Lecture 5Anxiety Disorders

David Saffen, Ph.D.Professor/Principal Investigator

Department of Cellular and Genetic MedicineFudan University, Shanghai, China

Email: saffen@fudan.edu.cn

OutlineA. Introduction

- Fear and anxiety- DSM-5 classifications- Current treatments- Epidemiology and societal burden - Famous individuals with anxiety disorders

B. Neurobiology, environment, genetics and epigenetics- Stress and the HPA axis- Brain regions implicated in fear and anxiety disorders- Drug targets - The influence of childhood trauma- Genetics and epigenetics

C. Developing new therapies to treat anxiety disorders- Novel therapeutic approaches and prevention

D. References, journal presentations, internet resources

A. Introduction

“The Scream”

Edvard Munch

• Fear: an emotional state triggered by a specific stimulus, which elicits defensive behaviors that subside when the stimulus is removed. For example, the presence of a snake or a growling dog or standing at the edge of a precipice.

• Anxiety: an emotional state that arises from general or non-specific stimuli that are perceived as being threatening in the future. This state is characterized by apprehensive mood with heightened arousal and vigilance.

Distinguishing fear and anxiety

• Physiological systems activated by fear and anxiety are closely related to those underlying the “flight or fight” response and responses to stress.

• Brain systems related to fear and anxiety overlap and include

the amygdala, hippocampus, cingulate cortex, prefrontal cortex

and hypothalamus.

• As discussed below, several disorders classified as “Anxiety disorders” in DSM-5 may more accurately be classified as

“Fear disorders.”

Subtypes of anxiety disorders (DSM-5)

- Generalized Anxiety Disorder (GAD)- Social anxiety disorder (Social Phobia)- Panic Disorder - Agoraphobia- Separation Anxiety Disorder-Selective Mutism- Specific Phobia- Substance/Medication-Induced Anxiety Disorder- Depressive Disorder Due to Another Medical Condition- Other Specified Depressive Disorder- Unspecified Depressive Disorder

Also:- Obsessive-Compulsive Disorder (OCD)- Post-Traumatic Stress Disorder (PTSD)

Diagnosis qualifications:

• The fear, anxiety, or avoidance causes clinically significant distress or interferes with social, occupational or other important areas of functioning.

• The fear, anxiety, or avoidance is not caused by medicines, substance abuse or physical ailments and is not better explained by another mental disorder.

Note: some levels of fear, anxiety and avoidance are normal responsesto perceived or real threats. It is only when these emotions and behaviors are produced inappropriately and at levels that that cause significant distress or interfere with daily functioning that they are recognized as clinical “disorders.”

Generalized Anxiety Disorder (GAD)

• Excessive anxiety and worry, occurring more days than not for at least six months

• Difficulty in controlling the worry

• Anxiety and worry associated with three of the following symptoms , for six months (only one symptom required for children)

- restlessness or feeling “keyed-up” or “on edge”

- being easily fatigued

- difficulty concentrating or mind “going blank”

- irritability

- muscle tension

- sleep disturbance (difficulty falling asleep or staying asleep, or

restless, unsatisfying sleep)

Social anxiety disorder (Social Phobia)

• Fear or anxiety about one or more social situations in which the individual is exposed to possible scrutiny by others.

• The individual fears that he or she will be negatively evaluated, humiliated or embarrassed.

• The social situation almost always evoke fear or anxiety.

• The social situations are avoided or endured with intense fear or anxiety.

• Fear or anxiety is out of proportion to the actual threat.

• The fear, anxiety or avoidance is persistent, typically > 6 months.

Agoraphobia• Marked fear or anxiety about two (or more) of the following situations:

- Using public transportation

- Being in open spaces

- Being in enclosed spaces

- Standing in line or being in a crowd

- Being outside of the home alone

• The individual fears or avoids these situations because of thoughts

that escape might be difficult or help not available in the event of

developing incapacitating or embarrassing symptoms.

• Agoraphobic situations almost always provoke fear or anxiety.

• Agoraphobic situations are actively avoided, require the presence of a companion or are endured with intense fear or anxiety.

