What is Tranylcypromine?

Introduction

Tranylcypromine (sold under the trade name Parnate among others) is a monoamine oxidase inhibitor (MAOI); more specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO).

It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.

Tranylcypromine is a propylamine formed from the cyclisation of amphetamine’s side chain; therefore, it is classified as a substituted amphetamine.

Brief History

Tranylcypromine was originally developed as an analogue of amphetamine. Although it was first synthesized in 1948, its MAOI action was not discovered until 1959. Precisely because tranylcypromine was not, like isoniazid and iproniazid, a hydrazine derivative, its clinical interest increased enormously, as it was thought it might have a more acceptable therapeutic index than previous MAOIs.

The drug was introduced by Smith, Kline and French in the United Kingdom in 1960, and approved in the United States in 1961. It was withdrawn from the market in February 1964 due to a number of patient deaths involving hypertensive crises with intracranial bleeding. However, it was reintroduced later that year with more limited indications and specific warnings of the risks.

Medical Uses

Tranylcypromine is used to treat major depressive disorder, including atypical depression, especially when there is an anxiety component, typically as a second-line treatment. It is also used in depression that is not responsive to reuptake inhibitor antidepressants, such as the SSRIs, TCAs, or bupropion.

Contraindications

Contraindications include:

  • Porphyria.
  • Cardiovascular or cerebrovascular disease.
  • Pheochromocytoma.
  • Tyramine, found in several foods, is metabolized by MAO. Ingestion and absorption of tyramine causes extensive release of norepinephrine, which can rapidly increase blood pressure to the point of causing hypertensive crisis.
  • Concomitant use of serotonin-enhancing drugs, including SSRIs, serotonergic TCAs, dextromethorphan, and meperidine may cause serotonin syndrome.
  • Concomitant use of MRAs, including fenfluramine, amphetamine, and pseudoephedrine may cause toxicity via serotonin syndrome or hypertensive crisis.
  • L-DOPA given without carbidopa may cause hypertensive crisis.

Dietary Restrictions

Tyramine is a common component in many foods, and is normally rapidly metabolised by MAO-A. Individuals not taking MAOIs may consume at least 2 grams of tyramine in a meal and not experience an increase in blood pressure, whereas those taking MAOIs such as tranylcypromine may experience a sharp increase in blood pressure following consumption of as little as 10 mg of tyramine, which can lead to hypertensive crisis.

Foods containing tyramine include aged cheeses, cured meats, tofu and certain red wines. Some, such as yeast extracts, contain enough tyramine to be potentially fatal in a single serving. Spoiled food is also likely to contain dangerous levels of tyramine.

Adverse Effects

Incidence of Adverse Effects

  • Very common (>10% incidence) adverse effects include:
    • Dizziness secondary to orthostatic hypotension (17%).
  • Common (1-10% incidence) adverse effects include:
    • Tachycardia (5-10%).
    • Hypomania (7%).
    • Paresthesia (5%).
    • Weight loss (2%).
    • Confusion (2%).
    • Dry mouth (2%).
    • Sexual function disorders (2%).
    • Hypertension (1-2 hours after ingestion) (2%).
    • Rash (2%).
    • Urinary retention (2%).
  • Other (unknown incidence) adverse effects include:
    • Increased/decreased appetite.
    • Blood dyscrasias.
    • Chest pain.
    • Diarrhoea.
    • Oedema.
    • Hallucinations.
    • Hyperreflexia.
    • Insomnia.
    • Jaundice.
    • Leg cramps.
    • Myalgia.
    • Palpitations.
    • Sensation of cold.
    • Suicidal ideation.
    • Tremor.

Of note, there has not been found to be a correlation between sex and age below 65 regarding incidence of adverse effects.

Tranylcypromine is not associated with weight gain and has a low risk for hepatotoxicity compared to the hydrazine MAOIs.

It is generally recommended that MAOIs be discontinued prior to anaesthesia; however, this creates a risk of recurrent depression. In a retrospective observational cohort study, patients on tranylcypromine undergoing general anaesthesia had a lower incidence of intraoperative hypotension, while there was no difference between patients not taking an MAOI regarding intraoperative incidence of bradycardia, tachycardia, or hypertension. The use of indirect sympathomimetic drugs or drugs affecting serotonin reuptake, such as meperidine or dextromethorphan poses a risk for hypertension and serotonin syndrome respectively; alternative agents are recommended. Other studies have come to similar conclusions. Pharmacokinetic interactions with anaesthetics are unlikely, given that tranylcypromine is a high-affinity substrate for CYP2A6 and does not inhibit CYP enzymes at therapeutic concentrations.

Tranylcypromine abuse has been reported at doses ranging from 120-600 mg per day. It is thought that higher doses have more amphetamine-like effects and abuse is promoted by the fast onset and short half-life of tranylcypromine.

Cases of suicidal ideation and suicidal behaviours have been reported during tranylcypromine therapy or early after treatment discontinuation.

Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects.

Interactions

In addition to contraindicated concomitant medications, tranylcypromine inhibits CYP2A6, which may reduce the metabolism and increase the toxicity of substrates of this enzyme, such as:

  • Dexmedetomidine.
  • Nicotine.
  • TSNAs (found in cured tobacco products, including cigarettes).
  • Valproate.

Norepinephrine reuptake inhibitors prevent neuronal uptake of tyramine and may reduce its pressor effects.

Pharmacology

Pharmacodynamics

Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase. Regarding the isoforms of monoamine oxidase, it shows slight preference for the MAOB isoenzyme over MAOA. This leads to an increase in the availability of monoamines, such as serotonin, norepinephrine, and dopamine, as well as a marked increase in the availability of trace amines, such as tryptamine, octopamine, and phenethylamine. The clinical relevance of increased trace amine availability is unclear.

It may also act as a norepinephrine reuptake inhibitor at higher therapeutic doses. Compared to amphetamine, tranylcypromine shows low potency as a dopamine releasing agent, with even weaker potency for norepinephrine and serotonin release.

Tranylcypromine has also been shown to inhibit the histone demethylase, BHC110/LSD1. Tranylcypromine inhibits this enzyme with an IC50 < 2 μM, thus acting as a small molecule inhibitor of histone demethylation with an effect to de-repress the transcriptional activity of BHC110/LSD1 target genes. The clinical relevance of this effect is unknown.

Tranylcypromine has been found to inhibit CYP46A1 at nanomolar concentrations. The clinical relevance of this effect is unknown.

Pharmacokinetics

Tranylcypromine reaches its maximum concentration (tmax) within 1-2 hours. After a 20 mg dose, plasma concentrations reach at most 50-200 ng/mL. While its half-life is only about 2 hours, its pharmacodynamic effects last several days to weeks due to irreversible inhibition of MAO.

Metabolites of tranylcypromine include 4-hydroxytranylcypromine, N-acetyltranylcypromine, and N-acetyl-4-hydroxytranylcypromine, which are less potent MAO inhibitors than tranylcypromine itself. Amphetamine was once thought to be a metabolite of tranylcypromine, but has not been shown to be.

Tranylcypromine inhibits CYP2A6 at therapeutic concentrations.

Research

Tranylcypromine is known to inhibit LSD1, an enzyme that selectively demethylates two lysines found on histone H3. Genes promoted downstream of LSD1 are involved in cancer cell growth and metastasis, and several tumour cells express high levels of LSD1. Tranylcypromine analogues with more potent and selective LSD1 inhibitory activity are being researched in the potential treatment of cancers.

Tranylcypromine may have neuroprotective properties applicable to the treatment of Parkinson’s disease, similar to the MAO-B inhibitors selegiline and rasagiline. As of 2017, only one clinical trial in Parkinsonian patients has been conducted, which found some improvement initially and only slight worsening of symptoms after a 1.5 year follow-up.

What is the Gut-Brain Axis?

Introduction

The gut-brain axis is the biochemical signalling that takes place between the gastrointestinal tract (GI tract) and the central nervous system (CNS).

The term “gut-brain axis” is occasionally used to refer to the role of the gut flora in the interplay as well, whereas the term “microbiota–gut–brain (MGB or BGM) axis” explicitly includes the role of gut flora in the biochemical signalling events that take place between the GI tract and CNS.

Broadly defined, the gut-brain axis includes the central nervous system, neuroendocrine and neuroimmune systems, including the hypothalamic-pituitary-adrenal axis (HPA axis), sympathetic and parasympathetic arms of the autonomic nervous system, including the enteric nervous system and the vagus nerve, and the gut microbiota. The first of the brain-gut interactions shown, was the cephalic phase of digestion, in the release of gastric and pancreatic secretions in response to sensory signals, such as the smell and sight of food. This was first demonstrated by Pavlov.

Interest in the field was sparked by a 2004 study showing that germ-free (GF) mice showed an exaggerated HPA axis response to stress compared to non-GF laboratory mice.

As of October 2016, most of the work done on the role of gut flora in the gut-brain axis had been conducted in animals, or on characterising the various neuroactive compounds that gut flora can produce. Studies with humans – measuring variations in gut flora between people with various psychiatric and neurological conditions or when stressed, or measuring effects of various probiotics (dubbed “psychobiotics” in this context) – had generally been small and were just beginning to be generalised. Whether changes to gut flora are a result of disease, a cause of disease, or both in any number of possible feedback loops in the gut–brain axis, remained unclear.

