by Sara Gottfried, MD and Kirti Salunkhe, MD
Anxiety is on the rise, and it occurs more commonly in women compared with men. Identifying anxiety in patients, performing root cause analysis, and collaborating on natural solutions beyond a pill-for-every-ill requires clinicians to practice both the art and science of medicine. Fortunately, the biological underpinnings of anxiety involving the gene/environment interface, along with a growing evidence base of natural remedies, provide a strong foundation for us to help our patients.
One of the most important developments in our understanding of anxiety is that in many cases, anxiety arises from gut-brain axis disruption. We used to believe that mental health concerns like anxiety and depression were unrelated to health in the rest of the body, but emerging data on the microbiome, dysbiosis, increased intestinal permeability, and resulting inflammation demonstrate otherwise. There is a bidirectional conversation between the gut and brain, and disruption of homeostasis may create the chronic inflammation that can cause or exacerbate anxiety in vulnerable individuals.
The American Psychological Association (APA) defines anxiety as “an emotion characterized by feelings of tension, worried thoughts, and physical changes such as increased blood pressure.”1 Anxiety is a normal response to stress and is an expected part of life. Normal anxiety is an emotion that helps an organism defend against a wide variety of threats.2 However, when it becomes difficult to control and affects the activities of daily living, anxiety can become disabling. Anxiety disorders are characterized by anxious apprehension or fear in response to a perceived threat.3 Anxiety, or anxious apprehension, is a “future-oriented” state in which the patient is concerned about potential threats, while fear occurs in response to an immediate threat.4
In 2015, the World Health Organization (WHO) estimated over 300 million people globally are affected by anxiety, which was ranked as the sixth-largest contributor to global disability.5 These figures reflect a 15% increase since 2005 and have been attributed to population growth and ageing.6
In the US, anxiety disorders are the most commonly diagnosed mental illness, affecting about 40 million adults aged 18 years or older—about 18% of the overall population—but only about 37% of people suffering with anxiety disorders receive treatment.1,7 According to a recent study commissioned by the Anxiety and Depression Association of America (ADAA), anxiety disorders cost the US more than $42 billion a year—almost one-third of the $148 billion total mental health bill for the US.8
The relationship between anxiety and women
Women experience a markedly greater prevalence of anxiety disorders than men, with a female-to-male ratio for any lifetime anxiety disorder being 3:2.9 Anxiety disorders also occur earlier in women, as compared to men, and may be diagnosed with several other psychiatric conditions; the most common being depression.10
Emerging evidence by imaging studies has shown there are several structural, and functional, gender-specific differences in areas of the brain specific to anxiety.11 These include the prefrontal cortex, hippocampus, and extended amygdala complex.11 A recent meta-analysis found that negative emotions were consistently associated with a stronger activation of the left central amygdala, thalamus, hypothalamus, and other brain regions in women, whereas positive emotions activated the left amygdala more in men compared to women.11
Interestingly, data show women have greater pain sensitivity than men, and it is a phenomenon due to thalamocortical processing or emotional appraisal of the stimulus and not spinal nociceptive activity.12,13 This disappears when trait anxiety is controlled for and likely depends on an interaction of hormonal fluctuations and exposure to stressors.14
In women, more often than in men, anxiety disorders are usually identified as a preexisting condition—before the onset of a major depressive episode—and anxiety often remains a major comorbidity with depression.15 Recent studies have also shown that anxiety disorders occurring as early as childhood and adolescence are strong predictors of later depressive episodes and, in girls, of later suicide attempts.16
As anxiety disorders are much more common in girls than in boys, and adolescent anxiety is associated with increased rumination in girls but not in boys, there is an urgent need to identify, prevent, or treat anxiety disorders in women as early as possible so as to be able to reduce the risk of later affective disorders.15
Anxiety disorders affect one in eight children.17 Research shows that untreated children with anxiety disorders are at higher risk to perform poorly in school, miss important social experiences, and engage in substance abuse.17 The types of anxiety disorders most commonly noted in children include:17
- Separation anxiety disorder—found in about 4% of children between ages 18 months to 3 years with reports of excessive anxiety away from home or when separated from parents or caregivers
- Generalized anxiety disorder—diagnosed when young children worry excessively about various things including grades, family issues, relationships with peers, and sports performance
- Social anxiety disorder—characterized by intense fear of social and performance-related activities. Other anxiety disorders in children can include selective mutism, obsessive compulsive disorder, posttraumatic stress disorder, and specific phobias.13
Figure 1: Anxiety disorders across the female lifespan12
