When SSRIs Fail: Causes of Depression

Clinical depression is far more than just the momentary blues or an off day. It is a serious mental health disorder with severe consequences that include self-harm and increased risk of major cardiovascular events. Nearly 15 percent of the population is affected by depression, many who struggle despite the standard medical treatment of SSRIs, (Selective Serotonin Reuptake Inhibitors, e.g. Celexa, Prozac, Zoloft, Paxil, etc.) SNRIs, MAOs, or tricyclic antidepressants. Often it takes several weeks of treatment before a person sees partial relief, and yet only one to two out of ten patients show significant clinical effects beyond a placebo or “sugar pill” effect. Medication failure rates vary depending on the studies, but the trend is alarming. Clearly, a very large percent of those who suffer from depression are not helped by antidepressants. This is known as treatment resistant depression.

There are some new paradigms shifts occurring with depression treatment and research. Rather than looking only at a neurotransmitter deficit or imbalance approach with serotonin, dopamine, or norepinephrine, scientists are looking at excess glutamate levels and NMDA receptor activity. Some are looking at the brain-gut pathway and how dietary tryptophan is transformed into serotonin or if it is shunted into other toxic compounds within the brain. Other scientists are looking at mitochondria insufficiency and depression.

Each research area focuses on a process that provokes inflammation within the brain. Each viewpoint essentially comes to a similar conclusion, focusing solely on propping up certain neurotransmitters within the brain is a nearsighted viewpoint, old school, and some even consider a myth. Individuals with treatment resistant depression or serious depression need more than a band-aid that may or may not work. This new information opens the door for better management, support, and relief.

There are certainly many important factors that influence depression management and success in addition to the three hot topics listed above. While they are not the focus of this article, they do deserve mention. These include brain inflammation from a high inflammatory diet; gluten intolerance and Celiac disease; cortisol/adrenal and melatonin imbalances; leaky blood brain barrier and traumatic brain injuries; estrogen, progesterone and testosterone imbalances; serotonin, dopamine, acetyl-choline, or GABA neurotransmitter imbalances; anemia or poor oxygenation to the brain; autoimmune reactions; gut flora imbalances; MTHFR and COMT methylation gene defects; loss of stress tolerance; poor blood sugar and blood pressure regulation and more. These concerns will further tax the brain especially in light of some of the new findings. Address them with the help of an experienced health care professional.

Glutamate – Friend or Foe?

Glutamate is a major excitatory neurotransmitter within the brain. We need glutamate to maintain alertness, focus, productivity, and energy, but it needs to be in balance. It plays important roles with how synapses stay pliable and flexible, if there is new synapse formation, or if the synapse stays “turned on”. A synapse is a structure that permits nerve cells to pass an electrical or chemical signal to another cell. The end of the nerve or pre-synaptic ending before the synapse occurs contains neurotransmitters, mitochondria, and other cell organelles. Increasing evidence suggests that several psychiatric disorders including major depression, schizophrenia, and bipolar have too much glutamate signaling present. The receptor or “catchers mitt” for glutamate is called the NMDA receptor. Too much glutamate dumped into the synapse or too much NMDA receptor activity is involved with the development of these disorders. This is a prime target area of research.

Scientists studying excess glutamate and NMDA activity are turning to the use of ketamine for the treatment of depression. The traditional medical use of ketamine is an anesthetic or a dissociative psychedelic. It is in the same class of meds as Propofol and nitrous oxide (laughing gas). Recommendations are being made to use this as treatment for depression because it blocks the NMDA receptor site, so that glutamate is not available for use. It is given in single or multiple intravenous doses, oral or intramuscularly, for medical treatment of severe clinical depression. Research shows that it works rather quickly for many with severe, unretractable depression, but at what long-term cost? How does it affect long-term mitochondrial health, liver detoxification, and addiction risks? Just a few years ago, Propofol was in the news as the drug involved with the overdose of the pop star Michael Jackson. The concern is simply, is there something safer and easier on the body that can help calm down the excess glutamate and NMDA activity? The answer is yes! But, before that question is answered, let’s look at another imbalanced pathway that provokes depression since they are related.

Tryptophan, Serotonin, and Quinolinic Acid

The management of tryptophan converting to serotonin within the brain has some complex moving parts. Tryptophan gets converted into serotonin with the help of zinc, B3, B6, folate, calcium, magnesium, iron and vitamin C. High levels of stress of any type and acute/chronic infections can change this process by provoking an immune system response. An enzyme called IDO (indoleamine 2,3-deoxygenase) becomes activated. It pushes tryptophan down a tricky path that may or may not be healthy depending on how much anti-inflammatory, antioxidant reserves you have. Instead of serotonin being made from tryptophan in this process, two other compounds are eventually made. They are kynurenic acid which is neuroprotective and quinolinic acid which is neurodegenerative. The quinolinic acid is a NMDA-agonist, i.e. quinolinic acid, NMDA, and inflammation are best friends and like to wreak havoc when kynurenic acid is lacking. Kynurenic acid is helpful and protective.

