bupropion and Adverse Drug Event studies

Bupropion: A propiophenone-derived antidepressant and antismoking agent that inhibits the uptake of DOPAMINE.
bupropion : An aromatic ketone that is propiophenone carrying a tert-butylamino group at position 2 and a chloro substituent at position 3 on the phenyl ring.

Research Excerpts

Excerpt	Relevance	Reference
"To compare the incidence, severity, and clinical course of frequently reported adverse events (AEs) after treatment with smoking cessation pharmacotherapies."	3.01	Frequently Reported Adverse Events With Smoking Cessation Medications: Post Hoc Analysis of a Randomized Trial. ( Dutro, MP; Ebbert, J; Fisher, M; Hays, JT; Jimenez-Ruiz, C; Li, J, 2021)
"Esketamine was approved for adults with treatment-resistant depression (TRD) in conjunction with an oral antidepressant, and for treating depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior."	2.82	Craving and addictive potential of esketamine as side effects? ( Orsolini, L; Salvi, V; Volpe, U, 2022)
" Thus, if following the appropriate guidelines according to package labels, the practitioner can feel safe in prescribing these medications."	2.52	Safety and tolerability of medications approved for chronic weight management. ( Fujioka, K, 2015)
" However, in the existing studies PHEN/TPM ER had a superior weight loss profile to lorcaserin but the incidence of adverse effects was lower with lorcaserin."	2.50	Tolerability and safety of the new anti-obesity medications. ( Aldhoon-Hainerová, I; Hainer, V, 2014)
" We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts."	1.37	FDA-approved drug labeling for the study of drug-induced liver injury. ( Chen, M; Fang, H; Liu, Z; Shi, Q; Tong, W; Vijay, V, 2011)
"Bupropion is an atypical antidepressant that is biotransformed in humans to its major active metabolite hydroxybupropion by cytochrome P450 2B6 (CYP2B6)."	1.37	Drug interaction study between bupropion and ticlopidine in male CF-1 mice. ( Hassan, HE; Moeller, BM; Molnari, JC; Myers, AL, 2011)
"5 million adverse drug reaction (ADR) reports for 8620 drugs/biologics that are listed for 1191 Coding Symbols for Thesaurus of Adverse Reaction (COSTAR) terms of adverse effects."	1.32	Assessment of the health effects of chemicals in humans: II. Construction of an adverse effects database for QSAR modeling. ( Benz, RD; Contrera, JF; Kruhlak, NL; Matthews, EJ; Weaver, JL, 2004)

Research

Studies (16)

Authors

Clinical Trials (1)

Trial Overview

Trial Outcomes

CO-Confirmed Continuous Abstinence for Weeks 9 Through 12 (Overall)

Timeframe	Studies, this research(%)	All Research%
pre-1990	0 (0.00)	18.7374
1990's	0 (0.00)	18.2507
2000's	4 (25.00)	29.6817
2010's	6 (37.50)	24.3611
2020's	6 (37.50)	2.80

Authors	Studies
Matthews, EJ	1
Kruhlak, NL	1
Weaver, JL	1
Benz, RD	1
Contrera, JF	1
Pedersen, JM	1
Matsson, P	1
Bergström, CA	1
Norinder, U	1
Hoogstraate, J	1
Artursson, P	1
Chen, M	1
Vijay, V	1
Shi, Q	2
Liu, Z	2
Fang, H	2
Tong, W	2
Ding, D	1
Kelly, R	1
Orsolini, L	1
Salvi, V	1
Volpe, U	1
Schwalsberger, K	1
Reininghaus, B	1
Reiter, A	1
Dalkner, N	1
Fleischmann, E	1
Fellendorf, F	1
Platzer, M	1
Reininghaus, EZ	1
Zhou, Q	1
Li, X	1
Yang, D	1
Xiong, C	1
Xiong, Z	1
Lothet, E	1
Fredrickson, C	1
Nguyen, KL	1
Bertels, K	1
Mullins, ME	1
Elliott, J	1
Johnston, A	1
Husereau, D	1
Kelly, SE	1
Eagles, C	1
Charach, A	1
Hsieh, SC	1
Bai, Z	1
Hossain, A	1
Skidmore, B	1
Tsakonas, E	1
Chojecki, D	1
Mamdani, M	1
Wells, GA	1
Ebbert, J	1
Jimenez-Ruiz, C	1
Dutro, MP	1
Fisher, M	1
Li, J	1
Hays, JT	1
Hainer, V	1
Aldhoon-Hainerová, I	1
Fujioka, K	1
Oncken, CA	1
Kranzler, HR	1
Molnari, JC	1
Hassan, HE	1
Moeller, BM	1
Myers, AL	1
Clark, SL	1
Adkins, DE	1
Aberg, K	1
Hettema, JM	1
McClay, JL	1
Souza, RP	1
van den Oord, EJ	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
A Phase 4, Randomized, Double-blind, Active And Placebo-controlled, Multicenter Study Evaluating The Neuropsychiatric Safety And Efficacy Of 12 Weeks Varenicline Tartrate 1mg Bid And Bupropion Hydrochloride 150mg Bid For Smoking Cessation In Subjects With[NCT01456936]	Phase 4	8,144 participants (Actual)	Interventional	2011-11-30	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

