Week 2 (Anxiety, Hearing, Alterations in Consciousness and Sleep) Flashcards
Normal developmental fears
Infancy: strangers, loud noises, separation
Early childhood: separation, monsters, dark
Middle childhood: real-world dangers, new challenges, health, school
Adolescence: social status, relationships, performance, the future
When is anxiety a disorder?
Avoidance
Interference
Distress
Duration
DSM-IV Anxiety Disorders
Generalized anxiety disorder (GAD)
Panic disorder/agoraphobia
Post-traumatic stress disorder (PTSD)/Acute stress disorder
Social phobia
Obsessive compulsive disorder (OCD)
Specific phobia
Seen predominantly in childhood: separation anxiety disorder (SAD), selective mutism (SM)
Prevalence of anxiety disorders
Most common class of mental disorders in general population
Lifetime prevalence of any anxiety d/o >15%
Women > men (except OCD, SoP)
Common in childhood: 75% have first episode by age 21.5; most common class of childhood disorders (10-15% of community children)
Comorbidity of anxiety disorders
Other anxiety disorders
Depression (genetic influence because similar pathways, runs in families, treated by same drugs; environmental influence secondary to anxiety-related disability)
Substance abuse (biological because overlapping risk factors; environmental because of self-medication)
Greater burden of non-psychiatric illness
If no anxiety/depression in childhood, are you likely to become anxious/depressed in adulthood?
Only 5% chance of anxiety/depression if healthy in childhood
Etiology of anxiety
Genetic: high heritability but complex genetics; “behaviorally inhibited” children 3x risk; cognitive biases in processing and attention
Environment: parents of anxious children more likely to model anxious cognitions and behavior, provide negative feedback/behave less warmly, act in a restrictive manner (grant less autonomy)
Agoraphobia
Fear and avoidance of place and activities from which it might be difficult to escape or get help
Commonly avoided places: crowds, school, wide open spaces, restaurants, parties, subway
Commonly avoided activities: leaving house, driving, waiting in line, being alone, travel, shower, exercise, caffeine, drugs, sex
Specific phobia
Intense anxiety/avoidance of specific stimuli, disproportionate to actual danger, which causes functional interference
Common fears: dark, animals, thunderstorms, water, elevators, illness/injury, airplanes, blood/injections, heights, doctor/dentist, choking
Generalized anxiety disorder (GAD)
Anxiety/worry about multiple things more days than not for >6 months
Difficult to control worry
3 or more of these symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance
Distress/impairment
Obsessive compulsive disorder (OCD)
Obsessions: intrusive, unwanted, distresing thoughts or urges that persist despite efforts to ignore or control them; concerns about contamination, illness/somatic, safety, right/wrong (scrupulosity); intrusive thoughts/images could be numbers/words, violent/sexual images
Compulsions: repetitive rituals aimed at neutralizing (but often unrelated to) the obsessive worry; repeating rituals could be cleaning/washing, checking, re-reading/writing, tapping/touching, counting; good/bad clothes, numbers
Compulsions more common in touretic OCD: ordering/arranging/symmetry, hoarding/collecting
Post-traumatic stress disorder (PTSD)
May develop after a person has experienced or witnessed a traumatic or terrifying event in which serious physical harm occurred or was threatened
Symptoms may include flashbacks, nightmares, and severe anxiety, as well as uncontrollable thoughts about the event
Anxiety disorder due to a general medical condition
Physical health problem can cause symptoms of anxiety
Ex: cardiac, endocrine, asthma/COPD, neuroendocrine tumor
Anxiety disorder due to a drug/substance
Substance-induced anxiety disorder is characterized by prominent symptoms of anxiety that are a direct result of abusing drugs, taking medications or being exposed to a toxic substance
Ex: inhaled beta-agonists (albuterol), stimulants, steroids, thyroid replacement, caffeine, decongestants, marijuana, cocaine, methamphetamine
Anxiety disorder not otherwise specified (NOS)
Prominent anxiety or phobias that don’t meet the exact criteria for any of the other anxiety disorders but are significant enough to be distressing and disruptive
Separation anxiety disorder (SAD)
Presence of 3 or more of the following:
Distress when separation is anticipated or occurs
Worry about harm befalling others
Worry that an untoward event will result in separaion
Refusal to go to school or elsewhere
Fear or reluctance to be alone at home or in other settings
Refusal to sleep away from attachment figures
Nightmares
Physical complaints at separation
Note: common to have GAD, specific phobia and depression as comorbidities
Developmental considerations with SAD
Ages 5-8: fears of harm befalling attachment figures, nightmares, school refusal
Ages 9-12: excessive distress at separation, school refusal
Ages 13-16: somatic complaints and school refusal, avoidance of developmentally appropriate socialization
Selective mutism (SM)
Consistent failure to speak in specific social situations despite speaking in other situations
Closely related to social anxiety disorder
Symptoms typically become problematic when children enter school
Uncommon (0.71% of K-2nd graders)
Screening questions for different anxiety disorders
GAD: “Would you describe yourself/your child as a worrier?”
