Anxiety

Anxiety is one of the most common mental health conditions in the world, with more than 40 million Americans (18% of the population) suffering from an anxiety disorder every year, according to the Anxiety and Depression Association of America (ADAA). Worldwide, almost 12% of people are affected by anxiety every year, and up to 30% meet the diagnostic criteria for an anxiety disorder at some point in their lives.

The ADAA further reports that, although anxiety disorders are considered treatable, only 36% of those affected go on to receive treatment. This is concerning because, in the absence of treatment, most anxiety disorders persist indefinitely.

Symptoms of an anxiety disorder include:

  • Chronic fear and worry
  • Hypervigilance
  • Elevated blood pressure
  • Increased heart rate
  • Trembling limbs
  • Fatigue
  • Irritability

Like depression, anxiety is the result of a complex interplay of genetics and environmental factors, with child abuse, family history of mental illness, substance abuse, and poverty, associated with increased risk for the development of an anxiety disorder. Notably, anxiety disorder often cooccur with other mental health disorders, such as depression, substance use disorder, and various personality disorders. Currently available treatments include selective serotonin reuptake inhibitors, benzodiazepines, and beta blockers, each of which come with a host of potential side effects, ranging from weight gain and hair loss to physical dependence and mania.

There are several different types of anxiety disorders, with the most common being generalized anxiety disorder (GAD) and social anxiety disorder (SAD), sometimes called social phobia.

Generalized Anxiety Disorder

According to the DSM-5, GAD is characterized by excessive, uncontrollable worry about events and activities which interferes with daily functioning. It is common for those who suffer from GAD to spend inordinate amounts of time agonizing over apparently mundane issues, including their health status, their financial status, relationships with family and friends, as well as their work performance. Approximately 2% of American and European adults experience GAD in any given year, with a lifetime incidence of close to 4%. Interestingly, women are twice as likely to be diagnosed with GAD as men.

GAD has been linked to disrupted functional connectivity of the amygdala. In one study, researchers found that connections between the central nucleus of the amygdala and brainstem, hypothalmus, and cerebellum were less functionally distinct than in healthy controls, with excess grey matter in the central nucleus. Additionally, there appeared to be diminished connectivity with the insula and cingulate areas of the brain (responsible for modulating the salience of sensory inputs), along with greater connectivity between the amygdala and the parietal and prefrontal cortex (responsible for executive functioning). Researchers speculate that this occurs because those with GAD attempt to modulate their overactive fear response with compensatory cognitive strategies. Overall, hyperactivity of the HPA axis appears to make the fear response non-specific, which over time becomes more and more ubiquitous as additional sensory experiences become linked with anxiety and the perception of threat.

Genetics are thought to be responsible for approximately a third of the risk for developing GAD, with onset often linked to certain life stressors in the presence of a specific variant of the DYNLL2 (dynein light chain 2) gene; the same study linked ALAD (δ-aminolevulinate dehydratase) to the development of SAD. Overall, GAD is six-times more common in children of those with the condition as compared to the general population.

In addition to genetics, substance-induced GAD is also common, with long term use of benzodiazepines, alcohol and nicotine all associated with the development of the disorder. This may be due to the effects these substances have on various neurotransmitter systems, as well as on levels of inflammation, oxidative stress, mitochondrial function, and neurogenesis, all mechanisms thought to be related to the development of GAD.

Unsurprisingly, environment is also a significant contributor to the development of GAD, with higher rates of diagnosis in individuals from low- to middle-socioeconomic status, as well as those who have been divorced, unemployed, or had lower levels of educational attainment.

Social Anxiety Disorder

SAD, on the other hand, is defined by a high degree of fear in one more types of social situations, to the point that both quality of life and functioning are impaired. Symptoms – which include all those typical to other anxiety disorders, as well as blushing, stammering, and nausea – are triggered by real or perceived scrutiny from others, particularly when the potential for public judgement exists.

According to ICD-10 guidelines, the main diagnostic criteria of social phobia “are fear of being the focus of attention, and fear of behaving in a way that will be embarrassing or humiliating”. The National Comorbidity Survey – which polled more than 8000 respondents – found that almost 8% of Americans suffer from SAD in any given year, with more than 13% of the population suffering from the condition at some point in their lives (making it the third most common mental health disorder, after depression and alcohol abuse). Importantly, SAD appears to have an early age of onset, with more than 50% of sufferers developing it by age 11, and 80% by age 20; this makes it likely that suffers are particularly vulnerable to developing other mental disorders, namely substance abuse and depression.

Although the exact neurobiological mechanisms underlying SAD are not yet fully understood, various explanations have been offered, with researchers pointing to imbalances in certain neurotransmitters and hyperactivity of some brain regions. For example, researchers have found that binding affinity of dopamine receptors in the striatum – a region that coordinates multiple aspects of cognition, decision making, motivation and reward sensitivity – is lower in SAD suffers than controls. Likewise, studies of serotonin have shown both reduced receptor binding and increased transporter binding. As with GAD, hypersensitivity of the amygdala as well as overactivity of the insula has been implicated in social phobia. Notably, the anterior cingulate cortex, a region known to be involved in the processing of pain, is also involved in the experience of the social pain of SAD (i.e. feeling excluded), and is a strong candidate among biomarkers of effective treatment of SAD.

Like GAD, genetics play a critical role in the development of SAD. One study showed that having a first degree relative with the disorder doubled or trebled the risk of developing social phobia, and although disentangling the effects of observational learning and psychosocial education from genetics alone has proved challenging, twins raised in separate households were up to 50 percent more likely to develop SAD than the general population if their sibling was also diagnosed.

Previous negative social experiences are also triggers for the development of social phobia, and up to half of those diagnosed with SAD report a specific experience as the catalyst for onset or worsening of their symptoms. Growing up with hypercritical parents has also been linked to SAD, and those with an insecure attachment style as infants are twice as likely to develop anxiety disorders of any type, including SAD.

As with GAD, onset of social phobia can be substance induced: While initially offering relief from anxiety, misuse of alcohol can worsen symptoms during withdrawal, with a comparable process taking place during discontinuation or withdrawal from benzodiazepines.

Treatment

While prognosis is generally considered positive in the presence of treatment, without care anxiety disorders can persist indefinitely and can bring about secondary depression, complicating a person’s mental healthcare overall. Moreover, anxiety remains a public health concern since only a minority of those affected go on to receive treatment.

While many who are treated with a combination of psychotherapy and anxiolytic medications do achieve a measure of remission, anti-anxiety medications themselves often come with significant side effects and abuse potential. For instance, benzodiazepines like Xanax™ and Ativan™ are among the most commonly abused medications in the world, and even when used appropriately can produce a bevy of side effects ranging from amnesia and confusion to grogginess and depression. Less common anxiolytics, for example gabapentinoid pregabalin (Lyrica™), can cause headache, dizziness, memory problems, and even angioedema. In short, existing medications alone rarely do more than manage symptoms, come with significant drawbacks, and cessation is associated with increased refractory anxiety.

As such, it is important to continue research into meaningful alternatives, which include psilocybin, deuterated etifoxine, and others.