Unit IV week 1 Flashcards
1
Q
Major Depressive Episode criteria
A
SIG-E-CAPS
requires depressed mood or diminished interest (anhedonia) and at least 5/9 criteria for at least 2 weeks, causing serious impairment in functioning
2
Q
SIG-E-CAPS
A
Major Depressive Episode criteria
Sleep - too much or too little Interest - decreased Guilt - increased Energy - decreased Concentration - decreased Appetite - decreased or increased Psychomotor agitation/retardation Suicidal ideation
3
Q
Mania and Hypomania criteria
A
DIGFAST
- Distractibility - attention too easily drawn to unimportant or irrelevant external stimuli
- Irritable/elevated/expansive mood
- Grandiosity (inflated self esteem)
- Flight of ideas, subjective experience of racing thoughts
-Activities
High potential for painful consequences (buying, sexual)
Goal directed or psychomotor agitation
- Sleep - decreased need for sleep
- Talkativeness
4
Q
Hypomania
A
4 days, not marked impairment in functioning, not psychotic
5
Q
Bipolar I
A
patients must have had mania, but also may have hypomania and major depressive episodes
6
Q
Bipolar II
A
patients must have had hypomania and MDE
7
Q
Major depressive disorder
A
has had MDE, but never hypomania or mania
8
Q
Cyclothymia
A
hypomania and subsyndromal depression
9
Q
Dysthymia
A
subsyndromal depression
10
Q
Schizophrenia
A
> 6 months
Delusions: fixed belief not amenable to change in light of conflicting evidence
Hallucinations: perception like experiences that occur without an external stimulus
Disorganized thinking or speech: frequent derailment or incoherence
Grossly disorganized or abnormal motor behavior (including catatonia)
Negative symptoms: alogia (poverty of speech), affective flattening (decreased expression of emotions, lack of expressive hand gestures), asociality (few friends)
11
Q
Schizoaffective disorder
A
if psychotic symptoms are present throughout, but mood symptoms are present majority of time = MDE + psychotic episode
12
Q
Schizophreniform disorder
A
> 1 month, but less than 6 months
13
Q
Pharmacotherapy for Psychosis (2)
A
1) Typical neuroleptics (first gen antipsychotics)
- Affect dopamine pathway - D2 antagonism
2) Atypical neuroleptics (second gen antipsychotics)
Effect serotonergic pathways
14
Q
Diencephalon = _________ + ___________
A
Thalamus (dorsal) + Hypothalamus (ventral)
15
Q
Hypothalamus
A
homeostasis, intimately associated with pituitary, amygdala, preoptic area, nucleus of the solitary tract, autonomic preganglionic motor nuclei
16
Q
Thalamus
A
gateway to cortex
Each area of cortex has corresponding thalamic relay nucleus
17
Q
Thalamocortical connections main features (3)
A
All connections are reciprocal
Right thalamus deals with contralateral side of body
Acts as gateway to cortex - EXCEPT for olfactory system (olfactory cortex → orbitofrontal cortex)
18
Q
Relay nuclei of thalamus
A
1) Anterior nucleus → Cortex (cingulate gyrus) (Limbic, emotions)
2) VA/VL nucleus → motor cortex (somatosensory)
3) LGN (visual)
4) MGN: inferior brachium → MGN → auditory cortex (auditory)
19
Q
Somatosensory nuclei of thalamus (2)
A
Face sensation via trigeminal pathway → VPM
Body sensation via medial lemniscus and spinothalamic tract → VPL
20
Q
Association nuclei of thalamus (2)
A
Pulvinar nucleus → parieto-occipital association cortex (visual)
Dorsomedian nucleus → frontal association cortex (frontal cortex)
21
Q
Two “other” nuclei of thalamus (2)
A
Centromedian nucleus (motor)
Reticular nucleus - sheet of cells on lateral surface, primarily inhibitory interneuron with connections to all other nuclei)
22
Q
3 Major circuit systems of thalamus
A
1) Thalamocortical
2) Lentiform Nucleus/Basal Ganglia
3) Limbic System
23
Q
Anterior limb of the internal capsule
origin:
destination:
runs where?
A
runs between caudate (medial) and lentiform nucleus (putamen/globus pallidus) (lateral)
Origin: anterior nucleus of thalamus, DM nucleus
Destination: cingulate gyrus and prefrontal cortex
24
Q
Genu of internal capsule
A
flexure of internal capsule
Contains fibers of corticobulbar tract
25
Posterior limb of internal capsule
runs where?
contains fibers from where?
origin and destination?
between thalamus (medial) and lentiform nucleus (putamen/globus pallidus) (lateral)
Contains corticospinal and ascending thalamocortical fibers
Origin: motor cortex, VPL/VPM
Destination: spinal cord and brainstem, and postcentral gyrus
26
Retrolenticular limb of internal capsule
origin
destination
Origin: Pulvinar and LGN
Destination: Parietal association cortex and visual cortex
27
Sublenticular limb of internal capsule
origin
destination
Origin: LGN and MGN
Destination: Visual cortex and auditory cortex
28
Broadmann's areas:
```
1-3 = ?
4 = ?
17 = ?
41 = ?
```
```
1-3 = Primary sensory
4 = Primary motor
17 = Primary visual
41 = Primary auditory
```
29
EEG
measures small field potentials at surface of skin overlaying skull
Voltages measured in EEG generated by neurons near surface - reflect synchronous synaptic input to cortical neurons
30
Thalamic Relay Neurons
Receive input from a sensory system, relays info to cortex via excitatory glutamatergic synapses onto pyramidal cortical neurons with soma in layer IV of cortex
31
Thalamic relay neurons do what when you are awake?
Awake → little inhibitory input to thalamic relay neurons, membrane potential rests at -55mV → fire series of APs at high frequency
32
Thalamic relay neurons do what when you are asleep?
Asleep → Thalamic reticular neurons release GABA and inhibit relay neurons → membrane potential at -85mV → fire bursts of APs on top of a Ca2+ spike
33
Ca2+ spikes during sleep in thalamic relay neurons are generated by what?
- Ca2+ spike happens with 3Hz frequency generated by T-Type Ca2+ channel
- Channel inactivated by depolarization
- When relay neurons inhibited by thalamic reticular cells, inactivation gate opens, and T-Type Ca2 channel generates Ca2+ spikes at 3Hz frequency
- Fast APs ride on top of this Ca2+ spike
34
Thalamic relay neurons send axons to _________ which then...
Relay neurons then send axons to cortical pyramidal cells → pyramidal cell fires at delta frequency → Slow EEG recording
35
EEG and slow wave sleep
Slow wave sleep stage is characterized by a pattern of slow wave oscillation of EEG at frequency of 3Hz (delta wave)
36
Ascending control of thalamocortical circuits comes from the _________ via ________, ________, and ________ neurons
Brain stem
ascending cholinergic, noradrenergic, and serotonergic neurons
37
When you are asleep and are stimulated by ______ from ________ neurons in the ___________ system you wake up and interrupt slow waves
ACh
Cholinergic neurons
Reticular activating system
38
__________ neurons from ___________ --> release noradrenaline in thalamus
activated during ____________
noradrenergic neurons
from locus coerulus
activated during fight/flight response
39
_________ neurons from __________ --> release serotonin in thalamus
serotonergic neurons from raphe nuclei
40
Absence Epilepsy
when child has sudden staring spells
Child stops what he/she is doing, stares for a few seconds, and then resume
EEG pattern similar to slow wave sleep (d waves of 3Hz)
41
Simple absence seizures
Impairment of consciousness
Minimal motor activity (eyelid fluttering, blinking)
Lasts 5-15s, average of 100 seizures a day
42
Complex absence seizures (5)
Impairment of consciousness
Prominent motor activity (myoclonic jerks, automatism, atonic)
More common than simple
Automatisms: persistence of action, mumbling, nonpurposeful movements
Autonomic features: pallor, change in HR/RR, mydriasis, micturition
43
Mice without T-type Ca2+ channel and anticonvulsants that block T-type Ca2+ channels
what impact?
