### Ahmet Akin Gülhane Military Medical Academy Department of Aerospace Medicine Eskisehir 26020, Turkey

Arvind K. Chaturvedi Civil Aerospace Medical Institute

Federal Aviation Administration Oklahoma City, OK 73125

May 2003

Final Report

This document is available to the public through the National Technical Information Service, Springfi eld, Virginia 22161. Offi ce of Aerospace Medicine Washington, DC 20591 

# Prevalence of Selective Serotonin Reuptake Inhibitors in Pilot Fatalities of Civil Aviation Accidents, 1990-2001 DOT/FAA/AM-03/7

## NOTICE

This document is disseminated under the sponsorship of the U.S. Department of Transportation in the interest of

information exchange. The United States Government assumes no liability for the contents thereof.

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### ACKNOWLEDGMENTS

The Government of Turkey is acknowledged for allowing the participation of Dr. Ahmet Akin in the FAA International Exchange Visitor Program at the FAA’s Civil Aerospace Medical Institute (CAMI), Oklahoma City, OK.

The authors wish to thank Dr. Dennis V. Canfi eld of CAMI for his timely advice, valuable comments, and assistance in the data gathering process and the manuscript development. Without his support, this study would not have been possible. The authors are grateful to Patrick S. Cardona of CAMI for providing assistance in drawing the chemical structures of SSRIs and to Dr. John W. Soper and Dr. James E. Whinnery of CAMI for critically and enthusiastically reviewing the manuscript. Their comments and suggestions improved the quality of this report.

iii1 

## P REVALENCE OF 

## S ELECTIVE 

## S EROTONIN 

## R EUPTAKE 

## I NHIBITORS IN 

## P ILOT 

## F

ATALITIES OF 

## C IVIL 

## A VIATION 

## A CCIDENTS 

## , 1990-2001

INTRODUCTION Selective serotonin reuptake inhibitors (SSRIs), a new generation of antidepressants, are effective medications for the treatment of depression (4,8). There are currently 5 drugs—fl uoxetine, sertraline, paroxetine, fl uvoxamine, and citalopram—classifi ed as SSRIs (Figure 1). However, in the United States, fl uvoxamine (Luvox ® ) is approvedonly for treating obsessive compulsive disorder (31). Fluoxetine was the fi rst SSRI marketed in the United States in 1988, followed by other SSRIs. Since their availability (Table I), fl uoxetine (Prozac ® ), sertraline (Zoloft ® ), paroxetine (Paxil ® ), and citalopram (Celexa ® ) have preferentially been prescribed because of low incidences of untoward adverse effects associated with their use, allowing these4 SSRIs to remain in the top 200 drugs of the most dispensed prescriptions in the United States pharmaceutical industry (9,10,27,28,37-41,47-49). By being a part of the general population, aviators are subject to similar social pressures as other individuals of the society. Therefore, aviators have the potential for the need-based use of SSRIs, but these psychotropic medications are not approved by United States aeromedical regulatory authorities for use by aviators in order to avoid a possible compromise with aviation safety (15,20,22). SSRIs are considered safe in comparison with other groups of antidepressants (6,30,44), though SSRIs have been linked to adverse effects primarily associated with the serotonin syndrome and drug metabolism inhibition (4,19,45). The former can be effectively treated, but the latter can lead to severe adverse effects in multi-drug users. All 5 SSRIs are extensively metabolized by the cytochrome P450 (CYP) enzyme system (4,17). Except for paroxetine and fl uvoxamine, other SSRIs have active metabolites, as well (4,5,17). Fluoxetine, sertraline, their active



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Figure 1: Chemical structures of selective serotonin reuptake inhibitors (SSRIs) and their
active metabolites.2 metabo lites, paroxetine, and fl uvoxamine inhibit certain CYP isoenzymes involved in the biotransformation of other drugs. Excluding citalopram, SSRIs inhibit their own metabolism by saturating their metabolizing CYP enzymes at higher SSRI (substrate) concentrations (17,19,33,34). Since patients with depression are frequently treated with multiple drugs, inhibition of the metabolism of these drugs by SSRIs can lead to drug-drug interactions, toxicity, and even death. Apparent association between the use
of SSRIs and an increased risk of suicide has also been suggested in a few deaths (18,23,29,51). However, it
should be remembered that the increased risk of suicide is an intrinsic risk of the disease itself (7,18). A study on the postmortem forensic toxicology of SSRIs has been published describing the cause and manner of death of 168 death-investigation cases (19). Fewer than 12 out of
the 168 deaths were due to an intentional acute overdose of an SSRI on its own; however, the contributory role of an SSRI in the deaths resulting from overdoses of other drugs could not be ruled out primarily because of the drug metabolizing enzyme inhibitory properties of SSRIs. Little is known about the postmortem aviation forensictoxicology of SSRIs. Since this fi eld is basically a humanperformance related postmortem forensic toxicology endeavor (42), fi ndings on the prevalence of SSRIs in aviation accident pilot fatalities with the concentrations of SSRIs in the associated postmortem biosamples will be useful in the investigations of SSRI-associated aviation accidents.Such information will also be important to aeromedical regulatory authorities for making a possible future decision on the use of SSRIs by aviators. Therefore, the Civil Aerospace Medical Institute’s (CAMI’s) Toxicology Database (Oklahoma City, O.K.), the Federal Aviation Administration’s (FAA’s) National Aviation Safety Data Analysis Center (NASDAC) Database (Washington, D.C.), and the National Transportation Safety Board’s (NTSB’s) Aviation Accident Database (Washington,D.C.) were searched to obtain the applicable information. Findings from those database searches are presented in this study. **��������** ��������������������������������������������������������������������������������������� ��������������������������������������������������������������������������������������������

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### MATERIALS AND METHODS

Postmortem Pilot Forensic Toxicology Samples During the investigation of aircraft accidents occurring within the jurisdiction of the United States, autopsied biological samples collected from pilot fatalities of civil aircraft accidents are submitted to CAMI for toxicological evaluation (3). Such sample submission is coordinated through the FAA’s Offi ce of Accident Investigation by the NTSB, which is responsible for investigating all United States civilian aircraft accidents. The collected samples are shipped to CAMI in the FAA’s TOX-BOX evidence containers (14).

