Anxiety/Depression Class Powerpoint Flashcards
noradrenergic model
-anxiety or depression theory?
- Describe it
- What part of brain is involved?
Anxiety
The premise of this model is that the autonomic nervous system is hypersensitive and overreacts to various
stimuli.
- Peripheral autonomic hyperactivity symptoms that are often associated with anxiety can be explained with this model.
- In situations of perceived threat or fear (or abnormal stimulation), the locus ceruleus (LC), acts as an alarm
center and activates NE release stimulating the parasympathetic and sympathetic nervous systems. - Over time and with chronic central noradrenergic overactivity, a downregulation of alpha-2 adrenoreceptors
occurs and leads to hypersensitivity = panic disorder.
GABA-receptor model
-anxiety or depression theory?
- Describe it
Anxiety
When GABA receptors are stimulated, causes calming
This model of anxiety theorizes that benzodiazepines ameliorate anxiety through potentiation of the
inhibitory activity of GABA
(in essence, they mimic GABA)
seratonin model
-anxiety or depression theory?
- Describe it
Anxiety
Anything that inhibits release of Serotonin will impact the person’s ability to be stable/less anxious
5-HT (aka serotonin) is primarily an inhibitory neurotransmitter that is used by neurons originating in the raphe nuclei of the brain stem and projecting through the brain
- Abnormalities in serotonergic functioning may play a role in
anxiety disorders. - It is postulated that great 5-HT activity reduces norepinephrine activity in the LC, inhibits defense/escape
response and reduces hypothalamic release of CRF. - The SSRIs acutely increase 5-HT levels by blocking the SERT and increasing the amount of 5-HT available
post-synaptically, and are efficacious in blocking the manifestations of panic and anxiety - Buspirone is a 5-HT1A partial agonist which is effective for GAD
**Once serotonin levels are low, this affects all of the other NTs as well. This is true of all NTs, but particularly serotonin
monoamine hypothesis
- What are monoamines?
-anxiety or depression theory?
- Describe it
Depression
Monoamines = compound with single amine group = dopamine, serotonin, NE
Monoamine hypothesis = Not enough serotonin, NE or dopamine being released into the synaptic cleft
(Depletion of these neurotransmitters in the CNS), which causes depression
- Supported by post-mortem studies, antidepressant MOAs and PET scans
neurotrophic hypothesis
-anxiety or depression theory?
- Describe it
Depression (but this mechanisms also shows up in the anxiety section so perhaps both)
Key idea if decreased levels of Brain Derived Neurotropic Factors (BDNF)
Over time with exposure to stress the body releases glucocorticoids. If this happens too often over too long a period of time (or is too acute), the amount of BDNF decreases.
Over time this changes the brain (such as smaller hippocampus)
depression results from decreased neurotrophic support, leading to neuronal atrophy, decreased hippocampal neurogenesis and loss of glia, and that antidepressant treatment blocks or reverses this neurotrophic factor deficit, and thereby reverses the atrophy and cell loss
What kind of drugs work on the Locus Ceruleus and what model that this pertain to?
Drugs that have a specific effect on the LC work for patients with panic disorder:
* Anxiolytics or drugs for panic (e.g. benzodiazepines) inhibit LC firing, decrease NE activity and can also block the effects of anxiogenic drugs (drugs that stimulate the LC).
This relates to the noradrenergic model of anxiety
What does GABA do? As in, what effect occurs when it binds the GABA receptors?
When GABA binds = calming
GABA is the major
inhibitory neurotransmitter in the CNS and has a strong regulatory or inhibitory effect on the 5-HT,
NE, and dopamine systems.
The GABA receptor controls tonic inhibition to reduce neuronal excitability.
When GABA binds to the GABA A receptor, neuronal excitability is reduced
So drugs (like benzos) are basically binding the GABA receptors to induce calming effect
How do benzos interact with GABA receptors?
What model does this pertain to?
