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3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) use may have long-term neurotoxic effects. In this study, positron emission tomography with the tracer alpha-[(11) C]methyl-l-tryptophan ((11) C-AMT) was used to compare human brain serotonin (5-HT) synthesis capacity in 17 currently drug-free MDMA polydrug users with that in 18 healthy matched controls. Gender differences and associations between regional (11) C-AMT trapping and characteristics of MDMA use were also examined. MDMA polydrug users exhibited lower normalized (11) C-AMT trapping in pre-frontal, orbitofrontal, and parietal regions, relative to controls. These differences were more widespread in males than in females. Increased normalized (11) C-AMT trapping in MDMA users was also observed, mainly in the brainstem and in frontal and temporal areas. Normalized (11) C-AMT trapping in the brainstem and pre-frontal regions correlated positively and negatively, respectively, with greater lifetime accumulated MDMA use, longer durations of MDMA use, and shorter time elapsed since the last MDMA use. Although the possibility of pre-existing 5-HT alterations pre-disposing people to use MDMA cannot be ruled out, regionally decreased 5-HT synthesis capacity in the forebrain could be interpreted as neurotoxicity of MDMA on distal (frontal) brain regions. On the other hand, increased 5-HT synthesis capacity in the raphe and adjacent areas could be due to compensatory mechanisms., (© 2014 International Society for Neurochemistry.)

Rationale: Several studies suggest users of 3,4-methylenedioxymethamphetamine (ecstasy) have low levels of serotonin. Low serotonin may make them susceptible to lowered mood., Objective: This work aims to study the acute effects on mood and impulsivity of lowering serotonin levels with acute tryptophan depletion in polydrug ecstasy users and to determine whether effects were different in men and women., Methods: In a double-blind cross-over study, participants who had used ecstasy at least 25 times (n = 13) and nonuser controls (n = 17) received a tryptophan-deficient amino acid mixture and a control amino acid mixture containing tryptophan, at least 1 week apart. Mood was measured using the profile of mood states, and impulsivity was measured with the Go/No-Go task., Results: The main result shows that a lowering of mood after acute tryptophan depletion occurred only in female polydrug ecstasy users (n = 7), relative to controls (n = 9). Results from the Go/No-Go task suggested that impulsivity was not increased by acute tryptophan depletion in polydrug ecstasy users., Limitation: The group sizes were small, when males and females were considered separately., Conclusions: Women polydrug ecstasy users appear to be more susceptible than men to the effects of lowered serotonin levels. If use of ecstasy alone or in conjunction with other drugs causes progressive damage of serotonin neurons, women polydrug ecstasy users may become susceptible to clinical depression.

Context: The hypothesis of a serotonin (5-hydroxytryptamine [5-HT]) dysfunction in obsessive-compulsive disorder (OCD) stems largely from the clinical efficacy of 5-HT reuptake inhibitors. Serotonergic abnormalities in the unmedicated symptomatic state, however, remain to be fully characterized., Objective: To investigate brain regional 5-HT synthesis, as indexed by positron emission tomography and the α-[(11)C]methyl-L-tryptophan trapping constant (K*), in treatment-free adults meeting criteria for OCD., Design: Between-group comparison., Setting: Department of Psychiatry and Montreal Neurological Institute, McGill University, and Department of Psychology, McGill University Health Centre, Quebec, Canada., Participants: Twenty-one medication-free patients with OCD (15 men with a mean [SD] age of 33.2 [9.3] years and 6 women with a mean [SD] age of 35.8 [7.1] years) and 21 healthy controls matched for age and sex (15 men with a mean [SD] age of 32.9 [10.1] years and 6 women with a mean [SD] age of 36.5.5 [8.6] years). Main Outcome Measure The α-[(11)C]methyl-L-tryptophan brain trapping constant K*, which was analyzed with Statistical Parametric Mapping (SPM8) and with proportional normalization (extent threshold of 100 voxels with a peak threshold of P ≤ .005)., Results: Compared with healthy controls, the patients with OCD exhibited significantly greater α-[(11)C]methyl-L-tryptophan trapping in the right hippocampus and left temporal gyrus (Brodmann area 20). In the larger subsample of all men, these same differences were also evident, as well as higher K* values in the caudate nucleus. Individual differences in symptom severity correlated positively with K* values sampled from the caudate and temporal lobe of the patients with OCD, respectively. There were no regions where the patients exhibited abnormally low K* values. Volumetric analyses found no morphometric alterations that would account for the group differences., Conclusion: The results support previous reports of greater striatal and temporal lobe activity in patients with OCD than in healthy controls and suggest that these disturbances include a serotonergic component. Previously reported glucose metabolic disturbances in OCD involving the orbitofrontal and cingulate cortices, in comparison, might reflect postsynaptic changes in the serotonergic system.

