APOS Clinical E-Mail Update #14
23 December 2004

In this Update:

Do serotonin reuptake inhibitors increase the risk of bleeding?

Meijer WEE, Heerdink ER, Nolen WA, Herings RM. Leufkens HGM, Egberts ACG.  Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants.  Arch Intern Med 2004;164:2367-2370.

In order to find whether serotonin reuptake inhibition by antidepressants is associated with an increased risk of bleeding, researchers in the Netherlands conducted a case-control study of more than 64,000 new antidepressant users.  They looked for patients who were hospitalized for a primary diagnosis of abnormal bleeding.  They found 196 cases of abnormal bleeding, and these were compared to controls matched for age and sex (n=192).  Exposure to serotonin reuptake inhibition was classified as high, intermediate, or low, based on the specific drug and its affinity for the serotonin transporter.  They did find a significant association between the degree of serotonin reuptake inhibition by antidepressants and the risk of hospital admission for abnormal bleeding as a primary diagnosis.  The odds ratio was 1.9 for intermediate degrees of serotonin reuptake inhibition and 2.6 for high degrees.

This group of first-time users of SSRIs was followed a mean 229 days from their prescription.  The sample was 73.5% women of mean age 58.  Patients with prior hospitalization for bleeding or current and prior use of aspirin, non-steroidal anti-inflammatory agents (NSAIDs), anti-coagulants, glucocorticoids, estrogens, progestagens, histamibne-2 inhibitors, and proton pump inhibitors were noted.  These variables were taken into consideration in the logistic regression model, so that those variables would not confound the effect of SSRIs.

A previous study by Dalton1 on a large population in Denmark showed that users of serotonin reuptake inhibitors (SSRIs) were hospitalized with upper gastrointestinal bleeding 3.6 times more often than persons of a similar age and sex.  The results corresponded to an excess of 3.1 upper GI bleeding episodes per 1000 treatment years of SSRI use.  The effect was potentiated by concurrent use of NSAIDs and lesser so by aspirin.

Almost all of the serotonin in the body resides in platelets.  Serotonin enhances platelet aggregation by its effect on adenosine diphosphate and thrombin, and SSRIs decrease intra-platelet serotonin content.  Typically, there are no abnormal tests of hemostatic function in patients taking SSRIs, even abnormalities in platelet aggregation.  Occasionally bruising or abnormal bleeding are noted in patients on these drugs despite no laboratory abnormality.  It is worth noting, however, that platelet aggregation studies must be done very carefully to be reliable.2

Depression itself may have a procoagulant effect.  Platelet activation in vivo, secretion, and aggregation before treatment, a condition that could promote clotting, was reversed by the effect of SSRIs on platelets after 6 weeks in a series of depressed patients.3

This study by Meijer et al looked at rates of hospitalization in new users of SSRIs.  In the Prescription Event Monitoring Database (PEM) in England, abnormal bleeding events during treatment with SSRIs were monitored.  The highest rate of adverse bleeding events occurred during the first month of SSRI treatment compared to the remaining months.4

It looks as if there is a small increased risk of bleeding in SSRI users, particularly when the prescription is new, and the bleeding is potentiated by aspirin, steroids, and anticoagulants.

For comparison assessment of risk, we can look at aspirin.  Aspirin acetylates COX-1 and irreversibly inactivates it.  Aspirin can slightly prolong bleeding time for up to 4 days after it is discontinued.  Platelet aggregation may be abnormal for one week.  Gastrointestinal bleeding for aspirin at normal doses is a serious clinical consideration.  However, a population based case-control study of low dose aspirin showed a two-fold risk of upper gastrointestinal complications.  The coating did not modify the effect.  The addition of NSAIDs added to the risk.5  A 2.3-fold increased risk of hospitalization for upper gastrointestinal bleeding due to low dose aspirin therapy has also been noted.6

The findings for SSRIs in this study show a similar increased risk for bleeding on a population basis, a risk similar to that for low dose aspirin, comparable to 0.3 to 1.7 per 1000 patient-years.  It is still remarkable that the association of bleeding problems and SSRIs is quite low, and that other biological factors of the patient may play a role in the unusual cases. — DG

1. Dalton SO, Johansen C, Mellemkjaer l, Sorensen HT, Norgard B, Olsen J.  Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding.  A population-based cohort study.  Arch Intern Med 2003;163:59-64.

