Comparative effectiveness of switching paroxetine formulation for treatment of major depressive disorder: an open-label multicenter study

Figures & data

Figure 1 Study flow diagram.

Notes: The study flow diagram shows the patient distribution in this study. A total of 350 patients agreed to switch the medication from IR to CR. Of these, 205 patients were enrolled. During the study period, 22 patients changed the dose, one prematurely dropped out because of the onset of adverse events, and three quit without clear reasons. A total of 179 patients completed the 8-week study with stable doses of CR paroxetine. However, 66 patients were excluded from the analysis because of poor adherence (<80% of the theoretical total dosage).
Abbreviations: IR, immediate release; CR, controlled release.

Table 1 Baseline characteristics

Characteristics	n=113
Gender, female, n (%)	57 (50.4)
Age, mean ± SD (years)	41.2±11.52
Disease duration, mean ± SD (years)	5.52±4.09
Diagnosis, n (%)
MDD	77 (68.1)
MDD with SAD	22 (19.5)
MDD with PD	9 (8.0)
MDD with OCD	2 (1.8)
MDD with other comorbidities	3 (2.7)
CR paroxetine initial dose, n (%)
12.5 mg	31 (27.4)
25 mg	37 (32.7)
37.5 mg	15 (13.3)
50 mg	30 (26.5)
BZD dose,a mean ± SD (mg/day)	10.24±10.5

Note:

a Diazepam equivalent dosage.

Abbreviations: SD, standard deviation; MDD, major depressive disorder; SAD, social anxiety disorder; PD, panic disorder; OCD, obsessive–compulsive disorder; CR, controlled release; BZD, benzodiazepine.

Table 2 Changes in depression/anxiety scores (n=113)

Scale items	Baseline	Week 8	P-value
HSDS score, mean ± SD
Total score	12.22±8.16	10.22±7.24	<0.001**
1. Sleep disturbance	2.11±2.40	1.65±2.19	0.0151*
2. Appetite	0.65±1.12	0.48±0.98@	0.161
3. Anxiety	1.98±1.70	1.70±1.61	0.052
4. Fatigue	1.36±0.94	1.22±0.90	0.095
5. Hyposexuality	1.30±0.99	1.05±0.96	<0.001**
6. Somatic disorder	1.10±0.91	1.00±0.88	0.153
7. Depression	0.71±0.73@	0.63±0.73	0.183
8. Disinclination	1.27±0.90	1.09±0.87	0.008**
9. Diminished ability to think	0.85±0.83	0.73±0.74	0.058
10. Lower satisfaction	0.87±0.88@	0.68±0.77	0.002**
HSAS score, mean ± SD
Total score	12.72±9.53	11.18±8.86	<0.001**
1. Cardiovascular	1.51±1.79	1.29±1.62	0.093
2. Respiratory	1.86±1.94	1.68±1.86	0.175
3. Autonomic nerve	2.71±2.13	2.42±1.92	0.043*
4. Gastrointestinal	1.13±1.00@	1.11±1.00	0.731
5. Distress	1.27±1.00‡	1.11±0.98	0.016*
6. Awful feeling	0.66±0.93	0.55±0.91	0.074
7. Anticipatory anxiety	1.01±1.01	0.82±0.90	0.006**
8. Sleeping	1.10±1.09	0.88±1.01	0.015*
9. Depersonalization	0.50±0.86	0.42±0.79	0.103
10. Anxiousness	1.00±0.97	0.92±1.01@	0.304

Notes: Evaluations were conducted at baseline, week 4, and week 8. Primary comparisons were made between baseline and week 8 scores. Data from week 4 were not included in the final analyses.

@ n=112. Paired t-test was used for the subitem scores (week 8 vs baseline), and ANOVA for HSDS/HSAS total scores at baseline, week 4, and week 8. HSDS scores: 0–9, no depression; 10–15, mild depression; 16–20, moderate depression; 21–30, moderately severe depression; and ≥31, severe depression. HSAS scores: 0–7, no anxiety; 8–15, mild anxiety; 16–20, moderate anxiety; 21–30, moderately severe anxiety; and ≥31, severe anxiety.

‡ n=111.

* Statistically significant at α=0.05.

** Statistically significant at α=0.01.

Abbreviations: HSDS, Himorogi Self-Rating Depression Scale; SD, standard deviation; HSAS, Himorogi Self-Rating Anxiety Scale; ANOVA, analysis of variance.

Figure 2 Clinical Global Impression – Severity in a dot-plot graph at baseline and at week 8.

