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Psychosomatics 48:1-9, January-February 2007
doi: 10.1176/appi.psy.48.1.1
© 2007 Academy of Psychosomatic Medicine
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Review

Potential Medical and Surgical Complications of Serotonergic Antidepressant Medications

Karl J. Looper, M.D.

Received January 4, 2006; revised July 14, 2006; accepted July 26, 2006. From the Dept. of Psychiatry, McGill University, Montreal, Canada and the Consultation–Liaison Service, Dept. of Psychiatry, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Canada. Send correspondence and reprint requests to Karl Looper, M.D., Sir Mortimer B. Davis Jewish General Hospital, Office A-540, 3755 Chemin de la Côte-Ste-Catherine, Montreal, Quebec, H3T 1E2, Canada. e-mail: karl.looper{at}mcgill.ca


  ABSTRACT

 
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 ABSTRACT
INTRODUCTION
 METHOD
 RESULTS
 CONCLUSIONS
 REFERENCES
 
Serotonergic antidepressants are the most widely used group of antidepressant medications. Although generally considered to have a favorable adverse-effect profile, serotonergic antidepressants are associated with potentially dangerous medical complications, some of which have only recently become apparent to patients and clinicians. This article reviews the association of serotonergic antidepressants and the following medical complications: syndrome of inappropriate antidiuretic hormone secretion, bleeding, serotonin syndrome, serotonin-discontinuation syndrome, and adverse pregnancy and neonatal effects. Physicians need to remain aware of these potential medical complications and integrate this information into their clinical decision-making, informed-consent process, baseline assessment, and follow-up monitoring.


  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHOD
 RESULTS
 CONCLUSIONS
 REFERENCES
 
The development of serotonergic antidepressant medications marked a change in the treatment of depression. In the years since newer antidepressants became available, there has been almost a threefold increase in the percentage of primary-care patients receiving antidepressants, an increase accounted for by the use of selective serotonergic reuptake inhibitors (SSRIs) and other newer drugs.1 The newer antidepressants held the promise of providing a similar therapeutic antidepressant effect with reduced adverse effects. In particular, the newer antidepressants have a reduced risk of the potentially dangerous cardiovascular effects of the tricyclic antidepressants, such as arrhythmia and orthostatic hypotension.2,3 However, in spite of these advantages, it has become apparent that the newer serotonergic antidepressants are not without medical risks. This article reviews some of the potential medical and surgical complications associated with serotonergic antidepressant medications.


  METHOD

 
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 ABSTRACT
 INTRODUCTION
 METHOD
RESULTS
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 REFERENCES
 
We searched electronic databases up to July 2006 on the intersection of the following search words: Antidepressant and 1) syndrome of inappropriate antidiuretic hormone secretion (SIADH); 2) bleeding; 3) serotonin syndrome; 4) discontinuation syndrome; and 6) pregnancy and neonatal effects, to identify reports of medical complications. The results of the electronic search were supplemented by manual searches of reference lists. Topic reviews were based primarily on reports containing original data, except for the review of serotonin syndrome, which is based on cases and review articles.


  RESULTS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
CONCLUSIONS
 REFERENCES
 
Syndrome of Inappropriate Anti-Diuretic Hormone Secretion (SIADH)
The syndrome of IADH secretion is an abnormal endocrinological state in which antidiuretic hormone is excessively released from the posterior hypothalamus.4 The action of ADH is mediated by the vasopressin2 receptor in the collecting ducts of kidney nephrons, causing the retention of water and, subsequently, the lowering of serum sodium levels. The diagnosis is made on the basis of the suboptimal dilution of urine in the presence of lower plasma osmolarity and intact kidney functioning. Thus, kidney-function tests are normal, but the serum osmolarity is over 100 mOsm/kg, while the urine osmolarity is below 280 mOsm/kg. Hyponatremia may be defined as a plasma sodium level less than 135 mOsm/kg, but symptoms usually occur at under 130 mOsm/kg.4

