Could intense mood swings indicate an underlying issue?

Almost everyone experiences the “emotional rollercoaster” at some point in life, but for those with bipolar disorder, the extreme emotional ups and downs do not end. Bipolar disorder, or manic depression, is one of the most common and severe mental illnesses diagnosed. About 5.7 million American adults, (age 18 and over) are affected every year. Both men and women are equally affected by the disorder, and it is found in all ages, races, ethnic groups, and social classes.

Figure 1. There are several subtypes of bipolar disorder.

So, what is bipolar disorder? Bipolar disorder is a condition characterized by extreme mood swings from the lows of depression to the highs of mania. When people are depressed, they feel sad or hopeless and lose interest in activities they once enjoyed. When their mood shifts in the opposite direction, they may feel euphoric and full of energy.

There are several subtypes of bipolar disorder, each with its own symptom pattern.

• Bipolar I disorder: At least one manic episode with periods of major depression, also known as “manic depression”
• Bipolar II disorder: Less severe than Bipolar I disorder, experiences of high energy levels but not as severe as mania, alternates with depression
• Cyclothymic disorder: Mild form of bipolar with less severe mood swings
• Rapid cycling: More than four episodes per year

The pathophysiology is poorly understood and there has not been a definite biological marker found to correlate with bipolar disorder. However, genetics play a role. First-degree relatives of a person with bipolar are about seven times more likely to develop bipolar disorder.

Although there is not a concrete understanding of bipolar disorder, testing for neurotransmitter levels may be helpful. Elevations in glutamate can correlate with bipolar disorder. Studies have shown that abnormal amounts of serotonin and dopamine play a role in either the manic or depressive side.

A large amount of data confirms that neurotransmitter systems may be dysfunctional in bipolar disorder, explaining symptom relief from pharmacological interventions that target these imbalances. Continued research is needed to determine how neurotransmitter imbalances, abnormalities in signaling, and neuroplasticity of cells may cause bipolar disorder.

Guest author: Choua Lee is a member of the Clinical Support and Education Department at NeuroScience, Inc. and is the resident expert in psychiatry.

References:

http://www.mayoclinic.org/diseases-conditions/bipolar-disorder/basics/definition/con-20027544

http://www.webmd.com/depression/guide/bipolar-disorder-manic-depression

Manji, Husseini K., Jorge A. Quiroz, Jennifer L. Payne, Jaskaran Singh, Barbara P. Lopes, Jenilee S. Viegas, and Carlos A. Zarate. “The Underlying Neurobiology of Bipolar Disorder.” Pubmed. World Psychiatry, Oct. 2003. Web.

Can oxidative stress shrink your brain?

With baby boomers growing older, the age of the population in the United States is increasing. About 50 million Americans are affected each year by over 600 neurodegenerative diseases. Neurodegenerative disease refers to conditions in which nerve cells progressively degenerate and/or die.  The most common neurodegenerative disorders are Alzheimer’s disease and Parkinson’s disease.

Figure 1. Oxidative stress can initiate a cascade that leads to cell death.

Neural decay and ageing related with these diseases increases with oxidative stress. A primary source of oxidative stress is reactive oxygen species (ROS). Some of these molecules are free radicals, all are highly reactive and destructive if present in excess. Mitochondria make most of the ROS found in the body during ATP production. ROS are also created when the enzyme monoamine oxidase (MAO) beginsthe oxidation of biogenic amine neurotransmitters (e.g. dopamine and serotonin).

In Parkinson’s disease, oxidative stress leads to a cascade of events that underlie the neural decay associated with this disease (Figure 1). Oxidative stress leads to mitochondrial abnormalities, which contributes to excitotoxicity. Excitotoxicity leads to protein accumulation and inflammation, which ultimately results in cellular damage and death. Excitotoxicity that leads to the death of neurons in termed neurotoxicity.

Neurotoxicity is seen in other neurodegenerative diseases as well. Normally, excitatory neurotransmission is essential for synaptic development and plasticity, as well as learning and memory. However, too much stimulation of glutamatergic receptors, the most excitatory in the central nervous system, induces neurotoxicity. This neurotoxicity contributes to neural cell damage. Hyperactivation of the AMPA-type glutamate receptors also creates oxidative stress that can contribute to neurodegeneration.

Assessing oxidative stress and neurotransmitters, specifically glutamate, can help identify therapy options that may help reduce or slow neurodegeneration.

References:

http://www.neurodegenerationresearch.eu/about/what/

Melo, A., et al. (2011). Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Therapeutic Perspectives. Oxidative Medicine and Cellular Longevity, 1-14.

Uttara, B., et al. (2009). Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options. Curr Neuropharmacol, 7(1): 65-74.

Is gluten making you overstimulated?

There has been a lot of controversy lately over gluten sensitivity, but the existence of celiac disease is something no one can argue against. Celiac disease affects 1 in 141 individuals in the United States and can cause intestinal damage.

Figure 1. Healthy villi (left) are destroyed in celiac disease (right). Image from http://celiacdisease.about.com/od/celiacdiseaseglossary/g/Villi.htm

Celiac disease is an immune reaction to gluten, a molecule that can be found in wheat, barley, and rye. The immune system produces antibodies against gliadin (a gluten protein) and transglutaminase, an enzyme that modifies gluten. These antibodies increase the immune response leading to increased pro-inflammatory markers. These inflammatory markers increase inflammation both locally and systemically and lead to the destruction of the villi and microvilli in the small intestines. The villi and microvilli are responsible for the absorption of nutrients. Without the villi and microvilli, the body may not absorb enough nutrients for optimal health leading to weight loss, diarrhea, or decreased growth (in children).

Figure 2. Glutamate is converted into GABA by glutamate decarboxylase, which can be blocked by gliadin antibodies.

In addition to the issues caused by insufficient nutrition, celiac disease can directly affect neurotransmitter levels that can contribute to symptoms . Gliadin antibodies block the enzyme glutamate decarboxylase. This enzyme is responsible for converting glutamate into GABA. If the glutamate decarboxylase is not functioning, glutamate will not be broken down. The result is an increase in glutamate levels and a decrease in GABA levels.

Glutamate is considered the most excitatory neurotransmitter. It is important for learning and memory. High levels are associated with urges, cravings, and intestinal complaints. They can interfere with focus and concentration and sleep. High levels can also be excitotoxic and cause damage to cells. GABA is the primary inhibitory neurotransmitter and is needed to feel calm and relaxed. Low levels of GABA are correlated with anxiousness and sleep difficulties.

If your patient has celiac disease, you may want to check the neurotransmitter levels to see if an imbalance in glutamate or GABA is present.

References:

http://www.mayoclinic.org/diseases-conditions/celiac-disease/basics/definition/con-20030410

Cryan, J.F., et al. (2005). Don’t worry ‘B’ happy!: a role for GABAb receptors in anxiety and depression. TRENDS in Pharmacological Sciences, 26(1): 36-43.

Dong, E., et al. (2012). Effects of microinjections of Group II metabotropic glutamate agents into the amygdala on sleep. Brain Res, 1452: 85-95.

Hadjivassi, R., et al. (2004). Gluten sensitivity: from gut to brain. Trends in Immunology, 11: 578-82.

Nikolaus, S., et al. (2010). Cortical gaba, striatal dopamine and midbrain serotonin as the key players in compulsive and anxiety disorders-results from in vivo imaging studies. Reviews in the neurosciences, 21(2): 119-39.

Rubio-Tapia, A., et al. (2012). The prevalence of celiac disease in the United States. Am J Gastroenterol, 107(10): 1538-44.

Sports can cause lasting brain trauma

What do baseball, football, and hockey all have in common? The answer is Post-concussion Syndrome (PCS). Any one of these sports, along with many other things we do that can cause trauma to the brain or spinal cord, can result in PCS.

So you may be asking yourself what is PCS? PCS is a mild traumatic brain injury that results as a cognitive deficit in attention or memory and has at least three of the following symptoms associated with it: fatigue, sleep disturbance, headache, dizziness, irritability, affective disturbances, apathy, or personality change.

PCS occurs when acceleration-deceleration forces are applied to the moving brain resulting in shearing of neural and vascular elements within the brain and spinal cord. This damage is followed by sudden neuronal depolarization and then a period of nerve cell transmission failure.

Who is affected by PCS? According to the CDC, infants and children ages 0 to 4, children and young adults ages 5 to 24, and older adults ages 75 and older, are more likely to develop PCS after a concussion. Several other factors contribute to increased incidence of PCS, including gender and history of prior concussions.

Females are at a greater risk of developing PCS. The reason for increased vulnerability is unknown, however some researchers believe that due to the fact that most women have smaller head and neck muscles compared to their male counterparts, this predisposes them to more injuries from rapid acceleration and deceleration.

Prior concussion equals increased likelihood of developing PCS. Three main conclusions can be drawn from the many studies surrounding PCS. Prior concussions can increase the risk of developing a subsequent concussion with less force necessary than the previous concussion. Multiple concussions will result in increased risk of cognitive dysfunction. A history of prior concussion is correlated with longer recovery time.

The important thing to remember about PCS is that it can be prevented by wearing proper protective gear during sports and recreational activities, buckling your seat belt, exercising regularly, and providing education on identifying concussion symptoms.

Guest author: Michele Serbus is a member of the Clinical Support and Education Department at NeuroScience, Inc. and is the resident expert in pediatrics.

References

Arciniegas DB, Anderson CA, Topkoff J, McAllister TW. Mild traumatic brain injury : a neuropsychiatric approach to diagnosis, evaluation, and treatment. Neuropsychiatr Dis Treat. 2005;1:311–327.

Daneshvar DH, Riley DO, Nowinski CJ, McKee AC, Stern RA, Cantu RC. Long-term consequences: effects on normal development profile after concussion. 2011 Nov;22(4):683-700, ix. doi: 10.1016/j.pmr.2011.08.009. Epub 2011 Sep 23.

Giza C. C., Hovda D. A. The neurometabolic cascade of concussion. J. Athl. Train. 2011;36, 228–235.

http://www.cdc.gov/concussion/headsup/pdf/Facts_for_Physicians_booklet-a.pdf

Lyme isn’t all you can get from a tick bite

You have tested negative for Lyme disease with ELISA, Western Blot and iSpot Lyme. However, you still have symptoms synonymous with Lyme disease like muscle and headaches, fatigue, chills and fever. Testing negative for Lyme disease, doesn’t always mean that you are in the clear, there is a chance that you could have a co-infection.

Figure 1. Incidence of reported cases of ehrilichiosis. Image from: http://www.cdc.gov/ehrlichiosis/stats/index.html

There are more than 12 tick-borne diseases is the United States alone, and more are being identified on a regular basis. Ehrilichiosis, Anaplasmosis, Bartonella and Babesiosis are considered to be the most common Lyme disease co-infections. All co-infections are transmitted by tick bites and some can be transmitted other ways as well.

Common Lyme Disease Co-infections

Ehrlichiosis: Ehrlichiosis can be caused by Ehrlichia chaffeensis, Ehrlichia ewingii, and Ehrlichia species. Symptoms include fever, headache, fatigue, and muscle aches, typically occuring within 1-2 weeks of the tick bite. Diagnosis of ehrlichios is based on symptoms and can later be confirmed by detection of antibodies.

Figure 2. Incidence of reported cases of anaplasmosis. Image from: http://www.cdc.gov/anaplasmosis/stats/

Anaplasmosis: Lxodes scapularis (the black-legged tick) and Ixodes pacificus (the western black-legged tick) commonly cause Anaplasmosis. Symptoms of this disease occur 1-2 weeks post-tick bite and may include: fever, headache, chills, and muscle aches. Physicians may initially diagnose Anaplasmosis based solely on symptoms and then confirm the diagnosis with PCR, blood smears, indirect immunofluorescence assays or enzyme immunoassays.

Bartonella: Three different Bartonella species cause cat scratch disease, trench fever and Carrión’s disease. Symptoms of these three may include: fever, headache, rash, bone pain and nodular lesions under the skin. A Bartonella infection is diagnosed by serology, PCR or bacterial culture depending on the specific disease.

Figure 3. Incidence of reported cases of babesiosis. Image from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6127a2.htm

Babesiosis: Lxodes scapularis tickstransmit Babesia microti. Many people infected with Babesia do not have symptoms of an infection. However, infected patients with symptoms, often experience  fever, chills, sweats, headache, body aches, loss of appetite, nausea and fatigue. Patients with symptoms of a Babesia infection can have a confirmed diagnosis by microscopy.

If you’ve been treated for Lyme disease or have tested negative, but still have persistent symptoms, you may consider talking to your primary care physician about the possibility of a co-infection. There are tests your health care practitioner can run to rule out co-infections.

References:

http://www.cdc.gov/parasites/babesiosis/
http://www.cdc.gov/parasites/babesiosis/disease.html
http://www.cdc.gov/parasites/babesiosis/diagnosis.html
http://www.cdc.gov/ehrlichiosis/
http://www.cdc.gov/ehrlichiosis/symptoms/index.html
http://www.cdc.gov/anaplasmosis/
http://www.cdc.gov/anaplasmosis/symptoms/index.html
http://www.cdc.gov/bartonella/
http://www.cdc.gov/bartonella/clinicians/index.html
http://www.niaid.nih.gov/topics/lymedisease/research/pages/co-infection.aspx
http://www.lymedisease.org/lyme101/coinfections/coinfection.html
http://www.lymedisease.org/lyme101/coinfections/babesia.html
http://www.lymedisease.org/lyme101/coinfections/ehrlichia.html
http://www.lymedisease.org/lyme101/coinfections/bartonella.html
http://www.lymedisease.org/lyme101/coinfections/other_tick_diseases.html

You’ve heard that beauty is in the eye of the beholder, but what about weight?

Figure 1. Patients suffering from AN have a distorted view of their own bodies many times thinking they are overweight when in fact they are dangerously underweight. Image from: http://theraphaelproject.com/blog/eating-disorders/

In the media, we often hear about the obesity epidemic. Another weight related problem that is becoming more and more widespread is anorexia nervosa.

According to DSM-IV, Anorexia nervosa (AN) is characterized by an intense fear of gaining weight or becoming fat even though the patient is below normal weight. The patient experiences a disturbance in the way they view their body weight and body shape (Figure 1), often thinking they are overweight when in fact they are critically underweight. Even though patients have a powerful pursuit of weight loss they are also inherently preoccupied with food and eating rituals. They also show an obsessive need to exercise and do so to an extreme point.

AN is one of the most homogenous psychiatric disorders in that the age of onset is very narrow, usually beginning at puberty, and there is a very stereotypic presentation of symptoms associated with the disease. The etiology of AN is unknown however there are many different theories as to what may cause AN.

Like many psychological diseases there seems to be a mix of causative factors that influences the onset and progression of AN. These include biological factors, psychological factors, and environmental factors.

• 

  Figure 2. A comparison in extracellular serotonin levels as well as serotonin receptor activity in healthy controls and in patients with AN. These abnormalities lead to a dysphoric mood, increased error detection, and increased inhibition in patients suffering from AN.

  Biological factors: It has been found that there might be up to an 80% genetic influence in the development of AN although it is unknown which genes may contribute to this risk. There has also been research on abnormalities in certain brain circuits, neurotransmitter function, and receptor function that may contribute to AN. One observation in patients with AN is that they seem to have an increased amount of extracellular serotonin levels as well as abnormal serotonin receptor activity (Figure 2). These abnormalities together seem to result in an increased feeling of satiety in AN patients as well as an anxious temperament. Serotonin increases with food intake and in patients suffering from AN this leads to an increase in anxiousness. Serotonin levels are reduced during starvation. In healthy controls this leads to an anxious and food driven temperament but in patients with AN, this reduction in serotonin reduces anxiety and leads to continuing food aversion behaviors.

• Psychological factors: Patients that develop AN tend to present with a certain set of personality traits. These include: negative emotionality, harm avoidance, perfectionism, inhibition, an inherent drive for thinness, and obsessive-compulsiveness. These personality traits make it easier for people to stick to extreme diets even when they are very hungry. It also drives them to lose more and more weight despite already being dangerously thin.
• Environmental: People are bombarded by media on a regular basis.  TV shows, movies, and magazines are dominated by very thin actors, actresses, and models. Photoshop is used to create body images that are incredibly difficult to reach for the average person, this may be a driving factor in the development of AN.

