Endocrinology in Psychiatry

Hey team!!

I just finished "Endocrine Psychiatry," a book by Edward Shorter and Max Fink, and I'd like to share my understanding of endocrinology in psychiatry from what I took away from this book and add some of my own insights to the findings presented.

To start, let me define endocrinology as the field of medicine dedicated to studying the various hormone systems in our body. Hormones are signaling molecules that a certain gland will secrete into the blood, where they enter general circulation and can affect every organ with receptors for that specific hormone. Cortisol is a glucocorticoid steroid, meaning it's an alteration of the typical 4-ring steroid structure. It is secreted by your adrenal gland during times when your body needs to focus, keep its eye on the prize, and deal with the here-and-now stressor. Cortisol is activated by the HPA axis (hypothalamic-pituitary-adrenal), and through a negative feedback loop, it turns off its own response. So when cortisol reaches receptors in the hypothalamus and pituitary gland, it tells them to "shut off," indicating that the stressor has been overcome, and it's time to move on to the next thing. This is all in the name of homeostasis, maintaining a sort of equilibrium that allows your body to function at its best, even as the environment is always changing.

Given that this is a stress response and people with certain psychiatric disorders are extremely and often chronically stressed, it would make sense that cortisol abnormalities would be a finding. And that's the case! Back in the day, we used to call people with depression as having "melancholia," and honestly, that name rocks! It represents a form of vegetative depression with sufferers having a form of motor retardation. These are the kinds of people who are slow to move and can even exhibit noticeable rigidity. This is on top of severe depressed mood with little to no pleasure out of life. Through a test known as the dexamethasone suppression test (DST), in which dexamethasone, a cortisol-like drug, is given, decreasing cortisol levels by inhibiting the HPA axis, just as naturally occurring cortisol does in the body through the negative feedback system. This is what happens in healthy, non-depressed, or non-melancholic patients. However, when given to people with melancholia, cortisol doesn't decrease; it stays high. This demonstrates an abnormal HPA axis/stress control response. And this is a biological test for a psychiatric condition, which we really don't see outside of neurological diagnoses (different from psychiatric).

The DST is not a perfect diagnostic tool for melancholia, but it's a damn good one. In comparison to comparable diagnostic tests like EEG (Electroencephalography) to diagnose seizures or an ECG (electrocardiogram) to diagnose acute myocardial infarction (heart attack) - which are standard practice yet have around 50-70% accuracy - the DST isn't too bad at around 60-80% accuracy.

The DST is an important test because a positive response (meaning cortisol stays high) predicts that these patients are at a much higher risk of suicide but will also remit ("become "cured") to electroconvulsive therapy (ECT) and tricyclic antidepressants at a much higher rate compared to depressed patients who have a negative response to the DST. And when these remitted patients are discharged, they show lower cortisol levels compared to when they were in the depressive episode. On a similar note, giving an IV of amphetamine to depressed patients and controls (healthy) has similar findings to the DST, where controls show marked increases in cortisol, but depressed patients have an idiosyncratic drop in cortisol by an average of 33%. This is all to show the biological differences that exist in the realm of psychiatry, a field often missing physical markers of disease.

What's also very interesting and intuitive to this endocrine influence on melancholia is that patients respond very well to drugs that work by blocking the production (synthesis) of cortisol in the brain and body. So-called "cortisol antagonists" are given to melancholic patients, which block all the effects of cortisol and help modulate and restore a healthy HPA axis. Low doses of cortisol are also given to maintain a healthy level of the stress hormone in the body, which is needed (you can't just block it all). Patients also seem to achieve remission within weeks and do not need to stay on the medications for long periods, an amazing finding that we don't see with standard psychotropic agents for depression. The two cortisol synthesis inhibitors were Aminoglutethimide and Mifepristone, with the latter not being as good but had to be used as Aminoglutethimide was no longer being produced due to so little clinical use.

The downfall of the DST and subsequent evidence-based and effective treatment of melancholia is a result of the DSM's influence on much of psychiatry. The DSM is the handbook by which all prescribers and clinicians use to diagnose and treat patients and is especially important for clinical trials of certain meds for specific diagnoses. You essentially check off specific symptoms, and if they have enough, that's your diagnosis. I've heard it be called “Chinese menu psychiatry,” and I laughingly agree with that term. The problem that you may have picked up on is the broadness of these diagnoses. Gone are the days of a spectrum of depressions stemming from various biological, psychological, and environmental factors with varying aspects of severity and symptoms, because there is one (unipolar) depressive disorder: major depressive disorder (MDD). It assigns this incredibly diverse and mixed group of people into one category. This strips patients away from their complexities and nuances (which we all have) and reduces evidence-based treatment based on diagnostic criteria. Because of the broadness of MDD, the DST has extremely low efficacy and has been essentially completely dismissed and forgotten. That's not because it’s a poor test but because it wasn't designed to test for major depressive disorder but a very specific kind of depression: melancholia, which has clear and unique features different from the umbrella term of “major depression.”

What do we do from here?

With the knowledge of DST responders and the role of endocrinology in psychiatry, which expands far greater than just cortisol and depression, and the failure of modern psychiatry to address these differences, what do we do? I believe we should stay thinking critically and remain opposed to reductionist diagnosis and treatment. We must take into account all the different systems that regulate our body and subsequent well-being. It doesn't take a genius to take notice that not all depressed patients are the same and respond to the same treatments. In my current understanding of depressive disorders, I believe that while every patient is unique with their reason for being depressed, there are still a few key differentiating factors that should be considered to help guide treatment. These factors include discriminating between melancholic depression (which is more rare) and reactive depression. Reactive depression can be further broken down into understanding how the patient sees the world and their role in it (awareness), their ability to cope and to what degree (skills), and if the depression is uniquely episodic and will pass with time. And within all of these breakdowns, how plastic is the patient's mind/brain? How rigid and stuck are they in their ways and their ability to think and look beyond the status quo? There are clearly other factors but I believe these are some key points to understand. These points can help guide treatment before understanding some possible neural circuits involved and the role of psychotropic drugs in modulating them. Treatment should be rooted in patient centered care and the rigidity of our past must be taken with a grain of salt. 

• Shorter, E., & Fink, M. (2010). Endocrine psychiatry: Solving the riddle of melancholia. Oxford University Press.