In female children, emerging research indicates specific behavioral and emotional symptoms in childhood are strongly linked to development of future anxiety disorders. Rouqette and colleagues evaluated a cohort of 932 young girls from an ongoing prospective study of kindergarteners in Quebec, Canada.18 Baseline data was acquired from participants aged 6 -10 years and was analyzed to assess for presence of mental disorders by age 15 and/or 22 years.14 Results revealed, at follow-up, more than 30% of participants had developed anxiety disorders. Furthermore, five major symptoms emerged as being strongly associated with the development of future anxiety disorders. These symptoms were:14
Interestingly, the study also looked at symptoms in early childhood that may be linked to major depression in later life but found none.14
During puberty, girls are especially vulnerable to the development and occurrence of anxiety disorders. It is during this time that increased rates of anxiety emerge for girls as they enter adolescence.19,20 Results from a recent cohort study of nearly one million Danish youth found that prior to puberty, males had higher rates of anxiety disorders, but this trend reversed with puberty, showing females had higher rates of anxiety disorders.21 In the US, Costello and colleagues conducted a longitudinal community study that annually assessed 1,420 youth from age 9 through 16 years and found a higher prevalence of most anxiety disorders in females.22
Puberty in women is marked by the start of menses (menarche) and its accompanying monthly fluctuations in the ovarian steroid hormones estradiol, progesterone, and their metabolites. These hormones are neuroactive, impacting neurotransmission at a number of receptors in the central nervous system (CNS).12 It is thought that hormonal fluctuations, initiated by onset of puberty, may play a role in the etiology of anxiety disorders; however, further confirmatory research in this area is still needed. Puberty is a time of increased psychosocial stressors, which may further contribute to occurrence of anxiety symptoms.12
Recent research findings have shown that as many as 80% of reproductive-aged women experience at least one physical, mood, or anxiety symptom during the luteal phase, and approximately 20% experience significant premenstrual symptoms.23 A smaller subset of women, 5–8%, experience premenstrual dysphoric disorder (PMDD), a mood disorder with a strong anxiety symptom component.19 Nillni et al. suggest common biopsychosocial pathways between anxiety disorders and PMDD.24
Estrogen and progesterone levels rise exponentially during pregnancy and drop rapidly within hours of delivery. Data have shown that psychosocial stress during the perinatal period can have profound effects on both the woman and fetus, with implications for development through childhood and into adulthood.25,26 O’Donnell et al. showed women with the most severe anxiety during pregnancy had children with a twofold increased risk for a behavioral or mental health disorder, after controlling for confounders including postnatal maternal mood and paternal pre- and postnatal mood.27
Results from a recent systematic review demonstrated an elevated prevalence of anxiety disorders during pregnancy (including generalized anxiety disorder, phobias, and panic disorders) and a meta-analysis suggested there may be an association between anxiety disorders and low birthweight or preterm births.28,29
With the aging of the population, it is estimated that 1.2 million women worldwide will be going through perimenopause or will be postmenopausal by the year 2030.30 Estimates of the prevalence of mood disorders during this phase of life are inconsistent and vary greatly but range from 12% to as many as 50% of women who will experience mood symptoms or disorders during this transitional time in their lives.31
Many studies have focused on risk of depression during the perimenopausal transition, but few have systematically investigated the relationship between menopause and anxiety even though the prevalence of anxiety during this transitional phase is substantial. As many as 51% of women aged 40–55 years report occasional tension, nervousness, or irritability, and 25% report frequent irritability or nervousness.32,33 During the menopausal transition, anxiety is associated with dysregulation of the monoaminergic pathways in the central nervous system.34 Fluctuations in estrogen levels during perimenopause can alter the serotonergic and noradrenergic systems. Some studies suggest that changes in mood and serotonin transmission are associated with hormonal status.35,36 The variability in estrogen levels rather than the diminished levels, per se, may be associated with mood symptoms.37 Research has shown that fluctuating levels of estradiol also increase the risk of vasomotor symptoms (VMS), which positively correlate with anxiety during perimenopause. It is also possible that impaired gamma-aminobutyric acid (GABA) receptor modulation of the hypothalamus-pituitary-adrenal axis during the menopausal transition may prolong the stress response, thereby increasing anxiety.28
During menopause women experience physical changes and somatic symptoms that are not only uncomfortable but also anxiety-provoking. Although cognitive changes that frequently occur during perimenopause are not typically associated with neurodegeneration, they may lead to undue worry about early-onset dementia.28 As there are parallels and overlapping symptoms between hot flashes and panic attacks, women prone to panic attacks cannot always differentiate between the two.28 Additional factors that contribute to late-life anxiety are poor coping skills, childlessness, financial strain, poor perceived health, and prior history of anxiety or trauma.28,29
Is it anxiety or depression?