Gut Flora

The gut flora is the complex community of microorganisms that live in the digestive tracts of humans and other animals. The gut metagenome is the aggregate of all the genomes of gut microbiota. The gut is one niche that human microbiota inhabit.

In humans, the gut microbiota has the largest quantity of bacteria and the greatest number of species, compared to other areas of the body. In humans, the gut flora is established at one to two years after birth; by that time, the intestinal epithelium and the intestinal mucosal barrier that it secretes have co-developed in a way that is tolerant to, and even supportive of, the gut flora and that also provides a barrier to pathogenic organisms.

The relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship. Human gut microorganisms benefit the host by collecting the energy from the fermentation of undigested carbohydrates and the subsequent absorption of short-chain fatty acids (SCFAs), acetate, butyrate, and propionate. Intestinal bacteria also play a role in synthesizing vitamin B and vitamin K as well as metabolising bile acids, sterols, and xenobiotics. The systemic importance of the SCFAs and other compounds they produce are like hormones and the gut flora itself appears to function like an endocrine organ; dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.

The composition of human gut flora changes over time, when the diet changes, and as overall health changes.

Enteric Nervous System

The enteric nervous system is one of the main divisions of the nervous system and consists of a mesh-like system of neurons that governs the function of the gastrointestinal system; it has been described as a “second brain” for several reasons. The enteric nervous system can operate autonomously. It normally communicates with the central nervous system (CNS) through the parasympathetic (e.g. via the vagus nerve) and sympathetic (e.g. via the prevertebral ganglia) nervous systems. However, vertebrate studies show that when the vagus nerve is severed, the enteric nervous system continues to function.

In vertebrates, the enteric nervous system includes efferent neurons, afferent neurons, and interneurons, all of which make the enteric nervous system capable of carrying reflexes in the absence of CNS input. The sensory neurons report on mechanical and chemical conditions. Through intestinal muscles, the motor neurons control peristalsis and churning of intestinal contents. Other neurons control the secretion of enzymes. The enteric nervous system also makes use of more than 30 neurotransmitters, most of which are identical to the ones found in CNS, such as acetylcholine, dopamine, and serotonin. More than 90% of the body’s serotonin lies in the gut, as well as about 50% of the body’s dopamine; the dual function of these neurotransmitters is an active part of gut-brain research.

The first of the gut-brain interactions was shown to be between the sight and smell of food and the release of gastric secretions, known as the cephalic phase, or cephalic response of digestion.

Gut-Brain Integration

The gut-brain axis, a bidirectional neurohumoral communication system, is important for maintaining homeostasis and is regulated through the central and enteric nervous systems and the neural, endocrine, immune, and metabolic pathways, and especially including the hypothalamic-pituitary-adrenal axis (HPA axis). That term has been expanded to include the role of the gut flora as part of the “microbiome-gut-brain axis”, a linkage of functions including the gut flora.

Interest in the field was sparked by a 2004 study (Nobuyuki Sudo and Yoichi Chida) showing that germ-free mice (genetically homogeneous laboratory mice, birthed and raised in an antiseptic environment) showed an exaggerated HPA axis response to stress, compared to non-GF laboratory mice.

The gut flora can produce a range of neuroactive molecules, such as acetylcholine, catecholamines, γ-aminobutyric acid, histamine, melatonin, and serotonin, which are essential for regulating peristalsis and sensation in the gut. Changes in the composition of the gut flora due to diet, drugs, or disease correlate with changes in levels of circulating cytokines, some of which can affect brain function. The gut flora also release molecules that can directly activate the vagus nerve, which transmits information about the state of the intestines to the brain.

Likewise, chronic or acutely stressful situations activate the hypothalamic-pituitary-adrenal axis, causing changes in the gut flora and intestinal epithelium, and possibly having systemic effects. Additionally, the cholinergic anti-inflammatory pathway, signalling through the vagus nerve, affects the gut epithelium and flora. Hunger and satiety are integrated in the brain, and the presence or absence of food in the gut and types of food present also affect the composition and activity of gut flora.

That said, most of the work that has been done on the role of gut flora in the gut-brain axis has been conducted in animals, including the highly artificial germ-free mice. As of 2016, studies with humans measuring changes to gut flora in response to stress, or measuring effects of various probiotics, have generally been small and cannot be generalised; whether changes to gut flora are a result of disease, a cause of disease, or both in any number of possible feedback loops in the gut-brain axis, remains unclear.

The history of ideas about a relationship between the gut and the mind dates from the nineteenth century. The concepts of dyspepsia and neurasthenia gastrica referred to the influence of the gut on human emotions and thoughts.

Gut-Brain-Skin Axis

A unifying theory that tied gastrointestinal mechanisms to anxiety, depression, and skin conditions such as acne was proposed as early as 1930. In a paper in 1930, it was proposed that emotional states might alter normal intestinal flora which could lead to increased intestinal permeability and therefore contribute to systemic inflammation. Many aspects of this theory have been validated since then. Gut microbiota and oral probiotics have been found to influence systemic inflammation, oxidative stress, glycaemic control, tissue lipid content, and mood.

Research

Probiotics

A 2016 systematic review of laboratory animal studies and preliminary human clinical trials using commercially available strains of probiotic bacteria found that certain species of the Bifidobacterium and Lactobacillus genera (i.e. B. longum, B. breve, B. infantis, L. helveticus, L. rhamnosus, L. plantarum, and L. casei) had the most potential to be useful for certain central nervous system disorders.

Anxiety and Mood Disorders

As of 2018 work on the relationship between gut flora and anxiety disorders and mood disorders, as well as attempts to influence that relationship using probiotics or prebiotics (called “psychobiotics”), was at an early stage, with insufficient evidence to draw conclusions about a causal role for gut flora changes in these conditions, or about the efficacy of any probiotic or prebiotic treatment.

People with anxiety and mood disorders tend to have gastrointestinal problems; small studies have been conducted to compare the gut flora of people with major depressive disorder and healthy people, but those studies have had contradictory results.

Much interest was generated in the potential role of gut flora in anxiety disorders, and more generally in the role of gut flora in the gut-brain axis, by studies published in 2004 showing that germ-free mice have an exaggerated HPA axis response to stress caused by being restrained, which was reversed by colonising their gut with a Bifidobacterium species. Studies looking at maternal separation for rats shows neonatal stress leads to long-term changes in the gut microbiota such as its diversity and composition, which also led to stress and anxiety-like behaviour. Additionally, while much work had been done as of 2016 to characterise various neurotransmitters known to be involved in anxiety and mood disorders that gut flora can produce (for example, Escherichia, Bacillus, and Saccharomyces species can produce noradrenalin; Candida, Streptococcus, and Escherichia species can produce serotonin, etc.) the interrelationships and pathways by which the gut flora might affect anxiety in humans were unclear.

In one study, germ-free mice underwent faecal transplants with microbes from humans with or without major depressive disorder (MDD). Mice with microbes from humans with MDD displayed more behaviours associated with anxiety and depression than mice transplanted with microbes from humans without MDD. The taxonomic composition of microbiota between depressed patients and healthy patients, as well as between the respective mice, also differed. Germ-free mice in another study also displayed behaviours associated with anxiety and depression as compared to mice with normal microbiota, and had higher levels of corticosterone after exposure to behavioural tests. Using rodents in microbiome and mental health studies allows researchers to compare behaviour and microbial composition of rodents to humans, ideally to elucidate therapeutic application for mental disorders.

Additionally, there is a link between the gut microbiome, mood disorders and anxiety, and sleep. The microbial composition of the gut microbiome changes depending on the time of day, meaning that throughout the day, the gut is exposed to varying metabolites produced by the microbes active during that time. These time-dependent microbial changes are associated with differences in the transcription of circadian clock genes involved in circadian rhythm. One mouse study showed that altering clock gene transcription by disrupting circadian rhythm, such as through sleep deprivation, potentially has a direct effect on the composition of the gut microbiome. Another study found that mice that could not produce the CLOCK protein, made by a clock gene, were more likely to develop depression. Stress and sleep disturbances can lead to greater gut mucosal permeability via activation of the HPA axis. This in turn causes immune inflammatory responses that contribute to the development of illnesses that cause depression and anxiety.

Autism

Around 70% of people with autism also have gastrointestinal problems, and autism is often diagnosed at the time that the gut flora becomes established, indicating that there may be a connection between autism and gut flora. Some studies have found differences in the gut flora of children with autism compared with children without autism – most notably elevations in the amount of Clostridium in the stools of children with autism compared with the stools of the children without – but these results have not been consistently replicated. Many of the environmental factors thought to be relevant to the development of autism would also affect the gut flora, leaving open the question of whether specific developments in the gut flora drive the development of autism or whether those developments happen concurrently. As of 2016, studies with probiotics had only been conducted with animals; studies of other dietary changes to treat autism have been inconclusive.

