Anxiety Disorders: Types, Prevalence, and Physiology

Anxiety and Related Disorders

• Anxiety is an emotional state caused by the perception of real or perceived threats that undermine an individual's sense of security.
• The one-year prevalence of anxiety disorders in adults over 18 in the U.S. is approximately 18.1%.
• Only 20.6% of those with anxiety disorders seek healthcare services.
• Anxiety disorders carry significant social and economic burdens.
• Obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are no longer classified as anxiety disorder

Epidemiology of Anxiety

• The one-year prevalence rate for all anxiety disorders in adults is 19.1%.
• Generalized anxiety disorder (GAD) and panic disorder (PD) each have a prevalence of about 3%.
• Social anxiety disorder (SAD) affects roughly 7% of adults.
• The lifetime prevalence of PTSD is around 7%.
• An estimated 1.6% of adults have OCD, with 2-4% of the pediatric population affected.

Physiology and Biochemistry of Fear and Anxiety

• Fear is a typical reaction to impending circumstances.
• A transition from normal fear to an anxiety disorder happens when concern is unwarranted by the situation or appears in inappropriate situations.
• The sympathetic nervous system activates when someone experiences fear to regulate energy expenditure from body reserves.
• Stress and epinephrine affect insulin secretion and glucose metabolism: Blood flow to skeletal muscle and the heart rate increases, and glucose levels rise.
• Epinephrine, norepinephrine, and cortisol are released, causing both short and long- term physiological changes for expected needs.
• The individual may do nothing at all the first time they are confronted with a terrifying circumstance and will experience a negative outcome.
• An avoidance response is any action that stops such an outcome.
• People become more vigilant of cues anticipating a frightening event and may become conditioned to avoid such indicators with time.

Brain Pathways in Anxiety

• Fear involves associative learning, hence not surprising that the brain pathways underlying emotional responses and memory formation.
• Important brain regions for the neural network associated with fear include amygdala, the hippocampus, and the limbic system.

Amygdala

• Transmits information from sensory cues (sound of brakes or a tarantula) to the brain stem to be converged and processed at the amygdala.
• The amygdala produces behavioral alterations through interaction to the hypothalamus (produces sympathetic response) and motor neurons (trigger motor response).

Hippocampus

• Visual and contextual cues (inside a car or a spiderweb) are received, processed, and transmitted to the amygdala.
• The hippocampus establishes avoidance conditioning and forming memories of fearful events, with responses from the amygdala triggering responses to a fearful event.

Pathophysiology of Fear & Anxiety Disorders

• Normal fear/conditioning becomes pathological when the response to a frightening experience is amplified or occurs in response to non-threatening events.
• Changes in cue processing by the amygdala or hippocampus might be a cause of anxiety disorders.

Neurotransmitters in anxiety

• Anxiety is linked to multiple neurotransmitters in the brain.
• Various aspects of emotion are potentially affected from these neurotransmitters being equally spread across the brain.

Gamma-aminobutyric acid (GABA)

• Anxiety and mood disorders are thought to have a link to increased GABA levels.
• By influencing neuronal excitability and rapid changes in fear arousal, GABA receptor subtypes control anxiety, panic, and response to severe stress.

Norepinephrine

• May be involved in the sympathetic nervous system to influence anxiety disorders.
• NE released by cells of the locus coeruleus travels across the brain.
• NE release in the amygdala during fearful situations causes an amplified fear response.

Serotonin

• Functions as an inhibitory neurotransmitter and aids in the regulation of additional neurotransmitters like NE.
• Anxiety may be linked to low levels of 5-HT in the brain.
• After being released into the synapse, 5-HT levels are managed through presynaptic autoreceptors and the serotonin reuptake transporter (SERT).
• Lowering 5-HT levels can trigger an imbalance of other neurotransmitters resulting in anxiety.

Dopamine

• Anxiety problems, particularly OCD, are linked to DA, though there isn't much evidence.
• DA imbalances produce tics and other neurological disorders in OCD patients.
• Elevated DA levels in the prefrontal cortex might be linked to OCD but there is minimal evidence for this.

