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Reply to Pradeep J Nathan and Ben J Harrison
Reply: Pronounced Cognitive Deficits Following an
Intravenous L-Tryptophan Challenge in First-degree Relatives
of Bipolar Patients Compared to Healthy Controls
S Sobczak
1
, A Honig*
,1
and Wim J Riedel
1
1
Department of Psychiatry, Institute of Brain and Behaviour, Maastricht University, University Hospital Maastricht (AZM), Maastricht, The
Netherlands
Neuropsychopharmacology (2003) 28, 2214– 2216, advance online publication, 10 September 2003; doi:10.1038/sj.npp.1300270
Sir
Thank you very much for your interest in our paper
‘Pronounced cognitive deficits following an intravenous
L-Tryptophan challenge in first-degree relatives of bipolar
patients compared to healthy controls’ (Sobczak et al,
2003b). We appreciate a critical review of the interpretation
of our research findings. Next, we will give our response on
the three major points of the letter.
GENERAL METHODOLOGICAL CONSIDERATION
If in an experiment, independent variable Xis manipulated
leading to a change in dependent variable Y, experimental
methodology only permits conclusions attributing the
change in Yto varying levels of X. Suppose that
the manipulation of Xinduces changes in Y, but these are
known to be actually accomplished by Z, in such a way that
it would have been more appropriate to manipulate Zrather
than X? One should attempt to either manipulate/control Z
or measure its known indicator(s). According to experi-
mental methodology, one may only speculate but not
conclude about the potential mediating influence of Z.
Obviously, Xrefers to tryptophan (Trp) and Yto cognitive
performance variables. Zrefers primarily to serotonin
(5-HT), as the fact that manipulating Trp primarily brings
about changes in 5-HT would be beyond dispute (but
see point 1). The aim of this experiment and a series of
other experiments was to study the role of serotonergic
vulnerability, expressed as responsivity to serotonergic
manipulations in healthy first-degree relatives of bipolar
patients (FH). We deliberately did not aim at assessing
dopaminergic effects as we assumed that the role of
dopamine in bipolar disorders is almost beyond dispute.
Therefore, it is only of methodological interest if we should
have considered dopaminergic factors in the present
experiment. Obviously, an experiment similar to the
present, in which dopaminergic turnover would be varied,
is also of great interest. Perhaps the best approach would be
when the two are combined.
However, several other downstream effects of manipula-
ting Trp should be considered as well. 5-HT is known to
have inhibitory influences on noradrenaline, acetylcholine,
and dopamine turnover (Robbins, 1997). In particular,
inhibitions of acetylcholine transmission brought about by
increased 5-HT turnover might explain the large effects of
Trp on delayed recall memory (Little et al, 1995). On the
basis of that, speculation about other potentially mediating
neurotransmitters to explain the effect of Trp on memory
would point much more into the direction of acetylcholine
than dopamine.
POINT 1: SPECIFICITY OF L-TRP CHALLENGE
The specificity of Trp as a serotonergic challenge has been
debated several times. Indeed, it has been suggested that
increasing Trp in the blood lowers tyrosine and phenyl-
alanine uptake due to competition for the amino-acid
transporter (van Praag et al, 1987). Dopamine lowers
prolactin release, and the increase in prolactin after Trp is
suggested to be due to a decrease in this inhibiting activity
of dopamine. Prolactin is only an indirect parameter of
brain dopaminergic activity. It has been shown that 5-HT
also has direct prolactin-stimulating effects via the 5-HT
2a/2c
receptors (Di Renzo et al, 1989, van de Kar et al, 1989). The
only way to investigate the central effects on these
neurotransmitters of Trp infusion is to assess 5-hydroxy-
indoleacetic acid (5-HIAA) and homovanillic acid (HVA) in
Online publication: 16 June 2003 at http://www.acnp.org/citations/
Npp061603030248/default.pdf
Received 04 June 2003; accepted 09 June 2003
*Correspondence: Dr A Honig, Department of Psychiatry, Institute
Brain and Behaviour, Maastricht University, University Hospital
Maastricht (AZM), PO Box 5800, Maastricht, The Netherlands, Tel:
+31 43 3877537, Fax: +31 43 3875444,
E-mail: adriaan.honig@spsy.azm.nl
Neuropsychopharmacology (2003) 28, 2214 –2216
&
2003 Nature Publishing Group All rights reserved 0893-133X/03
$
25.00
www.neuropsychopharmacology.org
the cerebrospinal fluid. These are invasive methods and, to
our knowledge, such a study has never been described.
Another indirect method is measurement of HVA in blood.
