Changes in healthcare resource use and costs associated with early versus delayed initiation of atypical antipsychotic adjunctive treatment in major depressive disorder

Figures & data

Figure 1. Study design.

Figure 2. Patient selection.

Table 1. Patient characteristics.

Baseline characteristics	AAP initiation in ≤1 year of first ADT use (Y1)	AAP initiation in >1–2 years of first ADT use (Y2)	AAP initiation in >2 years of first ADT use (Y3)	p value Y1 vs Y2	p value Y1 vs Y3
	(n = 506)	(n = 252)	(n = 622)
Age (years)
Mean (SD)	39.4 (16.6)	38.2 (15.1)	42.0 (14.2)	.341	.004
Median (Q1, Q3)	39 (22,54)	39 (22,51)	44 (31,53)	.351	.001
Gender, n (%)				.131	.001
Female	276 (54.55%)	152 (60.32%)	399 (64.15%)
Male	230 (45.45%)	100 (39.68%)	223 (35.85%)
Geographic region, n (%)				.007	.385
Northeast	122 (24.11%)	37 (14.68%)	124 (19.94%)
Midwest	141 (27.87%)	92 (36.51%)	184 (29.58%)
South	193 (38.14%)	103 (40.87%)	254 (40.84%)
West	50 (9.88%)	20 (7.94%)	60 (9.65%)
Payer type, n (%)				.076	.041
Commercial	257 (50.79%)	143 (56.75%)	319 (51.29%)
Self-insured	218 (43.08%)	102 (40.48%)	284 (45.66%)
Other	31 (6.13%)	7 (2.78%)	19 (3.05%)
Plan type, n (%)				.320	.827
HMO	47 (9.29%)	25 (9.92%)	52 (8.36%)
PPO	433 (85.57%)	220 (87.30%)	540 (86.82%)
Other	26 (5.14%)	7 (2.78%)	30 (4.82%)
Index AAP prescriber specialty, n (%)				.011	<.001
Psychiatrist	205 (40.51%)	80 (31.75%)	198 (31.83%)
Primary care physician	71 (14.03%)	54 (21.43%)	146 (23.47%)
Other/Unknown	230 (45.45%)	118 (46.83%)	278 (44.69%)
MDD severity, n (%)				.449	.130
Severe	126 (24.90%)	51 (20.24%)	115 (18.49%)
Moderate	88 (17.39%)	56 (22.22%)	119 (19.13%)
Mild	11 (2.17%)	6 (2.38%)	16 (2.57%)
Unspecified	270 (53.36%)	134 (53.17%)	360 (57.88%)
In remission	11 (2.17%)	5 (1.98%)	12 (1.93%)
Charlson Comorbidity Index
Mean (SD)	1.25 (2.01)	1.36 (2.03)	1.50 (2.07)	.487	.044
Median (Q1, Q3)	0 (0, 2)	1 (0, 2)	1 (0, 2)
Frequency, n (%)				.690	.020
0	266 (52.57%)	119 (47.22%)	266 (42.77%)
1	103 (20.36%)	57 (22.62%)	144 (23.15%)
2	49 (9.68%)	30 (11.90%)	80 (12.86%)
3	28 (5.53%)	14 (5.56%)	48 (7.72%)
4+	60 (11.96%)	32 (12.70%)	84 (13.50%)
Comorbidities, n (%)
CNS-related
Anxiety disorder	331 (65.42%)	171 (67.86%)	392 (63.02%)	.503	.405
Epilepsy	17 (3.36%)	9 (3.57%)	19 (3.05%)	.880	.772
Insomnia	113 (22.33%)	45 (17.86%)	123 (19.77%)	.153	.294
Obsessive-compulsive disorder	23 (4.55%)	12 (4.76%)	25 (4.02%)	.894	.663
Parkinson’s disease	2 (0.40%)	2 (0.79%)	2 (0.32%)	.604	1.000
Tourette’s syndrome	1 (0.20%)	0 (0.00%)	1 (0.16%)	1.000	1.000
Other
Asthma	41 (8.10%)	37 (14.68%)	51 (8.20%)	.005	.953
Cancer	42 (8.30%)	27 (10.71%)	64 (10.29%)	.276	.255
COPD	19 (3.75%)	11 (4.37%)	33 (5.31%)	.685	.217
Congestive heart failure	13 (2.57%)	8 (3.17%)	16 (2.57%)	.632	.997
Diabetes	47 (9.29%)	22 (8.73%)	70 (11.25%)	.801	.282
Hepatitis	3 (0.59%)	4 (1.59%)	6 (0.96%)	.229	.739
Hyperlipidemia	116 (22.92%)	50 (19.84%)	181 (29.10%)	.334	.019
Hypertension	130 (25.69%)	71 (28.17%)	198 (31.83%)	.466	.024
Liver disease	15 (2.96%)	4 (1.59%)	24 (3.86%)	.253	.414
Peripheral vascular disease	14 (2.77%)	2 (0.79%)	14 (2.25%)	.075	.580
Stroke	25 (4.94%)	15 (5.95%)	38 (6.11%)	.557	.395

