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MAJOR DEPRESSION
A Life Worth Living . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level I
Brian L. Crabtree, PharmD, BCPP
CASE SUMMARY
A 41-year-old woman presents to an outpatient mental health clinic
on referral by her family physician. She has complaints, signs, and
symptoms indicative of a major depressive episode with melancholic features. She has undergone treatment for alcohol use disorder within the last year. She is experiencing severe family stressors,
namely, her children have moved out of the home. She is already
receiving antidepressant therapy, mirtazapine, prescribed by her
family physician, without improvement, and complains of weight
gain as a side effect. Nondrug therapies such as psychotherapy and
a support group should be initiated concurrently with alternate
pharmacotherapy. Feasible drug treatment options for this patient
include selective serotonin reuptake inhibitors (SSRIs), agents with
mixed-reuptake-inhibition pharmacology, and tricyclic antidepressants (TCAs). Efficacy is determined by evaluating target signs and
symptoms; standardized rating scales may also be used. It is important to question the patient about adverse effects at each visit and to
encourage adherence to the prescribed therapy.
QUESTIONS
Problem Identification
1.a. Create a list of this patient’s drug therapy problems.
• Major depression, poorly responsive to current therapy
• Current use of St. John’s wort, with possible implications
for other medication therapy, including adverse drug–drug
interactions
• Stable problems not requiring treatment at this time include
headaches treated with acetaminophen. Headaches may be
improved by successful antidepressant therapy.
1.b. What signs, symptoms, and laboratory values indicate the
presence and severity of depression in this patient?1
• Sleep disturbance
• Fatigue (feeling tired much of the time)
• Increased eating (loss of appetite with weight loss is more
common, but increased eating can occur. This patient may
have increased eating as an adverse effect of mirtazapine.)
• Concentration impairment
• Feeling down and sad
• Anxiety (commonly comorbid with depression), “pounding
heart”
• Crying spells
• Anhedonia
• Social withdrawal
• Passive suicidal ideas (no active plan, but wants to “go to sleep
and not wake up”)
• Normal physical and laboratory exams help to rule out nonpsychiatric causes of depression
• Previous alcohol abuse and dependence
• The melancholia specifier is met by the inclusion of severe loss
of pleasure in usual activities, depressed mood with despondency, motor slowing, and guilt
1.c. What factors in the family history support a diagnosis of
depression?
• A sister has depression and anxiety and takes antidepressant
medication.
• Another sister committed suicide.
1.d.Is there anything in the patient’s medication history that
could cause or worsen depression?
• Oral contraceptives can worsen depression, but this is unlikely
in this case because of her long history of recurrent episodes
and the fact that she has not taken them for 2 months before
this presentation.
Desired Outcome
2.What are the goals of pharmacotherapy in this case?2
• Eliminate or significantly reduce symptoms. Remission
(symptom-free or nearly symptom-free) should be the goal of
treatment of depression although a majority of patients continue with residual symptoms.
• Restore functioning to premorbid levels, especially with regard
to employability.
• Prevent depressive relapse.
• Minimize medication side effects.
• Ensure adherence with the prescribed regimen.
Therapeutic Alternatives
3.a. What nonpharmacologic treatments are important in this
case? Should nonpharmacologic treatments be tried before
beginning medication?
• Psychotherapy, supportive counseling, and support groups
are important nondrug therapies. Because of the severe
psychosocial aspects of this patient’s depression, including
multiple unstable marriage relationships, current conflict
with her children, the history of alcoholism treatment, and
financial stress, it is important for her to work through issues
in her life with a therapist and support group for at least a
few months in addition to taking medication. Different types
of psychotherapy vary in cost, but support groups are usually
free of charge. Research indicates that psychotherapy combined with drug therapy in the treatment of major depression
is often associated with better response than with pharmacotherapy alone.3
• Pharmacotherapy should be initiated concurrently with nonpharmacologic therapy.
