A Review of Switching Strategies for Patients with Schizophrenia Comorbid with Metabolic Syndrome or Metabolic Abnormalities

Figures & data

Table 1 Relative MetS Risk of Commonly Used Antipsychotics

Drug		Receptor Antagonism (Based on Receptor Occupancy)			MetS Risk – Lipids	MetS Risk – Glucose	MetS Risk – Body Weight
		5-HT2C	H1	M3
FGAs	Haloperidol	–	–	–	Low	Medium	Low
	Sulpiride	–	–	Low	Low	Low	Low
	Chlorpromazine	High	High	Low	High	High	High
SGAs	Clozapine	High	High	High	High	High	High
	Olanzapine	High	High	Low	High	High	High
	Risperidone	Medium	Medium	–	Medium	Medium	Medium
	Paliperidone	Medium	Low	–	Medium	Medium	Medium
	Quetiapine	Low	High	Low	Medium	Medium	Medium
	Ziprasidone	Medium	Low	–	Low	Low	Low
	Aripiprazole	Low	Low	–	Low	Low	Low
	Amisulpride	–	–	–	Low	Low	Low
	Asenapine	High	High	–	Medium	Medium	Medium
	Lurasidone	Medium	Low	–	Low	Low	Low
	Serindole	High	–	–	Low	Low	Medium
	Cariprazine	Low	Low	–	Low	Medium	Low
	Brexpiprazole	Low	Low	–	Low	Low	Low

Notes: Receptor antagonism: Results are excerpted from Aringhieri et al,³⁸ Montastruc et al,⁴⁰  Stahl et al³⁶. Relative receptor antagonism ranking is based on receptor occupancy; “–” refers to no receptor occupancy. MetS risk of lipids/glucose/body weight: Relative MetS risk ranking is based on multiple international guidelines and meta-analyses, including Galletly et al,⁴² Hasan et al,⁴³ Zhao et al. ⁴⁴

Abbreviations: FGAs, first-generation antipsychotics; SGAs, second-generation antipsychotics; MetS, metabolic syndrome.

Table 2 Summary of Evidence for Switching to Antipsychotics with Lower MetS Risks

