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Safety and tolerability of long-acting injectable versus oral antipsychotics: A meta-analysis of randomized controlled studies comparing the same antipsychotics

Schizophrenia Research, Volume 176, Issue 2-3, October 2016, Pages 220 - 230

Abstract

Objective

We aimed to assess whether long-acting injectable antipsychotics (LAIs), which are initiated in a loading strategy or overlapping with oral antipsychotics (OAPs) and which cannot be stopped immediately, are associated with greater safety/tolerability issues than OAPs.

Method

Systematic review and meta-analysis of randomized controlled trials (RCTs) comparing LAIs and OAPs, including only LAI-OAP pairs of the same OAP (allowing oral risperidone and paliperidone as comparators for either risperidone or paliperidone LAI). Primary outcome was treatment discontinuation due to adverse events. Secondary outcomes included serious adverse events, death, ≥ 1 adverse event and individual adverse event rates.

Results

Across 16 RCTs (n = 4902, mean age = 36.4 years, males = 65.8%, schizophrenia = 99.1%) reporting on 119 adverse event outcomes, 55 (46.2%) adverse events were reported by ≥ 2 studies allowing a formal meta-analysis. Out of all 119 reported adverse events, LAIs and OAPs did not differ significantly regarding 115 (96.6%). LAIs were similar to OAPs regarding the frequency of treatment discontinuation due to adverse events, serious adverse events, all-cause death and death for reasons excluding accident or suicide. Compared to OAPs, LAIs were associated with significantly more akinesia, low-density lipoprotein cholesterol change and anxiety. Conversely, LAIs were associated with significantly lower prolactin change.

Conclusion

LAIs and OAPs did not differ on all serious and > 90% of individual adverse events. However, more studies focusing on adverse event frequencies, severity and time course associated with LAI vs OAP formulations of the same antipsychotic are needed. Additionally, adverse events data for LAIs after stopping overlapping oral antipsychotic treatment are needed.

Keywords: Long-acting injectable antipsychotics, Oral antipsychotics, Schizophrenia, Randomized controlled trial, Adverse events, Meta-analysis.

1. Introduction

Long-acting injectable antipsychotics (LAIs) were introduced in the 1960s in an attempt to improve the long-term treatment of schizophrenia (Kane and Correll, 2010). The use of LAIs is an important option because non-adherence rates that are as high as 50–75% can seriously compromise the efficacy of pharmacotherapy (Dolder et al, 2002, Kane et al, 2013, and Velligan et al, 2007). However, LAIs remain an underutilized treatment option in most countries and settings (Kane and Garcia-Ribera, 2009). The reasons for the low prescribing rate of LAIs are manifold and complex (Correll, 2014a, Correll, 2014b, Haddad et al, 2015, Hamann et al, 2014, Heres et al, 2006, and Heres, 2014), but one reason frequently cited is the fear that LAIs might be associated with significantly greater risk of common and, especially serious adverse events. Reasons for this fear include the fact that, different from oral antipsychotics (OAPs), LAIs are initiated in large single doses, either with a loading strategy or overlapping with OAPs, and that they cannot be discontinued rapidly (Nasrallah, 2007) should a serious adverse event emerge. However, it has also been postulated that LAIs that have lower peak to trough blood level variations (Sheehan et al., 2012) could be associated with less, rather than more adverse events than OAPs.

Due to the lack of clarity whether LAIs have a greater, similar or lower liability for adverse events than OAPs and due to the importance of the concerns about serious adverse events in the context of treatment that cannot be stopped immediately for or against a wider LAI use, we conducted a meta-analysis comparing adverse event outcomes in patients randomized to the same antipsychotic, either as an LAIs or OAPs.

2. Methods

We conducted a systematic, electronic database search from database inception without language restrictions, using MEDLINE/PubMed, Cochrane library, Embase, PsycINFO and CINAHL (last search: 06/2015). To avoid publication bias, we also included unpublished studies, such as conference proceedings and clinical trial registries (http://clinicaltrials.gov/). Search terms included synonyms of (1) antipsychotic(s); (2) schizophrenia and related disorders, (3) randomized; and (4) depot, (long-acting) injection(s), microsphere, decanoate, palmitate, enanthate, pamoate and once-monthly. The electronic search was supplemented by hand search of reference lists of relevant publications. At least 2 independent investigators (FM, KH, TK) independently conducted the literature search.

2.2. Inclusion criteria

We included randomized controlled trials (RCTs) that randomized patients to the same antipsychotic, either as an LAI and OAP formulation. In case that multiple antipsychotics were part of the OAP arm, we included only studies from which we could obtain data in the OAP group matching the specific antipsychotic used in the LAI group, contacting authors to provide subgroup data. Patients in the included studies had to be > 18 years old and have a diagnoses of schizophrenia or schizoaffective disorder according to study diagnoses. We included studies with a duration of at least 8 weeks that provided information about safety/tolerability outcomes. We excluded penfluridol, a once- weekly OAP, considering it neither a LAI nor OAP.

2.3. Data extraction and outcomes

Data were extracted independently by ≥ 2 reviewers (FM, KH, TK). Authors and companies were contacted to provide missing information and unpublished data. Any disagreements were resolved by discussion.

The primary outcome was the rate of treatment discontinuation due to adverse events. Key secondary outcomes included study-defined serious adverse events, and death. Other secondary outcomes included the proportion of participants experiencing at least one adverse event, and individual adverse event frequencies. We extracted all reported adverse events except for those that were clearly irrelevant to antipsychotics (e.g., influenza, arthropod bite). Since many studies did not explicitly report the number of deaths, but detailed all reasons for study discontinuation, we judged that there was no death if these reasons did not include death.

2.4. Risk of bias assessment

Risk of bias with respect to randomization sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other biases was assessed by at least 2 independent investigators (FM, KH, TK) using the risk of bias instrument described in the Cochrane Handbook (Higgins and Green, 2011).

