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174 Cards in this Set

  • Front
  • Back
Defn mental health
The successful performance of mental function, resulting in productive activities, fulfilling relationships with others, and the ability to adapt to change and cope with adversity
defn anxiety
An emotional state commonly caused by the perception of real or perceived danger that threatens the security of an individual -> normal response!
defn anxiety disorder
Persistent, severe anxiety symptoms and/or irrational fears that significantly impair normal daily functioning -> pathological anxiety
5 types of anxiety disorders
Generalized Anxiety Disorder (GAD)
Panic Disorder
Social Anxiety Disorder (SAD)
Posttraumatic Stress Disorder (PTSD)
Obsessive-Compulsive Disorder (OCD)
epidemiology of anxierty disorders
Prevalence
30 million adults; 16% Americans annually
13% children annually
Females > males

Cost
Direct + indirect costs
Increased health care utilization
Cardiovascular, cerebrovascular, GI, respiratory disorders

Onset
Most common before age 30

Comorbid conditions
55% have concurrent disease state
Major depressive disorder most common
Eating disorder, HTN, Irritable bowel, migraines
Etiology and pathophysiology of anxiety disorders
Genetics and inheritance
Increased risk with family history
3 fold increase for SAD
OCD risk of 11-12% with first degree relative

Environmental factors
Early life trauma increases risk
Endocrine abnormalities following trauma
History of child abuse  risk GAD, SAD, PTSD, and panic d/o
Stressful life events may trigger vulnerabilities

Biological contributions
Noradrenergic
GABA
Serotonin

An integrated view
Biological vulnerability + psychological vulnerability + experiences
generalized anxiety disorder
Annual prevalence rate of 2.5%
Average age of onset is 21 years
Cardinal feature: unrealistic or excessive anxiety and worry
Accompanied by at least 3 physiological or physical symptoms
Symptoms most days > 6 months
Symptoms cause significant distress and impairment in functioning
Not secondary to medical cause or drug/medication
cardinal feature of GAD
unrealistic or excessive anxiety and worry
clinical presentation of GAD
Psychological and cognitive symptoms
Excessive anxiety
Worries that are difficult to control
Feeling keyed up or on edge
Poor concentration

Physical symptoms
Restlessness
Fatigue
Muscle tension
Sleep disturbance
Irritability

Impairment
Social, occupational, or other important functional areas
Poor coping ability
GAD chronic course of illness
Chronic course of illness:
High relapse rate
GAD exacerbated/precipitated by stressors
Many patients develop a secondary mental health disorder
Panic disorder
Annual prevalence rate of 1.7%
Spontaneous attacks involving intense fear
Overwhelming sense of doom
Fear of dying or losing control
At least 4 physical symptoms
Followed by 1 month of persistent concerns about having another attack
panic disorder impact of QoL
Significant impact on QOL
Social and work impairment
High lifetime risk of suicide
Agoraphobia (35-50%) – anxiety about being in places or situations from which escape might be difficult or embarrassing
90% of those with agoraphobia have had panic attacks
symptoms of panic attack
Psychological and cognitive symptoms
Depersonalization
Derealization
Fear of losing control
Fear of going crazy
Fear of dying

Physical symptoms
Abdominal distress
Chills
Chest pain Feeling of choking
Dizziness or lightheadedness
Hot flashes
Palpitations Nausea
Parethesias Sweating
Shortness of breath
Tachycardia
Trembling or shaking
social anxiety disorder
Annual prevalence rate of 3.7%
Intense, irrational, persistent fear of being negatively evaluated
Blushing most common physical symptom
Interferes with normal functioning and/or causes significant distress
presentation of SAD
Fears
Being scrutinized by others
Being embarrassed or humiliated

Some Feared Situations
Addressing group of people
Eating or writing in front of others
Interacting with authority figures/strangers
Speaking in public
Use of public toilets

Physical symptoms
Blushing Butterflies in stomach
Diarrhea Sweating
Tachycardia Trembling

Generalized: Wide range of situations

Non-generalized: 1-2 specific situations
post traumatic stress disorder
Annual prevalence rate of 3.7%
increase reports with recent world events
Exposure to traumatic event required for diagnosis
At least one re-experiencing symptom (flashback)
At least 3 avoidance symptoms
Avoids reminders of the event
At least 2 symptoms of increased arousal
Falling or staying asleep, anger, concentration
Symptoms >1 month, distress/impairment in functioning
presentation of PTSD
Re-experiencing symptoms
Recurrent, intrusive, distressing memories of trauma
Recurring, disturbing dreams of the event
Feeling that event is recurring (flashbacks)
Physiologic reaction to reminders of trauma
Avoidance symptoms
Avoidance of conversations about the trauma
Avoidance of thoughts/feelings about trauma
Avoidance of activities that are reminders of event
Avoidance of people/places that arouse recollections
Inability to recall important aspect of the trauma
Anhedonia
Estrangement from others
Restricted affect
Sense of foreshortened future
Hyperarousal syptoms
Decreased concentration
Easily startled
Hypervigilance
Insomnia
Irritability/angry outbursts
Acute: Sx < 3months
Chronic: Sx > 3 months
PTSD prognosis
1/3 of patients have poor prognosis
Treated patients -> average duration = 36 mo
Untreated patients -> average duration = 5y
20% of patients attempt suicide
obsessive compulsive disorder
Annual prevalence of 1.5-2.5%
Obsessions
Recurrent, persistent idea, thought, impulse or image that is intrusive, inappropriate and causes anxiety
Contamination, doubts, need for order
Compulsions
Repetitive behavior or act performed in response to obsession to relieve the anxiety associated with obsession
Cleaning, counting, checking
presentation of OCD
Obsessions
Repetitive thoughts (feeling contaminated, etc)
Repetitive images (gruesome, or sexually explicit pictures)
Repetitive impulses (need for symmetry or specific order)

