Addressing the need for rapid treatment of agitation in schizophrenia and bipolar disorder: focus on inhaled loxapine as an alternative to injectable agents

Figures & data

Table 1 Rapidly-acting pharmacologic options for acute agitation

Agent	Dose (mg)	Advantages	Disadvantages
Lorazepam	0.5–2.0	Reliably absorbed when injected into the muscle; short half-life; no active metabolites; can potentially treat alcohol withdrawal; relatively inexpensive	No antipsychotic effect; potential for respiratory depression; risk for behavioral disinhibition (paradoxical reaction); development of tolerance
Haloperidol	0.5–7.5	Antipsychotic effect over time; relatively inexpensive	Akathisia; dystonia; will not treat underlying alcohol withdrawal
Ziprasidone	10–20	Antipsychotic effect over time; favorable extrapyramidal symptom profile compared to first-generation antipsychotics	Explicit warning in product labeling regarding prolongation of the QTc interval; will not treat underlying alcohol withdrawal; relatively more costly but availability of generic product will impact on price
Olanzapine	10 (5 or 7.5 when clinically warranted)	Antipsychotic effect over time; favorable extrapyramidal symptom profile compared to first-generation antipsychotics	Concomitant administration of intramuscular olanzapine and parenteral benzodiazepine is not recommended due to the potential for excessive sedation and cardiorespiratory depression; weight gain over time; will not treat underlying alcohol withdrawal; relatively more costly but availability of generic product will impact on price
Aripiprazole	9.75	Antipsychotic effect over time; favorable extrapyramidal symptom profile compared to first-generation antipsychotics	No dosage adjustment of aripiprazole is required when administered concomitantly with lorazepam but the intensity of sedation was greater with the combination as compared to that observed with aripiprazole alone and the orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone; will not treat underlying alcohol withdrawal; relatively more costly and remains under patent exclusivity at present

Table 2 Randomized controlled trials of inhaled loxapine – design

Study	Phase	Diagnosis	Subject demographics and clinical characteristics	N			Outcome variables
				Loxapine		Placebo
				5 mg	10 mg
Allen et al^Citation22	II	Agitation associated with schizophrenia	81% men; 44% African American; mean age 41 years; diagnosis of schizoaffective disorder 20%–22%; mean baseline PANSS-EC 17–18	45	41	43	Change in the PANSS-EC was measured 10 minutes to 24 hours after the administration of the first dose of inhaled loxapine. The primary endpoint used to statistically test loxapine versus placebo was at 2 hours postdose Change from baseline agitation at 2 hours after drug administration using the CGI-I, and proportion classified as CGI-I responders (as defined as a CGI-I score of one or two at 2 hours after drug administration, representing “very much improved” or “much improved”) Change from baseline on the BARS by time point and change in patient activity as measured with a wrist- worn actigraph (piezoelectric accelerometer)
Lesem et al^Citation23	III	Agitation associated with schizophrenia	70%–76% men; 53%–61% African American; mean age 42–44 years; mean baseline PANSS-EC 17–18	116	113	115	Change in the PANSS-EC was measured 10 minutes to 24 hours after the administration of the first dose of inhaled loxapine. The primary endpoint used to statistically test loxapine versus placebo was at 2 hours postdose Change from baseline agitation at 2 hours after drug administration using the CGI-I, and proportion classified as CGI-I responders (as defined as a CGI-I score of one or two at 2 hours after drug administration, representing “very much improved” or “much improved”) Change on the ACES at 2 hours postdose administration Post hoc determinations of PANSS-EC responder status were made, with response defined as a ≥40% reduction from baseline on the PANSS-EC at 2 hours postdose
Kwentus et al^Citation24	III	Agitation associated with bipolar I disorder (manic or mixed episode)	45%–53% men, 37%–51% African American, mean age 41 years, 28%–35% mixed episode, mean baseline PANSS-EC 17–18	104	105	105	5. Same as for Lesem et al^Citation23 above

Note: Copyright © 2011. John Wiley and Sons. Adapted with permission from Blackwell Publishing Ltd. Citrome L. Aerosolised antipsychotic assuages agitation: inhaled loxapine for agitation associated with schizophrenia or bipolar disorder. Int J Clin Pract. 2011;65(3):330–340.²⁸

Abbreviations: ACES, Agitation–Calmness Evaluation Scale; BARS, Behavioral Activity Rating Scale; CGI-I, Clinical Global Impressions – Improvement scale; PANSS-EC, Positive and Negative Syndrome Scale – Excited Component.

