Drug Therapy of Anxiety and Insomnia: Neurobiological Mechanisms

Anxiety and Insomnia

Drug Therapy of Anxiety and Insomnia H.C. 10.2063 H,Cd OCH. Cb =pH[H'] OH] CO UNH.

Understanding Anxiety

Anxiety Defensive behaviour (autonomic reflexes, state of alertness, corticosteroid secretion)

• Physiological adaptative anxiety anxiety is associated with subjective feelings (e.g. worry), physiological feelings (e.g. palpitations, trembling) and behavioural responses (e.g. avoidance)
• Pathological maladaptive anxiety emotional state with unpleasant content associated with alarm and fear, which arises in the absence of real danger or is disproportionate to the triggering stimulus

Anxiety as a Symptom and Disorder

Anxiety It can be a symptom of various psychiatric illnesses or the primary symptom of those pathologies classified by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as anxiety disorders

• pathologies in which the feeling of fear is involved (e.g. panic attacks and phobias)
• pathologies in which a more general sense of anxiety is involved (e.g. generalised anxiety disorder)

Anxiety Disorders Overview

PRIMEVIEW ANXIETY DISORDERS nature REVIEWS DISEASE PRIMERS Anxiety disorders are a group of psychiatric conditions that affect one in four individuals. They are characterized by excessive fear, anxiety, the avoidance of perceived threats and, in some cases, panic attacks.

Epidemiology of Anxiety Disorders

EPIDEMIOLOGY General risk factors for anxiety disorders include female sex and a family history of anxiety or depression. Early life risk factors include a withdrawn or inhibited temperament, over- involved or negative parental interactions, reduced peer relationships and physical or sexual abuse. In adults, several life stressors, such as family illness and relationship breakdowns, can contribute to the development of anxiety disorders. For the Primer, visit doi:10.1038/nrdp.2017.24

Diagnosis of Anxiety Disorders

W N AGORAPHOBIA In general, diagnosis of anxiety disorders involves clinical interviews to determine for which specific anxiety disorder the diagnostic criteria are met and to distinguish the symptoms from other psychiatric disorders (such as major depressive disorder and bipolar disorder). PANIC DISORDER SPECIFIC PHOBIA GENERALIZED ANXIETY DISORDER SELECTIVE MUTISM ... SOCIAL ANXIETY DISORDER SEPARATION ANXIETY DISORDER

Treatment Outlook for Anxiety

The use of computer-assisted, Internet-based treatments for anxiety, mostly CBT, has grown over the past 10 years OUTLOOK Further research to understand the precise risk factors, genetic factors and mechanisms of anxiety disorders is essential. This could also lead to the development of biomarkers and new therapies that specifically target distinct alterations in patients with anxiety disorders. -. 60-90% of patients with an anxiety disorder have a comorbid mental health condition, such as depression or substance use disorders Article number: 17025; doi:10.1038/nrdp.2017.25; published online 4 May 2017 @ 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. 10.1038/nrdp.2017.24

Quality of Life with Anxiety Disorders

QUALITY OF LIFE Anxiety disorders are one of the most persistent mental health disorders and, as such, can substantially reduce the quality of life of the patient. Regarding individual disorders, the disabilities and comorbid complications associated with panic disorder and generalized anxiety disorder are more severe than those caused by specific phobias. The time to seek treatment from the initial onset of anxiety often ranges from 3 to 30 years across countries Written by Louise Adams; designed by Laura Marshall

Neurobiology and Genetics of Anxiety

The neurobiology underlying the development of individual anxiety disorders is unknown, but some generalizations in the way anxiety is processed in the brain have been identified. Namely, bidirectional connections between the amygdala, prefrontal cortex, anterior cingulate cortex and the hippocampus are thought to underlie fear and anxiety. Dysfunction of these areas, in addition to the hypothalamic-pituitary-adrenal axis, might contribute to the development of anxiety disorders. Twin studies have revealed moderate genetic and substantial environmental influences. Few specific genetic risk factors have been identified, but this is likely to increase in the future. R

Management of Anxiety Disorders

MANAGEMENT Often, cognitive-behavioural therapy (CBT; a goal-orientated, skills-based therapy) is the first-line treatment for anxiety disorders. Other psychological therapies can include mindfulness and acceptance-based therapies and interpersonal therapy. Pharmacological treatment can be combined with psychological therapy, or can be used separately. Commonly used drugs include antidepressants, benzodiazepines, atypical antipsychotics and ß-adrenergic blockers. MECHANISMS DIAGNOSIS

Anxiety Disorders and Brain Regions

Anxiety Disorders Memory storage/ Perception Social interaction/ Affect/ Attention Sensory neocortex Social behavior/ Motivation/ Decision making/ Working memory/ Semantic memory/ Emotional learning Anterior cingulate cortex Cingulate gyrus Prefrontal cortex Basal ganglia Thalamus Depressive like bahavior Nucleus accumbens Dopamine Hippocampus Stress hormones Emotional memory/ Stress/ Anxiety - Amygdala Entorhinalcortex Declarative memory/ Spatial memory/ Long term explicit memory Memory consolidation/ Contextual regulation of emotional response Sympathetic activation/ . Hypothalamus VTA Emotional regulation of episodic memory/ Spatial memory/ Memory consolidation 10.1016/j.biopha.2023.114647

