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Evidence for serotonin function as a neurochemical difference between fear and anxiety disorders in humans?

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The relationships between serotonin and fear and anxiety disorders have been much studied yet many important questions remain, despite selective serotonin reuptake inhibitors having been the primary treatments for these disorders for some time. In order to explore this issue we performed a pooled analysis of six of our studies in remitted patients with a fear/anxiety disorder who were exposed to syndrome-specific aversive stimulation under acute tryptophan depletion. We based our analysis on the hypothesis that the inconsistencies observed in the studies could be predicted by Deakin and Graeff's theory about the dual role of serotonin in responses to threats, whereby serotonin is critical to prevent fear (panic) but not anxiety. In accordance with this view, our results give support to a dissociation of the disorders traditionally grouped under fear and anxiety-related disorders in terms of different roles of serotonin in modulation of responses to aversive stimulation. Implications for future studies and psychiatric nosology are discussed. © The Author(s) 2015.
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DOI: 10.1177/0269881115590603
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Introduction
The conceptualization of the boundaries of anxiety disorders is
an ongoing issue that is yet to be resolved (Starcevic, 2014). In
DSM-5, fear and anxiety disorders have been separated for the
first time, with panic disorder and generalized anxiety disorder
(GAD) in separate groups. Also, posttraumatic stress disorder
(PTSD) and obsessive–compulsive disorder (OCD) have been
removed from the anxiety disorders group. Moreover, the ICD11
draft document refers to “anxiety and fear-related disorders”,
which suggests different, but related conditions (Starcevic,
2014). In spite of a clear current demand for pathophysiological-
based psychiatric nosology (Insel, 2014; Insel et al., 2010;
Sanislow et al., 2010), none of the major re-conceptualizations
have enough neurobiological support.
One approach to this issue is to explore the neurochemical
basis of each disorder to look for patterns of similarity and differ-
ence. Serotonin (5HT) has long been implicated in the modula-
tion of aversive stimulation as well as anxiety and stress-related
psychiatric disorders. One hypothesis is that 5HT acts in these
disorders through modulation of stress (Davidson et al., 2005).
Increased synaptic levels of 5HT may have a crucial role in this
process (Charney, 2004). Animal models consistently give sup-
port to this view by demonstrating that brain 5HT systems are
critically involved in the response to stressors as well as in fear
and anxiety generation (Deakin, 2013; Deakin and Graeff, 1991).
In humans, most anxiety and fear disorders respond to some
extent to drugs that increase 5HT function, and the selective sero-
tonin reuptake inhibitors (SSRIs) are now generally accepted as
the first-line pharmacological treatments for these (Baldwin
et al., 2014). However, it is not clear if they work through the
same mechanisms in each disorder. One approach to explore this
issue is to use the acute tryptophan depletion (aTD) technique to
transiently lower brain 5HT and see what effect this has on the
disorder (Hood et al., 2005). Previous studies have reported that
aTD undermines the therapeutic effect of SSRIs in depression
(Delgado et al., 1990), and increases depressive symptoms
(Smith et al., 1997) and stress responses in drug-free recovered
patients (Harmer et al., 2003). On the other hand, aTD alone
seems to be insufficient to cause spontaneous relapse in fear/
anxiety disorders such as panic disorder (Goddard et al., 1994)
and OCD (Kulz et al., 2008; Smeraldi et al., 1996), but has been
shown to reverse the effects of SSRIs and so lead to transient
relapse in some people under fear/anxiety provocation challenges
Evidence for serotonin function as a
neurochemical difference between fear and
anxiety disorders in humans?
Felipe Corchs1, David J Nutt2, Dana A Hince3, Simon JC Davies4,
Marcio Bernik1 and Sean D Hood3
Abstract
The relationships between serotonin and fear and anxiety disorders have been much studied yet many important questions remain, despite selective
serotonin reuptake inhibitors having been the primary treatments for these disorders for some time. In order to explore this issue we performed a
pooled analysis of six of our studies in remitted patients with a fear/anxiety disorder who were exposed to syndrome-specific aversive stimulation
under acute tryptophan depletion. We based our analysis on the hypothesis that the inconsistencies observed in the studies could be predicted by
Deakin and Graeff’s theory about the dual role of serotonin in responses to threats, whereby serotonin is critical to prevent fear (panic) but not
anxiety. In accordance with this view, our results give support to a dissociation of the disorders traditionally grouped under fear and anxiety-related
disorders in terms of different roles of serotonin in modulation of responses to aversive stimulation. Implications for future studies and psychiatric
nosology are discussed.
