Benton Bramwell, ND, and Matt Warnock
It seems that chronic stresses commonly precipitate depression. Below, we review the prevalence of Major Depressive Disorder in the United States and explore evidence that informs our understanding of what is happening in the brain during depression and how effective treatments help to reshape and support healthier function of neuronal circuitry. Many effective interventions for depression, as outlined below, share effects that lead to enhanced Brain-Derived Neurotrophic Factor (BDNF) signaling.
Scope of Depression and Overall Effectiveness of Treatment
Based on data from a nationally representative sample, the lifetime prevalence of Major Depressive Disorder (MDD) in the United States is about 20.6% (SE 0.37), with an annual prevalence of 10.4% (SE 0.25).[1] The data also indicate a positive correlation between depression and anxiety disorders, as well as higher risk among females. Moreover, those with moderate or severe MDD in the last year showed decreases in mental, social, and emotional function (based on ratings of the Short-Form Health Survey) that were roughly 1 standard deviation below mean levels of those who had never experienced MDD. These findings underscore the widespread impact of MDD on functional capacity in daily life. Thus, the data speaks to MDD being a problem commonly encountered in life that has substantial effect on functional capacity. In addition, in a nationally representative sample of 484,732 adults, major depressive episodes are strongly associated with suicide attempts, with an adjusted odds ratio of 2.90 [95% CI 2.57-3.27].
Patients often respond to treatment over time, achieving complete remission rates of 70% to 90%; however, 10% to 30% of patients only see partial improvements or no improvement at all.[2] Additionally, since medications may take several months to work[3] and doctors may need to try several options sequentially, patients can experience long, frustrating delays before achieving potential remission rates. The STAR*D trial exemplifies serial treatment, encouraging outpatients who did not respond to initial treatment with Citalopram to try different additional treatment steps through a total of 4 steps of intervention.[4] The trial also monitored those who achieved remission. Most remissions occurred within the first two steps: 36.8% of subjects reached remission after the first step, 30.6% after the second step, 13.7% after the third step, and 13% after the fourth step. Those who completed the second step of treatment had been in treatment across the two steps for an average of 19.1 (SD6.9) weeks, while those who completed all 4 treatment steps were in cumulative treatment for an average of 37.9 (SD 8.9 weeks). Thus, in this example of serial treatment, it was not uncommon for a person to be in treatment for multiple months before entering remission. The cumulative remission rate across this study’s four steps was 67%.
What Is Happening in Brain Tissue When People Feel Depressed?
Understanding the changes in brain tissue as depression develops is challenging due to the sensitivity and inaccessibility of the tissue. Additionally, when imaging techniques like MRI and functional MRI reveal unique features in brain tissue, it raises questions about whether these findings are precipitating causes of depression, reflections of changes caused by the condition, or the result of other biological factors.[5] Many changes may also occur due to aging or be sex-specific differences. Given the complexity of MDD and individual variation in structure, there is not a single structural abnormality that can consistently explain MDD.[6] In this sense, perhaps the brain can be seen as wonderfully complex and powerful, with multiple potential points of failure.
Nonetheless, there are some general patterns seen in studies of functional MRI that seem to emerge during both depression and effective treatment. For example, functional MRI studies suggest increased hyperactivity of the amygdala and altered connectivity of the amygdala to other structures in both patients with depression and subjects with a history of depression.[7],[8] Interestingly, there is also evidence that treatment with SSRIs helps to reduce this hyperactivity of the amygdala.[9] In terms of communication between large brain networks, meta-analysis of fMRI studies suggests patterns of hypo- and hyperconnectivity (hypoconnectivity within the frontoparietal network and between frontoparietal tissue and parietal regions; hyperconnectivity within the default network) that could lend toward dwelling on internal thoughts instead of engaging with the outside world as well as altered connection between areas of cognition and emotional processing.[10] If the collective message of this data is that depression is characterized by changes in brain structure that are attempts to compensate when we do not feel safe connecting with our outside environment and those in it, then this is an important message to recognize. When seasoned clinicians who mentored us commented that much of the world’s difficulties are rooted in fear, they spoke with real insight.
