Accepted Manuscript

A hypothesis on the mechanism of action of high-dose thyroid in refractory

mood disorders

Tammas Kelly

PII: S0306-9877(16)30274-2
DOI: http://dx.doi.org/10.1016/j.mehy.2016.09.022
Reference: YMEHY 8372

To appear in: Medical Hypotheses

Received Date: 21 June 2016

Revised Date: 24 September 2016
Accepted Date: 27 September 2016

Please cite this article as: T. Kelly, A hypothesis on the mechanism of action of high-dose thyroid in refractory mood
disorders, Medical Hypotheses (2016), doi: http://dx.doi.org/10.1016/j.mehy.2016.09.022

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Title page
A hypothesis on the mechanism of action of high-dose thyroid in refractory mood disorders

Affiliations:
Tammas Kelly MD
Associate Clinical Professor of Psychiatry and Behavioral Sciences
George Washington University
GWU MFA Department of Psychiatry and Behavioral Sciences
2120 L St NW, Suite 600
Washington DC 20037
And
Director: The Depression & Bipolar Clinic of Colorado
400 East Horsetooth Road, Suite 300
Fort Collins, Colorado 80525

Contact info for corresponding author:

Tammas Kelly MD
The Depression & Bipolar Clinic of Colorado
400 East Horsetooth Rd
Fort Collins Colorado 80525
Phone: 970-484-5625
Email TamKelly@comcast.net

Funding: This work is entirely self-funded.

1
 Abstract

Multiple lines of evidence suggest the hypothesis that high dose thyroid

therapy corrects for cellular hypothyroidism found in bipolar disorders. Evidence

indicates that bipolar disorders are associated with mitochondrial dysfunction

which results in low cellular adenosine 5'-triphosphate (ATP) levels. Transport of

thyroid hormones into cells is energy intensive and dependent on ATP except in

the pituitary gland. Inadequate ATP levels makes it difficult to get thyroid

hormone into cells leading to cellular hypothyroidism. This creates a condition

where the blood and pituitary levels of thyroid hormone are normal but low in

other tissues. High dose thyroid therapy produces a gradient that is sufficient for

thyroid hormone to diffuse into cells correcting cellular hypothyroidism. If this

hypothesis is correct there are number of implications. The two most important

are: On average patients suffering from a bipolar disorder die 10 to 20 years

earlier than the general population. The medical sequelae associated with bipolar

disorders cause far more deaths than suicide. If high dose thyroid corrects for

cellular hypothyroidism it could well decrease the medical morbidity and

mortality associated with bipolar disorders that are the result of cellular

hypothyroidism. Thus high dose thyroid would be a first treatment that decreases

the considerable medical morbidity and mortality associated with the bipolar

2
disorders. This would stand in stark contrast to most psychiatric medications that

can that increase morbidity and mortality. It would also reinforce the safety of

HDT. The second implication is thyroid hormone blood levels in patients suffering

from a bipolar disorder do not accurately reflect the true thyroid status.

3
Title

A hypothesis on the mechanism of action of high-dose thyroid in refractory mood

disorders
Background
High dose thyroid (HDT), defined as doses of T3 > than 50mcg and T4 >

200mcg (1, 2), is remarkably helpful in the treatment of bipolar depression, often

helping even the most refractory cases reach full remission. Equally remarkable is

the absence of thyrotoxic side effects when treating bipolar disorders in doses

that give non-bipolar individuals significant thyrotoxicity. It is likely that HDT

therapy offers more than symptomatic relief of bipolar symptoms. There have

been two previous proposed hypotheses of the mechanism of action of HDT. The

first is that HDT increases serotonin neurotransmission (3). The second is HDT

modulation of the -adrenergic receptor response to catecholamines in the brain

(4). At best these are partial explanations of HDTs mechanism of action.

The thyroid system has long been thought to play an important role in

bipolar disorders. Even minor disturbances of the thyroid axis can have profound

effects on the outcome of bipolar disorders. Many studies indicate a potential

relationship between thyroid hormones and bipolar disorders but the exact role

of thyroid hormones has never been elucidated. The prevalence of thyroid

4
problems found in the bipolar disorders are no different than found in the general

population. (5).