Keywords
5-Hydroxytryptamine, tryptophan depletion, anxiety, fear
1 Institute and Department of Psychiatry, School of Medicine, University
of São Paulo, São Paulo, Brazil
2
Neuropsychopharmacology Unit, Division of Experimental Medicine,
Imperial College London, London, UK
3
School of Psychiatry & Clinical Neurosciences (M521), The University
of Western Australia, Perth, WA, Australia
4Centre for Addiction and Mental Health, University of Toronto, Toronto,
ON, Canada
Corresponding author:
Felipe Corchs, Institute and Department of Psychiatry, School of
Medicine, University of São Paulo, R. Dr. Ovidio Pires de Campos, 785,
05430-903 São Paulo, Brazil.
Email: felipe.corchs@hotmail.com
590603JOP0010.1177/0269881115590603Journal of PsychopharmacologyCorchs et al.
research-article2015
Original Paper
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2 Journal of Psychopharmacology
in panic disorder (Bell et al., 2002), social anxiety disorder
(SAnD) (Argyropoulos et al., 2004) and PTSD (Corchs et al.,
2009). This effect was also observed to some extent in panic dis-
order treated with cognitive-behavior therapy (CBT) (Bell et al.,
2011). On the other hand, no effect of aTD was observed in sub-
jective or physiological measures in 5HT antidepressants-remitted
GAD (Hood et al., 2010) and OCD (Hood, 2010).
The causes of this variation in the effects of aTD are still
unknown. It is, however, consistent with an existing, well-sup-
ported theory (Deakin, 2013; Deakin and Graeff, 1991) which
proposes that 5HT may have an apparently paradoxical dual role
in aversive contingencies. Although it can inhibit periaqueductal
gray matter (PAG)-mediated fight/flight responses from threats,
5HT can also facilitate amygdala-mediated anxiety responses.
This latter mechanism has been demonstrated both in animals
(Deakin, 2013; Deakin and Graeff, 1991) and humans (Blanchard
et al., 2001; Feinstein et al., 2013; Mobbs et al., 2007). These
different mechanisms may explain, at least in part, the different
types of emotions (Mobbs et al., 2007) and fear/anxiety disorders
(Deakin and Graeff, 1991; Gray and Mcnaughton, 2000) seen in
humans. Reactions to imminent, PAG-mediated threats relate to
the emotion named “fear” and, as proposed earlier (Gray and
Mcnaughton, 2000; Mcnaughton and Corr, 2004), may be more
closely related with phobic, escape-dominant behavioral syn-
dromes, such as specific phobias, SAnD, and panic. Potential,
amygdala-mediated threats seem to be linked to the emotion
named “anxiety” and related disorders, such as GAD and OCD
(Gray and Mcnaughton, 2000; Mcnaughton and Corr, 2004).
PTSD was not initially included in these clusterings and, actually,
may have a more complex categorization. However, the onset of
PTSD is driven by the fearful memory of harm or threat of harm,
and there is strong neurobiological evidence for the inclusion of
PTSD, together with panic disorder, social phobia and specific
phobias, in a cluster of disorders characterized by the major
involvement of brain “fear circuitry”, related to the responses to
threats or fearful stimuli (Andrews, 2009; Friedman et al., 2011),
which was one of the many reasons to exclude PTSD from the
anxiety disorders in the DSM-5. For these reasons, we included
PTSD in the fear-related disorders group.
The aTD plus challenge studies quoted above focused on each
disorder specifically by measuring their specific symptoms. In
the present study we focus on the category of responses to aver-
sive stimuli rather than specific symptoms, in a pooled sample.
Our main hypothesis is that differences in challenge-provoked
responses under aTD and non-depleted conditions can be
explained in terms of the cluster of fear versus anxiety-related
conditions.
Methods
Participants
Data from 66 subjects from six different studies were included in
the analysis (see Table 1). The sample was divided based on the
hypothesis: fear disorders (PTSD, panic disorder and SAnD; n =
47); and anxiety disorders (GAD and OCD; n = 19). According to
this grouping, the sample has the characteristics described in
Table 2. In all studies, diagnoses were based on the Mini-
International Neuropsychiatric Interview (MINI) (Sheehan et al.,
1998) and remission was considered if the subject had “good
improvement” or “very good improvement” (scores 2 or 1) on the
clinical global impression improvement scale (CGI-I) (Guy,
1976) for at least 3 months before the tests.
