Background
Mood disorders are a leading cause of morbidity and mortality. Major depressive disorder and bipolar affective disorder (characterised by periodic elevated and depressed pathological mood states) cause significant disability worldwide (Whiteford et al, 2013). These conditions are frequently chronic and debilitating, often with poor recovery between episodes (Mahli et al 2013, Marotta et al 2015). Despite advances in the treatment of affective disorders, there is often suboptimal response to current treatments (Rush et al 2006, Geddes and Miklowitz 2013, Vergunst et al 2013, Linde et al 2015) as well as poor tolerance of current pharmacological agents due to adverse effects. There remains a clear need to search for new treatment approaches.
Recently there have been promising preclinical and clinical data linking inflammatory processes to a range of psychiatric illness including depression and bipolar disorder. Multiple reviews have clearly demonstrated that major depressive disorder and bipolar disorder are associated with abnormal profiles of circulating pro- and anti-inflammatory immune biomarkers in affected patients (Goldstein et al 2009, Howren et al 2009, Dowlati et al 2010, Baumeister et al 2014). The evidence that affective disorders (or some subgroups thereof) are inflammatory related disorders comes from multiple sources including the observation that both major depressive disorder and bipolar disorder are associated with raised inflammatory markers in the absence of a medical illness (O’Donovan et al 2013, Baumeister et al 2014). More specifically depression has been associated with higher levels of positive acute phase proteins (APPs) and low levels of negative APPs (Dantzer et al, 2008) as well as increased levels of complement factors C3c and C4 and immunoglobulin M (IgM) and IgG (Song et al, 1994). Similarly in bipolar disorders, studies have revealed elevated levels of pro-inflammatory cytokines TNF- α and IL-4, and their receptors sTNFR1 and sIL-2R (Baumeister et al, 2014). However, a recent meta-analysis has indicated that the levels of inflammatory biomarkers in bipolar disorder may be dependent on the mood episode (i.e. manic, depressed, euthymic) (Munkholm et al 2013).
Inflammatory medical illnesses, both CNS and peripheral, are associated with greater rates of psychiatric comorbidities (especially major depressive disorder). For instance, in patients with Crohn’s disease and comorbid depression, bouts of physical disease activity tend to co-occur with depressive episodes (Mardini et al 2004). Furthermore, patients treated with cytokines for various illnesses have an increased risk of developing depressive illness (Van Gool et al, 2003) and treatment with cytokine IFN-α has corresponded with the development of depressive symptoms in up to 45% of patients (Capuron and Miller, 2011). Bipolar disorder has also been proposed as a multisystemic inflammatory disease due to the significant somatic comorbidity associated with it (Leboyer et al, 2012).
Recent evidence indicates that inflammatory changes with pharmacological treatment may differ based on clinical outcome: while IL-6 appears to reduce with pharmacological treatment, TNFa may reduce alongside treatment in people who show a good clinical response but remain elevated in non-responder patients in depressive episodes (Strawbridge et al., 2015). This is supported by a trial identifying a greater level of clinical response to infliximab (a TNFa antagonist) in depressed patients with high levels of TNFa (Raison et al., 2013).
The available evidence suggests that the addition of an anti-inflammatory medication may be efficacious in the treatment of mood disorders. Several recent reviews and meta-analysis have demonstrated that anti-inflammatory medication may be effective in the treatment of mood disorders (Ayorech et al 2014, Faridhosseini et al 2014, Fond G et al 2014, Kohler et al, 2015). However previous reviews have focussed on only one mood disorder (Ayorech et al 2014, Kohler et al 2015) while the more comprehensive reviews’ search was concluded over three years ago. In view of the ongoing problems of treatment resistance associated with unipolar and bipolar affective disorders, there remains a need to investigate novel treatments including anti-inflammatory medication. This review aims to update previous work and examine the most recent evidence for the use of anti-inflammatory drugs in the treatment of mood disorders.
Objectives
- To determine the efficacy of anti-inflammatory drugs:
In improving mood symptoms in unipolar depression and bipolar disorder
- To investigate the adverse effects of anti-inflammatory drug treatment, including the general prevalence of side effects.
Methods
Criteria for considering studies for the review
Types of studies
Randomised controlled trials and cross-over trials. For identified papers in non-English language, effort will be made to obtain a translated version.
Types of participants
Males and females of all ages with a diagnosis of major depressive disorder meeting criteria for ICD 10 Code F32-3 (WHO 1992) and DSM IV 296 (APA 1994), or bipolar affective disorder meeting criteria for ICD 10 Code F31 and DSM IV 296. All subtypes of major depressive disorder (mild, moderate, severe, with/without psychotic features) and bipolar disorder (rapid cycling, type I, type II and other) will be included. Dysthymia and cyclothymia will be excluded.
