Correspondence 838 www.thelancet.com/respiratory Vol 8 October 2020 University of Manchester, Manchester, UK (BD, IBC); Department of Psychiatry, Dow University of Health Sciences, Karachi, Pakistan (IBC); Ziauddin University Hospital, Karachi, Pakistan (IBC); and Centre for Affective Disorders, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK (AHY) 1 Husain MI, Chaudhry IB, Khoso AB, et al. Minocycline and celecoxib as adjunctive treatments for bipolar depression: a multicentre, factorial design randomised controlled trial. Lancet Psychiatry 2020; 7: 515–27. 2 Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2016; 16: 22–34. 3 McIntyre RS, Subramaniapillai M, Lee Y, et al. Efficacy of adjunctive infliximab vs placebo in the treatment of adults with bipolar I/II depression: a randomized clinical trial. JAMA Psychiatry 2019; 76: 783–90. 4 Salvadore G, Nash A, Bleys C, et al. A double- blind, placebo-controlled, multicenter study of sirukumab as adjunctive treatment to a monoaminergic antidepressant in adults with major depressive disorder. American College of Neuropsychopharmacology Annual Meeting; Hollywood, FL, USA; December 2018. 5 Husain MI, Chaudhry IB, Husain N, et al. Minocycline as an adjunct for treatment- resistant depressive symptoms: a pilot randomised placebo-controlled trial. J Psychopharmacol 2017; 31: 1166–75. 6 Chamberlain SR, Cavanagh J, De Boer P, et al. Treatment-resistant depression and peripheral C-reactive protein. Br J Psychiatry 2019; 214: 11–19. depression did not affect depressive symptoms. Furthermore, we reported that minocycline was clearly an effective adjunct in non-bipolar treatment-resistant depression, 5 a subtype convincingly associated with raised CRP. 6 In keeping with the current study, the effective anti-inflammatory cytokine inhibitor, infliximab, did not affect depression in bipolar patients selected for having CRP of at least 5 mg/L. 3 It seems a reasonable inference that in bipolar disorder, inflammation is not a pervasive mechanism of depression. We fully agree that stratification, use of target-specific drugs, and innovative trial designs are important for progress in developing the immune strategy for treating depression. For this to happen, an urgent need exists for the definition and validation of immune subtypes of depression and for feasible biomarkers for neuroinflammation. MIH is a principal investigator for a trial sponsored by COMPASS Pathways Limited, for which he receives salary support. BD has worked as scientific consultant to Autifony in the past 3 years and has share options in P1vtal.com. IBC has given lectures and advice to Eli Lilly, Bristol-Myers Squibb, Lundbeck, AstraZeneca, and Janssen Pharmaceuticals, for which he or his employing institution have been reimbursed. BHM currently receives research support from Brain Canada, the Canadian Institutes of Health Research, the UK Centre for Addiction and Mental Health Foundation (CAMH), the Patient-Centered Outcomes Research Institute, the US National Institutes of Health (NIH), Capital Solution Design (software used in a study funded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). Within the past 5 years, BHM has also received research support (medications for NIH-funded clinical trials) from Bristol-Myers Squibb, Eli Lilly, and Pfizer, and he directly own stocks of General Electric (less than US$ 5000). AHY has been commissioned to provide lectures and advice to all major pharmaceutical companies with drugs used in affective and related disorders and has undertaken investigator-initiated studies funded by AstraZeneca, Eli Lilly, Lundbeck, and Wyeth. *Muhammed Ishrat Husain, Bill Deakin, Imran B Chaudhry, Benoit H Mulsant, Allan H Young ishrat.husain@camh.ca Centre for Addiction and Mental Health, Toronto, ON M6J 1H4, Canada (MIH, BHM); Department of Psychiatry, University of Toronto, Toronto, ON, Canada (MIH, BHM); Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, varying between 1 mg/L in 60% and 5 mg/L in 30% of patients with depression. 2 No validated stratification algorithm incorporates the many other peripheral markers of inflammation, and none are convincingly predictive of neuroinflammation. Recent trials of anti-inflammatory drugs that stratified participants at baseline according to biochemical (CRP) and phenotypic (obesity) evidence of inflammation failed to show superiority of two drugs over placebo in patients with both unipolar and bipolar depression. 3,4 If our sample had an appreciable number of patients with a responsive immune pathogenesis, this was not reflected in greater variance in outcome measures in the actively treated groups. Regarding outcome, improvement in overall depressive symptoms must surely remain the gold standard in randomised controlled trials of pharmacological and psychosocial interventions in mood disorders. However, it is entirely appropriate to use exploratory and experimental measures to probe mechanisms such as anhedonia, but Miller and Pariante leave these measures undefined. There are several questionnaire and performance measures of anhedonia, which itself has several dissociable components. Using multiple nuanced outcome measures dilutes statistical power. Miller and Pariante cite two studies showing anti- inflammatory effects on anhedonia, but both are negative for depression, and one assessed anhedonia by a single item (work and interests) of the Hamilton Depression scale, which seems like a flimsy proof of concept for anhedonia as the primary outcome in an anti-inflammatory trial in depression. The suggestion that minocycline and celecoxib have too many off-target effects to interpret a negative effect has no basis. The unspecified off-target actions do not prevent the undoubted efficacy these drugs in treating inflam- matory disorders such as rheumatoid arthritis. The same actions in bipolar Cannabidiol for cannabis use disorder: too high hopes? In The Lancet Psychiatry, Tom Freeman and colleagues 1 reported results from a first of its kind, phase 2a randomised trial on the effect of different doses of cannabidiol for the pharmacological treatment of cannabis use disorder. The trial appears to be well designed, and the authors concluded that both 400 mg and 800 mg cannabidiol were safe and more efficacious than placebo at reducing cannabis use. As in previous cannabidiol trials targeting psychosis, 2 the safety profile was satisfactory, with no serious adverse events reported and only a small number of reported sleep-related problems in the cannabidiol 400 mg group. No sleep-related problems were reported in the cannabidiol