"A responder to this endpoint requires the answer no to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 12 (inclusive)." (NCT01456936)
Timeframe: Week 9 through Week 12

CO-Confirmed Continuous Abstinence for Weeks 9 Through 12, Non-psychiatric History Cohort

Intervention	percentage of participants (Number)
Varenicline 1.0 mg BID	33.5
Bupropion 150 mg BID	22.6
NRT Patch	23.4
Placebo	12.5

CO-Confirmed Continuous Abstinence for Weeks 9 Through 12, Psychiatric History Cohort

Intervention	percentage of participants (Number)
Varenicline 1.0 mg BID	38.0
Bupropion 150 mg BID	26.1
NRT Patch	26.4
Placebo	13.7

CO-confirmed Continuous Abstinence From Week 9 Through Week 24 (Overall)

Intervention	percentage of participants (Number)
Varenicline 1.0 mg BID	29.2
Bupropion 150 mg BID	19.3
NRT Patch	20.4
Placebo	11.4

"A responder to this endpoint requires the answer no to both questions 1 and 2 on the Nicotine Use Inventory at every visit from Week 9 to Week 24 (inclusive)." (NCT01456936)
Timeframe: Week 9 through Week 24

CO-confirmed Continuous Abstinence From Week 9 Through Week 24, Non-psychiatric History Cohort

Intervention	percentage of participants (Number)
Varenicline 1.0 mg BID	21.8
Bupropion 150 mg BID	16.2
NRT Patch	15.7
Placebo	9.4

CO-confirmed Continuous Abstinence From Week 9 Through Week 24, Psychiatric History Cohort

Intervention	percentage of participants (Number)
Varenicline 1.0 mg BID	25.5
Bupropion 150 mg BID	18.8
NRT Patch	18.5
Placebo	10.5

"Clinical Global Impression of Improvement (CGI-I), No Change Rating by Visit"

Intervention	percentage of participants (Number)
Varenicline 1.0 mg BID	18.3
Bupropion 150 mg BID	13.7
NRT Patch	13.0
Placebo	8.3

"The CGI-I is a clinician rated instrument that measures change in participant's psychiatric condition (or lack thereof in the stratum without psychiatric disorders) on a 7 point scale ranging from 1 (very much improved) to 7 (very much worse), with 4 = no change. The ratings were applicable even to those without psychiatric diagnoses (eg, those with no psychiatric symptoms would be rated as normal, not at all ill on the CGI-S at baseline and assuming no psychiatric symptoms emerge during the trial, would be rated as no change on the CGI-I at follow-up visits). For those participants with a psychiatric diagnosis, the clinician should rate the severity of the mental illness with respect to the clinician's experience with the psychiatric population to which the participant belongs." (NCT01456936)
Timeframe: Baseline to Week 24

7-Day Point Prevalence of Abstinence (Overall)