Types of Anxiety Disorders

Anxiety Disorders

1. GENERALIZED ANXIETY DISORDER What is it? Excessive or pervasive fears and worries that occur most days of the week for at least six months. Signs · Trouble sleeping · Restlessness . Difficulties with concentration · Irritability
2. SOCIAL ANXIETY DISORDER What is it? Irrational fears related to social situations, such as fears of being judged or humiliated, or fears of unwittingly offending others. Signs · Elevated heart rate · Blushing · Sweating · Trembling
3. SEPARATION ANXIETY What is it? Feelings of significant distress when not in proximity to, or unable to reach, loved ones. Signs · Unfounded fears of harm to loved ones · Difficulties sleeping · Hesitancy to leave loved ones · Depression when separated
4. SPECIFIC PHOBIA What is it? An intense (and often irrational) fear of a certain trigger, such as an object or situation. Signs · Difficulties breathing · Heart palpitations · Hot flashes or chills · Sweating
5. PANIC DISORDER What is it? A person struggling with a panic disorder often experiences sudden and reoccurring panic attacks, followed by excessive worrying about having another. Signs · Shortness of breath · Heart palpitations · Trembling or shaking · Feelings of impending doom

Management of Anxiety Disorders

Assessment and Initial Management

Managment of anxiety disorders Assessment and initial management Assess comorbid disorders, substance use, suicidal ideation, psychosocial stressors, social/emotional support Provide advice on lifestyle (exercise, healthy eating, sleep hygiene) Address substance use Provide psychoeducation Watchful waiting' and review

Treatment Planning for Anxiety

Treatment planning Choose initial treatment in collaboration with the patient, with consideration of severity, patient preference, previous response to treatment and availability Mobilise psychosocial supports Initial treatment based on severity* Mild Moderate CBT Severe CBT CBT plus medication' or Medication" or CBT plus medication"

Reviewing Treatment Response

Review response to initial treatment Review progress after 4-6 weekst At least partial response No response or deterioration Continue treatment Monitor progress and adverse effects Check adherence and review therapeutic engagement Rule out medication related effects as cause of current symptoms Review treatment goals and expectations Check treatment provided was consistent with guidelines Re-evaluate formulation Re-assess comorbidities (e.g. depression, substance misuse, personality difficulties)

Modifying Treatment for Anxiety

Remission No remission Modify treatment Augment or modify according to initial treatment choice Initially treated with dCBT Initially treated with face-to-face CBT Initially treated with medication Add CBT or Change to face-to-face CBT or Medication" Add medication" Increase medication dose within approved range or Both increase dose and add CBT 10.1177/0004867418799453

Drugs for Anxiety Disorders

Drugs used to treat anxiety disorders Benzodiazepines (e.g. lorazepam) Non-benzodiazepine anxiolytic drugs (e.g. buspirone) Antidepressant drugs (SSRI e.g. fluoxetine, SNRI e.g. venlafaxine , TCA e.g. imipramine) Antiepileptic drugs (e.g. pregabalin) Antipsychotic agents (e.g. olanzapine) B-antagonists (e.g. propranolol)

Benzodiazepines (BDZs)

Benzodiazepines (BDZs) R. 1 R2 N 1 2 A B 3) R3 4 5 N R2 R4 C Desmethyldiazepam C2H5 CH2 CH2-N C2H5 Z N F CI Flurazepam O O H OH N N N CI CI Lorazepam H3C N -N IZ I I N IN N CI ·N CI ·N CI NO2 Nitrazepam Triazolam Alprazolam Goodman & Gilman The pharmacological basis of therapeutics McGraw Hill Ed H HỌC O 2 3 4 9 N 5 8 7 6 CI CI Chlordiazepoxide H OH H IZ N N CI Oxazepam H3C -Z N CI Diazepam N-CH3 N N

Classification of Benzodiazepines

Benzodiazepines Anxiolytic BDZs Hypnotic BDZs Alprazolam Brotizolam Bromazepam Etizolam Clordesmetildiazepam Flunitrazepam Diazepam Flurazepam Lorazepam Quazepam Oxazepam Temazepam Prazepam Triazolam Long-acting BDZs (> 48 h) es. diazepam, clonazepam Intermediate-acting BDZs (24-48 h) es. alprazolam, nitrazepam Short-acting BDZs (8-24 h) es. lorazepam, oxazepam Ultrashort-acting BDZs (< 8 h) es. triazolam, midazolam

Benzodiazepine Half-Life and Uses

Benzodiazepines Half-life Overall Drug(s) Half-life of parent compound (h) Active metabolite of duration Main use(s) metabolite (h) of action Midazolam 2-4 Hydroxylated derivative 2 Ultrashort (<6 h) Hypnotic Midazolam used as intravenous anaesthetic and anticonvulsant Zolpidem b 2 No - Ultrashort (~4h) Hypnotic Lorazepam, oxazepam, temazepam, lormetazepam 8-12 No Short (12- 18 h) Anxiolytic, hypnotic. Lorazepam used as anticonvulsant Alprazolam 6-12 Hydroxylated derivative 6 Medium (24 h) Anxiolytic, antidepressant Nitrazepam 16-40 No - Medium Anxiolytic, hypnotic € Diazepam, chlordiazepoxide 20-40 Nordazepam 60 Long (24- 48 h) Anxiolytic, muscle relaxant Diazepam used as anticonvulsant Flurazepam 1 Desmethyl- flurazepam 60 Long Anxiolytic, hypnotic c Clonazepam 50 No - Long Anticonvulsant, anxiolytic (especially mania) Rang & Dale Pharmacology Elsevier Ed.