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The Centers for Disease Control and Prevention estimates that 1 in 10 American adults meet the criteria for a diagnosis of depression. Most of these people are prescribed  antidepressant medications, which are now the third most commonly prescribed drugs in America.
Adverse effects and poor clinical outcomes have caused innovative integrative physicians to evaluate and treat depression differently and to move away from the model of care dependent on selective serotonin reuptake inhibitors (SSRIs). Kelly Brogan, MD, is one of those physicians. Here Dr. Brogan discusses the rationale, strategy, and outcomes associated with her integrative treatment plan, which addresses the underlying causes of depression.


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A: SSRIs are likely ineffective because they are based on the monoamine hypothesis, which assumes an imbalance in serotonin and that simply increasing the level of serotonin will alleviate symptoms and reverse the condition. In the majority of patients, this is tangential to a true underlying cause. The fact is, increased serotonin is also associated with feeling badly. A low levels of serotonin metabolite (5H1AA) is indicative of increased serotonin turnover and the eventual increased serotonin in the synapse. Low 5H1AA has been associated with suicide, violent crime, alcoholism, bulimia, and exhibitionism.
Clinically we need to look at depression through a different lens. And that begins with identifying and ruling out any potential underlying cause or causes of the patient’s depression symptoms. We know that manifestation of distress can have many and varied emotional and physical origins. Depression can be linked to premenstrual syndrome, eating disorders, pain, irritable bowel syndrome, and other bodily illnesses.
With a focus on diagnostics, it is important to rule out autoimmunity (e.g., Hashimoto’s disease), hyperglycemia, and other physical conditions that can present as depression. In my clinical practice I start by correcting nutrient deficiencies, methylation aberrancies, and chronic inflammation. While many clinicians are aware that insulin resistance or thyroid problems can cause symptoms of depression, the connection between mental illness and methylation, inflammation, hormones, and the gut is often not considered. These should be key areas of focus.
Specific to methylation, the activity of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is critical to folate metabolism. Potential mutations in two alleles of the MTHFR gene A1298C and C677T, increase the risk of psychiatric pathology. Homocysteine is a marker of poor methylation and one of the many tests I request in patients with depression symptoms. Although estimates show a prevalence of C677T mutation from 2 to 20 percent in the general population, in my practice, over the past six years that I have been testing, all but three patients had  some form of MTHFR mutation. This underscores the high penetrance of this SNP in people suffering from depression.
We also know that folate deficiency can reduce MTHFR and subsequent methylation. Folate deficiency can cause global DNA hypomethylation, which is associated with increased cancer risk and other chronic illnesses.  Through the study of epigenetics we now know that we can influence our genes for more optimal expression. A key mechanism by which we can influence short-term DNA adaptation is via methylation. When there is a disconnect or dysfunction along the methylation pathway, problems can occur, including mental health problems potentially related to failed reduction of homocysteine, failed production of neurochemicals, or through impairment of s-adenosylmethionine, a critical methyl donor for fatty acids and antioxidants. Methylfolate (or 5MTHF) can help bypass genetic methylation mutations. Different forms of activated B12 (hydroxyl, methyl, and adenosylcobalamin) are also essential players in methylation along with methylfolate.
Research in this area has grown significantly with many clinical trials, including randomized, controlled trials, evaluating the use of methylfolate as a treatment for depression, either alone or in combination with medication. Most of the trials have employed high doses of up to 50 mg of methylfolate and reported partial to notable response rates.
It is important to note that folic acid is not methylfolate. In fact, individuals with gene variants, specifically C677T, should avoid folic acid because of the concern for limited breakdown and subsequent accumulation of this manmade agent. Currently commercial testing of blood folate does not distinguish between metabolized and unmetabolized forms. There is also concern that folic acid supplementation can mask B12 deficiency; however, methyfolate is not likely to do this. Concurrent B12 supplementation with methylfolate is recommended to help protect against potential deficiency.
