale, and a blood sample were obtained. Polysomnographic recordings were conducted from about 11:30 PM until about 6:30 AM on an adaptation night (including screening for sleep disorders), a baseline night, and 2 experimental nights following either the 25% TFD or the 100% TFD. Challenge nights were separated by at least 48 hours.

Electroencephalogram, bilateral electrooculogram, chin electromyogram, and electrocardiogram were recorded all night. Records were visually scored in 30-second epochs according to standard criteria18 by well-trained sleep technicians (interrater reliability of >0.80) blind to experimental condition. Sleep variables are briefly defined as follows. Time in bed is the time in minutes from "lights out" until "lights on." Total sleep time is the time in bed minus any awake time. Sleep efficiency is the TST divided by the time in bed, expressed in percentage value. Sleep latency (SL) is the time in minutes from "lights out" until the first onset of stage 2 or REM sleep, with less than 1 minute of wakefulness within the first 10 minutes. Wakefulness after sleep onset is the time spent awake after sleep onset. Rapid eye movement minutes is the total number of minutes of REM sleep. Rapid eye movement percent is the time spent in REM sleep divided by TST. Rapid eye movement latency is the time in minutes from SL until first onset of REM sleep. Rapid eye movement latency corrected is the time from SL until first REM minus any intervening minutes of wake. Rapid eye movement density is a visually estimated measure of ocular activity during REM sleep, scored on a scale of 0 to 4 per epoch, but presented as 0 to 8 per minute of REM.

For the sleep analysis, a post hoc comparison group of 10 healthy, never-depressed men was culled from our medical record archives by matching for age (43.1±11.5 years; range, 24-59 years), ethnicity, and time of year (±2 months).

Each morning, a General Sleep Questionnaire was administered. General Sleep Questionnaire items included the following: (1) how long did it take you to fall asleep last night; (2) how much total sleep do you feel that you had last night; (3) how many times did you wake up during the night; (4) how long do you feel you were awake in the night, in minutes; (5) rate the quality of your sleep on a scale of 1 to 10 (1=poor and 10=excellent); (6) rate how well rested you feel this morning on a scale of 1 to 10 (1=poor and 10=excellent).

Although we initially assumed that the 25% TFD would be a placebo, it was physiologically active; in fact, its effects on sleep were similar to the 100% TFD, in both normal controls19 and in study patients. Therefore we used a repeated measures analysis of variance for a within-subjects factor (baseline, 25% TFD, 100% TFD). Pairwise comparisons were done using Student t tests. Values less than .05 were considered statistically significant.

Change scores were calculated from pre-TFD to post-TFD for total and free plasma tryptophan at the 25%- and 100%-TFD strengths. Pearson product moment correlation coefficients were calculated between sleep electroencephalographic variables and plasma levels or between sleep and plasma change scores. All values were expressed as mean (±SE).

PLASMA TRYPTOPHAN MEASURES

Eight hours after ingesting the 100% TFD, total and free plasma tryptophan concentrations decreased significantly (P<.001, 61.4% [from 48±9 µmol/L to 19±4 µmol/L], and 52% [from 5±1 µmol/L to 2±1 µmol/L], respectively). With the 25% TFD, these measures decreased but not to a statistically significant degree (4% and 5.6%, respectively).

SLEEP MEASURES

At baseline, the SSRI-treated patients showed prolonged SL and RL and decreased TST, REM sleep (in minutes and percentage), and RD relative to the comparison group (Table 2). Compared with baseline, the TFDs, in a dose-dependent manner, were associated with significantly reduced SL and RL and increased TST, REM sleep (in minutes and percentage), and RD. The patients on the 100% TFD were restored to normal limits for TST, and while both SL and sleep efficiency somewhat improved, both remained outside normal limits. The REM sleep measures, however, "overshot," relative to the comparison group: RL went from too long to too short, and REM sleep (in minutes and percentage) and RD went from too low to too high.

Table Graphic Jump LocationTable 2. Results of All-Night Polysomnographic Measures*

None of the General Sleep Questionnaire items were significantly different across conditions (baseline, 25% TFD, 100% TFD).

None of the correlations between the absolute sleep measures and plasma tryptophan levels (total or free) were statistically significant. In addition, the sleep change scores (baseline to TFD night) did not correlate with the plasma tryptophan concentration change scores (from pre-TFD to post-TFD).