Intervention	percentage of participants (Number)
	Week 1 (N= 1986, 1974, 1986, 1982)	Week 2 (N= 1934, 1936, 1927, 1926)	Week 3 (N= 1880, 1892, 1880, 1863)	Week 4 (N= 1860, 1856, 1858, 1834)	Week 5 (N= 1828, 1816, 1822, 1802)	Week 6 (N= 1816, 1808, 1820, 1773)	Week 8 (N= 1758, 1756, 1755, 1738)	Week 10 (N= 1717, 1707, 1715, 1675)	Week 12 (N= 1558, 1572, 1540, 1492)	Week 13 (N= 1612, 16081602, 1575)	Week 16 (N= 1586, 1606, 1568, 1541)	Week 20 (N= 1563, 1573, 1523, 1510)	Week 24 (N= 1533, 1515, 1499, 1497)
Bupropion 150 mg BID	93.2	90.8	89.8	88.0	86.5	86.5	83.6	81.7	75.1	76.7	76.7	75.0	72.3
NRT Patch	94.6	90.5	88.7	87.1	85.5	85.1	82.8	80.4	72.2	75.2	73.9	72.2	71.1
Placebo	95.1	91.2	87.9	86.3	85.4	84.1	81.9	79.2	71.3	74.9	73.4	71.7	71.1
Varenicline 1.0 mg BID	94.2	90.8	88.3	86.6	85.7	85.2	82.4	80.6	72.9	75.9	74.2	73.4	71.8

"A responder to this endpoint requires the answer no to both questions 3 and 6 on the nicotine use inventory at that specific visit.~NUI Question 3 (Baseline through Week 24): Has the subject smoked any cigarettes (even a puff) in the last 7 days? NUI Question 6 (Baseline through Week 12): Has the subject used any other nicotine containing products in the last 7 days? NUI Question 6 (Week 13 through Week 24): Has the subject used any other tobacco products in the last 7 days?" (NCT01456936)
Timeframe: 24 Weeks

7-Day Point Prevalence of Abstinence, Non-psychiatric History Cohort

Intervention	percentage of participants (Number)
	Week 1	Week 2	Week 3	Week 4	Week 5	Week 6	Week 7	Week 8	Week 9	Week 10	Week 11	Week 12	Week 13	Week 14	Week 15	Week 16	Week 17	Week 18	Week 19	Week 20	Week 21	Week 22	Week 23	Week 24
Bupropion 150 mg BID	1.1	17.9	22.3	24.4	25.7	26.9	30.2	26.5	30.4	27.6	30.7	27.1	26.5	29.2	29.2	25.1	27.9	27.8	27.9	23.9	26.7	26.4	27.0	23.2
NRT Patch	0.9	14.2	20.0	23.5	25.1	26.8	31.3	28.0	32.1	28.0	32.1	27.6	26.9	29.4	29.2	24.9	28.1	28.2	28.1	23.7	26.5	26.3	25.3	23.6
Placebo	1.0	10.3	12.1	13.1	13.6	14.6	17.9	15.9	18.1	15.5	18.8	16.0	16.0	19.1	19.8	16.1	18.8	19.5	19.2	16.3	18.8	18.4	18.3	15.7
Varenicline 1.0 mg BID	1.3	18.8	26.3	30.4	33.4	35.8	39.5	37.4	41.6	38.7	42.5	39.6	36.8	39.5	38.5	33.1	36.4	36.2	35.7	30.8	33.9	33.8	33.0	29.8

7-Day Point Prevalence of Abstinence, Psychiatric History Cohort

Intervention	percentage of participants (Number)
	Week 1	Week 2	Week 3	Week 4	Week 5	Week 6	Week 7	Week 8	Week 9	Week 10	Week 11	Week 12	Week 13	Week 14	Week 15	Week 16	Week 17	Week 18	Week 19	Week 20	Week 21	Week 22	Week 23	Week 24
Bupropion 150 mg BID	1.0	21.3	26.6	27.7	29.8	31.4	35.2	31.0	34.9	31.0	34.1	30.5	30.7	33.5	33.2	28.5	31.9	31.3	31.2	27.5	30.3	29.9	30.6	26.0
NRT Patch	1.2	15.5	22.1	25.9	27.8	30.4	35.1	31.4	34.8	31.1	34.9	30.4	29.9	32.0	32.4	28.1	31.4	31.7	31.2	26.3	29.3	29.0	28.3	27.0
Placebo	1.5	11.4	13.6	14.5	14.9	15.9	19.2	16.7	19.0	16.9	20.8	17.8	17.2	20.4	21.3	18.2	20.1	20.8	20.8	18.2	20.1	20.3	20.3	17.4
Varenicline 1.0 mg BID	1.7	20.9	30.0	34.3	38.4	41.0	44.4	42.3	47.1	42.4	46.6	44.4	41.1	44.5	43.8	37.2	40.7	40.9	39.9	35.1	38.1	38.7	37.6	33.6

