Switching antipsychotics to partial dopamine D2-agonists in individuals affected by schizophrenia: a narrative review

Figures & data

Figure 1. Switch strategies for withdrawal of drug A (red) and introduction of drug B (blue)

Table 1. Switching strategies from a treatment with antipsychotic drug A to antipsychotic drug B.

Strategy
Nr	Characteristics	Drug A	Drug B	Figure
1	Abrupt switch	Immediate discontinuation	Immediate introduction at full dose	1 A
2	Gradual switch	Gradual discontinuation	Delayed introduction, and gradual dose increase	1B
3	Cross-taper switch (overlapping switch)	Gradual discontinuation	Immediate introduction, and gradual dose increase	1 C
4	Hybrid strategy: Gradual – immediate	Gradual discontinuation	Immediate introduction at full dose	1D
5	Hybrid strategy: Immediate – immediate/gradual	Immediate discontinuation	Immediate introduction, and gradual dose increase	1E
6	Hybrid strategy: Plateau switch (also known as overlap and taper)	Full dose then gradual discontinuation	Gradual or immediate introduction	1F

Figure 2. Literature search flow.

Table 2. Switching from a treatment with antipsychotics (drug A) to ARI (drug B) using different strategies.

Study (Nr)	Study type (duration)	Sample diagnosis	Reasons for switching	Previous antipsychotic medication	Discontinuation strategy	Switching strategy	Efficacy	Adverse effects	Discontinuation rate (n: total number of included patients)
Casey et al., (2003) (1)	Open multicentre study (8 weeks)	(Chronic) schizophrenia, schizoaffective disorder (DSM-IV) (Stable for at least 1 month before switch. No hospitalisation for an exacerbation for at least 2 months)	Adequate clinical reason for trying a new antipsychotic drug (i.e. ARI) other than current therapy (no details communicated)	For at least one month before switch: Olanzapine and risperidone (92%); haloperidol (5%), other typical AP (3%) (doses not precised)	Group 1: Immediate discontinuation	Group 1 (Strategy 1 – Figure 1A): Immediate initiation (30 mg/day ARI, single morning dose)	All 3 switching strategies: Favourable efficacy: Improvements in both positive and negative symptoms	All 3 switching strategies: Favourable safety and tolerability (EPS)). Most frequent AE: mild to moderate insomnia: Groups 1–3: 28% − 33%. Nausea (11–22%) and vomiting (2–12%): Lower in group 3 than in groups 1 (22%) and 2 (22%). Akathisia (mostly, low to moderate): Higher in group 3 (21%) than in groups 1 (15 %) and 2 (11%). SAE (hospitalisation): 7% (mostly worsening of schizophrenia)	Group 1 (n = 104): 31%
					Groups 2 and 3: Tapering off current AP treatment over the first 14 days (i.e. week 1: decrease of the dose to 50% of the previous week; 2nd week: decrease of the dose to 50 % of week 1; start of week 3: total discontinuation)	Group 2 (Strategy 4 – Figure 1D): Immediate initiation (30 mg/day ARI, single morning dose)			Group 2 (n = 104): 34%
						Group 3 (Strategy 3 – Figure 1C): Uptitrating of ARI: 1st week: 10 mg/day; 2nd week: 20 mg/day; 3rd week: 30 mg/day over 2 weeks			Group 3 (n = 103): 19%
Takeuchi et al., (2008) (2)	Randomised open-label, parallel group study (14 weeks)	Schizophrenia (DSM-IV)	n.a.	Risperidone, olanzapine and others	Group 1 (Wait group): Subsequent tapering of previous AP (biweekly by 25%) after 4 weeks ARI treatment	Group 1 (Strategy 6 – Figure 1F): Immediate add-on ARI (12 mg/day during 2 weeks), then titration between 12 and 30 mg/day	No clear differences between groups, and between baseline and endpoint	Group 1: Insomnia: 19%	Group 1 (n = 26): 4%
					Group 2 (No-wait group): Tapering of previous AP (biweekly by 25%)	Group 2 (Strategy 3 -m Figure 1C): Immediate add-on ARI (12 mg/day during 2 weeks), then titration between 12 and 30 mg/day		Group2: Insomnia: 26%	Group 2 (n = 27): 15%
