The Biology and Treatment of Clinical Depression

Professor Malcolm Lader OBE

April 2002

Clinical depression can vary in sufferers, but there are typical signs that make diagnosis much easier. We understand more than ever about the brain and its involvement in depression. But it is still difficult to tell which signs represent causes, and which are symptoms. Nevertheless better and better drug treatments have developed since the 1950s that benefit many sufferers.

Clinical depression is medically defined as a persistently lowered mood or a general loss of interest that has been ongoing for at least two weeks representing a marked change from previous or 'normal' functioning. This differs from the 'blues' or 'miseries' that affect most of us at some point but pass more quickly and are less severe. Depressed people feel differently about themselves, their world and their future.

Sufferers feel a sense of loss, reflected by a decline in pleasure and little interest in usual activities. Simple tasks become a struggle and the person is slowed down – 'walking through treacle', as the feeling is often described. On the other hand, some are anxious and agitated, and constantly seek reassurance. Feelings of inadequacy lead to low self-esteem. Hopelessness leads to helplessness and to thoughts of suicide – all too often the tragic outcome.

Physical changes

Appetite and sleep pattern are disturbed, weight may be lost and constant tiredness is common. Indeed sleep can be profoundly affected in depressed individuals. They may find it easy to fall asleep, but the sleep is often broken with many awakenings. They might wake early, say at 4am, and be unable to fall asleep again. Instead, they will lie awake, feeling miserable and dreading the day ahead. The close relationship between sleep and depression is illustrated by sufferers who find their mood lifted, at least temporarily, by voluntarily staying awake all night. The effects are lost when they eventually fall asleep, even if for a nap. In severely ill patients, symptoms such as loss of appetite and sleep are so serious that they suggest major physical changes have occurred. But it is difficult to say whether these symptoms are the cause or effect of depression.

Various hormones are controlled by a structure lying just underneath but attached to the brain called the pituitary gland. The most well-known is cortisol, which, normally active in times of stress, is over-active in depressives. Conversely, another hormone, regulated by the thyroid gland, is under-active. But it's difficult to know whether these are the cause of depression or a result of chronic stress that comes with the illness.

Toward a biological understanding

Various biological theories have developed in which the root cause of depression is thought to be physical. They are reinforced by observations, starting in the 1950s, that medicines could influence mood, for better or for worse. Reserpine for example, a sedative introduced from Indian herbal (Ayurvedic) medicine, was noted to induce depression in some of its users.

At about the same time, two groups of drugs were discovered (both by accident) that combated depression. Monoamine oxidase inhibitors (MAOIs) came from the search for drugs to treat tuberculosis. Tricyclic antidepressants (TCAs) were found during the quest for safer allergy medicines and tranquillisers. The drugs were found to alter chemical messengers, or hormones, in the brain called amine neurotransmitters.

A neurotransmitter is a type of hormone that is active at nerve endings, and amine refers to the type of chemical composition. The term chemical messenger is often used to describe hormones – substances with a wide range of activating and repressing functions throughout the body.

Signals in the brain travel through neurons (nerve cells) as electrical currents. However, there is a gap separating neurons (the 'synaptic cleft') that signals must cross. It crosses this gap to the next neuron not by electrical current but by neurotransmitter released from where it is stored, at the end of the neuron. The neurotransmitter passes across to the next neuron and changes its function – either making it electrically active ('excitation') or lowering its activity ('inhibition'). Our brains are held in a balance between excitation and inhibition.

The discovery of drugs that combated depression by altering brain hormone activity supported the suspicion that certain neurotransmitters were deficient or malfunctioning in depressed patients. But ethical and practical difficulties of demonstrating this in humans led to indirect approaches and slow progress. And animal studies were of limited use due to the inability of rats to describe how they were feeling!

Autopsy results from suicides (presumed to have been suffering from depression at the time of death) have indicated that neurotransmitter mechanisms in the cerebral cortex (the 'thinking' part of the brain) may be impaired. The most consistent finding is the association of violent suicide with low levels of some neurotransmitters in the brain. Of course, post mortem analyses are complicated by factors other than depression that may change brain chemistry. The mode of death, previous drug history, current therapy, and time between death and autopsy can all affect the results.

