WHAT TO DO WHEN
COMPICATIONS ARISE:
TREATING DEPRESSION AND ANXIETY IN
THE PRIMARY CARE SETTING
Jennifer A. Ganem MS, APRN
Londonderry Square
50 Nashua Road
Londonderry, NH 03053-3438
Phone: (603) 432-3399
Fax: (603) 432-3396
www.jenniferaganem.com
Jennifer A. Ganem MS, APRN
DISCLOSURES
• I was on the following Speaker Bureaus:
2003 - 2010 Shire Pharmaceuticals, Inc.
2004 - 2012 Forest Pharmaceuticals, Inc.
2006 - 2010 Novartis Pharmaceuticals Corporation
2008 - 2010 AstraZeneca Pharmaceuticals
• I presented a poster funded by Shire Development
LLC at the American Academy of Nurse Practitioners
National Conference (June 2012)
Jennifer A. Ganem MS, APRN
Objectives
At the end of this presentation you will be able to:
• Determine an effective way to manage common
complications including, but not limited to,
when to change or augment antidepressants
• Determine if pharmacogenetic testing is
warranted
Jennifer A. Ganem MS, APRN
In any given year,
in those age 18 and older in the US:
Mental Health Disorder
Occurs in:
Rated “severe” in:
Major Depression
9.5%
45%
Bipolar
2.6%
---
18.1%
---
Anxiety (all)
Jennifer A. Ganem MS, APRN
Major Depression Mnemonic
Thanks to Dr. Carey Gross of MGH
Patient must have a depressed mood or anhedonia for at least
two weeks and four of the following:
Sleep (insomnia or hypersomnia)
Interests (diminished interest in or pleasure from activities)
Guilt (excessive or inappropriate guilt; feelings of worthlessness)
Energy (loss of energy or fatigue)
Concentration (diminished concentration or indecisiveness)
Appetite (decrease or increase in appetite; weight loss or gain)
Psychomotor (retardation or agitation)
Suicide (recurrent thoughts of death, suicidal ideation or suicide
attempt)
Jennifer A. Ganem MS, APRN
Antidepressants
• Tricyclics
• Not first line because they are lethal in small amounts
• Several require blood monitoring and have a narrow window
• Several cause EKGs changes and require monitoring in
children, as well as adults with cardiac issues
• SSRIs
• First line for depression because they are not lethal in small
amounts
• Do not require blood or EKG monitoring*
• Three approved to be used in children/adolescents
• Several have anxiety indications as well
Jennifer A. Ganem MS, APRN
Antidepressants continued
• SNRIs
• Not lethal in small amounts
• One has an anxiety indication as well
• Can cause an increase in BP (dose-dependent effect)
• DNRI
• Not lethal in small amounts
• Can cause an increase in BP (dose-dependent effect)
Jennifer A. Ganem MS, APRN
The Black Box Warning
• December 2006, the FDA issued the black box warning; May
2007, it was updated to include patients up to age 24
• The warning includes ALL antidepressants and mood
stabilizers approved to treat the depressed phase of Bipolar
Disorder
“Antidepressants increased the risk compared to placebo
of suicidal thinking and behavior (suicidality) in children,
adolescents, and young adults in short-term studies of
major depressive disorder (MDD) and other psychiatric
disorders. Anyone considering the use of [Medication] or
any other antidepressant in a child, adolescent, or young
adult must balance this risk with the clinical need.”
