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Co-morbid depression with post-traumatic stress disorder (PTSD) is often treatment resistant. In developing a preclinical model of treatment-resistant depression (TRD), we combined animal models of depression and PTSD to produce an animal with more severe as well as treatment-resistant depressive-like behaviours.
Male Flinders sensitive line (FSL) rats, a genetic animal model of depression, were exposed to a stress re-stress model of PTSD [time-dependent sensitisation (TDS)] and compared with stress-naive controls. Seven days after TDS stress, depressive-like and coping behaviours as well as hippocampal and cortical noradrenaline (NA) and 5-hydroxyindoleacetic acid (5HIAA) levels were analysed. Response to sub-chronic imipramine treatment (IMI; 10 mg/kg s.c.×7 days) was subsequently studied.
FSL rats demonstrated bio-behavioural characteristics of depression. Exposure to TDS stress in FSL rats correlated negatively with weight gain, while demonstrating reduced swimming behaviour and increased immobility versus unstressed FSL rats. IMI significantly reversed depressive-like (immobility) behaviour and enhanced active coping behaviour (swimming and climbing) in FSL rats. The latter was significantly attenuated in FSL rats exposed to TDS versus unstressed FSL rats. IMI reversed reduced 5HIAA levels in unstressed FSL rats, whereas exposure to TDS negated this effect. Lowered NA levels in FSL rats were sustained after TDS with IMI significantly reversing this in the hippocampus.
Combining a gene-X-environment model of depression with a PTSD paradigm produces exaggerated depressive-like symptoms that display an attenuated response to antidepressant treatment. This work confirms combining FSL rats with TDS exposure as a putative animal model of TRD.
Post-traumatic stress disorder (PTSD) displays high co-morbidity with major depression and treatment-resistant depression (TRD). Earlier work demonstrated exaggerated depressive-like symptoms in a gene×environment model of TRD and an abrogated response to imipramine. We extended the investigation by studying the behavioural and monoaminergic response to multiple antidepressants, viz. venlafaxine and ketamine with/without imipramine.
Male Flinders sensitive line (FSL) rats, a genetic model of depression, were exposed to a time-dependent sensitisation (TDS) model of PTSD and compared with stress naive controls. 7 days after the TDS procedures, immobility and coping (swimming and climbing), behaviours in the forced swim test (FST) as well as hippocampal and cortical 5-hydroxyindoleacetic acid (5HIAA) and noradrenaline (NA) levels were analysed. Response to imipramine, venlafaxine and ketamine treatment (all 10 mg/kg×7 days) alone and in combination were subsequently studied.
TDS exacerbated depressive-like behaviour of FSL rats in the FST. Imipramine, venlafaxine and ketamine were ineffective as monotherapy in TDS-exposed FSL rats. However, combining imipramine with either venlafaxine or ketamine resulted in significant anti-immobility effects and enhanced coping behaviours. Only ketamine+imipramine (frontal-cortical 5HIAA and NA), ketamine alone (frontal-cortical and hippocampal NA) and venlafaxine+imipramine (frontal-cortical NA) altered monoamine responses versus untreated TDS-exposed FSL rats.
Exposure of FSL rats to TDS inhibits antidepressant response at behavioural and neurochemical levels. Congruent with TRD, imipramine plus venlafaxine or ketamine overcame treatment resistance in these animals. These data further support the hypothesis that exposure of FSL rats to a PTSD-like paradigm produces a valid animal model of TRD and warrants further investigation.
Although prescription rates of antidepressants for children and adolescents have increased, concerns have been raised regarding effects on neurodevelopment and long-term outcome. Using a genetic animal model of depression, this study investigated the long-term effects of pre-pubertal administration of fluoxetine (FLX) on depressive-like behaviour in early adulthood, as well as on central monoaminergic response to an acute stressor. We postulated that pre-pubertal FLX will have lasting effects on animal behaviour and monoaminergic stress responses in early adulthood.
Flinders sensitive line (FSL) rats received 10 mg/kg/day FLX subcutaneously from postnatal day 21 (PnD21) to PnD34 (pre-pubertal). Thereafter, following normal housing, rats were either subjected to locomotor testing and the forced swim test (FST) on PnD60 (early adulthood), or underwent surgery for microdialysis, followed on PnD60 by exposure to acute swim stress and measurement of stressor-induced changes in plasma corticosterone and pre-frontal cortical monoamine concentrations.