Toxicological Evaluation The submitted pilot fatality biological samples are routinely analyzed for the presence of combustion gases (carbon monoxide and hydrogen cyanide), alcohol/volatiles, and drugs (11-14,43). All of these foreign substances (analytes) in the samples are analyzed according to established standard laboratory procedures, including screening and confi rmatory/quantitative analyses (14). Analytes found in a pilot fatality case might not have necessarily been detected, or even analyzed, in each of the sample types submitted for toxicological evaluation from that particular accident pilot fatality. Analyses are dependent upon the nature of analytes, the sensitivity and specifi city of analytical methods used, and the availability of sample types and amounts.Drugs include a wide range of prescription, nonprescription, and illicit drugs. As with the majority of the drugs, SSRIs in the biosamples are screened by high performance liquid chromatography and by gas chromatography/mass spectrometry (GC/MS) and are confi rmed/quantitated by GC/MS. Types and names ofdrugs found by CAMI during postmortem forensic toxicology of pilot fatalities associated with 1989-1993 and 1994-1998 civil aviation accidents have been published elsewhere (11,12).

Databases Since 1990, toxicological fi ndings of civil aircraft accident fatalities are electronically stored in a database maintained at CAMI. In the present study, this CAMI Toxicology Database was descriptively examined for the presence of SSRIs, with or without any other drug(s)and/or ethanol, in pilot fatalities of civil aviation accidents that occurred during a 12-year (1990-2001) period. Additionally, the database was searched to ascertain the
number of 1990-2001 aviation accidents and associatedpilot fatalities (cases) from which CAMI received postmortem biological samples. For this report, such aviation
accidents are referred to as “CAMI accidents” and related pilot fatalities as “CAMI cases.” Fatalities (cases) included in the present study consisted of only pilots—copilots are not included. Information on the types of airman certifi cates of those SSRI-associated pilots was retrieved from the CAMI Toxicology Database and from the NTSB
Aviation Accident Database. The number of fatal aviation accidents reported by the NTSB for the 1990-2001 period was obtained from the FAA’s NASDAC Database.
The NTSB Aviation Accident Database was also used for obtaining information about the SSRI-related accidents, including the probable cause and/or factor(s) of those accidents, as determined and reported by the NTSB.



### RESULTS

Fatal Civil Aviation Accidents As reported in the FAA’s NASDAC Database, the
number of all the United States fatal civil aviation accidents for the 1990-2001 period was 5,449. Of these accidents, 4,570 were under the general aviation fl ight category (Title 14 CFR Part 91), 305 were under the air taxi and commuter fl ight category (Title 14 CFR Part 135), 168 were under the agricultural fl ight category (Title 14 CFR Part 137), 8 were under the ultralight fl ight category (Title 14 CFR Part 103), and the remaining 398 were under other fl ight categories (Table II). The Title 14 CFR Part 135 category included accidents of scheduled, as well as nonscheduled, fl ights. The NASDAC Database includes information primarily associated with the accidents of registered aircraft—information on the accidents of unregistered aircraft may not necessarily be
included in this database.

CAMI Aviation Accidents and Pilot Fatalities CAMI received postmortem biological samples for toxicological evaluation from 4,128 pilots (CAMI cases) associated with 4,184 fatal accidents (CAMI accidents) that occurred during the 12-year period (Table II). Out of these 4,184 accidents, 3,643 accidents with 3,611 pilot fatalities were related to general aviation fl ights, 220 accidents with 218 pilot fatalities were related to air taxi and commuter fl ights, 127 accidents with 127pilot fatalities were related to agricultural fl ights, 44 accidents with 44 pilot fatalities were related to ultralight fl ights, and 150 accidents with 128 pilot fatalities wererelated to other categories of fl ights. The CAMI Toxicology Database includes both registered and unregistered
aircraft accidents.4 SSRI-Involved Aviation Accidents and Pilot Fatalities Flight categories : Of the 4,184 CAMI accidents, SSRIs were found in 61 pilot fatalities (CAMI cases) associatedwith 61 aviation accidents (Table II). Of these 61 accidents, 56 involved general aviation fl ights, 2 air taxi and commuter fl ights, 2 agricultural fl ights, and 1 ultralight fl ight. Out of the 61 pilot fatalities, 22 had only SSRIs, and 39 also had other drug(s) and/or ethanol. Airman certifi cate categories: Out of these 61 SSRI-involved pilots, 37 held private pilot certifi cates (36 United States private pilot certifi cate holders and 1 Canadian private pilot certifi cate holder), 13 held commercial pilot certifi cates, 4 held airline transport pilot certifi cates, 3 held student pilot certifi cates, and 1 held a recreational pilot certifi cate. The 3 remaining pilots were non-certifi ed. Of the 37 private pilot certifi cate holders, 36 were involved in general aviation accidents, while 1 was involved in an ultralight accident. In the group of the 13 commercial pilot certifi cate holders, 9 were involved in general aviation accidents, 2 in air taxi and commuter accidents, and 2 in agricultural accidents. The remaining pilot fatalities—4 airline transport pilot certifi cate holders, 3 student pilot certifi cate holders, 1 recreational pilot certifi cate holder, and 3 non-certifi cated pilots—were involved in general
aviation accidents. Accidents and pilot fatalities: As is exhibited in Figure 2, there were no SSRI-associated pilot fatalities (cases) in the 1990 accidents, but the number of SSRI-involved
fatalities increased from 1 in the 1991 accidents to 18 in the 2001 accidents. In the 12-year accidents, the highest number of pilot fatalities was associated with fl uoxetine,
which was fi rst SSRI marketed in the U.S. in 1988. No fl uvoxamine-associated pilot fatality was seen during the 12-year period. The trend of SSRI-involved pilot fatalities and associated accidents was consistent with the pattern of the SSRIs dispensed in the U.S. pharmaceutical industry during the 1990-2001 period (Figure 2; Table I).
Fluoxetine: This SSRI was found in 33 pilot fatalities (cases). In 13 cases, only fl uoxetine and/or its primary active metabolite (norfl uoxetine) were detected (Table Table II. Operation Type-Based Comparative Categorization of 1990-2001 Fatal Civil Aviation Accidents Reported in the FAA' s National Aviation Safety Data Analysis Center (NASDAC) Database and in the CAMI's Toxicology Database

CAMI Toxicology Database ‡

Operation Type * FAA's
NASDAC
Database
Accidents † CAMI
Accidents CAMI Cases CAMI SSRI-Related Accidents (Pilot Fatalities)

General aviation (Title 14 CFR Part 91) 4,570 3,643 3,611 56

Air taxi and commuter (Title 14 CFR Part 135) 305 220 218 2

Agricultural (Title 14 CFR Part 137) 168 127 127 2

Ultralight (Title 14 CFR Part 103) 8 44 44 1

Other operation types 398 150 128
–

Total 5,449 4,184 4,128 61

* Code of Federal Regulations (CFR), Title 14—Aeronau tics and space, Chapter I, Subchapters F and G (16).

