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Supplementary material for Martinez et al: Antidepressant treatment and the risk of fatal and non-fatal self-harm in first episode depression� a nested case-control study

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Approach used for the categorisation of the severity of depression

Depression was identified by a predefined set of Read and OXMIS medical terms in the patient�s record indicative of major depressive disorder, bipolar disorder, dysthymic disorder or unspecified depression. Severity of depression was categorised by one of the authors (JC), in consultation with a psychiatrist (Dr EM Bain) with general practice experience, into �mild�, �moderate� and �severe�. If a patient had depression codes pertaining to different severities of depression, then the most severe category was assigned to the patient.

Method used for the estimation of duration of antidepressant exposure

Prescription duration was derived by dividing the quantity of antidepressant prescribed by the daily dose and adding a 7-day wash-out period. If no dosage instructions were entered on the prescription (18% of prescription information) we used the median of the substance-specific prescription duration of the same antidepressant from the complete study cohort. Where a new prescription for the same substance was issued within the calculated duration of the previous prescription, the overall treatment duration ended with the calculated prescription end-date plus a 7-day wash-out period.

The duration of a treatment episode was estimated from the duration of each prescription and the number of consecutive prescriptions of antidepressants allowing for gaps of up to seven days.

The duration of the first recorded treated depression episode was defined by the period between the first prescription of an antidepressant and the calculated treatment end-date plus a 180-day follow-up period. A gap of more than 180 days between the calculated end-date and a new prescription of an antidepressant defined a new episode of depression. Second and subsequent episodes of depression were not included in the analysis.

