CF-501: Biological Perspectives

Exam Two Study Guide

Week Five

 Take Home Points

o Acute pain is from tissue damage and carried by pain nerves. Chronic pain is at least 3 months in
duration and can be related to either cancerous or non-cancerous causes
o 25% of US population had moderate to severe pain
o Nociceptive pain is carried by special pain nerves to spinal cord, thalamus, limbic and cortical area of
the brain
o Important to assess for SUDs and MH issues as part of pain evaluation
o SNRIs, TCAs, and gabapentin can be used for chronic nerve (neuropathic) pain
o Opioids are very useful for acute pain, but often less useful for chronic, non-cancerous pain
 Can actually increase pain perception
 Leads to physical dependence
 Can result in addiction
 Can result in overdose
o Methadone is particularly risky for overdoses
o Primary reward pathway: VTA, Nucleus Accumbens, Prefrontal cortex
o Physiological Dependence to opioids involves: Thalamus and Brainstem
 Know the definitions of nociceptive and neuropathic pain.
o Nociceptive pain
 Pain from stimulation of nociceptos (the nerves that transmit pain signals)
 Pain from touch
o Neuropathic pain
 Pain that results from a lesion, damage or dysfunction in the sensory system
 Pain from nerve
 Understand what hyperalgesia means.
o Opioid induced hyperalgesia—
 increased sensitivity to pain due to
chronic opioid use
 paradoxical increase in pain sensitization
while on opioid therapy
 higher starting dose—increased
hyperalgesia
 tapering opioids—decreases hyperalgesia
o Increased sensitivity to pain, which may be caused
by damage to nociceptors or peripheral nerves and can cause hypersensitivity to stimulus, stimuli which
would not normally cause pain
 Know the different parts of the brain that are involved in the physiologic
dependence of opioids vs. addiction.
o Addiction
 VTA, Nucleus, Accumbens, Prefrontal cortex
o Physiological Dependence
 Thalamus, brainstem
 Know what medications can be used to treat neuropathic pain.
o Tricyclic antidepressants
 Amitriptyline,
 Nortriptyline
o Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
 Duloxetine
 Milnacipran
o Anticonvulsants
 Gabapentin
 Carbamazepine
 Pregabalin
 Understand that opioids are helpful for brief, acute pain and chronic pain related to cancer.
 Understand that the use of opioids for chornic, non-malignant (non-cancer) pain has the risk of physiologic
dependence, addiction, and hyperalgesia.
Week Six

 Know the neurotransmitters involved in anxiety disorders.

