ANXIETY/PANIC/DEPR

ESSION AGENTS
PA Pharmacotherapeutics Course
October 3, 2017 (1:30 – 3:30 pm)

Lecturer: Teresa Elsobky, Pharm.D., BCPP

Clinical Psychiatric Pharmacist
Assistant Professor of Pharmacy Practice
Bernard J. Dunn School of Pharmacy
Shenandoah University
Objectives
• At the end of the presentation, each student should be
able to:
• Explain the pharmacology of anti-anxiety agents and
antidepressants
• Identify appropriate, guideline-based pharmacological
treatment options for anxiety and depression
• Distinguish the drug properties of the different
pharmacological treatment options
• Create a pharmacological treatment plan for a sample patient
case
Introducing Our Patient: MG
Patient case: MG
• CC: “I am tired of this.”
• HPI:
• MG is a 23-year-old WF who was referred for a psychiatric evaluation by her cardiologist
• In the past two months, MG has presented to the Emergency Department four times for acute
complaints of rapid onset episodes of palpitations, shortness of breath, sweats, trembling,
and fears that she was going to die
• The symptoms seemed to peak within minutes, leaving her scared, worried, and with the
belief that she was having a heart attack
• Medical exams have found normal physical examinations, vital signs, lab results, toxicology
screens, and EKGs
• MG reported a total of five of these episodes in the past three months, with the episodes
occurring at work, at home, and while walking her dog
• She has developed a fear of having other episodes, which has led her to miss days of work
• Her sleep quality has declined and so has her mood
• MG believes that her medical evaluations were inaccurate since they were done after the
resolution of the symptoms of each acute episode
• She continues to suspect that something is wrong with her heart
Patient case continued…
• PMH:
• Psoriasis (increased itchiness and flakiness in the past three months)
• Medications:
• Topical steroid for psoriasis
• Acetaminophen 500 mg 1-2 tablets by mouth every 4-6 hours as needed for menstrual cramps
and headaches
• Multivitamin 1 tablet daily
• Allergies:
• None
• SH:
• Single, lives alone
• Works as a marketing consultant
• (+) 1 glass of wine 2-3 nights per week
• (-) Smoking
• (-) Illicit drug use
• FH:
• Mother had major depressive disorder (MDD); committed suicide by overdose four years
earlier
• Father –healthy
• Two brothers are healthy
ANXIETY DISORDERS
AND THEIR
TREATMENT AGENTS
Go to: pollev.com/anneschempp781
Overview of anxiety
• Anxiety is an emotional state commonly caused by the perception
of real or perceived danger that threatens the security of an
individual

• Anxiety may become excessive and/or debilitating

• May present with both physiological and psychological features

• Physiological: tachycardia, diaphoresis, shortness of breath
• Psychological: worry, anticipation of threats

• Individuals may develop an anxiety disorder when feelings of fear

and anxiety become frequent and excessive
Overview continued…
• Anxiety disorders are the most frequent mental illnesses found in
clinical practice and are also the most commonly misdiagnosed

• Anxiety disorders generally develop before the age of 30 years old

• Common risk factors include:

• Sex
• Social issues
• Family history of anxiety or depression
Types of anxiety disorders (not inclusive!)
• Generalized anxiety disorder (GAD)

• Panic disorder (PD)

• Social anxiety disorder (aka social phobia)

• Specific phobias

• Obsessive-compulsive disorder (OCD)

• Posttraumatic stress disorder (PTSD)

Managing anxiety disorders
• GOAL: remission of symptoms ***
• Response: improvement of symptoms after a therapy has been
initiated
• Management is divided into two phases:
• Acute phase
• Phase where the dose of the medication is being titrated
• When full response is reached (remission of symptoms), move into maintenance
phase
• Time range: minimum of 4 weeks, up to 12 weeks
• Maintenance phase
• Phase where the dose that achieved remission of symptoms is continued
• Time range: minimum of 1 year at adequate dose, up to lifelong therapy
 Anxiety Pharmacotherapy:
The Meds (pharmacology first)!
Selective Serotonin Reuptake Inhibitors (SSRIs)
• Some of these agents are first line options for GAD and PD
• Mechanism of action (MOA):
• Inhibit the reuptake of serotonin back into the presynaptic neuron by inhibiting the activity of
the serotonin transporter (SERT)
• This, in turn, keeps the serotonin in the synapse and allows it to exert its actions of regulating
mood, emotions, sleep and appetite
Brief Animation of how SSRIs work
• https://www.youtube.com/watch?v=ocSptPUBbuo
Available SSRI Agents
Generic Name Brand Name
Citalopram Celexa®

