Why Doesn’t Depression Medicine Work on Everyone?

First line treatment for depression involves talk therapy and antidepressant medication. Millions of Americans who struggle with depressive symptoms are prescribed antidepressant pills every year, and their effectiveness in part explains why they’re utilized so often in the treatment of depression.

But antidepressants neither cure depression, nor do they affect everyone equally. Firstly, there is no cure for depression yet. As a mental illness, depression is treated through thorough management, both pharmacological and through therapy. There are many things that have been documented to help reduce depressive symptoms and even help overcome depression, but it isn’t something we’ve found a ‘cure’ for.

In part, this is because depression is far too complex for a single simple cure. It’s an issue that often carries deep systemic roots, with many environmental factors that most therapists and psychiatrists can’t begin to influence. Depression can be caused, triggered, and influenced by a wide variety of physical, social, and genetic factors.

Antidepressants are widely effective, but there are many patients who don’t react positively to their medication. To understand why antidepressants work for some and not for others, it’s important to understand what an antidepressant tries to achieve.


How Antidepressants Work 

Antidepressant drugs are psychoactive substances that target the reuptake of certain neurotransmitters associated with depression and stress. In a nutshell, most antidepressants aim to increase the volume of norepinephrine, serotonin, and/or dopamine in the brain.

Most antidepressants are SSRIs (selective serotonin reuptake inhibitors), only targeting the reuptake of serotonin by preventing neurons from reabsorbing the brain’s serotonin, thus increasing how much of it flows between our cells.

There are several different brands and formulations of any given type of antidepressant, because our bodies and brains are extremely varied. Some people respond better to some substances than others.

When SSRIs fail – usually after two or three different brands – a psychiatrist will move onto other types of antidepressant medication. These include SNRIs (serotonin and norepinephrine reuptake inhibitors), MAOIs (monoamine oxidase inhibitors), TCAs (tricyclic and tetracyclic antidepressants), and more.

Non-antidepressant medication is also sometimes used either off-label or as part of a treatment study, including combination therapy (atypical antipsychotics and SSRIs) or experimental medication like ketamine.

When a patient does not respond well to any type of conventional antidepressant, they are officially ‘treatment-resistant’. That doesn’t mean no treatment will work, however. There are plenty of alternative ways to treat depression, from established methods to up-and-coming therapies.


Why Some People Are Treatment Resistant 

As a species, humans share a series of traits and characteristics. Yet on an individual level, any given two humans from different environments will have a series of genetic similarities and differences.

These include superficial differences, like height, hair color, and skin tone, as well as differences that are more difficult to pinpoint, such as certain genetic personality traits, muscle insertions, and differences in the structure and size of various portions of the brain.

This gets even more complicated when environmental factors are added to the mix, as they further change our personality, our bodies, and our brains.

All of this is to drive home the point that, although we’re all human, we have very different bodies, down to the way our cells communicate.

For years, researchers have been tackling the question of where depression originates in the brain, in an effort to both produce better treatments and determine whether any biomarkers could help determine whether antidepressants would be effective for someone, before they try them.

So far, we have no reliable way of telling whether someone is treatment-resistant, before they start treatment.


Depression in the Brain 

We know depression starts in the brain, but we can’t be sure that differences in the brains of depressed individuals and not depressed individuals aren’t caused by depression. For example: depression is linked to a smaller hippocampus. But that does not mean lower hippocampal volume causes depression. One hypothesis explains that frequent stress and attrition can cause the hippocampus to shrink, meaning the low volume may in fact be a consequence of depression and chronic stress.

We know depression is heavily linked with limbic and paralimbic systems – the many parts of the brain responsible for motivation, learning, reward, emotion, stress hormones, and mood – but the links aren’t fully understood. Brain imaging allows us to further research how our complex circuitry functions, but more time is needed to understand how conditions like depression develop, and why.

But there is some promise in research trying to differentiate between depression that is primarily genetic, and depression that is primarily environmental.

Differentiating between the two might help patients receive more personalized treatment, and better understand how they could affect their thoughts and symptoms.

As of yet, treatment-resistant depression can only be diagnosed once a person has gone through first-line depression treatment (taking more than one type of antidepressant for a period long enough to determine efficacy or lack thereof, in combination with frequent psychotherapy), but it does not spell a patient’s doom. There are still plenty of ways to treat treatment-resistant depression.


There Are Alternatives

Treatment-resistant depression is a subject of great interest among psychiatric researchers, with treatments that are established as well as treatments that are experimental. One treatment that has been effective in helping patients with treatment-resistant depression is transcranial magnetic stimulation, which attempts to correct the differences in the prefrontal cortex of the brain through magnetic waves, the same kind used in MRI machines.

The waves are generated by a machine and passed through the skin and skull through a specialized coil, penetrating only a few centimeters into the brain. There, they subtly affect the action potential of the neurons in targeted areas of the brain, often reducing depressive symptoms, and even causing a total remission of symptoms in some cases.

The treatment is entirely non-invasive and pain-free, and consists of five half-hour sessions per week, for four to six consecutive weeks. Unlike similar forms of neuromodulation for depression, transcranial magnetic stimulation does not require surgery, anesthesia, or a permanent device. The treatment is performed at a clinic under the supervision of a trained therapist, while fully awake.

Deep TMS is one of several different therapies developed to help patients with treatment-resistant depression, and as research continues, newer and better treatments will hopefully become available.

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