The Many Faces of Depression

We, humans, are complex creatures thanks to the head-spinning complexities of our neuronal organization. Each of our brains has woven together 100 billion densely packed neurons, each of those neurons making upwards of 10,000 synaptic connections with other neurons… bringing the total of synaptic connections to approximately 1000 trillion connections. That’s a lot of 1’s and 0’s.

It’s no wonder humans are so capable of producing incredible feats of engineering and art. It’s also no wonder that, despite working nearly perfectly the majority of the time, things can go awry. For every step forward our neurology affords us, it also opens us up to psychological difficulties.

Global statistics show that one of the most common of these unfortunate outcomes is a constellation of psychological and physiological symptoms that fall under the term “depression”. Over half a billion people every year report feeling a loss of positive mood, motivation, and/or enjoyment in life.

What is depression?

Depression, specifically unipolar depression, represents a class of disorders that are generally characterized by reductions in mood, motivation, and other related behaviours. Bipolar disorders, on the other hand, are characterized by depressive episodes, manic or hypomanic episodes (that is, elevations in mood, motivation and related behaviours), and mixed episodes; individuals with bipolar disorders can travel this spectrum. We’ll be focusing on just the unipolar disorders today, and we’ll visit bipolar disorders another time.

The DSM-V-TR (the latest diagnostic manual for psychological disorders) contains several disorders that fall under the unipolar “depressive disorders” category: Major Depressive Disorder (MDD), Persistent Depressive Disorder (PDD), Disruptive Mood Dysregulation Disorder (DMDD), and Premenstrual Dysphoric Disorder (PMDD). Although there are distinguishing factors among these disorders, a considerable degree of symptom overlap exists between them, sometimes making it difficult to discern one from another.

When you dive into this area, you’ll often hear that “depression is highly heterogeneous”, or so says the field’s top researchers. But what exactly does “highly heterogeneous” mean in this context?

For simplicity’s sake, we’ll define it here as “many forms”. Not only can depression be expressed through various forms, as I just mentioned, but there are also various forms within each diagnosis.

Indeed, when we talk to people about depression, what exactly are we talking about? Are we talking about low mood? Low motivation? How about a sudden change in feeding habits?

These are all possible symptoms of depression, but if we had to, could we identify a “classical” or “an average” case of depression?

The research comparing prevalence rates of specific symptoms suggests that, besides low mood, no, it doesn’t appear so. This is where the many forms of depression rears its ugly head; because depression can come in so many different shapes and sizes based on symptom presentation, it can become wildly difficult to define depression and even more difficult to develop a treatment plan.

Let me give you some examples:

In order to get a diagnosis of MDD, you need 5 out of 9 symptoms, with at least 1 of those being “depressed mood (persistent feelings of sadness)”. The other symptoms are, in no particular order, changes in feeding habits (increases/decreases), changes in sleep (increases/decreases), loss of pleasure/motivation (anhedonia), feelings of guilt, changes in physical movement (increases/decreases), fatigue, thinking about death or suicide, and concentration/decision-making issues.

Now it’s fairly rare for an individual to experience all of these symptoms simultaneously; it’s far more likely that they’ll present with some and not others. This is where the conversation gets interesting because we’ve begun to identify, beyond the DSM diagnoses, that there might be variations or “types” of depression within a single diagnosis.

Let me show you; if we do some quick maths to calculate all possible symptom outcomes for MDD (how many ways 5 can fit into 9), we can see that there are 126 possible combinations of symptoms that meet criteria. That means that there could be 126 discrete yet distinct forms of depression. But wait, that’s only for combinations of 5 (a minimum of 5 symptoms are required); what about for combinations above 5?

That would bring the total number of combinations to 256, meaning that there could be upwards of 256 different kinds of MDD (not to mention any of the other depressive disorders mentioned above, modifiers for each disorder, or bipolar disorders, or delineating between increases and decreases in sleep, movement, or feeding… we’d surely wind up in the 1000’s).