Abbreviations. HMO, Health Maintenance Organization; POS, Point-of-Service; PPO, Preferred Provider Organization; CNS, Central Nervous System; COPD, Chronic Obstructive Pulmonary Disease.

Table 2. Treatment history.

	AAP initiation in ≤1 year of first ADT use (Y1)	AAP initiation in >1–2 years of first ADT use (Y2)	AAP initiation in >2 years of first ADT use (Y3)
	(n = 506)	(n = 252)	(n = 622)
Time (months) from first ADT to index date
Mean (SD)	3.9 (3.8)	17.5 (3.5)	38.6 (8.4)
Median (Q1, Q3)	2.5 (0.5, 7.0)	17.4 (14.2, 20.5)	38.6 (31.6, 45.3)
Number of different antidepressants used during pre-index period since ADT start date
Mean (SD)	1.9 (1.1)	2.8 (1.3)	3.2 (1.5)
Median (Q1, Q3)	2 (1, 2)	3 (2, 4)	3 (2, 4)
Classes of antidepressants used immediately prior to index adjunctive AAP, n (%)
Tricyclic/tetracyclic	31 (6.13%)	15 (5.95%)	35 (5.63%)
MAOI	1 (0.20%)	0 (0.00%)	2 (0.32%)
SSRI	304 (60.08%)	145 (57.54%)	315 (50.64%)
SNRI	88 (17.39%)	68 (26.98%)	171 (27.49%)
Atypical antidepressant	124 (24.51%)	53 (21.03%)	179 (28.78%)
Other antidepressant	1 (0.20%)	0 (0.00%)	0 (0.00%)

Abbreviations. MAOI, Monoamine Oxidase Inhibitor; SSRI, Selective Serotonin Reuptake Inhibitor; SNRI, Serotonin-Norepinephrine Reuptake Inhibitor.

Figure 3. Unadjusted pre–post differences in healthcare resource utilization. *indicates a post–pre difference that was statistically significantly different from zero (p-value <.05). †indicates a post–pre difference that was statistically significantly different from that of cohort Y1 (p-value <.05).

Table 3. Unadjusted utilization of healthcare resources.

