School of Community Health Sciences, Division of Public Health medicine and Epidemiology, University Hospital, Queen's Medical Centre, Nottingham;
Deliberate Self Harm Team, The Litchurch Centre, Southern Derbyshire Mental Health Trust, Derby
Correspondence: Dr Stuart Donovan, The Croft, 44 Lower Stanton Road, Ilkeston, Derbyshire DE74LN, UK; fax: 0115 932 1453; e-mail: mercedes{at}redmerc.freeserve.co.uk
Declaration of interest Support was received from the University of Nottingham and the Southern Derbyshire Health Authority. An unconditional contribution to postage and data analysis costs was received from the pharmaceutical industry.
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ABSTRACT |
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Aims To compare the frequency of DSH in patients who had been prescribed a tricyclic antidepressant (TCA) or a selective serotonin reuptake inhibitor (SSRI) prior to the DSH event.
Method This was a prospective study in 2776 consecutive DSH cases attending an accident and emergency department. The incidence of DSH in TCA-treated cases and SSRI-treated cases is expressed as number of DSH events per 10 000 prescriptions of each antidepressant.
Results Significantly more DSH events occurred following the prescription of an SSRI than that of a TCA (P <0.001). The occurrence of DSH was highest with fluoxetine and lowest with amitriptyline.
Conclusions Merely prescribing safer-in-overdose antidepressants is unlikely to reduce the overall morbidity from DSH.
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INTRODUCTION |
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METHOD |
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Data about each case were collected from two sources. Demographic and DSH event-specific data were recorded from A&E attendance records. Data about antidepressants prescribed for depressive symptoms before the DSH event were collected from primary-care records via a postal questionnaire to the general practitioner (GP). All data were anonymised to maintain patient and GP confidentiality.
The number of prescriptions written for antidepressant drugs in the Southern Derbyshire Health Authority region (from Prescribing Analysis and Cost (PACT) data) during the time of the study was used to calculate the incidence of DSH, expressed as number of DSH cases per 10 000 prescriptions, for different antidepressant drugs. However, because not all DSH cases in this region attended the investigational site, the calculation of absolute incidences of DSH following the prescription of different antidepressants is not possible. Nevertheless, using the assumption that the available DSH case cohort is a representative sample of the whole region, the ratio of cases to prescriptions gives an incidence of DSH for different antidepressant drugs relative to one another. Incidences cited in this paper are therefore relative, not absolute.
Using the null hypothesis that there is no difference in the incidence of DSH in patients who had been prescribed different antidepressants, pairwise comparisons between the ratio of DSH events to prescriptions for each antidepressant were examined using PROC GENMOD in SAS (version 6.12 for Windows). The results are expressed as a comparison of these ratios with 95% confidence intervals and P-values.
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RESULTS |
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Methods of DSH
The most frequent method of DSH was overdose of a medicinal substance by
any amount exceeding the maximum recommended daily dose. This occurred in
79.0% (n=1096) of males and in 86.1% (n=1196) of females.
Other methods of DSH comprised hanging, strangulation, gassing, suffocation,
drowning, inhalation, laceration, use of firearms, jumping (e.g. from high
places), road traffic accident, burning, other self-violence (e.g.
headbanging) and ingestion of non-medicines. Laceration was the most frequent
non-overdose method of DSH in both males (16.4%) and females (12.6%). In a
minority (3.5%) of cases, a combination of overdose and other methods of DSH
was used. Overall, there were 12 fatalities in cases who reached A&E alive
(eight overdoses and four other methods). Paracetamol, either alone, or in
paracetamol-containing medications or in combination with any other overdose
and/or method, was the single most frequent substance taken in overdose by
both males and females and comprised 39.9% of all DSH cases. Other analgesics
were taken by 26.7% of cases. Antidepressant overdose, either alone or in
combination with any other overdose and/or method occurred in 16.5% of cases.
Drugs of any other kind were taken in overdose by 39.9% of cases.
Antidepressant overdose
Of the 458 (16.5%) cases involving antidepressant overdose, 204 (44.5%)
cases took one antidepressant in overdose as the sole method of DSH, 226
(49.3%) took one antidepressant in overdose in combination with any other drug
and/or method and 28 (6.1%) cases took more than one antidepressant in
overdose at the same time. The relative incidence of overdose with SSRIs was
greater than that with TCAs (16.0 v. 11.8 cases per 10 000
prescriptions respectively). This pharmacological class finding was strongly
influenced by the SSRI fluoxetine, for which the relative incidence of
overdose was significantly greater than that for the TCAs amitriptyline,
imipramine and dothiepin (19.4 v. 11.4 v. 9.8 v.
