Exploring a gene-x-environment model of treatment resistant depression: behavioural studies and response to fluoxetine treatment

Abstract

Background: Major depression with psychotic features presents with severe depressed mood and psychosis in the form of nihilistic-type delusions and hallucinations, and is known to be resistant to antidepressant monotherapy [1,2]. Further research is needed to understand its neurobiology and to improve pharmacotherapy. There is a need for developing animal models of treatment-resistant depression (TRD) [3]. In developing a preclinical model of TRD, we combined a gene-X-environment model of depression with a neurodevelopmental model of psychosis to produce an animal that displays psychotic-depressive-like manifestations that are more severe as well as resistant to standard antidepressant treatment.

Methods: Male Sprague-Dawley (S-D) control rats and Flinders Sensitive Line (FSL) rats, a genetic animal model of depression, were exposed to 8 weeks social isolation rearing (SIR; 1 rat/cage) from weaning (post-natal day 21) and compared to socially-housed controls (3 rats/cage) of either strain with/without SIR. At the end of social or isolation rearing, depressive-like and sensorimotor gating behaviour were analysed using the forced swim test (FST) and prepulse inhibition (PPI) test. Response to sub-chronic fluoxetine treatment (FLX; 10 mg/kg, s.c. x 14 days) was studied. Statistical analysis was performed using three-way ANOVA (FST) and two-way RM-ANOVA (PPI). Significance was measured at p < 0.05.

Results: Compared to social S-D rats, both FSL and SIR rats demonstrated significant depressive-like behaviour, displayed as increased immobility in the FST (p < 0.0001 and p = 0.0006, respectively), with significant sensorimotor gating disruptions as measured in the PPI test (p = 0.0024 and p < 0.0001, respectively). FSL+SIR rats exhibited significant depressive-like behaviour in the FST (p = 0.0078) in relation to S-D rats, but equivalent to FSL and SIR rats (p = 0.6659 and p = 0.9954, respectively). Similarly, FSL+SIR rats demonstrated significant sensorimotor gating disruptions (p = 0.0006) relative to SD rats, but equivalent to FSL and SIR rats (p > 0.9999, in both instances).

Fluoxetine (FLX) treatment significantly reversed depressive-like behaviour in FSL rats (p = 0.0016), although such behaviour was unaltered in SIR rats (p = 0.5195). Concerning PPI, FLX failed to improve sensorimotor gating deficits in FSL and SIR rats (p > 0.9999, both instances). However, FLX significantly increased depressive-like behaviour in FSL+SIR compared to S-D rats (p = 0.0005), and vs. FSL rats (p = 0.005) but equivalent to SIR rats (p = 0.9985). FLX tended to suppress PPI in FSL+SIR rats vs. S-D rats (p = 0.0993), as well as vs. FSL (p = 0.0676) and vs. SIR (p = 0.6978).

Conclusion: These results show that combining a genetic model of depression with an early life neurodevelopmental insult induces behavioural pathology akin to psychotic-depression that is resistant to standard antidepressant treatment, and even exacerbated by such treatment. This is indicated by increased depressive-like behaviour compared to FSL rats in the FST and a tendency towards sensorimotor gating suppression compared to FSL and SIR rats in the PPI test when treated with fluoxetine