† May not include fatal accidents of unregistered aircraft.

‡ Includes fatal accidents of registered, as well as unre gistered, aircraft from which postmortem biological samples were submitted for toxicological evaluation. Such aviation accidents are referred to as "CAMI accidents" and related pilot fatalities as "CAMI cases." Details are also given in the text of the Materials and
Methods section.5 III)—blood, the toxicologically preferred sample type,
was not available in 2 of these cases. Blood concentration ranges of fl uoxetine and norfl uoxetine were 61−1,121 ng·mL −1 and 52−1,388 ng·mL −1 , respectively. In the remaining 20 cases, other drugs—for example, analgesics,antihistaminics, benzodiazepines, narcotic analgesics, amphetamines and other sympathomimetics, cocaine and its metabolites, and/or tetrahydrocannabinol carboxylic acid—and/or ethanol were also detected (Table IV). Blood
was not available in 6 of the 20 cases. Blood fl uoxetine
and norfl uoxetine concentrations in those cases wherein other drugs and/or ethanol were present ranged from 11 to 778 ng·mL −1 and from 87 to 764 ng·mL −1 , respectively.Ethanol was found in only 3 cases—blood was not available in 1 of these cases. Blood ethanol concentrations in the 2 cases were 39 and 246 mg·dL −1 . Out of the 33 fl uoxetine-involved cases, the use of the SSRI, with or without other drug(s), was determined by the NTSB to be a contributing factor in 7 accidents, of which 1 pilot fatality had only fl uoxetine and norfl uoxetine, while the remaining 6 pilot fatalities also had other drug(s). All of these 7 accidents were of the general aviation category. The cause/factor of 1 accident was undetermined, and the fi nal reports of 3 accidents were not yet available in the NTSB database. The drug use was not reported to be a cause/factor in 22 of the 33 accidents by the NTSB.
Sertraline: Fourteen pilot fatalities (cases) had sertraline. In 4 cases, only sertraline and/or its active metabolite (desmethylsertraline) were detected (Table V). Blood concentration of this SSRI in 1 of the 4 cases was considerably high—sertraline: 13,102 ng·mL −1 and desmethylsertraline: 889 ng·mL −1 . In the remaining 10 cases, other drug(s) and/or ethanol were also detected (Table VI). Blood was not available in 1 of these 10 cases.In the 9 cases, the blood concentration range of sertraline was 47−1,860 ng·mL −1 and of desmethylsertraline it was 42−4,685 ng·mL −1 . Other drugs found in these 10 pilot fatalities were analgesics, sympathomimetics, diphenhydramine, and/or tramadol. Ethanol was found in 3 cases wherein no other drugs were detected—only sertraline was present. The NTSB determined the use ofthe SSRI, with other drug and/or ethanol, to be a contributing factor in 2 of the 14 sertraline-related accidents; both accidents were of the general aviation category. The



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Figure 2: Numbers of selective serotonin reuptake inhibitor (SSRI)-associated pilot fatalities (CAMI cases) in civil aviation accidents that occurred during 1990-2001. Postmortem biological samples from the pilots of fatal aircraft accidents were submitted to CAMI for toxicological evaluation. Details are given
in the text.6 Table III. Fluoxetine and Norfluoxetine Found in Pilot Fatality (Case) Biological Samples Without Other Drugs and/or Ethanol

Fluoxetine/Norfluoxetine (ng·mL −1 or ng·g −1 )

Case Blood Urine Liver SSRI Use a Contributing Factor in the Accident per NTSB Report *

1 1,121/1,388 592/809

– † Undetermined
2 200/300

– 6,200/15,000 Not mentioned
3 583/254 344/195 – Not mentioned

4 ND ‡ /52 ND/D § ND/155 Not mentioned 5 923/1,320

– 1,724/988 Not mentioned
6 61/D

– 20/ND Not mentioned
7 ND/55

– ND/1,182 Not mentioned
8 ND/ND

– 13/16 Not mentioned
9 211/861

– 10,161/36,277 Not mentioned
10 405/299

– 12,840/17,750 Yes (contraindicated drug-caused impaired judgment)
11 203/715

– D/D Not mentioned

12 ¶ Blood not
available – 700/1,500 Not mentioned

13 ** Blood not
available – 31,000/74,000 Not mentioned

* As reported in the NTSB Aviation Accident Database at the time of the writing of this report.

† No data, because the sample type was either not available or not analyzed.

‡ Not detected.

§ Detected; no quantitative value.

¶ Fluoxetine (200 ng·g –1 ) and norfluoxetine (200 ng·g –1 ) were also detected in kidney.

