The first blog in this series, “Eating for bipolar disorder,” explores factors associated with and possible contributors to bipolar disorder viewed through the lens of nutrition. But there are lesser-known facts bipolar disorder patients would benefit from us all becoming aware of.
Insulin resistance, food reactions, specifically gluten and casein, nutrient imbalances, eating disorders, and corticosteroid use are common in those with a bipolar diagnosis. Nutritional interventions are helpful and can greatly improve the quality of life when these aspects of the disease are present.
But as with most health issues, there’s more to the story.
In this second part of the series, we’ll discuss other influences in bipolar disorder:
- thyroid imbalances, with a particular focus on B12 deficiency
- perimenopause and menopause
- history of traumatic brain injury
- family history of mental illness
- childhood trauma
While a conscientious effort to eat a balanced, whole-food diet will likely support any mental health diagnosis, this blog doesn’t have the same “food” focus as the first.
More, it will provide those of us with bipolar friends, family, clients, or the diagnosis with more information about less discussed aspects of the condition.
In my practice, I have noticed a connection between thyroid disorders and mood disorders.
But this is simply my anecdotal experience. Does the research confirm what I’ve seen?
Remember, physiology and biochemistry don’t exist in a vacuum—our systems interact in incredible ways.
The connections between the thyroid (endocrine), neurotransmitters (nervous), and inflammation (immune) might explain how the thyroid intersects with mood disorders, including bipolar disorder.
Interestingly triiodothyronine, or T3, and thyroxine, T4, have been successfully used in conjunction with other mood-altering medications since the 1960s (1, 2). Their usefulness in bipolar disorder is still debated based on mixed findings and studies with small numbers of participants.
However, studies suggest that interactions between thyroid hormones and monoamine neurotransmitter systems—the catecholamines dopamine, epinephrine, and norepinephrine, serotonin, and histamine (yes, remember histamine is a neurotransmitter!)—may be one underlying reason why exogenous thyroid hormones positively impact mood disorders (3).
One study went so far as to call this group of neurotransmitters the “neural basis for emotions.”
“These monoamine neuromodulators might be the primary neural basis for emotions, and we suggested that emotions are nothing but neuromodulators” (4).
Remember that in part 1 of this series, catecholamine and serotonin imbalances were listed as contributors to bipolar disorder. It’s possible that the thyroid could be one of, likely multiple, mediators of these neurotransmitters’ role in the disease.
But what about links between the immune system, thyroid, and bipolar disorder?
A meta-analysis including over 2500 people from 30 studies found elevations of all cytokines—inflammatory, anti-inflammatory, and regulatory—in those with bipolar disorder compared to healthy controls. The authors conclude that this strengthens the hypothesis that inflammation is a driver of mood disorders, fully discussed here.
“There is increasing evidence suggesting that chronic, mild inflammatory processes in the periphery and the brain (neuroinflammation) are involved in the pathophysiology of [bipolar disorder]” (5).
Apropos of these findings, rates of autoimmune hypothyroid characterized by an increase in TPO antibodies but not hypothyroid without an autoimmune mechanism were higher in those with bipolar disorder (6,7).
Interestingly, these findings were independent of lithium use and its effect on the thyroid.
A little-known but cyclical side effect of this gold-standard bipolar medication is thyroid abnormalities, likely due to the suppression of T3 and T4. Hypothyroidism and goiter are the most common diagnoses in patients on long-term lithium therapy (8).
Perimenopause and menopause
The normal hormonal fluctuations during perimenopause and menopause are linked to various symptoms, including mood disturbances, regarded as typical during the menopausal years, regardless of mental health history.
But women with bipolar disorder may experience more severe mood fluctuations than their non-bipolar counterparts.
It has been observed that women with bipolar disorder are 77% more likely to experience severe mood disturbances during periods of hormonal fluctuations, including perimenstrual, postnatal, and menopausal periods (9).