Patients with acute affective episodes will be included, according to the following diagnostic criteria:
- Patients with depressive episodes, with or without psychotic symptoms (ICD-10 codes F31.3-31.5 or F33.0-33.3 and DSM-IV 296.21-4 or 296.31-4).
- Patients with a diagnosis of mixed affective disorder (ICD-10 code F31.6 and DSM-IV code 296.41-4).
- Patients with a diagnosis of hypomania or mania with or without psychotic symptoms (ICD-10 codes F30.0 or F31.0-31.2 and DSM –IV code 296.40 or 296.41-4).
Trials with ICD 9 and DSM III/IIIR diagnoses approximating to these codes will also be included.
Types of interventions
Anti-inflammatory treatments are defined as non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, pro-inflammatory cytokine inhibitors, and minocycline hydrochloride. For the purposes of this review the drugs will include ibuprofen, diclofenac, naproxen sodium, acetylsalicylic acid, celcoxib, anti-TNF-α, etanercept, infliximab, adalimumab and minocycline. Anti-inflammatories could be administered either as single or adjunctive therapy (in cross-over trials). Minimum length of therapy for inclusion will be one day. Criteria for maximum length of therapy or length of follow-up is not stipulated.
Anti-inflammatory treatments will be compared with:
- Placebo
- Antidepressant treatment
- Mood stabiliser treatment
- Combination treatment (e.g. antidepressant and mood stabiliser)
- Other treatment e.g. antipsychotic medication
- Other anti-inflammatory treatment
Outcome measures
All outcomes will be measured before and at the end of the study period.
Primary outcome measure
The primary outcome measure will be the efficacy of anti-inflammatory drugs in the treatment of acute mood symptoms.
For depressive episodes, efficacy of treatment will be measured by:
Changes (from baseline to endpoint) in validated depressive symptoms rating scales (BDI, HAM-D, MADRS, IDS)
For manic episodes, efficacy of treatment will be measured by:
Changes (from baseline to endpoint) in validated manic symptom rating scales (YMRS, ASRM)
For mixed affective episodes, efficacy of treatment will be measured by:
Changes (from baseline to endpoint) in validated symptom rating scales (BDI, HAM-D, MADRS, YMRS, ASRM)
Secondary outcome measures
Adverse effects:
Participants experiencing troublesome side effects of any nature will be considered.
Search methods for identification of studies
- Electronic databases
Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO and the National Institute of Health website Clinicaltrials.gov will be searched.
- Reference checking
Citation lists of relevant studies and reviews will be checked for relevant trials.
- Hand searching
The following conference proceedings during the past five years will be hand searched and authors contacted for further results/publication from any conference abstracts that appear relevant.
Society of Biological Psychiatry
American Psychiatric Association
British Association for Psychopharmacology
Royal College of Psychiatrists
European Congress of Neuropsychopharmacology
European Stanley Bipolar Meetings
International Society for Bipolar Disorders.
- Personal communication
The authors of significant papers over the last five years and other experts in the field will be contacted and asked if they are aware of any other studies.
Search terms
The following Medical Subject Headings (or similar headings) or text word terms will be used: major depressive disorder, depression, depressive symptoms, bipolar disorder, mania, manic symptoms in combination with anti-inflammatory, NSAID, acetylsalicylic acid, cyclooxygenase 2 inhibitor, COX-2, antibiotics, celecoxib, infliximab, etanercept or minocycline.
The following search string was used: [(Depression) OR (major depressive disorder) OR (depressive symptoms) OR (bipolar disorder) OR (mania) OR (manic symptoms)] AND [(anti-inflammatory) OR (NSAID) OR (acetylsalicylic acid) OR (cyclooxygenase 2 inhibitor) OR (COX-2) OR (antibiotics) OR (celecoxib) OR (infliximab) OR (etanercept) OR (minocycline) OR (N-acetyl cysteine) OR (NAC)) AND ((trial) OR (RCT) OR (treatment)]
Data collection and analysis
- Selection of trials
All studies generated will be evaluated against the pre-defined inclusion criteria by two of the review authors. Any disparities will be addressed by reaching agreement via an additional review author. A record of included and excluded studies (and reasons for exclusion) will be kept.
- Data extraction
This will be conducted by two review authors and will include quality assessment, description of participants, description of the intervention and control groups, psychometric data and outcomes. Disagreements will be resolved via further discussion with a third review author.
- Data analysis
Data will be entered in to the Review Manager software programme by one review author.
Assessment of bias
The bias risks of the randomised clinical trials included will be addressed based on the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions. We will extract data regarding quality based on five domains: sequence generation, allocation concealment, blinding of outcome assessors, use of intention-to –treat analysis and presence of for-profit bias.
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