Efficacy, tolerability, and safety of aripiprazole once-monthly versus other long-acting injectable antipsychotic therapies in the maintenance treatment of schizophrenia: a mixed treatment comparison of double-blind randomized clinical trials

Figures & data

Fig. 1.  Competing events structure of the mixed treatment comparison.

Table 1. Details of included studies assessing long-acting injectable antipsychotics

Study	Patient characteristics	Inclusion criteria^a	Exclusion criteria	Definition of relapse-related outcome	Medication	Notes
Kane (42)	Age: ~38–40 Male: 85% White: 59% BMI: not reported Duration (year): 12–17 Schizoaffective: 8 (7.6%) Outpatients only Total PANSS score at baseline: not reported N=105; 52 weeks	DSM-III schizophrenia or schizoaffective disorder for at least 2 years; need for maintenance AP treatment; baseline state of relative remission for ≥3 months during maintenance treatment	Treatment with lithium or antidepressants; women of childbearing potential; contraindication of haloperidol; BPRS ≥ 4 for conceptual disorganization/unusual thoughts or BPRS ≥ 5 for hallucinatory behavior/suspiciousness	Symptomatic exacerbation: an increase on one psychotic item of at least 2 scale points on one of the four items of the BPRS	Haloperidol depot: 200 mg/month; 100 mg/month; 50 mg/month (doses were combined for the MTC) Haloperidol depot: 25 mg/month (assumed equivalent to placebo)	Discontinuation due to other reasons than AEs included study termination, patient uncooperative and other
Kane (41)	Age: ~38–39 Male: 67% White: 72% BMI: 26.9 kg/m^2 Duration (year): 12–14 Schizoaffective: – Outpatients only Total PANSS score at baseline: ~55–58 N=1,065 24 weeks	DSM-IV schizophrenia Stability criteria: no dose change for oral olanzapine; CGI-I score ≤4; outpatient for ≥4 weeks; BPRS positive symptom subscale score <5 on conceptual disorganization, unusual thoughts, hallucinatory behavior and suspiciousness	Significant suicidal or homicidal risk; pregnancy/breastfeeding; acute/serious/unstable medical conditions; substance dependence within the past month	Psychotic exacerbation: an increase of any BPRS positive symptom item to a score >4, with an absolute increase ≥2 for the specific item or ≥4 on the positive symptom subscale since randomization; hospitalization as the result of worsening of positive psychotic symptoms	Olanzapine pamoate: 150 mg/2–weeks; 405 mg/4-weeks; 300 mg/2-weeks (doses were combined for the MTC) Olanzapine oral: 10/15/20 mg/day Olanzapine pamoate: 45 mg/4-weeks (assumed equivalent to placebo)	Discontinuation due to other reasons than AEs included loss to follow-up, protocol violation, lack of efficacy (not meeting the definition of relapse), physician decision, patient decision, and sponsor decision
Hough (38)	Age: ~39–40 Male: 55% White: 66% BMI: 27.2 kg/m^2 Duration (year): 12–13 Schizoaffective: – Outpatients only Total PANSS score at baseline: ~52–53 N=410 31 weeks for paliperidone palmitate 42 weeks for placebo depot	DSM-IV schizophrenia for ≥1 year before screening; PANSS score below 120 at screening. Stability criteria: PANSS total score ≤75; PANSS item scores ≤4 on delusions, conceptual disorganization, hallucinatory behavior, suspiciousness, hostility, uncooperativeness, and poor impulse control	Diagnosis other than schizophrenia; significant suicidal or aggressive behavior; substance dependence within the past months; significant medical conditions/treatment resistance; use of 4-week depot within 28 days or RLAI within 5 weeks before screening/oral AP within 2 days; admission to psychiatric hospital	Hospitalization for symptoms of schizophrenia; 25% increase in PANSS total score for two consecutive assessments for patients who scored >40 at randomization, or a 10-point increase for patients who scored ≤40 at randomization; self-injury, suicidal or homicidal ideation and aggressive behavior	Paliperidone palmitate: 25/50/100 mg/month Placebo depot	Time-to-relapse data were censored beyond day 220 for the paliperidone palmitate group (i.e., 220/731 weeks) and beyond day 295 for the placebo group (i.e., 295/742 weeks). Discontinuation due to other reasons than AEs included subject choice, not received any double-blind injections and other