Estimated NPS AE Rate (%), by Cohort

Intervention	percentage of participants (Number)
	Week 1	Week 2	Week 3	Week 4	Week 5	Week 6	Week 7	Week 8	Week 9	Week 10	Week 11	Week 12	Week 13	Week 14	Week 15	Week 16	Week 17	Week 18	Week 19	Week 20	Week 21	Week 22	Week 23	Week 24
Bupropion 150 mg BID	1.2	14.6	18.1	21.3	21.8	22.7	25.4	22.1	26.0	24.3	27.4	23.9	22.6	25.0	25.3	21.9	24.0	24.5	24.7	20.4	23.2	22.9	23.5	20.4
NRT Patch	0.7	13.0	17.9	21.1	22.4	23.3	27.5	24.6	29.4	25.0	29.4	24.9	24.0	26.8	26.0	21.8	24.8	24.7	25.1	25.1	23.7	23.6	22.2	20.1
Placebo	0.5	9.2	10.7	11.8	12.4	13.4	16.6	15.0	17.2	14.0	17.2	14.2	14.8	17.8	18.3	13.9	17.4	18.2	17.6	17.6	17.5	16.5	16.4	14.0
Varenicline 1.0 mg BID	1.0	16.8	22.7	26.6	28.5	30.8	34.8	32.7	36.2	35.1	38.6	35.0	32.7	34.7	33.4	29.1	32.3	31.7	31.6	26.6	29.7	29.1	28.5	26.1

"The primary safety endpoint is the occurrence of at least one treatment emergent severe adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent moderate or severe adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Estimated NPS AE rate (%) was calculated based on least-squares means analysis." (NCT01456936)
Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

HADS Total Score (Overall)

Intervention	percentage of participants (Least Squares Mean)
	Non-psychiatric cohort (N=3984)	Psychiatric cohort (N= 4074)
Bupropion 150 mg BID	2.44	6.62
NRT Patch	2.31	5.20
Placebo	2.52	4.83
Varenicline 1.0 mg BID	1.25	6.42

The HADS is a subject self-reporting scale completed in person at clinic visits at Baseline and Weeks 1 through 6, 8, 10, 12, 13, 16, 20, and 24. It contains 14 individual item responses ranging in increasing severity from 0 (normal) to 3 (most severe) for a total range of 0 to 42. Of the 14 items, 7 assess anxiety and 7 assess depression, providing 2 subscales with ranges of 0 to 21. For each subscale, 0 to 7 is considered normal, while 15 to 21 represents severe symptoms. (NCT01456936)
Timeframe: Baseline to Week 24

HADS Total Score, Psychiatric History Cohort

Intervention	Units on a scale (Mean)
	Week 1 (N= 1989, 1976, 1985, 1987)	Week 2 (N= 1938, 1937, 1931, 1929)	Week 3 (N= 1882, 1891, 1881, 1867)	Week 4 (N= 1858, 1854, 1863, 1831)	Week 5 (N= 1829, 1815, 1820, 1797)	Week 6 (N= 1816, 1807, 1821, 1771)	Week 8 (N= 1755, 1754, 1755, 1736)	Week 10 (N= 1717, 1709, 1716, 1669)	Week 12 (N= 1562, 1571, 1548, 1491)	Week 13 (N= 1610, 1608, 1603, 1570)	Week 16 (N= 1579, 1602, 1566, 1537)	Week 20 (N= 1555, 1569, 1525, 1509)	Week 24 (N= 1528, 1512, 1495, 1487)
Bupropion 150 mg BID	5.61	5.06	4.60	4.39	4.16	4.05	4.10	3.86	3.79	3.66	3.77	3.73	3.80
NRT Patch	4.95	4.74	4.48	4.31	4.08	4.01	3.96	4.00	3.78	3.71	3.78	3.72	3.82
Placebo	5.05	4.80	4.38	4.39	4.14	4.09	4.12	4.04	3.95	3.70	3.82	3.75	3.62
Varenicline 1.0 mg BID	5.03	4.68	4.31	4.15	3.94	3.82	3.82	3.85	3.64	3.60	3.67	3.65	3.62

Hospital Anxiety and Depression Scale (HADS) Total Score, Non-psychiatric History Cohort