Post-Switching of Drug	Study	Study Population	Switching Schedule	Follow-Up Period	Outcome
					Metabolic Parameters	Psychotic Symptoms	Discontinuation/Completion Rate
Amisulpride	Lin CC. et al^Citation69 Prospective and open label	92 inpatients with schizophrenia or schizoaffective disorder who were treated with SGAs; BMI > 27 kg/m^2	Initial group (n = 46): continue initial drug Switching group (n = 46): cross-tapering to Amisulpride within 4 weeks, maximum 1000 mg/d	12 months	Switching vs initial group: reduced body weight and BMI; improved TG and total cholesterol; increase HDL-C; reduced blood glucose; reduced blood pressure and heart rate; Switching group M12 vs baseline: reduced prevalence of MetS (30.4% vs 65.2%)	Switching group M12 vs baseline: no significant difference in BPRS and CGI-S scores	Switching group discontinuation rate: 28.3%
	Kim Y. et al^Citation70 Multi-center, prospective and open label	37 outpatients with schizophrenia unresponsive or intolerant to antipsychotics (mostly with weight gain).	Cross-titration: switching to Amisulpride within 7 days, dose 400–800 mg/d	6 weeks	Switching Week 6 vs baseline: reduced body weight	Switching at Week 6 vs baseline: improved CGI-CB, CGI-S and SSS scores	Switching completion rate: 75.7%
Aripiprazole	Stroup TS. et al^Citation73 Multi-center, parallel, randomized controlled study	215 patients with schizophrenia or schizoaffective disorder who were clinically stable after treatment with antipsychotics; increased risk of cardiovascular disease: BMI ≥ 27 kg/m^2; and non-HDL-C ≥130 mg/dl	Initial group (n = 106): continue initial drug. Switching group (n = 109): cross-tapering to Aripiprazole within 4 weeks, dose 5–30 mg/d	24 weeks	Switching vs initial group: reduced non-HDL-C, body weight, BMI, and TG levels	Switching vs initial group: no significant difference in efficacy failure rate, total PANSS, CGI-S, and SF-12 (MHS) scores; improved SF-12 (PHS) and IWQOL-lite scores	Switching vs initial group discontinuation rate: 43.9% vs 24.5%
	Newcomer JW. et al^Citation74 Multi-center, randomized, double-blind controlled study	173 patients with schizophrenia and schizoaffective disorder who were treated with olanzapine, with BMI ≥27 kg/m^2 and CGI-S score ≤4	Initial group (n = 85): Olanzapine continued Switching group (n = 88): cross-tapering to Aripiprazole within 2 weeks, dose 10–30 mg/d	16 weeks	Switching vs initial group: improved changes of body weight, fasting total TG, fasting total cholesterol and HDL-C; numerically better in the changes of LDL-C; no difference in the changes of glycemic parameters	Switching vs initial group: worse CGI-I endpoint scores (p < 0.001)	Switching vs initial group discontinuation rate: 36% vs 26%
	Wani RA. et al^Citation75 Randomized, double-blind, open label	62 patients with schizophrenia who were stable on Olanzapine, comorbid with MetS	Initial group (n = 31): Olanzapine 10–20 mg/d continued. Switching group (n=31): cross-tapering to Aripiprazole within 4 weeks, dose 10–30 mg/d.	24 weeks	All parameters of MetS (waist circumference, blood pressure, TG, rapid blood glucose and HDL-C): deteriorated in the initial group; improved in the switching group; Switching vs initial group: reduced prevalence of MetS: 42.8% vs 100% at week 24	Switching vs initial group: no significant difference in PANSS total and CGI-I scores at week 24	Switching vs initial group discontinuation rate: 32.2% vs 16.1%
	Casey DE. et al^Citation76 Multi-center, randomized controlled, open label	311 outpatients with schizophrenia or schizoaffective disorder who were stably treated with SGAs and FGAs	Group 1 (n = 104): Aripiprazole started at 30 mg/d and the initial drug discontinued; Group 2 (n = 104): Aripiprazole started at 30 mg/d and the initial drug gradually decreased within 2 weeks; Group 3 (n = 103): Aripiprazole titrated to 30 mg/d within 3 weeks (10 mg/d in the first week, 20 mg/d in the second week, 30 mg/d in the third week), and the initial drug gradually decreased within 2 weeks.	8 weeks	Week 8 vs baseline: Moderately reduced body weight in three groups, with no significant difference among groups. No significant difference among groups in blood pressure, heart rate and other laboratory parameters.	Continuous improvement in PANSS total, positive and negative, CGI-S and CGI-I scores in three groups.	Group 1 vs Group 2 vs Group 3 discontinuation rate: 31% vs 34% vs 19%
	Kim SW. et al^Citation77 Prospective and open label	61 patients with schizophrenia who were stably treated with SGAs	Cross-titration to Aripiprazole within 5–6 weeks, average final dose 18.8 mg/d.	26 weeks	Switching Week 26 vs baseline: improved the total cholesterol level; increased HDL-C level; reduced body weight; no difference in total TG, LDL, and blood glucose levels	Switching Week 26 vs baseline: improved cognitive functions; decreased PANSS total and factor scores.	Switching completion rate: 57.4%
	Chen YJ. et al^Citation78 Prospective, randomized, open label	52 outpatients with schizophrenia or with schizoaffective or bipolar disorder who were treated with typical or atypical antipsychotics; TG/HDL ≥ 3.5.	Switching to Aripiprazole group (N = 24): dose 5–30 mg/d; Switching to Ziprasidone group (N = 28): dose 40–160 mg/d; Cross-titration within 2 weeks.	52 weeks	Switching to Aripiprazole vs switching to Ziprasidone: both groups improved body weight, BMI, TG, HDL and TG/HDL	No statistically significant group × time interaction in PANSS, CGI-S, and YMRS scores.	Completion rate: 71.2%, no difference between groups
