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DEPRESSION
What is depression?
Unipolar (major) depression is a mental illness involving feelings of sadness,
loneliness, despair, low self-esteem and suicidal thoughts. These are frequently
accompanied by loss of appetite, concentration, interest and enjoyment, listlessness/lack
of energy, sexual dysfunction and sleep problems. Dysthymia is a name used
to refer to a milder form of depression that persists for two years or more.
Depression is often found together with anxiety (see Anxiety). In bipolar disorder
(formerly known as manic depression; see Bipolar Disorder) there are severe
mood swings from high states of agitation to deep despair.
The causes of depression are not well understood and genetic, social, psychological
and neurochemical (changes in brain chemistry) factors have all been suggested.
There is, however, evidence that neurotransmitters in the brain (in particular,
serotonin (5HT), noradrenaline (NA) and dopamine (DA), but also others) are
significantly affected in depression, and that clinical symptoms can be influenced
by medicines that interact with these substances and their receptors. Thus,
depression can be distinguished from everyday feelings of sadness. Depression
is a real illness, with at least a partly physical basis, and, once correctly
diagnosed, can be successfully treated in up to 80 per cent of cases.
Who does depression affect and what does it cost?
Depression affects all ages, but is most common among people between 25 and
44 years old. Major depression carries a significant suicide risk and of 4,000
male suicides in the UK annually, 70 per cent are depressed at the time of
their death. It is estimated that more than 2 million people in the United
Kingdom are diagnosed as having depression at any one time and many cases may
be neither recognised nor treated.
Although there is some evidence of a genetic basis in predisposing to severe
depression, this is probably not the case in milder forms. Experiences in childhood
are thought to play a role, notably parental neglect and/or physical or sexual
abuse. There are also clear gender and social biases: depression is more frequently
diagnosed in women and in people who are unemployed, separated, divorced or
widowed. Depression is commonly present in some illnesses such as cancer and
Parkinson's disease, and a recent report found that half of people with diabetes
in the UK also have depression. Post-natal depression affects about 10 per
cent of women in the first few months after childbirth.
Depression is the most common cause of admission to psychiatric hospitals
in the UK. Cost estimates that include indirect costs, such as lost productivity,
sickness and invalidity benefit, put the total societal cost of depression
in the region of £9 billion every year. Of that sum, direct treatment
costs account for £370 million.
Present treatments and shortcomings
Treatment options for people with depression include anti-depressant medicines
and psychiatric and social interventions, such as cognitive behavioural therapy
(CBT) and participation in self-help groups. Anti-depressant medicines are
not recommended for those with mild depression, whose condition is likely to
improve with time without medicines. Anti-depressant medicines are, however,
of real value in the management of moderate and severe depression and may be
used together with CBT or counselling, if available.
The first medicines for depression to be introduced were the tricyclic antidepressants
(TCAs), e.g. clomipramine (Anafranil, Novartis). TCAs are effective in treating
the symptoms of depression, but have a relatively wide range of side effects,
including dry mouth, dizziness, constipation, sweating and drowsiness, that
may discourage patients from persisting with taking them, especially as it
may take three weeks or more before their benefit is felt.
More modern anti-depressants have a range of ways of working in the brain,
mainly involving neurotransmitters such as serotonin and noradrenaline. The
range of medicines available includes:
- Selective Serotonin Reuptake Inhibitors - SSRIs - such as fluoxetine (Prozac,
Lilly), paroxetine (Seroxat, GSK), sertraline (Lustral, Pfizer) and citalopram
(Cipramil, Lundbeck)
- Serotonin and Noradrenaline Reuptake Inhibitors - SNRIs - such as venlafaxine
(Efexor, Wyeth)
- selective NorAdrenaline Reuptake Inhibitors - NARIs such as reboxetine
(Edronax, Pfizer)
- inhibitors of monoamine oxidase such as moclobemide (Manerix, Roche)
Current guidelines recommend starting anti-depressant treatment with a selective
serotonin reuptake inhibitor (SSRI) as these are generally better tolerated
than the older TCAs, although they can still cause side-effects (principally
nausea, headache and tremor) in some people that can be severe enough to make
some patients stop taking them. More recently introduced antidepressants include
mirtazapine (Zispin, Organon) which enhances the effect of both noradrenaline
and serotonin, the SSRI escitalopram (Cipralex, Lundbeck), and duloxetine (Cymbalta,
Lilly), a new SNRI.
What's in the development pipeline?
A great many compounds (more than 45) are undergoing clinical trials to evaluate
their effectiveness in treating depression. Those discussed below are only
a selection of those in clinical trials, chosen to illustrate the variety of
avenues being explored.