** Kidney contained 3,200 ng·g –1 fluoxetine and 18,000 ng·g –1 norfluoxetine, and lung contained 4,900 ng·g –1 fluoxetine and 56,000 ng·g –1 norfluoxetine.7Table IV.Fluoxetine and Norfluoxetine Found in Pilot Fatality (Case) Biological Samples with Other Drug(s) and/or EthanolCase SamplesFluoxetine/Norfluoxetine(ng·mL−1orng·g−1)Other Drugs/Their Metabolites (ng·mL−1or ng·g−1) and/orEthanol (mg·dL−1or mg·hg−1)SSRI Use [With OtherDrug(s)/Ethanol] aContributing Factor inthe Accident perNTSB Report*1 BloodUrine83/138D†/DTemazepam (44)Temazepam (D)Yes (prescription drug)2 BloodUrine197/87D/DAmphetamine (D), methamphetamine (16)Amphetamine (229), methamphetamine (1,578)Yes (drug-causedimpairment)3 BloodLiverKidney11/148D/DD/43Nordiazepam (93), etomidate (D),lidocaine (D), atropine (D)Nordiazepam (D), etomidate (D),lidocaine (100), atropine (D)–‡Not mentioned4 BloodLiverLung488/698D/DD/DPhenylpropanolamine (D), ephedrine (D), pseudoephedrine (D), chlorpheniramine (148),chlordiazepoxide (D), nordiazepam (152), diltiazem (D), salicylate (8,000), acetaminophen(21,900)Phenylpropanolamine (D), ephedrine (D), pseudoephedrine (D), chlorpheniramine (121),chlordiazepoxide (D), nordiazepam (D), diltiazem (D)Phenylpropanolamine (D), ephedrine (D)Yes (drug-causedimpairment of judgmentand performance)5 BloodUrineLiver89/10189/10198/100Amphetamine (603)Amphetamine (7,816), carbamazepine (2,300)Carbamazepine (4,400)Yes (medication-causedimpairment)6 BloodUrine778/764D/DDiphenhydramine (75), diltiazem (D)Diphenhydramine (D), diltiazem (D), acetaminophen (9,300)Not mentioned7 BloodUrineLiver293/333–1,170/1,790Nordiazepam (D)Temazepam (D), nordiazepam (31), oxazepam (D)Nordiazepam (46), salicylate (69,800)Not mentioned8 BloodUrineLiver642/676D/D1,639/1,601Phenylpropanolamine (D), ephedrine (D), tetrahydrocannabinol carboxylic acid (D)Phenylpropanolamine (D), ephedrine (D), tetrahydrocannabinol carboxylic acid (20),salicylate (215,500)Phenylpropanolamine (D), ephedrine (D)Not mentioned9 BloodUrine367/18573/33Ephedrine (D)Phenylpropanolamine (D), ephedrine (D), salicylate (31,000)Not mentioned8Table IV.Fluoxetine and Norfluoxetine Found in Pilot Fatality (Case) Biological Samples with Other Drug(s) and/or Ethanol (continued)Case SamplesFluoxetine/Norfluoxetine(ng·mL−1orng·g−1)Other Drugs/Their Metabolites (ng·mL−1or ng·g−1) and/orEthanol (mg·dL−1or mg·hg−1)SSRI Use [With OtherDrug(s)/Ethanol] aContributing Factor inthe Accident perNTSB Report*10 Blood§UrineVitreousfluidD/209ND¶/109–Ethanol (246), pseudoephedrine (D), doxylamine (270), dextromethorphan (D),dextrorphan (D)Ethanol (220), phenylpropanolamine (D), ephedrine (D), pseudoephedrine (D), doxylamine(D), dextromethorphan (D), dextrorphan (D)Ethanol (289)Not mentioned11 BloodLiverLung43/2422,252/D–Lidocaine (11,760), atropine (D)–Lidocaine (D), atropine (D)Not mentioned12 BloodLiverBrainMuscleND/400D/D––Ethanol (39)–Ethanol (36)Ethanol (55)Final NTSB reportnot yet available13 BloodLiverKidney–D/DD/DPropoxyphene (172), norpropoxyphene (1,037)–Propoxyphene (2,240), norpropoxyphene (31,714)Final NTSB reportnot yet available14 BloodLiverKidneyND/296–ND/DCocaine (10), benzoylecgonine (212), cocaethylene (D)Benzoylecgonine (352)–Not mentioned15**LiverKidney7/109D/24Hydrocodone (496)Hydrocodone (D)Yes (contraindicateddrug)16**LiverKidney2,215/861353/108Cimetidine (D), diltiazem (D)Cimetidine (D), diltiazem (D)Yes (unapprovedmedication)17**LiverKidney1,442/1,902448/582Desipramine (295), nordiazepam (251), phentermine (6,413),Bupropion (D), bupropion metabolite (D)Desipramine (97), nordiazepam (159), phentermine (3,486),Bupropion (D), bupropion metabolite (D)Not mentioned9Table IV.Fluoxetine and Norfluoxetine Found in Pilot Fatality (Case) Biological Samples with Other Drug(s) and/or Ethanol (continued)Case SamplesFluoxetine/Norfluoxetine(ng·mL−1orng·g−1)Other Drugs/Their Metabolites (ng·mL−1or ng·g−1) and/orEthanol (mg·dL−1or mg·hg−1)SSRI Use [With OtherDrug(s)/Ethanol] aContributing Factor inthe Accident perNTSB Report*18**LiverKidneyMuscle7/1458/26––Ethanol (164)Ethanol (15)Not mentioned19**LiverKidneyND/201ND/19Nordiazepam (269)Nordiazepam (191)Not mentioned20**LiverKidneyMuscleD/D–ND/DNordiazepam (D), verapamil (D), norverapamil (D)Nordiazepam (D), oxazepam (D)Verapamil (D), norverapamil (D)Final NTSB reportnot yet available*As reported in the NTSB Aviation Accident Database at the time of the writing of this report.†Detected; no quantitative value.‡No data, because the sample type was either not available or not analyzed.§Contained 12% carboxyhemoglobin.¶Not detected.**Blood not available.10 pilot fatalities associated with these 2 accidents not only had sertraline and/or desmethylsertraline but also had diphenhydramine or ethanol. The drug use was not mentioned to be a cause/factor in 9 accidents by the NTSB, and the fi nal reports of 3 accidents were not yet
available in the NTSB database.

Paroxetine: As is given in Table VII, paroxetine was found in 11 pilot fatalities (cases). In 3 cases, only paroxetine was present. In the remaining 8 cases, other drugs—antihistaminics, sympathomimetics, alprazolam,butalbital, codeine, morphine, quinine, and/or verapamil—were also present. Ethanol was not detected in any of the 11 fatalities. Blood was not available in 3 of the 11 cases. The blood concentration range of paroxetine, with or without any other drug(s), was 68−1,441 ng·mL −1

. The drug use was not established to be a cause/factor in 8 of the 11 accidents by the NTSB. The fi nal reports of 3 accidents were not yet available in the NTSB database. Citalopram: This SSRI was found in only 3 pilot fatalities (Table VIII). In 2 of these cases, only citalopram
and its active metabolites— N

-desmethylcitalopram and -desmethylcitalopram and
di- N- desmethylcitalopram—were detected, whereas acetaminophen and diphenhydramine were also detected
in 1 case. Blood was not available in 1 case. Ethanol wasnot detected in any of the citalopram-related pilot fatalities. In accidents associated with 2 of these 3 cases, the drug use was not established to be a cause/factor by the NTSB; the fi nal report of 1 accident was not yet available
in the NTSB database. 