- Benzodiazepines bind on the GABA A receptor at the alpha 1, 2, 3 and 5 subunits in combination with
a beta subunit and the ys subunit - The anxiolytic effects of benzos are mediated at the alpha 2 site while sedative effects results from
binding at the alpha 1 subunit.
GABA-receptor model of anxiety
To summarize, an imbalance of what 4 neurotransmitters may predispose a person to anxiety?
GABA
NE
Serotonin
Depoamine
T/F Genetics plays a role in whether a person develops anxiety
True
Why are females more likely to experience anxiety
May be related to:
1) Hormonal factors
2) Less internal locus of control
3) Greater reporting rates
(According to flow chart in Susan’s slides)
In anxiety, an ongoing sense of perceived threat leads to increased cortisol and epinephrine levels. Chronic activation of stress hormones over time causes death of neurons in __________ (what part of the brain?)
Hippocampus
–> the hippocampus shrinks in size!
Decreased neurons in the hippocampus is directly correlated with levels of what substance (hint: it’s the key substance in the neurotrophic hypothesis of depression)
BDNF
= Brain Derived Neurotrophic Factor
What part of the brain regulates the fear response?
(there are many parts of the brain involved in the pathogenesis of anxiety…)
The Amygdala
- maladaptive activation of fear response here leads to increased stress hormones (epi and cortisol)
Technically, in order to diagnose GAD, anxiety needs to persist for what length of time?
6 months
Brief description of how you would characterize GAD
- Unrealistic or excessive anxiety or worry
about a number of events or activities. - The worry is accompanied by physiologic
symptoms.
Brief summary of panic disorder
Begins as a series of unexpected or spontaneous
panic attacks involving an abrupt surge of intense
fear or intense discomfort
- Followed by at least one month of continuous
worry about having another attack. - Accompanied by physiologic and physical
symptoms
Why is it important to consider if a person is elderly when prescribing tx for anxiety/depression?
Decreased liver/kidney fx
Risk of dizziness, other side effects
Non-pharm tx of anxiety
Counselling
Stress management
Mediation, exercise, lifestyle changes
CBT
Sleep hygiene
After initiating an medication for anxiety/depression, how soon until follow up?
Want to see every 2-3 weeks according to Susan until good effect
Major downside/side effect of anxiolytic/hypnotic medications?
CNS depression
Contrast older vs newer sedative-hypnotic drugs in terms of how dose increase affects CNS depresion
Older generation sedative-hypnotics tend to exert linear dose-response slope whereby increases in dose further
than that required for therapeutic effect will further depress CNS function including respiratory and vasomotor
centers with eventual coma and death.
- Newer drugs (and also benzodiazepines) demonstrate a non-linear slope whereby after a certain dose, does not mean more CNS depression
What kinds of drugs are sedative-hypnotics?
Most common = benzos and barbituates
Rate of oral absorption of sedative-hypnotics depends upon _______ (specific characteristic of drug). This also affects the rate at which these drugs enter the CNS
lipophilicity
More lipophilic = faster absorption, more able to get into CNS
Are sedative-hypnotics safe in pregnancy? Breast feeding?
No, all cross the placenta and get into breast milk
Given they are lipophilic, what needs to happen for sedative-hypnotics to be cleared? What special enzymes might be involved in this?
*Clearance of sedative-hypnotics requires metabolism into a more hydrophilic form
(via Phase I and II
biotransformation utilizing CYP450 enzymes).
** Susan emphasized to not forget about CYP450s in lecture
**Will require functioning liver!
MOA of sedative-hypnotics?
The benzodiazepines, barbiturates and other
hypnotics drugs bind to the molecular components of the GABA(A) receptor in
neuronal membranes in the CNS.
causing INHIBITION of GABA (which stops excessive release of stress hormones, etc)
________ are the most effective and commonly
prescribed drugs for the rapid relief of acute anxiety symptoms
Benzos
Benzos : describe metabolism and & length of half lives
How does this relate to risk of toxicity?
