Impact of Ethnicity on Antidepressant Therapy Essay

Impact of Ethnicity on Antidepressant Therapy Essay

The Impact of Ethnicity on Antidepressant Therapy
Major depressive disorder is one of the most prevalent disorders you will see in clinical practice. Treatment for this disorder, however, can vary greatly depending on client factors, such as ethnicity and culture. As a psychiatric mental health professional, you must understand the influence of these factors to select appropriate psychopharmacologic interventions.Impact of Ethnicity on Antidepressant Therapy Essay. For this Discussion, consider how you might assess and treat the individuals in the case studies based on the provided client factors, including ethnicity and culture.

Case 3: Volume 1, Case #29: The depressed man who thought he was out of options

To prepare for this Discussion:
• Examine the case study and Take the pretest for the case study.
• Review the patient intake documentation, psychiatric history, patient file, medication history, etc. As you progress through each section, formulate a list of questions that you might ask the patient if he or she were in your office.
• Based on the patient’s case history, consider other people in his or her life that you would need to speak to or get feedback from (i.e., family members, teachers, nursing home aides, etc.).
• Consider whether any additional physical exams or diagnostic testing may be necessary for the patient.
• Develop a differential diagnoses for the patient. Impact of Ethnicity on Antidepressant Therapy Essay.Refer to the DSM-5 in this week’s Learning Resources for guidance.
• Review the patient’s past and current medications. Refer to Stahl’s Prescriber’s Guide and consider medications you might select for this patient.
• Review the posttest for the case study.

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ACTUAL ASSIGNMENT
PLEASE Addressed each of the following numbers with a subtopic, all the references used must have an in-text citation in each paragraph. All Articles used should come from USA and must be within last five years only that is from 2014 to 2018. Please do not begin a paragraph with author name(s) (PLEASE USE parenthetical/in-text citations)Impact of Ethnicity on Antidepressant Therapy Essay
Post a response to the following bullets
Ø Provide the case number in the subject line of the Discussion thread.
Ø List three questions you might ask the patient if he or she were in your office. Provide a rationale for why you might ask these questions.
Ø Identify people in the patient’s life you would need to speak to or get feedback from to further assess the patient’s situation. Include specific questions you might ask these people and why.
Ø Explain what physical exams and diagnostic tests would be appropriate for the patient and how the results would be used.
Ø List three differential diagnoses for the patient. Identify the one that you think is most likely and explain why.
Ø List two pharmacologic agents and their dosing that would be appropriate for the patient’s antidepressant therapy based on pharmacokinetics and pharmacodynamics.Impact of Ethnicity on Antidepressant Therapy Essay. From a mechanism of action perspective, provide a rationale for why you might choose one agent over the other.
Ø For the drug therapy you select, identify any contraindications to use or alterations in dosing that may need to be considered based on the client’s ethnicity. Discuss why the contraindication/alteration you identify exists. That is, what would be problematic with the use of this drug in individuals of other ethnicities?
Ø If your assigned case includes “check points” (i.e., follow-up data at week 4, 8, 12, etc.), indicate any therapeutic changes that you might make based on the data provided.Impact of Ethnicity on Antidepressant Therapy Essay
Ø Explain “lessons learned” from this case study, including how you might apply this case to your own practice when providing care to patients with similar clinical presentations

References/Resources
Note: All Stahl resources can be accessed through the Walden Library using this link. This link will take you to a log-in page for the Walden Library. Once you log into the library, the Stahl website will appear.

--Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY: Cambridge University Press.
--Note: To access the following chapters, click on the Essential Psychopharmacology, 4th ed tab on the Stahl Online website and select the appropriate chapter. Impact of Ethnicity on Antidepressant Therapy Essay.Be sure to read all sections on the left navigation bar for each chapter.
• Chapter 7, “Antidepressants”
--Stahl, S. M. (2014b). The prescriber’s guide (5th ed.). New York, NY: Cambridge University Press.
--American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: Author.

--Howland, R. H. (2008a). Sequenced treatment alternatives to relieve depression (STAR*D). Part 1: Study design. Journal of Psychosocial Nursing and Mental Health Services, 46(9), 21–24. doi:10.3928/02793695-20080901-06

Howland, R. H. (2008a). Sequenced treatment alternatives to relieve depression (STAR*D).Impact of Ethnicity on Antidepressant Therapy Essay. Part 2: Study outcomes. Journal of Psychosocial Nursing and Mental Health Services, 46(19), 21–24. doi:10.3928/02793695-20081001-05