2.5. Data analysis

We extracted adverse event data of only those patients who were randomized and who took ≥ 1 dose of study medication. The comparison of LAI versus OAP was performed across all pooled LAIs. In this analysis, we computed the pooled risk ratio (RR) and standardized mean difference (SMD) with its 95% confidence interval (CI) using the random-effects model (DerSimonian and Laird, 1986). RR values lower than 1 indicate superiority of LAI. SMD values lower than 0 indicate superiority of LAI. Number-needed-to-harm (NNH) was calculated where appropriate. With regard to the heterogeneity, Q, I2 and p-values were reported. In addition to the primary and secondary outcome analyses, we also conducted subgroup analyses of the primary outcome, seeking to identify potential moderators, methodological biases and whether the findings extended to clinically relevant sub-populations and treatment groups. These analyses included subgroups based on (1) medication group (first-generation LAI (FGA-LAI)/second-generation LAI (SGA-LAI)), (2) individual antipsychotic (e.g., fluphenazine, risperidone), (3) country, (4) treatment concealment (double-blind/rater-masked/open label), (5) sponsorship (pharmaceutical company or not), (6) treatment setting (outpatients at baseline or shortly after initiation of antipsychotic treatment/inpatients/mixed patient status), (7) study duration (< 52 weeks/≥52 weeks), (8) mean age (< 40 years/≥40 years) (9) lead-in with OAPs before randomization (studies with lead-in phase with OAPs vs. without lead-in phase with OAPs), (10) required OAP overlap after the beginning of LAI treatment (risperidone and aripiprazole vs. other antipsychotics) and (11) study hypothesis (non-inferiority studies/superiority studies). Comprehensive Meta-Analysis, version 3 (http://www.meta-analysis.com) was used for all analyses that were two-tailed with alpha = 0.05, without adjustments for multiple comparisons. Publication bias was assessed with the funnel plot, Egger's regression test (Egger et al., 1997) and the ‘trim and fill’ method (Duval and Tweedie, 2000), an iterative procedure to assess whether small, extreme included studies and/or potentially unincluded studies biased the true RR estimate.

3. Results

3.1. Search results and study and patient characteristics

Out of 1170 non-duplicated hits, we ultimately identified 16 eligible RCTs with 4902 participants (for details, see Supplemental Fig. 1). Out of 16 RCTs, Two studies were unpublished. Participant numbers ranged between 46 and 1065 (median = 155), and mean study duration was 51.6 (range = 12–104) weeks. Eight studies had double-blind, double-dummy design, 3 were rater-masked, and 5 were open. There were 5 FGA-LAI studies (fluphenazine = 4, zuclopenthixol = 1) and 11 SGA-LAI studies (risperidone = 6, aripiprazole = 2, olanzapine = 2, paliperidone = 1) (Table 1). Patients were on average 36.4 years old, 65.8% were males, and 99.1% had a diagnosis of schizophrenia.

Table 1

Description of included studies.

 

Study/Country na Blinding Study Duration
(wks)
Inclusion criteria Mean age (y.o.) % Male Medication Randomized # Mean dose
FGA
Fluphenazine
del Giudice et al. (1975)
USA
88 DBDD 69 IPs with SCZ who responded to oral FPZ and were discharged NR 100 FPZ enanthate
FPZ
27
61b
25 mg/2 wks (fixed)
21.7 mg
Rifkin et al. (1977)
USA
73c DBDD 52 Stable OPsd on FPZ depot or oral for 4 wks, no more than minor side effects, cooperative and compliant 23.7 67 FPZ decanoate
FPZ
23
28
NR (12.5–50 mg/2 wks)
NR (5–20 mg)
Hogarty et al. (1979)
USA
105 DBDD 104 Pts with SCZ who received major neuroleptic treatment during the Hp and was discharged 34.2 46 FPZ decanoate
FPZ
55
50
34 mg/2 wks
9.9 mg/d
Schooler et al. (1980)
USA
290 DBDD 52 Pts with SCZ discharged after acute phase treatment and being treated in community 29 59 FPZ decanoate
FPZ
143e
147e
34.2 mg/3 wks
24.8 mg/d
Zuclopenthixol
Arango et al. (2006)
Spain
46 RM 52 Pts with SCZ (DSM-IV) who had a violent episode in the previous year, with a score of at least 3 on the physical aggression subscale of the modified Overt Aggression Scale 34.0 83 ZUC-LAI
ZUC
26
20
233 mg/2 wks
35 mg/d
 
SGA
Olanzapine
Kane et al. (2010)
International
1065f DBDD 24 Clinically stable Pts with SCZ (DSM-IV) defined as having OP status for ≥ 4 wks, with a BPRS-P ≤ 4 on the following items: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content 38.9 65 OLA-LAI



OLA
599



322
150 mg/2 wks
405 mg/4 wks
300 mg/2 wks
(fixed)
14.3 mg/d
Detke et al. (2011)
International
524 OL 104 OPs with SCZ (DSM-IV) who had no acute Hp in the 8 wks prior to visit 1, PANSS-T < 70, CGI-S ≤ 4 at visit 1 and 2, but had ≥ 2 episode of clinical worsening in the past 2 years 40.9 67 OLA-LAI
OLA
264
260
386.6/4 wks
12.7 mg/d
Risperidone
Chue et al. (2005)
International
642 DBDD 12 Pts with SCZ (DSM-IV) and who remained symptomatically stable as indicated by a stable oral RIS dose and stable CGI scores for the last 4 wks of the oral RIS run-in period, PANSS-T ≥ 50 40.0 64.7 RIS-LAI

RIS
320g

322g
51.3 mg/2 wks

4.14 mg/d
Bai et al. (2007)
Taiwan
50 RM 48 Pts with symptomatically stable SCZ
(DSM-IV)and have been on oral RIS for ≥ 3 months, PANSS-T < 80, PANSS conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content are all < 4, CGI-I screening visit and baseline were same
46.4 50 RIS-LAI


