In the brain: the hardware is the software.

A few months ago, I made the somewhat controversial assertion that depression is not a chemical imbalance. In that post, I argued that depression is the result of dysfunctional neural circuitry. I’d like to expand a little more on that idea. (Warning, it’s going to get a little technical here, so continue at your own risk).

The brain is an incredibly powerful parallel processing machine. Each of the estimated 86 billion neurons is able to take multiple inputs and produce a stream of discrete signals that are relayed to connected cells. The sheer processing power of the brain is immense. However, like a microchip, the brain’s full speed is limited to a small set of hardware-encoded functions. For example, your brain can process high-definition stereoscopic video in real-time, while identifying faces and assigning emotions to each one, but it does not have an inbuilt method to perform simple addition*. The brain is incredibly powerful for the tasks it has evolved to do, while at the same time, it can appear remarkably limited compared to even the most basic computers.

Computers perform tasks described by their software. I see no reason to believe that the brain is any different in this regard. However, the brain does not have a separate storage unit like a hard disc drive that retains its software in non-volatile memory. The theoretical location where data is stored is called an engram**. The best evidence we have suggests that engrams are stored in neural circuits close to the brain regions that process them.

In other words, the software and the hardware are inseparable.

So when I assert that the cause of depression (and realistically, all psychiatric disorders) is dysfunctional neural circuitry, I am not throwing away every hypothesis on the subject. I am merely suggesting that the core problem–be it disruptive thoughts, relationship woes, past trauma, environment, diet, exercise, genetics, or even neurotransmitters–is manifest at the level of the circuit. The circuit doesn’t tell us the whole story, but it gives us a great model for how we try to identify the culprit***.

So I stand by my assertion that depression is caused by dysfunctional brain circuitry. But although this is a useful abstraction, it does little to define appropriate clinical targets. I just think that restructuring of neural circuits is much more accurate than any of the other high-level models of brain pathology that I’ve heard described.

* Thankfully, some of these brain functions can also performed at very high level of abstraction. But like high level, uncompiled programming languages, these functions will often be hit by a pretty hefty speed limit. Sadly, your arithmetic skills will always be a lot slower than JavaScript running in Internet Explorer 6 on your grandma’s old desktop.

** If you Google engram, you are likely to get lost on Scientology sites as they also believe in something called engrams. To my knowledge, this is a very different concept.

*** I doubt we’ll find a common circuit related to the Oedipus complex :).

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Biology and Psychology

As many of you know, I’ve been busy interviewing for medical residency programs in psychiatry. It’s been wonderful. I love meeting students, residents, and faculty who are passionate about mental health. And the interviews have actually been really fun! I haven’t had anyone really grill me or try to be intentionally difficult. I’ve found that the questions I’ve been asked stretch my intellect and help me to understand my chosen profession better.

One question that keeps coming up is whether I’m looking for a program that is more biological or psychological. I’m not a huge fan of this dichotomy. My understanding of neuroscience is that everything that happens to the brain has a root in biology*, just as everything that happens to a computer is the result of the flow of electrons through physical components. So whether you treat the brain with so-called “biological” or “psychological” interventions, you are absolutely working through biological processes. I like to say that psychotherapy uses the brain’s public API**, while psychopharmacology accesses a lower-level, private API. It’s not a perfect analogy, but I think it’s a nice start.

Beyond the philosophical point that the brain is an inherently biological organ, the fact is that both drugs and therapy have a profound impact on the biology of the brain. Some mental illnesses are treated equally well with medications or psychotherapy (and in many cases, people do better when they receive both). Studies are even beginning to show that either form of intervention can alter the gross structure of the brain. And why shouldn’t they? We don’t have a model for the way that the brain processes and records information that isn’t physical.

I’m a pragmatist. I will use whatever technique I need to to help my patients get better. Ideology matters much less to me than proven effectiveness.

* There is always the possibility that we can’t explain everything about the brain with biological principles. Many people (including me) believe that there is a spirit, soul, energy, or force that at least partially defines who we are. However, that doesn’t mean that we should toss away what we know about the physical world. I once had a brilliant and deeply religious neuroscience professor explain it by saying “I don’t know if the brain is everything, but it seems to be almost everything.” Take that for what it’s worth.

** API means application programming interface. It’s a term that software developers use to describe how one program interacts with another.

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Are mental illnesses diseases?

