MENTAL HEALTH 0095-4543/99 $8.00 + .

OO

DEPRESSION
Robert E. Rakel, MD

Depression is a primary care disease. Depressive symptoms are the

most common medical problems seen in a primary care practice (hyper-
tension is second). Unfortunately, many episodes of depression go unrec-
ognized. Surveys by the National Institutes of Mental Health (NIMH)
show that 70% of depressed patients do not get treated for their disease.21
Furthermore, more than half of patients with depression who commit sui-
cide have seen their personal physicians within the previous month, with
the depression going unrecognized. Suicide is the eighth leading cause of
death in the United States.
Depression will affect one third of adults in the United States some-
time during their lives. At any given time, 5% of adults are clinically de-
pressed, with women being three times as likely as men to suffer depres-
sion.21About twice as many patients have significant depressivesymptoms
that do not meet the criteria for major depression (Table 1).Most of these
patients have minor depression or dysthymia, which is more common in
men. Dysthymic disorder is a persistent condition, often beginning in
childhood.
If patients do not commit suicide, almost all recover from a single
episode of depression. Half of those seen at a tertiary care center however,
have a recurrence within 2 years. Major depression is a recurrent disorder,
and the risk of further episodes increases with each subsequent episode.
Although the median age at onset of depression is 25 years, the initial
episode can occur at any age.25
Depressed patients have a greater degree of functional disability than
patients with chronic medical problems such as diabetes, hypertension,
coronary artery disease, or arthritis. They lose more days of work, spend

From the Department of Family and Community Medicine, Baylor College of Medicine,
Houston, Texas

PRIMARY CARE

VOLUME 26 * NUMBER 2 JUNE 1999 211

212 RAKEL

Table 1. DSM-IV CRITERIA FOR MAJOR DEPRESSIVE DISORDER

Depressed mood or loss of interest or pleasure in almost all activities (anhedonia)
Duration of at least 2 weeks
Five or more of the following symptoms:
depressed mood most of the day, nearly every day (in children and adolescents, can be
irritable mood)
loss of interest or pleasure in almost all activities most of the day, nearly every day
significant weight loss or gain when not dieting (or decrease or increase in appetite)
nearly every day
insomnia or hypersomnia nearly every day
psychomotor agitation or retardation nearly every day (observable by others)
fatigue or loss of energy nearly every day
feelings of worthlessness or excessive or inappropriate guilt nearly every day
diminished ability to think or concentrate, or indecisiveness, nearly every day
recurrent thoughts of death (not just fear of dying) or suicidal ideation, or a suicide
attempt or plan
The symptoms cause clinically significant distress or impairment in social, occupational, or
other functioning
Symptoms are not caused by psychotropic drugs or a general medical condition and do
not occur within 2 months of the loss of a loved one

Modifiedfrom Criteria for Major Depressive Episode. The Diagnostic and StatisticalManual of Mental
Disorders, ed 4.American Psychiatric Association, 1994, p 327; with permission.

more time in bed, and have more bodily pain than do patients with
chronic medical conditions.

RISK FACTORS

Those at highest risk for a first episode of depression are persons with
a family history of the disease. The incidence is two to three times higher
if a first-degree relative has been affected.
Young maternal age also is a risk factor for depression. One study
found that 15- to 17-year-old women who become pregnant are more than
twice as likely to become depressed as adult mother^.^
Studies in twins show that depression can be at least partially caused
by genetic transmission. For monozygotic twins the concordance rate is
65%, and for dizygotic twins it is 14%.25
Risk factors for recurrent episodes include previous depression, onset
after age 60, long duration of individual episodes, substance abuse, as-
sociated anxiety disorder, and double depression (major depression su-
perimposed on pre-existing dysthymia).

