We can define psychiatric disorders as diseases of the brain whose precise cause we do not know. This is also the case with depression. For a long time, a serotonin deficiency hypothesis was assumed, which was later modified into a monoamine imbalance hypothesis. As is so often the case with psychiatric illnesses, the starting point was an accidental finding that a medication worked - in this case, a drug used to treat tuberculosis. Because this debate remains relevant today for understanding depression and its treatment, we present its history from its beginnings in the 1950s. How did the serotonin hypothesis of depression come about, what were the main findings, and who were the key players? What truth lies within it, or is it entirely off the mark?

Psychiatrische Störungen können wir als die Erkrankungen des Gehirns definieren, deren genaue Ursache wir nicht kennen. So ist es auch bei der Depression. Lange Zeit wurde eine Serotonin-Mangel-Hypothese präferiert, die später in eine Monoamin-Dysbalance-Hypothese geändert wurde. Wie so oft bei psychiatrischen Erkrankungen war der Ausgangspunkt ein Zufallsbefund , dass ein Medikament wirkt, in diesem Fall ein Mittel gegen Tuberkulose. Da diese Debatte auch heute noch für das Verständnis der Depression und ihrer Behandlung relevant ist, stellen wir sie seit ihrem beginn in den 1950er Jahren dar. Wie kam es zur Serotonin-Hypothese der Depression, was waren die wesentlichen Befunde und wer die entscheidenden Player? Was ist wahr an ihr oder ist sie vollkommen verfehlt?

After chlorpromazine was introduced as the first effectiveantipsychotic for the treatment of schizophrenia, the theory quickly emerged that antipsychotic efficacy was inseparably linked to extrapyramidal motor side effects. This view was already advocated in 1954 by the German psychiatrist Professor Hans-Joachim Haase. It is important for this anecdote that Hase means lare or rabbit in German.

In the early 1960s, clozapine was discovered in Switzerland. In contrast to the antipsychotics available at the time, it did not produce extrapyramidal motor side effects. The drug was therefore given the trade name Leponex, derived from the Latin words lepus (hare/rabbit) and ex (out), an amusing allusion to “Ha(a)se out”—symbolizing the refutation of Haase’s theory.

In the early 1970s, clozapine was withdrawn from the market in most countries following reports of agranulocytosis. In the German-speaking countries, however, it remained available because leading psychiatrists, including Hanns Hippius, recognized its unique clinical value and strongly advocated for its continued use. In the United States, only a small number of psychiatrists were still permitted to prescribe clozapine, generally with the intention of eventually switching patients to another antipsychotic. However, this often proved unsuccessful, as many patients relapsed after clozapine was discontinued. Against this background, John Kane and colleagues published a randomized double-blind trial in 1988 demonstrating the clear superiority of clozapine over chlorpromazine.

This landmark study triggered a surge in the development of new antipsychotic drugs, initially referred to as atypical antipsychotics and now more commonly known as second generation antipsychotics.

German-speaking psychiatrists deserve credit for recognizing that an antipsychotic could be effective without causing extrapyramidal motor side effects. John Kane and his colleagues deserve credit for demonstrating that clozapine is not merely effective but superior in efficacy. The psychiatrists in the German-speaking countries had assumed that clozapine possessed only relatively modest antipsychotic efficacy.