Learn Why Your Antidepressant Isn't Working: A New Treatment for Depression Has Changed the Game

Depression is a severe mental illness that affects millions of people every year. Left untreated, depression can cause significant suffering and impairment. Luckily, there is a new treatment for depression that is highly effective in treating the condition.

Unfortunately, many individuals suffering from depression are unfamiliar with this new therapy and are unsure how to utilize it.

Kim's journey with depression.

When she was 27 years old and getting her doctorate in marketing research, Kim Christian tried Prozac, a selective serotonin reuptake inhibitor medication to treat her depression. The demands of her new academic program were putting Kim under pressure, and she felt like giving up.

All of her motivation was gone, and she felt completely isolated from the world around her. She lost any sense of happiness and felt as if the only thing she could see were dark clouds looming over her head.

It seemed to work for a little while.

About a month after starting the new medication, she began to feel a slight sense of relief and lightness. The colors around her seemed a little brighter, and she had enough energy to start studying and exercising more. Her optimism returned for the first time in a year. But after only three months into the treatment, the colors became dull once again, she felt sad again, and her constant fatigue returned. Her depression symptoms were becoming worse.

Time for a different pill.

She eventually switched to another antidepressant medication called Celexa and has been on it for about ten years. However, it makes her emotionally numb, and she never ultimately gets rid of the depression. "It takes the edge off and prevents you from completely breaking down, but it's not a good way to live," she said.

Is there anything new for treating depression?

Kim's and many others' experiences, after years of unresponsive or mind-numbing therapy with conventional antidepressant medicines or even electroconvulsive therapy, are spurring a new — and some would say, long-overdue — change in our understanding and approach to treating mood disorders.

How have we treated depression for the past 50 years?

For the past 50 years, there have been two main ways to treat major depression: therapy and depression medications. The most common form of psychotherapy used in depression treatment is Cognitive- behavioral therapy (CBT).

Can you change your mind about depression?

CBT is based on the idea that maladaptive cognitions and behavior patterns cause depressive disorder. CBT emphasizes that with new skills and new ways of thinking, individuals can change how they feel.

In this type of therapy, the patient learns new skills to control their negative thoughts, change unhealthy behavior patterns, and cope with difficult situations. Unfortunately, CBT has been shown ineffective at reducing depressive symptoms for many individuals.

The 1989 National Institute of Mental Health's Treatment of Depression Collaborative Research Program (TDRCP) was the first major study comparing CBT to a pill-placebo control. The findings were disappointing for CBT. The success rate for CBT was no more effective than the placebo control group in reducing depression symptoms.

If therapy has not worked for many people, then what about medications?

Antidepressants aren't much better.

The antidepressant drugs that we use today were discovered serendipitously in the 1950s. At that time, researchers believed that these new drugs offered relief for people suffering from depression by boosting neurotransmitters (brain chemicals) like serotonin, dopamine, and norepinephrine in our brains.

These neurotransmitters belong to a class of chemical messengers known as monamines, and the drugs that increase these levels are called antidepressants.

Despite the early optimism for these medications to treat major depression, only about 1 out of 3 patients achieve remission with an initial antidepressant trial (meaning they experience at least a 50% reduction in symptoms). Unfortunately, this leaves 2 out of 3 patients still suffering from a chronic major depressive disorder.

So, what do we do next? The answer has been to add more pills, but even after six or more different antidepressant trials, nearly half of these patients do not achieve remission. Even worse, some people develop severe depression that may not respond to any medications, and it is called treatment-resistant depression. As people get older, the rate of treatment resistance goes up.

Why was there so little improvement in the patient's major depressive disorder symptoms in so many cases?

Maybe we weren't approaching this correctly from the start.

The reason why antidepressant medications haven't been effective for many who suffer from depression may be due to a faulty hypothesis about what causes depression in the first place.

For many years, researchers believed that low levels of neurotransmitters (known as monoamines) like serotonin, dopamine, and norepinephrine were to blame for depressive symptoms. In the 1960s, this became known and widely accepted as the Monoamine Hypothesis.