Escitalopram Lexapro®

Fluoxetine Prozac®

Fluvoxamine Luvox®

Paroxetine Paxil®

Sertraline Zoloft®
Serotonin Norepinephrine Reuptake Inhibitors
(SNRIs)
• Some of these agents are first line options for GAD and PD
• MOA:
• Inhibit the activity of SERT (like the SSRIs)
• In addition to inhibiting SERT, the SNRIs also inhibit the norepinephrine transporter (NET)
• These mechanisms allow serotonin and norepinephrine to stay in the synapse and exert their
actions on postsynaptic receptors

http://brainyinfo.com/antidepressants/snri/
Available SNRI Agents
Generic Name Brand Name

Venlafaxine Effexor®

Desvenlafaxine Pristiq®
(enantiomer of venlafaxine)

Duloxetine Cymbalta®

Milnacipran Savella®

Levomilnacipran ER Fetzima®
(enantiomer of milnacipran)
Benzodiazepines
• Primary site of action: GABAA receptor (a chloride ion channel)
Available Benzodiazepines
Generic Name Brand Name
Alprazolam Xanax®
Chlordiazepoxide Librium®
Clonazepam Klonopin®
Clorazepate Tranxene®
Diazepam Valium®
Estazolam Prosom®
Flurazepam Dalmane®
Lorazepam Ativan®
Midazolam Versed®
Oxazepam Serax®
Quazepam Doral®
Temazepam Restoril®
Triazolam Halcion®
Tricyclic Antidepressants (TCAs)
• MOA:
• Similar to SNRis (inhibit reuptake of serotonin and norepinephrine by inhibiting activity of
SERT and NET)
• Within this class, these is variability in affinity for SERT vs. NET
• Antagonize postsynaptic receptors, such as H1 and α, that leads to increased side
effects

quizlet.com
Available TCA Agents
Generic Name Brand Name
Amitriptyline Elavil®

Clomipramine Anafranil®

Desipramine Norpramin®

Doxepin Sinequan®

Imipramine Tofranil®

Nortriptyline Pamelor®

Trimipramine Surmontil®

Amoxapine Asendin®

Protriptyline Vivactil®
Monoamine Oxidase inhibitors (MAOis)
• Found to be a treatment option for treatment-resistant PD
• Mechanism of action:
• Inhibits the activity of monoamine oxidase (degradation of neurotransmitters) in the neuron
and increases neurotransmitters
• Some are irreversible, while are others are reversible; some are selective to one form of MAO,
while others are nonselective

http://www.neurosoup.com/maois
/
Available MAOi Agents
Generic Name Brand Name

Phenelzine Nardil®

Selegiline Emsam®

Tranylcypromine Parnate®

Isocarboxazid Marplan®

Moclobemide Manerix®
Pregabalin (Lyrica®)
• Could be a second line option for GAD
• MOA:
• Reduces calcium influx by binding to the presynaptic α2-δ subunit of
voltage-gated calcium channels
• In trials, it has been shown to produce anxiolytic effects similar to
certain benzodiazepines (lorazepam and alprazolam) and
venlafaxine

http://www.apiapollo.com/Pregabalin.html
Buspirone (Buspar®)
• A second line option for GAD
• MOA:
• Does not interact directly with GABA systems
• 5-HT1A agonist on presynaptic neurons (reduces the firing of serotonergic
neurons) and acts as a partial agonist at these receptors on postsynaptic
neurons
• Increases the release of norepinephrine and dopamine

google.com
Hydroxyzine (Vistaril®)
• An alternative option for GAD
• MOA:
• Chemical classification: an antihistamine
• In clinical trials, it has been shown to reduce anxiety symptoms

http://www.answers.com/topic/hydroxyzine
Second Generation Antipsychotics (SGAs)

• Some guidelines state that three of these agents (risperidone,

olanzapine, and quetiapine) can be used as augmentation with first
and second line therapies for treatment resistant GAD
 Anxiety Pharmacotherapy:
Treatment Guidelines second!
GENERALIZED ANXIETY
DISORDER (TREATMENT
GUIDELINES AND DRUG
PROPERTIES)
Pharmacotherapy Options for GAD
Guidelines First Line Second Line Txt-Resistant

WFSBP1 Guidelines Escitalopram* Imipramine Augmentation

Paroxetine* Buspirone* with:
Sertraline Hydroxyzine Alprazolam
Venlafaxine XR* Diazepam
Duloxetine* Risperidone
Pregabalin Olanzapine

IPAP2 Review and SSRI Partial or no Assess for co-

Algorithm SNRI response: morbidities
-Increase dose
Addition of a -Switch to another
benzodiazepine if antidepressant
rapid response -Augment

1World Federation of Societies of Biological Psychiatry *FDA-approved for GAD

2The International Psychopharmacology Algorithm Project
Factors to consider when choosing an agent
• Patient’s history of response