In healthy never-depressed individuals, acute tryptophan depletion (ATD) may selectively decrease the accurate recognition of fearful facial expressions. Here we investigated the perception of facial emotions after ATD in more detail. We also investigated whether bright light, which can reverse ATD's mood-lowering effect, can also reverse its effect on the perception of facial emotions. On two separate test days, spent in a room that was either bright (n = 14) or dim (n = 16), healthy never-depressed women completed a facial emotion perception task six hours after ingesting tryptophan-deficient and balanced amino acid mixtures. Treatments were administered double blind and in randomized order using a crossover design. In dim light ATD decreased recognition accuracy of anger, disgust, and surprise. The labeling of fear and sadness was not affected. In bright light no effects of ATD were seen. Bright light was identified as a potential confounding factor in task performance. The effects of ATD on facial emotion perception may be less emotion-specific than thought previously, and occurred in a direction opposite to what might be expected based on theories of mood-congruent bias.

The antidepressant selective serotonin transporter inhibitors (SSRIs) are clinically active after a delay of several weeks. Indeed, the rapid increase of serotonin (5-HT) caused by SSRIs, stimulates the 5-HT(1A) autoreceptors, which exert a negative feedback on the 5-HT neurotransmission. Only when autoreceptors are desensitized, can SSRIs exert their therapeutic activity. The 5-HT(1A) receptor antagonist pindolol has been used to accelerate the clinical effects of antidepressant by preventing the negative feedback. Using the alpha-[(11)C]methyl-L-tryptophan/positron emission tomography (PET), the goal of the present double-blind, randomized study was to compare the changes in alpha-[(11)C]methyl-L-tryptophan trapping, an index of serotonin synthesis, in patients suffering from unipolar depression treated with the SSRI citalopram (20 mg/day) plus placebo versus patients treated with citalopram plus pindol (7.5 mg/day). PET and Hamilton depression rating scale (HDRS-17) were performed at baseline, and after 10 and 24 days of antidepressant treatment. Results show that the combination citalopram plus pindol, compared to citalopram alone shows a more rapid and greater increase of an index of 5-HT synthesis in prefrontal cortex (BA 9). This research is the first human PET study demonstrating that, after 24 days, the combination SSRIs plus pindolol produces a greater increase of the metabolism of serotonin in the prefrontal cortex, an area associated to depressive symptoms.

We investigated the influence of bright light exposure on the mood-lowering effect of acute tryptophan depletion (ATD). Mildly seasonal healthy young women without a personal or family history of psychiatric disorders remained in either dim or bright light during two test days. Tryptophan-deficient and nutritionally balanced amino acid mixtures were administered in counterbalanced order. Mood state was assessed using the Profile of Mood States (POMS) and Visual Analogue Scales (VAS). In dim light, ATD decreased POMS scores across most subscales, indicating a worsening of mood. In bright light, mood was unaffected by ATD. Thus, bright light blocked the worsening of mood caused by ATD. This was also observed on the positive mood VAS. These results indicate a direct, immediate interaction between bright light and serotonin function. Bright light might help protect against ATD-induced mood change by increasing serotonin above the threshold level below which there is a lowering of mood.

Background: Little is known about the specific contribution of serotonin (5-HT) to the neurobiology of emotion and mood in healthy people. In an exploratory study, we sought to investigate the effect of rapid and sustained changes of emotional state on the trapping of 11C-labelled alpha-methyl-L-tryptophan (11C-alphaMtrp) used as a proxy of 5-HT synthesis, using positron emission tomography (PET)., Method: In a within-subject repeated-measure design, participants recalled autobiographical memories to self-induce sadness, happiness and a neutral emotional state during scanning to measure brain trapping of 11C-alphaMtrp. Three separate scan acquisitions, counterbalanced for order across subjects, took place at the McConnell Brain Imaging Center, Montréal., Results: Whole brain analysis revealed positive and negative correlations between experienced levels of emotions and 11C-alphaMtrp trapping in the right anterior cingulate cortex., Conclusion: These findings point to a mechanism whereby state-related changes in a proxy of 5-HT synthesis underscore aspects of the self-regulation of normal mood.

Purpose: Previous functional neuroimaging studies suggest that selective aspects of the brain serotonin (5-HT) system change during the aging process. Here, we assessed the effects of aging on the brain regional alpha-[(11)C]methyl-L: -tryptophan (alpha-[(11)C]MTrp) trapping rate constant (K*; microl.g(-1).min(-1)), which, with certain assumptions, could be taken as a proxy of 5-HT synthesis., Methods: Thirty-six healthy right-handed subjects had positron emission tomography (PET) scans following injection with alpha-[(11)C]MTrp [18 males aged 46.6 +/- 22.2 years (range 20-80 years) and 18 females aged 33.0 +/- 15.5 years (range 20-80 years)]. The trapping rate constant, K*, was calculated with the graphical method for irreversible ligands using the sinus-venous input function. A priori selected volumes of interest (VOIs) were defined using an automatic algorithm., Results: VOI analysis showed no correlation between age and brain regional K* values. As reported by others, significant age-related reductions of gray matter were observed in the thalamus and frontal and cingulate cortices; even with partial volume correction there was still no significant relationship between K* and age. Further exploratory SPM voxelwise correlation between age and alpha-[(11)C]MTrp trapping, using p = 0.05 (uncorrected), as well as voxel-based morphometry, was in agreement with the VOI analysis., Conclusion: The dissociation between age-related changes in brain anatomy and this index of serotonin synthesis suggests independent mechanisms underlying the normal aging process.