Yasuda, S.U., Zhang, L. & Huang, S.-M. (2008). The role of ethnicity in variability in response to drugs: Focus on clinical pharmacology studies. Clinical Pharmacology & Therapeutics, 84(3), 417–423. Retrieved from https://web.archive.org/web/20170809004704/https://www.fda.gov/downloads/Drugs/ScienceResearch/.../UCM085502.pdf.Impact of Ethnicity on Antidepressant Therapy Essay

The Impact of Ethnicity on Antidepressant Therapy

Major depressive disorder is one of the most prevalent disorders you will see in clinical practice. Treatment for this disorder, however, can vary greatly depending on client factors, such as ethnicity and culture. As a psychiatric mental health professional, you must understand the influence of these factors to select appropriate psychopharmacologic interventions.Impact of Ethnicity on Antidepressant Therapy Essay. For this Discussion, consider how you might assess and treat the individuals in the case studies based on the provided client factors, including ethnicity and culture.

 

Case 3: Volume 1, Case #29: The depressed man who thought he was out of options

 

To prepare for this Discussion:

  • Examine the case study and Take the pretest for the case study.
  • Review the patient intake documentation, psychiatric history, patient file, medication history, etc. As you progress through each section, formulate a list of questions that you might ask the patient if he or she were in your office.
  • Based on the patient’s case history, consider other people in his or her life that you would need to speak to or get feedback from (i.e., family members, teachers, nursing home aides, etc.).Impact of Ethnicity on Antidepressant Therapy Essay
  • Consider whether any additional physical exams or diagnostic testing may be necessary for the patient.
  • Develop a differential diagnoses for the patient. Refer to the DSM-5 in this week’s Learning Resources for guidance.
  • Review the patient’s past and current medications. Refer to Stahl’s Prescriber’s Guide and consider medications you might select for this patient.
  • Review the posttest for the case study.

 

ACTUAL ASSIGNMENT
PLEASE Addressed each of the following numbers with a subtopic, all the references used must have an in-text citation in each paragraph. All Articles used should come from USA and must be within last five years only that is from 2014 to 2018. Please do not begin a paragraph with author name(s) (PLEASE USE parenthetical/in-text citations)

Post a response to the following bullets

  • Provide the case number in the subject line of the Discussion thread.
  • List three questions you might ask the patient if he or she were in your office. Provide a rationale for why you might ask these questions.
  • Identify people in the patient’s life you would need to speak to or get feedback from to further assess the patient’s situation.Impact of Ethnicity on Antidepressant Therapy Essay. Include specific questions you might ask these people and why.
  • Explain what physical exams and diagnostic tests would be appropriate for the patient and how the results would be used.
  • List three differential diagnoses for the patient. Identify the one that you think is most likely and explain why.
  • List two pharmacologic agents and their dosing that would be appropriate for the patient’s antidepressant therapy based on pharmacokinetics and pharmacodynamics. From a mechanism of action perspective, provide a rationale for why you might choose one agent over the other.
  • For the drug therapy you select, identify any contraindications to use or alterations in dosing that may need to be considered based on the client’s ethnicity. Impact of Ethnicity on Antidepressant Therapy Essay.Discuss why the contraindication/alteration you identify exists. That is, what would be problematic with the use of this drug in individuals of other ethnicities?
  • If your assigned case includes “check points” (i.e., follow-up data at week 4, 8, 12, etc.), indicate any therapeutic changes that you might make based on the data provided.
  • Explain “lessons learned” from this case study, including how you might apply this case to your own practice when providing care to patients with similar clinical presentations

 

References/Resources

Note: All Stahl resources can be accessed through the Walden Library using this link. This link will take you to a log-in page for the Walden Library. Once you log into the library, the Stahl website will appear.

 

--Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY: Cambridge University Press.

--Note: To access the following chapters, click on the Essential Psychopharmacology, 4th ed tab on the Stahl Online website and select the appropriate chapter. Be sure to read all sections on the left navigation bar for each chapter.

  • Chapter 7, “Antidepressants”

--Stahl, S. M. (2014b). The prescriber’s guide (5th ed.). New York, NY: Cambridge University Press.

--American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: Author.Impact of Ethnicity on Antidepressant Therapy Essay

 

--Howland, R. H. (2008a). Sequenced treatment alternatives to relieve depression (STAR*D). Part 1: Study design. Journal of Psychosocial Nursing and Mental Health Services, 46(9), 21–24. doi:10.3928/02793695-20080901-06

 

Howland, R. H. (2008a). Sequenced treatment alternatives to relieve depression (STAR*D). Part 2: Study outcomes. Journal of Psychosocial Nursing and Mental Health Services, 46(19), 21–24. doi:10.3928/02793695-20081001-05

