Midterm Outline Flashcards
Outermost layer of cerebrum
Cerebral cortex
What does the limbic lobe consist of?
Surrounds upper brainstem Includes- hippocampus Amygdala Hypothalamus Parahippocampal gyrus Cingulate cortex
Plays a critical role in memory
Hippocampus
Important element of fear circuitry
Amygdala
Frontal cortex functions
Planning Attention Abstract thought Problem solving Judgement Inhibition of impulses
Cerebellum function
Motor coordination
Cognitive and affective processes
Thalamus role
Major rely station for incoming sensory information
Part of the brain that plays a critical role in neuroendocrine Regulation by affecting pituitary hormone release
Hypothalamus / mood motivation/ sex drive/ hunger/ temperature/sleep
Neuromodulatory nuclei in the midbrain
Dopaminergic ventral tegmental area
Neuromodulatory nuclei in the brainstem
Serotonergic raphe nuclei
Neuromodulatory nuclei in the pons
Noradrenergic locus coeruleus neurons
Cholinergic neurons are located where?
Basal forebrain and brainstem
Neuron doctrine theory
Neurons act as psychically discrete functional units within the brain communicating with each other through specialized junctions
Cell soma function
Housing the nucleus with its genomic DNA
Support neuronal function by supplying nutrition, maintaining homeostasis, stabilization of synapses, myelinating axons
Glia cells- 10x more than neurons
Play a role in synaptic transmission
Glia cells
Smal phagocytic cells
Microglia
Astrocytes and oligodendrocytes
Macroglia
Play a critical role in glutamatergic neurotransmission (function and transport)
Astrocytes (macroglia)
Mood disorders are associated with a reduction in the number of _____ in select brain regions
Glia
Characteristics of a neurotransmitter
Synthesized within presynaptic neuron
Released w:depolarization from pre synaptic neuron to exert an action on post synaptic neuron
Action can be replicated by a drug
Action on synaptic cleft is terminated by a specific mechanism
Amino acid neurotransmitters
Glutamate
GABA
Monoamine neurotransmitters
Dopamine Serotonin Norepinephrine Epinephrine Histamine
Small molecule neurotransmitter
Acetylcholine
Opioids Hypothalamic factors Pituitary hormones Substance P/VIP Leptin
Peptides
Rapid effect neurotransmitter receptors are either
Ion channels (NMDA glutamate receptors) or coupled to ion channels
G protein coupled receptors work —-
Via slower second messenger systems - involve multi enzyme cascade
Second messenger systems convert receptor signals into a coordinated set of cellular effects by….
Altering the function of multiple target proteins
Second messenger pathway involving glycogen synthase kinase(gsk) may mediate therapeutic efficacy of….
Lithium salts in bipolar disorder
By modifying gene expression in the nucleus, _______ can produce persistent changes in neural function
Transcription factors
Most widely studied neuronal transcription factor
CREB (cAMP response element binding protein)
Upregulated and phosphorylated in neurons in response to antipsychotic meds or drugs of abuse
CREB
BDNF and other related neurotrophic factors exert effects by…
As a growth factor during embryonic Neuro development and synaptic signaling
BDNF signaling modulates what?
CREB activity and gene expression ( neuroplasticity)
Included processes in the brain that continue into adulthood such as neurogenesis
Neurodevelopment
The capacity of the neural system to change in response to internal or external stimuli following predetermined rules
Neuroplasticity
Nerve fiber that carries away nerve impulses from the cell body
Axon
Branched extensions of a nerve cell that propagate the electrical stimulation received from another neuron
Dendrite
abnormally high or low concentrations of neurotransmitters in the area between two neurons
synapse. Can inhibit neurotransmitter synthesis, inhibit transport, vescicle formation, release/block post synaptic efforts or increase clearance rate from the synapse.
Can induce second messenger cascades that can influence intra-cellular processes, including gene transcription.
Enzymes via G proteins embedded within the cell membrane
Most conventional antipsychotic agents are extensively metabolized by the 2D6 isoenzyme of the….
Hepatic P450 enzyme system
Neurotransmitter is synthesized where?
presynaptic neuron
Biogenic amines
Serotonin and Histamine
catecholamines
Dopamine
Norepinephrine
Epinephrine
Amino acid neurotransmitters
Glutamate
Gaba
Glycine
An enzyme dopamine beta hydroxylase wil convert Dopamine into what?
