Effects Of Rapid Tryptophan Depletion Research Articles

P01-426 - A diminished serotonin level influences the performance in a modified AX-continuous performance task in adult ADHD

IntroductionAttention deficit disorder (ADHD) is a psychiatric disorder, which is characterized by deficits of executive functions (EF) and impulsivity. Whereas a variety of studies on the involvement of the dopaminergic system in ADHD exists, the impact of the serotonergic system to EF in ADHD in adults is underinvestigated.AimsTo ascertain the effects of rapid tryptophan depletion (RTD) and the resultant reduction of the central nervous levels of serotonin on the EF of male adult patients with ADHD.Methods20 ADHD patients and 20 healthy controls completed the RTD test on one day and a placebo on another day in a double-blind within subject crossover design.- In addition, the subtest alertness of the TAP and a modified Version of the Continuous performance test (AX-CPT) with three stimulus conditions (AX, AY, BX) were administered.ResultsStatistical analysis revealed significant shorter reaction times, more errors and more omission errors in the ADHD group in the AX-CPT. The omissions error rate increased in both groups in the RTD condition but not in the placebo condition. Statistical analyses did not yield any significant differences between groups in the subtest alertness and no significant interaction of group and effect of the RTD condition could be observed.ConclusionsIn addition to higher impulsivity of patients with ADHD as reflected by shorter reaction times and higher error rates, the results of the present study imply an involvement of the serotonergic system as reflected by RTD in sustained and selective attention.

Rapid tryptophan depletion following cognitive behavioural therapy for panic disorder

The aim of this study was to examine the effect of rapid tryptophan depletion (RTD) combined with a panicogenic challenge in patients with panic disorder who had responded to treatment with cognitive behavioural therapy (CBT). We hypothesised that RTD (compared with the control drink) would result in an increase in anxiety symptoms when provoked by a panicogenic challenge with the benzodiazepine antagonist, flumazenil. Nine patients with panic disorder who had responded to CBT received a tryptophan-free amino acid drink on one occasion and a control drink on the other in a double-blind crossover design. In addition, they received flumazenil and placebo infusions on each day. Our hypothesis regarding the effects of RTD was supported by findings of a significant interaction between RTD and flumazenil on measures from visual analogues scales (total) and the Spielberger State Anxiety inventory. A somewhat unexpected finding was that in this group of CBT responders, the panicogenic effect of flumazenil was not completely blocked by treatment. This meant that although four of the nine subjects (44%) reported a panicogenic effect of flumazenil on the RTD day, this was not significantly different from the rate of panic attacks in response to flumazenil on the control day. We suggest that the partial return of symptoms in response to flumazenil reflects a vulnerability to RTD in this group of panic disorder patients who had responded to treatment with CBT.

Diminished Serotonergic Functioning in Hostile Children with ADHD: Tryptophan Depletion Increases Behavioural Inhibition

Serotonergic (5-HT) functioning has been shown to account for a variety of behavioural characteristics, in particular aggressive and impulsive behaviour. This study explored the effects of rapid tryptophan depletion (RTD) and the ensuing reduction of brain 5-HT synthesis on behavioural inhibition in passive avoidance learning assessed in a computerized go/no-go task. 22 male patients with an ICD-10 diagnosis of ADHD were administered RTD within an amino acid drink lacking tryptophan, the natural precursor of 5-HT, thus lowering the central nervous 5-HT synthesis rate in a placebo-controlled double-blind within-subject crossover-design. 4 hours after RTD/placebo intake the patients were subjected to a go/no-go task for assessment of behavioural inhibition. Highly hostile aggressive patients showed increased inhibition errors under RTD compared to placebo. Low hostile aggressive patients showed lower rates of inhibition errors and thus better performance under RTD compared to placebo. The data suggest that in ADHD levels of trait-aggressive characteristics influence the susceptibility to changed behavioural inhibition after an acute 5-HT dysfunction. The detected influence of 5-HT could also be relevant as regards behavioural inhibition being subject to a developmental change in 5-HT functioning.

Influence of Rapid Tryptophan Depletion on Laboratory-Provoked Aggression in Children with ADHD

Background: The present study investigated the effects of rapid tryptophan depletion (RTD), and the ensuing reduction of central nervous system levels of serotonin (5-HT), upon reactive aggression in patients with attention deficit/hyperactivity disorder (ADHD). Furthermore, it was asked whether the relation between 5-HT function and behavioural aggression in patients is influenced by their age, the intensity of their attention problems or their comorbid symptoms. Methods: The study employed a double-blind, within-subject crossover design. On day 1, 22 male adolescent patients with ADHD were subjected to RTD and the subsequent reduction of central 5-HT levels. On day 2, they received a tryptophan-balanced amino acid mixture (BAL), which acted as a placebo. On both days, 4.5 h after the intake of the RTD/BAL amino acids, reactive aggressive behaviour was provoked using a competitive reaction time game, which consisted of both high and low provocation conditions. Results: The number of aggressive responses was significantly higher after low provocation during acute tryptophan depletion, in comparison to the placebo. Furthermore, this study provides evidence that neither age nor the intensity of attention symptoms in ADHD patients had an impact on the relation between 5-HT and reactive aggression. Conclusion: This study indicates that in children with ADHD, there is an inverse relationship between 5-HT and aggression.