Yasuda, S.U., Zhang, L. & Huang, S.-M. (2008). The role of ethnicity in variability in response to drugs: Focus on clinical pharmacology studies. Clinical Pharmacology & Therapeutics, 84(3), 417–423. Retrieved from https://web.archive.org/web/20170809004704/https://www.fda.gov/downloads/Drugs/ScienceResearch/.../UCM085502.pdf Impact of Ethnicity on Antidepressant Therapy Essay

323
PATIENT FILE
The Case: The depressed man who thought he was out of options
The Question: Are some episodes of depression untreatable?
The Dilemma: What do you do when even ECT and MAOIs do not work?
Pretest Self Assessment Question (answer at the end of the case)
If a patient has low blood levels of an antidepressant at standard doses,
what could this mean?
A. Pharmacokinetic failure
B. Genetic variant causing pharmacokinetic failure
C. Pharmacodynamic failure
D. Genetic variant causing pharmacodynamic failure
E. Noncompliance
Patient Intake
• 69-year-old man
• Chief complaint: unremitting, chronic depression
Psychiatric History
• Recurrent, unipolar major depressive episodes for the past 40 years,Impact of Ethnicity on Antidepressant Therapy Essay
with good response to treatment and good inter-episode recovery
until fi ve years ago
• Onset then of one long, waxing and waning major depressive episode
ever since
• Five years ago, relapsed on venlafaxine 225 mg after having had a
good response to it
• Two years ago had nine electroconvulsive therapy (ECT) treatments
with a partial response
• In the past few years since relapse on venlafaxine has tried
(adequate trials, no severe side effects)Impact of Ethnicity on Antidepressant Therapy Essay essentially every known
antidepressant and augmentation combination known or reported
in the literature, from many capable psychiatrists and numerous
consultations from local, regional, and national psychiatrists, and
distinguished medical centers
– 5 SSRIs
– Duloxetine
– Mitazapine
– 2 TCAs
– Augmentation with 5 different atypical antipsychotics
– Augmentation with
– Lithium
– Thyroid
– Buspirone
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PATIENT FILE
324Impact of Ethnicity on Antidepressant Therapy Essay
– L-methylfolate
– Others
• Following ECT, given the MAOI phenelzine (Nardil) up to 105 mg/day
with some orthostasis, some antidepressant response, wearing off
despite increasing doses, and then all response to phenelzine wore
off
• Trials even included the controversial and heroic combination of an
monoamine oxidase inhibitor (MAOI) and a tricyclic antidepressant
(TCA) phenelzine plus nortriptyline, all ineffective
• Came to you on phenelzine 90 mg, nortriptyline 50 mg, and
occasional lorazepam, for your treatment recommendations
Medical History
• Not contributory
• Other medications:Impact of Ethnicity on Antidepressant Therapy Essay
– Boniva for osteoporosis
– Avapro for hypertension
– Lipitor for hypercholesterolemia
– Flomax for enlarged prostate
– Melloxicam for arthritis
Social and Personal History
• Married, 3 children, 8 grandchildren
• Retired engineer
• Non smoker, no drug or alcohol abuse
Family History
• Several fi rst degree relatives: depression
• No family history of suicide
Patient Intake
• Severely depressed and demoralized
• No joy or pleasure; sad, feeling helpless, hopeless, worthless,
problems concentrating
• Past two years rates himself 9/10 in severity (10 worst)
• Wife states he is letting go and giving up
Of the following choices, what would you do?
• Add one of the new antipsychotics, asenapine, iloperidone or
lurasidone that he has not taken yet
• Augment the MAOI with a stimulant, which is one of the few
combinations he has not tried yet
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PATIENT FILE
325Impact of Ethnicity on Antidepressant Therapy Essay
• Discontinue the nortriptyline and augment the MAOI
• Discontinue the MAOI and augment the nortriptyline
• Discontinue both the TCA and the MAOI and prescribe something else
• Send to another psychopharmacologist; this patient is too sick and
the prognosis is poor
• Do a complete medical and endocrine and neurological evaluation to
see if any underlying condition has developed that has been missed
• Look into personal and family dynamics to see if this is really a
resistant depression disguising other problems
• None of the above
Further Investigation
Is there anything else you would especially like to know about this
patient?Impact of Ethnicity on Antidepressant Therapy Essay
• What about details concerning his medical and neurological status?
– During the past year the patient has had extensive medical,
endocrine and cancer workups, all negative
– During the past year has also had neurological evaluation, with
normal EEG, MRI
– Neuropsychological tests consistent with severe depression but
without signs of an early dementia
• What about personal and family dynamics?
– Patient and family are indeed quite concerned about his
depression, fearing he will die before he recovers
– Patient has a long standing supportive marriage and supportive
children and no major fi nancial problems
– Has coped with recurrent episodes of depression his whole
life, bouncing back after each setback, but now has given up,
frightening his family
– No obvious reason to suspect family or personal dynamics as the
source of his depression
– However, he does have extreme negativity and a cognitive
approach may be useful if he begins to get enough motivation to
participate in this approach
If you would give or refer him for an experimental or “off label” protocol,
test or treatment, which would you choose?Impact of Ethnicity on Antidepressant Therapy Essay
• Intravenous single injection of ketamine (NMDA N-methyl-d-aspartate
antagonist) in an experimental protocol