Compulsions
Repetitive activities (hand washing, checking, etc)
Repetitive mental acts (counting, repeating words, etc)
nonpharm therapy for anxiety disorders
Stress management, meditation, exercise

Psychotherapy
Cognitive Behavioral Therapy (CBT)
Effective for GAD, Panic d/o, SAD, PTSD, OCD
Often treatment of choice for mild symptoms
Gold standard for OCD: expose to stimuli (the obsession), refrain from compulsion
short term goals of therapy for OCD
Short term
decrease severity, frequency, duration of symptoms
Improve functioning
Long term goals of therapy for OCD
Long term
Remission with minimal or no symptoms
No functional impairment
SSRIs for anxiety disorders
Considered first line for ALL anxiety disorders
Established efficacy: GAD, panic disorder, SAD, PTSD, OCD
Give treatment trial of at least 8 weeks

Side effects usually mild and short lived
Somnolence or insomnia, headache, nausea
Paroxetine  more sedating
Fluoxetine, sertraline  more stimulating
Sexual dysfunction with all agents
**Start low and go slow
SNRI: venlafaxine
Effexor (immediate release)
Dosage forms: 25, 37.5, 50, 75, 100mg tablets
Dose
37.5mg BID/TID, increase by 75mg every week to max of 225mg
Effexor XR (extended release)
Dosage forms: 37.5, 75, 150mg capsules
Dose
37.5-75mg QD initially, increase by 75mg every week to maximum of 225mg
SNRI: duloxetine
Cymbalta (delayed release)
Dosage forms: 20, 30, 60mg capsules
Dose:
20mg BID initially, titrate up to 60mg daily (once daily or 30mg BID)
Also has indications for diabetic peripheral neuropathy and major depressive disorder
antidepressant TCAs for anxiety disorder
Imipramine, clomipramine, amitriptyline
Higher side effect burden vs. other antidepressants (i.e. “SLUD”)
Clomipramine is the only TCA used in OCD
benzodiazepines for anxiety disorders
Effective for acute anxiety symptoms (somatic and autonomic)
Effective for GAD, panic disorder, SAD
Not useful for PTSD or OCD

Use as a bridge to treat acute anxiety symptoms while SSRI begins to work, then discontinue!!!
side effects BZDs
Side effects most commonly related to CNS depression
Sedation, psychomotor impairment, ataxia
Tolerance to drowsiness
Impairment of memory, recall
potential abuse w/ BZDs
Potential for abuse/physical dependence
Abuse is rare, use caution in those with polysubstance or alcohol abuse
Physical dependence will occur
w/drawal of BZDs
Discontinuation: withdrawal
Anxiety, insomnia, irritability – common
Hallucinations, seizures – rare
TAPER
Buspirone (Buspar), what is it used for?
to treat GAD
Buspirone (Buspar)
Second-line agent for GAD only

Initial dose: 7.5mg BID
Titrate by 5mg/day every 2-3 days
Usual therapeutic dose: 30-60mg/day
Max benefit: 4-6 weeks

