Introduction

Anxiety disorder is a group of mental illnesses that relate to physical and emotional symptoms of fear, which is considered as ‘functional psychiatric disorders’ such as anxiety at work or anxiety prior to the exam. Students need to note that anxiety is a part of our daily life however, clinically anxiety disorders are identified when the illness produces significant functional impact. Anxiety symptoms may be associated to other psychiatric (eg depression) or physical disorders (eg hyperthyroidism).

Anxiety disorders are divided into many subgroups, each having unique features including epidemiology, pathogenesis, clinical presentation and treatment regimen but also share many of the common features. Examples of anxiety disorders are generalised anxiety disorder, panic disorder, obsessive compulsive disorder (OCD), acute stress disorder, post traumatic stress disorder (PTSD), social phobia and specific phobia (e.g. arachnophobia, ophidiophobia, acrophobia, agoraphonia, etc.).

The aetiologies of anxiety disorders are multi-factorial and not fully understood. Different types of anxiety disorder appear to have different aetiology and/or pathophysiology. The epidemiology of anxiety is very difficult to predict, which is mainly affected by variations and non-specific diagnostic criteria(s), culture’s perception and lack of awareness, difference between different types of anxiety disorders and interpretation of “significant functional impact”. Genetic factors exhibit significant risk in developing anxiety disorder, but significant stressors are often observed. Some individuals appear to be resilient to stress, but others can be very vulnerable. Family history appears to be associated with most type of anxiety disorders.

A. Generalised anxiety disorder (GAD) is a long-term disorder. It is very common and affects up to 5% of the population. Diagnostic criteria for GAD include excessive anxiety and pervasive and uncontrollable worry about a number of events or activities, and which occurs for a period of 6 months or longer. Common symptoms of GAD include restlessness, easily fatigue, difficulty concentrating or ‘mind gone blank’, irritability, muscle tension and sleep disturbance.

There is overlap between GAD and other anxiety disorders, and it often coexists with and may mask major depressive disorder and/or dysthymic disorder. Organic factors (eg hyperthyroidism, caffeine intoxication, stimulant use, alcohol/drug discontinuation syndrome) or adverse effects of prescribed drugs or over-the-counter medication must be excluded. An adjustment disorder, as defined in Adjustment disorder with anxious mood, must also be excluded. When middle-aged or older patients first present with anxiety symptoms, exclude depression or dementia as the primary cause of the anxiety symptoms.

B. Panic disorder is the reoccurrence of sudden onset of symptoms (panic episode/attack), such as fear of dying, fear of change or discomfort which may be presented with psychological induced physical symptoms, such as chest pain and shortness of breath. Care must be taken for clinical assessment to eliminate potential medical causes of the symptoms and or other mental illnesses. Patients who experience multiple panic episodes often develop personality changes e.g., avoidance behaviour, becoming very passive, dependence and withdrawal (social or mental).

Pathogenesis – Panic disorder is strongly associated with genetic predisposition and neurological dysfunction e.g. catechol-O-methyltransferase gene polymorphism, autonomic dysfunction, increased GABA-ergic tone, increased cortisol level etc.

The common stimulants for panic attacks are injury (accident and non-accident) and illness, interpersonal conflict or illness, use of stimulants (caffeine, decongestant, cannabis, cocaine, amphetamine), stimulant of social phobia or specific phobia, sudden treatment withdrawn (e.g. SSRI). Common symptoms include palpitation, sweating, chill, hot flush, shaking, SOB, chest pain, dizziness, headache etc.

C. Post-traumatic stress disorder (PTSD) – PTSD is an anxiety disorder develops after the patient is involved in, or has weakness, or was confronted by traumatic events such as injury, death or violation of one’s personal integrity. The severity and duration of PTSD varies widely among individuals. Exposure to traumatic events commonly results in a degree of psychological distress. In most instances, psychological symptoms of distress settle down in the days to weeks following the event. However, a minority of people exposed to traumatic events have persisting symptoms and develop acute stress disorder and/or posttraumatic stress disorder (PTSD). The symptoms of PTSD are divided into 4 main groups – develop the mentality of helplessness, intense fear or horror; experience repeating ‘flush back’, or intense psychological distress when confronted by cues that symbolised the event (e.g. Image, smell, person); avoidance, detachment or numbing response, ‘false amnesia’ of the event; and irritation, sleep disorder, extra vigilant, exaggerated responses. Children may only exhibit irritation or ‘unusual behaviour’, but with different characteristic symptoms at different age groups.

The pathogenesis of PTSD is associated with genetic predisposition, nature and proximity of trauma, prior experience of trauma (esp. during childhood) and posttraumatic factors (e.g. Social and psychological support).

D. Obsessive-compulsive disorder (OCD) – A condition that is characterised by one or more anxiety-provoking ideas, impulses (obsessions) or urges (compulsion), and requires taking specific/repeating actions until ‘it feels right’. These include cleanliness or contamination, safety, doubting one’s memory or perception, scrupulosity (psychological guilt, moral or religious issue), things that need to be arranged/done in a specific order, and intrusive thoughts of sexual or physical aggression. Common symptoms include frequent hand washing, cleaning, checking, hoarding, rituals, avoidance of human interaction, environment or situation.