One neural system that may exhibit gender differences is serotonin (5-HT), a neurotransmitter implicated in the regulation of mood, cognitive processes, and impulse-control. However, most of the available evidence of gender-related differences in this system has been indirect and at times contradictory. The objective of the present study was to follow up on preliminary evidence that there are gender differences in brain regional 5-HT synthesis, as measured by trapping of alpha-[(11)C]methyl-l-tryptophan (alpha-[(11)C]MTrp). Sixty-minute dynamic scans were performed in healthy volunteers, 28 women and 31 men. Functional images of the brain trapping constant, used as a proxy for 5-HT synthesis, which correlate in the rat brain with tryptophan's conversion into 5-HT, were transferred to the standardized 3D space. The voxel based comparison was performed by Statistical Parametric Mapping with proportional normalization. There was lower normalized alpha-[(11)C]MTrp trapping in females than males throughout much of the cerebral cortex, including the left middle frontal gyrus, the bilateral inferior frontal gyrus, the bilateral precentral gyrus, the left supramarginal gyrus, the bilateral inferior parietal lobule, the left superior temporal gyrus, the bilateral posterior cingulate gyrus, and the bilateral precuneus. There were no regions in which the normalized trapping was significantly higher in females than in males. Gender differences in sub-cortical sites were not found. Women, compared to men, may have lower rates of this tracer trapping, used as a proxy for 5-HT synthesis, throughout much of the cerebral cortex which is likely related to differences in 5-HT synthesis because relative differences in the normalized trapping should be the same as those in 5-HT synthesis. These differences may be related, at least in part, to previously suggested gender differences in affect, cognitive processes, and susceptibility to 5-HT-related neuropsychiatric and neurological disorders.

Background: Pharmacological evidence support that enhancement of serotonin (5-HT) neurotransmission is critical for treatment efficacy in obsessive-compulsive disorder (OCD). Surprisingly, acute tryptophan depletion (ATD), a procedure known to reduce 5-HT neurotransmission, carried out in remitted OCD patients on selective serotonin reuptake inhibitors (SSRIs) failed to worsen obsessive-compulsive (OC) symptoms. We hypothesized that the putative symptom exacerbation resulting from ATD would only be observed during symptom provocation but not at rest., Methods: Double-blind placebo-controlled ATD study conducted in 16 OCD patients with stable improvement under either SSRI (n = 8) or specialized cognitive behavior therapy alone (n = 8), coupled with gradual symptom provocation, performed 5 hours after drink ingestion., Results: Acute tryptophan depletion markedly reduced total and free plasma tryptophan levels but did not significantly increase obsessions or compulsions at rest or following symptom provocation. However, subjective distress in response to triggering situations was significantly higher during ATD; significant mood lowering was also present during ATD., Conclusions: These results are consistent with the view that relapses in OC core symptoms in remitted OCD patients may not depend solely on short-term changes in presynaptic 5-HT availability. In contrast to its apparent lack of effect on core OC symptoms, ATD affected the patient's mood and distress level resulting from provocation.

Low serotonin neurotransmission is thought to increase vulnerability to suicidal behavior. To test this hypothesis, we measured brain regional serotonin synthesis, as indexed by PET and alpha-[(11)C]methyl-L-tryptophan trapping, in 10 patients who had made a high-lethality suicide attempt and 16 healthy controls. Compared to healthy controls, suicide attempters had reduced normalized alpha-[(11)C]methyl-L-tryptophan trapping in orbital and ventromedial prefrontal cortex. alpha-[(11)C]Methyl-L-tryptophan trapping in these regions correlated negatively with suicide intent. Low serotonin synthesis in the prefrontal cortex might lower the threshold for suicidal behavior.

Purpose: The purpose of this study was to assess the reproducibility in healthy volunteers of alpha-[11C]methyl-L-tryptophan (alpha[11C]MT) brain trapping imaging with positron emission tomography (PET), using volumes of interest (VOIs) and voxel-based image analysis., Methods: Six right-handed healthy male volunteers (34.3+/-10.9 years) with a negative family history for psychiatric disorders were scanned twice in the resting condition, 22+/-17 days apart. An unbiased semiautomatic segmentation of the brain was used to define VOIs. The trapping constant K* (ml g(-1) min(-1)) for alpha[11C]MT was calculated for the whole brain and seven brain regions using the graphical method for irreversible tracers. In addition, parametric maps of K* were obtained from dynamic scans using the same method. Comparison of test and retest K* functional images was performed using SPM99. Student's paired t statistic was applied for comparisons of alpha[11C]MT brain trapping in a priori selected VOIs., Results: alpha[11C]MT brain trapping in VOIs showed a mean variability 2.6+/-1.8% (0.3-5%) for absolute and 1.5+/-2.1% (1.4-4.1%) for normalized K*. Intraclass correlations between test and retest conditions were 0.61+/-0.34 for absolute K* values and 0.73+/-0.20 for K* values normalized by global mean. SPM99 analysis using a height threshold of p=0.05 (two tailed) and an extent threshold of 100 voxels showed no significant differences between scans., Conclusion: Rest measurements in healthy male volunteers of the trapping constant for alpha[11C]MT, using PET, appeared to be stable during an average interval of 3 weeks.