Ziprasidone	Weiden PJ. et al^Citation81 Long-term, randomized controlled, open label	185 outpatients with schizophrenia or schizoaffective disorder treated with Risperidone, Olanzapine, or typical antipsychotics; clinically stable but needed switching due to psychotic symptoms or adverse events.	Risperidone-Ziprasidone group (n = 43); Olanzapine-Ziprasidone group (n=71); typical antipsychotics-Ziprasidone group (n = 71) Cross-tapering to Ziprasidone within one week, median dose 120 mg/d.	52 weeks (maximum 58 weeks)	Risperidone-Ziprasidone group and Olanzapine-Ziprasidone group vs baseline: improved body weight, BMI, total cholesterol and TG; typical antipsychotics-ziprasidone vs baseline: no significant changes in weight and lipid parameters	Risperidone-Ziprasidone group and Olanzapine-Ziprasidone group vs baseline: improved PANSS negative scores; no significant changes in PANSS total and positive scores; typical antipsychotics-Ziprasidone vs baseline: improved PANSS total and negative scores; no significant changes in PANSS positive scores	Risperidone-Ziprasidone group vs Olanzapine-Ziprasidone group vs typical antipsychotics-Ziprasidone group discontinuation rate: 58% vs 64% vs 58%
	Wang HH. et al^Citation82 Accessor-blind, randomized controlled, open label	148 patients with schizophrenia spectrum disorder	Olanzapine monotherapy group (n = 31); Ziprasidone monotherapy group (n = 49); Olanzapine-to-Ziprasidone group (n = 35): cross-titration to Ziprasidone within 2 weeks, maximum dose 160 mg/d Olanzapine combining Ziprasidone group (n=33): Olanzapine maximum dose 20 mg/d, Ziprasidone 160 mg/d	12 weeks	Switching vs combination: No difference of changes in weight gain, glucose and lipid measures, but were higher than Olanzapine monotherapy group	Efficacy of both switching and combination group was comparable Olanzapine monotherapy and better than Ziprasidone monotherapy in reducing overall psychotic and negative symptoms.	Olanzapine, Ziprasidone monotherapy vs switching vs combination group completion rates: 87.1% vs 61.2% vs 77.1% 81.8%
	Alptekin K. et al^Citation83 Open label, international multicenter study	319 patients with stable schizophrenia or schizoaffective disorder who were treated with Haloperidol, Olanzapine, or Risperidone, with persistent symptoms or troublesome side effects	Haloperidol-Ziprasidone (n = 99); Olanzapine-Ziprasidone (n = 82); Risperidone-Ziprasidone (n = 104)	12 weeks	Haloperidol-Ziprasidone vs baseline: increased body weight; Olanzapine-Ziprasidone vs baseline; reduced body weight Risperidone-Ziprasidone vs baseline: non-significantly reduced body weight All three groups showed neutral effect on metabolic parameters;	All three switching groups vs baseline: significant improvement in PANSS, CGI, BPRS, GAF; More improvement in Haloperidol-Ziprasidone and Risperidone-Ziprasidone vs Olanzapine-Ziprasidone	Haloperidol-Ziprasidone vs Olanzapine-Ziprasidone vs Risperidone-Riprasidone group discontinuation rate: 32% vs 40% vs 14%
	LI CH. et al^Citation84 Open label	213 schizophrenia outpatients with MetS, who have been treated with Clozapine for more than 2 years.	Switching group (n = 68), cross-tapering to Ziprasidone within 4 weeks, dose 120–160 mg/d; Combination group (n = 126)	24 weeks	Switching and combination group vs baseline: reduced BMI and TG levels; Switching vs combination: increased HDL-C levels	Switching vs combination and baseline: reduced PANSS total, negative, cognition and anxiety factor scores (p < 0.05)	Overall completion rate:194/213.
Quetiapine	Deberdt W. et al^Citation80 Multi-center, double-blind, randomized controlled study	133 patients with schizophrenia or schizoaffective disorder who were treated with Olanzapine were in stable condition but were overweight or obese with at least one cardiovascular risk factor	Initial group (n = 68): continued Olanzapine switching group (n = 65): cross-titration switching to Quetiapine within 1 week, dose 300–800 mg/d	26 weeks	Switching vs initial group: No significant difference in changes of body weight, BMI, fasting blood glucose, insulin, TG, HDL-C, LDL-C, or total cholesterol levels between study endpoint and baseline.	Switching vs initial group: No significant difference in time to relapse; both groups improved PANSS scores, but reduced faster PANSS scores in initial vs switching group	Switching vs initial group completion rate: 43.1% vs 70.6%
Lurasidone	Stahl SM. et al.^Citation36 Open label extension study	254 patients with schizophrenia who received 6-week treatment with fixed-dose Olanzapine 15 mg/d, Lurasidone 40 or 120 mg/d or placebo	Olanzapine-Lurasidone (n = 71): Lurasidone-Lurasidone (n = 118): Placebo-Lurasidone (n = 65): Placebo Open label extension study (n = 254)	24 weeks	Olanzapine-Lurasidone vs other groups: reduced body weight, BMI; improved blood lipid levels; all three groups showed minor improvement in blood glucose, insulin and glycosylated hemoglobin.	All three groups showed continuous improvement in PANSS total scores	Olanzapine-Lurasidone vs Lurasidone-Lurasidone vs placebo-Lurasidone group discontinuation rate: 56.3% vs 53.4% vs 58.5%
	Mattingly GW. et al^Citation79 Open, randomized controlled, extended study	223 patients with schizophrenia or schizoaffective disorder in stable stage who were treated with Lurasidone or Risperidone for at least 12 months.	Lurasidone-Lurasidone group (n = 136): continued Lurasidone 40–120 mg/d Risperidone-Lurasidone group (n = 87): switching from Risperidone to Lurasidone.	24 weeks	Lurasidone-Lurasidone group vs Risperidone-Lurasidone group: changes in body weight; total cholesterol; TG; glucose	The total PANSS scores of the two groups continued to improve and the CGI-S improved moderately.	Lurasidone-Lurasidone group vs Risperidone-Lurasidone group completion rate: 80.1% vs 74.7%

Abbreviations: BMI, body mass index; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; MetS, metabolic syndrome; BPRS, brief psychiatric rating scale; CGI-S, clinical global impressions-severity; CGI-CB, clinical global impressions-clinical benefit; SSS, subjective satisfaction scores; PANSS, positive and negative syndrome scale; SF-12 (MHS), medical outcomes survey-short form 12 item mental health score; SF-12 (PHS), medical outcomes survey-short form 12 item physical health score; IWQOL-lite, impact of weight on quality of life-lite questionnaire; LDL-C, low-density lipoprotein cholesterol; FGAs, first-generation antipsychotics; SGAs, second-generation antipsychotics; YMRS, young manic rating scale; GAF, global assessment of functioning.

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