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10. Causes of Depression

We do not know exactly how depressive illness is caused, but we are learning more and more about it. There are many components: genetic vulnerability, stresses, ‘life-events’ – major milestones good and bad, and some physical illnesses. Once initiated, there are biochemical, psychological and sociological mechanisms that inflame, or perpetuate, the illness.

10.1 Genetics

The genetic influence in manic depressive illness is about twice as great as in unipolar depression (where the only mood change is depression). If you have a manic depressive illness, the chances of a close relative developing any mood illness are about 20%. If you have a unipolar depressive illness, the chances are about 10%. Attempts have been made to separate out the influence of genes and environment.

Are siblings affected by the same illness because they share genes, or because they have been brought up together? If you look at twins, this question can be partially answered. Monozygotic or identical twins are babies formed from one fertilised egg cell dividing into two individuals – they share the same genes.

Dizygotic twins, on the other hand, grow in the womb together but are formed by two separate egg cells being fertilised. These individuals will not have the same genes. If the twins are brought up together, you can assume their treatment is very similar. If they develop an illness with some genetic causation, you would, however, expect the identical twins to have higher rates of the illness than non-identical twins. This is the case in depression. For an identical twin whose twin develops manic depressive illness, there is a 70% risk that he or she will develop the illness too. In non-identical twins, the rate is much lower, at 20%.

The genetic effect shown in twin studies looking at unipolar depression in identical twins shows a rate of about 50% illness in the twin, and 25% in a non-identical twin.

10.2 Neuro- (brain) chemistry theories of depression

 Hippocrates in 400 BC established that everything we suffer comes from the brain - it always has been, and always will be, ‘all in the mind’.

Mood and its disorders are closely linked with very basic brain functioning. People who are stressed show changes in their brain and body chemistry. Deep within the brain, the hypothalamus and the pituitary gland control the body’s response to stress, either by increasing or decreasing their output of brain hormones.

An increase in one of the hormones, CRF (corticotrophin-releasing factor), causes an outpouring of CRH (corticotrophin-releasing hormone).

CRF-containing nerve cells are found throughout the brain. If you put CRF into the brain of experimental animals, some of the symptoms of depression are mimicked – the animal stops eating adequately, its sleep rhythm changes, it stops grooming itself and it tends to neglect its offspring.

This substance in turn, stimulates the pituitary gland to produce a chemical, which  stimulates the adrenal glands (located above the kidneys) to make steroids, including cortisol. If stressed, we produce cortisol. The stresses can be of any kind – it could be a

bereavement, a physical illness, or bullying. There is evidence now that depressed people have some increase in the size of the adrenal glands – stress is causing them to work extra hard.

These changes in steroid levels are thought to affect the chemical transmitters – or neurotransmitters in the brain – and might, over a period of time, cause a depressive reaction to stress.

The probable physical explanation for depression is the socalled ‘monoamine’ theory of depression. If the brain becomes depleted of the monoamines, noradrenaline and serotonin, depression often results. Reserpine was a drug used in the treatment of high blood pressure. It was found to lower the levels of noradrenaline and serotonin in the brain (as well as lowering blood pressure), and it was noted that depression often followed.

Research in the late 1960s showed levels of noradrenaline and serotonin in the brain were lower in depressed people than in normal people. Drugs that caused the opposite effect (that is, encouraged the level of neurotransmitters to rise) have the effect of elevating mood, if it was low before (not if it was already normal).

10.3 Neurotransmitters

This next text is rather technical, but there is no easy way to explain the chemical processes that are going on inside our brains. Our brains function by a series of chemicals being exchanged, which causes different messages producing different patterns of response, depending on need. These messages are delivered by chemicals called neurotransmitters. Some transmitters excite the area of brain they serve, others dampen

activity. The same chemical in a different site in the brain can have an opposite effect. These chemical neurotransmitters are released in discrete amounts from granules or storage units within the nerve cells. The granules are triggered to release their contents when the nerve cell has been appropriately stimulated.

 What brain chemicals are involved in depression?

We now know there are over forty different types of neurotransmitters. There are three neurotransmitter systems in the central nervous system (CNS) that are affected by antidepressants:

• Noradrenaline (NA)

• Dopamine

• Serotonin (5-hydroxytryptamine or 5-HT)

Noradrenaline is the key chemical in controlling the state of activity in the brain. In depressive illness, there is a change in the nerve cell receptors and this causes a slowing down of the release of NA at the cell synapse. The whole system becomes run down and less active.

