Depression is not a chemical imbalance

Depression is not a chemical imbalance–that’s what the best data on the subject suggests.

Now please don’t misunderstand me. I believe that major depressive disorder is inherently biological. I just remain unconvinced that brain chemistry alone tells us much about depression. At it’s best, the “chemical imbalance hypothesis of depression” is an outdated theory. More cynical observers might say that it’s an oversold marketing message.

The belief that depression is a chemical imbalance comes from a misunderstanding of the monoamine theory of depression. According to this theory, depression is caused by dysfunction in one of the monoamine neurotransmitter systems. These neurotransmitters–serotonin, norepinephrine, and dopamine–are certainly related to mood, but changing the absolute levels of these chemicals in the brain has not been consistently shown to affect mood. Correlation (as I’m sure you’ve heard) isn’t causation.

The most convincing argument against the chemical imbalance hypothesis comes from clinical research into antidepressants. The most commonly prescribed antidepressants are the selective serotonin reuptake inhibitors, also known as the SSRIs. Within hours of taking these drugs, the effective level of serotonin is increased at every serotonin-containing synapse in the brain. But unfortunately, patients who take SSRIs feel no better than patients taking placebo for at least 2 weeks (and realistically, it takes most people 4-6 weeks to really start feeling any effect at all). If depression was caused by a simple chemical imbalance, we’d expect a much more rapid response. And this long time to effect happens with all FDA approved antidepressants, regardless of their action on the serotonin, norepinephrine, or dopamine systems. (I’ve heard some well-meaning doctors tell their patients that the drugs take 4-6 weeks to reach a significant dose in the bloodstream. However, the vastly different half-lives of these drugs and the remarkable consistency in their time to effect argues strongly against this explanation.)

So what causes depression? Depression seems to be related to dysfunctional brain circuitry. A depressed person may very well have problems with one of the monoamine neurotransmitter systems, but it is the system that is impaired, not necessarily the chemical concentration. For recovery to occur, neurons in the brain must find a way to appropriately reconnect with each other.

Thankfully, the brain is remarkably resilient. While as many as 20-40% of the population will experience at least one episode of major depressive disorder, a surprising number recover without any treatment. This isn’t to say that treatment doesn’t work (it does) or that the risk of untreated depression is trivial (it isn’t). It’s just to point out that the brain has mechanisms in place to rebuild dysfunctional synapses. And if you really want to kickstart recover, every known treatment for depression has been shown to increase the levels of neuronal growth factors. The most well known of these factors is brain-derived neurotrophic factor (BDNF), and it is increased by antidepressants, talk therapies, electroconvulsive therapy, and even experimental treatments like ketamine. However, the diverse targets of these therapies may trigger growth in different regions in the brain, which could explain why certain people respond better to one treatment than another. In most cases, the best initial treatment is a combination of antidepressants and cognitive-behavioral therapy.

Why does it matter that we stop talking about depression as a chemical imbalance? For one, an accurate understanding of science matters. When you realize that depression is caused by impaired brain circuitry, it makes sense that depression arises from a combination of genetic, environmental, and psychological factors. On a more human level, calling depression a chemical imbalance trivializes the disorder. A chemical imbalance sounds like something that can be rapidly reversed. It makes us think that there is a magic pill that can quickly fix things. It’s the biological equivalent of the words “why can’t you just snap out of it.” Overcoming depression–especially severe depression–takes time and appropriate treatment. Finally, thinking of depression as a problem with circuitry helps us conceptualize depression as a complex set of disorders with unique causes, manifestations, and treatments. It gives us a reason to approach all sufferers as individuals that cannot be treated with a one-size-fits-all approach.

This model of depression isn’t perfect, and my explanation is, of course, a gross oversimplification. But when we recognize that depression is a circuit problem, it enables us to take some responsibility for rebuilding and maintaining the circuitry that brings us happiness. This is what cognitive-behavioral therapists have been telling us all along. By learning how to combat the thought and behavior patterns that worsen depression, you can help yourself rebuild the faulty circuits within your own head. Conquering depression often takes the help of competent professionals, but recovery without learning to help yourself is almost impossible.

Why I’m Blogging

I hear a lot of good and bad things about blogging. Some people say it’s a waste of time–and I certainly see how it could be. I started blogging with a modest goal: to enhance my own learning. Writing makes me encapsulate what I learn into meaningful chunks. I can’t promise that what I’ve written will be helpful to anyone else, but it has been extremely useful to me. Now that I have a few posts under my belt, I’ve decided to lay out three main goals from this blog.