Norepinephrine within the vescicle
Hormone and neurotransmitter synthesized by norepinephrine in the cytoplasm by enzyme
Epinephrine
What is innervation
The nervous excitation necessary for the maintenance of the life
Involves a multi-enzyme cascade that work via slow messenger systems
G-protein-coupled receptors
Linked to cytoplasmic enzymes via proteins embedded within the cell membrane
G-protein-coupled receptors
2 G-protein-coupled receptors
Glutamate
GABA
transmembrane channel that opens or closes in response to binding
Ligand gated ion channel
When a ligand binds to a ligand gated ion channel what happens ?
A channel opens and allows ions like K, Ca, CL, NA through)
voltage gated ions rely on???
The difference in membrane potential. Not the same as a ligand gated ion channel
Glutamate is a what?
Ligand
what alters gene expression?
Chromatin. Seen in child abuse - chromatin structure changes
influencing monoaminergic function has been shown to result in several different changes in second-messenger systems and….
Gene expression/downstream effects
Gene function may be changed without a specific alteration in the code. This change in function may also be heritable.
Epigenetics
Bipolar modification of chromatin is an example of….
epigenetics
drug capable of producing a maximum response that the target system is capable of
Full agonist
drugs that bind to and activate a given receptor but not fully
Partial agonist
Ligand that binds to the same receptor binding site as an agonist and not only antagonizes of the agonist but exerts the opposite effects by suppressing receptor signaling.
Inverse agonist
compound that has the opposite effect. Decreases the activation of a synaptic receptor by binding and blocking neurotransmitters from binding or decreasing the ammt of time neurotransmitters are in the synaptic cleft
Antagonists
system level treatment adherence
mental health care coverage
fragmentation of pt care
distance to care
financial barriers
sociocultural adherence to treatment barriers
attitudes and beliefs about psychiatric symptoms and treatment
clinical influence on tx adherence
cognitive impairment
substance misuse
psychiatric sx
tx related influences to adherence
tx efficacy
side effects
dose timing/frequency
psychotherapy modality
SSRI mechanism of action
interact with the monoamine neurotransmitter system including the reuptake transporters that terminate the action of NE, SE, DOPAMINE
TCA’s and MAOI’s were postulated to work by
increasing noradrenergic or serotonergic neurotransmission and compensating for monoamine “deficiency”
More recent theory on how antidepressants work is that they help by creating»_space;>?
slower adaptive responses within neurons to these initial biochemical changes - downstream effects
SSRI’s have effects on what neurotransmitters?
Serotonin reuptake and some modest dopamine and norepine reuptake
SSRIs have shown to have NON monoaminergic effects including moderate and selective effects on ________receptor expression and editing
glutamate
SNRI’s inhibit and do what?
Inhibit reuptake of Serotonin and NE with minimal to no affinity to muscarinic cholinergic, histaminergic and adrenergic receptors
SNRI duloxetine has been shown to
provide marked upregulation of BDNF and protein and redistribution of neurotrophin=potential improvement of synaptic plasticity
Norepinephrine reuptake inhibitors mechanism of action
significant NE reuptake inhibition, weak affinity to serotonin reuptake, with several non-monoaminergic properties
Reboxitine
NRI that inhibits nicotinic acetylcholine receptors and increasing extracellular levels of ACH
Partial agonist of kappa opioid receptor
ANTIDEPRESSANT THAT AFFECTS GLUTAMATE RECEPTORS WITH A DECREASE OF GLUR3 EXPRESSION
mechanism of action of serotonin agonists/antagonists
trazodone and nefazodone are weak inhibitors of serotonin and NE reuptake.