• Send him for experimental DBS (deep brain stimulation)
• Oral riluzole (putative inhibitor of glutamate release)
• Acetylcholinesterase inhibitor in case this is really early dementia
• Send him for a quantitative EEG
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PATIENT FILE
326
• Send him for pharmacogenomics testing
• Send him for therapeutic drug monitoring
• I would not prescribe experimental treatments off label, nor send him
for an experimental protocol
Attending Physician’s Mental Notes: Initial Psychiatric
Evaluation
• There are very few remaining treatment options
Acetylcholinesterase inhibitor
• No evidence of dementia
• Treatment seems a long shot for his depression
TMS
• The patient may be a candidate for TMS
• However, TMS is not well documented to work in a case this severe,
especially in a case with less than robust responses to ECT
DBS
• DBS is a possibility, but only a research protocol, even though it
might save his life
• Only a few centers offer this procedure in the US and Canada
• Unclear how this will be paid as insurance probably does not cover
• However, some promising early results in treatment resistant
depression
• Will tell patient and family and referring psychiatrist about this and
provide literature but not advise action yet
Ketamine
• Intravenous single injection of ketamine is an experimental protocol
• Available as a research test at the NIMH (National Institute of Mental
Health) and a few universities
• A number of studies confi rm effi cacy in treatment resistant major
depression
• However, it only works for a few hours and then wears off and not
practical to repeat it
• Not only ketamine, but several NMDA 2B subtype selective
antagonists (NR2B selective antagonists) are in clinical testing, some
of which are orally administered
• Too early to tell whether this will pan out and not available for open
label administration, only double blind trials
Referenced EEG
• A new type of EEG protocol, referenced EEG reports promising results,
but not in patients this severe and still considered a research tool
• Only available in a limited number of research centers and not proven
to predict clinical response to specifi c antidepressants, especially in a
case like this
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PATIENT FILE
327
SPECT scans
• Some commercial clinics offer older imaging technology (SPECT is
Single Photon Emission Computed Tomography) as brain scans for sale
• They do generate color pictures of brain activity that can be
impressive looking to patients
• Scans are accompanied with an algorithm claiming to predict which
drug to use
• Although this looks has a high-tech, scientifi c appearance, and raises
hope, it is not well accepted in the scientifi c community and costs
several thousand dollars not covered by insurance
Genotyping
• This approach may be useful in vulnerable populations of patients
such as children or elderly and those who do not respond to many
medications
• Genetic variants of cytochrome P450 (CYP45) drug metabolizing
enzymes can in some cases explain unusually high or unusually low
blood and brain concentrations of drugs:Impact of Ethnicity on Antidepressant Therapy Essay
– 2D6
– 2C19
– 2D9
– Others
– This might be useful here since this patient seems not to respond
to a wide number of medications now, and also has no notable
side effects from them
– Is it possible that his drug levels are low due to a drug
metabolizing enzyme variant, some variant of drug absorption, or
possibly noncompliance?
• Genetic variants of multiple neurotransmitter based genes, upon which
many antidepressants act, may help explain both who responds to what
antidepressant, and who gets side effects from what antidepressant
Phenotyping
• Determining whether a patient has high or low blood levels of a drug
establishes the phenotypes of:Impact of Ethnicity on Antidepressant Therapy Essay
– Poor metabolizers
– Extensive metabolizers
– Compliance/adherence
– Pharmacokinetic variants can explain how he absorbs and
metabolizes his antidepressants and thus measurement of
genetic variants of CYP450 drug metabolizing enzymes may be
helpful in explaining why the patient is not responding, especially
if he does not generate adequate plasma and brain drug levels
(pharmacokinetic)
• Advised his local treating psychiatrist to augment phenelzine with
stimulant
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PATIENT FILE
328Impact of Ethnicity on Antidepressant Therapy Essay
Attending Physician’s Notes: First Interim Followup, Week 20
• Local/referring psychiatrist declined to augment MAOI with stimulant
as recommended
• Decided instead to give ECT again
• Local/referring psychiatrist thought eleven ECT treatments improved
him 60%
• Stopped MAOI prior to ECT and then started venlafaxine 225 mg/
mirtazapine 30 mg (“California rocket fuel”) as ECT began
• Post ECT, severe subjective memory problems, patient very
discouraged
• Nevertheless, given maintenance ECT; venlafaxine increased to 375
mg and mirtazapine increased to 45 mg
• After ninth maintenance ECT (20th overall), developed an expressive
aphasia, question of a stroke versus a complication of ECT; cardiac
catheterization was normal except for a possible patent foramen ovale
of unknown signifi cance
• Consulting neurologist thought patient’s aphasia was a complication
of ECT
• However, referring psychiatrist thought the patient’s aphasia was due
to a stroke so lowered venlafaxine to 225 mg, being afraid of potential
elevated BP, pulse and further cardiovascular/cerebrovascular
complications
• BP remained normal and under control; aspirin added to treatment
Case Outcome: First Interim Followup, Week 20Impact of Ethnicity on Antidepressant Therapy Essay