• History of familial response

• Patient’s concurrent medical illnesses and medications

• Presenting symptoms

• Potential for drug-drug interactions

• Side effect profile

• Patient preference

• Drug cost
SSRI Options

Escitalopram Paroxetine Sertraline

Efficacy Acute therapy (8-12 weeks): 60-68% response rates
Remission rates: 30%

Initial Dosing 10 mg/day 20 mg/day 50 mg/day

Dosing Range 10-20 mg/day 20-50 mg/day 50-200 mg/day

Black Box Suicidal ideation in children, adolescents, and

Warning young adults

Side Effects Insomnia, jitteriness, headache, nausea/vomiting,

diarrhea, weight gain, sexual dysfunction
 Pharmacokinetic Properties of SSRI Options
Agent Bioavailability Half-life Time to Protein Active
(%) (hours) Peak Binding Metabolite
(hours) (%) s
Escitalopram 80 27-32 5 56 None

Paroxetine 50 24-31 5-7 95 None

Sertraline 36 (increases by 27 6-8 99 None

30-40% when
taken with food)
Why do we care about pharmacokinetics?
• Helps us to understand what the body does to the drug

• Half-life à agents with a long half-life may be beneficial in

instances when doses are missed, for example
• Fluoxetine is the SSRI agent with the longest half-life (4-6 days)

• Active metabolites à if an agent has an active metabolite, this

needs to be taken into consideration because the drug will be
acting for a longer period of time in the body
• Fluoxetine is the only SSRI that has an active metabolite
Drug Interactions with the SSRI Options
• Two types of drug-drug interactions:
1. Pharmacokinetic – most common interactions for SSRIs
• **REMEMBER: what the body does to the drug**
• Includes liver enzyme interactions (cannot be inclusive of all drug
interactions)
• Example à Paroxetine is a strong CYP2D6 inhibitor; TCAs are CYP2D6
substrates; co-administration of these agents may lead to elevated drug
concentrations of the TCAs
• Citalopram and escitalopram are the two SSRI agents with the least
potential of pharmacokinetic interactions
Pharmacokinetic Interactions: Inhibitory
Potentials of CYP Liver Enzymes
CYP Liver Enzyme

SSRI Agent 2D6 3A4

Escitalopram + 0

Paroxetine ++++ 0

Sertraline + +
Drug Interactions continued…

2. Pharmacodynamic – what the drug does to the body

• An example – the concomitant administration of two or more
serotonergic agents, leading to serotonin syndrome
• This interaction leads to physiological changes
SNRI Options
Venlafaxine XR Duloxetine
Efficacy Acute therapy (8-12 weeks): 60-68% response
rates
Remission rates: 30%

Initial Dosing 37.5 or 75 mg/day 30 or 60 mg/day

Dosing Range 75-225 mg/day 60-120 mg/day

Black Box Suicidal ideation in children, adolescents, and

Warning young adults

Side Effects Jitteriness, nausea/vomiting, diarrhea,

headache, sexual dysfunction, elevated blood
pressure, insomnia
 Pharmacokinetic Properties of SNRI Options
Agent Bioavailability Half-life Time to Peak Protein Active
(%) (hours) (hours) Binding Metabolites
(%)
Venlafaxine 45 5 2 27 Yes (O-
XR desmethylvenlafaxine)

Duloxetine 50 12 6 90 None
Drug Interactions with the SNRI Options
• Have relatively fewer CYP interactions than the SSRI agents

• Venlafaxine is a substrate, but not an inhibitor, of CYP2D6 and other

CYP enzymes

• Inhibitory Potentials of CYP Liver Enzymes

CYP Liver Enzyme
SNRI Agent 2D6 3A4

Venlafaxine 0/+ 0

Duloxetine +++ 0

• Pharmacodynamic interactions also exist (same instance as SSRIs)

Pregabalin
Mechanism of action Reduces calcium influx by
binding to the alpha2-delta
subunit of the voltage-gated
calcium channels
Initial Dosing 50 mg three times a day
Dosing Range 150-600 mg/day

Side Effects Dizziness, somnolence,

peripheral edema, weight gain
Imipramine: a TCA Option

Mechanism of action Tricyclic antidepressant

Initial Dosing 50 mg/day

Dosing Range 75-200 mg/day

Side Effects Jitteriness, anticholinergic

effects (constipation, dry mouth,
blurred vision, difficulty
urinating, drowsiness), weight
gain, sedation, cardiac
arrhythmias, orthostatic
hypotension
 Pharmacokinetic Properties of Imipramine

Bioavailability Half-life Time to Peak Protein Active

(%) (hours) (hours) Binding Metabolites
(%)
Imipramine 22-77 6-34 1.5-3 63-96 Yes (desipramine)
Drug Interactions with Imipramine
• As stated earlier, TCAs are CYP2D6 substrates
• Combination of CYP2D6 inhibitor and imipramine may result in an increase
of imipramine drug concentration (pharmacokinetic interaction)

• TCAs generally do not induce or inhibit CYP enzymes

• Imipramine has the potential to inhibit CYP2C19, however

• Due to the multiple receptor binding affinities of TCAs, there is an

increased risk of side effects with this class of medications
• Examples of pharmacodynamic interactions:
• Imipramine + Benadryl® = increased risk of antihistamine and anticholinergic side
effects
• Imipramine + antihypertensive agents = increased risk of orthostatic hypotension
Buspirone

