Drug treatments

Posted in Causes and Treatment of Depression by admin on September 12th, 2008

The introduction of the antidepressive drugs for the treatment of depression was a major advance in this field. As with some other medical advances, their discovery involved an element of chance, but before these drugs could become available for the practical treatment of patients a great deal of basic laboratory and clinical research had to be carried out. The introduction of iproniazid, an inhibitor of the enzyme monoamine oxidase, followed laboratory work in the USA by Udenfriend and Brodie, who found that iproniazid reversed the depressant action of the drug reserpine in animal experiments, producing behavioural excitement. This they attributed to its action in increasing the level of neurotransmitter amines in the brain. These pharmacological findings encouraged some psychiatrists to try treating depressed patients with reserpine and iproniazid. It was only later that the use of reserpine was found to be unnecessary, since iproniazid was effective alone in increasing the concentration of neurotransmitter amines in the brain and so relieving the depression in patients with depressive illness.

Another drug, imipramine, a ‘tricyclic’ antidepressant, generally behaved as a sedative when tested on animals and it was first used in human patients as a treatment for schizophrenia. It was only as a result of the keen clinical observation of Kuhn that its antidepressant properties were noted. In fact, the basic scientists had no inkling that imipramine might be an antidepressant and it was only the information fed to them by the clinicians which led to their looking again for antidepressant properties in the laboratory. It was then that the ability of an astute research worker to make use of a laboratory error led to the beginning of our understanding of its mechanism of action. One of the technicians in Brodie’s laboratory mistakenly sent up rats belonging to someone else, which had been treated with imipramine for some days. Brodie administered reserpine and was surprised to find a reversal of the usual reserpine sedation effect—instead of being depressed, the rats became excited and overactive. He was astute enough to realise the significance of the mistake, and later the Nobel prize winner Axelrod and his colleagues showed that imipramine increased the level of free neurotransmitter amines in the brain by slowing down their re-uptake into their”inactive storage sites.

These observations illustrate a point of some importance, which is the need for close cooperation in research between the basic scientists working in the laboratory and the clinicians who are actively engaged in clinical treatment. As our understanding increases of the neurotransmitter mechanisms operating in the brain, so the pharmacologists are developing new drugs to modify these mechanisms in ways that can be helpful in the treatment of patients. But before any new drug can be brought into general clinical use, an immense amount of work is required in laboratory investigations to determine their safety and to identify possible side effects or unwanted interactions that might limit their application. In the clinical investigations of new drugs, it is a basic rule that the patient’s interests must always come first. It is, therefore, essential that any investigation that is proposed must be fully explained to the patient and his agreement obtained in writing. To safeguard any patients who do not fully understand the implications of research, agreement must also be obtained from the hospital Ethical Committee.

Mental illnesses tend to fluctuate in the severity of the symptoms, both spontaneously and because of environmental events, and improvement or other incidental changes in a patient’s condition might, therefore, be wrongly attributed to the treatment being given at the time.

A new drug can be tested against an inert substance, or ‘placebo’, but in the case of depressive illness we now have drugs of known therapeutic action and any new anti-depressant drug can, therefore, be tested against one of these standard drugs. The patients can be divided randomly into two or more identical groups of sufficient size to obviate, by the law of averages, any differences between the groups due to environmental or other effects. The only difference is that the one group is given the trial drug and the other a placebo or a standard remedy. In a ‘double blind’ controlled trial all the preparations are made up in identical form so that neither the patient nor the doctor who carries out their assessment knows which preparation a patient is receiving, and he cannot therefore be influenced by preconceived ideas. At the end of the trial the results of the treatment are analysed statistically to see which drug treatment is most beneficial. This method has proved immensely useful in identifying drugs that are of real value and those which are relatively ineffective and which might otherwise remain on the market and prevent improvement in treatment, perhaps for many years.

The antidepressant drugs have brought tremendous benefit to depressed patients and have greatly reduced the need for ЕСТ. Of equal moment has been the discovery of the benefit of treatment with lithium.6 In the old days many manic-depressive patients had to be hospitalised several times a year for years on end. For these patients with frequent mood swings between mania and depression lithium treatment can literally transform their lives. Cade has the credit for introducing lithium as a treatment for mania, and its usefulness in this condition has now been amply confirmed. The more important use of lithium as a prophylactic in preventing relapses in manic-depressive illnesses was noted by Maggs and established in extensive trials by Mogens Schou in Denmark. In manic-depressive disorders with frequent relapses up to 70% of patients treated with lithium have a marked or complete reduction in the frequency and severity of their attacks.

A patient’s response to treatment depends partly on the type of depressive illness from which he is suffering. While those with bipolar depression respond well to lithium, patients with unipolar depression are generally found to respond best to the tricyclic antidepressants. The response to treatment also depends partly on factors in the patient’s genetic make-up which determine the blood level of the drug that is reached after administration of a standard dose. It was shown by Hammer that there are large individual differences in the blood levels in patients receiving standard doses of antidepressants and, besides the influence of the genetic make-up, the blood levels that are reached are affected also by factors such as the intake of alcohol or other drugs. An important part of the treatment of many patients with depressive illness is, therefore, to have available the laboratory facilities that are required for carrying out the regular estimation of the levels of lithium or antidepressants in the blood.

Clearly there are many problems still remaining to be solved, but basic and clinical research have added greatly to our understanding of the factors involved in the causation of depressive illness and have resulted in a big improvement in the methods available for treatment. What was formerly regarded as an incurable condition requiring permanent hospital care is now generally accepted as an eminently treatable form of mental disorder. The saving in terms of human suffering, as well as in cost to the community, has been immense.