SYMPTOMS

Few depressed patients present to their physician complaining of be-

ing sad or depressed. Most present with somatic complaints or fatigue as
 DEPRESSION 213

their chief complaint. It is often difficult to distinguish these symptoms

from those related to organic disease. A high index of suspicion, previous
knowledge of the patient, and awareness of risk factors such as family
history assist in making an early and accurate diagnosis.
Insomnia, especially early morning awakening, is one of the classic
and most dependable early symptoms of depression. Patients complain-
ing of persistent insomnia are three times as likely to develop depression
within 1year than patients without persistent insomnia.8It has been noted
that sleep progressively worsens several weeks before the recurrence of
depression.20
The most common presenting somatic complaints involve loss of en-
ergy, unexplained pain, gastrointestinal symptoms, or headache.
Common Physical Complaints Presenting as Depression
Fatigue
Insomnia
Headache
Chronic pain
Dizziness
Palpitations
Abdominal cramping, bloating, heartburn
Numbness
Loss of appetite
Premenstrual syndrome
Irritable bowel disease often is associated with major depression. There is
strong evidence to suggest that it is the number of complaints rather than
the specific type of symptoms that correlate with depression. In fact, the
likelihood of a mood or anxiety disorder increases dramatically as the
number of physical symptoms increase.I5These are symptoms that cannot
be explained physically and have been a persistent problem over the past
month.
Psychosocial stress can play a significant role in precipitating the first
episode of depression, although this may not be true for subsequent epi-
sodes. Although patients may be reluctant to admit to depression or cry-
ing spells, they usually admit to being under considerable stress. They
may be more willing to accept treatment if it is couched in terms of en-
abling them to handle the stress, especially if they view depression as a
social stigma or personal weakness.

DYSTHYMIA

Dysthymia is chronic low-grade depression that often occurs with an

anxiety disorder or evolves into major depressive disorder. When major
depression is superimposed on dysthymia it is called "double depres-
sion". Dysthymic patients have a 68% lifetime prevalence of major de-
pression.'*
214 RAKEL

DIFFERENTIAL DIAGNOSIS

The following conditions should be considered in patients who ap-

pear depressed:
Bipolar disorder
Dementia
Schizophrenia and schizoaffective disorder
Somatoform disorder
Substance use disorder
Personality disorder
Anxiety disorder
Attention deficit hyperactivity disorder (ADHD)
General medical condition (e.g., thyroid or other endocrine prob-
lem)

POST-PARTUM DEPRESSION

Up to 85% of new mothers experience a depressed mood within 2

weeks of giving birth. Symptoms of insomnia, tearfulness, irritability, and
feeling overwhelmed begin on the 3rd to 7th postpartum day. Postpartum
blues resolve spontaneously over 6 to 12 weeks unless the mother has
postpartum depression, which occurs in 5% to 20% of women within 6
months of delivery.26
First-time mothers are more likely to become depressed than repeat
mothers, especially if they have inadequate social support or are having
marital difficulty.
A serum hemoglobin test to rule out anemia and a thyroid-stimulat-
ing hormone test to evaluate the possibility of hypothyroidism, which
occurs in 4% to 7% of patients in the 6-month postpartum period, should
be obtained.
Selective serotonin uptake inhibitors (SSRIs) are the drugs of choice,
especially if the mother is breast feeding or likely to become pregnant
again. The SSRIs probably are the safest drugs to use in pregnancy because
they do not appear to be teratogenic.I6

CHILDHOOD AND ADOLESCENT DEPRESSION

Depression is more difficult to diagnose in childhood and adolescence

because the presentation is not typical. Red flags that can alert the phy-
sician to depression in a child are recent changes in behavior or a drop in
school performance. Other warning signs include irritability, loss of in-
terest, short attention span, social withdrawal, deteriorating school per-
formance, low self-esteem, sexual promiscuity, and substance abuse.
Young children are less likely to internalize their behavior than are
 DEPRESSION 215

older adolescents and adults. The first sign of depression may be disobe-
dience, excessive acting up, temper tantrums, or running away.
The rate of suicide among adolescents and young adults in the United
States has tripled in the last 40 years, so any suicide threats or attempts
must be taken very seriously.
Risk-taking behaviors in adolescents that can serve as predictors of a
suicide attempt are physical fights, carrying a gun, cigarette use, alcohol
and other substance use, and lack of seat belt ~ s e . 2 ~
More than 50% of depressed adolescents also meet the criteria for an
anxiety disorder, conduct disorder, or ADHD.'O School avoidance is very
common, and most school-avoiding adolescents are depressed.