In all studies, patients were excluded if they had active major
depressive disorder, alcohol or substance use disorder, bipolar or
a primary psychotic disorder, or any physical condition that could
Table 1. Summary of participant and study details included in the pooled analysis presented here.
Study reference Diagnostic
category
Treatment* Challenge N (% of total);
female
Age [mean (SD)] Test order Number
depleted 1st
Argyropoulos etal. (2004) SAnD SSRIs Public speaking 14 (17.5); 5 39.93 (11.23) 6
Bell etal. (2002) PD SSRIs Flumazenil 14 (17.5); 7 40.57 (13.17) 6
Bell etal. (2011) PD CBT Flumazenil 9 (11.2); 4 36.22 (11.32) 5
Hood etal. (2010) GAD SSRIs CO2 7.5% 13 (16.2); 7 36.54 (11.39) 7
Hood (2010) OCD SSRIs ERP 6 (7.5); 2 39.83 (11.79) 4
Corchs etal. (2009) PTSD SSRIs Trauma-related script 10 (12.5); 7 31.70 (7.53) 5
Total 66 (100); 32 37.64 (11.29) 33
*Patients using SSRIs could not be receiving any sort of psychotherapy and those undergoing CBT could not receive any psychotropic medication. ERP: exposure and
response prevention.
Table 2. Demographic and baseline data for fear and anxiety disorder groups.
Females:males Age in years [mean (SD)] Mean baseline scores [aTD+sTD/2]
SSAI [mean (SD)] VAS SAD [mean (SD)]
Fear disorders 23:24 37.66 (11.42) 33.04 (7.94) 5.73 (9.64)1
Anxiety disorders 9:10 37.58 (11.30) 41.76 (10.36) 18.13 (19.94)
Group comparison Χ2(1) = 0.01; p = 0.91 t(64) = 0.03; p = 0.98 t(64) = –3.69; p<0.001 t(50) = –3.03; p = 0.004
1As VAS SAD was not measured in the PD SSRI study, n = 33 for the fear group for this analysis.
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Corchs et al. 3
make tests biased or risky to the patient. Each study was approved
by the research ethics committee of the site where it took place.
Two of the authors of this paper (SDH, DJN) were also authors of
all of the studies pooled.
Tryptophan depletion procedure
The experimental phase of the studies was designed in a dou-
ble-blind, placebo-controlled crossover fashion. Following a
standard procedure (Young et al., 1985) subjects took part in
two similar test days, 1 week apart, in which they consumed a
100 g mixture containing 15 large neutral amino acids. This
drink contained 2.3 g of tryptophan on the sham tryptophan
depletion (sTD) day and not on the acute tryptophan depletion
(aTD) day. The presence or absence of tryptophan in the amino
acid formula ingested was the only programmed difference
between test days. This determined acute tryptophan depletion
effect (aTD day), with the sTD day acting as a control condi-
tion to allow comparison with acute tryptophan depletion.
Subjects were instructed to have a low tryptophan diet the day
before each test and fast from midnight, as well as to take all
medications they might be using as usual on the test days. The
order of aTD and sTD condition was random and counterbal-
anced within each study, and presented in a double-blind fash-
ion. Female subjects took only 80% of the total amount because
of their lower body weight. Further details about experimental
procedures can be found in the original papers and in Hood
et al. (2005).
Aversive exposure challenge
Each study involved a specific challenge that represented a well-
established symptom provocation procedure, related to the anxi-
ety disorder under study (Table 1).
Challenges were performed between 4.5 and 7 h after the
drink, as this was estimated to be the peak time of aTD that could
be managed within the daily protocol of each study.
Psychological measures
As the aTD effects could have become obvious to the examiner
during the tests, the psychological effects of these procedures
were measured exclusively by self-rating scales.
During testing, the main assessment was of anxiety, measured
by the Spielberger State Anxiety Inventory (SSAI) (Spielberger
et al., 1970). Mood was assessed by a visual analog scale (VAS)
anchored to the term “sad” that followed standard practice for
theses scales (Bond and Lader, 1974). Subjects from the SSRI-
remitted panic disorder study (Bell et al., 2002) were not assessed
for mood using the same instrument (VAS) so could not be
included in the overall mood analysis.
