Diagnosis and Management of Depression 2018

© Stephen D. Sisson MD/Ambulatory Curriculum

Objectives
1. Diagnostic criteria for depression
a. Recommendations for screening for depression
2. Management options for treatment of depression
a. Picking a modality or modalities of treatment
b. When to use pharmacotherapy
c. When to recommend counseling
3. Pharmacotherapeutic options for treatment of depression
4. Basics of psychotherapy for the internist
5. Assessment of response to therapy
A. Augmentation therapy
6. Discontinuation of therapy

CASES

Case 1: Diagnostic criteria for depression

Ron Emanuel is a 28-year-old presenting with fatigue. He states he is tired all day long. Mr. Emanuel
goes to bed at 8:30PM, and sleeps until 6AM or so, yet still feels tired. He used to exercise, but no
longer has the energy. Past medical history is one of good health. He is taking no medications. Family
history is notable for depression in his father. Review of systems is notable for 20 pound weight gain
over the past year.

Physical exam is entirely normal. He had normal thyroid studies and a normal complete blood count
two months ago. HIV testing 6 months ago was negative.

Which ONE of the following statements is true?

A. Asking this patient if he is depressed is inappropriate, as it may prevent him from trusting you.
B. To diagnose a patient with depression, the patient must admit to feeling depressed or "blue"
or "down".
 C. Major depression is the most common psychiatric diagnosis in men between the age of 20 and
30.
D. Risk factors for depression include a positive family history of depression, as seen in this
patient.

Pop Up Answers
A. Incorrect. Although sensitivity is required to broach the subject, asking someone if they are
"depressed" or "blue" or "down" is an effective screen for a patient in whom depression is
suspected.
B. Incorrect. To diagnose an individual with depression, they must either admit to feelings of
depression or express anhedonia (lack of pleasure or enjoyment from activities that normally
cause pleasure or enjoyment).
C. Incorrect. Substance abuse and phobias are more common than major depression in young
men.
D. Correct. Risk factors for depression also include chronic medical illnesses, chronic pain
syndromes, substance abuse and other psychiatric disorders.

Summary answer
The correct answer is D: Risk factors for depression include a positive family history of depression,
as seen in this patient.

Introduction
Depression is the second most common chronic condition encountered by the internist. In the past,
psychiatrists and other mental health professionals were the chief providers of management for
depression, but recent national trends have demonstrated a greater role for internists in management
of depression. The advent of new pharmacotherapeutic agents (principally selective serotonin-
reuptake inhibitors) has resulted in more primary care physicians managing depression.

Worldwide, depression is the fourth leading cause of disability, with a greater impact on quality of life
than diabetes and arthritis. Estimates of the lifetime incidence of depression range from 5-12% for
men and 10-25% for women. The prevalence of depression in women is twice that of the prevalence
of men, and for both genders, the prevalence of depression increases with age.
Despite its widespread prevalence, depression is not the most common psychiatric diagnosis in women
or in men. In women, the most common psychiatric diagnosis is phobia, followed by major depressive
disorder, dysthymia and obsessive-compulsive disorder. In young men, the most common psychiatric
disorders are alcohol abuse, phobias and drug abuse. Middle aged men or older are more likely to have
dysthymia. Major depression is not common in young and middle-aged men, but remains an important
cause of disability in older men. Risk factors for depression are reviewed in Table 1.

Table 1: Risk factors for depression

Diagnostic criteria for depression

According to DSM-5, the definition of major depression is as follows:

For at least two weeks duration, the patient has one or two of:

A. Depressed mood
B. Loss of interest in nearly all activities (anhedonia)

AND three or four of (for at least five total):

 Insomnia or hypersomnia
 Feelings of worthlessness or inappropriate guilt
 Fatigue or loss of energy
  Diminished concentration or indecisiveness
 Substantial change in weight (>5%) or appetite
 Psychomotor agitation or retardation
 Recurrent thoughts of death or suicide

A shorter questionnaire to diagnose depression in a patient with low mood and anhedonia is the SALSA
questionnaire:

 Sleep disturbance
 Anhedonia
 Low Self-esteem
 Appetite disturbance

If two of the four SALSA items are positive, depression is diagnosed.

Another tool to evaluate a patient for possible depression is the Patient Health Questionnaire-9 (PHQ-
9) quick depression assessment. The PHQ-9 is filled out by the patient, so verification by the clinician
is important. An advantage to the PHQ-9 is that it can help to classify the severity of depression, and
can also be used to track depression over time, including assessment of response to therapy.

As we shall see, making the diagnosis is just one aspect of evaluating the depressed patient. The
functional status of the patient, support structures, medical and psychiatric comorbidities, and risk of
harm to self or others are important management issues set into motion once the diagnosis of
depression is made. In addition, there remains for some a social stigma associated with depression and
its treatment, and these should be addressed with sensitivity.

Dysthymia
Patients who do not fulfill the diagnostic criteria for depression may have a chronic mood disorder
known as dysthymia (depressed mood but failure to fulfill diagnostic criteria for depression, lasting at
least two years). Dysthymia is prevalent in the elderly, and is associated with greater medical burden
and poor health outcomes. These patients may respond to treatment with antidepressants. Therefore,
if when taking a history you determine that the patient does not quite fulfill the diagnostic criteria for
depression, the duration of symptoms becomes quite important. If the problems are recent, close
follow up is suggested. However, if on further questioning the patient has a long history of having three
or four depressive symptoms, consider the diagnosis of dysthymia, and consider treating them with
antidepressants.

Table 2: Section 1 Review

Case 2: Other considerations when diagnosing depression

Your next patient is Mike Pugh, a 63-year-old male who returns for follow up of hypertension. During
the visit, he mentions that his wife died unexpectedly four weeks ago, and ever since then, he has
gotten no sleep. He can only feel the empty place in the bed where his wife used to be. He struggles
to get through the day without frequent crying spells. He states his days are like 'roller coasters', with
positive memories of his wife followed by extreme sadness at her loss. He is functional, going to work
and spending time with family and friends, who are very supportive. He denies low self-esteem or guilt.
Which of the following is correct?

A. This patient should be diagnosed with depression and should be started on an

antidepressant.
 B. This patient is experiencing grief and should be offered supportive care.

Pop Up Answers

A. Incorrect. This patient is experiencing grief/bereavement, and does not fulfill diagnostic
criteria for depression.

B. Correct. This patient is experiencing grief/bereavement. Supportive care (including

consideration of anxiolytics) should be considered.

Summary answer
The correct answer is B: This patient is grief, and should be offered supportive care.

Introduction
Having reviewed diagnostic criteria for depression and dysthymia, we turn to other considerations in
the patient with a mood disorder.

DSM-5 and the bereavement exclusion

At times, patients may experience sadness for reasons other than depression or dysthymia. This is
particularly true in patients who have experienced recent loss, particularly of a loved one or a major
change in lifestyle (e.g., loss of job; retirement etc.). This period of sadness (or 'grief') resulting from
loss is known as bereavement. Bereavement may or may not coexist with depression. To differentiate
bereavement from depression, DSM-V notes the following:

 "In grief, painful feelings come in waves, often intermixed with positive memories of the
deceased; in depression, mood and ideation are almost constantly negative.
 In grief, self-esteem is usually preserved; in MDD (major depressive disorder), corrosive
feelings of worthlessness and self-loathing are common."