Working from Clinical Effect Back to Neuronal Circuitry: The Example of Ketamine
The challenges of placing observations within a clear context are not unique to imaging. However, there are instances where clinical benefits can be observed and subsequently traced back to specific brain tissues affected. This approach describes the ongoing research into the antidepressant effects of ketamine.
Homeostatic plasticity. One of the advancing hypotheses is that ketamine (and its enantiomer esketamine, which FDA approves for treatment of refractory depression) may exert antidepressant effects through actions of homeostatic plasticity. Homeostatic plasticity is the process by which neurons and nerve circuits maintain stable functionality. This involves mechanisms such as a neuron monitoring its own calcium levels and adjusting its firing rate by altering the number of glutamate receptors at synapses. On a larger scale, adjustments may also shift the balance of a network between inhibition and excitation. [11]
A team, including Kavalali and Monteggia, has worked extensively[12],[13] to elucidate and frame a working model of the antidepressant effects of ketamine reported clinically by Berman.[14] This model posits that ketamine’s rapid antidepressant action begins when spontaneous transmission in the hippocampus is interrupted as ketamine antagonizes the NMDA receptor, blocking its ion permeation pore. This blockade leads to unsuppressed translation of BDNF, and a rise BDNF levels within hours. Elevated BDNF levels then stimulate movement of AMPA receptors to and from synapses, a process referred to as synaptic trafficking. This trafficking enhances the strength of excitatory synaptic transmission.[15] Increased neurite growth is also characteristic of elevated BDNF levels. Additionally, the signaling responsible for these rapid effects is also suggested to lead to downstream signaling that begins the longer process of transcriptional changes. These changes include the phosphorylation of the transcriptional regulator MeCP2, involved in the regulation of gene expression that may enhance the effectiveness of subsequent ketamine treatments.
A key question is whether the dissociative (conscious altering) effects that sometimes occur with even low doses of ketamine are necessary for its antidepressant effects. At present, there does not appear to be a clear consensus on this important point. A systematic review of 8 studies in 2020 found that 3 of the studies showed a correlation between dissociative/psychotomimetic effects of ketamine and its antidepressant effects. If indeed it is the case that dissociative effects are not needed for ketamine to exert antidepressant effects, then this may be an important point of difference between ketamine and psychedelics such as psilocybin, characterized by serotonin agonism. Clinical trial data published on psilocybin,[16] for example, suggests that psychoactive symptoms seem integral to the production of the reported dramatic antidepressant effects.
However, it is also essential to highlight recent research reporting the potential for the creation of psychedelic analogs that show antidepressant but not hallucinogenic effects.[17] It may be the case that psychoactive effects are not needed for antidepressant effects of either ketamine or serotonin agonists. Perhaps most importantly, proof of principle research is showing that the plasticity and antidepressant effects of both ketamine and the psychedelics known for serotonin agonism both depend on endogenous BDNF signaling.[18]
If BDNF signaling is the most important, converging conduit for the acute and sustained antidepressant effects of both types of drugs, then several opportunities to harness that benefit may exist. One option may be the already occurring practice of administering subanesthetic amounts of ketamine. Another option may be the use of a combination of even smaller microdoses of ketamine and other like-acting BDNF-enhancing substances, similar to or including the non-hallucinogenic psychedelic analog previously referenced. All options should include administration in a safe setting where healthcare providers can address any arising medical needs.
Bright Lights, St John’s Wort, and a Little Bit of Spice
Bright light therapy, one of the least invasive and best-tolerated treatment options for nonseasonal MDD, may also produce effects linked with BDNF. In a randomized, double-blind, placebo-controlled trial, 32 subjects received light monotherapy (10,000-lux fluorescent white light box for 30 min/d), 31 received fluoxetine monotherapy, 29 received light therapy plus fluoxetine, and 30 received placebo.[19] The Montgomery-Åsberg Depression Rating Scale (MADRS) was used for assessment over 8 weeks of intervention. The mean (SD) changes for the light, fluoxetine, combination, and placebo groups, respectively, were 13.4(7.5), 8.8(9.9),16.9(9.2), and 6.5(9.6). The effect sizes for both the combination and light only group were large (for the combination group d = 1.11; 95% CI, 0.54 to 1.64; for the light only group d = 0.80; 95% CI, 0.28 to 1.31) while the effect size for fluoxetine was much smaller (d = 0.24; 95% CI, -0.27 to 0.74). Additional work reports an increase in BDNF levels in patients with major depression who respond to bright light therapy.[20] While treatment of depression already often includes multiple interventions along with pharmacotherapy, such as psychotherapy or behavioral therapy, perhaps it is time to start seeing a treatment program without a trial of bright light as less complete.
