Overview
This lecture covers drug treatment of anxiety and insomnia. It opens by framing the modest but statistically significant benefit of psychiatric drugs generally, then covers the societal burden of anxiety and its physiology (heightened sympathetic “fight or flight” activity), before working through non-pharmacological and pharmacological anxiety treatments (SSRIs, SNRIs, benzodiazepines, beta blockers). The bulk of the lecture is a detailed treatment of benzodiazepines as positive allosteric modulators of the GABAA receptor — their mechanism, side effects, tolerance, and dependence/withdrawal — before extending the same GABAergic framework to insomnia (causes, lifestyle treatment, and Z-drugs such as zopiclone) and briefly to other GABAergic drug uses (depression, general anaesthesia, muscle spasm).
Drug efficacy in context
- Excluding child mortality, many people had long lives even in the 1850s; modal age at death was 75.6.
- Eliminating cancer would only extend average lifespan by ~3 years; eliminating heart disease by ~2.5 years.
- Both drugs and psychotherapy give only modest benefit for mental health disorders: effect size/SMD of .36 (drugs) and .34 (therapy).
- Drugs often produce statistically significant but modest improvement.
Context for the whole lecture: pharmacological treatments for anxiety and insomnia are typically modestly, not dramatically, effective — this motivates the emphasis on non-pharmacological options and short courses of the more effective but riskier drugs.
Societal impact of anxiety and mental disorders
- Depression causes the largest societal impact (DALYs) of the mental disorders, followed by anxiety and schizophrenia.
- Mortality risk differs from disability burden. Ranked most to least deadly: eating disorders, schizophrenia, bipolar disorder, ADHD, depression, anxiety.
- Depressive and anxiety disorders (by DALY) are largest in the 20–39 year age bands and taper toward the youngest and oldest age groups.
What is anxiety
Anxiety is a psychological and physiological state responding to perceived threats, producing cognitive, physical, and emotional effects that interfere with normal activities. It causes an estimated $4 billion/year loss of work productivity in the US and affects 13% of people in the US.
Types of anxiety disorder:
- Generalised anxiety disorder (GAD): an ongoing state of excessive anxiety lacking any clear reason or focus; lifetime prevalence 6.2%.
- Social anxiety disorder: lifetime prevalence 13%.
- Panic disorder: lifetime prevalence 5.2%.
- Others: phobias, post-traumatic stress disorder, obsessive compulsive disorder.
Physiological cause and clinical presentation
Anxiety is caused by a heightened fight-or-flight response, resulting in elevated sympathetic nervous system activity.
- Psychological/emotional symptoms: anxiety, fear, nervousness, worry.
- Physical symptoms: palpitations, shortness of breath, dizziness, muscle tension.
Treatments for anxiety
Non-pharmacological
- CBT (SMD .39)
- Internet-based CBT (Hedges g .7–1.31)
- ACT (SMD .98)
- Mindfulness-based stress reduction (SMD 1.42)
- Exercise (SMD .425–.919)
- Fewer clinical trials exist for these compared with pharmacotherapy.
- Only ~20–30% of people adhere to exercise guidelines; aerobic activity can reduce baseline sympathetic nervous system activity.
Pharmacological — overview
- First line: SSRIs (e.g. escitalopram, SMD .23–.76); SNRIs (e.g. venlafaxine, SMD .5).
- Second line: benzodiazepines (SMD .4–1.25); anticonvulsants (e.g. gabapentin); beta blockers (e.g. propranolol); tricyclics.
SSRIs
Escitalopram is given as the first-line SSRI example; no further mechanism detail is given on this slide beyond its listing as first-line [slide does not elaborate].
SNRIs — venlafaxine (proposed mechanism)
Venlafaxine is a serotonin and noradrenaline reuptake inhibitor. Proposed steps by which it reduces anxiety:
- Reuptake inhibition increases noradrenaline in the synapse.
- This produces more α2 receptor activation.
- In the locus coeruleus, α2 activation normally prevents (inhibits) release of systemic noradrenaline — this suppresses the AC → cAMP → PKA signalling cascade in the postsynaptic-like autoreceptor pathway.
- Net effect: reduced central sympathetic outflow → decreased heart rate and blood pressure → fewer physical symptoms of anxiety.
Beta blockers — propranolol
- Propranolol is a non-selective β1 and β2 antagonist.
- Particularly useful in performance anxiety; reduces tremor.
- Blocks adrenaline binding at β1 and β2 receptors, reducing downstream AC → cAMP → PKA signalling and thereby reducing sympathetic nervous system effects and feelings of anxiety.