Parkinson’s Disease

As of 2015, one study had been conducted comparing the gut flora of people with Parkinson’s disease to healthy controls; in that study people with Parkinson’s had lower levels of Prevotellaceae and people with Parkinson’s who had higher levels of Enterobacteriaceae had more clinically severe symptoms; the authors of the study drew no conclusions about whether gut flora changes were driving the disease or vice versa.

Can the MHS: A Serve as a Clinically Useful Screening Tool for GAD?

Research Paper Title

A Brief Online and Offline (Paper-and-Pencil) Screening Tool for Generalized Anxiety Disorder: The Final Phase in the Development and Validation of the Mental Health Screening Tool for Anxiety Disorders (MHS: A).

Background

Generalised anxiety disorder (GAD) can cause significant socioeconomic burden and daily life dysfunction; hence, therapeutic intervention through early detection is important.

Methods

This study was the final stage of a 3-year anxiety screening tool development project that evaluated the psychometric properties and diagnostic screening utility of the Mental Health Screening Tool for Anxiety Disorders (MHS: A), which measures GAD.

Results

A total of 527 Koreans completed online and offline (i.e., paper-and pencil) versions of the MHS: A, Beck Anxiety Inventory (BAI), Generalised Anxiety Disorder-7 (GAD-7), and Penn State Worry Questionnaire (PSWQ). The participants had an average age of 38.6 years and included 340 (64.5%) females. Participants were also administered the Mini-International Neuropsychiatric Interview (MINI).

Internal consistency, convergent/criterion validity, item characteristics, and test information were assessed based on the item response theory (IRT), and a factor analysis and cut-off score analyses were conducted. The MHS: A had good internal consistency and good convergent validity with other anxiety scales.

The two versions (online/offline) of the MHS: A were nearly identical (r = 0.908). It had a one-factor structure and showed better diagnostic accuracy (online/offline: sensitivity = 0.98/0.90, specificity = 0.80/0.83) for GAD detection than the GAD-7 and BAI. The IRT analysis indicated that the MHS: A was most informative as a screening tool for GAD.

Conclusions

The MHS: A can serve as a clinically useful screening tool for GAD in Korea. Furthermore, it can be administered both online and offline and can be flexibly used as a brief mental health screener, especially with the current rise in telehealth.

Reference

Kim, S-H., Park, K., Yoon, S., Choi, Y., Lee, S-H. & Choi, K-H. (2021) A Brief Online and Offline (Paper-and-Pencil) Screening Tool for Generalized Anxiety Disorder: The Final Phase in the Development and Validation of the Mental Health Screening Tool for Anxiety Disorders (MHS: A). Frontiers in Psychology. doi: 10.3389/fpsyg.2021.639366. eCollection 2021.

Anxiety Youth vs Healthy Youth: Threat-Anticipatory Psychophysiological Response Differences

Research Paper Title

Threat-anticipatory psychophysiological response is enhanced in youth with anxiety disorders and correlates with prefrontal cortex neuroanatomy.

Background

Threat anticipation engages neural circuitry that has evolved to promote defensive behaviours; perturbations in this circuitry could generate excessive threat-anticipation response, a key characteristic of pathological anxiety. Research into such mechanisms in youth faces ethical and practical limitations. Here, the researchers use thermal stimulation to elicit pain-anticipatory psychophysiological response and map its correlates to brain structure among youth with anxiety and healthy youth.

Methods

Youth with anxiety (n = 25) and healthy youth (n = 25) completed an instructed threat-anticipation task in which cues predicted nonpainful or painful thermal stimulation; the researchers indexed psychophysiological response during the anticipation and experience of pain using skin conductance response. High-resolution brain-structure imaging data collected in another visit were available for 41 participants. Analyses tested whether the 2 groups differed in their psychophysiological cue-based pain-anticipatory and pain-experience responses. Analyses then mapped psychophysiological response magnitude to brain structure.

Results

Youth with anxiety showed enhanced psychophysiological response specifically during anticipation of painful stimulation (b = 0.52, p = 0.003). Across the sample, the magnitude of psychophysiological anticipatory response correlated negatively with the thickness of the dorsolateral prefrontal cortex (pFWE < 0.05); psychophysiological response to the thermal stimulation correlated positively with the thickness of the posterior insula (pFWE < 0.05).

Limitations: Limitations included the modest sample size and the cross-sectional design.

Conclusions

These findings show that threat-anticipatory psychophysiological response differentiates youth with anxiety from healthy youth, and they link brain structure to psychophysiological response during pain anticipation and experience. A focus on threat anticipation in research on anxiety could delineate relevant neural circuitry.

Reference

Abend, R., Bajaj, M.A., Harrwijn, A., Matsumoto, C., Michalska, K.J., Necka, E., Palacios-Barrios, E.E., Leibenluft, E., Atlas, L.Y. & Pine, D.S. (2021) Threat-anticipatory psychophysiological response is enhanced in youth with anxiety disorders and correlates with prefrontal cortex neuroanatomy. Journal of Psychiatry & Neuroscience. 46(2):E212-E221. doi: 10.1503/jpn.200110.

Book: CBT Journal for Dummies

Book Title:

CBT Journal for Dummies.

Author(s): Rob Wilson and Rhena Branch.

Year: 2012.

Edition: First (1st).

Publisher: Wiley.

Type(s): Hardcover.

Synopsis:

Keep track of the progress you are making with Cognitive Behavioural Therapy.

Cognitive Behavioural Therapy (CBT) is a hugely popular self-help technique that teaches you how to break free from destructive or negative behaviours and make positive changes to both your thoughts and your actions. CBT Journal For Dummies offers a guided space for you to keep a record of your progress, used in conjunction with either CBT For Dummies and/or alongside consultation with a therapist.

This book features an introduction to CBT, followed by a guided 100-day journal. Each chapter focuses on a new CBT technique, with information on how to use the journal space and assessment advice. Topics covered include; establishing the link between thoughts and feelings; preventing ‘all or nothing’ thinking; turning mountains into molehills; focusing on the present; using emotional reasoning; avoiding over-generalising; thinking flexibly; keeping an open mind; assessing the positives; coping with frustration; tackling toxic thoughts; naming your emotions; comparing healthy and unhealthy emotions; working through worry; defining your core beliefs; adopting positive principles; and much more.

  • Has a removable band, leaving a discreet black journal.
  • The small trim size makes it perfect to use on the go.
  • A CBT ‘thought for the day’ appears on alternate blank pages.
  • Content is progressive, encouraging you to keep working through the following days.
  • Coverage is generalized enough to be applicable to every user of CBT.

Book: Managing Anxiety with CBT for Dummies

Book Title:

Managing Anxiety with CBT for Dummies.

Author(s): Graham C. Davey, Kate Cavanagh, Fergal Jones, Lydia Turner, and Adrian Whittington.

Year: 2012.

Edition: First (1st).

Publisher: Wiley.

Type(s): Paperback, Audiobook, and Kindle.

Synopsis:

Don’t panic! Combat your worries and minimise anxiety with CBT!
Cognitive Behavioural Therapy (CBT) is a hugely popular self-help technique, which teaches you to break free from destructive or negative behaviours and make positive changes to both your thoughts and your actions. This practical guide to managing anxiety with CBT will help you understand your anxiety, identify solutions to your problems, and maintain your gains and avoid relapse.

Managing Anxiety with CBT For Dummies is a practical guide to using CBT to face your fears and overcome anxiety and persistent, irrational worries. You’ll discover how to put extreme thinking into perspective and challenge negative, anxiety-inducing thoughts with a range of effective CBT techniques to help you enjoy a calmer, happier life.

  • Helps you understand anxiety and how CBT can help.
  • Guides you in making change and setting goals.
  • Gives you tried-and-true CBT techniques to face your fears and keep a realistic perspective.

Managing Anxiety with CBT For Dummies gives you the tools you need to overcome anxiety and expand your horizons for a healthy, balanced life.

Book: Retrain Your Anxious Brain

Book Title:

Retrain Your Anxious Brain – Practical and Effective Tools to Conquer Anxiety.

Author(s): John Tsilimparis (MFT).

Year: 2014.

Edition: First (1st).

Publisher: Harlequin.

Type(s): Paperback, Audiobook, and Kindle.

Synopsis:

Control Anxiety Before it Begins

Trouble sleeping, panic attacks, knots in your stomach, excessive worry, doubts, phobiasanxiety comes in many shapes and sizes, and affects millions of people. But you do not have to suffer anymore. In Retrain Your Anxious Brain, renowned therapist and anxiety expert John Tsilimparis, MFT, shares the ground breaking programme he has created to help hundreds of people (himself included) free themselves from crippling anxiety and live healthier, happier lives.

Rather than just treating or masking symptoms, Tsilimparis’s innovative approach helps you identify and short-circuit anxiety triggers, so that you can stop anxiety before it starts. This customisable plan teaches you how to:

  • Alter the fixed thoughts that can cause anxiety.
  • Adjust your existing personal belief systems.
  • Challenge the idea of consensus reality.
  • Balance your dualistic mind.
  • Consciously create your own reality.

What is Generalised Anxiety Disorder (GAD)?

Introduction

Generalised anxiety disorder (GAD) is an anxiety disorder characterised by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily functioning, and sufferers are overly concerned about everyday matters such as health, finances, death, family, relationship concerns, or work difficulties. Symptoms may include excessive worry, restlessness, trouble sleeping, exhaustion, irritability, sweating, and trembling.

