Depression: The Tiny Brain Hypothesis

Art by Javad Alizadeh

By Mike Wang

Depression is not a mood. It’s a murderer. Like every serial killer, it leaves its signature at every scene, signed with Ambien, a shotgun, a leather belt.

Everyone knows someone who has committed suicide. The Surgeon General’s report lists depression-related suicide as the second leading cause of death in college students – and the most common cause of death for pre-meds. In high-income countries like the US, depression causes the greatest disease burden to society, outstripping heart disease and alcoholism financially, in adjusted life years, and in mortality.

In recent years, Healthline estimates that diagnoses of depression have gone up 20%, and prescriptions are on the rise too, with the National Center for Health Statistics estimating a 400% increase in prescriptions from 1990 to 2010.

We’ve had some painful cases of suicide here at JHU, when last academic year, two students committed suicide only months apart. While we might think that these cases are isolated and extreme, the numbers show it is more common than we think. It’s a hidden disease, but those who struggle with it are everywhere on campus.

Being ruined by depression, only to receive ineffective treatment afterwards, is an all-too-common phenomenon.

Take for example sophomore Hansel Romero, who has struggled with school while trying to keep his depression in check. He puts a lot of his time into projects such as “Not Yours Apparel,” as well as his acapella group the Vocal Chords in order to distract himself from the pain.

“Depression and anxiety have easily ruined my entire semester. My academic performance has severely suffered, at times because of lack of motivation, lack of desire to succeed or live on, at others for fear of panic attacks in class and other anxious episodes.” Romero said. “This whole semester has been a constant battle with my illnesses and added diagnoses.”

Depression is a difficult and poorly understood illness. Not just because depression can disable someone from the inside, but also because treatments have been mediocre at best. Being ruined by depression, only to receive ineffective treatment afterwards, is an all-too-common phenomenon.

Jessie Davidson, a ‘15 BME, described her college experience with depression as a crippling, hopeless struggle. As a painter who quickly greets everyone with a smile, you’d never guess she’d be part of the millions suffering from this curious disease. She’s gregarious, talented, accomplished, quick to compliment – everything a depressed person shouldn’t be. Her past tells a different story.

“Many days I would stand in the shower and just cry because I’m too tired to push aside the heaviness and go on with life. The pain, the darkness I felt was all so consuming that I became ambivalent to existence.”

Her doctor eventually prescribed her Lexapro, an antidepressant that treats serotonin imbalance, which is the purported culprit of major depression. Problem solved, right? Wrong. As with many cases, her relationship with antidepressants was plagued by unsatisfying results and unpleasant side effects.

“I cycled through several different doses of Lexapro that disrupted my sleep patterns, caused me to lose my appetite, and often times made me feel even more anxious. I finally settled with a dose that somewhat helped.” Davidson said.

“After a couple of weeks, I literally felt numb. Like my entire personality was being suppressed. After two years of taking it, I quit, and I didn’t wean myself off as I should have.”

Frustrated, numb and disillusioned, Davidson abruptly discontinued her medication, and her serotonin supply. Doing so can result in seizures, psychosis, and “brain zaps,” a sensation of being electrocuted repeatedly.

Many studies show that most people with clinical depression suffer brain degeneration, particularly in the hippocampus.

Aside from side effects, there’s another confounding and costly problem with antidepressant treatments. Half of all cases of depression do not respond to medication. Drug companies know this, and have synthesized an alphabet soup of drugs to take the pain away. TCA, MAOI, SSRI and NDRI’s are all classes of drugs that attack depression by treating the brain’s “chemical imbalance.”

A Red Herring?

Despite lackluster results, drugs remain society’s current weapon of choice to combat this silent epidemic. Whether they are from the pharmacy or the street, they’re both powerfully simple fixes for the pain that just won’t go away.

A uniting factor of antidepressants is that they all act on monoamines, the umbrella term that includes the classic feel-good neurotransmitters dopamine and serotonin. Another monoamine shown to be involved in depression is norepinephrine, a close cousin of adrenaline.