Context: The serotonin hypothesis of depression invokes a relative or absolute deficit of serotonin neurotransmission. Reduced synthesis of serotonin in the brain pathways mediating the expression of mood (ie, the limbic cortex) is a plausible candidate mechanism., Objectives: To measure and compare, using the alpha-[(11)C]methyl-l-tryptophan/positron emission tomography method, the brain trapping constant of alpha-[(11)C]methyl-l-tryptophan (K*, milliliters per gram per minute), an index of serotonin synthesis, in brain areas involved in the regulation of mood in patients with major depression (MD) and age- and sex-matched controls., Design: Between-group comparison., Setting: Department of Psychiatry and Montreal Neurological Institute, McGill University., Participants: Seventeen medication-free outpatients with a current episode of MD (9 women: mean +/- SD age, 41 +/- 11 years; 8 men: mean +/- SD age, 41 +/- 11 years) and 17 controls (9 women: mean +/- SD age, 37 +/- 15 years; 8 men: mean +/- SD age, 32.5 +/- 9.9 years). Main Outcome Measure Normalized K*, normalized to the global mean, was measured in the dorsolateral prefrontal, anterior cingulate, and mesial temporal cortices; the thalamus; and the caudate nucleus., Results: Compared with age- and sex-matched controls, normalized K* was significantly decreased bilaterally in female patients with MD in the anterior cingulate cortex, in the left anterior cingulate cortex in male patients with MD, and in the left mesial temporal cortex in male and female patients with MD (P<.001 for all). Exploratory analyses identified additional patient-control differences for normalized K* (eg, inferior frontal gyrus and superior parietal lobule), most of which, once corrected for 38 multiple comparisons, lost their significance. Morphometric measurements of the cingulate cortex divisions confirmed that the reduction of normalized K* in depressed patients was not attributable to a reduction in gray matter volume. Normalized K* in the anterior cingulate cortex did not correlate with ratings of depression severity collected at the time of scan., Conclusions: Reduction of normalized K*, an index of serotonin synthesis, in parts of the limbic and paralimbic cortices may contribute to the biochemical alterations associated with MD.

Objective: The administration of amino acid (AA) mixtures that are selectively deficient either in tryptophan or phenylalanine plus tyrosine can decrease serotonin or catecholamine synthesis, respectively. In the present study, we assessed whether a mixture that was simultaneously deficient in tryptophan, phenylalanine and tyrosine could induce sufficient protein synthesis that plasma levels of all 3 monoamine precursors would decrease., Design: Ten healthy volunteers (5 male, 5 female) were administered a tryptophan/phenylalanine/tyrosine-deficient AA mixture in an open-label study. Plasma concentrations of large neutral AAs were measured before and 5 hours after mixture ingestion., Results: The tryptophan/phenylalanine/tyrosine-deficient mixture lowered plasma concentrations of the 3 AAs by 67;, 78% and 77%, respectively (p < or = 0.001); their ratio to other large neutral AAs was decreased more, namely, by 87%, 90% and 90% (p < or = 0.001). Mood lowering was seen on 3 subscales of the bipolar Profile of Mood States, that is, elated-depressed, composed-anxious and clearheaded-confused, as well as 2 visual analog scales, bored and irritated (p < or = 0.05)., Conclusions: Acute tryptophan/phenylalanine/tyrosine depletion may be a suitable new method for rapidly decreasing serotonin and catecholamine transmission simultaneously.

Because serotonin is involved in the diachronic regulation of sleep, we tested the effect of a midmorning rapid deficiency in the serotonin precursor tryptophan on the next night's sleep. After a 48-h low-protein diet, 17 healthy volunteers received either a tryptophan-free mixture of amino acids or a placebo at 10:30 A.M., in a randomized double-blind cross-over design, resulting in a 77% decrease and 41% decrease of serum tryptophan at 3:30 P.M. and 9:30 P.M., respectively. Urinary sulfatoxy-melatonin excretion and mood were unaffected by the rapid tryptophan depletion (RTD), but rapid eye movement (REM) sleep latency increased by 21 min (from 91.5 +/- 4.5 min to 112.2 +/- 6.9 min), sleep fragmentation 58%, and REM density of the first REM sleep period doubled. The results show that midmorning RTD delays REM sleep latency during following night-time sleep, whereas evening RTD shortens REM sleep latency in previous studies, and suggest that the serotonin control of REM sleep latency is upregulated.