Symptoms must be consistent and ongoing, persisting at least six months, for a formal diagnosis of GAD. Individuals with GAD often suffer from other disorders including other psychiatric disorders (e.g. major depressive disorder), substance use disorder, obesity, and may have a history of trauma or family with GAD. Clinicians use screening tools such as the GAD-7 and GAD-2 questionnaires to determine if individuals may have GAD and warrant formal evaluation for the disorder. Additionally, sometimes screening tools may enable clinicians to evaluate the severity of GAD symptoms.

GAD is believed to have a hereditary or genetic basis (e.g. first-degree relatives of an individual who has GAD are themselves more likely to have GAD) but the exact nature of this relationship is not fully appreciated. Genetic studies of individuals who have anxiety disorders (including GAD) suggest that the hereditary contribution to developing anxiety disorders is only approximately 30-40%, which suggests that environmental factors may be more important to determining whether an individual develops GAD.

The pathophysiology of GAD implicates several regions of the brain that mediate the processing of stimuli associated with fear, anxiety, memory, and emotion (i.e. the amygdala, insula and the frontal cortex). It has been suggested that individuals with GAD have greater amygdala and medial prefrontal cortex (mPFC) activity in response to stimuli than individuals who do not have GAD. However, the relationship between GAD and activity levels in other parts of the frontal cortex is the subject of ongoing research with some literature suggesting greater activation in specific regions for individuals who have GAD but where other research suggests decreased activation levels in individuals who have GAD as compared to individuals who do not have GAD.

Traditional treatment modalities include variations on psychotherapy (e.g. cognitive-behavioural therapy (CBT)) and pharmacological intervention (e.g. citalopram, escitalopram, sertraline, duloxetine, and venlafaxine). CBT and selective serotonin reuptake inhibitors (SSRIs) are the respectively predominant psychological and pharmacological treatment modalities; other treatments (e.g. selective norepinephrine reuptake inhibitors (SNRIs)) are often considered depending on individual response to therapy. Areas of active investigation include the usefulness of complementary and alternative medications (CAMs), exercise, therapeutic massage and other interventions that have been proposed for study.

Estimates regarding prevalence of GAD or lifetime risk (i.e. lifetime morbid risk (LMR)) for GAD vary depending upon which criteria are used for diagnosing GAD (e.g. DSM-5 vs ICD-10) although estimates do not vary widely between diagnostic criteria. In general, ICD-10 is more inclusive than DSM-5, so estimates regarding prevalence and lifetime risk tend to be greater using ICD-10. In regard to prevalence, in a given year, about two (2%) percent of adults in the United States and Europe have been suggested to suffer GAD. However, the risk of developing GAD at any point in life has been estimated at 9.0%. Although it is possible to experience a single episode of GAD during one’s life, most people who experience GAD experience it repeatedly over the course of their lives as a chronic or ongoing condition. GAD is diagnosed twice as frequently in women as in men.

Diagnosis

DSM-5 Criteria

The diagnostic criteria for GAD as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (2013), published by the American Psychiatric Association, are paraphrased as follows:

  1. “Excessive anxiety or worry” experienced most days over at least six (6) month and which involve a plurality of concerns.
  2. Inability to manage worry.
  3. At least three (3) of the following occur:
    • Restlessness.
    • Fatigability.
    • Problems concentrating.
    • Irritability.
    • Muscle tension.
    • Difficulty with sleep.
    • Note that in children, only one (1) of the above items is required.
  4. One experiences significant distress in functioning (e.g. work, school, social life).
  5. Symptoms are not due to drug abuse, prescription medication or other medical condition(s).
  6. Symptoms do not fit better with another psychiatric condition such as panic disorder.

No major changes to GAD have occurred since publication of the Diagnostic and Statistical Manual of Mental Disorders (2004); minor changes include wording of diagnostic criteria.

ICD-10 Criteria

The 10th revision of the International Statistical Classification of Disease (ICD-10) provides a different set of diagnostic criteria for GAD than the DSM-5 criteria described above. In particular, ICD-10 allows diagnosis of GAD as follows:

  • A period of at least six months with prominent tension, worry, and feelings of apprehension, about everyday events and problems.
  • At least four symptoms out of the following list of items must be present, of which at least one from items (1) to (4).
    • Autonomic arousal symptoms:
      • (1) Palpitations or pounding heart, or accelerated heart rate.
      • (2) Sweating.
      • (3) Trembling or shaking.
      • (4) Dry mouth (not due to medication or dehydration).
    • Symptoms concerning chest and abdomen:
      • (5) Difficulty breathing.
      • (6) Feeling of choking.
      • (7) Chest pain or discomfort.
      • (8) Nausea or abdominal distress (e.g. churning in the stomach).
    • Symptoms concerning brain and mind:
      • (9) Feeling dizzy, unsteady, faint or light-headed.
      • (10) Feelings that objects are unreal (derealization), or that one’s self is distant or “not really here” (depersonalization).
      • (11) Fear of losing control, going crazy, or passing out.
      • (12) Fear of dying.
    • General symptoms:
      • (13) Hot flashes or cold chills.
      • (14) Numbness or tingling sensations.
    • Symptoms of tension:
      • (15) Muscle tension or aches and pains.
      • (16) Restlessness and inability to relax.
      • (17) Feeling keyed up, or on edge, or of mental tension.
      • (18) A sensation of a lump in the throat or difficulty with swallowing.
    • Other non-specific symptoms:
      • (19) Exaggerated response to minor surprises or being startled.
      • (20) Difficulty in concentrating or mind going blank, because of worrying or anxiety.
      • (21) Persistent irritability.
      • (22) Difficulty getting to sleep because of worrying.
  • The disorder does not meet the criteria for panic disorder (F41.0), phobic anxiety disorders (F40.-), obsessive-compulsive disorder (F42.-) or hypochondriacal disorder (F45.2).
  • Most commonly used exclusion criteria: not sustained by a physical disorder, such as hyperthyroidism, an organic mental disorder (F0) or psychoactive substance-related disorder (F1), such as excess consumption of amphetamine-like substances, or withdrawal from benzodiazepines.[21]

See ICD-10 F41.1

Note: For children different ICD-10 criteria may be applied for diagnosing GAD (see F93.80).

History of Diagnostic Criteria

The American Psychiatric Association introduced GAD as a diagnosis in the DSM-III in 1980, when anxiety neurosis was split into GAD and panic disorder. The definition in the DSM-III required uncontrollable and diffuse anxiety or worry that is excessive and unrealistic and persists for 1 month or longer. High rates in comorbidity of GAD and major depression led many commentators to suggest that GAD would be better conceptualised as an aspect of major depression instead of an independent disorder. Many critics stated that the diagnostic features of this disorder were not well established until the DSM-III-R. Since comorbidity of GAD and other disorders decreased with time, the DSM-III-R changed the time requirement for a GAD diagnosis to 6 months or longer. The DSM-IV changed the definition of excessive worry and the number of associated psychophysiological symptoms required for a diagnosis. Another aspect of the diagnosis the DSM-IV clarified was what constitutes a symptom as occurring “often”. The DSM-IV also required difficulty controlling the worry to be diagnosed with GAD. The DSM-5 emphasized that excessive worrying had to occur more days than not and on a number of different topics. It has been stated that the constant changes in the diagnostic features of the disorder have made assessing epidemiological statistics such as prevalence and incidence difficult, as well as increasing the difficulty for researchers in identifying the biological and psychological underpinnings of the disorder. Consequently, making specialized medications for the disorder is more difficult as well. This has led to the continuation of GAD being medicated heavily with SSRIs.

Risk Factors

Genetics, Family and Environment

The relationship between genetics and anxiety disorders is an ongoing area of research. It is broadly understood that there exists an hereditary basis for GAD, but the exact nature of this hereditary basis is not fully appreciated. While investigators have identified several genetic loci that are regions of interest for further study, there is no singular gene or set of genes that have been identified as causing GAD. Nevertheless, genetic factors may play a role in determining whether an individual is at greater risk for developing GAD, structural changes in the brain related to GAD, or whether an individual is more or less likely to respond to a particular treatment modality. Genetic factors that may play a role in development of GAD are usually discussed in view of environmental factors (e.g. life experience or ongoing stress) that might also play a role in development of GAD. The traditional methods of investigating the possible hereditary basis of GAD include using family studies and twin studies (there are no known adoption studies of individuals who suffer anxiety disorders, including GAD). Meta-analysis of family and twin studies suggests that there is strong evidence of a hereditary basis for GAD in that GAD is more likely to occur in first-degree relatives of individuals who have GAD than in non-related individuals in the same population. Twin studies also suggest that there may be a genetic linkage between GAD and major depressive disorder (MDD), which may explain the common occurrence of MDD in individuals who suffer GAD (e.g. comorbidity of MDD in individuals with GAD has been estimated at approximately 60%). When GAD is considered among all anxiety disorders (e.g. panic disorder, social anxiety disorder), genetic studies suggest that hereditary contribution to the development of anxiety disorders amounts to only approximately 30-40%, which suggests that environmental factors are likely more important to determining whether an individual may develop GAD. In regard to environmental influences in the development of GAD, it has been suggested that parenting behaviour may be an important influence since parents potentially model anxiety-related behaviours. It has also been suggested that individuals who suffer GAD have experienced a greater number of minor stress-related events in life and that the number of stress-related events may be important in development of GAD (irrespective of other individual characteristics).