RIS
25


25
Equivalent to oral 5.0 mg/dh

4.0 mg/d (Same dose as before the trial)
Kamijima et al. (2009)
Japan
205 OL 24 IP/OPs with SCZ (DSM-IV) who are taking RIS ≤ 6 mg/d with no change in dose for 28 days, 60 ≤ PANSS-T ≤ 120 42.7 62 RIS-LAI
RIS
153
52
32.3 mg/2 wks
3.4 mg/d
NCT00130923 (2012)
USA
95 RM 24 Pts with SCZ or SzAD who meets the Structured Clinical Interview for DSM-IV (SCID) criteria for an alcohol use disorder, Alcohol use on at least 5 days during the 4 wks prior to randomization 41.7 77.0 RIS-LAI

RIS
49

46
NR

NR
NCT00992407 (2014)
Korea
75i OL 52 Pts with SCZ or SzAD with pre-morbid GAF ≥ 71 34.5 25.0 RIS-LAI
RIS
37
38
NR
NR
Kaiser et al. (2015),
Subotnik et al. (2015)
USA
83 OL 52 Pts with a recent first episode of SCZ 21.5 78.5 RIS-LAI
RIS
40
43
26.3 mg/2 wks
3.6 mg/d
Paliperidone
Alphs et al. (2015); Starr et al. (2014)
USA
444 OL 65 Pts with SCZ (MINI ver6.0), CJS at least twice in the previous 2 years, with at least 1 instance of custody leading to incarceration, Release from most recent CJS custody within 90 days of screening 37.7 84.6 PAL-LAI

PAL, RIS
208j

85j
NR

NR
Aripiprazole
Fleischhacker et al. (2014)
International
662k DBDD 38 Pts with SCZ (DSM-IV-TR) criteria for 3 years and a history of symptom exacerbation when not receiving AP treatment. Pts needed to have been responsive to AP treatment in the past year 41.4 61.8 ARI-LAI

ARI
265

266
400 mg/4 wks

20 mg/d
Ishigooka et al. (2015)
International
455 DBDD 52 Pts with SCZ (DSM-IV-TR), BMI of 18.5–35. The stabilization criteria were defined as meeting all of the following criteria for 4 consecutive wks: 1) OPs status; 2) PANSS-T ≤ 80; 3) lack of specific psychotic symptoms on the PANSS, as measured by a score of < 4 on each of the following items: conceptual disorganization (P2), suspiciousness (P6), hallucinatory behavior (P3), and unusual thought content (G9);
4) CGI-S < 4; and 5) CGI-SS < 2 on part 1 and < 5 on part 2.
39.2 60.9 ARI-LAI

ARI
228

227
393.79 mg/4 wks

15.69 mg/d

aOriginal study sample size.

bOnly Group II (FPZ tablets and placebo injection) is included in the analysis because data about adverse events in Group I (only FPZ tablets) are not reported.

cPts allocated to placebo arm are not included in the analysis.

d100% Schizophrenia by clinical diagnosis but included 15% non-schizophrenia when assessed by research psychiatrists.

ePts entered maintenance phase are used in the analysis.

fVery low dose (OLA-LAI 45 mg/4 wks) group is not included in the analysis.

gPts who did not begin double-blind treatment are not included in the analysis.

hDepot dose based on prior oral dose.

iAll Pts are included in the analysis about discontinuation due to adverse events, Pts who did not begin treatment are not included in the other analysis.

jthe number which the authors used in the analysis on PAL-LAI versus PAL and RIS.

kARI-LAI 50 mg group is not included in the analysis.

AP, antipsychotics; ARI, aripiprazole; CGI-S, clinical global impression severity score; CJS, criminal justice system; DBDD, double-blind double-dummy; FPZ, fulphenazine; Hp, hospitalization; IP, inpatient; LAI, long-acting injectable antipsychotic; NR, not reported; OAP, oral antipsychotic; OL, open label; OLA, Olanzapine; OP, outpatient; PAL, paliperidone; PANSS, positive and negative symptom scale total score; Pt, patient; RIS, risperidone; RM, rater masked; SCZ, schizophrenia; SzAD, schizoaffective disorder; wks, weeks.

Altogether, 119 adverse event outcomes were reported, with 55 (46.2%) of them being reported by ≥ 2 studies, allowing for a formal meta-analysis, and with 44 (37.0%) adverse events being reported in > 500 patients (Table 2).

Table 2

Adverse event outcomes.

 

Outcome N n RR/SMD 95% CI Result: p-Value Heterogeneity: p-Value
Extrapyramidal symptom
Any extrapyramidal AE 3 1184 RR = 1.197 0.710, 2.018 0.499 0.024
Use of anti-EPS medications 5 1869 RR = 1.023 0.845, 1.238 0.818 0.338
AIMS average change 5 1888 SMD = 0.061 − 0.119, 0.241 0.508 0.026
SAS average change 3 1488 SMD = − 0.063 − 0.167, 0.042 0.238 0.437
DIEPSS total score average change 2 515 SMD = − 0.125 − 0.413, 0.163 0.394 0.133
BARS average change 5 1612 SMD = − 0.016 − 0.198, 0.165 0.861 0.093
Akathisia 7 2100 RR = 1.237 0.760, 2.014 0.393 0.180
Tardive dyskinesia 4 1439 RR = 1.213 0.257, 5.740 0.807 0.403
Dystonia 3 536 RR = 1.255 0.351, 4.480 0.727 0.758
Tremor 2 252 RR = 2.598 0.456, 14.799 0.282 0.342
Dyskinesia 2 491 RR = 3.212 0.592, 17.421 0.176 0.672
Extrapyramidal disorder 2 491 RR = 0.618 0.181, 2.106 0.442 0.476
Parkinsonism 2 491 RR = 0.519 0.117, 2.302 0.388 0.733
Muscle rigidity 2 243 RR = 0.921 0.028, 30.378 0.963 0.066
Musculoskeletal stiffness 1 95 RR = 8.460 0.468, 152.907 0.148 [glyph: sbnd]
Akinesia 1 51 RR=20.542
OAP superior
1.249, 337.941 0.034 [glyph: sbnd]
Dysphemia 1 45 RR = 0.413 0.018, 9.617 0.582 [glyph: sbnd]
Dysarthria 1 45 RR = 1.250 0.083, 18.763 0.872 [glyph: sbnd]
 