o Anxiety
 State of excessive arousal
 Activation of flight or fight mechanism
 Neurotic syndrome
 Common baseline state for many pathologic processes
o Neurotransmitters
 Increased levels of noradrenaline
 Decreased levels of GABA and serotonin
 Dopamine dysfunction in PTSD
 Know that all the drugs of abuse can cause substance-induced anxiety
o Anxiety symptoms are time related to acute intoxication or withdrawal from a mood-altering substance
o Can mimic any of the major depressive disorders
o Cause considerable distress and significantly complicates the treatment of addiction
o Drugs that cause anxiety
 Stimulants
 Amphetamines diet pills, caffeine
 Cannabinoids
 Both in acute intoxication and withdrawal
 Withdrawal from sedative hypnotics and alcohol
 Withdrawal from opioids
 Asthma medications
 Do NOT spend time memorizing all the DSM 5 criteria for anxiety or psychotic disorders
o Panic disorder
 Panic attacks
 Unexpected
 Expected
 Limited symptom attacks
 Agoraphobia
o Anxiety about being in places or situations from which escape might be difficult
o In which help may not be available in the event of panic symptoms
o The situations are avoided or are endured with marked distress or with anxiety
about having a panic attack
o Disturbance is not due to the direct effects of a substance or general medical
condition
 Patients with panic disorder are 18x more likely to make suicide attempts
 Etiology
 Abnormal noradrenergic activity (too much sympathetic function)
 Increased locus of coeruleus activity (flight or fight)
 Serotonergic dysfunction (modulates all other systems in the brain)
 Gaba-ergic dysfunction (too little inhibitory neurons, decreased frontal lobe activity)
o Less of the receptors in the brain v) Suffocation alarm (is it life threatening?)
 Catastrophic interpretation
 Specific Phobia
  Marked and persistent fear that is excessive and unreasonable, cued by the presence or
anticipation of a specific object or situation
o Arachnophobia
 Etiology
o Learning theory
 Exposure
 Stimulus generalization
o Functional imaging studies
 With anxiety there is increased blood flow in the lateral orbital cortex,
anterior insular cortex and cerebellum
 With treatment these abnormalities diminish, and you can see
increased blood flow in the posterior orbital cortex
 Social Anxiety Disorder
 Marked or persistent fear of one or more social or performance situations involving
exposure to unfamiliar people or scrutiny by others, fears of humiliation or
embarrassment
 In co-occurring this is increased with SUD
 Use substances as a social lubricant (Alcohol)
 Etiology
o Noradrenergic dysfunction
o Serotoninergeneric dysfunction
o Gaba-ergic dysfunction
o Learning theory
 Obsessive-Compulsive Disorder
 No longer considered an anxiety disorder
 Egocentonic
o Suicidal ideation
 Egodysonic
o I don’t want to kill myself, but its in my head, intrusive thoughts
 Obsessions
o Recurrent and persistent thoughts, images
 Compulsions
o Repetitive behaviors or mental acts
o Anxiety is secondary symptom
 Etiology
o Serotonergic dysfunction
o Dopaminergic dysfunction
o Cerebral cortical hyperfrontatlity
o Mid brain frontal cortex connection dysfunction
 Disconnect between caudate nucleus and frontal cortex
o Streptococcal infection sequalae
 PTSD
 Exposure to traumatic event
o Etiology
 Disruption of attachment
 ACEs and traumatic event
  Much more likely to be diagnosed with PTSD
o Serotonergic dysfunction
o Dopaminergic dysfunction
o Noradrenergic dysfunction
o Gaba-nergic dysfunction
o CRF dysfunction
 Generalized Anxiety Disorder
 Excessive anxiety and worry occurring more days than not for at least 6 months about a
number of events or activities
 Symptoms impair daily functioning
 Understand that benzodiazepines can be very helpful for acute anxiety, but do have abuse potential
o Benzodiazepines
 Rapidly effective
 Highly efficacious
 Globally effective
 Should be used for short term treatment of anxiety, less than 6 months
 Dependence and tolerance can develop
 Abuse potential
 Withdrawal potential
 Know the mechanism of action of the benzodiazepines
o Enhance the opening of the chloride ion channel
o Enhance the effect of the neurotransmitter gamma-
aminobutyric acid (GABA) at the GABA receptor,
resulting in sedative, hypnotic (sleep-inducing),
anxiolytic (anti-anxiety), anticonvulsant, and muscle
relaxant properties
o Half life of Benzio
 Xanax
 8 to 16 hours
 Librium
 More than 24 hours
 Valium
 More than 24 hours
 Know what other medications can be used for anxiety (SSRI, SNRI, TCA, MAO-I)
o SSRI (Selective Serotonin Reuptake Inhibitor)
 Helps to regulate
 Prozac
 Zoloft
 Advantages
 Medication of choice for depression and anxiety
 Broad wide scale use
 Fewer side effects
 Established efficacy for anxiety
 Safer in overdose
 Generally compatible with other medications
 Disadvantages
  Initial side-effects/intolerability
