Discuss Recent Developments in our Understanding of the Pharmacology and Biochemistry of Depression

Depression is a mental state which along with mania is classed as an affective disorder and can be defined as a pathological moodstate. Depression is usually phasic and is characterised by a return to normality during remission. Classification of depressive orders is very difficult because the disorders are heterogeneous and the symptoms range from mild to severe and can overlap with those of anxiety, schizophrenia and personality disorders.

Generally two main types of depression are recognised; bipolar and unipolar. With unipolar depression, the origins of the illness are unknown and there may be periods of normality. Another type of Unipolar depression has been identified as 'reactive depression' and is generally related to environmental circumstances such as bereavement and changes in financial circumstance and is not usually treated with drugs. With bipolar depression or manic-depressive psychosis, there is an oscillation between depression and mania though, again there are bouts of normality.

The discovery of antidepressant drugs resulted in various monoamine hypotheses of depression. The role of the catecholamines (noradrenaline and dopamine) was emphasised as the cause of depressive and manic disorders. (eg Bunney and Davis 1965, Schildkraut 1965,1978, Schildkraut and Kety 1967). It was proposed that deficiency of catecholamines, especially noradrenaline was associated with some depressions and an excess of catecholamines was associated with mania. It was discovered that many antidepressant drugs increase the availability of catecholamines at receptor sites, drugs such as the tricyclics and related antidepressants block presynaptic reuptake of catecholamines and monoamine oxidase inhibitors (MAOI) decrease their deamination resulting in increased amounts available for release. It was also noted that drugs such as amphetamine release catecholamines which have a temporary antidepressant effect and causes euphoria in non depressive people, though it tends to aggravate mania. How dopaminergic activity is related to depression is still uncertain. As in post mortem studies of depressive suicides no changes in brain dopamine concentrations have been found. However drugs which increase dopaminergic activity, for example amphetamine and L-Dopa have been found to improve depression and produce euphoria. Another factor which suggests that Dopamine maybe an important factor in depression is that patients with Parkinson's disease show a progressive degeneration of Dopamine containing neurons.

Depressive disorders are also associated with abnormal noradrenalin (NA) and serotonin (5-HT) concentrations on the brain. Investigations into plasma, cerebrospinal fluid (CSF) and postmortem brain tissue in patients with depression has been carried out. No consistent changes of noradrenaline were found in the plasma and csf but there is greater variability in concentration when compared with normal controls. There also appeared to be less serotonergic activity in some types of depression which some antidepressant treatments seemed to reverse.

Another challenge to monoamic theories came from the discovery of new antidepressant drugs which do not inhibit neurotransmitter reuptake nor inhibit MAO ...

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Another challenge to monoamic theories came from the discovery of new antidepressant drugs which do not inhibit neurotransmitter reuptake nor inhibit MAO (eg mianserin). Cocaine and amphetamine have also been found to be NA and 5-HT reuptake inhibitors but fail to have antidepressant properties. A further drawback to the traditional idea of NA and 5-HT synaptic deficiencies theories of depression was the realisation that drug affects at synapses develop rapidly, in a matter of hours or days, while the clinical effects take several weeks to develop. This time course discrepancy and discovery of "atypical" antidepressants which do not effect reuptake have led to fresh approaches to the study of depressive illness.

One idea is that the therapeutic effects of antidepressants are not due to changes in transmitter concentration but to changes in receptor sensitivity which occur over a longer time course, in response to the drugs administered in the body. Recent technological advances have given a greater understanding of monoamine receptors. New monoamine receptor subtypes have been identified and this has lead to receptors being classified by protein structure rather than on ligand based classifications. It has also been discovered that there are multiple receptors for each neurotransmitter. Also neurotransmitters are dynamic structures which depend on the supply of agonists of antagonists to make adaptive changes. For example a decrease in the supply of an agonist will result in a compensatory decrease of receptor sensitivity. Since many drugs act as agonists or antagonists at receptor sites this will lead to alterations of receptor sensitivity. It has been shown that chronic administration of antidepressant drugs leads to changes in adrenergic, serotonergic and dopaminergic receptors.

Most antidepressant drugs appear to affect catecholaminergic systems and serotonin systems in the central nervous system. There is evidence that both systems may be involved in affective disorders and this has led to concentration on serotonin receptor activity in depression. Recent studies have indicated that during chronic treatment of antidepressants marked changes occur in post 5-HT receptor sensitivity. The role of 5-HT in depression has become increasingly important since evidence has suggested that of eating behaviour, thermoregulation of sleep, certain hallucinatory states and maybe some neuro endocrine control mechanisms is strongly indicated in depressive illness. This is indicated by the effectiveness of some recently introduced antidepressant drugs which selectively inhibit the reuptake of serotonin and have been highly effective in the treatment of depressive disorders. These drugs known as selective serotonin reuptake inhibitors (SSRIs) include fluoxetine(prozac), fluvoxamine (faverin), paroxetine (seroxat) and citalopram. The main advantage of SSRI's are that they are as effective as the tricyclic antidepressants but have fewer side effects and are safer in overdose.

Evidence that neural transmission at 5-HT receptors is facilitated by chronic antidepressant treatment comes from electrophysiologic studies. Newer antidepressant drugs such as fluoxetine and indalpine facilitate 5-HT transmission at 5HT1 receptors by presynaptic disinhibition. As 5-HT is released into the synaptic cleft it binds to postsynaptic and presynaptic 5-HT1 receptors. Subsequent release of 5-HT is decreased by presynaptic 5-HT1 receptors reducing the amount of 5-HT released per action potential. The presynaptic receptor effectively decreases neural transmission at high firing rates. Chronic treatment with antidepressants such as fluoxetine blocks presynaptic 5-HT inhibition of 5-HT release, thus facilitating 5-HT transmission. By blocking presynaptic 5-HT inhibition, postsynaptic 5-HT receptor activity is enhanced. 5-HT uptake inhibitors also appear to be affective in the treatment of panic disorder, obsessive compulsion disorder, bulimia and cataplexy. This suggests that a disorder of the seroernergic system underlies a number of psychiatric disorders as well as the affective disorders.

Prolonged treatment with antidepressants, and in some studies ECT, does result in a decrease in the number of 5-HT2 binding sites in the central nervous system. It is not understood what the functional significance of such a decrease is, as it does not occur with all antidepressants. However, an involvement with high cerebral functions, short term memory and cognition is indicated by the decrease in the number of 5-HT2 binding sites in patients with dementia.

Recent biochemical and pharmacological developments have revealed complex changes in monoamine receptors with regard to depression. It would now appear that monoamine receptor changes are closely interrelated and involve receptor-receptor interaction by several monoamine neurotransmitters. Thus an explanation of depression in terms of any single transmitter or its receptor would seem unlikely.

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