By Kevin She
2 Dec 2015
Everyone feels nervous or worried at times, and this can be helpful when it motivates or warns us of danger. Anxiety disorders, however, cause strong unexpected or unhelpful feelings that seriously impact our lives including how we feel, think, and act. Anxiety disorders affect everyone differently. Many people with anxiety disorders may erroneously think that they should be able to overcome the conditions on their own or that it will disappear with time.
However, anxiety disorders are real illnesses that can impact our wellbeing. It is important to talk with your medical doctor about mental health concerns and potential treatments. There are many treatments that are effective, and medication can be an important part of a successful treatment program. Medication can alleviate some of the physical feelings of anxiety and may also make anxious feelings less frequent or less intense to make it easier to learn and implement helpful coping strategies as part of a holistic treatment program.
There is now much evidence from different branches of neuroscience showing that anxiety disorders generally develop when there is an imbalance favouring excitatory over inhibitory neurotransmission in the amygdala. Powerful pharmaceuticals that are prescribed for anxiety target this imbalance. There is increasing evidence that a number of traditional plant based medicines also target and alleviate this imbalance in a similar manner. Indeed, there is growing clinical evidence from well designed and well conducted randomized clinical trials showing that these naturally derived medicines can be an effective part of treatment programs to relieve anxiety disorders.
Medically recognized anxiety disorders are the most prevalent mental illness that affect Canadians. In any given year, between 12 – 20% of Canadians suffer from an anxiety disorder and one in four Canadians will have at least one anxiety disorder in their lifetime 1. Notably anxiety disorders are often concurrent, or “comorbid,” with other mental illnesses especially depression. Moreover, anxiety disorders are frequently unrecognized by generalist healthcare professionals. More than half of patients with anxiety disorders are undiagnosed by their primary care physician and even when recognized, less than a third of those will receive the correct specific anxiety disorder diagnosis 2, which can be important in developing a directed therapy program. Anxiety disorders can affect anyone at any age. Sometimes anxiety disorders are triggered by a specific event or stressful life experience. At other times, no external triggers can be identified.
There are a number of recognized anxiety disorders.
Phobias manifest as an intense fear regarding a specific thing like an object, animal, or situation. While almost everyone sometimes feel afraid, with phobias, patients change the way they live in order to avoid the feared object or situation, sometimes to excess not commensurate with the threat.
Panic disorder involves repeated and unexpected panic attacks, feelings of sudden and intense fear that lasts for a short period of time. Panic disorders seem to happen for no reason and patients who experience panic disorder may fear more panic attacks and worry that something bad will happen as a result of the panic attacks.
Agoraphobia is the fear of being in situations that the patient can’t escape or find help if they experience a panic attack or other feelings of anxiety. Patients with agoraphobia may avoid public places or even avoid leaving their homes.
Social anxiety disorder involves the intense fear of being embarrassed or of being evaluated negatively by others and exceeds mere shyness. As a result, patients with social anxiety disorder may avoid social situations leading to large negative impact on work or school performance and in relationships.
Generalized anxiety disorder is characterized by excessive worry around a number of everyday problems for more than six months in a row. Typically, the anxiety experienced is often far greater than expected, for example, intense anxiety over normally minor concerns. Generalized anxiety disorder is often accompanied by physical symptoms including tiredness, muscle tension, and sleep problems.
Some other mental illnesses are no longer classified as anxiety disorders in the DSM (Diagnostic and Statistical Manual of Mental Disorders) although fear and anxiety are major parts of these illnesses. Obsessive-compulsive disorder (OCD) manifests as unwanted thoughts, images, or urges that cause anxiety (obsessions) and excessive repeated actions intended to reduce the anxiety (compulsion). Obsessions or compulsions generally consume a lot of time and attention and cause significant amounts of distress. Post-traumatic stress disorder (PTSD) can occur after extreme experiences and after traumatic events such as abuse, an accident, a natural disaster, or during combat situations. PTSD symptoms include highly unpleasant and highly intense recollections of the event through nightmares or flashbacks, excessive avoidance of reminders of the traumatic experience or event, and feeling unsafe even when the patient is not in danger.
Everyone feels nervous or worried at times, and this can be helpful when it motivates or warns us of danger. Anxiety disorders, however, cause unexpected or unhelpful anxiety that seriously impacts our lives including how we feel, think, and act. The exact causes of anxiety disorders are very complex, vary between individuals, and are as yet incompletely understood. Like many other mental health conditions, anxiety disorders appear to be a result of a combination of genetics, possibly epigenetics, and psychological and experiential factors.
Anxiety disorders affect everyone differently. Many people with anxiety disorders may erroneously think that they should be able to overcome the condition on their own or that it will disappear with time. However, anxiety disorders are real illnesses that can seriously affect an individual’s well being. It is important to consult with a medical doctor about mental health concerns and potential treatment programs. These treatments should include reducing unhelpful coping strategies and building healthy behaviours to manage anxiety. Most anxiety disorder have specific treatments and goals but all include some combination of the following strategies.