I’ll always remember reading the Amazon reviews for the most recent version of the DSM-5. (For those who don’t know, the DSM-5 the handbook that mental health professionals in the United States use to describe and characterize all forms of mental illnesses.) Not surprisingly, many of the early reviews were not flattering–the science of psychiatry is still very young, and the DSM has always been better at categorizing symptoms than describing discrete disorders. But one line of criticism stuck out to me: the accusation that the DSM was describing normal human experience as diseases.

Now I’ll admit, on strictly philosophical grounds, describing a mental illness as a disease can be problematic. By some standards, a “disease” needs to involve an observable physiological process. For example, lupus qualifies as a disease because there are inflammatory markers that can be detected in the blood. Alzheimer’s dementia is a disease because there are characteristic brain changes that you can be detected when the brain is biopsied (although this is never done in a living patient). But for depression, schizophrenia, and almost all other DSM diagnoses, we really don’t have biological markers that adequately describe these disorders. This doesn’t mean they don’t have a biological basis. It just means that the diagnostic tools we use are still very limited. In deference to this distinction, the words “illness” and “disorder” are more commonly used than the word “disease” when used to describe psychopathology.

Some people will say that mental illnesses are not diseases, illnesses, or disorders because these words can be stigmatizing. I agree that putting a label on a person’s experience may be burdensome. I prefer to let people define their experience in their own words. The spectrum of symptoms associated with any DSM-defined diagnosis is immense, and how a person relates to their symptoms is very personal. However, I do believe that it is important for clinicians to use accurate terminology within the private medical record so that appropriate communication can occur between providers. But I would never suggest that a particular diagnosis defines who a person is or what he or she may achieve in life.

From a clinical perspective, DSM-diagnoses are defined as illnesses and disorders not because of their symptoms, but because of the impairment that people with them experience. This is an important distinction because people have widely divergent personalities, behaviors, and habits–and diversity alone is not a sign of illness. Impairment is usually defined as disruption of the person’s normal ability to function at work, school, or in relationships. However, impairment can also occur when symptoms cause a person to experience great personal distress. People are wonderfully diverse and incredibly adaptive and it just doesn’t make sense to describe symptoms as an illness if they don’t cause impairment.

Regardless of what we call these symptoms, I hope we can all agree that providing treatment to people in need should be an important priority.

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An Ideal Treatment For Depression

Depression is treatable. But that doesn’t mean that treatment is simple, or that many of the current treatments are incredibly effective. In fact, a huge proportion of people do not respond to the first treatment they receive.

While we develop better treatments for depression, I want to propose an ideal approach based upon the best science we currently have. I have not seen any studies that have tested this holistic approach. However, I do know many physicians and therapists who draw upon many of the principles outlined below. Incorporating every aspect of this treatment would be nearly impossible. I’m open to suggestions on how to package this treatment for maximum benefit.

Are you ready? These are the components that I would include in an ideal treatment for depression:

An appropriate workup
On paper, the criteria for diagnosing major depressive disorder are straightforward. A person must meet 5 of 9 criteria, and the presentation can’t be better explained by another disorder. Counting up the criteria is easy, and there is a simple mnemonic that medical students learn to rattle off in their sleep. However, ruling out other causes of depression is much more difficult. Sometimes depression has a physical cause that can be determined with laboratory tests. For example, low thyroid hormone often presents with symptoms of depression. But there are other mimics of major depressive disorder than can only be distinguished through subtle questioning. In some cases, ruling out other diagnoses cannot be done in a single visit. For example, bipolar disorder often begins with depressive episodes, and it is not uncommon for it to take many years before the correct diagnosis is established. Each of the different mimics of depression requires a different treatment approach, and in some cases, the wrong treatment can have catastrophic results. Diagnosis by a competent professional is absolutely critical.

Close follow-up
People with depression should receive close follow-up–especially in the first few weeks of treatment. Frequent return visits allow for quick treatment adjustments, and also allow clinicians to ensure that thoughts of suicide can be kept in check. On occasion, some people respond to certain treatments by becoming more depression, agitated, or suicidal, and it is critical that changes are made quickly.

Evidence-based treatments
An evidence-based treatment is one that has been repeatedly shown to work in well-designed human studies. This doesn’t mean that the treatment makes a huge difference for everyone who uses it. However, evidence-based treatments should form the foundation for an ideal treatment of depression.

Antidepressant medications provide a small but beneficial impact on depression. Even though they work through different mechanisms, they all tend to provide a similar benefit, and so the choice of which antidepressant to use is largely based on side effects and comorbid conditions. If the first one doesn’t work, a second one is usually tried. These drugs are not perfect, but in most cases, the benefits strongly outweigh the risks.