They primarily block serotonin 5HT2A receptors and demonstrate partial agonist properties as well
Able to release Serotonin presynaptically
stimulates Mu opioid receptors
may inhibit NMDA induced cyclic GMP elevation
Overall effect in the brain appears to be an increase in extracellular levels of serotonin- possible serotonin syndrome
Buspirone
full serotonin agonist at 5HT1A and partial agonist at 5TH1A post synaptic receptors
FDA approved for anxiety
Vortioxetine
Recently approved antidepressant
multiple 5HT receptor antagonist
Increases extracellular SE, NE, DOP in PFC and hippocampus-increases cell proliferation and survival
stimulates maturation of immature granul cells in hippocampus
NDRI’s mechanism of action
Primarily block reuptake of NE and DOP
Buproprion- dose dependent extracellular dopamine levels and NE
Alpha2 Adrenergic receptor antagonists
mirtazepine and mianserin
appears to enhance release of serotonin and NE by blocking alpha receptors
Mirtazepine appears to block 5HT receptors as well
Enhance release of NE and serotonergic transmission
First alpha 2 receptor antagonist approved for depression
Also a potent H1 receptor antagonist
TCA mechanism of action
Inhibit reuptake of NE and more potently than SE
Exhibits effects on glutamatergic system
Doxepine, amytriptyline, Nortriptyline-inhibity glycine
Trimipramine and clomiprimine - affinity for D2 receptors
Fairly potent blockers of HI, SE, ACH and Alpha receptors
MAOI mechanism of action
Inhibit MAO- enzyme found on outer membrane of the mitochondria= catabolizes(degrades) DOP, NE, SE following reuptake from the synapse
Either loaded into vesicles for subsequent re-release or broken down by MAO
MAO catabolizes a number of dietary pressor amines (DOP, Tyramine, triptamine, phenylithiamine.
Whats the concern?
Hypertensive crisis when consumption of dietary amines
Co-administering of Dopaminergic agents and MAOI’s can
cause hypertensive crisis
serotonin syndrome
How many days until MAO enzymatic activity is complete?
14 days
SNRI drugs
Venlafaxine
Desvenlafaxine
Duloxetine
Levomilnacipran ER
NRI antidepressants
Stratera-Atomoxetine
Reboxetine
Serotonin receptor antagonists/agonists antidepressants
trazodone nefazodone vilazodone(viibryd) vortioxetine(brintellix)
NDRI antidepressants
Buproprion
alpha 2 receptor antagonist antidepressants
Mirtazepine (Remeron)
TCA antidepressants
Imipramine Desiprimine Amitriptyline Nortriptyline Doxepine Trimipramine Protriptyline Maprotyline Amoxepine Clomiprimine (Anafranil)
MAOI antidepressants
Selegiline
phenelzine
Isocarboxazid
Tranylcypromine
eldery considerations for antidepressants
may have alterations in hepatic metabolic pathways
alteration in demethylation&hydroxylation(involved in metabolism of ssri’s and tca
Most common side effects of SSRI’s
nausea tremor excessive sweating flushing headache insomnia activation or sedation jitteriness dizzyness rash dry mouth sexual dysfunciton emergence
SSRI cognitive symptoms
mental slowing
apathy and emotional blunting
motor-bruxism (grind teeth)and akathisia(agitation, restlessness)
Less common side effects of ssri’s
diarrhea tremor bruxism rash hyponatremia SIADH worsening parkinson's tremors- pts needing more levodopa abnormal bleeding with normal labs hyperprolactinemia
which SSRI has the most research on reproductive safety?