Pre-pubertal FLX did not induce a late emergent effect on immobility in FSL rats on PnD60, whereas locomotor activity was significantly decreased. Acute swim stress on PnD60 significantly increased plasma corticosterone levels, and increased pre-frontal cortical norepinephrine (NE) and 5-hydroxyindole-3-acetic acid (5-HIAA) concentrations. Pre-pubertal FLX significantly blunted the pre-frontal cortical NE and 5-HIAA response following swim stress on PnD60. Baseline dopamine levels were significantly enhanced by pre-pubertal FLX, but no further changes were induced by swim stress.
Pre-pubertal FLX did not have lasting antidepressant-like behavioural effects in genetically susceptible, stress-sensitive FSL rats. However, such treatment reduced locomotor activity, abrogated noradrenergic and serotonergic stressor responses and elevated dopaminergic baseline levels in adulthood.
The time required in completing the 26 items of neurological examinations in the standard Neurological Evaluation Scale (NES) may limit its utility in pragmatic clinical situations. We propose the Short Neurological Evaluation Scale (S-NES) for use in busy clinical settings, and in research.
Using confirmatory factor analyses, we identified 12 items of neurological examination showing significant overlap with previously reported theoretical and empirical categories of neurological soft signs (NSS) in schizophrenia. This provided justification for the development of a shorter version of the NES based on the empirically identified NSS. In the present study, we relied on existing data to present an initial validation of the S-NES against the referent standard 26-item NES. We determined sensitivity, specificity, and likelihood ratios. Posterior-test probability was estimated using a Bayesian nomogram plot.
Using data derived from 84 unmedicated or minimally treated patients with first-episode schizophrenia, 12 empirically determined items of neurological examinations showed high agreement with the 26 items in the standard NES battery (sensitivity=96.3%, specificity=100%, and posterior-test probability=100%).
Within limitations of validity estimates derived from existing data, the present results suggest that the design of the S-NES based on empirically identified 12 items of neurological examination is a logical step. If successful, the S-NES will be useful for rapid screening of NSS in busy clinical settings, and also in research.
This study aimed to assess the feasibility of a low-literacy adaptation of the Alzheimer’s Disease Assessment Scale – Cognitive (ADAS-Cog) for use in rural sub-Saharan Africa (SSA) for interventional studies in dementia. No such adaptations currently exist.
Tanzanian and Nigerian health professionals adapted the ADAS-Cog by consensus. Validation took place in a cross-sectional sample of 34 rural-dwelling older adults with mild/moderate dementia alongside 32 non-demented controls in Tanzania. Participants were oversampled for lower educational level. Inter-rater reliability was conducted by two trained raters in 22 older adults (13 with dementia) from the same population. Assessors were blind to diagnostic group.
Median ADAS-Cog scores were 28.75 (interquartile range (IQR), 22.96–35.54) in mild/moderate dementia and 12.75 (IQR 9.08–16.16) in controls. The area under the receiver operating characteristic curve (AUC) was 0.973 (95% confidence interval (CI) 0.936–1.00) for dementia. Internal consistency was high (Cronbach’s α 0.884) and inter-rater reliability was excellent (intra-class correlation coefficient 0.905, 95% CI 0.804–0.964).
The low-literacy adaptation of the ADAS-Cog had good psychometric properties in this setting. Further evaluation in similar settings is required.
Brain structure differences and adolescent alcohol dependence both show substantial heritability. However, exactly which genes are responsible for brain volume variation in adolescents with substance abuse disorders are currently unknown. The aim of this investigation was to determine whether genetic variants previously implicated in psychiatric disorders are associated with variation in brain volume in adolescents with alcohol use disorder (AUD).
The cohort consisted of 58 adolescents with DSM-IV AUD and 58 age and gender-matched controls of mixed ancestry ethnicity. An Illumina Infinium iSelect custom 6000 bead chip was used to genotype 5348 single nucleotide polymorphisms (SNPs) in 378 candidate genes. Magnetic resonance images were acquired and volumes of global and regional structures were estimated using voxel-based morphometry. To determine whether any of the genetic variants were associated with brain volume, association analysis was conducted using linear regression in Plink.
From the exploratory analysis, the GRIN2B SNP rs219927 was associated with brain volume in the left posterior cingulate cortex (p<0.05), whereby having a G-allele was associated with a bigger volume.
The GRIN2B gene is involved in glutamatergic signalling and may be associated with developmental differences in AUD in brain regions such as the posterior cingulate cortex. Such differences may play a role in risk for AUD, and deserve more detailed investigation.