Initial Dosing 7.5 mg twice daily

Dosing Range 15-60 mg/day

Side Effects Nausea/vomiting, abdominal

pain, drowsiness, dizziness
 Pharmacokinetic Properties of Buspirone

Bioavailability Half-life Time to Peak Protein Active

(%) (hours) (hours) Binding Metabolites
(%)
Buspirone 4 2.5 <1 86 Yes
(needs to
be dosed
2-3 times
a day)
Drug Interactions with Buspirone
• Drugs that inhibit CYP3A4 can increase buspirone levels since
buspirone is a CYP3A4 substrate

• Likewise, drugs that induce CYP3A4 can decrease buspirone levels

• Both are pharmacokinetic interactions

Hydroxyzine

Mechanism of action Antihistamine

Initial Dosing 25 or 50 mg four times a day

Dosing Range 200-400 mg/day

Side Effects Dry mouth, headache,

somnolence
Benzodiazepines
Alprazolam Chlordiazepoxide Clonazepam
Initial IR: 0.75 mg daily 25 mg daily 0.25 mg 1-2
Dosing XR: 1 mg daily times a day

Dosing IR: 0.75-4 mg/day 25-400 mg/day 1-4 mg/day

Range XR: 1-10 mg/day
Benzodiazepines continued…
Clorazepate Diazepam Lorazepam Oxazepam

Initial IR: 0.75 mg daily 0.25 mg 1-2 25 mg daily 30 mg daily

Dosing XR: 1 mg daily times a day

Dosing IR: 0.75-4 mg/day 1-4 mg/day 25-400 mg/day 30-120 mg/day
Range XR: 1-10 mg/day

**only these 7 benzodiazepines have FDA

approval for GAD
Common side effects of benzodiazepines
• Drowsiness, fatigue

• Memory impairment and amnesia

• Respiratory depression

• Potential for dependence

• Withdrawal symptoms may occur

Pharmacokinetic Properties of Benzodiazepine
Options
Drug Half-life Time to Peak Protein Binding Active
(hours) (hours) (%) Metabolites
Alprazolam 12-15 1-2 80 None

Chlordiazepoxide 5-30 1-4 96 Yes, multiple

Clonazepam 30-40 1-4 85 None

Clorazepate Prodrug 1-2 97 Yes

Diazepam 20-80 0.5-2 98 Yes (oxazepam

is one of them)
Lorazepam 10-20 2-4 85 None

Oxazepam 5-20 2-4 97 None

Drug Interactions with the benzodiazepines:
IMPORTANT interactions to know!
• IMPORTANT: Benzodiazepines may cause CNS depression**

• Simultaneous use of another CNS depressant, such as alcohol,

with a benzodiazepine may result in additive CNS depressant
effects

• Other CNS depressants include antihistamines, antipsychotics,

and opioids
More drug interactions with benzodiazepines
• Pharmacokinetic interactions

• Drugs that inhibit CYP3A4 (ketoconazole, an antifungal, is an example) can

increase blood levels of alprazolam and diazepam

• Drugs that induce CYP3A4 (carbamazepine is an example) can decrease

benzodiazepine blood levels
Tolerance and dependence

• What is tolerance?

• What is dependence?
Benzodiazepine Withdrawal Syndrome
• Need to properly taper down dose
• Frequent withdrawal symptoms:
• Anxiety
• Insomnia
• Irritability
• Muscle aches and tension
• Nausea
• Blurred vision
• Palpitations
• Severe withdrawal symptoms:
• Seizures
• Psychosis
• Delirium and confusion
• Can occur within one day and extend to > 2 weeks, depending on dose
and agent patient was on
Drug properties to consider when predicting a
withdrawal syndrome

• The higher the dose, the more serious the abrupt withdrawal is

• The longer the half-life, the slower the elimination, the fewer and
less severe withdrawal symptoms occur

• The longer the half-life, the later the withdrawal symptoms will
occur
Serotonin Syndrome (SS)
• Any antidepressant that increases serotonergic neurotransmission
can increase the risk of developing SS

• Symptoms:
• Mental status changes (agitation)
• Autonomic instability (temperature > 38°C, diaphoresis)
• Neuromuscular abnormalities (tremor, hyperreflexia, spontaneous clonus,
muscle rigidity)

• Treatments:
• Lower the dose of the medication and discontinue it
• Benzodiazepines to control agitation and seizures that may occur
• Serotonin-production blocking agents (cyproheptadine is an antihistamine
that reduce the production of serotonin)
How long do we treat for?

