Anxiety Disorders and Neuropharmacology – Comprehensive Study Notes

Anxiety Disorders and Neuropharmacology – Comprehensive Study Notes

Mental health prevalence, impact, and costs (Canada)

• In any given year, the prevalence can be described as: $rac{2}{10}$ of Canadians.
• The leading cause ranking is inconsistent across slides:
  • Page 1 suggests it is the 1st leading cause of disability and premature death in Canada.
  • Page 2 states it is the 2nd leading cause.
  • Note the discrepancy across slides and the need to verify with current data.
• About $7\%$ of Canadians report taking at least one psychiatric drug.
• The annual cost of mental illness in Canada is estimated to be $50\,\text{B}$ (includes health care, social services, lost productivity, and reductions in health-related quality of life).
• Medication usage breakdown (antidepressants and others):
  • Antidepressants: $4.7\%$
  • Sedative/hypnotics: $3.1\%$
  • Mood stabilizers: $0.6\%$
  • Antipsychotics: $0.5\%$
• Discussion prompt: Despite a large portion of the population suffering from psychological disorders, funding for new, innovative medications is in decline; consider which disorders or diseases pharmaceutical companies should prioritize and what factors influence those decisions.

General reflections (Discuss…)

• The slides prompt consideration of priorities in drug development and the ethical, economic, and societal drivers shaping them.

Food for Thought: Challenges with psychiatric medication development

• Psychiatric disorders are difficult to diagnose and treat.
• Many disorders have overlapping symptoms and complex etiologies, including comorbidity with other disorders.
• Most current medications treat symptoms rather than underlying causes.
• From a financial perspective, firms are incentivized to develop drugs for chronic management rather than cures.
• Unclear if a true “cure” for psychological disorders will ever emerge.
• Clinical trials for new psychotropic drugs are challenging: time/resource intensive, outcomes can be subjective, and placebo effects are common.

Anxiety: Defining the field (Lecture Outline)

• Defining anxiety and its components.
• Individual factors related to anxiety.
• The neurobiology of anxiety.
• Key brain regions/systems involved in anxiety.
• Primary neurotransmitter systems implicated in anxiety.
• Drugs for treating anxiety: Barbiturates, Benzodiazepines (BDZs), and other agents.

Anxiety: Core concepts

• Anxiety is normal, evolutionarily adaptive; activates the sympathetic ANS to mobilize the fight-or-flight response.
• Approximately $0.25\%\,(\text{i.e., }\approx 25\%)$ of Canadians will suffer from an anxiety disorder at some point in life.
• Anxiety commonly co-occurs with other psychopathologies, particularly clinical depression.

Anxiety: Three-component model and stress dynamics

• Three components of anxiety:
  1) Bodily effects
  2) Upsetting thoughts
  3) Ineffective or maladaptive behaviour
• Each component can influence the others; stress is cyclical.

Anxiety: Individual factors

• Trait anxiety varies among individuals but likely has genetic contributions; rodent models use inbred strains to study neurobiology and treatments.
• Family and twin studies estimate heritability of anxiety disorders roughly $0.30\text{ to }0.60$ (i.e., 30%–60%).
• Early exposure to stress and neglect can alter the developing brain and cause lifelong heightened anxiety.
• Early stress alters the HPA axis, producing hyperactive hormonal responses to stress that can persist into adulthood.
• Stress can have opposing effects on brain structure: hippocampal atrophy and dendritic growth/arborization in the amygdala.
• CIS = chronic immobilization stress (label for a stress paradigm mentioned).

Timing, sex, and biological factors in anxiety

• Timing matters: sensitive/critical periods influence vulnerability and plasticity.
• Biological sex differences in neurotransmitter systems; hormonal changes during the menstrual cycle can affect HPA axis function (e.g., elevated estrogen can increase stress sensitivity).
• Women generally show higher rates of anxiety disorders than men.

The neurobiology of anxiety: The amygdala

• The amygdala is central to emotion processing, fear learning, and formation of emotional memories.
• It interacts with the hippocampus, prefrontal cortex (PFC), and striatum.
• Key regions within the amygdala:
  • LA: Lateral amygdala
  • CE: Central nucleus of the amygdala
  • ITC: Intercalated cell masses
  • B: Basal nucleus of the amygdala
• Anxiety disorders may reflect an imbalance between primitive emotion-generating centers (amygdala) and higher cortical control (PFC).

