a newsletter for members of the BNA - British Neuroscience ...

REPORTS MEETING REPORTS
So what has gone wrong? Dr Hendrie
thinks that the current drug discovery
strategy for depression is fundamentally
"flawed". It mainly focuses on developing
new drugs, by replacing the nonessential
parts of existing ones, without
understanding the pathology of
depression or how the drugs actually
affect the depressed brain. For decades,
therefore, every new drug has been just a
slight variation of its predecessors, in
large part because no one really knows
what depression is or what causes it.
"All antidepressant development is
based on the monoamine hypothesis,
but there is virtually no evidence to
support it," remarked Dr Hendrie. At the
level of neurons, the drugs’ action is seen
within hours, but the full clinical effect
can take up to eight weeks. So it seems
‘It’s a strange state of mind — if
you can describe your
depression then you probably
haven’t got it’.
that the drugs may not produce the
antidepressant effect directly, and other
pieces of the puzzle remain to be
determined. "According to brain imaging
studies, there is a reduction in the blood
flow in the brains of depressed patients,"
Dr Hendrie continued. "And other studies
showed that various brain structures,
such as the hippocampus, were smaller
in people with a history of recurrent
depression." As 90% of the brain is made
up of glial cells, Dr Hendrie conjectured
that manipulating the glial cell function
might represent a new avenue for
effective treatment of depression.
Dr Hagan, however, was not impressed.
"Antidepressant drugs are effective in up
to 70% of the patients. They are now
safer and better tolerated," he said. Early
generations of antidepressants can
cause serious side effects, such as dry
mouth, constipation and irregular
heartbeat, and the risk of a fatal
overdose. Prozac and Seroxat are as
effective but without the side-effects.
"Improved side effects and tolerability
are important for compliance in
depression, and compliance partly
dictates responses," he continued. Good
tolerability has also allowed treatment of
patients with other conditions such as
anxiety, panic attacks, social anxiety
disorder, obsessive-compulsive disorder
and post-traumatic stress disorder.
He recognized that the neurobiology of
depression was poorly understood and
that the monoamine theory could not
fully explain the drugs’ antidepressant
effect. "Nevertheless, monoamines are
still important targets for treating
depression," he maintained. "It works,
and therapeutic advances can be built
most successfully (but not exclusively) on
what is known." A new trend in
antidepressant development is to
develop drugs that have multiple targets.
For example, Eli Lilly’s Cymbalta raises
levels of both serotonin and
noradrenaline; GlaxoSmithKline’s
Wellbutrin XL affects noradrenaline and
dopamine. The rationale is that, by
aiming at multiple receptors, the drugs
will be either faster or capture a larger
percent of responders.
"Monoamine targets constitute less than
half of the current pipeline research
programmes in the pharmaceutical
industry," added Dr Hagan. He explained
that another important target was
corticotrophin-releasing factor (CRF) – a
crucial factor in the brain that triggers the
release of the stress hormone cortisol.
The link between stress and depression
is well documented, and there are high
levels of cortisol in the plasma of patients
with depression. Nearly every major
company is now pursuing CRF
antagonists, which probably are the lead
alternative to available antidepressants.
Dr Hagan said there were many
obstacles to developing novel
therapeutic approaches in tackling
depression. The main issue is that there
are few animal models to test the
theories. Depression in humans is often
defined by arbitrary and subjective
symptoms rather than concrete
physiological measures. Whether
animals get depressed is arguably still
debatable. Thus, animal models can, at
their best, only reflect pieces of the
symptoms or behaviours remotely
resembling depression in humans. Other
obstacles include the lack of indicators of
the drug response and efficacy, the
placebo effect and the heterogeneity of
the condition.
Though there are many hurdles to
overcome, Dr Hagan is optimistic that
the pharmaceutical industry is able to
accept the challenges. "But progress
requires a coordinated research strategy
between pharmaceutical, academic,
clinical and neuroscience communities,"
he concluded.
After the head-to-head discussion on the
current situation of antidepressant
development, Professor Wolpert revealed
his own struggle with depression and the
attempt to understand this devastating
condition. Over ten years ago, clinical
depression hit him without any warning –
he had a successful scientific career and
a happy family life. "It is a strange state of
mind – if you can describe your
depression then you probably haven’t
got it," he said. He couldn’t think, let
alone work, and was suicidal.
When eventually recovered, through a
combination of psychotherapy, drug
treatment and support from friends and
family, Professor Wolpert went into an
extensive literature research on
depression – from the history of the
melancholy temperament to contemporary
neuroscience – which led to his
critically acclaimed book "Malignant
sadness: the anatomy of depression".
"What is the origin of depression? And
does it have an evolutionary adaptive
function?" he asked. According to Freud,
sadness is the emotion most close to
depression. "Thus depression may be
sadness become unhinged," suggested
Professor Wolpert. "Sadness is a basic
and universal emotion. Its function is to
promote attachment to people, things
and aims." Depressive feelings are
experienced by all people and are a
normal component of anxiety,
disappointment and grief. Therefore, they
may have adaptive functions. "People
reassess their lives during depression –
it’s just that 10% kill themselves as a
result," he said.
Professor Wolpert was concerned with
the stigma associated with depression
and people’s tendency to resist taking
antidepressants. He said depression was
just another illness, like cancer and gall
bladder disease, and there was nothing
to be ashamed of. "If we can talk about
gall bladder disease, why can’t we talk
about depression?" he asked. From his
experience, antidepressants worked but
he thought that the monoamine theory
was probably given too much credence
and other approaches, such as
psychotherapy and social support, were
important as well. "We should try to
understand depression in both scientific
and humane terms, and use a more
holistic approach to help those in its
grip," remarked Professor Wolpert.
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