Studies of possible genetic contributions to the development of GAD have examined relationships between genes implicated in brain structures involved in identifying potential threats (e.g. in the amygdala) and also implicated in neurotransmitters and neurotransmitter receptors known to be involved in anxiety disorders. More specifically, genes studied for their relationship to development of GAD or demonstrated to have had a relationship to treatment response include:

  • PACAP (A54G polymorphism): remission after 6 month treatment with Venlafaxine suggested to have a significant relationship with the A54G polymorphism (Cooper et al. (2013)).
  • HTR2A gene (rs7997012 SNP G allele): HTR2A allele suggested to be implicated in a significant decrease in anxiety symptoms associated with response to 6 months of Venlafaxine treatment (Lohoff et al. (2013)).
  • SLC6A4 promoter region (5-HTTLPR): Serotonin transporter gene suggested to be implicated in significant reduction in anxiety symptoms in response to 6 months of Venlafaxine treatment (Lohoff et al. (2013)).

Pathophysiology

The pathophysiology of GAD is an active and ongoing area of research often involving the intersection of genetics and neurological structures. GAD has been linked to changes in functional connectivity of the amygdala and its processing of fear and anxiety. Sensory information enters the amygdala through the nuclei of the basolateral complex (consisting of lateral, basal and accessory basal nuclei). The basolateral complex processes the sensory-related fear memories and communicates information regarding threat importance to memory and sensory processing elsewhere in the brain, such as the medial prefrontal cortex and sensory cortices. Neurological structures traditionally appreciated for their roles in anxiety include the amygdala, insula and orbitofrontal cortex (OFC). It is broadly postulated that changes in one or more of these neurological structures are believed to allow greater amygdala response to emotional stimuli in individuals who have GAD as compared to individuals who do not have GAD.

Individuals who GAD have been suggested to have greater amygdala and medial prefrontal cortex (mPFC) activation in response to stimuli than individuals who do not have GAD. However, the exact relationship between the amygdala and the frontal cortex (e.g. prefrontal cortex or the orbitofrontal cortex (OFC)) is not fully understood because there are studies that suggest increased or decreased activity in the frontal cortex in individuals who have GAD. Consequently, because of the tenuous understanding of the frontal cortex as it relates to the amygdala in individuals who have GAD, it’s an open question as to whether individuals who have GAD bear an amygdala that is more sensitive than an amygdala in an individual without GAD or whether frontal cortex hyperactivity is responsible for changes in amygdala responsiveness to various stimuli. Recent studies have attempted to identify specific regions of the frontal cortex (e.g. dorsomedial prefrontal cortex (dmPFC)) that may be more or less reactive in individuals who have GAD or specific networks that may be differentially implicated in individuals who have GAD. Other lines of study investigate whether activation patterns vary in individuals who have GAD at different ages with respect to individuals who do not have GAD at the same age (e.g. amygdala activation in adolescents with GAD).

Treatment

Traditional treatment modalities broadly fall into two (2) categories:

  • Psychotherapeutic; and
  • Pharmacological intervention.

In addition to these two conventional therapeutic approaches, areas of active investigation include complementary and alternative medications (CAMs), brain stimulation, exercise, therapeutic massage and other interventions that have been proposed for further study. Treatment modalities can, and often are utilised concurrently so that an individual may pursue psychological therapy (i.e. psychotherapy) and pharmacological therapy. Both cognitive behavioural therapy (CBT) and medications (such as SSRIs) have been shown to be effective in reducing anxiety. A combination of both CBT and medication is generally seen as the most desirable approach to treatment. Use of medication to lower extreme anxiety levels can be important in enabling patients to engage effectively in CBT.

Psychotherapy

Psychotherapeutic interventions include a plurality of therapy types that vary based upon their specific methodologies for enabling individuals to gain insight into the working of the conscious and subconscious mind and which sometimes focus on the relationship between cognition and behaviour. Cognitive behavioural therapy (CBT) is widely regarded as the first-line psychological therapy for treating GAD. Additionally, many of these psychological interventions may be delivered in an individual or group therapy setting. While individual and group settings are broadly both considered effective for treating GAD, individual therapy tends to promote longer-lasting engagement in therapy (i.e. lower attrition over time).

Psychodynamic Therapy

Psychodynamic therapy is a type of therapy premised upon Freudian psychology in which a psychologist enables an individual explore various elements in their subconscious mind to resolve conflicts that may exist between the conscious and subconscious elements of the mind. In the context of GAD, the psychodynamic theory of anxiety suggests that the unconscious mind engages in worry as a defence mechanism to avoid feelings of anger or hostility because such feelings might cause social isolation or other negative attribution toward oneself. Accordingly, the various psychodynamic therapies attempt to explore the nature of worry as it functions in GAD in order to enable individuals to alter the subconscious practice of using worry as a defence mechanism and to thereby diminish GAD symptoms. Variations of psychotherapy include a near-term version of therapy, “short-term anxiety-provoking psychotherapy (STAPP).

Behavioural Therapy

Behavioural therapy is therapeutic intervention premised upon the concept that anxiety is learned through classical conditioning (e.g., in view of one or more negative experiences) and maintained through operant conditioning (e.g. one finds that by avoiding a feared experience that one avoids anxiety). Thus, behavioural therapy enables an individual to re-learn conditioned responses (behaviours) and to thereby challenge behaviours that have become conditioned responses to fear and anxiety, and which have previously given rise to further maladaptive behaviours.

Cognitive Therapy

Cognitive therapy (CT) is premised upon the idea that anxiety is the result of maladaptive beliefs and methods of thinking. Thus, CT involves assisting individuals to identify more rational ways of thinking and to replace maladaptive thinking patterns (i.e. cognitive distortions) with healthier thinking patterns (e.g. replacing the cognitive distortion of catastrophising with a more productive pattern of thinking). Individuals in CT learn how to identify objective evidence, test hypotheses, and ultimately identify maladaptive thinking patterns so that these patterns can be challenged and replaced.

Acceptance and Commitment Therapy

Acceptance and commitment therapy (ACT) is a behavioural treatment based on acceptance-based models. ACT is designed with the purpose to target three therapeutic goals:

  1. Reduce the use of avoiding strategies intended to avoid feelings, thoughts, memories, and sensations;
  2. Decreasing a person’s literal response to their thoughts (e.g., understanding that thinking “I’m hopeless” does not mean that the person’s life is truly hopeless); and
  3. Increasing the person’s ability to keep commitments to changing their behaviours.

These goals are attained by switching the person’s attempt to control events to working towards changing their behaviour and focusing on valued directions and goals in their lives as well as committing to behaviours that help the individual accomplish those personal goals. This psychological therapy teaches mindfulness (paying attention on purpose, in the present, and in a non-judgemental manner) and acceptance (openness and willingness to sustain contact) skills for responding to uncontrollable events and therefore manifesting behaviours that enact personal values. Like many other psychological therapies, ACT works best in combination with pharmacology treatments.

Intolerance of Uncertainty Therapy

Intolerance of uncertainty (IU) refers to a consistent negative reaction to uncertain and ambiguous events regardless of their likelihood of occurrence. Intolerance of uncertainty therapy (IUT) is used as a stand-alone treatment for GAD patients. Thus, IUT focuses on helping patients in developing the ability to tolerate, cope with and accept uncertainty in their life in order to reduce anxiety. IUT is based on the psychological components of psychoeducation, awareness of worry, problem-solving training, re-evaluation of the usefulness of worry, imagining virtual exposure, recognition of uncertainty, and behavioural exposure. Studies have shown support for the efficacy of this therapy with GAD patients with continued improvements in follow-up periods.

Motivational Interviewing

A promising innovative approach to improving recovery rates for the treatment of GAD is to combine CBT with motivational interviewing (MI). Motivational interviewing is a strategy centred on the patient that aims to increase intrinsic motivation and decrease ambivalence about change due to the treatment. MI contains four key elements:

  • Express empathy;
  • Heighten dissonance between behaviours that are not desired and values that are not consistent with those behaviours;
  • Move with resistance rather than direct confrontation; and
  • Encourage self-efficacy.

It is based on asking open-ended questions and listening carefully and reflectively to patients’ answers, eliciting “change talk”, and talking with patients about the pros and cons of change. Some studies have shown the combination of CBT with MI to be more effective than CBT alone.

Cognitive Behavioural Therapy

Cognitive behavioural therapy (CBT) is an evidence-based type of psychotherapy that demonstrates efficacy in treating GAD and which integrates the cognitive and behavioural therapeutic approaches. The objective of CBT is to enable individuals to identify irrational thoughts that cause anxiety and to challenge dysfunctional thinking patterns by engaging in awareness techniques such as hypothesis testing and journaling. Because CBT involves the practice of worry and anxiety management, CBT includes a plurality of intervention techniques that enable individuals to explore worry, anxiety and automatic negative thinking patterns. These interventions include anxiety management training, cognitive restructuring, progressive relaxation, situational exposure and self-controlled desensitisation.