Kim et al., (2009) (3)	Prospective randomised open label multicentre study (12 weeks)	Schizophrenia, schizoaffective disorder (DSM-IV)	Weight gain, inadequate control of symptoms, somnolence	Risperidone, olanzapine and others	Group 1: Gradual discontinuation of AP pre-treatment during the first 2 weeks	Group 1 (Strategy 3 – Figure 1C): 10 mg/day ARI, immediately, then adjustement (10–30 mg/day) (investigator’s judgement)	Group 1: Improvement score (CGI-improvement), at 12 weeks: 3.56 ± 1.29. Some superior clinical effect in group 1 vs group 2 (CGI-S (severity) score, PANSS (positive subscale), remission rate.	TEAE: Group 1 vs group 2: 25.6 % vs 4.4 % (insomnia); 16.5 % vs 4.4% (nausea); 10.4 % vs 4.4% headache).	Group 1 (n = 245): 38%
					Group 2: Standard of care (switch to non-partial D2-agonists AP)	Group 2: no switch to partial D2-agonist AP			Group 2 (n = 47): 27.7%
Lin et al., 2009 (4)	Observational study (12 weeks)	Schizophrenia (DSM-IV)	Metabolic problems (53.3%), hyperprolactinaemia (20%), drug efficacy (13.3%), EPS (11.1%), others	Mainly second generation AP (82.2 %) (doses not precised)	Group 1: Abrupt discontinuation	Group 1 (Strategy 5 – Figure 1E): Immediate ARI introduction but no information on dose titration	Clinical scores separately presented only for completers vs non-completers, and not according to switching procedure (group 1 vs group 2)	42.9% of the non-completers terminated treatment in the first 2 weeks of treatment. AE (in all patients): Insomnia:17.8%; anxiety: 8.9%, etc	Group 1 (n = 14): 21.4%
					Group 2: Graduate tapering	Group 2 (Strategy 4 – Figure 1D): Immediate ARI introduction but no information on ARI dose titration			Group 2 (n = 31): 35.5%
Pae et al., (2009) (5)	Randomised open-label study 12 weeks)	Schizophrenia (DSM-IV)	Insufficient efficacy or poor tolerance to current AP treatment	Risperidone, olanzapine, amisulpride, quetiapine	Group 1: Immediate discontinuation	All groups: 10 mg/day ARI immediately, then flexible adjustment (10–30 mg/day). Group 1: Strategy 5 – Figure 1E)	Group 1: Increase of severity (CGI-S) during week 1. Week 2: CGI-S (severity) (group 1) > CGI-S (groups 2 and 3 joined together). Week 4: No difference	No difference between groups regarding AE (headache, anxiety, insomnia, etc)	Group 1 (n = 31) 74%
					Group 2: Tapering off current AP treatment over the first 28 days (i.e. half of the dose after the first 2 weeks)	Group 2: Strategy 3 – Figure 1C			Group 2 (n = 29): 48%
					Group 3: Tapering off current AP treatment over the first 28 days, after maintenance of current dose for 2 weeks	Group 3: Strategy 3 – Figure 1C			Group 3 (n = 27): 44%
Ryckmans et al., (2009) (6)	Comparative, randomised, multicentre, open-label study (12 weeks)	Schizophrenia (DSM-IV-TR)	Insufficient efficacy and/or safety/tolerance issues	Risperidone	Groups 1 and 2: Tapering risperidone (week 1 and 2: current treatment; weeks 3 and 4: 50 % dose; week 5: 0 mg/day)	Group 1 (Strategy 3 – Figure 1C): ARI titration: week 1: 5 mg/day; week 2 and 3: 10 mg/day; week 4–5: 15 mg/day; after week 5: 10–30 mg/day)	Week 12 vs baseline: Similar marked improvement in PANSS scores: Group 1: − 14.8; group 2: − 17.2	No AE with a frequency > 10%.	Group 1 (n = 200): 3.5%
						Group 2 (Strategy 4 – Figure 1D): ARI fixed dose (weeks 1–5: 15 mg/day; then 10–30 mg/day)			Group 2 (n = 200): 5%
Stroup et al., (2011) (7)	Randomised controlled multicentre study (24 weeks)	Schizophrenia, schizoaffective disorder	Metabolic profile: Increased risk for cardiovascular disorders	5–20 mg/day, olanzapine, 200–1200 mg/day quetiapiine, 1–16 mg/day risperidone	Group 1: Week 1: Current treatement for 1 week, at the same doses; week 2: dose reduction 25–50%; after 3 weeks: medication stopped	Group 1 (Strategy 6–Figure 1F): Week 1: Initiation with 5 mg/day ARI; week 2: 10 mg/day; week 3: 15 mg/day if needed; after 3 and 4 weeks: 5–20 mg/day and 5–30 mg/day, respectively	Groups 1 and 2: Similar decrease in PANSS- (− 5.0 vs −3.9) and CGI-S scores. Decrease of SF-12 physical health and IWQoL scores: Group 1 > group 2	Moderate or severe AE (24 weeks, > 20 %: observed in both groups separately): Insomnia, sleepiness, dry mouth, akathisia/activation, problems with sex drive.	Group 1 (n = 109): Within 1 month (within 24 weeks): 16.8% (47.7%)(p < 0.001)
