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What neurotransmitters are involved in anxiety disorders?
- Corticotropin-releasing Factor (CRF)
What parts of the brain are involved in anxiety?
- locus ceruleus (LC)
- medial and dorsal raphe nuclei
- periaqueductal gray matter
What plays a critical role in the assessment of fear stimuli and learned response to fear?
What part of the brain is the primary NE-containing site, with widespread projections to areas responsible for implementing fear responses (vagus, lateral and paraventricular hypothalamus)?
the locus ceruleus
What area of the brain is integral to consolidation of traumatic memory and contextual fear conditioning?
What area of the brain is the principle area for integrating neuroendocrine and autonomic response to a threat?
What is the Noradrenergic Model of anxiety?
LC --> NE --> glutamate -->anxiety
- 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
What is the GABA Receptor Model of anxiety?
- drugs to reduce anxiety and produce sedation target GABAAGABAA receptors are ligand-gated ion channels
- When benzodiazepine ligands bind to GABA, the inhibitory effects of GABA binding to GABAA 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 GABAB receptor function
What is the Serotonin Model for anxiety?
- 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
What is seen on neuroimaging in pts with GAD?
- increased cortical activity
- decreased basal ganglion activity
benzodiazepine tx results in increased basal ganglion activity and decreased cortical activity
What is seen on neuroimaging in pts with panic disorder?
- abnormal activation of the parahippocampal region and the prefrontal cortex
- decreased GABA concentrations in the occipital region
What effect do pharmacotherapy and psychotherapy have on neuroimaging in pts with SAD?
decreased cerebral blood flow in the amygdala, hippocampus, and surrounding cortical areas
Which neurotransmitter is associated with the raphe nuclei?
Which neurotransmitter is associated with the locus ceruleus?
Which area of the brain is responsible for fear response (freezing or "fight or flight")?
the periaqueductal gray matter
What is the consequence of increased release of NE?
What is the most important inhibitory neurotransmitter in the CNS?
What is the consequence of increased glutamate?
What is the consequence of increased cholecystokinin (CCK)?
Which anxiety disorder is characterized by sustained, unrealistic or excessive anxiety or worry about many different things?
What causes GAD?
no identifiable trigger
Which neurotransmitters are involved in GAD?
What is the onset of GAD?
usually early in life (childhood or adolescence)
What is the first line therapy for GAD?
What drugs are used for GAD?
- pregabalin (in the European Union)
- propranolol - for somatic sx only, not to decrease anxiety
What should be used in patients who requre rapid anxiolytic effect?
What should be avoided in patients with a history of substance abuse?
What should be used in pts with past or current substance abuse
What should pts on buspirone or antidepressants be told to expect?
- delayed response
- some pts experience restlessness, jitteriness, increased anxiety sx, insomnia and HA (will go away with time)
Which antidepressants are approved for use in GAD?
Which drug is no good for comorbid conditions (depression, panic, PTSD, OCD, etc)?
Antihistamine used for GAD
mild, dose-dependent anticholinergic SE at high doses
What are the issues with a single dose of a benzodiazepine?
- 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
What are the issues with multiple doses of BZDs?
- 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
What are the advantages of BZDs in GAD?
- VERY rapid onset of anxiolysis
- safer than barbs
- generally well tolerated
- favorable sleep profile
- few significant DI = large therapeutic window
What are the disadvantages of BZDs in GAD?
- 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
What are the SE of BZDs?
- cognitive disfunction (anterograde amnesia, performance impairment, confusion)
- falls/delirium in the elderly
- social stigma
- psychomotor (ataxia, dysarthria, incoordination, diplopia, vertigo, dizziness)
What is the timeframe for BZD withdrawal symptoms?
- 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)
What are risk factors for developing BZD withdrawal?
- traits of dependency/neuroticism
- more psychopathology
- mild=mod alcohol use or hx of alcohol or drug abuse
- less educated
What are the sx of BZD withdrawal?
- anxiousness (same sx as original anxiety)
- increased sensory perception
- abnormal movement perception
- poor concentration
- psychotic sx
What are the risks for BZD withdrawal seizures?
- pts with low seizure thresholds
- abrupt d/c
- high potency BZD (alprazolam)
- short half-life, rapid elimination (alprazolam, triazolam)
- long duration of therapy (yrs)
What is the treatment for BZD withdrawal?
- taper off the offending agent
- switch to a BZD with long half-life
- barbs (probably would rather re-institute BZD and taper it)
How does bispirone work?