Other forms of psychological therapy include:

  • Relaxation techniques (e.g. relaxing imagery, meditational relaxation).
  • Metacognitive Therapy (MCT):
    • The objective of MCT is to alter thinking patterns regarding worry so that worry is no longer used as a coping strategy.
  • Mindfulness based stress reduction (MBSR).
  • Mindfulness based cognitive therapy (MBCT).
  • Supportive therapy:
    • This is a Rogerian method of therapy in which subjects experience empathy and acceptance from their therapist to facilitate increasing awareness.
    • Variations of active supportive therapy include Gestalt therapy, Transactional analysis and Counselling.

Pharmacotherapy

Historically, benzodiazepines (BZs) were used prominently to treat anxiety starting in the 1970s but support for this use attenuated in view of the risk for dependence and tolerance to the medication. BZs can have a plurality of effects that made them a seemingly desirable option for treating anxiety – i.e. BZs have anxiolytic, hypnotic (induce sleep), myorelaxant (relax muscles), anticonvulsant and amnestic (impair short-term memory) properties. While BZs are well appreciated for their ability to alleviate anxiety (i.e. their anxiolytic properties) shortly after administration, they are also known for their ability to promote dependence and are frequently abused. Current recommendations for using BZs to treat anxiety in GAD allow no more than 2-4 weeks of BZ exposure. Antidepressants (e.g. SSRIs/SNRIs) have become a mainstay in treating GAD in adults. First-line mediations from any drug category often include drugs that have been approved by the US Food and Drug Administration (FDA) for treating GAD because these medications have been proven safe and effective for treating GAD.

FDA-Approved Medications for Treating GAD

FDA-approved medications for treating GAD include:

  • SSRIs:
    • Paroxetine.
    • Escitalopram.
  • SNRIs:
    • Venlafaxine.
    • Duloxetine.
  • Benzodiazepines (BZs):
    • Alprazolam: Alprazolam is the only FDA-approved BZ for treating GAD.
  • Azapirones:
    • Buspirone.

Non-FDA Approved Medications

While certain medications are not specifically FDA approved for treatment of GAD, there are a number of medications that historically have been used or studied for treating GAD. Other medications that have been used or evaluated for treating GAD include:

  • SSRIs (antidepressants):
    • Citalopram.
    • Fluoxetine.
    • Sertraline.
    • Fluvoxamine (SSRI).
  • Benzodiazepines:
    • Clonazepam.
    • Lorazepam.
    • Diazepam.
  • GABA analogs:
    • Pregabalin (atypical anxiolytic, GABA analog).
    • Tiagabine.
  • Second-generation antipsychotics (SGAs):
    • Olanzapine (evidence of effectiveness is merely a trend).
    • Ziprasidone.
    • Risperidone.
    • Aripiprazole (studied as an adjunctive measure in concert with other treatment).
    • Quetiapine (atypical antipsychotic studied as an adjunctive measure in adults and geriatric patients).
  • Antihistamines:
    • Hydroxyzine (H1 receptor antagonist).
  • Vilazodone (atypical antidepressant).
  • Agomelatine (antidepressant, MT1/2 receptor agonist, 5HT2c antagonist).
  • Clonidine (noted to cause decreased blood pressure and other AEs).
  • Guanfacine (a2A receptor agonist, studied in paediatric patients with GAD).
  • Mirtazapine (atypical antidepressant having 5HT2A and 5HT2c receptor affinity).
  • Vortioxetine (multimodal antidepressant).
  • Eszopiclone (non-benzodiazepine hypnotic).
  • Tricyclic antidepressants:
    • Amitriptyline.
    • Clomipramine.
    • Doxepin.
    • Imipramine.
    • Trimipramine.
    • Desipramine.
    • Nortriptyline.
    • Protriptyline.
  • Opipramol (atypical TCA).]
  • Trazodone.
  • Monamine oxidase inhibitors (MAOIs):
    • Tranylcypromine.
    • Phenelzine.
  • Homeopathic preparations (discussed below, see complementary and alternative medications (CAMs))

Selective Serotonin Reuptake Inhibitors

Pharmaceutical treatments for GAD include selective serotonin reuptake inhibitors (SSRIs).[50] SSRIs increase serotonin levels through inhibition of serotonin reuptake receptors.

FDA approved SSRIs used for this purpose include escitalopram and paroxetine. However, guidelines suggest using sertraline first due to its cost-effectiveness compared to other SSRIs used for GAD and a lower risk of withdrawal compared to SNRIs. If sertraline is found to be ineffective, then it is recommended to try another SSRI or SNRI.

Common side effects include nausea, sexual dysfunction, headache, diarrhoea, constipation, restlessness, increased risk of suicide in young adults and adolescents, among others. Sexual side effects, weight gain, and higher risk of withdrawal are more common in paroxetine than escitalopram and sertraline. In older populations or those taking concomitant medications that increase risk of bleeding, SSRIs may further increase the risk of bleeding. Overdose of an SSRI or concomitant use with another agent that causes increased levels of serotonin can result in serotonin syndrome, which can be life-threatening.

Serotonin Norepinephrine Reuptake Inhibitors

First line pharmaceutical treatments for GAD also include serotonin-norepinephrine reuptake inhibitors (SNRIs). These inhibit the reuptake of serotonin and noradrenaline to increase their levels in the CNS.

FDA approved SNRIs used for this purpose include duloxetine (Cymbalta) and venlafaxine (Effexor). While SNRIs have similar efficacy as SSRIs, many psychiatrists prefer to use SSRIs first in the treatment of GAD The slightly higher preference for SSRIs over SNRIs as a first choice for treatment of anxiety disorders may have been influenced by the observation of poorer tolerability of the SNRIs in comparison to SSRIs in systematic reviews of studies of depressed patients.

Side effects common to both SNRIs include anxiety, restlessness, nausea, weight loss, insomnia, dizziness, drowsiness, sweating, dry mouth, sexual dysfunction and weakness. In comparison to SSRIs, the SNRIs have a higher prevalence of the side effects of insomnia, dry mouth, nausea and high blood pressure. Both SNRIs have the potential for discontinuation syndrome after abrupt cessation, which can precipitate symptoms including motor disturbances and anxiety and may require tapering. Like other serotonergic agents, SNRIs have the potential to cause serotonin syndrome, a potentially fatal systemic response to serotonergic excess that causes symptoms including agitation, restlessness, confusion, tachycardia, hypertension, mydriasis, ataxia, myoclonus, muscle rigidity, diaphoresis, diarrhoea, headache, shivering, goose bumps, high fever, seizures, arrhythmia and unconsciousness. SNRIs like SSRIs carry a black box warning for suicidal ideation, but it is generally considered that the risk of suicide in untreated depression is far higher than the risk of suicide when depression is properly treated.

Pregabalin and Gabapentin

Pregabalin (Lyrica) acts on the voltage-dependent calcium channel to decrease the release of neurotransmitters such as glutamate, norepinephrine and substance P. Its therapeutic effect appears after 1 week of use and is similar in effectiveness to lorazepam, alprazolam and venlafaxine but pregabalin has demonstrated superiority by producing more consistent therapeutic effects for psychic and somatic anxiety symptoms. Long-term trials have shown continued effectiveness without the development of tolerance and additionally, unlike benzodiazepines, it does not disrupt sleep architecture and produces less severe cognitive and psychomotor impairment. It also has a low potential for abuse and dependency and may be preferred over the benzodiazepines for these reasons. The anxiolytic effects of pregabalin appear to persist for at least six months continuous use, suggesting tolerance is less of a concern; this gives pregabalin an advantage over certain anxiolytic medications such as benzodiazepines.

Gabapentin (Neurontin), a closely related medication to pregabalin with the same mechanism of action, has also demonstrated effectiveness in the treatment of GAD, though unlike pregabalin, it has not been approved specifically for this indication. Nonetheless, it is likely to be of similar usefulness in the management of this condition, and by virtue of being off-patent, it has the advantage of being significantly less expensive in comparison. In accordance, gabapentin is frequently prescribed off-label to treat GAD.

Complementary and Alternative Medicines Studied for Potential in Treating GAD

Complementary and alternative medicines (CAMs) are widely used by individuals who suffer GAD despite having no evidence or varied evidence regarding efficacy. Efficacy trials for CAM medications often suffer from various types of bias and low quality reporting in regard to safety. In regard to efficacy, critics point out that CAM trials sometimes predicate claims of efficacy based on a comparison of a CAM against a known drug after which no difference in subjects is found by investigators and which is used to suggest an equivalence between a CAM and a drug. Because this equates a lack of evidence with the positive assertion of efficacy, a “lack of difference” assertion is not a proper claim for efficacy. Moreover, an absence of strict definitions and standards for CAM compounds further burdens the literature regarding CAM efficacy in treating GAD. CAMs academically studied for their potential in treating GAD or GAD symptoms along with a summary of academic findings are given below. What follows is a summary of academic findings. Accordingly, none of the following should be taken as offering medical guidance or an opinion as to the safety or efficacy of any of the following CAMs.