• Phone consultation one month after the post-ECT “event” and 20
weeks since initial evaluation in the offi ce
• Patient was still having memory problems, speech problems, and
worsening depression
• Taking venlafaxine 225 mg, plus mirtazapine 45 mg, plus alprazolam
prn, now augmented with aripiprazole 10 mg
• Before chasing after exotic testing and treatments considered in the
mental notes during the initial psychiatric evaluation 20 weeks ago
(listed above), perhaps it would be a good idea simply to send off
blood for therapeutic drug monitoring to see how well he is absorbing
his venlafaxine and whether there is any room for a rational and safe
dose increase
• Unclear why he is no longer responding to doses of venlafaxine that
have occurred would in the past, but this is frequently observed in the
progression of major depressive episodes over many years
• Specifi cally recommended getting drug levels of venlafaxine and its
active metabolite O-desmethyl-venlafaxine, and consider increasing dose
of venlafaxine XR to 300 mg or 375 mg while monitoring BP and mood
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329Impact of Ethnicity on Antidepressant Therapy Essay
PATIENT FILE
Case Outcome: Second Interim Followup, Week 24
• Phone consultation in another month showed patient’s aphasia had
resolved and memory improving, but mood still low; mood as bad as it
was prior to ECT
• Seems more clear that aphasia was due to ECT and not to a stroke
• Venlafaxine blood levels not obtained and dose stayed at 225 mg
• Aripiprazole was increased to 15 mg
• Requested blood levels of venlafaxine/O-desmethylvenlafaxine again,
and then to raise venlafaxine dose to 300 mg, as advised 4 weeks ago
Case Outcome: Third Interim Followup, Week 28
• Phone consult in another month, referring psychiatrist did get
venlafaxine/O-desmethylvenlafzine blood levels, both of which were
found to be low while taking a dose of 225 mg of venlafaxine XR
• Referring psychiatrist now agrees to increase venlafaxineXR to 300
mg and to discontinue aripiprazole
Case Outcome: Fourth Interim Followup, Week 32
• No improvement in depression
• Advised getting repeat venlafaxine/O-desmethylvenlafaxine blood
levels again at 300 mg and then raising the dose to 375 mg if still low
Case Outcome: Fifth Interim Followup, Week 36
• Phone consultation in another month
• Venlafaxine/O-desmethylvenlafaxine levels still low at a dose of 300
mg of venlafaxine XR, so raised the dose to 375 mg
• “A pretty good few weeks” then followed but then patient relapsed a bit
• No increase of BP and no apparent side effects from venlafaxine
• Given that the blood levels of venlafaxine/O-desmethylvenlafaxine were
so low on a dose of 300 mg/day, advised them to increase venlafaxine
to 450 mg/day and to get another set of therapeutic drug levels
Case Outcome: Sixth Interim Followup, Week 40
• Increased venlafaxine XR dose to 450 mg/day, then got blood levels
on this dose, which are only in the low normal range of the very
broad therapeutic range suggested by the laboratory of venlafaxine/Odesmethylvenlafaxine
• Aphasia and memory better, mood defi nitely improved enough so that
patient was no longer completely demoralized and was beginning to
have hope
• Suggested raising the dose by 75 mg, getting levels again and if
necessary, raising the dose again to 600 mg
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PATIENT FILE
330Impact of Ethnicity on Antidepressant Therapy Essay
Case Outcome: Seventh Interim Followup, Week 52
• Dose increased to 600 mg, with full remission of depression
• However, at 600 mg dose, began to have some irritability, insomnia
and 5–10 mm BP elevation, so reduced to 525 mg, and then to 450
mg of venlafaxine XR
• Tolerated it well at this dose
• BP normal by report
• Still in remission, now fi nally a year after the original consultation
• The case continues. . . .
Case Debrief
• A highly recurrent but readily treatable major depressive disorder
suddenly turned treatment-resistant in this patient’s 60s
• Not clear but hypothetically possible that this represents disease
progression secondary to changes in brain functioning
• This case was looking very complicated due to nonresponse
to standard and aggressive therapies at standard doses. Major
depressive disorder can be treatable even in the seemingly most
treatment-resistant cases
• In retrospect, this patient’s transient aphasia without evidence of
stroke was probably a rare complication of ECT
• Aggressive treatment does not have to be reckless but does have its
risks
• It is possible for experts to augment MAOIs with a stimulant, while
monitoring BP in heroic cases where the possible benefi t (which has
been reported with this combination) outweighs the risk (elevated BP,
cardio and cerebrovascular events)Impact of Ethnicity on Antidepressant Therapy Essay
• However, this did not happen here
• Another heroic if old-fashioned option is the combination of MAOI
with a TCA, well tolerated here but not effective
• Plasma drug level-guided heroic dosing of venlafaxine (or more
recently desvenlafaxine) can be useful for resistant cases as it was
here
• This may lead to venlafaxine dosing higher than 375 mg or
desvenlafaxine dosing up to 200 mg
Take-Home Points
• Never give up
• Consider therapeutic drug monitoring before exotic research options
• Therapeutic drug levels of antidepressants such as venlafaxine are
not well quantifi ed, but if absorption is low or metabolism is high (or
compliance is low), the blood levels of drug and active metabolites
can still guide dosage above the normal approved therapeutic range
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PATIENT FILE