Social: “Have you noticed yourself/your child avoiding social situations or feeling uncomfortable or afraid of doing something embarrassing in front of others at school, restaurants, parties, or when meeting new people?”
SAD: “Does your child worry a lot about being away from you; that something bad may happen to you or him/her while you’re apart?”
OCD: “Do you/does your child have intrusive thoughts that s/he can’t get rid of or rituals that bother him/her?”
Cognitive-Behavioral Triad of Anxiety
Thoughts
Feelings
Behaviors
Anxiety builds when “uncomfortable” situation and subsides when “safe” situation
Intervening at all 3 points of the Cognitive-Behavioral triad of anxiety
Thoughts: learn to talk back to your thoughts (“this is just my anxiety, there’s nothing real to fear”)
Behaviors: control your actions (graded exposure, avoidance is the enemy)
Feelings: learn to relax your body (breathing, progressive muscle relaxation, guided imagery, mindfulness/meditation)
Treating children with anxiety disorders
Children with anxiety disorders are highly responsive to therapy, and it is often possible to avoid using meds
CBT is key in children, but needs to be fun, emphasize rewards, and parental support is necessary
Meds can be important if therapy alone not enough, child is severely impaired/distressed, comorbidity, child/parent unable to adequately engage in therapy
SSRIs for treatment of anxiety
SSRIs have strongest support of all agents!
Excellent efficacy across different anxiety disorders
Excellent tolerability with mild-moderate side effects
Sedation: fluvoxamine, paroxetine
Activation: fluoxetine, sertraline (both have more GI side effects)
P450 interactions in fluvoxamine, paroxetine, fluoxetine
Less evidence for citalopram, escitalopram
Sexual side effects :(
Other drugs for treatment of anxiety
SNRIs: not first-line in OCD, serotonergic action key
TCAs: less effective, more side effects; clomipramine as augmenter or as monotherapy in OCD
Neuroleptics: limited efficacy data except in OCD, side effects; frequent augmenter in OCD (especially with tics)
Benzodiazepines: short-term or occasional use (especially in panic), limited by side effects (tolerance, dependence, cognitive impairment, rebound anxiety), paradoxical effects in children (disinhibition)
Benzo alternatives for PRNs: gabapentin/pregabalin (standing or prn), beta blockers (propanolol) in social phobia (prn)
Benzodiazepines
Bind allosteric site on GABA-A receptor-chloride channel complex (distinct from GABA binding site)
Positive allosteric modulators: produce little or no effect on chrloride conductance in absence of GABA, but enhance GABA-mediated increase in chloride conductance (increase efficiency of GABAergic synaptic transmission by membrane hyperpolarization and decrease firing rate of neurons)
All have anxiolytic, sedative and hypnotic properties
Dose-dependent continuum of CNS depression
Anxiolytics, sedatives, “tranquilizers” cause calm, relaxation then drowsy, sleepy; also cause paradoxical disinhibition (inhibitory pathways themselves get turned off so excitation occurs)
Hypnotics produce sleep
Anesthetics cause unconscious
Dose-response curves of barbiturates vs. benodiazepines
Barbiturates have steep response curve so easy to produce undesired effects (like drowsiness)
Benzodiazepines have shallow curve so wide safety margin and takes more drug to produce undesired effects
Pharmacokinetics of benzodiazepines
Absorption: well absorbed after oral administration
Distribution: very lipid soluble; distribute throughout body
Metabolism: primarily hepatic clearance, oxidation and subsequent conjugation (oxidation can produce active metabolites)
Which benzos do and do not have active metabolites?
