Inflammation Masquerading as Depression — A Case Study of the Beneficial Effects of Low-Dose Naltrexone in Eliminating Depression-Like Symptoms in my Hypermobile Daughter

By John Doe[1]

Since 2017, my wife and I have been on an incredible medical journey with our teenage daughter, who would eventually be diagnosed with a series of conditions related to joint hypermobility: Hypermobile Ehlers-Danlos Syndrome (hEDS); Postural Orthostatic Tachycardia Syndrome (POTS); Mast Cell Activation Syndrome (MCAS), Craniocervical Instability, Chiari Malformation, Tethered Cord Syndrome and ME/CFS. In a series of working papers, I am sharing observations we have made along the way in the hope that they may spur further research into the causes of and treatments for her conditions.

This working paper documents my daughter’s experience, in rapid succession, with two prescription medications that each, independently, eliminated mood symptoms that might otherwise have been mistaken for depression. The effect of these medications in eliminating the depression-like symptoms was dramatic — it was like turning off a light switch. The accident of this treatment pathway provides the basis for a hypothesis about the medical origins of these symptoms and the pathway through which the medications led to improvement.

The medication that has eliminated depression-like symptoms in our daughter for nearly three years is Low-Dose Naltrexone (LDN), a powerful anti-inflammatory agent. The administration of supplemental thyroid hormone had precisely the same effect immediately prior to starting LDN, until the thyroid adjusted by producing less natural hormone. Based on Lauren’s successive responses to supplemental thyroid hormone and LDN, I hypothesize that the depression-like symptoms were due to inflammation that interfered with the production and/or metabolism of thyroid hormones, which LDN resolved through the anti-inflammatory process of glial cell modulation. Chronic inflammation is a defining characteristic of most of our daughter’s conditions.

Lauren’s Story

Shortly before her 14th birthday, while on a camping trip in Maine, and after a particularly strenuous hike, our daughter Lauren (a pseudonym) had an episode of whole body tremors / shaking lasting about 10–15 minutes, prompting a visit to the emergency room. The tremors left her in a weakened state that made it difficult to walk. A month later, her condition had deteriorated to the point where she was unable to go to school. She was nauseous, extremely fatigued, had pain all over her body (and particularly around the sides of her torso) and felt a high degree of sadness and anxiety.

A doctor recommended the anti-depressant Fluoxetine, but given a lack of clear evidence that children and adolescents benefit from antidepressants (Cipriani et. al. 2016), and FDA warnings of suicide risk from such medication, we demurred and instead started her on psychotherapy. She also tried a range of treatments, including Omega 3 fatty acids and hydroxyzine. None of these approaches led to substantial improvement.

Diagnoses

It took nearly a year to get our first diagnosis. In late 2018, over the course of several months, Lauren was diagnosed with POTS, hEDS, and ME/CFS. In 2018, she developed MCAS and was diagnosed with Craniocervical Instability, Chiari Malformation and occult Tethered Cord, three neurological complications of hEDS.

Results of Thyroid Hormone Trial

Simultaneous with the diagnosis of POTS, and based on suggestions in the chronic fatigue literature, Lauren’s doctor prescribed a trial of a small dose of thyroid hormone to see if it would lead to improvement in her symptoms. The plan was to discontinue it if improvements were not apparent. With free T3 levels around the 25th percentile for her age and free T4 levels between the 50th and 75th percentiles for her age (Kapelari et. al 2008), her doctor prescribed liothyronine (T3) rather than the standard levothyroxine (T4). (Lauren’s TSH was on the low end of the reference range, at approximately the 10th percentile for her age.) Lauren found the ups and downs of the instant-acting T3 medication difficult to manage, but did much better when the medication was compounded into a sustained release formulation. At 12 mcg daily, provided in two six mcg sustained-release doses, she reported marked improvements in mood. Her depression-like symptoms vanished and her anxiety returned to levels that she found manageable. As she reported once she had stabilized on the sustained-release T3, “I had no idea how sad I was” in the spring, before starting the medication.