These instruments were applied at baseline (before ingestion
of the amino acid formula), immediately before the challenges,
and during/immediately after the challenge, when subjects were
given the rating scales and instructed to fill them in to reflect
the peak intensity of symptoms they felt during the challenge.
The Beck Depression Inventory and the Spielberger Trait
Anxiety Inventory (Spielberger et al., 1970) were applied only
at baseline.
Cardiovascular measures
Cardiovascular data (n fear:anxiety groups = total; systolic blood
pressure (SBP) 36:19 = 55, diastolic blood pressure (DBP) 31:19
= 50, heart rate (HR) 37:19 = 56) were obtained and analyzed
here. Missing data were due to random recording failure.
Blood pressure was measured 1–2 min after the stress test
(time of peak subjective anxiety) and was compared with that
immediately before the stress test. Further details on the methods
of SBP ascertainment can be obtained in our earlier publication
which included patients with panic disorder and SAnD (Davies
et al., 2006).
Plasma tryptophan levels
Blood samples for the measurement of total tryptophan were
taken before the amino acid drink and after the challenge, but
before re-feeding. Three subjects from the GAD study did not
have plasma tryptophan data at the time this paper was prepared
and were not included in the analysis.
Statistical analysis
The main analysis used a repeated measures analysis of variance
(ANOVA; sphericity assumed) with depletion condition (sTD vs.
aTD) and time (baseline, pre-challenge and peak post-challenge)
as within-subjects factors. Disorder group (fear vs. anxiety disor-
ders) and the depletion order were included as between-subjects
variables. In order to be conservative with the analysis, although
the pair-wise comparisons made were planned a priori, we used
Bonferroni corrected pair-wise t-tests to assess differences of
importance to the hypothesis following significant or trend sig-
nificant interactions. All tests were 2-tailed with alpha = 5% and
beta = 20%. We used the statistical package SPSS v. 22 (SPSS Inc,
Chicago, IL).
Results
Plasma tryptophan levels
Analysis of total plasma tryptophan levels revealed a main effect
of depletion condition (F(1,58) = 148.4; p < 0.001), and a signifi-
cant depletion condition by time interaction (F(1,58) = 173.6; p <
0.001). Tryptophan levels did not differ at baseline, that is, prior to
the drink (mean difference = 0.19, 95% CI –1.96–6.50, p = 0.74)
but were significantly lower at peak time of depletion in the aTD
compared with the sTD condition (mean difference = 20.0, 95% CI
17.1–23.0, p < 0.001). As shown in Table 3, tryptophan levels
decreased across the depletion condition (79.7% reduction) but
increased on the sham depletion day (99.9% increase). Disorder
group did not significantly interact with the within-subjects effects
(p > 0.05). Order of depletion, however, was involved in a signifi-
cant interaction with depletion condition and time (F(1,58) =
4.158, p = 0.046). This was a consequence of mean tryptophan
level under the sTD condition being 5.7 µg/mL lower (95% CI
0.03–11.5, p = 0.049) at peak time in the group depleted on day 2
compared with those depleted on day 1, although the results were
in the same direction for both depletion orders. Mean tryptophan
levels were not different between the two orders of depletion at any
other time point under either aTD or sTD conditions (all p > 0.68).
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4 Journal of Psychopharmacology
Psychological ratings
Spielberger State Anxiety Inventory. The mean SSAI scores
for the anxiety and fear disorder groups under sTD and aTD con-
ditions are displayed in Figure 1. Repeated measures ANOVA
revealed a near significant depletion by time by disorder group
interaction (F(2,124) = 2.95, p = 0.056), a significant depletion
by disorder group interaction (F(1,62) = 7.35, p = 0.009), and a
main effect of time (F(2,124) = 46.21, p < 0.001), depletion
(F(1,62) = 7.88, p = 0.007) and disorder group (F(1,62) = 18.69,
p < 0.001). Depletion order did not reach significance as a main
effect or in any interaction in this analysis (all p > 0.179). To
explore the source of the three-way interaction, both disorder
groups were subjected to repeated measures ANOVA separately.
The fear group displayed a significant depletion condition by
time interaction (F(2,90) = 7.35, p = 0.001) with significantly
Table 3. Effects of tryptophan (TRP)-depleted and control mixtures on plasma total tryptophan.