Fluoxetine
Discontinuation syndrome sx from SSRI’s
Dizzyness insomnia nervousness irritabilty nausea agitation
Venlafaxine facts
SNRI
several meta analysis show superior to SSRI’s (w/exception to escitalopram)
Often used as a front line tx
Often used for TRD
DC for ECT- study showed asystole
Venlafaxine common side effects
nausea insomnia sedation sexual dysfunction HA tremor palpitations dizzyness sweating tachycardia
Desvenlafaxine facts
SNRI CYP450 3A4/weak 2D6 common s/e- nausea, dry mouth, vomiting, constipation sweating tremor somnolence nervousness abnormal vision sexual dysfunction
Duloxetine facts
SNRI as effective as SSRI's primarily excreted in urine metabolized by CYP 450 2D6 good for somatic sx of depression such as pain
Duloxetine side effects
dry mouth HA Nausea somnolence sweating insomnia fatigue does NOT cause HTN
Atomoxetine facts
Strattera NE reuptake inhibitor FDA approved for ADHD single open trial for tx of depression s/e- nausea, increased BP, decreased appetite, insomnia
Buproprion facts
NDRI tx of depression and anxiety lacks anticholinergic properties CYP 450 2D6- if combined with other 2d6's- can increase levels lower incidence of gi side effects lower risk of wt gain
Buproprion common side effects
agitation insomnia wt loss dry mouth ha constipation tremor
Major: Sz- more likely with bulimia and head trauma
Trazodone facts
Serotonin antagonist
shown to be as effective as ssri’s but ordered less frequently
short half life but still sedating
common s/e- sedation, orthostatic hypotension, headaches
should be used with caution with pts with cardiac disease
LOWEST RISK OF ALL ANTIDEPRESSANTS FOR SZ
rare hepatoxicity/
reported overdoses
rare/serious-priapism penis and clitoris
Nefazodone facts
serotonin receptor agonist
CYP 3A4- serotonin syndrom when combined w/ssri’s
lower risk of wt gain than ssri’s(appetite reducing effects)
lower risk of sexual side effects
rare/serious s/e- priapism male and female
s/e-nausea, dry mouth, constipation, headache,blurred vision
increased risk of hepatoxicity
Vilazodone
Viibryd serotonin 5ht1a partial agonist and ssri studies show superiority for mdd possible less sexual side effects than ssri's GI and insomnia sx
Vortioxetine facts
Brintellix
serotonin agonist/antagonist
New for depression
Mirtazepine facts
alpha 2 adrenergic receptor antagonist
more sedation and wt gain than ssris
lower risk of HA or sexual dysfunction
TRD tx
combine SSRI or SNRI with a DNRI or two meds from different classes
Antipsychotic side effects
metabolic syndromes
TD
extrapyramidal sx
MS patients are at risk for?
2X more likely to be bipolar
Epidemiology risk factors for BP
similar for men and women, may have gender differences in illness features
no difference with race, ethnicity or socioeconomic
strongest established risk factor is family hx
Environmental risks for BP
pregnancy and obstetrical complications stressful life events TBI MS Epilepsy Decrease in omega fatty acid consumption
Clinical features of BP
increased activity or agitation for one week or more
If irritable-4 rather than 3 associated sx
If hospitalized, 1 wk criteria is null
Sx must be associated with market impairment-social, occupational or psychotic sx
Cyclothymia
2 yrs marked by periods of hypomania as well as periods of depressed mood and no more than two months without sx.
manic episode criteria
1 wk or more of elevated or irritated mood/increase in energy
during mood disturbance 3-4 sx of: inflated self esteem, decreased need for sleep, talkative, flight of ideas, distractibility, increase in goal directed activity, increase in pleasurable activities
Marked impairment in social and occupational functioning
Not attributable to a drug physiological effects
rapid cycling
patients with at least 4 distinct episodes in a year with switch to other pole or full recovery
Bipolar pathophysiology
impairment in inositol signaling Wnt/Gsk3 pathway abnormality circadian rhythm disruption Decreased density of oligodendrocytes changes in gene expression Increased volume in striatum and amygdala increased perfusion in PFC during mania decrease in perfusion in PFC during depression Metabolic abnormalities
Genetic changes in bipolar
Chromatin modification
acute and chronic stress may exert epigenetic effects
what drug can modify chromatin expression?
Clozapine
atypical bipolar depression sx
Reverse neurovegetative signs overeating carb craving hypersomnia some say irritability during depression is marked for bipolarity
median age of onset for MDD and BP
later on for MDD
greater onset of childhood sx is possible indicator for BP
Greater recurrence of bp episodes is indicator for BP
personality disorder sx facts
more pervasive, less episodic
will not typically remit like a mood episode will
although bpd pt’s have mania or hypomania or depressive sx they don’t meet full criteria for Bipolar
secondary mania
manic sx in the context of a medical illness
exposure to corticosteroids
late onset in a pt with no prior mood sx
other neurological or systemic sx
frequently used tool to assist in bipolar recognition
Mood DQ
Treatment strategies for bipolar
anticonvulsants
antipsychotics
traditional therapy- mood stabilizer (lithium or valproate)
psychoeducation and disease mgmt strategies
Mania treatment
Lithium Valproate SGA's combo. therapy may have greater efficacy start 1, if no improvement in a short period, add another or switch
first line for euphoric mania
lithium quetiapine valproate aripiprazole risperidone zipprazidone
mixed episode bipolar first line tx
valproate
aripiprazole
risperidone
ziprasidone
mixed state bipolar drug class of choice for first line
atypical antipsychotics
bipolar depression first line tx
Lamotrigine if without severe or recent hx of mania
if severe and or recent mania- antimanic + Lamotrigine
antidepressants for Bipolar facts
should be avoided
If given, needs to be with a mood stabilizer
psychosocial interventions for bipolar
cbt
interpersonal/social rhythm therapy (IPSRT)
family focused therapy
treatment intervention for bipolar
treat the predominant mood type (mania, hypomania, depression or mixed state)
other factors that may be contributing to cycling
thyroid
substance abuse
residual mood symptoms (manic and depressive) following an acute episode appear to be predictive of……
earlier recurrence
earlier onset of mood symptoms has been associated with?