Acute tryptophan depletion (ATD) induces depressive symptoms in 50-60% of selective serotonin reuptake inhibitor (SSRI) treated, recovered depressed patients. However, no reliable predictors of mood response to ATD have been established. In the present study, individual subject data of six ATD studies were pooled ('mega-analysis') in order to investigate the mediating role of clinical, demographic and biochemical characteristics in the mood response to ATD. A procedure was developed to make different versions of the Hamilton scale comparable. Recurrent depressive episodes, female gender, prior exposure to SSRI antidepressant treatment and previous serious suicidal thoughts/attempts all appear to be independent predictors of mood response to ATD. Chronicity of illness is the most powerful predictor. Residual symptoms of depression were not found to predict response to ATD. ATD may be useful to study the mechanism of action of SSRI antidepressants and individual biological vulnerability of the serotonin system. Whether the effects of ATD represent a reversal of the action of SSRI antidepressants or individual vulnerability probably depends upon the timing of the procedure in the course of remission of a depressive episode.

Background: The lowering of mood induced by an acute tryptophan depletion (ATD) has been proposed as a candidate endophenotype for the vulnerability to manic-depressive illness. This study tests this hypothesis in relatives of probands from well-characterized multiplex families affected with bipolar affective disorder (BAD)., Methods: In a double-blind, crossover design, 20 unaffected relatives (URs) and 19 control subjects received either a 100-g amino acid (AA) drink devoid of tryptophan or a placebo, respectively. Clinical and biochemical effects of ATD were compared between unaffected relatives of BAD probands and age- and sex-matched control subjects., Results: At 5 hours after AA drink ingestion, relative to the placebo, ATD resulted in 74% and 84% decreases in total plasma tryptophan concentrations in control subjects and relatives of patients with BAD, respectively. Unlike control subjects unaffected relatives experienced a lowering of mood during ATD but not with the placebo. Furthermore, URs tended to show increased impulsivity in the ATD condition. Measurements obtained before ingestion of the AA drink indicated that, relative to control subjects URs exhibited lower serotonin platelet concentrations, lower affinity, and fewer binding sites of the serotonin transporter for imipramine; these differences were unaffected by ATD., Conclusion: These results replicate and extend previous findings suggesting that URs of patients with BAD are more susceptible to low tryptophan availability. This finding may bear significance in the purported role of serotonergic mechanisms in the vulnerability to depressive syndrome and/or illness.

Objective: Neurotransmission of serotonin (or 5-hydroxytryptamine [5-HT]) is thought to be disturbed in patients exhibiting impulsive behaviors. However, until recently it has not been possible to test this hypothesis in the brains of living humans., Method: Unidirectional trapping of the 5-HT precursor analog alpha-[(11)C]methyl-L-tryptophan (alpha-[(11)C]MTrp) has been proposed as an index of 5-HT synthesis capacity. The authors measured brain regional alpha-[(11)C]MTrp trapping with positron emission tomography in medication-free subjects with borderline personality disorder (N=13) and a healthy comparison group (N=11). Impulsivity was assessed by using a laboratory measure of behavioral disinhibition, go/no-go commission errors., Results: Compared to healthy men, the men with borderline personality disorder had significantly lower alpha-[(11)C]MTrp trapping in corticostriatal sites, including the medial frontal gyrus, anterior cingulate gyrus, superior temporal gyrus, and corpus striatum. In the women with borderline personality disorder, significantly lower alpha-[(11)C]MTrp trapping was seen in fewer regions, but in both men and women, negative correlations with impulsivity scores were identified in the medial frontal gyrus, anterior cingulate gyrus, temporal gyrus, and striatum., Conclusions: Low 5-HT synthesis capacity in corticostriatal pathways may contribute to the development of impulsive behaviors in persons with borderline personality disorder.

Objectives: To assess the suitability of analyzing functional images of brain serotonin (5-HT) synthesis with statistical parametric mapping (SPM), and to investigate further possible sex-related regional differences., Design: Prospective study., Participants: Six healthy men and 5 healthy women., Intervention: Participants' brains were scanned with positron-emission tomography (PET) after intravenous injection of alpha-[11C]methyl-L-tryptophan (alpha-[11C]MTrp)., Outcome Measures: Tissue radioactivity images were converted into functional images using the Patlak plot approach, and analyzed with 2 methods for global normalization in the SPM program: proportional scaling and analysis of covariance (ANCOVA)., Results: The data structure suggests that PET alpha-[11C]MTrp data meet the criteria for analysis with SPM, and that the proportional scaling method is more appropriate than the ANCOVA method for normalization. Regional differences in 5-HT synthesis were identified between men and women, and the significance of these findings was supported by region of interest (ROI) analyses., Conclusion: SPM analyses of PET alpha-[11C]MTrp data may be of value for identifying regional differences in brain 5-HT synthesis between groups, and in investigating the effects of psychotropic drugs. Since we found regional differences between male and female subjects, men and women should not be grouped for data analysis in PET alpha-[11C]MTrp studies.

