Effects of acute tryptophan depletion on memory, attention and executive functions: A systematic review

Abstract

The serotonergic system is implicated in the regulation of mood and cognition. Acute tryptophan depletion (ATD) is an experimental procedure for lowering central serotonin levels. Here, the effects of ATD on psychomotor processing, declarative memory, working memory, executive functions and attention are discussed. The most robust finding is that ATD impairs the consolidation of episodic memory for verbal information. Semantic memory appears to be unaffected by ATD although a limited variety of tasks examined effects in this domain. Similarly, evidence suggests ATD does not influence verbal, spatial and affective working memory. Most studies investigating effects on executive functions have produced non-specific or negative findings. In terms of attention, ATD either does not affect or may improve focused attention and ATD likely does not impact sustained and divided attention or attentional set-shifting. Although ATD is known to affect mood in certain vulnerable populations, the effects of ATD on cognition in non-vulnerable participants are independent of mood changes. Suggestions for future directions and implications for psychiatric illnesses are discussed.

Introduction

Serotonin (5-hydroxytryptamine, 5-HT) is the neurotransmitter of a diffuse modulatory system implicated in mood regulation and cognition (Riedel, 2004, Schmitt et al., 2006). A number of psychiatric and mood disorders are related to serotonergic dysfunction including depression (Arango et al., 2002, Delgado, 2000), anxiety disorders (Deakin, 1998, Stein and Stahl, 2000), bipolar disorder (Mahmood and Silverstone, 2001), schizophrenia (Lee and Meltzer, 2001) and obsessive-compulsive disorder (OCD) (Zohar et al., 2004). Indeed medications that augment serotonergic activity are standard treatments for depression (Mace and Taylor, 2000) and anxiety disorders (Kent et al., 1998). Several of these psychiatric disorders are often accompanied by a cognitive impairment (Bearden et al., 2001, Elvevag and Goldberg, 2000, Porter et al., 2003a) that may be related to serotonergic dysfunction. Due to serotonin's significance in neuropathology and serotonin's potential role in cognitive dysfunction, research in this field has gained increasing attention in recent years.

Experiments involving pharmacological modulators of serotonergic activity are complicated by the existence of several types of 5-HT receptors that are differentially affected by serotonin-modulating agents (Barnes and Sharp, 1999, Buhot, 1997). As a result, the acute tryptophan depletion (ATD) technique for lowering whole-brain 5-HT levels has become increasingly popular. ATD is an experimental method for decreasing central serotonergic activity (Young et al., 1985). The ingestion of a solution containing large neutral amino acids that is deficient in l-tryptophan (TRP), the amino acid precursor necessary for 5-HT synthesis, induces a reliable and reversible lowering of specifically TRP concentrations in the blood (Boadle-Biber, 1993, Klaassen et al., 1999, Reilly et al., 1997, Smith et al., 1987, Van der Does, 2001). Central depletion is achieved by the combined effects of increased protein synthesis incorporating TRP in organs outside the central nervous system that reduces available precursor in plasma (Biggio et al., 1974), a decrease in the ratio of TRP to large neutral amino acids (Fernstrom and Faller, 1978), and competition between the large neutral amino acids and the precursor for transport into the central nervous system across the blood–brain barrier (Oldendorf and Szabo, 1976). A fundamental issue is the validity of the ATD method for lowering central 5-HT levels. Experiments in rats have shown that ATD did not only reduce TRP ratios in the blood plasma, but also in several brain regions such as the hippocampus and striatum (Lieben et al., 2004). Furthermore, 5-HT levels in the hippocampus, striatum, and cortex were reduced by around 50% (Blokland et al., 2002). ATD also reduces plasma and cerebrospinal fluid TRP levels and decreases brain 5-HT synthesis in humans (Nishizawa et al., 1997, Williams et al., 1999) and monkeys (Young et al., 1989). In humans, the ATD procedure is capable of decreasing plasma TRP by 45–90%, reaching maximum plasma depletion after 5–7 h (Reilly et al., 1997, Van der Does, 2001). Therefore, ATD is a valid and effective method for lowering central 5-HT levels.

Since 5-HT plays a major role in depression, the effects of ATD on mood in humans have been explored extensively. In a seminal study, Young et al. (1985) reported that ATD increased self-reported ratings of depression in healthy volunteers; a finding replicated by the same group (Smith et al., 1987). Other studies found small effects on mood (Ellenbogen et al., 1996, Weltzin et al., 1994) or no effect (Abbott et al., 1992, Oldman et al., 1994, Weltzin et al., 1995) (see Van der Does, 2001, Booij et al., 2003 for a review). A recent meta-analysis concluded that ATD decreases mood in patients with remitted depression, patients with depression taking anti-depressants, and participants with family histories of depression but not in healthy controls without family histories of depression (Ruhe et al., 2007). Another pooled ‘mega-analysis’ identified similar risk factors for mood response to ATD that included recurrent depressive episodes, prior anti-depressant treatment with serotonin-modulating medications, and female gender (Booij et al., 2002). Differences in mood effects in these groups are likely attributable to increased vulnerability to serotonergic fluctuations in populations with certain psychiatric conditions and in females (Booij et al., 2002, Jans et al., 2007, Ruhe et al., 2007). Given that ATD does not appear to affect mood in healthy volunteers without family histories of depression, any effects of ATD on cognition that might be discovered in this population are likely independent of mood changes.

The main aim of this review is to examine the exact impact that ATD, and thus indirectly 5-HT, has on several types of cognition, namely psychomotor processing, declarative memory (episodic and semantic), working memory, executive functions, and attention. Many research groups have used ATD to investigate serotonin's role in various cognitive domains in humans and in some instances, studies have produced conflicting results. Several factors complicate studies on 5-HT and cognition including: (i) variability in sample populations, e.g., healthy volunteers versus depressed patients; (ii) differences in methodology and cognitive assessments; and (iii) the interdependent nature of cognitive operations. Cognitive functions rely on more than one domain and thus no single neuropsychological assessment can tap a single cognitive domain. We will first summarize the literature examined and then we will attempt to dissociate the effects of ATD on memory, executive functions and attention.

Several reviews have analyzed the effects of ATD on cognition. Three descriptive reviews summarized the existing research at the time on ATD and cognition (Riedel, 2004, Riedel et al., 2002, Riedel et al., 2003). Recently, two articles reviewed the literature on ATD studies involving neuroimaging and electrophysiological techniques (Evers et al., 2007, Fusar-Poli et al., 2006). To our knowledge, this is the first systematic review of ATD effects on cognition.