As nature intended it, anxiety serves a useful purpose. Characterized by the fear or worry that something bad will happen, normal anxiety occurs occasionally in response to situations that threaten our sense of security. This helps us avoid harm and remember not to put ourselves in the same potentially dangerous situation in the future. Anxiety is a normal stress response that has been conserved throughout human evolution and is evident in all other animals.
However, when anxiety occurs inappropriately in response to normal everyday events, it can become a debilitating condition known as anxiety disorder. Anxiety disorders cause a person to be constantly “primed”, or “tense” in expectation of an impending threat to their physical or psychological well-being. Symptoms of anxiety disorders are often chronic, and can include difficulty concentrating, irritability, tense muscles, sleep disturbances, and trouble overcoming worries.
The conventional health care model typically attempts to alleviate anxiety with an array of psychoactive drugs that either mimic or manipulate neurotransmitter signaling. For instance, medications for anxiety might either increase the recycling of existing neurotransmitters or bind directly to neurotransmitter receptors and block or activate them, artificially altering mood. However, psychoactive drugs fall short of addressing the underlying causes of anxiety – hormonal and metabolic imbalances that emerge as our bodies attempt to adapt to chronic stress.
Recognizing and responding to underappreciated risk factors for anxiety disorders, such as elevated homocysteine and sex hormone imbalances, is an important aspect of any treatment regimen. Sadly, mainstream physicians often fail to address these subtleties, an oversight that undoubtedly contributes to the paltry 50% success rate of conventional anxiety treatments.
Anxiety is a multifaceted disorder, and must be addressed as such in order to achieve symptomatic relief. Clinical studies indicate that nutrients such as omega-3 polyunsaturated fatty acids, magnesium, and adaptogenic herbs like rhodiola can synergize with healthy eating habits and stress management techniques to effectively optimize the body’s stress response mechanisms and support healthy neurological communication. Moreover, compounds such as B-vitamins and amino acids can provide the raw materials the body needs to ensure proper neurotransmitter synthesis and signaling.
Anxiety disorders affect about 40 million American adults, or about 18.1% of the U.S. adult population over 18 years of age (Kessler 2010; Bulloch 2011; Roberson-Nay 2011). Nearly 15% of adults will experience an anxiety disorder in their lifetime (Kessler 2010; Bulloch 2011; Roberson-Nay 2011). By comparison, only 14.8 million American adults, or about 6.7% of the U.S. adult population, suffer from major depression. However, depression and anxiety are very much interrelated.
For up to 90% of all cases, anxiety disorders generally develop early in life—before the age of 35 with the greatest risk of onset between ages 10 and 25 (Kessler 2010; Kessler 2005a; Kessler 2005b). Also, women are twice as likely as men to suffer from generalized anxiety disorder (Kessler 2010; Kessler 2005a; Kessler 2005b). This last statistic suggests that an imbalance in female hormone levels during and after menopause, during menstruation, and after pregnancy may be tied to the etiology of anxiety. We will explore this connection in greater detail later in this protocol.
Types of Anxiety Disorders
Generalized anxiety disorder. Generalized anxiety disorder (GAD) is characterized by worry and tension in the absence of a real provoking environmental factor. A person with GAD is constantly apprehensive, anticipating disaster, and becoming overly concerned about their health, finances and work without cause.
People with GAD are frequently unable to relax and battle insomnia and poor concentration. Other symptoms may include restlessness, fatigue, irritability, muscle tension, high blood pressure, and sleep disturbances. Many people with mild GAD often manage to maintain their careers and function socially. However, severe cases can lead to job failure and avoidance of social situations.
GAD affects almost 6.8 million American adults (Weisberg 2009). Physicians diagnose GAD based upon the following criteria - an individual worrying excessively about everyday problems and exhibiting three or more GAD symptoms, on most days, for at least six consecutive months (Wyrwich 2011).