	AAP initiation in ≤1 year of first ADT use (Y1) (n = 506)				AAP initiation in >1–2 years of first ADT use (Y2) (n = 252)					AAP initiation in >2 years of first ADT use (Y3) (n = 622)
	Pre-index	Post-index	Pre–post difference		Pre-index	Post-index	Pre–post difference		p-value vs Y1†	Pre-index	Post-index	Pre–post difference		p value vs Y1†
			Post–pre	p-value*			Post–pre	p-value*				Post–pre	p value*
All-cause
Hospitalization
Patients with ≥1 hospitalization, n (%)	180 (35.57%)	91 (17.98%)	−89 (−17.59%)	<.001	72 (28.57%)	47 (18.65%)	−25 (−9.92%)	.009	.171	130 (20.90%)	76 (12.22%)	−54 (−8.68%)	<.001	<.001
Length of stay per hospitalization (days)
Mean (SD)	8.3 (8.2)	6.2 (5.0)	−2.1	.027	9.4 (18.1)	5.3 (4.1)	−4.2	.126		5.9 (4.6)	5.2 (3.7)	−0.7	.253
Median (Q1, Q3)	6 (4, 9)	5 (3, 8)		.012	5 (3, 8)	4 (3, 6)		.033		5 (3, 7)	4 (3, 6)		.265
Number of hospitalizations per patient
Mean (SD)	0.61 (1.30)	0.31 (0.89)	−0.30 (1.21)	<.001	0.44 (0.86)	0.29 (0.85)	−0.14 (1.05)	.060	.079	0.32 (0.82)	0.21 (0.86)	−0.11 (1.00)	.018	.005
Median (Q1, Q3)	0 (0, 1)	0 (0, 0)	0 (−1, 0)		0 (0, 1)	0 (0, 0)	0 (0, 0)			0 (0, 0)	0 (0, 0)	0 (0, 0)
Outpatient services
ED visits
Patients with ≥1 ED visit, n (%)	233 (46.05%)	153 (30.24%)	−80 (−15.81%)	<.001	101 (40.08%)	77 (30.56%)	−24 (−9.52%)	.025	.414	225 (36.17%)	184 (29.58%)	−41 (−6.59%)	.013	.007
Number of ED visits per patient
Mean (SD)	0.84 (1.24)	0.60 (1.39)	−0.24 (1.58)	.004	0.77 (11.36)	0.57 (1.21)	−0.20 (1.65)	.084	.730	0.83 (2.05)	0.63 (1.63)	−0.20 (1.76)	.060	.667
Median (Q1, Q3)	0 (0, 1)	0 (0, 1)	0 (−1, 0)		0 (0, 1)	0 (0, 1)	0 (−1, 0)			0 (0, 1)	0 (0,1)	0 (−1, 0)
Physician office visits
Patients with ≥1 office visit, n (%)	496 (98.02%)	503 (99.41%)	7 (1.38%)	.051	251 (99.60%)	251 (99.60%)	0 (0.00%)		.250	616 (99.04%)	618 (99.36%)	2 (0.32%)	.525	.240
Number of office visits per patient
Mean (SD)	18.97 (18.26)	27.09 (22.96)	8.12 (21.22)	<.001	22.85 (21.80)	24.58 (23.48)	1.73 (21.55)	.391	<.001	21.14 (20.13)	23.62 (22.91)	2.49 (20.50)	.042	<.001
Median (Q1, Q3)	13 (6, 25)	20 (10, 37)	4 (−3, 16)	<.001	15 (8, 31)	17 (9, 32)	1 (−7, 9)	.446	<.001	15 (7, 28)	17 (9, 30)	2 (−5, 8)	.008	<.001
Pharmacy fills