Tyrosine is a building block for the neurotransmitters noradrenaline and dopamine. Tyrosine can be found in food and is absorbed through the gut into the blood stream. It is then transported to the brain and pumped into nerve cells.

An enzyme works on the tyrosine to make dopa, and a second enzyme changes the dopa to dopamine. The third step converts dopamine to NA. The final product is stored in granules or vesicles in the nerve cells. The vesicles are released when the nerve is stimulated.

Serotonin (5-HT) is produced by enzymes from a chemical called tryptophan. Tryptophan in the blood is transported into serotonin nerve cells, where the tryptophan is converted into 5-HT by a series of chemical changes. The 5-HT made is stored in the nerve cell until the appropriate impulse arrives and the substance is released. 5-HT is made in specialised parts of the pons and medulla, structures in the mid-brain.

Nerve cells spread out from these areas into the cortex or surface of the brain, the spinal cord and the specialised part of the brain called the limbic system. 5-HT is a key chemical in maintaining very basic and important animal responses. It helps control the cycles of liveliness and sleep. It is very important in producing aggression (a basic survival need), and also maintaining background mood.

Where do my moods actually come from within my brain?

The part of your brain known as the limbic system is very important in the production and maintenance of mood.

This part of the brain forms the margin (or ‘limbus’) of the ‘newest’ – most recently evolved – part of the brain, the cortex. It is formed in the shape of a ‘C’. It includes the hippocampus, the amygdala, parts of the hypothalamus and thalamus, the nucleus accumbens and the basal nucleus. The last two are important in the production of acetylcholine (a neurotransmitter substance). The limbic system is joined by the cingulate gyrus and the parahippocampal gyrus.

The limbic system works with many other brain systems.

Neuroscientists suggest that if the limbic system function is decreased, depression results. If limbic system activity is increased, inappropriate elation of mood or mania results. If the limbic system is malfunctioning, psychotic illness can result. This is a momentous and exciting area of research.

The limbic system gives humans (and other higher animals) a way of coping with their environment, and other people and animals within that environment. Very basic survival behaviours like eating, drinking and reproducing are driven by the limbic system. Other parts of the limbic system are involved in feelings and emotions. Yet other parts of the limbic system link information received from all our senses to our state within.

The hypothalamus, part of the limbic system, is a control centre – like a thermostat – which regulates the body’s internal environment. One example of its many activities is the regulation of eating and drinking. That’s why appetite disturbance can be part of depression.

The limbic system is divided into two sub-systems.

• First there is the hippocampus and its connections. This maintains our attention, and the formation of memory. It receives processed information from all our senses (touch, smell, sight, taste, hearing).

• Secondly, the limbic system divides into the amygdala and its connections. This area links what our senses are telling us, and defines the feeling of anxiety (only when appropriate, we hope). It helps form emotional links with our sensations as they occur.

The sense of smell has major links with the limbic system, giving rise to powerful emotions with some smells. Memory can be very rapidly and powerfully triggered by a smell. The memory returns with the emotion felt at that time. In the animal kingdom, smells ‘cue’ not just memories; they are often vital to initiate mating. Scents are relatively unimportant in humans – although the perfume industry would tell us otherwise.

How can stress, social problems and unhappiness affect your brain chemistry?

For a long time, scientists have recognised that there must be more to depression than the monoamine theory (see above). The brain chemistry of depressive illness realistically needs to explain, in chemical terms, the effect of early experiences (such as the loss of a parent), the effect of stress (such as abuse), and the social factors that are implicated in depression. Genetics too are involved.

There is now evidence from animal research that antidepressants, given over some time, increase the production of ‘neuroprotective proteins’. These substances occur naturally and are important in the growth and normal functioning of nerve cells. Antidepressant treatment activates the system that triggers so-called transcription substances. These control the expression of some genes in brain cells. Levels of this substance, called brain-derived neurotrophic factor (BDNF), are increased in the hippocampus.

BDNF belongs to a group of growth factors that help control nerve cell activities, ranging from the differentiation (or specialisation) of cells, to keeping the cells alive, once the brain is developed. It has been shown that, if experimental animals are stressed, there is a decrease in the amount of BDNF in the hippocampus. This effect is opposed, or counteracted by, antidepressant treatment. It seems that stress ‘down-regulates’ or dampens, the expression of the substance that helps maintain lively healthy brain cells.