Weight and metabolic abnormality
Weight gain: AE 8 3021 RR = 0.983 0.789, 1.224 0.878 0.695
Weight gain: ≥ 7% 5 2415 RR = 0.990 0.821, 1.193 0.914 0.293
Body weight change 5 2448 SMD = − 0.035 − 0.115, 0.046 0.401 0.578
Increased appetite 2 817 RR = 1.139 0.648, 2.002 0.651 0.629
Weight loss: AE 2 1055 RR = 1.360 0.861, 2.149 0.188 0.357
BMI average change 1 83 SMD = 0.109 − 0.322, 0.540 0.620 [glyph: sbnd]
Fasting glucose 5 1962 SMD = 0.064 − 0.026, 0.154 0.162 0.844
Glucose unusual change 1 198 RR = 1.735 0.208, 14.499 0.611 [glyph: sbnd]
New onset fasting glucose ≥ 126 1 310 RR = 1.566 0.633, 3.872 0.331 [glyph: sbnd]
HbA1c change 1 83 SMD = 0.323 − 0.110, 0.757 0.144 [glyph: sbnd]
HbA1c unusual change 1 198 RR = 1.757 0.086, 35.994 0.715 [glyph: sbnd]
Total cholesterol 6 2115 SMD = 0.156 − 0.019, 0.331 0.080 0.007
Cholesterol unusual change 1 198 RR = 0.347 0.022, 5.446 0.451 [glyph: sbnd]
New-onset cholesterol abnormality 1 295 RR = 1.301 0.221, 7.670 0.772 [glyph: sbnd]
HDL-C 4 1977 SMD = − 0.005 − 0.094, 0.085 0.918 0.654
New-onset HDL-C abnormality 1 370 RR = 0.898 0.570, 1.416 0.643 [glyph: sbnd]
LDL-C 4 1950 SMD=0.096
OAP superior
0.006, 0.186 0.037 0.577
New-onset LDL-C abnormality 1 190 RR = 2.592 0.107, 62.836 0.558 [glyph: sbnd]
Triglycerides 5 2032 SMD = − 0.031 − 0.119, 0.058 0.496 0.908
New-onset triglyceride abnormality 1 318 RR = 1.168 0.575, 2.375 0.667 [glyph: sbnd]
Triglyceride unusual change 1 198 RR = 1.561 0.349, 6.988 0.560 [glyph: sbnd]
Uric acid 1 50 SMD = − 0.022 − 0.577, 0.532 0.937 [glyph: sbnd]
Uric acid unusual change 1 198 RR = 3.162 0.173, 57.735 0.437 [glyph: sbnd]
 
Prolactin and sexual function
Prolactin change/endpoint 8 2868 SMD=− 0.152
LAI superior
− 0.262, − 0.043 0.006 0.080
Abnormally elevated prolactin 2 718 RR = 0.929 0.402, 2.146 0.864 0.058
Prolactin decreased 1 198 RR = 0.117 0.005, 2.830 0.187 [glyph: sbnd]
Study defined hyperprolactinemia 2 838 RR = 0.597 0.070, 5.075 0.637 0.321
Amenorrhea 2 121 RR = 0.718 0.077, 6.685 0.771 0.625
Dysmenorrhea 1 640 RR = 1.006 0.063, 16.018 0.996 [glyph: sbnd]
Menstruation disorder 1 76 RR = 0.407 0.027, 6.229 0.519 [glyph: sbnd]
Galactorrhea 2 838 RR = 1.186 0.230, 6.117 0.838 0.761
Erectile dysfunction 2 321 RR = 5.281 0.929, 30.022 0.061 0.398
Ejaculation failure 1 640 RR = 0.335 0.014, 8.203 0.503 [glyph: sbnd]
Abnormal sexual function 1 640 RR = 0.503 0.046, 5.521 0.574 [glyph: sbnd]
Decreased libido 1 293 RR = 5.313 0.706, 39.977 0.105 [glyph: sbnd]
 