Recent research showed that patients suffering from severe depression and suicidality were found to have very high levels of inflammation and elevated NMDA activity as a result of long-term dysregulation of this pathway. The researchers’ recommended goal was to find ways to dampen the NMDA receptors and quinolinic acid in the brain.

Gut Bacteria Talk to Serotonin Pathways in the Brain

I mentioned above that acute or chronic infections can change this tryptophan pathway. Some amazing research on the gut microbiome identifies a link between the communication highway between the brain and the GI tract. Serotonin provides key functions in both the brain and gut. Accumulating evidence points to the health of the gut flora or microbiome in regulation of serotonin of the “brain-gut axis”. Research published in the Behavior Brain Research journal in January 2015 shows that the gut flora or microbes “talk” to the serotonin pathway and control how tryptophan is processed in this kynurenine pathway. If the system is intact, then serotonin production works appropriately. If the immune system and microbiota of the gut are stressed or imbalanced, then there is less serotonin produced and more damaging neurological metabolites (quinolinic acid) are present. Individuals with Small Intestine Bacteria Overgrowth (SIBO), candida albicans, H. pylori, or Leaky Gut Syndrome will struggle with this pathway. This can lead to common symptoms of brain fog, feeling dopey, depressed, moody, or just not themselves.

The application of SSRIs drugs acts to increase serotonin further downstream by causing the serotonin in the synapses to be recycled over and over like “robbing Peter to pay Paul”. The drug use and application generally fails to address the inflammation from this quinolinic acid/kynurenic acid imbalance and glutamate-NMDA excess activity. The SSRIs simply try to increase the amount of serotonin within the system at the synapses, but the underlying damaging inflammation is still ongoing. This process also affects cognitive health, which has great implications for all neurodegenerative concerns. When the brain is on fire with inflammation leading to depression, anxiety, sleep problems, cognitive changes, it has to be thoroughly addressed. SSRIs miss this inflammatory aspect.

New research published spring of 2015, shows that quinolinic acid inflammation can trigger a domino effect of free radical production in different brain tissues and can last for varying amounts of time. The study showed that a one time exposure of quinolinic acid in the hippocampus (memory, emotions, spatial orientation) caused very damaging free radicals (ROS) to occur for eight hours after exposure. In the cerebral cortex (thinking part of brain), it had a domino effect starting with depletion of antioxidants within one hour and lasted for up to 72 hours. The cerebellum had an increase in oxidative stress eight hours after the exposure. The cerebellum is the back part of the brain involved with balance and knowing where the body is in space. Other tissues had a delayed reaction with major free radical production that started from 8-72 hours. The longer this process of oxidative stress and high levels of glutamate, NMDA activity, and quinolinic acid excess go on, the more tissue damage occurs. Different areas of the brain have different susceptibility to this oxidative stress.

A single incident can provoke profound oxidative, pro-inflammatory stress in tissues hours or days later after a one-time exposure. Different tissues are affected with different breakdown rates, just like the foods in your refrigerator spoil at different rates. This is why one day, you may struggle with a certain depression-related symptoms like feeling physically sluggish and another day you feel like crying or lashing out. The symptoms reflect the areas of distress in the brain. Life has its daily challenges with stress from multiple directions. One exposure to quinolinic acid shows definite insult. Think about the daily and ongoing battles that may cause this process to be locked in place. This information means that we need to be even more proactive with fortification to quench the damage before it ping-pongs from tissue to tissue creating persistent damage. It also means that we need to prepared to handle each assault on this system as best as we can to stop the oxidative stress response from ultimate tissue damage.

Mitochondria, Quinolinic Acid, and Glutamate

A common link with excess glutamate, NMDA over activity, quinolinic acid/kynurenines imbalance is the disruptive impact to mitochondria health, function, and cellular life. Each potent neurotoxin causes oxidative damage which can ultimately lead to failure of energy production, cell death, and eventually neurodegeneration or failure of the brain related to mitochondrial damage. We see it as depression, stroke, Alzheimer’s, Parkinson’s, MS, chronic pain, etc. Twenty-five years ago, this information and understanding about the mechanisms of neurodegeneration was quite limited, but now the evidence is real. As researchers continue to delve into the different types and stages of depression, even more knowledge and refinement of treatments will occur. For now, we have some powerful proactive tools to use. Recent articles have delved into the topic of mitochondria health and depression with many suggestions for protecting and helping make new mitochondria.

Depression is more than just a neurotransmitter imbalance. It is a systemic response to inflammation. All of these factors mentioned in the article stress the mitochondria, which sets the stage for fatigue, neurological breakdown, and eventually big problems. Ketamine, SSRIs, and other anti-depressant treatments are indeed options in medicine, but certainly natural options exist to assist with medical treatment or provide help for protection and rejuvenation. Often children and adults struggle with bad diets and low quality nourishment of these simple, but vital nutrients now proven integral to stopping this neurological inflammation. How many lives could be saved or improved with this basic support? Your brain needs daily nourishment. Give it what it needs and don’t give up in the face of depression. The brain can change.