1. To learn how to write. My training has focused on technical writing–and I finally feel like I’m becoming comfortable with that style. I love how technical writing emphasizes clear communication of complex concepts. I can’t imagine a better format for writing as a professional. However, my skill at writing to a broader, non-technical audience is much weaker. I struggle to explain what I think with clarity. Hopefully, this blog will help me learn how to write in a crisp, authentic way.

2. To connect with others. There are so many smart people working on difficult problems within the behavioral health community, and I want to learn from them. I believe that there is immense innovation in the pipeline from patients, consumers, doctors, therapists, allied health professionals, academics, and entrepreneurs, and I want to be here as it unfolds. If you’re reading this, I’d love to get to know you better!

3. To advocate for better behavioral health. Behavioral health is misunderstood and often maligned–even within the broader healthcare community. There are many voices for good, and I want to add mine to the conversation. I don’t have many answers, but I am passionate about finding and implementing better solutions.

9 surprising facts about weight loss.

In my last post, I talked about the importance of behavioral change in preventing early death. This post is the first in a series looking at the evidence behind changing health-related behaviors.


It seems like every other commercial is for a product promising miraculous weight loss. If you’ve ever wondered what actually works, you aren’t alone. In fact, there was an article in the New England Journal of Medicine entitled “Myths, Presumptions, and Facts about Obesity.” That’s right, there is so much misinformation floating around that the authors felt that doctors needed things spelled out more clearly. I picked a few of these ideas out of the article to give you a flavor of what the best research is currently showing.

There is a caveat here. This article is entirely based on results confirmed in randomized controlled trials. That means that each of these facts has been demonstrated by randomly assigning people to groups, providing a different intervention to each group, and then measuring predetermined outcomes. It’s a slow, expensive process, but results from randomized controlled trials are the strongest form of medical evidence, which means that these observations typically trump experiments that happen in test-tubes, animals, or simpler human studies. I’m confident that there are exceptions to all of these rules, and that our understanding of these results will become more nuanced as we gather more data. But for now, these facts are based upon the best data we have.

1. Small sustained changes don’t necessarily produce large, long-term changes in weight.

You’ve heard the mantra: one pound of fat produces 3500 calories of energy. Therefore, if you decrease your caloric intake or increase your exercise by just 100 calories per day, you’ll lose about a pound a month so long as you keep doing that. But the data don’t support this notion. Initially, you will see this level of weight loss, but your body is remarkably effective at keeping your weight where it is. As you lose weight, your body requires fewer calories, making it harder to lose weight if you remain at the same caloric intake. While you might expect to lose 50 pounds over 5 years by cutting out 100 calories a day, studies predict that you’ll probably only lose 10 with this strategy.

2. Weight loss goals don’t need to be realistic to be effective.

Setting a realistic goal gives you a more realistic expectations about how much weight you will lose. That’s nice, but it has no effect on the amount of weight you will actually lose. In fact, some studies suggest that people with ambitious goals tend to lose more weight than those with more modest targets.

3. There is no advantage to trying to lose weight slowly. 

Slow and steady wins the race, right? Not with weight loss. In the short term, people who lose weight more rapidly lose more than people who lose weight slowly. In the long term, both groups tend to lose about the same amount of weight.

4. Weight gain and loss are influenced by both genetic and lifestyle factors.

There is absolutely a genetic predisposition towards obesity. That has become increasingly clear over the last few decades. However, genes are only one variable in the obesity equation. Lifestyle plays a significant role in your weight. And unlike your genes, you do have some level of control over your lifestyle.

5. Diets often work for short-term weight loss, but don’t expect the results to stick around for long.

Enough said. You already knew this, didn’t you? :)

6. Exercise is good for you even if it doesn’t result in weight loss.

Exercise is good for you! In the right dose, it is a well established tool for maintaining a healthy weight. But even if it doesn’t help you shed pounds, exercise is valuable for fighting off some of the ill effects that come from excess weight.

7. If you’ve lost weight and want to keep it off, your best bet is to continue your current weight loss program.

If you want to keep the weight off, you have to keep doing what you are doing. In this sense, obesity is a chronic condition, in that it must be managed through long-term behavioral change. More than anything, I believe that this is the reason obesity is so hard to treat.