High dose thyroid (HDT) has been shown to be effective for bipolar

depression in numerous studies including a recent double blind randomized

placebo controlled study. (6-10). HDT is recommend by major treatment

guidelines for both bipolar I and bipolar II depressions (11-14). HDT has been

shown to be as safe as or safer than most psychiatric medications used to treat

the bipolar disorders. Despite its effectiveness, safety and the desperate need for

effective treatments for bipolar depressions, HDT treatment has not gained wide

acceptance. This is primarily due to opposition from endocrinologists who

mistakenly believe that HDT causes the same harm as endogenous

hyperthyroidism. Some are wary of prescribing high doses of thyroid hormone

because of the morbidity and mortality associated with hyperthyroidism. A

recently published review shows that patients treated with high doses of

exogenously administered TH used for the treatment of bipolar disorders or to

suppress the return of thyroid do not experience an increased risk of

osteoporosis, cardiac abnormalities, or early death. This stands in stark contrast

to the high morbidity and mortality of hyperthyroidism. Therefore, high

circulating levels of TH are not responsible for the sequela of hyperthyroidism (2).

5
Understanding the mechanism of action of HDT could allow greater acceptance of

HDT as a treatment. HDT may well have profound benefits not yet realized.

The Hypothesis

It is hypothesized that high dose thyroid (HDT) treatment corrects for a

physiologic deficit in patients with bipolar disorders by correcting for cellular

hypothyroidism. HDT treatment often results in high circulating levels of THs. The

levels are sufficient to passively drive THs into cells by increasing the diffusion

gradient or by some as yet an unknown alternative mechanism.

Transport of THs into cells is complex and not fully understood. In many

tissues transportation of THs is energy intensive, dependent on adenosine 5'-

triphosphate (ATP) and dependent on a sodium gradient. There is evidence that

TH transportation into the pituitary may not be energy dependent or at least less

energy dependent than other tissues so that low adenosine 5'-triphosphate (ATP)

levels may have a disproportional effect on TH levels in peripheral tissues. In

other words, causing peripheral cellular hypothyroidism while pituitary TH levels

and serum levels of TH hormones are preserved. Mitochondrial dysfunction and

low cellular ATP states are present in the bipolar disorders.

6
 The logical progression behind the hypothesis (evidence and citations

discussed below) is: HDT is an effective treatment for bipolar depression. HDT

creates high circulating levels of THs. The high levels of TH are inexplicably well

tolerated whereas similar doses are not tolerable in non-bipolar individuals.

Dysfunctional mitochondria do not produce normal cellular levels of ATP.

Dysfunctional mitochondria and low ATP levels are found in bipolar disorders. TH

transportation is ATP dependent with the possible exception of the pituitary

gland. The pituitary gland uses different TH transporters than other tissues. TH

levels can be preferentially maintained in the pituitary and blood even when

peripheral tissues have low levels of TH. Neuroimaging studies indicate that HDT

corrects abnormal neurophysiology of bipolar disorders and these changes

directly correlate with improvement in bipolar depressive symptoms. The logical

conclusion is that HDT corrects for the cellular hypothyroidism.

Evaluation of the hypothesis

Definitions

To practice evidenced based medicine one must first use evidenced based

definitions. It is critically important to distinguish the fundamental differences of

hyperthyroidism and the consequences of HDT, hyperthyroxinemia (8).

7
Hyperthyroxinemia is defined as high circulating levels of TH due to thyroid

treatment with an absence of thyrotoxic symptoms. HDT is as safe as or safer than

most psychiatric medications (1, 2). Although hyperthyroidism and hyperthyroxinemia

are often equated (which is the bases of the medical objections to the use of

HDT), hyperthyroxinemia does not meet the formal definition of hyperthyroidism

regardless of how high the blood levels are. All definitions of hyperthyroidism and

thyrotoxicosis used here are consistent with the definitions used by the joint task

force of the American Thyroid Association and the American Association of

Clinical Endocrinologists management guidelines on hyperthyroidism.

Hyperthyroidism is dened as the overproduction of endogenous TH with

accompanying signs and symptoms of thyrotoxicosis. Thyrotoxicosis is defined by

the presence of signs and symptoms of high circulating levels of TH. Both

hyperthyroidism and thyrotoxicosis require conrmation by laboratory studies

showing high levels of TH. Thus hyperthyroidism is a subtype of thyrotoxicosis.

Subclinical hyperthyroidism is considered a mild form of hyperthyroidism and

defined by TSH levels below normal with normal T3 and T4 levels. It may or may

not be accompanied by thyrotoxic symptoms (15-18). Hyperthyroxinemia

fails to meet the definition of hyperthyroidism on two points. First the

8
source of HDTs therapy is external. The second is the lack of

thyrotoxicity.

