Anxiety disorders (AXDs) are very common among individuals in today’s stressful life. These generally begin during childhood, adolescence and early adulthood. As per 2017 WHO epidemiological data indicates 3.8% of the global population, nearly 280 million people worldwide, are affected by AXDs. Unfortunately, it affects 4.7% of females and 2.8% of males, and one in 13 universally experiences anxiety episodes as of 2017. In particular, 40 million people in the United States aged 18 and older, which is 18.1% of the population, every year, gets exposed to AXDs-related issues. AXDs happen to all of us at one point or another in our lifetime. And these are not limited to facing stressful issues at work or needing to make important decisions. Anxiety can last for lengthy periods of time and cause long term impact to the respective individual’s quality of life over time. The symptoms of AXDs can affect a person dramatically and his/her day-to-day life events1-4.
As per Barlow’s concepts7, anxiety is a future-oriented mood state linked with preparation for probable, upcoming adverse events. Fear is an alarming reaction to present or imminent danger. In the classification of AXDs, there are different types of AXDs as outlined below.
- Generalized Anxiety Disorder
Anxiety in a prolonged period, excessive fears, nervousness and discomfort are the key characteristics of generalized anxiety disorder. 6.8 million adults or 3.1% U.S. inhabitants have been affected, however, only 43.2% of people out of 6.8 million are intended to receive treatment for generalized anxiety disorder. The symptoms of generalized anxiety disorder found in many individuals are,
- Sense of agitation and restlessness
- Muscle tension
- Difficulty concentrating, focusing on the job or mind “goes blank”
- Persistent feelings of fear or worry
- Issues with sleep patterns
- Panic Disorder
Affects around 6 million adults in the U.S. population, unprecedented and repeated occurrences of extreme panic conditions cause panic disorder. People may experience occasional or frequent waves of panic associated symptoms such as sweating, dizziness, shortness of breath or sense of suffocation, heart palpitations, chest pain, trembling and abdominal problems.
- Post-Traumatic Stress Disorder
The development of anxiety-related episodes after exposure to a natural disaster or alarming incidents that resulted in physical injuries or threatened human lives. Natural calamities, brutal personal attacks, accidents and military warfare are the traumatic events which could trigger a post-traumatic stress disorder. This type of AXDs affects 7.7 million adults in the U.S., which is 3.5 % of the population.
- Obsessive-Compulsive Disorder
Repetitive unwanted obsessions and behaviors are the key indicators for the obsessive-compulsive disorder. 2.2 million adults in the U.S. including both men and women have been affected equally.
- Social Anxiety Disorder
Social anxiety disorder, also referred to as social phobia, is characterized by devastating anxiety events and exaggerated self-consciousness in daily social interactions. Social phobia is an alarming condition in which an individual’s inability to interact or talk in any type of social situation, for example, eating and drinking in the public. People with a social phobia are always concerned that their behaviors or activities will be judged as unacceptable by their peers. This sabotaging mindset makes them feel anxious and embarrassed and, consequently, causes them to avoid social events. Social anxiety disorder is evenly observed among men and women, similar to obsessive-compulsive disorder, it usually starts in childhood or early adolescence. This disorder affects 15 million U.S. adults.
- Separation anxiety disorder
This type of AXDs occurs in both children as well as adults. Affected people have fears of being separated from their loved ones. They tend to have a mindset that assumes harmful things will happen to their loved ones, as a result, increased anxiousness or fear surfaces and they would avoid the state of being alone or separated from their loved ones. Generally, nightmares about the separation from loved ones can happen to people with a separation anxiety disorder. The diagnosis of a separation anxiety disorder takes about 4 weeks for children and at least 6 months for adults.
Individuals with agoraphobia have extreme fear of panic, helplessness, or embarrassment They love a ‘safe’ housebound environment and do not like the scenarios below:
- Commuting through public transportation
- Working or interacting in open or enclosed spaces
- Waiting in the queue or spending time in a crowd
Agoraphobic individuals avoid the above situations and if they experience it in unavoidable circumstances, they may have feelings of embarrassment and intense fear.
- Selective mutism
People with selective mutism fail to speak or interact in particular social situations even though they possess natural language skills. Severe nervousness, worry about social humiliation, compulsive and clinging behaviors as well as mood tantrums are the main characteristics of people who are affected with selective mutism.