Diazepam, chlordiazepoxide and clonazepam have active metabolites and long effective half-lives; accumulate with repeated daily administration
Oxazepam and lorazepam are only conjugated (no CYP metabolism) and do not form active metabolites; accumulation is minor
Is the duration of action of benzos based upon their half life?
Not if they have active metabolites!
If drug has active metabolites (diazepam, chlordiazepoxide, clonazepam) then duration of action based on those active metabolites too!
Pharmacologic effects of benzodiazepines
CNS:
Anxiolytic (treatment of GAD)
Sedative (used before medical procedures like endoscopy)
Hypnotic (promotes sleep)
Anesthetic (note: benzos are not analgesic)
Anticonvulsant, muscle relaxant (produces some degree of skeletal muscle relaxation (suppression of spinal and supraspinal motor reflexes))
Adverse effects of benzodiazepines
Common adverse effects are extensions of their pharmacological actions: sedation, decreased intellectual function (confusion), anterograde amnesia (no memory acquisition or recall), psychomotor impairment (for days), withdrawal seizures; fatal OD rare unless combined with ethanol or other CNS depressant
Abuse only in those with a history of abuse
Few drug interactions due to wide safety margin (high TI) and no inhibition/induction of CYP450
Wide individual differences in sensitivity to benzodiazepines
Elderly more sensitive to all effects
In liver disease, increased sensitivity to those drugs that do CYP metabolism in liver (diazepam, etc) so use oxazepam or lorazepam instead for patients with liver disease
Flumazenil
Competitive antagonist at benzodiazepine binding site; used clinically to treat benzo OD
Tolerance, dependence and withdrawal with benzos
Tolerance develops (pharmacodynamic, not pharmacokinetic) to benzos in general (not individual types) for sedative and anticonvulsant activity (not anxiolytic effects)
Cross-tolerance between benzos and other CNS depressants
Physical dependence occurs if chronic use and get withdrawal upon cessation
WIthdrawal more apparent with shorter acting drugs (suddenly stop then immediately “off” drug as opposed to longer tapering built in to longer acting drugs)
Symptoms of withdrawal may mimic anxiety (jitteriness, insomnia, loss of appetite) or may be different (tremor, muscle twitching, paresthesias, seizures)
How do you minimize withdrawal from benzos?
Switch patient from short-acting to long-acting benzo and slowly reduce dosage of drug
Buspirone
Partial agonist of 5HT1A receptors
Structurally different from benzodiazepines, does NOT interact with GABA receptors
Best for previously untreated patients who might require long-term treatment of GAD, or who are abusers of CNS depressants
Not effective in panic attacks
Side effects: low incidence of headache, dizziness
Response occurs only after several weeks of tretment
No bad side effects: produces no sedation (just calming), no anticonvulsant or muscle-relaxant properties, little impairment of cognitive or psychomotor skills, no tolerance or withdrawal upon cessation, little or no abuse potential, no additive effect
Used for dyspepsia or IBS because there are 5HT1A receptors in fundus of stomach
Drug classes with anti-anxiety effects (other than benzos)
TCAs: effective in some patients with panic attacks
MAOIs: effective in some patients with panic attacks
Beta blockers (propranolol): prevent peripheral autonomic manifestations of anxiety (tremor, sweating, tachycardia and palpitations); don’t prevent anxiety itself
Insomnia
Difficulty falling asleep, staying asleep, and/or too early awakening
Caused by stress, emotional upset, aging, medical and psychiatric illness (sleep apnea, nocturnal myoclonus, depression), drugs, jet lag
Characteristics of the ideal hypnotic
Induce sleep rapidly
Produce normal sleep
Reduce number of awakenings
Wake up refreshed (no hangover)
Not cause tolerance or dependence
Safe (high TI, few side effects, no drug interactions)
Effects of hypnotics on sleep
Decrease latency of sleep onset
Increase duration of stage 2, non-REM sleep
Decrease slow-wave sleep (stages 3 and 4)
Reduce REM sleep (this is bad and can produce hangover the next day!)