6.9 cases per 10 000 prescriptions respectively; P <0.001)
(Table 1).
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Hospital admissions
Out of the total cohort of 2776 cases, 1534 (55.3%) were admitted to
hospital as a direct consequence of the DSH injury. Those patients who were
not admitted were either discharged from A&E or discharged themselves
against medical advice. One hundred and fifty-nine of the 204 (77.9%) cases
who took one antidepressant in overdose as the sole method of DSH were
admitted to hospital. The duration of stay in hospital expressed as days per
10 000 prescriptions, was greater after TCA overdose than after SSRI overdose,
both for general ward admissions (7.3 v. 4.1 days per 10 000
prescriptions respectively) and for intensive care ward admissions (3.6
v. 0.4 days per 10 000 prescriptions respectively), although this
difference did not reach statistical significance at these low numbers of
admissions (Table 2).
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Primary-care-derived data
Available database
A total of 2535 questionnaires were sent to GPs requesting information
about the antidepressant prescription history of each DSH case prior to the
DSH event. For 241 (8.7%) cases, a questionnaire was not sent either because
the identity of the GP was unknown or a repeat DSH event occurred within 1
month of a previous event. There were 1688 (66.6%) replies, 1497 of which were
evaluable for the purpose of this study. One hundred and ninety-one (11.3%)
replies were not included in the analysis either because information from the
GP about that patient was not available at the time of the request or because
erroneous responses on the GP questionnaire rendered the antidepressant
prescription history unevaluable. Overall, evaluable data about the
antidepressant prescription history prior to the DSH event were therefore
available for 53.9% of the total case cohort.
Antidepressant prescription history
Five hundred and eighty-four (39.0%) of the evaluable cases had been
prescribed an antidepressant at some time during the 12 months preceding the
DSH event and 186 (31.8%) of these had overdosed on their most recently
prescribed antidepressant. The most recent prescription prior to the DSH event
was for a TCA in 223 (38.2%) cases, for an SSRI in 312 (53.4%) cases and for
any other antidepressant in 49 (8.4%) cases.
However, the time interval between the most recent antidepressant prescription and the DSH event is an important consideration because the most frequent amount of antidepressant prescribed in one GP prescription is sufficient for 1 month's treatment (Donoghue & Tylee, 1996). At prescribed doses, therefore, the patient has theoretically run out of medication after 1 month (assuming full compliance even though it is recognised that patient compliance with antidepressant medication can be poor (Maddox et al, 1994)). As a consequence, patients who commit an act of DSH more than 1 month after the most recent antidepressant prescription are arguably in a different DSH risk group (relapse or untreated risk). For this reason, only those cases whose most recent prescription for an antidepressant was 30 days or less before the DSH event (treatment risk group) are evaluated here. Three hundred and seven (52.3%) cases met this criterion.
Pairwise comparisons of the relative incidence of DSH by any method following the prescription of named antidepressant drugs within 30 days prior the DSH event indicate that the relative incidence of any DSH event in patients who were prescribed the SSRIs fluoxetine, paroxetine and sertraline (19.8, 12.1 and 14.8 DSH events per 10 000 prescriptions respectively) was significantly higher than that in patients prescribed the TCAs amitriptyline, dothiepin and imipramine (3.0, 4.1 and 3.5 DSH events per 10 000 prescriptions respectively; P <0.001) (Table 3).
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Factors which could influence results
There are a number of factors which may have influenced the finding from
this study that the relative incidence of DSH is greater following the
prescription of SSRIs than after that of TCAs.
Limitations of study design
It was assumed from the start that the case cohort in this study is
representative of the whole region from which the prescription data were
drawn. This assumption was not tested.
In addition, because the GP reply rate to the questionnaires was less than 100% (as described previously), there is the risk of introducing further bias due to an incomplete dataset. However, this is a factor which is not unique to this study and the evaluable reply rate in this study was in the range which might reasonably be expected for prescription event monitoring studies (Freemantle et al, 1997).