Treatment for AN can be difficult as many people do not see it as a problem and choose to view it more as a lifestyle choice. Men with AN generally seek treatment less than women do as AN is seen as a “woman’s issue”. The first treatment needed may be medical attention for any issues due to extreme weight loss and starvation. The next steps for treatment are to restore the weight and for the patient to undergo psychotherapy. Medications are typically not effective for patients suffering from AN. The disease is one that is typically fought throughout a lifetime especially during times of increased stress. Patients may need to undergo continuing therapy to continue achieving a healthy weight. AN is a complex psychological disorder. Although it is one of the most homogenous of the psychological disorders there is not one known cause that leads to the onset and progression of AN.

Guest author: Alyson Betcher is a member of the Medical Education department at NeuroScience, Inc. 

References:

Kaye, W., Fudge, J., Paulus, M. (2009). New insights into the symptoms and neurocircuit function of anorexia nervosa. Nature Reviews, 10: 573-584.

http://www.mayoclinic.org/diseases-conditions/anorexia/basics/definition/con-20033002

Oxidative stress? Let’s take a look at DOPAC…

In the past several weeks, there have been a number of posts about oxidative stress and the effects that it can have on neurotransmitter pathways, including the tryptophan pathway and catecholamine synthesis. Dopamine metabolism can also contribute to oxidative stress.

Figure 1. The breakdown of dopamine by MAOB creates hydrogen peroxide and a hydroxide ion, both free radicals.

Dopamine is created from L-DOPA by the enzyme aromatic L-amino acid decarboxylase (AADC) (Figure 1). Dopamine is then broken down into DOPAL by monoamine oxidase B (MAOB) and DOPAC by aldehyde dehydrogenase (ALDH). The breakdown of dopamine to DOPAL creates a hydrogen peroxide molecule (H₂O₂). Hydrogen peroxide is a free radical and is also broken down into a hydroxide ion (HO^–), which is also a free radical. Normally, free radical synthesis through the breakdown of dopamine is well controlled by the body. If the body becomes overwhelmed with free radicals, illness or disease symptoms can occur. An elevated DOPAC level can indicate increased dopamine breakdown, leading to increased levels of free radicals. This oxidative stress can affect neurotransmitter pathways. The neurotransmitter pathways, in turn, can also impact the total oxidative stress in a patient.

So, if you see elevated DOPAC levels in a patient, make sure you think about oxidative stress as a contributing factor.

References:

Meiser, J., Weindl, D., Hiller, K. (2013). Complexity of dopamine metabolism. Cell Commun Signal, 11(1): 34-52.

Neuropharmacology: How do your drugs work?

Almost everyone uses medications at some point in their life, but what are they actually doing in the nervous system? Neuropharmacology is a branch of medical science dealing with the properties and actions of a drug on and in the nervous system. Drugs are grouped into one of the following based on how they work: neurotransmitter substrates, reuptake inhibition, receptor modification, and enzyme modulation (Figure 1).

Figure 1. Drugs can be classified into one of the following based on their mechanism of action: reuptake inhibition (1), receptor modification (2), neurotransmitter substrates (3), or enzyme modification.

Neurotransmitter substrates

Neurotransmitter substrates are amino acids that act as precursors for neurotransmitter synthesis. Neurotransmitter substrates, such as the drug Levodopa, will affect the amount of neurotransmitters available.

Reuptake inhibition

Reuptake inhibition is the prevention of neurotransmitter transport from the synapse back into the neuron that released it. This increases neurotransmitter levels outside the cells. These substances are commonly referred to as reuptake inhibitors. Examples of reuptake inhibitors include selective serotonin reuptake inhibitors (SSRI) like citalopram or fluoxetine, serotonin and norepinephrine reuptake inhibitors (SNRI) like venlafaxine and duloxetine, and norepinephrine and dopamine reuptake inhibitors (NDRI) like bupropion.

Receptor modification

Neuronal receptor modification includes the mimicry, enhancement, or blocking of neurotransmitter binding to its receptor. Therapeutic agents in this category include receptor agonists and receptor antagonists.

Receptor agonists can either act like or enhance the action of neurotransmitters. Mimics bind to a specific neurotransmitter receptor and cause a similar action. Agents that enhance the action of neurotransmitters bind to the neurotransmitter receptor along with the neurotransmitter. This amplifies the effect of the neurotransmitter. Clonazepam, diazepam, and zolpidem are all classified as receptor agonists.

Receptor antagonists have the opposite effect of agonists. They bind to neurotransmitter receptors, blocking the neurotransmitter from activating the receptor. This decreases neurotransmission. One common example of a receptor antagonist is diphenhydramine, which is commonly used to treat allergies. It is a histamine receptor antagonist. It reduces the symptoms of allergies by blocking peripheral histamine receptors. Diphenhydramine also blocks central histamine receptors that are involved in wakefulness. When it blocks receptors in the central nervous system, the drowsiness often felt with the use of this drug can occur.

Enzyme modulation

Enzyme modulators alter the activity of an enzyme. Some enzymes break neurotransmitters down into their inactive metabolites. Pharmaceutical enzyme inhibitors can slow the breakdown of neurotransmitters, leaving more neurotransmitters to transmit signals. Examples are monoamine oxidase inhibitors (MAOI) such as selegiline or phenelzine or acetylcholinesterase inhibitors (AChEI) such as carbamates.

Many pharmaceuticals affect the nervous system by altering the levels or activity of neurotransmitters. Identifying which neurotransmitters are out of balance will help to determine the appropriate therapy to improve patient outcomes. For more information on which neurotransmitters are affected by different pharmaceuticals, please see the Prescribing Information for Select Drugs reference document.

References:

http://www.merriam-webster.com

Muller, W.E., et al. (1998) Pharmcopsych. 31:16-21.

Turner, E.H., et al. (2006) Pharmcol Ther. 109:325-338.

What to expect when you’re expecting: do you expect environmental toxins?

Earth Day was first celebrated in 1970 and is meant to bring awareness to environmental protection. Ironically, since then, the amount of chemicals (i.e., insecticides, pesticides, manufacturing) used in the environment has increased. US industries make and import around 80,000 chemicals with an average of seven new chemicals approved each day. Of the top 20 chemicals discharged into the environment, nearly 75% are known or suspected to be toxic to the developing human brain.

A 2005 EWG study identified 287 different chemical in umbilical cord blood. 180 are known to cause cancer in humans and animals, 217 are toxic to the brain and nervous system, and 208 cause birth defects or abnormal development in animal tests.

This increase in exposure to toxic chemicals in the environment, including the home, can have drastic effects on children. Kids are more vulnerable to the effects of toxins than adults. Their ability to detoxify is not as well-developed as an adult’s. Kids also have more risk of toxic exposure from water, food, and air. This is because, pound-for-pound, kids drink, eat, and breathe more than adults. Kids also touch the ground more often and engage in more hand-to-mouth behaviors, making the risk even greater.

Exposure to toxic chemicals begins in the womb. The Environmental Working Group (EWG) ordered a study in 2004 to identify industrial chemicals, pollutants, and pesticides in human umbilical cord blood. The study, printed in 2005, found 287 different chemicals in the cord blood. Of these, 180 are known to cause cancer in humans and animals, 217 are toxic to the brain and nervous system, and 208 cause birth defects or abnormal development in animal tests.

Research has also found that acute leukemia is significantly linked with home and garden insecticide and fungicide use during pregnancy and childhood. Phthalates, substances added to plastics to increase flexibility, have been associated with increased allergies in children. Prenatal exposure to phthalates has also been linked to autistic behaviors. There have been reports that DDT exposure is associated with early menarche and shortened menstrual cycles. The National Academy of Sciences has also determined that environmental factors contribute to 28% of developmental disorders in children.

Industrial pollutants and toxins have become abundant in our environment, and prenatal and childhood exposure to these toxins is increasing. The total body burden of toxins should be kept as low as possible to support optimal health. Removal of toxins is important, including staying hydrated to flush out toxins as well as regular bowel movements. Maximizing children’s antioxidant reserves can also be beneficial to support their ability to detoxify. Neurotransmitter testing can also be of benefit to identify imbalances in the nervous system that may be due to toxic chemicals. Above all, the most important aspect is to minimize toxin exposure.

References:

Bornehag, CG., et al (2004). The Association between Asthma and Allergic Symptoms in Children and Phthalates in House Dust: A Nested Case-Control Study. Environ Health Perspect, 112(14): 1393-7.

Houlihan, J., et al. (2005). Body Burden: The Pollution in Newborns. Environmental Working Group. http://www.ewg.org/research/body-burden-pollution-newborns.

Menegaux, F, et al. (2006). Household exposure to pesticides and risk of childhood acute leukaemia. Occup Environ Med, 63: 131-4.

Miodovnik, A, et al. (2011). Endocrine disruptors and childhood social impairment. Neurotoxicology, 32(2): 261-7.

Ouyang, F, et al. (2005). Serum DDT, age at menarche, and abnormal menstrual cycle length. Occup Environ Med, 62: 878-84.

Flu bugs aren’t the only infection that cause stomach problems: Viruses may worsen IBD

As Easter approaches and kids eagerly wait for candy from the Easter Bunny, parents will be watching to make sure they don’t eat too much at once and get a stomachache.  All of us have experienced stomach upset from time-to-time and regardless of what caused it, it was an unpleasant experience. Unfortunately, unpleasant GI experiences occur on a much more frequent basis for individuals with Crohn’s disease or ulcerative colitis.

Crohn’s disease and ulcerative colitis are both inflammatory bowel diseases (IBD) that cause inflammation of the lining of the digestive tract. Resulting inflammation can lead to abdominal pain, severe diarrhea, and even malnutrition. In Crohn’s disease, the inflammation often spreads deep into the layers of the affected tissue and can affect various areas of the digestive tract¹. Ulcerative colitis, on the other hand, tends to only affect the colon and rectum².

While the initial cause of IBD remains unclear, some literature suggests that viral infections are associated with the onset and aggravation of IBD. Of these viral infections, cytomegalovirus (CMV) is of particular interest to the development and worsening of the conditions. Mucosal injury, or damage to the intestinal tract, is also a component of the chronic nature of these diseases³.

Figure 1. IBD, CMV infection, and mucosal injury can all contribute to symptoms that plague patients.

IBD, CMV infection, and mucosal injury can all contribute to the symptoms that plague patients³ (Figure 1).

• Patients with IBD are often treated with immunosuppressive medications to reduce symptoms.  These patients may also suffer from poor nutrition due to damaged intestinal tissues.  The combination of immunosuppressive medications and poor nutrition make it easier for CMV to infect or re-infect a host.
• IBD can also worsen mucosal injury.  Inflamed mucosa may play a crucial role in inducing and sustaining CMV reactivation as epithelial cells can serve as permissive hosts for CMV during inflammatory responses.  This means they could possibly create a friendly environment for CMV reactivation and replication which in turn enhances the chance of chronic viral infection. This process can result in an increase in CMV infections over time.
• CMV infection may be a result of mucosal injury, but it may also be a cause.  Reactivation of or new CMV infection is thought to cause severe colitis, particularly in patients with ulcerative colitis that are treated with immunosuppressive agents.

In addition to the physical symptoms IBD and CMV infection can cause, poor nutrient absorption by the damaged intestinal tract can also lead to malnutrition. This lack of nutrients may mean that the necessary building blocks for neurotransmitters and hormones are insufficient.  This deficiency can lead to symptoms like anxiousness, sleep difficulty, or fatigue. Identifying and addressing neurotransmitter and hormonal imbalances with targeted support may help ease a patient’s secondary symptoms.

Guest author: Rachel Rixmann is a manager of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in gastroenterology and nutrition.

References:

1. http://www.mayoclinic.org/diseases-conditions/crohns-disease/basics/definition/con-20032061

2. http://www.mayoclinic.org/diseases-conditions/ulcerative-colitis/basics/definition/con-20043763

3. Cytomegalovirus (CMV)-Specific Perforin and Granzyme B ELISPOT Assays Detect Reactivation of CMV Infection in Inflammatory Bowel Disease.  Nowacki, Tobias M et. al.  Cells 2012, 1, 35-50; doi:10.3390/cells1020035.

Carpe diem! Can you seize the day if seizures are contributing to your low mood?

Epilepsy is a brain disorder in which seizures occur as a result of abnormal neuron signaling.

Epilepsy is a brain disorder in which seizures occur as a result of abnormal neuron signaling. This irregular signaling may briefly alter a person’s consciousness, movements, or actions. However, having a seizure does not necessarily mean that a person has epilepsy. People are considered to have epilepsy when they have had two or more unprovoked seizures. Seizure symptoms can include convulsions, loss of consciousness, blank staring, lip smacking and/or jerking movements of the arms and legs.

One of the most-studied neurotransmitters that plays a role in epilepsy is GABA. Many of the drugs used to treat epilepsy affect GABA. These drugs alter the amount of GABA in the brain or change how the brain responds to it.

Another area of study in relation to epilepsy is depression. It’s estimated that 22% of epileptics have depression compared to 12% of the general population. This is believed to be due to the effect chronic epilepsy has on the hypothalamic-pituitary-adrenal (HPA) axis, specifically cortisol. Activity in the hippocampus leads to higher cortisol levels secreted from the adrenal glands. Elevated cortisol levels and hyperactivity of the HPA axis impair serotonin 5-HT1A receptors. This leads to decreased serotoninergic activity in the hippocampus. The resulting deficit in serotonergic activity can lead to the development of depression.

For patients with epilepsy, neurotransmitter and adrenal assessments can provide an important look at which neurotransmitters and hormones are out of balance and potentially contributing to the seizures or associated symptoms. Providing therapy that targets individual imbalances can help to improve symptoms and quality of life for a patient.

References:

http://www.ninds.nih.gov/disorders/epilepsy/epilepsy.htm

E Pineda, D Shin, R Sankar, A Mazarati. (2010). Comorbidity between epilepsy and depression: Experimental evidence for the involvement of serotonergic, glucocorticoid and neuroinflammatory mechanisms. Epilepsia, 51.

M Mula, B Schmitz. (1990). Depression in epilepsy: mechanisms and therapeutic approach. Ther Adv Neurol Disord, 2(5): 337-344.

Epigenetics: more than “there’s a gene for that”

As we increasingly look to our personal electronic devices for help with our daily tasks, we’ve been assured they can help us address nearly any issue we may encounter. Companies like Apple that there is no problem they cannot address with their’s trademark mantra, “There’s an app for that.”  With the decoding of the human genome, which was expected to shed light on health issues ranging from weight to depression or addiction to the continuing rise of autism and other disorders, the medical community has taken a similar approach, being driven by the belief, “There’s a gene for that.”

Figure 1: The flow of information from DNA to protein is largely influenced by regulatory factors acting on the processes of transcription and translation. Environmental factors also influence protein expression.

While in many cases there may be “a gene for that”, this may not be the end of the story. Until recently, it was believed that our genes were the primary determining factors in how we look, think, and behave. Within the past decade however, this paradigm has shifted. It is increasingly apparent that the expression and function of our genes are largely influenced by a network of regulatory and environmental factors. Exploration into how internal regulation and environmental factors influence the expression of genes has given rise to a new field called epigenetics.

Epigenetic studies provide insight into how a person’s genetic makeup interacts with environmental, dietary, and lifestyle factors. The application of these insights has led to a new paradigm in medicine known as functional genetics. The fundamental tenet of this emerging field is that environmental triggers play a major role in whether a particular gene is expressed in a way that favors sickness or health, ease or disease.

The insight into human heredity has come a long way from Mendel’s discoveries in 1866 to the completion of the reference sequence for the human genome in 2003. Advances in current technology allow for studies that look deeper into our genetic code. These advances help determine how our genes are regulated and how they interact in response to various environmental factors. The enormous amounts of data obtained from these studies give us the potential to create truly personalized approaches to managing our well-being.

Guest author: Curtis Christian is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in genetics.

References:

Baranov, V. S. (2009). Genome paths: A way to personalized and predictive medicine. Acta Naturae, 3, 70-80.