Other adverse event
Central nervous system
 Insomnia 10 3756 RR = 1.095 0.903, 1.328 0.354 0.601
 Somnolence 4 1833 RR = 1.116 0.741, 1.681 0.599 0.686
 Sedation 3 389 RR = 1.026 0.418, 2.516 0.956 0.675
 Post-injection delirium/sedation syndrome (olanzapine only) 2 1455 RR = 2.692 0.130, 55.897 0.522 [glyph: sbnd]
 Hypersomnia 1 45 RR = 0.413 0.018, 9.617 0.582 [glyph: sbnd]
 Headache 8 3206 RR = 0.784 0.601, 1.024 0.074 0.706
 Dizziness 3 862 RR = 0.710 0.331, 1.524 0.379 0.552
 Asthenia 1 45 RR = 3.714 0.159, 86.549 0.414 [glyph: sbnd]
 Hypoesthesia 1 45 RR = 0.413 0.018, 9.617 0.582 [glyph: sbnd]
 Paraesthesia 1 45 RR = 3.714 0.159, 86.549 0.414 [glyph: sbnd]
 Agitation 1 293 RR = 0.817 0.209, 3.193 0.772 [glyph: sbnd]
 Anxiety 7 3049 RR=1.495
OAP superior
1.132, 1.975 0.005 0.902
 Irritability 1 293 RR = 0.245 0.060, 1.003 0.051 [glyph: sbnd]
 Schizophrenia 3 1348 RR = 1.158 0.655, 2.048 0.614 0.679
 Psychotic disorder/psychosis/psychiatric symptom 4 1662 RR = 0.912 0.589, 1.412 0.678 0.965
 Hallucination, auditory 1 293 RR = 0.545 0.125, 2.383 0.420 [glyph: sbnd]
 Depression/depressed mood 3 433 RR = 1.157 0.537, 2.496 0.709 0.684
 Suicidal ideation/attempt 3 793 RR = 0.737 0.278, 1.950 0.539 0.894
 Obsessive thoughts 1 45 RR = 3.714 0.159, 86.549 0.414 [glyph: sbnd]
Cardiovascular adverse event
 Hypertension 3 1015 RR = 0.410 0.101, 1.667 0.213 0.175
 Hypotension 1 198 RR = 0.117 0.005, 2.830 0.187 [glyph: sbnd]
 Orthostasis 1 198 RR = 1.054 0.044, 25.473 0.974 [glyph: sbnd]
 Blood pressure average change (diastolic) 1 83 SMD = 0.249 − 0.183, 0.681 0.259 [glyph: sbnd]
 Blood pressure average change (systolic) 1 83 SMD = − 0.035 − 0.465, 0.396 0.874 [glyph: sbnd]
 QTc average change 1 317 SMD = 0.070 − 0.151, 0.291 0.533 [glyph: sbnd]
Gastrointestinal adverse event
 Diarrhea 3 347 RR = 0.593 0.155, 2.273 0.446 0.194
 Vomiting 3 586 RR = 0.801 0.153, 4.178 0.792 0.097
 Constipation 2 243 RR = 0.715 0.318, 1.608 0.417 0.723
 Nausea 2 99 RR = 0.398 0.043, 3703 0.419 0.975
 Dysphagia 1 198 RR = 1.054 0.044, 25.473 0.974 [glyph: sbnd]
 Dry mouth 1 293 RR = 0.817 0.342, 1.954 0.650 [glyph: sbnd]
 Hypersalivation 2 293 RR = 5.456 0.703, 42.311 0.105 0.861
Others
 UKU 1 50 SMD = − 0.515 − 1.078, 0.049 0.073 [glyph: sbnd]
 Local reaction at the injection site 4 1135 RR = 1.773 0.750, 4.189 0.192 0.082
 ALT level change 1 50 SMD = − 0.059 − 0.613, 0.496 0.836 [glyph: sbnd]
 ALT unusual change 1 198 RR = 0.971 0.368, 2.563 0.953 [glyph: sbnd]
 AST level change 1 50 SMD = 0.021 − 0.534, 0.575 0.941 [glyph: sbnd]
 AST unusual change 1 198 RR = 0.578 0.143, 2.334 0.442 [glyph: sbnd]
 γ-GTP unusual change 1 198 RR = 3.816 0.505, 28.832 0.194 [glyph: sbnd]
 LDH unusual change 1 198 RR = 1.757 0.086, 35.994 0.715 [glyph: sbnd]
 ALP unusual change 1 198 RR = 2.459 0.129, 46.816 0.549 [glyph: sbnd]
 BUN average change 1 50 SMD = 0.286 − 0.271, 0.843 0.314 [glyph: sbnd]
 Cr average change 1 50 SMD = 0.000 − 0.554, 0.554 1.000 [glyph: sbnd]
 CPK average change 1 50 SMD = 0.335 − 0.223, 0.894 0.239 [glyph: sbnd]
 CPK unusual change 1 198 RR = 1.503 0.446, 5.063 0.510 [glyph: sbnd]
 WBC unusual change 1 198 RR = 1.156 0.331, 4.038 0.820 [glyph: sbnd]
 Neutrophil unusual change 1 198 RR = 3.162 0.173, 57.735 0.437 [glyph: sbnd]
 Eosinophil unusual change 1 198 RR = 1.054 0.044, 25.473 0.974 [glyph: sbnd]
 Basophil unusual change 1 198 RR = 1.054 0.044, 25.473 0.974 [glyph: sbnd]
 Lymphocyte unusual change 1 198 RR = 3.162 0.173, 57.735 0.437 [glyph: sbnd]
 Hb unusual change 1 198 RR = 1.054 0.044, 25.473 0.974 [glyph: sbnd]
 Ht unusual change 1 198 RR = 1.054 0.044, 25.473 0.974 [glyph: sbnd]
 Plt unusual change 1 198 RR = 1.054 0.044, 25.473 0.974 [glyph: sbnd]
 Blurred vision 1 45 RR = 3.714 0.159, 86.549 0.414 [glyph: sbnd]
 Gaze palsy 1 198 RR = 0.694 0.064, 7.492 0.763 [glyph: sbnd]
 Fatigue 2 338 RR = 2.081 0.666, 6.496 0.207 0.699
 Vertigo 1 54 RR = 0.580 0.056, 6.022 0.648 [glyph: sbnd]
 Pain 1 95 RR = 10.340 0.588, 181.919 0.110 [glyph: sbnd]
 Back pain 3 878 RR = 0.786 0.426, 1.449 0.440 0.806
 Pyrexia 1 198 RR = 2.776 0.356, 21.653 0.330 [glyph: sbnd]
 Rash 1 198 RR = 1.041 0.293, 3.696 0.951 [glyph: sbnd]

Bolded: p-Values: p < 0.05 in result, p < 0.1 in heterogeneity;

AE, adverse event; AIMS, Abnormal Involuntary Movement Scale; ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; BARS, Barnes Akathisia Rating Scale; BMI, body mass index; BUN, blood urea nitrogen; CI, confidence interval; CPK, creatine phosphokinase; Cr, creatinine; DIEPSS, Drug-Induced Extrapyramidal Symptom Scale; EPS, extrapyramidal symptom; GPT, glutamic-pyruvate transaminase; Hb, hemoglobin, HDL-C, high density lipoprotein cholesterol; LDH, lactate dehydrogenase; Ht, hematocrit; LDL-C, low density lipoprotein cholesterol; N, number of studies; n, number of participants; Plt, platelet; RR, risk ratio (categorical outcomes); SAS, Simpson-Angus Scale; SMD, standardized mean difference (continuous outcomes); UKU, The UKU side effect rating scale; WBC, white blood cell.