On occasion, you may see a patient who is experiencing a grief reaction, typically due to the loss of a
loved one. Acutely, supportive care (including anxiolytics such as benzodiazepines) is appropriate. If a
patient is grieving, treatment with antidepressants is indicated if the process remains pronounced
for more than two months after the event, or if coexistent depression is diagnosed.

Medical disease and depression

When evaluating a patient whom you suspect may be depressed, it is important to rule out physical
disorders, even when psychological distress is evident, because underlying medical illness may result
in the coincident development of depression. Many mood disorders, particularly anxiety and
depression, may be primary evidence of an underlying medical disorder, and 10-15% of patients with
depression will have this as a manifestation of another medical disorder. The relationship between
depression and other medical disorders is complex and poorly understood, but the presence of
depression in some individuals (e.g., those with myocardial infarction) is associated with increased
mortality. Medical conditions commonly associated with the development of depression include
diabetes, MI, CVA, hypothyroidism, cancer, dementia and Parkinson disease.

Medications that have been prescribed to the patient, particularly beta-blockers and reserpine, should
also be considered as the cause of depression. Other medications, less likely to cause depression but
still to be considered, include steroids, anticonvulsants, and anti-Parkinson medications. More
recently, interferon alpha, used to treat hepatitis C and other disorders, has been demonstrated to
cause depression. The incidence of depression in patients treated with interferon alpha can be reduced
by the prophylactic administration of paroxetine.

Section summary

 Bereavement is a period of sadness resulting from loss that should be differentiated from
depression.

 Paroxysms of sadness with preserved self-esteem are more suggestive of bereavement than
depression.

 Bereavement lasting longer than 2 months should be treated with antidepressants.

 Medical disorders that can cause depression include myocardial infarction, chronic pain
syndromes, diabetes, stroke, cancer, hypothyroidism, dementia and Parkinson disease.
  Medications that cause depression include steroids, anticonvulsants, interferon, and anti-
Parkinson medications,

Case 3: Screening for depression

Your next patient is Tomas Regalado, a 53-year-old man who comes to establish primary care. Past
medical history is notable for hypertension. Both parents were diagnosed with depression, and his
sister completed suicide 12 years ago. You wonder about screening Mr. Regalado for depression.
Which of the following is true?

A. Screening for depression has been shown to reduce the prevalence of suicide when
introduced into a community.

B. Screening for depression consists only of asking if the patient is depressed or has
anhedonia.

C. There is no consensus on screening for depression, as no tool for screening exists.

D. Since screening for depression doesn’t involve any expensive testing, it is the most cost-
effective screening tool in a population.

Pop Up Answers

A. Incorrect. There is no evidence that screening reduces mortality from suicide.

B. Correct! Screening is as straightforward as assessing for depressed mood or anhedonia. If

either is present, further questioning and medical follow up is indicated.

C. Incorrect. Screening is as straightforward as assessing for depressed mood and/or

anhedonia, and is recommended by the US Preventive Services Task Force.

D. Incorrect. Screening involves medical decision making, as well as the systems to further
manage those with a positive result. The estimated cost for annual screening was $192,000
for each quality-adjusted life year.
Summary answer

The correct answer is B: Screening for depression consists only of asking if the patient is depressed
or has anhedonia.

In this section, we review issues related to screening for depression.

Screening for depression

Despite the high prevalence of depression, a significant portion of depressed patients goes
unrecognized or inadequately treated. There has been debate as to whether or not patients in the
general medical population should be screened for depression. Factors favoring screening for
depression include its high prevalence and the presence of effective therapy. Factors against screening
for depression include a variable response to therapy, the waxing and waning course of depression,
lack of information on appropriate intervals between screening, and cost. (One study showed that the
cost of annual screening for depression in a primary care practice would be $192,444 for each quality-
adjusted life year.) Despite this, the US Preventive Services Task Force recommends screening the
general medical population for depression, although the appropriate interval between screenings
remains unknown.

Screening may be as simple as asking two questions, which together can detect 95% of patients with
depression.

 The first question to ask a patient who may be depressed is any variation of "Are you
depressed?"

 Any sense that that is the case should be followed with a question along the lines of "Have you
found that you aren't enjoying activities that you normally enjoy doing, or that you have lost
interest in doing much?"

The definition of depression requires at least one of these two (depressed mood and/or anhedonia) to
be present to diagnose a patient with major depression. Answering "no" to both questions should not
close the book on this issue for future visits, and if some component of denial from the patient is
suspected, close follow up and repeat questioning is appropriate.
It is important to be open with the patient about your concerns, even saying something such as "I'm
concerned that you are becoming depressed. I'd like to discuss this further on our next visit, to see
how you are doing. I would like to see you feeling better." Setting an open, caring tone, and letting the
patient know that depression responds to treatment goes a long way in helping a patient respond to
treatment for depression. Developing a therapeutic alliance with a depressed patient is often more
difficult than with the non-depressed patient.

Section summary

 Depression screening in the general medical population is cost effective and recommended by
the US Preventive Services Task Force.

 Screening may be as simple as assessing for depressed mood and/or anhedonia.

Case 4: Initial management of depression: Suicide Risk

You are seeing a new patient, Eric Garcetti, who is a 72-year-old man who you have just diagnosed
with depression. Past history is notable for diabetes, complicated by peripheral vascular disease. He
also has a history of anxiety and hypertension. Medications include insulin, lisinopril, and buspirone.
You want to assess his suicide risk as part of your initial management of depression. Which ONE of the
following is true?

A. You should obtain a "contract for safety", having him promise to you that he will not harm
himself.
B. You should give him a benzodiazepine to treat his anxiety, which will reduce his risk of
suicide.
C. You should assess his thoughts about death, his level of intent on killing himself, and any
specific plans for hurting himself.
D. Since risk of suicide decreases with increasing age, his risk of suicide is low.

Pop Up Answers
A. Incorrect. Rather than obtaining a "contract for safety", more appropriate would be to
assess his suicidal ideation, suicidal intent, and specific plans for suicide, as well as access
 to the means for completing suicide. Contracting a patient with whom you do not have a
therapeutic alliance (such as a new patient, described here) is particularly ineffective.
B. Incorrect. Anxiety is a risk factor for suicide. In the depressed and anxious patient, the
focus is on treatment of depression, as anxiety will often improve as depression improves.
There is no evidence that treating anxiety in the depressed patient at risk of suicide
specifically alters suicide risk.
C. Correct. To assess suicidal risk, assess ideation, intent, and plan. You should also assess the
patient's access to a means for carrying out any plan.
D. Incorrect. Risk of suicide is greater in the elderly, especially those with severe comorbid
conditions (as seen here).

Summary answer
The correct answer is C: You should assess his thoughts about death, his level of intent on killing
himself, and any specific plans for hurting himself.

Initial management of depression: suicide risk assessment

Once diagnosed, management of depression is in many ways similar to management of other medical
disorders:

 Treatment is started

 Follow up for assessment of response occurs.

Just as it is important to know the treatment options for hypertension, it is important to be familiar
with the treatment options for depression. Similarly, it is important to know when to expect a response
to treatment for depression, and how to manage incomplete responses. The time frame for
assessment of response to treatment for depression is different than that for many other medical
disorders.