Becker, F., van El, C. G., Ibarreta, D., Zika, E., Hogarth, S., Borry, P… Cornel, M. C. (2011). Genetic testing and common disorders in a public health framework: How to assess relevance and possibilities. European Journal of Human Genetics, 19, S6-S44.

Knight, J. C. (2009). Genetics and the general physician: Insights, applications and future challenges.  Q J Med, 102, 757-772. doi:10.1093/qjmed/hcp115

Rose, M. R., Mueller, L. D., & Burke, M. K. (2011). Anecdotal, historical and critical commentaries on genetics: New experiments for an undivided genetics. Genetics Society of America

Young, E., & Alper, H. (2010). Synthetic biology: Tools to design, build, and optimize cellular processes. Journal of Biomedicine and Biotechnology, 2010, 130781. doi:10.1155/2010/130781

DNA, RNA, SNP – alphabet soup or an introduction to genetics?

Blue eyes or brown? Short or tall? Blond, redhead, or brunette? All the information that guides development of physical traits as well as the other aspects of the human body is encoded in long sequences of deoxyribonucleic acid (DNA). Sections of DNA, known as genes, tell the body how to develop and function. The human genome is made up of about three billion building blocks called nucleotides, which code for around 20,000 genes located on 23 chromosomes. Humans have two copies of each chromosome and thus two copies of each gene. Each parent donates one copy of a gene– one from the mother and one from the father.

Figure 1: The Central Dogma of Biology was coined by Francis Crick in 1953 to illustrate the flow of genetic information. First, DNA is used as a template to create a complimentary strand of ribonucleic acid (RNA) through a process called transcription. This RNA template is then used to create a protein by stringing together amino acids in a process called translation.

Genes consist of specific DNA sequences which use four different nucleotides: adenine (A), cytosine (C), guanine (G), and thymine (T). The DNA sequence is used to create protein via a two- step process, transcription and translation (Figure 1). The resulting protein performs the function coded by the gene.

Figure 2: A SNP is a change in the genetic code of an individual where a single nucleotide is replaced by another in the DNA sequence. Nucleotides: adenine (A), cytosine (C), guanine (G), and thymine (T).

Of the three billion nucleotides that make up the human genome, the majority (~99.7%) remain the same from person-to-person. The remainder can vary in a number of different ways. The most common variation is a single nucleotide polymorphism (SNP – pronounced ‘Snip’). A SNP occurs when a nucleotide at a specific position in the DNA sequence gets replaced with a different nucleotide (Figure 2). Thus far, approximately 10 million SNPs have been identified. Most SNPs are found in non-protein coding regions of DNA. However, SNPs in sections coding for genes can result in changes to the transcription/translation process. This can result in a slightly different protein, which may not function in the typical manner.

In some cases, individuals may never notice the change in the protein function. In others, the change could lead to symptoms such as anxiousness, poor bone health, and reactions to various environmental stimuli. Identification of SNPs in specific genes for use in guiding lifestyle and treatment choices to improve overall health and wellness is known as Functional Genetics.

Guest author: Curtis Christian is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in genetics.

References:

Koonin, E. V. (2012). Does the central dogma still stand? Biology Direct, 7(27).

Shakya, K., O’Connell, M. J., & Ruskin, H. (2012). The landscape for epigenetic/epigenomic biomedical resources. Epigenetics, 7(9): 982-986.

Tishkoff, S. A., & Kidd, K. K (2004). Implications of biogeography of human populations for race and medicine. Nature Genetics, 36(11): S21-S27.

Young, E., & Alper, H. (2010). Synthetic biology: Tools to design, build, and optimize cellular processes. Journal of Biomedicine and Biotechnology, 130781. doi:10.1155/2010/130781.

T3 and reverse T3: Slight differences, considerable clinical consequences

Thyroid disorders are fairly commonplace in medical practice. Most people have either heard of or know an individual that has hyperthyroidism (e.g. Grave’s disease) or hypothyroidism (e.g. Hashimoto’s disease).

Figure 1. T4 can be converted into either T3 or rT3. Conversion to rT3 is increased by stress, inflammation, and dieting.

The thyroid gland is a butterfly-shaped gland in the throat. The main hormone it produces is thyroxine (T4). T4 is produced in large amounts, has a low potency, and converts to triiodothyronine (T3). T3 is produced in small amounts from T4 and has a high potency in the body. T4 has four iodine molecules attached to a tyrosine molecule, but T3 only has three (Figure 1). However, if the iodine molecules are arranged a different way, T3 becomes reverse T3 (rT3).

Some rT3 is always created in the body, but the conversion of T4 to rT3 can be increased due to factors such as stress (high cortisol), inflammation (pro-inflammatory cytokines), and dieting. rT3 is an inactive byproduct that blocks T3 receptors. Even if levels of T3 are adequate, they may not be able to exert their function if rT3 is blocking too many T3 receptors. Elevations in rT3 may compete with otherwise normal T3 and T4 levels and impair health.

Reverse T3 is a valuable marker for identifying hypothyroidism when traditional lab work shows normal T3 levels. Make sure to include rT3 in your thyroid assessments to insure you are getting the most complete evaluation of your patient’s symptoms.

References:

http://nahypothyroidism.org/

van den Beld, AW, et al. (2005). Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab, 90(12): 6403-9.

Tetrahydro…what? It’s essential to understand the whole neurotransmitter pathway

Last week’s post covered the effect oxidative stress can have on the tryptophan pathway and potential decreases in serotonin synthesis. This week we will discuss how oxidative stress can also have a drastic effect on catecholamine (epinephrine, norepinephrine, and dopamine) synthesis.

Figure 1. BH4 is a necessary cofactor for the conversion of tryptophan to 5-HTP, phenylalanine to tyrosine and tyrosine to L-DOPA.

Tetrahydrobiopterin (BH4) is an essential cofactor in the synthesis of the monoamine neurotransmitters (Figure 1). BH4 is necessary for the conversion of phenylalanine to tyrosine, tyrosine to L-DOPA, and tryptophan to 5-HTP. However, BH4 is highly sensitive to oxidation and becomes irreversibly degraded to dihydroxyanthopterin (XPH2). Under conditions of oxidative stress, BH4 is rapidly destroyed and BH4-dependent enzymes are unable to perform their function. As a result of the decreased amount of BH4 available to act as a cofactor, lower levels of monoamines can be seen.  When BH4 is decreased, the body may not be able to properly convert precursors because their enzymes can’t function without BH4. This can lead to lower levels of monoamines such as dopamine, norepinephrine, epinephrine, and serotonin. Deficiencies in these neurotransmitters have been associated with a myriad of clinical complaints such as depression, fatigue, attention difficulties, insomnia, and anxiety. Understanding the connections between oxidative stress and neurotransmitters is extremely important. These connections have the potential to impact a patient’s response to therapy if there is inflammation or oxidative stress affecting neurotransmitter levels. Assessing both neurotransmitter levels and immune activity is essential to ensure that you are utilizing the most clinically effective approach for symptom relief.

References:

Haroon, E, et al. (2011). Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior. Neuropsychopharmacology, 1-28.

Neurauter, G., et al. (2008). Chronic immune stimulation correlates with reduced phenylalanine turnover. Curr Drug Metab, 9: 622-7.

Sprener-Unterweger, B., et al. (2014). Immune changes and neurotransmitter: Possible interactions in depression? Neuro-Psychopharmacology & Biological Psychiatry, 48: 268-76.

Is oxidative stress stealing your serotonin?

In recent posts, we’ve discussed oxidative stress and the innate systems the body uses to control free radical levels. When these systems are not functioning properly or free radicals are being produced too quickly for the body to keep up, problems start to arise. For example, an increase in free radical levels can affect immune activity and neurotransmitter levels by influencing neurotransmitter synthesis.

Free radicals can stimulate the adaptive immune response. This shift in immune activity can have a drastic effect on the tryptophan pathway and serotonin synthesis.

Figure 1. Immune upregulation can shunt tryptophan away from the serotonin pathway and into the kynurenine pathway.

During the adaptive immune response, there is an increase in pro-inflammatory cytokines. One of the functions of these immune messengers is to increase activity of the enzyme indoleamine 2,3-deoxygenase (IDO) (Figure 1). The increase in IDO activity shunts tryptophan away from the serotonin pathway and into the kynurenine pathway. One purpose of this shift is to convert kynurenine to kynurenic acid, which is neuroprotective. However, kynurenine can also be converted to quinolinic acid, which is neurodegenerative.

A possible result of shunting tryptophan down the kynurenine pathway is lower serotonin levels. When IDO activity is increased, there’s less tryptophan available for making serotonin. Low serotonin levels have been associated with clinical symptoms such as depression, insomnia, and anxiety.

As these connections show, it is important to consider the interactions between systems when designing interventions. Assessing neurotransmitter levels and immune activity can help identify a patient’s unique imbalances to help create personalized therapies. Be sure to check back next week to learn how oxidative stress affects catecholamine (norepinephrine, dopamine, and epinephrine) synthesis.

References:

Anisman, A. (2009). Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. J Psychiatry Neurosci, 34(1): 4-20.

Korbecki, J, et al. (2013). The effect of reactive oxygen species on the synthesis of prostanoids from arachidonic acid. J Physiol Pharmacol, 64(4): 409-21.

Sutti, S, et al. (2013). Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH. Hepatology, Epub ahead of print.

Wichers, M., Maes, M. (2004). The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-α-induced depression. J Psychiatry Nerosci, 29(1): 11-17.

Do you have a radioactive intruder in your home?

Radon is a natural radioactive gas derived from decaying radium and uranium, which are common environmental toxins. Human exposure to radon has been linked to increased risk of lung cancer and can lead to oxidative stress and inflammation. In fact, the World Health Organization lists radon as the leading cause of lung cancer, in many countries, after smoking.

The most common exposure to radon occurs simply by breathing it in. What makes radon especially dangerous is that it cannot be seen, tasted, or smelled and can be found in any environment, including our homes. In fact, radon gas is more concentrated indoors than outdoors. The level of environmental radon indoors depends on the amount of uranium in the surrounding rocks. Radon gas naturally gets released by the earth and enters our home through cracks, holes, and joints in the house.

Figure 1. Radon gives off alpha particles, which can contribute to oxidative stress.

Radon causes oxidative stress by giving off alpha particles, which are a highly charged form of particle radiation (Figure 1). They have two protons and two neutrons but no electrons. As these particles are given off, they tend to “stick” to the first surface they meet. This collision causes physical damage to body tissue by disrupting the bonds that hold molecules together. More specifically, DNA may be damaged by electron displacement as well as structural changes in interacting DNA molecules.

As particle radiation damage occurs, an inflammatory response begins. Inflammation then induces oxidative stress and impairs antioxidant capacity in cells. Oxidative stress creates an influx of reactive oxygen species which can further lead to mutation and DNA damage. The damage that occurs to DNA can lead to the development of many disorders including cancer.

Radon particles usually enter through the mouth and nose as free gas particles or attached to dust particles. Because alpha particles usually enter the body through the respiratory tract, radon exposure is highly correlated to lung cancer. In fact, the Environmental Protection Agency considers radon as the number one cause of lung cancer in non-smokers.

So, what can we do to eliminate or reduce radon exposure in our homes? The best way to lower exposure to radon is improve ventilation and eliminate cracks and holes that allow radon to enter into the home. The increased air flow and blocked entrance may help prevent dense pockets of radon gas from forming. Further, checking radon levels regularly and avoiding high risk areas would be good first steps to take to reduce radon induced damage.

Guest author: Brett Tuominen is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in environmental toxins.

References:

http://www.epa.gov/radon/

Appleton, D. J. (2005). Radon in air and water. In O. Selinus, B. Alloway, J. A. Centeno, R. B. Finkelman, R. Fuge, U. Lindh, & P. Smedley (Eds.), Essentials of medical geology—impacts of the natural environment on public health (pp. 227–262). London: Elsevier Academic Press.

Turner, M.C., Krewski, D., Chen, Y., et al. (2011). Radon and Lung Cancer in the American Cancer Society Cohort. Cancer Epidemiol Biomarkers Prev, 20:438-448. Published OnlineFirst January 6, 2011.

Did “Rain Man” teach you everything you know about autism?

Autism, by definition, is a behavioral/developmental disorder characterized clinically by delays and qualitative differences in communication and social interaction as well as repetitive behaviors and restricted interests.

Figure 1. The evolution of the proposed cause of autism.

In the movie “Rain Man” Dustin Hoffman’s character, Raymond, is an adult with autism.  Throughout the movie certain classic symptoms of autism are portrayed such as high intelligence, repetitive behavior, and limited eye contact.  However, the movie is not able to explain the reason behind the disorder – that exact reason has escaped researches for some time, but it is becoming more and more apparent that there are many contributing factors.

The proposed cause of autism has changed over time. Today’s theory of the pathophysiology of this disorder is rooted in the many biochemical and systemic factors that can affect the brain (Figure 1).

Figure 2. Many factors and various immunological and neurological components can affect a patient’s presentation.

To help identify the various factors that can contribute to the presentation of autism, one could ask the following questions:

1)     Is this individual’s body and brain getting what it needs to function optimally?  This can include vitamins; minerals; omega-3 fatty acids; and healthy, clean foods.

2)     Is something present in this individual’s body and brain that interferes with the ability to function optimally?  This can include internally- or externally-derived toxins, free radicals, or cytokines.  Intestinal dysbiosis, or the disruption of a normally-functioning GI system, can severely disrupt a patient’s health and is an emerging point of intervention (Figure 2).

Figure 3. “Background noise” factors can have an opposing relationship with a patient’s signal strength.

The net effect these immunological factors can have on the body has been called background noise in a recently described “signal-to-noise” ratio paradigm.  This model explains that when background noise increases (poor nutrition, oxidative stress, etc.) the body’s signal strength (brain transmission) decreases.  This may mean that the body’s neurotransmitters have become depleted or they may simply be unable to be heard over the background noise (Figure 3).

Providers can come to understand how better to treat autism by learning how the disorder may be caused.  The root cause is now believed to lie within multiple biochemical factors.  Decreasing exposure to potentially harmful factors and ensuring the body’s various systems are in good working order can result in beneficial outcomes.

Guest author: Rachel Rixmann is the manager of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in gastroenterology and nutrition.

References:

Compart, Pamela J. (2013). The Pathophysiology of Autism. Global Adv Health Med,2(6): 32-37.

MacFabe, Derrick. (2013). Autism: Metabolism, Mitochondria, and the Microbiome. Global Adv Health Med, 2(6): 52-66.

Ahh, the Superbowl: a championship game, new commercials, the half-time show…and cholesterol risk?

Many of us just recently enjoyed a Superbowl Sunday indulging in delicious food like sausages, chips, dips, wings, and more. While enjoying all these foods, did you stop to think about how they may impact your cholesterol levels?  This post discusses cholesterol and how elevated levels can impact overall health.

What is Cholesterol?

Cholesterol is a waxy, fat-like substance required for cell membrane permeability and fluidity. It is found within all cells and is necessary for your body to make certain steroid hormones and vitamin D as well as substances such as bile acids that help to digest foods. Your body actually makes all the cholesterol you need. Out of your total cholesterol levels, three-fourths is produced naturally and the other fourth comes from your diet. The dietary portion serves as a surplus of cholesterol and is obtained from animal products such as meat, eggs, and dairy.

Cholesterol flows through the bloodstream in small packages known as lipoproteins. It is unable to dissolve in the blood, so these transport proteins carry it to its destination. The lipoproteins carry cholesterol via low-density lipoproteins (LDL) and high-density lipoproteins (HDL). LDL is commonly referred to as the “bad” cholesterol, while HDL is considered the “good” cholesterol.

Figure 1: As blood flows through the arteries, LDL cholesterol can store itself in the artery walls. A plaque forms over time and can burst suddenly, causing a blood clot.

Bad Cholesterol

As LDL circulates throughout the bloodstream, some of it can be deposited into the wall of arteries. While LDL collects in the artery, white blood cells swallow and digest LDL, converting it to a toxic, oxidized form. Macrophages (a type of white blood cell) migrate to this area in the artery causing progressive inflammation. Over time, build up occurs in the artery wall creating plaque that can block the artery and impair proper blood flow, which leads to atherosclerosis. At any time, a sudden rupture of the plaque can occur, causing a blood clot to form on the ruptured area (Figure 1). This can lead to a heart attack if the clot breaks free and travels to the heart. Higher levels of LDL in the blood put patients at greater risk of stroke and heart attack.

