-
What neurotransmitters are involved in anxiety disorders?
- NE
- GABA
- 5-HT
- Corticotropin-releasing Factor (CRF)
- Cholecystokinin
-
What parts of the brain are involved in anxiety?
- amygdala
- locus ceruleus (LC)
- hippocampus
- medial and dorsal raphe nuclei
- hypothalamus
- periaqueductal gray matter
-
What plays a critical role in the assessment of fear stimuli and learned response to fear?
the amygdala
-
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?
the hippocampus
-
What area of the brain is the principle area for integrating neuroendocrine and autonomic response to a threat?
the hypothalamus
-
What is the Noradrenergic Model of 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
LC --> NE --> glutamate -->anxiety
-
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?
5-HT
-
Which neurotransmitter is associated with the locus ceruleus?
NE
-
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?
increased anxiety
-
What is the most important inhibitory neurotransmitter in the CNS?
GABA
-
What is the consequence of increased glutamate?
increased anxiety
-
What is the consequence of increased cholecystokinin (CCK)?
increased anxiety
-
Which anxiety disorder is characterized by sustained, unrealistic or excessive anxiety or worry about many different things?
GAD
-
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?
antidepressants
-
What drugs are used for GAD?
- antidepressants
- benzodiazepines
- buspirone
- hydroxyzine
- pregabalin (in the European Union)
- propranolol - for somatic sx only, not to decrease anxiety
- gabapentin
-
What should be used in patients who requre rapid anxiolytic effect?
benzodiazepines
-
What should be avoided in patients with a history of substance abuse?
benzodiazepines
-
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?
- venlafaxine
- duloxetine
- paroxetine
- escitalopram
-
Which drug is no good for comorbid conditions (depression, panic, PTSD, OCD, etc)?
hydroxyzine
-
Hydroxyzine
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?
- 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
-
What are the SE of BZDs?
- sedation
- 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
- female
- less educated
-
What are the sx of BZD withdrawal?
- anxiousness (same sx as original anxiety)
- Nausea
- anorexia
- depression
- derealization
- increased sensory perception
- abnormal movement perception
- HA
- sweating
- dizziness
- poor concentration
- tremors/shakes
- RAREseizures
- tinnitus
- delirium
- confusion
- 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
- propranolol
- clonidine
- 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
- effective
- 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?
- dizziness
- nervousness
- HA
- nausea
- somnolence/sedation (less than BZD and some actually get insomnia)
-
What anxiety disorder is characterized by unanticipated, brief attacks of extreme fear?
panic disorder
-
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?
- 5-HT
- 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
- 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
-
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
- BZD
- TCA - historical drug of choice, but limitations changed that
- MAOI
-
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?
- buspirone
- trazodone
- 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?
Obsessions
-
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?
Compulsions
-
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
- hoarding
- 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?
serotonin action
-
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?
age 7
-
In order to be classified ADHD, in how many settings must the symptoms have been present?
2 settings
-
Most children and adolescents have which type of ADHD?
combined type
-
Which gender is more susceptible to ADHD?
males
-
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)
- priapism
-
What baseline monitoring is recommended for a child on a TCA?
electrocardiogram
-
What patient group should not use bupropion?
seizure disorder
-
What concerns did Health Canada have regarding Adderall XR?
several cases of sudden death
-
What drugs can be used in ADHD?
- methylphenidate
- amphetamine
- atomoxetine
- bupropion
- TCA
- alpha agonist
|
|