Additionally, a longitudinal study of 50,273 midlife women with major depression (MDD) found that women with MDD and symptomatic menopausal transition were more likely to be later diagnosed with bipolar disorder than those with MDD and asymptomatic menopause (HR 1.14, 95% CI 1.07∼1.23) (10).
Sex hormones profoundly affect mood and vitality, and the fluctuating levels of estrogen and progesterone during the menopausal years are certainly a factor to consider for bipolar patients.
Estrogen protects the central nervous system, preventing neuroinflammation and regulating microglia (11), and declining estrogen may heighten neuroinflammation, potentially worsening bipolar symptoms.
Interestingly, recent research has explored the effects of selective estrogen receptor modular mediations (SERMs), such as Tamoxifen, as adjuvant therapy in adults and children with bipolar disorder (12). Although the results are promising, SERMs pose some potentially severe side effects, including a heightened risk of reproductive cancers.
Beyond sex hormones, the effects of menopause are far-reaching, affecting the homeostasis of multiple body systems. In particular, blood sugar regulation is essential for healthy menopausal years, particularly in bipolar patients.
The impact of blood sugar dysregulation on mental health is something I have seen firsthand in my clients with bipolar disorder and also those without a history of mental illness.
In many cases, extreme fluctuations in blood glucose have been the sneaky culprit behind stubborn symptoms like anxiety, mood swings, low mood, hyperactivity, fatigue, and insomnia. And again, this can occur even in those without any mental illness.
However, bipolar patients have a greater incidence of blood sugar dysregulation.
In part 1 of this series, you learned that 50% of bipolar patients have insulin resistance, which can exacerbate the severity of symptoms and overall disease progression due to the associated inflammatory response.
During menopause, insulin resistance usually increases, also increasing the potential for inflammation and blood sugar dysregulation.
In part 1, I go into more detail on herbal and lifestyle solutions to combat insulin resistance—be sure to review those suggestions if you need practical tips.
History of traumatic brain injury
A 1928 JAMA article titled “Punch Drunk” highlighted a condition experienced by boxers prone to be hit in the head, observing that this repeated injury often led to permanent behavioral changes (13).
Later, this condition garnered a more formal diagnosis—dementia pugilistica, the debilitating pathology that occurs in those who experience chronic brain injuries, such as contact athletes like boxers and MMA fighters.
We now know that individuals who experience a traumatic brain injury (TBI) are twice as likely to develop a psychiatric disorder (14), including an increased odds of bipolar disorder.
The link between TBI and the risk of bipolar has been well documented, although the odds vary between sources.
A Danish study of 113,906 individuals found that head injury increased the risk of bipolar by 28% (15), while another source reported a negligible risk of bipolar post-TBI (16).
A 2021 systematic review on TBI found that 74% of those affected experienced mania within one year of their head injury. However, some reported up to 31 years between the initial injury and their first manic episode (17).
Obviously, this is a highly individualized occurrence. But sustaining a head injury can lead to various complications that may increase the chances of developing bipolar disorder. The risk may be higher during adolescence when the brain is still developing, and the location and age at which the injury occurred may also affect the likelihood of later bipolar development.
Other factors to consider include:
- Oxidative stress increase, resulting in increased inflammation, mitochondrial dysfunction, and neuron cell death (18). Oxidative stress and mitochondrial dysfunction have been observed in bipolar patients, including increased oxidative stress within the brain, which may affect neurotransmitter signaling and uptake (19). Additionally, mitochondrial dysfunction has been hypothesized to be a critical factor in the etiology of bipolar (20).
- The formation of nervous system reactive autoantibodies has been reported post-TBI (21), resulting in an autoimmune reaction towards neuronal tissue. The connection between the immune system and bipolar has been studied since 1981, and immune dysfunction is strongly liked to bipolar disorder (22).