### DISCUSSION

Because SSRIs are popularly prescribed in the general population for effectively treating depression, and pilotsare also a part of the population, there have been genuine concerns whether pilots should offi cially be granted permission to use SSRIs. Such a decision would require the assurance that SSRIs can be prescribed without compromising aviation safety. The SSRI-use-related safety issue was discussed in great detail at the 2002Aerospace Medical Association (AsMA) scientifi c meeting (21,24,26,36,46,50). The reluctance of aeromedicalregulatory authorities to allow the use of SSRIs by aviators primarily stems from the very basic pharmacological nature of SSRIs as being psychotropic drugs. These drugs have the potential to affect the central nervous system (CNS), thus might impair performance and ultimately compromise aviation safety. Because of these reasons, the FAA has been reluctant to approve the use of SSRIs by aviators. Although pilots have the potential to use SSRIs, the presence of SSRIs in pilot fatalities is apparently less than expected, considering their heavy use in the general population (9,10,27,28,37-41,47-49), as only 61 SSRI-associated pilot fatalities were found out of the 4,128 pilot fatalities from the 4,184 CAMI accidents. The number of SSRI-associated pilot fatalities was higher in the general aviation fl ight category than in any otherfl ight categories, which is consistent with the higher number of general aviation fatal accidents than the aviation Table V. Sertraline and Desmethylsertraline Found in Pilot Fatality (Case) Biological Samples without Other Drugs and/or Ethanol



### Sertraline/Desmethylsertraline (ng·mL −1 

### or ng·g −1 

### )

Case Blood Urine Liver Brain SSRI Use a Contributing
Factor in the Accident per NTSB Report *



### 1 13,102/889 – † 

### 587/330 985/1,311 Not mentioned
2 211/498 D ‡ 

### /D – – Not mentioned
3 D/83 D/D D/D – Not mentioned

4 ND § 

### /D – D/283 – Final NTSB report not yet available

* As reported in the NTSB Aviation Accident Database at the time of the writing of this report.

† No data, because the sample type was either not available or not analyzed.

‡ Detected; no quantitative value.

§ Not detected.11**���������**����������������������������������������������������������������������������������������������������������������������������� ��������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������� ������������������������������������������������������������������������������������������������������������������������������������������������������� ���������������������������������������������������������������������������� ������������������������������������������������������������������������������������������ �������������������������������������������������������������������������� ��������������������������������������������������������������������������������������������������������������������������� ����������������������������������������������������������������������������������������������������������������������������� ����������������������������������������������������������������������������������������������������������������������������������������������������������������12Table VI.Sertraline and Desmethylsertraline Found in Pilot Fatality (Case) Biological Samples with Other Drug(s) and/or Ethanol (continued)Case SamplesSertraline/Desmethylsertraline(ng·mL−1or ng·g−1)Other Drugs/Their Metabolites (ng·mL−1or ng·g−1)and/or Ethanol (mg·dL−1or mg·hg−1)SSRI Use [With OtherDrug(s)/Ethanol] aContributing Factor in theAccident per NTSB Report*8 BloodUrineLiverBrainVitreous fluidMuscle1,672/2,983D/DD/D–––Ethanol (55)Ethanol (78)–Ethanol (57)Ethanol (71)Ethanol (41)Final NTSB report not yetavailable9 BloodLiver47/230D/DDiphenhydramine (251)Diphenhydramine (D)Yes (drug-caused impairment)10**LiverKidney23,239/49,5733,727/10,133Phenylpropanolamine (D), pseudoephedrine (D), ephedrine(D), diphenhydramine (1,157)Pseudoephedrine (D), diphenhydramine (213)Not mentioned*As reported in the NTSB Aviation Accident Database at the time of the writing of this report.†Not detected.‡Detected; no quantitative value.§No data, because the sample type was either not available or not analyzed.¶General aviation accident.**Blood not available.13 Table VII . Paroxetine Found in Pilot Fatality (Case) Biological Samples with or without Other Drug(s)
and/or Ethanol *

Case Samples Paroxetine (ng·mL −1

or ng·g −1 ) Other Drugs/Their Metabolites (ng·mL −1 or ng·g −1 ) SSRI Use [With or Without Other Drug(s)] a Contributing
Factor in the Accident

per NTSB Report †

1 Blood
Urine 68
19 None detected
None detected Not mentioned

2 Blood
Urine 96

D ‡ None detected
None detected Not mentioned

3 Blood
Urine

Liver – §

D

228 – Diphenhydramine (D), morphine (73), codeine (D), hydrocodone (72), dihydrocodeine (46) Diphenhydramine (149) Not mentioned

4 Blood ¶

Urine 283

D Pseudoephedrine (D) Phenylpropanolamine (D), ephedrine (D), pseudoephedrine (D) Not mentioned

5 Blood
Urine 374 1,040 – Alprazolam (D), -hydroxyalprazolam (D) Not mentioned

6 Blood
Urine 1,441

D Verapamil (D), norverapamil (D) Verapamil (D), norverapamil (D) Final NTSB report not yet available

7 Blood

Urine 619

D Phenylpropanolamine (D), ephedrine (D), pseudoephedrine (D) Phenylpropanolamine (D), ephedrine (D), pseudoephedrine (D) Final NTSB report not yet available

8 Blood
Urine
Liver 355

D

D – Codeine (49), morphine (1,658)

– Use of prohibited drugs, as a finding **

9 †† Liver Kidney 1,608
710 None detected
None detected Not mentioned

10 †† Liver
Muscle 24,400
208 Diphenhydramine (6,240)

– Not mentioned

11 †† Liver

Muscle

Heart D

– D Butalbital (681), quinine (D), Triprolidine (D) Butalbital (241) Quinine (D), triprolidine (D) Final NTSB report not yet available

* No ethanol was detected in this group of pilot fatalities.

† As reported in the NTSB Aviation Accident Database at the time of the writing of this report.