MOOD MEASURES

Although the mean 19-item HRSD score increased significantly about 8 hours after the 100% TFD compared with both baseline and the 25% TFD, the changes were small (<2 points total) and clinically insignificant. And, although the Depression subscale of the POMS did not change, other POMS subscales (Vigor, Elation, and Friendliness) significantly changed in a depressivelike direction following both the 25% and 100% TFDs (Table 3). In addition, the POMS subscale score of Confusion also increased significantly at the 100% TFD compared with the other 2 conditions.

Table Graphic Jump LocationTable 3. Effects of Tryptophan-Free Amino Acid Drinks (TFDs) on Mood Measures*

In our euthymic, fully remitted, male patients maintained on SSRIs, the TFD unexpectedly failed to reverse the antidepressant benefits of the SSRIs, previously reported by Delgado et al.7,16 Nevertheless, both the 25% and the 100% doses of TFD significantly reversed the REM-suppressing effects of SSRIs in a dose-dependent fashion, increased reduced TST, and shortened SL. In addition, the 100% TFD, but not the 25% TFD, significantly reduced both free and total plasma concentrations of tryptophan.

Our failure to reverse the antidepressant effects of SSRIs may reflect pronounced differences of our patient sample compared with patient samples previously reported. First, our patients had been treated for 2 to 13 months vs 2 to 6 weeks at the time of the TFD challenge. Second, our patients were less depressed (mean 24-item HRSD score at baseline, 1.75; range, 1-6); compared with others (modified 25-item HRSD mean score, 8.4; range, 1-19). Third, we administered the TFD in the midafternoon (3 PM) in contrast with the 9 AM ingestion typically used by other groups. Absolute plasma tryptophan levels20 as well as the ratio of tryptophan to other large neutral amino acids21 vary in a circadian fashion, which may influence tryptophan availability and transport into brain.

In patients treated with MAOIs who were remitted for approximately 2 to 3 weeks, administration of the tryptophan hydroxylase inhibitor, para -chlorophenylalanine (PCPA), which depletes serotonin, induced a relapse of depressive mood.22 These observations support the hypothesis that reversal of antidepressant treatment by any method of serotonin depletion is more likely in partially remitted patients than in fully remitted patients, and is more likely early rather than later in SSRI or MAOI treatment.

To an extent, the clinical studies with the TFD are consistent with this preclinical concept that different antidepressant treatments (tricyclic antidepressants, MAOIs, SSRIs, and electroshock therapy) induce a cascade of neurochemical changes that evolve with long-term treatment.23 The SSRIs seem to down-regulate somatodendritic serotonin1A and terminal serotonin1D inhibitory autoreceptors, as well as postsynaptic serotonin1A and serotonin 2 receptors.2331 Postsynaptic serotonin1A receptors are especially prominent in limbic brain regions.32 This tempts us to speculate that long-term SSRI treatment leads to serotonin1A-receptor sensitivity changes preferentially in limbic regions, as compared with brainstem regions involved with initiating REM sleep, such as laterodorsal tegmental/pedunculopontine tegmental nuclei. Thus, REM sleep may remain somewhat sensitive to the effects of acute tryptophan depletion, whereas mood may not.

Our results are consistent with the hypothesis that serotonin inhibits REM sleep. Not only were the patients receiving SSRIs REM suppressed at baseline sleep (pre-TFD challenge), but the TFD reversed the REM inhibition associated with SSRIs.

Our observations also suggest that serotonin itself is responsible for some of the "activating" side effects associated with SSRIs and MAOIs. The TFD reversed the prolonged SL and reduced TST of the patients. We have previously reported that ipsapirone, a serotonin1A-receptor agonist, increased SL and reduced TST in both normal controls and depressed patients.33 Furthermore, in an 8-week, double-blind trial of nefazodone (a so-called SARI, serotonin2 antagonist/reuptake inhibitor, that combines serotonin reuptake blocking properties with antagonism at serotonin2 receptors) and fluoxetine, SE fell in the group receiving fluoxetine but increased in the group receiving nefazodone.13 Perhaps the activating effects of the SSRIs are mediated through the serotonin2 receptor.