Panic disorder. Panic disorder is characterized by sudden attacks of fear and the sense of impending doom. A panic attack can cause elevated heart rate, sweating, dizziness, fatigue, shortness of breath, nausea, chest pain, and feelings of being cold and numb. In many cases these physical symptoms exacerbate the panic attack as the person may feel like they are dying or in terrible physical danger.
Panic attacks are often unpredictable and come on suddenly, but can be triggered by exposure to stimuli associated with past trauma, such as driving through an intersection where the person was involved in a major car accident. Panic attacks typically last about ten minutes. Episodes often appear without warning and with varying frequency. Panic disorder is very disabling, causing people to avoid places or situations that caused attacks before. As a result, people with panic disorder often lose their jobs or change their residence.
Nearly one third of people with panic disorder will become fearful of leaving their homes and develop agoraphobia, a fear of open spaces.
Panic disorder afflicts about 6 million Americans, and is also twice as common among women as men (Kessler 2010). The clinical definition of panic disorder is when a person experiences recurrent, unexpected panic attacks, at least one of which is followed by one or more of the following: persistent concern about future attacks, worrying about the implications of the attack, and/or a significant change in behavior related to the attacks (Roy-Byrne 2005).
Obsessive-compulsive disorder. Obsessive-compulsive disorder (OCD) is characterized by persistent, upsetting thoughts (obsessions) that can lead to anxiety and the use of ritualistic actions (compulsions) in an attempt to alleviate this anxiety (Bienvenu 2010; Merlo 2006).
A good example is a person obsessed with the presence of bacteria in the environment. In this case, a person with OCD may develop a compulsion to ritualistically and repetitively wash their hands, or engage in some other type of self-cleansing. The person with OCD does not find performing the ritual pleasurable, but it instead provides temporary relief from the anxiety.
While healthy people can demonstrate repetitive behaviors, such as double checking to see if the doors are locked, people with OCD perform rituals so repetitively that their behavior distresses them and can interfere with the performance of everyday tasks.
Approximately 2.2 million American adults suffer with OCD. Eating disorders, other anxiety disorders, and depression commonly accompany OCD. Recent research shows OCD affects men and women equally (Kessler 2010).
Phobia. Phobias are inexplicable and unjustifiable fears. Phobias may be a fear of certain objects or things. Social phobia, also known as social anxiety disorder, involves excessive self-consciousness and anxiety about everyday social situations. People with social phobia are chronically fearful of embarrassing themselves and being judged by others. They can experience dread weeks before a scheduled encounter or interaction, which may can interfere with everyday activities. Physical effects associated with social phobia can include blushing, sweating, nausea, and difficulty speaking.
About 15 million Americans are affected by social phobias (Kessler RC et al., 2010). Other anxiety disorders and depression may accompany social phobia. The clinical definition of social phobia is when a persistent fear of social situations causes people to either avoid them or experience them with great anxiety (Machado-de-Sousa 2010; Coelho 2010).
Posttraumatic stress disorder. Experiencing or witnessing a traumatic or terrifying life event such as a serious accident, violent crime, or natural disaster can precipitate a posttraumatic stress disorder (PTSD). People with PTSD may either relive the event in nightmares or have disturbing recollections of it during waking hours. Ordinary events can trigger flashbacks that may result in a loss of reality, causing the person to believe the event is happening again.
PTSD affects more than 5 million Americans and can occur at any age (Kessler 2010; Cantor 2009). Symptoms associated with PTSD can include an inability to sleep, hypersensitivity to external stimuli, feelings of detachment or numbness, and loss of memory surrounding the traumatic experience.
Physicians diagnosing PTSD consider whether the patient persistently re-experiences the traumatic event through memory, dreams, hallucinations, flashbacks, or physical reactions to internal or external triggers. For a diagnosis of PTSD, symptoms must be present for more than one month- but may occur years after the traumatic event (Kessler 2010; Cantor 2009).