Notes: [img] indicate the patients and [img] P indicate median values at baseline and week 8, respectively. The vertical axis shows the severity of patient symptoms. There was a significant improvement by week 8 (P<0.001; chi-square test), as shown by the change in medians from “mildly ill” for the immediate-release formulation to “borderline mentally ill” for the controlled-release formulation.

Figure 3 Satisfaction with paroxetine at baseline and week 8 in a dot-plot graph.

Notes: The results are in response to the question “To what extent are you satisfied with your current medication”? [img] indicate each patient and [img] indicate median values at baseline and week 8, respectively. The vertical axis shows the degree of satisfaction. No patients were assessed as “very dissatisfied” after the change in treatment. There was a significant improvement by week 8 (P<0.001; chi-square test) as determined by the change in medians from “slightly satisfied” to “moderately satisfied”.

Figure 4 Preference for paroxetine at baseline and week 8 in a dot-plot graph. Notes: The data are in response to the question “Do you prefer the current medication to the previous one”? [img] indicate each patient and [img]n indicate median values at baseline and week 8, respectively. The vertical axis shows the degree of patient satisfaction. No patients were assessed as “much worse” after the treatment change. There was a significant improvement by week 8 (P<0.001; chi-square test) as determined by the change in medians from “slightly better” to “moderately better”.

Table S1 Shift of HSDS scores from week 0 to week 8 in PPS (n=113)

Scores	HSDS (0W)
	0–9	10–15	16–20	21–30	≥31	Total
HSDS (8W)
0–9	47	9	2	0	1	59
10–15	4	12	9	2	1	28
16–20	1	1	10	3	0	15
21–30	0	0	1	9	0	10
≥31	0	0	0	1	0	1
Total	52	22	22	15	2	113

Notes: HSDS scores: 0–9, no depression; 10–15, mild depression; 16–20, moderate depression; 21–30, moderately severe depression; and ≥31, severe depression.

Abbreviations: HSDS, Himorogi Self-Rating Depression Scale; PPS, per-protocol set.

Table S2 Baseline characteristics

Characteristics	PPS, n=113	ITT, n=205	P-value
Gender, n (%)
Female	57 (50.4)	110 (53.7)	0.639@
Age, mean ± SD (years)	41.2±11.52	41.4±11.28	0.898‡
Diagnosis, n (%)
MDD	77 (68.1)	146 (71.2)	0.983¶
MDD with SAD	22 (19.5)	35 (17.1)
MDD with PD	9 (8.0)	16 (7.8)
MDD with OCD	2 (1.8)	3 (1.5)
MDD with other comorbidities	3 (2.7)	5 (2.4)
CR paroxetine initial dose, n (%)
12.5 mg	31 (27.4)	67 (32.7)	0.365§
25 mg	37 (32.7)	63 (30.7)
37.5 mg	15 (13.3)	27 (13.2)
50 mg	30 (26.5)	48 (23.4)

@ Notes: Fisher’s exact test.

‡ Student’s t-test.

¶ Chi-square test.

§ Mann–Whitney U test.

Abbreviations: PPS, per-protocol set; ITT, intention to treat; SD, standard deviation; MDD, major depressive disorder; SAD, social anxiety disorder; PD, panic disorder; OCD, obsessive–compulsive disorder; CR, controlled release.

Table S3 Baseline characteristics

Characteristics	PPS, n=113	ITT, n=205	P-value
CGI-S, n (%)
Normal	8 (7.1)	17 (8.3)	0.282§
Borderline medically ill	30 (26.5)	39 (19.0)
Mildly ill	52 (46.0)	91 (44.4)
Moderately ill	20 (17.7)	45 (22.0)
Markedly ill	3 (2.7)	6 (2.9)
Severely ill	0 (0.0)	0 (0.0)
Unknown	0 (0.0)	7 (3.4)
Satisfaction and preference for paroxetine (SSMQ), n (%)
Dissatisfied	4 (3.5)	9 (4.4)	0.801§
Slightly dissatisfied	26 (23.1)	40 (19.5)
Neutral	23 (20.4)	46 (22.3)
Slightly satisfied	25 (22.1)	44 (21.5)
Satisfied	30 (26.5)	42 (20.5)
Very satisfied	5 (4.4)	12 (5.9)
Unknown	0 (0.0)	12 (5.9)
Patient preference for CR paroxetine (MPQ), n (%)
Much better	6 (5.3)	14 (6.8)	0.737§
Moderately better	32 (28.3)	48 (23.4)
Slightly better	19 (16.8)	32 (15.6)
Similar	29 (25.7)	52 (25.4)
Slightly worse	22 (19.5)	36 (17.6)
Worse	5 (4.4)	13 (6.3)
Unknown	0 (0.0)	10 (4.9)

§ Note: Mann–Whitney U test.