- Many benzodiazepines are bio-transformed into active metabolites, some with long half lives (e.g. diazepam to desmethyldiazepam which has half life of 40hrs).
- Logically, those drugs that have active metabolites with long half lives will be more likely to
cause side effects/cumulative effects from accumulation. - if person is using daily/multiple times a day, metabolites are sitting around for a long time!
- Need to consider if taking other drugs that are inhibitors/stimulators of CYP 450s
MOA of benzos
BZD binds site on GABA-A Receptor –> binding triggers influx of chloride ions leading to hyperpolarization of membrane –> dec firing of neurons –> dec amygdala-centered circuit activity –> dec fear, panic, and phobia
Adverse effects of benzos
Addiction & physical dependence
Agression
Ataxia
CNS depression
Confusion
Disinhibition
Disorientation
Dizziness
Drowsiness
Increased falls
Psychomotor impairement
Anterograde amnesia
Inc pneumonia?
Vehicle accidents
(These are according to Rx files, bottom of page 182)
Why might lorazepam be a safer option when comparing benzos for use in someone who is using a lot of other medications?
Less CYPs in process of metabolism so may have less interactions with drugs that impact CYP450s
*Also may be better option in decreased liver fx for this reason
T/F Benzos need to be tapered
It depends! If using rarely or over a short period of time (a couple of weeks), won’t need to taper.
If longer/more frequent use, need slow taper
Example of how to taper benzo?
If tx is >8 weeks, how long should taper occur over?
If tx is 6 months, how long is taper?
If tx is 1 year?
25% per week reduction in
dosage until 50% of the dose is reached, and then dosage reduction by one-eighth every 4 to 7
days.
If therapy exceeds 8 weeks, a slow dosage taper over 2 to 3 weeks is recommended;
however, if the duration of treatment is 6 months, a taper over 4 to 8 weeks should ensue.
Long-term use of benzodiazepines (ie, 1 year or longer) requires a 2- to 4-month slow taper
(DiPiro et al., 2018).
S&S of benzo withdrawal? How long does it last?
Insomnia
Anxiety
Irritability
Sweating
GI
Tinnitus
Delirium
Seizures
Paresthesias
Lasts for a few days to a few weeks
As your patient is tapering off benzos, how often should you be monitoring?
Q 1-2 weeks
What is buspirone?
Anxiolytic
MOA of buspirone?
It has an affinity for brain dopamine D2 receptors as well as being a partial agonist at brain 5-HT1A receptors
Benefits of buspirone over a benzo?
Relieves anxiety without causing sedative, hypnotic or euphoric effect and has no anticonvulsant or muscle
relaxant properties; it also has low abuse probability.
T/F Buspirone is useful for generalized anxiety but less effective for panic disorders.
True
Talk about the metabolites of Buspirone. Are they active or inactive? Effects?
Rapidly absorbed orally but undergoes extensive first-pass metabolism to form several active metabolites
- The major metabolite has alpha-adrenoreceptor blocking actions
Side effects have to do with this –> rate changes, cognition changes
What are the side effects of Buspirone
According to Rx files: nausea, headache, dizziness, restlessness
According to Susan’s slides: * There are several side effects including cardiac and neuro.
CPS includes chest pain, tachycardia, numbness, weakness, paresthesias, and many more (so yes to cardiac/neuro!)
T/F Buspirone is addictive
False
T/f Buspirone causes dependency
False!
T/F Buspirone is sedating
False!
(do we get the point?)
Outline the pregnancy categories for meds (A,B,C,Z)
A = safe
B = likely safe (human data suggests low risk, or limited human data but likely safe)
C = caution (human and/or animal data suggest risk)
Z = contraindicated in pregnancy
What are the advantages of some of the newer sedative-hypnotics? Can you think of any?
