ADVERSE EFFECT PROFILE, SAFETY, AND DOSING OF ANTIDEPRESSANT MEDICATIONS

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ADVERSE EFFECT PROFILE, SAFETY, AND DOSING OF ANTIDEPRESSANT MEDICATIONS

Many medications are available for the treatment of depressive episodes. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) are commonly used,1 but other options include second generation atypical antidepressants (eg, bupropion, mirtazapine), tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). All of the available agents have similar efficacy,2,3,4,5 making safety and adverse effects important determinants when designing a treatment plan. This newsletter reviews the common adverse effects of antidepressant medication, highlighting similarities and differences between and among classes.

TRICYCLIC ANTIDEPRESSANTS

TCAs act at several receptors. Their efficacy in the treatment of depression is thought to stem from their blockade of serotonin and norepinephrine reuptake. Other receptor actions are linked to adverse effects. For example, alpha-1 adrenergic antagonism causes orthostatic hypotension and dizziness; blockade at cholinergic receptors causes dry mouth, blurred vision, urinary retention, constipation, and memory problems; antihistamine activity causes sedation and weight gain; and blockade of sodium channels in the heart and brain has the potential to cause cardiac arrhythmias and seizures. Within the class, the TCAs differ somewhat in their propensity to cause these adverse effects. TCAs are divided into tertiary and secondary amines based on chemical structure. The tertiary amines include amitriptyline, imipramine, trimipramine, and doxepin. These tend to cause sedation and are more likely than secondary amines to cause weight gain of up to 10-20 lb. Orthostatic hypotension is more common with amitriptyline, imipramine, and doxepin.6 Nortriptyline, desipramine, protriptyline, and maprotiline are secondary amines. Desipramine and protriptyline are less sedating, and some patients may find them slightly stimulating. Weight gain and orthostatic hypotension are less common with secondary amines. Nortriptyline is thought to be the least likely to cause orthostasis.6 All TCAs produce anticholinergic adverse effects, including dry mouth, blurred vision, constipation, urinary hesitancy, and urinary retention (especially if benign prostatic hypertrophy is comorbid). Amitriptyline and protriptyline are the most anticholinergic of the TCAs, and maprotiline is the least. Every TCA lowers the seizure threshold. These effects are clinically significant with maprotiline (significant risk with dose >200 mg/d), clomipramine, and amoxapine.6 Cardiac conduction is slowed by all TCAs by decreasing the influx of sodium through the fast-acting sodium channels of the myocardium and may manifest as prolonged PR intervals or prolonged corrected QT intervals. Complications can include atrioventricular (AV) block, bundle branch blocks, and a dose-dependent cardiac depression that leads to degeneration of the action potential into a sinusoidal wave. Other benign ECG changes are also possible and include flat or inverted T waves.6 Less common adverse effects of TCAs include the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and agranulocytosis.

MONOAMINE OXIDASE INHIBITORS

MAOIs increase serotonin and norepinephrine neurotransmission by inhibiting their degradation by the enzyme monoamine oxidase (MAO). This enzyme exists in 2 forms. MAO-A is found in the GI tract, liver, and brain and is an important part of the pathway to degrade serotonin, norepinephrine, and tyramine. MAO-B is found in the brain and degrades dopamine. In the United States, 3 monoamine oxidase inhibitors are available. The selective MAOI selegiline is a treatment for Parkinson disease that, at low doses, inhibits only MAO-B and, at higher doses, becomes less effective. The 2 nonselective MAOIs are phenelzine and tranylcypromine. These 2 MAOIs bind to the enzyme irreversibly, so their therapeutic and adverse effects remain until new MAO is generated, which takes approximately 2 weeks.7MAO normally degrades tyramine in the gut and liver. In the presence of MAOI, the enzyme MAO is not available to degrade tyramine, and tyramine reaches the systemic circulation. In the brain, circulating tyramine triggers the release of norepinephrine from presynaptic neurons. With MAO not available to degrade tyramine, a potentially life-threatening hypertensive crisis can be precipitated in patients taking MAOI agents. Symptoms of hypertensive crisis include severe throbbing headache, nausea, diaphoresis, and palpitations. To avoid these reactions, people taking MAOIs must vigilantly avoid all foods that contain tyramine. MAOIs also have dangerous interactions with numerous other drugs. The most notable examples occur with sympathomimetic agents (eg, pseudoephedrine, amphetamine, methylphenidate, cocaine), which can lead to hypertensive crises, and with serotonergic agents (eg, SSRIs, TCAs, meperidine, triptan antimigraine agents), which have the potential to cause serotonin syndrome. The most common adverse effects of MAOIs are hypotension and dizziness. Other common adverse effects include dry mouth, constipation, blurred vision, and sexual dysfunction. Tranylcypromine is less sedating and, in some people, may be sufficiently stimulating to cause insomnia and agitation. Tranylcypromine is less likely than phenelzine to cause weight gain.8