increased severity, greater chronicity and recurrence
panic disorder treatment
SSRI or SNRI
raise doses a week or so after acclimation
quetiapine drug class
atypical antipsychotic
individuals with social anxiety disorder are more at risk for what?
substance abuse
treatments for social anxiety disorder
SSRI, SNRI first line tx
Possible quetiapine
benzos, tca and maoi’s if necessary
propanolol and atenolol
lithium mechanism of action
recycling of inositol is inhibited
regulating intracellular ca
protein kinase activation
pharmacokinetics and pharmacodynamics of lithium
absorbed in the gut, rapidly distributed peak plasma in 1-2 hrs after first dose renal clearance half life renal clearance-24hrs steady levels reached in about 5 days
meds to avoid on lithium
NSAIDs and cox inhibitors (decrease renal flow and increase Li levels)
Thiazide Diuretics
lithium for children
No RCTs supporting it
lithium in psychotic disorders
ineffective in the tx of psychosis but has been studied as an adjunct in for schizophrenia and schizoaffective
lithium and etoh dependence
No proven effects
principles of lithium tx
labs- bun, cr, thyroid, ekg, electrolytes
check levels after 5 days and on every change in sx.
every 2 mo for first 6 mo for lithium levels
bun, cr and thyroid check every 6 mo
lithium dosing
0.6-0.8 (used to be 0.8-1.2)
begin at 600 once daily
can divide doses
adverse events lithium
hypothyroidism polyuria but may be helpful to carefully consider a diuretic like amiloride edema- give spironolactone decrease in Cr clearance-decrease in GFR rare sinus arrhythmias GI sx-give slow release formula tremor- propanolol or atenolol psoriasis acne
lithium toxicity s/s
lethargy tremor nv confusion visual changes vertigo hyperreflexia
sz
coma
arrythmia
lithium toxicity tx
Hold
IV fluids
tx electrolyte imbalance
anticonvulsants ineffective in tx bipolar
gabapentin topiramate oxcarbazepine pregabalin zonisamide tigabine
valproate and lithium facts
valproate proved to be an effective antimanic
valproate is an anticonvulsant
valproate slightly more tolerable than lithium
may be slightly efficacious than lithium
antipsychotics overall more effective in tx mania than anticonvulsants
valproate not fda approved for bp maintence and not suggested
inadequate data to support valproate as effective for acute bp depression
lamotrigine facts
anticonvulsant/mood stabilizer approved for maintenance tx of bp lamotrigine may not help with depression lamotrigine plus lithium effective in small randomized double blind -limited research Not efficacious for mania
carbamazepine facts
anticonvulsant
may be efficacious for mania but no solid data showing it effective for maintenance
significant withdrawal sx
oxcarbamazepine and gabapentin and levetiracetam for bp
no published placebo controlled studies
levetiracetam may cause sz
pregabalin facts
binds to voltage gated ca channels
good for fibromyalgia
maybe good for anxiety
not enough evidence to use for bipolar
tiagabine, zonisamide and topiramate facts for bp
anticonvulsants
Not effective for bp
topiramate (inhibit na gated ion channels)
tiagabine mechanism of action
inhibitor of gaba transporter
3 anticonvulsants that may help with bipolar
valproate
lamotrigine
carbamazepine