					Group 2: Continuation of current treatment	No switch			Group 2 (n = 106): 7.5% (27.4%)
Chen et al., (2012) (8)	Prospective, randomised, open-label study (12 months)	Schizophrenia, schizoaffective or bipolar disorder (DSM-IV-TR)	Risky metabolic profile	Mainly quetiapine, risperidone, olanzapine	Groups 1 and 2 : Discontinuation within 2 weeks	Groups 1 and 2: Target dose reached within 2 weeks (investigator’s judgement). Group 1: (Strategy 3 – Figure 1C) 5–30 mg/day ARI.	Time or group × time interaction effects for YMRS, CGI-S or PANSS total or subscale scores: ns. Changes in any of these measures from baseline were observed in either treatment group: ns	Group 1 (12 months): no patient discontinued treatment because of adverse effects. AE: insomnia (n = 9), nausea/gastrointestinal upset (n = 4), nervousness/anxiety (n = 5), tremor (n = 4)	Group 1 (n = 24): 33% (6 months)
						Group 2: (Strategy 3 – Figure 1C) 40–160 mg/day ZIPR			Group 2 (n = 28): 32% (6 months) (ziprasidone)
Hwang et al., (2015) (9)	Open-label, randomised, parallel study (8 weeks)	Schizophrenia, schizoaffective disorder (DSM IV) (chronic and stable)	Inadequate efficacy or adverse effects of the current medication	Sulpiride, flurazine, haloperidol, olanzapine, risperidone, amisulpride and others	Group 1 (Fast tapering): Within 1 week after initiation of ARI treatment for 2 weeks	Groups 1 and 2: (Strategy 6 – Figure 1F) immediate full dose (15 mg/day) ARI, given as a single morning dose	In both groups, significant decrease in total, negative and general psychopathology PANSS scores, but not in positive PANSS scores. Any PANSS score: no difference between groups,	EPS: no time-by-group interaction. BAS score: Higher in group 2 than in group 1	Group 1 (n = 26): 23.7%
					Group 2 (Slow tapering): Within 4 weeks (approx. 25%/week) after initiation of ARI treatment for 2 weeks				Group 2 (n = 27): 43.9% (p < 0.1: group 1 vs group 2)
Obayashi et al., (2020) (10)	Historical multicentre cohort study (real clinical practice) (6 months)	Chronic schizophrenia	Psychiatric symptoms, adverse effects, both	Risperidone (n = 72), olanzapine (n = 51), and others (n = 43), and combination therapy (n = 12)	Group 1 : Add-on switching: Previous AP treatment was not changed for at least one week. Then, previous AP was tapered off	Groups 1–3: ARI dose at start and target: flexible (clinical judgement). Group 1 (Strategy 6 – Figure 1F): During tapering off of previous AP, ARI was started for a 6-month treatment; starting dose: 8.62 ± 6.42 mg/day	Groups 1–3: Improvement (CGI score change): Group 1: in 66.7% patients; group 2: 56.5%; group 3: 46.5%	Group 1: adverse reactions in 28.9% patients; EPS: in 20% patients	Group 1 (n = 45): 28.9%
					Group 2 : Cross switching: Tapering off previous AP	Group 2 (Strategy 3 – Figure 1C): During tapering off previous AP, ARI (dose at start and target: flexible) treatment was started for a 6-month treatment; starting dose: 11.2 ± 6.43 mg/day	Group 2: 56.5%	Group 2: Adverse reactions: 21.0%; EPS: 12.9%	Group 2 (n = 62): 41.9%
					Group 3: Direct switching: Immediate stop of previous AP treatment	Group 3 (Strategy 1 – Figure 1A, or strategy 5 – Figure 1E): ARI was started immediately (dose at start and target: flexible); starting dose: 9.99 ± 6.55 mg/day	Group 3: 46.5%	Group 3: Adverse reactions: 16.9%. EPS: 7%	Group 3 (n = 71): 53.6%