Intervention	Units on a scale (Mean)
	Week 1 (N= 1026, 1017, 1015, 1015)	Week 2 (N= 1005, 1004, 996, 995)	Week 3 (N= 947, 961, 945, 926)	Week 4 (N= 935, 938, 929, 908)	Week 5 (N= 918, 918, 914, 895)	Week 6 (N= 917, 914, 912, 874)	Week 8 (N= 887, 893, 878, 859)	Week 10 (N= 864, 865, 864, 823)	Week 12 (N= 790, 803, 798, 749)	Week 13 (N= 813, 812, 814, 763)	Week 16 (N= 795, 805, 791, 748)	Week 20 (N= 784, 784, 763, 737)	Week 24 (N= 770, 764, 758, 729)
Bupropion 150 mg BID	7.58	6.99	6.51	6.36	6.03	5.87	5.96	5.72	5.66	5.44	5.62	5.54	5.69
NRT Patch	6.82	6.64	6.30	6.16	5.82	5.62	5.63	5.64	5.44	5.36	5.44	5.46	5.57
Placebo	6.70	6.42	6.02	6.04	5.80	5.75	5.63	5.55	5.42	5.09	5.37	5.26	5.04
Varenicline 1.0 mg BID	6.76	6.42	5.99	5.87	5.58	5.39	5.43	5.38	5.17	5.06	5.26	5.17	5.21

Occurrence of Neuropsychiatric (NPS) Adverse Events (AE) - the Primary Study Endpoint

Intervention	Units on a scale (Mean)
	Week 1 (N= 984, 972, 989, 992)	Week 2 (N= 961, 954, 963, 970)	Week 3 (N= 935, 930, 936, 941)	Week 4 (N= 923, 916, 934, 923)	Week 5 (N= 911, 897, 906, 902)	Week 6 (N= 899, 893, 909, 897)	Week 8 (N= 868, 861, 877, 877)	Week 10 (N= 853, 844, 852, 846)	Week 12 (N= 772, 768, 750, 742)	Week 13 (N= 797, 796, 789, 807)	Week 16 (N= 784, 797, 775, 789)	Week 20 (N= 771, 785, 762, 772)	Week 24 (N= 758, 748, 737, 758)
Bupropion 150 mg BID	3.58	3.07	2.64	2.36	2.24	2.18	2.16	1.96	1.83	1.85	1.90	1.93	1.87
NRT Patch	3.06	2.84	2.63	2.46	2.32	2.40	2.28	2.33	2.01	2.01	2.09	1.97	2.01
Placebo	3.38	3.20	2.77	2.77	2.48	2.48	2.64	2.57	2.46	2.38	2.34	2.31	2.25
Varenicline 1.0 mg BID	3.26	2.91	2.61	2.40	2.29	2.23	2.17	2.29	2.07	2.11	2.05	2.10	2.01

"The primary safety endpoint is the occurrence of at least one treatment emergent severe adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent moderate or severe adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide." (NCT01456936)
Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Occurrence of Severe-only NPS AEs in the Primary Endpoint, by Cohort

Intervention	percentage of participants (Number)
	Non-psychiatric cohort (N= 990, 989, 1006, 999)	Psychiatric cohort (N= 1026, 1017, 1016, 1015)	Overall (N= 2016, 2006, 2022, 2014)
Bupropion 150 mg BID	2.2	6.7	4.5
NRT Patch	2.5	5.2	3.9
Placebo	2.4	4.9	3.7
Varenicline 1.0 mg BID	1.3	6.5	4.0

"The primary safety endpoint is the occurrence of at least one treatment emergent severe adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent moderate or severe adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Only those events rated as severe are reported; this excludes any moderate events in the primary NPS AE endpoint." (NCT01456936)
Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Occurrence of the Components of NPS AE Primary Endpoint (Overall)

Intervention	percentage of participants (Number)
	Non-psychiatric cohort (N= 990, 989, 1006, 999)	Psychiatric cohort (N= 1026, 1017, 1016, 1015)	Overall (N= 2016, 2006, 2022, 2014)
Bupropion 150 mg BID	0.4	1.4	0.9
NRT Patch	0.3	1.4	0.8
Placebo	0.5	1.3	0.9
Varenicline 1.0 mg BID	0.1	1.4	0.7

The NPS AE composite results (as previously described) are for the two cohorts combined and are presented below. (NCT01456936)
Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Occurrence of the Components of Severe-only NPS AE Endpoint (Overall)

