Understanding Anxiety and Fear Responses

Anxiety

• Fear is a complex physiological, behavioral, and cognitive response to a threatening stimulus
• It's an adaptive response to threats and usually temporary
• The normal fear response has several components: defensive behaviors, autonomic reflexes, arousal and alertness, corticosteroid secretion, and negative emotions
• Anxiety is meant to increase the likelihood of survival in dangerous situations
• Symptoms include increased arousal, hypervigilance, tachycardia, physical preparedness (sympathetic nervous system activation)
• Anxiety is a longer-lasting response to danger
• It can have a specific cause related to something that signals danger or be caused by anticipated adverse consequences
• When anxiety persists beyond genuine risk or produces a response out of proportion to the possible threat, it's considered an anxiety disorder
• Currently recognized anxiety disorders include generalized anxiety disorder, panic disorder, post-traumatic stress disorder, social anxiety disorder, simple phobias, and obsessive-compulsive disorder

Therapeutic Strategies in Anxiety Disorders

• GAD (Generalized Anxiety Disorder):
  • Acute state: Benzodiazepines
  • Chronic state: SSRI/SNRI
• Phobia:
  • SSRI
  • Propranolol and exposure therapy
  • CBT (Cognitive Behavioral Therapy), biofeedback

Slow vs. Rapid-Acting Anxiolytic Drugs

• Benzodiazepines: rapid onset (effects within 30 minutes), useful for acute treatment, can be taken as needed
• Antidepressants and Buspirone: slow onset (require 3+ weeks for therapeutic effect)

Propranolol and Exposure Therapy

• Propranolol is a beta-blocker traditionally used for hypertension and arrhythmias
• Used in psychiatry for exposure therapy to treat phobias and PTSD
• Blocks adrenaline effects, reducing physical anxiety symptoms
• May influence emotional memory recall, potentially making it easier to confront fearful situations
• Exposure therapy systematically desensitizes individuals to feared imagery and stimuli

GABA

• GABA is the major inhibitory neurotransmitter in the brain
• Most inhibitory synapses use GABA as a neurotransmitter

GABA Receptors

• GABA interacts with two major receptor subtypes: GABA_A and GABA_B
• GABA_A receptors are found postsynaptically
• GABA_B receptors are found presynaptically and can inhibit synaptic release
• GABA_A receptors mediate inhibitory synaptic transmission throughout the CNS

GABA Receptors and Chloride Ions

• GABA_A receptors are permeable to chloride ions (Cl^-)
• Upon activation, Cl^- influx hyperpolarizes the membrane, inhibiting action potentials

GABA_B Receptors and Seizures

• GABA_B receptors are associated with second messenger systems rather than chloride channels
• Second messenger systems often result in opening K⁺ channels, leading to hyperpolarization
• Decreasing GABA release and drugs that activate GABA_B receptors can cause seizures

Behavioral Spectrum of GABA_A Activation

• Decreased GABA activity: seizures, high anxiety, and panic
• Slightly decreased GABA activity: increased anxiety
• Normal GABA activity
• Increased GABA activity: sedation
• Higher GABA activity: marked sedation and sleep.

Benzodiazepines

• Mechanism of Action: Enhance the effect of the neurotransmitter GABA, leading to central nervous system depression.
• Examples: Diazepam (Valium), lorazepam (Ativan), alprazolam (Xanax), and clonazepam (Klonopin).

Behavioral Spectrum of GABA_A Activation

• Normal GABA activity
• Slightly increased GABA activity: anti-anxiety
• High GABA activity: sedation
• Higher GABA activity: marked sedation and sleep

Clinical Importance of GABA_A

• Each of the five subunits of the GABA_A-benzodiazepine receptor complex is a different protein
• These can be classified into families based on structural similarities (coded as α, β, and γ subunits)
• GABA binds to the β subunit

Benzodiazepines as Rapid Onset Anxiolytics

• Used to treat acute anxiety
• Those used to treat anxiety have long biological half-lives
• They are no longer used in long-term therapy

Benzodiazepines acting on GABA_A receptors

• Benzodiazepines act as positive allosteric modulators on the GABA_A receptor
• This facilitates the opening of GABA-activated chloride channels, enhancing the inhibitory response to GABA
• Benzodiazepines bind specifically to a modulatory site separate from the GABA binding sites

