The first talk was by Rebecca Strawbridge who described recent meta-analytic work on augmentation strategies in treatment-resistant depression. These aimed to address twin questions, “what works?”, and “for whom?”. The first (“what works?”) meta-analysis included 26 studies (23 pharmacological; 3 psycho-therapeutic) of antidepressant augmentation in depressed patients who had not responded to two or more treatment trials. Effect sizes were at best moderate, the largest being that for NMDA-receptor agents (1.48; 3 trials, 1 each for ketamine, d-cycloserine and minocycline). The best evidence base (in terms of number of high quality studies) was for aripiprazole, then lithium. Rebecca noted that only a single quetiapine study was included in the analysis, despite the frequent use of this agent in clinical practice and its frequent appearance in treatment guidelines.
The second study adopted a less stringent definition of treatment resistence; requiring only one previous unsuccessful treatment. Significant predictors of treatment response included severity of treatment resistance (ie number of previous unsuccessful treatments), as well as early response to treatment (ie after 2 weeks). Rebecca notes that this latter finding is in line with recent findings suggesting that treatment response may be evident rather earlier than was traditionally thought.
Next up was Joel Parkinson, presenting his work on the effect of electro-convulsive therapy (ECT) on functional brain networks, measured using fMRI. He noted that while major depressive disorders were likely highly biologically heterogeneous, resting state fMRI studies had yielded a number of relatively consistent findings, including characteristic changes in prefrontal-limbic connectivity patterns associated with antidepressant response. The effect of ECT on brain connectivity is rather less well-studied, as – despite being a generally very effective treatment for symptoms of depression – tends currently to be deployed only as a treatment of last resort. Joel utilised a seed-based connectivity approach examining whole-brain connectivity (ie Pearson correlation coefificent between seed region and every other brain voxel) of thalamus, posterior cingulate cortex, various subdivisions of anterior cingulate cortex, amygdala and dorsolateral preforntal cortex. Significant findings included increased (pre-ECT) connectivity between amygdala and pcc, as well as regions of parietal cortex involved in the default-mode network, as well as increased connectivity between thalamus and regions of the cerebellum and medial prefrontal cortex. These increased connectivities then normalised with successful treatment. Joel contrasted these findings – of a reduction of increased connectivity with successful treatment of TRD with the increases in reduced connectivity seen in successful treatment of non-resistant depression – suggesting a fundamentally different biological basis for treatment-resistant depression.
The third talk was from Amy Gillespie, who described her work examining treatment-resistance in both schizophrenia and depression. In the case of the former, Amy presented results of a systematic review of imaging findings in patients with treatment-resistant schizophrenia – treatment resistance here defined as having had two unsuccessful trials of treatment. Neurochemical imaging findings included the absence of elevation of striatal dopamine synthesis capacity seen in treatment-responsive patients, but raised glutamate levels in frontal and cingulate regions. Structural neuroimaging findings included greater grey matter reductions in treatment-resistant relative to treatment-responsive patients.
Amy also described an empirical study investigating DNA methylation by clozapine and its association with treatment response. DNA methylation is an epigenetic process which modulates gene expression. Clozapine is considered the gold standard treatment for patients whose illness is resistant to other treatments, and is noted to alter DNA methylation in animal studies. Amy found that symptomatic improvement with clozapine was associated with variation in methylation of a promoter for a gene coding for a sub-unit of the glycine receptor (NMDA hypofunction hypothesis of schizophrenia klaxon!); methylation reduced with symptomatic improvement. Secondly, she found an associated between methylation of DPP-4 – a gene involved in glucose homeostasis and immune function – and response to treatment with clozapine.
As if that wasn’t enough, Amy then went on to describe her current research, on treatment resistance in depression and her testing of new agents in those with inadequate response to SSRI or SNRI medications. In particular, she is focusing on 5HT4 agonists, and using an experimental paradigm to investigate subtle differences in emotional processing after brief treatment (2 weeks), known to be predictive of response to conventional antidepressants.
Finally, Chiara Fabbri presented her research into the genetic basis of treatment resistance in depression. Chiara used machine learning to predict the occurrence of treatment resistant depression from a combination of genetic information and pertinent clinical information. She developed a scoring system wherein genes were grouped into pathways, and subject scores weighted by number of unhelpful genetic variants per pathway, multiplied by the expected impact of each variant on the function of the pathway in question, with rare variants associated with greater functional impact. Pathways associated with treatment resistance were clustered into 4 groups: cell growth and survival; neuronal signal transduction; endocrine signalling; and immune/inflammatory systems. These findings suggest that treatment-resistent depression has a distinct biological profile to treatment responsive depression. Chiara plans to use this model for drug-re-purposing purposes in treatment resistant depression – to find existing compounds that act on pathways predictive of treatment resistance – with the aim of finding badly-needed treatments for this hugely disabling condition.
Overall, this was a engaging and scientifically diverse session, with presentations on clinical, imaging, genetic and epigenetic aspects of treatment resistance, covering both schizophrenia and depression.