Web Table 1: Read and OXMIS medical codes for depression and severity grading

Read/OXMIS Code	Read/OXMIS Term	Grading
E113600	Recurrent major depressive episodes, in full remission	MILD
Eu33.14	[X]Seasonal depressive disorder	MILD
E204.00	Neurotic depression reactive type	MILD
E2B0.00	Postviral depression	MILD
1B17.00	Depressed	MILD
E290.00	Brief depressive reaction	MILD
Eu32z13	[X]Prolonged single episode of reactive depression	MILD
Eu33.13	[X]Recurrent episodes of reactive depression	MILD
E115600	Bipolar affective disorder, now depressed, in full remission	MILD
E200300	Anxiety with depression	MILD
Eu32000	[X]Mild depressive episode	MILD
Eu32z11	[X]Depression NOS	MILD
Eu33.12	[X]Recurrent episodes of psychogenic depression	MILD
1465.00	H/O: depression	MILD
E112600	Single major depressive episode, in full remission	MILD
Eu32.11	[X]Single episode of depressive reaction	MILD
Eu33.11	[X]Recurrent episodes of depressive reaction	MILD
Eu34100	[X]Dysthymia	MILD
E113100	Recurrent major depressive episodes, mild	MILD
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E118.00	Seasonal affective disorder	MILD
E2B1.00	Chronic depression	MILD
Eu32.12	[X]Single episode of psychogenic depression	MILD
Eu32y00	[X]Other depressive episodes	MILD
1B17.11	C/O - feeling depressed	MILD
E004300	Arteriosclerotic dementia with depression	MILD
E211200	Depressive personality disorder	MILD
Eu32.13	[X]Single episode of reactive depression	MILD
Eu3y111	[X]Recurrent brief depressive episodes	MILD
3004PP	POSTOPERATIVE DEPRESSION	MILD
Eu33000	[X]Recurrent depressive disorder, current episode mild	MILD
E112100	Single major depressive episode, mild	MILD
3091PL	DEPRESSION POSTVIRAL	MILD
E115100	Bipolar affective disorder, currently depressed, mild	MILD
Eu33.15	[X]SAD - Seasonal affective disorder	MILD
Eu34111	[X]Depressive neurosis	MILD
Eu41211	[X]Mild anxiety depression	MILD
2962AF	REACTION DEPRESSIVE AFFECTIVE	MILD
3000E	ANXIETY DEPRESSION	MILD
3004A	DEPRESSION	MILD
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u32400	[X]Mild depression	MILD
3004B	PREGNANCY DEPRESSION	MODERATE
E112.14	Endogenous depression	MODERATE
E112500	Single major depressive episode, partial or unspec remission	MODERATE
Eu31.11	[X]Manic-depressive illness	MODERATE
Eu31300	[X]Bipolar affect disorder cur epi mild or moderate depression	MODERATE
Eu31y11	[X]Bipolar II disorder	MODERATE
Eu33212	[X]Major depression, recurrent without psychotic symptoms	MODERATE
E115000	Bipolar affective disorder, currently depressed, unspecified	MODERATE
Eu31z00	[X]Bipolar affective disorder, unspecified	MODERATE
Eu33.00	[X]Recurrent depressive disorder	MODERATE
Eu33211	[X]Endogenous depression without psychotic symptoms	MODERATE
E113500	Recurrent major depressive episodes,partial/unspec remission	MODERATE
Eu20400	[X]Post-schizophrenic depression	MODERATE
Eu3y011	[X]Mixed affective episode	MODERATE
E112200	Single major depressive episode, moderate	MODERATE
E115500	Bipolar affect disord, now depressed, part/unspec remission	MODERATE
E2B..00	Depressive disorder NEC	MODERATE
Eu33z00	[X]Recurrent depressive disorder, unspecified	MODERATE
E002100	Senile dementia with depression	MODERATE
E002z00	Senile dementia with depressive or paranoid features NOS	MODERATE
E204.11	Postnatal depression	MODERATE
Eu02z16	[X] Senile dementia, depressed or paranoid type	MODERATE
2257.00	O/E � depressed	MODERATE
E115.00	Bipolar affective disorder, currently depressed	MODERATE
E11y.00	Other and unspecified manic-depressive psychoses	MODERATE
E11z200	Masked depression	MODERATE
Eu33z11	[X]Monopolar depression NOS	MODERATE
Eu53012	[X]Postpartum depression NOS	MODERATE
E112.00	Single major depressive episode	MODERATE
E112z00	Single major depressive episode NOS	MODERATE
Eu34114	[X]Persistant anxiety depression	MODERATE
Eu41200	[X]Mixed anxiety and depressive disorder	MODERATE
E112300	Single major depressive episode, severe, without psychosis	MODERATE
E115.11	Manic-depressive - now depressed	MODERATE
Eu32100	[X]Moderate depressive episode	MODERATE
Eu33200	[X]Recurr depress disorder cur epi severe without psyc sympt	MODERATE
Eu33y00	[X]Other recurrent depressive disorders	MODERATE
E112.12	Endogenous depression first episode	MODERATE
E113200	Recurrent major depressive episodes, moderate	MODERATE
Eu31y00	[X]Other bipolar affective disorders	MODERATE
Eu32y11	[X]Atypical depression	MODERATE
Eu53011	[X]Postnatal depression NOS	MODERATE
E112.13	Endogenous depression first episode	MODERATE
E115200	Bipolar affective disorder, currently depressed, moderate	MODERATE
E115z00	Bipolar affective disorder, currently depressed, NOS	MODERATE
E11y200	Atypical depressive disorder	MODERATE
E291.00	Prolonged depressive reaction	MODERATE
E002.00	Senile dementia with depressive or paranoid features	MODERATE
E113700	Recurrent depression	MODERATE
Eu31600	[X]Bipolar affective disorder, current episode mixed	MODERATE
Eu33213	[X]Manic-depress psychosis,depressd,no psychotic symptoms	MODERATE
ZV11111	[V]Personal history of manic-depressive psychosis	MODERATE
2962A	DEPRESSION CHRONIC	MODERATE
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3004AB	OBSERVED DEPRESSION	MODERATE
3004E	EXOGENOUS DEPRESSION	MODERATE
3004ER	REACTIVE DEPRESSION	MODERATE
3004M	MORNING DEPRESSION	MODERATE
Eu33300	[X]Recurrent depress disorder cur epi severe with psyc symp	SEVERE
2962EN	ENDOGENOUS DEPRESSION	SEVERE
E11..12	Depressive psychoses	SEVERE
E113.11	Endogenous depression - recurrent	SEVERE
E113300	Recurrent major depressive episodes, severe, no psychosis	SEVERE
E115300	Bipolar affect disord, now depressed, severe, no psychosis	SEVERE
E112.11	Agitated depression	SEVERE
E113.00	Recurrent major depressive episode	SEVERE
Eu31400	[X]Bipol aff disord, curr epis sev depress, no psychot symp	SEVERE
E001300	Presenile dementia with depression	SEVERE
E113000	Recurrent major depressive episodes, unspecified	SEVERE
E11y000	Unspecified manic-depressive psychoses	SEVERE
Eu32200	[X]Severe depressive episode without psychotic symptoms	SEVERE
62T1.00	Puerperal depression	SEVERE
E115400	Bipolar affect disord, now depressed, severe with psychosis	SEVERE
E130.11	Psychotic reactive depression	SEVERE
Eu33311	[X]Endogenous depression with psychotic symptoms	SEVERE
Eu33313	[X]Recurr severe episodes/major depression+psychotic symptom	SEVERE
ZV11112	[V]Personal history of manic-depressive psychosis	SEVERE
Eu32313	[X]Single episode of psychotic depression	SEVERE
Eu33312	[X]Manic-depress psychosis,depressed type+psychotic symptoms	SEVERE
Eu33314	[X]Recurr severe episodes/psychogenic depressive psychosis	SEVERE
2960AD	DEPRESSION AGITATED	SEVERE
Eu32314	[X]Single episode of reactive depressive psychosis	SEVERE
Eu33315	[X]Recurrent severe episodes of psychotic depression	SEVERE
E135.00	Agitated depression	SEVERE
Eu31500	[X]Bipolar affect dis cur epi severe depres with psyc symp	SEVERE
Eu32300	[X]Severe depressive episode with psychotic symptoms	SEVERE
E113400	Recurrent major depressive episodes, severe, with psychosis	SEVERE
Eu33316	[X]Recurrent severe episodes/reactive depressive psychosis	SEVERE
E112000	Single major depressive episode, unspecified	SEVERE
E113z00	Recurrent major depressive episode NOS	SEVERE
Eu32311	[X]Single episode of major depression and psychotic symptoms	SEVERE
E112400	Single major depressive episode, severe, with psychosis	SEVERE
E130.00	Reactive depressive psychosis	SEVERE
Eu32212	[X]Single episode major depression w'out psychotic symptoms	SEVERE
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2962C	PSYCHOSIS DEPRESSIVE	SEVERE
2969M	PSYCHOSIS MANIC-DEPRESSIVE	SEVERE
3004C	PUERPERAL DEPRESSION	SEVERE
2960AC	CHRONIC AGITATED DEPRESSION	SEVERE
2980	REACTION DEPRESSIVE PSYCHOTIC	SEVERE