Risk Factors and Associations
A variety of factors can increase the risk of anxiety disorder. Being female is a risk as it affects twice as many women than men. Age is another factor, with the greatest risk of onset affecting those between the ages of 10 and 25. Research shows children who are shy or likely to be the target of bullies are at a higher risk of developing anxiety disorders later in life. Anxiety disorders also tend to run in families, believed to have both a genetic and learned component. Lack of social connections, traumatic events, and certain medical conditions are also associated with an increased risk of anxiety disorders.
Anxiety can occur independently of or in conjunction with other psychiatric or medical conditions such as depression, chronic fatigue, cardiac disease, or respiratory compromise. Chronic anxiety is associated with a higher risk of illness and death from cerebrovascular and cardiovascular diseases such as hypertension, cardiac ischemia and arrhythmias. Also, chronic anxiety predisposes people to a range of neurological disorders (Culpepper 2009; Goodwin 2009; Gureje 2008). People with anxiety disorders are less able to deal with life’s occasional blows. Divorce, financial disaster, or other severe stressors may increase their risk of suicidal behavior (Ringbäck Weitoft 2005).
Homocysteine and the Methylation Cycle
Homocysteine is an intermediary within a metabolic cycle known as methylation. Methylation reactions, relying largely on B-vitamin cofactors (particularly, B6, B12, and folic acid), are critical for the proper synthesis of the neurotransmitters that play an important role in mood regulation.
As B-vitamin levels decline, the methylation cycle becomes impaired-leading to a concurrent increase in homocysteine levels (because it is no longer being recycled efficiently) and a disruption in neurotransmitter synthesis. The close relationship between neurotransmitter synthesis and homocysteine formation has lead some researchers to suspect that there is a link between homocysteine and mood. Indeed, studies suggest that levels of homocysteine are an effective marker for B-vitamin status, and that changes in homocysteine levels correlate with changes in mood.
Interestingly, homocysteine levels have predicted duration of PTSD (Levine 2008), suggesting that lowering homocysteine levels through supplementation with B-vitamins might reduce symptoms of mood disorders by freeing up metabolic resources involved in neurotransmission. Other studies have clearly tied genetic abnormalities such as a mutation in the folic acid-activating enzyme, MTHFR, to high homocysteine levels (and increased symptoms of mood disorders). This reinforces the notion that homocysteine metabolism is an important target in psychiatric imbalances (Coppen 2005). Supplementation with homocysteine-lowering B-vitamins was shown to relieve anxiety in 44 women with premenstrual anxiety (De Souza 2000).
Another compound involved in the methylation cycle is S-adenosylmethionine (SAM-e). SAM-e functions to donate methyl groups into the methylation cycle thereby facilitating the formation of neurotransmitters such as dopamine and serotonin. In clinical trials, SAM-e supplementation has been shown to be as effective as tricyclic antidepressants in treating depressive disorders (Papakostas 2009).
Given the role of healthy methylation in maintaining biochemical balances within the central nervous system, a target blood level of less than 7 – 8 µmol/L of homocysteine helps to ensure proper neurotransmitter metabolism and may balance mood during times of stress, depression and anxiety.
Impaired Stress Response: Anxiety, Depression, and the Hypothalamic-Pituitary-Adrenal Axis
Rarely does an anxiety disorder manifest itself alone. More typically, other mood disorders accompany it, particularly depression. In fact, depression and anxiety can both be viewed as manifestations of impaired stress response, the underlying physiology of which are both very similar.
When an individual experiences a stressor, physical or emotional, internal or environmental, the body initiates a complex system of adaptive reactions to help cope with the stress. This reactive response involves the release of glucocorticoids, also known as stress hormones, which stimulate adaptive changes in a variety of bodily systems.