As treatment for depression is started, the severity of illness and level of acuity must be assessed (as
we do in differentiating hypertensive emergency from hypertension. One of the initial management
issues to address is the patient's risk of harm to self or others. Patients who are suicidal need emergent
referral to a psychiatrist, and if the patient is unwilling, an emergency petition should be placed. There
is no evidence that physicians increase the risk of a patient considering suicide by asking about suicide
(specifically, ask about suicidal ideation, intent and plan). Since up to 15% of patients with untreated
depression complete suicide, addressing this issue with your patients in a way that you find
comfortable is important.

Risk factors for suicide

Consideration of factors that increase the risk of suicide should impact your decision for emergent
referral. A past history of suicidal behavior is associated with increased risk of suicide with recurrent
depression. Suicide risk is greater in depressed patients with coexisting anxiety or panic disorder,
substance abuse or agitation. Older individuals (age >65), men, Caucasian or Native American
individuals are at increased risk, as are those living alone (single/divorced etc.), those with a recent
stressful life event, those with serious medical illness, or family history of completed suicide. Finally,
those who have been prescribed more than one antidepressant in the past (thought to be a marker
for more severe depression) are at increased risk of suicide.

Table 3: Markers of increased risk of suicide

Assessing risk in your patient

There are approximately 30,000 suicides in the United States every year, nearly all of which occur in
outpatients. As the diagnosis of depression is made and therapy is initiated, the internist should have
a low threshold for involving psychiatry if there is any concern about a patient's suicide risk. Many
internists consider obtaining a promise from the patient to not harm him/herself (i.e., “contracting for
safety") an effective tool for managing patients. However, the value of this contract is likely
overestimated. For instance, if the physician hasn't developed a therapeutic alliance with the patient,
the patient may not view the physician as important enough to make the contract valid (this is
especially true in the Emergency Department, with new patients, or with patients held involuntarily).
In addition, the patient may not be competent to agree. It is better to assess suicide risk than to
contract for safety. In addition to the risk factors reviewed above, suicide risk can be assessed as
follows:

 Suicidal ideation: are these thoughts active or passive; are they persistent or controlling?

o Lowest risk is no thoughts of death; highest risk is suicidal thoughts with a specific plan

 Suicidal intent: how serious is the suicidal ideation?

o Suicide risk increases with more clear intent

 Suicidal plan: the more detailed and violent the plan, the greater the risk

Figure 1: Suicide risk assessment

When the suicidal plan is assessed, the patient should also be asked about having the means necessary
to carry out the plan (e.g., "I plan to kill myself with a gun, and I have a loaded gun in my bedside
table"). Should there be any concern about the safety of your patient after assessing suicide risk, an
emergency psychiatry consultation is recommended. Suicide risk should be assessed and documented
with every clinic visit until the physician has determined that the risk of suicide has resolved. As
response to therapy for depression waxes and wanes, assessment of suicide risk is a continuous
process during the treatment of depression. There is no perfect screen for suicide; some patients will
conceal their plans so that those around them are unaware.

Homicidal risk is less common in the depressed patient, but should be considered in the depressed
individual with a history of psychosis, aggression, substance abuse and impulsivity.

Section review

Case 5: Initial management of depression: Modality of treatment

Bill DiBlasio is a 38-year-old with a history of diabetes, who presents with complaints of being tired "all
the time," with poor sleep and mood swings. He also states that he is anxious. Mr. DiBlasio goes on to
say that he and his husband are on the verge of separating, which is causing financial concern (the
patient was fired from his job two months ago during a downsizing). Concerned, you screen him for
depression, and his clinical presentation is consistent with this diagnosis. He denies suicidal ideation,
intent, or plan. He has never been diagnosed with depression.
When choosing initial therapy in this individual, which ONE statement is correct?

A. Pharmacotherapy is a superior initial management choice to counseling in this individual.

B. The most appropriate management option at this point would be a sleeping aid.
C. Treatment of anxiety with a long-acting benzodiazepine is the most appropriate initial
management.
D. Counseling, either by a psychiatrist or by you, should be included in treatment.

Pop Up Answers:

A. Incorrect. While pharmacotherapy may ultimately be needed to treat this individual, he has
significant psychosocial stressors that should be considered when deciding on treatment.
B. Incorrect. Merely treating a single symptom in this individual is not appropriate.
C. Incorrect. Patients who are depressed with a component of anxiety should be treated for
depression first, as anxiety often responds to treatment for depression.
D. Correct! His psychosocial stressors are significant, and counseling will be an important part of
initial management.

Summary answer
The correct answer is D: Counseling, either by a psychiatrist or by you, should be included in
treatment.

The two steps in management of depression

After assessing suicide risk, there are two steps in the management of depression:

 Step 1: Pick a modality of treatment (pharmacotherapy or counseling or both)

 Step 2: Pick the appropriate medication and/or person to deliver counseling (discussed with
the next case).

We will start by considerations in picking a modality.

Picking a modality: Biochemical predisposition and psychosocial stressors

When determining the modality, it is useful to think of each person as having two contributors to the
development of depression: a biochemical predisposition to develop depression and a vulnerability to
psychosocial stressors that may result in depression. Some individuals (Patient A below) may have a
high biochemical predisposition to the development of depression, and only minor psychosocial
stressors (i.e., the routine frustrations of a normal life) will result in depression. Other patients may
have a low biochemical predisposition to the development of depression, and it will take major
psychosocial stressors (or rather, psychosocial stressors that hit upon an individual's vulnerabilities) to
result in depression (Patient B). Typical psychosocial stressors include loss, conflict, change, general
stress, isolation, failure or frustration. If any or several of these predominate, counseling is suggested
as a mainstay of treatment. It is important to avoid placing your value judgments on a patient's
stressors, and listen to their body language and other clues as to the contribution of psychosocial
stressors to their current medical state. Other considerations that would suggest better response to
counseling rather than pharmacotherapy include (besides prominent psychosocial issues):
pronounced interpersonal problems (e.g., break up of a relationship; unreasonable work demands
from a supervisor), history of a personality disorder, or poor compliance with medications.

Figure 2: Biochemical and psychosocial stressor contribution to depression

In these simplistic terms, individuals with a high biochemical predisposition to depression (Patient A)
would likely require some component of pharmacotherapy (with or without counseling) to see
improvement. For patient B, many suggest that this group would be more responsive to counseling,
and would be less likely to respond to only pharmacotherapy.

If a patient has a history of prior treatment for depression with good response to a particular modality,
that modality should be viewed as a good first choice. Alternatively, if a patient had a bad experience
with a modality in the past (e.g., failure to respond to a trial of pharmacotherapy), consideration of
another modality should be made, or even better, combination therapy should be considered. That is
not to say that reattempting single modality treatment, perhaps with a different class of
antidepressant if they failed pharmacotherapy, or a different counselor, if they failed counseling, is not
a reasonable option. However, combination therapy is viewed by some to be superior in this situation.

Single modality vs. combination therapy

If the patient is felt to have mild symptoms, then no treatment, with watchful waiting, may be
acceptable. This is most appropriate in someone with mild symptoms of short duration. They should
be seen back in clinic in 2-4 weeks. Patients with mild to moderate symptoms may be treated with
single modality treatment or combination treatment (i.e., pharmacotherapy plus counseling). Patients
with severe depression (for instance, symptoms that interfere with the normal activities of daily living)
should be treated with combination therapy (pharmacotherapy and counseling, with counseling
provided by a psychiatrist). Combination therapy should also be used for patients with a coexisting
personality disorder. If the patient is actively suicidal (as discussed above), emergency referral for
immediate psychiatric evaluation is required. These steps are reviewed in the figure below.
Figure 3: Initial management of depression

At times, extenuating circumstances may impact picking the modality of treatment. Some patients may
refuse pharmacotherapy but agree to counseling, while others may prefer pharmacotherapy. Many
will not have insurance coverage for counseling (other than visits with you).