3.b.What pharmacotherapeutic options are available for the
treatment of depression?
• Existing therapy with mirtazapine should be discontinued
concurrent with beginning alternate therapy because of poor
response and an adverse effect. The mirtazapine dosage could
possibly be increased, but she is already experiencing weight
gain at a dosage that is effective for many patients.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Major Depression
Lydia E. Weisser, DO, MBA
• Mental status examination findings help to determine drug
therapy target symptoms
CHAPTER 78
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• Frequent headaches
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SECTION 7
• Antidepressant medications are generally considered equally
effective. Comparative efficacy trials vary in outcomes, and
some meta-analyses suggest modest differences of questionable clinical significance.4 Choice of medication is usually
based on factors such as side-effect profile, ease and frequency
of dosing, and cost.
• SSRIs include the following agents:
✓Citalopram (Celexa, generics)
✓Escitalopram (Lexapro, generics)
Psychiatric Disorders
✓Fluoxetine (Prozac, generics)
✓Fluvoxamine (Luvox, Luvox CR, generics)
✓Paroxetine (Paxil, Paxil CR, Pexeva, Brisdelle [vasomotor
symptoms of menopause], generics)
✓Sertraline (Zoloft, generics)
• SSRIs are often considered antidepressants of first choice,
among the most commonly prescribed drugs in primary care,
and the most commonly prescribed antidepressants. Advantages include an extensive research basis, ease of use in a
once-daily regimen, efficacy at starting dosages, generally good
tolerability, and a wide therapeutic index. SSRIs are often more
easily tolerated than the TCAs. TCAs are no longer generally
considered first-line therapy.
• Disadvantages of SSRIs include their typical side-effect profile
and a propensity for drug–drug interactions. The most common side effects of SSRIs are GI (nausea and diarrhea), insomnia, somnolence, headache, sexual dysfunction, nervousness,
and restlessness. The most significant SSRI class drug–drug
interactions involve inhibition of drug-metabolizing enzymes
or serotonin syndrome.
✓Serotonin syndrome includes neurobehavioral (confusion,
agitation, and seizures), motor (myoclonus, rigidity, and
tremor), and autonomic (hypertension and hyperthermia)
features.
✓Drugs that also increase serotonin have the potential to
cause serotonin syndrome when combined with SSRI agents.
Important examples are meperidine, tramadol, dextromethorphan, and other antidepressants, particularly monoamine oxidase inhibitors (MAOIs).
✓Fluoxetine is a potent inhibitor of the CYP2D6 and 2C19
isoenzymes. Its active metabolite, norfluoxetine, is an inhibitor of the CYP3A pathway. Important and/or common
interactions include phenytoin, carbamazepine, propranolol,
metoprolol, morphine, and oxycodone. Although sometimes coprescribed, fluoxetine significantly slows clearance
of haloperidol, risperidone, and some antianxiety drugs
(eg, diazepam, alprazolam).
✓Paroxetine is a potent inhibitor of the CYP2D6 isoenzyme. Important and/or common interactions include those
with phenytoin, benztropine, trihexyphenidyl, propranolol,
metoprolol, opioids listed above, dextromethorphan, and
atomoxetine. Paroxetine 7.5 mg (Brisdelle) is FDA approved
only for managing vasomotor symptoms of menopause.
✓Fluvoxamine is a potent inhibitor of the CYP1A2 and 3A
pathways. Important and/or common interactions include
those with warfarin, carbamazepine, olanzapine, propranolol, metoprolol, and alprazolam.
✓Citalopram, escitalopram, and sertraline are associated with
fewer drug–drug interactions than other SSRIs because they
have minimal effect as inhibitors of metabolic enzymes.5
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
• Mixed serotonin effects and mixed reuptake inhibitors include
the following:
✓Venlafaxine (Effexor, Effexor XR, generics): affects serotonin
and norepinephrine reuptake.