Neurotransmitters and anxiety: CRF and the stress response

• Corticotropin-releasing factor (CRF) is released after threatening stimuli and acts on the pituitary to release glucocorticoids from the adrenal cortex in response to stress.
• CRF acts as a neurotransmitter in multiple brain areas associated with anxiety.
• Evidence links CRF to anxiety: in animal tests, CRF increases anxiety; stress triggers CRF release in the amygdala; CRF antagonists can block these behavioral effects.

Monoamines and anxiety: Noradrenergic, dopaminergic, and serotonergic systems

• Dysfunction in monoamine systems (NE, DA, 5-HT) is linked to major depression and anxiety disorders.
• Norepinephrine (NE): released during sympathetic activation; altered ANS responses in anxiety disorders; NE is important for emotional memory formation; β-adrenergic receptors can be blocked post-trauma to potentially disrupt traumatic memory formation (e.g., propranolol).
• Locus coeruleus (LC): primary site of NE synthesis; LC activity relates to arousal, vigilance, and awareness.
• GABA: main inhibitory neurotransmitter; top-down control of amygdala via GABAergic interneurons in the amygdala; drugs that enhance GABA reduce anxiety, seizures, and produce sedation.
• Serotonin (5-HT): Synthesis, release, transport, or reuptake disturbances can worsen anxiety and/or depression; 5-HT1A receptor has context-dependent anxiogenic or anxiolytic effects depending on brain location.
• Dopamine (DA): projections from VTA to medial prefrontal cortex (mPFC) and limbic regions respond to threats; DA release increases amygdala activation; stress affects dopamine in the mesolimbic system; dopaminergic signaling modulated by stress intensity, duration, and avoidability.

Anxiety and neurotransmitters: practical implications

• Beta-adrenergic blockade post-trauma (e.g., propranolol) as a strategy to interfere with traumatic memory formation.
• NE/Locus coeruleus contributes to arousal and wakefulness; anxiolytics can reduce LC firing to exert calming effects.
• GABA-A receptor–mediated inhibition is a primary target for anxiolytics (BDZs and barbiturates).
• Serotonin system modulation (SSRIs) takes weeks to achieve clinical benefit but has a high therapeutic index and lower abuse potential.

Anxiolytics: Drugs for treating anxiety (overview)

• Anxiolytics relieve tension, worry, and anxiety; many are sedative–hypnotic CNS depressants.
• Mechanism: largely through enhancing GABA transmission at GABA-A receptors.
• BDZs and barbiturates share receptor targets but differ in safety and risk profiles.

Barbiturates: History, pharmacology, and risks

• History:
  • Developed in 1862; first used clinically in 1912; ~2000 barbiturate formulations developed; ~50 marketed.
  • Popular in the mid-20th century as sedatives and sleep aids; declined in the late 1960s due to safety concerns.
  • Introduced alternatives (antipsychotics, then BDZs) in later decades.
• Today: Barbiturates are still used in specific medical settings (anesthesia, seizure control) but are rare for routine anxiety treatment.
• Recreational misuse and counteracting stimulants are common reasons for misuse.
• Pharmacokinetics: Barbiturates contain the barbiturate nucleus; lipid solubility and half-life determine onset and duration.
• Lipid solubility and half-lives (illustrative table):
  • Ultrashort: onset $ext{Onset} = 10 ext{--}20\,\text{s}$; duration $20\text{--}30\,\text{min}$; onset via rapid BBB crossing; example: Thiopental (Pentothal); used IV for anesthesia.
  • Short/Intermediate: onset $20\text{--}40\,\text{min}$; duration $5\text{--}8\,\text{h}$; example: Amobarbital (Amytal).
  • Long: onset >1\,\text{h}; duration $10\text{--}12\,\text{h}$; example: Phenobarbital (Luminal).
• Pharmacological effects: not analgesic; can disrupt REM sleep; cognitive impairment and sedation; high doses can cause coma or death from respiratory depression; dangerous with alcohol or opioids.
• Tolerance/dependence: metabolic and cross-tolerance occur; therapeutic index declines with tolerance; physical dependence poses risk of withdrawal with rebound hyperexcitability.
• Cautions: adverse effects include respiratory depression, sleep disruption, memory/cognition impairment, motor impairment, depression; narrow therapeutic-to-toxic range; potential for dangerous interactions with other CNS depressants.

