Table 1. Guidelines for Clinical Trial Design to Reverse Effects of Inflammation on the Brain and Behavior.

(1) Define sample population by immunologic status

(a) Designs include:

(i) Simple randomization design using drug and placebo in patients with high inflammation onlya

(ii) Match/mismatch design using drug only in patients with high and low inflammation with expectation of response in patients with high inflammation only (this design may be most appropriate for drugs with multiple off-target effects)

(b) Peripheral immune markers for stratification include CRP that is easily measurable in CLIA-certified laboratories and has standardized values

(2) Establish target engagement in the periphery and/or the brain

(a) Peripheral immunological markers should be monitored and correlated with treatment response when using drugs that target the immune systemb

(b) Central markers of inflammation include:

(i) Microglial activation as measured by TSPO ligands (PET)

(ii) Activity in inflammation-sensitive neurocircuits including those engaged in reward and threat sensitivity (fMRI)

(iii) Inflammation-sensitive neurometabolites including glutamate, myo-inositol, and glutathione (MRS)

(3) Pharmacologic specificity is uniquely available for a number of immune targets

(a) Monoclonal antibodies (mAbs) with high specificity and minimal off-target effects that are FDA-approved or in the final phases of approval include:

(i) mAbs against the cytokines and cytokine receptors TNF, IL-1, IL-6, IL-6R, IL17, and IL22/23

(ii) mAbs against B cells (CD20, B-cell activating factor)

(iii) mAb against adhesion molecules (α-4 integrin)

(4) Immune effects on the brain warrant symptom-specific primary outcome variables

(a) Symptom-specific outcomes measured objectively or clinically include:

(i) Anhedonia

(ii) Psychomotor retardation

(iii) Anxiety

(iv) Sleep

Abbrevations: CD: cluster of differentiation; CLIA: Clinical Laboratory Improvement Amendments; CRP: C-reactive protein; fMRI: functional magnetic resonance imaging; IL: interleukin; MRS: magnetic resonance spectroscopy; PET: positron emission tomography; TNF: tumor necrosis factor; TSPO: translocator protein.

^aAre being used in ongoing trials or will be used in proposed trials.

^bHave been used in published trials.