Anxiety 2024 PDF

“Anxiety” (2024). Introduce the concept of anxiety as pathophysiological state and list the current classification and complexity of anxiety disorders. Highlight the fear pathway as a template to understand anxiety as a brain disorder. Introduce the major drug therapies (Benzodiazepines) and discu...

“Anxiety” (2024). Introduce the concept of anxiety as pathophysiological state and list the current classification and complexity of anxiety disorders. Highlight the fear pathway as a template to understand anxiety as a brain disorder. Introduce the major drug therapies (Benzodiazepines) and discuss actions at receptors that are widely expressed in the brain can achieve some selectivity (anxiolytics). References Pharmacology 5th edition. Chapter 36. Anxiolytic and hypnotic drugs. Eds. Rang, H.P., Dale, M.M., Ritter, J.M. and Moore, P.K. Elsevier Churchill Livingstone. Essential introduction to all basic concepts. Neurobiology of mental illness 2nd edition. Chapter 34-43 Anxiety disorders. Eds. Charney , D.S. and Nestler E.J. Oxford University Press. Detail across all areas plus additional aspects for those interested. Kent, J.M., Mathew, S.J. and Gorman, J.M. (2002) Molecular targets in the treatment of anxiety. Biol. Psychiatry 52. 1008-1030. Broad coverage of molecular pathways and how they are targeted by therapy. Garanki, A., Mathew, S.J. and Charney, D.S. (2006) Neurobiology of anxiety disorders and implications for treatment. Mount Sinai Journal of Medicine. 73. 941-949. Good coverage of neurobiology of fear circuits and how they are modified to change behaviour. Mohler , H (2012) The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology 62. 42-53. Good detail about the role played by GABA in fear highlighting reasons why the general brain pathway can be selectively modulated to treat affective disorders (anxiety and depression).  Depression versus Anxiety Disorder Depression Anxiety Biological pathway Mood Fear Definition Symptoms and length of Symptom classification time are reported. and self reporting Example animal model Forced swim test Fear conditioning Brain pathways Circuit level connectivity Circuit level connectivity (Amygdala) Transmitter pathway Monoamines GABA Molecular Target Transmitter Transporter Inhibitory GABA receptor Drug Class Reuptake inhibitors Benzodiazepines Clinical confounds Side effects Withdrawal and addiction  Fear a physiological response when pathological it is anxiety Fear is a normal physiological response helps survival. Heightened sensory state, Vigilance HYPER AROUSED, heart rate, metabolic readiness, fight and flight response. Better still predict danger indeed fearful response is a learnt response. Anxiety is a pathophysiological state that detract from normal function and likely impede an organisms success. Thus, a medical condition. Anxious about your exams but do not want an anxious (fear) related state when taking your exams: increased heart rate, decreased salivation, upset stomach, increased respiration, scanning and vigilance (indecisive if out of context), jumpiness (ease of startle), frequent urination and defecation (diarrhoea), fidgeting, freezing (apprehensive expectation). Anxiety would be the activation of these responses to neutral or emotionally ambiguous cues. This interpretational aspects suggests important cognitive component. Fundamental to the fearfulness is the ability to use past experience to modulate or modify the behaviour. Indeed much of what is fearful has to be learnt by direct experience or observation. Monkeys not innately scared of snakes. Bitten to learn or observe others response to snake. This implies neuromodulatory mechanism and pathways underlying the fear response and anxiety pathophysiology.  An anxious state from multiple conditions (DSM-IV/V). Confound by co-morbidity, Substance abuse and a spectrum of interacting behaviours. Panic Attack Palpitations, pounding heart, sweating trembling, breathless, feeling of choking chest discomfort abdominal distress, dizzy or faint, feelings of unreality or detached from oneself, fear of losing control or going crazy paresthesias (numbness or tingling sensations), chills or hot flushes. These bouts should peak at 10 minutes. Agoraphobia Symptoms as above when placed in an environment where escape is difficult, embarrassing or Can not be made without support. Classified if not better explained by other conditions. Panic Disorder Recurrent panic attacks 10 minute peak. Or remain anxious about them recurring for up to month after an attack. My be associated with Agoraphobia. Not due to drug abuse. Are not better explained by co-morbid conditions. Specific Phobia Excessive fear to a specific cue often recognized by sufferer not the case for children. Anticipation of cue or avoidance of it interferes with normal life routine. Not explained by other conditions. Social Phobia Anxious state induced by social situation many criteria as for specific phobia. In children they must exhibit otherwise normal ability for social interaction in familiar setting. If aligned with another disorder this can not