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Obituary - Arvid Carlsson, MD, PhD (1923-2018)

September 10, 2018 11:00 | CINP Office (Administrator)

Arvid Carlsson (photo by Johan Wingborg) was born in 1923 and grew up in Lund where he also studied medicine. His thesis, which he defended in 1951, was on calcium and bone tissue, but a brief stay at the laboratory of the legendary Bernard Brodie at NIH made him change his field of interest to that of brain neurotransmitters. In 1959, he became professor of pharmacology at the University of Gothenburg where he came to stay for the rest of his career. Among his many awards are the Nobel Prize, the Japan Prize, the Wolf Prize and the Jahre Prize. He was married to Ulla-Lisa, also MD, who throughout his career provided strong support for him in his work, and had five children.

When Carlsson entered the field of neuropsychopharmacology, the discipline was still in its very infancy. After long-standing reluctance, the concept of chemical transmission taking place in the brain had recently achieved acceptance, but virtually nothing was known with respect to the identity of the transmitters used for this purpose. When visiting Brodie’s laboratory, which also hosted future Nobel Laureate Julius Axelrod, Carlsson was asked to explore the possible influence of reserpine, known to exert antipsychotic activity, on the release of serotonin. He suggested that one should also examine the possible influence of reserpine on catecholamines, but as this was beyond the interest of Brodie, Carlsson decided to conduct these experiments when back in Sweden. To this end, he established close collaboration with histologist Nils-Åke Hillarp, later recognized for the invention of the Falck-Hillarp immunofluorescence technique by means of which brain monoaminergic neurons could be mapped.

Without any knowledge of the vesicular monoamine transporter, which we now know is the molecular target of reserpine, Carlsson and Hillarp could confirm that the drug effectively depletes catecholamines by interfering with the storage of the monoamines. Moreover, Carlsson showed that the loss of normal motor activity displayed by rabbits after treatment with reserpine was dramatically reversed upon administration of the catecholamine precursor levodopa, and that this effect was not, as he had assumed, caused by the restoration of brain levels of noradrenaline, but closely related to the formation of dopamine. Highly controversial when it was first presented, this was the main discovery for which he was subsequently awarded the Nobel Prize.

Needless to say, Carlsson’s reports on these pivotal experiments, conducted in Lund in the late 50’s, had an enormous impact on the development of the field. First, they suggested that dopamine, by the time regarded merely as an intermediary in the formation of noradrenaline in the peripheral nervous system, was a brain neurotransmitter. Second, they constituted the first confirmation of the feasibility of the mode of thinking that has since then dominated neuropsychopharmacology, i.e. that behavioural aberrations may be caused by more or less specific transmitter aberrations and treated with drugs normalizing transmitter activity. Third, they paved the way for the subsequent introduction by George Cotzias of the use of levodopa as treatment of Parkinson’s disease. Fifty years later, there is still no more effective drug for this disabling condition.

In the 60´s, when Carlsson had moved to Gothenburg, he made another seminal discovery related to dopamine. The observations that reserpine is an antipsychotic drug, and that it reduces brain dopamine levels, had prompted several groups to explore the possibility that also other antipsychotic drugs, the recently discovered chlorpromazine and haloperidol, might reduce dopamine levels, but without obtaining support for this suggestion. Analysing transmitter turnover rather than merely transmitter levels, Carlsson however noted that these drugs elicits an increase in catecholamine turnover, and concluded that they may act as receptor antagonists, the increase in turnover most likely being an adaptive response mediated by a yet unidentified feed-back mechanism. Given that one, at the time, knew very little about synaptic regulation, including the existence of the kind of receptor Carlsson later named autoreceptor, and that receptor antagonism was far from an established mechanism of action for drugs influencing the brain, the conclusion drawn by Carlsson was a brave yet logical one, that has since then been confirmed in numerous studies.

The report on the mechanism of action of antipsychotics was published in a Scandinavian journal, Acta Pharmacologica et Toxicologica, and was for several years rarely cited; when the dopamine hypothesis of schizophrenia had gained acceptance, it however became a citation classic. It is of note that Carlsson never cared much for the prestige of journals, or their impact factor, reasoning that a finding of sufficient importance would sooner or laterbecome well-known, regardless of where it was published. He even suggested that it might be advantageous to publish in modest journals so that one could do the obvious follow-up experiments without too much of a competition from other groups.

Carlsson remained interested in the role of dopamine in schizophrenia for the rest of his career. Impressed by the vast physiological importance of dopamine transmission, he regarded blocking the dopamine D2 receptors in patients with schizophrenia being too drastic an interference, and suggested that partial D2 agonists, such as (-)-3-PPP, which was developed in his own laboratory, may have a more tolerable profile; he was hence one of the first proponents of the mode of action today exerted by aripiprazole and several other recently developed second-generation antipsychotics. However, in recent years he came to believe that there are even more effective ways of stabilizing dopaminergic activity than partial agonism. Active until the very end of his life, Carlsson hence, together with his daughter Maria, spent his last years developing a new kind of dopamine stabilizer, OSU6162, which had been shown to enhance the activity of low-activity animals and reduce it in those being hyperactive; at the age of 95, he published his last paper on this compound in the same month that he passed away. It is saddening that Carlsson did not live long enough to witness the outcome of the ongoing clinical trials where this intriguing drug is being evaluated for its proposed effect on mental fatigue.