  • Kava Kava (Piper methysticum) extracts:
    • Meta analysis does not suggest efficacy of Kava Kava extracts due to few data available yielding inconclusive results or non-statistically significant results.
    • Nearly a quarter (25.8%) of subjects experienced adverse effects (AEs) from Kava Kava extracts during six (6) trials.
    • Kava Kava may cause liver toxicity.
  • Lavender (Lavandula angustifolia) extracts:
    • Small and varied studies may suggest some level of efficacy as compared to placebo or other medication; claims of efficacy are regarded as needing further evaluation.
    • Silexan is an oil derivative of Lavender studied in paediatric patients with GAD.
    • Concern exists regarding the question as to whether Silexan may cause unopposed oestrogen exposure in boys due to disruption of steroid signalling.
  • Galphimia glauca extracts:
    • While Galphima glauca extracts have been the subject of two (2) randomised controlled trials (RCTs) comparing Galphima glauca extracts to lorazepam, efficacy claims are regarded as “highly uncertain.”
  • Chamomile (Matricaria chamomilla) extracts:
    • Poor quality trials have trends that may suggest efficacy but further study is needed to establish any claim of efficacy.
  • Crataegus oxycantha and Eschscholtzia californica extracts combined with magnesium:
    • A single12-week trial of Crataegus oxycantha and Eschscholtzia californica compared to placebo has been used to suggest efficacy.
    • However, efficacy claims require confirmation studies.
    • For the minority of subjects who experienced AEs from extracts, most AEs implicated gastrointestinal tract (GIT) intolerance.
  • Echium amoneum extract:
    • A single, small trial used this extract as a supplement to fluoxetine (vs using a placebo to supplement fluoxetine); larger studies are needed to substantiate efficacy claims.
  • Gamisoyo-San:
    • Small trials of this herbal mixture compared to placebo have suggested no efficacy of the herbal mixture over placebo but further study is necessary to allow definitive conclusion of a lack of efficacy.
  • Passiflora incarnata extract:
    • Claims of efficacy or benzodiazepam equivalence are regarded as “highly uncertain.”
  • Valeriana extract:
    • A single 4-week trial suggests no effect of Valeriana extract on GAD but is regarded as “uninformative” on the topic of efficacy in view of its finding that the benzodiazepine diazepam also had no effect.
    • Further study may be warranted.

Other Possible Modalities Discussed in Literature for Potential in Treating GAD

Other modalities that have been academically studied for their potential in treating GAD or symptoms of GAD are summarised below. What follows is a summary of academic findings. Accordingly, none of the following should be taken as offering medical guidance or an opinion as to the safety or efficacy of any of the following modalities.

  • Acupuncture:
    • A single, very small trial revealed a trend toward efficacy but flaws in the trial design suggest uncertainty regarding efficacy.
  • Balneotherapy:
    • Data from a single non-blinded study suggested possible efficacy of balneotherapy as compared to paroxetine.
    • However, efficacy claims need confirmation.
  • Therapeutic massage:
    • A single, small, possibly biased study revealed inconclusive results.
  • Resistance and aerobic exercise:
    • When compared to no treatment, a single, small, potentially unrepresentative trial suggested a trend toward GAD remission and reduction of worry.
  • Chinese bloodletting:
    • When added to paroxetine, a single, small, imprecise trial that lacked a sham procedure for comparison suggested efficacy at 4-weeks.
    • However, larger trials are needed to evaluate this technique as compared to a sham procedure.
  • Floating in water:
    • When compared to no treatment, a single, imprecise, non-blinded trial suggested a trend toward efficacy (findings were statistically insignificant).
  • Swedish massage:
    • When compared to a sham procedure, a single trial showed a trend toward efficacy (i.e. findings were statistically insignificant).
  • Ayurvedic medications:
    • A single non-blinded trial was inconclusive as to whether Ayurvedic medications were effective in treating GAD.
  • Multi-faith spiritually-based intervention:
    • A single, small, non-blinded study was inconclusive regarding efficacy.

Lifestyle

Lifestyle factors including: stress management, stress reduction, relaxation, exercise, sleep hygiene, and caffeine and alcohol reduction can influence anxiety levels. Physical activity has shown to have a positive impact whereas low physical activity may be a risk factor for anxiety disorders.

Substances and Anxiety in GAD

While there are no substances that are known to cause GAD, certain substances or the withdrawal from certain substances have been implicated in promoting the experience of anxiety. For example, even while benzodiazepines may afford individuals with GAD relief from anxiety, withdrawal from benzodiazepines is associated with the experience of anxiety among other adverse events like sweating and tremor.

Tobacco withdrawal symptoms may provoke anxiety in smokers and excessive caffeine use has been linked to aggravating and maintaining anxiety.

Comorbidity

Depression

In the National Comorbidity Survey (2005), 58% of patients diagnosed with major depression were found to have an anxiety disorder; among these patients, the rate of comorbidity with GAD was 17.2%, and with panic disorder, 9.9%. Patients with a diagnosed anxiety disorder also had high rates of comorbid depression, including 22.4% of patients with social phobia, 9.4% with agoraphobia, and 2.3% with panic disorder. A longitudinal cohort study found 12% of the 972 participants had GAD comorbid with MDD. Accumulating evidence indicates that patients with comorbid depression and anxiety tend to have greater illness severity and a lower treatment response than those with either disorder alone. In addition, social function and quality of life are more greatly impaired.

For many, the symptoms of both depression and anxiety are not severe enough (i.e. are subsyndromal) to justify a primary diagnosis of either major depressive disorder (MDD) or an anxiety disorder. However, dysthymia is the most prevalent comorbid diagnosis of GAD clients. Patients can also be categorised as having mixed anxiety-depressive disorder, and they are at significantly increased risk of developing full-blown depression or anxiety.

Various explanations for the high comorbidity between GAD and depressive disorders have been suggested, including genetic pleiotropy, meaning that GAD and nonbipolar depression might represent different phenotypic expressions of a common aetiology.

Comorbidity and Treatment

Therapy has been shown to have equal efficacy in patients with GAD and patients with GAD and comorbid disorders. Patients with comorbid disorders have more severe symptoms when starting therapy but demonstrated a greater improvement than patients with simple GAD.

Pharmacological approaches i.e. the use of antidepressants must be adapted for different comorbidities. For example, serotonin reuptake inhibitors and short acting benzodiazepines (BZDs) are used for depression and anxiety. However, for patients with anxiety and substance abuse, BZDs should be avoided due to their abuse liability. CBT has been found an effective treatment since it improves symptoms of GAD and substance abuse.

Compared to the general population, patients with internalising disorders such as depression, GAD and post-traumatic stress disorder (PTSD) have higher mortality rates, but die of the same age-related diseases as the population, such as heart disease, cerebrovascular disease and cancer.

GAD often coexists with conditions associated with stress, such as muscle tension and irritable bowel syndrome.

Patients with GAD can sometimes present with symptoms such as insomnia or headaches as well as pain and interpersonal problems.

Further research suggests that about 20% to 40% of individuals with attention deficit hyperactivity disorder have comorbid anxiety disorders, with GAD being the most prevalent.

Those with GAD have a lifetime comorbidity prevalence of 30% to 35% with alcohol use disorder and 25% to 30% for another substance use disorder. People with both GAD and a substance use disorder also have a higher lifetime prevalence for other comorbidities. A study found that GAD was the primary disorder in slightly more than half of the 18 participants that were comorbid with alcohol use disorder.

Epidemiology

GAD is often estimated to affect approximately 3-6% of adults and 5% of children and adolescents. Although estimates have varied to suggest a GAD prevalence of 3% in children and 10.8% in adolescents. When GAD manifests in children and adolescents, it typically begins around 8 to 9 years of age.

Estimates regarding prevalence of GAD or lifetime risk (i.e. lifetime morbid risk (LMR)) for GAD vary depending upon which criteria are used for diagnosing GAD (e.g. DSM-5 vs ICD-10) although estimates do not vary widely between diagnostic criteria. In general, ICD-10 is more inclusive than DSM-5, so estimates regarding prevalence and lifetime risk tend to be greater using ICD-10. In regard to prevalence, in a given year, about two (2%) percent of adults in the United States and Europe have been suggested to suffer GAD. However, the risk of developing GAD at any point in life has been estimated at 9.0%. Although it is possible to experience a single episode of GAD during one’s life, most people who experience GAD experience it repeatedly over the course of their lives as a chronic or ongoing condition. GAD is diagnosed twice as frequently in women as in men and is more often diagnosed in those who are separated, divorced, unemployed, widowed or have low levels of education, and among those with low socioeconomic status. African Americans have higher odds of having GAD and the disorder often manifests itself in different patterns. It has been suggested that greater prevalence of GAD in women may be because women are more likely than men to live in poverty, are more frequently the subject of discrimination, and be sexually and physically abused more often than men. In regard to the first incidence of GAD in an individual’s life course, a first manifestation of GAD usually occurs between the late teenage years and the early twenties with the median age of onset being approximately 31 and mean age of onset being 32.7. However, GAD can begin or reoccur at any point in life. Indeed, GAD is common in the elderly population.