Good Cholesterol

HDL, on the other hand, scavenges the bloodstream, removing harmful cholesterol (LDL) from where it doesn’t belong. HDL transports LDL to the liver where it undergoes reprocessing (kind of like recycling). HDL is essential for keeping the inner walls of arteries clean and healthy, which reduces the risk of atherosclerosis. Higher levels of HDL reduce the risk for heart disease while lower levels increase the risk.

Managing Your Cholesterol

Having your cholesterol levels checked regularly is important, especially if you have cardiovascular disease. Cholesterol can be affected by a wide variety of factors such as your age, gender, diet, and genetics. For patients with abnormal cholesterol levels, pharmaceuticals that help normalize cholesterol levels are an option. Lifestyle changes such as smoking cessation, regular exercise, and reduced dietary fat intake can also make a significant difference. Using these suggestions to maintain healthy cholesterol levels is always advised when it comes to living a happy and healthy life. You can help control your cholesterol levels with a little effort put towards a healthy lifestyle.

Guest author: Adam Westman is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in cardiology.

Neutralizing the threat of excess free radicals – your body’s natural defense system

In a previous post, we discussed the concept of oxidative stress and the association that it can have with numerous health concerns. It is also important to understand how the body controls free radicals and prevents oxidative stress from occurring. To review – we know that oxidative stress is the burden on the body as a result of an overproduction of free radicals. This occurs when the control mechanisms of the body that counter free radicals aren’t able to maintain a proper balance. The cause of this imbalance is often attributed to a stressor such as an immune reaction or environmental exposure. It is important to note that free radicals do not always have negative effects on the body; a problem only arises when the amount of free radicals is high enough to outweigh the body’s normal antioxidant defenses.

Figure 1: SOD converts free radicals to hydrogen peroxide. Catalase then degrades hydrogen peroxide into water and oxygen with the help of a variety of other enzymes and vitamins.

The body has several ways to deal with an excess of free radicals. The first line of defense includes the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase, and catalase. These enzymes help rid the body of free radicals by converting them into water and oxygen (Figure 1). After oxygen becomes a free radical, SOD converts it into hydrogen peroxide, then catalase and glutathione peroxidase continue the conversion into water and oxygen.

The enzymes discussed above are the first line of defense against free radicals. Their optimal function is dependent on certain antioxidants and mineral cofactors derived from the diet. Polyphenols, vitamins E and C, coenzyme Q10, and glutathione support the antioxidant enzymes. The body makes every effort to minimize the negative effects of free radicals by relying on its own enzymes, as well as antioxidants from the diet. Deficiencies in either of these defense systems can lead to a wide variety of oxidative stress-related clinical symptoms and conditions.

 Guest author: Deanna Fall is currently a scientific writer and research analyst for NeuroScience, Inc. and holds a bachelor’s degree in biology from Ferris State University in Big Rapids, Michigan and a master’s degree in health informatics at the University of Minnesota.  Deanna joined NeuroScience in 2009 with experience in pharmaceutical research and development in the field of neurotoxicology.

References:

Muller, FL, et al. (2007). Trends in oxidative aging theories. Free Radic Biol Med, 43(4): 477-503.

When you hear “craving,” do you think sweet, salty…or serotonin?

We all experience cravings from time to time – a piece of fudge, one more handful of potato chips, or another slice of that heavenly apple pie. These cravings might not be due to the temptation of all the goodies we have gotten used to over the holiday season. They might be due to the neurotransmitters involved in food cravings, including serotonin, dopamine and glutamate.

Serotonin is involved in appetite and hunger.  When carbohydrate-rich foods are consumed, insulin raises brain tryptophan levels, which increases the rate of production and release of serotonin.¹ Low serotonin levels can trigger carbohydrate cravings, which uncontrolled may lead to weight gain. Supporting serotonin may help decrease carbohydrate cravings.¹

In a previous entry, we discussed glutamate and dopamine as part of the pleasure/reward pathway. As part of the pleasure/reward pathway, dopamine and glutamate are associated with cravings.

When we eat something delicious, dopamine is released from the ventral tegmental area (VTA) of the brain and sent to the nucleus accumbens. The size of this dopamine release is measured and glutamate instructs the prefrontal cortex to remember which foods produced more of a dopamine release. Since a burst of dopamine creates pleasure, the body then is wired to crave the food that increased the dopamine level. This is how cravings begin.²

One specific addiction seen frequently, especially in America today, is compulsive eating. Foods we typically find ourselves craving include those that contain a lot of sugar. In fact, sugar has addictive properties similar to opioids and psychostimulants.³ Acting on these cravings may lead to unwanted weight gain.

Imbalances in serotonin, dopamine and glutamate may be making it more difficult to make the right food choices. Correcting these imbalances can help control cravings and potentially aid in weight loss efforts. If cravings are a chief concern, balancing neurotransmitters is a vital first step on the way to feeling happier and healthier.

Guest author: Tricia Walz is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in metabolic issues.

References:

(1). Wurtman, RJ., Wurtman, JJ. (1995). Brain Serotonin, Carbohydrate-Craving, Obesity and Depression. Obes Res. 3(4):477S-480S.

(2). Kalivas PW, Volkow ND. (2005). The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry, 162(8):1403-13.

(3). Gold, MS., et al. (2009). Food addiction? J Addict Med. 3: 42-45.

Patients with low mood all have unique neurotransmitter patterns

Depression is a common illness, approximately 1 in 10 people report symptoms of depression (http://www.cdc.gov/features/dsdepression/). Imbalances in monoamine neurotransmitters, especially serotonin and norepinephrine, are commonly indicated in depression.   Despite this knowledge, therapies addressing serotonin and norepinephrine imbalances are often ineffective.  This may be due to a broad range of other imbalances contributing to depressive symptoms.  If serotonin imbalances are being addressed, but serotonin imbalance is not the cause of the depression, symptom alleviation may not occur.

Recent research has uncovered other neurotransmitters are involved in depressive symptoms.  Researchers have found a correlation between the blockade of the NMDA (glutamate) receptor, using an NMDA antagonist, and the alleviation of depressive symptoms in some patients.   Another neurotransmitter with known involvement is dopamine; this is known due to dopamine reuptake inhibition leading to symptom alleviation in some patients.

Why is this important?

With so many potential imbalances within the neurotransmitters contributing to depression and mood disorders, determination of the appropriate treatment is difficult.  Looking at baseline neurotransmitter values may be a valuable tool in determining which direction to take when addressing imbalances.

To illustrate this, below are urinary neurotransmitter results for 3 patients with depressive symptoms and /or mood issues:

Figure 1 depicts results from 3 different patients suffering from depression. Figure 1a. Patient who may be experiencing depression symptoms due to a serotonin imbalance. Figure 1b. A patient with elevated glutamate, which may be a cause of depression. Figure 1c. A patient with depleted epinephrine and norepinephrine, which may be indicative of low adrenal function and may cause depressive symptoms. 

It has been illustrated here that a variety of neurotransmitter imbalances may contribute to depression.  It is also important to remember common underlying causes of neurotransmitter imbalances, such as diet, lifestyle, environment, psychological health, and the immune and endocrine systems.  While these imbalances may be addressed with specific therapies, it is always important to identify the root cause of the imbalance when trying to address the system as a whole.

Guest author: Jennifer Farley is a member of the Medical Education Department at NeuroScience, Inc. and one of the resident experts in psychiatric disorders.

Genetic control of methylation can affect your health

With the holiday season ending so does a peak travel period, as friends, family, and coworkers return from holiday getaways. In addition to stories of family celebration or tropical paradises visited, the travel experience can also bring stories of layovers, cancelled flights, and lost luggage. As annoying as such experiences can be, it is quite profound how much actually goes right during these chaotic times given the amount of information that needs to be kept straight. A series of tickets, tags, scanners, and check points coordinate information to transport millions of people and their belongings all around the world.

The body has a similar information system to instruct molecules where they should be, when they should be there, and what they should be doing. One part of this system involves methylation. The methylation pathway, which is the result of close communication between the methionine, folate, and biopterin cycles, plays a vital role in many biological processes (Figure 1).

Figure 1. Methylation biochemistry is the result of close communication between the methionine, folate, and biopterin cycles and plays a role in many biological processes.

The methylation pathway affects inflammation, detoxification, DNA and cellular repair, as well as maintenance of proper levels of neurotransmitters which can influence energy levels, mood, and cognitive function. This is due, in part, to the effect of methylation on gene expression. Proper function of the methylation cycle is needed for gene expression, as methyl groups on regions of DNA serve as markers for when to turn a gene on and off.  Different methylation patterns in a variety of genes can result in many poor physical and mental health outcomes, including cardiovascular and metabolic issues, as well as depression, psychiatric disorders, and other mental health conditions. DNA methylation is also becoming increasingly important in understanding the pathology of many types of cancer, as tumor cells may shift methylation patterns in a way that favors inactivation of tumor suppressor genes.

Since methylation plays such an important role in gene expression, mutations in genes within the methylation cycle can alter normal biological processes. One important gene in this cycle is for the enzyme methylenetetrahydrofolate reductase (MTHFR). This gene is responsible for an important step in the metabolism of folate (a B-Vitamin). A variety of mutations in the MTHFR gene can interfere with this process.

A common variant in this gene includes the C677T polymorphisms. These polymorphisms result in an amino acid substitution that causes a significant decrease in enzymatic function at elevated temperatures. Mutations like this in the MTHFR gene can interact with other genetic or environmental components and possibly contribute to a variety of conditions, including Alzheimer’s disease, Parkinson’s disease, autism, diabetes, arthritis, cardiovascular issues, chronic fatigue, and many types of cancer.

As many of us return from our holiday travels, we transition from feasting to considering New Year’s Resolutions that often include improvements in our health.  The good news is that we may not have to struggle as much with these goals as we have in the past.  It is now possible to test our genes for mutations that increase our risk for many health conditions.  Gaining this insight into which genes we actually carry and how to best support proper function of these genes can help ensure we experience many more happy holiday travels to come.

Guest author: Curtis Christian is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in genetics.

References:

Bai, J. L., Zheng, M. H., Xia, X., Ter-Minassian, M., Chen, Y. P., & Chen F. (2008). MTHFR C677T polymorphism contributes to prostate cancer risk among Caucasians: A meta-analysis of 3511 cases and 2762 controls. European Journal of Cancer, 45, 1443-1449.

Botto, L. D., & Yang, Q. (2000). 5, 10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: A huge review. American Journal of Epidemiology, 151(9), 862-877.

Carvalho, D. D., et al. (2012). DNA methylation screening identifies driver epigenetics events of cancer cell survival. Cancer Cell, 21, 655-667.

Coppede, F. (2014). Epigenetics biomarkers of colorectal cancer: Focus on DNA Methylation. Cancer Letters, 342, 238-247.

Phillips, T. (2008). The role of methylation in gene expression. Nature Education, 1(1), 116.

Szyf, M. (2013). DNA methylation, behavior and early life adversity. Journal of Genetics and Genomics, 40, 331-338.

Wu, Y. L., Ding, X. X., Sun, Y. H., & Sun, L. (2013). Methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and susceptibility to Parkinson’s disease: A meta-analysis. Journal of Neurological Sciences, 335, 14-21.

Wang, W. Hou, Z., Wang, C., Wei, C., Li, Y, & Jiang, L. (2013). Association between 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and congenital heart  disease: A meta-analysis. Meta Gene, 1, 109-125.

Yang, S., Zhang, J., Feng, C. & Huang G. (2013). MTHFR 677 T variant contributes to diabetic nephropathy risk in Caucasian individuals with type 2 diabetes: A meta-analysis. Metabolism Clinical and Experimental, 62, 586-594.

Norepinephrine: responsible for focus, mood, energy…and sleep?

Recently, we had a post about the importance of GABA, serotonin, and melatonin in sleep circuitry.  These calming markers are not the only factors important for sleep, however.

Figure 1. Light is absorbed through the retina and signals down the pathway to the superior cervical ganglion which uses norepinephrine to signal the pineal gland to synthesize melatonin. Image from Stehle, 2011.
Abbreviations: RET-retina, RHT-retinohypothalamic tract, SCN-suprachiasmatic nuclei, PVN-paraventricular nuclei, IMC-intermediolateral column of the spinal cord, SCG-superior cervical ganglion, NE-norepinephrine, PIN-pineal gland, MEL-melatonin

Did you know that norepinephrine, a neurotransmitter commonly seen as excitatory, is an important part of the sleep pathway?  In fact, healthy levels of the sleep hormone melatonin depend on norepinephrine.

Melatonin is primarily secreted by the pineal gland in both day-active (diurnal) and night-active (nocturnal) animals during darkness.  The photoperiod is responsible for melatonin synthesis as well as its secretion.  The pathway from light perception to melatonin synthesis also included norepinephrine.

The retina of the eye absorbs light (Figure 1) and a signal passes through the retinohypothalamic tract to the suprachiasmatic nuclei.  From there the signal passes to the paraventricular nuclei, then onto the intermediolateral column of the spinal cord, and finally to the superior cervical ganglion.  The superior cervical ganglion then uses norepinephrine to signal the pineal gland to synthesize melatonin from serotonin.

Even though norepinephrine is classified as an excitatory neurotransmitter, it has a very important role in the synthesis of melatonin, and, therefore, in sleep.  However, sleep depends on optimal norepinephrine levels.  Too little norepinephrine can lead to lowered melatonin synthesis and sleep issues and too much norepinephrine, as it is excitatory, can keep you awake.  If sleep is an issue, make sure to consider norepinephrine and not just calming neurotransmitters.

References

Challet, E. (2007). Minireview: Entrainment of the Suprachiasmatic Clockwork in Diurnal and Nocturnal Mammals. Endocrinology, 148(12): 5648-55.

Conti A, et al. (2000). Evidence for melatonin synthesis in mouse and human bone marrow cells. Journal of Pineal Research, 28(4): 193-202.

Reiter, RJ, et al. (2010). Melatonin: a multitasking molecule. Progress in Brain Research, 18.

Stehle, JH, et al. (2011). A survey of molecular details in the human pineal gland in the light of phylogeny structure function and chronobiological diseases. J. Pineal Res, 51: 17-43.

Is peace on earth evading you this Christmas season?

Last week’s blog post discussed fatigue during the holidays.  While some people can be worn out by the whirlwind of holiday activities, others can become overstimulated or anxious. The difference in response is due to neurotransmitters.

Figure 1. Stimulating neurotransmitters (e.g. norepinephrine, glutamate, and epinephrine) increase in response to stress. In a healthy response, compensatory neurotransmitters (e.g. GABA, serotonin, and glycine) should increase to compensate for the increase in stimulating neurotransmitters.

Neurotransmitters are generally categorized as excitatory or compensatory.  Excitatory neurotransmitters include epinephrine, norepinephrine, and glutamate.  They stimulate the nervous system and are important for focus, energy, and mood.  However, an excess of these neurotransmitters can lead to anxiousness and overstimulation.  Compensatory neurotransmitters, like serotonin and GABA, calm the nervous system down by suppressing the activity of excitatory neurotransmitters.  Metaphorically, an increase in excitatory neurotransmitters causes stimulation, like stepping on the gas pedal in a car.  Compensatory neurotransmitters slow the nervous system, like the brakes of a car.

Ideally, excitatory and compensatory neurotransmitter activity would be balanced.  However, during times of stress, excitatory neurotransmitter activity increases (Figure 1).  If the nervous system is functioning properly, compensatory neurotransmitter activity should also increase in order to reduce excitatory activity.  The body uses this mechanism to restore balance.

Problems can occur when compensatory neurotransmitters aren’t able to compensate for the rise in excitatory neurotransmitters.  As the excitatory and compensatory systems become dysregulated due to chronic stress, many symptoms can begin to occur.  Anxiousness and overstimulation are two common symptoms resulting from the excess of stimulating neurotransmitters compared to compensatory neurotransmitters.