Background: Recently we reported that, in vervet monkeys, ingestion of an amino acid mixture deficient in the catecholamine precursors, phenylalanine and tyrosine, produced a decrease in alcohol self-administration. We now report the results of a similar study in humans., Methods: Three groups of healthy female social drinkers were administered a nutritionally balanced amino acid mixture (B, n = 13), a mixture deficient in the serotonin precursor, tryptophan (Trp-free, n = 14), or a phenylalanine/tyrosine deficient mixture (Phe/Tyr-free, n = 12). Six hours after administration of the amino acid mixture, alcohol ingestion was measured during a free-choice "Taste Test.", Results: Compared to the B mixture, Phe/Tyr-free, but not Trp-free, significantly decreased the ingestion of alcohol [p < 0.02]. Neither Phe/Tyr-free nor Trp-free significantly decreased orange juice ingestion or the self-reported "Liking" of either substance. Some subjects experienced transient nausea and/or regurgitated the amino acid mixtures, but excluding these subjects did not change the results., Conclusions: The results suggest that (a) Phe/Tyr-free may be a suitable method for investigating the role of catecholamines in the self-administration and subjective effects of alcohol, (b) acutely decreased catecholamine neurotransmission might disrupt mechanisms mediating alcohol self-administration, and (c) acutely decreased serotonin neurotransmission seems not to alter alcohol self-administration.

Acute tryptophan depletion (ATD) lowers serotonin synthesis and elicits depressive symptoms in some, though not all, remitted patients with major depressive disorder (MDD). In the present study, eight medication-free remitted patients with MDD, seasonal pattern, were tested twice, once following the ingestion of a tryptophan-containing mixture, once following ATD. ATD significantly increased Hamilton depression scores (p < 0.001). Four of the patients had a family history of psychiatric disorders: substance abuse (n = 4), mood disorders (n = 3) or Cluster B personality disorders (n = 3). The mood-lowering response to ATD was significantly greater in those patients with, than without, affected relatives (p < 0.001). These preliminary findings (1) support the hypothesis that depressed states are related to disturbed serotonin neurotransmission and (2) suggest that depressive symptoms following ATD might identify a subgroup of patients at high genetic risk for disorders associated with affective lability and dysregulated impulse-control, conditions thought to be related to low serotonin neurotransmission.

Catecholamines have been implicated in the etiology and pathophysiology of mood and anxiety disorders. In the present study, we investigated the effects of experimentally reducing catecholamine neurotransmission by means of acute phenylalanine/tyrosine depletion (APTD). Healthy female volunteers ingested: (1) a nutritionally balanced amino acid (AA) mixture (n = 14); (2) a mixture deficient in the serotonin precursor, tryptophan (n = 15); or (3) one deficient in the catecholamine precursors, phenylalanine and tyrosine (n = 12). Mood was measured at three times: at baseline and both immediately before and after an aversive psychological challenge (public speaking and mental arithmetic) conducted 5 hours after AA mixture ingestion. Acute tryptophan depletion (ATD) lowered mood and energy and increased irritability scores. These effects were statistically significant only after the psychological challenge. The effect of APTD on mood was similar to that of ATD. APTD did not attenuate the anxiety caused by the psychological challenge. These findings suggest that, in healthy women, reduced serotonin and/or catecholamine neurotransmission increases vulnerability to lowered mood, especially following exposure to aversive psychological events.

Objective: A deficit in serotonergic neurotransmission has been linked to impulsive behavior, as well as to disorders characterized by disinhibition. The present study tested the hypothesis that young men at high risk for alcoholism demonstrate greater behavioral disinhibition after acute dietary depletion of tryptophan, the amino acid precursor of serotonin., Method: A double-blind, placebo-comparison, between-subjects study design was used. Nonalcoholic young men with a multigenerational paternal family history of alcoholism (N = 13) or with no family history of alcoholism (N = 15) in two previous generations were administered mixtures of tryptophan-deficient amino acid to achieve plasma tryptophan depletion. Comparison subjects with a multigenerational paternal family history of alcoholism (N = 1) and comparison subjects with no family history of alcoholism (N = 18) were given a balanced mixture. Five hours after this, all were tested on a modified Taylor task and a go/ no-go task measuring aggressive response and disinhibition, respectively., Results: Plasma tryptophan levels were reduced by 89% in both groups. Tryptophan depletion had no effect on aggressive response. In contrast, tryptophan-depleted individuals with a family history of alcoholism made more commission errors (responses to stimuli associated with punishment or loss of reward) than did tryptophan-depleted individuals with no family history of alcoholism and those receiving the balanced (comparison) mixture of amino acid in either group., Conclusions: Low serotonin levels may be implicated in the high disinhibition or impulsivity observed in some individuals with a genetic vulnerability to alcohol abuse or dependence.