Potential benefits
Lacks abuse potential, physical dependence, or withdrawal
Lack of potentiation of alcohol, or other sedative hypnotics
Acute situational anxiety
“Performance Anxiety”
Beta-blockers
Blunt the peripheral autonomic symptoms of arousal (e.g. tachycardia, sweating, blushing, tremor)
Propranolol 10-40mg 1 hr prior to event
Test dose at home
Benzodiazepines generally not recommended
4 important points when choosing BZDs
half life
active metabolites
how metabolized
lipophilicity (time to onset)
3 key components to insomnia
1. Sleep Disturbance
Difficulty falling or staying asleep
Non-restorative sleep
2. Impaired functioning
Fatigue, malaise, daytime sleepiness
Concentration or memory difficulty, vocational dysfunction
Mood disturbances, anxiety over sleep lost
3. Adequate opportunity for sleep
Primary insomnia
all other causes of not sleeping are ruled out
secondary insomnia
adjustment(shift changes)
inadequate sleep hygeine
psychiatric disorder
medical condition
substance/drug
Secondary insomnia:
Drug classes that can cause it
anticonvulsants
antidepressants
beta blockers
bronchodilators
decongestants
oral corticosteroids
stimulants
*also caffeine, alcohol and elicit drugs
anticonvulsants that can cause secondary insomnia
lamotrigine
antidepressants that can cause secondary insomnia
bupropion
fluoxetine
venlafaxine
beta blockers that can cause secondary insomnia
propanolol
metoprolol
bronchodilators that can cause secondary insomnia
theophylline
decongestants that can cause secondary insomnia
phenylpropanoloamine
pseudoephedrine
oral corticosteroids that can cause secondary insomnia
prednisone
dexamethasone
stimulants that can cause secondary insomnia
methylphenidate
dextroamphetamine
modafinil
pemoline
common medical conditions that can cause secondary insomnia
Restless Leg Syndrome (RLS)
Pain
Nocturnal Cough/Dyspnea
Heart failure, COPD
Menopause → hot flashes
GERD, BPH
sleep apnea
psychiatric disorders: BP D/O (mania), schizophrenia, psychosis, depression/anxiety
when should you refer insomnia to primary care physician?
secondary insomnia medical conditions all require referral
things TO initiate to help secondary insomnia sleep hygeine
Regular sleep-wake cycle
Comfortable, quiet, dark room
Relaxing routine before bedtime
Exercise routine
bedroom for sleep/intimacy
things to AVOID in secondary insomnia poor sleep hygeine
Use of alcohol, caffeine, nicotine, especially before bedtime
Late, heavy meals
Daytime napping
“Clockwatching”
treatment process for insomnia
1. Rule out secondary causes of insomnia
2. Identify previous therapy
3. Non-pharmacological therapy should drive treatment plan
4. Pharmacological therapy to reinforce good habits
goal of nonpharm therapy in insomnnia
modify behavior and change thought processes
pharmacotherapy treatment drug classes
1. GABA receptor agonists:
Benzodiazepines
Non-benzodiazepines
Valerian root

2. H1-receptor antagonists:
Tricyclic antidepressants
Trazodone, Mirtazapine
Antihistamines
Quetiapine

3. Melatonin receptor agonists:
Ramelteon
OTC melatonin
principles of pharmacotherapy for insomnia
1. Anything that binds to the benzodiazepine-receptor is a Class-IV controlled substances
2. Hypnotic agents (except eszopiclone, remelteon, zolpidem CR) are approved for short-term use.
Nightly use for > 4 months is not uncommon
3. Hypnotic agent selection should be dictated by duration of action, mechanism, side effect profile, and co-morbid conditions
No current guidelines for drug selection
4. Use agent to help change behavior and thought processes
MOA BZDs for insomnia
Mechanism: non-selective agonist binding at different GABAA receptor subtypes (α-1, α-2, α-3, or α-5 subunits)
-->Sedation, anterograde amnesia, anticonvulsant activity, anxiolysis, muscle relaxation, ethanol potentiation
side effects of BZDs for insomnia
Alteration of sleep architecture
Residual daytime sedation
Cognitive and psychomotor impairment
Anterograde amnesia
Rebound insomnia
Withdrawal symptoms when discontinuing
Tolerance to sedative effects (tachyphylaxis), physiologic dependence

use caution in the elderly
non BZDs for insomnia
(the Z hypnotic agents)
zolpidem (ambien)
zaleplon (sonata)
eszopiclone (lunesta)
MOA of the 3 Z hypnotics
Mechanism: selectively agonize the GABA receptors

More selective for the α-1 subunit of the GABAA receptor

Although eszopiclone not selective (alpha 1, alpha 3)

Lack of anticonvulsant and muscle-relaxant properties and potentially less effect on the sleep cycle
why were the 3 Z hypnotics developed?
to minimize the side effects associated with the use of BZDs
ambien vs ambien CR
ambien:
Immediate release
Sleep onset
Half-life = 2.5 hr

ambien CR:
2 layer release (IR and XR)
Sleep onset or maintenance
Half-life = 2.8 hr
Now has 6-month data

***they were found to be nearly similar, almost identical plasma concentrations
ambien CR has slightly larger AUC
describe eszopiclone (lunesta)
S-isomer of the hypnotic agent zopiclone, which has been available in other countries for over 20 years

Similar onset, but longer half-life (5-7 hours) than other non-benzodiazepines, likely making it better for sleep maintenance

FDA-approved for long-term use with studies up to 6 months showing no evidence of tolerance
describe zaleplon (sonata)
Ultra-short elimination half-life of 1 hour
Lack of daytime sedation, less psychomotor impairment or memory impairment

Dose appropriately – 10mg has been shown to decrease sleep latency to sleep persistence
Doses up to 20mg per night may be considered