Benzodiazepines (BDZs): Overview, pharmacokinetics, and uses

• BDZs replaced barbiturates starting in the 1960s due to better safety profiles but still have abuse potential, especially with long-term use.
• Pharmacodynamics: BDZs potentiate GABA-A receptor activity, leading to increased Cl- influx and neuronal inhibition; BDZ binding is distinct from barbiturates; a BDZ receptor exists and can be blocked by flumazenil (a competitive antagonist) without intrinsic activity.
• Global use: large-scale use in the past decade; BDZs remain widely prescribed for anxiety reduction and insomnia; high-efficacy and rapid onset, with relatively lower toxicity than barbiturates, but dependence can develop; caution with long-term use.
• Pharmacokinetics: onset is driven by lipid solubility (more soluble = faster onset, shorter apparent duration); metabolism varies among compounds; some have active metabolites that prolong duration.
  • Short-acting BDZs: often metabolized in a single step, inactive metabolites, quickly eliminated; half-life roughly $1 ext{--}12\,\text{hrs}$; commonly used for insomnia.
  • Long-acting BDZs: multi-step metabolism with active metabolites; half-life roughly $20 ext{--}125\,\text{hrs}$; used for presurgical anesthesia, alcohol withdrawal, or long-term anxiety support.
• Mechanism of action: all BDZs facilitate GABA activity at the GABA-A receptor (enhancement of Cl- influx); BDZ receptor activation increases GABAergic inhibitory effects; inverse agonists like β-carbolines produce opposite (anxiogenic) effects; flumazenil can block BDZ effects but has no own activity.
• Clinical uses: anxiolysis (GAD, panic disorder, OCD, social anxiety disorder); hypnotic use for sleep; muscle relaxation; anticonvulsant properties; can help prevent acute alcohol or barbiturate withdrawal.

Benzodiazepines: Cautions and safety considerations

• Adverse consequences: tolerance, dependence, withdrawal symptoms (generally milder than barbiturates but still present).
• Due to abuse risk, guidelines typically recommend short-term use only.
• Cautions: avoid in tasks requiring fine motor or cognitive accuracy; particularly cautious in elderly, children/adolescents, and pregnant or breastfeeding individuals.
• Perinatal considerations: BDZs can cross the placenta and accumulate in fetal circulation; risk of BDZ dependence or floppy infant syndrome (hypotonia) at birth.

Barbiturates vs. Benzodiazepines: A quick compare

• Barbiturates:
  • Oldest sedative-hypnotics; fatal at high doses; high risk with alcohol; strong tolerance and dependence; therapeutic usefulness wanes.
  • Today: mainly used for anesthesia and seizure control.
• Benzodiazepines:
  • Safer relative profile; less tolerance; safer therapeutic index but still risk of dependence and fatal overdose when combined with other CNS depressants.
  • Primarily used for anxiety reduction and insomnia; also muscle relaxants and anticonvulsants in some contexts.

Buspirone (BuSpar): A non-sedating anxiolytic option

• Buspirone is a second-generation anxiolytic that is a partial agonist at 5-HT1A receptors; it does not enhance GABA action and is not considered sedative.
• Advantages: reduces anxiety/depression without sedation or cognitive clouding; no withdrawal syndrome or abuse potential; does not augment other sedatives.
• Disadvantages: slow onset of anxiolytic effects relative to BDZs; not effective for alcohol/barbiturate withdrawal, insomnia, or seizures; lacks muscle relaxant effects.

Anxiolytics and antidepressants in anxiety treatment

• Anxiety and depression frequently co-occur; antidepressants can be used to treat anxiety.
• Antidepressants (especially SSRIs) have high therapeutic index and low abuse potential but typically require several weeks to show benefit; not ideal for acute anxiety attacks.
• Other antidepressants include tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), which can treat some anxiety disorders but come with adverse side-effects.
• SSRIs: first-line for many anxiety disorders due to safety profile; delays in onset require management of acute symptoms via other means if needed.

Novel and emerging approaches in anxiety treatment

• MDMA-assisted therapy has shown significant attenuation of PTSD symptoms in some trials when combined with psychotherapy.
• Ketamine has been explored for OCD and PTSD; early evidence suggests rapid relief in some cases.
• LSD and psilocybin are being investigated for anxiety disorders, particularly in conjunction with traditional therapies.
• Important caveat: these psychedelic approaches are typically adjuncts to conventional therapies (psychotherapy, medical monitoring) and require careful clinical oversight.