The experimental design reported in this study, in retrospect, was not optimal, because it was based on the assumption that the 25% TFD was a placebo. Order effects cannot be ruled out because the baseline night always occurred prior to the 2 TFD challenges. Second, the baseline night was not blinded in the same fashion as the experimental nights. Third, the subjects ate a low tryptophan diet and had blood samples drawn prior to bedtime on the TFD nights but not on the baseline night. Nevertheless, despite these unanticipated problems in research design, the sleep and mood data on the baseline nights fall within expected values for remitted patients currently treated with SSRIs. Second, the 25% and 100% TFDs were administered in random order, in a double-blind manner. Third, the 2 TFDs had the anticipated effects on plasma tryptophan concentrations and on polygraphic sleep measures.

The evidence that the TFD exerts its effects by reducing central serotonergic activity is circumstantial. By reducing plasma-free tryptophan levels, the TFD presumably limits synthesis of serotonin. Consistent with this hypothesis, brain serotonin neurons apparently use up available serotonin stores about 1 to 2 hours after tryptophan is depleted from superfusate in the slice preparation.34 Furthermore, serotonin release is diminished (1) in the slice after superfusion with a tryptophan-free large neutral amino acid (LNAA)–supplemented medium35; and (2) in the anesthetized rat, raphe neurons 2 hours after intake of a tryptophan-free amino acid load.36

In vivo, however, tryptophan transport from plasma across the blood-brain barrier apparently depends not only on plasma levels of tryptophan but on plasma levels of other LNAAs. A reduced ratio of trytophan to LNAAs may decrease brain tryptophan levels even without significantly changing absolute plasma tryptophan. In a recent study with a few subjects, a 25% TFD administered in the midafternoon did not significantly change the tryptophan-LNAA ratio in plasma samples taken prior to bedtime.37 In our study, the 25% TFD did not alter plasma concentrations of tryptophan though it had significant effects on some sleep and mood measures. If the 25% TFD has central effects without altering either the absolute plasma concentration of tryptophan or the tryptophan-LNAA ratio, the mechanism by which the TFD affects the brain would be in question.

In addition, continuous infusion of an amino acid mixture containing tryptophan in rats increased REM percentage and decreased non-REM percentage during the rest period.38 While not strictly comparable to our study, these findings raise the possibility that large amounts of amino acids increase REM sleep.

In summary, we did not find that the TFD reversed the antidepressant effects of SSRIs in euthymic, fully remitted, male patients who had received antidepressants for 2 to 13 months, even though it significantly reduced plasma tryptophan concentrations (at the 100% dose) and significantly altered polygraphic sleep measures (at both 25% and 100% doses). The failure of the TFD to induce depression is in contrast to previous studies reporting that the TFD induced a transient relapse in moderately remitted patients with a history of mood disorder who had been treated for about 4 to 6 weeks. As a preliminary explanation for these discrepant findings, we hypothesize that the TFD reverses the antidepressant effects of SSRIs only early in the course of antidepressant therapy or only in patients who remain mildly depressed. These speculations are consistent with hypotheses that successful treatment with antidepressant medications depends on a time-dependent cascade of neuropharmacologically induced events at critical sites within the brain, eg, alterations in affinity and number of selected serotonin receptor subtypes.

Accepted for publication January 14, 1998.

Research supported by grants MOI RR00827 from the University of California, San Diego (UCSD) General Clinical Research Center's Program (Michael Ziegler, MD, director); MH 57134-01 and MH 18825 from the National Center for Research Resources, National Institutes of Health, Bethesda, Md; MH 30914 from the UCSD Mental Health Clinical Research Center, San Diego Veterans Affairs Medical Center Research Service; MH18399 UCSD Fellowship in Clinical Psychopharmacology and Psychobiology (Michael Irwin, MD, director; Dr Bhatti recipient); the Stanley Foundation and NAMI Research Institute, Arlington, Va (Dr Gillin); the Swiss National Science Foundation, Basel, Switzerland (Dr Seifritz); and the Ciba-Geigy Jubiläeumsstiftung, Basel (Dr Seifritz).

Presented as a preliminary report at the Second International Congress for the World Federation of Sleep Research Societies, Nassau, the Bahamas, September 15, 1995.