Abbreviations: PPS, per-protocol set; ITT, intention to treat; CGI-S, Clinical Global Impression – Severity; SSMQ, Satisfaction with Study Medication Question; CR, controlled release; MPQ, Medication Preference Question.

Table S4 Depression/anxiety scores at baseline

Characteristics	PPS, n=113	ITT,@ n=201	P-value
HSDS score (week 0), mean ± SD
Total score	12.22±8.16	13.60±8.83	0.172
1. Sleep disturbance	2.11±2.40	2.25±2.44§	0.613
2. Appetite	0.65±1.12	0.77±1.18	<0.001**
3. Anxiety	1.98±1.70	2.22±1.76	0.248
4. Fatigue	1.36±0.94	1.51±0.95	0.186
5. Hyposexuality	1.30±0.99	1.39±1.03	0.481
6. Somatic disorder	1.10±0.91	1.25±0.95	0.169
7. Depression	0.71±0.73@	0.76±0.73§	0.567
8. Disinclination	1.27±0.90	1.31±0.91	0.742
9. Diminished ability to think	0.85±0.83	0.94±0.85	0.365
10. Lower satisfaction	0.87±0.88@	0.96±0.93¶	0.401
HSAS score (week 0), mean ± SD
Total score	12.72±9.53	13.95±9.77	0.281
1. Cardiovascular	1.51±1.79	1.66±1.79	0.406
2. Respiratory	1.86±1.94	2.07±2.02	0.386
3. Autonomic nerve	2.71±2.13	3.02±2.20§	0.246
4. Gastrointestinal	1.13±1.00@	1.19±1.03§	0.682
5. Distress	1.27±1.00‡	1.39±1.04	0.304
6. Awful feeling	0.66±0.93	0.73±0.94	0.509
7. Anticipatory anxiety	1.01±1.01	1.06±1.03	0.719
8. Sleeping	1.10±1.09	1.22±1.13	0.347
9. Depersonalization	0.50±0.86	0.61±0.90	0.172
10. Anxiousness	1.00±0.97	1.02±1.01	0.925

Notes: There were four subjects with missing data at baseline in ITT (n=205) group. Evaluations were conducted at baseline between PPS (n=113) and ITT (n=205) groups. HSDS scores: 0–9, no depression; 10–15, mild depression; 16–20, moderate depression; 21–30, moderately severe depression; and ≥31, severe depression. HSAS scores: 0–7, no anxiety; 8–15, mild anxiety; 16–20, moderate anxiety; 21–30, moderately severe anxiety; and ≥31, severe anxiety.

@ n=112.

‡ n=111.

§ n=200.

¶ n=199.

** Statistically significant at α=0.01 by Student’s t-test (non-paired).

Abbreviations: PPS, per-protocol set; ITT, intention to treat; HSDS, Himorogi Self-Rating Depression Scale; SD, standard deviation; HSAS, Himorogi Self-Rating Anxiety Scale.

Table S5 Depression/anxiety scores at week 8

Characteristics	PPS, n=113	ITT, n=153	P-value
HSDS score (week 8), mean ± SD
Total score	10.22±7.24	11.90±7.83	0.075
1. Sleep disturbance	1.65±2.19	1.93±2.30	0.289
2. Appetite	0.48±0.98@	0.63±1.04§	0.185
3. Anxiety	1.70±1.61	2.07±1.77	0.098
4. Fatigue	1.22±0.90	1.36±0.94	0.222
5. Hyposexuality	1.05±0.96	1.11±0.96	0.591
6. Somatic disorder	1.00±0.88	1.15±0.94	0.203
7. Depression	0.63±0.73	0.75±0.76	0.161
8. Disinclination	1.09±0.87	1.23±0.89	0.661
9. Diminished ability to think	0.73±0.74	0.84±0.76§	0.254
10. Lower satisfaction	0.68±0.77	0.85±0.85	0.106
HSAS score (week 8), mean ± SD
Total score	11.18±8.86	12.69±9.36	0.185
1. Cardiovascular	1.29±1.62	1.49±1.77	0.414
2. Respiratory	1.68±1.86	1.99±1.98	0.212
3. Autonomic nerve	2.42±1.92	2.67±2.03	0.342
4. Gastrointestinal	1.11±1.00	1.19±1.03	0.529
5. Distress	1.11±0.98	1.23±0.98	0.283
6. Awful feeling	0.55±0.91	0.63±0.93	0.416
7. Anticipatory anxiety	0.82±0.90	0.92±0.91	0.334
8. Sleeping	0.88±1.01	1.02±1.05¶	0.259
9. Depersonalization	0.42±0.79	0.55±0.88	0.268
10. Anxiousness	0.92±1.01@	1.03±1.03§	0.388