2. OíMalley P.  Selective serotonin reuptake inhibitors and abnormal bleeding: implications for the clinical nurse specialist.  Clin Nurse Specialist.  2004;18:65-67.

3. Musselman DL, Marzec UM, Manatunga A, et al.  Platelet reactivity in depressed patients treated with paroxetine: preliminary findings.  Arch Gen Psychiatry.  2000;57:875-882.

4. Layton D, Clark DWJ, Pearce GL, Shakir SAW.  Is there an association between selective serotonin reuptake inhibitors and the risk of abnormal bleeding? Results from a cohort study based on prescription event monitoring in England.  Pharmacoepidemiol Prescript.  2001;57:167-176.

5. De Abajo FJ, Garcia Rodgriguez LA.  Risk of upper gastrointestinal bleeding and perforation associated with low-dose aspirin as plain and enteric-coated formulations.  BMC Clincial Pharmacology 2001; 1:1.

6. Garcia Rodriguez LA, Cattaruzzi C, Troncon MG, Agostinis L.  Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs.  Arch Intern Med 1998;158:33.

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Are women more at risk for depression near their last menses?

Schmidt PJ, Haz N, Rubinow DR.  A longitudinal evaluation of the relationship between reproductive status and mood in perimenopausal women.  Am J Psychiatry 2004;161:2238-2244.

These researchers have been studying the individual variation of hormone-sensitive depressive states in women.  In this study they followed 29 asymptomatic women for an average of 5 years until that were menopausal or at least 6 months from their last period.  The women were followed with the Structured clinical interview for DSM-IV, menstrual and mood diaries, plasma levels of follicle-stimulating hormone every three months.  They studied the differences between the women who became depressed and those who did not.  They determined the timing of episodes of depression in relation to the last menstrual period.  They found 9 episodes of depression in the 24 months surrounding the last menstrual period.  No history of depression was found in 6 of the 9 women.  The risk for onset of depression was 14 times as high as for the time before menopause.

This is a small study with preliminary data, but it argues that the time close to the last menses is a vulnerable time for mood change.  These findings have implications for women treated for breast cancer who have cancer treatment that provokes menopause.  It is likely that some will be sensitive merely to the anti-estrogen hormonal manipulation and more likely to develop depression at this time.  There was no relation between the presence of hot flashes and the history of depression or premenstrual dysphoria in the women who became depressed.  The hormonal change that accompanies breast cancer treatment is one of the variables that is likely to affect mood. — DG

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Can methylphenidate help childhood cancer survivors in school and at home?

Mulhern RK, Khan RB, Kaplan S, Helton S, Christensen R, Bonner M, Brown R, Xiong X, Wu S, Gururangan S, Reddick WE.  Short-term efficacy of methylphenidate: a randomized, double-blind, placebo-controlled trial among survivors of childhood cancer.  J Clin Oncol 2004;22:4743-4751.

Methylphenidate is widely used in children for attention deficit disorder.  Survivors of childhood cancer have a number of reasons to have attentional difficulties.  This is a randomized, double-blind, placebo-controlled trial of 83 long-term survivors of acute lymphocytic leukemia and brain tumors, ages about 7 to 18 at the time of participation.  They underwent a 3-week home cross-over trial of twice-a-day placebo or low-dose methylphenidate (0.3 mg/kg; maximum dose, 10 mg b.i.d.) or double that dose.  Weekly parent and teacher reports and validated rating scales of social skills were used to judge outcome.  Teachers and parents found that drug was better than placebo although no dose different was observed.  Cognitive and attentional improvements were noted.  Three patients had adverse reactions that stopped their participation; these responses anxiety and agitation; wheezing and dizziness, and diplopia and abdominal pain all resolved the following day with cessation of drug and appropriate treatment.  A screening battery of psychological tests included the child behavior checklist, abbreviated Wechsler intelligence sale for children, Connerís continuous performance test, abbreviated Wechsler individual achievement test, social skills rating system, and side effect rating scales.  Patients with recurrent cancer, attention deficit disorder that predated cancer, psychoactive medications, drug abuse history or mood disorder were excluded.  The authors note that this is the first investigation to examine the effects of two standardized doses of methylphenidate on behavior at home and in the classroom among survivors of childhood cancer. — DG

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When women receive equivocal abnormal mammograms, how do they cope?

