Posted on Monday 23 November 2015

This post is just a remark about history, some of it my own. I wasn’t always a psychiatrist. I started my medical hegira as an Internist, and my first experience practicing was on an overseas Air Force Base seeing active duty soldiers and their dependents [only by referral]. There were a lot of symptoms, and a lot of negative work-ups – people whose psychological difficulties were expressing themselves as physical symptoms and complaints. I got right good at figuring that out, and listening to the stories [many becoming increasingly complex the longer I listened]. "So this is what depression is," I thought naively, and I began my abbreviated career as a jake-leg psychopharmacologist using the Tricyclic Antidepressants of the era [the patients thought that going to a mental health clinic had a negative impact on promotion, so they just wouldn’t go, neither active duty nor their dependents]. At the time, I didn’t know what follows – a couple of key pieces to the story of how the antidepressant drugs came to be:
by Walter A. Brown, M.D. and Maria Rosdolsky, M.D.
American Journal of Psychiatry. 2015 172[5]:426-429.

The major classes of psychotropic drugs were introduced in an extraordinary decade of discovery between the late 1940s and late 1950s. In the present climate of pessimism about the absence of new drug development, it may be instructive to look back at the research methods used during that era. The study that identified the first antidepressant is a case in point. It was conducted by Roland Kuhn, a Swiss psychiatrist working in a remote psychiatric hospital. Kuhn, like the other pioneering researchers of his day, was given access to new drug entities, and the method he used to discover their clinical effects was open-minded, exploratory, comprehensive, clinical observation…

By today’s clinical research standards, Kuhn’s method of unfettered, exploratory, clinical observation was substandard, haphazard, even messy. Yet it produced a major breakthrough—the discovery that a drug can alleviate depression—that has had a lasting impact on the treatment of depression and on the development of antidepressant drugs. Kuhn’s experience might usefully inform our strategies of drug development.
[The graphic is my rendition of Kuhn’s guestimate about response rates]
from Kuhn’s original report:
Über die Behandlung depressiver Zustände mit einem Iminodibenzylderival [G22355]
by Kuhn Roland
Schweiz Med Wochenschr 1957 87:1135–1140.

Symptoms of depressive mood that are obvious when observing the patient’s appearance often improve significantly under treatment with G22355. The facial expression loses rigidity, modulation and expression abilities return. The patients become livelier, the depressive whispering becomes louder, patients become more communicative, and moaning and whining can no longer be heard. If the patient was discontented, querulous or irritated, he changes into a friendly, content and amenable person. Hypochondriac and neurasthenic complaints are no longer dominant or disappear completely. Patients who had great difficulties in getting up in the morning, get out of bed early with their own initiative, at the same time as other patients. They initiate relationships with other people, start conversations, participate in the daily life of the clinic, write letters, and are again interested in their family matters. They start working spontaneously, get their work done, and the slowness in their life is replaced by a normal vitality. With these improvements, the patients become popular in the ward. Their mood and behavior appear to be balanced. Several times, family members were fascinated and told the physician that the patient had not been in such a good condition for a long time.

Most of the time, the patients notice the change, report it, are, of course, very joyous about it and talk about a miraculous cure. The feelings of heaviness, tiredness, weakness, depression, inner tension, rigidity and restlessness subside. The patients feel free again, inhibition of thoughts and activities disappears, thoughts and activities return. A sad, depressed, desperate and fearful mood turns into a neutral unburdened or somewhat cheerful mood with the feeling of healing and increasing strength. Feelings of guilt, delusions of impoverishment or culpability simply disappear or lose their affective importance, move into a distance, and the patient becomes indifferent and unconcerned with respect to these feelings. It happened that a pronounced suicidal intent of a patient suddenly disappeared! If sleep was disturbed by depressive symptoms, it normalizes quickly without sleep-inducing medications, even in cases who did not respond to common hypnotic agents. Nightmares, sometimes occurring in depressive people, with blood, dead bodies, terrible accidents, and gruesome atrocities, frequently accompanied by terrible fear, no longer occur under the treatment. Morning moodiness and other daytime fluctuations of the depressive state are no longer observed. If the patient had no appetite, his appetite returns. Sometimes, constipation due to depression improves.
And here’s the first ever controlled clinical trial of Imipramine:
British Medical Journal. 1959 2:5199:1052-1055.

All the cases included in the trial were out-patients, and anyone showing gross retardation or extreme agitation and those in whom the risk of suicide was considerable were automatically excluded, as they were admitted for in-patient treatment. Nevertheless, a number of the patients included were quite severely depressed…

The results of treatment were assessed as symptom free, greatly improved, somewhat improved, no change, or worse. For the purpose of assessing the value of the drug as a significant therapeutic agent, the first two of these categories have been combined as a good or worth-while result and the other three as a poor result. Patients showing a good result were able to return to their normal activities without undue effort…