Sham tryptophan depletion day Tryptophan depletion day
Time Baseline (pre-drink) Peak (pre-refeeding) Baseline (pre-drink) Peak (pre-refeeding)
Total TRP 11.16 (5.28) 22.32 (11.30) 11.36 (3.05) 2.31 (1.72)
Values of plasma are means (SD) in µg/mL.
Obs: N=62.
Figure 1. Mean Spielberger State Anxiety Inventory (SSAI) scores on the acute tryptophan depletion (aTD) and sham depletion (sTD) days (top: fear
disorders; bottom: anxiety disorders. **p < 0.01; ***p < 0.001). Error bars represent the standard error of the mean.
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Corchs et al. 5
higher SSAI scores observed in the aTD condition at pre-chal-
lenge (mean difference = 3.89, 95% CI 1.28–6.50, p = 0.004) and
challenge (mean difference = 8.77, 95% CI 4.77–12.76, p <
0.001), but not at baseline (p = 0.47; see Figure 1). In the anxiety
group, both the depletion condition by time interaction (F(2,34) =
0.53, p = 0.66) and the main effect of depletion condition (F(1,17)
= 0.007, p = 0.93) were not significant.
VAS SAD. The mean VAS SAD scores for the anxiety and fear
disorder groups under sTD and aTD conditions are displayed
in Figure 2. This measure was not recorded for the panic disor-
der SSRI study, therefore n = 33 for the fear group in this anal-
ysis. Repeated measures ANOVA revealed a significant
depletion by time by disorder group interaction (F(2,96) =
6.08, p = 0.003), a significant time by disorder group interac-
tion (F(2,96) = 6.70, p = 0.002), a significant depletion
condition by time interaction (F(2,96) = 4.31, p = 0.02), a main
effect of time (F(2,96) = 9.35, p < 0.001), and a main effect of
depletion condition (F(1,48) = 5.11, p = 0.028). Depletion
order did not reach significance as a main effect or in any inter-
action in this analysis (all p > 0.217). To explore the source of
the three-way interaction, both disorder groups were subjected
to repeated measures ANOVA separately. The fear group dis-
played a significant depletion condition by time interaction
(F(2,62) = 8.95, p < 0.001) with significantly higher VAS SAD
ratings observed under the aTD condition following the chal-
lenge (mean difference = 14.05, 95% CI 4.55–23.55, p =
0.005), but no difference noted at baseline (p = 0.16) or pre-
challenge time points (p = 0.68, see Figure 2). A significant
depletion by time interaction was also revealed for the anxiety
group (F(2,34) = 2.81, p = 0.039). Pair-wise comparisons
revealed significantly greater mean VAS SAD scores on the
Figure 2. Mean visual analog scale scores anchored to the term “sad” (VAS SAD) I on the acute tryptophan depletion (aTD) and sham depletion
(sTD) days (top: fear disorders; bottom: anxiety disorders. *p < 0.05, **p < 0.01). Error bars represent the standard error of the mean.
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6 Journal of Psychopharmacology
aTD day compared with nTD at only the pre-challenge time
point (mean difference = 5.74, 95% CI 0.88–10.61, p = 0.023).
Cardiovascular measures
Two CBT participants with panic disorder had no cardiovascular
data recorded. Heart rate and blood pressure data were not avail-
able pre-challenge on either sTD or aTD days for eight partici-
pants with social anxiety. Both SBP and DBP were not available
on the sTD day at challenge for one PTSD participant, and DBP
was not available at challenge on the aTD day for another PTSD
participant. DBP was also not available at baseline or pre-chal-
lenge on the aTD day for a further four SAnD participants.
Therefore, the following analyses are based on n = 36 (SBP), n =
31(DBP) and n = 37 (HR) for the fear group. No data were miss-
ing in the anxiety group. Supplementary analyses which included
only baseline and challenge time points, thereby including the
eight SAnD participants without pre-challenge scores, returned
similar results to that reported below (data not shown).