The most important brain chemical relating to depression is the neurotransmitter serotonin, which is involved in a variety of brain functions, including the control of emotion. It is sometimes referred to as the 'well-being' hormone. It's made in the brain from tryptophan – a building block of protein that is contained in fish and meat. One idea that is gaining ground is that depression is related to the way we vary in our brain reserves of serotonin. If these reserves are depleted then we will be prone to suffer from depression. One cause of such insufficiency is age: as we grow older our brain serotonin decreases. Another important factor is stress. So, environmental and genetic factors interact to generate depression. So the theory suggests.

Treating depression

Taking tryptophan supplements may help some depressed patients, as it's known that a diet devoid of tryptophan can result in a low mood. But the main approach to treatment is to manipulate neurotransmitters with drugs.

Neurotransmitters, like serotonin, must be inactivated by the body after doing their work, otherwise they would continue to act indefinitely. In people who have low serotonin levels, it is possible to elevate them by blocking the natural inactivation of the hormone.

Some enzymes are present at the sites of neurotransmitter action that will inactivate the neurotransmitter by breaking it down, once it has done its job. Using drugs to artificially prevent the enzyme from doing this means the neurotransmitter stays around longer, which elevates, say, serotonin levels and lightens mood.

Neurotransmitters are also inactivated when they are taken back into the neuron that released them. It's an example of nature's good housekeeping re-uptake means the hormone can be used again. Using drugs to block this process prolongs the effect of the neurotransmitters and compensates for any hormone deficiency.

However, drugs are rarely restricted to just one site of activity (they are rarely 'selective' or 'clean' drugs). They usually affect a variety of sites, both in the brain and also in the body ('non-selective' or 'dirty' drugs). And this can result in side effects – though not everyone will experience them. Also, many of these side effects wear off after a while.

MAOIs – monoamine oxidase inhibitors

Monoamine oxidase is an enzyme that breaks down serotonin and another neurotransmitter, noradrenalin which is also implicated in the regulation of mood but with less dramatic effects. The MAOIs prevent the enzyme from doing this. These antidepressants (eg phenelzine) were the first to be developed.

However, MAOI activity is complicated because monoamine oxidase is widely distributed in the body and has other functions aside from those in the brain. The enzyme also performs an important role in the gut, where it breaks down amines from foods like cheese and yeast. MAOIs allow amines in those foods to enter the blood circulation system, causing potentially dangerous rises in blood pressure.

Some medicines used in cough and cold remedies can also be hazardous when taken along with MAOIs. although these reactions are rare, they have led to limited use of these drugs. MAOIs are now usually reserved for severely ill patients who have failed to respond to other antidepressants.

TCAs – tricyclic antidepressants

TCAs block the re-uptake of serotonin and noradrenalin, to varying extents. Some act more on one neurotransmitter than the other. Until fairly recently, these antidepressants (eg imipramine, amitriptyline, prothiaden) were the mainstay of treatment.

But there is unwanted activity by the TCAs, again to varying extents. Re-uptake of acetylcholine, an important neurotransmitter in the brain and the body, is also blocked by most TCAs. This causes several side effects such as dry mouth, constipation and blurred vision. Confusion can occur in the elderly.

TCAs also have an anti-histamine effect and can create a feeling of sedation and 'spaceyness'. Thinking, attention, concentration and memory may be poor. Hunger for sweet or stodgy things is common, which can lead to weight gain.

Effects of TCAs on serotonin can also effect sexual functioning with possible failures of erection and loss of libido. Effects on the noradrenalin system may induce low blood pressure, sometimes to the extent that a sitting patient will faint if they stand up. The pulse races in compensation. Electrical activity can be affected in the heart – particularly dangerous in an overdose situation. Thus, suicidal patients can actually kill themselves with the medication given to help them.