Drugs like MDMA, methamphetamine, marijuana, and alcohol boost the user’s mood through altering these same chemical systems. Those who self-medicate might turn to these common street drugs to combat their own depressive symptoms. But with classic euphoriants there is a comedown, which can be worse than the high itself. The term “suicide Tuesday,” was coined by chronic ecstasy users to describe the inevitable feeling of intense depression that comes after a weekend-long bender. Thanks to the study of both legal and illicit drugs, monoamines have dominated the dialogue on depression.

The chemical imbalance theory, which says that depressed people don’t produce enough of the “feel good” chemicals serotonin, dopamine, and norepinephrine, can’t explain how antidepressants work.

Dr. Stewart Hendry, teaching professor of neuroscience both at Homewood and at the Johns Hopkins Medical Institute, says the effects of antidepressant drugs remain a confounding mystery, as antidepressants behave far differently than recreational drugs do.

“All antidepressants have the same characteristic that you have to be taking the drug for a couple weeks to see any effect,” Hendry said.

This is in contrast to drugs like cocaine and alcohol, whose effects come on within minutes. Hendry compares antidepressants to conventional drugs like antibiotics.

“Sure, antibiotics don’t work immediately, but it doesn’t take a couple of weeks for it to start killing bacteria. And here it’s taking a couple weeks to have any discernable effect. So that’s always been the issue.” Hendry said.

“Why would it take so long for serotonin to build up to the point that it can be effective?”

Interesting question, but why should we care? Antidepressants work! The issue is they work great for some people and not others like Davidson. Romero had a similar experience with antidepressants, cycling through a number of them in an effort to combat an unrelenting worsening of his own depression, which he struggles with to this day.

“My first treatment on this wave of depression began in April on Lexapro and Busiprone, which I was told would take about six months to make a real difference. Summer rolled on and I got worse. The school year came on and I got worse,” Romero said.

“There was a point in November where I finally admitted to myself that this treatment couldn’t be working, and that we needed to try something else. I’m waiting to find out exactly what the next steps will be.”

Neuroscientists and clinicians are scrambling to find the solution to this problem. After all, the clock is ticking, and people continue to suffer.

Order of the day, Special K

The chemical imbalance theory, which says that depressed people don’t produce enough of the “feel good” chemicals serotonin, dopamine, and norepinephrine, can’t explain how antidepressants work. What’s more, there are now promising experimental treatments that don’t touch the monoamines at all. One is TMS, or transcranial magnetic stimulation, which electrocutes the brain. The other treatment is none other than the horse tranquilizer and street drug ketamine – otherwise known as “Special K.”

Both have delivered results that current antidepressants cannot match, for reasons that are still unclear.

Depression, it’s all in your… blood?
Scientists have much to learn about antidepressants. The current theory cannot explain why 50 percent of depressed patients are unable to respond to their first medication, and there are effective antidepressants that don’t work on the “feel good” chemicals at all. This issue has given rise to a promising new theory of how depression works, and most importantly how and why treatments work for some and not others.

It started from one unexplainable and alarming observation. Many studies show that most people with clinical depression suffer brain degeneration, particularly in the hippocampus. The hippocampus is the seat of emotion and memory in the brain. It’s also part of the larger emotional circuit of the brain called the limbic system. Within the limbic system are connections to all parts of the brain, from memory to cognition and strangely, a very robust connection to smells.

In the hippocampus, we find a weird phenomenon we don’t find in any other part of the thinking brain. You might have heard that we’re born with all the neurons we’ll ever have, and as we age they continue dying off, and there’s nothing we can do about it. In that case, those who’ve experienced brain shrinkage are screwed, but the hippocampus is an exception to the rule. For reasons unknown, it continues to generate new neurons throughout life. For those like Romero and Davidson, the process slows and the hippocampus shrinks – sometimes up to 20%

This is all well and good, but the observation itself is not helpful. What neuroscientists needed to do was find out the relationship between shrinkage and depression. Did one cause the other? Is it a two-way relationship, or is this just another red herring?