Prolong total sleep time
Benzodiazepines for treatment of insomnia
All benzos can be used as hypnotics but don’t meet criteria for good hypnotic (have hangover effect, don’t produce normal sleep, have tolerance so only good short-term, produce withdrawal effects (insomnia, REM rebound which can produce nightmares))
Triazolam (Halcion): short half life (1.5 - 5.5 hours), little hangover, less accumulation but can produce increased wakefulness during last 1/3 of night, daytime rebound anxiety and anterograde amnesia for some
Temazepam (Restoril): half life between triazolam and flurazepam but slowly absorbed and sleep onset can be delayed
Nonbenzodiazepine hypnotics
Structure unrelated to benzodiazepines or barbiturates but still interact with GABA-A receptor!
Zolpidem (Ambien): relatively short half life (1.5 - 4.5 hours), no active metabolites
Zaleplon (Sonata): binds subtype of GABA-A receptor, very short duration of action, useful for patients who have difficulty falling asleep or awaken in the middle of the night
Eszopiclone (Lunesta): binds to subtype of GABA-A receptor; intermediate duration of action
How is melatonin synthesized?
5HT is turned to N-acetyl serotonin by NAT in the pineal gland
N-acetyl serotonin is turned to melatonin
Note: synthesis under control of postganglionic sympathetic fibers that innervate the pineal gland
Melatonin
Lipophilic hormone
Mainly produced and secreted at night by the pineal gland
Stimulated by darkness and inhibited by light
Light –> eyes/retinohypothalamic tract –> SCN of hypothalamus –> PVN of hypothalamus –> spinal cord –> preganglionic cell bodies in intermediolateral horn project out sympathetic ganglia –> superior cervical ganglion –> postganglionic sympathetic neurons along internal carotid –> pineal gland
Synthesis and release decreases with age
Ramelteon (Rozerem)
Melatonin receptor agonist
Targets MT1 and MT2 melatonin receptors (expressed in SCN and throughout brain)
Does not show binding to GABA-A receptors
Particularly for delayed sleep onset
Not shown to produce dependence or potential for abuse
Augments ongoing natural melatonin release
Other classes of drugs used as sedative-hypnotic agents
Antidepressants (given at bedtime to facilitate sleep)
Antihistamines (doxylamine, diphenhydramine)
NOT ethanol! Can cause REM rebound
What should people using sedative-hypnotic drugs for insomnia be aware of?
