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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@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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 TOP ABSTRACT INTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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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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| TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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METHOD |
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| TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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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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| TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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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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| TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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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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| TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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| TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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REFERENCES |
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| TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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Donoghue, J. & Tylee, A. (1996) The treatment of depression: prescribing patterns of antidepressants in primary care in the UK. British Journal of Psychiatry, 168, 164-168.[Abstract]
Donovan, S., Kelleher, M., Lambourn, J., et al (1999) The occurrence of suicide following the prescription of antidepressant drugs. Archives of Suicide Research, 5, 181-192.[CrossRef]
Freemantle, S., Pearce, G., Wilton, L., et al (1997) The incidence of the most commonly reported events with 40 newly marked drugs — a study by Prescription Event Monitoring. Pharmacoepidemiology and Drug Safety, 6, 1-9.[CrossRef]
Gunnell, D. & Frankel, S. (1994)
Prevention of suicide: aspirations and evidence. British Medical Journal,
308, 1227-1233.
Hawton, K., Fagg, J., Simkin, S., et al (1997) Trends in deliberate self-harm in Oxford, 1985-1995. Implications for clinical services and the prevention of suicide. British Journal of Psychiatry, 171, 556-560.[Abstract]
Henry, J., Alexander, C. & Sener, E.
(1995) Relative mortality from overdose of antidepressants. British
Medical Journal, 310, 221-224.
Isacsson, G., Holmgren, P., Wasserman, D.,
et al (1994) Use of antidepressants among people committing suicide
in Sweden. British Medical Journal, 308, 506-509.
Jick, S., Dean, A. & Jick, H. (1995)
Antidepressants and suicide. British Medical Journal, 310,
215-218.
Kravitz, H. (1990) Fluoxetine (Prozac) and suicide: causal or casual association? Suicide Research Digest, IV, 3.
MacNamara, A., Riyat, M. & Quinton, D. (1996) The changing profile of poisoning and its management. Journal of the Royal Society of Medicine, 89, 608-610.[Abstract]
Maddox, J., Levi, M. & Thompson, C. (1994) The compliance with antidepressants in general practice. Journal of Psychopharmacology, 8, 48-53.
Mann, J. & Kapur, S. (1991) The emergence of suicidal ideation and behaviour during antidepressant pharmacotherapy. Archives of General Psychiatry, 48, 1027-1033.[CrossRef][Medline]
MIMS Monthly Index of Medical Specialities. London: Haymarket Publishing Services. Updated monthly.
Möller, H.-J. (1992) Antidepressants — do they decrease or increase suicidality? Pharmacopsychiatry, 25, 249-253.[Medline]
Montgomery, S., Montgomery, D., Green, M., et al (1992) Pharmacotherapy in the prevention of suicidal behaviour. Journal of Clinical Psychopharmacology, 12, 27S-31S.[Medline]
Power, A. C. & Cohen, P. J. (1992) Fluoxetine and suicidal behaviour. Some clinical and theoretical aspects of a controversy. British Journal of Psychiatry, 161, 735-741.[Medline]
Rouillon, F., Phillips, R., Serrurier, D., et al (1989) Rechutes de depression unipolaire et efficacité de la maprotiline. L'Encéphale, XV, 527-534.
Smith, T. (1995) Differences between general practices in hospital admission rates for self-inflicted injury and self-poisoning: influence of socioeconomic factors. British Journal of General Practice, 45, 458-462.[Medline]
Teicher, M., Glod, C. & Cole, J. (1993) Antidepressant drugs and the emergence of suicidal tendencies. Drug Safety, 8, 186-212.[Medline]
Thomas, S., Bevan, L., Bhattacharyya, S., et al (1996) Presentation of poisoned patients to accident and emergency departments in the North of England. Human and Experimental Toxicology, 15, 466-470.[Medline]
Waern, H., Beskow, J., Runeson, B., et
al (1996) High rate of antidepressant treatment in elderly people who
commit suicide. British Medical Journal, 313, 1118.
Received for publication January 4, 2000. Revision received June 12, 2000. Accepted for publication June 13, 2000.
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