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

SSRIs were developed to inhibit serotonin reuptake pump, like TCAs, but without affecting alpha-adrenergic, histamine, or muscarinic receptors, as well as the fast-acting sodium channels. Although all SSRIs share this ability to block serotonin reuptake, SSRIs are chemically distinct within the class and have a wide range of half-lives (fluvoxamine, 16 h; paroxetine, 21 h; sertraline, 23 h; citalopram, 35 h; fluoxetine, 2-3 d; fluoxetine’s active metabolite norfluoxetine, 7-15 d).9 Sertraline also affects dopamine neurotransmission and paroxetine has some muscarinic-blocking properties.10 Nausea is a very common adverse effect of SSRIs, reported by up to 20% of patients receiving fluoxetine.11 Many SSRI adverse effects, such as nausea and headache, improve after 2-4 weeks of treatment.9 Sexual dysfunction, reported by as many as 60% of patients treated with an SSRI, does not tend to improve over the course of treatment. All of the SSRIs seem equally prone to cause sexual dysfunction, which can include erectile dysfunction, decreased libido, and impaired orgasm.9 A minority of patients experience anxiety, agitation, or insomnia with SSRIs; depending on the patient, SSRIs can be either sedating or activating.11 In some cases, the activation can be difficult to tolerate (eg, akathisia, which is associated with a very uncomfortable motor restlessness and need to move). Within the class, asthenia is associated more with fluvoxamine and paroxetine, while activation is associated more with fluoxetine and sertraline.9 Most commonly, SSRIs are weight neutral or cause an initial weight loss, although this weight loss is suspected to be only temporary.11,12 Among the SSRIs, paroxetine may be somewhat more likely to induce weight gain; one study found that 25% of patients taking paroxetine gained more than 7% of their body weight at 32 weeks of therapy.13 Other SSRIs seem no more likely to cause weight gain than placebo.8 Uncommon adverse effects of SSRIs include extrapyramidal effects, increased risk of bleeding, and SIADH. Paroxetine is more likely to cause anticholinergic effects, including dry mouth, sedation, and weight gain.9 SSRIs have benefits for some patients with concomitant medical illness. SSRIs have minimal effects on heart rate, heart rhythm, or blood pressure and are considered a good alternative to TCAs and MAOIs for patients with concomitant cardiac disease.11 SSRIs are not noted to lower the seizure threshold.11

Serotonin syndrome

Excess serotonin neurotransmission, which is most commonly due to overdose or drug interactions, can lead to the dangerous and potentially fatal serotonin syndrome. This syndrome is seen in 14-16% of persons who overdose on SSRIs. Symptoms can begin within hours of the dose change and include mental status change; autonomic instability; diaphoresis; tachycardia; hypertension; hyperthermia; neuromuscular changes such as mild tremor, rigidity, myoclonus, or hyperreflexia; and gastrointestinal symptoms such as hyperactive bowel sounds and diarrhea.14,15

SSRI discontinuation syndrome

While this discontinuation syndrome is referred to as SSRI discontinuation syndrome, similar symptoms are possible when discontinuing any serotonergic agent. The symptoms include dizziness, flulike symptoms, sleep disruption, paresthesias, lethargy, and nausea.16,17 Symptoms usually begin 1-5 days after stopping an SSRI and can be relieved if an SSRI is restarted, in which case symptoms usually resolve in 24 hours. Without treatment, symptoms may continue for up to 3 weeks.16,17 Discontinuation symptoms are uncommon in patients treated for less than 6-8 weeks and those whose dosage is slowly tapered.16 Drugs with shorter half-lives, such as paroxetine and fluvoxamine, have a higher association with discontinuation syndrome.16 Discontinuation syndrome has also been documented in patients being treated with venlafaxine and mirtazapine.16