Of course we know that there is rarely a one-pill solution for patients whose methylation is compromised. A diet that emphasizes whole, clean foods provides a foundation for healthy methylation. Addressing sleep issues and encouraging relaxation will also help. Diet and lifestyle counseling can provide big benefits in this patient population specific to optimal methylation.
It’s clear from the scientific literature that SSRIs are not effective for most of the patients diagnosed with depression. To successfully address this condition from an integrative perspective, the most effective treatment protocol is created from personalized diagnostics and then uses the many tools available to help correct underlying causes. In addition to methylation, another overlooked contributing factor is inflammation.
Related Published Research:
Andrews PW, Kornstein SG, Halberstadt LJ, Gardner CO, Neale MC. Blue again: perturbational effects of antidepressants suggest monoaminergic homeostasis in major depression. Front Psychol. 2011;2:159. [abstract]
Fava M, Mischoulon D. Folate in depression: efficacy, safety, differences in formulations, and clinical issues. J Clin Psychiatry. 2009;70(Suppl5):12-17. [abstract]
Prinz-Langenohl R,  Brämswig S, Tobolski O, et al. [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C: >T polymorphism of methlenetetrahydrofolate reductase. Br J Pharmacol. 2009;158(8):2014021. [abstract]
Sugden C. One-carbon metabolism in psychiatric illness. Nutr Res Rev. 2006; 19:117-136. [abstract]

I typically reassess in four to six weeks and then again after another six weeks. Outcomes measures include lab comparisons and patient subjective symptom relief. Typically after the second sixth-week evaluation, the majority of my sufficiently motivated patients experience 60 to 90 percent improvement in the presenting symptoms, and lab results are significantly improved or completely normalized.

While I use concrete measures in my practice, I certainly place high value on how the patient is feeling and whether their quality of life has been improved. Most of my patients report improved quality of life, which is my barometer.

I see my role as educator and health partner, as well as doctor. I take time to explain to my patients that in order to heal the brain, we need to heal the entire body and that means looking at some of the key underlying contributors to depression and addressing those causes.

A: Increasing scientific evidence is linking inflammation and depression. When looking through this lens we see depression as a nonspecific fever that is telling us very little about what is causing the body to react and protect itself in this way. As integrative practitioners, it’s our job to uncover the root of that fever. We begin by looking at markers of inflammation.
Serum markers of inflammation, most notably CRP levels greater than 3, correlate with resistant depression. Cytokines in the blood such as IL-1, IL-6, and TNF-alpha act as inflammatory messengers and have become predictive and linearly correlated with depression. O’Donovan et al found a link between suicidal ideation among patients with major depressive disorder and inflammatory markers. Patients with the highest inflammatory scores (specifically TNF-alpha, IL-6, IL-10, and CRP) also had correspondingly high levels of suicidal ideation.
Researchers have demonstrated that in many forms of depression monocytes express pro-inflammatory genes leading to increased cytokine secretion while simultaneously decreasing cortisol sensitivity, which is the body’s stress hormone and inflammatory buffer. This is a feedforward cycle that, once triggered, transfers inflammatory information to the nervous system. Inflammatory cytokines access the brain and then interact with nearly every pathophysiologic system associated with depression. This inflammatory response influences neurotransmitter metabolism, neural plasticity, and neuroendocrine function.
Several papers have also discussed the putative anti-inflammatory mechanisms of antidepressants, noting that IL-6 is down-regulated and in general there is a decreased inflammatory response. This may explain the transient benefits seen from the use of antidepressant medications in some people with depression. By increasing cAMP and activating brain-derived neurotrophic factor (BDNF), antidepressants may down-regulate inflammatory cytokines and enhance secretion of anti-inflammatory messengers such as IL-10. Additionally, antidepressants have been found to enhance glucocorticoid receptor sensitivity, bringing the HPA axis in line for some patients; however, the effect is eventually lost with chronic exposure to the medication.