ELDERLY DEPRESSION

Depression in the elderly often goes undiagnosed, because the vague

physical symptoms of depression mimic so many of the coexisting medi-
cal conditions in this age group. In addition, treating the medical condi-
tion may improve the depressive symptoms. Common medical conditions
associated with depression include congestive heart failure, hypothyroid-
ism, cancer, paJkinsonism, malnutrition, and infection. Many of the mul-
tiple medications an elderly person is likely to be taking can also cause
depressive symptoms (e.g. beta-blockers, reserpine, antihistamines, and
nonsteroidal anti-inflammatory drugs). Depression also is an independent
predictor of poor outcome in patients who have coronary artery disease.
The converse is also true (depression is a major risk factor for developing
coronary heart disease). Depressed men are twice as likely as nonde-
pressed men to suffer a myocardial infarction or have a sudden cardiac
death.9
The preferred drug for treating depression in the elderly is an SSRI
because of the excellent side-effect profile. In the case of recurrent de-
pression, however, the drug of choice is the one that worked well in the
past. The physician, therefore, does not run the risk of choosing a new
drug that may not be as effective. When treating the elderly, the rule is to
start low and go slow. Begin with one-third to one-half the normal adult
dose, but do not hesitate to eventually end up at the full adult dose if
necessary. Underdosing is one of the main reasons for unsuccessful treat-
ment of depression in the elderly2

DEPRESSION IN THE MEDICALLY ILL

Depression often co-exists with a serious medical illness and is sub-

stantially more common in hospitalized medical patients than in seriously
ill outpatients?
Approximately one-fourth of patients with cancer will have major
depression, 40% to 50% of patients with Parkinson's disease, and one-
third of those with dementia. It is a mistake to recognize that a medically
216 RAKEL

ill patient is depressed and think that it is a normal reaction to the un-
derlying illness. They may be related, but both should be treated.
Fatigue is not a useful diagnostic feature of depression in the medi-
cally ill, because 77% of all hospitalized medically ill patients have fatigue
or loss of en erg^.^ Disturbed sleep, concentration, and appetite are other
symptoms of depression that are also disrupted by medical illness.
Depression increases the risk of sudden cardiovascular death and is
a significant problem in the postmyocardial infarction period. In one
study, 45% of post-myocardial infarction patients had either major or mi-
nor depression (18%and 27% respectively)within 10 days of their infarct.
Forty-four percent of those with major depression still met the criteria for
depression 3 months later.23

SUICIDE

Most patients who commit suicide communicate their intent to others

before doing it, and most have seen a physician within the previous
month. In one series, over two-thirds of suicides had given evidence of
their intent by statement or previous attempt, but less than half of the
physicians were aware of the warning^.'^ Physicians often are reluctant to
ask if a patient is thinking of killing himself. Contrary to popular belief,
this is the best way to detect potential suicidal patients and is often a
welcomed opening for patients who are desperate and anxious to talk
about their feelings. Patients at highest risk for suicide are depressed al-
coholics and those who have attempted suicide in the past. The group at
greatest risk are white, elderly, unmarried men who live alone.

MIXED ANXIETY AND DEPRESSION

Anxiety and depression often coexist, and are being recognized in-
creasingly as a significant problem in primary care. Approximately 60%
of patients with depression have anxiety, and 25% of those patients have
panic attacks. Depression and anxiety occur so often together that some
feel depression without any anxiety is rare.
It often is difficult to differentiate anxiety from depression, because
many symptoms are common to both, such as easy fatigability, difficulty
concentrating, somatic complaints, motor tension, and excessive worry.
This is of increasing clinical importance because some drugs for depres-
sion may accentuate anxiety, and some drugs for anxiety, such as the ben-
zodiazepines, may accentuate the depression.
For patients with anxiety and depression, the most effective drugs
appear to be the sedating tricyclics, trazodone, or nefazodone. In these
patients, the anti-anxiety effect appears to occur well before the antide-
pressant effect.
Patients with anxiety and depression are more severely disturbed and
have more social dysfunction than those with only one or the other. They
 DEPRESSION 217

are also more refractory to treatment and more likely to have a prolonged
illness.

