Commentary on the Hamilton Rating Scale for Depression: 60+ Years Old and Still Relevant to the Assessment of Antidepressant Treatment Outcomes

In early 1960, approximately 9 months before John F. Kennedy was elected President of the United States, a 48 year old psychiatrist from the University of Leeds in the United Kingdom named Max Hamilton, M.B.B.S, D.P.M., published a paper in the Journal of Neurology, Neurosurgery and Psychiatry describing a new scale to assess the severity of an episode of depression.¹ Within a decade this scale, soon to be known as the Hamilton Rating Scale for Depression (HRSD) or—less elegantly—the HAM-D—had become the gold standard for measuring outcome in clinical trials of novel antidepressant medications. When later asked about why he chose to publish his paradigm-shifting scale in such an obscure journal, Hamilton modestly (and apparently truthfully) replied: “They were the only one who would take it”.²

Hamilton believed that the great success of the HRSD was at least partly attributable to good timing—his scale became available at the same time as the first studies were being designed to test the efficacy of a class of drugs that we now know as the tricyclic antidepressants (TCAs). However, good timing alone would not have sufficed and the enduring value of the HRSD was that it both assessed the severity of classical symptomatic depressive syndromes, but also was sensitive to change. The HRSD thus become the primary dependent measure used in many of the first generation of randomized clinical trials (RCTs) to use pill placebo as a control group. The HRSD held the exalted “Gold Standard” position for at least 40 years,³ before eventually being surpassed in the first decade of the 21^st Century by a scale developed almost 20 years later by Stuart Montgomery and Marie Åsberg (Montgomery Åsberg Depress Rating Scale).⁴ Although we more often use the MÅDRS in contempory studies of novel antidepressants, the HRSD is hardly obsolete and the psychometric advantages of the MÅDRS are modest at best.⁵

Before his death in 1988, Max Hamilton accomplished many things and received many honors, including becoming the Chair of the Department of Psychiatry at the University of Leeds, appointed as a member of the UK’s influential Medical Research Council, elected as the first President of the British Association for Psychopharmacology, selected as an honorary fellow of the Royal College of Psychiatrists, and—in 1980—he received the prestigious Paul Hoch prize for his contributions psychiatric research.

I was born about 10 years too late to get to meet Professor Hamilton, though I did receive a congratulatory note from him (along with a hand-written reprint request) following publication of one of my first papers in the area of depression treatment research.⁶ This note stayed thumbtacked to my bulletin board for the next 25 years as a reminder to aspire to such graciousness in relations to colleagues, particularly those still in training or early in faculty careers.

In researching Professor Hamilton’s career to prepare this Commentary, I learned several interesting facts about his life. First, he was German by birth and his family changed their last name, from Himmelschein (literally, the way the sky looks on some gorgeous dawns or sunsets), after immigrating to England in 1905. As the grandson of German immigrants who changed the pronunciation of their last name, I chuckled at the realization that, whether Himmelschein or Hamilton, his almost immortal rating scale would still be called the HRSD. Second, after graduating from medical school, he served six years as a medical officer in the Royal Air Force in the Second World War. This tempering experience shaped his interest in psychiatry and he completed his residency at the famous Maudsley Hospital in London. Third, he was not offered a faculty appointment at the Maudsley after residency, being functionally “cast out” by his service chief, Sir Aubrey Lewis. Of course, although Lewis was a titan in his own time, the outcast’s body of work greatly out-shown that of the “caster-outer”. So, you wonder, would there have been an HRSD had Hamilton stayed under Lewis’ tutelage at the Maudsley?

Which, of course, brings us to Leon Rosenberg’s labor of love, which provides a granular review of the HRSD from the vantage point of an experienced clinical trial researcher. We originally received this paper in 2020, just in time to celebrate the 60th birthday of the HRSD. Our review process and production scale was disrupted by a small event known as the CoVID19 pandemic and here we are, publishing two years later. I suspect that Professor Hamilton would have been more understanding of the delay than Sir Aubrey Lewis. And, if possible, he might have even sent Dr. Rosenberg a handwritten note to congratulate his accomplishment.

Michael E. Thase

May 5, 2022