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When antidepressants fail: Are we looking at a new kind of depression?

Depression is one of the most frequently diagnosed mental illnesses, with an estimated 15 percent of the global adult population experiencing depression at some point in life. Antidepressants are a common treatment, but between 30 and 40 percent of those taking the medication do not respond. Some research suggests that almost half of all depressed patients may have treatment-resistant depression.

A team of researchers at a Japanese university recently provided new insight concerning the problem of antidepressants’ notoriously high failure rates. The team identified the mechanisms behind what some are calling a new form of depression. Though preliminary, their work could lead to the development of new antidepressants that stand to make the overall pharmacological treatment of depression more successful.

“For almost 40 years I tried every antidepressant doctors threw at me, to no avail,” writer and producer Hyapatia Lee told the Genetic Literacy Project. “I felt belittled, ignored, and personally attacked because my body did not respond as others felt it should. … My doctors did not explain anything to me. They blamed me for my situation,” said the 57-year-old, who currently resides in Southern Colorado. “It should not be incumbent upon those of us suffering [with depression] to magically transform into medical professionals and researchers to diagnose ourselves at a time when we are severely incapacitated to begin with.”

Lee’s experiences with treatment-resistant depression led her to look outside conventional medicine. “I coped by turning to my Native American traditional leaders, elders, and roots,” she said. But it was the uncovering of underlying medical conditions that helped solve the problem decades later, after Lee “had been on just about every antidepressant you can name since the late 1970s.”

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The responses of Lee’s doctors may betray a certain blindspot in the medical community when it comes to treatment-resistant depression. Suggestions given to patients with treatment-resistant depression are frequently along the lines of reminding them to take their medication as directed, stop using drugs and alcohol, manage stress in their lives, get enough sleep and exercise, and focus on healthy eating. In other words, when regular treatment for depression doesn’t work, the finger is often pointed at the patient for what they are and are not doing in their lives to handle their depression.

And other treatment options for treatment-resistant depression include electroconvulsive therapy, repetitive transcranial magnetic stimulation and vagus nerve stimulation. These options do have rare but serious side effects and are not always effective. For example, electroconvulsive therapy (ECT) works well for some and not for others. Some ECT recipients felt no improvement in symptoms following treatment, some said the effects were initially beneficial but wore off quickly, while others said that ECT helped on some occasions but could not be counted upon to help each time. One individual named Tracy was discussed on the University of Oxford’s HealthTalk site: “Tracy suffered from post-natal depression as well as depression at other times of her life. She does not think ECT had any effect on her except to wipe her memory.”

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ECT 7 2 18The prevailing framework for treating depression is over 50 years old and is based on the monoamine hypothesis. Any other hypotheses that have since emerged are in their infancy, and have not led to pharmaceuticals with improved antidepressant activity.

The monoamine hypothesis of depression is based on the idea that depression is caused by decreased levels of serotonin, norepinephrine and dopamine. About 90 percent of antidepressants target the imbalance of these monoamine neurotransmitters. The monoamine hypothesis appears to hold true for most cases of depression, but certainly not all.

Some experts, such as Johan A. Den Boer, Senior Director of PRA Health Sciences in the Netherlands and professor of Psychopharmacology and Neuroscience at the University Medical Centre Groningen, have noted that “depression cannot be regarded as a single construct.” When expressed in this way, depression could be understood as several illnesses masquerading as one.

Patients who do not respond to monoamine-directed medications may have a newly discovered form of depression — one based on the levels of a protein called RGS8, encoded by the RGS8 gene, according to a study led by Hiroshima University. The results were published in Neuroscience in May.

The RGS8 protein controls a hormone receptor called MCHR1, or melanin-concentrating hormone receptor 1, which plays a role in regulating sleep, eating behaviors, and mood responses. Previous research has shown that RGS8 inactivates MCHR1, and having low or depleted levels of RGS8 leads to increased symptoms of depression. This points to a neuropeptide explanation for some instances of depression.

The Hiroshima study offered the first-known findings supporting “a modulatory role of RGS8 in the neurobiology of depressive-like behavior,” and was the first to examine RGS8’s effect in mouse models.

