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Depression and Anxiety Newsletter
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Series 2, Issue 2, 2007
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| REVIEW OF PRECAUTIONS OF ANTIDEPRESSANT THERAPY |
Michael Menaster, MD, MA
Private Practice of Psychiatry, San
Francisco, Calif |
OVERVIEW
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Antidepressants are useful in the treatment of various conditions,
including mood disorders, anxiety disorders, eating disorders, impulse
control disorders, and aggression. However, antidepressants are not
without limitations and precautions. This article addresses the more
serious problems to consider when using antidepressants to treat
patients for psychiatric disorders. |
SUICIDALITY
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Concern exists about an association between suicidality and antidepressant use.
All antidepressants presently bear a black box warning from the US Food and Drug
Administration (FDA) about suicidality in children and adolescents. The
association is controversial, with paroxetine (Paxil) currently at the center of
the controversy. In 2001, a United States District Court held “there was
sufficient evidence to support finding that homicides and suicide were caused by
Paxil” and denied a motion for a new trial.1
A study of 1,191 children and adolescents found that suicide-related events were
significantly more frequent with paroxetine than with placebo, with all but one
event occurring in children aged at least 12 years.2 A recent meta-analysis,
which used a Bayesian technique, found a strong association between paroxetine
and suicidality.3 A cross-sectional survey with a cohort analysis of 1,000
patients with bipolar disorder who were studied under naturalistic conditions
for at least one year found no association between paroxetine and suicidality in
those aged 21 years or younger. The study actually found a trend of decreased
suicidality in youths.4 In another view of this issue, toxicology testing
performed in New York City from 1993-1998 on individuals aged less than 18 years
who committed suicide revealed no paroxetine use and rarely any antidepressant
use immediately prior to suicide.5 Another study of 159,810 patients taking
antidepressants found that the risk of suicidal behavior in patients aged 10-19
years is not substantially different among those taking amitriptyline,
fluoxetine, and paroxetine.6 However, the risk of suicide was increased during
the first month of treatment, particularly during the first 9 days, in this same
study.6
A study of 15,390 patients with depression (mean follow-up, 3.4 years) found the
lowest risk of suicide with fluoxetine and the highest risk with venlafaxine.7
Curiously, overall mortality was lower with selective serotonin reuptake
inhibitor (SSRI)
use; this was attributed to decreased rates of cardiovascular- and
cerebrovascular-related deaths.7
Every psychiatric patient should be evaluated for suicidality. The risk factors
for suicidality include a history of suicide attempts, bipolar disorder,
depression, severe anxiety, personality disorder, substance abuse, a
first-degree relative who committed suicide, akathisia, and the spring season.
Ways to reduce the risk of suicide include therapeutic rapport, limiting
quantities of medications, frequent visits (particularly during the first 2
weeks of treatment), and psychosocial support. Anecdotally, no-harm contracts
have prevented several of the author’s patients from attempting suicide. |
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BIPOLAR DEPRESSION AND INDUCTION OF HYPOMANIA AND MANIA
Bipolar disorder has a community prevalence of 3.7% in the United States.8
Bipolar spectrum disorders (BSD) are diagnostic challenges for several reasons.
Depressive episodes in BSD last 3 times longer than manic episodes. Accordingly,
approximately 80% of patients with BSD present with depressive episodes. Not
surprisingly, clinicians often misdiagnose BSD.9 The consequences of
misdiagnosis can include loss of employment, excessive use of health care
services, impaired relationships, and an overall disturbed quality of life.
Compared with patients with schizophrenia and major depression, patients with
BSD have equally high or higher levels of impairment and disability.10
A thorough history and mental status examination are the criterion standards to
diagnose BSD. Risk factors for bipolar disorder include symptom onset between 18
and 27 years of age, family history of bipolar disorder, 3 generations of mood
disorder, mood swings, childbirth, spring or summer season, increased libido,
thrill seeking, hallucinations or other mood incongruent psychotic features,
anger, and racing thoughts. A popular screening instrument for BSD is the Mood
Disorder Questionnaire (MDQ).11 Most patients can complete this simple test
within 5 minutes. The test is available online at
http://www.psycheducation.org/PCP/handouts/mdq.doc.