 Persistent sexual dysfunction
 Often under dosed in anxiety
 Some significant
 SNRI (Serotonin-norepinephrine reuptake inhibitors)
 Effexor
 Cymbalta
 Pristiq
 Fetzima
o Inhibit serotonin and norepinephrine reuptake site, possible dopamine with
high does venlafaxine (effexor)
o Possibly less sexual dysfunction, but may elevate blood pressure
o Wide dose range and effective for anxiety and depression
 TCAs (Tricyclic antidepressants)
 Tofranil
 Elavil
 Norpramin
 Pamelor
 Now reserved to treat-refractory anxiety disorders
 MAO-Is
 Nardil
 Pamate
 Eldepryl
o i. Mostly used for treatment-refractory panic disorder and social phobia
 Know the mechanism of action of Buspar (buspirone)
o Buspirone- Buspar
 FDA approved for GAD
 Can also be used to augment an SSRI for OCD or
depression
 Works as a Serotonin partial agonist
 If there are elevated levels of serotonin,
buspirone will act as a weak antagonist, if
there are decreased levels of serotonin,
buspirone will act as a weak agonist
 The 5HT receptor slows down neuronal
activity and will decrease serotonin release
 Know the difference between the Positive and Negative symptoms of schizophrenia
o Positive symptoms
 Hallucinations, delusions, agitation, behaviors
o Negative symptoms
 Anhedonia (decreased feelings of pleasure) apathy, (loss of interest), blunted affect, poverty of
thought, emptiness, amotivational
o Cognitive symptoms
  Neurocognitive deficits in working memory, attention and in executive functioning, such as the
ability to organize and abstract, also difficulty understanding interpersonal causes and social
relationships
o Mood symptoms
 Patients often seem cheerful or sad I na way that is difficult to understand, they often are
depressed
o Schizophrenia- etiology
 Genetic: based upon family and twin studies
 Environmental: toxins, viral, inter-uterine
 Developmental: abnormal synaptic pruning, neurodegenerative disorder, smaller hippocampus
 Neurochemical
 Dopaminergic theory
 Glutaminergic theory
 Serotoninergic theory
 Clear that this illness is multifactorial and no one theory explains all forms of schizophrenia (or
psychosis in general)
 Also know what neurotransmitters and what regions of the brain are responsible for the Positive and
Negative symptoms
o Dopamine
 Too much dopamine in mid limbic = more positive symptoms
 Too little dopamine in frontal cortex = more negative symptoms
 There are also striatal dopamine pathways and blockade of this system cause the movement
side effects
o Glutamate and Serotonin
 Decreased glutamate (excitatory neurotransmitter) activity can lead to symptoms of psychosis
 Serotonin modulates most other neurotransmitters
 Activating serotonin2 receptors can increase dopamine release
 Newer antipsychotics will block the serotonin2 receptor resulting in increased DA
activity in the mesocortical and striatal systems
 Again, do NOT memorize all the DSM 5 criteria for the psychotic disorders
 Be able to describe the mechanism of action for the older (typical) antipsychotics and whether they help
positive or negative symptoms
o The first-generation antipsychotics
 Typical neuroleptics
 Most were very potent DA d2 receptor antagonists
 Lead to the DA hypothesis: only effect the positive symptoms
 Often have significant side effects
 Extrapyramidal (tremors, slurred speech), akathisia (movement disorder, restlessness),
anticholinergic, antiadrenergic, tardive dyskinesia (stiff jerky movements to face or
body), acute cardiac death
 Chlorpromazine
o First used for postoperative patients, calm agitated patients
 Be able to describe the mechanism of action for the (atypical) antipsychotics and whether they help positive
or negative symptoms – and how they differ from the older medications
o DA antagonism results is decreased DA in mesolimbic pathway and reduced positive symptoms
o Serotonin antagonism results in increased DA in mesocortical pathway and reduced negative symptoms
  Clozapine
 First medication of atypicals
 Had both DA d2 receptor antagonism, but also had Serotonin receptor antagonism
 Treated both the positive and negative symptoms
 Reduced risk of EPS and tardive dyskinesia
o Side effects
 Lowers seizure threshold
 Can cause hepatitis and lead to agranulocytosis, (decreased white blood
cells)
 Causes significant weight gain, sedation, hypersalivation, dizziness
 Know the mechanism of action for Abilify (aripiprazole)
o DA receptor partial agonist, reduces positive symptoms, partial agonist binds to DA partially activates it,
decreases DA in mesolimbic pathway
o Little weight gain, but significant risk of akathisia
o Can help with bipolar disorder, anxiety, depression
 Understand whether or not the compliance with antipsychotics is good or bad
o Compliance is terrible, anywhere from 70-100% of patients with schizophrenia stop their medication
 Know that the antipsychotics can cause movement side-effects, weight gain, and heart disease
o