There is some evidence that chronic severe depression causes some atrophy or shrinkage in the hippocampus. Depressive illness could therefore be seen as a very subtle form of degeneration in some nerve cells. Protective substances like BDNF might act to reverse this effect. We know, too, that electroconvulsive therapy (ECT) helps promote the BDNF and can induce positive, regenerative changes within the hippocampus.

So can the brain alter itself when you are stressed or depressed?

We used to think that the brain could never regenerate itself. We now know that neurones are generated throughout life, and that parts of the brain are ‘plastic’ or capable of change. The hippocampal cells’ vitality may be influenced by many elements, including genetic influences, raised steroid levels (as occurs in stress), some viral infections, lack of oxygen, low blood sugar levels, and psychologically stressful events. Antidepressants are thought to protect against this damage.

BDNF not only determines whether some nerve cells live or die. It also regulates the networks that nerve cells make with each other. BDNF can strengthen, or can dampen down, nerve connections. Changes in the patterns of connections between nerve cells help form memory, and determine responses to stress.

It allows the brain to be ‘plastic’ or malleable in its responses to the environment, so forming new patterns of response as required. These same mechanisms happen in the amygdala, and can produce fear responses when necessary.

Stresses may actually change these connecting patterns. This may go some way to explain the thinking, and emotional changes that occur in mood disorders. Antidepressants magnify nerve synapse connecting ability. It is likely that different antidepressants affect synapse connectivity in subtly different ways.

The picture is yet more complicated. Within the hippocampus, there are two types (1 and 2) of steroid receptors. These are very important in producing the body’s response to stress. Chemicals that are type 2 antagonists (i.e. work against them), have been shown to protect against the changes that would otherwise happen in the nerve endings of experimental animals that have been stressed. These substances are currently being researched as possible future antidepressant agents.

There is increasing evidence that early experience of stress can damage the hippocampus. If young rats are repeatedly separated from their mothers, changes in nerve connections in the hippocampus can be seen (they become less adaptable). We are now gathering evidence that early psychological trauma and abuse causes permanent damage – something we have known instinctively for a very long time.

 10.4 A simpler explanation

Can you explain to me in simple terms why I’m depressed? What’s actually happening to me?

There are various ways of understanding depression. You can explain it in terms of brain chemistry, of genetics, of people’s life circumstances. Sometimes it seems a natural response to what’s happened to you, sometimes it seems like a bolt from the blue, and we are still a long way from understanding everything about how the brain works.

Many people don’t seem to want a detailed explanation of the changes in brain chemistry, of the depletion of neurotransmitters that we find associated with depression. Of course that’s useful if you want to know exactly why antidepressants help, but we can use motorcars or computers for a much simpler explanation.

It’s as if people with depression have flat batteries. They’ve had too many demands on their circuits, not enough chance to recharge themselves, and they can’t start their motor one cold damp morning. Taking antidepressants is like having your battery charged up; it takes some time to recharge. (That’s why a full course of antidepressants takes some months.) When your battery is charged up, you can start your own engine, go for a good drive, and keep it topped up by taking care of it. That’s why looking after yourself – proper maintenance and recreation (i.e. re-creation) – is so important.

For computer experts, the analogy is that you’ve had too much data coming in and your hard drive is full of chaotic randomly stored stuff. You can’t process any more information, then the system becomes erratic, your usual programmes don’t work so

well. You start getting error messages, and finally the whole thing crashes while you’re trying to do something important. Perhaps,  counselling or psychotherapy is like defragmenting your hard drive, a process of tidying up untidy memories and thoughts to free up storage space so that you can cope with today’s activity, and, yes, we do have Helplines for humans  as well as for computers.

Actually the human brain is still light years more complex than our fastest computers, so these analogies have their limitations, but we can still use these devices without understanding a complicated explanation of their mechanisms!

Another model is a rather more philosophical one: people with depression have come to feel that they’re trapped; they’ve lost sight of the light at the end of the tunnel; they have lost the freedom of choice, and the control over their lives that we all need. Reminding ourselves that we always do have choice in our lives and starting to make some choices – however simple – can be a good start. (That’s why painting the kitchen ceiling or having your hair done can be good therapy.)

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