Anxiety and depression

Anxiety often occurs as a manifestation of depression. In patients who are both depressed and anxious,
initial therapy should focus on treatment of depression. Most patients who manifest anxiety as a
symptom of depression will respond to antidepressants, and will not need anxiolytics. Unfortunately,
this group of patients is among the most likely to experience side effects and discontinue therapy when
medications are prescribed, so early patient education anticipating side effects and frequent follow up
is needed to ensure compliance. In this group of patients, starting antidepressants at a low dose and
advancing slowly may diminish the risk of side effects. Some physicians will prescribe a short course of
anxiolytics to coincide with initiation of antidepressant pharmacotherapy. As mentioned earlier,
depressed patients with significant anxiety are at increased risk for suicide attempt.

Section summary

 The first step in treating depression is picking the modality/modalities of treatment (i.e.,
pharmacotherapy vs. counseling vs. combination therapy).

 Patients with mild depression may be treated simply with observation, single modality
treatment, or combination therapy.

 Patients with moderate or severe depression should be treated with combination therapy.

 Patients with active suicidal risk require emergent psychiatric evaluation.

 Patients with depression and anxiety should be treated for depression first, often with cautious
advancement of pharmacotherapy with attention to side effects.

Case 6: Non-pharmacologic management

You are still evaluating Mr. DiBlasio, who wants to discuss treatment options for depression. He doesn't
want to take any prescription medications, and asks about other options for treating depression.
Which of the following statements is true?

A. Exercise and yoga are recommended as effective first-line therapy in treating depression.

B. Cognitive therapy focuses on helping patients focus on pleasant memories to relieve the
symptoms of depression.

C. Interpersonal therapy focuses on problem-solving with the patient's interpersonal

relationships.

D. All of the above are true.

Pop Up Answers

A. Incorrect. Although these techniques may help treat depression, the evidence
demonstrating this is weak. The American College of Physicians recommends either
 second-generation antidepressants or cognitive behavioral therapy as first line treatment
of depression.

B. Incorrect. Cognitive therapy focuses on helping patients work through and correct false
beliefs about him/herself, and work out negative thoughts.

C. Correct. With interpersonal therapy, the focus is on addressing interpersonal relationships

and issues related to them.

D. Incorrect. Only one of the above statements is correct.

Summary answer

The correct answer is C: Interpersonal therapy focuses on problem-solving with the patient's
interpersonal relationships.

Introduction

As we've just learned, the first step in management of depression is picking the modality (or modalities)
of treatment. In this section, we briefly review non-pharmacologic management of depression. The
focus here is on what the internist can offer the patient, and is not meant to supplant the expertise of
those with expertise in counseling (i.e., psychologists; psychiatrists etc.). The more severe the
symptoms of depression, the more the internist should incorporate professional counselors in
treatment plans. Professional counselors should also be used when patients are not responding to
current therapy.

Non-pharmacologic treatment of depression

Perhaps the best known non-pharmacologic treatment of depression is counseling. However, other
methods used to treat depression include exercise (including yoga), acupuncture, omega-3 fatty acids,
and dietary supplements (e.g., St. John's Wort, discussed later in this module; s-adonosylmethionine,
or SAM-e). Although there may be evidence of some improvement in symptoms for each of these
when used as monotherapy, the quality of evidence for these therapies is low. The American College
of Physicians has reviewed this evidence, and recommends second-generation antidepressants (i.e.,
selective serotonin reuptake inhibitors and similar medications) or cognitive behavioral therapy as first
line treatment of depression.

The role of the internist in counseling

While a detailed explanation of counseling techniques is beyond the scope of this module, many of the
standard internist's skills required to discuss any of a number of sensitive issues with patients (e.g.,
life-threatening diagnoses; issues regarding sexuality) are important in counseling the depressed
patient. Empathic listening, supportive statements, and advice from an outside perspective are useful
in managing a patient who is depressed. Demonstrating a caring attitude, being available, and voicing
the expectation that the patient will get better is also part of managing depression. Different
approaches to counseling are listed in the table below; a combination of these methods may be used
by the internist in managing the patient with mild depression. More skilled counseling should be
provided by someone specifically trained in this area.

Table 4: Counseling approaches used in the depressed patient

Case 7: Introduction to pharmacotherapy

Edwin Lee is a 43-year-old computer programmer who complains of fatigue. He has trouble staying
awake past 8:30 in the evening, and stopped working out months ago. He is considering ending his
new marriage, because it's "too much work to make a relationship work", and he admits to having an
affair with his best friend's partner. He notes that his husband has been complaining that they "never"
are intimate, adding to stress. Mr. Lee has lost 15 pounds, wants to sleep all the time, and has frequent
crying spells. He enjoys nothing, complains of forgetfulness, but denies thoughts of suicide, and has no
intent or plan to harm himself. You diagnose him with depression, and confirm a normal physical
examination, complete blood count, and thyroid testing. You and the patient discuss treatment
options, and decide on pharmacotherapy.

Which of the following statements about treating this patient is correct?

A. Tricyclic antidepressants should be avoided because they increase the risk of suicidal
behavior, even in patients with low suicide risk

B. Selective serotonin reuptake inhibitors are more effective at treating depression than are
tricyclic antidepressants.

C. If this patient had responded to a specific antidepressant in the past, that agent should not
be used again to treat depression, as tolerance is likely.

D. Individuals who abruptly stop taking a selective serotonin reuptake inhibitor risk
experiencing paresthesias and dizziness.

Pop Up Answers

A. Incorrect. The class of agent used does not affect suicide risk. Tricyclic antidepressants are
more dangerous than other classes when taken in overdose, but they themselves do not
increase risk of suicidal behavior.

B. Incorrect. All classes of antidepressants have similar efficacy at treating depression.

C. Incorrect. If an individual has responded to an antidepressant in the past, that agent is

likely to be effective again.
 D. Correct! Abrupt discontinuation of many SSRIs can cause a withdrawal syndrome of
paresthesias, tinnitus and vertigo.

Summary answer

The correct answer is D: Individuals who abruptly stop taking a selective serotonin reuptake inhibitor
risk experiencing paresthesias and dizziness.

Pharmacotherapy

As with choosing therapy for any medical condition, a thoughtful approach works best when picking
an antidepressant. Just as when picking an antihypertensive, consideration is given to comorbidities
that may impact the class of agent chosen, so picking an antidepressant begins by selecting the class
of agent best for your patient, considering comorbidities and other clinical features. Factors to
consider include the patient's history, co-existing medical conditions, potential drug interactions, cost,
and anticipated side effects. Since all antidepressants are roughly equivalent in their efficacy, other
factors should influence your choice. That being said, APA guidelines suggest that since tricyclic
antidepressants (TCAs) are fatal in overdose and have significant side effects, they are now considered
second-line agents (after SSRIs, SNRIs, and bupropion). All antidepressants developed after TCAs are
typically referred to as 'second generation' antidepressants.