- Specific Phobia
Individuals with a specific phobia have extreme anxiety and fear towards specific types of circumstances and objects. A few examples of specific phobias are:
- Fear of animals such as a snake, dog, or insects and/or spiders
- A natural environment like fear of water, storms or heights
- Fear of needles (when blood is drawn)
- Situational phobia (flying, elevators and enclosed places)1
Research studies indicate that the imbalance between the levels of Gamma Amino Butyric Acid (GABA) and glutamate in the central nervous system (CNS) leads to anxiety-related disorders. Glutamate regulates excitatory functions whereas the inhibitory activities are maintained by the GABA. The physiological homeostasis between GABA and glutamate determines the appropriate functioning of the CNS. The two opposing amino acid neurotransmitters play an indispensable role in and constitute about 90% of all neurotransmission in the CNS. Glutamate is referred to as an ‘excitotoxin’ specifically when high levels of glutamate exist in the brain without being negated by GABA. The presence of a large amount of glutamate in the CNS leads to excessive acetylcholine that has an excitatory functionality. This in turn stimulates the sympathetic nervous system, followed by fear, anxiety, disturbed sleep patterns and nervousness. Chronic exposure to glutamate can result in many pathological conditions such as AXDs, migraines, schizophrenia, Parkinson’s disease, Huntington’s disease, seizures, fibromyalgia, autism, hyperactivity and bipolar disorder. GABA regulates the levels of glutamate in the CNS. It also controls several functions in the body such as normalizing the hypothalamic pituitary adrenal axis (HPA) and autonomic nervous system, appetite, body temperature, sleep, sexual desire and arousal as well as pituitary activity.
There are plenty of factors involved in the increased levels of glutamate which include inadequate diet, environmental toxins, genetic variables and traumatic events. Firstly, Glutamine present in both GABA and glutamatergic neurons is converted to glutamate catalyzed by phosphate-activated glutamine dehydrogenase. In the presence of glutamic acid decarboxylase (GAD), glutamate in GABAergic inhibitory neurons undergoes a decarboxylation reaction and converts into GABA. Mutations in the GAD gene cause a failure in the conversion of glutamate to GABA. Therefore, excessive levels of glutamate build-up in the CNS, thereby triggering the anxiety-related symptoms and can lead to AXDs. In another scenario, the mutation of methylenetetrahydrofolate reductase (MTHFR) results in the formation of glutamate, which further increases the glutamate burden in the CNS. The conversion of 5,10-methylene-THF to 5-methylfolate is disrupted by the mutation of MTHFR and when folate is not appropriately transformed into the form the body can directly use, 5-MTHF, then it can break down into glutamate. Thirdly, glutamate receptors can trigger other excitatory agents such as monosodium glutamate, glutamic acid, glutamine, aspartate, cysteine and homocysteine. The administration of methylfolate and trimethylglycine (or betaine) can convert homocysteine to methionine, which stops homocysteine from becoming an excitatory toxin augmenting glutamate5-6.
People with AXDs have to consult the physician for the type of treatment they need, which may be psychotherapy, medication and/or both to resolve the condition. Cognitive behavioral therapy, a type of psychotherapy, is presently very common and teaches individuals about different ways of behaving, thinking and reacting to conditions and objects which seem to invoke the anxiety. It also empowers individuals to learn and practice social skills and face the environments and situations that can cause anxiety. Curing AXDs using medications does not prevent anxiety but it can lessen the symptoms. Anti-anxiety drugs or anxiolytics (benzodiazepines), antidepressants and beta-blockers are the most common classes of medications used in the treatment of AXDs. Anxiolytics can reduce the symptoms of anxiety, extreme fear, panic attacks and worry. Benzodiazepines are typically used as first-line anxiolytic drugs in the treatment of generalized anxiety disorder. Benzodiazepines are very effective in alleviating anxiety and take less time to work as compared to antidepressants. However, using benzodiazepines over a long period of time leads to tolerance issues and patients may need higher doses that can pose adverse effects and dependency.
The next class of compounds is antidepressants, which are primarily prescribed and administered for depression-related symptoms, but are also very useful for treating AXDs. They may ease the anxiety associated symptoms by regulating the levels of monoamines, norepinephrine, serotonin and dopamine, in the CNS. Of these antidepressants, commonly used first-line agents for the treatment of AXDs include selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Effective antidepressant drugs, less-commonly used, are tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Beta-blockers are typically prescribed to treat high blood pressure, but they can also help in improving anxiety symptoms like trembling, shaking, rapid heartbeat and blushing. Beta-blockers can be recommended for a short period to reduce acute anxiety disorders.
