Olanzapine and fluoxetine combination therapy for treatment-resistant depression: review of efficacy, safety, and study design issues

Figures & data

Table 1 Selected serotonergic neuroreceptor targets of olanzapine with potential relevance for antidepressant augmentation in treatment-resistant depression^{13,42,45–47}

Neuroreceptor	Pharmacological activity	Functional consequence	Possible benefit in TRD
5-HT1A	Agonist	Enhance NE release in PFC and NAcc	Improved cognitive functioning
		Increase DA release in frontal cortex and NAcc	Improved mood, cognitive functioning and motivational drive
			Overcome SSRI induced suppression of central DA activity
5-HT2A	Antagonist	Enhance 5-HT and NE releasea	Reverse SSRI induced suppression of locus coeruleus firing
		Enhance DA release in PFCb	Improved regulation of mood and cognitive functioning
			Overcome SSRI induced suppression of central DA activity
5-HT2C	Antagonist	Enhance NE release in PFC and NAcc	Improved cognitive functioning
		Increase DA release in frontal cortex and NAcc	Improved mood, cognitive functioning and motivational drive
			Overcome SSRI induced suppression of central DA activity
5-HT6	Antagonist	Enhance DA release in PFC	Improved cognitive functioning
			Overcome SSRI induced suppression of central DA activity

a In presence of 5-HT reuptake inhibition.

b In presence of weak D2 receptor antagonism.

Abbreviations: TRD, treatment-resistant depression; DA, dopamine; NE, norepinephrine; PFC, ; SSRI, selective serotonin reuptake inhibitor; NAcc,;

Figure 1 Basic design features of acute phase studies of combined fluoxetine and olanzapine (FLX/OLZ) in treatment resistant depression. ^58,62–64

Abbreviations: FLX, fluoxetine; FLX (cont), FLX treatment continued into double-blind study phase; FLX/OLZ, fluoxetine + olanzapine combination therapy; NTP, nortriptyline; NTP (cont), NTP treatment continued into double-blind study phase; PLC, placebo; VLFX, venlafaxine.

Table 2 Definition of treatment-resistant depression and characteristics of lead-in phase

Study	Diagnosis	Retrospective failure	Prospective failure (lead-in)	N	Mean/mean modal dose (mg/day)	No. (%)responders (lead-in)	No. (%)randomized to double-blind treatment
Shelton et al^Citation58	DSM-IV (MDD, recurrent, without psychotic features)	Failure to respond to AD of two or more different classes (one non-SSRI), each ≥4 weeks, at “acceptable” doses, current episode	Open-label FLX (20–60 mg/day), 6 weeks Response = Reduction in HAM-D-21 score by ≥30%	34	NR	1 (2.9)	28 (82.4)
Shelton et al^Citation62	DSM-IV (MDD, without psychotic features) with SCID-I confirmation	Past failure to respond to SSRI (≥4 week trial), at therapeutic dosesa	Open-label trial of NTP (75–175 mg/day), 7 weeks Response = Reduction in MADRS score by ≥30%	946	NR	167 (17.7)	500 (52.9)
Corya et al^Citation63	DSM-IV (MDD, single episode or recurrent, without psychotic features)	Past failure to respond to SSRI (≥6 week trial), at therapeutic dosesa	Open-label trial of VLFX (75–375 mg/day), 7 weeks Response = Reduction in MADRS score by ≥30%	807	226 ± 100	200 (26.3)	483 (59.9)
Thase et al^Citation64	DSM-IV (MDD, recurrent, without psychotic features) with SCID-I confirmation	Failure to respond to non-SSRI AD (≥6 weeks), at therapeutic doses,b current episode	Open-label trial of FLX (50 mg/day), 8 weeks Response = Reduction in HAM-D-17 by ≥25% or HAM-D <18 or a >15% decrease between weeks 7 and 8	1, 313	47.4 ± 9.3	338 (28.9)	605 (46.1)

a Defined as citalopram 40 mg/day, fluoxetine 40 mg/day, paroxetine 40 mg/day, or sertraline 150 mg/day.

b Defined as paroxetine 40 mg/day, venlafaxine 150 mg/day, bupropion 300 mg/day, or trazodone 450 mg/day.

c Excluding patients who did not complete at least 5 weeks of open-label fluoxetine treatment.