• Fear or anxiety is out of proportion to the actual threat.

• The fear, anxiety or avoidance is persistent, typically > 6 months.

Panic Disorder• Recurrent unexpected panic attacks: an abrupt surge of intense fear or intense

discomfort that reaches a peak within minutes, during which four or more of the following symptoms occur:

- palpitations, pounding heart, or accelerated heart rate

- sweating

- trembling or shaking

- sensations of shortness of breath or smothering

- feelings of choking

- chest pain or discomfort

- nausea or abdominal distress

- feeling dizzy, unsteady, light-headed or faint

- chills or heat sensations

- paresthesias (numbness of tingling sensations)

- derealization or depersonalization

- fear of losing control or “going crazy”

- fear of dying

• A least one of the attacks has been followed by one or more month of:

- Persistent concern or worry about additional panic attacks or their

consequences and/or

- Significant maladaptive change in behavior related to the attacks

Obsessive Compulsive Disorder (OCD)

• Presence of obsessions or compulsions, or both

- Obsessions: recurrent or persistent thoughts, urges or images that are

intrusive and unwanted and cause marked anxiety or stress. The individual

attempts to ignore or suppress such thought, urges or images or to

neutralize them with other thoughts or actions (e.g. by performing a

compulsion).

- Compulsions: repetitive behaviors or mental acts performed in response to

obsessions or behaviors or mental acts aimed at preventing or reducing

anxiety or distress or preventing a dreaded event or situation

• The obsessions or compulsions are time-consuming or cause clinically significant distress or impairment in social occupational or other important areas of functioning.

• Specify: with good, fair or poor insight; with absence of insight/delusional beliefs

Post-traumatic stress disorder (PTSD)• Exposure to actual or threatened death, serious injury or sexual violence in one or

more of the following ways:

- directly experiencing or witnessing the traumatic event(s)

- learning that violent or accidental traumatic event(s) affected a family member

or close friend

- experiencing repeated or extreme exposure to details of the traumatic event(s)

• Presence of one or more of the following intrusion symptoms:

- recurrent, involuntary and intrusive distressing memories, dreams or “flashbacks”

about the traumatic events (s)

- intense or prolonged psychological distress or physical reactions to internal or

external cues that symbolize or resemble an aspect of the traumatic event(s)

• Persistence avoidance of stimuli associated with traumatic events

• Negative alternations in cognition and mood associated with traumatic event

• Marked alterations in arousal and reactivity associated with the traumatic events

• Duration of the disturbance > 1 month.

Antidepressants (SSRIs, SNRIs)[Note: often used at 1/2 dose used to treat depression]

- Fluoxetine (Prozac)- Paroxetine (Paxil)- Sertraline (Zoloft)- Citalopram (Celexa)- Escitaopram (Lexapro)-Venlafaxine (Effexor)

Anxiolytics (benzodiazepines, azapirones, gabapentinoids): - Clonazepam (Klonopin) - Lorazepam (Ativan)- Alprazolam (Xanax)- Buspirone (Buspar) [prescribed for GAD]- Gabapentin (Neurontin) [prescribed for GAD]- Pregabelin (Lyrica) [prescribed for GAD]

Beta-blockers- Propranolol (Inderal)

Modern therapeutic drugs

Cognitive-behavioral therapy (CBT)

Exposure and ritual prevention (ERP) therapy for OCD

Desensitization therapies

Virtual reality desensitization therapies

Computer-assisted/internet-based treatments (e-interventions)

Psychotherapy

4. Epidemiology and societal burden

• Prevalence: 28% lifetime (in US population); phobias and social anxiety disorder are most common; prevalence declines with age.

• An estimated 8% of US teens (age 13-18) have an anxiety disorder.Women are twice as likely as men to be affected.

• Anxiety disorders are associated with increased suicide ideation and in combination with other psychiatric disorders, especially depression or schizophrenia, increased rates of suicide.