‡ Detected; no quantitative value.

§ No data, because the sample type was either not available or not analyzed.

¶ Contained 17% carboxyhemoglobin and 0.31 μg·mL −1 cyanide.

** Air taxi and commuter accident.

†† Blood not available.14Table VIII.Citalopram and its Metabolites Found in Pilot Fatality (Case) Biological Samples with or without Other Drugs and/or Ethanol*Concentration (ng·mL−1or ng·g−1)Case SamplesCitalopramN-DesmethylcitalopramDi-N-desmethyl-citalopramOther Drugs/TheirMetabolitesSSRI Use [With or WithoutOther Drug(s)] a ContributingFactor in the Accident perNTSB Report†1 BloodLiver314D‡157D11650None detectedNone detectedNot mentioned2 BloodUrine462D114D24DDiphenhydramine (194)Diphenhydramine (D),acetaminophen (17,406)Final NTSB report not yetavailable3§LiverKidneyDDDDDDNone detectedNone detectedNot mentioned*No ethanol was detected in this group of pilot fatalities.†As reported in the NTSB Aviation Accident Database at the time of the writing of this report.‡Detected; no quantitative value.§Blood not available.15 accidents of other operation categories. This conclusion is supported by the observations that (i) 56 (92%) of the 61 SSRI-involved accidents and 3,643 (87%) of the 4,184 CAMI accidents were associated with the general aviation fl ights, (ii) all of the 9 accidents in which theuse of an SSRI was determined to be a contributing factor were of the general aviation category, and (iii) the majority of the 61 pilots held airman certifi cates at the levels that authorized them for fl ying under the general aviation category.
The number of fatalities associated with an individualSSRI was consistent with its marketing year—for example, fl uoxetine, marketed in 1988, was present in 33 pilot fatalities; whereas citalopram, marketed in 1998, was found in only 3 pilot fatalities. Although fl uoxetine, sertraline, paroxetine, and citalopram were found in the 61 pilot fatalities, fl uvoxamine was not detected in any of the total 4,128 CAMI aviation accident pilot fatalities. The absence of fl uvoxamine in the pilot fatalities could be because this medication has not yet been approved in the U.S. for the treatment of depression—this drug is approved in the U.S. only for the treatment of obsessive compulsive disorder (31). Additionally, fl uvoxamine is not a popularly prescribed medication—this drug has never been in the top-200 drug list of the most dispensed prescription drugs in the U.S. (9,10,27,28,47-49). The prevalence of fl uvoxamine, in relation to other SSRIs, was also considerably low in a general forensic toxicology death investigation study consisting of 168 cases (19). In this study, fl uvoxamine was present in only 5 death cases, whereas fl uoxetine was found in 60 death cases, sertraline in 75 death cases, and paroxetine in 28 death cases. SSRIs, themselves, may not exhibit considerableadverse effects on human performance at the recommended therapeutic doses, but depression, itself, has a signifi cant potential for performance impairment. Nonetheless, because of the pharmacological potencies and drug metabolism inhibitory properties of SSRIs andtheir metabolites (4,5,17,19,45), SSRIs may adversely affect the CNS function and cause drug-drug interactions. Since SSRIs inhibit their own metabolism at high doses (17,19,33,34), the potential for the inhibition of the metabolism of other drugs is further increased in those cases wherein SSRIs are taken in high doses. Thus, SSRIs taken in conjunction with other drugs might interactively cause drug toxicity, even when other drugs are taken in therapeutic doses. Blood concentrations of those other drugs could be higher than their typical therapeutic blood
levels because of the SSRI-caused inhibition of their metabolism, thereby their accumulation in blood. Out of those 61 SSRI-associated pilot fatalities, 39 (64%) pilot fatalities also had other drug(s) and/or ethanol in their system. Some of the drugs—such as atropine, lidocaine, etomidate, and analgesics—found in the pilot fatalities could have been administered by emergency health care providers at accident scenes, or at hospitals, for resuscitation, pain reduction, and/or surgicalprocedures. Whereas, other drugs—such as antihistaminics, benzodiazepines, sympathomimetics, cardiovascular medications, and even abused drugs—and ethanol were very likely present in the system of the pilots prior to theaccidents. Thus, pharmacodynamic and pharmacokineticlevel interactions of SSRIs and their active metabolites with other drug(s) and ethanol could realistically lead toperformance impairment and unpredictable toxicopharmacological effects. Such performance impairment and adverse effects may well be increased at fl ying altitudes because of the reduced availability of oxygen to the brain and other organs.
Inhibition of their own metabolism is known to cause changes in the ratios of the parent SSRIs and their metabolites (17,19,33): These ratios are less at low SSRI doses in comparison with the ratios at high SSRI doses. Therapeutic serum level ranges of fl uoxetine, sertraline, paroxetine, and citalopram are established to be 100–500, 25–50, 30–100, and 75–150 ng·mL −1 , respectively (4).The relationship between the plasma (or serum) concentrations of SSRIs and their whole blood concentrationsis not fully established, and the blood to plasma (or serum) concentration ratios of SSRIs may not necessarilybe equivalent to 1. Therefore, the SSRI blood concentrations found in the present study may not truly represent their plasma or serum levels. Although therapeutic, toxic, and lethal levels of SSRIs in whole blood are not clearlydetermined based on the postmortem forensic toxicology of death investigation cases, the lowest blood levels determined to have resulted in death were 630 ng·mL −1 for fl uoxetine; 1,500 ng·mL −1 for sertraline; and 400 ng·mL −1 for paroxetine (19). Anastos et al. (1) have concluded therapeutic and lethal concentrations of citalopram in blood to be 400 ng·mL −1 and 800 ng·mL −1 , respectively. The majority of pilot fatality blood SSRI levels, in the absence of other drug(s) and/or ethanol, observed in the present postmortem aviation forensic toxicology study fell below, or close to, the reported values in the deathinvestigation cases (1,19). The blood sertraline concentration of 13,102 ng·mL −1 found in 1 of the pilot fatalities (Table V) is approximately 4-fold higher than the upper blood value of the sertraline concentration range reported in the 75 sertraline-related death investigation case study (19). Therefore, the 13,102 ng·mL −1 blood sertraline levelcould be considered as a supra-toxic or lethal concentration. Reaching such a high concentration in blood could be attributed to (i) the intentional ingestion of a16 consider able amount of the SSRI, (ii) the contamination of the postmortem blood sample by the gastrointestinaltrack (GI) contents, and/or (iii) the postmortem redistribution of the SSRI among various body compartments, particularly from a higher concentration gradient of the SSRI in the GI track to a lower concentration gradient of the SSRI in the blood compartment. Including sertraline, SSRIs are chemically basic drugs,and extensive postmortem redistribution has been reported with basic drugs (2,32,35). Therefore, blood concentrations of SSRIs found after death may not necessarily represent their antemortem blood levels. In view of this, during the investigations of aviation accidents involving SSRIs, the postmortem blood levels of SSRIs should be carefully evaluated and interpreted, particularly when other drug(s) and/or ethanol are also present. As is truewith any drug, in the 13 pilot fatalities wherein the toxicologically preferred sample—blood—was not available, levels of SSRIs in other biological sample types cannot be correctly correlated with the degree of performance impairment or adverse effects, since such levels merely indicate the exposure of those victims to SSRIs. The NTSB has determined “the use of drug” as a contributing factor in at least 9 (15%) out of the 61 SSRI-related accidents, which does not necessarily imply only SSRIs—this may also very well refer to other drug(s) and/or ethanol present in those accident-related pilots. Final NTSB reports of 10 out of those 61 accidents are not yet available in the public domain database. Once those reports are fi nalized, the number of accidents wherein the use of an SSRI, with or without other drug(s) and/or ethanol, was a contributing factor may increase. The low number of SSRI-associated pilot fatalities has a realistic practical relevance, especially when SSRIs have been a popularly prescribed group of medications in the U.S. (9,10,27,28,37-41,47-49). Ideally, considering the prohibition for use of SSRIs by aviators, an SSRI should not have been found in any pilot fatality. The SSRI-related 61 pilots were identifi ed only because those pilots were victims of fatal accidents and their postmortem sampleswere toxicologically evaluated. Even though contributing roles of weather conditions, mechanical defi ciencies, and/or piloting errors cannot be completely ruled out in the 61 accidents, this number is of concern with reference to aviation safety. This concern is further deepened by
the fact that the 61 SSRI-associated accidents are 12% of the total (505) prescribed-medication related 1990-2001 CAMI accidents, particularly realizing that this percentage represents only 4 prescription drugs. On the other hand, the number of SSRI-associated pilots is a fraction of the pilot population and may not necessarily represent the true spectrum of the usage of SSRIs in aviators. Therefore, a well-designed population study on pilots could reveal a much higher usage of SSRIs in pilots, as refl ectedduring a presentation at the 2002 AsMA scientifi c meeting (21) and during an FAA aviation medical examiner seminar (25).