Patients with ≥1 pharmacy fill, n (%)	493 (97.43%)	506 (100.00%)	13 (2.57%)	<.001	250 (99.21%)	252 (100.00%)	2 (0.79%)	.499	.163	618 (99.36%)	622 (100.00%)	4 (0.64%)	.124	.008
Number of pharmacy fills per patient
Mean (SD)	22.11 (20.98)	45.93 (32.86)	23.82 (29.35)	<.001	40.10 (31.02)	50.83 (37.51)	10.73 (25.55)	<.001	<.001	41.5 (32.59)	53.32 (35.70)	11.48 (22.42)	<.001	<.001
Median (Q1, Q3)	16 (7, 31)	39 (23, 57)	18 (6, 32)	<.001	31 (19, 56)	43 (27, 61)	8 (−2, 21)	<.001	<.001	33 (19, 54)	44 (28, 68)	10 (0, 21)	<.001	<.001
MDD-related
Hospitalization
Patients with ≥1 hospitalization, n (%)	142 (28.06%)	59 (11.66%)	−83 (−16.40%)	<.001	53 (21.03%)	34 (13.49%)	−19 (−7.54%)	.025	.066	87 (13.99%)	45 (7.23%)	−42 (−6.75%)	<.001	<.001
Length of stay per hospitalization (days)
Mean (SD)	6.8 (6.2)	5.3 (3.6)	−1.5	.073	7.5 (7.1)	5.3 (3.6)	−2.2	.101		6.7 (4.4)	5.1 (3.1)	−1.6	.029
Median (Q1, Q3)	6 (3, 8)	5 (2, 7)		.094	6 (3, 8)	4 (3, 7)		.269		5 (4, 8)	4 (3, 7)		.032
Number of hospitalizations per patient
Mean (SD)	0.4 (0.7)	0.16 (0.52)	−0.21 (0.79)	<.001	0.3 (0.6)	0.17 (0.48)	−0.10 (0.71)	.038	.061	0.19 (0.57)	0.10 (0.42)	−0.09 (0.66)	.002	.005
Median (Q1, Q3)	0 (0, 1)	0 (0, 0)	0 (0, 0)		0 (0, 0)	0 (0, 0)	0 (0, 0)			0 (0, 0)	0 (0, 0)	0 (0, 0)
Outpatient services
ED visits
Patients with ≥1 ED visits, n (%)	77 (15.22%)	37 (7.31%)	−40 (−7.91%)	<.001	37 (14.68%)	21 (8.33%)	−16 (−6.35%)	.026	.890	63 (10.13%)	46 (7.40%)	−17 (−2.73%)	.088	.047
Number of ED visits per patient
Mean (SD)	0.2 (0.4)	0.11 (0.51)	−0.07 (0.65)	.031	0.2 (0.6)	0.11 (0.39)	−0.11 (0.64)	.015	.359	0.13 (0.50)	0.1 (0.65)	−0.01 (0.66)	.694	.184
Median (Q1, Q3)	0 (0, 0)	0 (0, 0)	0 (0, 0)		0 (0, 0)	0 (0, 0)	0 (0, 0)			0 (0, 0)	0 (0, 0)	0 (0, 0)
Physician office visits
Patients with ≥1 office visits, n (%)	395 (78.06%)	437 (86.36%)	42 (8.30%)	<.001	209 (82.94%)	208 (82.54%)	−1 (−0.40%)	.906	.061	477 (76.69%)	518 (83.28%)	41 (6.59%)	.004	.718
Number of office visits per patient
Mean (SD)	5.6 (9.0)	11.5 (14.8)	5.88 (13.11)	<.001	6.5 (8.9)	10.0 (13.8)	3.54 (11.59)	<.001	.016	6.1 (10.1)	8.5 (13.7)	2.37 (13.72)	<.001	<.001
Median (Q1, Q3)	3 (1, 6)	6 (2, 14)	3 (−1, 8)	<.001	3 (1, 8)	5 (2, 13)	1 (−1, 5)	.007	.001	2 (1, 7)	4 (1, 10)	1 (−1, 4)	<.001	<.001