Kane (40)	Age: ~40–42 Male: 60% White: 61% BMI: 28.6 kg/m^2 Duration (year): 14–15 Schizoaffective: – Outpatients only Total PANSS score at baseline: ~54–55 N=403 52 weeks (may be shorter)	DSM-IV-TR diagnosis of schizophrenia for ≥3 years; history of symptom exacerbation or relapse when not receiving AP treatment. Stability criteria: outpatient status; PANSS total score ≤80; PANSS score of ≤4 on conceptual disorganization, hallucinatory behavior and unusual thought content; CGI-S score ≤4; CGI-SS score ≤2 on part 1 and ≤5 on part 2	Diagnosis other than schizophrenia (DMS-IV-TR); significant medical/neurologic disorder; medically significant abnormal laboratory test or ECG results at screening; patients refractory to AP treatment	Exacerbations of psychotic symptoms/impending relapse: CGI-I score of ≥5 and an increase on any of the 4 PANSS items to a score >4 with an absolute increase of ≥2 or an increase >4 on the combined score of the items; hospitalization; risk of suicide as defined by CGI-SS score of 4 or 5 (part 1) or a score of 6 or 7 (part 2); violent behavior	Aripiprazole once-monthly: 300/400 mg/month Placebo depot	Based on the results of the preplanned interim analysis, the primary endpoint had been achieved, and the study was terminated early. Discontinuation due to other reasons than AEs included subject withdrew consent and other
Fleischhacker (37)	Age: ~41 Male: 60% White: 92% BMI: 27.7 kg/m^2 Duration (year): 13 Schizoaffective: – Outpatient status: NA N=749 53 weeks	DSM-IV diagnosis of schizophrenia for ≥1 year before screening; PANSS total score between 60 and 120 (inclusive); acutely symptomatic at screening; body mass index ≥15.0 kg/m^2	DSM-IV Axis I diagnosis not schizophrenia; decrease of >25% in PANSS total score (screening to baseline); substance dependence; treatment resistance; neuroleptic malignant syndrome; significant or unstable systemic disease; suicidal/violent behavior; pregnant	Lack of efficacy (not specified)	Paliperidone palmitate: 25/50/75/100 mg/month Risperidone LAI 25/37.5/50 mg/2-week	This study combined acute and maintenance treatment. Discontinuation due to other reasons than AEs included patient choice, loss to follow-up, pregnancy, death, and other
Fleischhacker (39)	Age: ~40–42 Male: 61% White: 58% BMI: 28.8 kg/m^2 Duration (year): 14 Schizoaffective: – Outpatients only	DSM-IV-TR diagnosis of schizophrenia for ≥3 years; history of symptom exacerbation or relapse when not receiving AP treatment.	Stability criteria: Outpatient status; PANSS total score ≤ 80; Lack of specific psychotic symptoms on the PANSS: score of ≤4 on: conceptual	Impending relapse (not further specified)	Aripiprazole once-monthly: 400 mg/month Aripiprazole oral: 10–30 mg/day Aripiprazole once-monthly	Discontinuation due to other reasons than AEs included patient withdrew consent and other
	Total PANSS score at baseline: not reported N=662 38 weeks	Stability criteria: outpatient on part 1 and ≤5 on part 2 status; PANSS total score ≤80; PANSS score of ≤4 on conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content; CGI-S score ≤4; CGI-SS ≤2 on part 1 and ≤5 on part 2	disorganization, suspiciousness, hallucinatory behavior, and unusual thought content; CGI-S score ≤4; CGI-SS ≤2 on part 1 and ≤5 on part 2		50 mg/month (assumed equivalent to placebo)