A Brain Allergy
The answer ultimately came not through studying depression, but multiple sclerosis. Multiple sclerosis (MS) is a disorder that causes one’s own white blood cells to attack the brain. MS patients are essentially allergic to their own brain. Over time, the body dissolves away its own neurons, leaving hard plaques (sclerosis) throughout the brain. And you thought your hay fever was bad.

The overlap of neuroscience with immunology has just been discovered, but it might provide the solution to the 50% out there who do not respond to medication.

This leads to a host of problems, including excruciating pain, partial paralysis, unexplained fatigue, blindness, and yes, depression. In fact, someone with MS is eight times more likely to commit suicide.

Sure, the statistic might be explained away by the terrible nature of the disease; pain, paralysis, and blindness is enough to make anyone miserable. Well, science says that’s not the case.

Results showed that depressive symptoms were directly correlated to the molecular signals of an immune attack.

Many MS patients exhibited the cardinal sign of depression – hippocampal shrinkage. Thanks to a connection between two very different patient populations, scientists had a lead. Scientists all across the world began exploring this curious connection.

Across the world in Germany, researchers simulated MS in healthy patients by injecting them with bacterial toxins, kicking their immune system into overdrive. Their immune response were plotted to subjects’ scores in a depression test. Results showed that depressive symptoms were directly correlated to the molecular signals of an immune attack.

In another study, researchers found out that patients who had high levels of that same MS signal molecule were more resistant to antidepressant treatment. Finally, in a study of MS patients with depression, it was shown that MS medication improved depression symptoms.

With the immune system’s effect on the brain documented, scientists then turned to conventional antidepressants to see if there was a reverse connection – if antidepressants influenced the immune system. They did.

In a separate study, Prozac, one of the most prescribed antidepressants, protected 60% more tissue from MS-related damage than controls. Lithium also reduced the severity of immune attacks against brain tissue.

Connecting the Dots
Thanks to MS patients, neuroscientists now knew there was a connection between depression and the immune system. We knew that MS and major depression patients had brain shrinkage, and we knew that immune chemicals interfered with antidepressant medications and hippocampal growth.

A major study reinforcing the connection came from a study by Monje et. al, where they isolated IL-2, a molecule that activates white blood cells. When they released it onto hippocampal tissue, the hippocampus stopped making new neurons. This study proved the immune system acts directly on the hippocampus to produce the hallmark sign of clinical depression.

So MS patients weren’t just being mopey – their overactive immune system acts directly on the hippocampus to produce the hallmark sign of clinical depression.

They now had their connection. The new immune theory also explained the role of stress in depression. The chemical responsible for stress is called cortisol, and too much of it over time messes up the immune system. That means long-term stress leads to depression via disturbances in the immune system.

What’s more, depression itself can drive the stress response, which would drive the immune system to shrink the hippocampus and reinforce the brain’s depression.

So what does this mean for people like Romero and Davidson? What’s being done to exploit the connection? Every 13 minutes someone commits suicide. The clock is ticking.

At JHU’s medical institute, doctors are holding nothing back, utilizing illegal street drugs and electric shocks to treat depression. JHU has famously used magic mushrooms to treat anxiety and addiction, and now they’re turning it up a notch.

It’s Special K. It fucks you up.

Ketamine is one of these radical treatments. It started as an anesthetic and ended as a street drug. It shares a family with the drug PCP, or “angel dust,” which induces schizophrenia-like symptoms.

Cases of PCP use have driven users to deglove the flesh off their hands while attempting to escape handcuffs. 90’s rapper “Big Lurch” famously cannibalized his housemate after taking a dose of PCP – ah, the golden age of hip hop.

In the clinic, ketamine has been used to reverse symptoms of depression in acutely suicidal patients. It takes effect in minutes instead of weeks. Many, including JHMI’s Solomon Snyder, the namesake of JHMI’s world-renowned Solomon H. Snyder Department of Neuroscience, consider it a promising therapy.

Ketamine has its detractors though, including the current chair of the very same neuroscience department, Dr. Richard Huganir. When asked about the treatment, he provided this pithy quote.

