Long-Term Effects of Anti-Depressant Drugs


How antidepressants affect the long-term course of depression. How does a drug treatment affect long-term outcomes? You got to go back to the Hippocratic oath. What does he say says - do no harm. What does that mean? Don't make your patients worse!

They come in at a certain level, don't give them a treatment that makes them worse five months later. What Hippocrates was saying, we in nature often have a natural capacity to recover from an illness, say depression, and your treatment in order to not do harm has to improve on that natural capacity to recover.

Imagine this just to understand this a bit better. Imagine you have a disease, people come in at a certain baseline of the symptoms, you give them a treatment. 50% are cured and 50% stay the same, their symptoms stay exactly the same - no one gets worse. But you cured 50% of your people with your treatment. Have you met your Hippocratic oath?

No! The point is, imagine in nature if 70% or 80% are cured. Your treatment has knocked down the cure rate from 80% to 50%. Until you know the natural recovery rate you can't assess the merits of your therapies.

The normal method of testing for the efficacy of drugs doesn't touch this at all over the long term. We just have these things six-week trials, you take it against the placebo and if it's a little better than placebo over the short term we say it's effective. Six weeks has nothing to do with long-term outcomes.

The first thing we have to do is figure it out what's the natural course of depression? What were scientists or research is saying what was the course of depression prior to the arrival of the antidepressants?

First of all, depression at this time was seen as mostly a disease a disorder of the middle-aged and elderly. Depression was basically middle-aged and up.

Depression Treatment Before Antidepressants

What was the prevalence of depression prior to the arrival of the drugs? Fewer than one in 1,000 suffered a clinical depressive episode each year.

Very few people were actually hospitalized for it in 1955 with only 7,000 first admissions.

Here's the course of medicated depression, both short term and then long term. What they found in these hospitalized cohorts is that after 10 months these are very depressed patients that 85% would be discharged and their depression would have lifted within 10 months. By the end of 10 months, it'd be about 85% percent and they would recover to what is known as the absence of depression.

These are comments by the leading depression experts in the countries in the 1960s who know that data. What did they say? "We can expect recovery. Most depressions are self-limited. Regardless of what one does the patient eventually would begin to get better. Most episodes will run their course and terminate with virtually complete recovery without specific intervention."

Because of this understanding of depression, the idea was we'll use antidepressants to speed up a natural recovery process.

How about long-term outcomes in the pre-antidepressant era? You'll see studies where people were hospitalized. You follow people, they've been hospitalized, then discharged. You follow them for 15-20 years, you'll find that about half of those patients never had another episode that required rehospitalization.

Again, this is a very depressed cohort. About 30% over the course of 13-15 years might have two to three episodes that require hospitalization.

You can also see that about 20% of the hospitalized cohort that became chronically ill.

The leading researcher on the long term course of depression writes in 1969: "Assurance can be given to a patient and his family that subsequent episodes of illness after first mania or the first depression will not tend toward a more chronic course."

There was an understanding that it was an episodic course.

Treatment Of Depression With Antidepressants

Let's move into the antidepressant era. –°linicians have started using these antidepressants in the 1960s. If you go back to what they say you start seeing this odd thing: "My patients are getting better faster, but are they relapsing a lot more back in the depression than they used to."

Right away with the introduction of these drugs you see this worry arise that there might be a paradoxical long-term effect that drugs, in fact, that help people with depression might predispose people to relapse back in the depression more frequently than before.

The Dutch psychiatrist has found in 1973 that it looks like antidepressants quote exerts a paradoxical effect on the recurrent nature of the vital depression. In other words, this therapeutic approach was associated with an increase in recurrent rate more relapses. And a decrease in cycle duration that means the depressive episodes are coming more frequently. Should this increase be regarded as an untoward long-term side effect of treatment with tricyclic antidepressants?

My point is, we're gonna follow this story of science from the beginning as it comes in so we've got a couple points now. Clinical perceptions and the first test of this worry that maybe it increases in the chronicity.

Now they do a lot of studies looking at how fast people relapse after recovery from a depressive episode. By 1997 Harvard researchers had a lot of studies that have studied this.

It used to be about 15 years before 50% would relapse. Now, it's 50% relapse within 14 months. You see the shortening of that period in this data.

The longer the patient is on the drug, the more that are likely to have frequent relapses as they come off.

The NIH did a trial in 1980s studying psychotherapy methods with and without drugs. After 16-week study, they have found that there were no difference at the end of 16 weeks before the four groups except among the very severely depressed.

Then they do a follow-up 18-month study and found that stay-well rate is highest for psychotherapy lowest for the drug treated group.

The results look even worse - patients using antidepressant were most likely to seek treatment following termination, produced the highest possibility relapse probability.

In this big study in the 1980s, they saw most chronicity in the drug treated patients.

Imagine you're a scientist and there is someone who's an expert in mood disorders in the 1980s and you went to school in the 1960s. You were taught that depression is an episodic problem. Now you got data showing it's a chronic problem. What's going on? What is the course of mood disorders?

Here's what they say. “Improved approaches to the description and classification of mood disorders and new studies have demonstrated the recurrence and chronic nature of these illnesses and an extent to which they represent a continual source of the stress and dysfunction."

We have these new studies they're showing it's run a chronic course but they're not blaming it on the drug, they're saying those old studies were flawed and we finally found the true course of depression.

What's the difference? This is the course of medicated depression that they're seeing today. They're not seeing the old course of unmedicated depression but they're saying this is an advance in science.

The recognition of the conception of depression has changed in the modern antidepressant era. It went from episodic, most patients would eventually recover. Now we have these studies have disproved this shown that depression is a highly recurrent and pernicious disorder.

You see in their own minds they've reconcieved of what is the course of depression.

There is the largest antidepressant trial ever conducted. It was funded by the NIH 4041 patients and conducted in real-world patients. The results were so bad, they fabricated the results.

They announced that 67% of people eventually remitted. It's just not true. They actually looked about remission, according to the protocol criteria only 38% ever remitted.

This study will guide clinical care in the United States because this is in real world patients. It's not in what happens in so many of the FDA studies, who only allow certain types of patients in. Those studies really don't tell us about real world patients, this is going to do it.

We're gonna have two parts of this study, we're gonna show that if you keep trying, you can find a drug that works and then people will stay well.

When they have announced the one-year results, you just can't make sense of it. You know why you can't make sense of it? Because the study results were horrific. Out of 4,000 41 patients who entered that study and got the best clinical care possible, there were only 108 who remitted - the depression went away.

The real stay well rate was less than 3%. That's the worst outcome I've ever seen from any study of depression ever.

You can see that this is consistent with the idea that regular treatment in fact increases the chronicity the disorder and maybe inducing many people a low level chronic depressed state.

This was another such study with real-world patients. It's much smaller. In this study, only 26% responded to antidepressants. Only half who responded stay better, only 6% remitted and were well at the end of one year.

These are two the only two studies I know about in real-world patients in modern times. Both found very poor stay well rates at the end of one year.