• Monitor efficacy every 2 weeks, initially

• Adequate trial of SSRI or SNRI = 4-6 weeks with

adequate dose

• Continue treatment for at least a year once patient

has responded to pharmacotherapy
PANIC DISORDER
(TREATMENT
GUIDELINES AND
DRUG PROPERTIES)
Pharmacotherapy Options for PD
Guidelines First Line Second Line Txt-Resistant

WFSBP1 Guidelines SSRI

Venlafaxine XR*

APA2 Guidelines SSRI Partial or no MAOi

SNRI response:
TCA -Increase dose
Benzodiazepine -Switch to another
CBT medication
-Augment

1World Federation of Societies of Biological Psychiatry

2 American Psychiatric Association *FDA-approved for PD
Factors to consider when choosing an agent
• Patient’s history of response

• History of familial response

• Patient’s concurrent medical illnesses and medications

• Presenting symptoms

• Potential for drug-drug interactions

• Side effect profile

• Patient preference

• Drug cost
SSRI Options
Citalopram Fluoxetine Fluvoxamine
Efficacy 60-80% response rate
Antipanic effect of SSRIs is delayed for at least 4
weeks (some patients do not respond for 8-12
weeks)
Initial Dosing 10 mg/day 5 mg/day 25 mg/day
Dosing Range 20-40 mg/day 10-80 mg/day 100-300 mg/day

Black Box Suicidal ideation in children, adolescents, and

Warning young adults

Side Effects Insomnia, jitteriness, headache, nausea/vomiting,

diarrhea, weight gain, sexual dysfunction
 Pharmacokinetic Properties of SSRI Options
Agent Bioavailability Half-life Time to Protein Active
(%) (hours) Peak Binding Metabolite
(hours) (%) s
Citalopram >/= 80 33 2-4 80 None

Fluoxetine 95 4-6 days 4-8 94 Yes

(norfluoxetine)

Fluvoxamine 53 15-26 2-8 77 None

Pharmacokinetic Interactions: Inhibitory
Potentials of CYP Liver Enzymes
CYP Liver Enzyme

SSRI Agent 2D6 3A4

Citalopram + 0

Fluoxetine ++++ ++

Fluvoxamine 0 +++
Clomipramine: another TCA Option

Mechanism of action Tricyclic antidepressant

Initial Dosing 25 mg/day

Dosing Range 25-250 mg/day

Side Effects Jitteriness, anticholinergic

effects (constipation, dry mouth,
blurred vision, difficulty
urinating, drowsiness), weight
gain, sedation, cardiac
arrhythmias, orthostatic
hypotension
 Pharmacokinetic Properties of Clomipramine

Bioavailability Half-life Time to Peak Protein Active

(%) (hours) (hours) Binding Metabolites
(%)
Clomipramine 50 12-36 2-6 98 Yes
Phenelzine

Mechanism of action Monoamine oxidase inhibitor

(nonselective)
Initial Dosing 15 mg/day
Dosing Range 30-90 mg/day

Side Effects Jitteriness, hypertensive crisis in

overdose, orthostatic
hypotension
 Pharmacokinetic Properties of Phenelzine

Bioavailability Half-life Time to Peak Protein Active

(%) (hours) (hours) Binding Metabolites
(%)
Phenelzine Unknown 11 Unknown Unknown None
Drug Interactions with MAOis
• Significant interaction to note:
• When MAOis are taken with certain foods, especially those high in
tyramine
• Examples of foods high in tyramine include aged cheeses, sour cream, yogurt,
cottage cheese, American cheese, wine, beer, sardines, canned or processed
meats, raisins, liver, soy sauce, coffee, chocolate, licorice
• Result: hypertensive crisis
• Symptoms include occipital headache, stiff neck, nausea, vomiting, sweating, and
sharply elevated blood pressure

• MAOis can also interact with buspirone and other antidepressants

• Increased risk of developing serotonin syndrome
How long do we treat for?
• Monitor efficacy every 1-2 weeks for the first 1-3
months of pharmacotherapy, and then every 2-4
weeks
• After dose is stabilized and symptoms have decreased,
monitor patient every 2 months

• SSRIs and SNRIs should work within 4-8 weeks, but

could be up to 12 weeks

• Benzodiazepines – effective for acute treatment

• Use short-term for only 2-4 weeks

• Continue treatment for 12-24 months

MAJOR DEPRESSIVE
DISORDER AND ITS
TREATMENT AGENTS
Go to: pollev.com/anneschempp781
Video: What people with depression want you to
know

• https://www.youtube.com/watch?v=IQr1G1OOEEQ
 An easy acronym
“SIGE CAPS”
• Sleep increased or depressed
• Interest and/or mood is diminished **
• Guilt or worthless feelings
• Energy is diminished

• Concentration is impaired
• Appetite increased or decreased
• Psychomotor retardation or agitation
• Suicidal thoughts, attempts, or plans