Channel Modulators - Benzodiazepines

• Benzodiazepines work by increasing the affinity of the GABA binding site for GABA
• This means GABA can activate the channels at a higher rate, increasing chloride transmission

Long-acting Benzodiazepines and Nordazepam

• Some long-acting agents (e.g., diazepam and chlordiazepoxide) are converted to a long-lasting active metabolite (nordazepam)
• Nordazepam has a half-life of about 60 hours
• This accounts for the tendency of many benzodiazepines to produce cumulative effects and long hangovers when given repeatedly

Benzodiazepines Adverse Effects

• Sedation: Dizziness and ataxia, Impaired coordination and balance, Cognitive impairment, Anterograde amnesia, Psychomotor slowing, Motor impairment
• Dependence and Withdrawal (with long-term use): Serious withdrawal effects, Tolerance (higher doses to achieve therapeutic effects), Risk of overdose (especially with alcohol)

Reuptake Inhibitors in Anxiety

• SSRIs (Selective Serotonin Reuptake Inhibitors): useful for long-term management of anxiety disorders, but may worsen anxiety initially
• SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors): useful for long-term management of anxiety disorders, but may worsen anxiety initially Commonly prescribed SSRIs: Fluoxetine (Prozac), Paroxetine (Paxil, Pexeva), Citalopram (Celexa), Escitalopram (Lexapro), Sertraline (Zoloft) Commonly prescribed SNRIs: Venlafaxine XR (Effexor XR), Duloxetine (Cymbalta), Desvenlafaxine (Pristiq)
• First-line for anxiety: Benzodiazepines are effective immediately but are contraindicated for long-term use
• First-line for anxiety: SSRIs and SNRIs take time to work, causing anxiety initially, but can be used long-term

Depression

• The central feature of depression is an unpleasant (dysphoric) mood present most of the day for a long period of time
• Often accompanied by intense mental anguish, inability to experience pleasure, generalized loss of interest, and sometimes anger and irritability
• Three effective treatments for major depressive disorder include antidepressant drugs, cognitive-behavioral psychotherapy, and electroconvulsive therapy

The Monoamine Hypothesis of Major Depression

• Suggests that depression is related to a deficiency in the amount or function of monoamines, including serotonin, noradrenaline, and dopamine.
• These neurotransmitters are involved in various mechanisms, contributing to depressive symptoms

Drugs which Block Reuptake of Monoamine Neurotransmitter Molecules from the Synaptic Cleft

• Tricyclic antidepressants (TCAs)
• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin-noradrenaline reuptake inhibitors (SNRIs)
• Norepinephrine-dopamine reuptake inhibitors (NDRIs)

Neurotransmitter Reuptake

• Specific transporter proteins remove most small-molecule neurotransmitters (or their metabolites) from the synaptic cleft, returning them to the presynaptic terminal for reuse

Tricyclic antidepressants (TCAs)

• Mechanism of action: block the transporter at serotonergic and noradrenergic synapses, leaving serotonin/noradrenaline in the synaptic cleft for a longer period, activating postsynaptic receptors for longer
• Example: Imipramine (Tofranil), Amitriptyline (Elavil), Nortriptyline (Pamelor)
• Adverse effects: antagonists at H1 receptors (drowsiness), adrenergic a1 receptors (postural hypotension), muscarinic receptors (dry mouth, confusion, and memory impairment), and blurred vision, cardiac arrhythmias in overdose, and potentiation of alcohol effects (severe respiratory depression)
• Overdose: Second most common cause of fatal drug poisoning in developed countries (1970s and 1980s), accounting for 20-25% of fatal cases in the UK and US

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Mechanism of action: inhibit the reuptake of both serotonin and norepinephrine, increasing the availability of neurotransmitters in the synaptic cleft
• Examples: Venlafaxine (Effexor XR), Duloxetine (Cymbalta), Desvenlafaxine (Pristiq)
• Differ from TCAs: TCAs block reuptake pumps of both serotonin and norepinephrine but are not selective. SNRIs are designed to specifically block serotonin and norepinephrine reuptake.