Anxiety and depression are health conditions that are often found coexisting together. Over 50% of people diagnosed with anxiety are also concurrently diagnosed with depression, but in order to appropriately treat anxiety (or depression), it is important to be able to differentiate between the two conditions (figure 2).38,39
Figure 2: Differences between anxiety and depression38-40
When the two conditions are compared, there is some overlap in symptoms. Sleep problems, trouble concentrating, and fatigue are commonly found in both anxiety and depression. Irritability may also manifest in forms of anxiety or depression. However, there are some distinguishing features.38,39 People with depression move slowly, and their reactions can seem flattened or dulled.38,39 People with anxiety tend to be more keyed up, as they struggle to manage their racing thoughts. Another distinguishing feature is the presence of fear about the future in people with anxiety. Depressed people who do not have anxiety are less likely to be concerned about future events, as they may be resigned into believing that things will continue to be bad.38,39
A. Etiology of anxiety
Anxiety disorders occur when a person regularly feels disproportionate levels of distress, worry, or fear over an emotional trigger.1 Identifying the reason(s) behind complaints and/or symptoms of anxiety can be the key to successful treatments.
The circuits and regions of the brain associated with anxiety disorders have recently begun to be understood with the development of functional and structural imaging.8 In the brain, the structure known as the amygdala appears to be key in modulating fear and anxiety.8 Patients with anxiety disorders often show heightened amygdala response to anxiety cues.8 The amygdala and other limbic system structures are connected to prefrontal cortex regions.8 Hyperresponsiveness of the amygdala may relate to reduced activation thresholds when responding to perceived threats.41,42 Anxiety and anxiety disorders have a complicated network of causal factors, many of which overlap and can be combined in some individuals.43 Some of the more common causes for anxiety are illustrated, and briefly described, below (figure 3).38,39
Figure 3: Common causes of anxiety disorders38,39
Genes and stress are widely acknowledged to be the
major contributors in psychopathology. Data show anxiety is approximately 4-6 times higher in first-degree relatives.4 In twin studies, heritability estimates have been in the range of 30-50%.44
The majority of genetic association studies of anxiety disorders have been candidate gene studies focused on genes related to monoaminergic neurotransmitter systems, neuropeptides, and hypothalamic-pituitary-adrenal (HPA) axis function, or as we describe it in Functional Medicine, the hypothalamic-pituitary-adrenal-thyroid-gonadal (HPATG) axis.