Counseling can be part of an effective treatment strategy for anxiety. Cognitive-behavioural therapy (CBT) is currently a popular form of therapy with demonstrable effectiveness for many patients with anxiety disorders 3, 4. The goal of CBT is to help the patient be more aware of how their feelings, thoughts, and behaviours interact and work together with the intention of identifying problem behaviours and replacing them with more helpful strategies. It is often the first treatment to try for mild or moderate problems with anxiety.
Support groups, in person or online, is often recommended as a way to share experiences, learn from others, and to connect with people who understand the condition.
Self-support strategies employ many different skills and can help some patients manage their anxiety 5. Stress management, problem-solving, relaxation, and mindfulness – the development of the ability to be aware of the present moment without judgment – may help control one’s anxiety. Other practices that support general wellness such as exercising, socializing, and eating well are also important.
Medication as part of a treatment strategy can help many patients manage their anxiety disorder more easily. Anxiety, depression, and insomnia are often “comorbidities” – two or more aversive conditions occurring at the same time – and treatment of one can sometimes alleviate the other. In some circumstances one of the factors contributes to the other, for example insomnia may contribute to anxiety and treating the insomnia may help alleviate the underlying cause of anxiety. In other cases, the prescription medications used for the pharmacological treatment of some forms of standalone clinical depression are also be effective in the treatment of some standalone anxiety disorders. The ability of one medication to treat multiple illnesses suggests that the different illnesses may have similar physical causes. These medications can alleviate some of the physical feelings of anxiety and may also make anxious thoughts less frequent or less intense and makes it easier to learn and implement helpful coping strategies.
The specific underlying physical causes of the different anxiety disorders are incompletely understood, but they are real diseases that can be managed with help. To compound the complexity of mental illness sometimes the same symptoms in different individuals may respond very differently to the same treatment or medication, suggesting that there can also be different causes to similar symptoms.
There are a number of medications with varying effectiveness and the range and severity of side effects in treating anxiety. These anxiolytics, a class of medicines that alleviate anxiety, typically act by making small changes in how neurotransmission in the brain and the central nervous system works. In particular, many anxiolytics commonly potentiate – to make more effective – the function of the brain’s endogenous inhibitory neurotransmitter GABA (gamma-aminobutyric acid) and it’s receptor, but being “allosteric modulators” they do not elicit a response on their own.
Indeed, there is now much evidence from different branches of neuroscience showing that, in both humans and animals, anxiety disorders generally develop when there is an imbalance favouring excitatory over inhibitory neurotransmission in the amygdala 6. The amygdala are two almond-shaped groups of neurons near the middle of the brain that processes memory, decision making, and emotional reactions including fear 7. This imbalance between excitatory and inhibitory neurotransmission in the amygdala leads to defects in detecting saliency in the context of fear 6. In neuroscience, the concept of saliency is the ability of the brain to detect and determine which of the multitude of sensations that we are constantly bombarded with every waking second are important or ‘salient.’ Saliency discrimination is considered to be a key mechanism for attention that facilitates learning. The ability to learn and to correctly discriminate potentially dangerous situations is an ancient and deep seated evolutionary adaptation for survival. While the specific mechanisms by which the excitatory/inhibitory neurotransmission balance in the amygdala is disrupted is incompletely understood, imbalances favouring excitation appear to cause many symptoms of anxiety. Temporarily restoring the balance to normal with medication can make the other aspects of holistic therapy program more effective in rewiring the brain through neuronal plasticity to cure anxiety disorders.
Historically, the pharmacological treatment for anxiety relied on using general depressants and sedatives such as alcohol, chloral hydrate, lithium bromide, or opiates. These early therapies are unfortunately associated with toxicities and undesirable side effects especially when used in larger doses and for longer periods of time. In addition to these undesirable effects, they also present a risk for the development of dependency, unpleasant physical symptoms if abruptly withdrawn, and potentially fatal overdoses.
Interestingly alcohol and chloral hydrate – chlorinated ethanol – are allosteric potentiators of the GABA receptor. Lithium bromide, a salt that dissociates into ions when dissolved, appears to act as an anxiolytic due to the bromide ions increasing the strength of signaling when GABA receptors are activated. Opioids act by binding opioid receptors in the brain and in the central nervous system that normally respond to the body’s own endogenous opioids such as the endorphins.
