Depression is a frequently misunderstood condition, the causes and effects of which are only properly beginning to be understood. James Kelly writes about the illness and how we are trying to treat it.

Depression is one of the most common psychiatric disorders, and the most commonly diagnosed mood disorder. Mood, as a clinical term, denotes a sustained emotional state lasting for several weeks or longer. Mood disorders are disorders in which the underlying features (symptoms) seem to be the result of disturbances in a person’s mood. They are usually divided into two groups, based on whether or not the individual in question has experienced a manic episode. Bipolar disorder is one in which episodes of mania and depression are experienced, whereas depressive disorders (such as major depression/unipolar depression) are those in which mania is not experienced. Major depression, or rather its underlying biochemical mechanisms, is our subject of interest.

The Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR), published by the American Psychiatric Association, standardises the classification of mental disorders, with its criteria for diagnosing depression being widely used. According to the current DSM, five or more symptoms from a set list – depressed mood for most of almost every day, loss of interest in everyday activities, insomnia/hypersomnia, fatigue/loss of energy, feelings of worthlessness/inappropriate guilt, diminished concentration, recurrent thoughts of death, etc – must be present during the same two week period and represent a change from previous functions in order to diagnose major depression. There are also exclusion factors, such as the presence of other mood/mental disorder, recent trauma/loss or mourning, to take into account. Following from this, it would seem that clinically diagnosed depression ultimately results from some internal, physiological problem.

In the fifth century BC, Hippocrates, the ancient Greek physician and father of western medicine, described unipolar depression. He believed that mood resulted from the balance between four humours; blood, phlegm, yellow bile and black bile, with an excess of black bile being the cause of depression. The ancient Greek word for depression is the same as it is for black bile, melancholia. While Hippocrates may not have been entirely on the mark, he was moving in the right direction. He realised that depression might have an internal, chemical cause.

Modern science’s understanding of depression is an example of therapeutic empiricism, with the observation of effect coming before a mechanistic understanding. The Monoamine Theory of Depression, proposed by Joseph J. Schildkraut in 1965, posited the idea that depression is the result of a functional deficit of monoamine neurotransmitters in certain brain regions, and that mania is the result of functional excess. The theory arose out of an association between the clinical effects of drugs that cause or alleviate the symptoms of depression and their known effects on neurotransmitters in the brain. Drugs that increased the level of monoamine neurotransmitters alleviated depression, while drugs that lowered neurotransmitter levels were seen to induce or increase depression. Monoamine neurotransmitters include serotonin, noradrenaline and dopamine. Initially, the thinking was that noradrenaline was the key mediator, but further studies revealed that serotonin played a more significant role in mood modulation. Some schools of thought have even attributed particular symptoms to deficits in specific monoamines – decreased serotonin and increased anxiety, decreased noradrenaline and apathy, decreased dopamine and lack of motivation – and recommended specific drug treatments based on the most strongly presenting symptoms.

A lot of research has been carried out to test the monoamine theory of depression, such as testing neurotransmitter metabolite concentrations and the concentrations of hormones released by neurotransmitter-mediated processes. While the results generally support the theory, there are still some anomalies. Inconsistencies can, to a certain extent, result from problems in testing methods, though some are less easily explained. Metabolism varies significantly between individuals; many receive drug treatment for other conditions (further increasing metabolic variation), drugs such as amphetamines and cocaine enhance monoamine activity but have no antidepressant action, and some effective antidepressants have no monoamine activity.

Another problem, somewhat unique to psychopharmacology, is the lack of good, comparable animal models. There is no known condition occurring in animals that corresponds to human depression. Procedures that produce symptoms similar to those of depression – social withdrawal, loss of appetite, etc – have been developed. These procedures include the delivery of repeated inescapable painful stimuli that results in a state of “learned helplessness” and apathy, the separation of mother and infant, and the use of monoamine-depleting drugs (such as reserpine). Apart from being inherently abhorrent, these procedures are often expensive and the similarities between the behavioural states they induce and depression are equivocal. However, like depression, these states can be altered by drugs with monoamine activity. The effects of learned helplessness and mother-infant separation can be reversed by antidepressants, or further exacerbated by drugs that prevent monoamine production, indicating a more than superficial similarity.

