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Abstract

Objective: This is the second of two articles reviewing the modern dietary technique of acute tryptophan depletion (ATD), a method of transiently reducing central serotonin levels in both healthy volunteers and clinical populations. This article details the clinical studies to date and discusses the implications of this research methodology.

Method: The authors present a review of clinical ATD studies collated from a MEDLINE search, unpublished communications and the authors' considerable experience with this paradigm.

Results: Following from the initial use of ATD in subjects with depressive illness, studies of anxiety disorders and other psychiatric illnesses have been reported. Sleep, aggressive and cognitive effects are also active areas of research and are reviewed here.

Conclusions: Acute tryptophan depletion remains a useful psychiatric research tool. The findings from the clinical studies reviewed here are summarized and implications for future research detailed.

Keywords

clinical psychopharmacology serotonin tryptophan

The previous article in this series outlined the rationale and described the methodology of the acute tryptophan depletion (ATD) procedure. This is a safe, transient method of reducing central serotonin (5-HT) levels by both reducing the availability of the 5-HT precursor tryptophan (TRP) and increasing competition for the active transport mechanism that delivers TRP into the brain. It is quickly reversed by resumption of a normal diet.

This article reviews the clinical application of ATD in the field of psychiatry from both healthy volunteer and patient studies.

Clinical effects

Mood effects

In healthy volunteers

The known link between 5-HT and affect led to the early studies of ATD in healthy volunteers focusing particularly on mood effects. The studies used exclusively male subjects and showed that ATDproduced some mood lowering (although never amounting to clinical depression)[1], [2]. These small mood effects were subsequently replicated by two other studies [3], [4]. Subsequent studies have however, tended to report that ATD results in few mood effects [5–13].

The discrepancies between the early and later findings may be explained by differences in the characteristics of the individuals tested. The studies that reported a mood-lowering effect of ATD involved subjects with mean baseline depression scores at the upper end of the normal range, whereas the more recent negative findings were obtained in subjects with lower depression scores. Studies that have included women have reported a sex 566 ACUTE TRYPTOPHAN DEPLETION: PART II difference, with a greater tendency for ATD to produce mood lowering in healthy women compared to men despite similar degrees of plasma TRP depletion [3], [4], [13], [14]. This suggests that women may be more predisposed to the effects of ATD than men and is interesting given the increased incidence of depression disorders in women and evidence suggesting that there may be sex differences in 5-HT metabolism [15]. An increased vulnerability to mood alteration during ATD has also been reported in euthymic subjects of both sexes who have a family history of affective illness [6], [16], [17], although this finding has not been replicated by all studies [18]. This suggests that a mood-lowering response to ATD might be a marker of vulnerability to alterations in 5-HT function. A greater mood response to ATD in females was also reported in healthy women with an SS polymorphism (i.e. two short alleles) of the promoter region of the 5-HT transporter gene (5-HTTLPR) [19]. Studies have reported that the SS allele is associated with reduced transcriptional activity of the serotonin transporter, and hence lower serotonin uptake activity. This may explain why women with this polymorphism have an increased vulnerability to manipulations of 5-HT [20], [21].

A small study in healthy volunteers investigated whether the effects of ATD could be explained by the administration of a selective serotonin re-uptake inhibitor (SSRI) per se. This reported no mood effects of ATD in healthy subjects given an SSRI for 6 weeks, implying that the use of an SSRI could not explain the effects of ATD [22].

In untreated depression

The effects of ATD in untreated depression were somewhat unexpected. It had been hypothesized that if decreased 5-HT function were associated with depression, then reducing TRP availability would lead to a transient worsening of the symptoms. A seminal study which included 43 patientswith untreated depression reported that ATDresulted in no further mood lowering over the course of the day; although the authors did note a bimodal response the next day with 37% of patients describing an improvement in symptoms and 23% a worsening [23]. This inability of ATD to cause a worsening of depressive symptoms in drug-free depressed patients has been replicated by three other studies [24–26]. One explanation for this is that 5-HT function is already so diminished that further lowering has little effect on symptom exacerbation (a floor effect). Another possibility is that, as reported by animal studies [27], ATD has its greatest effects in circumstances where 5-HT levels are enhanced, for example, in the presence of an SSRI.