Serotonergic functioning and trait‐impulsivity in attention‐deficit/hyperactivity‐disordered boys (ADHD): influence of rapid tryptophan depletion

The present study investigated the effects of rapid tryptophan depletion (RTD) and the ensuing reduction of central nervous levels of serotonin (5-HT) on reactive aggression with respect to personality factors comprising aspects of trait-impulsivity and -aggression in boys with attention-deficit/hyperactivity-disorder (ADHD). Twenty-two male adolescent patients with ADHD received the RTD test on one day, and, on another day a tryptophan balanced placebo in a double-blind within-subject crossover design. Impulsive personality factors and trait-impulsivity were assessed in advance of the study. Aggression was provoked using a competitive reaction time game 270 min after RTD/placebo intake. RTD had a significant effect on increased aggressive behaviour with which low-grade impulsive patients responded. High-grade impulsive patients were not affected by RTD or even responded with increased aggressive behaviour while receiving placebo treatment. The present study supports the hypothesis that 5-HT functioning in ADHD patients influences reactive aggression depending on aspects of trait-impulsivity. Future studies are necessary in order to detect the specific influence of ADHD as regards the relevance to 5-HT-induced changed aggressive responding.

Patients with a major depressive episode responding to treatment with repetitive transcranial magnetic stimulation (rTMS) are resistant to the effects of rapid tryptophan depletion

Repetitive transcranial magnetic stimulation (rTMS) appears to be efficacious in the treatment of major depression based on the results of controlled studies, but little is known about its antidepressant mechanism of action. Mood sensitivity following rapid tryptophan depletion (RTD) has been demonstrated in depressed patients responding to SSRI antidepressants and phototherapy, but not in responders to electroconvulsive therapy (ECT). We sought to study the effects of RTD in patients with major depression responding to a course of treatment with rTMS. Twelve subjects treated successfully with rTMS monotherapy underwent both RTD and sham depletion in a double-blind crossover design. Depressive symptoms were assessed using both a modified Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI). The differential change in depression scores across the procedures was compared. No significant difference in mood symptoms was noted between RTD and the sham-depletion procedure on either continuous measures of depression, or in the proportions of subjects that met predefined criteria for a significant degree of mood worsening. Responders to rTMS are resistant to the mood perturbing effects of RTD. This suggests that rTMS does not depend on the central availability of serotonin to exert antidepressant effects in major depression.

Effects of rapid tryptophan depletion on salivary cortisol in older people recovered from depression, and the healthy elderly

Reduced serotonin (5-HT) function and abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are thought to play a role in the aetiology of major depression. We sought to examine this issue in the elderly by assessing the effects of lowering brain 5-HT on salivary and plasma cortisol in elderly patients who had recovered from at least one episode of major depression and in a healthy, age matched comparison group. A double-blind, cross-over design involving administration of two nutritionally balanced amino acid mixtures (with or without tryptophan) was used. Salivary cortisol was measured at intervals before and after the drink. There was no effect of acute tryptophan depletion (ATD) on salivary cortisol (ATD by time; F=0.97, df=7,210, p=0.454) but a significant interaction between group and time (F=3.91, df=7,210, p=0.010). Healthy subjects showed a marked increase in cortisol levels 2-3 hours into the procedure regardless of drink composition while recovered depressed subjects did not. In elderly patients who had recovered from depression there was no evidence of greater vulnerability of hypothalamic 5-HT pathways to 5-HT depletion. However, they demonstrated reduced reactivity of the HPA axis compared to healthy subjects.

Effects of Rapid Tryptophan Depletion on Sleep Electroencephalogram and Mood in Subjects with Partially Remitted Depression on Bupropion

Serotonin has been implicated in both sleep and mood regulation. When central serotonin was depleted with a tryptophan-free amino acid drink (TFD), some studies have reported that the antidepressant benefits were reversed in partially remitted patients treated with SSRIs. Other studies showed that the TFD increased rapid eye movement (REM) sleep in both normal males and in remitted depression patients on selective serotonin reuptake inhibitors (SSRIs) without affecting mood. In this study, we administered a TFD to patients with remitted depression who were being treated with bupropion, an antidepressant whose mechanism of action apparently does not affect the serotonin system. We hypothesized that the TFD would increase the propensity for REM sleep without affecting depression ratings. Eight partially remitted depression subjects on bupropion were administered a TFD and a control drink containing tryptophan in double-blind, random order on separate days. The effects of these drinks were monitored with sleep electroencephalograms, mood ratings, and plasma tryptophan measures comparing baseline, TFD, and control nights. The TFDs reduced REM latency and stage 2 percent and increased REM time and percent. Subjective measures of elation, vigor, and friendliness significantly decreased on both TFD and control drinks but depression ratings did not. Plasma levels of tryptophan decreased with the TFD. Although the TFD altered REM sleep, certain mood measures, and plasma tryptophan levels, no relapses into depression were seen with our subjects. Bupropion alone did not affect sleep measures.

