Treatment-resistant depression: are animal models of depression fit for purpose?
BACKGROUND
Resistance to antidepressant drug treatment remains a major health problem. Animal models of depression are efficient in detecting effective treatments but have done little to increase the reach of antidepressant drugs. This may be because most animal models of depression target the reversal of stress-induced behavioural change, whereas treatment-resistant depression is typically associated with risk factors that predispose to the precipitation of depressive episodes by relatively low levels of stress. Therefore, the search for treatments for resistant depression may require models that incorporate predisposing factors leading to heightened stress responsiveness.


METHODS
Using a diathesis-stress framework, we review developmental, genetic and genomic models against four criteria: (i) increased sensitivity to stress precipitation of a depressive behavioural phenotype, (ii) resistance to chronic treatment with conventional antidepressants, (iii) a good response to novel modes of antidepressant treatment (e.g. ketamine; deep brain stimulation) that are reported to be effective in treatment-resistant depression and (iv) a parallel to a known clinical risk factor.


RESULTS
We identify 18 models that may have some potential. All require further validation. Currently, the most promising are the Wistar-Kyoto (WKY) and congenital learned helplessness (cLH) rat strains, the high anxiety behaviour (HAB) mouse strain and the CB1 receptor knockout and OCT2 null mutant mouse strains.


CONCLUSIONS
Further development is needed to validate models of antidepressant resistance that are fit for purpose. The criteria used in this review may provide a helpful framework to guide research in this area.
Department of Psychology, Swansea University, Singleton Park, Swansea, SA2 8PP, UK, p.willner@swansea.ac.uk.
Paul
P
Willner
Catherine
C
Belzung
D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy / Q000523:psychology; D003863:Depression / Q000188:drug therapy / Q000523:psychology; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy* / Q000523:psychology*; D004195:Disease Models, Animal; D006380:Helplessness, Learned; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use; D051379:Mice; D051381:Rats
D000928:Antidepressive Agents; D007649:Ketamine