Medication
Approved
Ages
Indication(s)
Dosage Range
buproprion
adults
MDD
100mg-300mg SR
150mg-450mg XL
citalopram
adults
MDD
10mg-60mg*
desvenlafaxine
adults
MDD
duloxetine
adults
escitalopram
fluoxetine
fluvoxamine
2D6
2C19
+
+
++
50mg
++
+
MDD, GAD
30mg-60mg
++
12-adults
adults
MDD
GAD
10mg-20mg
7-adults
8-adults
adults
OCD
MDD, Panic
Bulimia,
PMDD
10mg-60mg
6-adults
OCD
100mg-200mg
+
++
++
+
++
Medication
Approved
Ages
Indication(s) Dosage Range
levomilnacipran adults
MDD
paroxetine
MDD, GAD,
10mg-60mg
Panic,
Social,
PTSD, PMDD
sertraline
venlafaxine XR
adults
6-adults
adults
adults
40mg-120mg
50mg-200mg
OCD
MDD, GAD,
Panic,
Social,
PTSD, PMDD
MDD, GAD,
Social, Panic
75mg-225mg
2D6
+
2C19
+
++
+
+
++
+
vilazodone
adults
MDD
20mg-40mg
+
+
vortioxetine
adults
MDD
5mg-20mg
++
+
Jennifer A. Ganem MS, APRN
STAR*D
• Sequenced Treatment Alternatives to Relieve
Depression (STAR*D) was a collaborative study on
the treatment of depression, funded by the National
Institute of Mental Health.
• It’s the largest and longest study ever done to
evaluate depression treatment. Over a seven-year
period, the study enrolled more than 4,000
outpatients, aged 18-75 years.
• Its main focus was on the treatment of depression in
patients where the first prescribed antidepressant
proved inadequate.
Jennifer A. Ganem MS, APRN
STAR*D (continued)
• 2/3 of patients had one or more concurrent general
medical conditions
• 2/3 of patients had one or more concurrent
psychiatric condition
• Almost 40% had their first depressive episode prior
to age 18
• More than half of the patients met criteria for an
anxiety disorder
Jennifer A. Ganem MS, APRN
STAR*D (continued)
• 1/3 of patients DID NOT RESPOND until > 6 weeks
of treatment
• Used standardized symptom and side effect
measures at each visit
• This detects smaller changes than asking patients for their
global impression
• If > 20% reduction in symptoms, increase the dose
at week 6 and wait up to 10 weeks
Jennifer A. Ganem MS, APRN
STAR*D (continued)
Step
Treatment
Note
Likelihood of
remission
1
SSRI (citalopram)
2
Another SSRI
or SNRI
or DRI
or CBT
Despite substantial
pharmacological differences
between agents, there was no
substantial change in clinical
efficacy
31%
3
Augment with lithium
or augment with T3
T3 did better than lithium with
fewer side effects
14%
4
venlafaxine XR + mirtazapine
or tranylcypromine
37%
13%
Jennifer A. Ganem MS, APRN
Lessons Learned From STAR*D
• Patients and providers less likely to aim for
remission in those with treatment resistance
• Higher relapse rates occur in those with more trials
• Use standardized rating scales at each visit
• PHQ-9
• Reinforces the need for remission versus response!
Jennifer A. Ganem MS, APRN
PHQ-9: Depression Screening Tool
• 9 item scale designed to be used in primary care to screen for
depression and measure treatment response
• It is completed by the patient
• It’s use is reimbursed by most health insurances
• The adult and adolescent scales can be viewed at:
http://www.psychiatrictimes.com/all/editorial/
psychiatrictimes/pdfs/scale-PHQ-A.pdf
and
http://www.psychiatry.org/practice/dsm/dsm5/onlineassessment-measures#Disorder
Jennifer A. Ganem MS, APRN
Complication: Minimal Response
at an Average Dose at Week 6
• Increase dose to FDA maximum
• Wait until week 10 before changing medications or
augmenting
Jennifer A. Ganem MS, APRN
Complication:
Side Effects at Low Doses
• Start an agent that can be up-titrated in
incrementally small doses
Jennifer A. Ganem MS, APRN
Consider Pharmacogenetic Testing
(PGT)
• Non-invasive genetic test using an oral swab or
saliva specimen
• When a patient has:
• minimal response at average dose
• side effects at a low dose
• failed multiple antidepressants
Jennifer A. Ganem MS, APRN
Common PGT for Depression: CYP2D6
• Major pathway for:
• fluoxetine, fluvoxamine, paroxetine, vortioxetine,
duloxetine, venlafaxine, mirtazapine, TCAs
• aripriproazole
• Minor pathway for:
• citalopram, escitalopram, sertraline, levomilnacipran,
buproprion, vilazodone
• quetiapine, olanzapine
Jennifer A. Ganem MS, APRN
Common PGT for Depression: CYP219
• Major pathway for:
• citalopram, escitalopram, imipramine
• Minor pathway for:
• Fluoxetine, sertraline, vortioxetine, levomilnacipran,
venlafaxine, vilazodone, amitriptyline, nortriptyline
Jennifer A. Ganem MS, APRN
Common PGT for Depression: MTHFR
FOLIC ACID
 dihydrofolatereductase
Dihydrofolate
 dihydrofolatereductase
Tetrafolate
 serine hydromethyltransferase
5, 10 Methylene THF
methylenetetrahydrofolatereductase (MTHFR)
L-METHYLFOLATE
Jennifer A. Ganem MS, APRN
Common PGT for Depression: MTHFR
(continued)
• MTHFR (methylenetetrahydrofolatereductase)
• There is over 50 years of evidence linking folate
deficiency and depression
• Patients who are MTHFR+ may be at increased risk
for depression due to a reduced ability to convert
dietary folate into it’s active form of L-methylfolate
Jennifer A. Ganem MS, APRN
Common PGT for Depression: MTHFR
(continued)
• There is evidence that adding L-methylfolate to an
SSRI or SNRI, improved treatment outcomes as
compared to placebo or monotherapy alone
• There is evidence that L-methylfolate support the
production of neurotransmitters that naturally
help improve mood and boost antidepressant
response, especially in depressed patients with a
BMI >30
Jennifer A. Ganem MS, APRN
When to Test for MTHFR
• Mood disorders
• Schizophrenia
• Infertility and/or multiple miscarriages
• Migraines
• IBS
• Child or sibling with autism, spina bifida, cleft
lip/cleft palate
Jennifer A. Ganem MS, APRN
Why Consider PGT?
• To determine if:
• If a given mediation is appropriate for your
patient
• If the dose is appropriate
• If an ultrarapid metabolizer, dosage may need
to be increased
• If a slow metabolizer, dosage may need to be
decreased
• If l-methylfolate should be added to the regimen
Jennifer A. Ganem MS, APRN
Treatment of MTHFR +
• L-methylfolate 15mg po daily
Jennifer A. Ganem MS, APRN
Complication: Ending Treatment
• Treatment:
• Education about relapse rates
• Change medication or consider resuming brand-
name medication
• Change to a different type of therapy/therapist
• Prescribe a medication to treat side effects
Jennifer A. Ganem MS, APRN
Complication:
End of Drug Response
• Treatment:
• Change dosage or class of medicine
• Add or increase therapy
Jennifer A. Ganem MS, APRN
Complication:
Anxious Depression
• 53% of STAR*D participants were identified as
having anxious depression
• They were more likely to be unemployed, have less
education, more severe depression, and more
coexisting medical and psychiatric conditions
• They were harder to treat…
Jennifer A. Ganem MS, APRN
Complication:
Anxious Depression
(continued)
Anxious Depressed
Nonanxious Depressed
42% response
53% response
22% remission
33.4% remission
Step 1
Jennifer A. Ganem MS, APRN
Complication:
Increased Anxiety/Panic Attacks
• Given that about half of the patients presenting with
depression in primary care have a co-morbid
Anxiety Disorder, the potential to induce some
anxiety exists.
• Therefore, at the onset of treatment, let patients
know they may experience increased anxiety
symptoms
Jennifer A. Ganem MS, APRN
Managing Increased Anxiety < 1 month
• Consider using a benzodiazepine in the first month of treatment.
