Comprehensive Systematic Review Training Program

Module 1

Module 1: Workbook Introduction to Evidence-based Healthcare and the Systematic Review of Evidence

www.joannabriggs.org Comprehensive Systematic Review Training Program

Module 1: Workbook Introduction to Evidence-based Healthcare and the Systematic Review of Evidence

JBI/CSRTP/2017/0001

Published by The Joanna Briggs Institute. Adelaide, South Australia, Australia. © The Joanna Briggs Institute 2017

This Publication is copyright. Apart from any fair dealing for the purpose of private study, research, criticism or review as permitted under the Copyright Act, no part may be reproduced by any process or placed in computer memory without written permission. All inquiries should be made to the Joanna Briggs Institute.

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 2 Contents Activity 1: Example Systematic Reviews . 4 Ravindran and Silva 2013 . 5 Elliott et al 2015. 18

Activity 2: Question and Inclusion Criteria Development . 27

Activity 3: Logging into JBI SUMARI . 31

Activity 4: Logic Grid Development. 32

Activity 5: Uploading Search Results into JBI SUMARI. 34

Activity 6: Selecting Studies. 35 Vernaya and McAdam 2015 . 36

Activity 7: Developing a protocol in JBI SUMARI . 56

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 3 Activity 1: Example Systematic Reviews Scan over the two example papers that claim to be systematic reviews by Ravindran and Silva 2013 and Elliott et al 2015 provided in the subsequent pages of this workbook with a particular focus on the methods and results section. Answer the following questions: a) Are both papers examples of systematic reviews? Explain your reasoning.

b) Would you consider both examples to be of good quality? Explain your reasoning.

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 4 Journal of Affective Disorders 150 (2013) 707–719

Contents lists available at ScienceDirect

Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Review Complementary and alternative therapies as add-on to pharmacotherapy for mood and anxiety disorders: A systematic review

Arun V. Ravindran a,b,n, Tricia L. da Silva b,c

a Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8 b Division of Mood and Anxiety Disorders, Centre for Addiction and Mental Health, 100 Stokes Street, Toronto, Ontario, Canada M6J 1H4 c Institute of Medical Science, University of Toronto, 1 King's College Circle, Room 2374, Toronto, Ontario, Canada M5S 1A8

article info abstract

Article history: Background: Depressed and anxious patients often combine complementary and alternative medicine Received 22 January 2013 (CAM) therapies with conventional pharmacotherapy to self-treat symptoms. The benefits and risks of Received in revised form such combination strategies have not been fully evaluated. This paper evaluates the risk-benefit profile of 22 March 2013 CAM augmentation to antidepressants in affective conditions. Accepted 17 May 2013 Methods: PubMed was searched for all available clinical reports published in English up to December Available online 12 June 2013 2012. Data were evaluated based on graded levels of evidence for efficacy and safety. Keywords: Results: Generally, the evidence base is significantly larger for depression than for anxiety disorder. Anxiety disorders In unipolar depression, there is Level 2 evidence for adjunctive sleep deprivation (SD) and Free and Augmentation Easy Wanderer Plus (FEWP), and Level 3 for exercise, yoga, light therapy (LT), omega-3 fatty acids, Combination S-adenosylmethionine and tryptophan. In bipolar depression, there is Level 1 evidence for adjunctive Complementary and alternative medicine Depressive disorders omega-3s, Level 2 for SD, and Level 3 for LT and FEWP. In anxiety conditions, exercise augmentation has Systematic review Level 3 support in generalized anxiety disorder and panic disorder. Though mostly well-tolerated, these therapies can only be recommended as third-line interventions due to the quality of available evidence. Limitations: Overall, the literature is limited. Studies often had methodological weaknesses, with little information on long-term use and on potential drug–CAM interactions. Many CAM studies were not published in English. Conclusions: While several CAM therapies show some evidence of benefit as augmentation in depressive disorders, such evidence is largely lacking in anxiety disorders. The general dearth of adequate safety and tolerability data encourages caution in clinical use. & 2013 Elsevier B.V. All rights reserved.