It is becoming increasingly clear that St John’s wort (Hypericum perforatum) is as effective,[21],[22] and perhaps even more so[23] than SSRIs in the treatment of major depressive disorder, with fewer adverse effects. What is less clear is an understanding of which portions of neuronal circuitry are most affected by constituents of the herb. Interestingly, one of the actives from St. John’s wort, hyperforin, has been shown in vivo in mice to increase the number of receptors for BDNF (TrkB receptors) in brain cortex,[24] potentially explaining an effect in cortex circuitry mediated through BDNF signaling. With other reports of inhibition of multiple neurotransmitter uptake, including norepinephrine, epinephrine, serotonin, and glutamate, it also seems likely that St. John’s Wort affects a relatively large breadth of neuronal circuitry compared to pharmacotherapies that are selective in action to a single neurotransmitter.
An additional site of action may be upon vagal afferents synapsing in the Nuclear Solitary Tract (NST) of the medulla, with the NST impacting control of functions such as heart rate, blood pressure, and respiration through connections and projections to higher centers of the central nervous system, including the hypothalamus. St John’s wort has been shown to increase calcium levels in vagal afferents to the NST, thus facilitating glutamate release in its neurons.[25] There is also reference in the literature to St John’s wort, in combination with Eleutherococcus, successfully dampening a heightened functional connectivity between the right ventral caudate and the left orbitofrontal cortex evident in mild to moderate depression, while also reducing right ventral caudate volume.[26] These changes were associated with improved cognition in the patients.
Saffron (Crocus sativus) also shows potential as a supportive botanical in treating depression, although its effects may not be consistent enough to recommend its use as a standalone intervention.[27] Mechanistically, it appears that saffron’s antidepressant effects are at least associated with increased levels of proteins in the hippocampus, including BDNF, CREB, and phospho-CREB.[28] While we often think of synergism in terms of interactions occurring among botanical ingredients, there is also a potential for synergistic benefit across modalities. In this case, researchers have demonstrated a synergistic effect in a rodent model when combining both physical exercise and saffron. When rats were given aqueous extract of saffron or exercise singly or in combination, the combination of saffron and exercise was able to increase hippocampal levels of both BDNF and serotonin vs control while the single interventions did not.[29]
Closing Thoughts
Of course, there is still a lot to learn about how to best help patients with depression. Emerging evidence suggests that one of the most important mediators of antidepressant action is BDNF. Viewing effective BDNF signaling as the common goal of a comprehensive plan that includes appropriate medications, both botanical and pharmaceutical, as well as other BDNF-supporting interventions, such as bright light therapy, may hold promise for a more effective approach to treatment.
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Published May 18,2024
About the Authors
Benton Bramwell, ND, is a 2002 graduate of National College of Naturopathic Medicine who practiced primarily in Utah while helping to expand the prescriptive rights of naturopathic physicians in that state. Currently, he owns and operates Bramwell Partners, LLC, providing scientific and regulatory consulting services to both dietary supplement and conventional food companies. He and his wife, Nanette, have six children and two grandchildren; they live in Manti, Utah.
Matt Warnock is an accidental herbalist, who received his MBA and Juris Doctor from BYU, then worked as an attorney, litigator, and business consultant until 2000. He then joined RidgeCrest Herbals, a family business started by his father, and started learning about herbal medicine, focusing especially on complex herbal formulas. He has two U.S. patents for herbal formulations and methods. He lives near Salt Lake City with his wife, Carol; they are the parents of three children and four grandchildren.