Not surprisingly, targeted antioxidant supplementation has been proposed as a therapeutic tool to dampen the heightened oxidative stress and improve mitochondrial function in both TBI and bipolar (23, 24).
A few studies show that specific nutrients may be beneficial for improving bipolar symptoms, likely due to their antioxidant and anti-inflammatory effects. CoQ10 and omega-3 fatty acids are worthwhile options for those with bipolar disorder.
CoQ10 is a lipid-soluble antioxidant that is an electron carrier within the mitochondria. Its lipid-soluble properties set it apart from other antioxidants, and it is critically important for mitochondrial health (25).
Omega-3 fatty acids are key modulators of inflammatory pathways, and deficiency can result in heightened oxidative stress and increased inflammatory cytokines and inflammation (26).
Family history of mental illness
Bipolar disorder is greatly influenced by family history, with a heritability estimate of 85%, the highest of any psychiatric condition (27). For perspective, the heritability estimates of major depressive disorder and generalized anxiety disorder are 37% and 28%, respectively (28).
Based on studies of mental illness and SNPs (single nucleotide polymorphisms often informally called “genetic mutations”), bipolar is genetically linked to autism spectrum disorder, anorexia, major depression, and obsessive-compulsive disorder. However, the most significant genetic overlap is between bipolar and schizophrenia (29).
As a nutritional therapy practitioner, this information inspired me to dig deeper.
What happens at a foundational, cellular level that can make people with certain genetic expressions more susceptible to developing mental illness?
One possible connection is MTHFR.
Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that plays crucial roles in folate metabolism and DNA methylation. It helps maintain healthy folate levels and regulates gene activity. When MTHFR activity is low, it can lead to inflammation, cardiovascular and neurological diseases, and psychiatric disorders.
This low activity happens because genetically inherited MTHFR SNPs lead to a deficiency of the MTHFR enzymes. The result is that genes may not be turned off when needed, and certain vitamins and antioxidants are not metabolized efficiently, leading to an imbalance of critical biochemicals.
You inherited a copy of the MTHFR gene from each of your parents. If one of your parents has an MTHFR SNP, you have an increased chance of having the same MTHFR SNP.
So, is there a link between MTHFR and bipolar?
A growing body of scientific evidence says yes.
A 2018 review concluded that MTHFR affects the risk of developing mental illness, symptom severity, and response to pharmaceutical treatment (30).
Both MTHFR 677C>T and MTHFR 1298A>C have been linked to bipolar disorder (31), and different variations of the MTHFR gene appear to have contrasting effects on the risk of bipolar.
For instance, someone who is heterozygous for MTHFR 1298A>C may have double the odds of developing bipolar (p = 0.031, OR = 2.030, 95% CI = 1.068–3.862), but someone with MTHFR 677C>T may only have a 20% increased risk of bipolar (p = 0.044, OR = 1.254, 95% CI = 1.006–1.562).
Paradoxically, some genetic expressions of MTHFR may even help protect against bipolar (31).
For perspective, the incidence of MTHFR variants is quite common. While there is ethnographic variation in frequency, approximately 50% of the population has one or more variants.
Comparatively, the incidence of bipolar disorder is only 1% of the population worldwide (including people with MTHFR variants and those without).
So while this link isn’t completely clear, it tells us that knowing a bipolar patient’s MTHFR status may be helpful, especially when developing a clinical treatment plan.
One clinically effective method of tracking MTHFR enzyme function is by checking homocysteine levels. Homocysteine, an amino acid, tends to increase when MTHFR activity is low.
We touched on the role of homocysteine in psychiatric disorders in part 1 of this series. Still, it is worth mentioning again because of its strong connection with bipolar disorder and MTHFR.
The available literature shows a significant connection between elevated homocysteine and bipolar, and Salgre et al. (2017) even suggest that homocysteine be a peripheral biomarker for bipolar as it significantly increases during periods of mania (32).