 Understand that schizophrenia is treatable, but that residual symptoms and impairment often persist after
treatment
o Patients do not return to their premorbid level of functioning even with medications
o Psychoeducation is critical with patient
Week Seven

 Take Home Points

o Depression and SUD’s often co-occur
o Depression is a common consequence of use/withdrawal from mood-alternativing substances
o Antidepressidents are effective and new medications are safer than older medications
 TCA and MAOIs are more toxic and MAOIs need special diet
o Most antidepressants affect the neurotransmitters serotonin, norepinephrine, and dopamine
o There is often a slight delay between the start of medications and the therapeutic effect
 Not as long a delay than was previously thought
 Side-effects usually appear earlier and then resolve
o SSRIs/SNRIs are the most commonly used antidepressants
 Know what neurotransmitter the SSRIs directly affect
o Wellbutrin has less sexual side-effects and can help ADHD
o Look carefully for Bipolar symptoms when someone has an early onset depression or depression that
responds poorly to antidepressants (also ask about family history)
o Bipolar disorder and SUDs often co-occur
o Etiology of Bipolar Disorder is multifactorial, but clearly has strong genetic and physiologic contributions
o Lithium has anti-suicidal properties and is “Gold Standard” for Bipolar I Mechanism of action completed.
o Anticonvulsants (seizure meds) are commonly used for Bipolar Disorder Mechanism of action not clear.
o Atypical antipsychotics are also very helpful in Bipolar Disorder. Patients need to watch their diet and
weight.
 Do NOT memorize the DSM 5 criteria for Bipolar and Depressive Disorders
 Understand that the Bipolar and Depressive disorders are highly genetic, but we still do not fully understand
the biological etiology for these disorders
o Bipolar disorders
 Originally referred to as Manic Depressive Disorder
 Not major depressive disorder
 Know that Bipolar I disorder used to be called Manic Depression
 Characterized by cyclical patterns of mood and behavior
 Strong genetic and physiological etiologies, but not well understood
 Understand that the Bipolar and Depressive disorders are highly genetic, but we still do
not fully understand the biological etiology for these disorders
 Bipolar and SUDs often Co-occur
 Diagnosis and the conceptualization of bipolar has been expanded over the decades
 Use of substances can mimic bipolar through chronic use creates a pattern like bipolar,
bidirectional
 Diagnosing now there is bipolar spectrum, and these are individuals who responded well
to treatment and drugs
 To male diagnosis for bipolar patient must be abstinent for at least 1 year
o Bipolar: Depression
 Must be presence of at least one episode of mania or hypomania along with recurrent episodes
of depression
 Symptoms
 Early age of onset
 Recurrent episodes, depression with agitation, irritability, and peripartum depression
  Depression is much more common than mania/hypomania
 Often responds quickly to antidepressant, but effect is either brief or manic/hypomanic
symptoms appear
o Bipolar: Mania
 Distinct period of persistently elevated, expansive, or irritable mood, and increased energy level
lasting at least one week (or any duration of hospitalized)
 Hypomania
 Symptoms are less severe than mania
 Lasts at least for four days
 Does not necessitate hospitalization
 Know that Bipolar I disorder used to be called Manic Depression
 Understand that the Bipolar disorders are treatable, but often need multiple medications and often have
residual symptoms
o Lithium with an anticonvulsant or atypical antipsychotic
o Anticonbulsant with atypical antipsychotic, or two antipsychotic
 Know that anti-seizure (anticonvulsant) medications and atypical antipsychotics are often used
for bipolar disorder
 Recognize that the use of antidepressants is controversial for bipolar depression, but they are NOT used for
bipolar mania/hypomania
o Do very little for bipolar depression
o At worst they increase cycling
 TCAs and Effexor may have higher rates of cycling
 SSRIs and Wellbutrin have lower rates of cycling
 Only Lithium shows anti-suicidal effects
o Difference between bipolar I and bipolar II
 Bipolar I
 presence of at least 1 manic episode and recurrent episodes of major depressive
 Bipolar II
 presence of at least one hypomanic episode, never manic, with recurrent episodes of
major depression
 Bipolar Etiology
 Genetic: based upon family and twin studies
 Environmental: toxins, seasonal
 Developmental: neuroanatomical and functional abnormalities, neurogenerative
disorder, white matter abnormalities, kindling theory(Epilepsy)
 Neurochemical
o Monoamine Theory
o Ion Channel theory
o Second messenger system dysregulation
o Cell membrane abnormalities
 Clearly etiology is multifactorial, there are various theoretical etiologies that patients
might ask about
 Understand that there is high co-occurrence rates between bipolar disorder and substance use disorders
 Know that lithium is the GOLD-Standard for treating Bipolar I disorder. Know that lithium has anti-suicidal
properties, has a narrow therapeutic window, and does require monitoring blood levels to prevent toxicity
o Lithium
  Naturally occurring element, salt
 Effective for acute mania and bipolar maintenance therapy, can also help with depression
 Has anti-suicidal effect
 Needs blood monitoring for lithium level, the therapeutic dose and toxic dose are very close to