Early morning awakening
Rebound daytime anxiety
Amnesic episodes
Immune response gene regulation for extracellular vs. intracellular pathogens
Extracellular pathogens (bacteria) activate pro-inflammatory gene program: IL1B, IL6, TNF, NF-kB
Intracellular pathogens (viruses) elicit antiviral gene program: IFN genes, TFs such as IRFs (interferon regulatory factors)
Two efferent programs to modulate immune response genes
1) HPA axis: CRH –> ACTH –> GCs from adrenal gland –> GCs enter WBCs and (1) decrease expression of antiviral immune response genes (IFNA, IFNB) and (2) decrease expression of pro-inflammatory immune response genes (IL1B, IL6, TNF) and (3) induces transcription of anti-inflammatory NFKB1A and (4) antagonizes pro-inflammatory TFs (NF-kB and AP1) via protein-protein interactions
2) Sympathetic nervous system: epi from adrenal gland and NE from SNS nerve fibers act on beta adrenergic receptors on WBCs to (1) decrease expression of antiviral immune response genes (IFNA, IFNB) and (2) increase epression of pro-inflammatory immune response genes (IL1B, IL6, TNF) and (3) stimulates tx of TH2-type cytokine genes (IL4, IL5) and (4) suppresses expression of TH1-type genes (IFN, IL12)
Summary: HPA suppresses antiviral and inflammatory response (yet inflam present because reduced levels of GC-mediated gene transcription?); SNS suppresses antiviral but activates inflammation
Are there direct connections between brain and immune cells?
Yes!
Tyrosine hydroxylase nerve terminal in direct contact with lymphocyte
This allows quick regulation of immune cells by epi and NE?
What effect does stress have on disease?
Increased risk of infectious disease (viral?!)
Increased risk of cardiovascular disease
What is the relationship between depression, inflammation and cardiovascular mortality?
In MDD, have increased sympathetic stimulation (?) so have increased pro-inflammatory cytokines and increased cardiovascular mortality
Psychological stress and upper respiratory illness
Poor social ties are associated with increased susceptibility to the common cold
Higher psychological stress increases susceptibility and severity of common cold symptoms
Remember, common cold is a VIRAL illness! Decreased antiviral genes in depression/stress!
Do stress and depression affect vaccine effectiveness?
Yes, stress and depression make viral vaccines (pneumococcal, herpes zoster, hepatitis) less effective!
Association between shyness and HIV/AIDS progression
Social inhibition (shyness) accelerates progression of HIV/AIDS!
Association between stress and metastasis
Stress promotes metastasis!
Beta blockers being studied in Israel to determine whether they can prevent metastasis
Macroenvironmental sensing
Third way to regulate innate immune system and antiviral gene programs
CNS sensing what is going on externally and integrating info regarding general physiological conditions to lead to changes in innate immune system and antiviral gene programs
This is critical because for example, when we’re sleeping, CNS gives DIFFERENT signals to immune system than when we’re awake
Timeline of stress affecting immune system
SNS is fast acting, so initially get increased pro-inflammatory cytokines
GCs act later to suppress pro-inflammatory cytokines
In chronic stress/depression (high GC), why do you have high inflammation?
Because GC response elements (receptors) are downregulated!
Sleep-wake cycles and inflammation
Insomnia and shift work upregulates inflammatory markers
Sleep restriction activates pro-inflammatory cytokine genes and increased NF-kB activity
Molecular pathways between pro-inflammatory signals and neural activity
1) Interaction of circulating cytokines with cytokine receptors in the brain circumventricular organs that lack a functional BBB
2) Stimulation of brain vascular endothelial cells to release second messengers that stimulate subsequent cytokine production within the brain
3) Active transport of cytokines across the BBB via carrier molecules
4) Peripheral inflammatory stimulation of afferent nerves that subsequently stimulate CNS tissues to produce cytokines
Brain structures responding to pro-inflammatory signals
Hypothalamus: key role in the regulation of systemic physiological function and organism-level biobehavioral dynamics (metabolism, sleep, feeding)
Amygdala: mediates fear- or threat-related responses and processes social information
Hippocampus: key role in learning and short-term memory, general information processing, spatial information processing, and navigation and mobility
Pre-frontal cortex: complex information processing and planning
Anterior cingulate cortex: involved in a diverse array of cognitive-emotional interactions
Ventral striatum: involved in positive motivation and reward
What does injecting endotoxin do to mood?
Endotoxin causes inflammation and inflammatory cytokines increase depression
Also inhibits reward activity in the brain (ventral striatum?)