The benefits continued for four weeks, at which point she started to feel somewhat sad again. The sad feelings increased over the next two to four weeks. Thyroid lab tests after eight weeks showed similar levels to those she had before treatment started, suggesting the body had adjusted to the supplemental thyroid hormones by producing fewer natural hormones. At that point, her doctor increased the dosage of supplemental thyroid hormone to 15–18 mcg T3 and 6–12 mcg of T4 daily. Lauren’s mood symptoms once again improved.

Low-Dose Naltrexone

Shortly after the increase in thyroid hormone, her doctor prescribed Low Dose Naltrexone (LDN), a potent anti-inflammatory agent. The LDN was titrated up, starting at 0.5 mg for one week, 1 mg for the next week, 2 mg for the third week, and 3 mg thereafter. To avoid concerns with sleep interference, Lauren took the LDN in the morning. As soon as the LDN reached 2 mg, Lauren abruptly became hyperthyroid (a well-recognized phenomenon for people who take LDN at the same time as supplemental thyroid hormone). After some trial and error, she stabilized at a daily dose of around 6.9 mcg of T4 and no T3, down from an estimated 22.5 mcg combined T3 and T4 daily exposure previously. After Lauren had been stable at this lower dose for two months, we started to gradually reduce the T4 and eventually eliminated all supplemental thyroid hormone, with no loss of mood benefits.

Lauren is currently taking 3 mg of LDN daily, administered once daily in the morning, 30 minutes before food or other supplements (a practice we got into while taking the supplemental thyroid hormone) and has not had any recurrence of the depression-like symptoms that presented in 2017–2018, even as her day-to-day physical condition has worsened in other ways with the progression of her disease.

Discussion

There is growing recognition that inflammation is a root cause of depression-like symptoms (Lee and Giuliani 2019). There is only a modest amount of formal research, however, on the potential of the anti-inflammatory agent LDN to resolve these symptoms. A search of “depression” and “low-dose naltrexone” on clinicaltrials.gov revealed only one entry : a pilot study of the effects of LDN in reducing depression in 12 subjects (6 assigned to the treatment and 6 to the placebo). This pilot found a strong effect size for LDN in reducing depression, but the effects on the primary measures were not statistically significant in this very small group (Mischoulon et al. 2017). A broader search uncovered a recent case study which explored the generally beneficial response of 3 patients to LDN (Bolton et al. 2020).

Lauren’s unique treatment sequence provides insight into a possible pathway through which LDN may be helping to relieve her depression-like symptoms. I hypothesize that inflammation may have contributed to Lauren’s depression-like symptoms and heightened her anxiety by interfering with her body’s ability to produce and/or metabolize thyroid hormones. Under this hypothesis, the initial administration of supplemental thyroid hormone compensated for the inflammation by increasing the amount of available thyroid hormone. However, the body responded to the supplemental thyroid hormone by reducing the production of natural thyroid hormones. LDN provided a better solution — reducing the inflammation directly — leading to a reduced need for thyroid hormone. The need for supplemental thyroid hormone was not eliminated immediately at that point, since the body had already started producing a lower-than-normal level in response to the thyroid supplementation. With the inflammation now under control, however, it was possible to slowly reduce the amount of supplemental thyroid hormone, with the body adjusting to make up the difference until the need for supplemental thyroid hormone was eliminated.

Inflammation is known to interfere with the metabolism of thyroid hormones (Mancini et. al. 2016). While there are no definitive studies documenting the relationship between Lauren’s thyroid levels and inflammation, it is noteworthy that her low-normal TSH, low-normal free T3, and high-normal free T4 match the values described by one practitioner as indicative of inflammation that is responsive to LDN, with resulting improvements in patient symptoms and the production and/or metabolism of thyroid hormones (Holtorf 2016).

