Many world events are depressing. Wars, climate catastrophes, and mean people threatening democracy and social cohesion are depressing. Even the holidays can be depressing for many people.
I’m not a psychiatrist. But every day I work with people who are being treated for depression. And I’m the one treating them. Like with so many problems, primary care doctors end up being the first line of help. Available psychiatrists and counselors can be hard to find, expensive, and require a greater level of commitment from people than just seeing their family doctor. We follow guidelines for diagnosis and treatment, and most people seem to improve. But by necessity, convention, and patient preference, we rely heavily on medications like Lexapro and Zoloft. These SSRI’s increase serotonin levels in the brain. Yet even though I’m not a psychiatrist, I have watched the paradigms shifting during my two decades of practice. Depression is a big tent diagnosis. We are learning that it has many causes, and that for each individual there are multiple factors in play besides low serotonin.
One in five people in the United States is diagnosed with major depression during their lifetime, and one in 10 copes with depression in any given year. Women have twice the risk of depression as men.
In this double length post I’m going to highlight a recent study that piqued my interest in which depression was explained to patients as a natural adaptation to their troubled surroundings instead of a disease. I’ll touch upon a meta-analysis from last year that some consider the nail in the coffin for the serotonin hypothesis of depression. We will then review some of the newer causes of depression that are being discovered, acknowledged, and researched. And finally we will conclude with the evidence based treatments that have been shown to help people with depression.
If you are one of the 80% of people who believe that depression is simply a chemical imbalance in the brain, you are obviously not alone in this oversimplification. And by oversimplifying the cause, many are missing opportunities to better understand what they are feeling, why they are feeling it, and what should be done… besides just taking a pill.
Depression loosely defined
First of all let me state that “depression” is used in a more general sense in this post, i.e. not severe or treatment-resistant depression. Think garden variety. When someone is diagnosed with depression in a primary care setting, they are suffering from some combination of persistent feelings of sadness or emptiness, loss of interest or pleasure in activities, changes in appetite and sleep patterns, fatigue, difficulty concentrating, feelings of worthlessness or guilt, and even thoughts of death or suicide. Basic life functioning and relationships are affected.
Why serotonin might be involved in depression
For decades the medical consensus centered around “low serotonin levels.” As stated previously, when polled about the cause of depression, up to 80% chose a “chemical imbalance.” This prevailing idea was kicked off by research in the 1950’s centered around a tuberculosis drug which coincidentally made some people’s moods improve while taking it. As a side effect, the drug was found to increase amine levels including serotonin, and this spawned a pharmaceutical target. Specific drugs like Prozac and the rest of the SSRI’s (selective serotonin reuptake inhibitors) soon followed.
Evidence is building that depression is not that simple
Despite the fact that SSRI’s do help people more that placebo, the primary role of serotonin in depression has been overstated. I’ll quote an excellent article from Quanta Magazine that I read back in January of this year:
A literature review that appeared in Molecular Psychiatry in July was the latest and perhaps loudest death knell for the serotonin hypothesis, at least in its simplest form. An international team of scientists led by Joanna Moncrieff of University College London screened 361 papers from six areas of research and carefully evaluated 17 of them. They found no convincing evidence that lower levels of serotonin caused or were even associated with depression. People with depression didn’t reliably seem to have less serotonin activity than people without the disorder. Experiments in which researchers artificially lowered the serotonin levels of volunteers didn’t consistently cause depression. Genetic studies also seemed to rule out any connection between genes affecting serotonin levels and depression, even when the researchers tried to consider stress as a possible cofactor.
Are SSRI’s effective treatments?
So if serotonin is not the primary driver of depression, why are we still prescribing meds that increase it? Zoloft (sertraline) and Lexapro (escitalopram) are considered first line medications for primary care doctors and psychiatrists to utilize. And in my experience most people tell me they help. I was actually fairly surprised by the numbers found in meta-analyses though:
The rate of remission in milder depressive episodes… was greater with active drugs than placebo (50 versus 37 percent of patients); the rate of remission in more severe episodes was also greater with active drug than placebo (38 versus 25 percent).
These numbers certainly seem a bit low to me as a clinician. I feel like 75% of the people I treat report improvement. Other individual studies I found put the number in the 60-70% range, too. But there is an undeniable placebo effect that works at least 30% of the time. This may be explained by:
The small advantage of antidepressants over placebo in depressed patients is due in part to the nonspecific clinical effects of placebo treatment; receiving placebos in clinical trials is not equivalent to receiving no treatment. Depressed study patients who are treated with placebos receive nonspecific support by meeting regularly with clinicians and research assistants to discuss symptoms and functioning. Placebos may act by instilling hope, raising expectations of improvement, and motivating patients to please investigators.