Blood pressure. Mean SBP (mmHg) and DBP (mmHg) for the
anxiety and fear disorder groups under sTD and aTD conditions
are displayed in Figure 3. For SBP, although inspection of Figure
3 suggests that the fear disorder group under the sTD condition is
the only disorder group/depletion condition combination not to
show an increase in SBP following challenge, the repeated mea-
sures ANOVA failed to find the three-way interaction significant
(p = 0.159). ANOVA did reveal a significant effect of time
(F(2,102) = 9.32, p < 0.001), reflecting the significantly lower
SBP pre-challenge in comparison with baseline (mean difference
= 5.4, 95% CI 1.89–8.86, p = 0.001) and challenge (mean differ-
ence = 8.42, 95% CI 2.92–13.91, p = 0.001) when the means
Figure 3. Mean systolic blood pressure (SBP; top) and diastolic blood pressure (DBP, bottom) on the acute tryptophan depletion (aTD) and sham
depletion (sTD) days for the fear and anxiety disorder groups. Error bars represent the standard error of the mean.
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Corchs et al. 7
were collapsed across all other conditions (see Figure 3). ANOVA
also returned a significant disorder group by depletion condition
interaction (F(1,51) = 10.73, p = 0.002), because when collapsed
across time, SBP was significantly lower under aTD in the anxi-
ety group (mean difference = 6.04, 95% CI 1.53–10.55, p =
0.010), but the 3 mmHg mean increase in SBP under aTD condi-
tion in the fear group was not significant (p = 0.067).
Order of depletion did impact on the results for SBP. The
depletion condition by depletion order interaction (F(1,51) =
5.41, p = 0.024) reflected the lack of depletion effect for those
depleted on the first day (mean difference = 1.70, 95% CI –2.01–
5.41) in comparison with higher SBP when not depleted for those
depleted on the second test day (mean difference = 4.73, 95% CI
0.61–8.85, p = 0.025). In addition, ANOVA also found a signifi-
cant disorder group by depletion order interaction (F(1,51) =
5.31, p = 0.025). When collapsed across all other factors, SBP in
the anxiety group was substantially lower in those depleted on
the second day, but not significantly so (mean difference = 9.19,
95% CI –3.96–22.33, p = 0.167). However, for the fear group,
SBP was almost significantly higher in those participants depleted
on the second day (mean difference = 9.38, 95% CI –0.05–18.81,
p = 0.051).
For DBP, the pattern of means was very similar to that
observed for SBP. Repeated measures ANOVA revealed a signifi-
cant main effect of time (F(2,92) = 12.03, p < 0.001) and disorder
group by depletion condition interaction (F(1,46) = 9.86, p =
0.003). Again, inspection of Figure 3 suggests that the fear disor-
der group under the sTD condition is the only disorder group/
depletion condition combination not to show an increase in SBP
following challenge, but the repeated measures ANOVA failed to
find the three-way interaction significant (p = 0.182). The disor-
der group by time interaction (F(2,92) = 3.23, p = 0.044) reflected
the observation at DBP was significantly higher in the anxiety
group compared with the fear group at baseline (mean difference
= 7.54, 95% CI 1.95–13.13, p = 0.009), and challenge (mean dif-
ference = 11.88, 95% CI 4.07–19.68, p = 0.004) but not at pre-
challenge (p = 0.106). ANOVA for DBP also found a main effect
of disorder group (F(1,46) = 7.77, p = 0.008).
ANOVA also found a significant disorder group by depletion
order interaction (F(1,46) = 5.06, p < 0.029). When collapsed
across all other factors, DBP in the anxiety group did not vary
with respect to order of depletion (mean difference = 2.84, 95%
CI –6.58–12.25, p = 0.547). However, for the fear group, DBP
was significantly higher in those participants depleted on the sec-
ond day (mean difference = 10.46, 95% CI 3.18–17.74, p = 0.006).
Heart rate. Disorder group and depletion condition had no
impact on HR, as repeated measures ANOVA found no main
effect or interaction involving these factors significant (all p >
0.08). ANOVA did return a main effect of time (F(2,104) = 8.90,
p < 0.001) reflecting significantly higher HR at challenge com-
pared with baseline (mean difference = 4.73, 95% CI 1.45–8.01,
p = 0.002) and pre-challenge (mean difference = 3.64, 95% CI
0.4–6.89, p = 0.023) means.