E. Phobias – There are varieties of phobias including social phobia and specific phobias. The pathogenesis of phobia is not well understood but some phobias are related to genetics, previous exposure to event/trauma, cognitive distortion and neurological dysfunction.

📺 Watch the following lecture on introduction, symptoms and different types of anxiety disorders (18 minutes)

Treatment and management

The following general rules for managing anxiety disorders with some variations depending on the nature of the disorder.

1.      Identify the precipitating factor(s)

• Avoid or eliminate the factors
• Social support and reassurance may be all that is required.

2.      Psychotherapies

• Consider as first line intervention therapy for all anxiety disorders. The psychotherapies are psychological, including counselling, relaxation, problem solving, stress management, and cognitive behavioural therapy (CBT).

3.      Pharmacotherapy

Use as an adjunct to psychotherapy is the most recommended therapy for most anxiety disorders.

Solo therapy without psychological intervention is usually not recommended.

Treatment of anxiety disorders requires careful consideration of the individual patient, probable cause and severity of the symptoms. Psychological therapies are important as well as drug treatments and, for most patients, drug treatments alone are unlikely to achieve long-term recovery.

Classes of anxiolytic drugs

• Antidepressant drugs (SSRIs, SNRIs, TCAs and MAOIs, receptor-blocking antidepressants) are effective anxiolytic agents – already discussed
• Benzodiazepines are used for treating acute anxiety and insomnia.
• Gabapentin and pregabalin drugs have anxiolytic properties – will be discussed as Anti-epileptic drugs later
• Buspirone is a 5-hydroxytryptamine (5-HT)1A-receptor agonist with anxiolytic activity but little sedative effect.
• Some atypical antipsychotic agents (e.g. quetiapine) can be useful to treat some forms of anxiety but have significant unwanted effects.
• β-Adrenoceptor antagonists (e.g. propranolol) are used mainly to reduce physical symptoms of anxiety (tremors, palpitations, etc.); no effect on affective component.

Pharmacotherapy should be commenced from the lower end of the recommended dose. Benzodiazepines (e.g., diazepam) can be given for short term therapy. Selective serotonin reuptake inhibitors (SSRIs, e.g., sertraline, citalopram, escitalopram) are the most effective pharmacotherapy for GAD and other anxieties. Please note that the antidepressants have already been discussed in the previous lecture.

In addition, the serotonin and noradrenaline reuptake inhibitors venlafaxine and duloxetine and atypical anti-depressants such as mirtazapine have demonstrated efficacy for GAD. Tricyclic antidepressants (TCAs, e.g., amitriptyline) are equally effective but not considered as 1st line due to adverse effects. Buspirone is another choice. Please refer to eTG for more details with dose and frequency.

Benzodiazepines and related drugs

You will need to review the GABA_A receptor/chloride ion channel in order to understand how anxiolytics and sedative hypnotics work.

GABA receptors are subdivided into GABA_A and GABA_B receptors. All GABA_A receptors are ligand-gated chloride channels, located in the membranes of postsynaptic cells. It is a very complex receptor system, made up of 5 protein subunits (pentamer) with up to 6 different types (with subtypes) of subunit.

The predominate subunits of GABA_A receptors are α, β and γ. The neurotransmitter GABA binds to the interface between the α and the β subunit, on the GABA_A receptor. When the GABA_A receptor-ionophore complex is activated by GABA there is an increase in chloride permeability and influx of chloride into the cell. This causes hyperpolarisation and decreased excitability of the neuron. This is because GABA is the main inhibitory neurotransmitter in the CNS. GABA is involved in about 30% of all CNS synapses, in many pathways and brain areas. Anxiolytic effects are mediated by GABA_A receptors containing the α₂ subunit, while sedation occurs through those with the α₁ subunit.

GABA_A receptors have several modulatory sites at which drugs act. These drugs include benzodiazepines, barbiturates and ‘z drugs’.

📺 Watch the following video on YouTube. The video can be found at https://www.nature.com/articles/s41401-018-0185-5/figures/1

📺 Watch part 1 of the lecture

Benzodiazepines (BZDs)

Benzodiazepines can be used on an ‘as needed’ basis to treat acute symptoms of anxiety.

First line treatment of anxiety disorders is non-pharmacological. Psychotherapy (such as cognitive behavioural therapy or CBT), long-term coping methods and lifestyle changes are the mainstay of treatment. However, if symptoms are severe, do not respond to CBT or continue to worsen, drug treatment may be added. Drug treatment for anxiety disorders include antidepressants (such as sertraline) and benzodiazepines (such as alprazolam). Antidepressants are first line drugs as BZDs can cause unwanted side effects and chronic use can lead to dependency. BZDs are effective for acute treatment of anxiety disorders (such as when waiting for the lag in therapeutic effect upon initiation of an antidepressant) or used on an ’as needed’ basis (such as before boarding an aeroplane in a patient with a fear of flying).