Mice without T-type Ca2+ channel cannot be induced to have these seizures
anticonvulsants that block T-type Ca2+ channels are effective against absence epilepsy
44
Generalized seizure
seizure activity in entire brain
May start in a focal area, but then goes generalized
Tonic (rigid)
Clonic (on/off)
45
Childhood absence epilepsy
Onset 4-8 years, remission in 80% by adulthood
46
Juvenile absence epilepsy
onset 4-30 years
Less frequent absence seizures, duration may be longer, some preserved awareness
47
Juvenile myoclonic epilepsy
infrequent absence seizures
GTC/myoclonic seizures (surrounding sleep) are predominant features
No remission, but may be responsive to treatment
48
EEG results in:
Typical absence seizure
normal background organization and frequencies
Ictal discharges:
- Abrupt onset and offset
- Generalized 3Hz spike and wave
- Frontal maximum
Spikes may become fragmented and irregular during sleep
49
EEG results in:
Atypical absence seizures
often abnormal background with slowing and disorganization
Ictal discharges at 2-2.5Hz, more irregular
50
Treatment of epilepsy (2 drugs)
Valproic Acid
Ethosuximide - acts on T-type Ca current
51
Declarative Memory
ability to recollect events or facts that have a specific temporal and spatial context
HIPPOCAMPUS important for formation of declarative memory
52
Procedural Memory
ability to learn new motor skills
Cerebellum, striatum and frontal cortex important for formation of procedural memory
53
Short-Term Memory
lasts for fractions of a second to seconds
Occurs in SENSORY CORTEX
54
Working Memory
lasts seconds to minutes
Located in FRONTAL LOBES where executive function (ability to react in morally appropriate way) is also located
55
Long-Term Memory
lasts for days and years
Stored in CORTEX
56
Long term memory storage is in _______________
evidence?
NEOCORTEX
fMRI and lesion studies indicate long term-term declarative memory is stored in neocortex
57
Patient HM
Had bilateral symmetric removal of half of rostrocaudal extend of hippocampus, adjacent entorhinal cortex, and amygdaloid complex
Produced severe anterograde amnesia
Capable of recollecting memories before surgery, but cannot recollect facts after surgery
Deficit in declarative memory and semantic knowledge
Procedural memory was NOT affected
58
Associative memory
learning to associate several cues with a particular fact or object
59
Long Term Potentiation and Associative Memory
Input 1 = axons representing large number of cues required before you learn
during learning what happens?
During learning, you stimulate postsynaptic cell vigorously and repeatedly through all axons of input 1 → synapse strengthens (elicit depolarization of postsynaptic neuron when a smaller subset of axons in input 1 is stimulated)
EX) permit recall of movie title with four cues instead of eight
60
Potentiation occurs ONLY when...
Potentiation occurs ONLY when reinforcement and relevant sensory stimulus are turned on at the SAME time
61
What happens when input 2 (axons that have not undergone LTP) are stimulated?
stimulating subset of those axons would not result in postsynaptic depolarization ensuring you respond correctly
62
Mice experiment: mice learn to use visual cues provided by objects around pool to locate hidden platform, and can still do this when some objects removed
what happens when area ______ of hippocampus of mice is damaged
CA3
mice have harder time finding submersed platform with reduced number of cue
63
LTP in _____ area important for associative memory
CA3
64
Dentate gyrus
one layer of neuron cell bodies arranged in spiral semicircle
65
Ammon’s horn
larger spiral semicircle of neuronal cell bodies surrounding dentate gyrus
CA3 neurons and CA1 neurons of Ammon’s horn region are involved in long term potentiation, and serve basis for memory consolidation
66
Input to hippocampus from _______ via ______ path. This input synapses on ________ and ________ neurons on Ammon's horn
From entorhinal cortex via perforant path
Perforant path axons synapse on dentate gyrus and CA3 neurons in Ammon’s horn
Entorhinal cortex gets widely distributed input from neocortex
67
Input to hippocampus (3)
1) Entorhinal cortex
2) Moss fibers
3) Schaeffer collateral axons
68
Mossy fibers
cells from dentate gyrus that synapse on the CA1 neurons
69
Schaeffer collateral axons
originate from CA3 neurons and synapse onto CA1 neuron
70
Hippocampus and LTP:
| Two characteristics
1) Only synapses that are being stimulated during tetanus undergo LTP
2) LTP only takes place when titanic burst large enough to cause cell depolarization in postsynaptic neuron
**The only synapses whose effectiveness is increased are those that are being stimulated by release of NTs (glutamate) and are simultaneously being depolarized postsynaptically as a result of depolarization elicited by large summated input elicited by the tetanus
71
Molecular basis for LTP
1) NMDA receptor requires glutamate binding and depolarization of postsynaptic membrane to remove Mg2+ and allow Ca2+ to flow into cell
2) Ca2+ IN stimulates Calmodulin → stimulate calcium/calmodulin dependent protein kinase II (CAMKII)
3) CAMKII phosphorylates itself causing prolonged activation of CAMKII
72
EPSP size in LTP is increased how? (2)
→ increases EPSP size by:
1) incorporating AMPA receptors in postsynaptic membrane
2) phosphorylation of AMPA receptors making them more responsive to glutamate → STRUCTURAL CHANGE
73
Synapse formation in learning and memory
Synapses are NOT static: synapse formation and destruction can contribute significantly to learning
74
Adult neurogenesis in learning and memory
Adult Neurogenesis:
Occurs in olfactory bulb - involved in olfactory learning
Hippocampus - involved in declarative learning
Cerebellum - involved in procedural learning
75
Alzheimer’s Disease pathophysiology
Early stage: affects synaptic transmission in limbic and association cortices
Loss of ability to encode new declarative memories in an individual with otherwise normal intelligence, motor, and sensory functions
APP, when cleaved by B and y secretases → neurotoxic AB protein
→ AB proteins assemble and cause cognitive impairment through loss of synapses and subsequent neurodegeneration
76
Kluver-Bucy Syndrome
removal of amygdala
- Alteration in feeding
- Attempting to make with individuals of other species
- Lack of concern of previously feared objects
77
Conditioned fear
Sound conditioned to shock
Sound = auditory system, Conditioned stimulus
→ thalamus → auditory cortex and amygdala (lateral nucleus of amygdala)
Shock = pain system, unconditioned stimulus
→ somatosensory thalamus (VPL) → somatosensory cortex and amygdala
*Amygdala involved in this learning
78
Emotional limbic system (6 structures)
1) amygdala
2) cingulate gyrus
3) mediodorsal nucleus of thalamus
4) ventral basal ganglia (ventral caudate and putamen)
5) insular cortex
6) hypothalamus
79
Limbic System and Amygdala in Emotion
Emotions expressed by autonomic visceral (hypothalamus) and somatic motor actions (reticular formation in brainstem)
-role in conditioned fear learning
80
Conditioned flavor aversion
Two cues separate in time (food flavor and malaise) → change neural circuit resulting in learned aversion for food
EX) Cancer patient receives taste and olfactory stimulation from eating food, and gets sick within ½ hour → avoid food in future
Happens with single episode of malaise and can last for years
81
Where does conditioned flavor aversion?
INSULAR CORTEX
82
Mechanism of conditioned flavor aversion
Muscarinic receptors in insular cortex are essential for CFA acquisition
Muscarinic stimulation of neurons in insular cortex → activate kinases and phosphorylate NMDA receptors → affects response to stimulation from fibers coming from amygdala
Stimulation through amygdala → associative learning that causes aversion to food that was paired with malaise
83
Limbic System is responsible for what 4 main functions
HOME
Homeostasis
Olfaction
Memory
Emotion
84
Papez circuit is made up of what 4 components
1) Hypothalamus with mamillary bodies
2) Anterior thalamic nucleus
3) Cingulate gyrus
4) Hippocampus
85
Papez circuit
cingulate gyrus → hippocampus → Hippocampus projects to hypothalamus (via fornix) → anterior thalamic nuclei → cortex
proposed as anatomic basis for central functions of emotion and peripheral expression
86
Theory of emotion: amygdala responsible for what?
Amygdala: responsible for formation and storage of memories associated with emotional event
87
Amygdala gets input from where?