Everyone thought Prozac was the answer.

The "monoamine hypothesis" was the leading theory explaining the biological cause of depression. From this hypothesis came early new pharmacologic treatments for depression - SSRIs (selective serotonin reuptake inhibitors). If you are familiar with Prozac, Zoloft, Paxil, Celexa, Lexapro - these are all examples of SSRIs. By preventing your brain cells from reabsorbing serotonin, SSRIs leave more serotonin in the brain.

Unfortunately, new evidence indicates that low monoamine neurotransmitter levels are not what causes depression. In fact, this research suggests that low levels of these fundamental transmitters may be the consequence of being depressed and not the cause.

A new way to treat depression: A New Understanding of the Brain Emerges.

About ten years ago, two breakthroughs in research came together to understand better the causes of certain mood disorders, including major depression. First, research focused on a newly discovered neurotransmitter in the brain called glutamate. Glutamate is the primary excitatory neurotransmitter in our brain, meaning it causes our neurons to activate.

Excitatory neurotransmitters stimulate activity in your neurons and are also known as fast neurotransmitters. This new research showed that glutamate was crucial for regulating mood and supporting cognitive functions like memory and learning.

I'm sorry... you've been disconnected.

Second, new brain imaging techniques were developed, which shed light on brain connections and how they regulate our moods, memory, and thought processes. The latest research showed that depressed patients had unusual and altered connections between certain areas in their brains (specifically the frontal and prefrontal cortex).

This new understanding of brain connectivity, or how the different regions of our brains communicate with each other, and that glutamate may be responsible for regulating our moods and building new connections has helped us to understand why new treatments such as ketamine infusion therapy have been so rapidly effective for reversing the symptoms of depression, anxiety, and PTSD - sometimes within just minutes.

Have we become "Disconnected" from life?

Individuals with depression have shown significant deficits in connections between different parts of their brains than healthy individuals. This new theory is called the "disconnection syndrome" and can be used to describe how depression affects not one or two but several of the brain's critical communication networks.

This exciting research overturns the old monoamine hypothesis, suggesting that depression may be caused by a lack of neurotransmitters like serotonin, dopamine, and norepinephrine. We now know, and can see, that depression may be due to a decrease in the brain's connectivity or "synaptic pruning," which may occur for several reasons.

There are three primary reasons why our brain network may break down. Metabolic/genetic resiliency, chronic stress and cortisol production, and continuing neuroinflammation are key factors in the disconnection syndrome.

Metabolic/Genetic Resiliency.

A fundamental factor to developing depression seems to be an underlying predisposition to allow neural connections to break down. Metabolic resiliency is the process by which the body and brain maintain their "state of readiness."

It allows us to be prepared for new stressors, infections, or new life situations that require energy and focus.   Under normal conditions, metabolic resiliency will work to maintain a certain balance within our bodies - but if it is damaged or dysfunctional, it may cause reductions in new brain growth and function.

We know, for example, that certain metabolic or genetic disorders like low thyroid levels, low testosterone, and diminished activated folate levels (due to an MTHFR variant) reduce our metabolic resiliency and can cause changes in the brain that may contribute to depression.

MTHFR is a key enzyme

MTHFR is an enzyme that helps to create new neurotransmitters in the brain from what's known as activated folate or 5-methyltetrahydrofolate (5-MTHF).  However, sometimes the MTHFR gene is defective, preventing this new compound from being made.

MTHFR dysfunction disables the body's ability to produce new serotonin, dopamine, or noradrenaline, which can significantly impact brain chemistry. It also disrupts the new cell growth needed for new brain cells in the hippocampus that are often reduced in depression.

About 70% of people who suffer from treatment-resistant depression have a defective MTHFR enzyme, contributing to their lack of metabolic resiliency. MTHFR deficiency can be quickly ruled out with a simple blood test.  It should always be considered when patients have not responded to traditional antidepressants and other treatments.

Chronic stress and cortisol production.