A significant number of compounds in trial are modulators of the neurotransmitters
noradrenaline, serotonin and/or dopamine. Dual reuptake inhibitors (5HT/NA)
under development include desvenlafaxine (Wyeth, completed Phase 3), Org 4420
(Organon, Phase 2) and F-2695 (Pierre Fabre, Phase 1), while GSK has an extended
release version of the dual NA/DA reuptake inhibitor bupropion. Triple
reuptake inhibitors (5HT/NA/DA) under investigation include DOV 216,303 (Dov Pharma,
Phase 2), GSK 372475 (GSK/NeuroSearch, Phase 2), DOV 102,677 and DOV 21,947
(Dov Pharma, both at Phase 1) and Sepracor's S-225289 (also Phase 1). In addition,
AstraZeneca has a sustained release form of quetiapine (Seroquel SR) in Phase
3 study and Lundbeck has a new SSRI (Lu AA21004) at Phase 2. While belonging
to the same general approach to treatment, these compounds may have differing
effects on the individual symptoms of depression,with varying durations of
action, dosing frequencies and side-effect profiles.
Several other families of substances acting in the brain have been implicated
in depression, and these avenues too are being explored in the search for new
medicines. Receptors for the neuropeptide Substance P (also known as Neurokinin-1)
are found widely in brain areas involved in stress responses and anxiety and
depression. NK1 receptor antagonists have therefore been seen as prime candidates
for medicines for depression and anxiety. However, many such compounds have
failed to demonstrate useful clinical effects in earlier trials. Compounds
of this type still being investigated include casopitant (GSK) at Phase 2 and
GSK 823296, at Phase 1.
A considerable number of other neurotransmitter or neurohormone systems are
also being probed for their influence on depression. For example, Servier's
agomelatine, in Phase 3 trials for depression, interacts with melatonin (MT1 and MT2) receptors as well as 5HT2C receptors. Likewise, sanofi-aventis has
both a NK2 antagonist, saredutant, and the beta-3 adrenergic agonist SR 58611
(Amibegron) in Phase 3 trial. At Phase 2, Novartis is studying the benzodiazepine
receptor agonist AC-5216, Organon has the glutamatergic AMPAkine Org 24448
(farampator), EPIX Pharma has a combined 5HT1A and sigma receptor agonist (PRX-00023),
Targacept is working on the selective nicotinic antagonist mecamylamine, sanofi-aventis
has a vasopressin-1B receptor antagonist (SSR 149415) and Tetragenex are trialling
nemifitide, a melanocyte inhibitory factor-1 antagonist, while many other targets
are being explored in Phase 1 studies.
Stress, such as major illness, adverse life events, etc, is a potential trigger
for depression. Under stress, the hypothalamus in the brain produces a locally
acting hormone corticotropin releasing factor (CRF) which stimulates the pituitary
gland to release adrenocorticotropic hormone (ACTH) into the bloodstream. Circulating
ACTH stimulates the adrenal glands to release the steroid cortisol, which is
known to be able to depress mood. This system, which is known as the HPA-axis,
normally regulates itself, as cortisol acts on glucocorticoid receptors in
the brain to reduce the production of CRF. Much research is focused on trying
to intervene in this complex series of events, with several inhibitors of the
type-1 receptor for CRF under study. The most advanced CRF-1 antagonist is
BMS-562086 (Bristol-Myers Squibb), which has reached Phase 2 trial. The company
has two further CRF-1 antagonists in Phase 1 trials (DMP696 and DMP904), but
in animal models these have shown greater efficacy against anxiety than in
treating depression. Other companies with CRF-1 antagonists are GSK (876008,
Phase 2), Ono (ONO 2333Ms), sanofi-aventis (SSR 125543) and Taisho/Janssen
(TS-041) all at Phase 1. Organon also has a modulator of the HPA-axis (Org
34517) in Phase 2 study.
The longer-term future
One of the most unsatisfactory features of current antidepressants is that
they take several weeks to have an effect, leading patients to stop taking
them before their effect is felt. It has been found in a small study in the
United States that the anaesthetic ketamine given intravenously is capable
of producing an improvement in depressive symptoms within hours. Ketamine itself
is not suitable for widespread use as an antidepressant, because of its hallucinogenic
properties, but this study finding is important as it shows that it is possible
to develop more rapidly acting medications for depression.
Another important recent discovery concerns the way in which the widely used
SSRI fluoxetine acts. It has been known for some time that this compound triggers
the growth of new brain cells in a region of the hippocampus. It has now been
found that fluoxetine acts on a specific type of cell called amplifying neural
progenitors. Having discovered this target, it may be possible to investigate
it in more detail, and to develop other compounds that have a more potent nerve-cell
stimulatory effect, without some of the sideeffects of fluoxetine.
Lastly, it is becoming accepted that the category of unipolar depression is
probably too broad for one treatment to be effective in all cases. The variations
in hormone and neurotransmitter imbalances between individuals are probably
considerable, and it may be desirable to develop more nuanced sub-divisions
of depression in order to have a higher probability of success by matching
antidepressant to a specific sub-category, rather than relying upon observation
or experiment.
As yet, these new lines of research are far from delivering new treatments,
but, given the intensity of efforts to improve therapy of this widespread condition,
it is possible to be optimistic about the future outlook for those affected
with depression.
FOR FURTHER INFORMATION CONTACT:
Rethink, severe mental illness
5th floor, Royal London House, 22-25 Finsbury Square
London, EC2A 1DX
Phone: 020 8974 6814 (Helpline)
Website: www.rethink.org
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