If anxiousness or overstimulation is a problem, neurotransmitter assessment can provide insight into which neurotransmitter imbalances may be contributing to clinical symptoms as well as help determine an individualized therapy program.

References:

Cryan, JF, et al. (2005). Don’t worry ‘B’ happy!: a role for GABAb receptors in anxiety and depression. TRENDS in Pharmacological Sciences, 26(1): 36-43.

Nikolaus, S, et al. (2010). Cortical gaba, striatal dopamine and midbrain serotonin as the key players in compulsive and anxiety disorders-results from in vivo imaging studies. Reviews in the neurosciences, 21(2): 119-39.

Do you have enough energy to rock around the Christmas tree?

Family, food, gifts, and fun are all part of the joy of the holidays for most people.  For many, fatigue is also a part of the holiday season.  Staying up late for holiday parties or the stress of finding a last minute gift can wear a person down; but what if the tired and worn out feelings persist beyond the holidays?  In cases like this, a busy schedule may not be to blame.  It may be adrenal fatigue.

Figure 1. Early-stage adrenal fatigue is characterized by elevated levels of adrenal neurotransmitters and hormones.

Adrenal fatigue occurs when the adrenal glands can no longer produce enough adrenal hormones and neurotransmitters for optimal function.  This happens when stress has been constant.

Adrenal fatigue can be divided into three stages:

Figure 2. Mid-stage adrenal fatigue is characterized by dysregulated levels of adrenal neurotransmitters and hormones.

1. Early-stage:  This stage is the body’s normal response to stressful events such as hosting a holiday party or finding the perfect gift for that difficult family member.  Early-stage (Figure 1) is characterized by elevated levels of epinephrine, norepinephrine, cortisol, and DHEA, and serotonin levels may be optimal or imbalanced.  Often, the clinical presentation in early stage includes overstimulation, anxiousness, sleep disturbances, trouble focusing, and feeling stressed.  In a healthy situation, the body will be able to recover with a little relaxation.  However, when stress is chronic, like the difficult family member moves in next door, adrenal fatigue can progress to mid-stage.
   

   Figure 3. Late-stage adrenal fatigue is characterized by depleted levels of adrenal neurotransmitters and hormones.

2. Mid-stage: DHEA, epinephrine, and norepinephrine can appear variable in the mid-stage of adrenal fatigue and serotonin starts to become depleted in this stage (Figure 2).  Cortisol is dysregulated as shown by any of several patterns, including an “L-shaped” curve where levels are low in the morning and elevated in the evening.  Clinically, individuals in mid-stage adrenal fatigue are often “wired and tired” (indicating both anxiousness and fatigue) and have low mood.
3. Late-stage: In late-stage adrenal fatigue, DHEA, cortisol, epinephrine, norepinephrine and serotonin levels are typically low (Figure 3).  Symptoms common in late-stage adrenal fatigue include fatigue/exhaustion, difficulty dealing with stress, cognitive decline, and weight management difficulties.

Adrenal fatigue occurs over time.  Addressing issues in the early stages is helpful, and lifestyle changes to reduce stress are also beneficial.  Testing adrenal hormone and neurotransmitter levels can help a practitioner determine what therapy will be most beneficial to support adrenal activity as opposed to just treating symptoms.

Hormonal changes in menopause: Is it all downhill from here?

The last several weeks, this blog has discussed hormones during the reproductive cycle  as well as neuro-endo connections (e.g.  serotonin, estradiol, testosterone, dopamine, progesterone, and GABA).  This week we will look at hormonal changes approaching menopause.

Figure 1. As women age, ovarian reserve falls, eventually leading to hormone fluctuations and the onset of menopause.

Around age 38 the ovarian reserve declines rapidly significantly decreasing fertility (Figure 1).  At this point, there are far fewer follicles that can be recruited and, as a result, less egg maturation and release.  This ovarian depletion results in hormonal fluctuation.  All of this eventually leads up to a woman’s final menstrual period, which is on average around age 51.

The first hormone to begin decreasing during perimenopause is progesterone (Figure 2).  As the number of follicles decreases, ovulation and the resulting corpus luteum formulation occurs less frequently. This significantly decreases the amount of progesterone produced. As progesterone levels begin to fall, gonadotropin releasing hormone (GnRH) increases, and as a result, follicle stimulating hormone (FSH) increases in an attempt to recruit a follicle. At the onset of menopause, when ovarian reserve is almost completely diminished, estradiol levels decrease dramatically and estrone becomes the most abundant type of estrogen in the body.

Figure 2. Progesterone is the first hormone to decrease during perimenopause followed by an increase in FSH and then a decrease in estradiol (E2).

Although progesterone and estrogen levels fall drastically, hormone synthesis doesn’t stop altogether during menopause. When the ovarian reserve is depleted, and the ovaries are no longer producing hormones, other tissues in the body become the main producers of hormones. The adrenal glands are one of these tissues. They produce progesterone and androstenedione, the precursor to testosterone. Some of this testosterone converts into estrogen.

Adrenal fatigue or burnout can cause additional issues for women in perimenopause as exhausted adrenals cannot synthesize as many hormones as healthily functioning adrenals. Adipose (fat) tissue also produces estrogen. Individuals with higher body mass indexes (BMIs) and more adipose tissue have higher circulating hormone levels.

While it is natural for hormone levels to change throughout perimenopause and menopause, patients entering menopause with healthy adrenal gland activity and normal adipose stores have any easier transition with fewer symptoms. It is also important to keep in mind that with hormonal changes neurotransmitter activity also changes adding another layer to supporting a healthy transition to menopause.

References:

Nussey, Stephen, and Saffron Whitehead. Endocrinology: An Integrated Approach. Oxford: BIOS Scientific, 2001.

Widmaier, et al. (2008). Vander’s Human Physiology; Eleventh Edition.

Oh baby! Did you know immune function can affect fertility?

Fertility issues can cause a lot of heartache for couples who are having difficulty conceiving.  According to the CDC, about 10% of reproductive-age women are infertile.  Infertility, however, is not always simply an endocrine imbalance.  Chronic stress and immune system status are two factors that can affect fertility and are often overlooked.

Infertility can be separated into male and female factor infertility.  Male factor infertility is more easily diagnosed, identified by changes in the count, mobility, and shape of the sperm. Female factor infertility is typically more difficult to assess.  Most cases are caused by ovulatory problems including irregular or absent menstrual cycles, Polycystic Ovary Syndrome (PCOS) or endometriosis. Other risk factors for female factor infertility include poor diet, athletic training, and being under/overweight.  However, immune system imbalances and chronic stress can affect fertility and contribute to conception issues, as well.

Figure 1. During the luteal phase and during pregnancy, the immune system should be biased toward a Th2 response.

During the luteal phase of a woman’s cycle and during a healthy pregnancy, the body’s regulation of Th1/Th2 immune balance changes.  To promote pregnancy, the body increases Th2 immune activity and naturally suppresses T cell Th1 activity (Figure 1) and decrease the release of pro-inflammatory cytokines.   This is important because too much Th1 activity may lead to rejection of an embryo.  In fact, heightened Th1 activity has been noted in women with recurrent pregnancy loss and implantation failure.  Examples of Th1 activity include the cytokines TNF-alpha, IL-2, and INF-gamma and are commonly seen with chronic inflammation.  A rise in Th1 activity can also be the result of adrenal fatigue.

Adrenal fatigue is an indicator of stress.  Stress is a broad-spectrum risk factor for infertility.  Many things can lead to additional stress on the body including damaged GI tract, underlying inflammation, environmental toxin exposure, adrenal fatigue, disrupted thyroid function, or sympathetic dysfunction.

For additional information on some infertility connections, see Module 3 of the Reproductive Endocrinology Curriculum: Hormones throughout the Life Cycle: Cycling Females (log-in required).

References:

Joon Yun, et al. (2004). Autonomic dysfunction may be an under-recognized cause of female fertility disorders.  Medical Hypotheses, 63(1):172-7.

Kwak-Kim JY, et al. (2003). Increased T helper 1 cytokine responses by circuating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum Reprod, 18(4):767-73.

Makhseed, M, et al. (2001).Th1 and Th2 cytokine profiles in recurrent aborters with successful pregnancy and with subsequent abortions. Hum Reprod, 16 (10): 2219-2226.

Polgar K, et al. (1996). Immune interferon gamma inhibits translational mobility of a plasma membrane protein in preimplantation stage mouse embryos: a T-helper 1 mechanism for immunologic reproductive failure.  Am J Obstet Gynecol, 174(1 Pt 1):282-7.

Progesterone and neurotransmitters: the under-recognized relationship

Hormones and the nervous system are linked in ways that may not be obvious. In recent weeks, we’ve explored the connections between estrogen and serotonin and testosterone and dopamine. Progesterone is another hormone that has many implications in the nervous system.

Figure 1. During the follicular phase, estradiol peaks around day 12, this estradiol peak and subsequent dropoff signal LH secretion. This sequence of events allows ovulation to occur around day 14. After day 14, during the luteal phase, the corpus luteum secretes progesterone.

Normally, progesterone is recognized for its role in the luteal phase of the menstrual cycle (Figure 1). During the luteal phase, progesterone levels increase, signaling an egg has been released from the ovary. However, the increase in progesterone has effects beyond reproduction. The luteal rise of progesterone is thought to be the cause of many pre-menstrual syndrome (PMS) symptoms including bloating and irritability and when progesterone levels decline, anxiety and insomnia become more common. This occurs because progesterone has a calming effect.

Figure 2. Allopregnanolone, a metabolite of progesterone, enhances GABAA receptor activity.

Progesterone’s calming effect is due to its metabolite allopregnanolone, which enhances GABA_A receptor activity¹. gamma-Aminobutyric acid (GABA) is a calming neurotransmitter. Poor GABA activity has been linked to premenstrual dysphoric disorder (PMDD)² as well as low mood, anxiety, and sleep disorders. When progesterone levels decrease, GABA_A receptor activity also declines (Figure 2). This decrease in GABA receptor activation results in increased nervous system excitability, which frequently results in sleep disturbances and anxiousness.

Figure 3. Progesterone increases MAO activity which increases the degradation of monoamine neurotransmitters, leading to a decrease in these neurotransmitters.

Another contributing factor is progesterone’s effect on monoamine oxidase (MAO).³  Progesterone has been shown to increase MAO activity. The result is lower levels of the stimulating monoamine neurotransmitters norepinephrine and dopamine. Serotonin, however, is also a monoamine neurotransmitter, and healthy levels are important for sleep. (Figure 3). Too much progesterone could actually add to sleep difficulties by decreasing the serotonin levels.

Progesterone also plays a role in neurotransmission. In the central nervous system, progesterone is made by glial cells and supports neuronal signaling. Researchers are also exploring progesterone’s role in myelin formation during nerve regeneration.⁴

While progesterone is known for its role in embryo implantation and the maintenance of pregnancy, it also has essential nervous system functions. For more information on the assessment of neuroendocrine connections, check out the Reproductive Endocrinology Curriculum (health care provider login required).

Guest author: Megan Geitz is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in endocrinology and women’s issues.

References:

1. Follesa, P., et al. (2000). Allopregnanolone synthesis in cerebellar granule cells: roles in regulation of GABA_A  receptor expression and function during progesterone treatment and withdrawal. Molecular Pharmacology, vol 57; no. 6:1262-1270.
2. Cunningham, J.,et al. (2009). Update on research and treatment of premenstrual dysphoric disorder. Harv Rev Psychiatry, 12(2):120-137.
3. Luine,V.N., et al. (1983). Gonadal hormone regulation of MAO and other enzymes in hypothalamic areas. Neuroendocrinology.36(3):235-241.
4. Schumacher, M., et al. (2012). Progesterone synthesis in the nervous system: implications for myelination and myelin repair. Frontiers in Neuroscience, 6:10. 

What do you do when counting sheep just doesn’t cut it? Look at neurocircuitry!

Most of us can attest to having trouble getting a good night’s sleep from time-to-time. We lie awake worrying about something that happened during the day, or the room is the wrong temperature or a scary movie we just watched seems a little too plausible. These little disturbances are common, but if you have trouble sleeping most nights there may be a more serious problem. According to the Centers for Disease Control and Prevention (CDC), 70 million Americans suffer from chronic sleep problems.  Sleep is a complex process influenced by many neurotransmitters and hormones.

Figure 1. A simplified representation of sleep-wake neurocircuitry shows the major brain centers and neuroendocrine parameters involved. Thick arrows represent active pathways during sleep. The absence of daylight leads to a net inhibition of excitatory efferent projections to central and peripheral systems active during wakefulness. Green arrows are excitatory pathways, red are inhibitory pathways.
Abbreviations: 5-HT-Serotonin, Ach-Acetylcholine, ACTH-Adrenocorticotropic hormone, AD-Adrenaline (Epinephrine), Cort-Cortisol, CRF-Corticotropin-releasing factor, DA-Dopamine, DMH-Dorsal medial hypothalamus, DRN-Dorsal raphe nucleus, GABA-Gamma-aminobutyric acid, Glut-Glutamate, HA-Histamine, HCRT-Hypocretin (orexin) neuropeptide precursor, LC-Locus ceruleus, LH-Lateral hypothalamus, Mela-Melatonin, MRN-Medial raphe nucleus, NE/NA-Norepinephrine/Noradrenaline, PVN-Paraventricular nucleus, RVLM-Rostral ventrolateral medulla, SCN-Hypothalamic suprachiasmatic nucleus, TMN-Tuberomammillary nucleus, VLPO-Ventral lateral preoptic area, VTA-Ventral tegmental area

During the day, wake-promoting brain centers in the brain such as the hypothalamic suprachiasmatic nucleus (SCN), tuberomammillary nucleus (TMN) or locus ceruleus (LC) use excitatory neurotransmitters such as glutamate, histamine, and norepinephrine to keep us awake (Figure 1).  Sleep is the result of a signal cascade that starts when the brain senses a lack of sunlight to the eye.  When the brain senses darkness, inhibitory neurotransmitters and hormones including GABA, serotonin, and melatonin reduce the activity of the wake-promoting brain centers.

Imbalances in neurotransmitters and hormones can lead to excessive activity in the wake-promoting brain centers.  This can contribute to sleep difficulties.  Neurotransmitters and hormones can become imbalanced by a number of different factors including stress, poor diet, infections, toxins, and hypersensitivities.

If your patients are not getting their healthy dose of quality sleep each night, assessing their neurotransmitter and hormone imbalances can provide the information required to develop personalized treatments for their sleep difficulties.

References:

Black, J, et al. (2005). Sleep and Wakefulness: Neurophysiologic Pathways and Pharmacologic Targets. A CME-Certified Monograph.

Chou, TC, et al. (2003). Journal of Neuroscience, 23(33):10691-702.

Freeman, DA, et al. (2007). Behav Neurosci, 121(40):689-97.

Lechin, F, et al. (2002). Neurocircuitry and Neuroautonomic Disorders: Reviews and Terapeutic Strategies. Basel (Switzerland): S. Karger AG.

Pace-Schott, EF, et al. (2002). Chapter 128: Basic Mechanisms of Sleep, In Davis, KL, et al (Eds.), Neuropsychopharmacology: The Fifth Generation of Progress (1859-1877).

Saper, CB, et al. (2005). Nature, 437(27):1257-63.

Simonneaux, V, et al. (2003). Pharmacol Rev, 55(2):352-95.

Dopamine and testosterone – two important pieces of the neuroendocrine puzzle

Figure 1. Testosterone plays many different roles in the body.

Barry Bonds, Marion Jones, Roger Clemons, Manny Ramirez…the list of athletes that have made the news for taking performance enhancing drugs is long and seems to grow daily. These news stories put hormones such as testosterone in a negative light, but this hormone is essential to human health.

Testosterone is the principal anabolic and sex hormone that plays a wide variety of roles in the body including sexual desire and function, muscular hypertrophy, densification of bones, and hair growth. Although testosterone is largely responsible for those traits and characteristics considered “masculine,” both sexes require it for proper sexual and physical development¹. Testosterone also has effects on other systems in the body (Figure 1), including the nervous system.

The previous neuro-endocrine connection blog discussed the interactions between estrogen and serotonin; this time, the relationship between testosterone, prolactin, and dopamine will be discussed.