Of 55 cases of endogenous depression treated, 27 received imipramine and 28 the placebo. On imipramine 20 responded well, while 7 did badly. On the placebo, 6 did well and 22 badly. This is a highly significant difference, and, with Yates’s correction applied, P<0.01. Of the 42 cases of reactive depression 22 received imipramine and 20 the placebo. Of those given imipramine 13 were improved and 9 were not; while of the 20 controls 4 improved and 16 showed a poor result. This, too, is a significant result [P<0.02]. When improvement occurred it was nearly always evident by the end of the third week,  sometimes as early as the fourth or fifth day. The mean was 9 to 10 days…
Back in those days, I didn’t see anything like Dr. Kuhn’s kind of response to the TCAs – not even close. There were more psychiatrists on our base than internists, busy doing Air Force things. One was a draftee like me and a friend – a very thoughtful guy. I told him about my lackluster experience with the TCAs. He asked me about the cases. After telling him about a number of them, he said he thought I was seeing a lot of people with bad life situations, or neurotic people, or personality disorders, or homesickness, etc. – a lot of unhappiness – but not many people who were clinically depressed. He suggested I do some reading. I took his suggestion [and I’m still at it], but I sort of got his point. I had been using the term depression in an imprecise generic way – expecting a drug to work because of the moniker "antidepressant" without really understanding what either really meant.

Flash forward: A few years later, I was in a psychiatry residency, spending my first year on inpatient units, and I had the second version of my thought, "So this is what depression [really] is." It wasn’t a reported symptom or a way of saying "my life’s a mess". It was something you could see, even feel, as soon as the patient walked into the room. And the distinction made above between Endogenous and Neurotic Depression wasn’t severity – both were severe. I don’t think I had ever seen that kind of palpable depression before my psychiatric residency program except in the occasional patient on Reserpine. But in those days, I understood what my friend had been trying to tell me back on the base a few years earlier.

And in that first year of residency, I did see the kind of dramatic results Kuhn described in this group of patients. I didn’t keep up with the numbers, but the Number Needed to Treat [NNT] of 2 or 3 feels right. I’ve only seen a few in the decades that followed. I just wasn’t in a setting where such patients end up being sent. And when I did see a case, it was only to refer them to someone with in-patient privileges and experience. Whether they were treated in the hospital or not, their treating doctor needed the hospital back-up in case of emergent suicidality. In-so-far as I know, the treatment of these patients has not changed in the forty years since I started in psychiatry. I think that’s remarkable…
    Bernard Carroll
    November 24, 2015 | 2:42 PM

    Well, for 35 of those 40 years the endogenous or melancholic depressions were de-emphasized in what DSM-III called major depressive episode. Little wonder that little progress in treating them has occurred. They are a minor part of the overall depressed population and Pharma had no interest in anything but blockbusters for the much larger MDE pool.

    The difference between endogenous and neurotic (or between melancholic and reactive) depressions is obvious when we see classical cases of either subtype. In practice, clinicians displayed low reliability for making this differential diagnosis in too many fuzzy cases. And let’s not even speak of the situation in primary care! But any clinician who has encountered a patient with endogenous/melancholic depression and who has seen the Lazarus-like response to effective treatment is in no doubt that subtypes matter.

    November 24, 2015 | 3:51 PM

    I know this wasn’t that much of a post, but I really enjoyed reading Kuhn’s paper and his description of the response. These patients are very ill, and I’ll bet he was turning cartwheels to have a way the ‘set them free.’ I’ll also bet a lot of readers who have followed the ins and outs of “KOL psychiatry” haven’t seen the kind of response one can get with these drugs [when they’re given to the right person in the right dosage in the right setting]. No statistics required – as Dr. Carroll says, Lazarus-like response. To my mind, the KOLs have not only oversold the modern drugs, they’ve denigrated and marginalized the illnesses where careful diagnosis and appropriate treatment is actually as advertised. Another more recent place where that’s equally apparent is in the modern treatment of Catatonia with Benzodiazepines. Again, it may not sound like a big deal, but when you see how ill these patients are and see the symptoms ‘melt,’ it’s a major breakthrough…

    Joseph Arpaia
    November 26, 2015 | 2:23 PM

    There is a difference between someone who is severely depressed without much going wrong in their life and someone who is severely depressed because of marital distress, oppression at work, severe financial stress, a child who is addicted to drugs, severe pain, … . Most “major depressive disorder” particularly in people from a lower socioeconomic class is really “adjustment disorder with depressed mood”. Antidepressants are somewhat of an emotional analgesic for the latter, but not all that helpful. Its amazing how often I see a depressed patient who is unemployed improve after getting a job that pays a living wage. From my perspective the rise in anxiety and depression parallels the rise in parasitic capitalism or “economism” as it is sometimes called.

    November 27, 2015 | 10:56 AM

    In private outpatient psychiatric practice I have lost since lost confidence in my ability to predict which patients with depressive symptoms will respond to antidepressants. Solution? A trial of medication for just about everybody with significant symptoms of anhedonia, anergia, depressed mood, sleep disturbance(especially middle stage insomnia) and feelings of helplessness, hopelessness and being overwhelmed. I initiate medication in such patients regardless of external circumstances and previous personal problems or childhood trauma. Thinking that adverse life events are “a reason to be depressed” and withholding medication as a result is in my opinion a serious mistake. I should know. I have done it – only to be amazed at the occasional improvement in such patients when another physician gives them an antidepressant.In short, when in doubt, medicate for depression. If it doesn’t help, and if a trial of another agent is not indicated or, if undertaken, does not help, stop the medication. Psychotherapy can proceed while this is going on.

    In many years of outpatient practice I have yet to see a single patient harmed by an antidepressant(excluding, of course, suicides using tricyclics). I do not believe the claims and warnings that antidepressants CAUSE suicide or thoughts of suicide.

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