The trend for an improvement in symptoms the day after ATD has only been replicated by one study which also included the use of IV-TRP as a neuroendocrine challenge [26]. The explanation given by the authors is that ATD may result in an upregulation of post-synaptic 5-HT receptors because of the decreased release of 5-HT at the synapse. When 5-HT levels are restored (by the next day), the net effect is an enhancement of 5-HT function, resulting in an improvement of symptoms.

In remitted depression

The effects of ATD have been most extensively studied in remitted patients still receiving antidepressant treatment. The hypothesis behind these studies was that if, as proposed, a time-dependent process of neuronal adaptation led to an enhancement of 5-HT neurotransmission with antidepressant treatment, then acute depletionwould be expected to rapidly reverse the beneficial effects. This has now been tested in studies which have examined the effects of ATD in patients who had responded to a variety of antidepressant treatments. These have shown that ATD resulted in a transient reversal of clinical efficacy and the return of depressive symptoms in patients who had responded to treatment with SSRIs (6/7 published reports, [28–34], but not [35]), monoamine oxidase inhibitors (MAOIs) (2/2 published reports, [29], [33]) and phototherapy (2/2 published reports, [36], [37]).

There is, however, considerable individual variability among patients in their susceptibility to the moodlowering effects of ATD with only about 50–60% of patients treated with an SSRI, MAOI or phototherapy experiencing an increase in depressive symptoms following ATD (and lower rates in some studies, 5/12 subjects [28]; 7/21 subjects [32]). The factors involved in determining the depressive response to ATD have not yet been determined. There is some evidence that there is a threshold for TRP depletion that needs to be exceeded before behavioural effects occur [38]. In the three partly negative studies [28], [32], [35] ATD reduced plasma TRP levels by only 45–58%, which is a smaller drop than the levels typically reported [34] and as described in Part I, 25% strength drinks which produce smaller TRP depletion have reduced mood effects. It has been suggested that ATD has its greatest effects in patients who have only recently or only partially recovered [35] and in patientswith recurrent or chronic depression [34]. There is also some evidence that women are more vulnerable to the effects of ATD [39], as are depressed subjects with a history of suicidal ideation [40]. An interesting recent study pooled data from six ATD studies in patients with remitted depression (71 subjects) in order to investigate the predictors of the mood response to ATD more thoroughly. This study reported that recurrent depressive episodes, female gender, prior (but not necessarily current) treatment with an SSRI and previous serious suicidal thoughts/attempts were independent predictors of a depressive response to ATD [41]. The strongest predictor was chronicity (single vs recurrent episodes of depression) suggesting that there may be differences in 5-HT vulnerability between these groups of patients. In contrast to the previous literature this study also reported that the degree and duration of remission were not important factors in determining the mood response to ATD.

In contrast to the effects of ATD in patients treated with serotonergic agents, ATD has little effect in patients remitted on noradrenergic tricyclic antidepressants (3/3 published reports [29–31]). Interestingly, catecholamine depletion studies (which use α-methylparatyrosine (αMPT) to block the enzyme, tyrosine hydroxylase and thus the synthesis of noradrenaline (NA)[nd dopamine) result in a similar transient depressive relapse in patients who had been successfully treated with noradrenergic drugs but not those on serotonergic antidepressants [42]. This suggests that increasing 5-HT or NA neurotransmission is important for the specific function of different antidepressants.

The first study comparing the effects of ATD in depressed patients treated with either SSRIs or cognitive behavioural therapy (CBT) has recently been published [43]. The CBT group were resistant to the depressive effects of ATD, as measured by the Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory (BDI), whereas the SSRI-treated group were not. Acute tryptophan depletion comparisons between pharmacologically remitted versus psychologically remitted patients have significant heuristic potential, and the results of similar studies are eagerly awaited. The effects of ATD in patients remitted on treatments other than antidepressants have also shown that ATD did not result in mood worsening, bupropion [44], electro-convulsive therapy [45] and sleep deprivation [37].

In patients with a past history of depression

Patients who have had previous episodes of depression are known to be vulnerable to further depressive episodes and it might be expected that ATD in this group would result in the relapse of depressive symptoms. Seven studies have examined this specifically, using subjects with a past history of depression who were well at the time of the study and on no medication [37], [40], [42],[46–49].

