Review of Precautions of Antidepressant Therapy

July 28, 2007
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.

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.
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

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

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 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

1. Tobin v SmithKline Beecham Pharmaceuticals, 164 F Supp 2d 1278 (D Wy 2001). Available at: Courts opinion.pdf. Accessed July 19, 2007.

2. Apter A, Lipschitz A, Fong R, et al. Evaluation of suicidal thoughts and behaviors in children and adolescents taking paroxetine. J Child Adolesc Psychopharmacol. 2006;16(1-2):77-90.

3. Aursnes I, Tvete IF, Gaasemyr J, Natvig B. Even more suicide attempts in clinical trials with paroxetine randomised against placebo. BMC Psychiatry. 2006;28;6:55.

4. Bauer MS, Wisniewski SR, Kogan JN, Marangell LB, Sachs G. Brief report: paroxetine in younger and adult individuals at high risk for suicide. Psychopharmacol Bull. 2006;39(1):31-7.

5. Leon AC, Marzuk PM, Tardiff K, Teres JJ. Paroxetine, other antidepressants, and youth suicide in New York City: 1993 through 1998. J Clin Psychiatry. 2004;65(7):915-8.

6. Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA. 2004;292(3):338-43.

7. Tiihonen J, Lonnqvist J, Wahlbeck K, Klaukka T, Tanskanen A, Haukka J. Antidepressants and the risk of suicide, attempted suicide, and overall mortality in a nationwide cohort. Arch Gen Psychiatry. 2006;63(12):1358-67.

8. Hirschfeld RM, Calabrese JR, Weissmann MM, et al. Screening for bipolar disorder in the community. Am J Psychiatry. 2003;64(1):53-9.

9. Frye MA, Calabrese JR, Reed ML, et al. Use of health care services among persons who screen positive for bipolar disorder. Psychiatr Serv. 2005;56(12):1529-33.

10. Pini S, de Queiroz V, Pagnin D, et al. Prevalence and burden of bipolar disorders in European countries. Eur Neuropsychopharmacol. 2005;15(4):425-34.

11. Hirschfeld RM, Williams JB, Spitzer RL, et al. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry. 2000;157(11):1873-5.

12. Post RM, Calabrese JR. Bipolar depression: the role of atypical antipsychotics. Expert Rev Neurother. 2004;4(6 Suppl 2):S27-33.

13. Yatham LN, Goldstein JM, Vieta E, et al. Atypical antipsychotics in bipolar depression: potential mechanisms of action. J Clin Psychiatry. 2005;66 Suppl 5:40-8.

14. American Psychiatric Association (APA). Practice Guidelines for the Treatment of Psychiatric Disorders. APA Web site. Available at: Accessed July 15, 2007.

15. Zipes DP, Libby P, Bonow RO, Braunwald E. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. Philadelphia, Pa: Elsevier Saunders; 2005.

16. Beliles K, Stoudemire A. Psychopharmacologic treatment of depression in the medically ill. Psychosomatics. 1998;39:S12-19.

17. Schlienger RG, Fischer LM, Jick H, Meier CR. Current use of selective serotonin reuptake inhibitors and risk of acute myocardial infarction. Drug Saf. 2004;27(14):115-65.

18. Janicak PG, Davis JM. Preskorn SH, et al. Principles and Practice of Psychopharmacology. 4th ed. Philadelphia, Pa: Lippincott, Williams, & Wilkins; 2006.

19. Effexor XR (venlafaxine HCl) Extended-Release Capsules Product Overview. Wyeth Pharmaceuticals, Inc. Web site. Available at: Accessed July 15, 2007.

20. Effexor (venlafaxine hydrochloride) [package insert]. Philadelphia, Pa: Wyeth Pharmaceuticals, Inc.; 2006. Available at: Accessed July 15, 2007.

21. Bahk WM, Pae CU, Chae JH, Jun TY, Kim KS. Even low-dose treatment of venlafaxine may provoke recurrence of hypertension in an Asian patient? Gen Hosp Psychiatry. 2001;23(4):232-4.

22. Menaster M. Venlafaxine and cardiac illnesses. eMedicine from WebMD. Depression and Anxiety Feature Series 1, Issue 8. 2006. Available at: Accessed July 15, 2007.

23. Montgomery SA. Antidepressants and seizures: emphasis on newer agents and clinical implications. Int J Clin Pract. 2005;59(12):1435-40.

24. Peck AW, Stern WC, Watkinson C. Incidence of seizures during treatment with tricyclic antidepressant drugs and bupropion. J Clin Psychiatry. 1983;44(5 Pt 2):197-201.

25. Davidson J. Seizures and bupropion: a review. J Clin Psychiatry. 1989;50(7):256-61.

26. Pesola GR, Avasarala J. Bupropion seizure proportion among new-onset generalized seizures and drug related seizures presenting to an emergency department. J Emerg Med. 2002;22(3):235-9.

27. Oncken CA, Duckrow RB. Seizure associated with sleep deprivation and sustained-release bupropion. Nicotine Tob Res. 2003;5(1):131-3.

28. Ross S, Williams D. Bupropion: risks and benefits. Expert Opin Drug Saf. 2005;4(6):995-1003.

29. Enns MW. Seizure during combination of trimipramine and bupropion. J Clin Psychiatry. 2001;62(6):476-7.

30. Balit CR, Lynch CN, Isbister GK. Bupropion poisoning: a case series. Med J Aust. 2003;178(2):61-3.

31. Belson MG, Kelley TR. Bupropion exposures: clinical manifestations and medical outcome. J Emerg Med. 2002;23(3):223-30.

32. Harris CR, Gualtieri J, Stark G. Fatal bupropion overdose. J Toxicol Clin Toxicol. 1997;35(3):321-4.

33. Bupropion: seizures in an infant exposed through breast-feeding. Prescrire Int. 2005;14(78):144.

34. Chaudron LH, Schoenecker CJ. Bupropion and breastfeeding: a case of a possible infant seizure. J Clin Psychiatry. 2004;65(6):881-2.

35. Shepherd G, Velez LI, Keyes DC. Intentional bupropion overdoses. J Emerg Med. 2004;27(2):147-51.

36. Fava M, Rush AJ, Thase ME, Clayton A, et al. 15 years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL. Prim Care Companion J Clin Psychiatry. 2005;7(3):106-13.

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