A 2019 study on newly diagnosed psychiatric inpatients in New Delhi, India, found that 35% of patients had increased homocysteine levels compared to 13% in healthy controls. Within that group, 50% of bipolar patients had hyperhomocysteinemia (33).
But none of these patients had low folate levels, even though valproic acid and lamotrigine, commonly prescribed medications for bipolar disorder, may deplete folate.
Additionally, when MTHFR activity is reduced, folate metabolism is impaired, resulting in suboptimal production of the active form of folate known as methyl-folate. Because methyl-folate is needed to convert homocysteine to methionine—the essential amino acid precursor for antioxidants like glutathione and SAMe—the lack of methyl-folate means homocysteine is not metabolized and instead begins to rise.
Interestingly, the New Delhi study found that bipolar patients were deficient in another nutrient; 28% were deficient in B12, marked as a serum level <211 pg/mL.
I would be remiss to ignore that other sources consider anything under 300 pg/mL borderline deficient, so a larger number of patients likely had early-stage B12 deficiency in this study.
This is important to note because:
“Early-stage vitamin B12 deficiency may present with subtle and slight cognitive impairments. Hence, early recognition is crucial to prevent irreversible damage…
The diagnosis is complicated by the limitations of current assay techniques, as a low serum vitamin B12 level does not always indicate vitamin B12 deficiency and a normal level does not always exclude it. However, individuals with biologically significant vitamin B12 deficiency almost always have elevated blood plasma levels of total homocysteine and methylmalonic acid.”
B12 is another cofactor for folate metabolism and the conversion of homocysteine to methionine. Hence, low B12 can lead to hyperhomocysteinemia.
Thankfully reducing homocysteine to healthy levels can often be achieved by increasing the consumption of foods rich in folate and B12, such as leafy greens, citrus, liver, and well-souced meats and fish.
And methyl-folate and B12 aren’t the only cofactors that can aid the homocysteine to methionine conversion! Betaine, present in quinoa, beetroot, and spinach, can also fill the role.
Genes affect susceptibility to bipolar disorder in many ways. But remember that external factors, like diet and lifestyle, can positively impact the onset and severity of the disease, even in the presence of genetic predisposition.
It is well known that childhood trauma can have long-term consequences that continue into adulthood, affecting mental health and risk of chronic illness.
Childhood trauma, often referred to in the literature as adverse childhood experiences (ACEs), are traumatic experiences that impact a child’s well-being. This includes abuse, bullying, financial instability, the death of a parent or sibling, substance abuse in the family, and emotional and physical neglect.
Additionally, non-violent parental behaviors, often regarded as common, are capable of causing trauma for the child.
For example, here are two questions from the “Risky Families Questionnaire,” a tool that is sometimes used to assess the risk of ACE:
“How often would you say there was quarreling, arguing, or shouting between your parents?”
“Would you say that the household you grew up in was well-organized and well-managed?”
Unfortunately, ACEs are prevalent among all populations. According to the CDC, 61% of adults in the US have experienced at least one ACE, and 16% have experienced four or more. ACEs increase the risk of many health problems through adolescence and adulthood, including an increased risk of mental illness.
For adults with bipolar, having experienced childhood trauma dramatically impacts the course of the disease.
A 2020 study of 2,675 bipolar patients found that adults who experienced two ACEs had a staggering 329 times the odds (OR: 329.24 95%, CI: 45.86–2363.70) of experiencing psychotic symptoms when compared to patients with no ACEs (34).
You may have noticed the wide confidence interval, ranging from 45.86 to 2363.70, indicating a lower precision level. However, even an odds ratio of 4 would be notable.
Odds this high are rarely, if ever, seen in the literature. An odds ratio of 2? That’s likely clinically significant. Odds of 4? That’s large.
So an odds ratio of 329 is remarkable.
Still, this study doesn’t mean ACEs cause bipolar disorder, but rather that there’s a strong connection.
Additionally, ACEs’ impact extends beyond simply affecting well-being and emotional resilience.