Do not use propranolol in people with asthma (non-selective β2 blockade risks bronchospasm) — stated in red on the slide as a key contraindication.
Benzodiazepines for anxiety
Benzodiazepines were once the most commonly prescribed drugs (1977) but can lead to serious drug dependency; once dependency develops, abrupt (“cold turkey”) cessation can cause seizure and death. They should only be used for 5–14 days to reduce dependency risk.
Mechanism (non-specific CNS depression): benzodiazepines increase GABAA receptor activity in the brain, which:
- Inhibits general CNS activity
- Reduces anxiety (a non-specific effect)
- Is used to induce sleep
- Acts as an anticonvulsant
- Acts as a muscle relaxant
Benzodiazepine and Z-drug pharmacology
GABAA receptor structure
- GABAA is a pentameric receptor (5 subunits), typically drawn as 2×α, 2×β, 1×γ (with alternative γ1-3 or δ, ε, θ, π subunits noted).
- Subunits arrange around a central Cl⁻ pore; each subunit contributes transmembrane segments (M1–M4).
- GABA binds between the α and β subunits (“GABA site”).
- Other labelled binding sites around the receptor: benzodiazepine (BZ) site (at the α–γ junction), barbiturate site, ethanol binding site, neurosteroid (NS) allosteric site, NS direct site.
- Subunit arrangement determines the activity/pharmacology of the receptor.
Mechanism of benzodiazepine action
Benzodiazepines (e.g. diazepam, midazolam) and Z-drugs (e.g. zopiclone) are positive allosteric modulators (PAMs) of GABAA:
- They do not have an effect in the absence of GABA (they are not agonists themselves).
- They bind to a different site than the endogenous agonist GABA — specifically the α–γ junction (the benzodiazepine site).
- When GABA is bound, benzodiazepine binding increases activation of GABAA and increases the frequency of ion channel opening.
- This increases Cl⁻ influx beyond that produced by GABA alone (no Cl⁻ influx with no ligand; normal Cl⁻ influx with GABA alone; increased Cl⁻ influx with GABA + benzodiazepine together).
- Increased Cl⁻ influx increases hyperpolarization of neurons, decreasing general neurotransmission throughout the brain.
How GABA inhibits neurotransmission
Activation of GABAA causes an influx of Cl⁻, making the membrane potential more negative and inhibiting action potential generation.
Comparison of GABA receptor subtypes:
| GABA_A | GABA_B | |
|---|---|---|
| Receptor type | Cl⁻ ion channel | Gi-coupled GPCR |
| Activation time | Milliseconds | ~100 milliseconds |
| Effect | Inhibition of action potential | Inhibition of action potential |
| Agonist | GABA, muscimol | GABA, baclofen |
Kinetics: GABA_A produces a faster and deeper hyperpolarizing deflection than GABA_B, with gradual recovery toward baseline; both are markedly slower/different in shape from the excitatory AMPA (fast sharp spike) and NMDA (slower spike) receptor-mediated potentials.
Benzodiazepine side effects
- High therapeutic index — very safe relative to barbiturates (difficult to overdose on).
- Drowsiness, decreased alertness, ataxia.
- Interact with other CNS depressants such as alcohol, barbiturates, and antihistamines.
Tolerance
- Tolerance to benzodiazepines is often associated with a decrease in GABAA receptors in particular brain areas.
- Also associated with changes in the coupling between the GABA and benzodiazepine binding sites on the receptor complex.
Dependence and withdrawal
- Physical dependence is the presence of withdrawal symptoms upon stopping a drug regimen.
- Withdrawal symptoms can be very severe: anxiety, irritability, insomnia, depression, tachycardia, profuse sweating, nausea, perceptual changes, and potentially seizure activity.
- Withdrawal must be gradual — abrupt withdrawal can be fatal.
- Other drugs may be used to facilitate withdrawal; psychotherapy is often necessary.
Benzodiazepine dependency and withdrawal is the recurring high-yield safety point of this lecture: limit use to 5–14 days, and never withdraw abruptly once dependence has developed.
Insomnia
Insomnia is a lack of sleep that leads to impairment of normal function.
- Intermittently affects 1/3 of adults; symptoms include excessive daytime sleepiness, irritability, and lack of energy.
- Chronic insomnia affects 1 in 10 adults; defined as insomnia for 3 nights a week over 3 months. Can lead to depression, anxiety, and reduced quality of life.
- Sleep deprivation has negative cognitive consequences: increased risk-taking behaviour (potentially via altered dopaminergic signalling) and increased desire for high-calorie foods.