“It’s Special K. It fucks you up.”

Folks, you heard it here first.

Dr. Hendry is not at all surprised by the chairman’s stance. “If you took out 90% of Dr. Huganir’s brain, the remaining 10% would still know more about [its mechanisms] than I do. That is an informed opinion.”

This perfectly reflects the nature of depression research. Even the brightest neuroscientists in the world can’t come to an agreement about what’s going on.

Despite its controversial nature, patients across the country fly to remote clinics that offer this experimental treatment.

New explorations into the mechanism behind ketamine’s effects point directly to its ability to increase neuron growth through manipulating one of the basic growth pathways, called mTOR. Ketamine also has the double-whammy effect of inhibiting the same immune signal (IL-2, mentioned before) that halts neuron growth.

The other treatment, Transcranial Magnetic Stimulation (TMS), involves using an extremely powerful and focused magnet to control brain signals. Sorry, your tinfoil hat won’t work with this puppy.

It’s only used for extreme cases such as catatonic depression, where patients are so depressed they stop talking, moving, and eating, because TMS is highly invasive. Patients need to be anaesthetized and paralyzed before treatments, as TMS causes seizures. It’s about as mysterious as it is effective.

“If you could explain to anyone why [TMS] is so useful for many forms of depression, you’ve gone a lot of the way to explaining why some treatments don’t work at all. But can you? Does anyone have a good model of why it works?” asked Hendry.

The hippocampal regrowth theory does. TMS uses electrical signaling to prompt neuron regeneration.

Regardless of how unexplainable these radical treatments might be, Romero is thoroughly fed up with his depression and will try anything.

“I’m open to any treatment, no matter the stigma, especially if it’s been proven to be effective.”

The Depression Revolution
Unfortunately, both of these cutting edge treatments are not available to the general public, and most hospitals in the US do not offer such treatments. It’s a bummer for sure, but these treatments will hopefully yield valuable insight into the lesser-known mechanisms behind depression.

Recent research has revolutionized the way we should see depression. We now know it is a body-wide illness rooted in biological processes – not thoughts. What’s more, we know it’s not just a matter of screwed-up chemicals. The chemical imbalance is part of a larger problem of hippocampal regeneration.

The overlap of neuroscience with immunology has just been discovered, but it might provide the solution to the 50% out there who do not respond to medication – people like Romero and Davidson, where treatment is vital, if not critical.

In order to function, both have turned to coping mechanisms that get them through the day and give life meaning.

“I try to keep myself really busy – almost overwhelmingly so – with all of my different passions so as to never have to really stop and think about my illnesses. It doesn’t always work and there are holes in it as a coping mechanism, but it keeps me going and these things are what I enjoy,” Romero said.

One of his passions is Not Yours Apparel, a company that uses apparel to raise awareness of social issues like sexual assault and mental health.

“Right now, our focus is on sexual violence, and proceeds from our sales go to the Joyful Heart Foundation, which helps victims of sexual assault. Our next prospective topic will be mental illness, and I fully intend to use my experiences to drive my company’s mission forward however I can,” Romero said.

For Davidson, the solution is more holistic. She says her family and friends help keep her going.

“The things that keep me going, that keep me living life and pushing forward even on the bad days, are the people I live life with. I have two adorable little nephews, five and one, and I want them to remember me as the cool aunt.”

Davidson also believes that it’s the small things in life that can bring real happiness.

“I enjoy the little successes and have learned to focus on that. I got to work early today. I have free time to paint, I had a really awesome conversation with a coworker, I had an awesome run.”

Until neuroscience fits all the puzzle pieces of depression together, it’s up to Romero and Davidson’s inner strength to fill in what’s missing.

There is, however, extreme promise over in East Baltimore. With this remarkably revolutionary theory centered around adult hippocampal growth, researchers have peeled away the inadequate monoamine theory that neuroscience has been focusing on for decades.

With that, hopefully we’ll find a definitive treatment for clinical depression. But for now, the universal prescription for those with depression is just to keep on keeping on.