We gratefully acknowledge the technical assistance of Arlene Schlosser, Caroline Ruiz, Lesley Wetherell, Sheila Neely, Bev Robertson, and the Research Fellows at UCSD. We thank Shah Golshan, PhD, our statistical consultant, for his assistance. We are also grateful to the UCSD General Clinical Research Center (Michael Ziegler, MD, director) for supporting inpatient "scatter beds" for hospitalization of patients on the UCSD MHCRC in the San Diego Veterans Affairs Medical Center, and to its Core Laboratory for developing the tryptophan assay, with special thanks to Theodore Ciaraldi, MD, and Eric Fusselman.

Reprints: J. Christian Gillin, MD, Psychiatry Service (116A), UCSD and VA San Diego Health Care System, 3350 La Jolla Village Dr, San Diego, CA 92161.

Maes  MMeltzer  HY The serotonin hypothesis of major depression. Bloom  FEKupfer  DJeds.Psychopharmacology: The Fourth Generation of Progress New York, NY Raven Press1995;933- 944
Delgado  PLPrice  LHMiller  HLSalomon  RMAghajanian  GKHeninger  GRCharney  DS Serotonin and the neurobiology of depression: effects of tryptophan depletion in drug-free depressed patients. Arch Gen Psychiatry. 1994;51865- 874
Gessa  GLBiggio  GFadda  FCorsini  GVTagliamonte  A Effect of oral administration of tryptophan-free amino acid mixtures on serum tryptophan, brain tryptophan, and serotonin metabolism. J Neurochem. 1974;22869- 870
Young  SNErvin  FRPihl  ROFinn  P Biochemical aspects of tryptophan depletion in primates. Psychopharmacology. 1989;98508- 511
Biggio  GFadda  FFanni  PTagliamonti  AGessa  GL Rapid depletion of serum tryptophan, serotonin, and 5-hydroxyindoleacetic acid by a tryptophan-free diet. Life Sci. 1974;141321- 1329
Moja  EAStoff  DMGessa  GLCastoldi  DAssereto  RTofanetti  O Decrease in plasma tryptophan after tryptophan-free amino acid mixtures in man. Life Sci. 1988;421551- 1556
Delgado  PLCharney  DSPrice  LHAghajanian  GKLandis  HHeninger  GR Serotonin function and the mechanism of antidepressant action: reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry. 1990;47411- 418
Young  SNSmith  SEPihl  ROErvin  FR Tryptophan depletion causes a rapid lowering of mood in normal males. Psychopharmacology. 1985;87173- 177
Nicholson  ANPascoe  PA Studies on the modulation of the sleep-wakefulness continuum in man by fluoxetine, a 5-HT uptake inhibitor. Neuropharmacology. 1988;27597- 602
Kupfer  DJPerel  JMPollock  BGNathan  RSGrochocinski  VJWilson  MJMcEachran  AB Fluvoxamine versus desipramine: comparative polysomnographic effects. Biol Psychiatry. 1991;2923- 40
Staner  LKerkhofs  MDetroux  DLeyman  SLinkowski  PMendlewicz  J Acute, subchronic and withdrawal sleep EEG changes during treatment with paroxetine and amitryptiline: a double-blind randomized trial in major depression. Sleep. 1995;18470- 477
Beasley  CM  JrSayler  MEWeiss  AMPotzin  JH Fluoxetine: activating and sedating effects at multiple fixed doses. J Clin Psychopharmacol. 1992;12328- 333
Gillin  JCRapaport  MErman  MKWinokur  AAlbala  BJ A comparison of nefazodone and fluoxetine on mood and on objective, subjective, and clinician-rated measures of sleep in depressed patients: a double-blind 8-week clinical trial. J Clin Psychiatry. 1997;58185- 192
Hamilton  M Development of a rating scale for primary depressive illness. Br J Social Clin Psychology. 1967;6278- 296
McNair  DLorr  MDroppleman  L EdITS Manual for the Profile of Mood States.  San Diego, Calif EdITS1981;
Delgado  PLPrice  LHMiller  HLSalomon  RMLicinio  JKrystal  JHHeninger  GRCharney  DS Rapid serotonin depletion as a provocative challenge test for patients with major depression: relevance to antidepressant action and the neurobiology of depression. Psychopharm Bull. 1991;27321- 330