Intervention	participants (Number)
	Anxiety	Depression	Feeling Abnormal	Hostility	Agitation	Aggression	Delusions	Hallucination	Mania	Panic Disorder	Paranoia	Psychosis	Homicidal Ideation	Suicidal Behavior	Suicidal Ideation	Suicide
Bupropion 150 mg BID	5	4	1	1	40	12	1	4	10	20	1	2	0	2	3	0
NRT Patch	6	7	0	1	40	9	2	2	5	14	0	4	1	1	5	0
Placebo	5	6	0	0	33	11	0	2	8	10	2	1	0	1	5	1
Varenicline 1.0 mg BID	5	7	0	0	35	17	1	6	7	7	1	4	0	1	5	0

"The NPS AE endpoint was the occurrence of at least 1 treatment-emergent severe AE of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least 1 treatment-emergent severe AE of agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Only those events rated as severe are reported; this excludes any moderate events in the primary NPS AE endpoint." (NCT01456936)
Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Occurrence of the Components of the NPS AE Primary Endpoint, Non-psychiatric History Cohort

Intervention	participants (Number)
	Anxiety	Depression	Feeling Abnormal	Hostility	Agitation	Aggression	Delusions	Hallucination	Mania	Panic Disorder	Paranoia	Psychosis	Suicidal Behavior	Suicidal Ideation	Suicide	Homicidal Ideation
Bupropion 150 mg BID	5	4	1	1	1	2	0	1	1	2	1	2	2	0	0	0
NRT Patch	6	7	0	1	6	0	0	0	0	1	0	4	0	1	0	1
Placebo	5	6	0	0	2	1	0	0	0	2	2	1	1	0	1	0
Varenicline 1.0 mg BID	5	7	0	0	1	2	0	0	2	0	1	4	1	1	0	0

"The safety endpoint is the occurrence of at least one treatment emergent severe adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent moderate or severe adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Each of these 16 components is reported below." (NCT01456936)
Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Occurrence of the Components of the NPS AE Primary Endpoint, Psychiatric History Cohort

Intervention	participants (Number)
	Anxiety (severe)	Depression (severe)	Feeling abnormal (severe only)	Hostility (severe)	Agitation (moderate and severe)	Aggression (moderate and severe)	Delusions (moderate and severe)	Hallucinations (moderate and severe)	Mania (moderate and severe)	Panic (moderate and severe)	Paranoia (moderate and severe)	Psychosis (moderate and severe)	Homicidal ideation (moderate and severe)	Suicidal behavior (moderate and severe)	Suicidal ideation (moderate and severe)	Suicide (moderate and severe)
Bupropion 150 mg BID	1	0	0	1	11	3	0	0	1	4	1	0	0	1	1	0
NRT Patch	0	0	0	1	19	2	1	0	2	1	0	1	1	1	2	0
Placebo	3	0	0	0	11	3	0	0	2	3	0	0	0	0	3	1
Varenicline 1.0 mg BID	0	1	0	0	10	3	0	1	0	0	0	0	0	0	0	0

Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Non-psychiatric History Cohort

Intervention	participants (Number)
	Anxiety (severe)	Depression (severe)	Feeling abnormal (severe only)	Hostility (severe)	Agitation (moderate and severe)	Aggression (moderate and severe)	Delusions (moderate and severe)	Hallucinations (moderate and severe)	Mania (moderate and severe)	Panic (moderate and severe)	Paranoia (moderate and severe)	Psychosis (moderate and severe)	Homicidal ideation (moderate and severe)	Suicidal behavior (moderate and severe)	Suicidal ideation (moderate and severe)	Suicide (moderate and severe)
Bupropion 150 mg BID	4	4	1	0	29	9	1	4	9	16	0	2	0	1	2	0
NRT Patch	6	7	0	0	21	7	1	2	3	13	0	3	0	0	3	0
Placebo	2	6	0	0	22	8	0	2	6	7	2	1	0	1	2	0
Varenicline 1.0 mg BID	5	6	0	0	25	14	1	5	7	7	1	4	0	1	5	0

"The safety endpoint is the occurrence of at least one treatment emergent severe adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent moderate or severe adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Only those events rated as severe are reported; this excludes any moderate events in the primary NPS AE endpoint." (NCT01456936)
Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Occurrence of the Components of the Observed Severe-only NPS AE Primary Endpoint, Psychiatric History Cohort