^aEither study or ‘stable’.

DSM = Diagnostic and Statistical Manual of Mental Disorders; BPRS = Brief Psychiatric Rating Scale (unusual thought content, conceptual disorganization, hallucinations, suspiciousness); CGI-I = Clinical Global Impressions-Improvement of Illness; AP = antipsychotic; ECG = electrocardiogram; CGI-S = Clinical Global Impressions-Severity of Illness; CGI-SS = Clinical Global Impressions-Severity of Suicidality; MTC = mixed treatment comparison, disc's = discontinuations; AE = adverse event.

Fig. 2.  Evidence network. Notes: For the safety analyses, haloperidol depot was not included since no safety data were reported in Ref. (42).

Table 2. Reported efficacy, tolerability, and safety data used in the MTC

Study name	Treatment arms	Time horizon (weeks)	Relapses	AE-related disc's	Non-AE-related disc's	Completers	Total Nr of patients	Nr of patients experiencing >7% weight gain (total Nr of patients)	Nr of patients experiencing EPS (total Nr of patients)
Kane (42)	Haloperidol depot^a	52	17	1	18	44	80	NA	NA
	Placebo^b	52	15	0	2	8	25	NA	NA
Kane (41)	Olanzapine pamoate^c	24	68	21	91	419	599	100 (599)	52 (599)
	Olanzapine oral	24	23	8	33	258	322	68 (322)	28 (322)
	Placebo^b	24	42	6	20	76	144	12 (144)	12 (144)
Hough 2010 (38)	Paliperidone palmitate	31	36	3	28	139	206	12 (206)	21 (206)
	Placebo	42	97	2	27	78	204	6 (204)	12 (204)
Kane (40)	Aripiprazole once-monthly	52	27	9	31	202	269	17 (269)	45 (269)
	Placebo	52	53	5	15	61	134	7 (134)	14 (134)
Fleischhacker (37)	Paliperidone palmitate	53	95	29	100	155	379	50 (346)	67 (379)
	Risperidone LAI	53	56	25	105	184	370	52 (338)	76 (370)
Fleischhacker (39)	Aripiprazole once-monthly	38	22	8	39	196	265	42 (265)	52 (265)
	Aripiprazole oral	38	21	7	60	178	266	43 (266)	46 (266)
	Placebo^b	38	29	7	34	61	131	8 (131)	18 (131)

disc's = discontinuations; EPS = extrapyramidal symptoms; MTC = mixed treatment comparison; Nr = number.

^aPooled dose approach (200, 100, and 50 mg once-monthly, respectively).

^bSubtherapeutic dose of the active long-acting injectable comparator.

^cPooled dose approach (150 and 300 mg biweekly, and 405 mg four-weekly).

Table 3. Hazard ratios and 26-week probabilities for efficacy outcomes, random effects mixed treatment comparison

Treatment	HR	LCrI	UCrI	26-week probability (%)	LCrI (%)	UCrI (%)	Treatment is best (%)
	Relapse
Placebo	1.00			27.6	18.5	39.3	0.0
Aripiprazole once-monthly	0.26	0.12	0.51	8.4	3.3	17.1	9.4
Haloperidol depot	0.37	0.10	0.97	9.6	1.9	25.4	16.7
Olanzapine pamoate	0.40	0.13	0.91	11.5	3.5	27.3	2.6
Paliperidone palmitate	0.44	0.14	1.00	12.2	3.4	28.7	0.9
Risperidone LAI	0.27	0.05	0.84	7.7	1.2	23.8	34.5
Aripiprazole oral	0.34	0.10	0.84	10.3	2.9	25.3	9.1
Olanzapine oral	0.23	0.07	0.55	7.3	2.0	18.3	26.9
	Discontinuation due to AEs
Placebo	1.00			2.5	1.0	5.0	0.3
Aripiprazole once-monthly	0.74	0.17	2.12	2.1	0.3	6.8	9.2
Haloperidol depot	4.26	0.04	25.56	5.5	0.1	43.9	29.0
Olanzapine pamoate	1.24	0.14	4.03	3.0	0.3	11.8	5.9
Paliperidone palmitate	4.69	0.16	22.24	8.5	0.3	46.9	2.3
Risperidone LAI	5.92	0.09	26.91	8.4	0.2	53.0	9.0
Aripiprazole oral	0.68	0.07	2.33	1.9	0.1	7.4	25.3
Olanzapine oral	0.77	0.09	2.92	2.2	0.2	9.2	18.9
	Discontinuation due to other than AEs
Placebo	1.00			11.3	5.8	18.8	0.6
Aripiprazole once-monthly	0.80	0.25	1.55	8.8	2.6	21.1	27.1
Haloperidol depot	3.29	0.39	13.96	27.8	3.9	83.5	3.9
Olanzapine pamoate	1.27	0.27	3.56	14.0	2.9	39.3	5.4
Paliperidone palmitate	1.49	0.28	4.14	14.9	2.9	42.5	4.9
Risperidone LAI	2.00	0.18	6.59	16.8	1.7	58.1	12.1
Aripiprazole oral	0.95	0.21	2.66	11.6	2.4	33.6	16.0
Olanzapine oral	0.85	0.17	2.27	9.7	1.9	29.3	30.0
	Continuing treatment
Placebo				58.7	46.6	68.4	0.0
Aripiprazole once-monthly	N/A	N/A	N/A	80.8	65.6	89.6	28.8
Haloperidol depot	N/A	N/A	N/A	57.1	5.3	85.3	2.9
Olanzapine pamoate	N/A	N/A	N/A	71.5	42.9	86.7	1.9
Paliperidone palmitate	N/A	N/A	N/A	64.4	24.4	83.8	0.6
Risperidone LAI	N/A	N/A	N/A	67.1	14.3	89.3	9.3
Aripiprazole oral	N/A	N/A	N/A	76.3	50.3	89.6	15.1
Olanzapine oral	N/A	N/A	N/A	80.8	57.4	91.8	41.5