Denckla  WDDewey  HK The determination of tryptophan in plasma, liver, and urine. J Lab Clin Med. 1967;69160- 169
Rechtschaffen  AKales  A A Manual for Standardized Terminology, Techniques, and Scoring Systems for Sleep Stages of Human Subjects.  Los Angeles UCLA Brain Information Service/Brain Research Institute1968;
Bhatti  TSeifritz  EMoore  PClark  CGolshan  SStahl  SRapaport  MKelsoe  JGillin  JC Effects of a tryptophan-free amino acid drink challenge on normal human sleep EEG and mood. Biol Psychiatry. 1998;4352- 59
Fernstrom  JDWurtman  RJHammarstrom-Wiklund  BRand  WMMunro  HNDavidson  CS Diurnal variations in plasma concentrations of tryptophan, tyrosine, and other neutral amino acids: effect of dietary protein intake. Am J Clin Nutr. 1979;321912- 1922
Eriksson  TVoog  LWalinder  JEriksson  TE Diurnal rhythm in absolute and relative concentrations of large neutral amino acids in human plasma. J Psychiatr Res. 1989;23241- 249
Shopsin  BFriedman  EGershon  S Parachlorophenylalanine reversal of tranylcypromine effects in depressed patients. Arch Gen Psychiatry. 1976;33811- 819
Blier  Pde Montigny  C Current advances and trends in the treatment of depression. TIPS. 1994;15220- 226
Jolas  THaj-Dahmane  SKidd  EJLanglois  XLanfumey  LFattaccini  CMVantalon  VLaporte  AMAdrien  JGozlan  HHamon  M Central pre- and postsynaptic 5-HT1A receptors in rats treated chronically with a novel antidepressant, cericlamine. J Pharmacol Exp Ther. 1994;2681432- 1443
Chaput  Yde Montigny  CBlier  P Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments: an in vivo electrophysiologic study in the rat. Neuropsychopharmacology. 1991;5219- 229
Stahl  SM 5-HT1A receptors and pharmacotherapy. Psychopharm Bull. 1994;3039- 43
Spurlock  GBuckland  PO'Donovan  MMcGuffin  P Lack of effect of antidepressant drugs on the levels of mRNAs encoding serotonergic receptors synthetic enzymes and 5-HT transporter. Neuropharmacology. 1994;33433- 440
Sprouse  JSAghajanian  GK Electrophysiological responses of serotoninergic dorsal raphe neurons to 5-HT1a and 5-HT1b agonists. Synapse. 1987;13- 9
Varrault  ALeviel  VBockaert  J 5-HT1a-sensitive adenylyl cyclase of rodent hippocampal neurons: effects of antidepressant treatments and chronic stimulation with agonists. J Pharmacol Exp Ther. 1991;257433- 438
Traber  JGlaser  T 5-HT1A receptor-related anxiolytics. TIPS. 1987;8432- 437
Neumaier  JFRoot  DCHamblin  MW Chronic fluoxetine reduces serotonin transporter mRNA and 5-HT1B mRNA in a sequential manner in the rat dorsal raphe nucleus. Neuropsychopharmacology. 1996;15515- 522
Palacios  JMWaeber  CHoyer  DMengod  G Distribution of serotonin receptors. Ann N Y Acad Sci. 1990;60036- 52
Gillin  JCSohn  J-WStahl  SMLardon  MKelsoe  JRapaport  MRuiz  CGolshan  S Ipsapirone, a 5-HT1a agonist, suppresses REM sleep equally in unmedicated depressed patients and normal controls. Neuropsychopharmacology. 1996;15109- 115
Lin  RCCosta  ENeff  NHWang  CTNgai  SH In vivo measurement of 5-hydroxytryptamine turnover rate in the rat brain from the conversion of C14-tryptophan to C14-5-hydroxytryptamine. J Pharmacol Exp Ther. 1969;170232- 238
Schaechter  JDWurtman  RJ Serotonin release varies with brain tryptophan levels. Brain Res. 1990;532203- 210
Gartside  SECowen  PJSharp  T Effect of amino acid loads on hippocampal 5-HT release in vivo evoked by electrical stimulation of the dorsal raphe nucleus and d-fenfluramine administration. Br J Pharmacol. 1992;107448PAbstract
Krahn  LELu  PYKlee  GDelgado  PRLin  S-CZimmerman  RC Examining serotonin function: a modified technique for rapid tryptophan depletion. Neuropsychopharmacology. 1996;15325- 328
Danguir  JNicolaides  S Intravenous infusions of nutrients and sleep in the rat: an ischymetric sleep regulation hypothesis. Am J Physiol. 1980;238E307- E312