one another, narrow therapeutic window, also can negatively affect liver and kidney function
 Can cause nausea, diarrhea, tremor, hypothyroidism, renal failure, weight gain, increase in thirst
and urination
 Know that anti-seizure (anticonvulsant) medications and atypical antipsychotics are often used for bipolar
disorder
 Understand that the mechanisms of action for lithium, anticonvulsants, and antipsychotics for Bipolar
disorders are complicated and not fully understood
 Know that all of the drugs of abuse can cause substance-induced mood disorders
 Know that the atypical (newer) antipsychotics can be helpful for mania/hypomania, depression, agitation,
psychosis, and anxiety
 Know that gabapentin (Neurontin) is NOT a medication for Bipolar disorder, but can be used for anxiety and
neuropathic pain
o Widely misrepresented as a mood stabilizer
o No significant benefit as a mood stabilizer
o May help patients with co-occurring pain and anxiety
 Understand the Monoamine Hypothesis for Depression and know the neurotransmitters involved
o Depression is caused by dysregulation of one or more of the monoamines (Norepinephrine NE),
serotonin, and dopamine (DA)
o Evidence is based on the fact that antidepressants typically increase or modulate these
neurotransmitters
 SSRIs, Serozone, Trazadone- serotonin
 SNRIs, TCA, Remeron-serotonin and NE
 MAOIs all three monoamines, inhibits the enzymes which breakdown and metabolize all of the
monoamines
 Bupropion- DA and NE
o NE dysregulation i) Impaired attention, decreased working memory, slowed cognition, depressed mood,
motor slowing, fatigue, pain
o Serotonin dysregulation
 Depressed mood, anxiety, obsessions/compulsions, appetite changes, reduced libido, sleep
changes, agitation, abdominal symptoms
o DA dysregulation
 Depressed mood, decreased energy, decreased motivation/drive, poor concentration, motor
slowing, apathy
 Recognize that medications and therapy in combination is better than either one alone
o With combination of medication and psychotherapy, treatment response rates can reach 80%,
symptoms get better, there is also a gender bias in favor of women because of who actually seeks
treatment
o What we call depression is actually a very heterogenous group of illness with come common clinical
features but different etiologies
o Depressive disorders are probably more accurately described as syndromal illnesses rather than discrete
disease entities
o Major depressive disorder
  Symptoms last more than two weeks
 Symptoms can remit after 9 to 12 months, depression runs its course
 Do know that ECT (electroconvulsant shock therapy) is still used and is still the most rapid antidepressant,
anti-manic, and anti-suicidal treatment available
 Know the mechanisms of action, neurotransmitters targeted, and major side-effects for:
o SSRI
 Most widely prescribed antidepressant
 Inhibit the reuptake pump for SR
 Fewer side effects
 Sexual side effects, insomnia, hypersomnia, increase/decrease in appetite, nausea,
constipation/diarrhea, headache, akathisia, mania, anxiety, suicidality(+/-)
 Increase synaptic SR
 Down regulation of the SR receptors in response to the increased SR
 This down regulation is thought to contribute to some of the therapeutic effects, and
the decrease in side effects after a few weeks
 Fluoxetine (Prozac), Sertraline (Zoloft)
o SNRI
 Inhibit SR and NE reuptake side, possibly DA with high dose venlafaxine
 Less sexual dysfunction
 May elevate blood pressure
 Wide dose range
 Effective for anxiety and depression
 Trazadone
o Antagonizes serotonin 2 receptors, alpha 1, and antihistamine 1
o Inhibits SR reuptake sites
o Most often used for insomnia
 Mirtazepine
o Antagonizes serotonin 2 and 3receptors, alpha 2, and antihistamine 1
o Does not inhibit SR/NE reuptake sites
o Helpful for depression/anxiety, helps treat insomnia
o TCA
 First antidepressant, clinically observed to be effective
 Thought to work by inhibiting the reuptake pump for SR and or NE
 Also has significant anticholinergic (constipation, dry mouth, blurred vision), antihistaminergic(
weight gain and sedation), and alpha 1 adrenergic (dizziness and low blood pressure) blockade.
 Results in many of the side effects
 Can be fatal in overdose due to cardia arrythmias
o MAO-I
 First antidepressant, clinically observed to be effective
 Inhibit the enzyme, monoamine oxidase, which breaks down/metabolizes catecholamines, NE,
DA, and SR
 Can be very effective for severe depression and anxiety
 Increase side effects and most require patients to maintain a tyramine free diet and to avoid
many decongestants and other antidepressants
 The risk is due to having a hypertensive crisis and stroke
 Ex. phenelzine, Tranylcypromine
o Wellbutrin (bupropion) – important to note that has less sexual side-effects than the other
 Norepinephrine and dopamine Reuptake Inhibitor
 This is the only medication of its class
 Inhibition of both NR and DA uptake sites
 Effective for anergic/motivational depressive states
 Poor for most anxiety disorders, can cause panic
 Off-label use for ADHD
 Side effects: headache, tremor, anxiety, restlessness, insomnia, blurred vision
 No/rare sexual side effects, can reduce the sexual side effects from SSRIs
 Therapeutic Effect
 Believed to be directly attributed to the down regulation, the increase in monoamines
happens immediately, therapeutic effect can take weeks because of the down
regulation of receptor sites
Week Eight