Carlsson also made important contributions to the field of antidepressants. After the serendipitous discovery by Roland Kuhn in 1957 of an antidepressant effect of the tricyclic drug imipramine, it had been reported by Julius Axelrod, in 1962, that this compound blocks the reuptake of noradrenaline, and suggested by Joseph Schildkraut, in 1965, that facilitation of noradrenergic transmission be a common denominator for antidepressants. In the late 60’s, Carlsson however showed that tricyclic antidepressants also inhibit serotonin reuptake in brain and proposed that this effect may contribute to their antidepressant properties. He suggested to Ivan Östholm, head of research at a small, nearby drug company, Hässle AB, which was a subsidiary of Astra, that they together should develop a reuptake inhibitor influencing serotonin but not noradrenaline, the result of this endeavour being zimelidine, the first of the selective serotonin reuptake inhibitors (SSRIs). Whereas clinical trials with this drug provided proof of the concept that depression may be treated by drugs selectively influencing serotonin, zimelidine unfortunately had to be withdrawn from the market because of a rare and reversible Guillain-Barré-like side effect. Needless to say, the suggestion that selective serotonin reuptake inhibition be a feasible mechanism for treating depression however did survive, the followers of zimelidine still being first line of treatment not only for depressed mood but also for a number of anxiety disorders, obsessive compulsive disorder and premenstrual dysphoric disorder.

Asked why he had become so successful, Carlsson often underlined that he had been lucky, arriving to exactly the right place (Brodie’s lab) at exactly the right time, i.e. in the very infancy of a field that soon was to expand enormously, and also, after having returned to Sweden, having the opportunity to collaborate with a scientist with exactly the right complementary competence, Nils-Åke Hillarp. But while luck may have a played a significant role for a researcher making one important discovery, it can hardly be the major factor for someone who, like Carlsson, has made a string of seminal discoveries. Instead Carlsson’s achievements must be explained by a unique talent for scientific thinking: like few others, he could select the most promising leads from many possible alternatives, mobilize the required rethinking to interpret puzzling results in an unconventional way, and recognize a pattern, invisible to others, from a number of disparate observations. He also displayed an entrepreneurial ability to get things done, and – not least – such a genuine interest in the scientific problems that he, throughout his 70-year-long career, always avoided leading positions within the faculty as well as prestigious but time-consuming honorary assignments. His focus was always on solving scientific problems.

Carlsson showed impressive creativity also with respect to how to conduct preclinical, academic research. For example, having a group of synthesis chemists working at his laboratory, providing him with novel molecules, was an unconventional but highly successful move. Several pharmacological tools resulting from this endeavour have been tremendously useful for neuropsychopharmacologists around the world, including the prototype 5-HT1A agonist 8-OH-DPAT. Moreover, as an external advisor, he prompted the above-mentioned company, Hässle AB, to profoundly change its modus operandi, hence playing a key role for its spectacular success in the 1970’s, when it developed, e.g. metoprolol for hypertension and omeprazole for peptic ulcer. Carlsson was also an atypical preclinical neuroscientist in the sense that he early on realised the importance of continual interaction with clinicians, as illustrated, e.g. by his involvement in clinical trials suggesting antipsychotic effects of the dopamine synthesis inhibitor alpha-methyl-p-tyrosine and the partial agonist (-)-3-PPP, respectively. Thus, he was a pioneer also with respect to being translational in his research.

Having good self-esteem, and firmly believing in his ideas, Carlsson often defended his stance in scientific matters with considerable stringency and vigour. He also possessed a significant personal integrity that prompted him, now and then, to make authoritative contributions to the public debate, mainly on issues of research politics. But while he could be feared as opponent in a debate, he was friendly and easy-going in private encounters, conversations with him often being interleaved with joke and laughter. And although he was probably the most internationally renowned researcher in his field, he never showed the slightest trace of conceit. Thus, throughout his professional life, the intellectual issues at stake – never prestige or position – remained central for him. Young PhD students who turned to Carlsson to discuss scientific issues were encouraged and inspired by such encounters, not least because he seemed to put as much value on them as the junior interlocutor did. Numerous colleagues throughout the world have similar experiences.

A preclinical pharmacologist with strong interest also in clinical matters, Carlsson can be said to personalize the spirit of CINP, of which he was a great friend and supporter. He usually attended the CINP congresses, was CINP President in 1978-80, hosted the CINP World Congress in Gothenburg in 1980, presented the final keynote lecture at the CINP World Congress 2012 in Stockholm and was named Honorary President in 2012. While it is sad that this pioneer in neuropsychopharmacology, and true friend of CINP, has now left us, we should be pleased that he, throughout his long professional life, had the fortune of making such important contributions for millions of patients around the world. Like no one else, Carlsson has showed us the societal usefulness and importance of basic neuropsychopharmacological research.

by Elias Eriksson & Torgny H Svensson

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