Discussion
Our results give support to what is being proposed for the revi-
sion of the ICD11, that the group of disorders traditionally called
“anxiety disorders” can be divided up into two distinct but related
groups (Starcevic, 2014). We showed that decreasing the func-
tion of the 5HT system in patients in clinical remission leads to
psychological and physiological exacerbation in response to
stressors in the fear disorders (PTSD, panic and SAnD) though
not in the anxiety disorders (GAD and OCD). Specific phobias
were not tested. Importantly, these differences could not be
explained by differences in the degree of depletion achieved in
the different disorder groups.
These data are in concordance with previous theories and
their predictions (Deakin and Graeff, 1991; Graeff and Zangrossi,
2010; Gray and Mcnaughton, 2000). According to these theories,
fear disorders would be related to aversive contingencies in
which the organism needs to move away from the threat and in
which 5HT acutely modulates sensitivity to fear-related stimuli.
Once undermined by aTD, a relapse occurs.
In contrast to the fear disorders, these theories also predict
that anxiety disorders would be related to aversive contingen-
cies in which the organism has to approach the threat
(Mcnaughton and Corr, 2004). In these cases, 5HT-mediated
therapeutic effects seem to happen through chronic enhance-
ment (through SSRIs, for example) and consequent long-lasting
neural changes – acute 5HT depletion causes no effects (Graeff
and Zangrossi, 2010).
Epidemiological studies have also proposed similar re-formu-
lation of the traditional group of “anxiety disorders” (see, for
example, Andrews et al., 2008; Krueger, 1999). However,
rethinking psychiatric classification based on different patterns
of neurobiological and behavioral functioning rather than on
clinical observation and clustering of symptoms is proposed to be
the best way to overcome the fragilities recognized in the current
nosologies, such as proposed by the Research Domain Criteria
(RDoC) project, initiated by the National Institute of Mental
health (NIMH) (Insel, 2014; Insel et al., 2010; Sanislow et al.,
2010). In this sense, the present study gives evidence to a neuro-
chemical dissociation of what has previously been clustered in a
single group named “anxiety disorders”.
One explanation for our findings is that response to challenge
under aTD conditions does not depend on the disorder in ques-
tion, but on the nature of the stimuli used in the challenge: that is,
fear-provoking stimuli versus anxiety-provoking stimuli. Rather,
as proposed in the original theory, it is possible that individual
differences in a subject’s sensitivity to each of these sorts of stim-
ulations could relate to the specific type of clinical anxiety disor-
der being experienced (Gray and Mcnaughton, 2000). In spite of
being a solid theory derived from many studies with animals, this
view has little and only indirect support in humans. Taken as a
whole, emotional reactions to aversive contingencies seem to be
the result of a complex interaction between the different sorts of
aversive contingencies and individual variability in sensitivity to
each. The participation of 5HT in response inhibition in each case
seems to be dependent on those variables rather than on diagnos-
tic criteria. It must be noted that in panic disorder, panic attacks
frequently occur in the absence of identifiable relevant environ-
mental stimuli. With respect to the theories herein assumed
(Deakin and Graeff, 1991; Gray and Mcnaughton, 2000;
Mcnaughton and Corr, 2004), panic attacks would be expected to
occur in response to imminent, inescapable threats, and sponta-
neous activation of the organic-related systems could account for
the unexpected attacks seen in the disorder.
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8 Journal of Psychopharmacology
Yet, according to Deakin and Graeff’s theory (1991), the anti-
fear effect of SSRIs is mediated by chronically increased synap-
tic 5HT and thus was reversed by aTD. In contrast, anti-anxiety
effects of SSRIs involve down-regulation of 5HT transmission in
the amygdala, putatively mediated by their well-known ability to
down-regulate 5HT2c function. Thus aTD had little further effect
on SSRI-treated anxiety disorders, since the SSRIs had already
reduced 5HT function.
It should also be noted that definitions based on subjective
emotional states may have led to some of the conceptual prob-
lems psychiatry has been facing (Ledoux, 2012, 2014). The pre-
sent study is an initial step that may help contribute to a longer
journey towards a better, more objective psychiatric nosology.
Yet, it is still based on the formal and current diagnostic criteria.
Future studies that categorize a clinical population based on indi-
vidual sensitivity and pattern of behavioral responses to each
type of aversive contingency and related neurobiology, rather
than on subjective descriptions, are needed.