✓Desvenlafaxine (Pristiq, Khedezla): affects serotonin and
norepinephrine reuptake. This is the major active metabolite
of venlafaxine.
✓Duloxetine (Cymbalta): affects serotonin and norepinephrine reuptake.
✓Milnacipran (Savella, Savella Titration Pack): affects serotonin and norepinephrine reuptake.
✓Levomilnacipran (Fetzima): affects serotonin and norepinephrine reuptake with preference for norepinephrine.
✓Mirtazapine (Remeron, generics): affects norepinephrine and
serotonin release via α-2 antagonism. Mirtazapine does not
inhibit serotonin or norepinephrine reuptake.
✓Bupropion (Wellbutrin, Wellbutrin SR, Wellbutrin XL,
Aplenzin, generics): affects dopamine and norepinephrine
reuptake.
✓Trazodone (Oleptro, generics): affects serotonin reuptake,
blocks serotonin (5-HT2) receptors.
✓Nefazodone (generics): affects serotonin reuptake, blocks
5-HT2 receptors.
✓Vilazodone (Viibryd): affects serotonin reuptake and partially agonizes the serotonin type 1A (5-HT1A) receptor.
✓Vortioxetine (Brintellix): affects serotonin reuptake, blocks
5-HT3 receptors, and agonizes 5-HT1A receptors
• Mixed reuptake inhibitors may also be used as first-choice
agents, but there is no evidence for superior efficacy compared
with SSRIs. These drugs also have their own advantages and
disadvantages. Advantages of the mixed reuptake inhibitors are
largely related to adverse effect profiles (eg, fewer serotoninrelated side effects). They may also be useful in patients who
fail to respond to SSRIs, although research is inconclusive on
this point. Bupropion is associated with less sexual dysfunction
than SSRIs, but it is contraindicated in patients with a history
of seizures or eating disorder. Vilazodone did not separate
from placebo regarding sexual adverse effects and weight
changes in clinical trials. Venlafaxine, bupropion, trazodone,
and levomilnacipran are available in extended-release formulations for once-daily administration. Duloxetine, mirtazapine,
vortioxetine, desvenlafaxine (a metabolite of venlafaxine), and
vilazodone can also be administered once daily. Vilazodone
is recommended to be taken with food. Duloxetine has
been researched particularly in depressed patients who have
prominent physical symptoms such as pain. Duloxetine is also
FDA-approved for peripheral neuropathy due to diabetes and
for fibromyalgia. Trazodone is primarily used in low dosages
as a sedative. Nefazodone is used less commonly because of a
boxed warning regarding hepatotoxicity.
• TCAs are the oldest antidepressant agents. Some of these
drugs (many of which are available generically) include the
following:
✓Amitriptyline (Elavil, Endep, generics)
✓Desipramine (Norpramin, Pertofrane, generics)
✓Doxepin (Silenor, generics)
✓Imipramine (Tofranil, Tofranil-PM, generics)
✓Nortriptyline (Pamelor, generics)
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✓Phenelzine (Nardil, generics)
✓Tranylcypromine (Parnate, generics)
✓Selegiline (Emsam)
• MAOIs are not usually used as first-line agents because of necessary dietary restrictions and the associated risk of a hypertensive reaction. Foods high in tyramine such as aged cheeses,
aged or cured meats, and soy products should generally be
avoided. Drugs with sympathomimetic effects, including nonprescription decongestants such as pseudoephedrine should
be avoided. MAOIs should not be combined with SSRI antidepressants. Selegiline is available in a patch formulation and
does not require dietary modification at 6 mg/day, the lowest
strength. Higher strengths do require dietary restrictions.
• Antipsychotic drugs (aripiprazole, quetiapine, and olanzapine):
Aripiprazole (Abilify) and quetiapine (Seroquel XR) are FDAapproved for adjunctive treatment in combination with antidepressant drugs for patients who have inadequate response to
antidepressant monotherapy. Olanzapine is approved in combination with fluoxetine for patients who fail usual therapy.
