Antidepressants - Going Backwards: HISTORY of Depression and Antidepressants

Ethan: A little background about the ancient history of depression up to modern times. So depression is actually a much more modern term that replaced a previous term called melancholy or melancholia. Babylonian texts described this as ‘distress’, the Sumerians as ‘cutting off or shortening of life’. Texts from King Hammurabi, circa 1792 BC, describe it as a spiritual condition, with anorexia, weakness and weight loss, impaired concentration and memory, insomnia, symptoms of depression that are more consistent with what was previously termed melancholy, or biologic depression.

From the 5^th to the 3^rd centuries, BC, Greek medical texts also describe it as melancholia. From Hippocrates days in the Christian Church, physicians and ministers in Europe, in the 17^th and 18^th centuries debated whether melancholy was a serious, but treatable, medical, or psychological illness, an inherent temperament, or a temporary and often understandable feeling. And whether or not it was related to other forms of mental illness, such as mania.

Lucky for us, we've come a long way in how we treat depression and melancholy. Treatment in ancient times consisted of beatings, physical restraints, starvations, and other attempts to drive demons out. Hippocrates favorite treatments were, a little bit nicer, bloodletting, baths, exercise, and diet changes. In the middle ages, depression was attributed to the devil or demons or witches, with treatments such as exorcisms, drownings, burning, locking people up in asylums. In 1621, Robert Burton, an English author and fellow of Oxford University, who suffered from melancholy himself, published, ‘Anatomy of Melancholy, describing it, and I quote, ‘I write of melancholy, by being busy to avoid melancholy. There is no greater cause of melancholy than idleness, no better cure than business. Melancholy was a disease so frequent in our miserable times, as few there are that feel not the smart of it. So universal a malady, an epidemic disease that so often, so much, crucifies the body and mind. He further describes it as obsession to delusion, putting forth several remedies then saying they are all useless, in characteristic self contradiction.’

At this time, newer treatments began to emerge, diet changes, enemas, horseback, riding vomiting, spinning stool to put the brain contents back into their correct positions. I can only imagine recommending to a patient now to sit on a spinning stool and tell them that it will fix their depression. Ben Franklin developed an early form of ECT or ElectroConvulsive Therapy, and tested it on himself. He did lose memory for the incident and was confused afterwards, but felt strangely elated and unusually sharp the next morning. In the early 20^th century, lobotomies produced a calming effect, though they destroyed executive function. Early 19^th century, psychiatry merged. Emil Kraeplin distinguished manic depression from dementia precox, now known as schizophrenia, and melancholy became depression shortly after. Sigmund Freud reported it as being a response to loss, either real or symbolic, the failure to achieve a goal. The person's unconscious anger over their loss led to self-hatred and self-destructive behavior. Behavioral theories emerged, suggesting that depression is a learned behavior and could be unlearned. In the 1960s and ‘70s, Aaron Beck helped to develop cognitive theories of depression, saying the way that people interpret negative events could contribute to symptoms of depression. Martin Seligman later suggested that learned helplessness could play a role in the development of depression, as people give up on trying to change their situation. In the 1970s, medical model of mental disorders emerged, suggesting that all mental disorders primarily were caused by physiologic factors that can be treated with medication, focusing on genetics, brain chemistry, hormones, and brain anatomy, all playing an important role in the development and increased use of antidepressants in the treatment of depression.

There have been multiple shifts over the last 75 years in what's considered a first-line antidepressant. In the 1950s, Isoniazid, a tuberculosis medication, was found to help treat patients with both depression and tuberculosis. Isoniazid’s mechanism of action was reverse engineered to discover it had MAOI activity. Isoniazid is problematic as an antidepressant, because it's an irreversible and non-selective MAOI inhibitor, which means it could result in hepatotoxicity, hypertensive crisis, and brain bleeds, and there were better options in the same class. Around 1956, Ronald Kuhn investigated Imipramine in extended studies and was able to show effectiveness. Imipramine, like Clomipramine, are two tri-cyclic antidepressants that have dual action on serotonin and norepinephrine. In 1961, Frank Ayd, showed that Amytriptyline, or Elavil, had similar effects to Imipramine, and that was followed by a whole host of marketing these tricyclic antidepressants. Desipramine, Nortriptyline, Doxepin. TCAs were also found to have some impact on anxiety, migraines and chronic pain, though they also had some pretty serious cardiac side effects in overdose. What I was taught is that a patient could take 8 to 10 times their effective dose and potentially have a fatal cardiac arrhythmia.

In the 1970s, 5 new SSRIs were designed by 5 different pharmaceutical companies and weren’t put into practice until the eighties. These were Fluoxetine, or Prozac, Fluvoxamine, or Luvox, Paroxetine, or Paxil, Sertraline, or Zoloft, and Citalopram, or Celexa. Since the emergence of the SSRIs in the United States, we've abandoned using more effective medications for depression, the MAOIs, which have more activity at more monoamines because they block the re-uptake of all the monoamines.

Ken: The recognized side effects of a drug are inversely proportional to the time for which it's been available, Gilman's Axiom number 13. People are so naive about this sort of thing. I never used SSRIs by themselves because it was obvious from large numbers of patients like that who'd got better with Amitriptyline or Clomipramine, that got worse with SSRIs, and had just as many side effects and had difficulty getting off them.