Intervention	participants (Number)
	Anxiety	Depression	Feeling abnormal	Hostility	Agitation	Aggression	Delusions	Hallucinations	Mania	Panic	Paranoia	Psychosis	Homicidal ideation	Suicidal behavior	Suicidal ideation	Suicide
Bupropion 150 mg BID	1	0	0	1	0	1	0	0	0	1	0	0	0	1	0	0
NRT Patch	0	0	0	1	2	0	0	0	0	1	0	0	0	0	0	0
Placebo	3	0	0	0	0	0	0	0	0	1	0	0	0	0	1	1
Varenicline 1.0 mg BID	0	1	0	0	0	1	0	0	0	0	0	0	0	0	0	0

"The safety endpoint is the occurrence of at least one treatment emergent severe adverse event of anxiety, depression, feeling abnormal, or hostility and/or the occurrence of at least one treatment emergent moderate or severe adverse event of: agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, suicidal behavior, or completed suicide. Only those events rated as severe are reported; this excludes any moderate events in the primary NPS AE endpoint." (NCT01456936)
Timeframe: Treatment emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Non-psychiatric History Cohort

Intervention	participants (Number)
	Anxiety	Depression	Feeling abnormal	Hostility	Agitation	Aggression	Delusions	Hallucinations	Mania	Panic	Paranoia	Psychosis	Homicidal ideation	Suicidal behavior	Suicidal ideation	Suicide
Bupropion 150 mg BID	4	4	1	0	1	1	0	1	1	1	0	1	0	1	0	0
NRT Patch	6	7	0	0	4	0	0	0	0	0	0	1	0	0	1	0
Placebo	2	6	0	0	2	1	0	0	0	1	0	0	0	1	0	0
Varenicline 1.0 mg BID	5	6	0	0	1	1	0	0	2	0	0	0	0	1	1	0

"The C-SSRS is a semi-structured interview designed to evaluate an individual's degree of suicidal ideation, preparatory acts or behavior to actual attempt, ranging from wish to be dead to active suicidal ideation with specific plan and intent. Answers at screening are for lifetime history. Answers for all other visits are since last visit.The scale is also used to record any completed suicides." (NCT01456936)
Timeframe: Lifetime, Baseline and Treatment-Emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Overall

Intervention	participants with positive responses (Number)
	Suicidal Behavior (Screening lifetime)	Suicidal Ideation (Screening lifetime)	Suicidal Behavior (Baseline)	Suicidal Ideation (Baseline)	Suicidal Behavior (treatment emergent 12 weeks)	Suicidal Ideation (treatment emergent 12 weeks)
Bupropion 150 mg BID	9	43	0	1	0	4
NRT Patch	7	50	0	0	1	3
Placebo	6	49	0	1	1	6
Varenicline 1.0 mg BID	6	48	0	0	0	7

"The C-SSRS is a semi-structured interview designed to evaluate an individual's degree of suicidal ideation, preparatory acts or behavior to actual attempt, ranging from wish to be dead to active suicidal ideation with specific plan and intent. Answers at screening are for lifetime history. Answers for all other visits are since last visit. The scale is also used to record any completed suicides." (NCT01456936)
Timeframe: Lifetime, Baseline and Treatment-Emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Positive Responses for Suicidal Behavior and/or Ideation by Columbia Suicide Severity Rating Scale (C-SSRS) - Psychiatric History Cohort

Intervention	participants with positive responses (Number)
	Suicidal Behavior (Screening lifetime)	Suicidal Ideation (Screening lifetime)	Suicidal Behavior (Baseline)	Suicidal Ideation (Baseline)	Suicidal Behavior (treatment emergent 12 weeks)	Suicidal Ideation (treatment emergent 12 weeks)
Bupropion 150 mg BID	152	400	0	6	1	19
NRT Patch	118	383	0	2	1	23
Placebo	129	398	1	4	3	31
Varenicline 1.0 mg BID	143	386	0	6	0	34

"The C-SSRS is a semi-structured interview designed to evaluate an individual's degree of suicidal ideation, preparatory acts or behavior to actual attempt, ranging from wish to be dead to active suicidal ideation with specific plan and intent. Answers at screening are for lifetime history. Answers for all other visits are since last visit. The scale is also used to record any completed suicides." (NCT01456936)
Timeframe: Lifetime, Baseline and Treatment-Emergent is first dose date to last dose date (up to 12 weeks) plus 30 days.

