Get over it: depression is real

“Get over it!”

I am not talking to the people who are clinically depressed and saying “snap out of it.” I am talking to the people who continue to question the legitimacy of major depressive disorders and I’m saying “get over yourself.” I can tell you right now that when you have close friends or relatives go through this, you will no longer try to explain away concerns by telling people that everyone has bad days, that they are simply tired and cranky, and that once they get fresh air they’ll realize life is just dandy.

Depression is a chronic illness and we need to treat patients – and their friends and families – with the respect and care they deserve. It’s like diabetes or high blood pressure: it’s real and it’s treatable. So, the next time someone asks you if depression is a real illness or someone being wimpy about their sadness, please set them straight for me. Further, if you recognize the symptoms we’ll talk about, dare yourself to start a conversation with the person you’re concerned about; as far as treatment goes, the sooner the better. (I’ve already talked a bit about how the Affordable Care Act will impact coverage of psychiatric illness. In the future, I promise you posts about alcoholism, anxiety, schizophrenia, and obsessive compulsive disorder. And, yes, you guessed it: these will all come to you from the perspective of someone who has friends and family who have suffered.) 

Back to the basics

A recent seminar at the medical school at Michigan left many students with questions (some as blatantly inappropriate as “when did we decide depression was an illness we should prescribe drugs for?”), so I’ll go back to cover a few basics. The Diagnostic and Statistical Manual of Mental Disorders (DSM) IV defines major depressive disorder as a syndrome, where the diagnosis requires a patient to have at least five of the nine symptoms, consistently, for more than two weeks. These symptoms are what you might presume: depressed mood most of the day, diminished interest in almost all activities, significant weight loss or gain, sleep changes,  physical agitation, intense fatigue, excessive guilt and feelings of worthlessness, diminished concentration and indecisiveness, and suicidal thoughts. For this post, I’m focusing on major, unipolar depression, but some of what we’ll talk about is also applicable to bipolar disorder, particularly given that people with bipolar tend to experience “lows” that are longer and more severe than the “highs.”

Over the course of a lifetime, 16% of people get depressed. That’s a lot. Of those people, only half get treated, despite what we now know about the host of associated problems, ranging from loss of productivity to increased cancer mortality. A few other interesting numbers: nearly 15% of women experience post-partum depression, about half of patients who have experienced a heart attack also develop depression, and more than a quarter of adult Americans suffer from a diagnosable mental disorder in a given year. Those numbers are so high that it’s essentially impossible that you don’t know someone who has dealt with mental illness.

Disease progression in depression is an interesting phenomena and it has much to do with brain chemistry, some of which remains incompletely understood. What we do know for sure, though, is that after one episode, there is a 50% chance of another depressive period; after a second episode, there is an 80% chance of a third. For the first depressive period, a relatively great stressor is required, but the threshold for stress lowers during subsequent episodes until eventually the trigger is endogenous. Suicidal thoughts and behaviors, arguably the most alarming symptom of depression, are actually more related to impulsiveness than severity of depression. In fact, hospitalization is basically recommended just to give patients the time to change their minds. In studies of people with suicidal intentions who had jumped off the Golden Gate Bridge and survived, it’s found that the vast majority changed their minds on the way down. Apparently for some people the impulsiveness passes rather quickly. And, no, I’m obviously not at all proud that our quintessentially Californian bridge is the world’s leading suicide site.

So what’s one to do? Think about treatment. And then start right away.

Behavioral changes are the first line of attack. Most doctors, psychologists, psychiatrists, and therapists will recommend changes in exercise, sleep hygiene, and the like. In conjunction with these lifestyle changes, cognitive behavioral therapy (CBT) can have enormously positive influences. What exactly is CBT? It’s the best thing since sliced bread (which actually sometimes gets stale, anyhow). CBT addresses specific maladaptive behaviors and thought processes, providing patients with explicit goals and systematic tools. It’s incredibly effective for a whole host of disorders, including substance abuse, eating disorders, and major depression. This – I promise you – is solid evidence-based practice. For many psychiatric illnesses, current environmental stressors are a much better predictor of disease progression than are early life factors. That is to say, recent life stress and chronic stress matter more than a dysfunctional childhood. Psychodynamic and Freudian types of talk therapy analyses are decidedly out of vogue…since they are ineffective and were never based on hard science. CBT, in contrast, won’t necessarily uncover all of your secret histories and deepest conflicts, but will give you concrete tools to take with you out the door and apply to your life, right that day. It helps you identify your own, specific, individual negative beliefs and behaviors and learn to replace them with positive, healthy ones. The principle of the therapy in some ways stems from the age-old advice that even if you can’t change a situation you can change the way you think and respond.

For many people, behavioral changes are not enough, though, as the brain chemistry is already too out of whack to rebalance itself without some help. There is nothing wrong with needing medication and taking it says absolutely nothing about a person’s intellect, personality or strength. If you are even remotely tempted to think otherwise, please feel free to join the rest of us in this century, along with common sense, decency, and science.

In case I get a reader who doesn’t speak Science (and since I’m not completely fluent in that language myself), we’ll stick with fairly basic information on drugs. The vast majority of doctors start off by prescribing a selective serotonin reuptake inhibitor (SSRI, such as Prozac), which increases serotonin in the synapse of nerves. To make a long story short, serotonin is a neurotransmitter that relays messages between brain cells that regulate mood, appetite, sleep, learning, and sexual desire. Interestingly, the biochemical change happens in hours yet the antidepressant effect usually takes weeks. We don’t completely understand the mechanistic pathways involved and we haven’t ever measured levels of serotonin in a living human brain. We’ve measured blood levels of neurotransmitters such as serotonin (and, yes, levels are lower in depressed people), but we actually don’t know how well blood levels correspond to brain levels. Additionally, there is dispute among researchers about exactly why SSRIs are effective, with some scientists claiming that it has less to do with the increased serotonin-mediated messages and more to do with a regeneration of brain cells that is induced by serotonin.

