Curing insanity with malaria

Sometimes the history of medicine is very, very surreal. For example, consider that in 1927, a physician named Julius Wagner-Jauregg received the Nobel Prize in medicine, for...deliberately infecting his patients with malaria. As a treatment for psychosis.

This often worked.

Well, it did kill around 15% of the patients, but it was nonetheless seen as a miracle cure.

General paralysis of the insane was first identified and described as a distinct disease in the early 19th century. It was initially thought to be caused by an ‘​​inherent weakness of character’. The initial symptoms were of mental deterioration and personality changes; patients suffered a loss of social inhibitions, gradual impairment of judgment, concentration and short-term memory. They might experience euphoria, mania, depression, or apathy. Delusions were common, including “ideas of great wealth, immortality, thousands of lovers, and unfathomable power” – or, on the more negative side, nihilism, self-guilt, and self-blame.

It was a progressive disease, and nearly always a death sentence. As the condition advanced, the patient would develop worsening dementia, motor and reflex abnormalities, and often seizures; death usually took 3 to 5 years from the initial symptoms. In the 19th century, cases of general paralysis could account for up to 25% of admissions to asylums.

Some physicians were drawing a connection between general paralysis and syphilis infection as early as the 1850s; however, it took until much later for this explanation to be generally accepted within the medical community, and full confirmation via pathology examinations of the brains of patients who had died of the disease would have to wait until 1913.

In 1909, an antisyphilitic drug compound was discovered via a process of trialing hundreds of newly synthesized organic arsenical chemicals, looking for one that would have anti-microbial activity but not kill the human patient; this was the first research team effort to optimize biological effects of a promising chemical, which is now the basis of a huge amount of pharmaceuticals research. Unfortunately, arsphenamine, also known as Salvarsan or “606”, was difficult to prepare and administer, and was still fairly toxic to the human patient as well as the syphilis.

Julius Wagner-Jauregg was a Viennese psychiatrist, but a psychiatrist with a particular interest in experimental pathology, and in brains. Already in the mid-1880s, he was noticing an odd pattern; many of his psychiatric patients were showing improvements in their mental condition after recovering from bouts of other illnesses that resulted in fever.

Wagner-Jauregg formed two hypotheses. One, some cases of insanity had ‘organic’, biological causes and were related to physical dysfunctions in the brain; two, one disease could be fought by another. He tried deliberately inducing fevers in his patients, by injecting them with tuberculin, a sterile protein extract from cultures of the tubercle bacillus responsible for tuberculosis. However, this was inconsistent at producing a fever, and the results were disappointing.

In 1917, a soldier ill with malaria was admitted to Wagner-Jauregg’s ward. No, I am not at all sure why a malaria patient was being treated in a psychiatric ward! And, apparently, neither was Wagner-Jauregg:

“Should he be given quinine?” [my assistant Dr. Alfred Fuchs] asked. I immediately said: “No.” This I regarded as a sign of destiny. Because soldiers with malaria were usually not admitted to my wards, which accepted only cases suffering from a psychosis or patients with injuries to the central nervous system.

Wagner-Jauregg would have known that malaria is especially likely to cause repeated, intermittent paroxysms of high fever. Also, unlike with general paralysis, quinine was available as a treatment and reasonably safe. Since general paralysis was still mostly incurable, he must have felt that there wasn’t much to lose. He made the bold choice to draw blood from the sick soldier and inject it into nine of his psychiatric patients diagnosed with general paralysis. It is deeply unclear from sources on this whether he bothered to obtain consent from any of the patients involved. Six of the nine saw improvements in their psychiatric condition, and only one patient is reported to have died of the fever.

(Unfortunately, but perhaps unsurprisingly given his predilection for mad science, Wagner-Jauregg was later a proponent of eugenics, and backed a proposal for a law that would ban “people with mental diseases and people with criminal genes” from reproducing. His application to join the Nazi party was, apparently, rejected on the basis that his first wife was Jewish.)

In 1921, Wagner-Jauregg published a report claiming therapeutic success in treating GPI patients with malaria, and this became the standard treatment until the discovery of penicillin in the 1940s. Tens of thousands of patients were treated with deliberate malaria infections. Special psychiatric clinics were opened for this purpose. There were various attempts to produce fevers in safer ways, mostly via hot baths, electric blankets, or “fever cabinets” but sometimes via injection of toxic sulfur compounds; none were as successful as malaria.

According to a historical cohort study, despite the high risk of this treatment – between 5% and 20% of patients would die from the ‘cure’ – patients treated with malariotherapy did have significantly better chances than they would otherwise. 70% were alive a year after admission, compared to 48% of untreated cases; at 5 years, 28% of malaria-treated patients were alive versus only 8% at baseline. Patients who had only recently contracted syphilis – and thus presumably had less irreversible neurological damage – could be cured entirely, especially if the malarial fever was followed by Salvarsan treatments.

Graph of survival after admission

It wasn’t a great treatment, and it was obviously far from safe, but given the prognosis for general paralysis and the lack of other good options, it’s not surprising that it was seen as revolutionary.

Even now, it’s not fully understood how the fever resulted in a cure; it’s unlikely that the patients’ body temperatures were high enough for a prolonged enough period to directly kill the spirochetes responsible for syphilis infection. Another hypothesis is that the infection stimulated the patient’s immune system to a higher level of activity, which also boosted the body’s defenses against the syphilis infection.

Even once penicillin was discovered, the treatment wasn’t immediately accepted, and was often given in combination with malariotherapy; this was done in the United States and in the Netherlands up to the mid-1960s, and in the United Kingdom until the 1970s.

The popularity of pyrotherapy during this period resulted in significantly more research effort going toward the biological study of malaria, including its mode of transmission and treatment. The first permanent laboratory colonies of mosquitoes, and the isolation of various malaria strains, were both established during this time period. Testing of synthetic drugs for malaria treatment was another related advance. It seems likely that malaria is much better understood now than it would be if this historical interlude had never happened.

Wagner-Jauregg’s work here also pioneered the field of ‘stress therapies’ for psychiatric illnesses, including induced insulin coma therapy for schizophrenia. Electroconvulsive therapy, also popularized during this time period, is still used as a treatment for refractory depression today.