Highly processed visual information, piriform/olfactory input, and other visceral sensory inputs
88
Parts of Amygdala (3)
1) Centromedial Amygdala = output
2) Basolateral Amygdala (BLA) = input
3) Intercalated cells = islands of cells between two structures
- Important in fear extinction
89
Fear conditioning: pair auditory stimuli (CS) with shock (US)
Sensory stimuli reach ___________ --> ?
Sensory stimuli reach basolateral nuclei of amygdala (BLA) → form associations with memories of stimuli
auditory stimuli undergoes LTP for predictions of adverse events and stimuli
90
The basolateral amygdala (BLA) elicits fear behavior through connections with...(2)
BLA elicits fear behavior through connections with central nucleus of amygdala (CEA) and related bed of nuclei of stria terminalis (BNST)
91
What are fear behaviors?
Fear behavior = freezing, tachycardia, increased respiration, stress-hormone release
92
Central nucleus of amygdala mediates what?
expression of emotional responses
93
Lesion of amygdala does what to fear and positive conditioning?
Lesion of amygdala prevents acquisition of fear and positive conditioning
94
Dopaminergic neurons from VTA project to ________ in _________
stimulation of this area does what?
project to nucleus accumbens in ventral striatum
Stimulation of nucleus accumbens is highly reinforcing
Excessive dopamine in this circuit excessively reinforces networks that were active during behavior that produced the dopamine surge
95
VTA also projects to ______ and _______ creating what two pathways?
projects to amygdala, and VMPFC = mesolimbic and mesocortical dopaminergic pathways
96
Iowa Gambling Task and the Ventromedial PFC
Iowa Gambling Task: lesions to VMPFC means patients tend to continue to draw from “bad” decks even though they know they are losing
Healthy participants show anticipatory emotional response (stress response) preceding explicit knowledge of correct strategy
97
Implications of Iowa gambling task findings in patients with VMPFC lesion
VMPFC injured patients never develop anticipatory physiologic reaction to impending punishment
BUT had intact stress responses to receipt of actual rewards and punishments
→ VMPFC important for predictions of consequences but not necessary for registering actual consequences
Implies VMPFC role in suppression of behaviors felt to be excessively risky, especially in context of social function
Impairment in ability to estimate risk/reward associated with certain behaviors, and ability to select behaviors based on risk/reward calculations
98
What happens to your decision making when you damage your VMPFC?
VMPFC damage → engage in behaviors that are detrimental to well-being
99
What happens in the Iowa Gambling task when you have a lesion in your amygdala
Amygdala damage → similar performance on Iowa gambling task as VMPFC, but these patients ALSO failed to show conductance responses to actual receipt of rewards and punishments
→ amygdala triggers emotional bodily states in response to rewards and punishments associated with specific behaviors or stimuli
→ VMPFC represents relations between inputs and outputs that the amygdala has constructed
-A set of predictions of likely consequence of different actions
100
Amygdala
links aversive and appetitive stimuli with physiologic responses, action patterns, perceptions, and predictions
critical integrative structure projecting to VTA and nucleus accumbens
101
Insula
constitutes primary olfactory, gustatory, and visceral sensory cortex
Links between insula, VMPFC, and amygdala relate these senses to emotion
102
VMPFC and ventral striatum
are (Respectively) critical for generating and reinforcing predictions about risks and rewards associated with actions
103
VTA
Reward and punishment salience) signals contribute to synaptic plasticity and associative learning in amygdala, ventral striatum and VMPFC
midbrain structure with dopaminergic cells innervating all the reward pathway structures
104
Hippocampus
memory circuit involved in mediating associations between biologic stimuli (or drugs of abuse) and environmental cues
105
Prefrontal cortex and drugs of abuse
critical for executive function in providing control over impulses from destructive behavior
Impairment following chronic drug abuse important mediator in loss of control over drug intake (Addiction)
106
Function of the reward pathway
mediate pleasure (reward) and the strengthening of behaviors (reinforcement associated with natural reinforces (food, water, sex)
Produces motivational states
Modulation of physiological and behavioral responses ensuring survival and reproduction
107
Reward
something brain interprets as intrinsically positive
108
Reinforcing stimulus
increases probability of behaviors paired with it will be repeated - not all reinforcers are rewarding (can reinforce avoidance behaviors)
109
Mesolimbic system
Stimulation of VTA neurons by natural reinforcers → dopamine release in nucleus accumbens
dopamine pathway, final common pathway of reinforcement and reward
Dopamine affects motivation and attention to a salient stimuli
110
Mesolimbic system and drugs of abuse
ALL drugs with dependence liability share this final common pathway of increasing synaptic dopamine levels in nucleus accumbens
More intense/direct effect drug has on dopamine neurons, the greater addiction potential
111
Reactive reward system is made up of what 3 structures?
VTA (dopamine cell bodies) + nucleus accumbens (where DA neurons project) + amygdala (connects VTA and NA)
112
Reactive reward system:
amygdala connects to _________ as a relevance detector
Amygdala connects to _________ to signal what?
Learning conditioned in amygdala
Amygdala → connects back to VTA as a relevance detector (for anything relevant to previous drug abuse experience)
Amygdala → connects to nucleus accumbens to signal emotional memories triggered by internal or external cues
→ initiate impulsive-automatic-obligatory actions to find/take more drugs
113
Reactive reward system and drug abuse
**drug addiction produces changes whereby the “reactive reward” system hijacks the normal reward circuitry
repeated exposure to drugs of abuse results in pathologic “learning” to trigger drug-seeking behaviors when presented with internal (craving, withdrawal) or external (environmental associations) cues
114
Function of reactive reward system
signal immediate prospect of pleasure or pain and provides motivational and behavioral drive to achieve that pleasure or avoid that pain
115
Reflective reward system connects _______ to ______ including projections to what 3 areas for what purpose?
connects PFC to nucleus accumbens
Orbitofrontal projections → regulate impulses
Dorsolateral PFC → analysis of situation
VMPFC → integration of impulsiveness and cognitive flexibility with its regulation of emotions
116
Reflective reward system and drugs of abuse
balance between reactive reward drives and reflective reward decisions determine whether output of reward circuitry converted into short term rewards (drug seeking) or long term
117
Compulsive drug use: Repetitive drug-induced rewarding experiences → what 4 things
1) Alter reward circuits so drug ingestion and cues that merely predict pleasure will activate MESOLIMBIC DOPAMINE RELEASE
2) Amygdala learns that drug causes pleasure and drug cues with pleasure
3) Drug cues → DOPAMINE RELEASE in NAc → GABA output from NAc → thalamus → prefrontal cortex
4) Absence of activity in reflective reward system → drug seeking behavior initiated
118
Highest addictive potential for drugs of abuse with:
Modes of administration?
Rate of onset?
IV and inhalational routes are associated with most rapid rise in brain levels of drug and greater likelihood to produce addiction
Rate of onset: abuse liability increased with faster onset of action
119
Highest addictive potential for drugs of abuse with:
Termination effects?