Of the anxiety disorders, panic disorder (PD) has received the most attention.38 In candidate gene studies of panic disorder, several loci have shown nominal association in independent samples, which include the 5HTTLPR polymorphism of SLC6A4, the val158met polymorphism (rs4680) of COMT, and a promoter length polymorphism of MAOA.45 Nominally significant results have also been reported between panic disorder (or panic attacks) with variants in other monoaminergic genes (HTR1A and HTR2A), GABA receptor genes (GABRB3 and GABRA5), stress hormone genes (CRHR1), neuropeptidergic/neurotrophic genes (BDNF, NPSR1, ACE), and others, but a recent comprehensive meta-analysis of the 23 most widely studied candidate variants found no robust associations.46
Fewer candidate gene studies and no genomewide association analyses of subjects (GWAS) have been reported for social anxiety disorder (SAD), phobic disorders, or generalized anxiety disorder (GAD).12 Nominally significant associations with SAD have been reported for several candidate loci including COMT, CTNND2, and CNTNAP2.46-48
Comorbid or concurrent medical/health issues in some individuals may lead to symptoms of anxiety, and in some cases, anxiety complaints and symptoms may be the first indication of an underlying medical condition.9 Common medical causes for anxiety include:9
Furthermore, results from recent research suggests that abnormalities in specific areas of the brain may be involved in the pathophysiology of some anxiety disorders. Brambilla and colleagues conducted a systematic review of the literature from 1996-2002 for all anatomical MRI studies evaluating mood and anxiety disorder patients.49 They found anatomical abnormalities in the orbital frontal regions and basal ganglia in those patients diagnosed with obsessive compulsive disorder, the temporal lobe was found to be abnormally reduced in panic disorder, and abnormal hippocampal shrinkage was demonstrated in posttraumatic stress disorder.50
Studies on brain chemistry have shown that abnormal functioning of the major neurochemicals such as serotonin, norepinephrine, dopamine, and GABA systems as well as abnormal chemoreceptor reactivity leads to anxiety (table 1)50,51
Table 1: Major neurochemicals associated with anxiety50,51
In women, the “fight-or-flight” response is activated more readily than in men and stays activated longer—partly as a result of the action of estrogen and progesterone.10 Furthermore, there is some evidence to suggest that the female brain does not process serotonin as quickly as the male brain. Recent research noted that women are more sensitive to low levels of corticotropin-releasing factor (CRF), the hormone that organizes stress responses, making them twice as vulnerable as men to stress-related disorders.10
Results from studies have shown that specific anxiety disorders including GAD, PD, and posttraumatic stress disorder have all been associated with substance abuse.52 Grant et al. conducted an epidemiologic study on more than 43,000 adults regarding associations between mood disorders and substance abuse.53 Their data showed that approximately 17.7% of respondents with a substance abuse disorder in the prior 12 months also met criteria for an independent anxiety disorder, and 15% of those with any anxiety disorder in the past 12 months had at least one cooccurring substance abuse disorder.54 Based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, Conway and colleagues found the relationship between anxiety disorders and drug use disorders was stronger than the relationship between anxiety and alcohol use disorders.54 Associations between substance abuse disorders and specific anxiety disorders were also significantly positive (p < 0.05).55 The odds ratios for abuse were more positive than those for dependence and were more positive for women as compared to men.55 Marijuana use disorders were the most common drug use disorder (15.1%), followed by cocaine (5.4%), amphetamine (4.8%), hallucinogen (3.7%), and sedative (2.6%) use disorder in those with anxiety disorders.55
The impact of trauma on anxiety was evaluated in a study by Kinderman and colleagues, who analyzed the responses of over 32,000 participants, aged 18–85 years, who completed an online survey to explore the causes and consequences of stress.55 The study found that traumatic life events were the single biggest determinant of anxiety and depression, followed by a family history of mental illness and income and education levels.55 Relationship status and social factors made smaller—but still significant—contributions to stress. However, the results also revealed that a person’s thinking style was as much a factor in the level of anxiety and depression a person experienced.55