BUY A PLAGIARISM-FREE PAPER HERE

331Impact of Ethnicity on Antidepressant Therapy Essay
Performance in Practice: Confessions of a
Psychopharmacologist
• What could have been done better here?
– Did it take too long to get to therapeutic drug monitoring?
– Was the second set of ECT treatments not a good idea?
• Possible action item for improvement in practice
– Consider therapeutic drug monitoring earlier in the treatment
algorithm for cases where there are inadequate therapeutic actions
and low side effects
– Consider genetic testing, especially in treatment resistant cases,
the elderly and children
Tips and Pearls
• High doses of drugs taken orally sometimes deliver normal doses
of drug to the brain because of various pharmacokinetic or genetic
factors
• The point is how much drug is getting into the brain, not how much is
taken by mouth
• The future promises better guidance of drug and dose selection by
genetic tests and neuroimaging
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PATIENT FILE
332Impact of Ethnicity on Antidepressant Therapy Essay
Two-Minute Tute: A brief lesson and psychopharmacology
tutorial (tute) with relevant background material for this case
– Genotyping in depression
– Ketamine treatment of resistant depression
– Brain changes in chronic depression
– Development of treatment resistant depression
Table 1: Genotyping Neurotransmitter-Related Enzymes
and Receptors in Patients with Treatment Resistant
Depression?
• Still considered research tools by many
• However, beginning to be available for clinical practice
applications
• Published results are not always consistently replicated
• Include variants of genes for many candidates:
– Serotonin related receptors
• SERT (the serotonin transporter)
• 5HT1A receptor
• 5HT2A receptor
• 5HT2C receptor
– Various glutamate receptors
– Dopamine regulating enzymes and receptors
• COMT (catechol-O-methyl-transferase)
• MTHFR (methylene tetrahydrofolate reductase)
• D2 receptor (dopamine)
– Hypothalamic-pituitary-adrenal (HPA) axis
• CRH1 receptor (corticotrophin releasing hormone)
• CRH binding protein
• Cortisol binding protein regulators (FKBP5)
– Measuring cytochrome P450 enzyme genotypes
– Ion channels
• KCNK2
• CACNA1Impact of Ethnicity on Antidepressant Therapy Essay
– Growth factors
• BDNF (brain derived neurotrophic factor)
• Many others
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Table 2: Glutamate, Ketamine and the Future of
Treatments for Resistant Depression
• Ketamine, like PCP/phencyclidine, is an antagonist at NMDA
(N-methyl-d-aspartate) receptors
• Several groups have reported that ketamine can at least
transiently improve symptoms in patients with treatment resistant
depression
• Ketamine blocks NMDA receptors, and some experimental
treatments target a subtype of these receptors, the NR2B
receptor, hypothesizing that this is the receptor through which
ketamine acts
• A novel hypothesis has been proposed for ketamine that it
activates the mammalian target of rapamycin (mTOR) pathway
• This leads to increased synaptic signaling proteins
• It also increases the number and the function of new spine
synapses, at least in the prefrontal cortex of rats
• These effects of ketamine are the opposite to the synaptic
defi cits that result from exposure to stress and thus could be the
hypothetical mechanism of any therapeutic action of ketamine in
treatment resistant depression, where the effects of stress upon
the brain may render standard antidepressants ineffective
Table 3: Are Brain Changes Progressive in Depression?
• A frontal-limbic functional disconnection is present in depression
and correlates with the duration of the current depressive episode
• Hippocampal volume loss is greater with longer periods of
untreated depression
• The likelihood that a life stress precipitates a depressive episode
is greatest for the fi rst episode of depression and declines with
each subsequent episode, although the risk of subsequent
episodes increase as though prior episodes of depression
as well as life stressors are causing subsequent episodes of
depression
• More episodes of depression as well as residual symptoms both
predict poorer outcome in terms of more relapses
• Antidepressants may boost trophic factors, normalize brain
activity, suggesting that successful and early treatment may
attenuate progressive maladaptive brain changes and improve
the clinical course of the illness
• Symptomatic remission may be the clinician’s benchmark for
enhancing the probability of arresting disease progression
• Sustained remission may be a clinician’s benchmark for
reversing the underlying pathophysiology of major depression
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0.0
0.2
0.4
0.6
0.8
1.0
