Iloperidone in the treatment of schizophrenia: an evidence-based review of its place in therapy

Figures & data

Core evidence clinical impact summary for iloperidone in schizophrenia

Outcome measure	Evidence	Implications
Disease-oriented evidence
Schizophrenia pathophysiology and iloperidone mechanism of action	From clinical trials and observational studies: moderate	Iloperidone arises as a potential alternative to treat schizophrenia. However, since the pathophysiology of the disease is not fully elucidated, there are some gaps in the literature concerning drugs activities.
Iloperidone as therapeutic choice	From clinical trials,observational studies and meta-analyses: clear	Iloperidone is an optimal alternative as monotherapy for the treatment of schizophrenia, due its proven efficacy and promising safety profile, particularly for patients who are intolerant to prior treatments.
Patient-oriented evidence
Reduction in positive and negative symptoms: acute efficacy	From clinical trials and meta-analyses: clear	Iloperidone was more effective than placebo and similar to haloperidol,risperidone and ziprasidone in several psychometric scales and in symptoms assessment.
Maintenance of effectiveness and safety	From clinical long-term trials: clear	Iloperidone proved to have long-term efficacy and favorable safety profile compared to placebo and haloperidol.
Prevention of relapse in stabilized patients	From clinical trials:moderate	Few studies have evaluated this outcome.Iloperidone is better than placebo and equivalent to haloperidol in time to relapse.
Adverse events	From clinical trials,observational studies and meta-analyses: clear	Iloperidone is an alternative to avoid elevation in EPS and prolactin levels.The incidence of weight gain and other side effects (dizziness, orthostatic hypotension, dry mouth, sedation, extension of QTc interval) are common but can be prevented by drug titration and monitoring.
Adherence with treatment	From clinical trials,observational studies and meta-analyses: moderate	Some patients may discontinue treatment due to adverse events or inefficacy.However, drugs seem to be well tolerated among patients, especially for long periods.
Effectiveness in treatment-resistant schizophrenia	From clinical trials:insufficient	Clozapine remains the therapeutic option for treating resistant schizophrenia.
Economic evidence
	Pharmacoeconomic studies: insufficient	No formal cost-effectiveness analysis has been conducted.

Figure 1 Flowchart of the systematic review process and final included studies.

Abbreviation: RCTs, randomized controlled trials.

Table 1 Characteristics of included RCTs and extension trials

Study	Treatment	N	Study design	Location	Age (years)	% Males
RCT	•IIoperidone 12 mg 2x/day	593	Prospective, multicenter,	USA, India	40±10.3	79.6
Cutler et al^47	•Ziprasidone 80 mg 2x/day		randomized, Phase III,
Lavedan et al^48	•Placebo		double-blind, placebo- and ziprasidone- controlled trial
Thompson et al^49
Volpi et al^50
RCT	•IIoperidone 4 mg/day	621	Multicenter,	USA	38-40	71.2
Potkin et al^51(1)	•IIoperidone 8 mg/day		randomized, doubleblind, placebocontrolled trials
	•IIoperidone 12 mg/day
	•Haloperidol 15 mg/day
	•Placebo
RCT	•IIoperidone 4-8 mg/day	616			38-40	70.5
Potkin et al^51(2)	•IIoperidone 10-16 mg/day
	•Risperidone 4-8 mg/day
	•Placebo
RCT	•IIoperidone 12-16 mg/day	706			37-40	62.0
Potkin et al^51(3)	•IIoperidone 20-24 mg/day
	•Risperidone 6-8 mg/day
	•Placebo
RCT	•IIoperidone 12-24 mg/day gradual switch	500	12-week, open-label, randomized trial	USA	43.3±11.0	67.0
Citrome et al^55
Weiden et al^56	•IIoperidone 12-24 mg/day immediate switch
	Initial therapies were risperidone or olanzapine or aripiprazol
RCT	•IIoperidone 8 mg 2x/day	158	12-week, open-label, randomized trial	USA	18-65	Not reported
Potkin et al^53	•IIoperidone 12 mg 2x/day
	•IIoperidone 24 mg/day
	•Ziprasidone 80 mg 2x/day
	•Quetiapine 375 mg 2x/day
RCT	•IIoperidone 4-12 mg 2x/day	303	REPRIEVE study;	USA, India, Ukraine	38.3± 11.2	58.7
Weiden et al^54	•Placebo		randomized, doubleblind placebo-controlled trial
Extension trial	•IIoperidone 12 mg/day	173	25-week, open-label	USA, India	39.9±10.3	76.3
Cutler et al^57	•IIoperidone 24 mg/day		extension trial
	•Placebo
Extension trial	•IIoperidone 12 mg/day	489	Prospective,	>3 countries	39.9± 10.7	62.3
Kane et al^58	•Haloperidol 12 mg/day		randomized, multicenter, open-label flexible-dose, extension phase