TREATMENT

Depressed patients should receive treatment for at least 6 months

after resolution of symptoms. In many cases treatment should continue
beyond this, sometimes for years. When discontinuing treatment, the dose
should be gradually tapered over 2 months while watching for the re-
emergence of depression.
Most patients (75% or more) have multiple episodes of depression."
Those experiencing three or more episodes should be placed on long-term
maintenance medication. When prolonged maintenance is needed, recur-
rences can be prevented by using the same drug at full dosage.

Psychotherapy

A combination of supportive psychotherapy and pharmacotherapy

is the most effective approach for treating mild to moderate depression.
Limited psychotherapy of this nature can easily be provided by the pri-
mary care physician at the frequent visits required to monitor drug effec-
tiveness.
Cognitive behavioral therapy is an effective form of psychotherapy
that provides encouragement and attempts to improve the patient's self-
esteem. The physician helps the patient replace the negative thinking as-
sociated with depression with a more realistic and positive approach to
daily living.

Exercise

Running has been shown to be about as effective as psychotherapy

in treating mild to moderate depression. Physicians without the skills or
time to provide psychotherapy can combine a regular exercise program
with pharmacotherapy. The added cardiovascular benefit should make
this a standard recommendation for patients who are receptive to an ex-
ercise program.'2

ElectroconvulsiveTherapy

Electroconvulsive therapy is very effective, achieving remission in

over 90% of patients within 1 to 2 weeks. It usually is reserved for patients
who do not respond to medication, those who are suicidal, and patients
with psychotic or catatonic features. Treatments usually are given three
times a week until the patient improves.
218 RAKEL

Bright Light Therapy

Bright light therapy is effective for patients with seasonal affective

disorder. The bright light is used primarily in the morning hours using
one of a variety of available devices. Most of these patients also do best
if bright light therapy is given in combination with pharmacotherapy.

Pharmacotherapy

All drugs currently approved for treating depression are equally ef-
fective, and no drug seems to work more rapidly than another. A newly
selected drug, however, may fail to be effective one-fourth of the time.
The best drug to use in recurrent depression is the one that worked well
in the past if the patient can tolerate the side effects.
Because all antidepressants are equally effective most physicians
choose a drug based on its side-effect profile (Table 2). If the patient’s
primary complaint is tiredness, an activating SSRI may be preferred,
whereas if anxiety is a major component a more sedating drug may work
best. Cancer patients who have anorexia and weight loss may do better
receiving a tricyclic that is associated with increased appetite and weight
gain. The most troubling side-effects are those with excessive anticholin-
ergic activity, namely dry mouth, blurred vision, constipation, memory
disturbance, and urinary retention. These can be a special problem for the
elderly who already have these problems.
Most primary care physicians prefer to select a drug that is npt lethal
if taken in overdose (Table 31, especially because most patients who com-
mit suicide by ingestion do not stockpile their medicines but take the last
prescription given. The lethal dose for a tricyclic antidepressant is 1.5 g
or about ten times the daily therapeutic dose.
The best first-line drug to use is either an SSRI (fluoxetine, sertraline,
paroxetine, fluvoxamine) or one of the newer agents such as venlafaxine,
nefazodone, or mirtazapine. The remaining drugs fall into the tricyclic or
miscellaneous categories (see Table 3). The tricyclic agents were first on
the market, and although as effective as all other agents, they have more
severe side effects and are lethal in overdose. A final category are the
monoamine oxidase inhibitors (MAOIs),but these are rarely used in pri-
mary care because of their severe side-effects, the most serious of which
is potentially fatal hypertensive crisis if taken with certain drugs or foods
containing tyramine. They cannot be given safely with another antide-
pressant.
Therapeutic blood levels of antidepressant drugs are of little help
except when determining levels of toxicity in a tricyclic overdose or in
assessing patient compliance.

