No Wonder Treatment Resistance Has Been Such a Mystery! Clue: Look in the Cerebral Spinal Fluid!

A man in his forties, Greg had never experienced life without depression. Treating mood disorders didn’t seem to be his psychiatrist’s forte. (Oh boy…) At least not in his case. Every accomplishment, every failure, struggled for expression beneath the darkness of that clinging lead blanket.

People had always admired his quiet humility and unrelenting integrity.

But they had no idea of the courage he required to face every single day. As a child, just to face each day of school…As a young man, to walk from his apartment to his car, and from his car into the building — to start another work day.

Complex Disorders Make Things Worse

Social anxiety filled him with self-doubt, self-consciousness, and dread. Agoraphobia made it incredibly difficult to walk out the door to face another day. To walk into a salon to get a haircut. Or to shop for groceries. 

Family gatherings were impossible. He’d show up late, linger as long as he could bear, then quietly slip out to seek refuge in the safety of his car, and drive home to the quiet security of his apartment where his cat purred when she saw him.

His family became accustomed to his disappearances. “Has anyone seen Greg?”


“Well, I guess he went home…”  :::sighhhh:::

His days filled with thoughts of ending his life, his nights with planning a suicide that would work.

No one grasped the shame he felt that he couldn’t function like others he saw.

Of course, he’d sought treatment. Prescriptions of Zoloft, Wellbutrin, and Lexapro tried his patience. Oh and then Effexor, Abilify… He hated taking the pills, but had had the highest hopes for relief that never came…

Psychotherapy never seemed to make any difference. He’d seen a lot of therapists.

In fact, it was worse than that. It was maddening… nothing that came up was new to him. It was boring and frustrating. And the effort required to go… to push through the dread and phobias to get there… just became too big a price to pay and he stopped going.

He’d heard it said that there’s a difference between a good therapist and a great one. He hadn’t found a great one, apparently. Treating mood disorders came to seem like a cruel game to him.

Decades of Complex Treatment Resistant Disorders

In his twenties, he had beat all odds by starting and developing a consulting company. When he was in his thirties, with a long list of brilliant consultants on his payroll, and rivers of money streaming in, an episode of severe depression and crippling phobias threatened to bring his company to its knees. His mind shut down and he withdrew. It had been 15 years since he felt desperate enough to seek a psychiatrist’s care.

So he tried once again.

Once again, he took the latest antidepressant medicine…Cymbalta…for five miserable months. He tried to give it every chance. But his suicidal thoughts only increased. Depression, anxiety, and desperation made it nearly impossible to work, much less carry the load of generating new clients, advising his team, and keeping the payroll covered. 

Then recently, he learned about IV ketamine for depression. He scoffed at the idea. As far as he was concerned, this was yet just another shiny new penny. Obviously, people clamored to get in on it. Articles that dismissed the validity of ketamine for depression drew him in. It was easier to find ammunition to protect himself from any more risk of disappointment …until something happened.

His cousin had been severely depressed all her life, too. He’d heard that depression runs in families. But it happened that she went for IV ketamine treatment. It was a rocky process for her. Because of major stressors in her life, she had ups and downs. But eventually, she seemed to be better than he’d ever seen her.

He was reluctant to ask questions. He didn’t want to be swept into the “ketamine frenzy.” He knew disappointment was a huge risk. But this was someone he knew well and trusted. And he wanted to know if he could get better.

Ketamine Slashes Depression in More People When the Causes of Failure Are Explored

She told him she didn’t experience it quite like others she’d heard about.

Others who simply received six infusions and by the third were feeling great, caused her to have unrealistic expectations. She wanted a wow. But she had to just take it a step at a time.

She didn’t improve until the 4th infusion, then felt better and better…almost great…until a terribly stressful bout in the hospital seemed to end the benefits she’d experienced with ketamine. The depression came back. So she’d go for another infusion… a “booster” she called it. And again she’d improve dramatically…

Until another severe stressor, and she’d lose it again. This pattern had continued for a few infusions. She felt like she was on a see-saw.

But finally, she began to improve every week. Still, she had a cloak of fatigue that colored her joy in shades of gray.

She explored various supplements that might help, and found a “smart coffee” product that gave her the extra little spring and energy she needed, and just the right touch of mood enhancement, so she could enjoy her day. It bumped her just enough past the remarkable effects of ketamine, that she finally felt truly better. Soon after that, she realized she had achieved remission. She was bubbly. Her eyes sparkled. She sang spontaneously and laughed infectiously all the time.

She could cope with difficulties like she hadn’t been able to before. Daily tasks became routine instead of insurmountable. Her hope for the future and what she could accomplish began to rise.

Greg had watched her transformation. He knew how wonderful she felt now. Quietly, he secretly longed for the same.