For each HVA measurement, 1 ml blood is needed. As
the amount of blood taken from subjects is limited and
other blood parameters (ie hormones, amino acids) are
also important to assess, we chose not to include HVA
measurements.
Large neutral amino acids (LNAAs; leucine, valine, iso-
leucine, Trp, tyrosine, phenylalanine) compete for trans-
porter uptake at the level of the blood–brain barrier. The
ratios of Trp/LNAAs, phenylalanine/LNAAs, and tyrosine/
LNAAs might give another indication of the availability of
serotonergic, respectively dopaminergic, precursors in the
brain. In the present study, the ratio of Trp/LNAAs
increased significantly to a value of 2.3 from a baseline
value of 0.13. This is an increase of 1669%. The ratio
tyrosine/LNAAs decreased after Trp loading, but this was
not significant (F(1,42) ¼0.017, NS). The ratio phenylala-
nine/LNAAs was significantly lower after Trp
(F(1,42) ¼88.98, Po0.05). The ratio decreased from 0.11
at baseline to 0.0013. This is a decrease of 103%. As the
increase in the ratio of Trp is much higher than the decrease
in the ratio of phenylalanine, and the ratio of tyrosine did
not change at all, we suggest that the effects of the Trp
loading are more likely attributable to central serotonergic
effects than to dopaminergic effects.
5-HT acts as a neuromodulator, and important functional
interactions between brain 5-HT and dopaminergic systems
are known. 5-HT inhibits dopaminergic activity in the
mesolimbic system but stimulates this activity in nigro-
striatal structures (Manji and Potter, 1997). Thus, we cannot
fully exclude that other neurotransmitters are involved in
the cognitive effects of Trp and 5-HT.
Despite this we suggest that the cognitive effects of Trp
challenge are primary serotonergic mediated because the
detrimental effects of Trp on attention and planning in
healthy FH have also been found after acute tryptophan
depletion (ATD) (Sobczak et al, 2002c). Thus, it seems that
both an increase and decrease in Trp impair the same
cognitive domains that are regulated by the frontal lobe
(Sobczak et al, 2003b). The specificity of ATD has been
pointed out by Klaassen et al (1999). They found a decrease
in mood and impaired memory performance after ATD but
not after lysine depletion. This supports the hypothesis that
ATD affects brain 5-HT functioning and not brain protein
metabolism in general.
POINT 2: COGNITIVE DEFICITS ON BASELINE ARE
MEDIATED BY DOPAMINE
The second suggestion made by Nathan and Harrison
(2003) is that the baseline cognitive deficits in FH may
be a result of dysregulation of dopaminergic activity in
mesocortical regions.
It must be emphasized that the FH subjects in this study
were free of any clinical psychiatric symptoms. Thus,
cognitive impairments were not related to altered mood
states (Sobczak et al, 2003b). Therefore, if there was a
dopaminergic dysfunction in these subjects at baseline, it
would only have affected cognition and not mood.
Independent of Trp, cognitive performance was more
impaired in relatives of type I bipolar patients (FH I)
compared to relatives of type II patients (FH II). This
suboptimal baseline performance in FH I resulted in more
pronounced cognitive deficits after Trp (ie on planning).
These findings agree with an association of serotonergic
vulnerability and cognitive impairments in FH I subjects.
FH II subjects were characterized by mood changes after
ATD and Trp challenge (Sobczak et al, 2002a, b). Taking
these findings together, we speculate that FH II subjects
share more symptoms of primary affective disorders in
which 5-HT plays a prominent role, whereas FH I subjects
show characteristics of primary psychotic disorders in
which cognitive deficits persist and functional deficits in
other neurotransmitters like noradrenaline, acetylcholine
and dopamine, or even structural brain abnormalities, may
also be involved.
POINT 3: FUTURE STUDY ON THE ROLE OF 5-HT AND
DOPAMINE
Indeed the search for biological markers of bipolar
disorders is just in its infancy. The present findings must
first be replicated in a larger research population including
relatives of type I and type II bipolar patients. Of interest is
whether there is a biological distinction between type I and
type II patients and their relatives. The vulnerability to
serotonergic, dopaminergic, and noradrenergic dysfunction
should be investigated using ATD, specific serotonergic
challenge procedures, and a phenylalanine/tyrosine deple-
tion test. Abnormalities in cholesterol and fatty acids have
also been associated with altered brain neurotransmitter
activity and psychopathology (Sobczak et al, 2003a; Hibbeln
and Salem, 1995; Swartz, 1990). Thus, research into the
interaction of neurotransmitters, cholesterol, and fatty acids
in humans and their association with psychopathology is
still a challenge.
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Neuropsychopharmacology
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