Contents

1. Introduction...... 708 1.1. Caveat...... 708 2. Methods...... 708 3. Resultsanddiscussion...... 708 3.1. Physicaltherapies...... 708 3.1.1. Exercise...... 710 3.1.2. Yoga...... 711 3.1.3. Lighttherapy(LT)...... 711 3.1.4. Sleepdeprivation(SD)...... 712 3.1.5. Acupuncture...... 712 3.2. Herbalremedies...... 713 3.2.1. FreeandEasyWandererPlus(FEWP)...... 713 3.3. Nutraceuticals...... 713 3.3.1. Omega-3fattyacids...... 713 3.3.2. S-adenosylmethionine(SAM-e)...... 713 3.3.3. Dehydroepiandrosterone(DHEA)...... 714 3.3.4. Tryptophan...... 714

n Corresponding author. Tel.: +1 416 979 6933; fax: +1 416 260 4171. E-mail address: [email protected] (A.V. Ravindran).

Ravindran and Silva 2013 Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 5 708 A.V. Ravindran, T.L. da Silva / Journal of Affective Disorders 150 (2013) 707–719

3.3.5. Folate...... 714 3.3.6. Inositol...... 714 3.3.7. N-acetylcysteine(NAC)...... 715 4. Conclusionsandfuturedirections...... 715 Roleoffundingsource...... 715 Conﬂictofinterest...... 715 Acknowledgments...... 715 References...... 715

1. Introduction herbal remedies and nutraceuticals as augmentation to medication in mood and anxiety disorders and published in English up to Epidemiological studies have consistently shown that depres- December 2012. The disorders covered in this review include: sive and anxiety disorders are among the most common mental major depressive disorder (MDD), dysthymia, psychotic depres- illnesses. The 1-year prevalence of depressive illness ranges from sion, treatment resistant depression (TRD), chronic depression, 4% to 11% worldwide, while that of anxiety disorders is 3% to 18% bipolar disorder, seasonal affective disorder, generalized anxiety globally (Alonso, 2007; WHO, 2000). disorder (GAD), panic disorder (PD), obsessive-compulsive disor- fi Though pharmacotherapy is generally the rst line of treat- der (OCD), social anxiety disorder (SAD) and post-traumatic stress ment for depression and anxiety, it has limitations. Many patients disorder (PTSD). Study results were evaluated using the standard continue to be symptomatic despite adequate treatment, and in criteria for considering the strength of evidence for efficacy and spite of several antidepressant trials, including combinations of tolerability (see Table 1). Data from randomized, controlled trials drugs (Rush et al., 2004; Yonkers et al., 2003). Their side effects (RCTs) and meta-analyses for the CAMs that showed the strongest and the high costs associated with medication use can also be a evidence (Levels 1 or 2) are summarized in Tables 2–4. deterrent to compliance (Sajatovic et al., 2011; Zivin et al., 2009). Complementary and alternative medicine (CAM) therapies are interventions and products that are perceived to be as effective as conventional pharmacotherapy, but more natural and economical, with fewer side effects and available without need of prescription 3. Results and discussion (Andreescu et al., 2008; Ravindran et al., 2009). They include physical therapies (e.g. exercise, acupuncture), nutraceuticals CAM therapies were used as adjunct to a range of psychotro- (i.e. dietary and nutritional supplements such as vitamins and pics, such as selective serotonin reuptake inhibitors (SSRIs), minerals) and herbal remedies (i.e. plants and plant extracts). selective norepinephrine reuptake inhibitors (SNRIs), tricyclic An ever-growing number of patients with depression and anxiety antidepressants (TCAs), atypical antipsychotics (AAPs), monoa- report using CAM therapies to treat their symptoms, often in mine oxidase inhibitors (MAOIs), mood stabilizers, and addition to conventional medications, and usually without med- benzodiazepines. ical supervision (Wahlström et al., 2008). Clinical experience with CAM agents is relatively limited, but patient use of these agents is increasing significantly. It is therefore 3.1. Physical therapies of value to evaluate the benefits and risks of their use as adjunct to pharmacotherapy. This paper will review the evidence for the Physical therapies encompass physical practices, such as exer- safety and efficacy of established CAMs as augmentation or cise and yoga, and non-invasive biological treatments, such as combination with medication for mood and anxiety disorders. light therapy and acupuncture. While popular culture perceives Only those CAMs that have a reasonable body of published most physical therapies as aids to improve physical fitness and research, thus warranting clinical consideration of their use, will relieve stress, some (e.g. light therapy) are known mainly for their be evaluated. “Augmentation” describes the addition of an agent to benefits to mood. existing antidepressant or anxiolytic treatment; “combination” describes the concurrent use of two or more agents with individual antidepressant or anxiolytic effects; “add-on” describes either Table 1 Criteria for levels of evidence and lines of treatment. strategy (Lam et al., 2009). Levels of evidence Criteria 1.1. Caveat Level 1 Meta-analysis or replicated double-blind (DB), randomized controlled trial (RCT) that includes a placebo condition This review does not suggest that CAM therapies should be fi considered rst when managing treatment-refractory patients. Level 2 At least one DB–RCT with placebo or active comparison For patients who are partially or completely non-responsive to condition first-line psychotropics, addition of evidence-based pharmacother- Level 3 apy (e.g. lithium, atypical antipsychotics) or psychotherapies Prospective uncontrolled trial or case series or high quality retrospective studies (e.g. cognitive-behaviour therapy, interpersonal therapy) should be considered first (Lam et al., 2009; Parikh et al., 2009). Level 4 Anecdotal reports or expert opinion

