Quetiapine and its metabolite norquetiapine: translation from in vitro pharmacology to in vivo efficacy in rodent models

Abstract

Background and purpose: Quetiapine has a range of clinical activity distinct from other atypical antipsychotic drugs, demonstrating efficacy as monotherapy in bipolar depression, major depressive disorder and generalized anxiety disorder. The neuropharmacological mechanisms underlying this clinical profile are not completely understood; however, the major active metabolite, norquetiapine, has been shown to have a distinct in vitro pharmacological profile consistent with a broad therapeutic range and may contribute to the clinical profile of quetiapine.

Experimental approach: We evaluated quetiapine and norquetiapine, using in vitro binding and functional assays of targets known to be associated with antidepressant and anxiolytic drug actions and compared these activities with a representative range of established antipsychotics and antidepressants. To determine how the in vitro pharmacological properties translate into in vivo activity, we used preclinical animal models with translational relevance to established antidepressant-like and anxiolytic-like drug action.

Key results: Norquetiapine had equivalent activity to established antidepressants at the noradrenaline transporter (NET), while quetiapine was inactive. Norquetiapine was active in the mouse forced swimming and rat learned helplessness tests. In in vivo receptor occupancy studies, norquetiapine had significant occupancy at NET at behaviourally relevant doses. Both quetiapine and norquetiapine were agonists at 5-HT1A receptors, and the anxiolytic-like activity of norquetiapine in rat punished responding was blocked by the 5-HT1A antagonist, WAY100635.

Conclusions and implications: Quetiapine and norquetiapine have multiple in vitro pharmacological actions, and results from preclinical studies suggest that activity at NET and 5-HT1A receptors contributes to the antidepressant and anxiolytic effects in patients treated with quetiapine.

Figure 1

Occupancy of rat noradrenline transporter (NET) in locus coeruleus following s.c. administration of norquetiapine, desipramine or reboxetine. Data are presented as mean relative occupancy ± SEM (n = 6 animals per treatment group).

Figure 2

Effects of norquetiapine, desipramine or reboxetine in the forced swim test in male BALB/c mice. Vehicle (saline) and sertraline were used as controls in each experiment. Data are presented as mean immobility time ± SEM (n = 10 animals per treatment group). Note: * indicate a mean value significantly different from the vehicle (P < 0.05).

Figure 3

Effects of norquetiapine, desipramine or reboxetine on learned helplessness in male Wistar rats. Non‐inducted animals (no shock), saline only (vehicle) and imipramine‐treated controls were included in each experiment. A low dose (norquetiapine, 0.5 mg·kg⁻¹; desipramine, 3 mg·kg⁻¹; and reboxetine, 10 mg·kg⁻¹) and a high dose (norquetiapine, 5 mg·kg⁻¹; desipramine, 10 mg·kg⁻¹; and reboxetine, 30 mg·kg⁻¹) of each test compound were evaluated. Data are presented as mean escape failures ± SEM (n = 12 animals per treatment group). Note: * indicate a mean value significantly different from the vehicle (P < 0.05); ^# indicate an uninduced (no shock) mean value significantly (P < 0.05) different from shock + vehicle (vehicle).

Figure 4

Effects of norquetiapine (n ≥ 6 per dose), quetiapine (n ≥ 8 per dose) and diazepam (n ≥ 3 per dose) on punished responding in male Long–Evans rats. Punished (A) and unpunished (B) response rates across doses are displayed as means ± SD. In combination studies (C and D), peak efficacy doses of norquetiapine (5 mg·kg⁻¹) and quetiapine (10 mg·kg⁻¹) were delivered either without or following WAY100635 (0.1 mg·kg⁻¹) co‐administration. Note:* indicate a mean value significantly different from the vehicle (P < 0.05); ^# indicate WAY100635 pretreatment mean value significantly (P < 0.05) different from test drug only.

Figure 5

Effects of quetiapine (A and C) and norquetiapine (B and D) following prenatal stress on elevated plus maze performance of adult Sprague–Dawley rats. Prenatal stress suppressed spontaneous exploration of open arms in the elevated plus maze in both experiments; measured as % time spent in open arms (^† P ≤ 0.01). (B) Norquetiapine at both 5 and 10 mg·kg⁻¹ doses restored the fraction of time spent in open arms (** P < 0.01). (D) Neither dose of quetiapine was effective. The data displayed are average ± SEM.