The researchers generated mice whose brains overexpressed RGS8. The mice were then tested alongside wild type mice (aka, the normal form of the species) to assess depressive behaviors. The mice did a swim test, which is a common and reliable method to gauge levels of depressive response in rodents. The mice with overexpressed RGS8 showed shorter immobility times compared to the wild type mice, indicating less depressive behaviors.

Research on these findings is only preliminary, but RGS8 is a promising candidate in efforts to create new antidepressant drugs for some individuals with treatment-resistant depression.

Kristen Hovet is a journalist and writer who specializes in psychology, health, science and the intersection of sociology and culture. Follow her on her website,  Facebook or Twitter @kristenhovet.

 

9 thoughts on “When antidepressants fail: Are we looking at a new kind of depression?”

  1. We use to differentiate depression as functional or organic. Now the primary focus is on neurotransmitters. This has been very good for the pharmaceutical industry but has not helped in determining who has and who doesn’t have depression. If the dysfunction is too little of a neurotransmitter, why can’t that be evaluated as a sign as opposed to current checklist of symptoms? Does this have any implication on normal sadness as opposed to major depressive disorder? How does psychotherapy impact an organic disorder? Does depression represent a continuum or is major depressive disorder categorically different?

  2. “The prevailing framework for treating depression is over 50 years old and is based on the monoamine hypothesis”

    I’d distinguish the prevailing “framework” from the prevailing treatment options. I’m a cardiologist, not a psychiatrist, but as long ago as my medical school days we were critiquing the “monoamine” approach as what one of my psychiatrist colleagues ridiculed as comparable to an Aspirin Deficiency theory of headaches: headaches must be caused by a deficiency of aspirin, since taking aspirin leads to headache relief. Manipulating neurotransmitters may be a (slightly) more effective way of producing a beneficial outcome for patients with MDD, but my psychiatrist pals seem to recognize that these knee-jerk assumptions about causes — the “framework” — are groundless.

    As an alternative, consider Arthur Kleinman’s approach to “Core Depressive Syndrome,” including the fact that, from a global point of view, the Western (including American) experience of the phenomenon we call Depression is highly unusual, and only emerged in the late 19th and early 20th century.

  3. “A new kind of depression”? Unlikely. Is the implication there has been a genetic mutation resulting in a new kind of depression. I don’t think so. Unlike DavidT suggests, depression has been around at least as long as mankind. We usually refer to sadness. But why is a person sad? Is this a result of some social environmental factor? Or is this the result of some sort of neuro pathology? Is this a medical problem? With the monoamine hypothesis calling it a medical problem is stronger. The goal is then to correct the monoamine dysfunction. But what if there is an environmental stressor? Is the cause neurological or environmental? The answer is not known. What treatment is best, biological or psychological? Again the answer is not known. Will this “new kind of depression” get a new code in the DSM? I doubt it, and hope not. Don’t we already have enough subtypes? Adding a new subtype with a dearth of data is not a good idea. Why we don’t even know if Major Depressive Disorder is a discrete category or just on a continuum of sadness.

    • Depression is far more than just being sad. And why would you object to a distinct disorder getting a distinct code in the DSM? If the evidence is there?

      • Because it leade further to diagnostic expansion and diagnostic dilution. Already atypical depression, seasonal depression, premenstrual depression, melancholia. Now another? Based on what? More symptoms for the checklist but still no signs. The assumption is that this a brain disorder. If so why if you have a postmortem brain you can do any macroscopic or microscopic test a never be able to tell if the person was even suffering from depression. Are disorders in DSM suppose to be medical problem? Is this a medical problem?

  4. “Suggestions given to patients with treatment-resistant depression are frequently along the lines of reminding them to take their medication as directed, stop using drugs and alcohol, manage stress in their lives, get enough sleep and exercise, and focus on healthy eating. In other words, when regular treatment for depression doesn’t work, the finger is often pointed at the patient for what they are and are not doing in their lives to handle their depression.”

    If you’re depressed, it’s a very good idea indeed to refrain from drugs & alcohol , manage stress, get adequate sleep and exercise, and eat a healthy diet. This is quite simply unarguable.

      • I agree. However, the passage I quoted implies that making the practical suggestions listed amounts to blaming the patient. This simply isn’t true. On the contrary, not advising e.g. a weed-smoking depressive/schizophrenic to refrain from cannabis is quite frankly a dereliction of duty.

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