Diseases

Depression

Depression is a mental disorder with feelings of sadness, loneliness and despair. It can be treated with anti-depressant medicines in up to 80% of patients. The challenge is to develop medicines that more accurately target the brain functions concerned. Pharmaceutical companies are rising to the challenge, so millions more people with depression can lead better lives.

What is depression? Top

Clinical depression can be either a temporary or a chronic mental disorder, with feelings of sadness, loneliness, despair, low self-esteem and self-reproach. These are frequently accompanied by listlessness and sleep problems, and less often by agitation, withdrawal from contact with other people and appetite loss. Dysthymia is a name used to refer to a milder form of depression that persists for two years or more. In bipolar disorder (formerly known as manic depression) there are severe mood swings from high states of agitation to deep despair.

Although there is some evidence of a genetic basis in predisposing to severe depression, this is probably not the case in milder forms. In some cases, experiences in childhood may play a role, notably parental neglect, physical or sexual abuse. There are also clear gender and social biases: depression is more frequent in women and in people who are unemployed, separated, divorced and widowed. Depression must be distinguished from everyday feelings experienced by everyone from time to time - being ‘a bit down’ or ‘fed-up’.

Who does depression affect? Top

Depression affects people of all ages, but is most common among people between 25 and 44 years old. It represents the third most important cause of early death, following cardiovascular disease and cancer, because major depression carries a high suicide risk. Of the 30,000 males committing suicide in the EU annually, 70 per cent are depressed at the time of death. Depression is the most common cause of admission to psychiatric hospitals.

The 2007 WHO World Health Survey studied adults aged 18 years and older to obtain data for the prevalence of depression. Observations were available for some 245,000 participants from 60 countries in all regions of the world. Overall, one-year prevalence for a depressive episode was 3.2 per cent. It is estimated that some 23 million people in the EU are diagnosed as having depression at any one time and as many as three in four cases may be neither recognised nor treated. According to the pan-European study DEPRES which analysed data on nearly 79,000 people in six European countries, only 18 per cent of patients with severe depression received treatment with anti-depressant medicines.

 

FIGURE 1: Modes of action of common antidepressive drugs on brain synapses
Note: Although serotonin (S) and noradrenaline (NA) release and receptors are shown on the same synapse, they are usually on different neurones.

Present treatments Top

Treatment usually involves anti-depressant medicines, which may be combined with psychiatric assessment and support such as cognitive behavioural therapy and participation in self-help groups. The anti-depressant medicines which are currently available have a range of mechanisms of action in the brain, mainly involving the action of substances called neurotransmitters - serotonin and noradrenaline. The range of medicines available includes:

  • selective serotonin reuptake inhibitors - SSRIs
  • inhibitors of both serotonin and noradrenaline reuptake - SNRIs
  • selective noradrenaline reuptake inhibitors - NARIs
  • inhibitors of monoamine oxidase - MAOIs

Older compounds include the tricyclic antidepressants (TCAs) and lithium salts. At the time of their discovery 50 years ago, TCAs were a major advance and they are effective in treating the symptoms of depression. Unfortunately, all share a relatively wide range of side effects, including dry mouth, dizziness, constipation, sweating and drowsiness. This is a discouragement for patients whose motivation is already low. They are also slow acting and it may take three weeks or more before benefit is felt. Some 70 per cent of people with depression respond to them.

The selective serotonin reuptake inhibitors (SSRIs) have a more favourable side effect profile than the tricyclic antidepressants, making patients more likely to continue taking them. However, SSRIs may also produce side effects (principally nausea, headache and tremor) which can be severe enough to make some patients stop taking them.

The principal mechanism of dual reuptake inhibitors (SNRIs) consists of inhibiting reuptake of serotonin and noradrenaline equally, without affecting reuptake of dopamine or acting on post-synaptic receptors. Such accurate targeting has been suggested as lying behind the clinical effectiveness and tolerability of these antidepressants. Other recent additions to the range of new antidepressants are specific noradrenaline reuptake inhibitors (NARIs).

What’s in the development pipeline? Top

Research into antidepressants continues to be very active. There is a need to explore improved treatments for depression, especially for its more severe manifestations. Up to 30 per cent of patients with a major depressive disorder fail to respond to current medications, especially if psychotic symptoms are present.

Because the neurotransmitter systems on which antidepressants work are widely present throughout the brain, compounds already approved or under development for other central nervous disorders, such as anxiety, schizophrenia, or Parkinson’s disease may also have an application in depression. Among the conventional antidepressants in development, a highly selective 5HT₁ᴀ receptor inhibitor is in late phase trial. Also acting at the 5HT₁ᴀ receptor, but as an agonist (stimulant) rather than antagonist (inhibitor), is a compound which is expected to have potential as an anxiolytic as well as an antidepressant.

Several other compounds with mixed actions are in Phase 3 clinical trial. One compound is an SSRI but also antagonises 5HT₂ᴀ receptors and augments adrenergic transmission. Another molecule is a 5-HT₁ᴀ receptor stimulator that also acts as an antagonist at 5-HT₂ᴀ receptors and is expected to be a fast-acting antidepressant because of this combination of properties. Triple reuptake inhibitors which interfere with serotonin, noradrenaline and dopamine are also being studied. Research projects are trying to combine the two antidepressant principles - noradrenaline reuptake inhibition and serotonin reuptake inhibition - with stimulation of the dopaminergic system in the brain.

Another approach is the development of antagonists to neurokinin-1 (NK 1), the receptor for the peptide neurotransmitter known as ‘substance P’, which is involved in pain and mood. Many such compounds have failed to demonstrate useful clinical effects, but other molecules are still being investigated in Phase 1/2 clinical trials. The inhibition of monoamine oxidase-A has been known for some years to be associated with anti-depressant activity. Clinical research is ongoing on reversible MAOIs.

Stress such as major illness or adverse life events is a potential trigger for depression. Under such circumstances, the hypothalamus in the brain produces a locally acting hormone corticotrophin releasing factor (CRF) which stimulates the pituitary gland to release adrenocorticotrophic 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. 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 longer-term future Top

The existing therapies for depression still leave room for improvement and the development of alternative approaches. One of the most unsatisfactory features of current antidepressants is that they take several weeks to have an effect. It has been found in a small study that the anaesthetic ketamine given intravenously is capable of producing an improvement in depressive symptoms within hours. Because of its hallucinogenic properties, the anaesthetic itself is not suitable for widespread use as an antidepressant, but the study finding underlines that it is possible to develop more rapidly acting medications.

An important recent discovery concerns the way in which particular molecules of the family of SSRIs act. It has been known that one of these triggers the growth of new brain cells in a region of the hippocampus and it has now been found that it acts on a specific type of cell called amplifying neural progenitors. The hypothesis that reversing hippocampal cell loss in depression may be the active principle is a fascinating new development. Having discovered this target, it may be possible to investigate it in more detail, and to search for compounds that have a more potent nerve-cell stimulatory effect.