Lines of treatment Criteria 2. Methods First line Level 1 or level 2 evidence plus clinical support Second line Level 3 evidence or higher plus clinical support Third line Level 4 evidence or higher plus clinical support A search of the psychiatric literature, using PubMed, was Not recommended Level 1 or level 2 evidence for lack of efﬁcacy conducted for all articles relating to the use of physical therapies,

Ravindran and Silva 2013

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 6 A.V. Ravindran, T.L. da Silva / Journal of Affective Disorders 150 (2013) 707–719 709 0.012). ≤ 0.001). p 0.001). 0.009). o p o ¼ p p 0.008), 0.05). ¼ o 0.032) and 0.05). 0.0007). p placebo ( p ¼ SPA augmentation o o cial only 4 p + p p fi sertraline ( n psychotropics. 4 sham rTMS ( ¼ placebo + placebo + active rTMS partial SD ( + placebo ( + bright LT + 4 + sertraline CBZ placebo and + cacy results + medication alone ( partial SD 4 fi 0.001). CBZ 4 4 Total SD in SD responders ( No group differences. Combination bene TSD No group differences. Ef 0.00001) and Total SD but the degree of superiority was small. Partial SD 0.044). psychotropics medication alone ( CBZ 0.012). CBZ o ¼ ≤ o ¼ placebo for discontinuation ( 4 4 placebo for continued improvement. p p p FEWP p + + + n CBZ CBZ FEWP + 4 ¼ 0.009). placebo ( o medication. medication medication p 4 ¼ + + FEWP FEWP + + cacy results placebo alone ( placebo alone ( placebo alone ( fi 4 4 4 alone ( Mania: CBZ Ef Depression: CBZ CBZ CBZ FEWP control treatments total late + + SPA + sham rTMS + sham rTMS + sertraline bright LT + placebo placebo + + + partial SD Existing psychotropics SD Control treatments Paroxetine TSD Existing psychotropics + Existing+ antidepressants total SD partial SD Placebo CBZ Placebo or psychotropics FEWP Comparator CBZ Psychotropics SD Existing+ psychotropics + FEWP Existing psychotropics FEWP FEWP Existing psychotropics FEWP + + total SD + bright LT partial SD total SD Existing psychotropics + + + Comparator FEWP FEWP SD paroxetine placebo + + + + + Existing psychotropics Existing psychotropics active rTMS active rTMS Existing psychotropics Total SD + + 12 weeks FEWP 12 weeks FEWP – – 12 weeks CBZ Duration Agent 26 weeks CBZ 4 4 weeks Bright LT − 7 weeks Existing psychotropics 1 2 weeks Total SD 1 week Existing psychotropics 6 weeks Sertraline Duration Agent 1 week Existing antidepressants 1 week Existing psychotropics 111 ¼ 2 ¼ 2 ¼ 37 49 2 5 26 1 ¼ 2 124Bipolar mania 93 ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ 18 2 74 16 84 ¼ 6 8 ¼ 8 ¼ ¼ ¼ ¼ ¼ ¼ 80 15 41 37 20 non-seasonal depression 235 14MDD 188 26 ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ Monotherapy Augmentation Bipolar depression (unipolar and bipolar patient samples) MDD N MDD MDD Unipolar depression Bipolar depression MDD Bipolar depression Post-partum depression Depression and medical illness Monotherapy Combination Neurotic depression Bipolar depression N Bipolar depression Bipolar mania Bipolar depression Unipolar depression Monotherapy Augmentation 0.05. 0.05. o o p p cant at cant at RCT Meta-analysis Total RCT Type RCT RCT RCT RCT fi fi DBRCT Total Type Meta-analysis Total DBRCT Total Meta-analysis Total ) Results statistically signi Results statistically signi Zhang et al., 2007a n n Wu et al., 2009 Zhang et al., 2007a Tuunainen et al., 2004 Reynolds et al., 2005 Study Study Eichhammer et al., 2002 Qin et al., 2011 Gorgulu and Caliyurt, 2009 Kreuzer et al., 2002 Zhang et al., 2007b Giedke et al., 2003 (Continuation phase of Zhang et al., 2012a Table 2 Evidence for sleep deprivation as augmentation for depressive disorders. Table 3 Evidence for FEWP as augmentation for depressive disorders.