Abbreviations: AP: Antipsychotics; ARI: Aripiprazole; ZIPR: ziprasidone.

Ratings: AE: Adverse effects; BAS: Barnes Akathisia rating scale; CGI: Clinical Global Impression scale; CGI-S (severity); IWQoL: Impact of weight on Quality of life; PANSS: Positive and negative symptoms scale; SAE: Serious adverse events; TEAE: Treatment-emergent adverse events.

n.a.: not available; ns: not significant.

Table 3. Switching from a treatment with antipsychotics (drug A) to BREX or CARI (drug B) using different strategies.

Study (Nr)	Study type (duration)	Sample diagnosis	Reasons for switching	Previous antipsychotic medication	Discontinuation strategy	Switching strategy	Efficacy	Adverse effects	Discontinuation rate (n: total number of included patients)
Brexpiprazole (BREX)
Correll et al. (2019) (11)	Open label (8 weeks)	Schizophrenia (DSM-IV)	Acute exacerbation of psychotic symptoms (PANSS total score > 80)	> 10 % of the patients: Risperidone > olanzapine > quetiapine > haloperidol > aripiprazole	Group 1–4: Length of tapering phase (conversion time): Group 1: 1–7 days	Groups 1–4: Strategy 3: Cross tapering switch (Figure 1C). Initiate on 1 mg/day BREX, then adjust 1–4 mg/day BREX over 1–4 weeks (investigator’s judgement), while gradually reducing the dose of other antipsychotic	292/ 404 (72.3%) patients: conversion to BREX and completion of 8-week study: Group 1: 2.4%; group 2: 6.5%; group 3: 11.0%; group 4: 80.1%. No difference in improvement in total PANSS or CGI-S scores from baseline	TEAE (n = 404): Insomnia: 11.1%; Headache: 7.2%, agitation: 6.2%; akathisia: 5.2%	Patients who received at least one BREX dose in the conversion phase (n = 404): 13.4%
					Group 2: 8–14 days
					Group 3: 15 –21 days
					Group 4: 22–33 days
Ichinose et al., (2021) (12)	Open label study (8 weeks) (improvement of side effects)	Schizophrenia, schizoaffective disorder (DSM-V)	Side effects: extrapyramidal symptoms, weight gain, hyperglycaemia, hyperlipidaemia, hyperprolactinaemia, etc	> 10 % of the patients: Risperidone, blonanserin, olanzapine or paliperidone *	Groups 1 and 2: Gradual discontinuation	Groups 1 and 2 together: BREX dose not fixed (at endpoint: 1.9 ± 0.3 mg/day). Group 1: Strategy 6 – Figure 1F	PANSS total score, CGI-S: No significant changes (baseline vs endpoint)	DIEPSS: significant decrease (p = 0.008). Body weight and BMI: significant decreases	Groups 1 (n = 24) and 2 (n = 13): 27% (includes worsening of schizophrenia: (n = 10); irritation (n = 2); insomnia (n = 2))
						Group 2: Strategy 3 – Figure 1C