And going back to where we started, is it not probable that the combinations of symptoms are a byproduct of an immensely complex array of neuronal signalling, with each signal carrying an ability to influence emotion or behaviour in one of the several domains listed above? In other words, do symptom combinations represent specific neuronal vulnerabilities? Are there people walking around with specific vulnerabilities through which depression can sneak in? Or are there symptoms that benefit from specific kinds of treatments while other symptoms are worsened?

For example, loss of concentration or decision-making is thought to manifest out of reduced metabolism in the outer, upper, front corners of the prefrontal cortex (known as the dorsolateral PFC), while impacted feeding behaviours may be manifest out of altered functioning of a midbrain structure called the hypothalamus. The point here is that symptoms of depression can be (cautiously) attributed to altered neuronal performance in particular areas of the brain, resulting in significantly different brain-wide signalling. I’ll couch this section in caution because, as a field, we’re moving away from the simplistic view of anatomical specificity (i.e., the amygdala being the “fear centre”) and towards a more holistic perspective where the “quiet” areas of the brain during any given task are just as important as the “loud” areas of the brain. We’re more concerned with what the whole brain is doing at a given moment and less with what a specific area is doing.

I don’t intend for this article to be a reason to run and hide from the 256 different ways we can be depressed, but rather to point out a weakness in diagnostic psychiatry. We have one name for something that has at least 256 faces. We also have one primary approach for something with at least 256 faces. Yet no matter your symptom presentation, treatments are largely the same: cognitive-behavioural therapy (CBT) in conjunction with a type of antidepressant medication.

As far as I can tell, this is a problem, and our ability to “cure” depression confirms that (depending on who you ask, our success rates are anywhere from 20-70%). Even this statistic smells funny - a success range of 20-70% should raise your eyebrows. Why such a range; How could something work 20-70% of the time? Even Sex Panther has a better success rate (Anchorman, 2004). Well, one reason could be that sometimes our treatments, by luck or otherwise, are tailored to a specific combination of symptoms, and sometimes not. Sometimes we get lucky, and sometimes, we don’t. I’ll give you another hair-raising example.

If you suspect that you have a unipolar depressive disorder, you might seek out some help from a clinician. I think that’s a great idea. And maybe you’re so lucky that you get paired up with an evidence-based clinician who has read about the successes of selective serotonin reuptake inhibitors (SSRIs) in treating depression. And under the guise of a depressive disorder, your clinician prescribes one to you. Here’s the catch; it is quite possible that you have a bipolar disorder and just haven’t had a manic/hypomanic episode yet. In fact, if you have had at least one previous depressive episode, your chances are far from 0. Why would that matter? Because when you give an SSRI to an individual with bipolar disorder, you raise their likelihood of a manic episode substantially. Accurate diagnosis matters because treatments are decided based on them. When we have the wrong diagnosis or a low-resolution perspective, we run the risk of making things much, much worse.

I suspect if people knew about this, there might be more of an active debate taking place. Take something like cancer, for example; there are hundreds of different forms, and treatments are generally tailored toward the specific kind of cancer. A glioblastoma doesn’t get the same treatment as Hodgkin’s Lymphoma, but they’re both cancers. Every couple of days, a new treatment for a very specific kind of cancer is tested. The same certainly can’t be said for depressive disorders.

I believe that we aren’t far off from gaining a larger appreciation of how the many faces of depression differ from each other. How populations of neurons are impacted, why they’re impacted, why them and not other populations? Types of depression that stem from neuroinflammation while other depressions stem from viruses or social pressures… there is plenty of nuance here to be appreciated.

Next week, we’ll take a deeper dive into some recognized “phenotypes” of depression that might give us a foot in the door regarding symptom-specific treatments. We’ll also look at how some researchers and clinicians are applying a new kind of lens, known as a “transdiagnostic approach” as a way to work around these blurry diagnostic boundaries.