Table 3 Randomized controlled trials of inhaled loxapine – efficacy results

Study	Outcomes	Loxapine versus placebo NNT (95% CI) for CGI-I response at 2 hours		Loxapine versus placebo NNT (95% CI) for PANSS-EC response at 2 hours		Loxapine versus placebo NNT (95% CI) for requiring only first dose by 24 hours and no rescue medication*
		5 mg	10 mg	5 mg	10 mg	5 mg	10 mg
Allen et al^Citation22	Loxapine 10 mg, but not 5 mg, was superior to placebo on change in the PANSS-EC at 2 hours; mean 2 hour PANSS-EC scores were nine, eleven, and 13 for loxapine 10 mg, loxapine 5 mg, and placebo, respectively. The 5 mg dose effect size was intermediate between placebo and the 10 mg dose, suggesting a possible dose response relationship. The 10 mg dose separated from placebo as early as 20 minutes postdose, in contrast to the 5 mg dose which never separated from placebo to a statistically significant degree. Scores on the CGI-I scale at 2 hours after dose administration showed statistically significant effects of both the 10 mg (mean CGI-I 2.3) and 5 mg (mean CGI-I 2.6) loxapine dose versus placebo (mean CGI-I 3.2). BARS scores at 2 hours after inhalation demonstrated a statistically significant change from baseline for the 10 mg, but not the 5 mg dose group. Time to administration of first rescue medication (intramuscular lorazepam 0.5–2 mg) and overall use of rescue medication demonstrated advantages for both doses of inhaled loxapine versus placebo. Proportions of subjects receiving rescue medication were 15%, 11%, and 33% for those randomized to loxapine 10 mg, loxapine 5 mg, and placebo, respectively.	4 (3–12)	3 (2–5)	NA	NA	5 (3–22)	6 (NS)
Lesem et al^Citation23	Both doses of loxapine, 5 and 10 mg, were superior to placebo on change in the PANSS-EC at 2 hours, with mean 2 hour PANSS-EC scores of approximately nine, ten, and twelve for loxapine 10 mg, loxapine 5 mg, and placebo, respectively. Both doses of loxapine demonstrated superiority to placebo as early as 10 minutes postinhalation. Scores on the CGI-I scale at 2 hours after dose administration showed statistically significant effects of both the 10 mg (mean CGI-I 2.1) and 5 mg (mean CGI-I 2.3) loxapine dose versus placebo (mean CGI-I 2.8). A Kaplan–Meier survival analysis of the time to a second dose of medication (if needed) demonstrated superiority of loxapine 10 mg over placebo, but not so for the 5 mg dose, suggesting a possible dose response. Proportions of subjects receiving rescue medication (intramuscular lorazepam, permitted after a second dose of randomized medication) were 5%, 6%, and 16% for those randomized to loxapine 10 mg, loxapine 5 mg, and placebo, respectively. Once randomized, no patient dropped out for failure to follow the inhalation instructions or an inability (or refusal) to take a dose of study drug. The ACES scores at 2 hours demonstrated that no patient had a score of nine (unarousable), and the mean ratings for the groups receiving inhaled loxapine were in the range of mild calmness (5 mg group: 4.7; 10 mg group: 4.9, where four = normal and five = mild calmness).	5 (3–11)	4 (3–6)	5 (3–9)	4 (3–6)	12 (NS)	7 (4–52)
Kwentus et al^Citation24	Both doses of loxapine, 5 and 10 mg, were superior to placebo on change in the PANSS-EC at 2 hours, with mean 2 hour PANSS-EC scores of approximately eight, nine, and 13 for loxapine 10 mg, loxapine 5 mg, and placebo, respectively. Both doses of loxapine demonstrated superiority to placebo as early as 10 minutes postinhalation. Scores on the CGI-I scale at 2 hours after dose administration showed statistically significant effects of both the 10 mg (mean CGI-I 1.9) and 5 mg (mean CGI-I 2.1) loxapine dose versus placebo (mean CGI-I 3.0). Survival analysis of the time to a second dose of medication (if needed) demonstrated superiority of both loxapine 10 and 5 mg over placebo. Proportions of subjects receiving rescue medication (intramuscular lorazepam, permitted after a second dose of randomized medication) were 9%, 9%, and 21% for those randomized to loxapine 10 mg, loxapine 5 mg, and placebo, respectively. The ACES scores at 2 hours demonstrated that no patient had a score of nine (unarousable), and the mean ratings for the groups receiving inhaled loxapine were in the range of mild calmness (5 mg group: 4.7; 10 mg group: 5.1, where four = normal and five = mild calmness).	3 (2–4)	3 (2–3)	3 (3–5)	3 (2–3)	7 (4–51)	3 (3–5)