Dopamine and Testosterone

Dopamine and testosterone have a direct relationship. Dopamine, a neurotransmitter, plays a role in many different functions including cognition, movement, and feelings of pleasure and reward². The relationship between dopamine and testosterone stems from the interaction both have with prolactin.

Figure 2. Dopamine increases testosterone levels by decreasing prolactin secretion from the pituitary.

Prolactin is a hormone that has many different roles including breast milk production and sexual gratification. The release of prolactin from the pituitary gland is ultimately controlled by pituitary releasing hormone (PRH) produced by the hypothalamus. The increase in prolactin leads to a decrease in testosterone production in the leydig cells of the testes.

The activity of PRH is countered by dopamine, which is also released from the hypothalamus. An up-regulation of dopamine stimulates the release of prolactin inhibitory factor (PIF). PIF inhibits the pituitary from releasing prolactin. Because prolactin inhibits gonadotropin-releasing hormone (GnRH) secretion, the inhibition of prolactin caused by dopamine, increases the secretion of GnRH, therefore increasing the secretion of testosterone ³ (Figure 2).

This is yet another example of the connections between the endocrine and nervous systems.  By understanding these relationships, clinicians can more effectively determine the root cause of clinical symptoms and select more effective treatment options for patients.

Guest author: Megan Geitz is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in endocrinology and women’s issues.

References:

1. Horstman, Astrid M., et al. (2012). The role of androgens and estrogens on healthy aging and longevity. J Gerontol A Biol Sci Med Sci, 67(11):1140-52.

2. Dalley J.W. and Everitt B.J. (2009). Dopamine receptors in the learning, memory and drug reward circuitry. Semin. Cell Dev. Biol. 20:403-10.

3. Zeitlin, S.I., et al. (2000). Hyperprolactinemia and erectile dysfunction. Rev Urol, 2(1):39-42.

Senile ovaries? There must be a better explanation…

Remember, radiation may not be the best choice to treat menopause!

Did you know in menopause the ovaries become senile?  According to this 1950s women’s health tutorial, posted on Huffington Post, they do.  Back then, they also recommended using radiation to treat “the menopause”.  Thankfully, we’ve come a long way since then and realized that interactions between the endocrine and nervous systems can contribute to and exacerbate menopausal symptoms.

For more information on the role neurotransmitters can play in hot flashes, please view the webinar “The Science of Being Hot: Clinical Neuroendocrinology for Hot Flashes and Night Sweats” on the NeuroScience YouTube channel and previous posts: Temperature fluctuations: due to weather seasons or seasons of change within you and Thought you knew everything about estrogen? What about its effects on the nervous system?

 

Temperature fluctuations: due to weather seasons or seasons of change within you?

The seasons have just changed and temperatures have dropped.  Everyone feels comfortable at different temperatures, and right now in Wisconsin, it’s not uncommon to see some people wearing winter jackets while others are wearing shorts.  During menopause, a woman’s temperature comfort range changes and is the main cause of hot flashes.  Hot flashes are commonly blamed on the sudden change in hormone levels, but neurotransmitters also play a major role in hot flashes and temperature regulation.

One of the most significant connections is estradiol and serotonin.  Serotonin and estrogen receptors are present together in many of the same tissues throughout the body.  Activation of the estradiol receptor E2-β increases the number of the serotonin receptor 5-HT2_A.  This is important because the 5-HT2_A receptor is involved in mood, cognitive function, and temperature regulation.

Figure 1. At reproductive age, the temperature range that women feel comfortable is wide because of the abundance of serotonin and estradiol. As women age, estrogen levels decrease, leading to a smaller comfort range for temperatures. The smaller comfort range can easily lead to hot flashes.

5-HT2_A receptors found in the hypothalamus regulate body temperature and work in conjunction with estradiol to influence the thermoregulatory set point (Figure 1).  For example, a pre-menopausal, “healthy” individual should have an abundance of estradiol and serotonin in circulation leading to estrogen binding and an upregulation of 5-HT2_A receptors and a wide thermoregulatory set point.  As women age estrogen levels decline, resulting in less 5-HT2_A receptors and a narrowing of the thermoregulatory set point.  This narrowing of the temperature range at which women feel comfortable is thought to be a change that leads to hot flashes.

So when you look to open a window when others reach for a sweater, consider your estrogen and serotonin levels. For more information on the role neurotransmitters can play in hot flashes, please watch the webinar “The Science of Being Hot: Clinical Neuroendocrinology for Hot Flashes and Night Sweats” on the NeuroScience YouTube channel.

References:

Blum I, et al. (1996). The effect of estrogen replacement therapy on plasma serotonin and catecholamines of postmenopausal women. Isr J Med Sci, 32:1158-62.

Roepke, T, et al. (2011). Front Biosci, 16:125-34.

Rybaczyk, LA, et al. (2005). An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology. BMC Women’s Health.

Tick bites: Scarier than ghosts and goblins

We hope you have a happy and safe Halloween!

This Halloween when you see vampires and zombies, remember that nature can be the best at being gross.  A recent post in the New York Times includes a video that helps explain how the ticks that carry Lyme disease are able to attach and remain on the skin for days with their unique, saw-like mouthparts.  You can read the full article and see the video here.

For more information on Lyme disease testing, check out Pharmasan Labs’ iSpot Lyme test at www.ispotlyme.com.

Thought you knew everything about estrogen? What about its effects on the nervous system?

Fatigue, weight gain, irritability, sleep issues, and depression are all issues we’ve dealt with either ourselves, or experienced by someone close to us. Many people associate these symptoms with hormone imbalances, but what might not be so obvious is that these symptoms can also be linked to neurotransmitter imbalances. Likewise, the difference in rates of psychiatric disorders between genders suggests that hormones play an important role in conditions commonly associated with nervous system imbalances (Figure 1)¹.

Figure 1. This table, published in the Journal of Abnormal Psychology, depicts the incidence of psychiatric disorders between women and men (1).

These interactions demonstrate that the nervous and endocrine systems are intricately coupled, and both are involved in almost every bodily function including cognition, mood, reproduction, sleep, and temperature regulation. The correct balance of neurotransmitters and hormones is critical to preventing symptoms, as well as supporting overall health.

Hormones play an active role in brain function and affect neurotransmitter levels. For example, many women going through menopause experience depression, anxiety, and insomnia, which can also be correlated to neurotransmitter imbalances.  The interactions between estrogen and serotonin illustrate this point quite well.

Estradiol supports serotonin levels

Estradiol supports serotonin levels through two different mechanisms (Figure 2). Estradiol increases tryptophan hydroxylase, the rate limiting enzyme in the synthesis of serotonin². Additionally, estradiol inhibits the enzyme monoamine oxidase (MAO), which degrades monoamine neurotransmitters such as serotonin ³.

Figure 2. Estradiol increases tryptophan hydroxylase which will increase the synthesis of serotonin (2). Estradiol decreases MAO activity, which decreases the rate of monoamine neurotransmitter degradation, leading to increased levels of these neurotransmitters (3).

Estrogen affects serotonin receptor expression

Both estrogen and serotonin receptors coexist in a variety of tissues. Estradiol activation of E2-beta receptors stimulates an increase in serotonin receptor sites (5HT2a). 5HT2a receptors are involved in mood, cognition, and the inhibition of pain². By increasing the number of serotonin receptors, estradiol up-regulates serotonin activity.

This interaction plays a critical role during menopause, specifically in the incidence of hot flashes. Estrogen and serotonin influence the thermoregulatory set point through the hypothalamus ⁴. A pre-menopausal woman will have an abundance of estradiol and serotonin in circulation. This also means there will be binding of estrogen receptors and an up regulation of 5-HT2a receptors, leading to a wide thermoregulatory set point.

Figure 3. Estradiol and serotonin have been shown to work together in the hypothalamus to regulate the thermoregulatory set point.

As aging occurs, estrogen levels decline, leading to a decline in serotonin receptors, and potentially serotonin stores. With this decline in serotonin activity, the thermoregulatory set point narrows. This is one mechanism that leads to hot flashes and night sweats in menopausal females (Figure 3).

Additionally, estradiol can act as a central analgesic, and pain sensation is inhibited by the activation of some serotonergic neurons. The up-regulation of the 5HT2a receptors in the brain might play a role in this pain inhibition².

The interactions between estrogen and serotonin provide evidence that symptoms and conditions typically thought of as exclusively related to hormones can also be influenced by the nervous system.  In the next few weeks, we will be covering additional connections between the endocrine and nervous systems, including the interactions between dopamine and testosterone as well as progesterone and GABA.  For additional information on the connection between sex hormones and neurotransmitters, see Module 10 of the Reproductive Endocrinology Curriculum (log in required).

Guest author: Megan Geitz is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident experts in endocrinology and women’s issues.

References:

1. Eaton, Nicholas R., et al. (2012). An invariant dimensional liability model of gender differences in mental disorder prevalence: evidence from a national sample. Journal of Abnormal Psychology. 121(1):282-289.

2. Rybaczyk, L.A., et al. (2005). An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology. BMC Women’s Health, 5:12.

3. Luine,V.N., et al. (1983). Gonadal hormone regulation of MAO and other enzymes in hypothalamic areas.  Neuroendocrinology.36(3):235-241.

4. Berendsen, Hemmie H.G. (1999). The role of serotonin in hot flushes. Maturitas. 36:155-164.

The roller coaster of female hormones – are you enjoying the ride?

Figure 1. Neuroendocrine signaling of the female reproductive cycle. (a) The hypothalamus secretes gonadotropin releasing hormone (GnRH) which signals the anterior pituitary to secrete follicle stimulating hormone (FSH) and luteinizing hormone (LH). (b) FSH levels peak around day 3 of the menstrual cycle, and LH spikes around day 14, which signals for ovulation to occur. (c) During the follicular phase, FSH stimulates the growth and development of the follicle. Around day 14, the follicle ruptures, releasing the egg. In the luteal phase, the ruptured follicle forms the corpus luteum which secretes progesterone. (d) During the follicular phase, estradiol peaks around day 12 and progesterone peaks on day 21 of the luteal phase. (e) Estradiol secretion throughout the follicular phase causes the build-up of the endometrial lining. In the luteal phase, progesterone prepares the uterus for embryo implantation.

Every woman has probably experienced at some point the decreased patience or craving for chocolate that can occur once a month.  It is well known that women have a monthly cycle in which there are hormonal variations, but do you know what is happening throughout the month that can cause mood changes and other symptoms?  Here is a brief overview:

The average female cycle is 28 days long and is spilt into two main phases: the follicular phase, lasting from the onset of menses to ovulation, and the luteal phase, lasting from ovulation to the onset of menses.  The luteal phase is fixed at fourteen days long, and the follicular phase averages about 14 days but can be more variable.  This variability can occur because the follicular phase is dependent on estradiol reaching levels that can trigger the release of luteinizing hormone (LH).  The time it takes estrogen to reach the right amount can vary depending on each individual.

As explained in the previous post, sex hormones are controlled via mechanisms in the brain.  Follicle stimulating hormone (FSH) and LH are released from the pituitary, following a signal from the hypothalamus, and follow specific trends throughout the cycle.  FSH peaks first on about day 3 of the cycle and is responsible for recruiting a follicle.  As the recruited follicle matures, estradiol builds gradually until it peaks around day 13.  During this time, estradiol facilitates the growth of the endometrial lining.  The peak in estradiol stimulates an LH surge 12-24 hours after the estradiol peak, which induces ovulation.   After ovulation, the follicle forms the corpus luteum and progesterone levels begin to rise.  Progesterone peaks on day 21 of a regular cycle, or 7 days before the menses. If ovulation doesn’t take place progesterone will not increase and a peak will not be seen on day 21.  The cycle begins again when the drop in progesterone and estradiol cause the shedding of the endometrial lining, or menses.

As the female cycle is characterized by hormone patterns, dysregulated patterns can result in a variety of clinical symptoms which we will detail in a coming blog post.  More information on the hormone patterns associated with the female cycle can be found in Module 3 of the Reproductive Endocrine Curriculum found here (log in required).

References:

Nussey, S.S., Whitehead, S.A. (2001). Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers.

Widmaier, et al. (2008). Vander’s Human Physiology; Eleventh Edition. McGraw-Hill.

It’s 4th and long…are you confident in your endocrine system?

Figure 1. Ernest Henry Starling, an English MD, coined the term “hormone” in 1905.

In the game of football, a team’s ultimate goal each drive is to score a touchdown, but to get to this point, there are many lines of communication that must occur smoothly.  The coach relays plays to his players on the field, and those players implement the play calls to achieve their goal of scoring.  The endocrine system is like a team in that it utilizes signals (play calls) from the hypothalamus (the coach).  Effective communication between the players of the endocrine system can lead to balanced hormone production.  Balanced hormone production is important in managing patient symptoms and ineffective communication can potentially lead to improper levels of hormones being synthesized.

Ernest Henry Starling, an MD in London, coined the term “hormone” in a series of lectures given to the Royal College of Physicians in London in 1905.  Hormones are defined as “a regulatory substance produced in an organism and transported in tissue fluids such as blood or sap to stimulate specific cells or tissues into action.”  Hormones are substances that are produced by the endocrine system in the body and influence the way the body grows or develops.  The pituitary gland, located in the brain, is considered the “master control” of the endocrine system; however, the hypothalamus actually controls the pituitary and is the overarching control of the endocrine system.

Figure 2. Hormones, and the endocrine system itself, are controlled by the hypothalamus in the brain. The hypothalamus sends signals to the pituitary, initiating a signal cascade to affect hormone synthesis and function.

Figure 2 (above) illustrates the top-down control of the stimulation and production of endocrine hormones.  Hormone signaling and synthesis primarily begins in the hypothalamus with the hormones seen here: prolactin releasing hormone (PRH), thyrotropin releasing hormone (TRH), corticotropin releasing hormone (CRH), growth hormone releasing hormone (GHRH), and gonadotropin releasing hormone (GnRH).  Each elicit the release of subsequent hormones synthesized in the anterior pituitary and have endocrine targets, with the exception of prolactin.  The endocrine targets then secrete hormones that have effects in nonendocrine targets, such as the skin or heart.

In terms of the sex hormones, GnRH from the hypothalamus signals the anterior pituitary to secrete follicle stimulating hormone (FSH) and luteinizing hormone (LH), the gonadotropin hormones.  FSH and LH signal to endocrine cells to secrete androgens or estrogens and progesterone for males and females respectively.  FSH and LH are also able to signal directly to the germ cells of the gonads to have a nonendocrine target effect.

Just like any football team trying to win a championship, if any part of endocrine communications is not functioning optimally, the system won’t work and the end goals are not achieved. During a regular sex hormone workup, do not overlook factors such as leptin, insulin, and thyroid hormones, which are affected by hypothalamic activity.  More information on the top-down control of sex hormones can be found in Module 2, Part A of the Reproductive Endocrinology Curriculum, which is available here (log in required).

References:

Nussey, S.S., Whitehead, S.A. (2001). Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers.

Widmaier, et al. (2008). Vander’s Human Physiology; Eleventh Edition. McGraw-Hill.

Sorry Dracula, but blood isn’t the only way to test hormones

Figure 1. Saliva and serum are both used to measure hormone in a clinical setting.

Hormones are found in a variety of biological fluids including saliva, cerebral spinal fluid, blood, serum and urine.  Saliva and serum are the most popular forms for testing, although they represent different forms of hormones.  Saliva represents the free (unbound) or biologically active portion of hormones while serum measures total levels of bound and unbound hormones.

There are many arguments why a practitioner would choose to measure serum or salivary levels of hormones over the other, but validity of testing should not be one of them.  Literature has explored the significant correlation between serum and saliva for assessing hormone levels.

• Worthman et al (1990) measured salivary and serum estradiol levels in women under ovulation-inducing therapy.  They found that free levels of estradiol in saliva and serum are strongly correlated (p<0.0001).
• 

  Figure 2. Salivary and serum progesterone are significantly correlated in healthy women during the regular menstrual cycle.

  De Boever (1986) found that there is a correlation between paired saliva and serum progesterone in healthy women during the regular menstrual cycle (p<0.001) (Figure 2).