  • US: Approximately 3.1% of people age 18 and over in a given year (9.5 million).
  • UK: 5.9% of adults were affected by GAD in 2019.
  • Australia: 3% of adults
  • Canada: 2.5%.
  • Italy: 2.9%
  • Taiwan: 0.4%.

What is Exposure Therapy?

Introduction

Exposure therapy is a technique in behaviour therapy to treat anxiety disorders. Exposure therapy involves exposing the target patient to the anxiety source or its context without the intention to cause any danger. Doing so is thought to help them overcome their anxiety or distress. Procedurally, it is similar to the fear extinction paradigm developed studying laboratory rodents. Numerous studies have demonstrated its effectiveness in the treatment of disorders such as generalised anxiety disorder (GAD), social anxiety disorder, obsessive-compulsive disorder (OCD), post traumatic stress disorder (PTSD), and specific phobias.

Brief History

The use of exposure as a mode of therapy began in the 1950s, at a time when psychodynamic views dominated Western clinical practice and behavioural therapy was first emerging. South African psychologists and psychiatrists first used exposure as a way to reduce pathological fears, such as phobias and anxiety-related problems, and they brought their methods to England in the Maudsley Hospital training programme.

Joseph Wolpe (1915-1997) was one of the first psychiatrists to spark interest in treating psychiatric problems as behavioural issues. He sought consultation with other behavioural psychologists, among them James G. Taylor (1897-1973), who worked in the psychology department of the University of Cape Town in South Africa. Although most of his work went unpublished, Taylor was the first psychologist known to use exposure therapy treatment for anxiety, including methods of situational exposure with response prevention – a common exposure therapy technique still being used. Since the 1950s several sorts of exposure therapy have been developed, including systematic desensitisation, flooding, implosive therapy, prolonged exposure therapy, in vivo exposure therapy, and imaginal exposure therapy.

Medical Uses

Generalised Anxiety Disorder

There is empirical evidence that exposure therapy can be an effective treatment for people with generalised anxiety disorder, citing specifically in vivo exposure therapy, which has greater effectiveness than imaginal exposure in regards to generalized anxiety disorder. The aim of in vivo exposure treatment is to promote emotional regulation using systematic and controlled therapeutic exposure to traumatic stimuli.

Phobia

Exposure therapy is the most successful known treatment for phobias. Several published meta-analyses included studies of one-to-three hour single-session treatments of phobias, using imaginal exposure. At a post-treatment follow-up four years later 90% of people retained a considerable reduction in fear, avoidance, and overall level of impairment, while 65% no longer experienced any symptoms of a specific phobia.

Agoraphobia and social anxiety disorder are examples of phobias that have been successfully treated by exposure therapy.

Post Traumatic Stress Disorder

Virtual reality exposure (VRE) therapy is a modern but effective treatment of post-traumatic stress disorder (PTSD). This method was tested on several active duty Army soldiers, using an immersive computer simulation of military settings over six sessions. Self-reported PTSD symptoms of these soldiers were greatly diminished following the treatment. Exposure therapy has shown promise in the treatment of co-morbid PTSD and substance abuse.

Obsessive Compulsive Disorder

Exposure and response prevention (also known as exposure and ritual prevention; ERP or EX/RP) is a variant of exposure therapy that is recommended by the American Academy of Child and Adolescent Psychiatry (AACAP), the American Psychiatric Association (APA), and the Mayo Clinic as first-line treatment of obsessive compulsive disorder (OCD) citing that it has the richest empirical support for both youth and adolescent outcomes.

ERP is predicated on the idea that a therapeutic effect is achieved as subjects confront their fears, but refrain from engaging in the escape response or ritual that delays or eliminates distress. In the case of individuals with OCD or an anxiety disorder, there is a thought or situation that causes distress. Individuals usually combat this distress through specific behaviours that include avoidance or rituals. However, ERP involves purposefully evoking fear, anxiety, and or distress in the individual by exposing him/her to the feared stimulus. The response prevention then involves having the individual refrain from the ritualistic or otherwise compulsive behaviour that functions to decrease distress. The patient is then taught to tolerate distress until it fades away on its own, thereby learning that rituals are not always necessary to decrease distress or anxiety. Over repeated practice of ERP, patients with OCD expect to find that they can have obsessive thoughts and images but not have the need to engage in compulsive rituals to decrease distress.

The AACAP’s practise parameters for OCD recommends cognitive behavioural therapy, and more specifically ERP, as first line treatment for youth with mild to moderate severity OCD and combination psychotherapy and pharmacotherapy for severe OCD. The Cochrane Review’s examinations of different randomised control trials echoes repeated findings of the superiority of ERP over waitlist control or pill-placebos, the superiority of combination ERP and pharmacotherapy, but similar effect sizes of efficacy between ERP or pharmacotherapy alone.

Techniques

Exposure therapy is based on the principle of respondent conditioning often termed Pavlovian extinction. The exposure therapist identifies the cognitions, emotions and physiological arousal that accompany a fear-inducing stimulus and then tries to break the pattern of escape that maintains the fear. This is done by exposing the patient to progressively stronger fear-inducing stimuli. Fear is minimised at each of a series of steadily escalating steps or challenges (a hierarchy), which can be explicit (“static”) or implicit (“dynamic” – refer to Method of Factors) until the fear is finally gone. The patient is able to terminate the procedure at any time.

There are three types of exposure procedures. The first is in vivo or “real life.” This type exposes the patient to actual fear-inducing situations. For example, if someone fears public speaking, the person may be asked to give a speech to a small group of people. The second type of exposure is imaginal, where patients are asked to imagine a situation that they are afraid of. This procedure is helpful for people who need to confront feared thoughts and memories. The third type of exposure is interoceptive, which may be used for more specific disorders such as panic or post-traumatic stress disorder. Patients confront feared bodily symptoms such as increased heart rate and shortness of breath. All types of exposure may be used together or separately.

While evidence clearly supports the effectiveness of exposure therapy, some clinicians are uncomfortable using imaginal exposure therapy, especially in cases of PTSD. They may not understand it, are not confident in their own ability to use it, or more commonly, they see significant contraindications for their client.

Flooding therapy also exposes the patient to feared stimuli, but it is quite distinct in that flooding starts at the most feared item in a fear hierarchy, while exposure starts at the least fear-inducing.

Exposure and Response Prevention

In the exposure and response prevention (ERP or EX/RP) variation of exposure therapy, the resolution to refrain from the escape response is to be maintained at all times and not just during specific practice sessions. Thus, not only does the subject experience habituation to the feared stimulus, but they also practice a fear-incompatible behavioural response to the stimulus. The distinctive feature is that individuals confront their fears and discontinue their escape response. The American Psychiatric Association recommends ERP for the treatment of OCD, citing that ERP has the richest empirical support.

While this type of therapy typically causes some short-term anxiety, this facilitates long-term reduction in obsessive and compulsive symptoms. Generally, ERP incorporates a relapse prevention plan toward the end of the course of therapy.

Mindfulness

A 2015 review pointed out parallels between exposure therapy and mindfulness, stating that mindful meditation “resembles an exposure situation because [mindfulness] practitioners ‘turn towards their emotional experience’, bring acceptance to bodily and affective responses, and refrain from engaging in internal reactivity towards it.” Imaging studies have shown that the ventromedial prefrontal cortex, hippocampus, and the amygdala are all affected by exposure therapy; imaging studies have shown similar activity in these regions with mindfulness training.

Research

Exposure therapy can be investigated in the laboratory using Pavlovian extinction paradigms. Using rodents such as rats or mice to study extinction allows for the investigation of underlying neurobiological mechanisms involved, as well as testing of pharmacological adjuncts to improve extinction learning.

Book: Pocket Therapy for Anxiety

Book Title:

Pocket Therapy for Anxiety: Quick CBT Skills to Find Calm (New Harbinger Pocket Therapy).

Author(s): Edmund J. Bourne.

Year: 2020.

Edition: First (1st).

Publisher: New Harbinger.

Type(s): Paperback and Kindle.

Synopsis:

Quick, simple, and effective anxiety relief that fits right in your pocket-so you can manage your symptoms anytime, anywhere.

If you suffer from anxiety, you may try to avoid the situations that cause you to feel uneasy. But avoidance is not the answer-and letting your fears and worries constantly hold you back will ultimately keep you from living the life you truly want. So, how can you learn to cope with your anxiety in the moment? This little book can help you face your fears and take charge of your anxiety-wherever or whenever it shows up.

From the author of The Anxiety and Phobia Workbook and Coping with Anxiety, Pocket Therapy for Anxiety offers immediate, user-friendly, and evidence-based strategies to help you manage anxiety, panic, and fear. The exercises in this book can be done in the moment, whenever you feel anxious, and will help you move past your fears and start living the life you were meant to live.

You will learn to:

  • Relax your body and mind.
  • Stop expecting the worst.
  • Get regular exercise and eat right to stay calm.
  • Turn off worry and cope on the spot.
  • And much, much more…

Do not let anxiety keep you one step behind. This little book will show you how to face your fears, overcome panic when it happens, and take charge of your anxiety for good!