Furthermore, that this is an observational cross-sectional study rather than a randomised controlled trial leads to the question of whether patients prescribed TCAs were similar in terms of DSH risk to those prescribed SSRIs.
Each of these limitations weakens conclusions which can be drawn from this study although some of the uncontrolled DSH risk factors can be examined to estimate the likelihood of their effect on the result, as follows.
Dosage of antidepressant prescribed
Dosing below the upper daily dose recommended for use in primary care
treatment (Monthly Index of Medical Specialities) was more common for
TCAs (30-75% of the upper recommended daily dose) than for SSRIs (51-125%)
particularly fluoxetine (although the tablet strength of fluoxetine makes
underdosing difficult). Subtherapeutic dosing, therefore, does not appear to
offer an explanation for the excess of DSH events following the prescription
of the SSRIs.
Duration of exposure to antidepressants
Antidepressant drugs have a latent period before their antidepressant
effect becomes maximal so that patients who have been exposed to an
antidepressant for a short time may be at a different DSH risk level than
those exposed for a longer time. Exposure times of the DSH cases to
antidepressants prior to DSH were, however, similar for TCAs (40% of cases
exposed for up to 4 weeks, 16% for 4-12 weeks and 44% for >12 weeks) and
SSRIs (37%, 17% and 47%, respectively). Thus, there is no evidence from this
study that differences in exposure time provide an explanation for the
differences in the relative incidence of DSH following prescription of TCAs or
SSRIs.
Antidepressant prescription switches
The prescription of different antidepressants before the most recent
antidepressant is an important consideration because possible carry-over
effects from the previous antidepressant cannot be ruled out, particularly
when the switch was made in close time proximity before the DSH event. In
those cases who had been prescribed a different antidepressant at some time
before the most recent antidepressant (n=164), a greater proportion
of cases switched from TCAs to SSRIs (41 of 67 cases: 61%) than from SSRIs to
TCAs (29 of 82 cases: 35%). This serves to suggest that SSRIs may have been
more frequently prescribed when TCAs had, for whatever reason,
failed. Hence a greater proportion of more difficult to
treat patients may have been prescribed SSRIs and this may manifest as
a greater risk of DSH. The prescription of some SSRIs to a higher DSH-risk
group may, therefore, offer part of the explanation of the relative incidence
findings of this study.
Effect of co-prescribed medication
Polypharmacy in depressed patients is not uncommon and the potential
association between the co-prescription of medication other than
antidepressants and the occurrence of DSH cannot be ruled out. An evaluation
of the proportion of patients who were co-prescribed other psychotropic
medication with antidepressants within 1 month prior to the DSH event revealed
little difference between the TCAs (72 of 102 cases: 71%) and the SSRIs (117
of 180 cases: 65%). However, differences in the nature of the psychotropic
medication co-prescribed (hypnotics, anxiolytics, antipsychotics) cannot be
evaluated within the confines of this study, and therefore the potential
influence of this parameter on the relative incidence findings of this study
remains unclear.
Influence of age
The age of those DSH cases prescribed TCAs was higher than those prescribed
SSRIs (42.3 years v. 33.8 years, respectively). Further exploration
of this variable reveals that SSRIs were more frequently prescribed to the
17-34-years age group than TCAs (192 of 312 cases (61.5%) v. 89 of
223 cases (40.0%), respectively). That younger age is an independent variable
for the occurrence of DSH (Hawton et
al, 1997) may be a contributory factor to the higher
incidence of DSH seen in cases who had been prescribed SSRIs.
Prior history of DSH
An important factor in the prediction of DSH is whether it has occurred
before in the same individual. In the present study, 120 of 180 cases (67%)
who had been prescribed an SSRI and 55 of 102 cases (54%) prescribed a TCA had
a known history of previous DSH at any time in the past. Thus, there is some
indication from this study that SSRIs may have been preferentially prescribed
to some patients who may have been at greater risk of DSH at the time of
prescription by virtue of their DSH history. This suggestion makes empirical
sense in that the prescription of less toxic-in-overdose SSRIs to higher
DSH-risk patients would reduce complications in the event of subsequent
antidepressant overdose. This factor may therefore have contributed to the
finding of the greater relative incidence of DSH by any method following the
prescription of SSRIs.
Other potential influential factors
There are a number of other possible factors which may have influenced the
result but which are beyond the scope of exploration from the study database.