Notes:

* In contrast to the Phase III studies, the Phase II study did not include the possibility of a second dose of inhaled loxapine but did allow rescue medication with intramuscular lorazepam; additional NNT data from Citrome;²⁹ CGI-I responders defined as subjects who have a CGI-I score of one (very much improved) or two (much improved) at 2 hours after inhalation; PANSS-EC responders defined as subjects who have a ≥40% reduction from baseline on the PANSS-EC at 2 hours after inhalation. Copyright © 2011. John Wiley and Sons. Adapted with permission from Blackwell Publishing Ltd. Citrome L. Aerosolised antipsychotic assuages agitation: inhaled loxapine for agitation associated with schizophrenia or bipolar disorder. Int J Clin Pract. 2011;65(3):330–340.²⁸

Abbreviations: ACES, Agitation–Calmness Evaluation Scale; BARS, Behavioral Activity Rating Scale; CGI-I, Clinical Global Impressions – Improvement scale; CI, confidence interval; NA, not available; NNT, number needed to treat; NS, not significant; PANSS-EC, Positive and Negative Syndrome Scale – Excited Component.

Table 4 Randomized controlled trials of inhaled loxapine – pooled tolerability results: incidence and number needed to harm versus placebo (95% confidence interval)

Adverse event	Placebo (N = 263)		Loxapine 5 mg (N = 265)		Loxapine 10 mg (N = 259)
	n (%)	n (%)	NNH (95% CI)	n (%)	NNH (95% CI)
Dysgeusia	13 (4.9)	30 (11.3)	16 (10–58)	37 (14.3)	11 (7–23)
Sedation/somnolence	25 (9.5)	32 (12.1)	39 (NS)	31 (12.0)	41 (NS)
Throat irritation	1 (0.4)	2 (0.8)	267 (NS)	7 (2.7)	44 (23–472)
Any extrapyramidal symptom adverse event	1 (0.4)	5 (1.9)	67 (NS)	4 (1.5)	86 (NS)
Akathisia	0	1 (0.4)	265 (NS)	1 (0.4)	259 (NS)

Abbreviations: CI, confidence interval; NNH, number needed to harm; NS, not significant.

Table 5 Inhaled loxapine in subjects with asthma or chronic obstructive pulmonary disease – pulmonary findings

Outcome	Asthma			COPD
	Placebo (N = 26)	Loxapine 10 mg (N = 26)		Placebo (N = 27)	Loxapine 10 mg (N = 26)*
	n (%)	n (%)	NNH (95% CI)	n (%)	n (%)	NNH (95% CI)
≥10% reduction in FEV1	3 (12)	22 (85)	2 (2–2)	18 (67)	20 (80)	8 (NS)
≥20% reduction in FEV1	1 (4)	11 (42)	3 (2–6)	3 (11)	10 (40)	4 (2–16)
Any airway adverse event	3 (12)	14 (54)	3 (2–6)	3 (11)	5 (19)	13 (NS)
Adverse event of bronchospasm	1 (4)	7 (27)	5 (3–23)	1 (4)	0	NA
Albuterol use	3 (12)	14 (54)	3 (2–6)	4 (15)	6 (23)	13 (NS)

Note:

* Spirometry data not available for one subject, thus N = 25.

Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; FEV₁, volume of air exhaled in the first second of a forced exhalation starting from a position of full inspiration; NA, not applicable; NNH, number needed to harm; NS, not significant.

AllenMHFeifelDLesemMDEfficacy and safety of loxapine for inhalation in the treatment of agitation in patients with schizophrenia: a randomized, double-blind, placebo-controlled trialJ Clin Psychiatry201172101313132121294997

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LesemMDTran-JohnsonTKRiesenbergRARapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapineBr J Psychiatry20111981515821200077

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KwentusJRiesenbergRAMarandiMRapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapineBipolar Disord2012141314022329470

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CitromeLAerosolised antipsychotic assuages agitation: inhaled loxapine for agitation associated with schizophrenia or bipolar disorderInt J Clin Pract201165333034021199198

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CitromeLInhaled loxapine for agitation revisited: focus on effect sizes from two Phase III randomised controlled trials in persons with schizophrenia or bipolar disorderInt J Clin Pract201266331832522226343

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