Take before going to bed or after lying in bed and having difficulty sleeping (up to 4 hours before wake time)
Middle of the night dosing evaluated
OTC insomnia therapy: valerian root
Mechanism unknown, effects at GABA receptors have been suggested
Dose: range from 1.5 to 3gm of actual herb or root (400-900mg of extract)
Generally regarded as safe, but hepatotoxicity has been reported
Do not use in patients with liver dysfunction
Avoid use with other sedating drugs including benzodiazepines
how is H1 associated with sedation?
H1 binding associated with muscarinic (anticholinergic) and adrenergic binding

Commonalities:
Next day “hangover” effect
Weight gain
Anticholinergic side effects (“SLUD”)
Tachyphylaxis
what is the goal of sedation through H1 receptor binding?
to identify a new drug or dose of existing drug that will bind histamine, but not other receptors
what is an example of a new drug that binds only H1 receptors?
TCA with antidepressive maintenance dose of 150-300mg per day
High affinity for histamine receptors; low-affinity for muscarinic, serotonin, norepinephrine, and alpha receptors
Recent trials evaluating doxepin 1, 3, and 6mg
(low dose= H1 binding only)
TCAs in insomnia treatment
Nortriptyline, amitriptyline, doxepin
All provide sedation through binding to H1-receptors
Effective for inducing sleep continuity, daytime sedation is significant
Disadvantages: side effects - dry mouth, dry eyes, constipation, urinary retention, dizziness upon standing
***use caution in the elderly
side effects of TCAs
dry mouth, dry eyes, constipation, urinary retention, dizziness upson standing
trazodone in insomnia treatment
Sedation through H1-receptor binding improves sleep continuity
Popular choice for insomnia in patients prone to substance abuse
Frequently used in SSRI- and bupropion-induced insomnia at doses of 25-75mg
Side effects: serotonin syndrome, oversedation, dizziness, priapism (1:6,000 men)
Minimal data to support its use
which receptor does trazodone work on?
H1 receptor binding
mirtazepine (Remeron) in insomnnia treatment
Mirtazapine (Remeron®)
7.5mg, 15mg, 30mg, 45mg tablets
Sedation and weight gain are more prominent at lower doses
High affinity for H1-receptors and has also been shown to increase melatonin
Good choice for thin, depressed elderly patient with insomnia
which drug option is the best for a thin elderly person with insomnia?
mirtazepine
atypical antipsychotics in insmonia treatment
Quetiapine, ziprasidone, risperidone, olanzapine, aripiprazole
Side effects: EPS, dry mouth, orthostasis
why/when are atypical antipsychotics used for insomnia
when comorbid psychiatric illness exists (not primary care)
also b/c more selective for histamine
antihistamines used to treat insomnia
diphenhydramine
doxylamine
use of antihistamines in insomnia treatment
Diphenhydramine and doxylamine
Both FDA-approved for insomnia treatment
Other 1st-generation antihistamines could work
Sedation through H1 receptor binding
Anticholinergic side effects limit use in elderly
Constipation, dry eyes, dry mouth, urinary retention, confusion
Found in several OTC sleep-specific aids
Unisom®, Tylenol PM®, Advil PM®
****use caution in the elderly
what drug is a melatonin agonist?
ramelteon (Rozerem)
Mechanism: high affinity for M1 and M2 melatonin receptors to aid sleep promotion and maintain the circadian rhythm
Highly metabolized by the liver (1.8% reaches bloodstream)
advantages of ramelteon
Not a controlled substance, does not produce residual effects (memory impairment, daytime sedation), long-term use acceptable
warnings for ramelteon
Warnings:
Do not use with Luvox® (fluvoxamine) or in liver failure
Can cause increased prolactin levels (cessation of menses, decreased libido, galactorrhea in females)
Lack of good clinical data – role currently undefined
No trials evaluating it compared to current hypnotic agents
herbal melatonin agonists?
melatonin supplement
Hormone from the pineal gland to maintain sleep/wake cycle
Dosing ranges from 0.3mg to 5mg
Normal daytime concentration: 2-10 pg/ml,
Normal nighttime concentration: 100-200 pg/ml
Too much can cause daytime sleepiness, impaired mental and physical performance, and hyperprolactinemia
Adjustment Insomnia (shift work, jet lag)
Avoid use with warfarin, fluvoxamine, liver dysfunction, seizure disorder, or in children
key points for insomnia
The diagnosis of insomnia requires a sleep disturbance plus impaired functioning with adequate opportunity to sleep
Secondary causes of insomnia must be evaluated, identified, and treated
Pharmacotherapy must be used to reinforce non-pharmacologic therapy
Patient age and co-morbidities, and duration of action, side effect profile, and cost of medication should drive selection
antianxiety sedative defn
BZDs for anxiety disorders
antidepressents
mood elevating agents
mood stabilizing drugs
lithium
antipsychotic/neuroleptic drugs
used to treat psychosis and mania
psychotropic drugs
acting on the mind
mood vs affect
mood: sustained/persistent emotional state (climate)

affect: emotional display from moment to moment (weather)
types of depression
reactive (most common)
major depression(endogenous)
bipolar(manic depressive)
reactive depression features
Loss (life events)
illness, drugs (antihypertensives, alcohol, hormones), senility