Abbreviations: AD, antidepressant; DSM-IV, Diagnostic and Statistical Manual for Mental Disorders, 4th Edition; FLX, fluoxetine; HAM-D, Hamilton-Depression Rating Scale (17 or 21 item scale); MADRS, Montgomery-Asberg Depression Rating Scale; MDD, major depressive disorder; NR, not reported; NTP, nortriptyline; SCID, Structured Clinical Interview for the DSM; SSRI, selective serotonin reuptake inhibitor; VLFX, venlafaxine.

Table 3 Characteristics of studies of combined fluoxetine and olanzapine in treatment-resistant major depression

Studya	Study design			Medication use		Outcomes
	Design	Duration	Randomization/blinding	Comparator groups, N, dose	Additional medications	Outcome measures	Results
Shelton et al^Citation58	Double- blind RCT	8 weeks	Described/not described	FLX/OLZ, N = 10, 52.0/13.5 mg/day FLX, N = 10, 52.0 mg/day OLZ, N = 8, 12.5 mg/day	NR	Δ MADRS Δ HAM-D Δ CGI-D Responseb	FLX/OLZ > FLX and OLZ FLX/OLZ > OLZ FLX/OLZ > OLZ FLX/OLZ > OLZ
Shelton et al^Citation62	Double- blind RCT	8 weeks	Described/described	FLX/OLZ, N = 146, 8.5/35.6 mg/day FLX, N = 142, 35.8 mg/day OLZ, N = 144, 8.3 mg/day NTP, N = 68, 103.5 mg/dayc	Lorazepam PRN, up to 2 mg/day)	Δ MADRS Δ HAM-A Δ CGI-S Responseb Remissiond	FLX/OLZ > NTP (weeks 1–4) FLX/OLZ > FLX (weeks 2–5) FLX/OLZ > OLZ (weeks 2, 4, 6, 7) No significant between groups difference FLX/OLZ > OLZ (week 8) No significant between groups difference No significant between groups difference
Corya et al^Citation63	Double- blind RCT	12 weeks	Described/described	FLX/OLZ, N = 243, fixed doses FLX, N = 60, 37.5 mg/day OLZ, N = 62, 7.9 mg/day VLFX, N = 59, 275.4 mg/day OFC 1/5, N = 59, 1.0/5.0 mg/daye	BZD PRN, up to equivalent of LOR 4 mg/day	Δ MADRS CGI-D HAM-A Responseb Remissiond BZD use	FLX/OLZ > OLZ (weeks 1–12) FLX/OLZ > FLX (weeks 1–11) FLX/OLZ > VLFX (weeks 1–6) FLX/OLZ > OLZ FLX/OLZ > OLZ FLX/OLZ > OLZ FLX/OLZ > OLZ FLX > FLX/OLZ
Thase et al^Citation64, f	Double- blind RCT	8 weeks	Described/described	FLX/OLZ, N = 198, 8.6/48.8 mg/day FLX, N = 203, 49.5 mg/day OLZ, N = 197, 8.7 mg/day	BZD allowed, dose unspecified	Δ MADRS Responseb Remissiong Time to response Time to remission Onset of actionh	FLX/OLZ > FLX and OLZ FLX/OLZ > FLX and OLZ FLX/OLZ > FLX and OLZ Time required for 25% of patients to achieve response: FLX/OLZ (30 days) <FLX (55 days) and OLZ (53 days) Time required for 25% of patients to achieve remission: FLX/OLZ (52 days) <FLX (71 days) FLX/OLZ (6.4 days) = OLZ (6.8 days) <FLX (10.0 days)

a Notes: All studies were supported or sponsored by Eli Lilly and Company.

b Categorical treatment responder defined as a ≥ 50% improvement in MADRS scores from baseline.

c Mean (SD) NTP plasma level by study visit ranged from 87.9 ± 37.5 ng/L to 114.5 ± 31.2 ng/L.

d Categorical remitter status defined as two consecutive MADRS total scores ≤ 8.

e There were 5 dosing arms for FLX/OLZ. The highest 4 doses were pooled. The lowest dose, OLZ 1/5 (OLZ 1 mg/FLX 5 mg), was used as a control group.

f Randomized, double-blind trial was run as two identical concurrent studies. Pooled results are reported in Table Y.