Benzodiazepine
Length of Action
Dosage Range
alprazolam
2-4 hours
0.25mg-1mg up to QID
lorazepam
4-6 hours
0.5mg-2mg up to TID
clonazepam
6-8 hours
0.5mg-2mg up to TID
Jennifer A. Ganem MS, APRN
Managing Increased Anxiety >1 month
Medication
Age
Indication
Dosage Range
buspirone
adults
GAD
15mg-30mg BID
hydroxyzine
children adults
Antihistamine
< 6yo
50mg up to TID
Off label for
anxiety
> 6yo
50mg-100mg up to TID
*safety data 6-18
gabapentin
Anticonvulsant
Off label for
anxiety
propranolol
adults
HTN
Up to 3600mg daily
in divided doses
(beta-blocker)
Off label for Social
Phobia
10-40mg single dose
30 minutes prior to social event
Jennifer A. Ganem MS, APRN
Complication:
Patient Becomes Pregnant
• Educate about the benefits and risks of continuing
on antidepressant
• Consider continuing medication if patient is currently
depressed or has experienced more two or more episodes of
depression
• http://www.perinatalweb.org/assets/cms/uploads/files/WA
PC_Med_Chart_2012_v9.pdf
Jennifer A. Ganem MS, APRN
Complication:
Patient Becomes Pregnant (continued)
• Only Paxil is Pregnancy Category D, the rest are
Category C
• Don’t change medications if it’s working; why
expose the fetus to more agents?
• Maximize the dose of the current medication before
augmenting with another agent
Jennifer A. Ganem MS, APRN
Resources Regarding
Medication Use During Pregnancy
• www.womensmentalhealth.org
• www.emorywomensprogram.org
• www.motherisk.org
Jennifer A. Ganem MS, APRN
Complication:
Sustained Depression
• Treatment:
• Change dosage or class of medicine
• Add or increase therapy
• Augment with another antidepressant, mood
stabilizer approved for augmentation
• Augment with lithium or T3
• Add or increase therapy
Jennifer A. Ganem MS, APRN
Complication: Depression Turns to
Hypomania…
• Bipolar patients present to us when depressed and
unless specifically asked they often do not report
hypomanic symptoms
• Keep in mind that bipolar patients are in a
depressed phase three times more than they are in
a hypomanic/manic phase so they may consider
hypomania “normal”
Jennifer A. Ganem MS, APRN
What Does Hypomania Look Like?
Distractibility
Indiscretion or excessive risk taking
Grandiosity
Flight of ideas or racing thoughts
Activity increase
Sleep deficit without fatigue
Talkativeness or pressured speech
Jennifer A. Ganem MS, APRN
MDQ: Screening Tool for Mania
• The Mood Disorder Questionnaire is a 15-item yes/no
self-report
• It was designed for adults, but can be used with patients
>12 years of age
• It can be repeated to measure improvement following
treatment
• It can be viewed at:
http://www.dbsalliance.org/site/PageServer?
pagename=education_screeningcenter_mania
Jennifer A. Ganem MS, APRN
Mood Charting
• Encourage patients to use mood charting to get a sense of
what happens over time
• Wellness Tracker (www.dbsalliance.org/wellness_tracker)
• Free iOS and Android
• Tracks mood, sleep, medication, symptoms, exercise, medication, etc.
• At-a-glance summary of trends
• Download PDF reports
• T2 Mood Tracker (t2health.dcoe.mil/apps/t-2mood-tracker)
• Free iOS and Android
• Tracks anxiety, stress, depression, general well-being
• Download PDF reports
• Mood Tracker (www.moodtracker.com)
• Browser based tool
• Tracks moods and medication
• Has medication reminder
• Provides audio relaxation and stress relief meditations
• Can share profile with provider
Jennifer A. Ganem MS, APRN
STEP-BD
(Systematic Treatment Enhancement Program for Bipolar Disorder)
• NIMH funded study that revealed adding an
antidepressant medication is no more effective than
placebo in treating depressed phase of Bipolar
Disorder but also didn’t show that an
antidepressant triggered manic switching
• Bottom line: Use a mood stabilizer approved for
antidepressant augmentation and/or to treat
bipolar depression!