He scheduled a series of ketamine infusions with a local psychiatrist. After 6 infusions, he’d experienced a lifting of the depression and suicidal thoughts, but in less than a week those depressive symptoms — and the suicidal thoughts — began to creep back in.

Then, he received another, with good then fleeting results, then another.

His fear that he was so treatment resistant…and had been for so long…that he was beyond help…well, it engulfed him. It settled into his mind like stone and wouldn’t budge.

He knew it. He decided he just couldn’t be helped.

When Treating Mood Disorders Sometimes We Have to Fight and Not Let Go

Then one day he read an article about neurometabolic abnormalities and how they can have such profound impact on the brain that depression can dominate mood.

He remembered reading somewhere that treatment resistance in some cases can be overcome. One way is by treating underlying conditions like low testosterone, thyroid, and folate deficiencies. He’d dismissed it at the time, but now he asked his doctor to order these lab tests.

The article he read focused on a study in the American Journal of Psychiatry.

The study was initiated because of a particular young man who suffered with treatment refractory (same as treatment-resistant) depression for most of his life, as well as unrelenting suicidal thoughts and several suicide attempts.

It was remarkable to Greg that the young man’s experience and symptoms were so parallel to his own.

The authors of the study knew that treating mood disorders could be challenging, so they took their exploration of this man’s serum levels a step further. They performed a lumbar puncture to collect cerebral spinal fluid.

They discovered his CSF (cerebral spinal fluid) levels were much lower than his serum levels. So even though it seemed that his serum levels of key hormones, nutrients, and metabolites were “normal” there were severe deficiencies in his brain.

In particular, he had a severe deficiency of CSF tetrahydrobiopterin, a critical component you need to manufacture neurotransmitters like serotonin, dopamine, and norepinephrine in your body. After they treated him with sapropterin, a compound with a molecular structure very similar to tetrahydrobiopterin, their subject experienced a dramatic and long-lasting remission of his depression symptoms.


Study Shows Surprising Results for Treatment Resistant Patients

Because of this discovery, they conducted a study of 33 adolescents and young adults with treatment resistant depression who hadn’t responded to at least 3 trials of antidepressant medication, and 16 healthy control subjects for comparison. They created profiles of each of them using urine levels, serum levels, and CSF levels of a wide variety of metabolic compounds.

They found that CSF metabolite levels were abnormal in 21 of those 33 subjects. The most common abnormality occurred in 12 of the 21 participants. In these, the serum levels were normal but the CSF level of 5-methyltetrahydrofolate (5-MTHF) was low.

There was one patient in that group who had a low CSF level of 5-methyltetrahydrofolate (5-MTHF) as well as low CSF tetrahydrobiopterin.

These patients were treated with folinic acid and the one who also had low CSF tetrahydrobiopterin was also treated with sapropterin. All of these patients showed improvement in depression symptoms as a result of treating these CSF deficiencies. 

It’s important to note that the healthy control subjects had no CSF deficiencies.

The conclusion the authors reached was that checking the CSF levels of metabolites produced a surprisingly large group of people who had normal serum levels but severe deficiencies in their CSF metabolites.

So — they expect that examination of CSF metabolites can identify unexpectedly high percentages of treatment resistant patients who have treatable metabolic conditions. And treatment of those deficiencies just may resolve their depression symptoms.

Until recent years, it wasn’t clear that treating mood disorders could be such a complex process, but that so many who have not been helped can be.

Greg (whose name has been changed to protect his privacy) is currently undergoing treatment for his metabolic deficiency. We’ll talk about the results when he has completed treatment. Meanwhile, we applaud him for taking the emotional risk and making the effort to find solutions for his illness.

Greg’s story is important to help us understand why we need to dig deeper and sometimes include specialists on our treatment team to find remission and resilience for our treatment resistant patients in every case that we can.

The more we learn about all the factors that enter in to balanced wellbeing, the more avenues we can explore.

In the past, psychiatry depended largely on observing a patient for signs of their illness, and listening to them describe how they felt. But as we advance further into the 21st century, we’re stockpiling more and more tools to help in the diagnosis and treatment of our patients.

At Innovative Psychiatry, in treating mood disorders we encourage our patients to include specialists to explore their possible deficiencies and treat them. We work with the entire health team because often, it requires a team effort.

After all, the goal of your recovery is our top priority.

If anything about Greg’s story or this study sounds familiar to you, and if you’ve not found joy or resilience with other treatments, call us. We’re committed to provide the support you need to feel again, to enjoy life and relationships again. To live again.

IV ketamine treatment combined with treatment of serum and CSF level deficiencies can restore your hope, your initiative, your motivation, and your creativity.

Don’t sell yourself short. Let us help.

To the bounding renewal of your very best self, 

Lori Calabrese, MD offers innovative psychiatric treatment like IV Ketamine
Lori Calabrese, M.D.
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