3.2. Primary outcome: treatment discontinuation due to adverse events (Fig. 1)

Treatment discontinuation due to adverse events was not significantly different between LAIs and OAPs (RCTs = 14, n = 3570, RR = 1.163, 95%CI = 0.887–1.524, p = 0.275).

Fig. 1

Fig. 1

Forest plot of treatment discontinuation due to adverse events (RCTs = 14, n = 3570, RR = 1.163, 95% CI 0.887–1.524, p = 0.275).

ARI, aripiprazole; FPZ, fluphenazine; LAI, long-acting injectable antipsychotic; OAP, oral antipsychotic; OLA, Olanzapine; PAL, paliperidone; RIS, risperidone.

 

3.3. Key secondary outcome 1: serious adverse events (Fig. 2)

The incidence of serious adverse events was not significantly different between LAIs and OAPs (RCTs = 6, n = 1848, RR = 0.907, 95%CI = 0.662–1.242, p = 0.542).

Fig. 2

Fig. 2

Forest plot of serious adverse events (RCTs = 6, n = 1848, RR = 0.907, 95% CI 0.662–1.242, p = 0.542).

ARI, aripiprazole; LAI, long-acting injectable antipsychotic; OAP, oral antipsychotic; OLA, Olanzapine; RIS, risperidone.

 

3.4. Key secondary outcome 2: death (Fig. 3a and b)

Across 14 studies with information, a total of 9 deaths occurred in 6 studies. Altogether, 3 deaths occurred in the LAI groups (n = 2311) and 6 deaths occurred in the OAP group (n = 1816), without significant group difference (RCTs = 14, n = 4127, RR = 0.613, 95%CI = 0.177–2.128, p = 0.441). Focusing on deaths excluding suicide and accident, there was also no significant difference between LAIs and OAPs (RCTs = 13, n = 3603, RR = 0.695, 95%CI = 0.110–4.399, p = 0.699).

Fig. 3

Fig. 3

a. Forest plot of death (RCTs = 14, n = 4127, RR = 0.613, 95% CI 0.177–2.128, p = 0.441).

ARI, aripiprazole; FPZ, fluphenazine; LAI, long-acting injectable antipsychotic; OAP, oral antipsychotic; OLA, Olanzapine; PAL, paliperidone; RIS, risperidone; ZUC, zuclopenthixol.

b. Forest plot of death for reasons excluding accident and suicide (RCTs = 13, n = 3603, RR = 0.695, 95% CI 0.110–4.399, p = 0.699).

ARI, aripiprazole; FPZ, fluphenazine; LAI, long-acting injectable antipsychotic; OAP, oral antipsychotic; OLA, Olanzapine; PAL, paliperidone; RIS, risperidone; ZUC, zuclopenthixol.

 

3.5. At least one adverse event (Fig. 4)

The incidence of at least one adverse event was not significantly different between LAIs and OAPs (RCTs = 7, n = 2686, RR = 1.026, 95%CI = 0.984–1.071, p = 0.231).

Fig. 4

Fig. 4

Forest plot of at least one adverse event (RCTs = 7, n = 2686, RR = 1.026, 95% CI 0.984–1.071, p = 0.231).

ARI, aripiprazole; LAI, long-acting injectable antipsychotic; OAP, oral antipsychotic; OLA, Olanzapine; PAL, paliperidone; RIS, risperidone.

 

3.6. Extrapyramidal side effects (Table 2)

There were no significant differences between LAIs and OAPs regarding the risk of any extrapyramidal side effects (EPS), use of anti-EPS medications and mean score changes on any scales for EPS. Regarding individual EPS, only one study with fluphenazine decanoate reported data about akinesia, showing higher rates of akinesia than with oral fluphenazine (n = 51, RR = 20.542, 95%CI = 1.249–337.941, p = 0.034, NNH = 3). No significant differences between LAIs and OAPs were observed regarding other EPS.

3.7. Weight and metabolic abnormalities (Table 2)

Among studies of FGA-LAIs, only one study (del Giudice et al., 1975) reported adverse events about weight change, and none reported metabolic adverse events. SGA-LAIs were associated with significantly greater increases in low-density lipoprotein (LDL) cholesterol change than OAPs (RCTs = 4, n = 1950, SMD = 0.096, 95%CI = 0.006–0.186, p = 0.037). There were no differences between LAIs and OAPs regarding weight change and other metabolic parameters.

No FGA-LAIs study reported adverse events related to prolactin or sexual functioning. Participants randomized to LAIs increased prolactin significantly less than the respective OAPs (RCTs = 8, n = 2868, SMD = − 0.152, 95%CI = − 0.262 to − 0.043, p = 0.006). There were no significant between-group differences related to sexual and reproductive functioning.

3.9. Other adverse event (Table 2)

Participants on LAIs had a significantly greater risk of anxiety than in OAPs group (RCTs = 7 (only SGA-LAIs), n = 3409, RR = 1.495, 95%CI = 1.132–1.975, p = 0.005, NNH = 40). None of the other adverse events differed significantly between LAIs and OAPs.

3.10. Subgroup analyses (Supplemental Table 1)

There were no significant differences between LAIs and OAPs in any subgroup analyses. However FGA-LAIs trended toward a higher risk of treatment discontinuation due to adverse events than the respective FGA OAPs (RCTs = 3, n = 370, RR = 2.872, 95%CI = 0.917–8.993, p = 0.07).

3.11. Publication bias (Supplemental Fig. 3)

Although the funnel-plot was asymmetrical, imputing missing studies did not change the lack of difference regarding the primary outcome, treatment discontinuation due to adverse events (RR = 1.049, 95%CI = 0.764–1.440).