The practice of using HDT is categorized in different ways by

different specialties. Endocrinology uses either TSH suppressive

therapy or superphysiologic doses variously defined as TSH levels

below the accepted normal range, TSH levels below 0.1 u/ml or any

alteration of thyroid hormone levels outside normal lab values.

In psychiatry HDT is generally defined as doses of T3 > 50mcg or

doses of T4 > 200mcg. Doses lower than that would be considered

augmentation (1, 2, 7, 10, 19, 20). For the purposes of this paper, HDT

will be used.

Support of the hypothesis

The HDT hypothesis is supported by direct evidence and indirect evidence

discussed in detail below. The direct evidence supports: 1. The effectiveness of

HDT for the treatment of bipolar depression. 2. That HDT corrects

neurophysiology abnormalities characteristic of bipolar disorder. 3. That HDT is

9
well tolerated for individuals suffering from a bipolar disorder and poorly

tolerated by non-bipolar individuals. 4. That dysfunctional mitochondria and low

ATP are part of the pathophysiology of the bipolar disorders. 5. That T3 levels can

be low in peripheral tissues while normal levels are maintained in the pituitary

and blood. 6. That TH transportation in the pituitary is different than other parts

of the body which results in cellular hypothyroidism in areas where TH

transportation is ATP dependent.

The indirect evidence is: The similarity of bipolar depression symptoms to

hypothyroid symptoms and similarity of medical sequela associated with the

bipolar disorders and the medical sequela of hypothyroidism.

Evidence that HDT is a beneficial treatment of bipolar depression

HDT treatment of patients with bipolar disorders has been repeatedly

shown to be effective and well-tolerated. No studies of HDT treatment report

hypomania or frank mania. (6, 8-10, 21-24) . There have been two randomized

double-blind placebo-controlled studies. The first is considered a failed study

due to the high placebo response. An ad hoc sub-analysis of the data

showed that HDT was efficacious for women (25). The second double-blind

placebo-controlled study did show efficacy. This study was published at the end of

2015 by Bauer and associates (6) and consisted of 25 bipolar depressed pts.
10
Fifteen patients were treated with 300 mcg a day of T4, and 10 pts were treated

with a placebo. Both groups continued receiving other bipolar medications that

were not changed prior to or during the study. The active treatment group

showed significant improvement. This was also a FDG-PET study. The results of

the FDG-PET portion of the study are discussed below. (6).

HDT is recommended in at least 4 treatment guidelines including the well-

respected Texas Algorithm bipolar guideline and the Canadian Network

for Mood and Anxiety Treatments (CANMAT) and International Society for

Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the

management of patients with bipolar disorder: update 2013(11, 13, 26, 27).

Evidence of normalization of neurophysiology with HDT

Two [F-18]-2-fluorodeoxyglucose positron emission tomography (FDG-PET)

studies have shown that HDT therapy corrects abnormal brain physiology found in

bipolar depression. The first FDG-PET study showed normalization of a

hypermetabolic state in the prefrontal and limbic areas of the brains of HDT

treated subjects. A group of ten women suffering from refractory bipolar

depression was compared to a matched control group of ten healthy women.

FDG-PET scans showed that compared to healthy controls, women with bipolar

disorders had increased activity in the right subgenual cingulate cortex, left
11
thalamus, medial temporal lobe (right amygdala, right hippocampus), right ventral

striatum, and cerebellar vermis. In addition, the group with bipolar disorders

showed reduced bilateral activity in the middle frontal gyri. Over a seven-week

period, 100 mcg of T4 was added to the existing medications in the bipolar group

and increased up to 400 mcg by the third week. The average dose was 320 mcg.

Seven women became euthymic, and three patients showed improvement. None

of the patients dropped out due to side effects. FDG-PET scans showed decreased

brain activity that was indistinguishable from normal brain activity of the control

group in the right subgenual cingulate cortex, left thalamus, right amygdala, right

hippocampus, right dorsal and ventral striatum, and cerebellar vermis. The

decreased activity of the left thalamus, left amygdala, left hippocampus, and left

ventral striatum were correlated with decreased depressive symptoms (9).

In the second FDG-PET study, which was the first randomized double blind

placebo controlled study showing the efficacy of HDT treatment discussed above,

Bauer and colleagues found that HDT therapy significantly reduced

hyperfunctioning areas of the brain. FDGPET imaging showed a significant

decrease in regional activity in the left thalamus, right amygdala, right

hippocampus, left ventral striatum and the right dorsal striatum. Decreases in the

12
left thalamus, left dorsal striatum and the subgenual cingulate were correlated

with a reduction in depression scores. (6).