>60% cases
Symptoms: depression, anxiety, tension, guilt. May respond spontaneously
major depression features
Precipitating life events do not explain the level of depression. Unresponsive to changes in life. May occur at any age (childhood-old age). Biologically determined (family history

25% of all cases. Core syndrome plus “vital” signs: abnormal:abnormal sleep, motor activity, libido, appetite. Responds to antidepressants, ECT. Recurs through life
bipolar depression features
Characterized by episodes of mania. Cyclic; mania alone is rare. Depression alone is occasional. Usually observe mania-depression

10-15% of cases. May be misdiagnosed as endogenous. Lithium stabilizes mood. Mania may require antipsychotic drugs also. Depression managed with antidepressants
older drugs to treat depression
Tricyclic compounds (e.g. imipramine, amitriptyline)

Monoamine Oxidase Inhibitiors (MAOIs) (e.g. tranylcypromine)
newer drugs to treat depression
Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. fluoxetine, fluvoxamine)

Atypical drugs (e.g. bupropion, trazodone, mirtazapine
NE reuptake inhibitors (TCAs)
amytriptyline
desipramine
maprotiline
SSRIs
fluoxetine
venlafaxine
fluvoxamine
atypical antidepressents
bupropion
mirtazepine
nefazodone
trazodone
MAOIs
phenelzine
tranylcypromine
selegiline
SNRIs
venlafaxine (5HT>NE)
amitriptyline (NE>5HT)
atypicals that block 5HT uptake
trazodone
how do heteroceptor mechs work with SSRIs and TCAs?
SSRIs increase NE
TCAs increase 5HT
structure activity relationship of TCAs
THREE ring structure that resembles phenothiazine antipsychotics...
antihistamin structure
structure activity relationship of SSRIs
why advantageous compared to TCAs
Major drawback of older drugs (TCAs) is “multiple or diverse” pharmacological actions e.g. antihistamine, anticholinergic, alpha receptor blockade etc

SSRIs are more selective
( for serotonin vs NE
structure activity relationship of MAOIs:
hydrazide vs. nonhydrazide
Hydrazide structure: e.g. phenelzine, isocarboxazid (no longer marketed)

Non hydrazide structure: e.g. tranylcypromine
Older MAOIs inhibited both MAOB and MAOA
Newer drugs e.g. Deprenyl inhibits MAOB not MAOA
ADME TCAs
Significant 1st pass metabolism
High protein binding
High lipid solubility
Large volumes of distribution (Vd)
Metabolism:
Phase I: ring structure (CYP1A2, CYP3A4) and aliphatic side chain,
Phase II: glucuronide conjugation
Active metabolites of some agents
ADME SSRIs
Venlafaxine has a short elimination t1/2 ~5 hr
CYP3A4
Bioactivation: Fluoxetine has an active metabolite, norfluoxetine with t1/2 of 7-9 d
Inhibition of drug metabolizing enzymes (**P450)
CYP2C9-Fluvoxamine
CYP2C19-Fluvoxamine
CYP2D6-Fluvoxamine, fluoxetine, sertraline
CYP3A3/4- Fluvoxamine, nefazodone
ADME atypical drugs
Active metabolites
trazodone, nefazodone, bupropion into amphetamine-like compounds
Some have extremely short t1/2
t1/2 of nefazodone is 3 hr
t1/2 of trazodone is 6 hr
ADME MAOIs
Measuring MAO activity (inhibition) is a better predictor of drug effect than drug levels
biogenic amine theory of depression
Biogenic Amine Theory Depression results from decreased amine (NE, 5HT) dependent synaptic transmission I.e. decreased availability of amines.
According to this hypothesis, depression can be alleviated by drugs that increase the availability of NE and 5HT
This can be achieved by
Inhibition of MAO, an enzyme that degrades monoamines
Inhibiting neurotransmitter re-uptake e.g. TCAs

Based on mechanism of reserpine action: Reserpine depletes amines (catecholamines, 5HT) and produces depression

May explain action of major antidepressant classes: TCA, MAOIs, SSRIs increase NE/5HT neurotransmission
drawback of biogenic amine theory
NE and 5HT levels increase immediately following MAOIs and TCAs. However, a person suffering from depression may not experience significant relief for as long as 6 to 8 weeks.
supersensitivity theory of depression
Supersensitivity Theory (up-regulation)
Supersensitivity is a compensatory response of the postsynaptic neuron when it receives too little stimulation by agonists.
The neuron tries to make up for a lack of stimulation by increasing receptor responsiveness.
Over time, the postsynaptic neuron may also compensate for lack of stimulation by synthesizing additional receptor sites. This process is known as up-regulation.
This hypothesis proposes that depression is the result of a adaptive changes (supersensitivity and up-regulation) in receptor sites, which results from too little stimulation by monoamines, i.e., a deficiency of NE and 5HT in the cleft.
Chronic administration of TCAs or MAOIs alters the responsiveness and/or the number of postsynaptic receptor sites
serotonin only hypothesis of depression
Based on the effects of drugs known as selective 5HT reuptake inhibitors, or SSRIs.
Serotonin-only Hypothesis emphasizes the role of 5HT in depression and downplays NE.
drawbacks to serotonin only hypothesis of depression
Does not explain why there is a delay in onset of clinical relief