Neuroimaging research shows that experiencing childhood trauma changes the brain. More specifically, childhood trauma alters gray matter in the prefrontal regions, hippocampus, and thalamus (35).
…These alterations seem to indicate that BD [bipolar disorder] patients with a history of CAs [childhood adversities] are characterised by volume reductions in all these regions when compared with HC [healthy controls] or similar group without a history of CAs. Lastly, studies investigating WM [white matter] integrity showed an association between a history of CAs in BD and a reduction of volumes and fractional anisotropy (FA) in the CC [corpus callosum], uncinate fasciculus and corona radiata when compared with HC or BD patients without CAs” (35).
The next logical question is, is the reduction in gray and white matter permanent?
It’s not entirely clear, but it’s possible that brain volume can increase through therapeutic interventions for brain morphology in patients with bipolar disorder. However, research in this area is still new.
Thankfully, a handful of therapeutic interventions increase brain volume and/or function in various populations.
- Lithium therapy has been studied for its ability to increase cerebral gray matter in bipolar patients (36).
- Mindfulness meditation seems to be effective at improving brain function, including increasing gray and white matter (37).
- Hyperbaric oxygen therapy has been shown to be a successful therapy for TBI patients (38), increasing the regeneration of nerve fibers in white and gray matter (39). A fascinating 2021 review noted that the duration of hyperbaric therapy is vital to its success. The authors found that long-term treatment (> 20 days) improved mitochondrial function and decreased reactive oxygen species. However, less than five days of treatment could increase inflammation and damage mitochondria (40).
Do you need bipolar disorder support?
Bipolar disorder is a diagnosis that is professionally and personally important to me. If you or someone you love is living with this diagnosis and needs support, please schedule a free 15-minute consultation call.
We can discuss the aspects of the diagnosis most impactful to you and if nutritional therapy is a good fit.
- https://pubmed.ncbi.nlm.nih.gov/26938433/, https://www.sciencedirect.com/science/article/abs/pii/S0149763414000724?via%3Dihub
Inositol and bipolar disorder and bipolar meds
Lastly, inositol has been proposed not only as a possible antidepressant agent but also as a molecule capable of counteracting the side effects of mood stabilizers, such as lithium and sodium valproate, which are common drugs used for the treatment of mood disorders, in particular BD . Previous studies suggested that lithium and valproate may reduce the concentrations of inositol within the CNS. It was proposed that lithium and sodium valproate may induce alterations in the PI cycle, thus lowering mI concentrations [91,103]. However, the so-called “inositol depletion hypothesis” remains the most controversial hypothesis for the mechanism of action of lithium and sodium valproate in BD . In this context, several studies have shown how the administration of these drugs changes the levels of inositol in the brain. For example, Davanzo et al.  found a significant reduction in brain inositol levels after lithium intake in patients with BD during a (hypo)manic episode. Another study, conducted by Sharma et al. , showed similar results. Sodium valproate was found to decrease inositol biosynthesis . On the contrary, Patel et al.  investigated differences in mI concentrations after lithium administration, showing no significant change in mI levels after 42 weeks of treatment in patients with bipolar depression. Thus, the accuracy of the inositol hypothesis as an explanation for the clinical efficacy of lithium and sodium valproate remains uncertain . Although the reduction in the concentration of inositol in the CNS may play a role in determining the effects of these drugs, the reduction of peripheral inositol levels observed in other tissues may explain some of the side effects, resulting from the intake of lithium and sodium valproate. For instance, a reduction in inositol concentration in the kidney could account for the polyuria/polydipsia developed by treated patients , as well as for the hypothyroidism and weight gain, which are common side effects of these molecules . For these reasons, reducing or moderating these side effects through inositol supplementation has been recently evaluated .
In conclusion, inositol as monotherapy or in addition to conventional antidepressant drugs did not seem to influence clinical outcomes in mood disorders.