Psychotherapy has also been shown to be effective for the treatment of depression. There are many different forms of psychotherapy, and each has it’s proponents and detractors. For depression, cognitive-behavioral therapy seems to be the most well-studied treatment. The effect tends to be modest with initial treatment, but the odds of success increase if the patient connects well with the therapist. For this reason, I make sure that my patients keep trying until they find someone they work well with. Notably, the combination of psychotherapy and antidepressants is much more effective than either treatment alone.

Electroconvulsive therapy is a treatment where a seizure is induced through electrical current. The patient is under general anesthesia and does not experience any pain. Electroconvulsive therapy is far and away the most effective treatment for major depressive disorder. However, it does entail considerable risks, and so it is generally not recommended as first-line treatment of depression. The treatment carries an unfortunate stigma, but it is incredibly impactful. An ideal treatment plan for depression must include electroconvulsive therapy as an option for severe depression that does not improve after an adequate trial of therapy and medicine.

Theoretically effective treatments
There are many treatments that might be successful based upon theoretical or anecdotal evidence. In some cases, small studies may have shown some benefit. Unfortunately, a lot of these treatments don’t have a sponsor with the funding to prove or disprove their efficacy. However, those with minimal risk should absolutely be considered as adjuncts to the evidence-based therapies found above.

Healthy diet


Quality sleep

Weight loss

Obtaining and maintaining meaningful work

Spirituality and meditation

Practicing gratitude


Quality relationships

Nutritional supplements may also be effective. It’s really not fair to lump all nutritional supplements into one category. Most products that have been tested aren’t any better for you than a placebo. However, there are some supplements that show encouraging results in smaller studies. As with any other medication, talk to your doctor before taking a nutritional supplement.

Addressing socially mediated risks for depression
People who live in poverty, have a history of abuse, or suffer from chronic medical conditions are also at risk for depression. There is no easy answer to any of these problems, but it seems clear that finding effective methods to fight poverty, protect people from the horrors of abuse, and provide affordable, high-quality healthcare are critical elements for preventing and treating depression.

There must be a better way to treat depression. I’m grateful that we have antidepressants and psychotherapy, but I believe that there is so much more that can be done to help people overcome depression. I look forward to innovation that can help us produce and implement better treatments for depression!

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Thoughts on Residency

As many of you know, I’m a student finishing my final year of medical school. After I graduate, I plan to spend the next four or five years in a residency program training to become a psychiatrist. It’s not a decision that I came to easily.

Deciding on psychiatry wasn’t too tough–it was the decision to complete a residency that I found challenging. I’ve always felt a pull to do more than just practice medicine. Part of this drive has come from my medical school, which has encouraged me to learn the skills needed for a career that includes medical research. But I also completed a minor in business as an undergraduate, and the thought of actually implementing medical research has always excited me. Over the last two years, I’ve thought long and hard about whether residency was the right choice to help me achieve my long-term goals.

Here are a few reasons why I think that residency will be valuable:

  1. Residency will help me become an excellent clinician. I love building personal connections with patients, and clinical medicine embodies the spirit of service that initially drew me to medicine. No matter how my career changes in the future, I always want to spend at least some time seeing patients.
  2. Residency (and especially a psychiatry residency), will help me become a better team player. I’m going to see countless examples of great leadership. I’ll learn how to rely on the strengths of a team of diverse professionals, and have opportunities to do my best and fail in a supervised environment. Rotating between teams at regular intervals will also be an incredible opportunity to learn from hundreds of colleagues in only a few years.
  3. Residency will help me understand the actual problems facing people with mental illness. Textbooks can only go so far, and I find that my experience with people is much more nuanced than anything written in the Diagnostic and Statistical Manual of Mental Disorders. It is through these interactions that I hope to develop and refine hypotheses about how we can improve mental health care. Developing patient-centered interventions far away from the front lines seems like a foolhardy prospect.
  4. Residency will make me scale my efforts. I am good at putting my head down and getting work done. Now I need to learn to shed the superman complex and rely on others. I know that I won’t be able to design, code, and market apps on my own anymore–and that’s a good thing. Being further constrained for time will force me to leverage my efforts and further build my ability to lead.
  5. Residency will help me build a network of mentors, colleagues, and friends that I’ll be able to work with and serve for a long, long time. It’s no secret that mental health workers are some of the most compassionate and dynamic people around. I look forward to being a card-carrying member of the mental health community.

To sum it up: I’m expecting residency to be extremely challenging and immensely rewarding. What more could I ask for in the next stage of my career?

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