While there are gaps in the full understanding of how exactly inflammation influences depression, we do know that this is likely a contributing factor that needs to be clinically evaluated and addressed. Preliminary data involving medically healthy depressed patients and patients with inflammatory disorders illustrates that by inhibiting proinflammatory cytokines and/or their signaling pathways, we may be able to improve mood.
With my patients previously diagnosed with depression, I start by doing a broad blood work panel that includes vitamin levels (specifically vitamin D, folate, and B12), hormonal parameters, autoantibodies, chemistry, genetic assay, etc. I also do a four-point adrenal assessment and test stool, salivary cortisol, fasting glucose, insulin, and HgA1C. In addition, I track homocysteine, hsCRP, TSH, free T3, free T4, rT3, and autoantibodies.
I carefully consider what type of diet will be best for each patient; however, with most of my patients I lean toward a higher natural fat Paleo-type diet. The goal with diet is to confer the insulinstabilizing benefits of a high-fat diet that also has a slower-burning metabolic shift to protect cortisol, thyroid, and sex hormones. Increasing natural fats may also help protect the 60 percent lipid content of the central nervous system.
In addition to diet, herbs and spices may also play a palliative role in depression via their anti-inflammatory effects. A small, randomized study demonstrated that curcumin was as effective as fluoxetine (Prozac) in major depressive disorder. Here are additional adjuvant treatments that I feel can produce a high yield with low risk:
  • Folate and B12
  • Probiotics
  • SAMe
  • Vitamin D
  • Essential Fatty Acids
  • Light Therapy
  • Cranial Stimulation
In my clinical practice I also often refer to these tools depending on the circumstance of each patient:
  • High-dose inositol
  • Amino acids (both specifically and in combination)
  • Adaptogenic herbs such as ashwagandha (Withania somnifera) or Rhodiola rosea
  • Homeopathics
From a lifestyle perspective, I counsel these patients about increasing their activity levels and helping them find ways to manage stress. For example, both yoga and meditation have been shown in clinical studies to ease symptoms of depression. If my patient is receptive, I will discuss these and other lifestyle techniques with them.
Related Published Research:
Carvalho LA, Bergink V, Sumaski L, et al. Inflammatory activation is associated with a reduced glucocorticoid receptor alpha/beta expression ratio in monocytes of inpatients with melancholic major depressive disorder. Transl Psychiatry. 2014;4:e344. [abstract]
Gibney SM, Drexhage HA. Evidence for a dysregulated immune system in the etiology of psychiatric disorders. J Neuroimmune Pharmacol. 2013;8(4):900-920. [abstract]
Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in pathophysiology of major depression. Biol Psychiatry. 2009;65(9):732-741. [abstract]
O’Donovan A, Rush G, Hoatam G, et al. Suicidal ideation is associated with elevated inflammation in patients with major depressive disorder. Depress Anxiety. 2013;30(4):307-314. [abstract]
Raison CL, Miller AH. Malaise, melancholia and madness: the evolutionary legacy of an inflammatory bias. Brain Behav Immun. 2013; 31:1-8. [abstract]
Rao NP, Varambally S, Gangadhar BN.. Yoga school of thought and psychiatry: Therapeutic potential. Indian J Psychiatry. 2013;55(Suppl2):S145-S149. [abstract]
Sanmukhani J, Satodia V, Trivedi J, et al. Efficacy and safety of curcumin in major depressive disorder: a randomized controlled trial. Phytother Res. 2013;Jul6. [abstract]
Wium-Anderson MK, Ørsted DD, Nielsen SF, Nordestgaard BG.. Elevated C-reactive protein levels, psychological distress, and depression in 73,131 individuals. JAMA Psychiatry. 2013;70(2). [abstract]
A: When antidepressant drugs were first introduced, we were told that they would correct a chemical imbalance in the bran that was causing the depression. We were also assured these drugs were safe, as well as effective. Since then, they have become “gold standard” treatments. However, over 6 decades, the scientific literature has now painted a significantly different picture.