Selective Serotonin Reuptake Inhibitors

The SSRIs act by increasing serotonin in the synapse as a result of
blocking its reuptake at the presynaptic nerve. The advantages of SSRIs
Table 2. ANTIDEPRESSANT SIDE-EFFECTS

Insomnia/ Ortho. Sexual

Drug Anticholingergia Sedation Agitation Hypoten. Arrhythmia Nausia Wt. Gain* Dysfunction
Amitriptyline (Elavil) ++++ ++++ 0 ++++ +++ 0 ++++ ++
Desipramine (Norpramin) + + + ++ ++ 0 + +
Doxepin (Sinequan) +++ ++++ 0 ++ ++ 0 +++ ++
Imipramine (Tofranil) +++ +++ + ++++ +++ + +++ ++
Nortriptyline (Vivactil) + + 0 ++ ++ 0 + +
Protriptyline (Vivactil) ++ + + ++ ++ 0 0 ++
Trimipramine (Surmontil) + ++++ 0 ++ ++ 0 +++ +
Amonapine (Asendin) ++ ++ ++ ++ +++ 0 + ++
Maprotiline (Ludiomil) ++ ++ 0 + + 0 ++ 0
Mirtazapine (Remeron) + ++ 0 + 0 0 +++ 0
Trazodone (Desyrel) 0 ++++ 0 + + + + 0
Nefazodone (Serzone) 0 +++ 0 + + + 0 0
Bupropion (Wellbutrin) 0 0 ++ 0 + + 0 0
Venlafaxine (Effexor) 0 0 ++ 0 0 ++ 0 +
Fluoxetine (Prozac) 0 0 +++ 0 0 +++ 0 ++
Paroxetine (Paxil) 0 0 +++ 0 0 +++ 0 ++
Sertraline (Zoloft) 0 0 +++ 0 0 +++ 0 ++
Fluvoxamine (Luvox) 0 0 +++ + 0 +++ 0 ++
0 =
none
+ =minimal
+ + = mild
+ + + = moderate
+ + + + = strong
* Over 13 Ibs
Adnptedfrom Depression Guideline Panel: Depression in Primary Care: Detection, Diagnosis, and Treatment. Quick Reference Guide for Clinicians, number 5. Rockville,
MD: Agency for Health Care Policy and Research; 1993. US Department of Health and Human Services publication no. 93-0552.
h,
Table 3. ANTIDEPRESSANT FORMS AND DOSAGES
N
0
Initial Dose Range Safe in
Drug Dosage Forms(rng) (rng/d) (rng/d) Frequency Half-life Overdose
SSRIs
Fluoxetine (Prozac) 10,20 mg Pulvules, 20 mgl5mL liquid 20 20-60 2-9 d Yes
Sertraline (Zoloft) 50, 100 scored tablets 50 50-200 1-4 d Yes
Paroxetine (Paxil) 10, 20, 30, 40 coated tablets 20 20-50 10-24 h Yes
Fluvoxamine (Luvox) 50, 100 scored tablets 50 50-300 15 h Yes
Citalopram (Celexa) 20. 40 scored tablets 20 20-60 35 h Yes
Miscellaneous
Venlafaxine (Effexor) 25, 37.5, 50, 75, 100 scored tablets 75 75-375 5-11 h Yes
37.5, 75,150 XR (extended release) 37.5 75-375 5-11 h Yes
Nefazodone (Serzone) 100, 150,200,250 scored tablets 200 200-600 2-4 h Yes
Trazodone (Desyrel) 50, 100, 150, 300 scored tablets 150 150-600 4-9 h Yes
Bupropion (Wellbutrin) 75, 100 tablets 200 200-450 8-24 h Yes
100, 150 SR tablets 150 200-450 8-24 h Yes
Tricyclics
Amitriptyline (Elavil) 10, 25, SO, 75, 100, 150 coated tablets 50-75 50-300 31-46 h no
Clomipramine (Anafranil) 25, 50, 75 tablets 25 25-250 19-37 h no
Doxepin (Sinequan) 10,25,50, 75, 100, 150 capsules, 10 mg/mL solution 50-75 25-300 8-24 h no
Imipramin (Tofranil) 10, 25,50 coated tablets 50-75 30-300 11-25 h no
Trimipramine (Surmontil) 25, 50,100 capsules 50-75 50-300 7-30 h no
Desipramine (Norpramin) 10, 25, 50, 75, 100, 150 coated tablets 50-75 25-300 12-24 11 no
Nortriptyline (Pamelor) 10, 25, 50, 75 capsules, 10 mg/5mL solution 25-50 30-100 18-44 h no
Protriptyline (Vivactil) 5, 10 coated tablets 10-15 15-60 67-89 h no
Arnoxepine (Asendin) 25,50,100, 150 scored tablets 100-1 50 50-600 8h Yes
Tetracyclics
Malprotiline (Ludiomil) 25, 50, 75 scored tablets 50-75 50-225 21-25 h no
Mirtazapine (Remeron) 15, 30 scored tablets 15 15-60 20-40 h yes (3
MAOI's
Phenelzine (Nardil) 15 coated tablets 45 45-90 2-4 h no
Tranycypromine (Pamate) 10 coated tablets 30 30-60 2.4-2.8 h no