Four studies reported greater rates of depressive relapse after ATD than after the control drink [37],[46–48]; three did not [40], [42], [49]. These findings imply that deficient 5-HT function may play a part in triggering depressive episodes in patients with a vulnerability or susceptibility to changes in 5-HT function. The vulnerability factors are similar to those described earlier and may include gender [39], a history of self-injurious behaviour [40], [47], [50], and an inherited polymorphism of the 5-HT transporter promoter region ([19], [51], [52] but not [53]).

Acute tryptophan depletion response as a predictor of later clinical relapse

Two prospective studies have investigated the hypothesis that the response to ATD may predict patients at risk of future depressive episodes [39], [54]. Both reported a relationship between a depressive response to ATD in patients with remitted depression and later clinical relapse.

Quality of mood effects

Qualitative descriptions of the effects of ATD suggest that the transient return of mood and thought content is of a similar nature to that present before treatment [29]. In general, however, studies do not report these details. The change in rating scores suggest that although ATD does result in a significant increase in depressive symptoms these are not of the magnitude seen in a full clinical relapse. The study that examined the pooled data from six ATD studies ([41], described earlier) reported that although approximately 50% of depressed patients did report a clinical worsening of mood in response to ATD, only about 20% fulfilled the criteria for a ‘full relapse’. In view of this the authors suggested that ‘depressive exaggeration’ or ‘partial relapse’ may more accurately reflect the mood changes produced by ATD.

Anxiety effects

In healthy volunteers

There have been a number of studies in which anxiety ratings have been recorded following ATD. These have included studies designed specifically to address this issue [55–57] and others which have just included measures of anxiety in addition to ratings of other effects [1–3],[5], [6], [13], [22],[58–61]. Most of these studies reported that ATD had very little (if any) effect on ratings of anxiety. The small anxiogenic effect reported in four studies included increased ratings of ‘nervousness’ from visual analogue scales (VAS) [55] and the Spielberger State Anxiety Inventory (SSAI) [56]. The two other positive studies tended to report minor increases in anxiety ratings in male subjects who also reported an increase in depressive symptomatology [1], [6].

The second type of studies combine ATD with an anxiety-provoking challenge given at the time ofmaximal TRP depletion, that is, about 5 hours after consumption of the amino acid drink. These have included pharmacological panicogenic agents, for example, yohimbine [55], the central cholecystokinin agonist CCK-4 [62], 5% CO2 [57], [63] and 35% CO2 [56], and behavioural challenges, for example, a simulated public speaking paradigm [12], [64]. Acute tryptophan depletion in combination with these challenges in healthy volunteers only produced small increases in ratings of nervousness or anxiety in some studies (although never amounting to panic) [55–57].

An interesting recent study investigating the ability of healthy volunteers to recognize different facial expressions found that ATD impaired the recognition of fearful facial expressions, but only in females [65]. The authors suggested that this finding reflected anxiolytic effects being produced by reducing 5-HT and again provides some evidence for a particular vulnerability in women.

In patients with panic disorder

Studies of patients with untreated panic disorder have consistently shown that ATD alone produces no exacerbation of anxiety [57], [66], [67].

Three studies have investigated the effects of ATDcombined with a panicogenic challenge at the time of peak plasma TRP depletion in patients with untreated panic disorder. Two of these reported that when ATD was combined with5%and 35%CO2 patients reported an increase in anxiety and an increased rate of panic attacks [57], [67]. A small study also reported that ATD in panic disorder patients resulted in an increase in the rate of ventilation during room air breathing compared with healthy volunteers [63].

Our group recently published the first study examining the effects of ATD, using the benzodiazepine-antagonist flumazenil as the panicogenic challenge, in patients with panic disorder remitted on SSRIs [68]. We reported that flumazenil produced a panic attack in seven out of 14 patients when tryptophan depleted in contrast to one out of 14 on the control day, suggesting that increased 5-HT availability was important in maintaining the response to SSRIs in panic disorder.

