Immune modulation in psychiatric disorders: Are we there yet?

At a talk at WFSBP in Vancouver, Professor Michael Berk, Deakin University, Melbourne, Australia asked whether there is clinical trial evidence for anti-inflammatory approaches in psychiatric disorders. He started off by quoting former National Institute of Mental Health director Steven Hyman, who in 2012 claimed that “Drug discovery is at a near standstill for treating psychiatric disorders…”.¹ How do we discover new treatments? According to Professor Berk there are three routes:

1. Hypothesis driven, single target engagement strategy
2. Systems and network biology approach, e.g.  targeting inflammation and oxidative stress
3. Leveraged serendipity

The third route - chance finding and reverse engineering - was the way all antidepressants and antipsychotics came about said Professor Berk, and at the same time highlighted the declining rate of new psychiatric treatment discoveries and the increasing cost for developing new drugs. How do we change this?

Inflammation seems to underpin the pathology of most of our common psychiatric disorders

Turning to systems and network biology, Professor Berk highlighted that inflammation seems to underpin the pathology of most of our common psychiatric disorders; and together with oxidative and nitrosative stress, it causes mitochondrial dysfunction. Subsequent neurotrophic disturbance cause damage to cellular components. Worsened by HPA-axis abnormalities and epigenetic changes, there are ensuing structural abnormalities, cognitive and functional decline and increased vulnerability for further episodes.²

Professor Berk stated that importantly, all these pathways are druggable, and that there is now a plethora of approaches that have shown to be promising.

Of those, he presented data on e.g. a tetracyclic antibiotic tested as an adjunctive treatment in major depressive disorder (MDD)³ and bipolar depression; various lipid-lowering medications⁴; nonsteroidal anti-inflammatory drugs (NSAIDs)⁵; and angiotensin inhibitors in MDD and schizophrenia⁶.

Professor Berk concluded by saying that inflammation, neurogenesis and stress response systems provide novel targets, and that drug repurposing could bypass many of the pitfalls in drug discovery.

Célia Fourrier, University of Adelaide, Adelaide, Australia presented preliminary results from the PREDICT study⁴, a still ongoing randomized, placebo-controlled trial of an NSAID adjunctive to a multimodal antidepressant in patients with MDD.

No significant differences were seen between the two treatment groups in the primary outcome, which was the change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to study endpoint. Similarly, no differences between the groups were detected in any of the secondary outcomes, which measured clinical global impression, well-being, emotional blunting and cognitive function.

Dr Fourrier said that future research would likely utilize a personalized treatment approach, with the hypothesis being that an adjunctive anti-inflammatory medication would increase antidepressant efficacy in those patients with high levels of inflammation at baseline. Dr Fourrier argued that such a study could contribute to the development of a decision aid for depression medication, based on e.g. a pre-treatment blood test measuring inflammation markers.

The final speaker of the session, Professor Roger McIntyre, University of Toronto, Toronto, Canada, brought together the concepts of inflammation and metabolism, and the implications they might have for disease modeling and development of potential new treatments in psychiatry.

Obesity and metabolic syndrome have been shown to be associated with cognitive deficits in patients with bipolar disorder.⁸

Professor McIntyre then introduced the concept of “metaboptosis”, referring to premature cellular aging and death because of alterations in glucose-insulin homeostasis.⁹ A meta-analysis of clinical trials of a peroxisome proliferator-activated receptor-gamma agonist licensed for type 2 diabetes, tested as monotherapy and augmentation therapy in depression provided an indication of a positive effect on remission rates in MDD.¹⁰

Finally, Professor McIntyre jokingly said that the most effective anti-aging intervention is to stop eating and showed data from a recent study with two groups of healthy non-obese individuals, one group eating as normal, and the other subjected to a 25% reduction in calorie intake over two years.¹¹

The group eating less performed significantly better on a working-memory task. Professor McIntyre concluded that altering your diet might have beneficial effects on mood and cognition, just as pharmaceutical and psychotherapeutic interventions can have, but simply eating less could also be beneficial.