*Initialdaily adult dose. Elderly persons should receive half the starting dose.
**Startin divided doses (tid)-maintenance may be once daily at bedtime [qd (hs)]
***Initialdose 100 mg bid for 3 days then 100 mg tid
 DEPRESSION 221

are that they have no anticholinergic side-effects, no arrhythmic potential,

no orthostatic hypotension, and no weight gain. Patients being prepared
for surgery should have their bleeding time checked, because these drugs
have been reported to increase bleeding time.
Despite their much improved safety profile they do have some side-
effects, notably nausea, agitation, insomnia, and sexual dysfunction (de-
creased libido, ejaculatory and erectile dysfunction, and anorgasmia). The
reported incidence of sexual dysfunction varies from 12% to 50% (see
Table 2), but patients usually do not volunteer this information and reveal
the problem only if asked.
The gastrointestinal side-effects of SSRIs can be prevented by taking
the drug with a large glass of water and a Sertraline has been associ-
ated with more diarrhea than the other SSRIs but is generally thought to
be gentler (i.e., neither activating or sedating). Paroxetine is more sedating
than the other three SSRIs.
Fluoxetine is more likely to be activating, which is an advantage in
patients who are lethargic. Its long half-life is an advantage if compliance
is uncertain or if the patient misses a dose.'
Other Agents
Venlafaxine has gastrointestinal and sexual dysfunction side-effects
similar to the SSRIs and can cause hypertension at doses greater than 225
mg per day. It is especially useful in patients who do not respond to other
agent^.^ Bupropion and venlafaxine are chemically related drugs that are
safe in overdose and have no significant anticholinergicactivity, sedation,
or weight gain. Like the SSRIs, however, they can cause agitation. Bup-
ropion lowers the seizure threshold, increasing the risk of seizures espe-
cially if the patient has a history of seizures. The risk increases almost
tenfold in doses above 450 mg per day, which is the maximum recom-
mended dose.
Nefazodone and trazodone are sedating drugs. Nefazodone causes
no sexual dysfunction, which makes it a good alternative for the SSRIs.
Sexual dysfunction also is uncommon with bupropion and mirtazapine.
Tricyclics
Most tricyclic antidepressants are given as a single dose at bedtime.
Anticholinergic side-effects and the cardiac arrhythmias that lead to death
from overdose are the major drawbacks. The tricyclics slow intraventric-
ular conduction, prolonging the QRS, PR, and QT intervals. This can cause
complete heart block or ventricular arrhythmias in overdose. They have
been shown effective in the treatment of chronic pain even when depres-
sion is not present. Amoxapine can have Parkinson-like side effects and
lead to tardive dyskinesia.
MAOls
The MAOIs are reserved for patients who fail to respond to other
antidepressants. Patients should be given a list of foods to avoid that
222 RAKEL

contain tyramine. There are also dangerous interactions with meperidine,

antihypertensive agents, SSRIs, and the tricyclics.