4. Discussion

In this systematic review and meta-analysis, we examined 119 different adverse event outcomes from 16 RCTs and 4902 participants. Previous meta-analysis comparing LAIs with OAPs included mostly studies where the specific antipsychotics in the LAI and OAP groups differed, and adverse event outcomes were scarcely considered, if at all (Fusar-Poli et al, 2013, Haddad et al, 2009, Kirson et al, 2013, Kishimoto et al, 2013, Kishimoto et al, 2014, Leucht et al, 2011b, Taylor and Ng, 2013, and Zhornitsky and Stip, 2012). The present study systematically reviewed all reported adverse events, focusing on RCTs and the head-to-head comparison of the same antipsychotic with the only difference being their use as an LAI or OAP formulation.

Overall, we found that 1) out of all 119 reported adverse events, LAIs and OAPs did not differ significantly regarding 115 adverse events (96.6%); 2) LAIs were similar to OAPs regarding outcomes signaling the severity and relevance of adverse events, i.e., the frequency of treatment discontinuation due to adverse events, serious adverse events, all-cause death and death for reasons excluding accident or suicide; 3) isolated adverse event advantages existed for OAPs (i.e., akinesia, low-density lipoprotein cholesterol change and anxiety) as well as LAIs (prolactin change); and 5) overlapping adverse events were scarcely reported in RCTs that directly compared the same LAI and OAP, with only 55 (46.2%) of the relevant adverse events being reported by ≥ 2 studies and 44 (37.0%) adverse events being reported in > 500 patients. Although some adverse events may not have shown at an earlier time point than 5 half-lives of the respective LAI (Lee et al., 2015), all of the eligible and meta-analyzed RCTs had a long-term study duration, which was > 12 weeks.

The result of no difference in adverse events in > 90% of recorded outcomes is valid because the same LAI and OAP antipsychotics were compared head-to-head (pooling oral risperidone and paliperidone). Nevertheless, due to the difference in pharmacokinetics, adverse events associated with LAIs might last longer and advance to more severe stages ones once they occur than those emerging during OAP treatment, which can be stopped rapidly. Therefore, we were particularly interested in examining adverse events that would signal severity and seriousness. However, results of this meta-analysis indicate that despite the inability to discontinue LAIs abruptly, neither treatment discontinuation due to adverse events nor incidence of serious adverse events nor death were significantly more likely during LAI than OAP treatment. Similarly, recent meta-analyses comparing LAIs with OAPs also reported a lack of discontinuation due to adverse events, even when mixing together different antipsychotics in most of the OAP comparison group (Fusar-Poli et al, 2013, Kishimoto et al, 2013, and Leucht et al, 2011a). In exploratory subgroup analyses, FGA-LAIs studies showed a trend toward higher discontinuation due to adverse events than FGA-OAPs, while this was not the case with SGA-LAIs. Although few RCTs compared FGA-LAIs and SGA-LAIs, no difference in the proportion of discontinuation due to adverse events was reported in a head-to-head trial of haloperidol decanoate and paliperidone palmitate (McEvoy et al., 2014).

There were no relevant differences in almost all EPS between LAIs and OAPs, but LAIs were associated with a greater incidence of akinesia. The results in previous meta-analysis were consistent. In a systematic meta-review of FGA-LAIs, no clear differences were demonstrated between LAIs and OAPs for EPS requiring adjunctive anticholinergic medication (Adams et al., 2001). The review about fluphenazine decanoate and enanthate from the Cochrane group reported that extrapyramidal adverse events were significantly less common with fluphenazine decanoate compared with pooled OAPs (Maayan et al., 2015). On the other hand, there was a greater risk of developing EPS with SGA-LAIs than OAPs in a meta-analysis of SGA-LAIs (Fusar-Poli et al., 2013). However, since only pooled period incidence data are available, it is unclear to what degree at least some of this increased incidence of EPS may be due to the LAI initiation with overlapping OAP treatment, such as with risperidone LAI and aripiprazole LAI. Thus, although there is some possibility that LAIs have a higher risk of some EPS, the difference is small and does not lead to greater treatment discontinuation, indicating either mild or transient forms of EPS.

There were not differences regarding weight gain and all metabolic adverse events between LAIs and OAPs, except for LDL-cholesterol. Fusar-Poli et al. (2013) reported in a meta-analysis of SGA-LAIs that no significant differences in weight gain were observed between SGA-LAIs and OAPs, suggesting that the metabolic effects are independent of the route of administration. However, the finding of increased LDL-cholesterol pooling data from each 2 studies of aripiprazole and olanzapine may suggest that increased adherence could result in an isolated increase of adverse metabolic effects.

LAIs were associated with a significantly lower change in serum prolactin levels, although there were no significant differences in any sexual or reproductive symptoms related to prolactin increase. Although FGAs as a group probably more strongly adversely influence prolactin and sexual functioning, we were unable to compare SGA-LAI and FGA-LAI effects versus the respective OAPs, as no study of FGA-LAIs reported these adverse events.

Our results also indicated that LAIs had a significantly greater risk of anxiety than OAPs. A prior meta-analysis showed that SGA-LAIs were effective in reducing anxiety levels when compared with placebo, and there was no difference between SGA-LAIs and OAPs (Fusar-Poli et al., 2013). The difference in findings may be related to the differences in the OAP comparator group, but the differences were also not large (NNH = 40).

Results of this meta-analyses have to be interpreted in the context of several limitations.

There was a limited number of studies available for these analyses and specific adverse events.

Although patient report was the general method, the type of adverse events reported and the ways to report adverse events varied across studies, including reporting thresholds. For example, some studies reported adverse events occurring in ≥ 3% of participants and others reported those occurring in ≥ 5%. Thus, due to this reporting bias that excluded very rare events from being mentioned in most publications and due the likely lack of power to detect such rare adverse events, we were unable to include a comparison of some potentially important adverse events, such as neuroleptic malignant syndrome, water intoxication, etc.