SIADH tends to occur in the first weeks of serotonergic antidepressant treatment.5 The clinical symptoms of hyponatremia are initially nonspecific; these include malaise, nausea, headache, lethargy, and myalgia, progressing to confusion and, eventually, loss of consciousness and convulsions. Many medications and medical conditions may contribute to hyponatremia or SIADH.4,6 (See Table 1.) Among psychiatric medications, the serotonergic antidepressants are the most frequently associated with SIADH, but case reports have also implicated tricyclic antidepressant, antipsychotic, and mood-stabilizing medications.4 Studies of serotonergic antidepressant use in elderly populations identify 12%–25% of patients7,8 as developing laboratory levels of hyponatremia and 12% as having a clinical syndrome.7 Age, female gender, and other medications and medical conditions causing hyponatremia are the identified risk factors.9


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TABLE 1. Causes of Hyponatremia



The treatment of hyponatremia involves addressing the underlying cause, such as, for example, stopping medications that are contributing to the syndrome, water restriction, and sodium replacement.6 Severe hyponatremia (Na<115 mOsm/kg) is a medical emergency because it can cause cerebral edema, particularly if the hyponatremia has developed rapidly. Sodium replacement must be carefully regulated to avoid osmotic demyelination and neurological damage,10 a rare complication of rapid sodium correction. Elderly patients or those at risk of developing hyponatremia due to other medications or medical conditions should have a baseline sodium test before serotonergic antidepressant treatment is initiated, as well as a follow-up measure in the first month of treatment. Patients should be warned that if they feel generally unwell in the weeks after the initiation of a serotonergic antidepressant, they should contact their physician for a complete assessment, which includes measurement of the serum sodium level.

Risk of Hemorrhage
Serotonin is released by platelets to promote platelet aggregation.11 Serotonin-reuptake inhibitors act on the serotonin transporter on platelet cell membranes, leading to a depletion of serotonin in the platelets, which decreases coagulation and may lead to a bleeding diathesis in vulnerable individuals.12 Case reports have associated SSRIs with a wide range of bleeding incidents.13–17 Large, population-based studies have investigated the association between the use of antidepressants that inhibit serotonin reuptake and hemorrhage (Table 2). The most commonly studied outcome was gastrointestinal (GI) bleeding, with five of six studies demonstrating an association between the use of serotonergic antidepressants and GI hemorrhage.18–22 The remaining study was focused on patients receiving warfarin treatment, which disrupts coagulation, possibly to a degree that is not further significantly changed by the presence of a serotonergic antidepressant.23 Serotonergic antidepressants have also been associated with uterine bleeding,24 but not stroke25 or intracranial bleeding.26 The clinical relevance of the risk of hemorrhage with SSRIs was demonstrated in a study of 520 patients admitted for orthopedic surgery. Patients on SSRI antidepressants had twice the volume of intra-operative blood loss and an odds ratio (OR) of 3.7 for requiring blood transfusions during the admission, a risk not observed with other antidepressant medications.27


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TABLE 2. Large Case-Control and Cohort Analyses of the Association Between Bleeding and the Use of Serotonergic Antidepressants



Most,18,19,21,24 but not all studies20 found that the risk of bleeding with serotonergic antidepressants is clearly increased by the concomitant use of acetylsalicylic acid (ASA) or nonsteroidal anti-inflammatory medications (NSAIDs), which predispose patients to GI bleeding. The risk of bleeding has also been associated with increased age and a previous history of bleeding,21 and was observed to increase between successive groupings of serotonergic antidepressants categorized on the basis of low, intermediate, or high level of their potency for the serotonin receptor (Table 3).19,21,24 The clinical interpretation of the increased risk with serotonergic activity is limited by a lack of information on the effects of other drug characteristics that may influence bleeding; these include dose, blood drug-level, protein-binding, and the activity of metabolites.28 However, bleeding has not been associated with non-serotonergic antidepressants, and one study reported that the risk of bleeding returned to normal after the serotonergic antidepressant was discontinued.19


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TABLE 3. Antidepressants’ Degree of Inhibition of Serotonin Reuptake



The increased risk of bleeding associated with the use of serotonergic antidepressants should be discussed with patients who have other risk factors for GI bleeding or any history of recurrent bleeding. The increased bleeding associated with surgery is of concern and requires further study to establish appropriate safety protocols. Abruptly stopping or interrupting treatment with serotonergic antidepressants is not advisable in light of the discontinuation-syndrome that may occur.29 Physicians may decide to use antidepressants that do not (or minimally) inhibit serotonin reuptake (Table 3) in patients with a high risk of hemorrhage.

