Anxiety

• NE
• GABA
• 5-HT
• Corticotropin-releasing Factor (CRF)
• Cholecystokinin

• amygdala
• locus ceruleus (LC)
• hippocampus
• medial and dorsal raphe nuclei
• hypothalamus
• periaqueductal gray matter

the amygdala

the locus ceruleus

the hippocampus

the hypothalamus

• the ANS of anxious pts is hypersensitive and overreacts to various stimuli
• many pt display sx of peripheral autonomic hyperactivity
• in response to a threat, the LC serves as an alarm center, activating NE release and stimulating SNS and PNS
• chronic central noradrenergic overactivity down-regulates alpha₂ receptors in pts with GAD (alpha₂ receptors are hypersensitive in some pts with panic disorder)
• pts with SAD appear to have hyperreactive adrenocortical response to psychologic stress

LC --> NE --> glutamate -->anxiety

• drugs to reduce anxiety and produce sedation target GABA_A
• GABA_A receptors are ligand-gated ion channels
• When benzodiazepine ligands bind to GABA, the inhibitory effects of GABA binding to GABA_A receptors are enhanced which decreases 5-HT, NE and DA effects
• growth hormone response to baclofen in pts with generalized SAD suggests an abnormality in central GABA_B receptor function

• no definitive evidence shows a clear abnormality in 5-HT function
• abnormalities in serotonergic functioning through release and reuptake at the presynaptic autoreceptors (1A/1D), the serotonin reuptake transporter (SERT) site, or effect of 5-HT at the postsynaptic receptors (1A, 2A, 2C) may play a role in anxiety disorders
• increased 5-HT function may increase avoidance behavior
• decreased 5-HT function may increase aggression

• increased cortical activity
• decreased basal ganglion activity

benzodiazepine tx results in increased basal ganglion activity and decreased cortical activity

• abnormal activation of the parahippocampal region and the prefrontal cortex
• decreased GABA concentrations in the occipital region

decreased cerebral blood flow in the amygdala, hippocampus, and surrounding cortical areas

5-HT

NE

the periaqueductal gray matter

increased anxiety

GABA

increased anxiety

increased anxiety

GAD

no identifiable trigger

• 5-HT
• NE

usually early in life (childhood or adolescence)

antidepressants

• antidepressants
• benzodiazepines
• buspirone
• hydroxyzine
• pregabalin (in the European Union)
• propranolol - for somatic sx only, not to decrease anxiety
• gabapentin

benzodiazepines

benzodiazepines

• buspirone
• hydroxyzine

• delayed response
• some pts experience restlessness, jitteriness, increased anxiety sx, insomnia and HA (will go away with time)

• venlafaxine
• duloxetine
• paroxetine
• escitalopram

hydroxyzine

Antihistamine used for GAD

mild, dose-dependent anticholinergic SE at high doses

• food and anticholinergics slow the onset (good if you experience a rush SE)
• lipid soluble drugs have short DOA d/t rapid redistribution out of the brain

• accumulation a problem for chronic insomniacs
• clinical significance of accumulation is mitigated by tolerance
• impaired metabolism with age, liver dysfunction, and alcohol abuse (use one that is glucuronidated, not oxidated)
• tolerance can sometimes develop as quickly as one dose
• may cause daytime sedation

• VERY rapid onset of anxiolysis
• safer than barbs
• generally well tolerated
• favorable sleep profile
• few significant DI = large therapeutic window

• withdrawal/addiction/dependence
• some pts don't like them
• rare disinhibition rxns (usually kids and elderly)
• many pts don't reach remission
• higher rate of recurrence vs SSRI

• sedation
• cognitive disfunction (anterograde amnesia, performance impairment, confusion)
• falls/delirium in the elderly
• social stigma
• psychomotor (ataxia, dysarthria, incoordination, diplopia, vertigo, dizziness)

• 1-8 days after d/c
• max intensity 2-18 days after d/c
• can occur after 8weeks of use at therapeutic doses
• usually lasts 1-2 wks (maybe months)

• traits of dependency/neuroticism
• more psychopathology
• mild=mod alcohol use or hx of alcohol or drug abuse
• female
• less educated

• anxiousness (same sx as original anxiety)
• Nausea
• anorexia
• depression
• derealization
• increased sensory perception
• abnormal movement perception
• HA
• sweating
• dizziness
• poor concentration
• tremors/shakes

• RARE
• seizures
• tinnitus
• delirium
• confusion
• psychotic sx

• pts with low seizure thresholds
• abrupt d/c
• high potency BZD (alprazolam)
• short half-life, rapid elimination (alprazolam, triazolam)
• long duration of therapy (yrs)

• taper off the offending agent
• switch to a BZD with long half-life
• propranolol
• clonidine
• barbs (probably would rather re-institute BZD and taper it)

• presynaptic 5-HT 1_A agonist
• postsynaptic 5-HT 1_A partial agonist
• complex effects on DA system

45mg/d in 2-3 divided doses DON'T UNDERDOSE!