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Web Table 2: Read and OXMIS medical codes for completed suicides

Read/OXMIS code	Read/OXMIS term	Read/OXMIS code	Read/OXMIS term
9670A	BARBITURATE OVERDOSE	TKx0.00	Suicide + selfinflicted injury-jump/lie before moving object
SL...15	Overdose of drug	U200z00	[X]Intent self poison nonopioid analgesic unspecif place
TK...13	Poisoning � self-inflicted	U209.00	[X]Intent self poison/exposure to alcohol
TK00.00	Suicide + selfinflicted poisoning by analgesic/antipyretic	U20A400	[X]Int self poison org solvent,halogen hydrocarb,in highway
TKx5.00	Suicide and selfinflicted injury by crashing motor vehicle	U20y.00	[X]Intent self poison/exposure to unspecif chemical
U2...00	[X]Intentional self-harm	U22..00	[X]Intentional self harm by drowning and submersion
U202.16	[X]Overdose � benzodiazepine	U24..00	[X]Intent self harm by rifle shotgun/larger firearm disch
U204.12	[X]Overdose � amitriptyline	U2z..00	[X]Intentional self harm by unspecified means
U20C.00	[X]Intent self poison/exposure to pesticide	U45..00	[X]Other+unspecified firearm discharge undetermined intent
U2D4.00	[X]Intent self harm by crash motor vehicl occ street/highway	U4B..00	[X]Falling jumping/pushed from high place undeterm intent
U2y..00	[X]Intentional self harm by other specified means	9947TA	STRANGULATION ATTEMPTED
TK3..00	Suicide + selfinflicted injury by hang/strangulate/suffocate	TK0..00	Suicide + selfinflicted poisoning by solid/liquid substances
TK5..00	Suicide and selfinflicted injury by firearms and explosives	TK20.00	Suicide + selfinflicted poisoning by motor veh exhaust gas
U2...13	[X]Suicide	TK31.00	Suicide + selfinflicted injury by suffocation by plastic bag
U20..00	[X]Intentional self poisoning/exposure to noxious substances	TK51.00	Suicide and selfinflicted injury by shotgun
U200000	[X]Int self poison/exposure to nonopioid analgesic at home	TK6z.00	Suicide and selfinflicted injury by cutting and stabbing NOS
U202.17	[X]Overdose � barbiturate	TKx4.00	Suicide and selfinflicted injury by electrocution
U205z00	[X]Intent self poison narcotic drug unspecif place	TKz..00	Suicide and selfinflicted injury NOS
U208z00	[X]Intent self poison oth/unsp drug/medic unspecif place	U221.00	[X]Intent self harm by drowning/submersn occ resid instit'n
U209z00	[X]Intent self poison alcohol unspecif place	U2C..00	[X]Intent self harm by jumping / lying before moving object
U20By00	[X]Int self poison other gas/vapour other spec place	U2D..00	[X]Intentional self harm by crashing of motor vehicle
U21..00	[X]Intent self harm by hanging strangulation / suffocation	U30..11	[X]Deliberate drug poisoning
U27..00	[X]Intentional self harm by smoke, fire and flames	9947TS	STRANGULATION
U2D0.00	[X]Intent self harm by crash of motor vehicl occurrn at home	SN47z00	Asphyxiation or strangulation NOS
9947TR	ASPHYXIA DUE STRANGULATION	TK03.00	Suicide + selfinflicted poisoning tranquilliser/psychotropic
TK70.00	Suicide+selfinflicted injury-jump from residential premises	TK04.00	Suicide + selfinflicted poisoning by other drugs/medicines
TK7z.00	Suicide+selfinflicted injury-jump from high place NOS	TK4..00	Suicide and selfinflicted injury by drowning
TKxz.00	Suicide and selfinflicted injury by other means NOS	U2...11	[X]Self inflicted injury
U2...14	[X]Attempted suicide	U200.00	[X]Intent self poison/exposure to nonopioid analgesic
U202.00	[X]Intent self poison/exposure to sedative hypnotic	U200.12	[X]Overdose - ibuprofen
U202.11	[X]Overdose - sleeping tabs	U202.12	[X]Overdose - diazepam
U204z00	[X]Intent self poison psychotropic drug unspecif place	U202.14	[X]Overdose - flurazepam
U205000	[X]Int self poison/exposure to narcotic drug at home	U205.11	[X]Overdose - heroin
U209000	[X]Int self poison/exposure to alcohol at home	U208.00	[X]Int self poison/exposure to other/unspec drug/medicament
U20B.11	[X]Self carbon monoxide poisoning	U210.00	[X]Intent self harm by hanging strangulat/suffocat occ home