Serotonin Syndrome
The serotonin syndrome is a toxic state resulting from excessive serotonin stimulation.30 The incidence of serotonin syndrome is very low, estimated as 0.4 cases per 1,000 patient-months of regular treatment,31 but fairly common in overdosage, where it occurs in approximately 15% of cases.32 Although most psychiatrists are aware of the classic drug interaction of monoamine oxidize inhibitor (MAOI) and SSRI antidepressants, few are aware of the broad range of medications and mechanisms (Table 4) by which a serotonin syndrome may occur.33,34 Frequently-prescribed medications such as opioid analgesics35 and tryptans;36 unprescribed medications, for example, preparations containing dextromethorphan;37 natural products, such as St John’s wort;38 and illicit drugs, including 3,4-methylenedioxymethamphetamine (MDMA)39 all have serotonergic effects and may lead to the development of serotonin syndrome. Drugs that inhibit the metabolism of SSRIs by hepatic enzymes may also be contributing factors.


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TABLE 4. Drugs and Mechanisms of Increased Serotonin



Serotonin syndrome typically presents shortly after the initiation or increase of a serotonergic medication, and it remains a clinical diagnosis because no reliable diagnostic test is available. The clinical presentation typically consists of mental status changes, neuromuscular signs, autonomic symptoms, and changes in vital signs (Table 5).30,33,40–43 Of these signs and symptoms, the most specific to the clinical diagnosis are: clonus, hyperreflexia, agitation, diaphoresis, and tremor (data from a study of 2,222 cases of overdoses of serotonergic drugs).43 Laboratory abnormalities are found in a minority of cases, and these may include leukocytosis, elevated creatine kinase and heptic transaminases, and metabolic acidosis.33 Treatment is supportive, including hydration, sedation, antipyretic medications, and intubation and ventilation in severe cases with respiratory distress or an unprotected airway. There may be a specific role for serotonin-antagonist medications such as cyproheptadine in reversing serotonin syndrome.33 In a review of cases published in the medical literature,41 cyproheptadine was the most commonly-reported effective pharmacologic treatment for serotonin syndrome. It is advisable to avoid the use of dopamine-antagonist medications in the treatment of serotonin syndrome, which can be difficult to distinguish from neuroleptic malignant syndrome (NMS) in patients previously exposed to both serotonin-stimulating and dopamine-antagonist medications, and because of the possible overlap of these two toxic syndromes.34,42,44


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TABLE 5. Symptoms of Serotonin Syndrome



The interaction between the serotonergic and dopaminergic systems is observed clinically in the occurrence of extrapyramidal effects with the use of serotonergic antidepressants34 and has been demonstrated physiologically by the inhibiting effects of serotonergic projections from the raphe nuclei to multiple sites of the dopaminergic system.45 To avoid the development of serotonin syndrome, physicians need to be aware of all serotonergic drugs taken by the patient, including over-the-counter medications, illicit substances, and medications that may interact with serotonergic drugs through the CYP450 pathway, and physicians should inform patients about this possible toxic reaction.

Serotonin-Discontinuation Syndrome
A discontinuation syndrome provoked by non–habit-forming drugs is not new in psychiatry or medicine;46 it has been observed with tricyclic antidepressants47,48 and antihypertensive medications.49–51 Although many patients stopping a serotonergic antidepressant experience some degree of emotional and physical symptoms, a discontinuation syndrome develops in approximately 20%–25% of patients.29,52 The clinical syndrome consists of neuropsychiatric, emotional, and physical symptoms (Table 6).29,53 The onset is usually within days of stopping or reducing the medication and lasts approximately 1–2 weeks, but may persist for up to several weeks.29,54,55 Serotonergic antidepressants with longer half-lives, such as fluoxetine and sertraline, are less frequently associated with the discontinuation syndrome;56–60 however, this pattern was not seen in all studies,61 which indicates that other factors, such as duration of antidepressant use,29 are contributing to the development of the syndrome. Patients with prolonged serotonin-discontinuation syndrome may be switched to fluoxetine as a tapering strategy;62 however, discontinuation may also occur on fluoxetine, and it may only emerge after several weeks of decreasing or discontinuing the medication,63 which is consistent with the known pharmacokinetics of fluoxetine.