In patients with social anxiety disorder

Successful treatment with SSRIs, and neurochemical challenge tests, suggest a 5-HT abnormality in social anxiety disorder (SAD). A recent study by our group examined the effects of ATD in 14 SSRI responders. In light of the findings from other ATD studies, ATD was combined with three behavioural challenges at the time of peak depletion (an autobiographical script, a verbal task and a neutral script). Tryptophan depletion was found to induce a significant increase in anxiety when listening to the anxiety-provoking autobiographical script, supporting the idea that 5-HT is important in maintaining the response to SSRIs in SAD [69].

In patients with obsessive-compulsive disorder (OCD)

Selective serotonin re-uptake inhibitors and serotonergic tricyclic antidepressants have been used successfully in the treatment of OCD, suggesting a serotonergic involvement in this condition. It was hypothesized that, as with depression and panic disorder, ATD might be expected to exacerbate obsessive compulsive symptoms in this group of patients. Three studies have examined the effects of ATD in OCD in drug-free patients [70], [71] and in SSRI-remitted patients still taking medication [72]. These have all shown that ATD had no effect on OCD symptoms, although two studies reported that it did produce some mood worsening [71], [72]. The lack of effect of ATD on OCD symptoms compared with the relapse of symptoms in depression and untreated panic disorder suggests that the treatment of OCD may be less dependent on the synaptic availability of 5-HT than these other conditions. Alternatively, it may be a reflection of the design of these studies, because in none of the OCD studies described earlier was ATD combined with a challenge (as used in the panic disorder studies); and it may be that if this were done, ATD would produce a relapse in symptoms.

Pooled anxiety studies

Our group has recently completed a pooled analysis of 53 patients who underwent ATD in our research laboratory. This cohort included patients with SSRI and CBT-remitted panic disorder, and subjects with SSRIremitted SAD. Two control groups were used, both normal volunteers and patients with the chronic medical illness irritable bowel syndrome (IBS). This study confirmed a significant effect of ATD in subjects with remitted anxiety disorders in combination with an anxiogenic provocation; this was not seen in IBS patients or normal volunteers. As few as one previous depressive episode was strongly associated with depressive-symptom induction in the patients with remitted anxiety disorders. Acute tryptophan depletion had a greater impact upon women than men, with significantly larger LNAA:TRP ratios (i.e. more depleted) and more transient nausea 2 hours after consuming the non-depleting mixture.

Memory and cognitive effects

The most consistent finding from studies in healthy young subjects is an adverse effect of ATD on measures of delayed recall and recognition [58], [73], [74]. Studies have also suggested that ATD has an adverse effect on functions controlled by the ventral prefrontal cortex; that is, decision-making tasks [75], reversals on a visual discrimination test [75] and on an affective set-shifting task [74]. In contrast, studies have tended to suggest that ATD has little effect on traditional executive function tasks (see [76]). Although one study reported that ATD resulted in impairment on tasks of working memory [77].

Acute tryptophan depletion has also been reported to result in improvements in measures of focused attention, which may be a result of the inhibitory effect of 5-HT on other neurotransmitters involved with attentional processes (NA and acetylcholine) [78–80]. Interestingly, ATD does not produce changes in other measures of frontal functioning [79]. Two studies have suggested that ATD produces changes to emotional processing rather than other aspects of execution and this results in a shift of affectivememory bias toward negative or mood-congruent affective stimuli functioning [81], [82].

The complex nature of monoaminergic interactions may in part explain these contradictory reports, with a recent study showing that simultaneous depletion of serotonin, noradrenaline and dopamine using combined precursor depletion, elicited impaired sustained attention in healthy female volunteers, while having no effects on cognitive measures previously shown to be sensitive to serotonin or catecholamine depletion alone [83]. The same group has also recently demonstrated differential effects of ATD (impaired delayed memory recall) and catecholamine depletion (impaired spatial memory) in healthy female volunteers [84].

A recent detailed review of cognitive changes induced by ATD [85] is recommended for the interested reader.

Effects on sleep

The role of 5-HT in sleep is complex. Increased 5-HT function results in a disruption of sleep continuity and changes in sleep architecture, that is, the suppression of rapid-eye-movement (REM) and slowwave sleep. Alarge body of work has examined the sleep changes seen in depression. The classical abnormalities reported include reduced sleep continuity (difficulty getting off to sleep, waking during the night and waking early in the morning)[nd changes to sleep architecture (reduced latency to REM sleep, increased REM sleep duration, percentage of REM sleep time and REM density) [86]. Serotonergic antidepressants, such as SSRIs suppress these REM sleep variables in healthy volunteers and depressed patients [87].