drugs with shortest half lives tend to have higher abuse liabilities
Withdrawal effects more severe for drugs with short half lives → continued drug administration just to prevent withdrawal
120
Psychosis
characterized by derangement of personality and loss of contact with external reality - primary disorder in thinking
121
Four components of psychosis
1) Hear voices and have other sensations that are not real = Hallucinations
2) Believe they are influenced by unseen forces around them = Paranoid Delusions
3) Being tormented, harmed, followed, tricked, or spied on = Persecutory Delusions
4) Have other disorders in thought, typically idiosyncratic associations that are evidenced in disorganized speech or writing = formal thought disorder
122
Schizophrenia
inability to discern what is real and not real, to think clearly, have normal emotional responses, and act normally in social situations
123
Schizophrenia positive and negative symptoms
Positive Symptoms:
- Hallucinations, generally auditory
- Delusions, belief that external forces conspiring against him/her
Negative symptoms (deficit symptoms):
- Inability to pay attention, loss of sense of pleasure, loss of will or drive, disorganized or impoverished thoughts and speech, flattened affect, social withdrawal
- Cognitive deficits
124
Diagnostic criteria for schizophrenia
- at least 2 symptoms
- Social/occupational dysfunction in work, interpersonal relationships, or self care
- Duration of symptoms for at least 6 months
- Illness not due to a medication, medical condition, or substance abuse
- Illness not part of autism or developmental disorder
(High likelihood of substance abuse)
125
Prevalence and age of onset of Schizophrenia
Prevalence: 1% of world population, 2.4 million people
Age of onset: late adolescence, early adulthood, continue throughout life
-Earlier behavioral dysfunction, primarily social and learning difficulties
126
Drugs that can resemble schizophrenia (5)
1) Dopamine agonism (cocaine, amphetamine)
2) Norepinephrine agonism (cocaine, amphetamine)
3) Serotonin agonism (hallucinogens, LSD)
4) NMDA antagonism (dissociative anesthetics, phencyclidine, ketamine)
5) Acetylcholine antagonism (anticholinergics, atropine)
127
Dopamine theory of schizophrenia
1) HYPERactivity of mesolimbic system --> POSITIVE SYMPTOMS
| 2) HYPOactivity of mesocortical system --> NEGATIVE symptoms
128
Mesolimbic system
dopamine neurons from VTA release dopamine to nucleus accumbens → regulate reward pathways and emotional processes
- integration of sensory input and motor responses with affective or emotional data
- Antipsychotic agents (via D2 block) are most effective in reducing positive symptoms (delusions, hallucinations, disordered cognition)
129
Mesocortical system
dopamine neurons from VTA and substantia nigra release dopamine to prefrontal cortex → regulate areas involved in cognitive processing and motor control
DLPFC and VMPFC involved in communication and social abilities
Hypoactivity due to cell loss in PFC → negative symptoms (poverty of speech, anhedonia, lack of motivation, social isolation)
130
Glutamate Model of schizophrenia
glutaminergic hypoactivity → psychosis
131
Mechanism behind glutamate model of schizophrenia
Glutamate binds dopamine neurons → produce regional hyperactivity and hypoactivity in dopamine neuron release
**Increased cortical output due to loss of cortical GABA inhibition→ increase mesolimbic DA release → Positive symptoms
**Increased cortical output due to loss of cortical NMDA-glu neurons→ loss of cortical GABA inhibition → increased activity of cortical glutamate neurons → decreased mesocortical DA release → Negative symptoms
132
GABAergic model of schizophrenia
reduced parvalbumin positive interneurons in laminar III of prefrontal cortex
133
Main Neuropathological Findings in schizophrenia (4)
1) decreased size and packing density of pyramidal neurons in PFC
2) Reduced GABAergic interneuron proteins and neuronal function in layer III of DLPFC
- Inhibitory interneuron deficit - in number, expression of various peptides and proteins, and migration from cortical subplate
3) Decreased dendritic spines and presynaptic axonal inputs
4) Decreased cortical gray matter and enlargement of lateral ventricles
134
Nigrostriatal pathway
dopaminergic tract (substantia nigra → striatum)
Plays central role in planned and coordinated movement
135
Tuberoinfundibular pathway
hypothalamic neuronal release of DA in pituitary → inhibit prolactin release
136
Serotonin Neuronal Systems and psychotic symptoms
-where are 5HT2A receptors located?
5HT2A-R located on glutamate pyramidal neurons in cortical regions and on dopamine nerve terminals in striatum
137
Serotonin Neuronal Systems and psychotic symptoms
Activation of 5HT2A receptors on DA neurons in PFC → ?
Activation of 5HT2A receptors on glutamate pyramidal cells in PFC → ?
Activation of 5HT2A receptors on DA neurons in PFC → decrease DA release → NEGATIVE symptoms
-Blockage of these receptors by ATYPICAL agents results in increased DA release, and alleviation of negative symptoms of schizophrenia
Activation of 5HT2A receptors on glutamate pyramidal cells in PFC → stimulation of DA neurons in VTA → increase DA release in mesolimbic pathway → POSITIVE symptoms
138
Typical Antipsychotics (1st generation)
high D2/5HT2A ratio
Good D2 block, good efficacy against positive symptoms, but high incidence of extrapyramidal toxicity
Typical Agents: Chlorpromazine, Haloperidol
139
Atypical Antipsychotics (2nd generation)
low D2/5HT2A ratio
Poor D2 block, good 5HT2A block → good efficacy against negative symptoms
Atypical Agents: Aripiprazole, Clozapine, Olanzapine, Quetiapine
140
Side effects of antipsychotics:
ANS side effects
- caused by what mechanism?
- most significant in what drug?
dry mouth, tachycardia, loss of accommodation, etc.
(MUSCARINIC BLOCKADE)
(Chlorpromazine especially)
141
Side effects of antipsychotics: orthostatic hypotension - caused by what mechanism?
a1 adrenergic block
142
Side effects of antipsychotics: sedation
- caused by what mechanism?
- most significant in what drug?
Sedation: via ANTIMUSCARINIC and ANTIHISTAMINIC activity
| Chlorpromazine especially
143
```
Side effects of antipsychotics:
Extrapyramidal signs (4)
```
via DOPAMINERGIC BLOCK (most with high potency Haloperidol, high D2 side effects)
1) Acute dystonia (swollen tongue, tinnitus, trismus)
2) Akathisia: motor restlessness, inability to sit still
3) Pseudo Parkinsonism: tremor, bradykinesia, rigidity, shuffling gait
4) Tardive dyskinesia: involuntary repetitive movement of lips, tongue
144
Side effects of antipsychotics: what is side effect most associated with Clozapine
Agranulocytosis
145
Side effects of antipsychotic drugs (10)
1) ANS: dry mouth, tachycardia, loss of accommodation, etc.
2) Orthostatic hypotension
3) Sedation
4) Extrapyramidal signs
5) Agranulocytosis
6) Weight gain
7) altered thermoregulation (poikilothermia, due to block of hypothalamic DA receptors)
8) Photosensitivity
9) Lowered seizure threshold
10) Neuroleptic malignant syndrome
146
Monoamine theory of depression
Effective antidepressant drugs share property of enhancing NE-5HT-DA availability in synapse
Monoamines = Dopamine, NE, Serotonin
Deficit in NE/5HT can induce depression
147
Limitations of monoamine theory of depression
Does not totally explain etiology of depression
Mood elevation effects take 2-3 weeks for onset, but effects on amines occur immediately
Some new drugs have no effect on amine reuptake
148
Neurodegenerative hypothesis of depression:
Depression associated with neuronal loss in PFC and hippocampus and antidepressant therapies act by inhibiting-reversing this loss by stimulating neurogenesis
149
Pro Depressive pathway
stress-induced activation of Hypothalamus-Pituitary-Adrenal axis switches on gene expression that promotes neuronal apoptosis and neuronal cell death due to excitotoxic actions of glutamate via NMDA receptors
150
Antidepressive pathways
monoamines (NE and 5-HT) act on G-protein coupled receptors and brain-derived neurotrophic factor (BDNF) act on kinase-linked receptor to switch on genes that promote neurogenesis and protect against apoptosis
151
Epidemiology of Mood Disorders
Neuropsychiatric disease account for half of all causes of disability worldwide
Depression affects 120 million people worldwide
Anxiety disorders are the most common psychiatric illness in the US followed by mood disorders
152
Signs/symptoms of depression + diagnostic criteria
SIGECAPS
5 or more symptoms that have persisted for 2 weeks or more, are a change from previous function, and patient experiences sad mood or anhedonia
153
Signs/symptoms of bipolar disorder (4)
1) Manic mood and behavior (euphora, grandiosity, pressured speech, impulsivity, excessive libido, recklessness, social intrusiveness, diminished need for sleep)
2) Dysphoric mood and behavior (depression, anxiety, irritability, hostility, violence, or suicide)
3) Psychosis (Delusions and hallucinations)
4) Cognitive symptoms (Racing thoughts, distractibility, disorganization, and inattentiveness)
154
3 depression subtypes
1) Atypical
2) Psychotic
3) Melancholic
155
Atypical depression
mood reactivity, leaden paralysis, reverse neurovegetative symptoms (increased appetite, weight gain, hypersomnia)
156
Psychotic depression
often with auditory hallucinations, nihilistic delusions
157
Melancholic depression
mood worse in morning, early morning awakening, anorexia, weight loss, guilt, psychomotor retardation
158
Bipolar I vs. Bipolar II disorder
Bipolar I: mania
| Bipolar II: hypomania + major depression
159
Manic symptoms include...