 Know the different types of stimulants around the world

 Understand that stimulant use is a problem throughout the world, but has been a particular problem in the
US
 Know well the acute effects of stimulants
 Know the long-term side-effects/consequences of stimulant use disorders
 Know the symptoms of stimulant withdrawal and that stimulant withdrawal does not typically require
hospitalization or medications (unless there is psychosis)
 Also understand the mechanism of action of the stimulants – neurotransmitters involved and what parts of
the nervous system is activated
 Know the differences in mechanisms of action between cocaine, amphetamine/methamphetamine, and
methylphenidate (Ritalin)
 Understand the risk of stimulant-induced psychosis and what causes the psychosis
 Know the pharmacologic effects of cocaine and the amphetamines
 Recognize that Khat, Ephedra, and Betel Nut are all naturally occurring stimulants and that most synthetic
stimulants are derived from Khat
 Know the three major symptom domains for ADHD
 Understand that attention is both the ability to maintain conscious focus AND the ability to inhibit other
irrelevant information
 Understand the importance of the prefrontal cortex in maintaining focus and attention
 Know the major neurotransmitters involved in attention
 Know the epidemiology of ADHD and the natural course of symptoms over the lifespan
 Know that ADHD is one of the most common behavioral disorders of childhood and is highly genetic
 Recognize that there are rating scales to measure symptom severity, but there is NO gold standard diagnostic
test for ADHD
 Recognize that there are non-pharmacologic treatments for ADHD, such as Cognitive Behavioral Therapy (CBT)
 Know the difference between non-stimulant medications and stimulant medications for ADHD
 Understand that the stimulants and atomoxetine (Strattera) are FDA-approved for ADHD. The
antidepressants are NOT FDA-approved, but some have been found to be helpful for ADHD
 Know how to assess for stimulant medication misuse and ways to reduce the risk of abuse