These unaccountable factors include: the clinician's personal judgement of
risk of DSH at the time of prescription regardless of previous DSH history;
differences in the compliance of patients to taking TCAs or SSRIs; differences
in efficacy and/or tolerability of TCAs and SSRIs in a routine primary care
setting (as opposed to a clinical trial); differences in severity of
depressive illness in those prescribed TCAs or SSRIs; differences in
antidepressant prescription frequency for conditions other than depressive
illness (e.g. chronic pain, enuresis, obsessive-compulsive disorder, weight
management) which may affect the denominator (total number of prescriptions)
for the relative incidence calculations to different degrees for different
antidepressants; a pharmacological effect of increased suicidality in
susceptible individuals.
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DISCUSSION |
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Antidepressant overdose v. all methods of DSH
It is important to appreciate the distinction between the risks associated
with antidepressant overdose and the risk of any form of DSH during treatment
with antidepressants at therapeutic doses. In the present study, less than
one-third of DSH cases who had been prescribed an antidepressant overdosed on
that antidepressant. The majority of DSH cases who had been prescribed an
antidepressant harmed themselves by means other than antidepressant overdose.
The finding in this study that the morbidity after TCA overdose, measured in
terms of the duration of stay in hospital to effect recovery, is greater than
that seen after overdose with SSRIs is not surprising, given the known
overdose toxicities of these two classes of antidepressant
(Henry et al, 1995).
However, this study has also indicated that the risk of DSH by any method is
greater in patients who had been prescribed an SSRI than in those who had been
prescribed a TCA prior to the DSH event. Although not measured in this study,
this gives rise to speculation that the overall morbidity may be higher after
DSH in patients who had been prescribed an SSRI.
Cause and effect
It is difficult to attribute the cause of DSH behaviour to antidepressant
treatment when such behaviour can also occur spontaneously during the course
of depressive illness. Establishment of cause and effect for the different
apparent risks of DSH associated with different antidepressants seen in this
study is therefore almost impossible.
Nevertheless, although non-fatal DSH is not a proxy for suicide because DSH is not always synonymous with failed suicide, it is a risk factor (Gunnell & Frankel, 1994). The findings of this present study are consistent with findings of previous studies which have examined the occurrence of suicide in patients who had been prescribed different antidepressants (Isacsson et al, 1994; Jick et al, 1995; Waern et al, 1996; Donovan et al, 1999). Each of these previous studies indicated that, for whatever reason, the frequency of suicide, by any method, was greater in patients who had been prescribed an SSRI than that in patients who had been prescribed a TCA.
Preferential prescription of saferin-overdose antidepressants?
Several authors have speculated on possible mechanistic factors linking
suicidality and different pharmacological classes of antidepressants
(Kravitz, 1990;
Mann & Kapur, 1991;
Möller,
1992; Montgomery et
al, 1992; Power &
Cohen, 1992; Teicher et
al, 1993). Equally relevant, however, is the pragmatic
consideration that prescribers are heeding advice to prescribe
safer-in-overdose antidepressants to patients who are perceived to be at
greater risk of DSH. This effectively loads the dice against
antidepressants such as the SSRIs, so that this manifests as an apparent
excess of selfharm behaviour in patients who had been prescribed these
antidepressants. The truth is likely to be multi-factorial and probably lies
somewhere between mechanistic and pragmatic explanations.
Clinical relevance of results
Recognition of patients at risk of DSH in primary care is difficult and so
the prescription of safer-in-overdose antidepressants is a laudable action to
lessen complications in the event of antidepressant overdose. However, in the
population described in the present study, the advantage of SSRIs over TCAs in
terms of reduced overdose toxicity does not extrapolate to a reduced risk of
DSH by any method. Notwithstanding the possibility that those cases who had
been prescribed an SSRI in this study may be in some way at a higher risk
level than those prescribed a TCA, this present snapshot of the situation does
not give rise to hope that the prescription of safer-in-overdose
antidepressants will lessen the overall morbidity from DSH and its burden on
hospital acute services. Until the situation is further clarified by future
studies, the choice of antidepressant for patients at higher risk of DSH
should not be based solely on overdose toxicity. The increased risk of DSH by
any method in patients prescribed SSRIs should not be underestimated.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Received for publication January 4, 2000. Revision received June 12, 2000. Accepted for publication June 13, 2000.