Jennifer A. Ganem MS, APRN
Mood Stabilizers
Medication
Approved For
Antidepressant Augmentation
Approved for
Bipolar Depression
aripriprazole
Y
N
lamotrigine
N
Y (maintenance)
lurasidone
N
Y
olanzapine
Y
Y
quietapine
Y
Y
Jennifer A. Ganem MS, APRN
Complication:
Patient Becomes Suicidal
• Refer to the local ER to determine the level of care
needed to maintain his safety
Jennifer A. Ganem MS, APRN
Additional Resources:
• National Alliance for the Mentally Ill
http://www.nami.org/
• National Institute of Mental Health
http://www.nimh.nih.gov/index.shtml
• Depression and Bipolar Support Alliance
http://www.dbsalliance.org/site/PageServer?pagename=home
• National Suicide Prevention Hotline
1-800-273-TALK (8255)
Jennifer A. Ganem MS, APRN
References:
Bandelow, B., Sher, L., Bunevicius, R., Hollander, E., Kasper, S., Zohar, J.,… WFSBP Task Force on Anxiety
Disorders, OCD and PTSD. (2012). Guidelines for the pharmacological treatment of anxiety disorders, obsessivecompulsive disorder and posttraumatic stress disorder in primary care. International Journal of Psychiatry in Clinical
Practice, 16(2), 77-84. doi: 10.3109/13651501.2012.667114
Fava, M, Rush, A.J., Alpert, J.E., Balasubramani, G.K., Wisniewski, S.R., Carmi, C.N,,…Trivedi MH.(2008). Difference
in treatment outcome in outpatients with anxious versus nonanxious depression: A STARD*D report. American
Journal of Psychiatry, 165(3):342-51.
Gaynes, B. N., Rush, A. J., Trivedi, M. H., Wisniewski ,S. R., Balasubramani, G. K., Spencer, D. C.,… Fava, M. (2007).
Major depressive symptoms in primary care and psychiatric care setting: a cross sectional analysis. Annals of Family
Medicine, 5(2), 126-134. doi:10.1370/afm.641
Ginsberg, L. D., Oubre, A. Y., Daoud, Y. A. (2011). L-methyloflate Pluss SSRI or SNRI from Treatment Initiation
Compared to SSRI or SNRI Monotherapy in a Major Depressive Episode. Innovative Clinical Neuroscience, 8(1), 19-28.
Hidalgo, R. B., Tupler, L. A., & Davidson, J.R. (2007). An effect-size analysis of pharmacologic treatments for
generalized anxiety disorder. Journal of Psychopharmacology, 21(8), 864-872. doi: 10.1177/0269881107076996
Kessler, R. C., Chiu, W. T., Demler, O., & Walters, E. E. (2005). Prevalence, severity, and comorbidity of twelve-month
DSM-IV disorders in the National Comorbidity Survey Replication (NCS-R). Archives of General Psychiatry, 62(6), 617627. doi:10.1001/archpsyc.62.6.617
Kupka, R. W., Altshuler, L. L., Nolen, W. A., Suppes, T., Luckenbaugh, D. A., Leverich, G. S.,… Post, R. M. (2007).
Three times more days depressed than manic or hypomanic in both bipolar I and bipolar II disorder. Bipolar Disorder,
9(5), 531-535. doi:10.1111/j.1399-5618.2007.00467.x
Papakotstas, G. I., Shelton, R. C., Zajecka, J. M, Etemad, B., Rickels, K., Clain, A.,…Fava M. (2012). L-Methylfolate as
Adjuctive Therapy for SSRI-Resistant Major Depression: Results of Two Randomized, Double-Blind Parllel-Sequential
Trials. American Journal of Psychiatry, 169(12):1267-74.
Rakofky, J. (2016) RELAPSE: Answers to why a patient is having a new mood episode. Current Psychiatry, 15(2), 5354.
Rush, J.A. (2007) STAR*D: What have we learned? American Journal of Psychiatry, 164 (2), 201-204.
Sachs, G., _Nierenberg, A.,A, Calabrese, J.R., Marangell, L.,B, Wisniewski, S.,R, Gyulai ,L,…Thase ME. (2007).
Effectiveness of adjunctive antidepressant treatment for bipolar depression; a double-blind placebo-controlled study.
New England Journal of Medicine, 356(17):1711-22.
Stahl, S. M. (2007). Novel Therapeutics for Depression: L-methylfolate as a Trimonoamine Modulator and
Antidepressant-Augmenting Agent. CNS Spectrums, 12 (10), 39-44.