As just stated, all antidepressants are equivalent in their efficacy at treating major depression. Head-
to-head studies of second generation antidepressants (i.e., SSRIs; SNRIs; etc.) demonstrated that they
are all equally effective, regardless of patient factors (e.g., age; gender; ethnicity; comorbidities) or
when considering initial response to therapy or maintenance of remission. About one half of patients
will respond to the first antidepressant prescribed regardless of the agent chosen.

Failure of one agent in a particular class does not exclude a chance of response to other agents in that
same class (although failure to respond to one tricyclic antidepressant (TCA) usually means other TCAs
won't work; SSRIs seem to give more opportunity for one SSRI to work if another SSRI hasn't). If two
agents in the same class fail to produce benefit, switching to another class is indicated. No washout
period is needed when switching among SSRIs, or when switching between classes. Features of the
different classes of antidepressants (including side effects) are discussed further below.

Merely the act of prescribing an antidepressant sends a strong signal to your patient that they have a
treatable illness, and that they can and will get better, initiating the recovery period. Patient education,
particularly about the delay in response to therapy, and the type of side effects to expect, will impact
the likelihood of continuation of therapy. Unfortunately, up to 50% of medical outpatients who are
started on an antidepressant fail to complete one month of treatment. Abrupt discontinuation of
short-acting SSRIs (i.e., most SSRIs other than fluoxetine) can temporarily worsen side effects such as
paresthesias, tinnitus and vertigo. While these withdrawal effects are unlikely in a patient recently
started on therapy, patients who have been treated for a prolonged period with any of these
medications should have their dose tapered over several weeks.

Prescribing practices

When making the original prescription, there are unique considerations that should be applied to the
dispensation of antidepressants. The first consideration is the risk that the patient may use the
medication to harm him or herself. Several hundred people complete suicide annually with tricyclic
antidepressant overdose (desipramine is particularly dangerous with overdose), which is a large part
of why they are now considered second-line agents. Some have raised concern that specific classes of
antidepressants increase the risk of suicidal behavior relative to other classes. However, a case-control
study of 555 suicidal patients compared with 2062 depressed but not suicidal patients showed that
there was no association between the drug used to treat depression and the risk of suicidal behavior.
Bearing this in mind, a few important points can be made:

 While the class of antidepressant used does not impact the risk of suicidal behavior, this study
showed that the relative risk for suicidal behavior was highest in the 9 days after being
prescribed an antidepressant.

 Also, while the class of antidepressant used does not impact the risk of suicidal behavior,
tricyclic antidepressants are dangerous and may be fatal with overdose, and should be
prescribed with caution in patients at increased risk for suicidal behavior.
  While overdose with SSRIs is not fatal, all patients given the initial diagnosis of depression
should probably not be given a prescription for more than a one-month supply.

 Since 2007 the FDA has mandated a "black-box" warning on all antidepressants when being
prescribed to adults ages 18-24, because of concerns about increased suicide risk.

The second consideration to be given to all classes of antidepressants is to consider dose adjustment
in populations susceptible to side effects. Elderly patients, patients with a significant anxiety
component, and patients with panic disorder should be started on a low dose of whatever medication
is chosen. Some advocate using a low dose of a benzodiazepine in the first few weeks of treatment of
the depressed individual who has a significant anxiety component. Anticipation of side effects, and
being available to discuss them, is important to all patients, but particularly so in these populations.

Finally, giving antidepressants to patients with underlying bipolar disorder can precipitate a manic
episode, and should be avoided. Psychiatrists, not internists, typically manage bipolar disorder.

Knowing that in general all classes of antidepressants are equally effective in the management of
depression, you may enhance the likelihood of a good response by simply asking if the patient has
been treated for depression in the past, and if so, did a particular medication work well for them. There
is even some suggestion that a family history of responding to a particular antidepressant predicts a
good response in other family members. Beyond that, consideration should be given to the likelihood
of intolerable side effects, drug interactions, coexisting medical conditions, and patient preference
when prescribing an antidepressant. Classes of antidepressants are discussed in the next section of
this module.

Section review
Case 8: Pharmacotherapy part 2

Your next patient is Catherine Pugh, a 68-year-old with a history of multiple back surgeries and chronic
sciatica. Her daughter, who had contacted you earlier that week to tell you that the patient has been
increasingly tearful and withdrawn, accompanies the patient. Mrs. Rawlings-Blake used to play bridge
weekly with friends, but stopped 3 months ago because she said she couldn't keep track of her cards.
She is always tired and naps frequently. With further questioning, she admits to at least 5 or 6 months
of depressed mood, poor sleep, and enjoying little.

Past medical history is as noted. Current medications include gabapentin and ibuprofen. Physical exam
is unremarkable. Blood work is obtained, showing a normal TSH, CBC and basic metabolic panel. EKG
shows a left bundle branch block, which has been present for at least 8 years.

Which ONE of the following statements is correct?

A. Venlafaxine or other serotonin/norepinephrine reuptake inhibitors would be a good choice for

treatment in this patient.

B. Because of her poor sleep and neuropathic pain, a tricyclic antidepressant such as amitriptyline
100mg nightly would be a good choice for treatment of depression.

C. Because of her fatigue, an antidepressant such as trazodone would be appropriate.

D. Sexual side effects are greatest when tricyclic antidepressants are used, due to their well-
described anticholinergic side effects.

Pop Up Answers

A. Correct! SNRIs such as venlafaxine are useful in patients with chronic pain and depression.
However, close attention should be paid to her blood pressure, as at higher doses, venlafaxine
can raise blood pressure.

B. Incorrect. Tricyclics should be used with caution in the elderly. Her left bundle branch block
makes this an especially poor choice. While amitriptyline has a proven role in neuropathic pain,
the risks outweigh the benefits in this patient.
 C. Incorrect. Trazodone, which is a serotonin reuptake inhibitor/antagonist, is sedating, and
would likely worsen her fatigue. Tricyclic antidepressants and alpha-2 antagonists (e.g.,
mirtazapine) are other sedating antidepressants. They have a greater role when an individual
has trouble falling asleep or staying asleep.

D. Incorrect. Anticholinergic side effects of tricyclic antidepressants include constipation, urinary

retention, and dry mouth. Sexual side effects (including delayed ejaculation) are more
commonly associated with SSRIs and SNRIs.

Summary answer

The correct answer is A: Venlafaxine or other serotonin/norepinephrine reuptake inhibitors would

be a good choice for treatment in this patient.

Introduction

Classes of antidepressants include tricyclic antidepressants, selective serotonin reuptake inhibitors,

serotonin/norepinephrine reuptake inhibitors, dopamine reuptake inhibitors, serotonin-reuptake
inhibitor/antagonists, and alpha-2 antagonists (see table below). Since all classes of antidepressants
are equally effective at treating depression, patient preference, salutary effects, and side effects play
a large role in picking an agent. Features of each class are discussed below.

Tricyclic antidepressants (TCAs)

TCAs have been in use the longest, and because of this, are quite inexpensive. However, even though
the drugs themselves are cheap, they require EKGs, serum level monitoring, and hospitalization with
overdose, taking away cost advantage when viewed on a population basis. The anticholinergic side
effects (dry mouth, constipation, urinary retention) are particularly troublesome in the elderly.