• Researchers found that salivary testosterone levels positively correlated with free serum testosterone in eugonadic men (r=0.92, p=0.0001) (Arregger 2007).  The results showed that salivary testing can be used as a noninvasive approach to the diagnosis of male androgen deficiency.

While the correlation between serum and salivary levels is strong, sex hormone binding globulin (SHBG) levels can affect the ratio between free and bound hormone levels.  It is not possible to accurately compare saliva and serum hormone levels in a patient with either low or high SHBG levels.  More information on the correlation and serum and salivary hormone levels can be found in Module 5 of the Reproductive Endocrinology Curriculum, which is available here (log in required).

References:

Worthman, CM, et al. (1990). Sensitive salivary estradiol assay for monitoring ovarian function. Clin Chem, 36:1769-73.

Boever, JD, et al. (1986). Direct solid-phase chemiluminescence immunoassay for salivary progesterone. Clin Chem, 32:763-7.

Arregger, AL, et al. (2007). Salivary testosterone: a reliable approach to the diagnosis of male hypogonadism. Clin Endocrinol (Oxf), 67(5): 656-62.

What is oxidative stress?

Oxidative stress has become somewhat of a buzzword in healthcare today, but what exactly does oxidative stress refer to?

Figure 1. Oxidative stress is an imbalance between the amount of free radicals and antioxidants in the body.

Simply put, oxidative stress refers to the burden on the body as a result of an over-production of free radicals (Figure 1).  Free radicals are unstable molecules produced by normal metabolism (such as from mitochondrial energy production) that are necessary for certain immune function, like neutrophil phagocytosis.  However, when there is an abnormally high amount, they can cause damage to cells and lead to a variety of health complications.  The body has certain defense mechanisms to mitigate the damage caused by free radicals such as superoxide dismutase, glutathione peroxidase, and catalase.  When these defenses fail to maintain proper balance, the resulting clinical effects can be significant.

Figure 2. Oxidative stress is associated with a number of diseases.

When left unchecked, free radicals can stimulate the over-production of pro-inflammatory cytokines which contribute to autoimmune and cardiovascular disease, among others.  Oxidative stress has also been found to be related to most chronic and neuropsychiatric conditions including: autism, attention-deficit hyperactivity disorder, hypertension, arthritis, asthma, Alzheimer’s disease, Parkinson’s disease, diabetes, and psoriasis (Figure 2).

Oxidative stress is ubiquitous in many ill patients.  Based on correlations with neuropsychiatric and other conditions, identification of oxidative stress levels could be utilized to investigate clinical symptoms.  Monitoring and controlling oxidative stress has the potential to improve current health as well as prevent future clinical complaints.

References:

Li, Xinyuan, et al. (2013). Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol, 6:19.

Patel, VP, Chu, CT. (2011). Nuclear transport, oxidative stress, and neurodegeneration. Int J Clin Exp Pathol, 4(3):215-29.

Rommelfanger, KS, Weinshenker, D. (2007). Norepinephrine: The redheaded stepchild of Parkinson’s disease. Biochemical Pharmacology, 74:177-90.

Psychoneuroimmunology: Where kynurenic acid fits

Psychoneuroimmunology. It’s a mouthful, but that’s to be expected when trying to find one word to describe the interaction of the nervous, endocrine, and immune systems and the impact this has on health and disease. Robert Ader, considered the founding father of this emerging medical paradigm, coined the term in the late 1970s. The role of the immune system in influencing behaviors is one of the most intriguing concepts in medical research as well as clinical practice. An upregulated immune system has significant effects on the tryptophan pathway, including increasing the level of kynurenic acid, and those effects lead to depressive-like behavior.

Figure 1. The activated IDO enzyme shunts tryptophan dow the kynurenine pathway to kynurenic acid as well as increasing serotonin breakdown leading to depressive-like behavior. Adapted from Corona 2013.

Indoleamine 2,3-dioxygenase (IDO) is an enzyme present in microglial cells of the nervous system. This enzyme, turned on by pro-inflammatory mediators, is responsible for the “tryptophan steal.” Inflammation activates microglia to release this enzyme. Once activated, IDO shunts the serotonin precursor tryptophan down the kynurenine pathway (Figure 1). This increases the ratio of kynurenine:tryptophan and may decrease serotonin synthesis.

IDO also metabolizes 5-hydroxytryptophan (5-HTP) as well as serotonin into 5-hydroxykynuramine. This means in the presence of immune activation, serotonin turnover is increased. This is characterized by a greater 5-HIAA:serotonin ratio. In fact, after administering an IDO inhibitor to mice whose immune systems were upregulated, depressive-like behavior lessened and there were also decreased ratios of 5-HIAA:serotonin and kynurenine:tryptophan.

A rapidly growing body of evidence supports the fact that inflammation has a notable effect on behaviors. More advanced tools, such as kynurenic acid, to assess the impact of inflammation on nervous system function will help manage behavioral disorders whose mechanism is rooted in immune modulation. This is psychoneuroimmunology in motion.

References:

Ader, R. (2007) Psychoneuroimmunology. Burlington, MA: Elsevier Academic Press.

Corona AW, Norden DM, Skendelas JP, et al. (2013). Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX3CR1)-deficient mice. Brain Behav Immun, 31:134-42.

http://www.journals.elsevier.com/brain-behavior-and-immunity/

“Stressed” is “desserts” spelled backwards: Why weight gain is due to stress

The increased incidence of diabetes in society today is well-known.  According to the Centers for Disease Control and Prevention (CDC), more than one-third of U.S. adults are obese and 11.3% of U.S. adults have diabetes.  What is less known is the role that norepinephrine can play in insulin release and the development of metabolic syndrome and type 2 diabetes.

Figure 1. Normal function of a pancreatic beta cell involves insulin granules docking at the edge of the cell to release insulin in the extracellular space (Gribble, 2010).

Normally, insulin granules are docked at the edge of pancreatic beta cells to release insulin in response to protein and glucose in the blood (Figure 1).  Insulin causes muscles and fat tissue to absorb glucose from the blood.  Too much glucose in the blood can be toxic and is a hallmark sign of diabetes and metabolic syndrome.

Some individuals have too many α2A-adrenergic receptors that norepinephrine binds to on the pancreatic beta cells that produce insulin (Figure 2). These additional receptors block the insulin granules from docking at the edge of the beta cells, which reduces the amount of insulin released.  Too much norepinephrine activity can lead to less insulin release in individuals who are genetically wired with too many receptors.  Less insulin released can’t regulate blood glucose, leading to higher glucose levels (hyperglycemia) and the development of adrenergic diabetes.  When α2A-adrenergic receptors are blocked by antagonists, insulin granules begin docking again and insulin release returns to normal.

Figure 2. The susceptible genotype for adrenergic diabetes has increased numbers of α2A-adrenergic receptors on pancreatic beta cells. This inhibits the docking of insulin granules preventing the release of insulin (Gribble, 2010).

One clinical result of excess α2A-adrenergic receptors is stress-induced hyperglycemia.  Stress-induced hyperglycemia is characterized by elevated blood glucose in response to stress.  This could be caused by increased norepinephrine being released as a response to stress decreasing the amount of insulin that would control blood sugar.  Genetic differences that cause varying levels of the α2A-adrenergic receptors aid our understanding why one patient may be susceptible to stress-induced hyperglycemia, while another may not.

Remember these connections the next time you or a patient is experiencing chronic stress and consider addressing a patient’s stress response as a primary therapy in cases of stress-induced hyperglycemia or as part of your comprehensive blood sugar management approach.  Excessive norepinephrine release from a stress response can lead to metabolic issues due to subsequent decreased insulin release.

References:

http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf

http://www.cdc.gov/obesity/data/adult.html

Gribble FM. Phil D.  (2010). a2A adrenergic receptors and type 2 diabetes.  New Eng J Med, 4: 361-362.

Kyrou I. Tsigos C. (2007). Stress mechanisms and metabolic complications.  Horm Metab Res, 39(6): 430-8.

Lyme disease study from Pharmasan Labs selected as 2013 feature paper

Cells, a peer-reviewed, international, open access journal, has selected Pharmasan Labs’ research study entitled “An Enhanced ELISPOT Assay for Sensitive Detection of Antigen-Specific T-Cell Responses to Borrelia burgdorferi” as a Feature Paper of 2013.  Feature Papers are selected for their significant contributions to the science of cell biology, molecular biology and biophysics. The study is available at http://www.mdpi.com/2073-4409/2/3/607/.

Lead-authored by Chenggang Jin, MD, PhD, Head of Immunology at Pharmasan Labs, the study tested and validated a novel T cell-based assay for the detection of antigen-specific T cell response to Borrelia burgdorferi, the causative agent of Lyme disease. Through a clinical study of Lyme-positive patients, Dr. Jin’s team demonstrated that the new assay, called iSpot Lyme™, provides significantly higher specificity and sensitivity levels, compared with the Western Blot assay that is currently used as a diagnostic measure.

The publication comes on the heels of the Centers for Disease Control and Prevention’s announcement last month that Lyme disease is a full ten times more prevalent than previously thought. CDC estimates now place the number of infected patients at 300,000 people each year.

“We are honored to have our research selected for Cells’ Featured Papers of 2013,” said Pharmasan Labs’ Dr. Jin. “More importantly, we’re hopeful that our evaluation of both antibody response and T cell response to Borrelia infection will provide new insights into the pathogenesis, diagnosis, treatment and monitoring of Lyme disease, which is a potentially serious and increasingly common infection.”

Co-authored by Diana R. Roen of Pharmasan Labs, Dr. Gottfried H. Kellermann of NeuroScience, Inc. and Paul V. Lehmann of Cellular Technology Limited, the study received the Best Abstract Award from the American Association for Clinical Chemistry in July, and was presented at the 13^th International Conference on Lyme Borreliosis and Other Tick-Borne Diseases (ICLB) in August.

It’s all in your head: The neurocircuitry of addiction

According to the National Institute on Drug Abuse, abuse of tobacco, alcohol, and illicit drugs costs over $600 billion annually due to crime, lost work productivity, and healthcare expenses.  Brain chemistry can be one of the reasons why it is so difficult to conquer addictions.

Did you know that addictive drugs and normal learned behaviors stimulate the same neural pathways?  As such, the neurological reward and emotional sense of pleasure associated with the achievement of normal biological cues are also stimulated by addictive drugs.  The difference between the two is that drugs cause a much higher degree of neuronal pathway stimulation and neurotransmitter release.  This flood of neurotransmitters causes prolonged changes in the brains’ neurocircuitry responsible for sensing satisfaction and reward; and appears to play a key role in addiction.

There has been extensive research illustrating the neurotransmitters and neural adaptations involved in addiction.  Simply put, the development of addiction occurs when neuronal projections from the ventral tegmental area (VTA) increase dopamine signaling within the pleasure sensing nucleus accumbens.  This pathway is reinforced through repeated exposures to the substance, which causes the prefrontal cortex to learn and eventually repeat the behavior that led to the neurotransmitter release.

The neural circuits of the VTA, nucleus accumbens, and prefrontal cortex are critical in learning both natural and addictive behavior.

Here is a closer look at the neurocircuitry of addiction and how dopamine and glutamate are key neurotransmitters involved (Figure 1):

1. Upon exposure to a naturally rewarding stimulus or a drug, there is an increase in
   

   Figure 1. Dopamine and glutamate are key players in the neurocircuitry of addiction.

   dopamine signaling from the VTA to the nucleus accumbens.  The nucleus accumbens ‘perceives’ this dopamine signal and measures the ‘goodness’ of the reward based upon the size of the dopamine release.

2. Glutamate projections from the nucleus accumbens instruct the prefrontal cortex to remember the environment and behaviors which lead to the occurrence of ‘goodness’.
3. Excess signaling of glutamate neurons in the prefrontal cortex stimulates the nucleus accumbens, triggering addiction-seeking behaviors at the expense of naturally rewarding behaviors.

Addiction occurs as the result of dopamine signaling in the nucleus accumbens, and glutamate projections from the prefrontal cortex are key plays in drug seeking and relapse.  Glutamate and dopamine both play roles in addiction, and assessing imbalances can help successfully treat addictive behaviors.

Guest author: Jennifer Farley is a manager of the Clinical Support & Education Department at NeuroScience, Inc. and one of the resident experts in psychiatric disorders.

References:

Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW. (2002). The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci, 22(20):9134-41.

Goldstein RZ, Volkow ND. (2002). Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry, 159(10):1642-52.

Kalivas PW, Volkow ND.  (2005). The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry, 162(8):1403-13.

Roberts AJ, Koob GF. (1997). The neurobiology of addiction: an overview. Alcohol Health Res World,  21(2):101-6.

http://www.drugabuse.gov/related-topics/trends-statistics

Lyme disease infection rate ten times higher than previously reported

Lyme disease may be ten times more common than previously reported, the CDC says.

The Centers for Disease Control and Prevention (CDC) recently released preliminary results of three ongoing studies indicating Lyme disease infection is ten times higher than previous studies showed. In a press release on Monday, August 19, 2013, the CDC stated “Each year, more than 30,000 cases of Lyme disease are reported to CDC, making it the most commonly reported tick-borne illness in the United States. The new estimate suggests the total number of people diagnosed with Lyme disease is roughly 10 times higher than the yearly reported number. This new estimate supports studies published in the 1990s indicating that the true number of cases is between 3- and 12-fold higher than the number of reported cases.”

“We know that routine surveillance only gives us part of the picture, and that the true number of illnesses is much greater,” Paul Mead, M.D., M.P.H., chief of epidemiology and surveillance for CDC’s Lyme disease program, said in the press release. “This new preliminary estimate confirms that Lyme disease is a tremendous public health problem in the United States, and clearly highlights the urgent need for prevention.”

Adult ticks are approximately the size of a sesame seed.

The enormity of the implications for health care in the United States led national media outlets (CBS, NBC, The Boston Globe, Fox News) to run this story. The New Yorker pointed out the 800-pound gorilla in the room, “underreporting of Lyme disease obscures the true burden of the illnesses, on individuals as well as on health-care systems.”

The CDC’s new projections indicate a much greater infection rate than most Lyme disease experts imagined. The startling aspect of the report is that this 10-fold rate increase only reflects reported cases of Lyme disease. It does not include individuals whose diagnosis may have been missed.

Current antibody-based testing for Lyme disease detects only 30-50% of cases. This means the rate of infection in people who have sought medical testing could, in fact, be 50-70% higher. The true number of people infected is probably even higher since not all people realize a tick has bitten them. New advances in Lyme testing hold great promise to better identify infected people.

The iSpot Lyme™ test detects Lyme disease more reliably. With a sensitivity of 84% and a specificity of 94%, you can be more confident in your diagnosis using iSpot Lyme. If you are not familiar with iSpot Lyme, go to Modern Health Care Professional Lyme Learning Center or read the article in Holistic Primary Care. This new CDC report has brought nation-wide attention to the health crisis of Lyme disease. Hopefully it will also bring about better options for those suffering from Lyme disease.

Amino acids…how can diet affect mental health?

We all know we need food to survive. However, the type of food we eat enhances our survival. When we eat protein-containing foods, they are broken down into amino acids which are the building blocks for neurotransmitters.For example, tryptophan is a precursor to serotonin, and tyrosine is a precursor to the neurotransmitters dopamine, epinephrine, and norepinephrine.¹ It is important to understand the role neurotransmitter precursors play, because neurotransmitters are critical for proper mental health. Imbalances in neurotransmitters can result in low mood, anxiousness, and compulsive behavior.^{2, 3, 4}

Amino acids are made when protein is broken down in the small intestines and within cells.³ There are two groups of amino acids (Table 1). Nonessential amino acids can be made by the body from protein or other amino acids. Essential amino acids can only be obtained through the diet. Low protein diets mean fewer amino acids are available for making neurotransmitters. In addition, it is important to eat adequate amounts of amino acids, because they must compete with other dietary proteins for intestinal absorption and transport across cell membranes and the blood-brain barrier (BBB).^{5, 6}

Figure 1. The blood-brain barrier acts as a wall to protect the brain and keep harmful substances out.