Some additional points deserve attention. Firstly, in spite of
active major depressive disorder being an exclusion criterion,
residual and/or overlapping depressive symptoms may have
influenced the results. In depression, aTD alone suffices to pro-
duce mood changes (Delgado et al., 1990; Smith et al., 1997). In
the present paper, it is clear from the results that mood and anxi-
ety actually have distinct patterns of response to aTD. Differently
from VAS SAD, significant differences in anxiety levels between
aTD and sTD conditions were observed only after the challenge,
allowing the distinction between aTD effects alone from aTD +
challenge effects.
Secondly, the reader should be aware that, with the exception
of one study examined here (Bell et al., 2011), all patients were
treated with serotonergic antidepressants. It is possible that the
differential response of the clinical groups to aTD could reflect
different mechanisms of 5HT drugs in these disorders. We have
no indication, however, that the non-SSRI-treated group (who
had been treated with CBT instead) differed in any significant
manner from the SSRI-treated cohort.
Finally, it must be noted that our data suggest some level of
influence of depletion order over plasma tryptophan and cardio-
vascular results. This is not a usual finding in tryptophan deple-
tion studies. Exclusion of one outlying participant from the
plasma tryptophan analysis (the only participant out of the
whole dataset who did not show lower plasma tryptophan under
the depletion condition) removed the order effect, suggesting
this was a spurious finding. The observed effect in the cardio-
vascular data is more difficult to explain, as there were no obvi-
ous outliers in this dataset. It is possible that there is a “real”
interaction between order of depletion and BP responses, per-
haps as a consequence of altering serotonergic activity within a
learning or habituation context. At this stage, however, this and
other potential reasons are highly speculative but worthy of fur-
ther consideration. Importantly, depletion order did not influ-
ence our primary measures, viz SSAI and VAS SAD, and the
order effects observed do not undermine the arguments pre-
sented here.
Given the importance of 5HT in fear/anxiety-related disor-
ders, and the evidence presented herein, it is proposed that the
monoamine system might be a major focus of investigation in
this sense.
Acknowledgements
Caroline J. Bell, Ann S. Rich, Spilios V. Argyropoulos, Sam Forshall,
Mariona Adrover, Jon Nash, John Potokar, Neil C. Rich, Harry J. Witchel
Declaration of Conflicting Interests
Dr. Corchs, Davies, Bernik and Hince declared no potential conflicts of
interest with respect to the research, authorship, and/or publication of this
article. The authors declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this article:
Prof. Hood declares unrestricted educational grants – Servier, Pfizer,
Wyeth; Speaker’s Fees / Honoraria – Astra-Zeneca, Boehringer, Bristol-
Myers-Squibb, Cephalon, Eli-Lilly, Janssen-Cillag, Lundbeck, Pfizer,
Sanofi-Aventis, Servier, Wyeth; Advisory Board – GSK (Aropax), Eli-
Lilly (Cymbalta), Pfizer (Pristiq – Chair), Lundbeck (Vortioxetine);
Travel Support –Astra-Zeneca, Boehringer, Bristol-Myers-Squibb,
Cephalon, Eli-Lilly, Janssen-Cillag, Lundbeck, Pfizer, Sanofi-Aventis,
Servier, Wyeth; Clinical trials support – Park-Davis, Pfizer, Raine
Foundation, Sanofi-Aventis, Servier, University of Western Australia,
Wyeth, Wellcome Trust (UK) Prof. Nutt declares Consultancies – Pfizer
(W-L), GSK (SKB), MSD, BMS, Esteve, Novartis, Asahi, Organon,
Cypress, Lilly, Janssen, Takeda, Phamacia, Therasci, Passion for Life,
Hythiam, Servier, Roche, Sanofi-Aventis, Actelion, Lundbeck, Wyeth;
Speaking honoraria (in addition to above) – Reckitt-Benkiser, Cephalon;
Grants or clinical trial payments – MSD, GSK, Novartis, Servier, Janssen,
Yamanouchi, Lundbeck, Pfizer, Wyeth, Organon, AZ, Cephalon, P1vital,
MoDefence, NHS; Worked for the UK Government’s Committee on
Safety of Medicines; Advisory Council on the Misuse of Drugs, British
National Formulary.
Funding
The authors disclosed receipt of the following financial support for the
research, authorship, and/or publication of this article: Fundação de
Amparo à Pesquisa do Estado de São Paulo (State of São Paulo Research
Foundation; Grant Nos. 2008/04122-5 and 99/ 00170-4 for the support of
the PTSD study (Corchs et al 2009).
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