|
There are now several major types of antidepressant drugs, but the earliest found to successfully treat depression were the monoamine oxidase inhibitors and tricyclic antidepressants. Like many pharmacological breakthroughs, the first major antidepressant was discovered by accident.
Iproniazid (the first MAO inhibitor) itself was originally developed to fight tuberculosis. It in addition to effectively treating tuberculosis, Iproniazid was observed to elevate mood and stimulate activity in many patients. These effects led researchers to investigate the ability of Iproniazid to treat the symptoms of depression.
After promising preliminary findings reported in 1957, Iproniazid was prescribed widely to patients with major depression. Within the first year it was available as an antidepressant four hundred thousand depressed people received Iproniazid treatment.
Subsequent studies demonstrated the ability of this drug to block the activity of monoamine oxidase, the enzyme that destroys the monoamine neurotransmitters (norepinephrine, serotonin and dopamine). It is this interaction that is the basis of MAOI antidepressants, and a reaction that we will explore in depth in later sections. Early problems stemmed largely from controversies surrounding proper dosing, as too much Iproniazid caused liver problems and too little reduced effectiveness greatly.
Although Iproniazid is no longer used as an antidepressant, the effectiveness of the drug led to further interest in the idea that depression might be alleviated by appropriate drugs. The discovery of the effects of drugs like Iproniazid was made completely on the basis of studies for other conditions. They were not developed like most drugs today, out of a desire to prove a particular theory of neurochemical function. The exact mechanism of their action was largely unknown. What was evident in early applications of Iproniazid was that it was far superior to any previous treatment.
Around the same time Iproniazid and the early tricyclic antidepressants were being studied, an antipsychotic drug known as Resperine was observed to induce depression in a small number of patients. Together these findings provided a basis for the monoamine theory of depression. It was known for some time that drugs like amphetamines and cocaine make people feel good because they increase activity at the synapse of monoamines, namely serotonin, epinephrine and dopamine.
In an attempt to merge the findings of early antidepressant and antipsychotic drugs, the theory suggested that reduced levels of monoamine activity provided a biological basis for mood disorders. Increased availability of monoamines in the brain led to anxiety and mania while reduced availability led to depression. The theory has evolved as our understanding of depression has expanded, and will be explored in greater depth in further sections. The evolution of MAOI antidepressants has been primarily one of increasing specificity of action. As our knowledge of brain chemistry and physiology advances, we are increasingly able to target increasingly specific areas of monoamine dysfunction while eliminating side effects. The term "selective" is often heard here, denoting the ability of a drug to alter the properties of desired brain circuits while leaving others intact.
Although neither the precise pathology of depression nor the regulation of normal mood may yet be said to be completely understood, the monoamine theory has proven invaluable in the development of therapies for the treatment of depression and other mood or anxiety disorders.
|