### CONCLUSIONS

Findings from the present study clearly suggest low numbers of accidents wherein drug use was determined to be a contributing factor and/or wherein pilot fatalities had SSRIs in the presence or absence of other drug(s) and/or ethanol. Nevertheless, the absolute number of
SSRI-related accidents and associated fatalities cannot becondoned. In the upcoming years, the number of SSRIassociated fatal aviation accidents may potentially increase as the use of SSRIs in the general population, including pilots, increases as a function of time. Information on the prevalence of SSRIs in aviation accident pilot fatalities along with SSRI concentrations in biological samples will continue to be useful in the investigations of accidents
wherein SSRIs and other substances are involved. Additionally, fi ndings from this study should guide futureresearch and be utilized in making a possible future decision concerning the use of SSRIs by aviators.



### REFERENCES

1. Anastos N, McIntyre IM, Lynch MJ, Drummer OH. Postmortem concentrations of citalopram. J

Forensic Sci 2002; 47:882-4.

2. Anderson WH, Prouty RW. Postmortem redistribution of drugs. In: Baselt RC, Ed. Advances in analytical toxicology, Vol II. Chicago, IL: Year Book Medical Publishers, Inc., 1989; 70-102.

3. Aviation Safety Research Act of 1988, Public Law 100-591 [H.R. 4686]. 100th U.S. Cong., 2nd Sess., 102 Stat. 3011 (Nov 3, 1988).

4. Baldessarini RJ. Drugs and the treatment of psychiatric disorders: Depression and anxiety disorders. In: Hardman JG, Limbird LE, Gilman AG, Eds. Goodman & Gilman’s The pharmacological basisof therapeutics, 10th ed. New York, NY: McGrawHill, 2001; 447-83.

5. Baselt RC. Disposition of toxic drugs and chemicals in man, 6th ed. Foster City, CA: Biomedical Publications, 2002.17 6. Baumann P. Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake
inhibitors. Clin Pharmacokinet 1996; 31:444-69.

7. Beers MH, Berkow R, Eds. The Merck manual of diagnosis and therapy, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories, 1999;
1525-44.

8. Bezchlibnyk-Butler KZ, Jeffries JJ. Clinical handbook of psychotropic drugs, 11th ed. (revised). Seattle, WA: Hogrefe & Huber Publishers, 2001;

3-13.

9. Buckley B. Prescriptions grow 7% to 2.4 billion; sales increase 16% to $94 billion. Pharm Times 1999; 4:16-22.

10. Buckley B. Top 200 drugs of 1996: Rx volume up
4%. Pharm Times 1997; 4:27-51.

11. Canfi eld D, Flemig J, Hordinsky J, Birky M. Drugs
and alcohol found in fatal civil aviation accidents between 1989 and 1993. Washington, DC: U.S. Department of Transportation, Federal Aviation Administration; 1995 Nov. Report No: DOT/
FAA/AM-95/28. 1

12. Canfi eld DV, Hordinsky J, Millett DP, Endecott B, Smith D. Prevalence of drugs and alcohol in fatal
civil aviation accidents between 1994 and 1998. Aviat Space Environ Med 2001; 72:120-4.

13. Chaturvedi AK, Smith DR, Canfi eld DV. Bloodcarbon monoxide and hydrogen cyanide concentrations in the fatalities of fi re and non-fi re associated civil aviation accidents, 1991-1998. Forensic Sci Int
2001; 121:183-8.