Anxiety disorders: DSM-5 classifications and prevalence

• DSM-5 categories include:
  • Anxiety disorders (generalized anxiety disorder, panic disorder, specific phobias, social anxiety disorder, etc.)
  • Obsessive-compulsive and related disorders (OCD, etc.)
  • Trauma- and stressor-related disorders (PTSD and related conditions)
• Anxiety disorders are frequently comorbid with other psychopathologies, especially depression.
• Lifetime prevalence of various anxiety disorders varies by disorder and population; references provided in course materials.

Public health and education prompts: introspection and responsibility

• Why do people opt for pharmacological solutions over non-pharmacological approaches for anxiety and sleep?
• Who bears responsibility for safe and effective pharmacotherapy? Roles of pharmaceutical companies, physicians, and patients.
• How can patients be more engaged in research, adherence, and safe prescription practices?

Extra slides: mechanisms of BDZ addiction (conceptual overview)

• A BDZ can activate GABA-A receptors, reducing inhibition (disinhibition) of dopaminergic neurons in the ventral tegmental area (VTA).
• This disinhibition increases glutamatergic signaling to dopaminergic neurons, strengthening glutamate receptor expression on these neurons.
• The net effect is enhanced dopaminergic activity in reward pathways, contributing to the addictive properties of BDZs.
• Reference: Rigel & Kalivas (2010). Nature; discussion on the lack of inhibition leading to abuse.

Anxiety disorders and psychedelics: a brief synthesis

• MDMA-assisted therapy has shown promise for severe PTSD and safety in clinical trials.
• Ketamine shows potential for OCD and PTSD treatment in combination with psychotherapy and careful clinical oversight.
• Psychedelics (LSD, psilocybin) are under investigation for anxiety disorders, often within controlled research settings.
• Across these approaches, therapy is typically a combination of pharmacological and psychotherapeutic modalities.

Final notes: prevalence, treatment, and critical thinking

• Anxiety disorders represent a significant portion of mental health burden, with complex etiologies, including genetic, developmental, and environmental factors.
• Treatments span a spectrum from GABAergic agents (BDZs, barbiturates) to serotonin-based medications (SSRIs, TCAs, MAOIs), to novel therapies (MDMA, ketamine, psychedelics) in conjunction with psychotherapy.
• The safety profile, pharmacokinetics, and risk of dependence differ substantially across drug classes; short-term use is often recommended for BDZs, whereas barbiturates carry higher risks and are less favored for anxiety management.
• Ethical considerations include balancing patient autonomy with safety, addressing the societal costs of medication, and ensuring evidence-based, patient-centered care.

Key equations and numerical references (LaTeX)

• Prevalence representation: $rac{2}{10}$
• Antidepressants usage: $4.7\%$, Sedative/hypnotics: $3.1\%$, Mood stabilizers: $0.6\%$, Antipsychotics: $0.5\%$
• Overall mental illness cost: $50\,\text{B}$ dollars per year
• General lifetime and sex differences: $0.25\text{ (i.e., }25\%)$ approximate lifetime prevalence of anxiety disorders in populations
• Barbiturate pharmacokinetics (illustrative table values):
  • Ultrashort onset: $10\text{--}20\,\text{s}$; duration: $20\text{--}30\,\text{min}$; example: Thiopental
  • Short/Intermediate onset: $20\text{--}40\,\text{min}$; duration: $5\text{--}8\,\text{h}$; example: Amobarbital
  • Long onset: >1\,\text{h}; duration: $10\text{--}12\,\text{h}$; example: Phenobarbital
• BDZ half-lives:
  • Short-acting: $ext{half-life} \approx 1\text{--}12\,\text{hrs}$
  • Long-acting: $ext{half-life} \approx 20\text{--}125\,\text{hrs}$

Quick study prompts

• Explain how CRF links to the HPA axis and anxiety, including the pathway from threat to cortisol release.
• Compare and contrast BDZs and barbiturates in terms of mechanism, safety, and clinical use.
• Describe the role of the amygdala and its subnuclei (LA, CE, ITC, B) in fear processing and anxiety regulation.
• Discuss why SSRIs may take weeks to become effective for anxiety disorders and how this shapes clinical practice for acute anxiety symptoms.
• Evaluate the ethical considerations of using psychedelics or MDMA in treating anxiety disorders, including safety, patient selection, and integration with psychotherapy.