Note: *P values <0.05 versus comparators.

Abbreviation: RCT, randomized controlled trial; BPRS, Brief Psychiatric Rating Scale; CGI-S, Clinical Global Impressions-severity; PANSS, Positive and Negative Syndrome Scale; T, total; P, positive; N, negative; GP, general psychopathology; EPS, extrapyramidal symptoms; ECG, electrocardiogram; REPRIEVE, A Randomized Trial of Iloperidone for Prevention of Relapse in Schizophrenia.

Table

Iloperidone main outcomes	Iloperidone incidence of adverse events	Conclusion
BPRS*, CGI-S*, PANSS-T*, PANSS-P*, PANSS-N*, PANSS-GP, drug discontinuation (35% being 16% adverse event-related)	Dizziness (17%), sedation (13%), weight increased (11%), tachycardia (9%), dry mouth (9%), nasal congestion (8%), heart rate increased (8%), hypotension (7%), somnolence (4%), agitation and anxiety (3%), EPS (3%)	Similar amount of adverse events and relevant changes on disease scales were observed with both active treatments. Iloperidone was effective, safe and well tolerated in schizophrenic patients with acute exacerbation.
Combined analyses: BPRS*, CGI-S*, PANSS-T*, PANSS-P*, PANSS-N*, PANSS-GP*, drug discontinuation, (1) 60.7%, (2) 48.0%, (3) 44.5%	Not evaluated	At least one iloperidone dosing group in each study demonstrated significantly better efficacy than placebo. Comparable efficacy score reductions were observed mainly for iloperidone 20-24 mg/day versus those receiving haloperidol or risperidone. These trials indicate that iloperidone is effective in schizophrenia.
CGI response rates: gradual switch: 17.5% (week 2), gradual switch: 81.2% (week 12), immediate switch: 26.1% (week 2), immediate switch: 84.4% (week 12)	Reported as: gradual switch and immediate switch, respectively, dizziness (8.8% and 14.2%), dry mouth (9.2% and 13.1%), fatigue (4.2% and 2.7%), insomnia (3.3% and 6.5%), nasal congestion (4% and 2%), nausea (4.2% and 4.2%), palpitations (1.3% and 3.8%), sedation (3.8% and 3.8%), somnolence (5.8% and 4.6%), weight increase (3% and 2%)	Switching to iloperidone can be accomplished either with a gradual crossover or immediate discontinuation of the prior antipsychotic; however, the immediate-switch method is associated with greater proportion of initial dizziness.
Assessment of heart rate-corrected QT interval, drug discontinuation related to adverse events: 3%	ECG abnormalities (21%), akathisia (8%), EPS (8%), psychosis (2%)	No patients experienced QTc changes of clinical concern (>Q500 ms). The only cardiovascular adverse events with iloperidone were nonconcentration-dependent tachycardia that was mild in most patients and did not lead to further sequelae.
Relapse rate: 17.9%, time to relapse: 139 days, PANSS-T*, drug discontinuation (50.3% being 3.2% adverse event-related)	Dizziness (11.6%), somnolence (8.3%), dry mouth (6.8%), headache (6.4%), insomnia (5.6%), weight increase (5.4%), nausea (5.1%), schizophrenia (2.4%)	Flexible dosing of iloperidone with a modal dose of 12 mg/day was effective in preventing relapse in subjects previously stabilized on iloperidone. The adverse event profile showed low EPS.
PANSS-T and CGI-S: no signal of worsening, laboratory parameters (glycemia, lipids): normal values, drug discontinuation (56.9% being 24.4% adverse event-related)	Headache (13.9%), weight increase (9.2%), dizziness (6.9%), nausea (6.4%), sedation (6.4%), insomnia (5.2%), nasopharyngitis (4.6%), dry mouth (4.0%), somnolence (3.5%), psychotic disorder (3.5%), retrograde ejaculation (1.7%), suicidal (0.6%)	This study further supports the long-term safety and tolerability of iloperidone for schizophrenia, including its favorable effect on metabolic laboratory parameters and low propensity to cause akathisia or EPS.
PANSS, CGI-S, BPRS: no signal of worsening, laboratory parameters (glycemia, lipids): normal values, drug discontinuation (36.4% being 3.8% adverse event-related)	Insomnia (21.1%), headache (8.6%), anxiety (8.1%), agitation (6.7%), dizziness (5.8%), akathisia (3.5%), tremor (3.3%), bradykinesia (1.3%), dystonia (1.1%), EPS (0.6%), death (0.5%)	Iloperidone is equivalent to haloperidol in time to relapse and presented a better profile in the EPS Rating Scale scores. The long-term efficacy and favorable safety profile of iloperidone make this drug a suitable option for maintenance therapy.