Severity and time course of adverse events were not reported. The latter is particularly important for LAIs that require oral cotreatment after the initial injection, as the reported adverse event frequencies with such LAIs (i.e., risperidone and aripiprazole) could very well be due to oral antipsychotic effects during the first few weeks.

Adverse events reported in several studies included items related to psychiatric symptoms, such as schizophrenia, psychosis, suicidal ideation, etc. Although these symptoms could be deterioration of the illness rather than adverse reactions to antipsychotic treatment, they were counted as adverse events in several outcomes, including in the rate of treatment discontinuation due to adverse events, which can complicate the interpretation of the findings, even though this methodology was applied to LAIs and OAPs.

In some of the studies included in this meta-analysis, patients had already been stabilized on OAPs before randomization, which likely led to a preselection of patients who were not only responding to but also tolerant of that OAP. However, in subgroup analyses, we found no differences regarding the primary outcome “discontinuation due to adverse effects” among patients in studies with vs. without lead-in with the respective OAP. Nevertheless, we cannot rule out potential differences in individual adverse event rates, for which there were insufficient data to conduct meaningful subgroup analyses.

Although there was no significant difference on the primary outcome in overall and subgroup analyses, this meta-analysis cannot rule out that there may be differences between LAIs and OAPs in specific adverse event risks because of the possibility that the power to detect minimally important differences was insufficient for the overall analyses and because there were insufficient data to conduct subgroup analyses for each individual adverse event. This limitation applies particularly to the post-injection delirium/sedation syndrome that has been associated solely with olanzapine LAI and which has led to a black box warning and required post-injection observation time. Although for completeness sake, we compared the rates of the post-injection delirium/sedation syndrome with olanzapine LAI vs oral olanzapine, we recognize that due to the very low incidence rate of this potentially serious adverse event, the sample size was too small to yield informative results. To estimate the risk of such rare events, especially if they only occur with one formulation, post-marketing surveillance data are far more appropriate than RCTs.

Controlled trials must take special care not to impose undue risks on subjects, especially as they could be long lasting with LAI treatment, leading to exclusion of certain subjects and careful/controlled dosing and titration schedules. Therefore, the results of this meta-analysis might be a conservative estimate for some or all of the adverse event risks compared to LAI use in the general clinical population. While our findings are still relevant, the limitations outlined above calls for the conduct of more real-world comparative studies of the same antipsychotic used either in a LAI or oral formulation.

In conclusion, results from this meta-analysis suggest that based on the still relatively limited evidence, there are few and mostly small differences in the tolerability of LAIs and OAPs. Notably, the results indicate that compared with OAPs that can be stopped readily, LAIs were not associated with more adverse events that would be serious or lead to treatment discontinuation or, even, death. Therefore, the pharmacokinetic difference of giving LAI treatment in one bolus that will stay in the system for weeks or months to come should not deter clinicians and patients from using LAIs when appropriate and potentially helpful.

Conflict of interest

FM has received speaker's honoraria from Sumitomo Dainippon, Eli Lilly, Janssen, Novartis, Otsuka and Pfizer.

TK has received consultant fees from Sumitomo Dainippon, Novartis, Otsuka and speaker's honoraria from Banyu, Eli Lilly, Sumitomo Dainippon, Janssen, Novartis, Otsuka and Pfizer. He has received grant support from the Pfizer Health Research, Takeda, Tanabe-Mitsubishi, Dainippon Sumitomo Pharma, Otsuka Pharmaceutical and Mochida Pharmaceutical Company.

KH is an employee of Sumitomo Dainippon Pharma, Japan.

JK has received honoraria for lectures and/or consulting from Alkermes, Bristol Myers Squibb, Eli Lilly, Forrest Labs, Forum, Genentech, Intracellular Therapies, Janssen, Johnson and Johnson, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Reviva, Roche, and Sunovion. He has received grant support from Genentech, Johnson and Johnson and Otsuka Pharmaceutical. He is a shareholder of MedAvante and Vanguard Research Group. He has received grant support from Otsuka and the National Institute of Mental Health.

CC has been a consultant and/or advisor to or has received honoraria from AbbVie, Actavis, Actelion, Alexza; Alkermes, Bristol-Myers Squibb, Cephalon, Eli Lilly, Genentech, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, Lundbeck, Medavante, Medscape, Merck, Otsuka, Pfizer, ProPhase, Reviva, Roche, Sunovion, Supernus, Takeda, Teva, and Vanda. He has received grant support from the American Academy of Child and Adolescent Psychiatry, the Bendheim Foundation, Bristol-Myers Squibb, the National Institute of Mental Health, Novo Nordisk A/S, Otsuka Pharmaceutical, Takeda and the Thrasher Foundation.

Contributors

All authors contributed to the study design and interpretation of results. FM contributed to literature search, data extraction/entering, statistical analysis, and writing of the report. TK contributed to literature search, data extraction, and writing of the report. KH contributed to literature search, data extraction/entering, statistical analysis, and writing of the report. CUC contributed to literature search, data extraction, statistical analysis, and writing of the report. All authors participated in critical revision of manuscript drafts and approved the final version.

Role of funding source

There is no funding source to declare.

Acknowledgements

We thank Drs. Subotnik and Alphs who kindly provided unpublished data for our analysis.

Appendix A. Supplementary data

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Supplementary material.

 

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Footnotes

a Yamanashi Prefectural KITA Hospital, Yamanashi, Japan

b The Zucker Hillside Hospital, Psychiatry Research, North Shore - Long Island Jewish Health System, Glen Oaks, NY, USA

c Keio University School of Medicine, Tokyo, Japan

d Hofstra Northwell School of Medicine, Hempstead, NY, USA

e The Feinstein Institute for Medical Research, Manhasset, NY, USA

f Sumitomo Dainippon Pharma Co., Ltd., Medical Affairs, Tokyo, Japan

g Albert Einstein College of Medicine, Bronx, NY, USA

Corresponding author at: The Zucker Hillside Hospital; 75–59 263rd Street, Glen Oaks, NY 11004, USA.