SUPPLEMENTARY MATERIAL Supplementary Table 1. Antidepressant adequate dosage as defined in the Massachusetts General Hospital Antidepressant Treatment Questionnaire

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SUPPLEMENTARY MATERIAL

Supplementary Table 1. Antidepressant adequate dosage as defined in the Massachusetts General Hospital Antidepressant Treatment Questionnaire

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Category GPI Category Generic Name

Minimum Therapeutic

Dosage (Ages 18-64)

Minimum Therapeutic

Dosage (Age 65+)

SSRI Selective Serotonin Reuptake Inhibitors

Citalopram 20 mg/day 10 mg/day Escitalopram 10 mg/day 5 mg/day Fluvoxamine 50 mg/day 25 mg/day

Fluoxetine (including combination with

olanzapine)

20 mg/day 10 mg/day

Paroxetine 20 - 25 mg/day

10 - 12.5 mg/day Sertraline 50 mg/day 25 mg/day SNRI Serotonin-Norepinephrine

Reuptake Inhibitors

Desvenlafaxine 50 mg/day 50 mg/day Duloxetine 60 mg/day 30 mg/day Levomilnacipran 40 mg/day 20 mg/day Venlafaxine 150 mg/day 75 mg/day Serotonin Modulators Serotonin Modulators

Trazodone 300 mg/day 200 mg/day Vilazodone 40 mg/day 30 mg/day Vortioxetine 10 mg/day 5 mg/day

Nefazodone 300 mg/day² 300 mg/day Norepinephrine-

Serotonin Modulator

Alpha-2 Receptor

Antagonists (Tetracyclics) Mirtazapine 15 mg/day 7.5 mg/day

Tricyclic and tetracyclic antidepressants

Tricyclic Agents

Amitriptyline 150 mg/day 100 mg/day Amoxapine 150 mg/day 100 mg/day Clomipramine 150 mg/day 100 mg/day

Doxepin 150 mg/day 100 mg/day

Desipramine 150 mg/day 100 mg/day Imipramine 150 mg/day 100 mg/day Maprotiline 150 mg/day 100 mg/day Nortriptyline 75 mg/day 50 mg/day Protriptyline 30 mg/day 20 mg/day Trimipramine 150 mg/day 100 mg/day

MAOI Monoamine oxidase

inhibitors

Isocarboxazid 30 mg/day 20 mg/day Phenelzine 45 mg/day 30 mg/day

Selegiline 6 mg/24-hr patch

6 mg/24-hr patch Tranylcypromine 30 mg/day 20 mg/day

NDRI Norepinephrine Dopamine

Reuptake Inhibitor Bupropion 300 mg/day 150 mg/day

GPI, generic product identifier; MAOI, monoamine oxidase inhibitor; NDRI, norepinephrine dopamine reuptake inhibitor; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

Notes:

1. Massachusetts General Hosptial (MGH) Antidepressant Treatment Response Questionnaire (ATRQ), Geriatric Population, version 3. 2016.

2. Massachusetts General Hosptial (MGH) Antidepressant Treatment Response Questionnaire (ATRQ), Non-Geriatric Population, version 2. 2015.

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Supplementary Table 2. Non-antidepressant augmentation medications (FDA approved, and other options commonly considered for MDD) used for identification of TRD

Category Generic Name

Atypical APs Aripiprazole

Brexpiprazole

Olanzapine (in combination with fluoxetine only)

Quetiapine

Anticonvulsants Carbamazepine

Divalproex Lamotrigine

Valproate Non-benzodiazepine GABA-receptor modulators Buspirone

Amphetamine-related psychostimulants

Amphetamine Dexmethylphenidate Dextroamphetamine Lisdexamfetamine

Methylphenidate Methamphetamine Amphetamine Mixtures - (with

dextromethorphan)

Modafinil-related psychostimulants Armodafinil

Modafinil Thyroid hormones

Levothyroxine Liothyronine

Liotrix (triiodothyronine and tetraiodothyronine)

Lithium Lithium

AP, antipsychotic; FDA, US Food and Drug Administration; MDD, major depressive disorder; TRD, treatment-resistant depression.