Barbiturates, first synthesized and marketed in Germany in 1902, were once the prescription anxiolytic of choice for the treatment of anxiety disorders showing more controllable and predictable effects when used at the correct doses. However, they have largely been withdrawn from use for anxiety due to its narrow therapeutic window – the dose between where the medicine has its intended effect and the dose where undesirable effects occur. Unfortunately for barbiturates, a major undesirable effect is lethal overdose. Indeed, barbiturates have been used as agents to carry out capital punishment by lethal injection, infamously in Nazi Germany. In addition to the risk of overdose, regular use of barbiturates leads to tolerance and dependency.
Barbiturates bind to specific parts of GABA receptors in the central nervous system and potentiate GABAergic neurotransmission as an allosteric modulator; it makes GABA receptors much more responsive to a given amount of GABA neurotransmitter released at a given synapse (the junction between two neurons where neurotransmission primarily occurs).
Currently, benzodiazepines are the preferred anxiolytic for treating anxiety primarily due to their safety in comparison to barbiturates. Some of the most common benzodiazepines include Valium (diazepam), Xanax (alprzaolam), Klonopin (clonazepam), and Ativan (lorazepam). The first benzodiazepine, Librium (chlordiazepoxide), was discovered serendipitously and started the growth of a family of pharmaceuticals that became the most widely prescribed medication of all time8.
Like ethanol, chloral hydrate, and barbiturates, benzodiazepines are also allosteric potentiators of GABA receptors. All of these allosteric potentiators bind to different locations the receptor and should never be mixed because they have additive or synergistic effects and should never be taken together. These binding sites are distinct from the site that GABA normally binds to activate the receptor. All of these different allosteric potentiators of the GABA receptor also have differences in how well and how strongly they bind to different subtypes of GABA receptors, leading to the differences in their pharmacokinetics and pharmacodynamics – the physiological effects that they have at different doses in different individuals.
In Canada, guidelines for the prescription of benzodiazepines recommend that they only be used for no more than two weeks due to the perceived lack of evidence that they are effective when used for longer periods of time and that prolonged use increases the risk of developing dependency 9. However, benzodiazepines are commonly prescribed chronically for long periods of time and there is emerging evidence that they remain effective. However, vigilant evaluation of dosage and the development of tolerance are necessary to ensure that they remain effective and dependency remains a serious risk 10. Some common side effects of benzodiazepines include drowsiness, sedation, dizziness, and loss of balance. At higher doses, more serious side effects include confusion, disorientation, amnesia, breathing difficulties, and depression. More rare yet severe side effects include agitation, hallucinations, and nightmares. Benzodiazepines can also make it harder to learn and remember new information and to do certain physical and mental tasks.
Throughout history, plants and plant parts (natural health products/herbal medicines) have been a valuable source of medicines across all cultures. Human inquisitiveness and the ability for observation have allowed us to identify and use medicines from the natural world. Many of today’s mainstream pharmaceuticals owe their origins to traditional plant based remedies; for example, Aspirin (acetylsalicylic acid) from willow bark for fevers and pain, quinine from chinchona tree bark for treating malaria (the origin of tonic water used in ‘Gin & Tonic’), opiates from opium poppies for pain, and Foxglove (digitalis) for congestive heart failure. While the philosophy behind modern pharmaceuticals is to identify a single “active ingredient” that can be chemically produced through medicinal chemistry, there has been a mini renaissance on research once again in medicinal plants. There are an increasing number of traditional plant based medicines that have been tested through randomized clinical trials (RCT) that show they are empirically effective to a statistically significant degree, and more importantly, with appreciable effect size in treating illnesses. However, not all studies are equal and even many of the ‘good’ ones require further study in larger numbers of patients.
Valerian root (Valeriana officinalis) has traditionally been used to treat anxiety and sleep disorders. There is growing clinical evidence from RCTs showing it to be effective 11, 12, 13 in treating anxiety and anxiety disorders and is safe to use and well tolerated even in large doses. Laboratory studies show that valerenic acid from valerian root is both orally bioavailable 14, 15 and able to cross the blood brain barrier 16. Perhaps not surprisingly valerenic acid is, like many of the anxiolytics mentioned above, an allosteric potentiator of GABA receptors in the brain 17, 18, 19.
Lemon balm (Melissa officinalis) has traditionally been used to treat stomach conditions and anxiety and there is some clinical evidence that it is effective in treating anxiety and stress 20, 21. The suspected active ingredient in Lemon balm is rosmarinic acid, which is orally bioavailable and able to pass the blood brain barrier 22. Rosmarinic acid inhibits the activity of GABA transaminase, which normally metabolizes GABA, similar to valproic acid drugs like Valpro and Depakote that are used to control epilepsy and bipolar disorders. By inhibiting GABA transaminase, this potentially leads to an accumulation of GABA both at the synapse and potentially increasing GABA availability to be loaded into synaptic vesicles for use in neurotransmission. Not surprisingly, a combination of valerian root (increase response to GABA) and lemon balm (increase GABA) appears quite effective in relieving stress and anxiety 23.