Most BZD end in the suffix (-pam or -zolam). Agents differ in pharmacokinetics, but not in effects. They can be classified as ultra short-acting, short-acting, intermediate-acting and long-acting based on half-life. Some BZDs include:

• Alprazolam
• Bromazepam
• Clobazam
• Diazepam
• Flunitrazepam
• Lorazepam
• Nitrazepam
• Oxazepam
• Temazepam.

Mechanism of actions of BZDs

Benzodiazepines bind to an allosteric site on the GABA receptor-ionophore.

BZDs are selective for GABA_A receptors. They bind specifically to an allosteric modulatory site on the GABA_A receptor, thought to be at the interface of the α and γ subunits. This then facilitates GABA binding to the GABA_A receptor as BZDs change the conformation of the active site and increase the affinity of GABA for the receptor. BZDs potentiate inhibitory effects of GABA by increasing the frequency of chloride channel opening and therefore exert anxiolytic and sedative effects. BZD do not occupy the entire GABA_A receptor or at the active site and they definitely DO NOT bind to a so-called “BZD receptor”.

BZD inverse agonists reduce binding of GABA to GABA_A receptors and thus GABA effects decrease and symptoms of anxiety increases. Flumazenil is a BZD antagonist and is used to treat BZD overdose. It has no effect on GABA binding to GABA_A receptors but it does block BZD agonists, such as diazepam, and inverse agonists from binding.

 

Therapeutic effects of BZDs include:

• Reduction in anxiety (anxiolytic) and aggression.
• Induction of sleep (sedative/hypnotic).
• Reduction in muscle tone (muscle relaxing).
• Anticonvulsant (antiepileptic).
• Anterograde amnesia (memory-impairing effects) for minor surgical or invasive procedures.

Adverse effects which limit the use of BZDs include:

• Drowsiness, confusion, amnesia, blurred vision and impaired coordination.
• Acute toxicity in overdose (prolonged sleep without serious respiratory or CNS depression).
• Enhanced respiratory and CNS depression with other sedating drugs such as alcohol, sedating antihistamines, opioids, other sedative/hypnotics and some antidepressants (eg mirtazapine).
• Tolerance and dependence (and therefore potential for abuse).
• BZD have a limited capacity in producing fatal CNS depression when used alone.

Barbiturates

Barbiturates have largely been superseded by BZDs.

Barbiturates act on the GABA_A receptor–ionophore complex as channel modulators and increase the duration of the chloride ion channel opening. Barbiturates bind to GABA_A with α and β subunits, similar to GABA. These drugs are fatal in overdose and are rarely used. Phenobarbital (phenobarbitone) is used mainly as an antiepileptic and thiopental is used to induce general anesthesia.

📚 Read/Explore. Read “Anxiolytic and Hypnotic Drugs” in Chapter 45 Nervous System (page 569-578) in Rang and Dale’s Pharmacology 9th Ed.

📺 Watch the following lecture on management of anxiety disorders with the main focus on Benzodiazepines (20 minutes)

Lecture Material: 

MP_W9_Lecture_CNS_Anxiolytics

Summary

• BZD are used for their anxiolytic, sedative, hypnotic, muscle relaxing and memory impairing effects.
• BZD can be used to manage acute symptoms of anxiety disorders and on an ‘as needed’ basis in anxiety. They are also used in the management of epilepsy, insomnia, muscle spasms and in minor surgical procedures.
• BZDs bind to an allosteric site on the GABA_A receptor and increase the affinity of GABA for the GABA_A receptor. In turn, the frequency of chloride channel opening increases and neuronal excitability decreases.
• Adverse effects of BZD include sedation, in-coordination, confusion, amnesia, blurred vision, tolerance and dependency.
• Barbiturates act as channel modulators on the GABA_A receptor-ionophore complex and increase the duration of the chloride ion channel opening.

💡Learning Activity

Q1) Which of the following statements about the pharmacological actions of benzodiazepines is correct?

1. They bind orthosterically to GABA_A receptors to increase the duration of channel opening.
2.  BZD have a preference for GABA_B receptors.
3. When used alone, BZDs are potentially life threatening in overdose due to respiratory and CNS depression.
4. Alprazolam is an ultra short acting BZD and is indication for use in panic attacks.
5. BZDs can cause sedation, confusion and blurred vision so patients should be counselled not to drive or operate machinery.
6. Activation of the α₂ subunit on the GABA_A receptor is associated with anxiolytic effects.

Q2) As most benzodiazepines have both anxiolytic and hypnotic effects, the benzodiazepine of choice is usually selected according to its required pharmacokinetic profile. What may be the preferred drug of choice in treating a patient with acute anxiety? (Tip – think about half-life)

1. Alprazolam
2. Phenobarbital
3. Zolpidem
4. Flunitrazepam
5. Carbamazepine.