Figures

Tables

Table Graphic Jump LocationTable 1. Demographic, Diagnostic, and Baseline Mood Variables of the Subjects
Table Graphic Jump LocationTable 2. Results of All-Night Polysomnographic Measures*
Table Graphic Jump LocationTable 3. Effects of Tryptophan-Free Amino Acid Drinks (TFDs) on Mood Measures*

References

Maes  MMeltzer  HY The serotonin hypothesis of major depression. Bloom  FEKupfer  DJeds.Psychopharmacology: The Fourth Generation of Progress New York, NY Raven Press1995;933- 944
Delgado  PLPrice  LHMiller  HLSalomon  RMAghajanian  GKHeninger  GRCharney  DS Serotonin and the neurobiology of depression: effects of tryptophan depletion in drug-free depressed patients. Arch Gen Psychiatry. 1994;51865- 874
Gessa  GLBiggio  GFadda  FCorsini  GVTagliamonte  A Effect of oral administration of tryptophan-free amino acid mixtures on serum tryptophan, brain tryptophan, and serotonin metabolism. J Neurochem. 1974;22869- 870
Young  SNErvin  FRPihl  ROFinn  P Biochemical aspects of tryptophan depletion in primates. Psychopharmacology. 1989;98508- 511
Biggio  GFadda  FFanni  PTagliamonti  AGessa  GL Rapid depletion of serum tryptophan, serotonin, and 5-hydroxyindoleacetic acid by a tryptophan-free diet. Life Sci. 1974;141321- 1329
Moja  EAStoff  DMGessa  GLCastoldi  DAssereto  RTofanetti  O Decrease in plasma tryptophan after tryptophan-free amino acid mixtures in man. Life Sci. 1988;421551- 1556
Delgado  PLCharney  DSPrice  LHAghajanian  GKLandis  HHeninger  GR Serotonin function and the mechanism of antidepressant action: reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry. 1990;47411- 418
Young  SNSmith  SEPihl  ROErvin  FR Tryptophan depletion causes a rapid lowering of mood in normal males. Psychopharmacology. 1985;87173- 177
Nicholson  ANPascoe  PA Studies on the modulation of the sleep-wakefulness continuum in man by fluoxetine, a 5-HT uptake inhibitor. Neuropharmacology. 1988;27597- 602
Kupfer  DJPerel  JMPollock  BGNathan  RSGrochocinski  VJWilson  MJMcEachran  AB Fluvoxamine versus desipramine: comparative polysomnographic effects. Biol Psychiatry. 1991;2923- 40
Staner  LKerkhofs  MDetroux  DLeyman  SLinkowski  PMendlewicz  J Acute, subchronic and withdrawal sleep EEG changes during treatment with paroxetine and amitryptiline: a double-blind randomized trial in major depression. Sleep. 1995;18470- 477
Beasley  CM  JrSayler  MEWeiss  AMPotzin  JH Fluoxetine: activating and sedating effects at multiple fixed doses. J Clin Psychopharmacol. 1992;12328- 333
Gillin  JCRapaport  MErman  MKWinokur  AAlbala  BJ A comparison of nefazodone and fluoxetine on mood and on objective, subjective, and clinician-rated measures of sleep in depressed patients: a double-blind 8-week clinical trial. J Clin Psychiatry. 1997;58185- 192
Hamilton  M Development of a rating scale for primary depressive illness. Br J Social Clin Psychology. 1967;6278- 296
McNair  DLorr  MDroppleman  L EdITS Manual for the Profile of Mood States.  San Diego, Calif EdITS1981;
Delgado  PLPrice  LHMiller  HLSalomon  RMLicinio  JKrystal  JHHeninger  GRCharney  DS Rapid serotonin depletion as a provocative challenge test for patients with major depression: relevance to antidepressant action and the neurobiology of depression. Psychopharm Bull. 1991;27321- 330
Denckla  WDDewey  HK The determination of tryptophan in plasma, liver, and urine. J Lab Clin Med. 1967;69160- 169
Rechtschaffen  AKales  A A Manual for Standardized Terminology, Techniques, and Scoring Systems for Sleep Stages of Human Subjects.  Los Angeles UCLA Brain Information Service/Brain Research Institute1968;