SSRIs and suicidality in children

Suicidality has been reported in clinical trials of antidepressant treatment for children and adolescents. Because suicide is such a common symptom of depression, discerning whether suicidal ideation and suicide attempts are due to treatment or underlying disease is challenging. Other hypotheses to explain the suicidality include lack of improvement of underlying depression, activating adverse effects, or akathisia. In 2004, the US Food and Drug Administration (FDA) reviewed 24 trials of SSRIs used for any indication in the pediatric population, looking for adverse events including suicide attempts, suicidal ideation, or preparation for imminent suicide attempt. This analysis found that the relative risk of a suicide-related event was increased with SSRI treatment (RR 1.66; 95% CI, 1.02-2.68); in the subset of trials in which SSRIs were prescribed for depression, the risk of suicide-related event was 4% with an SSRI versus 2% without an SSRI. Most of the events were suicidal ideation and no completed suicides were reported. Most of the data analyzed were short-term, and most of the events occurred early in the course of treatment.18,19,20 In response, the FDA issued a Public Health Advisory warning of increased risk of suicidal thoughts and behaviors among children treated with SSRIs. Manufacturers were mandated to include a black box warning describing the increased risk of suicidality in children. Fluoxetine is the only SSRI that the FDA has approved for the treatment of depression in children.21 While the FDA has not prohibited the use of SSRIs in children with depression, they urge careful consideration of the potential risks and benefits, extensive patient and parent education, and careful monitoring, especially in the first weeks of treatment and after dose adjustments.22

ATYPICAL ANTIDEPRESSANTS

Bupropion

Bupropion affects dopamine and norepinephrine reuptake with minimal effects on serotonin, acetylcholine, and histamine. Its half life ranges from 6-24 hours, and its 3 active metabolites are hydroxybupropion, threohydrobupropion, and erythrohydrobupropion.23 Bupropion has been noted to lower the seizure threshold, especially at doses of more than 450 mg/d and especially with rapid dose escalation. This risk is higher with the immediate release form (0.4%) of bupropion compared with the sustained release preparation (0.1%).23 Bupropion can be activating and may cause agitation, anxiety, or insomnia in some patients.24 Common adverse effects of bupropion include headache, nausea, constipation, dry mouth, and dizziness.24,23 Bupropion is less likely than other antidepressants to cause sexual dysfunction.25,23 It has also been associated with a slight weight loss in some patients.8,24

Mirtazapine

Mirtazapine promotes serotonin and norepinephrine neurotransmission by acting as an antagonist at the presynaptic alpha-2 adrenergic receptor and at the postsynaptic 5-HT2 and 5-HT3 receptors. It also affects histamine-1 receptors, which may cause the adverse effects of sedation and weight gain, and antagonizes alpha-1 adrenergic, which may cause dizziness.26 Among the newer antidepressants, mirtazapine is the most likely to cause significant weight gain, which averages 2 kg over 8 weeks.24 The risk of significant weight gain is estimated to be less with mirtazapine than with TCAs.8 Mirtazapine may also cause dry mouth and constipation.27 When compared to tricyclic antidepressants, mirtazapine was noted to cause less dyspepsia, less drowsiness, and less anticholinergic adverse effects.27 Serotonergic adverse effects (eg, nausea, vomiting, headache) were reported as less frequent with mirtazapine (24.2%) than with fluoxetine (38.8%). Sexual dysfunction was also reported as less frequent with mirtazapine than with SSRIs.27 Mirtazapine may increase cholesterol and triglyceride levels and, rarely, may cause neutropenia. Transient elevations in liver function tests have been noted, but they generally normalize with discontinuation of the medication.26,27

Venlafaxine

Venlafaxine blocks the serotonin reuptake inhibitor at all doses. At higher doses, it also blocks norepinephrine reuptake.28 New onset hypertension has been noted in patients treated with venlafaxine, especially at higher doses.29 Approximately 5% of patients treated at the higher end of the dosing spectrum may have elevations of diastolic blood pressure of 15 mm Hg or more. Slight elevations of resting heart rate have also been noted.28

Duloxetine

Duloxetine inhibits the reuptake of both norepinephrine and serotonin with minimal effects on dopamine or cholinergic or histamine receptors.30 Common adverse effects include nausea, diarrhea, constipation, insomnia, somnolence, fatigue, anxiety, headache, and dry mouth. These were usually rated as mild or moderate and were most common in the first weeks of treatment.29,30 Sexual dysfunction is a possible adverse effect, noted in 50.2% in one study.29 Duloxetine does not appear to cause weight gain.31 Studies of duloxetine have not consistently shown changes in blood pressure and heart rate. In those studies that demonstrated a statistically significant difference in blood pressure and heart rate, the difference was not thought to be clinically significant.29 No effects have been noted on ECG intervals.30

