Review of Precautions of Antidepressant Therapy

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.
 
 
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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