|dc.description.abstract||The current investigation focused on the development and validation of an animal model of treatment resistant depression (TRD). In addition, an in-depth review of biomarkers of depression was included which aimed to identify relevant biomarkers that would support the construct validity of the model. In order to publish this work, however, the scope of the review was extended to include biomarkers of mood and psychotic disorders (i.e. depression, bipolar disorder and schizophrenia). Insights into psychotic disorders are therefor limited to the biomarker review (Manuscript A) while the study itself focuses on depression, more specifically TRD. Despite significant research efforts aimed at understanding the neurobiological underpinnings of mood and psychotic disorders, the diagnosis and evaluation of the treatment of these disorders are still based solely on relatively subjective assessment of symptoms which may be partly to blame for the incidence of poor treatment outcome and treatment resistance. Therefore, biological markers aimed at improving the current classification of mood and psychotic disorders, and that will enable clinicians to categorize their patients and diagnose these disorders on a biological basis into more homogeneous clinically distinct subgroups, are urgently needed. The attainment of this goal can be facilitated by identifying biomarkers that accurately quantify and reflect pathophysiologic processes in these disorders and developing animal models that accurately emulate the aberrancies identified in patients suffering from non-response to pharmacotherapy.
The high occurrence of non- or partial response to antidepressant treatment in the depressed population creates a major problem in effectively treating and managing the disorder. Up to half of patients fail to achieve a full response when treated with first-line antidepressant drugs and, even after applying several treatment strategies in this population, approximately 30% of these patients still do not respond to treatment. As with depression, TRD is believed to be heterogeneous in nature and, although most pathophysiological factors contributing to depression appear to be similar in TRD, many of these conditions are significantly exaggerated in the resistant form, resulting in more severe symptoms. However, a shortage of suitable and validated animal models of TRD is a major contributing factor to our current lack of understanding of the pathophysiology of TRD. Recent studies have therefore set out to explore the processes that underlie treatment resistance in animal models.
In recent years it has become widely accepted that genetic susceptibility combined with adverse environmental situations are an important prodromal confluent for the development of depression. Thus, animal models that are based on this construct may contribute significantly to our knowledge of mood and anxiety disorders.
The Flinders sensitive line (FSL) rat is a well-studied genetic animal model of depression with robust construct, predictive and face validity. Considering the strong comorbidity between depression and post-traumatic stress disorder (PTSD), and that depression in patients with PTSD is more treatment resistant, we have developed an animal model of TRD based on the premise that exposing animals genetically predisposed to depressive-like behaviour to a PTSD-related paradigm would yield a model presenting with exacerbated and pronounced depressive-like behaviour that are resistant to traditional antidepressant treatment. To this end we have considered time-dependent sensitization (TDS; or stress re-stress) as a model of PTSD. TDS is based on a trauma plus contextual reminder principle of PTSD, and has previously shown good predictive, construct and face validity for PTSD.
In the first section of the study, subsequent to confirming the depressive-like phenotype of the FSL rat relative to that of the FRL rat, exposing FSL rats to TDS resulted in either bolstered or sustained reduction in coping response and increased depressive-like behaviours, combined with altered monoaminergic profiles in the hippocampal and frontocortical brain regions. Furthermore, the addition of TDS to FSL rats significantly abrogated the antidepressant-like effects of imipramine at most behavioural levels (climbing and immobility) and with respect to limbic serotonergic signalling.
Drug-centred approaches to manage TRD emphasize the use of agents with improved efficacy as well as the combination of drugs with different mechanisms of action. Hence, to extend the predictive validity of the model, we investigated sub-chronic treatment in TDS-exposed FSL rats with either a serotonin and noradrenaline reuptake inhibitor (SNRI), i.e. venlafaxine, or a N-methyl-D-aspartate (NMDA) receptor antagonist, i.e. ketamine, as monotherapy and in combination with imipramine in an augmentative approach. In the second section of the study, we subsequently demonstrated that non-response is not only observed with the traditional antidepressant, imipramine, but also following treatment with either ketamine or venlafaxine as monotherapy. However, combining either venlafaxine or ketamine with imipramine led to enhanced antidepressant-like effects as measured in the FST, together with altered response in monoaminergic signalling in the animal model of TRD.
Taken together, an in-depth review of the literature revealed that mood and psychotic disorders are currently associated with a multitude of biomarkers that still require illumination regarding their exact etiological or diagnostic roles and that it is of the utmost importance that proposed biomarkers with confirmed involvement in the trait and state of mood and psychotic disorders be dissected to a point of absolute comprehension. We confirmed that monoamines remain a major biomarker for the pathophysiology of depression and, as the majority of clinically available and effective antidepressants still remain those that target monoaminergic signalling, correlates that are associated with said monoaminergic functioning was identified as strong markers of depression, forming the foundation of the neurochemical analyses applied in our investigation. The results from the current investigation confirm the hypothesis that exposure of FSL rats to a PTSD-like paradigm results in more severe depressive-like behaviour that is resistant to traditional antidepressant treatment, albeit responsive to treatment regimens that combine various mechanisms of antidepressant action. The model therefore provides an important example of a gene-x-environment approach to mimic TRD and provides a foundation for further investigation into the underlying pathophysiology responsible for treatment resistance in these animals||en_US