Table 2 Characteristics of included observational studies

Study	Treatment	N	Studydesign	Location	Age(years)	Gender	Adverseevents	Iloperidonerelated	Conclusion
Achalia and Andrade^59	Iloperidone 8-16 mg/day	1	Casereport	India	29	Male	VPCs	Probably	Clinically significant and symptomatically distressing; diagnosed as VPC. It may be an uncommon adverse effect of iloperidone, possibly mediated by iloperidone-induced alpha 2c adrenoceptor blockade.
Das et al^70	Iloperidone 6-12 mg 2x/day	57	Caseseries	India	17-39	Notreported	23 patients nasal congestion,8 hypotension, 10 fatigue and dizziness,4 dry mouth,4 weight gain,3 tachycardia,2 mild hypoglycemia	Probably	Adverse events were experienced after taking iloperidone for at least 4 weeks. Nasal congestion was the most extensive and frequent complaint in this specific population.
Dutta et al^60	Iloperidone 8 mg/day	1	Casereport	India	35	Female	Galactorrhea	Yes	Iloperidone can cause hyperprolactinemic galactorrhea even at low dosage and after a considerable period into the treatment.
Freeman et al^71	Iloperidone 8 mg 2x/day	2	Caseseries	USA	22, 21	Males	Retrogradeejaculation	Yes	Clinicians should be aware of the potential for newer antipsychotics with strong alpha 1 blockade such as iloperidone to cause retrograde ejaculation as an adverse event.
Muzyk et al^72	Iloperidone 1-4 mg 2x/day	1	Casereport	USA	24	Male	Angioedema	Yes (iloperidone and haloperidol association)	This case revealed a potential interaction of drugs (iloperidone and haloperidol) and highlighted the risk of cross-sensitivity between different antipsychotics in the cardiovascular system.
Ravani et al^73	Iloperidone 1-8 mg/day	5	Caseseries	India	31, 29, 19, 30, 32	Males	Ejaculatorydysfunction	Yes	The ejaculatory dysfunctions following treatment with iloperidone could be due to the blocking of alpha 1 adrenergic receptor.
Rodriguezet al^74	Iloperidone 6 mg/day	1	Casereport	USA	42	Male	Priapism	Yes	This case highlights important risk factors that should be considered when using iloperidone given it is a potent blocker of the alpha adrenergic receptor action.

Abbreviation: VPC, ventricular premature contraction.

Table 3 Iloperidone clinical profile

Advantages	Disadvantages
Low propensity to cause EPS	Requires slow titration to therapeutic doses, which may delay onset of therapeutic effect
Low propensity to cause prolactin increase	Risk of orthostatic hypotension,sedation and dizziness
Low propensity to change lipid and glycemic profile	Not indicated for patients with any risk for clinical QTc prolongation
No dose adjustment required on basis of renal functioning	Potential interactions with agents that inhibit or induce CYP2D6 and CYP3A4

Abbreviation: EPS, extrapyramidal symptoms.