**essential features (must have at least one to hold diagnosis of

MDD)
Assessing Depression: PHQ-9 Scale
Managing MDD
• Euthymia: a patient’s baseline state, no depressive symptoms
• GOAL: remission of symptoms; patient returns to euthymic state ***
• Response: improvement of symptoms after a therapy has been initiated
• Management is divided into three phases:
• Acute phase
• Phase where the dose of the medication is being titrated
• When full response is reached (remission of symptoms), move into continuation phase
• Time range: 6 – 12 weeks
• Continuation phase
• Phase where the dose that achieved remission of symptoms is continued
• Time range: 4 – 9 months
• Maintenance phase
• The time after continuation phase where management involves “watchful waiting” or
treatment is continued at dose that achieved remission of symptoms
• Time range: years – lifelong
Managing MDD continued…
• Relapse – return of depressive symptoms during the acute or
continuation phase

• Recurrence – return of depressive symptoms during the

maintenance phase
 Managing MDD:
A depiction
Remission
Relapse Recurrence
Euthymia
Increased

Relapse
severity

Response
Symptoms

Syndrome

Treatment phases Acute Continuation Maintenance

(6 to 12 wk) (4 to 9 mo) (³1 y)
Time
 Depression Pharmacotherapy:
The Meds (pharmacology first)!
Mixed Serotonergic Agents
• All these agents are treatment options for MDD
• 3 agents in this class, all with slightly different mechanisms of
action
• Trazodone (Desyrel®)
the-medical-dictionary.com

• Nefazodone (Serzone®)
medlibrary.org

• Vilazodone (Viibryd®)

www.medicinescomplete.com
Bupropion (Wellbutrin®)
• Unique agent as it has no effect on serotonin
• MOA:
• Classically known as a NDRI (norepinephrine dopamine reuptake inhibitor)
• Also involved with the presynaptic release of NE (norepinephrine) and DA
(dopamine) into the synaptic cleft

www.pharmacy-and-drugs.com
Mirtazapine (Remeron®)
• Another unique agent that is an option for MDD
• MOA:
• Presynaptic α2 receptor antagonist that, in turn, enhances the presynaptic
release of NE and serotonin
• Antagonizes 5-HT2 and 5-HT3 receptors à leads to lower anxiety levels and
GI side effects
• H1 antagonist

dailymed.nlm.nih.gov
Vortioxetine (Trintellix®)
• New medication approved by the FDA in 2013 for the treatment of
MDD

• MOA:
• Inhibits the reuptake of serotonin
• 5-HT1A receptor agonist
• Partial 5-HT1B receptor agonist
• 5-HT1D, 5-HT3, and 5-HT7 receptor antagonist
Depression Pharmacotherapy:
Treatment Guidelines second!
How to pick an antidepressant?
• Since the effectiveness of antidepressants is generally comparable
between classes and within classes of medications, the APA
(American Psychiatric Association) guidelines state to:
• Pick an antidepressant based on:
• Side effect profile
• Safety and tolerability
• Pharmacological properties (half-life, drug interactions)
• Historical response to medications
• Cost
• Patient preference
SNRIs not discussed earlier
• Desvenlafaxine (Pristiq®)
• Initial and usual doses are 50 mg/day, with no additional benefit seen with
higher doses
• Extended release tablets à dosed once a day
• Half-life is 11 hours and there are no active metabolites
• Relatively new SNRI compared to the others in its class
TCAs not discussed earlier
• Amitriptyline
• Initial dose: 25 mg/day; dose range is 100-300 mg/day

• Nortriptyline
• Amitriptyline’s metabolite
• Initial dose: 25 mg/day; dose range is 50-150 mg/day
• Half-life can reach up to 88 hours, while amitriptyline’s half-life can reach
46 hours
MAOis not discussed earlier
• Selegiline
• A transdermal patch
• Initial dose is 6 mg/24 hours and the maximum dose is 12 mg/24 hours
• Dose may be increased by 3 mg/day increments every 2 weeks

• Tranylcypromine
• Initial dose: 10 mg/day; dose range is 20-60 mg/day

• Pharmacokinetic properties are not determined

Mixed Serotonergic Agents
Nefazodone Trazodone Vilazodone
Initial Dosing 100 mg/day 50 mg/day 10 mg/day
Dosing Range 300-600 150-g00 mg/day 10-40 mg/day
mg/day
Note Carries a BBW Place in therapy
for liver failure has not been
determined yet
Side Effects Orthostatic Orthostatic Diarrhea,
hypotension, hypotension, nausea,
dizziness, sedation, vomiting,
somnolence, dizziness trouble
dry mouth, sleeping
nausea,
asthenia
 Pharmacokinetics of mixed serotonergic agents
Agent Bioavailability Half-life Time to Protein Active
(%) (hours) Peak Binding Metabolite
(hours) (%) s
Nefazodone 20 2-4 1 99 Yes

Trazodone Unknown 6-11 1-2 92 Yes

Vilazodone 72 25 4-5 > 95 Not

determined
Drug Interactions with the mixed serotonergic
agents
• Nefazodone is an inhibitor of CYP3A4
• Example: nefazodone can increase triazolam levels, so reduce triazolam
dose by 75%