These studies suggest that cellular bioenergetics play a role in bipolar

disorders and that HDT treatment can significantly impact both symptoms and

neurophysiology.

High TH levels without thyrotoxic symptoms

The Texas Medication Algorithm Project Procedural Manual for bipolar

disorder recommends T3 doses up to 160 mcg and T4 up to 500 mcg. The TH

blood levels with HDT routinely exceed the upper limit of normal for laboratory

measurements. Yet most studies of HDT remark how well patients tolerate HDT

(6-10, 21, 24).

In the first FDG-PET study discussed above the mean dose of T4 was 320

mcg. TH levels at the start of the study were all within normal limits. The mean TH

levels were significantly increased: free T4 index 19.3 (reference range: 4.510.5),

total T4 14.5 ng/dl (reference range: 4.911.4) and free T3 index 217.5 (reference

range: 78162). TSH was significantly decreased to TSH 0.02 mU/l (reference

range: 0.34.7). No patients discontinued treatment due to side effects(9). In the

second FDG-PET study discussed above TH levels at the start of the study were all

within normal limits. The mean levels were significantly changed in the treatment

13
group. TSH was suppressed from 2.35 to 0.02 mU/l. Free T4 increased from 1.11

to 2.53 ng/dl and free T3 increased from 2.80 to 5.62 ng/dl. TH levels were

essentially unchanged in the control group. No patients discontinued treatment

due to side effects (6).

Patients with affective disorders demonstrate a fundamentally different

response to HDT therapy compared to non-affectively ill individuals. HDT

treatment was evaluated in a group of patients with refractory affective disorders

(bipolar depression and major depression) and a control group of healthy

volunteers. All individuals in the study had normal thyroid levels with similar

averages prior to the start of treatment. Both groups were treated the same: T4

was started at 100 mcg a day and, and if tolerated, increased to 500 mcg a day

over the next four weeks. This dose was maintained for an additional four weeks.

In the group with refractory depression, mean HAM-D scores decreased from 27.0

to 10.7 while the non-depressed control groups HAM-D scores increased from

0.9 to 5.2. None of the patients in the refractory depression group discontinued

treatment, and all reached 500 mcg without intolerable adverse effects. In

contrast, 38% of the control group discontinued due to thyrotoxic symptoms

many before the full dose of 500 mcg was reached. At the end of the study TSH

was equally suppressed for both groups. For the depressed group end thyroid

14
levels were elevated: total T4 156.67 ng/l and total T3 1.86 ng/l. TSH was

suppressed to 0.1 mU/l. (22).

Mechanisms of cellular hypothyroidism

TH transportation across cell membranes

The hypothesis rests on the supposition that cellular hypothyroidism is present.

Unfortunately, there is no direct way to measure cellular thyroid levels(28). TH is

transported across cell membranes by an ATP dependent process (discussed

below in detail). When ATP is low, less TH is transported across cell membranes

leading to cellular hypothyroidism. Why does this deficit not cause overt

hypothyroidism? Entry of T3 and T4 into the pituitary are facilitated by TH

transporters that are different than transporters in peripheral tissues and is not

energy dependent or at least less energy dependent. The pituitary controls TH

production and is largely responsible for controlling TH blood levels.

TH transportation is energy dependent

Multiple studies have shown that TH uptake in human livers is ATP

dependent and limits iodothyronine metabolism. Even small changes in ATP levels

lowers intracellular T3 levels. T4 transport is more energy dependent than T3 but

15
it is uncertain to what degree. This has been established in vitro and in vivo in

rats (29). Gerg Tth and his group states, It is now widely accepted that the

cellular uptake of THs is effected by energy dependent, carrier-mediated

processes (30). Other researchers support this (29, 31, 32).

Pituitary TH transportation vs. TH transportation in peripheral tissues

A 2001 review paper concluded that the pituitary gland appears to have a

different TH transportation system than other parts of the body (29). An earlier

paper noted that T3 and T4 are transported via different transporters, except in

the pituitary, where T3 and T4 share the same transporter (33). Other research

supports that pituitary and peripheral tissues have different TH transportation(34,

35)

A 2014 review paper concluded that TH transportation in peripheral tissues

is energy dependent while pituitary TH transport is not energy dependent (32).

Low TH in peripheral tissues vs. normal levels in the pituitary and

blood.

In the normal rat, T3 levels are the same in the pituitary and the liver. In uremia,

rats intercellular T3 levels have been found to be lower in the liver than in the

pituitary (36).