Article	Year
Craving and addictive potential of esketamine as side effects? Expert opinion on drug safety, 2022, Volume: 21, Issue:6 Topics: Adult; Bupropion; Craving; Depressive Disorder, Major; Drug-Related Side Effects and Adverse Reactio	2022
A comprehensive review and meta-analysis of neurological side effects related to second-generation antidepressants in individuals with major depressive disorder. Behavioural brain research, 2023, 06-05, Volume: 447 Topics: Antidepressive Agents; Antidepressive Agents, Second-Generation; Bupropion; Depressive Disorder, Maj	2023
Pharmacologic treatment of attention deficit hyperactivity disorder in adults: A systematic review and network meta-analysis. PloS one, 2020, Volume: 15, Issue:10 Topics: Adult; Amphetamine; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Bayes	2020
Tolerability and safety of the new anti-obesity medications. Drug safety, 2014, Volume: 37, Issue:9 Topics: Anti-Obesity Agents; Benzazepines; Benzoxazines; Bupropion; Chemistry, Pharmaceutical; Drug-Related	2014
Safety and tolerability of medications approved for chronic weight management. Obesity (Silver Spring, Md.), 2015, Volume: 23 Suppl 1 Topics: Anti-Obesity Agents; Benzazepines; Bupropion; Delayed-Action Preparations; Drug-Related Side Effects	2015
What do we know about the role of pharmacotherapy for smoking cessation before or during pregnancy? Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco, 2009, Volume: 11, Issue:11 Topics: Animals; Benzazepines; Bupropion; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Fem	2009

Article	Year
Frequently Reported Adverse Events With Smoking Cessation Medications: Post Hoc Analysis of a Randomized Trial. Mayo Clinic proceedings, 2021, Volume: 96, Issue:7 Topics: Adult; Bupropion; Drug Tapering; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Ma	2021
Pharmacogenomic study of side-effects for antidepressant treatment options in STARD. Psychological medicine, 2012, Volume: 42, Issue:6* Topics: Antidepressive Agents; Bupropion; Citalopram; Depressive Disorder, Major; Drug-Related Side Effects	2012

Article	Year
Assessment of the health effects of chemicals in humans: II. Construction of an adverse effects database for QSAR modeling. Current drug discovery technologies, 2004, Volume: 1, Issue:4 Topics: Adverse Drug Reaction Reporting Systems; Artificial Intelligence; Computers; Databases, Factual; Dru	2004
Prediction and identification of drug interactions with the human ATP-binding cassette transporter multidrug-resistance associated protein 2 (MRP2; ABCC2). Journal of medicinal chemistry, 2008, Jun-12, Volume: 51, Issue:11 Topics: Administration, Oral; Animals; Antineoplastic Agents; Antipsychotic Agents; Antiviral Agents; ATP Bi	2008
FDA-approved drug labeling for the study of drug-induced liver injury. Drug discovery today, 2011, Volume: 16, Issue:15-16 Topics: Animals; Benchmarking; Biomarkers, Pharmacological; Chemical and Drug Induced Liver Injury; Drug Des	2011
Translating clinical findings into knowledge in drug safety evaluation--drug induced liver injury prediction system (DILIps). PLoS computational biology, 2011, Volume: 7, Issue:12 Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Da	2011
Sex-Related Differences in the Pharmacological Treatment of Major Depression - Are Women and Men Treated Differently? Psychiatria Danubina, 2022,Summer, Volume: 34, Issue:2 Topics: Bupropion; Depression; Depressive Disorder, Major; Drug-Related Side Effects and Adverse Reactions;	2022
Intentional overdose of a novel dextromethorphan-bupropion combination antidepressant. The American journal of emergency medicine, 2023, Volume: 72 Topics: Antidepressive Agents; Antidepressive Agents, Second-Generation; Bupropion; Dextromethorphan; Drug O	2023
Drug interaction study between bupropion and ticlopidine in male CF-1 mice. Biological & pharmaceutical bulletin, 2011, Volume: 34, Issue:3 Topics: Animals; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Brain; Bupropion; Cytochrome P-450 CYP2B6;	2011
Adverse drug reaction update. Adverse drug reactions and toxicological reviews, 2002, Volume: 21, Issue:3 Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Bupropion; Chemical and Drug Induced Liver Injury;	2002

bupropion and Adverse Drug Event