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TABLE 6. Symptoms of Serotonin Discontinuation Syndrome



Serotonin-discontinuation syndrome is a fairly common and disruptive effect of serotonergic medications. Patients should be informed of this possible adverse effect before starting a serotonergic antidepressant and should be advised to not discontinue abruptly or unsupervised. Serotonergic antidepressants, including fluoxetine, should be gradually tapered to reduce discontinuation effects. Close monitoring is particularly important because of the possibility that impulsive and self-harming behavior may be increased during the discontinuation period.64,65

Adverse Pregnancy and Neonatal Effects
Serotonergic antidepressants cross the placenta and enter the circulation of the fetus.66 Until recently, SSRI antidepressants have been considered relatively safe for use in pregnancy.67,68 However, recent studies have reported a range of possible complications for pregnancy outcomes in women taking SSRI antidepressants.

Two reports of data analyses regarding birth outcomes in women taking paroxetine found a 1.5–2-fold increase in congenital malformations, particularly cardiovascular malformations, in newborns of women taking paroxetine as compared with other antidepressants.69,70 One earlier study reported an increased risk of minor malformations after exposure to fluoxetine during gestation,71 and there has also been a report of spontaneous abortions in pregnant women on SSRI antidepressants.72 However, two metaanalyses of prospective studies did not find an increased risk of congenital malformations associated with SSRI antidepressants.73,74

Antidepressants have been associated with neonatal complications, including premature delivery and low birth weight,75,76 and neonatal distress,75,77 including respiratory problems, hypoglycemia, cyanosis, jitteriness, convulsions, decreased Apgar score, and the need for special-care nurseries.78 These neonatal effects are not specific to SSRI antidepressants; in fact, tricyclic antidepressants had a more severe effect than SSRIs in one study.75 The cause of these neonatal effects has not yet been clarified, but might include direct toxic effects of the antidepressant during gestation and a withdrawal syndrome in newborns.79,80 Persistent pulmonary hypertension of the newborn has also been associated with the use of SSRI antidepressants in the later period of pregnancy.81 The long-term effects on child development have not been established, but, of several small prospective longitudinal studies of children exposed to SSRIs during the fetal period, one indicated the possibility of subtle effects on motor development;82 two did not identify any developmental effects;71,83,84 and one study found no association between in-utero antidepressant exposure, but did find an effect of maternal mood on subsequent behavior in 4-year-old children.75

Little research has been done on the use of antidepressants during lactation. Antidepressants are found in the breast-milk,85,86 but levels may be very small,87 and appear to differ among serotonergic antidepressants.86 The few small-scale studies examining the possible effects on newborns have not identified any behavioral or developmental effects.77,88,89

The concern regarding the use of SSRI antidepressants in pregnant women underlines the importance of scientific investigation of high-risk groups, and the fact that medical complications are not always apparent early in the course of commercial availability of pharmaceutical products. Although a range of antidepressants are routinely used to treat depression in pregnant women,90 the greatest experience and safety information exists for fluoxetine,91 which should, in theory, have the lowest risk of withdrawal symptoms in newborns because of its relatively long half-life. Risks of antidepressant use must be weighed against the risks of not treating emotional disorders during pregnancy.92 Women who discontinue an antidepressant during pregnancy are more than twice as likely to have a relapse of depression than those that maintain treatment.93 Depression and anxiety have been associated with increased disability, need for treatment, and interventions during pregnancy.94 Depressive symptoms have also been found to be associated with negative parenting behaviors,95 insecure attachment,96 and subsequent internalizing behaviors in the child.84 These findings emphasize the importance of careful assessment and treatment of emotional disorders during pregnancy.


  CONCLUSIONS

 
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 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 CONCLUSIONS
REFERENCES
 
Although serotonergic antidepressants have improved the availability of treatment for emotional disorders, they are not without potentially dangerous medical and surgical risks.97 Furthermore, as our experience with these "newer antidepressants," grows, new health concerns continue to come to light. Physicians who prescribe antidepressant medications need to remain aware of the established and emerging awareness of medical complications associated with serotonergic antidepressants (Table 7). Physicians need to integrate information about medical risks of serotonergic antidepressants into their clinical decision-making, informed-consent process, baseline assessment, and follow-up monitoring.


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TABLE 7. Recommended Reading




  REFERENCES

 
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