16
 A 1986 review paper cited many lines of experimental evidence that T3

levels can be low in peripheral tissues yet normal in the pituitary (37). This

conclusion was based on human and animal research. The animal studies included

both in vivo and in vitro research. The lines of research included: Fasting states;

nonthyroidal illnesses and three different medications amiodarone,

benzodiazepines and SKF L-94901 (an experimental medication) (34). A 2008

review paper concluded that there are at least 10 different active, energy-

dependent TH transporters have been identified in humans and that under

normal circumstances, They guarantee that intracellular levels of THs are higher

than in blood plasma or interstitial fluids (31). Thus if the TH transporters are

disrupted intercellular TH levels may suffer.

Mitochondrial dysfunction and low ATP with bipolar disorders

There is a consensus of evidence that mitochondrial dysfunction is present

in bipolar disorders and plays a key role (38-41). Mitochondria, through the

production of adenosine 5-triphosphate (ATP), provides 95% of cells energy

needs. Brain imaging studies as well as other methods have established the

presence of low ATP levels in individuals suffering from bipolar disorders. This is

considered a hallmark of decreased energy metabolism (29, 38, 41, 42).

Sodium dependent thyroid transportation

17
Abnormally elevated intercellular calcium is a well-replicated ndings in bipolar

disorders (43). An alternative explanation or possibly a contributing factor to the

difficulties of getting TH across cell membranes is the possible disruption caused

by high cellular calcium levels among bipolar individuals. Some TH transports are

dependent on a sodium gradient (29, 44). While no specific discussion could be

located in the in the literature it is possible that the presence of an

overabundance of the cation form of calcium would be disruptive to the sodium

gradient making it difficult for the TH to be transported. One could further

speculate that low ATP levels could disrupt the Na/K ATP dependent ion pump

and that this may disrupt the sodium gradient.

Intriguing supportive evidence

While of limited value in support of the hypothesis the following similarities are

intriguing and might be expected in the presence of cellular hypothyroidism.

It may not be coincidental that symptoms of hypothyroidism and bipolar

depression are so alike. Depression and hypothyroidism are so similar that

hypothyroidism must be ruled out before a diagnosis of depression can be given.

Signs and Symptoms of hypothyroidism include weakness, sleepiness, lethargy,

fatigue, weight gain, menstrual disruption, slow movement, depression, anorexia,

18
muscle pains, joint pains, constipation, memory difficulties, low attention span,

slow calculations, lack of enthusiasm, anxiety, and irritability (45). These are

strikingly similar to signs and symptoms common in bipolar depressions.

There is overlap between the medical sequelae of hypothyroidism and bipolar

disorders. Both are associated with vitamin D deficiency, diabetes mellitus,

depression, hypertension, and heart disease (28, 46).

Discussion and the consequences of the hypothesis

There is sufficient evidence to support the hypothesis that HDTs

mechanism of action is correcting cellular hypothyroidism. No other hypothesis

could be formulated to encompass the data as currently understood. As shown by

FDG-PET imaging studies, HDT treatment can reverse over activity in brain regions

that are involved in bipolar depression while significantly reducing bipolar

depressive symptoms (6, 9). HDT treatment of patients with bipolar disorders has

been repeatedly shown to be helpful and well-tolerated (6-10, 21-24). The same

doses that produce significant improvement or even euthymia in patients with a

bipolar disorder cause significant thyrotoxic side effects in the non-affectively ill

(22).

19
The ample evidence connecting bipolar disorders with mitochondrial dysfunction

also indicates an association with low ATP levels (38, 39). The brain has the

highest concentration of mitochondria and the highest metabolic activity of the

body (6, 9, 32). Since mitochondria produce 95% of cells energy needs in the

form of ATP, disturbances of mitochondrial function would have consequences

(38, 39). There is evidence that the TH transport system is energy dependent but

that the pituitary gland that controls TH blood levels has a different TH

transporter that that is not energy dependent or less energy dependent. This

leads to normal pituitary levels and normal blood of levels of TH, even though the

rest of the body is experiencing cellular hypothyroidism.

There are very serious implications and ramifications of this hypothesis,

some potentially so controversial that it could initially lead to outright rejection of

the hypothesis. The implications are: The medical sequelae associated with

bipolar disorders cause a high morbidity and mortality rate. The medical

complications are the single largest cause of death in bipolar disorders eclipsing

the rate of death by suicide by a considerable margin (46).