• Trazodone is a substrate of CYP3A4, but does not inhibit or induce it

• Caution when combining with CYP3A4 inducers or inhibitors

• Vilazodone is also a substrate of CYP3A4

• Caution when using with other serotonergic agents due to risk of SS

Bupropion
• Initial dose: 150 mg/day; dose range is 150-450 mg/day

• Side effects include:

• Nausea
• Vomiting
• Tremor
• Insomnia
• Dry mouth
• Lowers seizure threshold

• Interesting fact: bupropion is actually used as a smoking cessation agent

• Another interesting fact: bupropion could be used to mitigate sexual

dysfunction side effects of SSRI agents
Bupropion continued…
• Pharmacokinetic properties
• Half-life is 10-21 hours
• 3 active metabolites exist for bupropion, so take into consideration when
using this medication

• Drug Interactions
• Use with MAOis may increase the risk of hypertensive crisis
• Medications that also lower the seizure threshold (examples:
antipsychotics, antihistamines)
• One of bupropion’s metabolites inhibits CYP2D6 (like fluoxetine and
paroxetine)
Mirtazapine
• Initial dose is 15 mg/day; dose range is 15-45 mg/day

• Side effects include:

• Somnolence and sedation
• Dry mouth
• Weight gain
• Constipation

• Interesting fact: in clinical practice, mirtazapine is used as an

appetite stimulant
Mirtazapine continued…
• Pharmacokinetic properties
• Half-life is 20-40 hours
• No active metabolites

• Drug Interactions
• Other serotonergic agents as the risk of SS is increased
• Sedating effects of mirtazapine may be enhanced when given with CNS
depressants such as alcohol or benzodiazepines
• Mirtazapine is a substrate of CYP2D6, CYP3A4, and CYP1A2
• Inhibitors may increase mirtazapine blood levels and inducers may decrease
mirtazapine levels
Vortioxetine
• Initial dose: 5 or 10 mg/day; dosing range = 5-20 mg/day

• Side effects:
• Sexual dysfunction
• Nausea/vomiting
• Dizziness
• Dry mouth
• Diarrhea/constipation
Vortioxetine continued…
• Pharmacokinetic properties
• Half-life is ~ 66 hours
• No active metabolites

• Drug Interactions
• Other serotonergic agents as the risk of SS is increased
• Vortioxetine is metabolized by CYP2D6
• Inhibitors of CYP2D6 will increase concentration of vortioxetine, while inducers
will decrease concentration of vortioxetine
Consider this for the SSRI Agents!
Consider for…
• Paroxetine for underweight
patients
• Paroxetine for insomnia
• Fluoxetine and sertraline for
psychomotor retardation
• Fluoxetine for overweight or
obese patients
Avoid or use caution in…
• Paroxetine for overweight or
obese patients
• Citalopram and escitalopram in
QTc prolongation or torsades
risk
• Fluoxetine and sertraline in
agitation or insomnia
• Paroxetine in pregnancy
Consider this for the SNRI Agents!

Consider for… Avoid or use caution in…

• Psychomotor retardation • Hypertension

• Chronic pain • Agitation or insomnia

Consider this for Bupropion!

Consider for… Avoid or use caution in…

• Sexual dysfunction concern • Seizure disorders

• Smokers • Hypertension

• Psychomotor retardation • Agitation or insomnia

• Fatigue or sleepiness

• Overweight or obese patients

Consider this for Mirtazapine!

Consider for… Avoid or use caution in…

• Agitation • Overweight or obese patients

• Insomnia • Hyperlipidemia

• Underweight patients/low
appetite
Initial Treatment
Severity Level PHQ-9 Score Initial Treatment
Strategies
Mild 10-14 Evidence-based
monotherapy:
psychotherapy or
pharmacotherapy