g Categorical remission status defined as MADRS total score ≤ 10 at study endpoint.

h Onset of action was defined as time required for 50% of patients to achieve a ≥ 25% reduction in MADRS total score from baseline

Abbreviations: BPRS, Brief Psychiatric Rating Scale; BZD, benzodiazepine; CGI-D, Clinical Global Impressions-Depression scale; CGI-S, Clinical Global Impressions-Severity scale; FLX, fluoxetine; FLX/OLZ, fluoxetine + olanzapine combination therapy; HAM-A, Hamilton Anxiety Scale; LOR, lorazepam; MADRS, Montgomery-Asberg Depression Rating Scale; NTP, nortriptyline; OLZ, olanzapine; VLFX, venlafaxine.

Table 4 Treatment-emergent adverse effects

		Discontinuation due to TEAEs, no. (%)	Δ weight (kg), mean (SD)	SWG (%)	Δ total cholesterol (mmol/L), mean (SD)	Δ triglycerides (mmol/L), mean (SD)	Δ PRL (nmol/L), mean (SD)	Glucose (mg/dL)	EPS
Shelton et al^Citation58	FLX/OLZ (N = 10)	0 (0.0)	+6.7 (4.5)	–	–	–	–	–	–
	FLX (N = 10)	0 (0.0)	+0.9 (1.3)	–	–	–	–	–	–
	OLZ (N = 8)	1 (25)	+6.1 (2.6)	–	–	–	–	–	–
Shelton et al^Citation62	FLX/OLZ (N = 146)	10 (6.8)	+3.3 (3.5)	7.8	+ 0.36	–	+0.36	NDa	NDa
	FLX (N = 142)	4 (2.8)	−1.42 (2.6)	0.0	+ 0.06	–	+0.05	NDa	NDa
	OLZ (N = 144)	14 (9.7)	+2.9 (3.0)	4.3	+ 0.12	–	+0.26	NDa	NDa
	NTP (N = 68)	2 (2.9)	+0.2 (3.1)	0.0	+ 0.03	–	–0.01	NDa	NDa
Corya et al^Citation63	FLX/OLZ (N = 243)	–	+4.3 (4.1)	–	+ 0.24	–	–	–	NDb
	FLX (N = 60)	–	–	–	−0.04	–	–	–	NDb
	OLZ (N = 62)	–	+3.5 (3.7)	–	−0.09	–	–	–	NDb
	VLFX (N = 59)	–	–	–	+ 0.05	–	–	–	NDb
	OFC 1/5 (N = 59)	–	–	–	–	–	–	–	NDb
Thase et al^Citation64	FLX/OLZ (N = 198)	27 (13.5)	+4.9 (3.5)	–	+ 0.84 (1.8)	+ 2.2 (6.8)	+0.15 (0.5)c	+0.78 (2.7)	NDd
	FLX (N = 203)	5 (2.4)	+0.4 (2.3)	–	+ 0.04 (1.8)	+ 0.88 (5.4)	+0.04 (0.3)c	0.17 (1.2)	NDd
	OLZ (N = 197)	32 (16.1)	+5.5 (3.9)	–	+ 0.15 (34.0)	+ 2.9 (10.2)	+0.22 (0.7)c	+0.46 (1.6)	NDd

a No significant differences between comparator groups. Values not reported.

b No significant changes from baseline were observed. Values not reported.

c Original results reported in micrograms/L. Conversion to nmol/L was based on an estimated molecular weight of 23,000 Da for PRL (Sinha, 1995).

d No significant increases in measures of EPS from baseline in FLX/OLZ group. EPS measures for FLX/OLZ group reported as similar to that of OLZ group. Results of comparisons with FLX not provided. Values not reported.

Abbreviations: TEAES, treatment-emergent adverse effects; –, not reported; EPS, extrapyramidal side effects; FLX, fluoxetine; FLX/OLZ, combined fluoxetine + olanzapine; ND, no significant differences between comparator groups were reported (see text); NTP, nortriptyline; OFC 1/5, low-dose olanzapine (1 mg) + fluoxetine (5 mg); PRL, prolactin concentration; SWG, substantial weight gain (defined as an increase in weight ≥ 10% from baseline); VLFX, venlafaxine.

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