* Paired t-test (mean) and non-parametric Wilcoxon signed-rank test (median) were used to compare pre- vs post-index measures. p-values <.05 were considered significant and shown in italics.

† Pre–post differences of cohorts Y2 and Y3 cohorts were compared to those of cohort Y1 using paired t-test for means, non-parametric Wilcoxon signed-rank test for medians, Chi-square test for categorical variables, or Fisher’s exact test for small cell values. p-values <.05 were considered significant and are shown in italics.

Figure 4. Unadjusted pre–post differences in healthcare costs. *indicates a post–pre difference that was statistically significantly different from zero (p-value <.05). †indicates a post–pre difference that was statistically significantly different from that of cohort Y1 (p-value <.05).

Table 4. Unadjusted costs of healthcare services.

	All-cause					MDD-related
	Pre-index	Post-index	Pre–post difference		p-value vs Y1†	Pre-index	Post-index	Pre–post difference		p-value vs Y1†
			Post–pre	p-value*				Post–pre	p-value*
AAP initiation in ≤1 year of first ADT use (Y1), n = 506
Total
Mean (SD)	$27,518 (89,637)	$21,412 (40,818)	−$6,107	.163		$5,714 (13,590)	$7,669 (11,934)	$1,955 (15,849)	.015
Median (Q1, Q3)	$7,861 ($3,286, $60,674)	$10,361 ($5,872, $20,323)	$2,027 (−$5,281, $8,849)	<.001		$1,140 ($304, $5,550	$4,575 ($1,789, $8,865)	$2,052 (−$707, $5,938)	<.001
Pharmacy
Mean (SD)	$1,855 (10,967)	$6,244 (15,170)	$4,389 (8,140)	<.001		$507 (5,249)	$3,707 (7,048)	$3,199 (3,466)	<.001
Median (Q1, Q3)	$452 ($138, $1,307)	$3,787 ($1,387, $6,804)	$2,770 (−$578, $5,605)	<.001		$60 ($16, $185)	$2,606 ($448, $5,151)	$2,413 ($314, $4,920)	<.001
Medical
Mean (SD)	$25,663 (89,013)	$15,168 (37,110)	−$10,496 (85,022)	.015		$5,206 (12,635)	$3,962 (9,596)	−$1,244 (15,269)	.078
Median (Q1, Q3)	$6,503 ($2,461, $18,284)	$5,590 ($2,191, $12,312)	−$458 (−$7,417, $2,900)	.032		$775 ($195, $5,358)	$865 ($268, $2,894)	$0 (−$2,095, $940)	.623
Hospitalization
Mean (SD)	$17,873 (87,548)	$3,928 (14,405)	−$13,945 (83,731)	<.001		$3,844 (12,056)	$1,524 (6,964)	−$2,320 (13,726)	<.001
Median (Q1, Q3)	$0 ($0, $7,083)	$0 ($0, $0)	$0 (−$5,443, $0)			$0 ($0, $2,311)	$0 ($0, $0)	$0 (−$101, $0)
ED visits
Mean (SD)	$863 (1,963)	$541 (1,539)	−$322 (2,188)	.004		$154 (520)	$90 (472)	−$64 (679)	.041
Median (Q1, Q3)	$0 ($0, $904)	$0 ($0, $375)	$0 (−$561, $0)			$0 ($0, $0)	$0 ($0, $0)	$0 ($0, $0)
Physician office visits
Mean (SD)	$2,424 (3,131)	$3,380 (3,748)	$956 (3,655)	<.001		$820 (1,762)	$1,525 (2,523)	$705 (2,477)	<.001
Median (Q1, Q3)	$1,347 ($631, $2,905)	$2,167 ($953, $4,490)	$378 (−$390, $1,645)	<.001		$272 ($53, $741)	$570 ($18, $1,668)	$188 (−$81, $919)	<.001
AAP initiation in >1–2 years of first ADT use (Y2), n = 252
Total
Mean (SD)	$24,760 (59,341)	$26,380 (51,021)	$1,620 (45,996)	.743	.181	$5,436 (10,940)	$9,030 (13,948)	$3,594 (14,256)	<.001	.166
Median (Q1, Q3)	$9,034 ($4,013, $19,784)	$11,212 ($6,226, $22,710)	$2,084 (−$5,090, $8,445)	.013	.927	$1,535 ($466, $4,864)	$5,407 ($1,866, $9,734)	$2,272 (−$321, $6,574)	<.001	.298
Pharmacy
Mean (SD)	$4,292 (16,156)	$8,386 (18,013)	$4,094 (9,747)	.008	.661	$657 (1,141)	$4,434 (5,004)	$3,778 (4,754)	<.001	.057
Median (Q1, Q3)	$1,202 ($349, $3,476)	$4,862 ($2,161, $8,928)	$3,125 ($265, $6,261)	<.001	.728	$213 ($107, $586)	$3,391 ($628, $5,989)	$2,667 ($235, $5,243)	<.001	.582