Under short-term circumstances, stress-induced changes prioritize functions involved in escaping danger such as redirection of blood flow to the muscles from most other body parts, dilation of pupils, and inhibition of digestion for energy conservation. During this time, fatty acids and glucose (blood sugar) are liberated from storage sites into the bloodstream where they are readily available for utilization by the muscles. This is known as the fight-or-flight response. This reactive and adaptive protection system originates in the brain. When a threat is perceived by the hypothalamus (a brain region), chemical signals are sent to the pituitary gland (another brain region). The pituitary gland then sends chemical signals to the adrenal glands (endocrine glands atop the kidneys), which in turn releases the stress hormone cortisol. Cortisol then goes on to initiate many of the physiological changes that allow the organism to respond to the impending danger.
The fight-or-flight response is shared among nearly all animals in that the need to escape from imminent danger is paramount for the survival of the species. However, modern humans live in an environment filled with emotional stressors, such as financial worries, deadline pressures at work or school, as well as unnecessary physical stressors such as excessive caloric intake, obesity, and inactivity. All of these modern stressors chronically activate the hypothalamic-pituitary-adrenal axis, leading to adverse health consequences such as increased rates of cardiovascular disease, diabetes, and mood disorders like depression and anxiety.
The relationship between chronic stress, depression, and anxiety is complex and incredibly powerful. The chronic elevations in glucocorticoids (primarily cortisol) caused by excessive stressors in industrialized societies lead to actual physical changes in brain structure.
For example, dendrites, the branches of neurons that receive signals from other neurons, are shifted into less functional patterns upon chronic exposure to glucocorticoids. This has been documented in key brain regions associated with mood, short-term memory, and behavioral flexibility (Krugers 2010). Furthermore, glucocorticoids cause receptors for the mood-regulating neurotransmitter serotonin to become less sensitive to activation (van Riel 2003; Karten 1999). Other detrimental effects of chronic stress include both increased susceptibility to neuronal damage and impaired neurogenesis, the process by which new neurons are “born” (Krugers 2010).
Interestingly, emerging research suggests that psychoactive drugs, like those used in anxiety and depression, may stabilize mood not only by acting upon neurotransmitter levels, but by modulating the action of glucocorticoids receptors in the brain itself (Anacker 2011). These new findings strongly support the idea that in order to alleviate mood disorders, controlling stress response is an important aspect of treatment. Indeed, several genetic and epidemiological studies have linked excessive stress, and the inability to efficiently adapt to stress, to increased rates of anxiety and depression (Strohle 2003; Binder 2010;).
Diagnosis and Treatment of Anxiety Disorders
Because anxiety and depression may have similar or even overlapping symptoms, diagnosis and treatment of anxiety disorder can be difficult. A person can swing back and forth between anxiety and depression. However, as many of the same neural mechanisms are involved in both, sometimes treatment for one can be effective for the other.
While several screening tests are available to help determine the cause, type, and severity of anxiety, the diagnosis of anxiety disorders remains somewhat subjective and based on observation (Risbrough 2010). Once a doctor diagnoses an anxiety disorder, treatment will often integrate several approaches, including but not limited to diet and lifestyle changes, relaxation and massage therapy, psychotherapy, behavioral or cognitive-behavioral therapy, and drug intervention.
Cognitive-behavioral therapy involves modifying thought patterns that influence anxiety and fear. It helps individuals recognize cognitive distortions, exaggerated and irrational thoughts that produce reactions such an anxiety and panic. Special tools then help the person detect distorted thinking and replace distorted thoughts with more accurate ones. Cognitive-behavioral therapy is a first-line treatment (Hunot 2007; Tolin 2010) and is effective in treating all anxiety disorders (Hunot 2007; Tolin 2010).
Behavior therapy uses several techniques such as diaphragmatic breathing exercises and exposure therapy. Diaphragmatic breathing teaches people how to control the physical signs of anxiety by taking slow, deep breaths to help control hyperventilation. Exposure therapy relies on small, progressive exposures to the frightening trigger, helping people build confidence and control anxiety.