One extremely important fact that must be accounted for by any theory of depression is the temporal disparity between an antidepressant’s direct biochemical effect and its antidepressant effect. The former occurs within a matter of hours, while the latter takes weeks. This, coupled with the anomalies unexplained by the monoamine theory of depression, suggests that secondary, adaptive changes in the brain are responsible for improvement rather then the direct drug effects.

Since 2004, a new theory coming out of research into the role of monoamines in depression has gained notice. There is a lot of evidence suggesting that an association between neurodegeneration and reduced neurogenesis (the naturally occurring formation of new neurons from stem cells) and depression. Imaging and post-mortem studies in humans have shown shrinkage of the hippocampus, an area that experiences significant neurogenesis, and prefrontal cortex, an area associated with complex cognitive behaviours and personality expression. Functional imaging, which gives real-time images of the brain, shows a decrease in activity in these areas. Inversely, an increase in activity is observed during the manic phase, in individuals suffering from bipolar disorder. Shrinkage and decreased function in the hippocampus and prefrontal cortex also occur in animals subjected to chronic stress of various kinds. In these animals, antidepressants and electroconvulsive therapy have both been shown to promote neurogenesis and restore normal non-depressed function. The relation between this theory and the monoamine theory comes from the known neurogenic properties of serotonin. Serotonin, in a process mediated by a chemical called brain derived neurotrophic factor (BDNF), is important in neuron development in embryos. Perhaps this effect actually continues throughout life. Interestingly, BDNF production is reduced by prolonged stress. It is now being posited that serotonin plays a vital role in preventing neurodegeneration in the prefrontal cortex, and protects neurogenesis in the hippocampus. The mechanisms of these processes are currently not well understood.

A logical fallacy and leap in reasoning in the 1930s; the idea that epilepsy and schizophrenia were mutually exclusive and as such that inducing convulsions would treat schizophrenia, led to the use of electroconvulsive therapy (ECT). While useless in treating schizophrenia, it was shown to be quite effective in treating severe depression. Current ECT involves the patient being lightly anaesthetized and artificially ventilated, and given short-acting neuromuscular blockers (drugs that paralyse so as to avoid physical injury). The most recent transcranial magnetic stimulation has been used, a technique in which changing electromagnetic fields induce a weak electric current in the brain avoids the need for anaesthetic drugs. The success rate is at least as good as tricyclic antidepressants, at between sixty and eighty per cent. However, with confusion and memory loss lasting from days to weeks, it is not without its disadvantages. It was thought that studies using ECT would clarify our biochemical understanding of depression, but with no change to serotonin levels and only a slight increase in noradrenaline activity, confusion still remained. Further research may eventually prove the links between neurogenesis, ECT and depression.

While our understanding of the physiology and biochemistry of depression has greatly improved since the sixties, the drugs currently used are not so far advanced. Drugs affecting monoamine-mediated neurotransmission still remain the most effective way of treating depression, with improvement reported in sixty to seventy per cent of cases. These drugs fall into three major classes; Monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs).

MAOIs were the first drugs used clinically as antidepressants. They inhibit monoamine degradation, but are now used infrequently. Tricyclic antidepressants, so named for their chemical structure, prevent the re-uptake of monoamines. SSRIs are the most commonly used antidepressants (prozac belongs to this group) and work by selectively inhibiting the uptake of serotonin. MAOIs were superceded by tricyclic antidepressants and SSRIs, which were more effective with fewer side-effects. Tricyclic antidepressants are currently reserved for severe depression and SSRIs, the most recently developed class, are used to treat mild to moderate depression. While the success rate is undeniable, the use of therapies based on somewhat uncertain science seems frightening. This fear is further compounded by the fact that it is our mental faculties on the line. However, considering that major depression affects eight to twelve per cent of the population globally, it is something we will have to live with for now.