DIGFAST (see previous lecture)
160
Hypomanic symptoms
same as mania, but do not persist as long (four days) and do not cause such a degree of social impairment as seen in mania
161
What is the differential diagnosis for a patient with mood symptoms (4)
1) Mood disorder
2) Medical illness
- Endocrine, infections, CNS, metabolic
3) Substance abuse
- Cocaine, alcohol, amphetamine/stimulants, hallucinogens, benzodiazepines
4) Medication side effect: amantadine, methyldopa withdrawal, interferon, steroids, chemo agents
162
Pathophysiology of major depression depression
1) Altered gene expression of important neuronal growth factors
2) NOT a chemical imbalance
3) No single area of brain pathology
4) Involves alterations in neural circuitry
163
Major depression most likely involves alterations what neural circuitry (3)
1) Frontal cortex and hippocampus: memory, worthlessness, hopelessness, guilt, suicidality
2) Striatum and amygdala: anhedonia, anxiety, motivation
3) Hypothalamus: insomnia/hypersomnia, energy, appetite, libido
164
Suicide: risk factors and epidemiology
Men = 79% of completed suicides, but women attempt suicide 2-3x more often than men
11th leading cause of death all ages in US, 2nd leading cause of death 25-34 years old
42,000 deaths annually
165
SSRIs (fluoxetine, paroxetine)
mechanism of action
use
block 5HT presynaptic reuptake pump
Safe, effective, with multiple indications (GAD, social anxiety, panic, OCD, PTSD)
166
SSRIs (fluoxetine, paroxetine)
Side effects (5)
diarrhea, nausea, jitteriness/anxiety, sexual side effects, **drug interactions (P450 inhibition)
167
SNRIs
mechanism of action
block NE and 5HT reuptake pumps
168
SNRIs
side effects (4)
Safe, better tolerated than TCAs
Minuses: sexual side effects, sweating, **increased diastolic BP, withdrawal syndrome (flu-like, electric shocks)
169
Mirtazapine
```
mechanism of action
side effects (2)
```
block 5HT2A, 5HT2C, 5HT3, a2 adrenergic receptors
Minuses: Daytime somnolence, weight gain
170
Bupropion
mechanism of action
NDRI (norepinephrine dopamine reuptake inhibitor)
increases whole body NE, weakly blocks reuptake of DA
171
Bupropion
side effects (5) - contraindicated in what 2 patients?
and benefits compared to others (2)
```
tremor
insomnia
anxiety
aggravation of psychosis
higher seizure risk
```
(contraindicated in eating disorder patients and those with seizure disorder)
No sexual side effects, weight neutral
172
Trazodone and nefazodone
mechanism of action
side effects (1)
most potent action is blockade of postsynaptic 5HT2, but also blocks 5HT and NE reuptake
Side effects: drowsiness (used as hypnotic agent), only minor problems with OD
173
Tricyclics
mechanism of action
block reuptake of 5HT and NE, as well as H1, muscarinic cholinergic receptors and a1
better for chronic pain of neuropathic origin
174
Tricyclics
side effects (7)
1) sedation
2) antimuscarinic effects (blurred vision, constipation, dry mouth, urinary hesitance)
3) orthostatic hypotension (a1 block)
4) EKG abnormalities and arrhythmias→ sudden death in OD
5) weight gain
6) sexual side effects
7) dangerous in OD (10 days can be lethal)
“Dirty drugs”
175
MAOIs
mechanism
SSRIs + MAOIs → ?
irreversible inhibition of MAO-A and MAO-B, increasing 5HT and NE
SSRIs + MAOIs → serotonin syndrome
-Hyperthermia, muscle rigidity, myoclonus
176
MAOIs
side effects (9)
```
hypotension
orthostasis
dry mouth
constipation
urinary retention
sexual side effects
weight gain
```
**hypertensive crisis (tyramine reaction (beer, wine cheese) due to acute increase in NE release)
seizures, shock hyperthermia in OD
177
Vilazodone
mechanism of action
new antidepressant, SSRI + 5HT1A partial agonist
178
Timeline of response to antidepressants
why?
All current treatments have a 4-16 week delay before achieving antidepressant effect - why?
Alteration of NTs in short term lead to downstream changes - may alter expression of BDNF → increase neuronal growth (specifically hippocampal volume)
179
What would the ideal drug do for treatment of bipolar disorder
ideally want drug that would be anti-manic, anti-depressive, and prevent future episodes - few drugs truly work in all 3 phases
180
3 anti-manic drugs
lithium, divalproex, carbamazepine
181
Lithium
best studied and proven drug
- Effective antimanic, reasonable preventative agent, some antidepressant effect
- Prevention of future episodes
- Antisuicidal properties
- Neuroregenerative effects
182
Lithium side effects
tremor, nausea, diarrhea, metallic taste, thirst, cognitive dulling
Blunted thoughts, confusion, weight gain, diminished sex drive
- Narrow therapeutic window
- Toxic/lethal in overdose
**Renal effects → anti-ADH action → polyuria-polydipsia
**Hypothyroidism
183
Divalproex
good for mania
Rapid loading, safe and effective
Weight gain, sedation
Not effective for bipolar depression
184
Best treatment for bipolar depression
Quetiapine, Lurasidone, lithium possibly lamotrigine are best treatments thus far
- Very difficult to treat
- Antidepressants can make bipolar depression worse
185
Best drugs to prevent bipolar mania and depression (maintain steady state) (4)
Lithium, aripiprazole, olanzapine, lamotrigine
186
Diagnostic criteria for personality disorder
| really long card, just read it
- Enduring pattern of inner experience and behavior that deviates markedly from expectations of individuals culture. In at least 2 areas:
1) Cognition: ways of perceiving and interpreting self, other people, and events
2) Affectivity: range, intensity, lability, and appropriateness of emotional response
3) Interpersonal functioning
4) Impulse control
- inflexible and pervasive across a broad range of personal and social situations
- leads to significant distress or impairment in social, occupational, or other important areas of functioning
- Pattern is stable and of long duration (in adolescence or early adulthood)
- Not better accounted for as another mental disorder
- Not due to physiologic effects of a substance or a general medical condition
187
Cluster A personality disorders include (3)
"Weird"
1) Paranoid
2) Schizoid
3) Schizotypal
188
Paranoid personality disorder
Cluster A
distrustful, suspicious
Vigilant, “The Survivor”
189
Schizoid personality disorder
Cluster A
interpersonal detachment
Solitary, “The Loner”
Diagnostic criteria:
Restricted range of expression of emotions, pervasive pattern of detachment from social relationships
190
Schizotypal personality disorder
Cluster A
odd thoughts and behavior, interpersonal awkwardness
Idiosyncratic, “The Different Drummer”