0 50 100Impact of Ethnicity on Antidepressant Therapy Essay
Recovery
with
no symptoms 1-3 121 224
no symptoms 3+ 34 79
1+ mild symptoms 1-3 57 34
1+ mild symptoms 1-3 57 34
Previous
episodes
n
Median
weeks
well
150 200 250 300 350 400 450 500
Survival distribution function
Weeks to first relapse with any depressive
episode (major, minor, dysthymia)
Survival distribution function=cumulative proportion of cases surviving to a given interval
More episodes of major depression and residual symptoms
predict worse outcomes
Figure 1: More Episodes of Major Depression and Residual Symptoms
Predict Worse Outcomes. In other words, the depression you have,
the more depression you get. Depression begets depression. Lack of
remission begets relapse. This shows the importance of doing everything
possible to reduce the number of episodes of depression, and also to
treat every symptom to the point of remission when there is an episode of
depression. The name of the game is sustained remission in the modern
conceptualization of the treatment of depression.Impact of Ethnicity on Antidepressant Therapy Essay
Residual symptoms and episode count thus add to the complexity of
diagnosing and treating depression and can lead to worse outcomes.
• The main fi nding of this study was that depressed patients who
experienced recovery with no symptoms remained well for a median
of 4.3 years (224 weeks) before depression recurrence, compared
to approximately six months for patients who recovered with residual
symptoms. Therefore, recovery with residual symptoms from
depression was an important clinical marker associated with rapid
episode relapse in depression
• Asymptomatic recovery included those patients with at least 80%
of well interval weeks rated as the following: “Subject is returned to
‘usual self’ without any residual symptoms of the major depressive
disorder, although signifi cant symptomatology from underlying
conditions may continue.”Impact of Ethnicity on Antidepressant Therapy Essay
• Even the mildest residual symptoms, however, can negatively
impact outcomes. Patients with residual subthreshold depressive
symptoms (recovery with 1+ mild symptoms)—one or more mild
residual depressive symptoms—experienced on average a faster time
to relapse than did asymptomatic patients.
• Episode count, too, was a negative prognosticator. Patients with
more than three major depressive episodes (MDEs) tended to relapse
earlier than those with histories of three or fewer episodes, although
this did not reach signifi cance.
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PATIENT FILE
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BACKGROUND
• Patients with MDD (as diagnosed using Research Diagnostic Criteria,
or RDC) were followed naturalistically for 10 years or longer.
• Patients were divided on the basis of intake MDE recovery into
recovery with residual subthreshold depressive symptoms (recovery
with 1+ mild symptoms; N=82) and asymptomatic recovery
(N=155) groups. Trained raters interviewed patients every six months
for the fi rst fi ve years and every year thereafter.
• Depressive symptomatology was rated using the Longitudinal Interval
Follow-up Evaluation (LIFE) Psychiatric Status Rating (PSR) scales.
• Recovery with 1+ mild symptoms as defi ned by the PSR includes
those experiencing one or more depressive symptoms but of no more
than a mild degree.Impact of Ethnicity on Antidepressant Therapy Essay
• P values (given according to color of lines on slide graphic): Orange vs
green, P<.0001; orange vs blue, P<.0001; orange vs red, P<.0001;
green vs blue, P=.013; green vs red, P=.004; blue vs red, P=.283.
0
2
4
6
8
10
0 1 2 3 4 5 6 7-8 9-11
Risk (odds ratio)
Number of previous depressive episodes
Likelihood of recent life stress
precipitating depression
Risk (OR) of depression onset per month
Figure 2: Progression of Depression: Adverse Effects of Each Episode on
Future Episodes Which Become More Spontaneous and Less Triggered
by Stress. These data are consistent with the notion that symptoms of
depression and episodes of depression “kindle” subsequent episodes of
depression.
• The kindling hypothesis states that previous episodes of depression
change the brain, making patients more likely to experience
subsequent episodes of depression
• After 4 to 5 episodes, the best predictor of subsequent episodes of
depression is the number of previous depressive episodes, not stress
• Does this suggest that recurrent depression is a progressive disease?
BACKGROUND:
• Female twins from a population-based registry (N=2,395) were
interviewed 4 times during a period of 9 years, forming a study
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PATIENT FILE
336Impact of Ethnicity on Antidepressant Therapy Essay