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Mechanism of Action: These transporters are highly specific, block the transporter, leaving serotonin in the synaptic cleft for a longer period.
• Examples: Fluoxetine (Prozac), Sertraline (Zoloft), Paroxetine (Paxil), Citalopram (Celexa)

Selective Serotonin Reuptake Inhibitors (SSRIs)

• SSRIs are currently among the most commonly prescribed antidepressants due to their efficacy and favorable side effect profile compared to older antidepressants, like TCAs.
• SSRIs are highly lipophilic.
• Their popularity stems from ease of use, safety in overdose, relative tolerability, cost, and broad spectrum of uses

SSRI/SNRIs and Suicidality

• Risk of suicidality and aggression in children and adolescents may double with SSRI/SNRI treatment

First-line in Anxiety

• Benzodiazepines are effective immediately, but have side effects and are contraindicated for long-term use
• SSRIs and SNRIs take time to work, may initially worsen anxiety, but can be used longer term

Ketamine

• Single intravenous, sub-anaesthetic dose of ketamine (a non-competitive NMDA channel blocker) produces a rapid, but short-lasting decrease in depressive symptoms
• This is without the usual delay, unlike other antidepressants

Esketamine

• An analogue of ketamine, available as a nasal spray
• Has milder side effects compared to ketamine
• Could be used with oral antidepressants to treat resistant cases
• Administered in clinics with patients observed for 2-3 hours

Electroconvulsive Therapy (ECT)

• Highly effective against depression
• Administered with modern anesthesia; relatively safe
• Single most effective treatment option for serious major depression when other medications fail

Transcranial Magnetic Stimulation (TMS)

• Non-invasive neuromodulation technique using magnetic fields to stimulate specific brain areas
• Effective for patients with major depressive disorder (MDD) who don't respond to first-line pharmacological treatments (treatment-resistant depression)

Schizophrenia

• Affects about 1% of the population
• Predominantly affects young people (average onset age of 18 in men, 25 in women)
• Characterized by psychosis (loss of contact with reality)
• Symptoms include difficulty processing information, disorganized thoughts, distortions of reality, delusions, hallucinations, incoherence, catatonia, and aggressive/violent behavior
• Divided into groups: Negative symptoms (decrease/loss of function and motivation), Positive symptoms (exaggeration of normal function, such as agitation, incoherent speech, hallucinations, delusions, paranoia), Cognitive symptoms (reduce ability to think clearly and perform daily tasks, such as impaired attention/concentration, working memory, executive function, reasoning/problem-solving)

Classification of Antipsychotic Drugs

• First-generation (typical, classical, or conventional): Chlorpromazine, Haloperidol, Fluphenazine
• Second-generation (atypical): Risperidone, Olanzapine, Quetiapine, Aripiprazole, Clozapine

Antipsychotic Agents Mechanisms of Action

• Five subtypes of dopamine receptors (D1 through D5)
• Typical antipsychotics block D2 (dopaminergic) receptors
• Atypical antipsychotics block D2 and D4 dopamine, and 5-HT2A receptors

Typical Antipsychotics

• Dopamine receptor blockade: Chlorpromazine, Haloperidol These typically induce extrapyramidal side effects (EPS), such as pseudoparkinsonism, acute dystonia, akathisia, and tardive dyskinesia
• Higher risk and duration of EPS-related side effects

Atypical Antipsychotics

• These typically block D2 and 5-HT2A receptors, and there's a lower risk of EPS
• More effective in treating negative symptoms. Examples include Risperidone, Olanzapine, Quetiapine Aripiprazole, Clozapine

Hyperprolactinaemia

• Antipsychotic drugs binding to D2 receptors can increase prolactin secretion leading to elevated prolactin levels, causing decreased libido, impotence, and gynecomastia in males, and amenorrhea (stopping menstruation) and infertility in females.

Typical Antipsychotic Drugs and EPS

• High-potency agents (haloperidol and fluphenazine) have a higher incidence of EPS, especially at higher doses
• Lower-potency agents (chlorpromazine and thioridazine) have lower EPS rates but are more likely to cause sedation

Atypical Antipsychotics - Common Adverse Effects

• Generally have a lower risk of EPS compared to typical antipsychotics
• Some (olanzapine and clozapine) are associated with metabolic side effects like weight gain, diabetes, and dyslipidemia

Why are Atypical Antipsychotics Better with EPS?

