Therapy Analysis - Depression
What we already know
In 1965, Schildkraut’s monoamine theory of depression postulated a central deficit in monoaminergic transmission as the ‘villain’ in depressed patients. This deficit was thought to be the cause of a number of symptoms, such as feelings of misery, low self-esteem, loss of motivation and concentration, sleep disturbances and loss of appetite.
The monoamine theory of depression is largely based on the observation that drugs increasing synaptic levels of monoamine neurotransmitters, such as noradrenaline (NA) and serotonin (5-hydroxytryptamine or 5-HT), are able to alleviate the symptoms of depression. The drug reserpine, an indole alkaloid which depletes monoamines, provided some pharmacological evidence to support this theory, as its use has been linked with severe depression in some individuals. Conversely, drugs such as imipramine - the first monoamine oxidase (MAO) uptake inhibitor, which blocks NA uptake, has been found to alleviate the symptoms of depression.
The evidence in support of the monoamine hypothesis is far from unequivocal. This is borne out by the fact that some drugs which improve mood do not affect monoamine levels. Even so, the apparent efficacy of manipulating monoaminergic transmission has led to the development of a number of drugs that successfully relieve the burden of depression for many people. Unfortunately there are drawbacks - side-effects and lack of efficacy in some individuals has driven the search for improved variations on existing drugs. In the 1980s, a more specific alternative to the MAOIs known as selective serotonin re-uptake inhibitors (SSRIs), which increase synaptic levels of 5-HT, proved to be as effective as antidepressants but with fewer severe side-effect profiles. The SSRIs are still the most widely prescribed antidepressants, and as such companies are constantly developing and marketing new variations of this tried and tested class of drugs (Graph 1).
In 1986, Eli Lilly first launched its SSRI fluoxetine (Prozac), which despite its age, is still a hugely popular choice for doctors medicating depressed patients. However, even with the availability of SSRIs, not all depressed patients receive adequate symptom relief. These ‘blockbuster’ SSRIs are not without significant side-effects. A notable example is paroxetine (Seroxat), which was surrounded by controversy in 2004 when it was linked with the risk of self-harm and suicide on withdrawal from the drug. SSRIs are also contraindicated in children, where the risks are deemed to outweigh the benefits. The field of depression is still a very active area of research, not only due to the need for new and improved drugs without the obvious side-effects of SSRIs and MAOIs, but also because of the apparent holes in the monoamine hypothesis. It is well documented that the time delay between commencement of treatment and onset of symptom relief suggests that it is not the initial increase in synaptic monoamine levels that effects the change in mood. It is more likely that the resulting change in monoamine receptor expression, along with further downstream signalling changes, is responsible for the therapeutic effect. Of course, this delayed-onset is another driving force behind research into improved therapies, particularly when those needing treatment are at risk of suicide or other harmful behaviour. And compliance with antidepressants is less than perfect when the side-effects appear long before the patient experiences any obvious benefit.
Even though SSRIs are an improvement on MAOIs in terms of side-effects, the potential link with suicide risk, particularly in children and adolescents, is reason enough to continue the hunt for new therapies.