Augmentation Therapy
In the past, if one drug was not effective the practice was to change
drugs. Most of the time however, the drug given is partially effective and
rather than switch drugs entirely, a second agent from another class (ex-
cept an MAOI) can be added. Augmentation of the partially effective drug
also can be achieved using buspirone, lithium, or thyroid hormone (e.g.,
levothyroxin).Thyroid augmentation appears more useful in patients who
have dysthymia than in those with major depression.'
The most common reason for treatment failure is underdosing.
If an adequate dose of an SSRI does not achieve the anticipated effect,
consider adding an agent from another class, for example, a tricyclic.
Switching to another SSRI is also an option, because failure to one does
not predict poor response to another.'

St. John's Wort

This herbal extract of the plant Hypericurn perforaturn has been found
to be more effective than placebo and almost as effective as standard anti-
depressants, although most studies have not been well controlled. The
extract contains hundreds of compounds, but hypericin is thought to be
the active ingredient. The usual regimen is to gradually increase the dos-
age to 300 mg three times a day.24Patients taking St. John's Wort with an
SSRI are at risk for developing serotonin syndrome.

Serotonin Syndrome
Serotonin syndrome, although not very common, is a potentially se-
vere drug interaction resulting in confusion, myoclonus, and gastrointes-
tinal tract activation. The symptoms of excessive serotonin are altered
mental status, agitation, hyperreflexia, diaphoresis, shivering, tremor, di-
arrhea, fever, hypotension, nausea and vomiting, and dizziness.13
This syndrome can occur when SSRIs are used along with other drugs
that increase serotonin (e.g., lithium, buspirone, tricyclic antidepressants,
bupropion, MAOIs, dextromethorphan, and weight-loss medications such
as phentermine or dexfenfluramine, although the latter has been removed
from the market. St. John's Wort reportedly has some monoamine oxidase
activity and should not be combined with a blocker of serotonin.
Although severe episodes can be fatal, most patients recover com-
pletely with supportive care alone. The first step is to discontinue the
offending agents. Symptoms may be reversed by giving a serotonin an-
tagonist such as cyproheptadine or propranolol. Clonazepam may be used
to relieve the myoclon~s.'~
 DEPRESSION 223

Discontinuation Syndrome
Since 1959, a variety of symptoms (51 in one study) have been noted
with the discontinuation of an antidepressant. These are usually flu-like
symptoms, including nausea and vomiting, anxiety, tremor, and arrhyth-
mia. These symptoms are usually mild and transient and usually do not
appear related to the recurrence of depression, although this may be dif-
ficult to differentiate. They are more likely to occur following rapid with-
drawal of the drug but can also occur with gradual withdrawal.
The syndrome has been described with all classes of antidepressants.
Among the SSRIs, the incidence is highest for paroxetine, which has a
short half-life, and lowest for fluoxetine, which has a long half-life. The
most common symptoms associated with discontinuation of the SSRIs are
dizziness, nausea, lethargy, headache, problems with balance, shock-like
sensations, and paresthe~ia.'~ Some patients describe the dizziness as hav-
ing a swimming or spaced-out quality that is exacerbated by movement.I7

INDICATIONS FOR REFERRAL

Although most patients with mild to moderate depression can be

managed by the primary care physician, severe and complicated cases
should be referred. These include:
Suicidal ideation
Psychosis
Lack of response to treatment
Associated substance abuse
Need for electroconvulsivetherapy
Lack of family or social support

CONCLUSION

Depression is a common problem in primary care that too often goes

undiagnosed. When treated, depression often is undertreated. Depressed
patients often present with physical symptoms, especially fatigue, insom-
nia, and unexplained pain.
Many investigators consider depression a chronic illness, analogous
to arthritis or hypertension, with recurrent exacerbations that require
long-term treatment. The longer an episode lasts, the greater the chance
of recurrence.
All antidepressants are equally effective, and choice usually is made
on the basis of side effects. Augmentation therapy should be considered
when the response to a drug is inadequate.

References

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Philadelphia, WB Saunders, 1997, pp 1154-1161
224 RAKEL

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Address reprint requests to

Robert E. Rakel, MD
Department of Family and Community Medicine
Baylor College of Medicine
5510 Greenbriar Street
Houston, TX 77005