Research into environmental factors and their effects on anxiety suggests that traumatic events in early life can make a person vulnerable to anxiety disorders.38 Parenting style, family environment, and culture may influence susceptibility to developing generalized anxiety disorder.39 Traumatic and stressful events, such as abuse, the death of a family or friend, or divorce, may also contribute to anxiety, and in addition, the use of (and withdrawal from) addictive substances such as alcohol, caffeine, and nicotine, often used to “self-medicate,” can further increase anxiety.56,57
Figure 4: Major types of anxiety disorders58
B. Types of anxiety disorders
Another key difference between depression and anxiety is that one is a single condition and the other is a group of conditions.38 Depression is essentially one condition, even though it manifests with many different symptoms that may differ between people.38 Anxiety, on the other hand, is considered an “umbrella term” that may cover a variety of specific conditions (figure 4).58
Social phobia disorders: Also known as social anxiety disorders (SAD), this condition is characterized by overwhelming anxiety and excessive self-consciousness in everyday social situations including eating or drinking in front of others or speaking in formal or informal situations.1,10
Generalized anxiety disorder: Also referred to as GAD, this condition is characterized by chronic anxiety, exaggerated worry, and tension even with little or any provocation.1,10
Panic disorder: This condition is commonly characterized by unexpected and repeated episodes of intense fear accompanied by physical symptoms that may include chest pain, heart palpitations, shortness of breath, dizziness, or abdominal distress.1,10
Obsessive compulsive disorder: Also known as “OCD,” this condition is characterized by recurrent, unwanted thoughts or obsessions and/or repetitive behaviors or compulsions, such as hand washing, counting, checking, or cleaning in the hopes that performing them will prevent further obsessive thoughts or make them go away. Performing these actions provides only temporary relief, and not performing them markedly increases anxiety.1
Posttraumatic stress disorder: Often referred to as “PTSD,” this condition is a disorder that may develop after exposure to a frightening event or ordeal in which severe physical harm occurred (or was threatened) such as violent personal assaults, natural or human-caused disasters, accidents, or combat.1
C. The gut-brain axis, anxiety, and the vagus nerve
The gut-brain axis is a complex network that integrates the colonies found in the microbiome with the nervous system and brain. The gut microbiome influences the function of the brain by modulation of both immune and endocrine systems, HPATG axis, neurotransmitter pathways, and growth factors.59 Emerging evidence from preclinical and human studies has reiterated scientific understanding that the gut microbiome not only affects the digestive, metabolic, and immune functions, particularly in females, but also regulates the mental and emotional state, bidirectionally, via the gut-brain axis.60 The gut-brain axis includes the brain, the spinal cord, the autonomic nervous system (ANS), comprised of the sympathetic, parasympathetic, and enteric nervous systems, as well as the HPATG axis.61
The gut microbiota has an important impact on the gut-brain axis by directly influencing neuroendocrine and metabolic systems.62 Emerging data support the role of microbiota in influencing anxiety and depressive-like behaviors.63 Results from studies conducted on germ-free animals demonstrated that microbiota influence stress reactivity and anxiety-like behavior and regulate the set point for HPATG activity. Thus, these animals generally show a decreased anxiety and an increased stress response with augmented levels of ACTH and cortisol.64,65
A growing body of work is implicating the microbiome and vagus nerve in a variety of psychological processes and neuropsychiatric disorders.66,67 These include mood and anxiety disorders, neurodevelopmental disorders such as autism spectrum disorder and schizophrenia, and even neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases.68
The vagus nerve, the longest nerve in the body, the tenth cranial nerve (of 12 pairs of cranial nerves), extends from its origin in the brainstem, through the neck and thorax down to the abdomen and has both afferent (80%) and efferent (20%) fibers.12 Because of its long path in the human body, the vagus has been called the “wanderer nerve.”69 The vagus nerve is responsible for the regulation of internal organ functions, such as digestion, heart rate, and respiratory rate, as well as vasomotor activity and certain reflex actions, such as coughing, sneezing, swallowing, and vomiting.70 Its activation leads to the release of acetylcholine (ACh) at the synaptic junction with secreting cells, intrinsic nervous fibers, and smooth muscles.71 ACh binds to nicotinic and muscarinic receptors and stimulates muscle contractions in the parasympathetic nervous system (PNS).