Acute discomfort with and reduced capacity for close relationships as well as by cognitive or perceptual distortions and eccentricities of behavior
191
Antisocial personality disorder
cluster B
disregard and violation of others rights
Adventurous, “The Challenger”
Pervasive pattern of disregard/violation of rights of others
192
Borderline personality disorder
cluster B
instability of relationships, self image, effects
Mercurial, “Fire and Ice”
Often due to childhood abuse, problems with mentalizing
Similar to bipolar disorder and PTSD
Pervasive pattern of instability of interpersonal relationships, self-image, and affects, and marked impulsivity
193
Histrionic personality disorder
cluster B
emotionality and attention seeking
Dramatic, “Life of the Party”
194
Narcissistic personality disorder
cluster B
grandiosity and lack of empathy
Self-Confident, “Star Quality”
195
cluster B personality disorders (4)
```
"Wild"
1) Antisocial
2) Borderline
3 Histrionic
4) Narcissistic
```
196
Cluster C personality disorders (3)
"Worried"
1) Avoidant
2) Dependent
3) Obsessive-Compulsive:
197
Avoidant personality disorder
Cluster C
worries of inadequacy and being judged negatively
Sensitive, “The homebody”
198
Dependent
Cluster C
need to be taken care of
Devoted, “The Good Mate”
199
Obsessive-Compulsive:
Cluster C
orderliness, perfection, need to be in control
Conscientious, “The Right Stuff”
200
Axis II disorder refers to which class of disorders
personality disorder and intellectual disabilities
No longer use “Axes” in DSM 5
201
Sedative - Hypnotic Agents
2 agents
-what mechanism? (2)
Benzos and Barbiturates
Graded dose-dependent CNS depressant effects
Augment GABA inhibition and/or inhibit glutamate excitation
202
sedative drugs vs. hypnotic drugs
Sedative drugs → decrease activity, moderate excitement, and calm recipient
Hypnotic drugs → produce drowsiness, facilitate onset + maintenance of sleep
-Resembles natural sleep and from which recipient can be easily aroused
203
GABA receptor-Cl- Ion Channel
Cl- into cell → membrane hyperpolarization → decreased CNS neuronal excitability
- Benzos bind alpha/gamma subunit in presence of GABA
- Barbiturates can directly interact with GABA receptor
204
Benzodiazepines mechanism
bind alpha or gamma subunit → facilitate channel opening, but do NOT directly initiate chloride current
INTENSIFY GABA → enhance channel opening ONLY in presence of GABA
No effect on excitatory NTs → CANNOT induce/maintain surgical anesthesia
205
A1 subunit of GABA receptor-Cl- Ion channel
Expressed where? (1)
responsible for what effects of benzos (3)
highly expressed in cortex
Sedative (sleep), amnestic, and anticonvulsant actions of benzos
206
A2/A5 subunit of GABA receptor-Cl- Ion channel
expressed where? (2)
responsible for what effects of benzos (4)
→ highly expressed in limbic system/brain stem
Myorelaxant, motor impairing, anxiolytic, and ethanol-potentiating effects of benzos
207
Barbiturates mechanism of action
PROLONG GABA effect
- At high concentrations can interact directly with GABA receptor (presence of GABA not required for effect)
- Also depresses glutamate (excitatory NT)
→ greater CNS depression and full surgical anesthesia can be obtained
→ Lower safety margin
208
Z drugs mechanism of action
interact with benzodiazepine binding site as agonists on GABA receptor (Cl- channel)
bind only to A1 subunit of GABA channel
→ enhance channel opening ONLY in presence of GABA
209
Flumazenil
antagonist of benzo binding site, reverses CNS effect of benzos
NOT effective in barbiturate or ethanol toxicity
210
Uses of benzodiazepines (3)
1) Sleep
2) Anxiolysis
3) Adjuncts for anesthesia (for anxiolytic and amnesia properties)
*Declining use due to abuse potential - used in acute and situational anxiety
Much greater dosage increments required to achieve CNS depression - greater margin of safety than with barbiturates
211
Side effects of benzodiazepines (6)
1) Additive effects with other drugs can cause CNS depression (alcohol, opioid analgesics)
2) Anterograde amnesia - impaired ability to learn new information while retrieval of previously information is intact
3) Sedation and performance impairment
4) Strange sleep-related behavior
5) Severe allergic reactions
6) Psychologic and physiologic dependence
212
How can you reduce risk of benzo psychological/physiological dependence?
How can you increase risk?
Schedule IV controlled substance
Reduce risk with: lowest effective dose, intermittent basis, shortest duration possible
Increased risk if: high dose, regular use, prior abuse history
213
Distribution of benzos
very lipid soluble, enter CNS
214
Metabolism/Excretion of benzos
CYP450 oxidation (phase I) and conjugation by glucuronidation (phase II) → elimination in urine
Many phase I metabolites are active → unwanted CNS effects, daytime sedation, etc.
215
Z drugs use
bind only to A1 subunit of GABA channel
Use: sleep WITHOUT anxiolysis
Reduced potential for dependence
216
Treatment of Generalized Anxiety Disorder
SSRIs, SNRIs
BDZs (acute and situational anxiety)
Can also use buspirone (weaker anxiolytic, time to onset longer)
NOT NDRIs
217
Treatment of Panic disorder
SSRIs
Acutely: high potency BDZs
Can also use BDZs, TCADs, MAOIs for chronic treatment
218
Treatment of Social Anxiety Disorder
performance vs. generalized
Generalized: SSRIs, SNRIs
Performance: B-blockers (propranolol), high potency BDZs
219
Treatment of Obsessive-Compulsive Disorder
CBT most effective
| Also: SSRIs, SNRIs, atypical antipsychotics
220
Treatment of PTSD
CBT = pharmacotherapy (SSRIs, SNRIs)
221
Drug list: Benzodiazepines (4)
1) Diazepam
2) Alprazolam
3) Lorazepam
4) Oxazepam
222
Diazepam
Benzodiazepines
used to treat status epilepticus
Rapid oral absorption, poor IM bioavailability
223
Alprazolam
Benzodiazepines
Rapid oral absorption
Acute management of anxiety, high potency
224
Lorazepam
Benzodiazepines
Reliable IM absorption
Metabolized directly to inactive glucuronides (NO P450 step) → shorter half life, less cumulative effects → USE IN ELDERLY with impaired phase I metabolic pathways and patients with hepatic dysfunction
225
Oxazepam
Benzodiazepines
Slow oral absorption
Metabolized directly to inactive glucuronides (NO P450 step) → shorter half life, less cumulative effects → USE IN ELDERLY with impaired phase I metabolic pathways and patients with hepatic dysfunction
“OLD LIVERS” (use in elderly)
226
Barbiturates uses (2)
Anticonvulsants - inhibit formation and spread of seizure activity in cortical neurons
Anesthesia
227
Barbiturates Side Effects:
1) Can cause medullary depression (respiratory and vasomotor centers) and coma/death
2) High abuse potential
3) Inducers of CYP450!