14. Chaturvedi AK, Smith DR, Soper JW, Canfi eldDV, Whinnery JE. Characteristics and toxicological processing of postmortem pilot specimens from fatal civil aviation accidents. Washington, DC: U.S. Department of Transportation, Federal Aviation Administration; 2002 Aug. Report No:
DOT/FAA/AM-02/14. 1

15. Code of Federal Regulations (CFR). Title 14— Aeronautics and space, Chapter I, Part 67—Medical standards and certifi cation, Subpart B: 107, Subpart C: 207, and Subpart D: 307. Washington, DC: U.S. Government Printing Offi ce, 2002.

16. Code of Federal Regulations (CFR), Title 14— Aeronautics and space, Chapter I, Subchapters Fand G. Washington, DC: U.S. Government Printing Offi ce, 2002.

17. DeVane CL. Metabolism and pharmacokinetics of selective serotonin reuptake inhibitors. Cell Mol
Neurobiol 1999; 19:443-66.

18. DeVane CL. SSRI safety considerations. Pharm

Times 2002; 4:18-24.

19. Goeringer KE, Raymon L, Christian GD, Logan BK. Postmortem forensic toxicology of selectiveserotonin reuptake inhibitors: A review of pharmacology and report of 168 cases. J Forensic Sci 2000; 45:633-48.

20. Guide for aviation medical examiners. Washington, DC: U.S. Department of Transportation, FederalAviation Administration, Offi ce of Aviation Medicine; 1999 Oct:70.

21. Hudson DE. SSRI use in professional aircrew [abstract]. Aviat Space Environ Med 2002; 73:244-5.

22. Ireland RR. Pharmacologic considerations for serotonin reuptake inhibitor use by aviators. Aviat Space Environ Med 2002; 73:421-9.

23. Jick SS, Dean AD, Jick H. Antidepressants and
suicide. BMJ 1995; 310 (6974):215-8.

24. Jones DR. Aeromedical regulation of serotonin reuptake inhibitors in aviators [abstract]. Aviat Space Environ Med 2002; 73:245.

25. Jones DR. Psychiatric factors in aviation medicine—FAA aviation medical examiners basic seminar. Oklahoma City, OK: U.S. Department of Transportation, Federal Aviation Administration, Civil Aerospace Medical Institute; 2002 Sep.

26. Lange M. Maintenance SRI use in professional pilots: The Canadian experience [abstract]. Aviat Space Environ Med 2002; 73:244.

27. Latner AW. The top 200 drugs of 1999: The more things change, the more they stay the same. Pharm

Times 2000; 4:16-32.

28. Latner AW. The top 200 of 2000: Drugs of the new
millennium. Pharm Times 2001; 4:14-29. 1 This publication and all Offi ce of Aerospace Medicine technical reports are available in full-text from the Civil Aerospace Medical Institute Publications' Web site: http://www.cami.jccbi.gov/aam-400A/index.html Copies may be purchased from the National Technical Information Service, Springfi eld, Virginia 22161.18 29. Milner DA, Hall M, Davis GG, Brissie RM, Robinson CA. Fatal multiple drug intoxication following acute sertraline use. J Anal Toxicol 1998; 21:545-8.

30. Peretti S, Judge R, Hindmarch I. Safety and tolerability considerations: Tricyclic antidepressant vs. selective serotonin reuptake inhibitors. Acta Psychiatr Scand 2000; 101:17-25.

31. Physicians’ desk reference, 56th ed. Montvale, NJ: Medical Economics Company, Inc., 2002.

32. Pounder DJ, Jones GR. Post-mortem drug redistribution—a toxicological nightmare. Forensic Sci

Int 1990; 45:253-63.

33. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors: An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet 1997; 32 (1, Suppl.):1-21.

34. Preskorn SH. Pharmacokinetics of antidepressant: Why and how they are relevant to treatment. J Clin Psychiatry 1993; 54 (9, Suppl.):14-34.

35. Prouty RW, Anderson WH. The forensic science implications of site and temporal infl uences on postmortem blood-drug concentrations. J Forensic

Sci 1990; 35:243-70.

36. Silberman WS. The Federal Aviation Offi ce of Aerospace Medicine’s view on the use of SSRI’s in airmen [abstract]. Aviat Space Environ Med 2002; 73:245.

37. Simonsen LLP. Top 200 drugs of 1990: What are pharmacists dispensing most often? Pharm Times 1991; 4:57-71.

38. Simonsen LLP. Top 200 drugs of 1991: What are pharmacists dispensing most often? Pharm Times 1992; 4:47-66. 39. Simonsen LLP. Top 200 drugs of 1992: What are pharmacists dispensing most often? Pharm Times 1993; 4:29-44.

40. Simonsen LLP. Top 200 drugs of 1993: Price of average Rx up only 2.9%. Pharm Times 1994; 4:

1994; 4:

18-32.

41. Simonsen LLP. Top 200 drugs: Rx prices still moderating as managed care grows. Pharm Times 1995; 4:17-23.

42. SOFT/AAFS forensic toxicology laboratory guidelines. Colorado Spring, CO: Society of Forensic Toxicologists, Inc., and American Academy of
Forensic Sciences; 1997.

43. Soper JW, Chaturvedi AK, Canfi eld DV. Prevalenceof chlorpheniramine in aviation accident pilot fatalities, 1991-1996. Aviat Space Environ Med 2000; Aviat Space Environ Med
71:1206-9.

44. Stahl SM. Psychopharmacology of antidepressant

. London, UK: Martin Dunitz Ltd., 1997; 39-59.

45. Stahl SM. Psychopharmacology of antidepressant. London, UK: Martin Dunitz Ltd., 1997; 101-8.

46. Thibeault C. President’s page. Aviat Space Environ
Med 2002; 73:831.

47. Top 10 drugs of 2001 [editorial]. Pharm Times 2002; 4:10-5.

48. Top 200 drugs of 1995 [editorial]. Pharm Times 1996; 4:27-36.

49. Top 200 drugs of 1997: IMS analysis describes major market shifts [editorial]. Pharm Times 1998; 4: 1998; 4:
31-49.

50. Van Syoc D. Serotonin reuptake inhibitors in aircrew [abstract]. Aviat Space Environ Med 2002; 73: 2002; 73:
244.

51. Vermeulen T. Distribution of paroxetine in three

postmortem cases. J Anal Toxicol 1998; 21:541-4.