What are some of the other contributing factors in depression?
If serotonin levels are not the primary cause of depression, and increasing serotonin levels only helps with clinical remission in as low as 50% of patients treated, then what else is going on?
Natural adaptation
I read a very interesting study recently that looked at framing the diagnosis of depression for patients in a different way. Instead of telling them that depression is a disease, they were educated that depression can be an adaptation to one’s stressful environment. In this sense, depression is a functional signal that alerts the individual that something in his or her life needs more attention. The study showed that this different sort of explanation created more positive beliefs that people could overcome their depression, consider depression as an adaptive response that could lead to new insights, and feel less stigma associated with mental illness.
I texted my good friend (who is an actual, brilliant psychiatrist) about this “depression as an adaptation” paradigm. Off record, he told me that it is both helpful and potentially harmful. At best it looks at the whole person - biologically, psychologically, and socially. But the problem is the execution of a therapy built upon this understanding. Providers may step in and offer solutions, missing the fact that the patient is smart enough to solve those problems and isn’t solving them for a reason. There are tradeoffs between the problems we have and the problems created by dealing with them.
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* This post was originally published on a substack I write called Examined — please sign up with me if you appreciate this article ;}
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Other neurotransmitters
There is ongoing research into other neurotransmitters in our brains such as tryptophan, norepinephrine, dopamine, GABA, and glutamate - all of which affect mood regulation and behavior. Yet the same insufficiencies that reduce depression to simply a chemical imbalance of serotonin likely apply to each of these as well.
There is a lot of evidence coming out right now about the gut, our microbiome, and the neurotransmitter signaling between these worlds and how it affects our mood, behavior, and risk of depression. “Modified diet, fish and omega-3 fatty acid intake, macro- and micro-nutrient intake, prebiotics, probiotics, synbiotics, postbiotics, fecal microbiota transplantation, and 5-HTP regulation may all be utilized to alter the gut microbiota as a treatment approach.” Until these specific interventions are better ironed out, eating a healthy diet is foundational for so many things. Of course you’ve heard that ad nauseam… but it’s true nonetheless.
Genetics
This is a big one, but also a very tangled one. Over 200 genes have been identified as being associated with a higher risk of developing depression, and several hundred more are possibly related. Such complexity across multiple chromosomes defies a simple mechanism to explain or treat depression. Dr. John Krystal, Chair of Psychiatry at Yale, noted in this article that:
…studies of twins suggest that genetics may account for 40% of the risk of depression. Yet the currently identified genes seem to explain only about 5%.
Moreover, simply having the genes for depression doesn’t necessarily guarantee that someone will become depressed. The genes also need to be activated in some way, by either internal or external conditions.
And then there’s epigenetic switches that are turned on and off between generations in a family. These are often triggered and controlled by stress. It gets really complicated quickly, just like our families at the Thanksgiving table.
Brain structure
Our current brain wiring and connections play a large part in depression as well. Brain scans (functional MRIs) have shown that the brains of acutely depressed people differ structurally from those of a non-depressed control group. People experiencing depression showed fewer connections within the “white matter” of the nerve fibers in their brains, for example. And the best part of this finding has been the ability of the brain to remodel itself to some degree:
After the depressed group underwent six weeks of treatment, Dr. Repple’s team ran another round of brain scans. This time, they found that the general level of neural connectivity in the depressed patients’ brains had increased as their symptoms lessened. To get the increase, it didn’t seem to matter what kind of treatment the patients received, so long as their mood improved.
A possible explanation for this change is the phenomenon of neuroplasticity. “Neuroplasticity means that the brain actually is able to create new connections, to change its wiring,” Repple said. If depression occurs when a brain has too few interconnections or loses some, then harnessing neuroplastic effects to increase interconnectedness might help lift a person’s mood.
Chronic inflammation
Impaired brain connections in depressed patients might be influenced by inflammation, which can degrade synaptic connections and contribute to mood disorders. For example, in one study inflammation was induced using interferon alpha treatment, and depressive symptoms were triggered.
However, in real life cases, the source of inflammation contributing to depression might be from autoimmune disorders, infections, stress, lifestyle and diet, or viruses like Covid. I have definitely seen people with new anxiety and depression problems after Covid. Researchers are also exploring the chicken-and-egg relationship between inflammation and depression, questioning whether depression causes inflammation or vice versa, and considering the complexities in developing anti-inflammatory treatments for depression.