1. The single most important implication is if HDT is correcting for cellular

hypothyroidism it implies that the use of HDT may decrease the

considerable medical morbidity and mortality associated with the

20
 bipolar disorders. This would be a leap forward in our understanding of

and treatment of the bipolar disorders. Giving us for the first time a

treatment, that not only can help control the symptoms of bipolar

disorder but also decrease the considerable medical morbidity and

mortality associated with bipolar disorders.

2. There is a link between suicide attempts and thyroid axis disturbance

(47). It is possible that correcting cellular hypothyroidism may decrease

the suicide rate beyond just symptom relief.

3. It further legitimizes HDT as a valid treatment for bipolar depression.

4. It furthers our knowledge of the pathophysiology of the bipolar

disorders.

5. It reinforces the research showing that HDT is as safe as, or safer than,

many alternative bipolar treatments.

6. It explains why HDT is so well tolerated in patients with bipolar disorders

yet the same doses in non-affectively ill individuals causes

thyrotoxicity.

7. The bipolar disorders have been linked to thyroid axis disturbances but

the exact link has yet to be found. The hypothesis gives a plausible

explanation of the long sought after link. That is, if cells are already TH

21
 deprived any further disturbance of the ATP axis will have a

disproportionate effect. Alternatively, the effect is additive. Either way

any disturbance in the TH axis is more noticeable.

8. It increases our understanding of the role of low intercellular ATP levels

and the mitochondrial dysfunction found in the bipolar disorders.

9. The potentially controversial ramification is: Normal methods of

determining TH levels would be useless in the bipolar disorders. Low

thyroid levels would still indicate hypothyroidism but normal thyroid

levels would not necessarily be indicative of normal cellular thyroid

levels. The idea of cellular hypothyroidism and the possibility that blood

levels of TH do not necessarily give a true indication of a pts TH status is

sure to cause an abreaction both because it challenges the long held

belief that blood TH measurements give an accurate picture of thyroid

status and because it would increase the complexity of all evaluations of

thyroid status.

10. Since HDT does not universally help all patients suffering from a bipolar

disorder, response to HDT may represent a biologic marker for a type of

bipolar disorder that isnt readably separated on the basis of symptoms.

22
 11. Bipolar relapses are complex and likely multifactorial. Many relapses

appear to be triggered by stress. Both physical stress and psychological

stress has been shown to shunt T4 to reverse T3 (32). Reverse T3 is

thought to be biologically inactive. One possible explanation or

contributing factor to relapses could be the shunting of T4 to reverse T3

instead of T3 in the face of an already existing cellular hypothyroid state.

Weaknesses

The hypothesis may well be an oversimplification of complex events. The

pathophysiology of bipolar disorder is not fully understood. The hypothesis

presented here is not an all-encompassing model of bipolar pathophysiology and

would explain a portion of the pathophysiology. Likewise, TH transporters are

complex and not fully understood. Future research is expected to yield a better

understanding of tissue specific regulation of THs(48). Even if the hypothesis

presented here is overly simplistic, it may, like the RutherfordBohr model of the

atom, (key to the understanding of the behavior of atoms despite the fact that it

was eventually eclipsed by quantum physics), could represent a stepping stone to

further our knowledge.

23
 Even though HDT helps the majority of bipolar pts, HDT does not

universally help all. This would necessitate the need of a heterogeneous schema

of the bipolar disorders. Indeed, this is already widely suspected.

Though not a specific weakness of the hypothesis it runs counter to firmly

held beliefs in the field of endocrinology. The hypothesis is in danger of being

dismissed out of hand without regard to the evidence.

Alternative hypothesis

There are two other hypotheses of HDTs mechanism of action, the first is

that HDT increases serotonin neurotransmission (3). The second is HDT

modulation of the -adrenergic receptor response to catecholamines in the

brain(4). The three hypothesis are not mutually exclusive. All may be correct in

part or in whole. The hypothesis presented here may be the underpinning cause

of the other hypothesizes.

The future

The hypothesis presented here will need to be tested. The ability to verify

the hypothesis is contingent on the ability to measure cellular thyroid levels in

humans, a better understanding of TH transporters and or a better understanding

24
of pathophysiology of bipolar disorders. At present there seems to be no gold

standard for testing for cellular thyroid levels in humans (28). Showing

improvement of the medical outcomes in bipolar pts treated with HDT and

comparing the results to non HDT treated pts is possible but difficult and time

consuming.

Conflicts of interests

Dr. Kelly has no conflicts of interest in this paper. Dr. Kelly is a paid speaker for

Actavis

Funding

This work is entirely self-funded.

25
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