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How do psychotropic drugs work?
For decades, patients with psychiatric
disorders such as schizophrenia have
been prescribed psychotropic drugs to
alleviate their symptoms. Surprisingly,
scientists still do not fully understand
how these drugs work on a molecular
level, so clinicians generally prescribe
medications on a trial-and-error basis.
To better inform our knowledge of this
process and ultimately develop medica-
tions with less severe side effects,
Sabine Bahn and colleagues at the
University of Cambridge, Imperial
College London, and GlaxoSmith-
Kline (all in the U.K.) conducted a
metabolomics study. In JPR (DOI
10.1021/pr800892u), they report
the metabolic changes induced by
various psychotropic drugs in rat
brains.
To tailor drug therapy for pa-
tients with psychiatric disorders, a
logical starting point might be to
exploit what is already known
about how these disorders de-
velop. However, the molecular
bases of the disorders are mysteri-
ous as well, says Bahn. “We don’t
know what causes symptoms, so
therefore we don’t have drugs that
are specifically designed for the
diseasesand we don’t have ani-
mal models that reflect the disease
because we don’t know what
causes it,” she explains. “So, we
are in a vicious cycle and haven’t
really made much progress over
the last hundred years.”
Because all of these issues are interre-
lated, an examination of drug action also
could shed light on how psychiatric dis-
orders develop, according to Bahn. The
researchers’ assumption was that if the
drug works well in patients, then it is
affecting molecules that could be in-
volved in the disease process. So, if a
drug decreases the amount of a particu-
lar metabolite, then that metabolite’s
levels may be aberrantly elevated in
patients.
Another potential benefit from the in-
vestigation is the identification of mol-
ecules that are responsible for the extreme
side effects that most patients taking psy-
chotropic drugs experience. The medica-
1618 Journal of Proteome Research • Vol. 8, No. 4, 2009
tions can cause parkinsonian-like move-
ments, severe obesity (patients sometimes
double in weight), diabetes, cardiovascular
disease, and sedation. The side effects are
so difficult to deal with that many patients
stop taking their pills. “If we had better
drugs that more specifically treat the dis-
ease and its pathology, then patients may
be more willing to stay on the medica-
tions,” says Bahn.
In the JPR study, the metabolic effects of
What’s on your mind? Researchers apply metabolomics
methods to learn how antipsychotics and mood stabilizers
work in the brain.
seven psychiatric drugs (five antipsychotics
that are usually prescribed for the treat-
ment of schizophrenia and two mood sta-
bilizers that are prescribed for bipolar dis-
order) and one antiepileptic drug were
investigated. Some antipsychotics also are
prescribed for bipolar disorder, so the re-
searchers were interested to see whether
similar metabolites would be produced by
these drugs. In addition, the two mood
stabilizers have antiepileptic properties.
However, not all antiepileptics have mood-
altering effects, so the antiepileptic drug
phenytoin was included in the study as a
negative control.
The drugs were administered to normal
rats for 21 days, and then these rats and a
control group of rats were sacrificed. Tis-
sue from the frontal cortex, hippocampus,
10.1021/pr900128c
and striatum of each rat was analyzed
with NMR to quantify metabolite levels.
Although each drug produced its own
signature of metabolic changes, some
drugs within the same class had similar
responses. For example, most of the an-
tipsychotics produced changes in the
frontal cortex. Bahn points out that the
frontal cortex is involved in the halluci-
nations and delusions that patients with
schizophrenia typically experience. Also,
the unique metabolic signatures
suggest a reason why patients may
respond to one drug and not an-
other. The mood stabilizers and
some of the antipsychotics had
many similar effects, as expected.
Unlike all of the other medications
tested, the antiepileptic drug
phenytoin induced changes only
in the striatum.
The results also revealed a few
clues about mechanisms. Com-
pared with control N-acetylaspar-
tate (NAA) levels, the amounts of
NAA were increased in the fron-
tal cortices of rats given one of
the mood stabilizers or one of
the antipsychotics (except cloza-
pine or olanzapine). Bahn says
that NAA is a marker for neu-
ronal integrity and that an in-
crease in this metabolite could
indicate that the neurons in the
frontal cortex have increased vi-
ability. “In patients, we found
NAA levels were also altered but
in the opposite direction, so
maybe these drugs are replenishing the
lack of NAA in the diseased brain,” she
explains. In addition, molecules in-
volved in energy metabolism, neu-
rotransmitter metabolism, and oligo-
dendrocyte function were differentially
regulated by various drugs.
The real challenge for the researchers
will be to integrate these metabolomics
data with the gene expression and pro-
teomics data they already have collected.
This study is just one part of a larger
project that is designed to address
mechanistic issues by examining several
types of samples, including cerebrospi-
nal fluid and serum samples from hu-
mans and rats, says Bahn.
—Katie Cottingham
© 2009 American Chemical Society