Depression as an umbrella term
Some are advocating for reframing "depression" as an umbrella term encompassing various related conditions. While different types of depression may share common symptoms like fatigue, apathy, appetite changes, suicidal thoughts, and sleep disturbances, they may stem from diverse combinations of environmental and biological factors, including chemical imbalances, genes, brain structure, and inflammation. In the future, depression won't be treated as a singular entity but rather as a range of conditions requiring personalized therapeutic approaches. In some ways we do this already, as each person’s story, goals, and treatment preferences are unique. This shift toward a nuanced understanding of depression's complexity may involve diagnostic tools to determine the most effective treatment for an individual, encompassing cognitive behavioral therapy, lifestyle changes, neuromodulation, talk therapy, medication, or a combination thereof.
Clinical treatment summary
With the risk of this post getting too long, and in recognition that treatment plans for people must be individually discussed and uniquely tailored to their situation and preferences, I will simply distill the current guidelines. The experts writing for UpToDate recommend that for the initial treatment of (unipolar) major depression, medication plus psychotherapy, rather than pharmacotherapy alone or psychotherapy alone, has good quality evidence.
The following bullet points are sourced from an article in American Family Physician, and follow guidelines established by the Department of Veterans Affairs. These guidelines are slightly different than the expert opinion above, and give different recommendations for therapy + meds based on mild versus severe symptoms. The key points are:
• In uncomplicated major depression, combining medications and psychotherapy is not more effective than monotherapy.
• For severe, persistent, or recurrent major depression, combining medications and psychotherapy is more effective than monotherapy.
• Continuing medications for at least six months after symptom remission will reduce relapse by nearly one-third.
• When patients with symptom remission are at high risk of relapse, cognitive behavior therapy, interpersonal therapy, or mindfulness-based cognitive therapy can reduce relapse risk.
Other treatments that have been studied and show measurable benefit include:
Exercise improves symptoms in major depression. Bibliotherapy, or reading literature as psychological support, is more effective than usual care. Light therapy improves symptoms whether they follow a seasonal pattern or not. Biofeedback and meditation may have slight benefit as adjunctive therapies, although evidence is very low quality.
Additional options
Here is a quick rehash of some non-pill based interventions that can help, some of which have already been mentioned but deserve their own paragraph here.
Psychotherapy, particularly cognitive-behavioral therapy (CBT), provides a structured approach to identifying and modifying negative thought patterns. Regular exercise, even in the form of moderate activities like walking, has been shown to positively impact mood. Adopting a healthy lifestyle, including maintaining a balanced diet, regular sleep patterns, and minimizing alcohol and substance use, contributes to overall well-being. Mindfulness practices and meditation foster self-awareness and reduce stress. Social support, whether through relationships with friends and family or participation in support groups, is very helpful. Sunlight exposure during daylight hours can positively influence mood, and creative outlets such as art and music can be uplifting. I am partial to the blues. Volunteering and engaging in community service provide a sense of purpose, especially in those who are not working or are retired. Mind-body techniques like yoga and tai chi combine physical movement with mindfulness.
Take away
Depression severity exists along a continuum, and is really a complicated umbrella term that encompasses a variety of states and causes, some known and some being discovered and researched. It is perhaps best understood as part biology, part psychology, and part social circumstance. The reductionist paradigm in which a simple chemical imbalance is to blame, specifically a deficit of serotonin, has largely been discredited. Instead there is complex interplay between multiple neurotransmitters in the brain, our environments, genetics, guts, and inflammation, to name a few of the leading contributors. Treatment in the future will better encompass all of these factors and more. Ultimately life circumstances play a large role in depression, and some models consider depression as an adaptation. For anyone who has been depressed, or is currently depressed, the feelings can really impact the arcs of our lives, the relationships we sustain, and the opportunities we seize or let go. In terms of what is recommended in quick primary care settings, most guidelines and evidence suggest that starting with a combination of medication and therapy works best, but there are other methods we can harness to help ourselves like exercise, healthy diet, and enough sleep. If you need help ask for help, be compassionate with yourself, and realize that the roads leading to what can feel like a dead end are many, overlapping, and easily taken. A pill is often part of the solution, but is rarely the only intervention that is working. Connection, hope, and expectation of improvement might be essential parts of that little serotonin-enhancing pill.
* This post was originally published on a substack I write called Examined — you can sign up with me if you appreciate this article :)