TCAs are used for the treatment of other medical disorders. They have demonstrated effectiveness in
migraine prophylaxis, and are also useful in the management of neuropathic pain, chronic pain
syndromes, and insomnia. When TCAs are used, drug levels will need to be followed. TCAs are best
used in the depressed patient who is agitated or sleepless, and in those with chronic pain complaints.
They should be avoided in those with heart disease and in the elderly. Because of their risk with
overdose and significant side effect profiles, they are now considered second line agents.

Commonly used tricyclic antidepressants are amitriptyline, nortriptyline, desipramine and imipramine.

 Amitriptyline (brand name Elavil): Typical starting dose 50mg nightly; may increase to 300mg.
The most sedating of the TCAs, with the most anticholinergic side effects.

 Nortriptyline (brand name Pamelor): Typical starting dose 25mg three to four times daily;
maximum dose 150mg total/day. Nortriptyline has the fewest anticholinergic side effects of
TCAs.

 Desipramine (brand name Norpramin): Typical starting dose 75mg daily or in divided dose;
maximum daily dose 300mg. Particularly fatal with overdose.

 Imipramine (brand name Tofranil): Typical starting dose 25mg three to four times daily;
maximum daily dose 300mg.

Selective serotonin reuptake inhibitors (SSRIs)

SSRIs have revolutionized outpatient management of depression. Once-a-day dosing, long-term safety,
and few drug interactions (see below) have made them increasingly popular. The American College of
Physicians endorses this class of antidepressants as first-line treatment of depression, based on patient
preferences, side effect profiles, and cost. The efficacy of different SSRIs is similar; a randomized trial
comparing the effectiveness of paroxetine, fluoxetine and sertraline have demonstrated them to have
similar efficacy and side effects (although sertraline is the most likely to cause diarrhea, and paroxetine
may have the worst sexual side effect profile).

Some SSRIs have proven useful in treatment of panic disorder; depressed patients with features of
panic disorder should be considered ideal candidates for SSRIs. Unlike TCAs, SSRIs are not particularly
sedating; SSRIs are better in the patient with psychomotor retardation rather than agitation. Common
side effects of SSRIs include paresthesias, GI disturbance (diarrhea is a common complaint, especially
with sertraline), and sexual disturbance (especially with paroxetine), all of which may lead to
discontinuation (sexual disturbance is particularly of concern in younger, sexually active adult males).
To minimize side effects, starting a patient on one-half the intended dose for the first one to two weeks
may help. All SSRIs interfere with cytochrome P450 system, thus risk important drug-drug interactions.
Fluoxetine has the longest half-life of this class, and has the most drug interactions. As mentioned
above, short-acting SSRIs (escitalopram, paroxetine, sertraline) lead to withdrawal symptoms if not
tapered.

In summary, SSRIs are ideal in most depressed patients, but may offer added benefit in patients with
coexisting panic disorder and in those with psychomotor retardation. They should be avoided in
patients in whom sexual dysfunction or GI disturbance is problematic.

Commonly used SSRIs include fluoxetine, sertraline, paroxetine, citalopram and escitalopram.

 Fluoxetine (brand name Prozac): Typical starting dose 20mg daily; maximum dose 80mg daily.
The longest half-life of all SSRIs, and the most drug interactions.
 Sertraline (brand name Zoloft): Typical starting dose 50mg daily; maximum dose 200mg daily.
 Paroxetine (brand name Paxil): Typical starting dose 20mg daily; maximum dose 50mg daily.
 Citalopram (brand name Celexa): Typical starting dose 20mg daily; maximum dose 40mg daily.
Citalopram should not be used at doses >40mg due to risk of QT prolongation.
 Escitalopram (brand name Lexapro): Typical starting dose 10mg daily; maximum dose 20mg
daily.

SSRIs and serotonin syndrome

One risk of SSRIs that has been well documented, but about which few physicians seem to be aware,
is the development of serotonin syndrome. In serotonin syndrome, brainstem 5HT receptors become
hyper stimulated, typically from the co-administration of an SSRI and another agent that increases
serotonin levels. Symptoms include change in mental status, autonomic hyperactivity (diaphoresis,
tachycardia, rigors), and neuromuscular disorders (hyperreflexia, clonus, muscle hypertonicity). Drugs
commonly used by internists that should be avoided in patients on SSRIs include levodopa,
amantadine, sumatriptan, and dextromethorphan (think of this last interaction when making
recommendations for treating a patient on an SSRI for cough or cold). In addition, use of an SSRI with
tramadol (brand name Ultram) may result in serotonin syndrome. While cases of serotonin syndrome
are usually mild and managed with supportive care, fatalities have been reported.

Serotonin/norepinephrine reuptake inhibitors and other agents

Venlafaxine, desvenlafaxine and duloxetine are newer agents used to treat depression, which act as
serotonin/norepinephrine reuptake inhibitors. These agents have side effect profiles similar to SSRIs,
although the risk of hypertension is higher. Duloxetine and venlafaxine are the most likely of all second
generation antidepressants to be discontinued due to side effects (usually nausea/vomiting). Similar
to TCAs, these drugs may be more effective in treatment of depression in patients with coexisting
chronic pain syndromes. These drugs are particularly symptomatic with withdrawal, and should be
tapered upon discontinuation.

 Venlafaxine (brand name Effexor): dosing is started at 37.5mg twice daily, which may be
increased to a total daily dose of 375mg.
 Desvenlafaxine (brand name Pristiq): dosing is 50mg daily.
 Duloxetine (brand name Cymbalta): dosing is started at 20mg daily, which may be increased
to 60mg daily. Some use a maximal dose of 120mg daily.

Trazodone (brand name Desyrel) and nefazodone (brand name Serzone) are serotonin reuptake
inhibitors/antagonists. These agents are sedating, and trazodone in particular is often used to aid in
sleep in the depressed patient. Anticholinergic and sexual side effects are not seen with these agents,
although priapism is a risk. Trazodone (as an antidepressant) is dosed at 50mg three times daily, and
may be increased to a maximal daily dose of 600mg. For sleep, dosing is started at 50mg at bed time.
Nefazodone is started at 100mg twice daily, also with a maximal daily dose of 600mg.

Bupropion (brand name Wellbutrin) is a dopamine/norepinephrine-reuptake inhibitor that is often

used in combination with SSRIs in those patients who are not responding to SSRIs alone.
Gastrointestinal and sexual side effects are uncommon with this medication, making it a good
complement to SSRI therapy, or even as monotherapy in someone intolerant of side effects. Because
of risk of seizure associated with this medication, initial dosing is low, which is then increased. Standard
bupropion is started at 100mg twice daily for three days, and then is increased to 100mg three times
daily. Sustained release and extended release bupropion formulations are started at 150mg daily for
three days, and then increased to 150mg twice daily. Buproprion can make some patients agitated or
anxious, so if these symptoms start to predominate, bupropion should be reconsidered.

Mirtazapine (brand name Remeron) is a norepinephrine/serotonin modulator that enhances

norepinephrine release. Sedation is common, so nighttime dosing is recommended. Weight gain is
most common with this medication relative to all other second generation antidepressants. Rarely,
agranulocytosis can occur with this drug. Because of this (rare) risk, the manufacturer recommends
evaluating for agranulocytosis should stomatitis or infection occur while on this medication. Merely
stopping the medication may result in recovery from agranulocytosis. Dosing is initiated at 15mg
nightly, with maximum dose of 45mg nightly. Mirtazapine has a faster onset of clinical improvement
than other second generation antidepressants.