Causes of insomnia
- Psychological: anxiety, depression, dementia, psychosis (symptoms include excessive daytime sleepiness, irritability, lack of energy).
- Physical: movement disorders, respiratory disorders, pain, bladder disorders.
- Drugs: alcohol (reduces sleep quality), caffeine and amphetamine (prevent sleep), beta blockers, diuretics.
- Environment: technology, work, family, financial stress; prevalence has increased ~13% over the past 5 years.
Treatment of insomnia
Lifestyle changes (sleep hygiene — habits that help achieve a good night’s sleep):
- Go to bed and get up at the same time each day.
- Avoid exercise for 2–3 hours before bedtime.
- Avoid caffeine and nicotine.
- Avoid drinking before bed (alcohol can interrupt REM sleep).
- Keep the room at a low temperature.
- Avoid screens for 1 hour before bed.
- Don’t lie in bed awake.
Drugs: benzodiazepines; Z-drugs, e.g. zopiclone.
Z-drugs for insomnia
- Use for only 5–14 days — longer use can cause dependence; use alongside sleep hygiene to improve sleeping routine.
- Zopiclone is a positive allosteric modulator for GABAA.
- Short duration of action (< 6 hours).
- Side effects: confusion, fatigue, drowsiness, muscle weakness; wide safety margin when taken alone for short periods.
- Management: avoid in pregnant women; drug interaction with nicotine (CYP induction); don’t take with alcohol.
Warning
Warning
Other uses of GABAergic drugs
- Depression: acute treatment with a benzodiazepine, usually after a traumatic event.
- General anaesthesia: sevoflurane, propofol (IV and gaseous); modulate GABAA receptor activity.
- Muscle spasm: benzodiazepines and baclofen (a GABA_B agonist); used to treat muscle spasms in multiple sclerosis and Huntington’s disease.
Warning
Warning
Summary (as given on final slide)
- Drugs sometimes offer similar efficacy to lifestyle changes.
- Lifestyle changes would be better treatments for insomnia and anxiety than medication in many cases.
- Anxiety is caused by elevated sympathetic nervous system activity.
- Benzodiazepines enhance GABAA receptor activity and are used as anxiolytics and sedatives.
- Benzodiazepines and Z-drugs have significant side effects and dependence risk.
Self-test
- Define anxiety as presented in the lecture, and give its psychological/emotional and physical symptom groups.
- List the three named types of anxiety disorder with their lifetime prevalences, and name at least two other named forms of anxiety.
- Describe the fight-or-flight physiological mechanism underlying anxiety’s clinical presentation.
- List the non-pharmacological treatments for anxiety given in the lecture.
- Distinguish first-line from second-line pharmacological treatments for anxiety, with an example drug for each class listed.
- Describe the proposed step-by-step mechanism by which venlafaxine (an SNRI) reduces the physical symptoms of anxiety.
- Explain why propranolol is useful in performance anxiety, and state a contraindication.
- Describe the mechanism of benzodiazepines as positive allosteric modulators of GABAA, in the correct order of steps.
- Distinguish GABA_A from GABA_B receptors in terms of receptor type, activation time, and agonists.
- Explain how GABAA receptor activation inhibits neurotransmission at the level of the neuron’s membrane potential.
- List the recognised side effects of benzodiazepines, and explain why their therapeutic index is described as high.
- Explain the mechanistic basis proposed for benzodiazepine tolerance.
- Define physical dependence, list the withdrawal symptoms described, and explain why withdrawal must be gradual.
- Define insomnia and distinguish intermittent from chronic insomnia using the criteria given.
- List the four categories of causes of insomnia given in the lecture with at least two examples each.
- List the sleep hygiene measures for treating insomnia.
- Describe the key features, use restrictions, and management precautions for zopiclone as a Z-drug.
- A patient has been taking diazepam for anxiety for several months and abruptly stops all at once. Predict what could happen and why, and describe what should have been done instead.
- List the other clinical uses of GABAergic drugs described in the lecture, with one example drug/agent for each.
- Integrative: both benzodiazepines and venlafaxine (SNRI) are used to treat anxiety but act on completely different neurotransmitter systems. Explain the mechanistic difference between how each reduces anxiety symptoms.
Answers
Reveal answers
- Anxiety is a psychological and physiological state responding to perceived threats, producing cognitive, physical, and emotional effects that interfere with normal activities. Psychological/emotional symptoms: anxiety, fear, nervousness, worry. Physical symptoms: palpitations, shortness of breath, dizziness, muscle tension.
- GAD (6.2%), social anxiety disorder (13%), panic disorder (5.2%). Others named: phobias, post-traumatic stress disorder, obsessive compulsive disorder.