Post-Traumatic Stress Disorder Disability-Adjusted Life Years(DALY), a measure of the burdenof disease; one DALY = one yearof “healthy” life lost, due to living with disability or earlydeath. (data from WHO)

= > 58.5 per 100,000

= 51.5 - 54 per 100,000

Comorbidities

Major depression

Alcohol and other substance abuse disorders

Personality Disorders

Also associated with physical conditions, including:

thyroid, cardiac, respiratory and seizure disorders

rare endocrine tumors (e.g. pheochromocytomas)

substance intoxication (cocaine) and withdrawal (alcohol)

Risk factors

Childhood maltreatment (including sexual abuse)

Physical punishment

Parental history of mental disorders

Low socioeconomic status

Overly protective or harsh parenting

Female gender

Diagnostic tools

Composite International Diagnostic Interview (WHO)

Mini-International Neuropsychiatric Interview

Structured Clinical Interview for DSM-5

Self-report questionnaires:Generalized Anxiety Disorder 7-item scale (GAD-7)Overall Anxiety Severity and impairment scaleSpence Children’s Anxiety ScaleGeneralized Anxiety Disorder Questionnaire IV

Famous individuals with anxiety disorders

Kim BasingerAmerican actress, model:

panic attacks, agoraphobia,social anxiety, depression

John SteinbeckAmerican author,

Nobel Prize in Literature (1962)

Anxiety and depression

Emily DickensonAmerican Poetsocial anxiety, agoraphobia

Johnny DeppAmerican actor:

panic attacks

Adele, English singer:panic attacks, social phobia,

severe stage fright

Sir Laurence OlivierBritish ActorSocial anxiety

B. Neurobiology, environment,genetics and epigenetics

The biology of fear

• Two distinct aspects of the emotion of fear:

Subjective experiences

Somatic and behavioral responses

• Subjective experiences can be studied in humans, while somatic and behavioral responses can be studied in humans and animals

Charles Darwin “The Expression of

Emotions in Man and Animals” 1872

William James“What is an Emotion?”Mind 9, 188-205,1884

Ivan Pavlovdeveloped theexperimental

foundations of classical conditioning

and extinction

Joseph LeDoux New York University

Antonio DamasioUniversity of Iowa

University of Southern California

Seymour BenzerCalifornia Institute

of Technology

Eric KandelColumbia University

Nobel Laureate

A biology-based taxonomy of anxiety disorders

Fear-related Anxiety-related

Panic disorderSocial phobiaAgoraphobia

PTSD

GAD

Circuitry for Pavlovian fear conditioning

Sound: Conditioned

Stimulus (CS)

Shock:UnconditionedStimulus (US)

Lateral

Nucleus

Central Nucleus

Amygdala

Direct and indirect pathways linkingauditory CS to the amygdala

Auditory CS AuditoryThalamus

Auditory Cortex

slow

fast

Defensive Behaviors

AutonomicResponses

HormonalResponses

An updated model for fear conditioning postulates a role for the amygdala central nucleus in fear memory formation in addition its

role as an output nucleus for the initiation of fear responses

Wilensky AE et al,J Neurosci, 2006

The neurological substrates of emotion

• The amygdala and brain stem mediate the first (unconscious) stages of emotional responses. Producing a preprogrammed and evolutionarily highly conserved somatic response: e.g. tightening of skeletal muscles, increase in heart rate, etc.

• The changes are detected and evaluated by the insular cortex (insula), which relays this information to higher cortical areas where the subjective experience of the emotions are generated.

• The ventral prefrontal cortex – generation of “moral” emotions, e.g. indignation, etc.

• Dorsolateral prefrontal cortex - top-down control of emotions

Shin LM and Liberzon I, 2010

dACC = dorsal anterior cingulate cortexrACC = rostral anterior cingulate cortex

Magnetic resonance (MRI) images of brain regions implicated in fear, stress and anxiety disorders

Additional important brain regions include: orbital frontal cortex (OFC), medial prefrontal cortex (mPFC)ventrolateral prefrontal cortex (vlPFC) dorsolateral prefrontal cortex (dlPFC)

Neural circuits implicated in anxiety-related behaviors in rodent brain

Calhoon GG and Tye KM, Nature Neuroscience, 2015

Benzodiazepines and the GABAA receptor

Inferred structure of GABAARBased on the structure of the nicotinic acetylcholine receptor

Gabapentinoids(Bind the a2d subunit of voltage-dependent calcium channels:

indirectly facilitate GABAergic neurotransmission)

Gabapentin (Neurontin) Pregabalin (Lyrica)

Prescribed for the treatment of epilepsy, neuropathic pain, fibromyalgia, restless legs syndrome and generalized anxiety disorder

Propranolol and beta-adrenergic receptors

Note: propranolol

blocks symptoms

of anxiety at both

peripheral and

central levels.