• Central nervous system (CNS) stimulants (methylphenidate and
dextroamphetamine) are not used as first-line agents because
of their stimulant side-effect profile and controlled-substance
regulatory status. They are sometimes used as adjunctive
agents in medically ill or elderly patients.
Optimal Plan
4.a. What drug regimen (drug, dosage, schedule, and duration)
is best for this patient?
• If the patient could tell us the name of the sister’s medication
and how she responds to it, this information could possibly
serve as the basis for an initial choice of treatment for this
patient, although the basis for this judgment is mainly intuitive
and has not been established in well-designed controlled trials.
In the absence of such information, the choice is not clear.
• Use of a medication that can be given once daily and is likely
to be effective with the initial dosage is desirable. The SSRI
antidepressants fit this description well. A mixed reuptake
inhibitor would also be appropriate for initial treatment. A
TCA would be an acceptable first-line treatment because of the
melancholic features but should be used with caution because
of toxicity in overdose.
✓Example of initial SSRI regimens is fluoxetine, 20 mg PO
once daily, or sertraline, 50 mg PO once daily, in the morning. The dosage of fluoxetine can range up to 80 mg/day. The
dosage of sertraline can range up to 200 mg/day. Fluoxetine
and sertraline are usually given in the morning to minimize
the risk of insomnia. Among the other SSRIs, paroxetine is
often associated with drowsiness, and it is not unusual for it
✓Patients who respond well to fluoxetine may benefit from a
dosage formulation for weekly administration called Prozac
Weekly. It is indicated for patients who have responded to
at least 3 months of daily therapy with fluoxetine. Prozac
Weekly is a 90-mg capsule containing enteric-coated pellets
that dissolve in the lower GI tract. It should be started 7 days
after stopping daily administration of fluoxetine. Prozac
Weekly is not indicated for initial treatment.
• Other SSRIs, or mixed reuptake inhibitors would also be
appropriate as first-line therapy for this patient. Refer to
the textbook chapter on depressive disorders for a listing of
the usual starting dosages.
✓Sustained-release dosage forms that allow for single daily
dosing are available for bupropion (Wellbutrin XL), venlafaxine (Effexor XR), and levomilnacipran (Fetzima).
Another sustained-release dosage form of bupropion
(Wellbutrin SR) is also available but may require divided
daily dosing.
✓Duloxetine (Cymbalta), desvenlafaxine (Pristiq), vilazodone (Viibryd), vortioxetine (Brintellix), and mirtazapine
(Remeron) can be given once daily.
✓Trazodone, nefazodone, and immediate-release formulations of venlafaxine and bupropion usually require more
than one dose per day.
✓Nefazodone is no longer considered first-line therapy
because of a risk of potentially fatal hepatotoxicity. The
product label includes a boxed warning about this risk.
TCAs often cause side effects that increase the likelihood
of nonadherence, but prescription costs are lower for TCAs
than for branded antidepressants. Some TCAs, including
imipramine, desipramine, and nortriptyline, can be monitored with serum concentrations as an additional parameter
in assessing and adjusting therapy.
✓If the patient responds satisfactorily, antidepressant therapy
should be continued for at least 6–12 months before an
attempt is made at tapering reduction. For a patient such
as this with a strong family history of depression, including
suicide, it is appropriate to continue medication at the same
dosage longer. Patients with a history of recurrent episodes
are often treated on an indefinite maintenance basis.
4.b. How should the patient be advised about the herbal therapy,
St. John’s wort?
• She should be advised to stop taking the St. John’s wort
because it could interact adversely with both the mirtazapine
she is currently talking and any antidepressant medication that
will be recommended as well as her Ortho-Novum. Although
she has not taken the contraceptive recently, it is likely she
will take it in the future. St. John’s wort is a strong inducer of
cytochrome enzymes, particularly the 3A3/4 pathway, which
enhances metabolic clearance of many coadministered drugs
leading to subtherapeutic drug levels.