- Anxiety is caused by a heightened fight-or-flight response, resulting in elevated sympathetic nervous system activity, which produces the psychological and physical symptoms.
- CBT, internet-based CBT, ACT, mindfulness-based stress reduction, exercise.
- First line: SSRIs (e.g. escitalopram), SNRIs (e.g. venlafaxine). Second line: benzodiazepines, anticonvulsants (e.g. gabapentin), beta blockers (e.g. propranolol), tricyclics.
- Venlafaxine inhibits noradrenaline reuptake, increasing noradrenaline in the synapse; this produces more α2 receptor activation; in the locus coeruleus, α2 activation prevents release of systemic noradrenaline, suppressing the AC → cAMP → PKA cascade; net effect is reduced central sympathetic effects, decreased heart rate and blood pressure, and fewer physical symptoms of anxiety.
- Propranolol is a non-selective β1/β2 antagonist that blocks adrenaline’s action, reducing sympathetic nervous system effects such as tremor — useful in performance anxiety. Contraindicated in people with asthma (non-selective β2 blockade risk).
- (1) No effect without GABA present. (2) Binds a different site to GABA, at the α–γ junction. (3) When GABA is bound, benzodiazepine binding increases activation of GABAA and increases the frequency of channel opening. (4) This increases Cl⁻ influx above what GABA alone produces. (5) Increased Cl⁻ influx increases neuronal hyperpolarization, decreasing general neurotransmission.
- GABA_A: Cl⁻ ion channel, activates in milliseconds, agonists GABA and muscimol. GABA_B: Gi-coupled GPCR, activates over ~100 milliseconds, agonists GABA and baclofen. Both inhibit action potentials.
- GABAA activation causes Cl⁻ influx, making the membrane potential more negative (hyperpolarization), which inhibits generation of an action potential.
- Drowsiness, decreased alertness, ataxia; interaction with other CNS depressants (alcohol, barbiturates, antihistamines). High therapeutic index because benzodiazepines are very safe relative to barbiturates and difficult to overdose on.
- Tolerance is associated with a decrease in GABAA receptors in particular brain areas, and with changes in the coupling between the GABA and benzodiazepine binding sites on the receptor complex.
- Physical dependence is the presence of withdrawal symptoms upon stopping a drug regimen. Symptoms: anxiety, irritability, insomnia, depression, tachycardia, profuse sweating, nausea, perceptual changes, potentially seizure activity. Withdrawal must be gradual because abrupt withdrawal can be fatal.
- Insomnia is a lack of sleep leading to impairment of normal function. Intermittent insomnia affects 1/3 of adults. Chronic insomnia affects 1 in 10 adults and is defined as insomnia for 3 nights a week over 3 months.
- Psychological (anxiety, depression, dementia, psychosis), physical (movement disorders, respiratory disorders, pain, bladder disorders), drugs (alcohol, caffeine/amphetamine, beta blockers, diuretics), environment (technology, work, family, financial stress).
- Consistent bed/wake time; avoid exercise 2–3 hours before bed; avoid caffeine and nicotine; avoid drinking before bed (alcohol interrupts REM sleep); keep the room cool; avoid screens for 1 hour before bed; don’t lie in bed awake.
- Zopiclone is a positive allosteric modulator of GABAA with a short duration of action (< 6 hrs); use for only 5–14 days to avoid dependence, alongside sleep hygiene. Side effects: confusion, fatigue, drowsiness, muscle weakness (wide safety margin when taken alone short-term). Management: avoid in pregnant women, avoid with alcohol, watch for nicotine drug interaction via CYP induction.
- Abrupt cessation (“cold turkey”) after dependence has developed can cause seizure and death, because withdrawal must be gradual to avoid severe adverse reactions. Instead, the dose should have been tapered gradually, potentially with other drugs to facilitate withdrawal and psychotherapy support.
- Depression (acute treatment with a benzodiazepine, usually after a traumatic event); general anaesthesia (sevoflurane, propofol); muscle spasm in MS or Huntington’s disease (benzodiazepines, baclofen).
- Benzodiazepines act directly on the GABAergic (inhibitory, Cl⁻ channel) system as a positive allosteric modulator of GABAA, producing broad, non-specific CNS depression (sedation, anxiolysis, anticonvulsant and muscle-relaxant effects) with a high dependence risk. Venlafaxine acts on the noradrenergic (and serotonergic) system by inhibiting reuptake, increasing synaptic noradrenaline and consequent α2 autoreceptor-mediated suppression of central sympathetic outflow — a more targeted, first-line approach without the same GABAergic dependence liability.