Data have suggested the vagal afferent pathways are involved in the activation/regulation of the HPATG axis, which in turn coordinates the adaptive responses to stressors of any kind.72 Environmental stressors, as well as elevated systemic proinflammatory cytokines, activate the HPATG axis through secretion of the corticotropin-releasing factor (CRF) from the hypothalamus.73 The CRF released stimulates adrenocorticotropic hormone (ACTH) secretion from pituitary gland.74 This stimulation, in turn, leads to cortisol release from the adrenal glands. Cortisol is a major stress hormone that affects many human organs, including the brain, bones, muscles, and body fat.74
If the vagus nerve is unable to activate the relaxation signal, the sympathetic nervous system remains active and will lead to increased symptoms of anxiety and could lead to impulsive (and possibly detrimental) behaviors.67
The vagus nerve also represents the main component of the parasympathetic nervous system (PNS).74 The PNS is one of three divisions of the autonomic nervous system (ANS), the other two being the sympathetic nervous system (SNS) and the enteric nervous system (ENS) (figure 5).61
Figure 5: Autonomic nervous system61
The PNS oversees a vast array of crucial bodily functions, including control of mood, immune response, digestion, and heart rate.67 The vagus nerve is responsible for establishing connections between the brain and the gastrointestinal (GI) tract, sending information about the state of the GI tract to the brain.68
Research has shown that the vagus is able to sense the microbiota and then transfer this gut information to the central nervous system, where it is integrated and then subsequently generates an adapted, or inappropriate, response as required.75 Increasing vagal tone activates the parasympathetic nervous system and allows the individual to relax more quickly after a stressful situation, which results in a positive impact on emotional balance and overall health.68,69
The enteric nervous system (ENS) produces more than 30 neurotransmitters and has more neurons than the spine.55 Hormones and peptides that the ENS releases into the blood circulation cross the blood–brain barrier (e.g., ghrelin) and can act synergistically with the vagus nerve, for example to regulate food intake and appetite.76
The gut is an important control center of the immune system, and the vagus nerve has immunomodulatory properties.77 As a result, the vagus plays important roles in the relationship between the gut, the brain, and inflammation.68 There are also new treatment options for modulating the brain–gut axis, for example, vagus nerve stimulation (VNS) through various means such as exposure to cold, diaphragmatic breathing, and meditation techniques.61 These treatments have been shown to be beneficial in mood and anxiety disorders and in other conditions associated with increased inflammation.78,79
D. Nutritional impacts on anxiety disorders
A relatively new field of study is that of nutritional psychiatry, and it is one that holds promise for addressing conditions related to mental and emotional health. Felice N. Jacka, PhD, a leader in this nascent field, notes that a consistent evidence base from the observational literature confirms that the quality of individuals’ diets is related to their risk for common mental disorders.80
An increasing body of data and information confirm the utility of selected nutraceuticals as adjunctive treatments for mental disorders and as monotherapies for conditions such as depression, ADHD, and anxiety, to name a few.77 New studies, focused on understanding the biological pathways that mediate the observed relationships between diet, nutrition, and mental health, are pointing to the immune system, oxidative biology, brain plasticity, and the microbiome-gut-brain axis as key targets for nutritional interventions.77
However, despite anxiety disorders’ being the most commonly diagnosed mental health disorder (when compared to depressive mood disorders), there are a dearth of robust clinical data regarding the impact of nutrition on anxiety.81 There are limited randomized controlled trials evaluating the effects of foods, nutrition, or specific nutritional supplements on anxiety disorders in general, or in specific anxiety disorders.82
In 2009, Jacka et al. assessed a cohort of the Hordaland dataset (a large Scandinavian epidemiologic study) and found that overall dietary pattern does correlate with anxiety: Specifically, increased consumption of Western foods, or a more modern dietary pattern, correlated with an elevated risk for anxiety disorder by about 25%-29%.82 Additionally, in another analysis, the group found a correlation between anxiety and the nutrient choline.83 Patients who consumed the lowest amount of choline had about 33% higher risk of having anxiety disorder.84