Mood stabilizers (such as lithium and anticonvulsants) and atypical
antipsychotics are the proper treatment for bipolar depression. The atypical
agents, including olanzapine, risperidone, and quetiapine, are efficacious in
treating the manic and the depressive phases of bipolar disorder.12 At first
blush, the idea that an antipsychotic would treat depression is
counterintuitive. However, atypical antipsychotics, by definition, have
serotonin (5-HT) activity in addition to dopaminergic activity. Specifically,
atypical antipsychotics, antidepressants, and electroconvulsive therapy (ECT)
treat depression by down-regulating 5-HT(2A) receptors.13 Monotherapy with
antidepressants is not recommended in patients with BSD because of the risk of
inducing a manic episode.13
ELEVATIONS IN BLOOD PRESSURE WITH VENLAFAXINE
The American Psychiatric Association (APA) Practice Guidelines list venlafaxine
as one of several optimal antidepressants.14 Because venlafaxine is not highly
protein-bound and lacks significant cytochrome P-450 inhibition, a
well-respected cardiology textbook recommends venlafaxine in patients with
depression and comorbid cardiovascular conditions.15 The text asserts that
venlafaxine has few cardiovascular adverse effects and no effects on ECGs in
patients without preexisting cardiovascular disease.15 In fact, venlafaxine is
associated with a slightly decreased risk of acute myocardial infarction.16,17
Nevertheless, venlafaxine is associated with elevated blood pressure (BP), which
is consistent with its norepinephrine mechanism of action. For a detailed
discussion of the relationship between venlafaxine and elevated BP, as well as a
discussion of the medical indications for ECGs in patients who are prescribed
venlafaxine, please see
Venlafaxine and Cardiac
Illnesses,
an issue of the previous eMedicine Depression and Anxiety Feature Series.18
With venlafaxine immediate release (IR), BP elevations are dose-dependent and
are uncommon at dosages less than 225 mg/d.19 For venlafaxine extended release (XR),
the incidence of sustained hypertension (diastolic BP >89 mm Hg or >10 mm Hg
above baseline for 3 visits) with venlafaxine is 3% in patients taking less than
101 mg/d, 5% in patients taking 101-200 mg/d, 7% in patients taking more than
200 mg/d, and 13% in patients taking more than 300 mg/d, with 2% of patients
taking placebo.20 Elevations in BP are independent of age, gender, baseline BP,
renal status, and hepatic status.20 Preexisting mild BP elevations are not a
risk factor for elevated BP as an adverse effect of venlafaxine.21
Clinicians should obtain baseline BPs and check BPs regularly in patients taking
any form of venlafaxine, particularly those patients taking 225 mg/d or more.
Of note, elevated BP occurs most commonly within the first 2 months of venlafaxine treatment.20
SEIZURES
Seizures are an uncommon but possible adverse effect of nearly every
antidepressant.23 The antidepressant most associated with seizures is bupropion
(Zyban, Wellbutrin). The incidence of seizures with bupropion dosages of 450
mg/d or less ranged from 0.35-0.44%; the cumulative 2-year risk of seizures in
patients who received the maximum recommended dosage of 450 mg/d or less was
0.48%.24 The risk of seizure is dose-dependent, particularly with bupropion
dosages above the recommended maximum of 450 mg/d.24,25
Well-known risk factors, and, thus, contraindications, to bupropion use include
head trauma, seizures, substance abuse, eating disorders, and dosages higher
than 450 mg/d. Other risk factors include sleep deprivation and a history of
attention-deficit/hyperactivity disorder.26,27 Concomitant use of other
medications that lower seizure threshold may also predispose patients to
seizures.28 For instance, the literature reported a case of a patient who had a
seizure while taking trimipramine and bupropion.29
For SSRIs and mirtazapine, the risk of seizure is generally considered to be low
(0.0-0.4%) and not significantly different from the incidence of first seizure
in the general population (0.07-0.09%).23 Seizure risk with tricyclic
antidepressants at therapeutic doses is 0.4% to 1-2% and is dose-dependent.23,24
Patients without risk factors for seizure had a seizure incidence of
approximately 0.6-0.9% when taking imipramine at dosages greater than 200 mg/d.
At lower doses, the frequency of seizures dropped to approximately 0.1% or less
for imipramine.25 Fortunately, in patients not predisposed to seizures, the
potential of seizure caused by antidepressant use is low.23
One study of bupropion overdoses found a 37% incidence of seizures.30 The
seizures were dose-dependent and involved dosages significantly higher than the
average therapeutic dose. All seizures were brief and self-limiting, and no
patients died.30 Another study, which involved 385 patients who overdosed, found
that 26% of patients experienced significant clinical effects and 11% had
seizures, most of which occurred within 6 hours of the overdose. Associated
symptoms included agitation, tachycardia, and hallucinations; if those symptoms
persist, seizures are more likely even beyond 6 hours after the overdose.31 A
third study evaluated 7,348 cases of bupropion overdose in children and
adolescents. Most of these overdoses involved the sustained-release (SR) form of
bupropion. Fifteen percent of these patients had seizures.32
A study published in 2002 reported that, after cocaine intoxication and
benzodiazepine withdrawal, bupropion was the third leading cause of
drug-related, new-onset seizures. Of greater concern is that all bupropion-related
seizures in this study occurred in patients on a therapeutic dose of 450 mg/d or
less.26 Although rare, patients have died after overdosing on bupropion and
having seizures.33 Seizures may also occur in infants who received bupropion
through breast milk.34,35
As a part of a good history, clinicians should ask patients if they have ever
had a seizure, eating disorder, substance abuse, or head trauma. Individuals who
have any of these histories are not good candidates for bupropion. Despite the
possibility of seizures, Fava et al from Harvard assert that “bupropion has
played and will continue to play an important role as a treatment for major
depressive disorder in adults, as well as for other related disorders.”36
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REFERENCES
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(venlafaxine%20HCl)%20Extended-Release%20Capsules/Effexor%20XR%C2%AE%20
(venlafaxine%20HCl)%20Extended-Release%20Capsules_overview.html. Accessed July 15,
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34. Chaudron LH, Schoenecker CJ. Bupropion and breastfeeding: a case of
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J Emerg Med. 2004;27(2):147-51.
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bupropion XL. Prim Care Companion J Clin Psychiatry.
2005;7(3):106-13. |
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Michael Menaster, MD, MA
Private Practice of Psychiatry,
Adjunct Professor of Psychology,
Golden Gate University,
San Francisco, Calif
Reviewer, Journal of Clinical Psychiatry |
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