Rapid Tryptophan Depletion Plus a Serotonin 1A Agonist: Competing Effects on Sleep in Healthy Men

In the present study, we hypothesized that the REM-suppressing effects of 5-HT1A receptor stimulation would counteract the REM-disinhibiting effects of rapid tryptophan depletion (RTD), and vice versa. We administered RTD plus ipsapirone (10 mg, p.o.) or RTD plus placebo to 10 healthy men. In contrast to our previous findings but partially consistent with other studies, RTD in combination with placebo did not produce a significant enhancement of any REM sleep measure. The combination of RTD and ipsapirone produced a significant suppression of REM sleep that was remarkably similar to the effect of ipsapirone alone. These data appear to deepen the mystery of variable and inconsistent RTD-induced responses in healthy subjects. In the case of REM sleep measures, this differs markedly from the consistent RTD-induced REM-disinhibiting effect seen in medicated depressed patients.

Effects of rapid tryptophan depletion on brain 5-HT(2) receptors: a PET study.

The mechanism by which rapid tryptophan depletion (RTD) paradigm induces depressive relapse in recently remitted patients with depression is unknown. To determine the effects of RTD on brain 5-HT(2) receptors using positron emission tomography (PET) and (18)F-labelled setoperone. Ten healthy women under went two PET scans. Each scan was done 5 h after the ingestion of either a balanced or a tryptophan-deficient amino acid mixture, and the two test sessions were separated by at least 5 days. The RTD decreased plasma free tryptophan levels significantly but it had no significant effects on mood. Subjects showed a significant decrease in brain 5-HT(2) receptor binding in various cortical regions following the RTD session. When taken with the evidence that antidepressant treatment is associated with a decrease in brain 5-HT(2) receptors, these findings suggest that a decrease in 5-HT(2) binding following RTD might be an adaptive response that provides protection against depressive symptoms.

315. Effects of rapid tryptophan depletion on brain 5-HT2 receptors: a PET study

315. Effects of rapid tryptophan depletion on brain 5-HT2 receptors: a PET study

Effects of Rapid Tryptophan Depletion in Patients With Seasonal Affective Disorder in Remission After Light Therapy

Previous studies show that rapid tryptophan depletion reverses the effects of therapy with serotonergic, but not noradrenergic, antidepressant drugs in patients with remitted nonseasonal depression. The objective of this study was to investigate the effects of rapid tryptophan depletion in patients with seasonal affective disorder (SAD) that was in clinical remission after light therapy. Patients who met DSM-III-R criteria for recurrent major depressive episodes, seasonal (winter) pattern (equivalent to SAD), were treated with a standard course of light therapy. Ten patients with SAD in clinical remission after light therapy underwent rapid tryptophan depletion in a placebo-controlled, double-blind crossover study. Behavioral ratings and plasma tryptophan levels were obtained before and after rapid tryptophan depletion. Plasma total and free tryptophan levels were significantly reduced to 20% of normal levels by the rapid tryptophan depletion. The depletion session resulted in significant increases in depression scores compared with the sham control session. Six of 10 patients had a clinically significant relapse of their depression following the tryptophan depletion session. Rapid tryptophan depletion appears to reverse the antidepressant effect of bright light therapy in patients with SAD. This suggests that the therapeutic effects of bright light in SAD may involve a serotonergic mechanism.

Serotonin Function and the Mechanism of Antidepressant Action

Brain serotonin content is dependent on plasma levels of the essential amino acid tryptophan. We investigated the behavioral effects of rapid tryptophan depletion in patients in antidepressant-induced remission. Twenty-one patients who were depressed by DSM-III-R criteria received a 24-hour, 160-mg/d, low-tryptophan diet followed the next morning by a 16-amino acid drink, in a double-blind, placebo-controlled (acute tryptophan depletion and control testing), crossover fashion. Total and free tryptophan levels decreased 87% and 91%, respectively, during acute tryptophan depletion. Fourteen of the 21 remitted depressed patients receiving antidepressants experienced a depressive relapse after the tryptophan-free amino acid drink, with gradual (24 to 48 hours) return to the remitted state on return to regular food intake. Control testing produced no significant behavioral effects. Free plasma tryptophan level was negatively correlated with depression score during acute tryptophan depletion. The therapeutic effects of some antidepressant drugs may be dependent on serotonin availability.