228
Pentobarbital and Phenobarbital
Barbiturates
stop seizures at doses that do not cause severe sedation or effects on mental/motor activity
229
Thiopental
(short acting barbiturates) → induce and maintain surgical anesthesia
230
Buspirone
mechanism and uses
5HT1A partial agonist
Use:
1) Weaker anxiolytic effect than benzodiazepines, but fewer side effects
2) No sedation, anticonvulsant, or myorelaxant action
*Requires 2 weeks for onset of anxiolytic effect, 4-6 weeks for max efficacy
231
Opioids
Reinforcing effects/CNS action
interact with endogenous opioid receptors (mu)
Euphoria, sedation, anxiolytic
232
Opioids
Acute toxicities (3)
Respiratory depression, pinpoint pupils, coma
233
Opioids
Acute toxicities treatment
cardiopulmonary status
Naloxone (Narcan) = opiate antagonist, short acting, requires repeated doses
234
Opioids
Risk for tolerance
Develops rapidly - does not develop evenly in all organ systems affected
Most rapid tolerance for: euphoria, respiratory depression, analgesia, sedation, and vomiting
Little tolerance to: constipation and pupil constriction
235
Opioids
Dependence
develops rapidly, can be present after 1-2 weeks of use
236
Opioids
Withdrawal
bothersome, but NOT medically dangerous
| Restlessness, fever, chills, joint/muscle pain, vomiting, diarrhea, tachycardia, hypertension
237
Protracted Withdrawal Syndrome
anxiety, insomnia, drug craving can persist for up to 6 months
238
Opioids
Withdrawal treatment (3 drugs)
Clonidine → alleviate SNS overactivity symptoms (nausea, vomiting, cramps, sweating tachycardia, increased BP) in acute withdrawal
Methadone → substitute opioid
Buprenorphine → partial mu agonist
239
Opioids major drugs
heroin, morphine, oxycodone, methadone, fentanyl, hydrocodone, codeine, loperamide (anti-diarrheal)
240
CNS Stimulants
Major drug classes
amphetamine, methamphetamine, cocaine
MDMA (hallucinogen + CNS depressant)
241
CNS Stimulants
actions in CNS (meth vs. cocaine)
interact with catecholamine NTs (dopamine) → cause release or block reuptake of catecholamines
Cocaine: DAT inhibitor, blocks DA uptake
Methamphetamine: DAT reverses transporter, increase DA release
242
CNS Stimulants
Effects leading to abuse
elevation of mood, exhilaration, increased energy, alertness, decreased appetite
243
CNS Stimulants
Acute Toxicity
SNS overactivity (rapid pulse, increased BP, elevated body temp, sweating, increased motor activity, fatal arrhythmias, chest pain → MI)
Vasoconstriction of fetal blood supply in pregnant women
244
CNS Stimulants
Acute Toxicity Treatment
cardiopulmonary support, gastric lavage, control elevated body temp
Seizures → diazepam
Phentolamine → BP control
DO NOT USE B-BLOCKERS (unopposed alpha stimulation)
BDZs: help calm patient down, decrease HR and BP
245
CNS Stimulants
Tolerance
yes, to anorexia, euphoria, hyperthermia
Supersensitivity may develop to movement and psychotomimetic / paranoia effects
246
CNS Stimulants
Dependence
strong psychological dependence, lack of physiological effects
247
CNS Stimulants
Withdrawal
prolonged sleep, fatigue, depression → intense craving and drug seeking over 1-10 weeks
248
CNS Stimulants
Withdrawal treatment
behavioral
TCADs and bupropion: relieve depression and reduce craving
249
CNS depressants
Major drug classes
alcohol, benzodiazepines, barbiturates
250
CNS depressants
Effects leading to abuse
euphoria, sedation, loss in inhibition
251
CNS depressants
Acute Toxicity
Respiratory depression, coma (Extremely rare with BDZs)
252
CNS depressants
Acute Toxicity Treatment
Ethanol
BDZs
Barbs
Ethanol: supportive, plus fluids-electrolytes-thiamine**
Benzodiazepines: flumazenil
Barbiturates: supportive
253
CNS depressants
Tolerance
develops rapidly to barbiturates, moderately rapid to ethanol, and less with BDZs
254
CNS depressants
Physical Dependence
appears within weeks
255
CNS depressants
Withdrawal
significant risk of mortality due to seizures (grand mal), fever, delirium (including psychosis)
256
CNS depressants
Withdrawal treatment
Treatment: substitute with BDZs → loading dose, then taper to prevent seizures
257
Nicotine Action in CNS and effects leading to abuse
nicotinic neuronal receptor agonist (N-N)
increased alertness
258
Nicotine Acute Toxicity
nausea, vomiting, abdominal pain, salivation, diarrhea, headache, dizziness, hypotension, difficulty breathing, weak, irregular pulse, terminal convulsions, death by respiratory failure
259
Nicotine Acute Toxicity Treatment
Treatment: gastric lavage, induction of vomiting, activated charcoal
260
Nicotine tolerance?
yes (nausea, first morning rush is the best)
261
Nicotine Physical Dependence?
moderate development of dependence
262
Nicotine Withdrawal
irritability, impatience, hostility, depressed mood, difficulty concentrating, restlessness, increased appetite, weight gain
263
Hallucinogens
Major drug classes
Indoleamines (serotonin-like): LSD, DMT, mushrooms (psilocybin)
Phenylethylamines (amphetamine-like): Mescaline, MDMA, MDA, DMA
264
Hallucinogens Action in CNS
agonist at 5HT2 postsynaptic serotonin receptors
Phenylethylamines also induce dopamine release with effects on DA receptors
MDMA: SERT reverse transporter → 5HT release
265
Hallucinogens
Effects leading to abuse
altered sensory perception, enhanced insight
266
Hallucinogens
Acute Toxicity
panic reaction, anxiety with hallucinations, paranoia, confusion
At very high doses: temperature >103F, cardiovascular collapse, convulsions, rhabdomyolysis, kidney failure
267
Hallucinogens
Acute Toxicity Treatment
stabilize cardiopulmonary function, treat convulsions and hyperthermia
Benzodiazepines and “talking down”
Antipsychotic agents
268
Hallucinogens Tolerance?
not commonly seen since frequent/repeated use unusual
269
Hallucinogens Physical Dependence?
does not develop
270
Hallucinogens Withdrawal?
no clinically significant withdrawal known
271
Marijuana
Action in CNS
CB1 agonist in CNS
272
Marijuana
Effects leading to abuse
euphoria, “mellowness”, changes in perception
273
Marijuana
Acute Toxicity
tremors, decreased muscle strength, balance, and motor coordination, increased reaction time, increase HR, seizures in epileptics, temporary delirium, paranoia with anxiety or confusion
274
Marijuana
Acute Toxicity Treatment
general support and reassurance
275
Marijuana Tolerance?
develops rapidly to most effects (feelings of intoxication)
Disappears rapidly
276
Marijuana Physical Dependence?
high potential - behaviors of preoccupation, compulsion, reinforcement, and withdrawal after chronic use
277
Marijuana Withdrawal?
not common, probably due to long half life of cannabinoids
278
Dissociative Anesthetics
Major Drugs
Phencyclidine, Ketamine
279
Dissociative Anesthetics
Actions in CNS
NMDA receptor antagonist
280
Dissociative Anesthetics
Effects leading to abuse
euphoria, heightened emotionality
281
Dissociative Anesthetics
Acute Toxicity
Delirium, increased respirations, HTN, tachycardia, hyperpyrexia, muscle rigidity, increased deep tendon reflexes, stereotypies, blank stare → stuporous, then comatose, seizures common → death from respiratory or cardiac complications
TRAUMA leading cause of PCP mortality
282
Dissociative Anesthetics tolerance, dependence, and withdrawal?
none
283
Ethanol absorption
rapid throughout entire GI tract - more rapid in SI (surface area)
Presence of food slows absorption
284
Ethanol distribution
water soluble, distributed in total body water → brain, liver, kidney, lung, less alcohol distribution into fat
Placenta is permeable to ethanol
Women have higher BAC
Initial CNS within 5 min
Peak effect within 15-60
285
Ethanol metabolism
2-10% expired unchanged in air and urine
1st pass metabolism: gastric mucosa
90-98% in Liver
Metabolism occurs at constant rate (zero order kinetics): 7-10 grams of alcohol per hour
Max rate = 220g/day
286
Ethanol metabolism and the liver (2 enzymes)
90-98% in Liver: ethanol → acetaldehyde → acetic acid
Alcohol dehydrogenase (ADH): in liver cytosol and mitochondria
CYP2E1: ethanol metabolism at higher BAC
287
5 metabolic derangements with alcohol metabolism and their effects?