It was hypothesized that ATD in healthy volunteers would produce a reduction in 5-HT function that would be reflected by changes in the sleep electroencephalogram (EEG), possibly producing similar changes to those seen in depressed patients. One study reported findings consistent with this, that is, reduced REM latency after ATD [61], although another reported no change to REM latency or amount [88].

In patients with remitted depression it was hypothesized that ATD would result in an increased propensity for REM sleep similar to that seen in depressed patients. Two studies have investigated this and reported that in SSRI [35] and MAOI [89] remitted patients ATD resulted in sleep EEG changes characteristic of depressed patients, that is, reduced sleep and REM latencies and increased REM percentage and density. Interestingly these findings were associated with no deterioration in mood, suggesting that sleep may be a particularly sensitive index of central TRP levels and 5-HT function.

Effects on aggression

The role of 5-HT in aggressive and impulsive behaviour has been the subject of much research. Decreased central 5-HT function as measured by cerebrospinal fluid concentrations of the major 5-HT metabolite 5-hydroxy indoleacetic acid (5-HIAA) has been implicated in impulsive aggressive acts, including violent offending, arson and suicide [90]. This link is particularly strong for individuals with several psychopathological syndromes associated with poor impulse control [91]. Animal studies have confirmed these findings and shown that reduced central 5-HT function is associated with low social status and inappropriate aggression [92].

Acute tryptophan depletion studies in humans reported that ATD produces an increase in impulsive responding [93] and ratings of aggression during provocation tasks, particularly in subjects with high trait aggression but has little effect in thosewith lowtrait aggression [59],[94–96].

In patients with Alzheimer's disease

The effects of ATD have also been examined in Alzheimer's disease and reported a significant impairment in cognitive functioning, suggesting that compromised serotonergic function (in combination with a cholinergic deficit) may make an important contribution to the cognitive decline seen in this group of patients [97]. Interestingly ATD produced no mood effects in either patients with Alzheimer's disease or normal controls, suggesting that the vulnerability of patientswith Alzheimer's disease to depression may not be solely secondary to reduced 5-HT function.

Effects of acute tryptophan depletion on other disorders

Bipolar disorder

A role for 5-HT in mania and the effects of antimanic treatments has been hypothesized [98], [99] although to date no ATD studies have yet been performed in acutely manic patients. In two small studies of recently remitted manic patients ATD has been reported to have either no effect [100] or to cause a transient worsening of manic symptoms [101]. In a larger study of patients euthymic for at least 3 months, ATD had no effect on mood symptoms [102].

Schizophrenia

There is some evidence that 5-HT may be at least partially responsible for some of the negative symptoms of schizophrenia. Supporting this is the fact that many antipsychotics are high-affinity antagonists at 5-HT receptors.

The effects of ATD in schizophrenia, however, appear to be quite limited. An early study in a group of schizophrenic subjects reported delayed improvement in psychotic symptoms with a 4-day TRP-deficient diet [103]. In another study, ATD exacerbated depressive symptoms and had no effects on positive or negative psychotic symptoms [104]; whereas in another, it worsened negative symptoms [105]. In two recent studies of antipsychotic-treated schizophrenic patients, ATD produced no change in mood, or positive or negative symptoms [106], [107]. It did, however, result in an impairment in measures of executive function [106].

Eating disorders

There is considerable evidence for a role for 5-HT in the control of feeding, with a reduction in 5-HT function being shown to lead to impaired satiety and weight gain in animals.

Reduced 5-HT function has also been implicated in bulimia nervosa (BN). Studies in acutely ill untreated subjects with BN reported that ATD resulted in an increase in subjective ratings of irritability and caloric intake [108] and desire to overeat and purge [109]. A similar study in a group of 10 women in clinical remission from the condition reported that ATD produced an increase in ratings of body image concern and the subjective loss of control of eating [50]. In both untreated and treated BN patients and those in remission, there was also a vulnerability to the mood-lowering effects of ATD.

A recent study in patients with anorexia nervosa (AN)[nd healthy controls reported that ATD resulted in a decrease in measures of anxiety in the patient group (both ill and recovered from AN) [110]. The authors suggested that reducing TRP through dietary intake restriction may represent a mechanism through which individuals with AN modulate anxiety.