Physicians and researchers are looking at alternative approaches to treating AXDs due to the many drawbacks they’ve come across with today’s ‘standard of care’, negatives such as:
- relapse of treated individuals
- tolerance and dependency
- insufficient information on treatment selection for the individual patient
- the optimal duration of the treatment and
- adverse events occurring with pharmacological treatments1,8.
To overcome the above problems, Deplin® was considered to treat anxiety-related symptoms. Deplin® is a prescription classified as a “medical food” for use under the supervision of a physician for the adjunct clinical management of depression and schizophrenia. Deplin® helps in regulating monoamine synthesis and is also useful in the management of depression by augmenting the therapeutic benefits of antidepressants. The formulation is comprised of 5-methyltetrahydrofolate (5-MTHF) or L-methylfolate, which is very different from the typical over-the-counter (OTC) folate vitamin products. In clinical trials, the adverse effects of Deplin® were similar to that of the placebo group (almost none). Deplin® is available in tablets and capsules, administered once a day There are two different doses available for treating depression,- Deplin® 7.5 and Deplin® 15. The details of each formulation is below:
- Deplin® 7.5 consists of 7.5 mg of 5-MTHF and 90.31 mg of Algae-S powder
- Deplin® 15 contains 15.0 mg 5-MTHF and 90.31 mg of Algae-S powder10
5-MTHF, the most bioavailable folate, has metabolic advantages as compared to other therapeutic interventions. A change in the pH of the gastrointestinal tract does not affect the absorption of 5-MTHF (so it is more readily available for the body to use). The bioavailability of 5-MTHF is not interrupted by any metabolic-related issues (like genetics, i.e. MTHFR) or diseases. 5-MTHF plays a clear role in the synthesis of monoamines, which is made up of three active processes. In the first step, 5-MTHF supports the production of the important cofactor, called tetrahydrobiopterin, BH4. Secondly, the activation of the rate-limiting enzymes tyrosine hydroxylase and tryptophan hydroxylase for the synthesis of monoamines takes place. In the absence of BH4, the enzymes tyrosine hydroxylase and tryptophan hydroxylase become inactive, this condition does not support the binding of enzymes with their amino acid substrates such as tyrosine and tryptophan that are the precursors for monoamines. Finally, the presence of 5-MTHF forms the appropriate amounts of BH4, the activation of both enzymes tyrosine hydroxylase and tryptophan hydroxylase leads to the synthesis of dopamine, norepinephrine and serotonin9.
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Deplin® or 5-MTHF has advantages in the treatment of anxiety disorders including depression, some of these include:
- this active form crosses the blood brain barrier easily
- may maintain the balance of glutamate and GABA levels in the CNS
- supports the individuals with MTHFR mutations by reducing glutamate levels
- can increase the levels of monoamines in the CNS (this means more serotonin gets generated)
So if you plan to supplement for anxiety disorders, make sure you’re using a reliable source for the active L-5-MTHF (or L-Methylfolate). Check out Methyl-Life™ as they are selling the purest methylfolate on the planet in professional-strength doses, Their therapeutically nutritional products are optimized to help you balance and elevate your mood and anxiety..
- Craske MG, Stein MB. Anxiety. Lancet. 2016, 388(10063), 3048-3059.
- Martin EI, Ressler KJ, Binder E, Nemeroff CB. The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology. Clin Lab Med. 2010, 30(4), 865-891.
- Liang SL, Carlson GC, Coulter DA. Dynamic regulation of synaptic GABA release by the glutamate-glutamine cycle in hippocampal area CA1. J Neurosci. 2006, 26(33), 8537-8548.
- Wierońska, JM, Stachowicz, K, Nowak, G, Pilc, A. The Loss of Glutamate-GABA Harmony in Anxiety Disorders. 2011, 135-157. (https://doi.org/10.5772/19919).
- Barlow DH. Anxiety and its Disorders: The Nature and Treatment of Anxiety and Panic. 2nd ed. New York: Guilford Press; 2002.
- Nemeroff CB. The role of GABA in the pathophysiology and treatment of anxiety disorders. Psychopharmacol Bull. 2003, 37(4):133-146.
- Stahl SM. L-methylfolate: a vitamin for your monoamines. J Clin Psychiatry. 2008, 69(9):1352-1353.