Linda Booij

Monoamine depletion in psychiatric and healthy populations: review

A number of techniques temporarily lower the functioning of monoamines: acute tryptophan depletion (ATD), alpha-methyl-para-tyrosine (AMPT) and acute phenylalanine/tyrosine depletion (APTD). This paper reviews the results of monoamine depletion studies in humans for the period 1966 until December 2002. The evidence suggests that all three interventions are specific, in terms of their short-term effects on one or two neurotransmitter systems, rather than on brain protein metabolism in general. The AMPT procedure is somewhat less specific, affecting both the dopamine and norepinephrine systems. The behavioral effects of ATD and AMPT are remarkably similar. Neither procedure has an immediate effect on the symptoms of depressed patients; however, both induce transient depressive symptoms in some remitted depressed patients. The magnitude of the effects, response rate and quality of response are also comparable. APTD has not been studied in recovered major depressive patients. Despite the similarities, the effects are distinctive in that ATD affects a subgroup of recently remitted patients treated with serotonergic medications, whereas AMPT affects recently remitted patients treated with noradrenergic medications. The evidence also suggests that ATD and APTD affect different cognitive functions, in particular different memory systems. Few studies investigated cognitive effects of the procedures in patients. Patients who are in remission for longer may also be vulnerable to ATD and AMPT, but the relationship with prior treatment is much weaker. For these patients, individual vulnerability markers are the more important determinants of depressive response, making these techniques potentially useful models of vulnerability to depression.

Predictors of mood response to acute tryptophan depletion: A reanalysis

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.

The Effects of High-Dose and Low-Dose Tryptophan Depletion on Mood and Cognitive Functions of Remitted Depressed Patients.

It has frequently been demonstrated that acute tryptophan depletion (ATD) induces a transient depressed mood in some patients who are in remission from depression. However, the effects of ATD on cognitive processes in remitted depressed patients have not been investigated. The aim of the present study was to investigate the effects of different extents of depletion on mood and cognitive tasks involving neutral and emotional stimuli. Twenty patients in remission or in partial remission from depression received ATD in a double-blind, crossover design. Mood was assessed at both sessions before, at +6.5 h and +24 h afterdepletion. Cognitive assessment in both sessions started at +4.75 h, and also before and after the whole procedure. The ATD mixtures induced the expected reductions of plasma tryptophan levels. High-dose ATD induced a depressive response in a subsample of patients and impaired theprocessing of positive information independent of mood change. Attention for neutral stimuli (Stroop interference) improved in a dose-dependent manner. ATD may affect mood and cognition via different pathways: one implicated in mood regulation and the processing ofemotional information, and one for the processing of neutral information. The first pathway may be more important for discriminating vulnerability to impaired serotonin function. The comparison of the effects of high-dose and low-dose ATD is useful for those studies aiming to investigate the relationships among 5-HT, mood and cognition.

Tryptophan Depletion Affects Heart Rate Variability and Impulsivity in Remitted Depressed Patients with a History of Suicidal Ideation

BACKGROUND Depression is a major risk factor for cardiovascular disease. An important risk factor for cardiovascular disease, low heart rate variability, often has been found in depressed patients and has been associated with impulsivity. The present study investigated whether experimental lowering of serotonin would decrease heart rate variability and increase impulsivity in remitted depressed patients, in particular in those patients with disturbed impulse control. METHODS Nineteen patients in remission from depression received high-dose and low-dose acute tryptophan depletion in a randomized, counterbalanced, double-blind crossover design. Heart rate variability and impulsivity were assessed during each acute tryptophan depletion session and during a baseline session. Suicidal ideation during past depression was used as an index for individual differences in impulse control. RESULTS High-dose acute tryptophan depletion led to a larger increase in depressive symptoms than did low-dose acute tryptophan depletion. High-dose acute tryptophan depletion decreased heart rate variability and increased impulsivity and anxiety, but only in patients with a history of suicidal ideation. Symptom effects of high-dose acute tryptophan depletion correlated with low heart rate variability at baseline. CONCLUSIONS Depressed patients who have problems with controlling impulsivity might be more at risk for developing cardiovascular disease, possibly related to increased vulnerability to impaired 5-hydroxytryptamine function.

Cognitive and Serotonergic Vulnerability to Depression: Convergent Findings

Cognitive reactivity (CR) is a psychological vulnerability marker of depression, whereas response to acute tryptophan depletion (ATD; a serotonergic challenge procedure) is a biological vulnerability marker. The aim of this study was to investigate the relationship between these markers. Thirty-nine remitted depressed patients participated in 2 ATD sessions in a double-blind crossover design. CR, assessed prior to the ATD sessions, predicted depressive response to high-dose ATD. CR also diminished the effects of 2 known predictors of ATD response: gender and residual symptoms. Neuroticism and behavioral inhibition were unrelated to ATD response. CR is associated with an increased sensitivity to reductions of serotonin concentrations. These findings present a small step toward unifying cognitive and neurobiological theories of depression.

Cognitive therapy does not prevent a response to tryptophan depletion in patients also treated with antidepressants

BACKGROUND Acute tryptophan depletion (ATD) induces depressive symptoms in remitted depressed patients treated with serotonergic medications, but not in patients treated with noradrenergic medications or electroconvulsive therapy. A recent study suggests that cognitive therapy (CT) protects against the effects of ATD, but the evidence is questionable. The present study compared the effect of ATD in patients who were treated with antidepressant medication and CT (n = 17) versus antidepressant medication alone (n = 23) during their latest episode. METHODS Forty remitted depressed patients underwent high-dose and low-dose ATD in a randomized double-blind crossover design. RESULTS There were no differences in response to ATD between treatment groups. This applied to groups defined by lifetime and by recent CT experience. CONCLUSIONS Cognitive therapy does not protect against the effects of rapidly lowered plasma tryptophan levels in remitted depressed patients who are also treated with antidepressant medication.