group that contained 97,515 person-months and 1380 onsets of
MDD
• To assess the interaction between life-event exposure and the number
of previous episodes of MDD in predicting future MDD episodes,
discrete-time survival, a proportional hazards model, and piece-wise
regression analyses were used
• This pattern of results was unchanged by the addition of measures
of event severity and genetic risk, as well as the restriction to
“independent stressful life events”
• The same pattern of results emerged when within-person changes in
the number of episodes were examined
HYPOMANIA
DYSTHYMIA
recurrent
poor interepisode
recovery
bipolar
spectrum
treatment
resistence
Figure 3: is Major Depressive Disorder Progressive? Studies as well as
direct observations of cases over long periods of time suggest that one
episode of major depression may not only increase the chances of having
another, but that subsequent recurrences may not be followed by remission
and only by partial treatment responses, ultimately with episodes recurring
that may become treatment resistant.Impact of Ethnicity on Antidepressant Therapy Essay
What proportion of major depressive disorders remit?
HYPOMANIA
DYSTHYMIA
33% 20% 6-7% 6-7%
67% remisson
after 4 treatments
47%
40%
33% nonremitters
after 4 treatments
antidepressant
treatment #4
antidepressant
treatment #3
antidepressant
treatment #2
antidepressant
treatment #1
67%Impact of Ethnicity on Antidepressant Therapy Essay
Figure 4: What proportion of major depressive disorder remit?
Approximately one-third of depressed patients will remit during treatment
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PATIENT FILE
337
with any antidepressant initially. Unfortunately, for those who fail to remit
the likelihood of remission with another antidepressant monotherapy goes
down with each successive trial. Thus, after a year of treatment with four
sequential antidepressants taken for twelve weeks each, only two-thirds of
patients will have achieved remission.
100%
0%
3Impact of Ethnicity on Antidepressant Therapy Essay
months
not in
remission
60%
6
months
12
months
Relapse rate
After 1 treatment
in remission
33%
100%
0%
3
months
not in
remission
67%
6
months
12
months
Relapse rate
After 2 treatments
in remission
50%
100%
0%
3
months
not in
remission
70%
50%
6
months
12
months
Relapse rate
After 3 treatments
in remission
50%Impact of Ethnicity on Antidepressant Therapy Essay
100%
0%
3
months
not in
remission
6
months
12
months
Relapse rate
After 4 treatments
in remission
70%
30%
Figure 5: What Proportion of Major Depressive Disorders Relapse? The
rate of relapse of major depression is signifi cantly less for patients who
achieve remission. However, there is still risk of relapse even in remitters,
and the likelihood increases with the number of treatments it takes to get
the patient to remit. Thus, the relapse rate for patients who do not remit
ranges from 60% at twelve months after one treatment to 70% at six months
after four treatments, but for those who do remit it ranges from only 33%
at twelve months after one treatment all the way to 70% at six months after
four treatments. In other words, the protective nature of remission virtually
disappears once it takes four treatments to achieve remission.
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PATIENT FILE
338Impact of Ethnicity on Antidepressant Therapy Essay
Posttest Self Assessment Question: Answer
If a patient has low blood levels of an antidepressant at standard doses,
what could this mean?
A. Pharmacokinetic failure
– Pharmacokinetics is the body acting upon a drug; so, if the
body does not absorb or metabolize a drug in a way that normal
therapeutic levels are delivered to the brain via the blood, a low
blood level at standard doses can mean a pharmacokinetic failure
B. Genetic variant causing pharmacokinetic failure
– Genetic variants of CYP450 enzymes can cause excessive
metabolism of a drug and thus pharmacokinetic failure
C. Pharmacodynamic failure
– Pharmacodynamics is the drug acting upon the body, in this case,
transporters in the brain; so, if a patient has low blood levels of an
antidepressant, there is not adequate opportunity to see if the drug
will work, and this is not considered a pharmacodynamic failure; a
pharmacodynamic failure occurs when the brain does not respond
to normal levels of drug
D. Genetic variant causing pharmacodynamic failure
– Genetic variants are considered to cause pharmacodynamic
failures when despite adequate levels of drug, there is no
therapeutic response
E. Noncompliance
– low blood levels are more often caused by noncompliance/
nonadherence than they are by pharmacokinetic failures
Answer: A, B and E
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