1) Increased blood lactate → acidosis, behavioral disturbances
2) Increased Mg2+ excretion → convulsions
3) Decreased uric acid excretion → gout attacks
4) Increased acetyl-CoA → increased fatty acid synthesis, decreased fat break down → fatty liver
5) Increased NADH → decreased Krebs cycle activity, decreased gluconeogenesis → hypoglycemia
288
Alcohol mechanism of action
inhibits glutamate binding to NMDA receptor
289
Antabuse (disulfiram)
Inhibits aldehyde dehydrogenase → 5-10 fold increase in acetaldehyde → nausea, vomiting, respiratory and CVD collapse, convulsions
Disulfiram-like symptoms with metronidazole
290
Effects of ethanol on: CNS (4)
1) Sedative-Hypnotic: CNS depressant effect (similar to barbiturates)
- Increase GABA + decrease glutamate
- Anxiolysis
2) Anticonvulsant: BUT hyperexcitability upon withdrawal
- May precipitate convulsions
3) Analgesic effects, sleep effects
4) Emetic effect → stimulate CTZ → induce vomiting
291
Effects of ethanol on: Liver
damage due to increased NADH + direct toxicity
**Fatty liver
**Alcoholic hepatitis → jaundice, ascites, vomiting, anorexia
Alcoholic cirrhosis → jaundice, portal HTN, esophageal varices
292
Effects of ethanol on: Kidney
diuresis (decreased ADH secretion, increased fluid intake)
293
Effects of ethanol on: GI tract
Esophagitis, ulcers, gastritis (due to inflammatory effect of alcohol) → epigastric pain, vomiting, hematemesis
**Pancreatitis (due to secretory effect of alcohol) → weight loss, blood loss, abdominal pain, shock
294
Effects of ethanol on: Cardiovascular
Vasodilation, heart disease, HTN
Can be CARDIOPROTECTIVE due to decreased platelet aggregation and increased HDL levels
295
Effects of ethanol on: Fetus
Fetal Alcohol Syndrome
Prenatal or postnatal growth retardation and altered morphogenesis (especially facial dysmorphology)
Small head, epicanthal folds, low nasal bridge, small eye openings, short nose, thin upper lip, flat midface, smooth philtrum, underdeveloped jaw
296
Ethanol: tolerance and withdrawal
Tolerance: moderate level of tolerance occurs
-Cross tolerance with other CNS depressants
Withdrawal: can be life threatening: anxiety, insomnia, tremor, seizures, visual hallucinations, delirium tremens
297
Treatment of alcohol withdrawal (2)
BZDS: action at GABA receptors prevents emergence of CNS hyperexcitability following withdrawal of alcohol
Clonidine: effective for signs of autonomic hyperactivity
298
Drug-Drug Interactions with Alcohol:
Additive effects with all ______________
Cross tolerance to ____________ and _______________
Can promote GI bleeding if taken with ___________
Increase risk of hepatotoxicity with ______________
Additive effects with all CNS depressants (acute)
Cross tolerance to sedative-hypnotic drugs and general anesthetics
Can promote GI bleeding if taken with aspirin
Increase risk of hepatotoxicity with acetaminophen
299
Acute alcohol intoxication:
| Treatment
support respiration, administer IV fluids (glucose, thiamine, and electrolytes (K+, Mg2+))
No specific antidote available
300
Substance abuse disorder
Physical dependence (tolerance and withdrawal), craving, diminished capacity to control one’s substance use (use becomes priority)
301
Characteristics of a substance abuse disorder: 6
1. Substance is taken in larger amounts or over a longer period than was intended
2. Persistent desire or unsuccessful efforts to cut down or control substance use
3. Lots of time spent in activities necessary to obtain or use substances or recover from its effects
4. Craving, strong desire, urge to use substance
5. Continued use despite persistent or recurrent social or interpersonal problems caused/exacerbated by effects of substance
6. Substance use despite knowledge of problem with substance
302
Definition of tolerance (2)
1. Need for markedly increased amounts for intoxication/desired effect
2. Markedly diminished effect with continued use of same amount of substance
303
Withdrawal
experiencing characteristic withdrawal syndrome or substance is used to relieve or avoid withdrawal symptoms
304
Biological mechanisms of substance use disorder (2)
1. Genetic component:
- 1st degree relative with substance use problem increases risk of substance use
- Twin and adoption studies
2. Neurobiology: all substances of abuse increase dopamine release in nucleus accumbens
- Motivational systems and reward (VTA → nucleus accumbens)
- Frontal regions involved in learning, cognitive control or inhibition (PFC)
- Regions involved in mood and stress reactivity
305
Screening for substance abuse disorders: At risk
increased risk for future abuse
Men: >5 drinks/day or 14/week
Women: >4/day or >7/week
→ Brief intervention
306
Screening for substance abuse disorder: substance abuse disorder
→ treatment, referral, possible medication
307
Symptoms of alcohol withdrawal (3) and treatment
1. Alcohol = CNS depressant, withdrawal will be opposite
2. Tachycardia, diaphoresis, tremulousness
3. Potentially life threatening (delirium tremens)
TX: long acting benzodiazepine taper
308
Symptoms of opioid withdrawal and treatment
- Intoxication: drowsiness to coma, slurred speech, impaired attention or memory
- Muscle aches, nausea, lacrimation, rhinorrhea, pupillary dilation, piloerection, diarrhea - Not life threatening
TX: supportive medication, clonidine, methadone/buprenorphine
309
3 treatments of alcohol abuse disorders
1. Antabuse (Disulfiram)
2. Revia and vivitrol (Naltrexone)
3. Campral (acamprosate)
310
Antabuse
Inhibits acetaldehyde dehydrogenase
Alcohol → (ADH, alcohol dehydrogenase)→ Acetaldehyde → (ALDH) → Acetic acid
Antabuse blocks ALDH (aldehyde dehydrogenase)
→ antabuse reaction: flushing, headache, nausea, dizziness, tachycardia
* *DO NOT start unless patient does not have alcohol in system
* *DO NOT use if pregnant
311
Revia and vivitrol
opioid antagonist
| Blocks euphoria from alcohol, and cravings for alcohol
312
Campral (acamprosate)
GABA/glutamate effects?
Reduces CNS hyperexcitability
DO NOT use in pregnancy
313
3 treatments of opioid use disorders
1. methadone
2. bupreneorphine
3. naltrexone
314
Methadone
long acting opiod agonist
315
Buprenorphine
partial opioid agonist
- Can precipitate withdrawal
Retention in treatment and reduction in opioid use
-Office-based
- Buprenorphine + Naloxone → prevents injection of buprenorphine
316
Naltrexone in treatment of opioid disorders
- can precipitate withdrawal
- Blocks effects of heroin
- Poor retention
317
3 treatments of nicotine use disorders
1. Nicotine replacement therapy
2. Bupropion (Wellbutrin/Zyban)
3. Chantix (varenicline)
318
Side effects of nicotine replacement therapy
rash, tachycardia
319
Bupropion
nicotinic receptor antagonist? Dopamine reuptake inhibitor
| - Doubles quit rates
320
Chantix (varenicline)
- partial a4B2 agonist, conflicting reports of depression and suicidal ideation
- Worries about mood changes, suicidality, small increase in CV events
321
Principles of motivational interviewing
aims to facilitate and enhance a person’s intrinsic motivation to change addictive behavior in a highly empathetically supportive but strategically directed conversation about the person’s use of substances and related life events
322
OARS in motivational interviewing
Open ended questions
Affirmations
Reflective listening
Summarizing
323
Techniques used in motivational interviewing (4, aside from OARS)
Express empathy
Roll with resistance
Develop discrepancies
Support self-efficacy
324
Contingency management
Detection + Reinforcers provided with behavior + Reinforcers are withheld when behavior does not occur
325
7 principles of contingency management
1. Utilize a behavior that can be reliable detected (e.g. refraining from drug use and determined by urine drug screens)
2. Develop a behavioral plan where reinforcers are provided with behavior
3. Develop a behavioral plan, where reinforcers are withheld when behavior does not occur
4. Identify and utilize reinforcers, which are motivating for this patient
5. Positive reinforcers may change behavior more than punishment
6. The more quickly that reinforcers can be paired with the behavior, the more likely behavior is to change
7. Fish bowl method can reduce costs
326
Aripiprazole
atypical antipsychotic
- low D2/5HT2A ratio
- partial agonist of D2 receptor
327
Quetiapine
atypical antipsychotic
most sedative potential, used questionably as a hypnotic agent in certain clinical settings
328
Benefits of using atypical antipsychotics? (3)
1) Preferred for patients with negative symptoms and cognition deficits
2) Decreased risk of EPSE symptoms
3) Selective effect on mesolimbic vs. nigrostriatal dopamine neurons
- -> Little hyperprolactinemia
329
Extrapyramidal side effects of antipsychotics can each be treated with what?
1) Acute dystonia (swollen tongue, tinnitus, trismus)
- -> TX: anticholinergic
2) Akathisia: motor restlessness, inability to sit still
- -> TX: B-blocker, benzo, anticholinergic
3) Pseudo Parkinsonism: tremor, bradykinesia, rigidity, shuffling gait
- -> TX: anticholinergic agents
4) Tardive dyskinesia: involuntary repetitive movement of lips, tongue
Possibly due to D2 receptor supersensitivity
--> TX: none effective
330
Neuroleptic malignant syndrome
side effect of antipsychotics
(medical emergency, treat immediately)
Similar to malignant hyperthermia
TX: dantrolene sodium
331
NADH and alcohol metabolism
Ethanol metabolism generates NADH that promotes production of lactate from pyruvate → lactic acidosis