Bhatti  TSeifritz  EMoore  PClark  CGolshan  SStahl  SRapaport  MKelsoe  JGillin  JC Effects of a tryptophan-free amino acid drink challenge on normal human sleep EEG and mood. Biol Psychiatry. 1998;4352- 59
Fernstrom  JDWurtman  RJHammarstrom-Wiklund  BRand  WMMunro  HNDavidson  CS Diurnal variations in plasma concentrations of tryptophan, tyrosine, and other neutral amino acids: effect of dietary protein intake. Am J Clin Nutr. 1979;321912- 1922
Eriksson  TVoog  LWalinder  JEriksson  TE Diurnal rhythm in absolute and relative concentrations of large neutral amino acids in human plasma. J Psychiatr Res. 1989;23241- 249
Shopsin  BFriedman  EGershon  S Parachlorophenylalanine reversal of tranylcypromine effects in depressed patients. Arch Gen Psychiatry. 1976;33811- 819
Blier  Pde Montigny  C Current advances and trends in the treatment of depression. TIPS. 1994;15220- 226
Jolas  THaj-Dahmane  SKidd  EJLanglois  XLanfumey  LFattaccini  CMVantalon  VLaporte  AMAdrien  JGozlan  HHamon  M Central pre- and postsynaptic 5-HT1A receptors in rats treated chronically with a novel antidepressant, cericlamine. J Pharmacol Exp Ther. 1994;2681432- 1443
Chaput  Yde Montigny  CBlier  P Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments: an in vivo electrophysiologic study in the rat. Neuropsychopharmacology. 1991;5219- 229
Stahl  SM 5-HT1A receptors and pharmacotherapy. Psychopharm Bull. 1994;3039- 43
Spurlock  GBuckland  PO'Donovan  MMcGuffin  P Lack of effect of antidepressant drugs on the levels of mRNAs encoding serotonergic receptors synthetic enzymes and 5-HT transporter. Neuropharmacology. 1994;33433- 440
Sprouse  JSAghajanian  GK Electrophysiological responses of serotoninergic dorsal raphe neurons to 5-HT1a and 5-HT1b agonists. Synapse. 1987;13- 9
Varrault  ALeviel  VBockaert  J 5-HT1a-sensitive adenylyl cyclase of rodent hippocampal neurons: effects of antidepressant treatments and chronic stimulation with agonists. J Pharmacol Exp Ther. 1991;257433- 438
Traber  JGlaser  T 5-HT1A receptor-related anxiolytics. TIPS. 1987;8432- 437
Neumaier  JFRoot  DCHamblin  MW Chronic fluoxetine reduces serotonin transporter mRNA and 5-HT1B mRNA in a sequential manner in the rat dorsal raphe nucleus. Neuropsychopharmacology. 1996;15515- 522
Palacios  JMWaeber  CHoyer  DMengod  G Distribution of serotonin receptors. Ann N Y Acad Sci. 1990;60036- 52
Gillin  JCSohn  J-WStahl  SMLardon  MKelsoe  JRapaport  MRuiz  CGolshan  S Ipsapirone, a 5-HT1a agonist, suppresses REM sleep equally in unmedicated depressed patients and normal controls. Neuropsychopharmacology. 1996;15109- 115
Lin  RCCosta  ENeff  NHWang  CTNgai  SH In vivo measurement of 5-hydroxytryptamine turnover rate in the rat brain from the conversion of C14-tryptophan to C14-5-hydroxytryptamine. J Pharmacol Exp Ther. 1969;170232- 238
Schaechter  JDWurtman  RJ Serotonin release varies with brain tryptophan levels. Brain Res. 1990;532203- 210
Gartside  SECowen  PJSharp  T Effect of amino acid loads on hippocampal 5-HT release in vivo evoked by electrical stimulation of the dorsal raphe nucleus and d-fenfluramine administration. Br J Pharmacol. 1992;107448PAbstract
Krahn  LELu  PYKlee  GDelgado  PRLin  S-CZimmerman  RC Examining serotonin function: a modified technique for rapid tryptophan depletion. Neuropsychopharmacology. 1996;15325- 328
Danguir  JNicolaides  S Intravenous infusions of nutrients and sleep in the rat: an ischymetric sleep regulation hypothesis. Am J Physiol. 1980;238E307- E312

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 49

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

The Rational Clinical Examination
Make the Diagnosis: Depression

The Rational Clinical Examination
Original Article: Is This Patient Clinically Depressed?