Behavioral interventions that modulate inflammation
Cognitive behavioral therapy
Aerobic exercise
Meditation
Tai Chi Chih: boosts viral immunity and response to vaccination
Effects of group psychotherapy on recurrence and survival of malignant melanoma
Increased coping
Reduced depression
Increased natural killer activity
Lower rates of recurrence and death
Features of personality disorders
Deeply engrained
Inflexible
Maladaptive
Stable
Impairs function
Distresses others
Definition of personality disorder: PDs represent failure to develop a sense of self-identity and the capacity for interpersonal functioning that are adaptive in the context of the individual’s cultural norms and expectations
Personality disorder clusters A, B, C
Cluster A = Mad = odd or eccentric = paranoid, schizoid, schizotypal = social deficits, perceptual distortions, cognitive impairment = psychosis
Cluster B = Bad = dramatic, emotional or erratic = histrionic, antisocial, borderline, narcissistic = impulsivity, aggression, affective instability, emotionality = substance misuse, sociopathy
Cluster C = Sad = anxious or fearful = avoidant, dependent, obsessive-compulsive = anxiety/behavioral inhibition, compulsivity = depression, anxiety disorders, social phobia, somatoform disorders, eating disorders
Schizoid personality disorder
Pervasive pattern of detachment from social relationships and a restricted range of expression of emotions in interpersonal settings
Experience of illness: anxiety because of forced contact with others
Problemati behaviors: delay seeking care, appears unappreciative
Management strategies: provide clear explanations, avoid over involvement in personal and social issues
Schizotypal personality disorder
Pervasive pattern of social and interpersonal deficits marked by acute discomfort with, and reduced capacity for close relationships as well as by cognitive or perceptual distortions and eccentricities of behavior
Prominent features: odd beliefs, socially isolative
Experience of illness: odd interpretations of illness
Problematic behaviors: delay seeking care, odd beliefs, odd behavior
Management strategies: tolerate odd beliefs and behaviors, avoid over involvement
Paranoid personality disorder
Pervasive distrust and suspiciousness of others such that their motives are interpreted as malevolent; this begins by early adulthood and is present in a variety of contexts
Prominent features: distrust, suspicion
Experience of illness: heightened sense of fear and vulnerability
Problematic behaviors: feal that physician will harm leads to arguments and conflict
Management strategies: adopt a professional stance, provide clear explanations, be empathetic to fears, avoid direct challenge to paranoid ideation
Narcissistic personality disorder
Pervasive pattern of grandiosity, need for admiration, and lack of empathy that begins by early adulthood and is present in a variety of contexts
Experience of illness: anxiety caused by doubts of personal adequacy
Problematic behaviors: demanding, attitude of entitlement, denial of illness, alternating praise and devaluation of physician
Management strategies: validate concerts, give attentive and factual responses to questions, channel patient’s skills into dealing with illness
Histrionic personality disorder
Pervasive and excessive emotionality and attention-seeking behavior which begins by early adulthood and is present in a variety of contexts
Problematic behaviors: overly dramatic, attention seeking behavior, inability to focus on facts and details, somatization
Management strategies: avoid excessive familiarity, show professional concern for feelings, emphasize objective issues
Borderline personality disorder
Pervasive pattern of instability of interpersonal relationships, self-image, affects, and marked impulsivity that begins by early adulthood and is present in a variety of contexts
Experience of illness: terrifying fantasies about illness
Problematic behaviors: fear of rejection and abandonment of self-destructive acts, idealization and devaluation of physician
Management strategies: avoid excessive familiarity; schedule regular visits; provide clear, non technical explanations; tolerate angry outbursts but set limits; maintain awareness of personal feelings; consult psychiatrist
Antisocial personality disorder
Pervasive pattern of disregard for, and violation of, the rights of other that begins in childhood or early adolescence and continues into adulthood
Experience of illness: anger, entitlement, fear
Problematic behaviors: anger, impulsive behavior, deceit, manipulative
Management strategies: set clear nonpunitive limits