Less side effects & general concerns that come with Benzos
- Zolpidem
- Zaleplon
- Eszopiclone
- Ramelteon & tasimelteon
- Suvorexant
What are some “alternative” drugs that are used in anxiety?
- Pregabalin
- Hydroxyzine
- Antipsychotics
- Quetiapine
- St. John’s Wort, Valerian root, passionflower
- *micronized progesterone
What are considered the first line agents for treatment of GAD?
Antidepressants - SSRIs & SNRIs
The anti-anxiety response provided by anti-depressants is delayed by approx. _______ weeks with the
exception of newer agents where patients may see relief within ____ weeks (e.g. escitalopram).
4-6 weeks
2 weeks
What are the benefits of using micronized progesterone for anxietY?
Managing menstrual cycle
Improved sleep
Most common side effects of SSRIs and SNRIs according to Susan’s slide?
Sleep disturbance
GI stuff
Why does Susan suggest starting with a half dose of SSRIs when you start them?
How quickly to go to full dose?
To avoid side effects (nausea, dizziness)
Start at 1/2 dose for first week, then go to full on second week.
If you discontinue an SSRI very quickly, what main symptom of withdrawal occurs?
Dizziness
A diagnosis of major depressive disorder (MDD) is given when an individual experiences one or more
major depressive episodes without a history of a ________ or __________episode.
manic or hypomanic
T/F If a fetus is exposed to MDD or anxiety while in utero, there is no increased risk of developing these issues in the future
False! This predisposes the fetus to the same problems
T/F Genetics increases risk of developing depression
True
What is Beck’s cognitive model of depression?
S&S of depression
(those in DSM 5)
Anhedonia (loss of interest/pleasure)
Anergia (fatigue)
Insomnia or hypersomnia
Feelings of worthlessness/guilt
Poor cognition/concentration
Depressed mood
Changes to appetite and weight (gain or loss)
Psychomotor agitation or retardation
Recurrent thoughts of death or suicide
(additional not in DSM)
Loss of libideo
Mood varies by time of day
Worse in winter (SAD)
Onset in month after delivery
Anxiety
Hallucinations
Delusions
Effect of food on absorption of SSRIS?
Food has little affect on absorption (except sertraline - food will increase absorption)
Which SSRI has the fewest drug interactions?
Citalopram
** SSRIs commonly cause cytochrome 450 inhibition, therefore may affect metabolism of many other drugs
(see table bottom of page 185 in rx files)
T/F Dosage adjustment of SSRIs should occur in cases of hepatic impairment
True!
Are metabolized in liver with CYP450-dependent enzymes and other forms of conjugation
**Highly dependent on CYPs!
T/F TCAs are highly lipophilic
True! Pass readily into CNS
Tricyclic antidepressants have variable first pass metabolism in liver. What effect does this have on dosage adjustments?
If two drugs are competing to get metabolized, TCAs will lose the battle and not get metabolized as quickly (they are not favoured to attach to receptor and be metabolized). So want to give pt more time for patient to adjust to this medication to assess if it’s working at the current dose
Slide said initial treatment period is 4-8 weeks.
Dosage can be gradually reduced to improve tolerability, unless relapse occurs
MAOIs are metabolized by ________ (a process)?
Acetylation
What does it mean when someone is a “slow acetylator” when it comes to plasma levels of MAOIs?
Metabolize these drugs slowly
So will exhibit elevated plasma levels
How are MAOIs discontinued? Just stop it and start another drug right away?
what is the risk here?
No, need “washout” period to allow metabolites and drug to leave the body
*The nonselective MAOIs used in treatment of depression are irreversible inhibitors; thus, it takes up to 2 weeks for MAO activity to recover, even though the parent drug is excreted in 24 hours
What is the risk of starting another med too quickly with MAOI (such as SSRI/SNRI)?
Risk of serotonin syndrome
Risks to liver
Foods containing ______ have to be avoided
Tyramine
risk of HTN crisis