Acute tryptophan depletion (ATD), which is thought to lower serotonin levels, can result in a lowering of mood. In the present study we compared the effect of ATD with acute phenylalanine/tyrosine depletion (APTD) in healthy women. Although considerable evidence relates catecholamines to the regulation of anxiety, there was no difference in anxiety responses in the ATD and APTD groups when the women underwent a mildly stressful psychological challenge. Both ATD and APTD caused a similar lowering of mood. Both depletions also increased heart rate. These results suggest that APTD is a useful method for studying the effect of low catecholamine levels in humans, and that catecholamines are involved in the regulation of mood.

Background: Acute tryptophan depletion (ATD), a means of reducing brain serotonin synthesis, lowers mood in normal males with a multi-generational family history of major affective disorder (MAD) and in normal women devoid of any family history of psychiatric illness. As both a family history of MAD and female sex are factors predisposing to depression, the hypothesis that a mood lowering response to ATD may reflect a susceptibility to depression was further investigated in young women with an extensive, multi-generational family history of MAD. In addition, the temporal stability of mood change following repeated trials of ATD was also assessed in this study., Methods: To deplete tryptophan, a tryptophan deficient amino acid mixture was ingested on two separate occasions. The control treatment, administered on a third occasion, was a nutritionally balanced amino acid mixture containing tryptophan., Results: A marked lowering of plasma tryptophan (85-90 %) was achieved by both depletions. In comparison to the balanced condition, family history positive (FH +) women showed no lowering of mood to either the first or second ATD (N = 13) and N = 12, respectively). Mood change between the two ATD trials (N = 13) exhibited poor temporal stability., Conclusions: These results may indicate that serotonin responsiveness is not an important characteristic of vulnerability to depression in these women. Alternately, these negative results may be due to the exclusion of a large number of FH + women who had already experienced an episode of depression, resulting in the selection of a biased FH + sample who are resistant to the mood lowering effects of ATD.

The method for measuring serotonin synthesis in human brain uses [11C]alpha-methyl-L-tryptophan as a tracer and positron emission tomography. The alpha-methyl-L-tryptophan is converted to alpha-methylserotonin, which is not a substrate for monoamine oxidase and therefore accumulates in the brain. In a pilot study published recently, rates of serotonin synthesis were found to be higher in men than in women. This was due to the lower plasma free tryptophan in the women under the experimental conditions used, and does not necessarily reflect the situation in all circumstances. Acute tryptophan depletion lowered brain serotonin synthesis by 90% or more. Patients with borderline personality disorder, who exhibit emotional lability and impulsivity, may have lower brain serotonin synthesis rates than healthy controls.

Low serotonin has been associated with aggressive behavior and impulsivity. Executive functions (cognitive abilities involved in the initiation/maintenance of goal attainment) have also been related to aggression. We tested whether dietary depletion of tryptophan, the amino acid precursor of serotonin, would increase disinhibition (impulsivity) in aggressive male adolescents. Cognitive-neuropsychological variables predictive of disinhibition were explored. Stable aggressive and nonaggressive adolescent men received balanced and tryptophan-depleted, amino acid mixtures separately (counterbalanced, double-blind). Commission errors on a go/no-go learning task (i.e., failures to inhibit responding to stimuli associated with punishment/nonreward) measured disinhibition. Aggressive adolescent males made more commission errors as compared to nonaggressives. Lower executive functioning was significantly related to commission errors over and above conventional memory abilities. Tryptophan depletion had no effect on commission errors in the aggressive adolescents, possibly because of a ceiling effect.

We tested in normal human subjects a less invasive method to obtain plasma input function required in the calculation of the brain serotonin synthesis rate measured with positron emission tomography (PET) and alpha-[11C]methyl-tryptophan (alpha-MTrp). The synthesis rates derived with the arterial input function were compared to those derived from venous plasma and venous sinus time-radioactivity curves obtained from dynamic PET images. Dynamic PET images were obtained for the lengths up to 90 minutes after an injection of alpha-MTrp (400 to 800 MBq). Input functions were generated from both artery and vein in three subjects, and from artery only in two subjects. Net unidirectional uptake constants of alpha-MTrp (K*; mL/g/min) were calculated in several brain regions graphically using data between 20 and 60 minutes after injection with different input functions. In the five subjects with arterial sampling, we tested two methods for correcting the input functions from the venous samples: (1) normalization to the mean exposure time at 20 minutes from arterial curve; and (2) the use of the venous sinus curve for the first 20 minutes. Venous curves coincided with the arterial ones after about 20 minutes. When the venous curves were used, there was an underestimation of the area under the curves up to 20 minutes, resulting in a 5% to 30% overestimation of K* values. Combined use of the sinus curve up to 20 minutes and venous curve from 20 to 60 minutes as an input function resulted in the K* (mL/g/min) values larger by 7.1 +/- 3.8% than the K* values estimated with the arterial input function. Normalization of the venous curve to the exposure time at 20 minutes obtained from the arterial plasma curve resulted in a bias in the K* of about -0.34 +/- 3.32%. The bias from the K* values was propagated to the serotonin synthesis rates. The use of a combination of the venous blood samples and venous sinus as the input function resulted in an acceptable bias in the serotonin synthesis rates from the tissue time-radioactivity curves generated by PET.