Autism

Serotonergic abnormalities have been implicated in the pathophysiology of autism with some positive benefits of SSRIs being demonstrated. One study has investigated the effects of ATD in medication-free adult patients with autistic disorder and reported a significantworsening of behavioural (whirling, flapping, pacing, banging, hitting self and rocking) and emotional symptoms [111].

Premenstrual syndrome

One study has investigated the effects of ATD during the menstrual cycle in patients with late luteal phase dysphoric disorder (LLPDD). This reported that although ATD did not produce an increase in depressive symptomatology, a subgroup of subjects did complain of an increase in LLPDD-related symptoms and irritability [14]. Unfortunately no study has been performed in healthy controls to investigate whether women in general are more vulnerable to mood effects with ATD during different phases of the menstrual cycle. Many of the ATD studies of women with other conditions claim to perform the testing during the follicular phase of the menstrual cycle, although this is difficult to verify.

Discussion

Themost consistent finding of ATDis a mood-lowering response in patients recovered from depression – particularly in those taking serotonergic antidepressants. This is in contrast to patients recovered on noradrenergic antidepressants who are more vulnerable to effects of catecholamine depletion [42]. These studies suggest that enhanced synaptic 5-HT is important in maintaining the antidepressant response to SSRIs. The mood-lowering effects of ATD seem to be more pronounced in studies which have included patients early in their recovery (i.e. during the first few weeks), possibly suggesting that 5-HT processes are more important at this stage with later effects involving intracellular mechanisms downstream from the synapse or 5-HT receptors.

The literature reports that ATD does not worsen the symptoms of currently depressed patients and does not induce significant depressive symptoms in healthy volunteers (without risk factors for depression). These findings suggest that depression cannot be explained by a simple deficit in 5-HT neurotransmission.

There does, however, appear to be a group of subjects who are particularly vulnerable to the effects of ATD. This group includes patients with a past history of depression (currently on or off treatment), those with a history of suicide attempts, females, healthy volunteers with a family history of depression and subjects with a polymorphism of the 5-HTT [19], [51]. In the previous review in this series we hypothesized that ATD acts by challenging the 5-HT system. It seems that vulnerable individuals are unable to mount a compensatory response, reflecting an impairment of 5-HT function. This vulnerability may be the result of genetic effects (e.g. involving 5-HT receptors or transporters), environmental effects, ‘scarring effects’ from a previous episode of depression or any combination of the above.

The clinical implications of ATD are as yet unproven. Follow-up studies of healthy subjects at risk of depression who have reported mood responses to ATD will give insights into the validity of ATD as an indicator of 5-HT and clinical vulnerability. Two prospective studies have reported that there is a relationship between a depressive symptom response to ATD and future clinical depressive episodes, suggesting that this approach may be useful in identifying patients at risk of future clinical relapse. It would be very informative to investigate the impact of ATD in untreated patients with anxiety and other disorders, as well as in other cohorts of patients remitted by psychological therapies such as CBT, to further delineate the role of 5-HT illness and recovery. The marked effects of ATD in women, and the intricacies of neurotransmitter and neuroendocrine interplay warrant careful consideration in future research using this methodology.

Despite its limitations, ATD remains a useful psychiatric research tool [112]. It is hoped that our ongoing work in this area, and the contributions of other groups, shall continue to improve our understanding of the role of serotonin and other systems in psychiatric disorders.

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Acute Tryptophan Depletion. Part II: Clinical Effects and Implications

Abstract

Keywords

Clinical effects

Mood effects

In healthy volunteers

In untreated depression

In remitted depression

In patients with a past history of depression

Acute tryptophan depletion response as a predictor of later clinical relapse

Quality of mood effects

Anxiety effects

In healthy volunteers

In patients with panic disorder

In patients with social anxiety disorder

In patients with obsessive-compulsive disorder (OCD)

Pooled anxiety studies

Memory and cognitive effects

Effects on sleep

Effects on aggression

In patients with Alzheimer's disease

Effects of acute tryptophan depletion on other disorders

Bipolar disorder

Schizophrenia

Eating disorders

Autism

Premenstrual syndrome

Discussion

References