Drug therapy is often used in combination with psychotherapy to manage the biochemical and physiological abnormalities that produce anxiety, including alterations in the levels of serotonin, norepinephrine, and cortisol (the stress hormone).
Drug therapy can present a number of problems, including poor success rates, side effects, withdrawal symptoms, the development of increased tolerance to the drug, and only acting on a small component of the neurological mechanism involved in anxiety.
Pharmaceutical treatment of anxiety disorders involves manipulating or mimicking the action of neurotransmitters within the brain (typically GABA and serotonin; but sometimes dopamine and norepinephrine). However, these drugs usually do not resolve the over-activation of the hypothalamus-pituitary-adrenal axis that often underlies mood disorders.
Using medications to try to improve brain chemistry can offer relief, at least in the short term. However, medications neither restore normal levels of neurotransmitters, nor promote normal brain function. Instead, they manipulate the brain chemistry to achieve their desired effects.
Over time, the brain can get used to medications, resulting in them losing their effectiveness and requiring either higher doses or different drugs. Stopping them can frequently lead to withdrawal symptoms that feel worse than the original problem.
The following are types of drugs frequently prescribed to treat anxiety disorders:
Benzodiazepines act in part by modulating and extending the life of gamma-aminobutyric acid (GABA), an inhibitory (calming) brain neurotransmitter (Durant 2010). Benzodiazepines can relieve anxiety symptoms quickly. However, they can become habit forming. Some people develop a tolerance to them, requiring an increased dosage. When benzodiazepines are reduced or removed, some individuals can experience withdrawal symptoms, such as life-threatening seizures, confusion, memory loss, hyperanxiety, and reemergence of the original symptoms (Cloos 2009). Commonly prescribed benzodiazepines include Valium® (diazepam), Xanax® (alprazolam), Klonopin® (clonazepam), and Ativan® (lorazepam).
While these drugs are highly effective in calming anxiety, they may also be habit-forming – a factor that dramatically limits their usefulness and possibly their long-term safety. Many benzodiazepenes can also cause significant impairment, a highly undesirable effect.
Azapirones do not have the tolerance and dependency issues associated with benzodiazepines. These anti-anxiety drugs are partial serotonin receptor agonists. BuSpar® (buspirone) is an azapirone prescribed to treat general anxiety disorder. However, it may take several weeks before the effects of these drugs become apparent. Side effects can include nausea, headaches, and dizziness.
Antidepressants are sometimes effective for treating anxiety, especially when it occurs in conjunction with depression. Types of antidepressant drugs include selective serotonin reuptake inhibitors (SSRIs) as well as the less common tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). These drugs can have significant side effects. In 2004 the U.S. Food and Drug Administration (FDA) announced that the most popular class of antidepressants, SSRIs, must carry a strong black-box warning advising patients of the dangers of increased suicide among adolescents using SSRIs. Popular SSRIs include Prozac® (fluoxetine), Zoloft® (sertraline), Luvox® (fluvoxamine), Paxil® (paroxetine), and Celexa® (citalopram).
Beta-blockers such as Inderal® (propranolol) or Tenormin® (atenolol) are used primarily to treat heart conditions. However, they are often prescribed for social phobia to help reduce heart palpitations as well as other physical symptoms of anxiety. Side effects can include sexual dysfunction, slow pulse, drowsiness, fatigue, dry mouth, numbness or tingling of fingers or toes, dizziness, diarrhea, nausea, weakness, and cold hands and feet (Bourin 2002).
Pregabalin is an anticonvulsant drug that is sometimes used to treat anxiety. Its effects become apparent quickly-some studies suggest within one week. Also, it appears to be effective in preventing a relapse of anxiety disorder (Feltner 2011; Greist 2011) as well as helping ease withdrawal symptoms after discontinuation of benzodiazepine therapy (Hadley 2012). This drug often causes dizziness and drowsiness.