First Antidepressant
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When were drugs for mental illness invented?
Schizophrenia and psychotic disorders
Modern research into the treatment of mental disorders began with the discovery of chlorpromazine, which was introduced into psychiatry in 1952.
Chlorpromazine was the first antipsychotic drug in the history of psychiatry. Specifically it had an effect on the symptoms of schizophrenia and other psychotic disorders.
Gradually the processes in the brain affected by chlorpromazine were identified. This meant that the discovery of the drug's effects on schizophrenics led to the formulation of hypotheses about the biology of schizophrenia.
Depression
A similar story subsequently played out in depression research. This followed the introduction of tricyclic antidepressants.
The first of the tricyclic antidepressants was imipramine. Imipramine and chlorpromazine are similar chemically and so it seemed logical to test the substance for antipsychotic effects. However, it turned out that imipramine had no impact whatsoever on psychoses. Next, imipramine was tested on patients suffering from depression. It had a convincing effect and the first real antidepressant drug was born.
1958 - the first antidepressant
Like chlorpromazine, imipramine was widely used when it was launched in 1958. Imipramine is still used today for the treatment of depression and for comparisons with new antidepressants.
Around 60 different tricyclic antidepressants have since been developed.
Since 1960 it has been known that neurotransmitters:
- Are released into the synapse when the nerve is stimulated
- Activate the receptors in the synapse, and
- Are then reabsorbed into the nerve cells
This mechanism was first demonstrated for noradrenaline.
Gradually it emerged that imipramine and other tricyclic antidepressants inhibited the reuptake of both noradrenaline and serotonin from the cleft into the nerve cell.
1965 - the amine hypothesis for depression
These discoveries led to the development of the amine hypothesis for depression. This hypothesis was first put forward in 1965 and was as follows:
- Depression is due to a deficiency of noradrenaline and/or serotonin in the nervous system
- Administering antidepressant medications inhibits the reuptake of these neurotransmitters
- Inhibiting the reuptake of these neurotransmitters leaves more of them in the synapse
- This counters the deficiency and eases the depression
The theory triggered hundreds of studies. Levels of noradrenaline, serotonin and their metabolites were tested in the following fluids taken from a mixture of depressed, manic and healthy people:
Generally speaking these studies have not showed clear results. Some depressed patients do have a low content of one of the degradation products of serotonin in their spinal fluid but it has since emerged that this finding has little to do with depression - rather it is seen in people who suffer from impulse-control disorders.
A modernized version of the amine theory might look like this:
External traumas or internal biological disruptions lead to intense excitation of the serotonergic and adrenergic system. This means that the nerve cells' stocks of serotonin and noradrenaline gradually decline. To counter the shortage of serotonin and noradrenaline, the number of receptors increases. This higher number of receptors disrupts the functioning of the nervous system and leads to a risk of depression developing.
Another possibility is that there is nothing wrong with either the neurotransmitters or the receptors. Instead the problem may lie with the reuptake mechanisms which clear the neurotransmitters from the synaptic cleft.