HR=hazard ratio; LCrI=95% lower credible interval; UCrI=95% upper credible interval.

Fig. 3.  Sensitivity analyses results: Hazard ratio of relapse in alternative models.

Table 4. Odds ratios and 26-week probabilities for safety outcomes, fixed effects mixed treatment comparison

Treatment	OR	LCrI	UCrI	26-week probability (%)	LCrI (%)	UCrI (%)	Treatment is best (%)
	Clinically significant (>7%) weight gain
Placebo	1			5.4	3.6	7.2	89.7
Aripiprazole once-monthly	2.24	1.22	3.96	11.2	6.5	18.4	0.3
Haloperidol depot	–			–	–	–	–
Olanzapine pamoate	2.42	1.25	4.48	12.0	6.6	20.3	0.3
Paliperidone palmitate	2.47	0.78	6.21	11.9	4.2	26.1	4.5
Risperidone LAI	2.70	0.77	7.22	12.8	4.2	29.1	4.9
Aripiprazole oral	2.45	1.25	4.48	12.1	6.6	20.3	0.4
Olanzapine oral	3.24	1.64	6.14	15.3	8.5	25.9	0
	EPS
Placebo	1			9.1	6.8	11.5	37.9
Aripiprazole once-monthly	1.68	1.07	2.55	14.3	9.7	20.4	0.3
Haloperidol depot	–			–	–	–	–
Olanzapine pamoate	1.14	0.58	2.12	10.1	5.5	17.6	24.0
Paliperidone palmitate	1.99	0.89	3.94	16.3	8.2	28.4	2.5
Risperidone LAI	2.43	0.99	5.23	19.1	9.0	34.5	0.8
Aripiprazole oral	1.43	0.83	2.33	12.5	7.7	19.0	6.4
Olanzapine oral	1.14	0.54	2.24	10.2	5.1	18.4	28.1

OR=odds ratio; LCrI=95% lower credible interval; UCrI=95% upper credible interval.

Kane JM , Davis JM , Schooler N , Marder S , Casey D , Brauzer B et al. A multidose study of haloperidol decanoate in the maintenance treatment of schizophrenia. Am J Psychiatry. 2002; 159(4): 554–60.

 Google Scholar

Kane JM , Detke HC , Naber D , Sethuraman G , Lin DY , Bergstrom RF et al. Olanzapine long-acting injection: A 24-week, randomized, double-blind trial of maintenance treatment in patients with schizophrenia. Am J Psychiatry. 2010; 167(2): 181–9.

 Google Scholar

Hough D , Gopal S , Vijapurkar U , Lim P , Morozova M , Eerdekens M . Paliperidone palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: A randomized, double-blind, placebo-controlled study. Schizophr Res. 2010; 116(2–3): 107–17.

 Google Scholar

Kane JM , Sanchez R , Perry PP , Jin N , Johnson BR , Forbes RA et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: A 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2012; 73(5): 617–24.

 Google Scholar

Fleischhacker WW , Gopal S , Lane R , Gassmann-Mayer C , Lim P , Hough D et al. A randomized trial of paliperidone palmitate and risperidone long-acting injectable in schizophrenia. Int J Neuropsychopharmacol. 2012; 15(1): 107–18.

 Google Scholar

Fleischhacker WW , Sanchez R , Perry PP , Jin N , Peters-Strickland T , Johnson BR et al. Aripiprazole once-monthly for the treatment of schizophrenia: A doubleblind, randomized, non-inferiority study vs. oral aripiprazole. December 2–6, 2012; Hollywood, FL, USA: 51st Annual Meeting of the American College of Neuropsychopharmacology.

 Google Scholar