Another important nutrient with regards to mental health are the long chain omega-3 fatty acids. Kiecolt-Glaser et al. evaluated the effects of supplementing omega-3 fatty acids on anxiety and inflammation in a 12-week study with 68 medical students.84 The students were randomized to receive either omega-3 fatty acids (2.5 g/day 2,085 mg EPA/348 mg DHA) or placebo. Assessments included Beck Anxiety Inventory scale and serum IL-6 for inflammation.85 Results showed those students assigned the omega-3 fatty acid intervention showed a 20% reduced level of anxiety along with 14% reduction in IL-6 levels as compared to those receiving placebo.85
Beyond specific nutrients, fermented foods and their influence on the microbiome have also been a subject of interest regarding potential impact on anxiety states. Results from a recent study by researchers from the University of California, Los Angeles, and France looked at fermented milk products, including kefir and yogurt, on brain activity.85 The investigators used functional MRIs to compare individuals who ingested the fermented dairy product on a daily basis with control participants.85 The results showed a significant influence of the fermented foods on brain circuitry, and the investigators surmised that ingestion of fermented foods can alter some of the circuitry that processes somatic senses and emotions—potentially, this may be quite useful in patients with anxiety.85
Along those findings, a 2015 cross-sectional study looked at neuroticism, fermented foods, and social anxiety.86 The results indicated those individuals who had higher neuroticism but ate more fermented foods reported less social anxiety.86
Specific health conditions related to nutritional issues may also impact anxiety disorders. Research has shown that there is an increased prevalence of anxiety in patients of celiac disease (CD).87,88 Data suggests that up to 22% of patients with CD develop neurologic or psychiatric dysfunction, and as many as 57% of people with neurological dysfunction of unknown origin test positive for antigliadin antibodies (found in CD).89,90
Researchers followed 35 patients with CD for 1 year after the patients had been placed on a gluten-free diet.91 At baseline, approximately 72% of the participants had significant levels of anxiety, compared with 24% of 59 healthy controls.91 At the end of the study, patients eating a gluten-free diet reported a significant drop in anxiety of 25%, with no significant change in the control group.91 Furthermore, the gluten-free diet did not improve the depressive symptoms in those patients with CD.91 The implication is that a gluten-free diet can improve anxiety but not necessarily depression.
Type 2 diabetes (T2D) is another medical condition that is often associated with anxiety. A recent study found that there is a 20% increased likelihood for people with T2D to have concurrent anxiety as opposed to those without diabetes.92 To confirm this, Anderson and colleagues conducted a meta-analysis of the literature regarding anxiety and glycemic control.93 Upon reviewing data the investigators found significant correlations between hyperglycemia and anxiety.93
E. Common complaints, signs, & symptoms
GAD is one of the most common mental disorders clinicians will see in their clinics.94
Patients with anxiety disorders may present with varying complaints depending on the type of anxiety disorder; clinicians may notice different symptoms as well. These have been categorized broadly into the two most common types of anxiety disorders (generalized anxiety disorder and panic disorder) with their relevant complaints (and physician noted signs and symptoms) detailed in the table below (table 2).
Table 2: Comparison of clinical presentations of GAD and PD95
F. Management & treatment options
Conventional medical treatment usually consists of psychotherapy combined with pharmacotherapy.96 Antidepressant agents are the drugs of choice in the treatment of anxiety disorders, particularly the newer agents, which have a safer adverse effect profile and higher ease of use than the older tricyclic antidepressants (TCAs). The most commonly utilized are the selective serotonin reuptake inhibitors (SSRIs). However, some physicians find that the older antidepressants, including TCAs and monoamine oxidase inhibitors (MAOIs), to be effective in the treatment of some anxiety disorders.96 Behavioral therapy and cognitive behavioral therapy (CBT) have also demonstrated efficacy through controlled studies.97 Computerized CBT has been recommended for panic and phobia by the National Institute for Health and Clinical Excellence guidelines (NICE).98
Lifestyle, Functional, and integrative healthcare practitioners treat underlying causes of illnesses and not just symptoms. The holistic approach of these medical modalities involves assessments of clinical imbalances by a patient’s medical history, physical examination, and lab tests.