When we experience chronic stress, the body's cortisol levels remain elevated for days and sometimes weeks or months at a time. We now understand that ongoing stress may contribute to depression by reducing the formation of new brain cells and disrupting new connections between neurons called synapses.

Chronic stress, whether from external factors such as a job or family difficulties, or internal sources like compulsive negative thinking patterns, causes cortisol production to increase even more over time. Prolonged high levels of cortisol reduce the formation of new neurons (neurogenesis). And high levels of glucocorticoids (cortisol) can also damage new connections between neurons (synapses) and deplete the neurochemicals vital to cortical communication.

We also know that new neurons (neurogenesis) may be necessary to form new memories, and disruption of new brain cell growth might explain why some people experience memory loss during a bout of depression.


Brain tissue becomes inflamed when damaged by physical injury, infection, toxins, or metabolic disease. Even slight neuroinflammation can alter brain connectivity and how new memories, cells, and connections form in the brain.

When we are stressed or sick, pro-inflammatory cytokines like IL-1B, IL-6, and TNF alpha increase in the brain and cause new synapse formation to stop. Recent research has found that individuals with depression and anxiety disorders have much higher levels of these pro-inflammatory cytokines in the brain's blood vessels, suggesting that the new connections between neurons may be damaged by neuroinflammation.

Fortunately, scientists have discovered a new usage for an older medication that accomplishes just that. It improves metabolic resiliency, reduces your stress response and cortisol levels, inhibits neuroinflammation, and promotes the production of glutamate in such a way as to promote brain growth and connections within minutes.

It's time to change our understanding of what depression is and how we treat it.

Wouldn't it be great if new treatments for depression were not only effective but also provided immediate relief of symptoms at their very first use?

This new understanding of the disconnection syndrome is not only changing how we see and treat mental health issues, but it is also helping us to understand unknown causes of depression and new ways to reverse it.

In addition to increasing metabolic resiliency, ketamine infusion therapy helps restore new brain network connections by working on the glutamate system, promoting new synaptic growth.

Ketamine infusion therapy offers new hope by repairing the damage.

The exciting news is that ketamine is not just another new antidepressant; it is a glutamate-enhancing drug that reduces stress levels and cortisol production and is an anti-inflammatory agent with new clinical applications.

Ketamine infusions have been shown in research to improve metabolic resiliency, reduce cortisol levels, and decrease IL-1, IL-6, and TNF levels quickly while promoting new neuronal growth and connection by increasing glutamate production.

Not only that, but ketamine infusion therapy was demonstrated to be effective at reducing symptoms of anxiety, post-traumatic stress disorder, bipolar depression, postpartum depression, and suicidal thoughts. It may also help individuals with treatment-resistant obsessive-compulsive disorder (OCD).

Many researchers refer to ketamine as the "master molecule" due to its ability to repair connections in the brain, damaged by stress, injury, infection, inflammation, and metabolic issues.

Toward a New Future.

This new understanding of depression looks at it in an entirely new way, offering new hope to millions who suffer from this debilitating condition.

Taken together, this new research that has helped us to understand the connection between depression, glutamate, and brain connectivity also indicates that genetic predispositions toward mood disorders may become activated by chronic stress, increased cortisol production, and neuroinflammation.

As a result of these new findings, new treatments for depression that focus on new brain network connections and the factors that influence them are the new future of psychiatry. New pharmacologic treatments that use ketamine to reconnect critical areas of the brain quickly have become a new wave in therapy for certain mood disorders.

If you would like to know more - please get in touch with us.

Don't hesitate to reach out to us if you suffer from any of these conditions or want more information on ketamine infusions for depression treatment. We would be glad to help.


RESTORE is the new "Gold Standard" in ketamine-based therapy

The RESTORE infusion program is an advanced program that unlocks the full benefit of ketamine. It is the most rapidly acting, effective, and longest-lasting ketamine-based infusion available today.

If you would like to learn more about the RESTORE program, please feel free to visit our website and clinical research center (ketamineinstitute.com). We are also available to assist you with a free private consultation. Please feel free to call us at 800-850-6979. We want to help.

We don't treat patients. We treat people - one person at a time.