4.c.What alternatives are appropriate if the patient fails to
respond to initial therapy?
• In the absence of significant side effects, initial therapy should
be optimized with dosage increases and a trial of at least 4
weeks. The most common reasons for poor response to initial
therapy are underdosing and inadequate length of therapy. If a
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Major Depression
• MAOIs include the following:
to be given at bedtime. The frequency of dosage adjustments
depends on clinical response and tolerability, keeping in
mind that several weeks are required for optimum effect.
CHAPTER 78
• Tricyclics may be particularly useful in patients with melancholic features of depression,6 but they require especially
careful adjustment to find the correct dosage and commonly
cause bothersome side effects, particularly sedation, anticholinergic effects, and orthostatic hypotension. They also are
problematic in patients with comorbid nonpsychiatric disease
such as cardiovascular disease or benign prostatic hyperplasia
and especially in elderly individuals. Research has shown the
TCAs to be less well tolerated than many other antidepressants, including an overdose situation with patients who may
have suicidal ideas.
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SECTION 7
switch to a different agent is advisable, a drug from a different
chemical class may be considered. The SSRIs are not a chemical class, however, and many patients respond to one SSRI
after failing another.
Psychiatric Disorders
• If an SSRI was used initially, options include a different SSRI
or non-SSRI antidepressant. Nefazodone would most likely
not be tried next because of the hepatotoxicity risk. Because
of dietary restrictions and adverse drug–drug interactions,
MAOIs are reserved for particularly difficult or otherwise
refractory patients or for patients with atypical depression.
• If the patient fails multiple trials of antidepressants, augmenting strategies may be implemented to enhance response. The
antipsychotic drugs aripiprazole and quetiapine are FDAapproved for adjunctive treatment of depression in patients
who show an inadequate response to antidepressant monotherapy. Among mood stabilizing drugs, lithium has been used
for antidepressant augmentation. Less well-established alternatives include thyroid hormone supplementation, pindolol,
and antidepressant combinations. Electroconvulsive therapy is
often effective treatment for refractory patients.
• Pharmacogenetic testing to assist with personalized treatment
selection for patients who fail to respond to multiple drug trials
or who experience intolerability on multiple trials is an emerging trend. It is a highly active area of research but is not yet
considered standard of care in routine practice.7
Outcome Evaluation
5.What clinical and laboratory parameters are necessary to
evaluate the therapy for efficacy and adverse effects?
• The principal drug therapy outcomes are the target signs and
symptoms identified in the history, review of systems (ROS),
and physical examination, particularly the mental status examination findings. Some clinicians also use standardized rating
scales such as the Hamilton Depression Rating Scale. Patient
self-rated scales include the Beck Depression Inventory. Various Internet-based versions of standardized rating scales are
available for both clinicians and patients.
• Monitoring of potential adverse effects should be specific to
the antidepressant agent being used. With SSRIs, common side
effects include GI disturbance such as nausea and diarrhea;
CNS effects such as irritability, jitteriness, and headache; sleep
disturbance such as insomnia; and sexual disturbances including erectile dysfunction, anorgasmia, and loss of libido. Side
effects are assessed primarily on the basis of the clinical interview. Some differences may exist within the SSRIs, but these
adverse effects are common to all agents in the group. Paroxetine is especially associated with a discontinuation syndrome.
Patients should be counseled to not stop therapy abruptly.
• Assess for the occurrence of side effects at each clinical interaction because side effects are the most common reason for
nonadherence to antidepressant therapy. Interview patients
briefly during clinic visits or visits to the pharmacy for prescription refills. A general question such as “Are you having
any problems with your medication?” can be asked within the
context of reassurance that some side effects are common but
may be temporary. If side effects are particularly bothersome
or interfere with daily function or quality of life, encourage
the patient to report these so that appropriate adjustments in
therapy can be made.