Does not explain the role of NE in depression
permissive hypothesis of depression
Suggests that mood is controlled by a balance of NE and 5HT, not by absolute levels of these neurotransmitters or their receptors.
According to this hypothesis, the control of emotional behavior results from a balance between 5HT and NE.
The Permissive Hypothesis suggests that low levels of 5HT permit abnormal levels of NE to cause depression or mania. If 5HT cannot control NE, and NE falls to abnormally low levels, the patient becomes depressed.
On the other hand, if the level of 5HT falls and the level of NE becomes abnormally high, the patient becomes manic.
epidemiology of depression
Lifetime incidence of 12% (men) and 20% (women)
Highest rates among adults 25-44 years old
~8-18% have a first degree relative with h/o depression
More common in populations with a great burden of medical care (e.g. nursing homes, hospitals, those suffering from multiple medical conditions)
pathophysiology of depression
Monoamine-deficiency – lack of, or lack of response to serotonin and norepinephrine
Agents that increase these can treat depression
Depleting these in humans can cause a relapse of depression (but not an initial episode)
People with depression may have serotonin receptors that are less sensitive
Dopamine may also play a role
Frequent depression in Parkinson’s disease
Bupropion – inhibits the reuptake of dopamine
Dopamine-agonists may be effective
what is the MAIN reason for depression
monoamine deficiency
serotonin and NE
things needed for diagnosis of depression
depressed mood
Depressed mood
Diminished interest or pleasure
Weight loss, gain (appetite)
Insomnia or hypersomnia
Psychomotor agitation or
retardation
Fatigue or loss of energy
Feelings of guilt/worthlessness
Concentration difficulty
Thoughts of death
Suicidal ideation
requirements for depression diagnosiss
Symptoms present daily for at least 2 weeks
Clinically significant distress or impairment
Social, occupational, or other functioning
Not due to a substance or medical disorder
Not better accounted for by bereavement
Not a manifestation of bipolar disorder
clinical rating scales for depression
NOT for diagnosis, screening tools to identify and assess severity along with treatment effect
Hamilton Rating Scale for Depression (Ham-D)
Filled out by the health care professional
Mild (10-13), Mild-moderate (14-17)
Moderate-severe > 17)
Beck Depression Inventory
Filled out by the patient
Mild (<15), Moderate (15-30), Severe (> 30)
what are clinical rating scales for depression used for?
NOT diagnosis
they are used for screening to identify and assess severity along with treatment effect
what must all patients with depression be screened for?
suicide
why screen for suicide?
8th leading cause of death in the U.S.
Detailed plan with the intention and ability to carry it out indicates a high risk of suicide
Suicidal ideation is a medical emergency
Change in personality, decision to make a will or give away possessions, purchase of a gun or toxic substance
Suicide risk may increase in a person recovering from depression
Use caution with antidepressant and quantity you choose
what are conditions to rule out for depression
Hypothyroidism, anemia
Influenza, mononucleosis
Electrolyte imbalances
Psychiatric disorders
Alcoholism, anxiety disorders, schizophrenia
Bipolar disorder
what baseline exams should depression patients have?
All patients should have a physical exam, mental status exam, CBC, thyroid function test, and electrolyte panel
drug classes that can precipitate/worsen depression
antihypertensives
hormone therapy
acne therapy
dopamine antagonists
antidepressant options
Selective Serotonin Receptor Inhibitors (SSRI’s)
Tricyclic antidepressants (TCA’s)
Serotonin-Norepinephrine Reuptake Inhibitors (SNRI’s)
Miscellaneous:
Trazodone
Bupropion
Mirtazapine
Atypical Antipsychotic - Abilify® (aripiprazole)
Monoamine Oxidase Inhibitors (MAOI’s)
SSRIs for depression
Mechanism
selective reuptake inhibition of serotonin
First-line therapy
Similar or superior efficacy to others
Lower side effects, safer, convenient dosing
Generally choose cheapest available
Recognize differences between agents
which SSRI has longest half life
fluoxetine
which SSRI is most activating?
fluoxetine
which SSRI is most sedating?
paroxetine
TCAs for depression MOA
Mechanism: block the reuptake of NE and 5-HT
Also bind to α1, histamine-1, and muscurinic receptors (anticholinergic side effects)
tertiary vs secondary amine TCAs
Tertiary cross the blood-brain barrier (BBB) and therefore have more CNS side effects
More sedation, confusion, anticholinergic side effects (SLUD)
Amitriptyline most common tertiary TCA
Nortriptyline most common secondary TCA
how are TCAs used for depression?
2nd or 3rd line therapy for monotherapy
Good efficacy, but high rate of side effects
Use extreme caution in the elderly
SLUD, confusion
Main use is augmentation or in patients who have certain co-morbid conditions
Neuropathic pain, depression with insomnia
May be superior for severe or melancholic depression
MOA SNRIS
selective serotonin and norepinephrine reuptake inhibition
side effects of SNRIs
Bind α1 and ß1 receptors
Increased HR, BP (HTN), tremor, agitation
Dizziness
Stimulation of noradrenergic receptors in the sympathetic nervous system  net reduction in cholinergic tone
“Pseudoanticholinergic” – dry mouth, constipation, urinary retention
venlafaxine
Effexor (immediate release)
Dosage forms: 25, 37.5, 50, 75, 100mg tablets
Dose
37.5mg BID/TID, increase by 75mg every week to max of 225mg
Effexor XR (extended release)
Dosage forms: 37.5, 75, 150mg capsules
Dose
37.5-75mg QD initially, increase by 75mg every week to maximum of 225mg
high/low dose venlafaxine
37.5 BID/TID
max 225 mg/day