Extended-release quetiapine (brand name Seroquel), a second-generation antipsychotic, may have a

limited role in treatment of depression in those not responding to other agents. Due to sedation and
risk of weight gain and diabetes, this agent should be reserved for those patients not responding to
the medications listed above.

St. John's Wort

Finally, a word about St. John's Wort (Hypericum perforatum). St. John's Wort is not under the purview
of the FDA, and thus is not subject to the standard requirements of purity and efficacy that
pharmaceuticals must endure. Because of this, contaminants and dosing irregularities may be present
in St. John's Wort, and patients who choose to self-medicate should be aware of the inherent risk in
using this substance. That said, although ineffective for the treatment of moderate to severe
depression, there is some evidence that St. John's Wort is effective for the treatment of mild
depression, and that side effects are minimal.

Pharmacotherapy is reviewed in the tables below.

Table 5: Review of antidepressants
Table 6: Focus on side effects

Table 7: Pharmacology review

Case 9: Assessing response to therapy
Vincent Gray is a 54-year-old with a history of hypertension who you diagnosed with depression four
weeks ago. Over the past 6 months, you had noted he was becoming increasingly withdrawn and less
conversant, had stopped exercising, and always seemed on the verge of tears. Upon further
questioning, you found him to have been clinically depressed for at least 4 months. After a discussion
of treatment options, you both decided on treatment with sertraline, starting at 50mg daily.

Since the diagnosis, you have spoken with him on several occasions to see how he is doing, and you
saw him in clinic 10 days ago to assess suicide risk and review side effects. Finding none, his dose was
increased to 100mg daily. Today (four weeks into treatment) Mr. Gray states that he is feeling "no
better." He denies suicidal ideation, intent, or plan. Although he is no longer waking up at 4 AM, and
fatigue has improved, his mood is poor, and he'd rather just stay home and watch The History Channel
all day long. He continues to have poor work performance, and sex with his partner is "out of the
question." He feels pressure to get better because his boss has remarked on his poor work
performance, and his partner has a wandering eye.

The most appropriate management at this point is:

A. Discontinue sertraline and start a tricyclic antidepressant.

B. Continue sertraline, but increase the dose to 200mg daily.
C. Discontinue sertraline and start buspirone to treat anxiety.
D. As pharmacotherapy is ineffective in this individual, he should be referred for counseling.

Pop Up Answers

A. Incorrect. TCAs are sedating and can worsen fatigue. There is some clinical evidence that the
patient is improving, as terminal insomnia has resolved. Switching medication classes is not
indicated.
B. Correct. His sleep disorder is improving, he is more energetic in his concerns, and it is too early
to expect a complete response to therapy. He has no side effects, so advancing therapy may
improve his clinical response.
 C. Incorrect. Anxiety in a depressed individual often improves with treatment for depression.
D. Incorrect. It is premature to assume poor response to pharmacotherapy. However, the
addition of counseling is reasonable at any time during treatment if response is considered
inadequate.

Summary answer
The correct answer is B: Continue sertraline, but increase the dose to 200mg daily.

There are four things to consider when seeing a patient back after initiating antidepressant therapy:

1. Is the patient still safe from suicide risk?

2. Are side effects significantly interfering with the likelihood of response?
3. Is counseling needed?
4. Is the patient responding to therapy?
a. If not, should the dose be increased, should the agent be changed, or should
augmentation therapy be tried?

Item 1: Is the patient still safe from suicide risk?

A patient's risk of completing suicide increases early in response to therapy, and remains elevated for
a month. For some patients, the symptoms of depression may be profound enough to remove the
motivation to follow through with the act of suicide. As the patient responds to therapy, he/she may
have improvement in energy level (while depressed mood persists), and then be able to follow through
with a suicide plan. In addition, seeking medical evaluation may be a marker for worsening depression,
and therefore increased suicide risk. It is for this reason that close follow up with any patient treated
for depression is important, and a straightforward discussion with the patient about suicidal ideation,
intent, and/or plan should take place. Suicide risk should be assessed as described earlier.

In addition to reevaluating the patient's risk for suicide, the patient should be reevaluated for a switch
to mania from the unmasking of undiagnosed bipolar disorder.
Item 2: Are side effects significantly interfering with the likelihood of response?
It is difficult to overstate the importance of patient education when starting antidepressants, and
particular attention should be paid to the risk of developing side effects. While often transitory, some
side effects may persist, and may cause a patient to discontinue therapy. When you see a patient back
after initiating antidepressants, asking the patient specifically about side effects is important. Many
patients, when educated, will decide to continue with the medication, and watchful waiting may allow
time for side effects to diminish. If side effects are significant, decreasing the dose or changing the
timing of the medication may be needed to continue therapy. For some patients, what they note as
side effects from the medication may actually be a symptom of their depression (e.g., disordered sleep;
poor sex drive).

Item 3: Is counseling needed?

As we learned earlier, depression is a spectrum of diseases resulting from biologic predisposition and
sensitivity to certain psychosocial stressors. If pharmacotherapy has been chosen as initial
management, the passage of time will allow both you and the patient to reevaluate the initial
treatment plan. It may become clear over time that pharmacotherapy alone (or pharmacotherapy at
all) was not the appropriate choice, and the addition of (or substitution of) counseling, either by you
or by a psychiatrist, is indicated. If it becomes apparent that interpersonal problems, life stressors,
conflict or loss have played a significant role in the patient's development of depression, then
counseling should be recommended. Counseling should be recommended if the patient is not having
an adequate response to pharmacotherapy.

Item 4: Is the patient responding to therapy?

Some patients, if appropriately interviewed, will have evidence of response to therapy within 3-4
weeks. Although they may not sense any improvement in mood or anhedonia, asking about some of
the other symptoms that contributed to the diagnosis of depression, such as energy level, sleep,
appetite, anxiety or ability to concentrate, may reveal subtle improvements. As mentioned earlier,
some will follow their patients with the PDQ-9 questionnaire, which may show an improvement in
score as the patient responds to treatment. If partial response is the case (as seen in the patient above,
whose sleep disturbance and fatigue improved), positive reinforcement and continuation of current
therapy is indicated. If the dose of medication has been tolerated, advancing the dose to higher levels
may be done early in the course of therapy. However, at 3-4 weeks of therapy, lack of response does
not mandate a change in management (although many would increase the dose of the chosen
antidepressant if there was no response at that time). Even without changing the dose, additional
weeks of therapy can result in continued improvement in response.

If there is no response to the chosen treatment(s) in the patient after 6-8 weeks of therapy, and the
patient has been on a full, therapeutic dose of a particular agent, it is time to reassess the chosen
regimen. If there has been absolutely no response to the chosen medication after 6-8 weeks, then
either another medication should be chosen, or psychotherapy should be added. Increasing the
dosage of a medication that has produced no clinical improvement after 6-8 weeks of treatment,
despite adequate time on a therapeutic dose, should not be done.

Case 10: Management of partial therapeutic response

You are treating Michael Nutter, a 39-year-old male, for depression. He has been on fluoxetine 40mg
daily for four weeks, after tolerating fluoxetine 20mg daily for two weeks. He assesses his response at
"60%", saying his energy is improved, sleep is improved, concentration is improved, and sadness is
better, but still there. He is no longer missing days from work, but remains socially unengaged. He'd
like to feel even better.