Ishigooka et al., (2020) § (13)	Open label study (8 weeks) as part of a longterm study (52 weeks)	Schizophrenia	Need for chronic antipsychotic treatment (investigator’s opinion); considered for monotherapy with BREX	> 5 % of the patients: Aripiprazole (n = 82), olanzapine, risperidone or paliperidone	Constant dose treatment with current AP during 2 weeks, followed by its tapering off during 2 weeks	Strategy 6 – Figure 1F: Immediate initiation of BREX. Weeks 1 and 2: 1 mg/day; weeks 3 and 4: 1–2 mg/day; week 5: 1–3 mg/day; weeks 6 and 7: 1–4 mg/day	No substantial change in PANSS total score, from baseline till week 8	During this phase, no notable change in AE, except decrease of nasopharingitis (from 9.5% to 6.1%)	Whole group (n = 200): 17.0% (Consent withdrawal: 9.5%; adverse events: 5.5%; etc). Discontinuation rate during the 4-week-switch and 4-week post-switch phase: 9.5% and 8.3%, respectively.
Ishigooka et al., (2021) § (14)	Open label study (8 weeks) as part of a longterm study (52 weeks)	Schizophrenia	Need for chronic antipsychotic treatment (investigator’s opinion); considered for monotherapy with BREX	Only atypical AP (except clozapine). Aripiprazole (n = 82); other atypical AP: n = 104 (risperidone (33), paliperidone (16), olanzapine (36), quetiapine (8))	Constant dose treatment with current AP during 2 weeks, followed by its tapering off during 2 weeks	Strategy 6 – Figure 1F: Immediate initiation of BREX. Weeks 1 and 2: 1 mg/day; After 2 to 3 weeks: 2 mg/day (4-week switch period), then 1–4 mg/day	From baseline to week 56: Small decreases in the PANSS- and CGI-S scores	Most common TEAEs: Nasopharyngitis, schizophrenia, headache, akathisia, etc	Whole group (n = 186): 45.2% (32.9% ARI subgroup; 54.8% other AP (consent withdrawal: 20.7 % (ARI), 27.9% (other AP); AE: 8.5% and 15.4%, respect., exacerbation of schizophrenia (6.1% and 12.5%, respect.))
Cariprazine (CARI)
Nemeth et al., (2017) (15)	Phase II/III clinical study (26 weeks)	Schizophrenia, predominent negative symptoms	High PANSS-FSNS score	n.a.	Tapering off of current AP within the first 2 (- 4) weeks	Strategy 3 – Figure 1C. Immediate uptitration of CARI: days 0–6: 1.5 mg/day; days 7–13: 3 mg/day; Day 14: target dose: 4.5 mg/day	n.a. for the 2 (- 4) –week switch phase	n.a. for the 2 (- 4) –week switch phase	Whole group: n = 227: Uptitration phase (2 (- 4) –weeks)): CARI: 4%; risperidone: 2%

AP: Antipsychotics; BREX: Brexpiprazole; CARI: Cariprazine.

Ratings: AE: Adverse effects; CGI: Clinical Global Impression scale; CGI-S (severity); DIEPSS: Drug Induced Extrapyramidal Symptoms scale; PANSS: Positive and negative symptoms scale; TEAE: Treatment-emergent adverse events.

n.a.: not available; §: These 2 studies are parts from the same clinical trial (NCT 01456897).

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