Medical
Mean (SD)	$20,468 (53,985)	$17,994 (43,527)	−$2,474 (45,934)	.572	.162	$4,779 (10,901)	$4,596 (12,341)	−$183 (13,237)	.860	.347
Median (Q1, Q3)	$5,822 ($2,280, $16,331)	$4,544 ($1,950, $13,677)	−$769 (−$6,859, $2,335)	.090	.989	$777 ($165, $3,350)	$812 ($210, $2,790)	$0 (−$879, $821)	.950	.620
Hospitalization
Mean (SD)	$8,927 (40,009)	$5,029 (18,067)	−$3,898 (43,245)	.159	.074	$2,996 (9,696)	$2,470 (10,730)	−$526 (12,629)	.564	.082
Median (Q1, Q3)	$0 ($0, $2,804)	$0 ($0, $0)	$0 ($0, $0)			$0 ($0, $0)	$0 ($0, $0)	$0 ($0, $0)
ED visits
Mean (SD)	$641 (1,372)	$539 (1,801)	−$102 (2,086)	.473	.186	$216 (763)	$172 (1,078)	−$44 (1,276)	.598	.777
Median (Q1, Q3)	$0 ($0, $573)	$0 ($0, $330)	$0 (−$363, $0)		.398	$0 ($0, $0)	$0 ($0, $0)	$0 ($0, $0)
Physician office visits
Mean (SD)	$2,831 (3,392)	$3,209 (5,223)	$378 (5,540)	.336	.087	$928 (1,784)	$1,259 (2,035)	$331 (1,993)	.053	.037
Median (Q1, Q3)	$1,728 ($858, $3,515)	$1,803 ($880, $3,437)	−$15 (−$879, $756)	.897	<.001	$340 ($95, $1,044)	$509 ($139, $1,496)	$47 (−$186, $561)	.036	.003
AAP initiation in >2 years of first ADT use (Y3), n = 622
Total
Mean (SD)	$17,966 (48,270)	$21,664 (47,142)	$3,698 (31,453)	.172	.008	$3,735 (7,442)	$7,549 (9,881)	$3,813 (11,713)	<.001	.024
Median (Q1, Q3)	$8,319 ($3,314, $17,150)	$12,341 ($7,030, $22,298)	$3,779 (−$1,547, $9,290)	<.001	.003	$1,284 ($438, $3,452)	$5,288 ($2,532, $9,571)	$3,048 ($466, $6,664)	<.001	.001
Pharmacy
Mean (SD)	$3,771 (13,299)	$7,941 (16,643)	$4,170 (6,010)	<.001	.605	$745 (1,159)	$4,425 (3,883)	$3,680 (3,716)	<.001	.026
Median (Q1, Q3)	$1,322 ($438, $3,411)	$5,370 ($2,383, $9,122)	$3,250 ($590, $6,786)	<.001	.274	$283 ($101, $847)	$3,616 ($1,067, $6,790)	$2,968 ($460, $5,892)	<.001	.044
Medical
Mean (SD)	$14,195 (38,349)	$13,723 (35,897)	−$472 (31,334)	.823	.007	$2,990 (7,394)	$3,124 (8,917)	$134 (11,026)	.774	.079
Median (Q1, Q3)	$5,348 ($1,863, $13,495)	$5,083 ($2,019, $12,957)	−$32 (−$4,868, $3,909)	.808	.023	$425 ($109, $2,102)	$673 ($146, $2,330)	$27 (−$553, $736)	.041	.072
Hospitalization
Mean (SD)	$4,805 (20,305)	$3,935 (23,503)	−$870 (26,634)	.485	.003	$1,724 (6,559)	$1,237 (6,913)	−$487 (9,207)	.203	.008
Median (Q1, Q3)	$0 ($0, $0)	$0 ($0, $0)	$0 ($0, $0)			$0 ($0, $0)	$0 ($0, $0)	$0 ($0, $0)
ED visits
Mean (SD)	$783 (2,441)	$672 (2,392)	−$112 (2,453)	.415	.133	$98 (463)	$97 (556)	−$1 (651)	.983	.111
Median (Q1, Q3)	$0 ($0, $661)	$0 ($0, $400)	$0 (−$271, $0)		.022	$0 ($0, $0)	$0 ($0, $0)	$0 ($0, $0)
Physician office visits
Mean (SD)	$3,212 (15,077)	$3,388 (7,849)	$176 (11,063)	.796	.129	$792 (1,622)	$1,233 (3,008)	$440 (3,084)	.001	.118
Median (Q1, Q3)	$1,660 ($754, $3,169)	$1,844 ($896, $3,455)	$185 (−$622, $1,115)	.018	.001	$271 ($40, $750)	$425 ($118, $1,204)	$92 (−$112, $479)	<.001	.007

* Paired t-test (mean) and nonparametric Wilcoxon signed-rank test (median) were used to compare pre- vs post-index measures. p-values <.05 were considered significant and are shown in italics.

† Pre–post differences of cohorts Y2 and Y3 were compared to those of cohort Y1 using paired t-test for means, non-parametric Wilcoxon signed-rank test for medians, Chi-square test for categorical variables, or Fisher’s exact test for small cell values. p-values <.05 were considered significant and are shown in italics.