Genetics of anxiety disorders

• Estimated heritability from twin studies: range 0.30 -0.50; 0.43 for panic disorder; 0.32 for GAD

• Odds ratios for siblings of anxiety disorder probands = 4 – 6, depending on the disorder.

• Candidate gene for which there is support for association in small-scale case-control association studies include: BDNF, PACP-PAC1 receptor, FKBP5, COMT, CCK, GAD1, SERT, MAOA, HTR1A, HTR1B, BABRB3m GABRA5. However, no robust associations detected in recent meta-analysis (Howe et al, 2015)

• Currently no replicated SNPs have been identified with genome-wide significance for association with anxiety disorders. Gene-based association between neuregulin 1 and PTSD has recently been reported. (Kilaru V et al. Translational Psychiatry 6, 2016)

• Anxiety is a frequent symptom of several “syndromic” disorders, including:

Williams syndrome (~ 3M bp deletion on Ch7q, 22q11.2 deletion syndrome,

Rett syndrome (MEPC2 mutations) and Fragile X syndrome (CGG expansion

in 5’UTR of FMRP gene on X chromosome)

Childhood experiences are important factors that influence the development anxiety disorders

• Sexual or physical abuse in childhood is associated with increased rates of mixed anxiety and depression, generalized anxiety disorder (GAD), phobias, post-traumatic stress disorder (PTSD) and suicide ideation in adults.

• Childhood trauma can also produce anxiety disorders in young children and adolescents, which predispose the individuals to continue to suffer from these disorders as adults.

Stress

• Homeostasis: the maintenance of a stable internal state that promotes survival

• Stress: a stimulus that disrupts physiological homeostasis

• Allostasis: a process by which the body attempts to restore homeostasis

• In response to stress, the body mounts an “allostatic” response aimed at restoring physiological homeostasis

Stress andthe HPA

axis

5-HT = 5-hydroxytryptamineNE = norepinephrineGABA = gamma-amino butyric acidCRF = corticopropin-releasing factorPOMC = proopiomelanocortinACTH = adrenocorticotropic hormoneb-LPH = beta-lipocortinCortisol = the major glucocorticoid in

humans

(PVA = paraventricular nucleus)Hippocampus

Amygdala

-

+

cortisol

The effects of stress on DNA

(CpG) methylation and gene expression

in the rat brain

PFC = prefrontal cortexNAc = nucleus accumbensAmy = amygdalaPVN = paraventricular nucleusVTA = ventral tegmental areaDR = dorsal raphe nucleusLC = locus ceruleusBDNF = brain-derived NFCRF = corticotropin releasing FP11 = S100-A10GDNF = glia-derived NFAVP = arginine-vasopressinGR = glucocorticoid receptorMeCP2 = MeCpG binding protein-2HDAC2 = histone deacetylase-2CREB = transcript factorFSL = Flinder’s sensitive linesus = susceptible mouse lineres = resilient mouse lineLG = licking and grooming

Vialou V et al, 2013

Chromatin modifications

regulated by stress or antidepressant

treatments

HDAC = histone deacetylaseHMT = histone methyltransferaseHAT = histone acetyltransferaseM or Me = methyl-groupP = phosphateA or Acet = acetyl-groupPol II = RNA polymerase II H = histidineLR/HR = low-responding/

high-responding

Vialou V et al, 2013

Early childhood experience and epigenetic regulation of the stress response

Hyman SE, Nature

Neuroscience 12, 2009

C. Developing new therapies to treat anxiety disorders

Extinction learning and memory reconsolidation

Ressler and Mayberg, 2007

New learning is not simply a reversal of previous learning;