• Typical antipsychotics block dopamine (D2) receptors in the striatum, which prevents inhibition of GABAergic neurons, leading to EPS
• Typical antipsychotics have no activity at 5-HT2A receptors and do not promote their activation of GABA neurons
• Atypical antipsychotics block dopamine (D2) receptors to a lesser degree, preventing excessive GABAergic neuronal activation and reducing EPS risk
• Inhibit 5-HT2A receptors to stop the activation of GABA neurons.

Differences between Typical and Atypical Antipsychotic Drugs

• Typical antipsychotics block D2 receptors, causing higher risk of EPS and tardive dyskinesia, less effective treating negative symptoms. Examples: haloperidol, chlorpromazine
• Atypical antipsychotics block multiple receptors, including D2 and 5-HT2A, causing a lower risk of EPS and being more effective for negative symptoms. Examples: risperidone, olanzapine

Aripiprazole

• Partial agonist at D2, D3, and 5-HT1A receptors
• Antagonist at 5-HT2A receptors
• Has a better side effect profile
• Stabilizes dopamine and serotonin within the nucleus accumbens, ventral tegmental area, and frontal cortex, effectively managing positive, negative, and cognitive symptoms in schizophrenia.

Cariprazine

• Partial agonist at D2, D3, and 5-HT1A receptors
• Not an antagonist at 5-HT2A receptors
• Relatively effective for treating schizophrenia negative symptoms, with minimal EPS

Antipsychotic Drugs Drawbacks

• Not all schizophrenic patients respond to drug therapy (30% "treatment-resistant")
• Clozapine is an option when other antipsychotics are ineffective, despite its severe drawbacks (agranulocytosis, myocarditis, cardiomyopathy, and metabolic syndrome).

Bipolar Disorder

• Usually appears in early adult life
• Less common than major depression
• Strong hereditary tendency (but no specific genes identified)
• Involves swings between manic and depressive moods
• Treatment goals: preventing manic episodes, relieving depressive symptoms, and avoiding rapid cycling

Drugs used in Bipolar Disorder

• Treatment Goals: Prevent manic episodes, alleviate depressive symptoms, avoid rapid cycling
• Mood stabilizers are used to control mood swings, examples include: Lithium, Carbamazepine, Valproate, Lamotrigine
• Lithium—first drug used to manage bipolar disorder, controls flight of ideas and hyperactivity; takes several weeks for symptom reduction; can cause serious side effects (e.g., nausea, vomiting, diarrhoea, tremor, toxicity from overdose); risks include prolonged treatment (renal toxicity, thyroid issues).

Antiepileptic Drugs Effective In Bipolar Disorder

• Carbamazepine, valproate, and lamotrigine have fewer side effects and are effective in preventing mood cycling between manic and depressive states
• Also used to treat epilepsy

Sodium Channel Inhibitors

• Many antiepileptic drugs bind to sodium channels in the deactivated state, preventing them from returning to the resting state. This reduces the number of functional channels, which may play a role in controlling the bipolar cycle

Carbamazepine

• Stabilizes the inactivated state of voltage-gated sodium channels

Atypical Antipsychotics

• Effective for bipolar mania, not necessarily for rapid cycling between mania and depression
• Examples of atypical antipsychotic drugs include olanzapine and risperidone.

Use of SSRIs and Bipolar Disorder

• SSRIs and SNRIs can precipitate mania, leading to misdiagnosis of bipolar disorder, especially in patients with unipolar depression
• Antidepressants should be used cautiously in patients with bipolar disorder or a history of mania, and combined with mood stabilizers

Recommended Strategies in Bipolar Disorder

• Antidepressant monotherapy is high risk for inducing mania and should not be used alone
• Preferred treatments pair antidepressants with mood stabilizers or antipsychotics
• Mood stabilizers (e.g., lamotrigine) and atypical antipsychotics (e.g., aripiprazole) are preferred
• SSRIs should be used with caution, always in combination with mood-stabilizing agents