XR:
37.5/day
max 225 mg/day
duloxetine
Cymbalta (delayed release)
Dosage forms: 20, 30, 60mg capsules
Dose:
20mg BID initially, titrate up to 60mg daily (once daily or 30mg BID)
Also has indications for diabetic peripheral neuropathy and generalized anxiety disorder
duloxetine high/llow dose
20BID
Max 60 mg/day
desvenlafaxine
Pristiq® (desvenlafaxine)
Venlafaxine -2D6->desvenlafaxine

Has greater NE reuptake inhibition
Easier to dose, more predictable response
50mg daily, 100mg tablet available
trazodone
Mechanism
Block 5-HT reuptake & 5-HT2a & 5-HT2c receptors
Also block histamine-1 and α1 receptors
Higher doses needed to block reuptake and receptors – difficult to tolerate
Dosage forms: 50, 100, 150, 300mg tablets
Dose:
50-150mg TID initially, increase by 50mg weekly to maximum of 400mg
Commonly used at low dose in SSRI- or buproprion-induced insomnia
trazodone high/low dose
50-100 TID
Max 400 mg/day
bupropion
Mechanism
Weak inhibitor of norepinephrine and dopamine uptake, no effect on serotonin
Lowers the seizure threshold, especially in bulimic patients
Contraindicated in bulimic and anorexic patients
Immediate release higher incidence, may be due to peak concentrations
Can be added to SSRI
Does not cause sexual dysfunction
dosing for bupropion
IR, SR, XL
Dose:
Wellbutrin: 100mg BID x 3 days, then 100mg TID (max = 450mg TID-QID)
Wellbutrin SR: 150mg QD x 3 days, then 150mg BID (max = 200mg BID)
Wellbutrin XL: 150mg QD x 3 days, then 300mg QD (max = 450mg QD)
mirtazapine
Mechanism:
Enhances the release of 5-HT/NE by blocking α2-adrenergic autoreceptors and 5-HT2A/5-HT2C
Little affinity for α1 or muscurinic
High affinity for histamine-1 receptors
Sedation, weight gain (appetite increase), and dry mouth are more prominent at lower doses

useful for thin, depressed geriatric pt. w/ insomnia
mirtazapine high/low dose
7.5 QHS
max 45 mg
MAOIs
Phenelzine, tranylcypromine
Non-selective for MAOA and MAOB
Mechanism:
Inhibit the monoamine oxidase (MAO) enzyme to increase NE, 5-HT, and DA
Last resort for treatment of depression, and only prescribed by those with experience using them
Side effects: hypotension and anticholinergic
Wait 2 weeks after stopping other antidepressants (5 weeks for fluoxetine)
Wait 2 weeks when switching from MAOI
*Last resort for depression
MAOIs serotonin syndrome
medication restrictions
Amphetamines
Appetite suppressants
Buspirone
Carbamazepine
Decongestants
Pseudoephedrine
Phenylpropanolamine
Dextromethorphan
Levodopa
Methylphenidate
Methyldopa
Sumatriptan
Tryptophan
Other antidepressants
Cyclobenzaprine
Ephedrine
Dopamine
*not all inclusive, screen all medications
three phases of pharmacotherapy for depression
Acute: achieve remission, 6-12 weeks

Continuation: keep symptoms in remission using full-dose therapy, 6-12 months

Maintenance: long-term therapy for those at high risk for relapse (prior episodes, strong family history)
adequate trial for depression pharmacotherapy
Full therapeutic doses for 6-8 weeks and in some cases up to 12 weeks (if no response, failure)
response defn
Usually defined as a 50% reduction in symptoms
remission defn
A return to normal mood and normal functioning

Use Ham-D (< 6 is remission) or other clinical rating scale to monitor for response and remission
If a drug has given a response, you can possibly obtain remission by adjusting the dose or augmenting the therapy
considerations in agent selection initial depression therapy
Cost, dosing convenience
Co-morbidities (e.g. depression with insomnia)
Side effect profile
Previous response to therapy, family members response to therapy
Drug-drug/drug-disease interactions