Not a single human study has confirmed the legitimacy of the “monoamine hypothesis” as a cause of depression (or anxiety, OCD, bulimia, panic, etc). This hypothesis puts forth the idea that depression is caused by a chemical imbalance in the brain, such as a deficiency of serotonin. The monoamine hypothesis grew out of observations of mood-related side effects in the treatment of tuberculosis patients with iproniazid, which has some inhibitory impact on the breakdown of monoamines. However, based on research to date, it’s clear that we need to deconstruct the serotonin model of care for patients struggling with depression.
Many analyses have demonstrated that antidepressant drugs are ineffective in mild-to-moderate cases of depression. Benefits in depressed individuals also disappear with long-term use.. Fournier et al did find in their JAMA 2010 meta-analysis that there is evidence that antidepressant medications have a 10% advantage over placebo, for the severely depressed. Extensive research by Kirsch and colleagues demonstrates that benefits from antidepressant medications are not clinically significant, and any efficacy in trials can be attributed to an “active” placebo response. Kirsch found that when controlling for placebo response, differences between treatment and non-treatment were reduced to non-clinically significant changes. In Kirsch’s studies, the increased benefit of the medications in extremely depressed individuals was correlated with a decrease in responsiveness to placebo and not an increase in responsiveness to medication.
Perhaps the most troubling aspect associated with antidepressant medications is the increased risk of relapse and the effects associated with oppositional tolerance. In a sense, the body fights the effects of the drug, becomes tolerant, and then when the drug is discontinued, there is relapse as the system struggles for equilibrium. Antidepressants interfere with the natural self-regulation of serotonin and other brain neurotransmitters. Once medication is stopped, the brain overcorrects and that can trigger new, even more severe, depression.
Studies also indicate that antidepressant medications are not well tolerated. A 2009 retrospective chart analysis of 367 outpatients with major depressive disorder demonstrated that more than 63 percent discontinued their antidepressant without telling their physician. This can be very harmful to the patient, as discontinuation of antidepressants requires methodical tapering by a trained healthcare professional. 
Related Published Research:
Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010;303:47-53. [abstract]
Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: A meta-analysis of data submitted to the Food and Drug Administration. PloS Medicine. 2008;5(2). [abstract]
Kirsch I, Sapirstein G. Listening to Prozac but hearing placebo: A meta-analysis of antidepressant medication. Prevention & Treatment. 1998;2(2). [abstract]
Lopez-Munoz F, Alamo C, Juckel G, Assion H-J. Half a century of antidepressant drugs. J Clin Psychopharmacol. 2007;27(6). [abstract]
Sawada N, Uchida H, Suzuki T, et al. Persistence and compliance to antidepressant treatment in patients with depression: A chart review. BMC Psychiatry. 2009;9:38. [abstract]
A: DSM-IV criteria for major depressive disorder is represented by at least 5 of these 9 symptoms present on a near daily basis:
  • Feelings of sadness, emptiness, or irritability
  • Decreased interest in or pleasure from any daily activities
  • A 5% change in weight or significant change in appetite
  • Change in sleep patterns that can include insomnia or hypersomnia
  • Psychomotor agitation or change in activity levels
  • Loss of energy and fatigue
  • Inappropriate or excessive feelings of guilt or worthlessness
  • Inability to concentrate or indecisiveness
  • Thoughts of suicide and death
These symptoms must last for a minimum of two weeks to warrant a depression diagnosis. Symptom intensity must be assessed to characterize the degree of depression, with a Major Depressive Episode characterized by functional impairment. Severe episodes, beyond being typically inclusive of suicidality, can also manifest psychotic symptoms that are “mood congruent” such as paranoia and persecutory auditory hallucinations.
Related Published Research:
​Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), fourth edition. [abstract]
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Kelly Brogan

As an undergraduate at Massachusetts Institute of Technology, Kelly Brogan, MD, studied Cognitive Neuroscience and worked with Harvard undergraduates to create a public forum for the discussion of alternative medicine, directing conferences for the Hippocratic Society. She attended Cornell Medical School where she was awarded the Rudin Scholarship...
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