References

1. sen T, Dording C, Neault NB, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:177-87. 2. Arroll B, Macgillivray S, Ogston S, et al. Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. Ann Fam Med. 2005;3:449-55. 3. Furukawa TA, McGuire H, Barbui C. Meta-analysis of effects and side effects of low dosage antidepressants in depression: systematic review. BMJ. 2002;325:991. 4. Kennedy SH. Continuation and maintenance treatments in major depression: the neglected role of monoamine oxidase inhibitors. J Psychiatry Neurosci. 1997;22:127-31. 5. MacGillivray S, Arroll B, Hatcher S, et al. Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systemic review and meta-analysis. BMJ. 2003;326:1014-7. 6. DP, Jefferson JW. Tricyclic Antidepressants. In: Handbook of Medical Psychiatry. 2nd ed. St. Louis, MO: Mosby; 2004. 7. DP, Jefferson JW. Monoamine Oxidase Inhibitors. In: Handbook of Medical Psychiatry. 2nd ed. St. Louis, MO: Mosby; 2004. 8. Fava M. Weight gain and antidepressants. J Clin Psychiatry. 2000;61(suppl)11:37-41. 9. Masand PS, Gupta S. Selective serotonin-reuptake inhibitors: an update. Harv Rev Psychiatry. 1999;7(2)69-84. 10. Vaswani M, FK, Ramesh S. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:85-102. 11. Mourilhe P, Stokes PE. Risks and benefits of selective serotonin reuptake inhibitors in the treatment of depression. Drug Saf. 1998;18:57-82. 12. Malone M. Medications associated with weight gain. Ann Pharmacother. 2005;39:2046-54. 13. Fava M, Judge R, Hoog SL, et al. Fluoxetine versus sertraline and paroxetine in major depressive disorder: Changes in weight with long-term treatment. J Clin Psychiatry. 2000;61:863-7. 14. Boyer EW, M. The serotonin syndrome. NEJM. 2005;352:1112-20. 15. Lane R, Baldwin D. Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J Clin Psychopharmacol. 1997;17:208-21. 16. Ditto KE. SSRI discontinuation syndrome. Awareness as an approach to prevention. Postgrad Med. 2003;114:79-85. 17. Coupland NJ, Bell C, Potokar JP. Serotonin reuptake inhibitor withdrawal. J Clin Psychopharmacol. 1996;16:356-62. 18. Cheung AH, GJ Emslie, TL Mayes. The use of antidepressants to treat depression in children and adolescents. CMAJ. 2006;174:193-200. 19. Bridge JA, Salary CB, Birmaher B, et al. The risks and benefits of antidepressant treatment for youth depression. Ann Med. 2005;37:404-12. 20. Hammad TA. Results of the analysis of suicidality in pediatric trials of newer antidepressants. Psychopharmacologic Drugs Advisory Committee and the Pediatric Advisory Committee. 2004. Available at: http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4065S1_08_FDA-Hammad_files/frame.htm . Accessed August 7, 2006. 21. Hazell P, O’Connell D, Heathcote D, Henry D. Tricyclic drugs for depression in children and adolescents. The Cochrane Database of Systematic Reviews 2002; 2. Art. No.:CD002317. 22. US Food and Drug Administration. FDA Launches a Multi-Pronged Strategy to Strengthen Safeguards for Children Treated with Antidepressant Medications. FDA News. October 15, 2004. Available at: http://www.fda.gov/bbs/topics/news/2004/NEW01124.html . Accessed August 7, 2006. 23. DP, Jefferson JW. Bupropion. In: Handbook of Medical Psychiatry. 2nd ed. St. Louis, MO: Mosby; 2004. 24. Hansen RA, Gartlehner G, Lohr KN, et al. Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder. Ann Intern Med.2005;143(6):415-26. 25. Rothschild AJ. Sexual side effects of antidepressants. J Clin Psychiatry. 2000;61(suppl 11):28-36. 26. DP, Jefferson JW. Mirtazapine. In: Handbook of Medical Psychiatry. 2nd ed. St. Louis, MO: Mosby; 2004. 27. Holm KJ, Markham A. Mirtazapine: a review of its use in major depression. Drugs. 1999;57:607-31. 28. DP, Jefferson JW. Venlafaxine. In: Handbook of Medical Psychiatry. 2nd ed. St. Louis, MO: Mosby; 2004. 29. Dugan SE, Fuller MA. Duloxetine: a dual reuptake inhibitor. Ann Pharmacother. 2004;38:2078-85. 30. Raskin J, Goldstein DJ, Mallinckrodt CH, Ferguson MB. Duloxetine in the long-term treatment of major depressive disorder. J Clin Psychiatry. 2003;64:1237-44. 31. Hudson JI, Wohlreich MM, Kajdasz DK, et al. Safety and tolerability of duloxetine in the treatment of major depressive disorder: analysis of pooled data from eight placebo-controlled clinical trials. Hum Psychopharmacol. 2005;20:327-41.

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