The BBB (Figure 1) consists of the endothelial cells lining the blood vessels in the brain. These cells serve as a fortress that guards and protects the brain from foreign substances.⁷ The tight junctions of the BBB make it difficult for foreign materials in the blood to enter the brain.⁸ Because of this obstacle, amino acids are assigned to specific carriers or transporters that allow them to get through the BBB.^{8, 9}

Optimal health is built on a solid foundation and amino acids are its primary building blocks. In turn, an optimal nervous system is built on a foundation of healthy neurotransmitter levels, which requires a steady supply of amino acids in the diet. These kinds of strong foundations are critical for good mental health.

Guest author: Rachel Rixmann is a manager of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in gastroenterology and nutrition.

References

1. Savelieva KV, Zhao S, Pogorelov VM et al. (2008). Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. PloS ONE 3 (10): e3301.

 2. Delgado, P L, & Moreno, F A. (2000). Role of norepinephrine in depression. The Journal of clinical psychiatry, 61(1): 5−12.

 3. Nikolaus, S, Antke, C, Beu, M, et al. (2010). Cortical gaba, striatal dopamine and midbrain serotonin as the key players in compulsive and anxiety disorders−−results from in vivo imaging studies. Reviews in the neurosciences, 21(2): 119−139.

 4. Moeller SJ, Tomasi D, Honorio J, Volkow ND, Goldstein RZ. (2012). Dopaminergic involvement during mental fatigue in health and cocaine addiction. Transl Psychiatry, Published online Oct. 23.

 5. Berg, J., et al. (2002). Biochemistry. 632-633.

 6. http://faculty.washington.edu/chudler/bbb.html

 7. Matthews, D.M., Leonard, L. (1965). Absorption of protein digestion products: A review. Gut.

 8. Pietz, J., et al. (1999). Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest, 103(8): 1169-1178.

 9. Feurté, S., Gerozissis, K., Regnault, A., Paul, F.M. (2001). Plasma Trp/LNAA ratio increases during chronic ingestion of an alpha-lactalbumin diet in rats. Nutr Neurosci, 4(5):413-8.

 10. Oldendorf,W.H., Szabo,J. (1976). Amino acid assignment to one of three blood-brain barrier amino acid carriers. Am.J.Physiol, 230:94-98.

 11. http://www.sdmags.net/2012/01/breaching-the-blood-brain-barrier/

Epinephrine: Ally or enemy in the fight against metabolic issues?

Our nervous system controls all of our bodily processes, including metabolism.  Communication within this system is vital to maintaining balance within the body and can be disrupted by metabolic syndrome.

What is metabolic syndrome?

Figure 1. Waist size, cholesterol, blood pressure, and blood sugar levels are all risk factors of metabolic syndrome. Patients with metabolic syndrome typically have at least three of these risk factors. (Adapted from NIH)

According to the American Heart Association, more than 47 million Americans have metabolic syndrome.  Metabolic syndrome is defined as a combination of conditions which include increased blood pressure, high blood sugar levels, excess body fat around the waist, and abnormal cholesterol levels. The combination of these conditions significantly increases the risk of heart disease, stroke, and diabetes (Figure 1).

Epinephrine correlations with metabolic syndrome

Healthy adrenal function, specifically healthy epinephrine levels can be protective against metabolic syndrome.  Ziegler and colleagues (2012) point out that low epinephrine production can be correlated with obesity in their recent publication on metabolic syndrome.

Historically, excess epinephrine has been viewed as part of the problem for individuals experiencing metabolic disturbances leading to hypertension and insulin resistance.  Ziegler, et al. note that the impacts of epinephrine on metabolism are much different in the short- and long-term.  The short-term effects of epinephrine are to raise systolic blood pressure and blood glucose.  Longer-term consequences of beta2 receptor stimulation by epinephrine however, are decreased peripheral vascular resistance, lower exercise blood pressure, and enhanced insulin sensitivity.

Our nervous system plays a major role in metabolic syndrome and epinephrine is not the only neurotransmitter involved.  Look for a forthcoming post detailing the effects norepinephrine has on stress, insulin release, and hyperglycemia.

Guest author: Tricia Walz is a member of the Clinical Support & Education Department at NeuroScience, Inc. and the resident expert in metabolic issues.

References

 Baker, RG., et al. (2011). NF-κB, Inflammation, and Metabolic Disease. Cell Metab. 13(1): 11-22.

 Despres, JP., et al. (2008). Abdominal Obesity and the Metabolic Syndrome: Contribution to Global Cardiometabolic Risk. Arterioscler Thromb Biol. 28: 1039-49.

 Kyrou, I., Tsigos, C. (2007). Stress Mechanisms and Metabolic Complications. Horm Metab Res. 39(6):430-8.

 Ziegler, MG. (2012). Epinephrine and the Metabolic Syndrome. Curr Hypertens Rep. 14(1):1-7.

 http://www.nhlbi.nih.gov/health/health-topics/topics/ms/

 http://www.mayoclinic.com/health/metabolic%20syndrome/DS00522

Hidden metals might be making you sick

What do processed cheeses, deodorants, toothpastes, astringents, and tattoos have in common?  Few people are aware that these items may contain aluminum in them.  For most people, this isn’t a problem, but it’s a different story for people with metal hypersensitivities. For those individuals, these exposures can cause an inflammatory response and symptoms such as chronic fatigue, pain, and headaches.

Often when metals are thought to be a problem, tests looking for toxic levels in the individual are performed.  These tests provide insight into toxicity levels and how much of a metal a patient currently has in their body will be used. Just looking at the amount of a metal in the body isn’t good enough for people with metal hypersensitivities though.  For individuals that have a hypersensitivity to a given metal, even trace amounts of exposure can be enough to cause a significant immune reaction and associated clinical symptoms.  There is no such thing as a “safe limit” of exposure for these individuals.

The MELISA® (Memory Lymphocyte Immunostimulation Assay) is different than tests measuring the level of a metal in the body.  It measures the response of the immune system when it encounters a particular metal (methodology information). It is for this reason that MELISA testing is a useful tool for determining the root cause of chronic clinical conditions.

Since even tiny amounts of metal can trigger an immune reaction, it is very important that people who are hypersensitive to a certain metal avoid all contact with it. This isn’t always easy in everyday life as there are many hidden sources of metals that may be surprising; for instance, aluminum in toothpaste or copper in wine.  The documents below list additional hidden sources of metals that could be causing an inflammatory response in patients with metal hypersensitivities.

MELISA is a registered trademark of the MELISA Medica Foundation.

Hidden sources of metal exposures can still trigger an immune reaction.

Download a PDF of the hidden metals resource sheet.

Attention! Calling all neurotransmitters!

Inattention, trouble focusing, impulsivity, hyperactivity…  All children have trouble with these at some times, but for the 5-10% of school-age children with attention-deficit hyperactivity disorder (ADHD), these issues are a constant daily struggle.

ADHD is correlated with underlying biochemical imbalances

For many children, ADHD is correlated with an underlying biochemical imbalance. Photo credit: Corbis

Children with ADHD have been shown to have abnormalities in urinary excretion of the neurotransmitters β-phenylethylamine (PEA) and the catecholamines (epinephrine, norepinephrine, and dopamine).  Decreased PEA levels have been associated with inattentiveness, and research demonstrates that urinary PEA levels are significantly lower in ADHD patients.  Both decreased and increased levels of epinephrine and increased levels of a norepinephrine metabolite have also been observed in individuals with comorbid anxiety and ADHD.  This suggests that sympathetic adrenal function may be altered in subjects with ADHD.  Clinically, PEA, epinephrine, and norepinephrine affect attention, memory, focus, and energy.  Imbalances in any of these neurotransmitters correlate with the symptoms of inattention, focus issues, and hyperactivity commonly seen with ADHD.

Urinary neurotransmitter testing can help monitor ADHD treatment

Neurotransmitter testing can be a useful tool for monitoring ADHD treatment.  A study in 2002 by Kusaga et al found that responders to methylphenidate, a stimulant that inhibits the reuptake of norepinephrine and dopamine, had significantly increased urinary PEA levels.  Non-responders, however, did not demonstrate a significant change.  Methylphenidate increases urinary epinephrine and norepinephrine levels as well.  This example illustrates how changes in biomarkers can provide insight into the response of an individual patient to a particular intervention.

ADHD is a disorder that affects a significant number of children.  Urinary neurotransmitter testing can be beneficial in identifying the underlying biochemical imbalances present in children with ADHD.  Neurotransmitter testing can also be used to help monitor and adjust ADHD treatment regiments to suit a patient’s individual biochemistry; thus increasing treatment efficacy and improving clinical outcomes.

References:

Mood, blues, and reuptake pathways: Why common interventions are not always effective

According to Harvard Health Blog, about 1 in every 10 Americans takes an antidepressant.  The most commonly prescribed class of antidepressants is Selective Serotonin Reuptake Inhibitors (SSRIs).

Figure 1. Mechanism of action for SSRI medications: serotonin is released from the pre-synaptic neuron to bind receptors on the post-synaptic neuron. Normally, the serotonin is then reuptaken into the presynaptic neuron and repackaged. SSRIs block the reuptake channels, keeping the serotonin in the synapse for longer to act on the post-synaptic neuron.

SSRIs block the removal of serotonin from the synapse, allowing serotonin to signal longer on the post-synaptic neuron (Figure 1).  The net effect is to allow serotonin signaling to occur following what would otherwise be an insufficient release of serotonin. It has been estimated that, at best, approximately 50% of patients using SSRI medications achieve positive clinical outcomes while some are effective for no more than 5% of patients.

Why don’t SSRIs work more often?

Lack of symptom improvement may be attributed to a number of things including: improper absorption, slow metabolic breakdown, and existing serotonin levels.  SSRIs do not create more serotonin and therefore require a certain circulating levels of serotonin to have its desired clinical effects. This can be observed through 2 common clinical outcomes:

1. Patients taking SSRIs for depression experience reoccurrence of symptoms over time.
2. Antidepressant efficacy can be improved when serotonin synthesis is supported.

People suffering from depression often begin with low serotonin stores and it is hypothesized that extended use of SSRI medications will deplete serotonin stores further, regardless of baseline levels.  It is well documented that serotonin support increases serotonin synthesis.  In the handful of published studies, serotonin support along with SSRIs have been shown to be safe, effective, and further highlight the need to manage serotonin stores in depressed patients.

Guest author: Jennifer Farley is a manager of the Clinical Support & Education Department at NeuroScience, Inc. and one of the resident experts in psychiatric disorders.

References:

Delgado, PL., et al. (2000). Role of norepinephrine in depression. J Clin Psychiatry, 1:5-12.

Nelson, JC. (2000).  Augmentation strategies in depression. J Clin Psychiatry, 61:213-219.

vanPraag, HM. (1984). In search of the mode of action of antidepressants: 5-HTP/tyrosine mixtures in depression. Adv Biochem Psychopharmacol, 39:301-314.

vanPraag, HM. (1996). Serotonin precursors in the treatment of depression. Adv Biochem Neuropsychiatry Clin Neurosci, 8(2):168-71.

The Kynurenine Pathway: Implications for inflammation and mood

When you’re sick, the last thing you want to do is drag yourself to work and deal with your normal routine. Even socializing with friends does not sound pleasant anymore. You may experience low energy, sleep issues, low appetite, and low mood, to name a few. This “sickness behavior” shares many of the same symptoms as depression. This behavior is thought to have evolved to encourage people to slow down and rest when ill in order to maintain the resources needed to clear an infection¹. In most cases, these symptoms will be short lived, and the body will return to normal once the infection has cleared. However, in instances of long term immune up-regulation, these symptoms may become more persistent and result in a long term depressive state. Over the years, a great deal of research has linked inflammation to depression, and many different theories regarding the mechanism by which this may occur have been proposed.

Figure 1. Neuropsychiatric side effects of immunotherapies based on the administration of pro-inflammatory cytokines. Image from Schiepers 2005.

Immune cells produce cytokines which help regulate immune responses in the body. The activities, as well as the classifications, of cytokines vary greatly. Typically cytokines are discussed in the context of pro-inflammatory and anti-inflammatory capacities. Pro-inflammatory cytokines activate the inflammatory response and anti-inflammatory cytokines dampen that response. Cytokines are suspected to access the brain by crossing the blood- brain barrier in vulnerable areas, being transported by active transport, as well as being produced directly in the brain by astrocytes and microglia³.

The link between pro-inflammatory cytokines and depressive symptoms was discovered by observing patients receiving immunotherapy. Certain pro-inflammatory cytokines are sometimes given as immunotherapy for disorders such as cancer, chronic hepatitis C, and multiple sclerosis (MS). This therapy has been shown to cause a variety of side effects in patients, many of which are similar to symptoms of depression³. Figure 1 shows the different cytokines given as immunotherapy and the neuropsychiatric effects they can have on patients³.

The exact mechanism by which pro-inflammatory cytokines cause depressive symptoms in patients is unknown; however, as stated previously, many different mechanisms have been proposed. Many researchers believe that both chronic stressors and the presence of pro-inflammatory cytokines in the central nervous system influence similar pathways and result in similar consequences. Some of these consequences include: increased corticotrophin releasing hormone (CRH) leading to increased glucocorticoid levels, variations in monoamine levels and activity, and alterations in different growth and anti-apoptotic factors leading to decreased neuroplasticity². One of the most extensively studied consequences is the variation in monoamine levels and activity, specifically of serotonin.

Inflammation has been shown to affect serotonin through activation of the kynurenine pathway. Pro-inflammatory cytokines activate the enzyme indoleamine 2,3-dioxygenase (IDO). IDO shuttles tryptophan, the precursor to 5-hydroxytryptophan (5-HTP), down the kynurenine pathway rather than down the pathway that would result in the synthesis of serotonin (Figure 2). Activation of the kynurenine pathway can result in depletion of tryptophan and consequently, depletion of serotonin. Furthermore, 5-HTP and serotonin itself can be substrates for IDO leading to further depletions⁴.

Figure 2. Indoleamine 2,3-dioxygenase (IDO) degrades tryptophan through the kynurenine pathway. Image from Dantzer 2008.

In addition to decreasing serotonin levels in the body, the kynurenine pathway also results in the synthesis of multiple metabolites that can have neurotoxic effects. These metabolites include 3-hydroxy-kynurenine (3-OH-KYN) as well as quinolinic acid. 3-OH-KYN exerts its damaging effects by increasing reactive oxygen species (ROS) in the brain. This increase in ROS leads to oxidative stress and possibly neuronal apoptosis⁴. Overproduction of ROS is linked to an increase in Monoamine oxidase (MAO) activity, which could deplete monoamine levels in the brain leading to a depressed mood⁴. Quinolinic acid is a potent N-methyl-D-aspartate (NMDA) receptor agonist. Overstimulation of these receptors leads to an increased calcium influx into target neurons resulting in neuronal damage⁴. Increased influx of calcium into cells may also lead to the generation of ROS⁴. Both metabolites have been found to be elevated in certain neurodegenerative disorders such as Huntington’s disease and Parkinson’s disease⁴.

The increase in IDO activity brought about by increased pro-inflammatory cytokine levels is just one way in which the immune system affects the nervous system. There are undoubtedly many other mechanisms to be investigated in which the immune system and nervous system can affect one another. For patients who present with depressive symptoms, it may be beneficial to investigate possible underlying inflammatory issues. Full symptom relief is unlikely to be achieved until the underlying inflammatory issue is controlled or resolved.

Guest author: Alyson Betcher is a member of the Clinical Support & Education Department at NeuroScience, Inc. and one of the resident experts in psychiatric disorders.

References:

1. Anisman, A. (2009). Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. J Psychiatry Neurosci; 34(1): 4-20.

2. Hayley, S., Poulter, M., Merali, Z., Anisman, H., (2005). The pathogenesis of clinical depression: stressor and cytokine – induced alterations of neuroplasticity. Neuroscience; 135: 659-678.

3. Schiepers, O., Wichers, M., Maes, M., (2005). Cytokines and major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry; 29: 201-217.

4. Wichers, M., Maes, M. (2004). The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-α-induced depression. J Psychiatry Neurosci; 29(1): 11-17.

5. Dantzer, R., et al. (2008). From Inflammation to Sickness and Depression: When the Immune System Subjugates the Brain. Nature Reviews Neuroscience, 9(1): 46–56.