Notes: There were 52 dropouts at week 8 in ITT (n=205) group. Evaluations were conducted at week 8 between PPS (n=113) and ITT (n=153) groups. HSDS scores: 0–9, no depression; 10–15, mild depression; 16–20, moderate depression; 21–30, moderately severe depression; and ≥31, severe depression. HSAS scores: 0–7, no anxiety; 8–15, mild anxiety; 16–20, moderate anxiety; 21–30, moderately severe anxiety; and ≥31, severe anxiety.

@ n=112.

‡ n=111.

§ n=152.

¶ n=151.

Abbreviations: PPS, per-protocol set; ITT, intention to treat; HSDS, Himorogi Self-Rating Depression Scale; SD, standard deviation; HSAS, Himorogi Self-Rating Anxiety Scale.

Table S6 Changes in depression/anxiety scores in ITT (n=150)

Scale items	Baseline	Week 8	P-value
HSDS score, mean ± SD
Total score	13.39±8.60	11.87±7.87	0.002**
1. Sleep disturbance	2.25±2.46	1.95±2.32	0.080
2. Appetite	0.77±1.22	0.64±1.05	0.235
3. Anxiety	2.19±1.78	2.04±1.77@	0.259
4. Fatigue	1.47±0.96	1.37±0.89	0.148
5. Hyposexuality	1.33±1.01	1.10±0.97	<0.001**
6. Somatic disorder	1.20±0.93	1.15±0.94	0.373
7. Depression	0.78±0.77	0.74±0.77	0.462
8. Disinclination	1.35±0.92	1.23±0.90	0.075
9. Diminished ability to think	0.97±0.90	0.83±0.77	0.020*
10. Lower satisfaction	0.99±0.95	0.85±0.86	0.019*
HSAS score, mean ± SD
Total score	13.76±9.72	12.35±9.28	0.002**
1. Cardiovascular	1.65±1.81	1.47±1.78@	0.141
2. Respiratory	2.09±2.03	1.96±1.99	0.309
3. Autonomic nerve	2.92±2.17	2.69±2.04	0.071
4. Gastrointestinal	1.24±1.03	1.20±1.04@	0.630
5. Distress	1.42±1.04	1.22±0.98‡	0.004**
6. Awful feeling	0.75±0.98	0.63±0.93	0.029*
7. Anticipatory anxiety	1.07±1.02	0.92±0.92@	0.019*
8. Sleeping	1.24±1.13	1.02±1.07	0.007**
9. Depersonalization	0.63±0.93	0.54±0.89@	0.091
10. Anxiousness	1.04±1.01	1.02±1.04@	0.764

Notes: Primary comparisons were made between baseline and week 8 scores in ITT group. Data from week 4 were not included in the final analyses. HSDS scores: 0–9, no depression; 10–15, mild depression; 16–20, moderate depression; 21–30, moderately severe depression; and ≥31, severe depression. HSAS scores: 0–7, no anxiety; 8–15, mild anxiety; 16–20, moderate anxiety; 21–30, moderately severe anxiety; and ≥31, severe anxiety.

@ n=149.

‡ n=148.

* Statistically significant at α=0.05.

** Statistically significant at α=0.01 by Student’s paired t-test.

Abbreviations: ITT, intention to treat; HSDS, Himorogi Self-Rating Depression Scale; SD, standard deviation; HSAS, Himorogi Self-Rating Anxiety Scale.

Table S7 CGI-S, SSMQ, and MPQ scores at baseline

Characteristics	PPS, n=113	ITT, n=205	P-value
CGI-S, n (%)
1. Normal	8 (7.1)	17 (8.3)	0.282
2. Borderline mentally ill	30 (26.5)	39 (19.0)
3. Mildly ill	52 (46.0)	91 (44.4)
4. Moderately ill	20 (17.7)	45 (22.0)
5. Markedly ill	3 (2.7)	6 (2.9)
6. Severely ill	0 (0.0)	0 (0.0)
Unknown	0 (0.0)	7 (3.4)
SSMQ, n (%)
1. Dissatisfied	4 (3.5)	9 (4.4)	0.801
2. Slightly dissatisfied	26 (23.0)	40 (19.5)
3. Neutral	23 (20.4)	46 (22.4)
4. Slightly satisfied	25 (22.1)	44 (21.4)
5. Satisfied	30 (26.5)	42 (20.5)
6. Very satisfied	5 (4.4)	12 (5.9)
Unknown	0 (0.0)	12 (5.9)
MPQ, n (%)
1. Much better	6 (5.3)	14 (6.8)	0.737
2. Moderately better	32 (28.3)	48 (23.4)
3. Slightly better	19 (16.8)	32 (15.6)
4. Similar	29 (25.7)	52 (25.4)
5. Slightly worse	22 (19.5)	36 (17.6)
6. Worse	5 (4.4)	13 (6.3)
Unknown	0 (0.0)	10 (4.9)

Notes: Evaluations were conducted at baseline between PPS (n=113) and ITT (n=205) groups.

