The Strange History of Antidepressants

Ironically, despite the horrors of war, armed conflict has a way of advancing medicine. Gruesome injuries sustained on the battlefield provide opportunities for surgeons to experiment and test new approaches for treatment. During World War II for example, blood poisoning, bronchitis, and other infectious diseases contracted by soldiers created a demand for broad spectrum antibiotics, which encouraged British scientists to find new ways to produce penicillin on a mass scale.

Sometimes, weapons of war themselves have applications other than mass destruction. Consider hydrazine (N2H4), a chemical compound that received renewed recognition by the military-industrial complex in 1937 Germany.

The chemical reactions that turn hydrazine (N₂H₂) into nitrogen (N₂), hydrogen (h₂), and ammonia (NH₃)

As part of their aggressive military posture against the Allies, German scientists sought new chemicals they could use to propel their V-2 rockets, which would enable a series of long-distance bombing attacks. Hydrazine was just the chemical they were looking for. Hydrazine degrades rapidly, and in the process, produces high volumes of nitrogen and hydrogen gas. This chemical reaction generates significant amounts of heat and energy, just what the German armed forces needed to terrorize Allied cities from London to Liege. Collectively, between the civilian and military deaths from V-2 shelling and the forced labor used in concentration camps to produce these rockets, the V-2 rockets killed more than 21,000 people (Tools of War: History of Weapons in Early Modern Times, Syed Ramsey).

As we know, the Second World War ended in a decisive loss for Germany and the other Axis countries. The Marshall Plan that followed the end of WWII led to a disarmament of Germany’s capacity for making weapons of war, so they no longer had no need for rocket propellant. But the German government still had barrels and barrels full of the volatile hydrazine, unused and leftover from their enormous wartime stockpile. So the remaining chemical was sold at a discount to pharmaceutical companies for the manufacture of different compounds, substances that could potentially help people rather than destroy them.

One of those bargain-savvy buyers of this hydrazine was the Hoffman-La Roche laboratory based in New Jersey. Soon after the war concluded, they began experimenting with the dangerous rocket fuel. Their objective? Develop a cure for one of the oldest and deadliest diseases – the dreaded “White Plague” of antiquity – tuberculosis (TB). A deadly, infectious pulmonary disease, almost one in seven people with TB died from the side effects: muscle wasting (which gave the disease one of it’s early names consumption) and the characteristic persistent cough that destroys lung tissue, causing patients to cough blood. Many were sent away to TB clinics to receive treatment; often times they would still die, even under close supervision by medical professionals. In these years before an effective vaccine or drug regime could be developed, any treatment would be an improvement over the status quo.

Through the tedious trial and error of chemists, the Hoffman La-Roche lab developed two potentially promising compounds using the leftover rocket fuel: iproniazid and isoniazid. Both of the drugs were found to destroy the offending bacterium that causes TB in the laboratory, but, these medications were less effective at curing the symptoms of the disease in a clinical setting. Despite the treatment, patients who received these compounds were still coughing and spitting up blood. There was no lessening of their symptoms, at least not until they had been on the drug for months. Worse still, the drugs produced severe side effects, including damage to the liver.

Sea View Hospital on Staten Island

To minimize the airborne spread of the disease, patients with TB were often isolated from other sick patients by being sent to specialized clinics such as Sea View Hospital in Staten Island, New York. As with other patients before them, the patients at Sea View who were on the iproniazid / isoniazid treatment regime didn’t show any rapid, noticeable improvement. But, the Sea View doctors did notice something else that was pretty amazing: While the symptoms stayed the same on these drugs, the patients were less concerned about their often-fatal condition. In the words of one doctor, as quoted in the newspaper headlines of the day:“[patients were] dancing in the halls, tho’ there were holes in their lungs.”

These hydrazine-derived drugs weren’t so great at curing TB, and, in many cases, were even toxic. So what did these drugs do to make these terminally ill patients happier? This curiosity led scientists to study how the drug changes a patient’s mood and mindstate. It turns out, iproniazid and isoniazid, the two compounds derived from rocket propellant, interfere with the body’s natural system of chemical signaling. In particular, these compounds affected neurotransmitters called monoamines, the most well-known being dopamine and serotonin. Neurons use these chemicals to communicate, and these medicines increase the amount of the chemical messengers. When a drug boosts these monoamines, they can improve a patient’s mood – as was first observed with these TB medications.

Subsequently, these rocket fuel derivatives — these failed TB drugs — became the first antidepressants.

Fast forward 60 years to the present day. According to one estimate, depressive disorder is a remarkably common mental illness, affecting almost one in five Americans. Many of today’s most effective antidepressant drugs still rely on manipulating the brain’s concentration of monoamines, particularly serotonin. The drug fluoxetine, better recognized by its trade name Prozac, is one of the most frequently prescribed medications for depression. Chemically, fluoxetine works in the brain to increase the amount of serotonin around the neurons. It’s still not quite clear how increasing serotonin can elevate mood, but this neurochemical strategy seems to work for many patients with depression.

The findings from the iproniazid and isoniazid TB trials represented a dramatic paradigm shift in the treatment of depression. Prior to this era, depression was believed to belong strictly to the world of psychologists. And while medicinal strategies represent an advancement in understanding how the depressed brain works, treating depression with drugs alone often doesn’t work. Many depression treatment regimes include both medicinal and psychological treatment, reminding us further of the remarkable complexity of our brains.

In case you are wondering, hydrazine isn’t just a chemical left behind in the era of Axis and Allies. It still has applications today, from NASA to Nissan: hydrazine is used to power small thrusters in space flight, helping astronauts make precise navigational maneuvers, and its explosive properties are used to quickly inflate airbags during a car crash!