• Laboratory data monitoring is not always indicated with
antidepressant therapy. The SSRIs can cause hyponatremia
in some patients, and electrolyte monitoring at 6 months and
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
annually may be prudent. The TCAs are well known for their
cardiac effects; electrocardiographic (ECG) monitoring at
baseline and annually is advisable, especially in patients older
than 40 years of age.
Patient Education
6.What information should be provided to the patient to
enhance adherence, to ensure successful therapy, and to minimize adverse effects?
• Patient education should be individualized to patient needs
and the agent being used. Important points with this case
include these items.
• Fluoxetine (example):
✓ The name of this medication is fluoxetine (Prozac). It is used
for your depression.
✓Take this medication every day in the morning.
✓Medication for depression often takes up to 6 weeks, or even
longer, to be optimally effective. Do not be discouraged if
you do not feel better in the first few days.
✓Some symptoms may improve before others. Sleep, energy,
and appetite sometimes get better before the depressed feeling goes away.
✓If you miss a dose, take it as soon as you remember. If you
forget until the next day, skip the missed dose and continue
with the regular schedule.
✓Common side effects to watch for with this medication
include upset stomach, a jittery feeling, headaches, and
sleep disturbance. These do not occur with every patient,
and some of these side effects are similar to the symptoms
of depression. If they are caused by depression, they should
improve as the medication works. If they are caused by medication, the symptoms may linger or get worse. It is possible
that side effects will occur before your depression improves,
so it is important to continue treatment as prescribed, if the
side effects are not too bothersome, until the medication
has had time to work properly. If you feel your depression is
worsening or you have thoughts of harming yourself, contact
your physician immediately.
✓If you have questions or problems with your medication,
contact your physician or pharmacist for more information
and assistance.
■■ CLINICAL COURSE: ALTERNATIVE THERAPY
Mrs Flowers understands that she must stop the St. John’s wort she
has been taking because of an interaction with her prescribed mirtazapine and Ortho-Novum, but she wonders if it would have been
helpful if she had started it when she first began feeling depressed.
See Section 19 (Complementary and Alternative Therapies) in
this Instructor’s Guide for questions and answers about the use of
St. John’s wort for treatment of depression.
REFERENCES
1. American Psychiatric Association. Depressive disorders. In: Diagnostic
and Statistical Manual of Mental Disorders, 5th ed. Washington, DC,
American Psychiatric Association, 2013. p. 155–188.
2. Teter CJ, Kando JC, Wells BG. Major depressive disorder. In: DiPiro JT,
Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic
Approach, 9th ed. New York, NY, McGraw Hill, 2014. p. 1047–1066.
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6. Perry PJ. Pharmacotherapy for major depression with melancholic
features: relative efficacy of tricyclic versus selective serotonin reuptake
inhibitor antidepressants. J Affect Disord 1996;39:1–6.
7. Bishop JR, Stevenson JM, Burghardt KJ. Pharmacogenetics in mental health. In: Johnson JA, Ellingrod VL, Kroetz DL, Kuo GM, eds.
Pharmacogenomics: Application to Patient Care, 3rd ed. Lenexa, KS,
American College of Clinical Pharmacy, 2015. p. 115–134.
CHAPTER 78
3. Cuijpers P, Dekker J, Hollon SD, Anderson G. Adding psychotherapy
to pharmacotherapy in the treatment of depressive disorders in adults:
a meta-analysis. J Clin Psychiatry 2009;70:1219–1229.
4.Linde K, Kriston L, Rucker G, et al. Efficacy and acceptability
of pharmacological treatments for depressive disorders in primary
care: systematic review and network meta-analysis. Ann Fam Med
2015;13:69–79.
5. Spina E, Santoro V, D’Arrigo C. Clinically relevant pharmacokinetic
drug interactions with second-generation antidepressants: an update.
Clin Ther 2008;30:1206–1227.
Major Depression
Copyright © 2017 by McGraw-Hill Education. All rights reserved.