• safe in OD
• low abuse potential
• effective
• lacks sedation
• no withdrawal effect
• no cognitive impairment
• no interaction with alcohol
• well tolerated

• maybe delayed onset of action
• less patient acceptance than BZD
• no benefit in pts who used BZDs within prior 4 wks
• NOT effective for panic disorder
• rarely causes insomnia

• dizziness
• nervousness
• HA
• nausea
• somnolence/sedation (less than BZD and some actually get insomnia)

panic disorder

there isn't one, at least initially......if there's a trigger, it's a phobia

• 5-HT
• NE maybe more than in GAD
• possibly DA

• amygdala - symptoms of attacks
• prefrontal cortex - extinction of conditioned fear
• hippocampus - context for fear/anxiety

at least one panic attack followed by at least one month of:

• concern about more attacks
• worry about consequences (going crazy, losing control, heart attack)
• significant behavioral change

starts abruptly, peaks within 10 min with at least 4 of the following:

• palpitations, pounding heart, increased HR
• sweating
• trembling or shaking
• SOB, choking
• chest pain or discomfort
• nausea, abdominal distress

may include some of the following also:

• dizziness
• derealization
• fear of losing control or going crazy
• fear of dying
• paresthesias
• chills or hot flushes

• anxiety of being in places or situations from which escape might be difficult or embarrassing, or in which help might not be available in the event of a Panic Attack
• situations are avoided or endured with great distress
• may exist with or without Panic Disorder

• SSRI/SNRI - 1st line d/t tolerability
• BZD
• TCA - historical drug of choice, but limitations changed that
• MAOI

to prevent panic attacks (once started, they are so brief that drugs aren't really helpful)

• Start low and go slow
• Ultimately high doses are necessary
• panic pts are very susceptible to early side effects from drugs

• buspirone
• trazodone
• gabapentin (probably)
• hydroxyzine (probably)

Obsessions

Compulsions

an anxiety disorder characterized by the presence of obsessions and compulsions

• serotonergic dysregulation in the cortico-striatal-thalamic-cortical circuits (CSTC)
• lesions impair the ability to inhibit inappropriate responses (stuck in a continuous loop of neuronal circuit)
• one variant may be related to streptococcal infections in children (PANDAS-pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections)
• another variant may involve DA systems in the CSTC
• another mechanism is glutamatergic neurotransmission - maybe

• disgust regarding bodily waste
• concern over dirt/germs
• fear of harm to self/others
• concern about becoming ill
• "forbidden" sexual thoughts
• fear of embarrassing acts
• fear of losing things
• need for symmetry or exactness
• need to know or remember
• need to say sorry or apologize
• need to count
• need to check

• cleaning/washing rituals
• checking health status
• seeking reassurance about health
• avoiding public settings
• hoarding
• arranging rituals
• counting rituals
• checking rituals

• SSRI (fluoxetine, fluvoxamaine, sertraline, paroxetine, citalopram)
• clomipramine - may be more effective than SSRI, but not as safe
• AAPs as adjunct in severely ill or refractory pts (risperidone, quetiapine)

relatively high risk of dose-dependent seizures limits the dose to <250 mg/d

serotonin action

about 40% (small, even at maximum doses)

• start at typical dose of drug (these pts will tolerate SE, unlike panic pts)
• need high doses for max effect (guidelines state that these doses may even be above the manufacturer's recommended max dose ---this does not apply to clomipramine)

1-2 yrs before considering a gradual taper

a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequently displayed and severe than is typically observed in indivuduals at a comparable level of development.

age 7

2 settings

combined type

males

Predominantly Inattentive type

• excessive motor activity as toddler
• usually first diagnosed during elementary when school adjustment is compromised
• relatively stable through early adolescence
• sx begin to attenuate in late adolescence and adulthood

• diversion for substance abuse far less likely
• treatment persistence is greater
• less switching of stimulants occurs
• compliance is better
• no need for in-school dosing

0.62 vs 0.91 or 0.95

• can be given in late afternoon or evening
• less pronounced effects on appetite and sleep

may produce more nausea or sedation

several weeks at full therapeutic dose

• severe liver disease
• suicidal ideation
• sudden death (cardiac)
• priapism

electrocardiogram

seizure disorder

several cases of sudden death

• methylphenidate
• amphetamine
• atomoxetine
• bupropion
• TCA
• alpha agonist