- presynaptic 5-HT 1A agonist
- postsynaptic 5-HT 1A partial agonist
- complex effects on DA system
What is the usual therapeutic dose of bispirone for anxiety?
45mg/d in 2-3 divided doses DON'T UNDERDOSE!
What are the advantages of buspirone in anxiety?
- safe in OD
- low abuse potential
- lacks sedation
- no withdrawal effect
- no cognitive impairment
- no interaction with alcohol
- well tolerated
What are the disadvantages of bispirone?
- 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
What are the SE of buspirone?
- somnolence/sedation (less than BZD and some actually get insomnia)
What anxiety disorder is characterized by unanticipated, brief attacks of extreme fear?
What is the trigger for panic disorder?
there isn't one, at least initially......if there's a trigger, it's a phobia
What neurotransmitters are involved with panic disorder?
- NE maybe more than in GAD
- possibly DA
What is believed to be the location of pathology for panic disorder?
- amygdala - symptoms of attacks
- prefrontal cortex - extinction of conditioned fear
- hippocampus - context for fear/anxiety
What are the sx of panic disorder?
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
What are the sx of a panic attack?
starts abruptly, peaks within 10 min with at least 4 of the following:
- palpitations, pounding heart, increased HR
- trembling or shaking
- SOB, choking
- chest pain or discomfort
- nausea, abdominal distress
may include some of the following also:
- fear of losing control or going crazy
- fear of dying
- chills or hot flushes
What is agoraphobia?
- 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
What drugs are used for Panic Disorder?
- SSRI/SNRI - 1st line d/t tolerability
- TCA - historical drug of choice, but limitations changed that
What is the goal of therapy in Panic Disorder?
to prevent panic attacks (once started, they are so brief that drugs aren't really helpful)
How should pts be dosed in panic disorder?
- Start low and go slow
- Ultimately high doses are necessary
- panic pts are very susceptible to early side effects from drugs
What should not be used to treat panic disorder?
- gabapentin (probably)
- hydroxyzine (probably)
How would you classify peristent ideas, thoughts, impulses, or images that are experienced as intrusive and inappropriate and cause marked anxiety or distress?
How would you classify repetitive behaviors or mental acts the goal of which is to prevent or reduce anxiety or distress, not to provide pleasure or gratification?
What is OCD?
an anxiety disorder characterized by the presence of obsessions and compulsions
What is the etiology of OCD?
- 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
What are some common obsessions in OCD?
- 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
What are some common compulsions with OCD? (may or may not be related to an obsession)
- cleaning/washing rituals
- checking health status
- seeking reassurance about health
- avoiding public settings
- arranging rituals
- counting rituals
- checking rituals
What are the treatments for OCD?
- 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)
What is the main problem associated with clomipramine in OCD?
relatively high risk of dose-dependent seizures limits the dose to <250 mg/d
What is required for clinical effect in OCD?
What is the typical reduction in sx with drug therapy in OCD?
about 40% (small, even at maximum doses)
How should you dose OCD pts?
- 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)
How long should successful drug therapy be continued for OCD?
1-2 yrs before considering a gradual taper
What is ADHD?
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.
In order to be classified ADHD, sx must have occurred before what age?
In order to be classified ADHD, in how many settings must the symptoms have been present?
Most children and adolescents have which type of ADHD?
Which gender is more susceptible to ADHD?
Which type of ADHD is more prominent in females?
Predominantly Inattentive type
What is the natural course of ADHD?
- 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
What are the advantages of long-acting formulations of stimulants in ADHD?
- 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
What is the magnitude of response from atomoxetine compared to stimulants?
0.62 vs 0.91 or 0.95
What are the advantages of atomoxetine over stimulants for ADHD?
- can be given in late afternoon or evening
- less pronounced effects on appetite and sleep
What are the disadvantages of atomoxetine vs stimulants in ADHD?
may produce more nausea or sedation
For how long and at what dose should a pt be treated with atomoxetine to observe full effects in ADHD?
several weeks at full therapeutic dose
What FDA warnings are associated with atomoxetine?
- severe liver disease
- suicidal ideation
- sudden death (cardiac)
What baseline monitoring is recommended for a child on a TCA?
What patient group should not use bupropion?
What concerns did Health Canada have regarding Adderall XR?
several cases of sudden death
What drugs can be used in ADHD?
- alpha agonist