Ethan: At the same time, the classification of depression has been extremely watered down. I saw a really interesting study, maybe not the most scientific, but a survey of 242 teachers. By their mid thirties, according to DSM 3 criteria, 79% of them would qualify as being depressed. This watering down of the diagnosis over time, taking out sub classifications of depression, has led to less reliable treatments. Lumping every patient with depressive symptoms together, as opposed to parsing out what we can sub classify very basically into neurotic depression or situational depression and biologic, AKA genetic, or melancholic depression; tell us a little bit about how that treatment arc over time has evolved and what impact do you think it has on the treatment of depression.

Ken: I think it's got a lot to do with the things we've already talked about; the power of the drug companies, the insensitivity and inappropriateness of the rating scales and the way the trials are done, the dominance of RCTs. The blurring of the diagnostic criteria and lumping everything together, that obviously inhibits your ability to understand mechanisms and causality and therefore do proper science. The whole thing just becomes a joke. Add to that, the fact that, the whole sociopolitical climate has become risk averse, and that particularly applies to medicine. So it seems to me, sort of product of advertising and heaven knows what else, that everybody expects something to be wonderful, but not to have any problems. Medicine doesn't work like that; the more powerful a drug is, the more likely it is to have side effects. So what's happened in relation to what you were explaining, Ethan, is that the diagnosis has become blurred, the way of measuring improvement is not very satisfactory at all. As a result of that, you've got no proper, concrete outcomes. Drugs that have minimal side effects, get over the line to be accepted by the FDA, and practicing clinicians don't realize that the older drugs actually produce a much better result, because they've been persuaded that you can't take any risk, you're gonna get sued if you do this or you do that; they follow the guidelines and give these supposedly safe drugs. I actually described this as being the Anodyne Era - don't do any harm, but don't do any good either - that really seems to me to sum up negative versus positive risk. The psychologists have described the phenomenon, Risk of omission, the risks of doing something because of the treatment you've given, like a side effect, are rated much more highly than what, in fact, is the much more important risk of not treating people properly and therefore they commit suicide. But because that's a risk of omission, people are able to forget about it, or it wasn't my fault. And I think that's disastrous. It's just a misunderstanding of risk.

I'll give you an example of the tricyclic antidepressants. I remember a little while ago, probably in the early ‘90s, some barrister or QC in Australia, wrote a letter to one of the journals in collaboration with an associate professor in Melbourne, that argued the mere prescription of a tricyclic antidepressant was negligence because they were dangerous compared to these wonderful, safe new drugs. And I thought, ‘What a spurious argument.’ If you really believe somebody's suicidal, they should be in hospital. If they won't go into hospital and you don't think they're sectionable, so to speak, or you're not gonna try to compel them to go into hospital, then you don't give them three months supply of the drug and say, ‘Bye-bye. I hope this works.’ You give them a small supply and say, ‘I'll see you in three days time or seven days time, or whatever,’ and you find somebody responsible to look after the drugs if possible, et cetera, et cetera. So there are all sorts of simple, practical, good clinical practice measures that you can take to make sure that somebody who you think is suicidal is not going to be able to do it.

Another point in relation to that whole argument is, what proportion of patients who commit suicide use their prescription drug in order to achieve that objective? Obviously it varies a bit from time period to time period and jurisdiction to jurisdiction, but generally speaking, if you look at all the figures that are available, it's actually a very small proportion of people who successfully commit suicide, who use the drug that's prescribed. And that usually, of course, isn't antidepressants, it's benzodiazepines. So alcohol and benzodiazepines probably account for most of it a lot of the time. So this argument that the tricyclic is what's gonna kill them is again a very weak argument. It's a question of the area under the curve. If you are using an anodyne treatment like an SSRI, which doesn't really work very well on the percentage of patients, especially with severe depression, who failed to respond to SSRI, is very considerable, then the time period which they're at risk for suicide is enormous until somebody eventually gives them an effective treatment. Whereas if you give them a tricyclic that works like Clomipramine, after three or four weeks, their risk of suicide is much diminished. So the time period that they're exposed to risk is much shorter. So the total risk is hugely less. An interesting statistic that, I've never heard anybody else comment on this, if you look at the Fatal Toxicity Index of all these different drugs, that is the difference between the therapeutic dose and how much you have to take to harm yourself, of course for Tricyclics, that's a somewhat narrower margin than it is for most, not all, but most of the newer drugs, like SSRIs. But, take Clomipramine, so the FTI is higher, but if you look at the prescription rate in the population and you take a 100,000 people who've been treated with Clomipramine and you compare them with a 100,000 people who've been treated with various other antidepressants, what do you think you find? You actually find that far fewer patients on Clomipramine commit suicide despite the fact it's got a higher Fatal Toxicity Index if you take an overdose? I find it very difficult to imagine an explanation for those very reliable observations other than the fact that the reason people don't take an overdose of it is because it works better and they feel better, so they're not suicidal anymore.

Ethan: Prescribing based on fear as opposed to considering both your fears about a medication and also their likelihood of being effective to prevent the bad outcome.

Ken: And, of course, fear is very frequently irrational. That's exactly the case with MAOIs. People's avoidance of them is based on ignorance and fear. I compared it to children going to a haunted house, ‘I've seen a ghost, I've seen a ghost, I saw a case of this, or it does this, it does that.’ It's pathetic. Get up to speed. Learn about it.