U290.00	[X]Intentional self harm by sharp object occurrence at home	U29..00	[X]Intentional self harm by sharp object
U44..00	[X]Rifle shotgun+larger firearm discharge undetermin intent	9779DL	DELIBERATE OVERDOSE (DRUG)
SL...14	Overdose of biological substance	SN47100	Suffocation by strangulation
TK05.00	Suicide + selfinflicted poisoning by drug or medicine NOS	TK...00	Suicide and selfinflicted injury
TK1..00	Suicide + selfinflicted poisoning by gases in domestic use	TK06.00	Suicide + selfinflicted poisoning by agricultural chemical
TK52.00	Suicide and selfinflicted injury by hunting rifle	TK60.00	Suicide and selfinflicted injury by cutting
U200.13	[X]Overdose � aspirin	U20..11	[X]Deliberate drug overdose / other poisoning
U201.00	[X]Intent self poison/exposure to antiepileptic	U202.13	[X]Overdose - temazepam
U202.15	[X]Overdose � nitrazepam	U202.18	[X]Overdose - amylobarbitone
U204000	[X]Int self poison/exposure to psychotropic drug at home	U20A.00	[X]Intentional self poison organ solvent,halogen hydrocarb
U207.00	[X]Intent self poison/exposure to oth autonomic drug	U20B000	[X]Int self poison/exposure to other gas/vapour at home
U2B..00	[X]Intentional self harm by jumping from a high place	U242.00	[X]Int slf hrm rifl s'gun/lrg frarm dis sch/ins/pub adm area
U2B4.00	[X]Intent self harm by jump from high place occ street/h'way	U291.00	[X]Intent self harm by sharp object occ resident instit'n
TK...15	Attempted suicide	U29z.00	[X]Intentional self harm by sharp object occ unspecif place
TKx0000	Suicide + selfinflicted injury-jumping before moving object	U2A1.00	[X]Intent self harm by blunt object occ resident instit'n
U20A.11	[X]Self poisoning from glue solvent	U2C1.00	[X]Int self harm jump/lying befr mov obje occ resid instit'n
9947HN	ASPHYXIA DUE HANGING	U2y0.00	[X]Intentionl self harm by oth specif means occurrn at home
TK...14	Suicide and self harm	U41..00	[X]Hanging strangulation + suffocation undetermined intent
TK7..00	Suicide and selfinflicted injury by jumping from high place	TK...11	Cause of overdose - deliberate
TKx1.00	Suicide and selfinflicted injury by burns or fire	TK02.00	Suicide + selfinflicted poisoning by oth sedatives/hypnotics
TKx2.00	Suicide and selfinflicted injury by scald	TK0z.00	Suicide + selfinflicted poisoning by solid/liquid subst NOS
TKxy.00	Suicide and selfinflicted injury by other specified means	TK10.00	Suicide + selfinflicted poisoning by gas via pipeline
U200.11	[X]Overdose � paracetamol	TK1y.00	Suicide and selfinflicted poisoning by other utility gas
U202000	[X]Int self poison/exposure to sedative hypnotic at home	TK21.00	Suicide and selfinflicted poisoning by other carbon monoxide
U204.00	[X]Intent self poison/exposure to psychotropic drug	TK61.00	Suicide and selfinflicted injury by stabbing
U204.11	[X]Overdose � antidepressant	TKx..00	Suicide and selfinflicted injury by other means
U204.13	[X]Overdose � SSRI	U202z00	[X]Intent self poison sedative hypnotic unspecif place
U205.00	[X]Intent self poison/exposure to narcotic drug	U207z00	[X]Intent self poison oth autonomic drug unspecif place
U205y00	[X]Int self poison narcotic drug other spec place	U20B200	[X]Int self poison other gas/vapour school/pub admin area
U2zz.00	[X]Intent self harm by unspecif means occ at unspecif place	U2A0.00	[X]Intentional self harm by blunt object occurrence at home
9947TC	SUICIDE ATTEMPT STRANGULATION	U2A3.00	[X]Intent self harm by blunt object occ sports/athlet area
TK01.00	Suicide + selfinflicted poisoning by barbiturates	3009C	SUICIDE ATTEMPT
TK07.00	Suicide + selfinflicted poisoning by corrosive/caustic subst	3009D	SUICIDE
TK1z.00	Suicide + selfinflicted poisoning by domestic gases NOS	3059FN	SELF-INFLICTED INJURY
TK30.00	Suicide and selfinflicted injury by hanging	9651D	OVERDOSE ASPIRIN
TK3y.00	Suicide + selfinflicted inj oth mean hang/strangle/suffocate	9779A	OVERDOSE DRUG(S)
TK3z.00	Suicide + selfinflicted inj by hang/strangle/suffocate NOS	9779L	OVERDOSE DRUG SUICIDAL
TK6..00	Suicide and selfinflicted injury by cutting and stabbing	9779NA	SUICIDAL OVERDOSE (DRUG)