Heckman BD, Fisher EB, Monsees B, Merbaum M, Ristvedt S, Bishop C.  Coping and anxiety in women recalled for additional diagnostic procedures following an abnormal screening mammogram.  Health Psychology.  2004;23:42-48.

Epidemiological studies show that approximately half of women who obtain regular mammograms will experience at least one false-positive result.  Such a result will undoubtedly result in an increase in anxiety until follow up testing rules out the presence of cancer.  Models of stress and coping suggest that avoidance coping, that is the use of cognitive and behavioral strategies designed to distract oneself in the face of an acute and uncontrollable stressor, may be particularly efficacious in this situation.  However, research examining the relationship between coping and adjustment in the face of a false-positive mammogram is limited.  In this study, researchers assessed 98 women undergoing mammography at three time points: immediately after mammography (Time 1), after receiving questionable screening results and being told that follow up testing would be necessary (Time 2), and after being notified that they were negative for breast cancer (Time 3).  They hypothesized that higher levels of anxiety would be associated with less use of cognitive and behavioral avoidance coping strategies at Time 2, and lower levels of anxiety would be associated with more frequent use of avoidance coping at Time 3.  Contrary to expectations, in cross-sectional analyses, the researchers found that higher levels of state anxiety were associated with greater use of cognitive and behavioral avoidance and approach coping strategies at Time 2.  This was independent of a womanís family history of breast cancer.  Similarly, at Time 3, lower levels of state anxiety were associated with greater use of all four coping strategies, not just avoidance coping.  However, in prospective analyses, cognitive avoidance coping did predict levels of state anxiety above and beyond that predicted by the other three types of coping strategies.  It is important to note that in general, anxiety levels declined to well within the normal range by Time 3.  This study appears to document what we all know: questionable mammogram results make women acutely anxious and women use a variety of strategies in order to reduce their anxiety. — KD

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Which cancer patients benefit from expressive writing about their cancer experience?

Zakowski SG, Alona R, Morton C, Johnson P, Flanigan R. Written emotional disclosure buffers the effects of social constraints on distress among cancer patients.  Health Psychology.  2004;23:555-563.

The beneficial effect of James Pennebakerís technique of written emotional disclosure on psychological and physical symptoms has been documented in previous research.  Whether this technique is more beneficial among individuals who routinely experience negative social responses to their emotional expression is not known.  To determine whether cancer patients would benefit from written emotional disclosure and whether this beneficial effect would be particularly pronounced among patients who reported high levels of social constraints, researchers randomized 104 prostate or gynecological cancer patients to an emotional disclosure condition or a control condition.  Patients in the emotional disclosure condition were instructed to write continuously for 20 minutes on three consecutive days about their deepest thoughts and feelings regarding their cancer experience.  Patients in the control condition were instructed to write about their daily activities in a non-emotional manner.

Researchers found that expressive writing did not result in a reduction in distress among cancer patients.  This, of course, begs the question of whether the patients, as a group, were significantly distressed.  At baseline, only 22 of the 104 patients reported clinically significant distress.

Researchers did find that expressive writing buffered the effects of social constraint such that those who initially reported higher levels of constraint reported a level of distress comparable to patients who reported lower levels of constraint if given the opportunity to engage in expressive writing.

Persons who initially reported higher levels of constraint and who did not engage in emotionally expressive writing, continued to report a higher level of distress at 6-month follow-up.  This suggests that patients who experience negative responses to emotional expression about their cancer experience may benefit from written emotional disclosure.  Researchers also found that patients with higher levels of social constraint continued to cope by avoiding cancer-related thoughts, unless given the opportunity to participate in emotional disclosure.  In their discussion of potential mechanisms for these effects, the authors point out that a patientís personality or interpersonal style may contribute to his or her perceptions of social constraints, and thus, interventions ought to be individually tailored based on needs (i.e., is the distress clinically significant?) and deficits (i.e., is there a greater need for emotional expression?). — KD

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DG:  Donna B. Greenberg, MD, Associate Professor of Psychiatry at Harvard Medical School and Psychiatric Consultant in the Massachusetts General Hospital Cancer Center, Dana Farber Partners Cancer Care

KD:  Kristine Donovan, PhD, MBA, Assistant Professor, DIO, Moffitt Cancer Center at the University of South Florida