Moderate 15-19 Evidence-based

monotherapy:
psychotherapy or
pharmacotherapy

Severe >/= 20 Combination of

psychotherapy and
pharmacotherapy
STAR*D Trial
• STAR*D Trial
• Sequenced Treatment Alternatives to Relieve Depression
• Funded by the National Institute of Mental Health
• Largest and longest study ever conducted to evaluate
depression treatment
• Goal: to assess the effectiveness of depression treatments in
patients diagnosed with MDD
• 4 levels in the study
• Those participants who did not reach remission in one level could
proceed to the next level of treatment
STAR*D Trial continued…
• Who participated?
• 7-year period, study enrolled 4,041 outpatients
• Ages 18-75 years old
• 1,165 excluded, so 2,876 participants were actually evaluated
• Treatment Levels
• Level 1: Citalopram was given to participants for 12-14 weeks
• Level 2: Switch to sertraline, bupropion SR, venlafaxine XR or
psychotherapy, or add bupropion SR, buspirone, or psychotherapy to
citalopram from level 1
• Level 3: Switch to mirtazapine or nortriptyline, or add lithium or
triiodothyronine (T3) to their current regimen
• Level 4: Switch to tranylcypromine or combination of venlafaxine XR with
mirtazapine
STAR*D Trial continued…
• Results
• Outcome measure in this trial was remission of symptoms, not response
• In level 1, ~33% reached remission and another 10-15% responded
• It took approximately 7 weeks to reach remission
• In level 2, in the switch group, ~25% reached remission, and in the add-on
group, ~33% reached remission
• In level 3, in the switch group, 12-20% reached remission, and in the add-on
group, ~20% reached remission
• In level 4, 7-10% reached remission
• Investigators conclude: ~50% of participants reached remission after 2
treatment levels, and over the course of all 4 levels, almost 70% of those
who did not withdraw reached remission
STAR*D Trial continued…
• What can we take away from this trial?
• If a patient fails one SSRI, it does not mean that he/she will fail another
• Monoamine oxidase inhibitors are limited because of their tolerability
profiles
• Patients with difficult-to-treat depression can get well after trying different
treatment strategies, but the odds of reaching remission lessen with every
additional treatment strategy needed
• Those who reach remission have a better chance of remaining symptom-
free compared with those who just experience symptom response
• Provide medications at optimal doses, maintain diligent monitoring, and try
different treatment choices
Assessing the Adequacy of Antidepressant
Interventions
• APA Guidelines
• 4-6 weeks of treatment at target dose is needed before
concluding that a patient is unresponsive or partially
responsive to a specific therapy
• If patient has not reached remission, may consider
switching a patient to an agent within the same class or to
an agent from a different class
• Augmenting the first therapy with a non-MAOi
antidepressant from a different class or augmenting with
a non-antidepressant therapy (lithium, T3, second-
generation antipsychotic) are also second-line options
Assessing the Adequacy of Therapeutic
Interventions continued…
• After 7-10 days
• Improved sleep
• Reduced anxiety
• After 7-21 days
• Improved self-care
• Improved thinking, concentration
• Increased energy, activity level
• Appetite impairments resolve
• After 2-4 weeks
• Improved mood
• Reduced suicidal ideation (SI)
Back to our patient: MG
Recap of Patient case: MG
• CC: “I am tired of this.”
• HPI:
• MG is a 23-year-old WF who was referred for a psychiatric evaluation by her cardiologist
• In the past two months, MG has presented to the Emergency Department four times for
acute complaints of rapid onset episodes of palpitations, shortness of breath, sweats,
trembling, and fears that she was going to die
• The symptoms seemed to peak within minutes, leaving her scared, worried, and with the
belief that she was having a heart attack
• Medical exams have found normal physical examinations, vital signs, lab results, toxicology
screens, and EKGs
• MG reported a total of five of these episodes in the past three months, with the episodes
occurring at work, at home, and while walking her dog
• She has developed a fear of having other episodes, which has led her to miss days of work
• Her sleep quality has declined and so has her mood
• MG believes that her medical evaluations were inaccurate since they were done after the
resolution of the symptoms of each acute episode
• She continues to suspect that something is wrong with her heart
Patient case continued…
• PMH:
• Psoriasis (increased itchiness and flakiness in the past three months)
• Medications:
• Topical steroid for psoriasis
• Acetaminophen 500 mg 1-2 tablets by mouth every 4-6 hours as needed for menstrual cramps and
headaches
• Multivitamin 1 tablet daily
• Allergies:
• None
• SH:
• Single, lives alone
• Works as a marketing consultant
• (+) 1 glass of wine 2-3 nights per week
• (-) Smoking
• (-) Illicit drug use
• FH:
• Mother had major depressive disorder (MDD); committed suicide by overdose four years earlier
• Father –healthy
• Two brothers are healthy
In Conclusion
• Anxiety is a normal human emotion, that when excessive,
may result in an anxiety disorder
• Anxiety disorders are frequently misdiagnosed
• Major depressive disorder is a DSM-5 diagnosable
condition Treatment guidelines help healthcare
professionals make treatment recommendations and
choices
• There is overlap between the agents that can be used to treat
anxiety disorders (especially the two discussed in this
presentation) and MDD
Valuable MDD Resources
• VA/DoD Clinical Practice Guidelines for the Management
of Major Depressive Disorder (2016):
https://www.healthquality.va.gov/guidelines/MH/mdd/VAD
oDMDDCPGFINAL82916.pdf

• APA Practice Guideline for the Treatment of Patients With

Major Depressive Disorder (2010):
http://psychiatryonline.org/pb/assets/raw/sitewide/practic
e_guidelines/guidelines/mdd.pdf
Questions??
Thank you for your time and attention!
ANXIETY/PANIC/DEPR
ESSION AGENTS
PA Pharmacotherapeutics Course
October 3, 2017 (1:30 – 3:30 pm)

Lecturer: Teresa Elsobky, Pharm.D., BCPP

Clinical Psychiatric Pharmacist
Assistant Professor of Pharmacy Practice
Bernard J. Dunn School of Pharmacy
Shenandoah University