Acute tryptophan depletion (ATD) induces transient clinical relapse in medicated patients with major affective disorder. Our objective was to determine whether this effect persists once patients are euthymic and off antidepressants. Thus, we examined the effects of ATD in fully remitted, medication-free, former patients with major depression (n = 14). ATD had no significant effect on mood. These results suggest that the previous report that ATD substantially lowers mood in pharmacologically treated patients reflects a reversal of mechanisms involved in the therapeutic effects of antidepressants. Alternatively, ATD might induce clinical relapse only in subgroups that have yet to be identified.

We investigated (1) the mood response of normal women, without a family history of major affective disorder, to acute tryptophan depletion, and (2) the temporal stability of the mood change, within subjects, when rechallenged at least 1 month later. To deplete tryptophan, a tryptophan deficient amino acid mixture was ingested. The control treatment was a nutritionally balanced amino acid mixture containing tryptophan. A marked lowering of plasma tryptophan (80% to 90%) was achieved by both depletions. Compared to the balanced condition, the women exhibited a significant lowering of mood after the first tryptophan depletion on the elation-depression (p < .05), energetic-tired (p < .005), confident-unsure (p < .01), and clearheaded-confused (p < .01) scales of the bipolar profile of mood states. Whereas a lowering of mood was not found in a comparable sample of males studied earlier, these results were similar to those obtained in healthy males at genetic risk for major affective disorder (MAD). Inasmuch as a family history of MAD and female sex are predisposing factors to depression, these results suggest that a mood-lowering response to acute tryptophan depletion may occur preferentially in subjects with a susceptibility to lowered mood. However, the mood response to tryptophan depletion exhibited poor temporal stability in individual subjects.

Methods: A double-blind placebo-controlled cross-over study in which plasma tryptophan was manipulated by administration of a tryptophan-deficient amino acid mixture. In the placebo condition, all subjects received a nutritionally balanced amino acid mixture that contained tryptophan. To further standardize baseline amino acids, each subject was provided with a low-protein diet the day before amino acid challenges. Subjects were euthymic, healthy men aged 18 to 30 years with either a multigenerational family history of affective illness or no family history of psychiatric illness in the present or in the two previous generations. Each subject was screened with a structured clinical interview to rule out a personal history of psychiatric illness., Results: Plasma tryptophan was reduced by 89% 5 hours after the administration of the tryptophan-deficient amino acid mixture. Six of 20 subjects with a family history of affective illness and none of 19 subjects without a family history of psychiatric illness showed a lowering of mood of 10 or more points on the Profile of Mood States depression scale (P = .012, Fisher's Exact Test) 5 hours after tryptophan depletion. No significant mood changes were observed following the control treatment (balanced amino acid mixture) in either group., Conclusions: Our data support the hypothesis that subjects with no prior depressive episodes but with a multigenerational family history of major affective disorder show a greater reduction in mood after tryptophan depletion. They are also consistent with theories that implicate deficient serotonergic function as one possible etiological factor in major depressive disorders.

Investigates the link between tryptophan hydroxylase (TPH) and suicide completion. Association between the gene that codes TPH and suicidal behavior; Genotyping of a sample of suicide completers; Public-health problem of suicidal behavior; Evidence that subjects with suicidal behavior have reduced serotonergic neuro-transmission.

Involvement of the brain serotonin (5-HI) neurotransrnitter system in obsessive-compulsive disorder (OCD) was originally suggested on the basis of therapeutic effects found with the semi-selective serotonin uptake inhibitor, clomipramine. More recent studies directly comparing clomipramine with non-selective or norepinephrine-selective uptake inhibitors, such as desipramine or nortriptyline, as well as studies with new, more selective serotonin uptake inhibitors, including fluvoxamine and fluoxetine, have supported that hypothesis. Clomipramine's antiobsessional effect has been augmented with the serotonin precursor, L-tryptophan, or with lithium, which has prominent serotonergic effects. Patients whose OCD symptoms improved on clomipramine worsened when the drug was discontinued (regardless of duration of therapy) and improved when clomipramine was reinstituted. OCD symptoms also worsened when metergoline, a 5-HT antagonist, was given to patients who had improved with clomipramine. Metergoline given alone had no effect. Administration of m-chlorophenylpiperazine (m-CPP), a 5-HT receptor agonist, to untreated OCD patients increased their anxiety, depression, and dysphoria, and exacerbated their OC symptoms. After 4 months of clomipramine therapy, m- CPP failed to produce the same behavioural effects, suggesting an alteration of a 5-HT subsystem (possibly downregulation of some 5-HT receptors). The data reviewed suggest an important role for an abnormal brain 5-HT subsystem in patients with OCD. [ABSTRACT FROM AUTHOR]

Comments on an article about the use of alpha-methyl-L-tryptophan (alpha-MTrp) as tracer for measuring the rate of hydroxytryptamine synthesis in the brain. Overview of a study on alpha-MTrp; Information on the alpha-MTrp model; Regional differences in lumped constant.