SSRIs – selective serotonin re-uptake inhibitors

SSRIs also block the re-uptake of neurotransmitters. These antidepressants (eg Prozac, fluoxetine, paroxetine, citalopram and sertraline) act, with varying degrees of selectivity, on serotonin and not on noradrenalin.

This selectiveness doesn't make SSRIs more effective than TCAs, but it does improve their side effect profiles. As they also don't alter neurotransmitters such as acetycholine and histamine, patients are generally more able to tolerate the SSRIs than the TCAs.

Despite this, these drugs do have side effects, mostly due to increasing serotonin at sites in the brain other than those influencing mood. One effect is nausea, very occasionally to the point of vomiting. Loss of appetite may occur. In fact, Prozac can help treat the appetite disorder bulimia. Diarrhoea may result but is not usually persistent. Some tremor and abnormal movements have been noted and anxiety levels may rise. Sexual side effects include delayed ejaculation and failure to reach orgasm in women. But dry mouth and blurred vision are uncommon and effects on the heart and blood circulation are minimal. And, the SSRIs are much safer in overdosage than the TCAs.

Some concern has been expressed over stopping SSRI treatment – there may be withdrawal reactions, raising fears that these drugs are as addictive as tranquillisers like valium. The withdrawal symptoms, such as bad coordination, fatigue and dizziness are usually short-lived, though some patients have reported prolonged reactions. However, there is no craving for the SSRI drugs, distinguishing it from true addiction

Ultimately, although depression does show biological characteristics, it is a complex disorder and difficult to untangle from environmental influences. A note of caution is essential. It's unclear whether the biological changes seen in depression are primary and cause of the illness or are secondary and are symptoms. The possibility that some at least of those biological changes are influenced by genetic predisposition has been gaining ground.

Treatment with antidepressants involves altering brain biochemistry and does help – nevertheless, psychological and social factors remain important. The task for researchers in this field is to discover how these factors interact.

Resources

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Websites

Mind
www.mind.org.uk
Raises awareness of mental health and campaigns for the rights of people experiencing mental distress and anxiety.

Depression and Antidepressants
www.antidepressants.co.uk
Links to websites on antidepressants and depression.

Depression Alliance
www.depressionalliance.org
Run by fellow sufferers. Contains information about symptoms, treatments and local groups.

Depression.com
www.depression.com
Offers advice to those with depression on how to manage their mental health.

Wing of Madness
www.wingofmadness.com
Website about clinical depression.

Depression Timeline - Channel 4
It was once seen as the work of Satan, but nowadays we know it as the work of biochemicals in the brain. See the history of our understanding of depression through the centuries.

Books

Depression by Constance Hammen (Psychology Press, 1997) £11.95
Particularly for students and professionals, this book covers clinical and diagnostic facts, and demographics such as why depression is more common in women and the young. Also considers genetic and biological factors, current treatment and developments.

Depression by M H Lader and P J Cowen (Oxford University Press, 2001) £40.00
A reference book aimed primarily at health professionals working in other specialities it sources significant recent developments including self-help treatments, suicide and self-harming, neurobiology and sexual dysfunction.

Managing Depressive Disorders by Katharine J Palmer (Adis International, 2000) £27.99
Intended for psychologists and psychiatrists, this book looks at different aspects of depressive disorders such as dysthymia, double depression, recurrent brief depression, seasonal affective disorder and psychotic depression.

Essential Psychopharmacology of Depression and Bipolar Disorder by Stephen M Stahl and Nancy Muntner (Cambridge University Press, 2000) £18.95
Easy to follow and fully illustrated. Explains the basic neuroscience of mood disorders and enables readers to understand the pharmacology of antidepressant drugs and their interaction on neurotransmitter pathways.

Antidepressant Therapy at the Dawn of the Third Millennium by Mike Briley and Stuart Montgomery (Martin Dunitz, 1999) £24.95
An illustrated overview of antidepressant therapy detailing the mechanisms of antidepressant agents. Synaptic function and dysfunction are looked at as a target for treatment and a cause of depression.

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