Abbreviations: CGI-S, Clinical Global Impression – Severity; SSMQ, Satisfaction with Study Medication Question; MPQ, Medication Preference Question; PPS, per-protocol set; ITT, intention to treat.

Table S8 CGI-S, SSMQ, and MPQ scores at week 8

Characteristics	PPS, n=113	ITT, n=154	P-value
CGI-S, n (%)
1. Normal	10 (8.8)	14 (9.1)	0.179
2. Borderline mentally ill	50 (44.2)	53 (34.4)
3. Mildly ill	40 (35.4)	65 (42.2)
4. Moderately ill	13 (11.5)	19 (12.3)
5. Markedly ill	0 (0.0)	3 (1.9)
6. Severely ill	0 (0.0)	0 (0.0)
Unknown	0 (0.0)	0 (0.0)
SSMQ, n (%)
1. Dissatisfied	0 (0.0)	1 (0.6)	0.482
2. Slightly dissatisfied	1 (0.9)	2 (1.3)
3. Neutral	31 (27.4)	44 (28.6)
4. Slightly satisfied	20 (17.7)	32 (20.8)
5. Satisfied	47 (41.6)	57 (37.0)
6. Very satisfied	14 (12.4)	18 (11.7)
Unknown	0 (0.0)	0 (0.0)
MPQ, n (%)
1. Much better	16 (14.2)	22 (14.3)	0.781
2. Moderately better	44 (38.9)	55 (35.7)
3. Slightly better	15 (13.3)	25 (16.2)
4. Similar	36 (31.9)	48 (31.2)
5. Slightly worse	2 (1.8)	3 (1.9)
6. Worse	0 (0.0)	1 (0.6)
Unknown	0 (0.0)	0 (0.0)

Notes: There were 51 dropouts at week 8 in ITT (n=205) group. Evaluations were conducted at week 8 between PPS (n=113) and ITT (n=154) groups.

Abbreviations: CGI-S, Clinical Global Impression – Severity; SSMQ, Satisfaction with Study Medication Question; MPQ, Medication Preference Question; PPS, per-protocol set; ITT, intention to treat.

Table S9 Changes of CGI-S, SSMQ, and MPQ scores in ITT (n=151) group

Characteristics	Week 0	Week 8	P-value
CGI-S, n (%)
1. Normal	10 (6.7)	14 (9.3)	<0.001**
2. Borderline mentally ill	31 (20.7)	53 (35.3)
3. Mildly ill	71 (47.3)	63 (42.0)
4. Moderately ill	36 (24.0)	18 (12.0)
5. Markedly ill	2 (1.3)	2 (1.3)
6. Severely ill	0 (0.0)	0 (0.0)
SSMQ, n (%)
1. Dissatisfied	7 (4.6)	1 (0.7)	<0.001**
2. Slightly dissatisfied	35 (23.2)	2 (1.3)
3. Neutral	36 (23.8)	44 (29.1)
4. Slightly satisfied	35 (23.2)	29 (19.2)
5. Satisfied	32 (21.2)	57 (37.7)
6. Very satisfied	6 (4.0)	18 (11.9)
MPQ, n (%)
1. Much better	8 (5.3)	22 (14.6)	<0.001**
2. Moderately better	36 (23.8)	55 (36.4)
3. Slightly better	23 (15.2)	22 (14.6)
4. Similar	43 (28.5)	48 (31.8)
5. Slightly worse	31 (20.5)	3 (2.0)
6. Worse	10 (6.6)	1 (0.7)
Unknown	0 (0.0)	0 (0.0)

Notes: A total of 150 subjects were evaluated using CGI-S. Evaluations were conducted in ITT group between week 0 and week 8.

** Statistically significant at α=0.01 by Wilcoxon signed rank-sum test.

Abbreviations: CGI-S, Clinical Global Impression – Severity; SSMQ, Satisfaction with Study Medication Question; MPQ, Medication Preference Question; ITT, intention to treat.