Supplementary Figure 1. Likelihood of having any pre-existing condition relevant for AEs associated with specific non-antidepressant augmentation medications among patients with TRD newly initiating non-antidepressant augmentation medications at TRD onset vs. the non-TRD MDD cohort

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Prevalence n (%) ≥1 pre-existing condition for AEs with: TRD

Non-TRD MDD

Thyroid hormones 68.4 40.3

Atypical antipsychotics 66.3 56.3

Modafinil-related psychostimulants 61.9 35.9

Non-benzodiazepine GABA-receptor modulators

49.6 43.0

Amphetamine-related psychostimulants 41.0 39.3

Anticonvulsants 20.8 17.3

Higher likelihood in TRD vs. non-TRD MDD cohort

OR = 1

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Abbreviations: AE, adverse event; CI, confidence interval; FDA, US Food and Drug Administration;

MDD, major depressive disorder; MDE, major depressive episode; OR, odds ratio; TRD, treatment- resistant depression.

* Significant at the 5% level Notes:

1. Pre-existing conditions were identified based on the “Warnings and Precautions” and “Adverse Reactions” sections of the FDA Prescribing Information for each medication included in each class of non-antidepressant augmentation medications.

2. For the TRD cohort, the index date was defined as the date of TRD onset during the first MDE. TRD onset was defined as the initiation of a new antidepressant treatment course (either a claim for a new antidepressant of adequate dose or a claim for a new non-antidepressant augmentation medication with ≥1 day of overlap with an antidepressant of adequate dose) after absence of a response to two antidepressant treatment courses of adequate dose and duration.

3. ORs, 95% CIs, and p-values were calculated with univariate generalized estimating equations using logistic regression to account for the matched pairs.

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Supplementary Figure 2. Likelihood of specific pre-existing conditions relevant for AEs associated with atypical APs among patients with TRD newly initiating atypical APs at TRD onset vs. the non-TRD MDD cohort

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Prevalence n (%) TRD

Non-TRD MDD

Cardiovascular 26.9 26.5

Obesity/weight gain 22.8 21.4

Hyperlipidemia/dyslipidemia 18.8 20.0

Insomnia 17.2 8.1

Hypothyroidism 12.5 9.3

Suicidal behavior/ideation 12.2 3.3

Extrapyramidal symptoms 2.5 1.6

Sedation/somnolence 1.6 1.7

Tremor 1.6 0.8

Abbreviations: AE, adverse event; AP, antipsychotic; CI, confidence interval; MDD, major depressive disorder; MDE, major depressive episode; OR, odds ratio; TRD, treatment-resistant depression.

Higher likelihood in TRD vs. non-TRD MDD

cohort

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1. Pre-existing conditions were identified based on the “Warnings and Precautions” and “Adverse Reactions” sections of the FDA Prescribing Information for each medication included in each class of non-antidepressant augmentation medications.

Appendix Figure 3. Likelihood of potential severe or moderate DDIs among patients with TRD newly initiating non-antidepressant augmentation medications at TRD onset vs. the non-TRD MDD cohort

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Number of dispensed medications with

potential for DDIs

Prevalence n (%)

TRD

Non-TRD

MDD OR (95% CI)³ P-value³

Atypical antipsychotics

≥1 100.0 98.1 -- --

≥2 97.8 56.8 36.18 (17.03, 76.86) <0.001*

≥3 80.9 31.8 9.82 (7.33, 13.16) <0.001*

Amphetamine-related psychostimulants

≥1 100.00 100.00 -- --

≥2 90.2 58.7 7.83 (4.27, 14.37) <0.001*

≥3 55.7 30.2 3.52 (2.41, 5.14) <0.001*

Thyroid hormones

≥1 100.0 44.1 -- --

≥2 68.4 12.9 15.22 (9.58, 24.19) <0.001*

≥3 27.4 3.4 10.44 (6.24, 17.46) <0.001*

Anticonvulsants

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≥1 100.0 57.6 -- --

≥2 57.5 9.4 19.48 (11.80, 32.16) <0.001*

≥3 12.3 0.7 16.66 (7.91, 35.07) <0.001*

Modafinil-related psychostimulants

≥1 100.0 63.9 -- --

≥2 47.6 23.6 3.04 (1.26, 7.34) 0.013*

≥3 14.3 6.6 2.22 (0.64, 7.71) 0.208

Non-benzodiazepine GABA-receptor modulators

≥1 95.5 90.9 2.10 (1.16, 3.80) 0.014 *

≥2 62.7 38.5 2.79 (2.15, 3.62) <0.001 *

≥3 34.0 16.2 2.81 (2.13, 3.70) <0.001 *

CI, confidence interval; DDI, drug-drug interaction; MDD, major depressive disorder; MDE, major depressive episode; OR, odds ratio; TRD, treatment-resistant depression.

1. The number of dispensed medications with potential for DDIs for each class of non-antidepressant augmentation medications were identified during a 90-day window before and after index date or among prescriptions with days of supply that overlap the index date.

Higher likelihood in TRD vs. non-

TRD MDD cohort

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