Prefer SSRI’s as first-line therapy
antideprresant drug selection for peripheral neuropathy
duloxetine, TCA, venlafaxine
antidepressant drug selection for insomnia
mirtazapine, TCA, trazodone
paroxetine, citalopram, escitalopram
antidepressant drug selection for concurrent anxiety
SSRIs that cause more sedation, paroxetine, citalopram, escitalopram
antidepressant drug selection for erectile dysfxn
bupropion, mirtazapine, duloxetine
b/c no 5HT effects
STAR D Trial
Outpatients with non-psychotic major depressive disorder eligible for medication as first step
Not achieving remission or not tolerating a step gave eligibility for next step

Goal:
Identify what it takes to achieve remission in patients with depression

Sponsored by the NIH
1st large study providing guidance on which therapy to choose and why
Previously, algorithms based on expert clinical opinion
level 1 STAR D Trial
Level 1: All received citalopram
level 2 STAR D Trial
Level 2: those who did not have remission or did not tolerate citalopram had several options
Switch: cognitive therapy, venlafaxine XR, sertraline, or bupropion SR
Augment: add cognitive therapy, bupropion SR, or buspirone
Participants could decline all 3 augmentation, all 4 switch, either or both cognitive, or all except cognitive therapy
results STAR D Trial Level 1
Level 1
1/3 had remission and ½ had a response
Mean citalopram dose = 55mg, ~12 weeks treatment
results STAR D Trial level 2
Level 2
Switch: Bupropion SR, Sertraline, Venlafaxine XR
¼ had remission, ¼ had response
Not significantly different – all considered acceptable
Augment: Citalopram + bupropion SR or buspirone
1/3 had remission, 1/3 had response
Bupropion SR was better tolerated and may have better reduction than buspirone
what are steps 3-4 used for in STAR D trial?
reserved for psychiatrists or those highly experience with depression
Star D Switch therapy
Switch therapy
Citalopram was discontinued without a tapering or washout period
Bupropion SR
150mg x 7, 200mg x 20, 300mg x 14, 400mg
Sertraline
50mg x 14, 100mg x14, 150mg x 35, 200mg
Venlafaxine
37.5mg x 7, 75mg x 7, 150mg x 14, up to 375mg
Star D augmentation therapy
Augmentation therapy
Bupropion SR
200mg x 14, 300mg x 14, 400mg
Buspirone (indicated for generalized anxiety)
15mg x 7, 30mg x 7, 45mg x 21, 60mg
Star D conclusions
Conclusions
Switching therapy or augmenting therapy are both viable options for initial failure
suggested algorithm based on Star D Trial
1. Initiate SSRI as first line therapy, if appropriate
2. If response, but not remission, augment with bupropion SR (preferred) or buspirone
3. If no response, switch to sertraline, venlafaxine XR, or bupropion
4. After these steps, refer to a psychiatrist
options for resistant depression
Augment SSRI
Low dose TCA (25-50mg of most)
Low-medium dose mirtazapine (15-30mg)
Augment antidepressant
Lithium (blood level goal of 0.6-1.0 mEq/L)
Thyroid hormone (50-75mcg triiodothyronine)
Add atypical antipsychotic
Add stimulant (e.g. methylphenidate)
Add anticonvulsant (lamotrigine 100-200mg)
Switch to an MAOI

****Reserve for psychiatrists or those highly experienced with depression
Treatment duration acute phase
May require hospitalization if suicide risk or psychosis with risk to self and others
Generally 6-12 weeks
Goal: obtain remission
Start low dose, titrate to max tolerated
Augment or switch, if necessary
Treatment duration maintenance phase
Maintenance phase:
Continue therapy for 12-36 months or indefinitely to prevent relapse
High risk patients
Multiple episodes of depression
Previous suicidal risk
Chronic major depression or dysthymia (low-grade depression)
Strong family history of resistant depression
high risk patients in need of maintenance depression treatment
High risk patients
Multiple episodes of depression
Previous suicidal risk
Chronic major depression or dysthymia (low-grade depression)
Strong family history of resistant depression
blackbox warning
serotonin and suicide
FDA Black Box Warning for all antidepressants
Risk of suicidality in children, adolescents, and adults younger than 25 years
Clearly warn the patient and family about risk
Patient Medication Guide distributed with each new prescription and refill
Risk appears greatest in the first few weeks of therapy
Monitoring:
Weekly visits for first 4 weeks
Biweekly until 12 weeks
As clinically indicated beyond 12 weeks
serotonin syndrome symptoms
hyperreflexia, tremor, clonus, diaphoresis, agitation, HTN, increased bowel sounds (diarrhea), mydriasis
role of the pharmacist in depression
Serotonin Syndrome
How do I identify it?
When should I call the physician when a drug interaction seems possible?
Patient counseling
Onset of effect
Side effect profile
Therapeutic recommendations
Selection of least expensive product
Choosing agent given side effects