underlie social phobia. Obsessive Recurrent obsessive thoughts or images intrusive and inappropriate to time or place. Try to neutralize intrusion by distracting routines. Patient recognize the obsessive nature. Compulsions respective behaviours compulsive (e.g. hand washing) or inappropriate/excessive behaviours designed to reduce distress. Recognition of the excess. Time consuming routines 1 hour a day Interfering with social or working relations. Not due confounding Disorder (OCD) condition. Define if patient has poor or good insight into their condition. Post-traumatic stress Experienced traumatic or near death experience in which intense fear response ensued. Intrusive recurring memory, dreams or sense of event. Intense response to internal or external cues associated with event. Disorder (PTSD) Physiological response by event cues. Persistent avoidance of cue. Diminished expectations quality of life (e.g. career, family etc). Irritability, insomnia, hyper vigilant difficulty concentrating. Impact on social function and symptoms persist for greater 1 month. 1-3 months (ACUTE); >6 months (Chronic), appears 6 months post traumas (Delayed Onset) Acute stress disorder Cause and ensuing outcomes similar to PTSD. Shorter term classified lasting between 2 days and 4 weeks and occurs within 4 weeks of trauma. Individual shows dissociative behaviour during or following trauma, amnesia, depersonalization. No substance abuse or other underlying cause. Generalized Anxiety Anxiety or worry for more days than not for 6 months. Uncontrolled worry Associated with restlessness, fatigue, lack of concentration blank mind, irritability, muscle tension, sleep disturbances. Anxiety can not be specified but brings Disorder (GAD) about disruption of normal life. Is not part of an associated syndrome. Animal models to unpick the fear circuit. Based on psychological paradigms 1. Accessing the core fear circuit. 2. Implicating additional modulation. 3.Making a clear case for neuronal plasticity.  Amygdala an almond at the heart of the fear pathway. -ve modulation Association Core Fear Pathways Centre +ve modulation EMOTIONAL RESPONSE Inputs from several relay/integrating centres. EMOTIONAL RESPONSE Orbital cortex Hippocampus Central amygdala Striatum (Choice behaviour (Learning, place) Bed nucleus stria terminalis (avoidance behaviour) emotional memory) (Autonomic responses, attention) Routes to anxiety pharmacotherapeutic treatment of anxiety disorders. Medical work up, care about co-morbidity drugs regime/therapy focused at predominant symptom. Current preferred treatment route prioritizes an order of treatments. 1. SSRI. Selective serotonin reuptake inhibitors (increase 5HT levels) 2. Tricyclic antidepressant drugs (increase 5HT and Noradrenalin levels) 3. Benzodiazepines (Potentiate GABA mediated inhibition in CNS and periphery) 4. Anticonvulsant drugs (Stabilize nerve activity, e.g. valporate) 5. Monoamine Oxidase inhibitors (elevate 5-HT levels) not favoured. Classification Prevalence Symptom Panic disorder 4% Panic attacks good response to 5HT therapies. 70-80 %. Particularly susceptible to tricyclic antidepressants. Generalized Anxiety disorder 5% Often co-morbid with mood disorders and preferred therapy aimed to facilitate treatment (may chose drug that treats anxiety and helps sleep (sedative). Social Anxiety Disorder 10% Target the dysfunction at point required (e.g. beta-blockers when public speaking) Post-traumatic stress disorder 7-8 % Re-occurring stress 8-12 weeks for full efficacy). Anxiolytic, sedative, hypnotic, muscle relaxant (now know these effects are through distinct GABAA receptor types. Receptors expressed broadly in the anatomical regions of the circuit including BZ sensitive GABA receptors in amygdala. Excellent efficacy but amnesic. Very limited toxicity (cf barbiturates that they superseded) Big problem associated with protracted use of the drug. Use has become restricted due to tolerance and withdrawal problems. Acute treatment One strategy is to taper the BZ in combination with SSRI treatment.  Non-drug Therapies have Efficacy and Brain Mechanisms Approach Basic Clinically Does it work Evidence for premise provided based on changes in trial. brain structure and function Psychoanalysis Unconscious NHS Much Evidence for Mind. debated and against Mindfulness Live in the NHS Mixed Meditation present. outcome changes brain state. Cognitive Rationalizing NHS Mixed fMRI some behavioural /organizing outcome evidence for therapy. thought activity process. changes. Family therapy Defining life NHS Anecdotal Reward MRI events and and trial signals social based. associate organization with family scores. https://www.nhs.uk/mental-health/talking-therapies-medicine-treatments/talking- therapies-and-counselling/types-of-talking-therapies/  The wider context of the Neuropharmacology of Affective disorders is both current, debated and incompletely understood. Prozac, used by 40m people, does not work say scientists “Analysis of unseen trials and other data concludes it is no better than placebo” Health editor Sarah Bozely Tuesday February 26 2008