LDN is an equal mix of two isomers: levo- and dextro-naltrexone. The levo-naltrexone in LDN upregulates the production of endorphin system by temporarily blocking the opiate receptors. The dextro-naltrexone in LDN suppresses the production of pro-inflammatory cytokines (Dickson 2016). While each of these isomers could in theory contribute independently to mood improvements, I hypothesize that it is the anti-inflammatory properties of dextro-naltrexone that have led to the improvements noted here. LDN’s anti-inflammatory properties have been noted as beneficial for a number of conditions, including Fibromyalgia (see below) and Complex Regional Pain Syndrome (Chopra and Cooper, 2013).

While the literature on hEDS and POTS sometimes discusses hypo- and hyperthyroidism in the context of considering differential diagnoses and co-morbid conditions, the hypothesis that I posit in this case study is not typically addressed. For example, in a recent article on the psychiatric and psychological aspects of Ehlers-Danlos Syndrom there is no mention of thyroid function or discussion of the role of inflammation (Bulbena et al. 2017). Similarly, in a journal issue devoted to POTS, the thryoid pathway is not discussed in chapters on hEDS and POTS (Roma et. al. 2018) or the psychological symptoms of POTS (Raj, Opie and Arnold, 2018).

LDN has received somewhat more attention in the research literature on Fibromyalgia as a result of a series of studies of the effects of LDN of patients with Fibromyalgia. A number of small studies have shown that LDN leads to improvements in patients with Fibromyalgia (Younger, Parkitny and McLain 2014; Younger et. al. 2013; Younger and Mackey 2009). One study shows that LDN reduced the plasma concentrations of a number of pro-inflammatory cytokines in patients with Fibromyalgia (Parkitny and Younger, 2017), which the authors suggest may be the mechanism for the benefits of LDN for Fibromyalgia patients.

Inflammation is a defining characteristic of several of Lauren’s conditions, including hEDS, craniocervical instability, and Chiari malformation.

Questions for Future Research

This case study suggests a number of questions for future research:

1. To what extent do patients with hEDS, POTS, ME/CFS, MCAS or one of the neurological complications of hEDS experience inflammation that interferes with their production and/or metabolism of thyroid hormones? If so, what is the exact source of the inflammation?
2. Are there markers in conventional laboratory tests that could be used to help identify the patients that experience this condition?
3. Are there identifiable subpopulations of patients for whom LDN is effective in reducing this inflammation and relieving associated mood symptoms
4. Supplemental thyroid hormone is generally administered in the morning, before eating or taking other supplements. Does the LDN need to be administered in the same manner to be effective in addressing depression-like symptoms? (I am particularly concerned with the co-administration of LDN and antihistamines since high levels of antihistamines like loratadine can adversely affect Lauren’s mood.)

With respect to potential biomarkers, prior to treatment, Lauren’s TSH was at about the 10th percentile, her free T3 was at about the 25th percentile and her free T4 was between the 50th and 75th percentiles, as adjusted for her age (Kapelari et al. 2008). Lauren’s initial labs also showed reduced total T3 and T4 levels, though it is difficult to get clear information on age-adjusted reference levels. We have not gotten her thryoid levels checked since phasing out the supplemental thryoid hormone to see if they have changed, though we hope to do so at a future time.

It would be useful know if if similar patterns are observed in other individuals with these conditions and symptoms. Holtorf (2016) also observed the following in patients with this type of inflammation: sex hormone-binding globulin (SHBG) below 60 nmol/L, “a slow relaxation phase of the brachioradialis reflex (RBR) — slower than 110 milliseconds — and low resting metabolic rates.”

Conclusion

This case study suggests that inflammation can masquerade as depression, causing depression-like symptoms in some patients with hEDS, POTS, MCAS, and ME/CFS. The unique treatment pathway supports a hypothesis that the inflammation acts by adversely affecting the production and/or metabolism of thyroid hormones. Research is needed to examine if this hypothesis is valid and, if so, whether LDN may help ameliorate these important symptoms in other individuals.

I would welcome feedback or corrections.

References (will standardize citation format shortly)

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[1] I am using this pseudonym to protect the privacy of my daughter.