Hormones

• The brain starts a sympathetic cascade that activates the HPA axis when someone is under stress.
• In reaction to stress, the hypothalamus produces corticotropin-releasing hormone (CRH).
• The adrenal glands release cortisol and epinephrine by the HPA axis to negatively return feedback to the sympathetic response.
• People with anxiety disorders have decreased cortisol levels and elevated CRH levels.
• The severity of PTSD increase with lowered amounts of cortisol, which results in an extended stress response.

Neuroimaging in anxiety

• Studies using functional magnetic resonance imaging (fMRI) have examined the brains of people with anxiety disorders. The patients show heightened activity in the fear pathways, including the amygdala, anterior cingulate cortex (ACC), ventromedial prefrontal cortex (vmPFC), and insular cortex.
• Increase in activity correlates to the severity of the patient's symptoms.
• Drugs used to treat anxiety can work by reducing activity in these brain regions.

Clinical Presentation and Diagnosis of Anxiety

• Complete physical exams, mental status exams, medication reviews, and basic lab workups are crucial in evaluating individuals showing indications of anxiety.
• Medical issues, psychiatric disorders, and medications can trigger anxiety symptoms which must be investigated and addressed before diagnosis.
• The DSM-5 categorizes anxiety disorders and establishes diagnostic standards for all anxieties, including OCD and PTSD.
• Symptoms need to impair a patient socially and occupationally as well as not be the consequence of a drug use, medical condition, or psychiatric disorder.

Generalized Anxiety Disorder

• GAD patients manifest an unparalleled intensity, duration, and/or frequency of anxiety and concern to the likelihood of the feared event. Also struggle to have a break from worrying and their thoughts.
• Depression and GAD are similar in presentation.

Panic disorder

• People with this condition have acute panic episodes and underlying anxiety.
• The occurrence of terror during panic episodes have to be in a defined streak of time.
• Individuals may have symptoms like breathlessness, heart palpitations, chest discomfort, choking, or a fear of "losing control."
• Panic attacks can commonly be confused as myocardial infarctions (heart attacks).

Social Anxiety Disorder

• Social anxiety disorder (SAD) is clinically significant anxiety caused from being exposed to certain social situations or being observed and performance/scrutiny by others which causes avoidance behaviors.
• SAD individuals have a fear that in performance or social situations, they will become embarrassed.

Specific phobias

• Although prevalent, are commonly insufficient or distressing.
• Vary from other anxieties due to the specific fear which is excessive without resulting in pervasive anxiety.

Obsessive Compulsive Disorder

• Repetitive obsessions and compulsions characterize OCD.
• Obsessions trigger anxiety/distress while compulsions are ritualistic behaviors that serve to neutralize the anxiety .
• Obsessions are seen as not within one's control with the recognition that it is self-generated.

Post-Traumatic stress disorder

• Symptoms of increased arousal, attempts to block out reminders of the trauma, and personality changes define PTSD.
• Re-experiencing, avoidance, negative alterations in cognition and mood, and altered arousal/reactivity are the four symptom clusters from the trauma exposure.
• PTSD can occur at any age but manifests within 3 months after the trauma.

Therapeutic Agents for Anxiety Disorders: Definitions and Types

• An anxiolytic is a drug that relieves anxiety. Some can have sedative effects.
• Benzodiazepines are a class of meds used for sleep and anxiety.
• Newer meds are replacing benzodiazepines as they pose a risk of misuse.

Pharmacologic Approaches for Anxiety Disorders

• GABAergic effects, shown by benzodiazepines
• Boosting the availability of 5-HT.

Benzodiazepine Receptor Agonists

• BZDRAs include benzodiazepines (BZDs) and non-benzodiazepine GABA agonists to boost sleep, known as hypnotics when used in treatment.

Benzodiazepines

• These are a group of CNS depressants with hypnotic, muscle relaxant, and anti-seizure capabilities, and are primarily used for anxiety and sleep disorders.

Benzodiazepine Formulation, Delivery, and Absorption

• For oral use, benzodiazepines are ingested quickly and largely, they are known to undertake extensive first pass metabolism, lowering oral availability.

Chemistry and Pharmacodynamics of Benzodiazepines

• Benzodiazepine name corresponds to the drug's pharmacophore ring structure and are GABAergic.
• Increase of the influx or action time of chloride occurs at its binding site on ligand gated channels.

Clinical considerations

• Common treatments used for general anxiety disorder include nonpharmacologic and pharmacologic.