New learning requires activation of NMDA-type glutamate receptors

*

*May be facilitated by D-cycloserine

D-cycloserine: an allosteric activator of the NMDA glutamate receptor

Context-dependentextinction in rodents

Maren, Phan and Liberzon, 2013

Maren, Phan andLiberzon, 2013

mPFC

amygdala

Likhtik E et al,Nature, 2008

ITC = intercalated neuronsLA = lateral nucleus BL = BLA = basolateral nucleusCEA = central nucleus

Amygdala (rat)

D. References, journal presentationsand internet resources

References (1)• Craske MG and Stein MB, Anxiety, Lancet, June 24, 2016

• Dias BG, Banerjee SB, Goodman JV and Ressler KJ, Towards new approaches to disorders of fear and anxiety, Current Opinion in Neurobiology 23, 346-352, 2013

• Calhoon GG and Tye KM, Resolving the neural circuits of anxiety, Nature Neuroscience 18, 1394 –1404, 2015

• Shin LM and Liberzon I, The neurocircuitry of fear, stress and anxiety disorders, Neuropsychopharmacology Reviews 35, 169-191, 2010

• LeDoux J, Emotional circuits in the brain, Annual Review of Neuroscience 23, 155-184, 2000

• Wilensky AE et al, Rethinking the fear circuit: the central nucleus of the amygdala is required for the acquisition, consolidation and expression of Pavlovian fear conditioning, Journal of Neuroscience 26, 12387-12396, 2006

• LeDoux JE, Coming to terms with fear, Proc. Natl. Acad. Sci. USA 111, 2871-2878, 2014

• Smoller J, The Genetics of Stress-related disorders: PTSD, Depression and Anxiety disorders, Neuropsychopharmacology Reviews, August 31, 2015

• Scott S, Parenting quality and children’s mental health: biological mechanisms and psychological interventions, Current Opinion in Child and Adolescent Psychiatry 25, 301-306, 2012

• Ressler KJ and Mayberg HS, Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic, Nature Neuroscience 10, 1116-24, 2007

References (2)

• Caldji A, et al, Environmental regulation of the neural epigenome, FEBS Letters 585, 2049-2058, 2011

• Zovkic IB and Sweatt JD, Epigenetic mechanisms in learned fear: implications for PTSD, Neuropsychopharmacology Reviews 38, 77-93, 2013

• Vialou V, Feng J, Robison AJ and Nestler EJ, Epigenetic mechanisms of depression and antidepressant action, Annual Reviews Pharmacology and Toxicology 53, 59-87, 2013

• Zhang TY, et al, Maternal care and DNA methylation of a glutamic acid decarboxylase 1 promoter in rat hippocampus, Journal of Neuroscience 29, 30, 13130-13137, 2010

• Piccolo FM and Fisher AG, Getting rid of DNA methylation, Trends in Cell Biology, 1-8, 2013

• Gavin DP, Chase KA and Sharma RP, Active DNA demethylation in post-mitotic neurons: a reason for optimism, Neuropharmacology 75, 233-245, 2013

• Schiller D et al., Preventing the return of fear in humans using reconsolidation update mechanisms, Nature 463, 49-53, 2010

• Maren S, Phan, KL and Liberzon I, The contextual brain: implications for fear, conditioning and psychopathology, Nature Reviews Neuroscience 14, 417- 428, 2013

• Alberini CM and LeDoux JE, Memory reconsolidation, Current Biology 23, R746-50, 2013

Journal Presentations

Research articles:

• Weaver I, et al Epigenetic programming by maternal behavior, Nature Neuroscience 847- 854, 2004

• Franklin TB et al, Epigenetic transmission of the impact of early stress across generations, Biological Psychiatry 68, 408-415, 2010.

Internet resources

• National Institute of Mental Health (NIMH-NIH)

http://www.nimh.nih.gov/health/topics/anxiety-disorders/index.shtml

• Anxiety and Depression Association of America

www.adaa.org

• Anxietycenter.com

http://www.anxietycentre.com

• Calmclinic.com

http://www.calmclinic.com

● Anxiety, Panic and Health

http://anxietypanichealth.com/