Identification of suicides

Potential cases of suicide were identified from a list of OXMIS/Read medical terms indicative of suicide and by review of all free text entries for patients who had died of any cause during the observation period.

The Read/OXMIS medical terms and the extracted free text were used by two of the authors independently (CM and DG), blinded to drug exposure category, to assess the likelihood of a suicide, the method and the date of suicide. Where there was disagreement, a consensus opinion was reached. Patients with a code of suicide or with a clear free text entry of suicide were classified as "definite suicide". Other deaths were coded as probable or possible suicides or �unknown� depending on the mode of death and drugs taken in overdose. Subjects with a clearly stated natural cause of death were not considered further.

For all definite, probable or possible cases of suicide and those deaths where the cause of death was unknown, we contacted the general practice to obtain the patient�s date of birth using the anonymised patient identifier. This patient identifier together with the patient�s gender, date of birth and date of death were then provided to the Office for National Statistics (ONS) who provided the cause of death for all matched death certificates.

Suicide verdicts coded with E950-E959 (ICD-9) or X60-X84 (ICD-10) and open verdicts coded as E980-E989 (ICD-9) and Y10-Y34 (ICD-10) on the death certificates were defined as suicides. In keeping with other studies we included as suicides people coded as either suicide or undetermined deaths, as most deaths in this latter category are suicides [1].

We obtained death certificate data from ONS for 73 of 117 (62%) of the possible suicides. It was not possible to obtain a unique match to ONS death certificate data using gender, date of birth and date of death for the remaining cases.

All 32 cases of suicide coded by CM and DG as "definite" for whom ONS death certificate data were obtained were recorded as suicides on the death certificates. Amongst those coded "probable", 67% (8/12) were recorded as suicides; amongst those coded "possible", 50% (4/8) were recorded as suicide and 8% (2/24) of the deaths where the cause was unknown were recorded as suicides. As the coding of "definite" and "probable" suicides was reasonably accurate, we assumed that all deaths without death certificate information coded as probable suicides were indeed suicides. We excluded possible suicides (n=3) without death certificate support for the cause of death from further analysis.

[1] Linsley KR, Schapira K, Kelly TP. Open verdict v. suicide � importance to research. Br. J. Psychiatry, May 2001; 178: 465 - 468.

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Web Table 3: Cumulated exposure to specific antidepressants during the entire observational period

�	Number of patients with depression	Person-years
SSRI substance	99829	37775
Citalopram	13723	4708
Fluoxetine	43031	13974
Fluvoxamine	9446	<