8. Structured meal planning (including meal replacements) can be effective tools for weight loss.

While eating a balanced diet containing a variety of foods is sure to be exciting and delicious, this strategy alone is not very effective for weight loss. Consciously choosing to eat less in a structured manner, however, does work. There are a million products that will offer to do this for you and the principle behind them is sound. Deciding which one (if any) is best for you is an entirely different matter.

9. For the right person, bariatric surgery can produce long-term weight loss and a longer life.

Have you ever heard of a gastric bypass, lap band, or stomach stapling? It turns out that these interventions actually work. They are certainly not for everyone, and they come with a litany of potentially awful side effects. However, in the right person, these procedures are almost miraculous. Some critics will tell you that choosing bariatric surgery is “taking the easy way out.” Nothing could be further from the truth. Bariatric surgery requires an incredible commitment to a strict dietary program and prolonged nutritional supplementation. It may enforce dietary changes through increased satiety and horrible symptoms after binge-eating, but it does not in any way represent an easy way to weight loss. Choosing bariatric surgery is not a moral failing. These patients are incredibly courageous. They take drastic measures to improve their health, and I have nothing but the highest respect for anyone who receives this intervention.

I’ll go into more depth about many of these ideas in the future. For now, I highly recommend that you just read the paper. And since the paper isn’t behind a paywall, you really don’t have any excuse not to!

Behavior is the wild west of medicine

In 2010, I was getting ready to graduate from college and start medical school. I was excited for the a new challenge and confident that a career in medicine would be a way for me to make some small impact in the world. Medicine, it seemed, was the ideal way to help. And then I stumbled upon some data that really bothered me.

It came from a review article in the New England Journal of Medicine–the flagship journal for clinical research. Among other ideas, it revealed that healthcare plays only a minor role in preventing premature death. Behavior, it turns out, has a much bigger upside for preventing death than just about anything else we can do. And among causes of premature death linked to behavior, obesity and smoking are far and away the biggest opportunities to really make a difference. The actual delivery of healthcare is a fairly minor factor in how long people live.

5-26-2014--Contributions to Premature Death

Modified from NEJM

Fortunately, most physicians get this. They know that behavior is important, and they try to talk with their patients about smoking cessation, exercise, diet, and illicit drug use. But we are still failing to move the needle in producing substantial behavioral change. Part of the reason for this is that many behaviors are really, really hard to change. Another reason is that evidence-based behavioral change therapies are few and far between–especially regarding obesity. Physicians also receive very little training about how behavior and its determinants should be approached. Likewise, their appointments tend to be shorter than they’d like them to be, preventing them from addressing every issue they want to cover. Some have even lost faith in behavioral change and focus their attention in a manner that reflects this. Whatever the problem may be, the evidence suggests that physicians have a long way to go in promoting better behavioral health.

Some might argue that it is the job of public health professionals and policy makers to address these issues. I agree wholeheartedly. These problems are complex enough to require a system-wide approach. However, I don’t think that the medical community can pass the buck onto others. We need to be at the forefront of the design and implementation of behavioral health strategies. Because realistically, helping patients to quit smoking, lose weight, and even just to take prescribed medicine may be the most important things that can be done in a routine doctor’s visit.

These challenges are tough. I don’t expect that we will find many easy solutions. But I do believe that discovery and implementation of effective, evidence-based behavioral change therapies is one of the most pressing concerns in medicine today.

Over the next few weeks, I’ll be looking into the literature to find out about therapies that actually do work for behavioral change. I’m planning to write about therapies for smoking cessation, obesity, alcoholism, medication compliance, opiate addiction, and motivational interviewing (I’m not going to make any promises about a particular order). Let me know if there is any other treatment that you are curious about.

How many states reduced their suicide rate in the last five years?

Think about it for a moment before you read on. I was expecting that a few states would have improved, but that the paucity of public funding for mental health would ensure that a big difference hasn’t been made. I was still shocked to learn that not a single state (including Washington D.C) was able to meaningfully reduce their suicide rate over the last 5 years. Suicide rates actually increased in 18 states!

5-5-2014--Suicide-Rates

Modified from JAMA

The data come from the Commonwealth Fund. A nice summary is published in the Journal of the American Medical Association. Surprisingly, neither of these articles even mention suicide rates in the body of the text. I don’t believe that there is a magic bullet that will help us fix this problem, but I know that nothing will happen until we start seriously talking about suicide in the United States.