Appropriate options at this point include all of the following EXCEPT:

A. Increasing his fluoxetine to 60mg daily

B. Adding sertraline to fluoxetine

C. Adding counseling to fluoxetine

D. Adding bupropion to fluoxetine

Pop Up Answers

A. Incorrect. Increasing the dose of the same medication is appropriate, as long as there is
some clinical response. Ideally an agent should be tried at the maximal dose tolerated
before giving up on it as ineffective.
 B. Correct. Using two antidepressants from the same class to treat depression is not
appropriate.

C. Incorrect. Adding counseling to treat a partial response to pharmacotherapy is

appropriate.

D. Incorrect. Bupropion is commonly used in combination with SSRIs to augment a partial

response.

Summary answer

The correct answer is B: Adding sertraline to fluoxetine.

Managing a partial response

In this section, we review management of a partial response to pharmacotherapy after an adequate

trial of medications (i.e., 6-8 weeks). If a partial response has occurred after 6-8 weeks of therapy,
several options are available:

1. Increase the dose of the current medication

2. Change the medication
a. A medication from the same class is acceptable; no washout is needed when
switching
b. It is best not to change from the first medication if it has not been tried at the
maximally-tolerated therapeutic dose
3. Add psychotherapy
4. Augmentation therapy

It is important not to accept a partial response to therapy as "good enough" when treating depression.
Those patients with an incomplete response have greater psychosocial disability and a much greater
risk of relapse. Other considerations should be made when a patient has an incomplete response, and
are listed in Table 7.
Table 7: Potential reasons for incomplete response

Augmentation therapy

At times, patients may have a moderate response to therapy, but reach a ceiling of response. In these
patients, augmentation therapy may be tried. Augmentation therapy has been done with bupropion,
mirtazapine, triiodothyronine, lithium, and second-generation (atypical) antipsychotics. In general, the
combination of two different classes of antidepressants (often an SSRI or SNRI plus either bupropion
or mirtazapine) produces greater rates of clinical remission than does either agent alone, including
when used as initial therapy for depression.

Bupropion has found widespread utility as augmentation therapy, especially in combination with
SSRIs. In one study, about 1/3 of individuals with inadequate response to citalopram had significant
improvement when sustained-release bupropion was added. The combination of an SSRI and
bupropion is also commonly used when side effects limit further escalation of the SSRI dose, because
the side effects of bupropion do not overlap with those of SSRIs. Mirtazapine has proven similarly
effective when used in combination with SSRIs and SNRIs.

Another form of augmentation therapy involves the addition of either triiodothyronine or lithium to
the current antidepressant regimen. Augmentation therapy is effective for all classes of
antidepressants, and response may be seen in as little as 72H (although 6 weeks of therapy is needed
to assess non-responders). Up to 50% of patients with a partial response to the initial antidepressant
chosen will get significant improvement with augmentation therapy. Lithium is the better studied of
the two choices, and the standard dosing is 600-800mg/day, to achieve a serum level of at least 0.5
mEq. Triiodothyronine is not as well studied as lithium, and is believed to be less consistently effective
in augmentation therapy.

Finally, risperidone (an atypical antipsychotic) has also been used for augmentation therapy in patients
treated with SSRIs for mild to moderated depression and who had an incomplete response. In those
treated with risperidone for augmentation therapy, there was a statistically significant decrease in
depression symptoms, and nearly one-quarter had complete remission of symptoms. In this study,
risperidone was started at 0.25mg daily for three days, then 0.5mg daily for 12 days, then 1mg daily.
After 1 month, the dose could be increased to 2mg if appropriate. Another combination studied was
the augmentation of fluoxetine with olanzapine, but was associated with significant weight gain.

Figure 4 reviews management options, including augmentation therapy.

Figure 4: Management of depression

Case 11: Continuing and discontinuing therapy
You are seeing Marty Walsh, a 56-year-old lawyer, whom you are treating for depression with
sertraline. It is 6 months later, and Mr. Walsh has had a nice response to sertraline (the dose was
increased to 100 mg after 4 weeks of therapy, and has been maintained ever since). He is back at the
gym, work performance has improved, and his home life is "great." Mr. Walsh does have an occasional
"down" day, but is otherwise well. Over the past 6 months, Mr. Walsh admits that he was treated for
depression twice before during his life, but he blames those episodes on work-related stress. Only the
most recent episode seemed to come from "out of the blue."

You discuss long-term management options for his depression. Which ONE of the following statements
would be correct to tell Mr. Walsh?

A. His risk of relapse in the first year after discontinuation of treatment is approximately 30%.

B. Patients with multiple episodes of depression are the most likely to relapse.

C. He has no risk factors for recurrence, and sertraline should be discontinued.

D. Lithium should be added to prevent his "down days".

Pop Up Answers

A. Correct. Unfortunately, about 1/3 of patients with depression will relapse in the first year when
treatment is discontinued.

B. Incorrect. Patients with incomplete response to treatment are more likely to relapse than
those with multiple episodes of depression.

C. Incorrect. His past bouts of depression make the risk of relapse more likely. Treatment should
be continued for at least two years before considering discontinuation.

D. Incorrect. There is no indication for augmentation therapy at this point.

Summary answer
The correct answer is B: His risk of relapse in the first year after discontinuation of treatment is
approximately 30%.
Discontinuing treatment

A significant portion (10-12%) of patients with depression will develop chronic symptoms. Short of
that, one-third of patients will have a recurrence within one year of discontinuing treatment, and the
majority (ranging from 60-75%) will have a recurrence within 10 years. However, not all patients need
chronic treatment with antidepressants or psychotherapy. Unlike hypertension, diabetes, and
elevated cholesterol, for which we have well-defined, objective criteria for measuring response to
treatment, response to treatment for depression is entirely dependent on the patient's subjective
symptoms.

In all patients treated for depression, treatment should continue for at least 4 months after clinical
response (typically for a total of 6 months; many recommend a total of 9 months). However, there
should be several considerations before discontinuing treatment that will help to define the risk of
relapse, including adequacy of response to treatment (if residual symptoms persist, risk of recurrence
is high), upcoming psychosocial stressors (don't discontinue therapy before a major, expected life
event) and the presence of other psychiatric disorders that have responded to treatment (such as
anxiety disorder or panic disorder). Risk factors for recurrence are reviewed in Table 8.

Table 8: Risk factors for recurrence

If the risk of recurrence is high, medications should be continued for at least two years, if not longer.
Some physicians advocate that if a patient has had 3 episodes of depression, lifetime therapy is
indicated (known as "Three strikes and you're on"). Maintenance therapy has been demonstrated to
be effective with sertraline, imipramine, and nortriptyline.
Remission and discontinuing medications

Remission is defined as:

 No less than 3 weeks of absence of both sad mood and reduced interest

 No more than 3 remaining symptoms of the major depressive episode

If the patient is in remission and has been on an adequate duration of therapy (i.e., 6-9 months total),
then discontinuation of medications may be considered. Risk factors for recurrence should be
reviewed, and you and the patient should make an informed decision about discontinuing
pharmacotherapy. Medications should be tapered over several weeks or risk withdrawal symptoms
(which include mood fluctuations, jitteriness, and energy changes). The longer the patient has been on
pharmacotherapy and the higher the dose of medication should result in longer tapers. Medications
that are particularly prone to induce withdrawal symptoms are paroxetine and venlafaxine. During
tapering, both the patient and the physician should monitor for recurrence of symptoms of depression
(and resume therapeutic doses should they occur).
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