Lifestyle medicine and integrative physicians encourage lifestyle and behavioral changes in their patients. This includes the addition of regular physical exercise and dietary modifications. In patients of anxiety, the lifestyle and integrative medicine practitioner often recommends the implementation of mindful exercise techniques such as yoga, tai chi, or qigong to stimulate the body’s production of serotonin and endorphins.99 Dietary modifications include adding nutrients such as omega-3 fatty acids and probiotics to a mainly plant-based or Mediterranean diet to provide essential nutrients to help production of neurotransmitters and reduce anxiety.100
Functional Medicine practitioners also look into the genetic makeup of a patient and review environmental factors such as diet, physical activities, traumatic experiences, and exposure to toxic substances. Furthermore, Functional and many integrative medicine physicians often start treating anxiety by addressing HPATG dysfunction and adrenal imbalance to reduce stress.100 Meditation, exercise, reinforcing individual circadian rhythms (through sleep), and improving gut health by appropriate dietary intake are the pillars of this medical modality in treating anxiety.100 Adding fermented foods, removing unnecessary medications, and addressing nutrient deficiencies are also important.100
Physicians practicing natural medicine are skilled at helping their patients conquer anxiety using comprehensive natural treatment plans that incorporate dietary and lifestyle therapies along with scientifically supported natural remedies (and pharmaceuticals as needed) for anxiety. Naturopaths usually begin by addressing any underlying contributing factors causing or exacerbating the anxiety.101 These can include nutrient deficiencies, food intolerances (gluten in particular), dysglycemia, caffeine, drug and alcohol abuse, as well as history of trauma. Next, managing stress and optimizing lifestyle habits such as sleep, exercise, and increased consumption of fresh fruits, vegetables, and omega-3-rich foods.102
Table 3: Summary of recommended treatment options for adult anxiety95,96,99-102
Integrative internist Myles Spar, MD, MPH acutely observed the following difference in his male versus female patients with anxiety: Men with anxiety reach for the beer bottle, while women with anxiety reach for the phone. Personalized lifestyle medicine involves much more than just social connection or a way to ease the overactive HPATG axis—it involves addressing the root cause in a systems biology framework in addition to mainstream medicine mechanistic understandings and therapy options. As always, take care and consult with the prescribing pharmacist before combining pharmaceuticals with supplements and other natural ingredients to avoid any possible untoward interactions or adverse events.
The recent evidence linking the gut-brain-microbiome axis in anxiety is increasingly an important factor to consider in your patients with anxiety. Mental health reflects both gut and brain health, and vice versa. Foundational elements of personalized lifestyle medicine, like addressing nutrition, sleep, movement, HPATG dysregulation, and social genomics and connection, are essential to creating a more adaptive stress response.
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Sara Gottfried, MD is a board-certified gynecologist and physician scientist. She graduated from Harvard Medical School and the Massachusetts Institute of Technology and completed residency at the University of California at San Francisco. Over the past two decades, Dr. Gottfried has seen more than 25,000 patients and specializes in identifying the underlying cause of her patients’ conditions to achieve true and lasting health transformations, not just symptom management.
Dr. Gottfried is the President of Metagenics Institute, which is dedicated to transforming healthcare by educating, inspiring, and mobilizing practitioners and patients to learn about and adopt personalized lifestyle medicine. Dr. Gottfried is a global keynote speaker who practices evidence-based integrative, precision, and Functional Medicine. She recently published a new book, Brain Body Diet and has also authored three New York Times bestselling books: The Hormone Cure, The Hormone Reset Diet, and Younger.
Kirti Salunkhe, MD originally trained and practiced in India as an Ob/Gyn, later joining Intermountain Healthcare in Salt Lake City, Utah, as a research physician in the Interventional Cardiology division. She was a member of University of Utah’s Selection Committee for medical students and postgraduate advisor at the College of Nursing. Dr. Salunkhe was actively involved in industry-sponsored and original clinical research activities and mentoring research assistants, and she founded a pilot program increasing awareness of heart health in women and special populations of the Intermountain region.
Dr. Salunkhe has served as Sr. Medical Director for medical marketing and communications divisions of WPP, Interpublic Group, and Publicis—the top 3 global advertising holding companies—developing academic programs, digital initiatives, and other enduring materials for peer-to-peer education, publications, and promotional strategies in Cardiology, Nutrition, and Women’s Health. Most recently, Dr. Salunkhe was Sr. Director, Medical Affairs for Metagenics and the Metagenics Institute and Director of the former Functional Medicine Research Clinic in Gig Harbor, WA. Dr. Salunkhe has published in numerous peer-reviewed journals, coauthored several book chapters, and presented original research at both national and international conferences.