Other commonly used drugs include serotonin and norepinephrine reuptake inhibitors (SNRIs, such as Cymbalta) and norepinephrine and dopamine reuptake inhibitors (NDRIs, such as Wellbutrin). The pertinent biochemistry here is that norepinephrine is a stress hormone affecting attention and memory and dopamine is a neurotransmitter implicated in the reward-driven learning system. The rest of the antidepressants out there fall into one of three categories: tricyclic antidepressants (yup, the chemical structure has three rings; they’re not used much anymore), atypical antidepressants (they don’t fit neatly in another category; they’re often taken in the evening to help with sleep), and monoamine oxidase inhibitors (MAOIs, usually prescribed as a last resort since there can be deadly interactions with certain foods). A little side note: MAOIs were discovered back in the 1950s, during trials for new drugs to treat tuberculosis. It turned out that the medication had psychostimulant effects on the tuberculosis patients. The history of medicine is crazy! (Pun intended. Pun always intended, tasteful or otherwise.)

For many, finding the right medication takes a while. It’s a process of trial and error that frustrates patients for many reasons: some medications take up to two full months to have effect, the side effects are often worse at the beginning, and there can be withdrawal symptoms if you stop too abruptly. There are a few recent developments that can help patients find the right medication, including a blood test to check for specific genes we think affect how your body uses antidepressants. The cytochrome P450 (CYP450) genotyping test is one such predictor of how an individual might metabolize a medication.

Last resorts include ketamine and electroconvulsive therapy; we usually save these for patients whose depression has resisted other forms of treatment. Ketamine causes brief psychotic episodes, working much like phencyclidine (PCP, aka “angel dust”) and other hallucinogens used recreationally. After a few hours, ketamine then works as an antidepressant through its action as a glutamate antagonist. In striking contrast to other drugs options, electroconvulsive therapy (ECT) is a treatment that actually involves passing electrical currents through the brain, theoretically to affect levels of neurotransmitters and growth factors. Despite the suspicion surrounding ECT and its side effects, it typically gives immediate relief even when other treatments have failed. Of all depressed people treated, only 1 to 2% receives ECT.

Sadly, there’s still so much we don’t know

Depression is undoubtedly a veritable illness, but it’s not only “misunderstood” in the social sense of the term, but also within realm of science. Given that it does have a biological basis, perhaps it’s worth considering how evolution allows this to continue happening. Why would this ever confer an advantage? Why are there still people in the population who are predisposed? How on earth does this play into survival of the fittest? I have a few speculative thoughts, based – as per usual – on personal observation and somewhat anecdotal evidence.

Rates of depression are much higher in first-world countries, which might suggest something about how our lifestyles have changed faster than evolution can keep up. We are experiencing stress and anxiety at a whole new level, what with this new-fangled concept of “long-term goals” and “delayed gratification.” I’m certainly in no position to pooh-pooh lengthy endeavors, given that I’m committed to another decade of education and training, but I do sometimes wonder if perhaps people in third-world countries – living closer to that hunter-gatherer lifestyle – are better adapted to their types of daily stress. There is evidence related to other mental illnesses, too; for instance, schizophrenic people have a much better prognosis in rural India, likely due to the familial and social structures in place and the markedly decreased stigmatization compared to industrialized areas.

The strong correlation between depression and anxiety is also worth touching on. At first glance, it may seem counterintuitive that these two are related, since they appear confusingly contradictory, but it turns out that many people experience both and that one predisposes you to the other. Without going into too many details, suffice to say that once you look at the neurotransmitters involved in states of arousal (the nervous energy kind, but also the sexual kind) and depression, it actually makes a lot of sense. There have been some particularly interesting recent studies with medical interns and residents (generally stressed, anxious people) about the differences in rates of depression between men and women. While about 20% of men developed depression, a full 40% of women did. Further, having a child during internship increased the likelihood of depression for women but had no effect of risk for men. More broadly, people who attended medical school outside of the United States were significantly less depressed. I’m not even going to try to go into that – way too many confounders and way too much opportunity to say things that are far from politically correct – but you can use your imagination as to why that might be.

There are some promising directions for future depression treatment research and it’s these questions we should be addressing, not the silly ones about whether it’s a major problem or not. Given what we see in patients with both depression and immune dysregulation, is it likely that cytokines play a role in disease onset? Would anti-inflammatory drugs alter depressive symptoms?  Since we see so much depression after strokes and heart attacks, should we investigate other cardiovascular factors? As about 40% of variance in depression can be attributed to genetics, should we devote more effort to searching for specific genetic polymorphisms? How useful is functional magnetic resonance imaging (fMRI) in studying the changes in activity and connectivity of depressed patients? Is it relevant that depressed people have smaller hippocampi and that their amygdalae are more strongly connected to their prefrontal cortices?

Scientist or not, I hope you learned something today…or, at the very least, revisited and reflected on important issues. If you take away anything at all, let it be this: depression is real, chronic, and treatable. Some of the most incredible people I know have dealt with it and mental illness should never, EVER be stigmatized. Let’s get on with it, progress with research, and talk about it openly.