Ravindran and Silva 2013

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 7 710 A.V. Ravindran, T.L. da Silva / Journal of Affective Disorders 150 (2013) 707–719

3.1.1. Exercise Exercise has been evaluated in both aerobic (sustained, exer- tive) and non-aerobic forms. Its antidepressant action has been proposed to derive from its positive effect on neurogenesis cant

fi (notably through hippocampal growth and increased expression of brain-derived neurotrophic factor (BDNF), B-endorphins, vascular endothelial growth factor and serotonin) (Lucassen et al., 2010) and reduced inflammation and oxidative stress 0.31). Signi cant heterogeneity ¼ fi

p (Eyre and Baune, 2012). Exercise is also noted to increase in endo- cannabinoid and atrial natriuretic peptide (ANP) levels (Dietrich and McDaniel, 2004; Ströhle et al., 2006) and modulate stress reactivity through effects on hypothalamic-pituitary adrenocortical (HPA) axis n activity and cortisol production (Lucassen et al., 2010). placebo for bipolar depression placebo for bipolar depression placebo for depressive disorders placebo for unipolar and bipolar depression 4 4 4 4 There are at least 10 studies in the literature on the use of adjunctive exercise for unipolar depression. An early open trial 0.029). No group differences for mania. 0.04). No group differences for mania. 0.002), but publication bias and heterogeneity 0.07), but not mania ( cacy results ﬁ o o ¼ ¼

fi reported exercise augmentation bene cial for depression and p p p p ( ( weaken results. Omega-3 ( heterogeneity of studies weaken results. and publication bias noted. ( No group differences. Signi Ef anxiety in patients with various psychiatric conditions, but only depressive improvement was maintained at one-year follow-up (Martinsen et al., 1989b). Other small open trials have also found adjunctive exercise beneficial for MDD (e.g. Dimeo et al., 2001; placebo Omega-3 placebo Omega-3 placebo placebo placebo Omega-3 + + + + + Trivedi et al., 2006). However, several RCTs have found no group differences between exercise add-on and exercise and/or medication alone in unipolar depressed patients (Blumenthal et al., 1999; Mota-Pereira et al., 2011; Oeland et al., 2010; Veale et al., 1992: Study 1). Interestingly, in one of these studies, onset of improvement was fastest with medication alone (Blumenthal et al., 1999), but at 6-month follow-up, depression was lower and relapse and Existing psychotropics Existing psychotropics Placebo Placebo Comparator remission higher with exercise alone (Babyak et al., 2000). Preliminary results from an ongoing RCT have also suggested the superiority of exercise as add-on to antidepressants alone in omega-3 Existing psychotropics omega-3 Existing psychotropics omega-3 Existing psychotropics severe MDD (Schuch et al., 2011). Among RCTs evaluating exercise + + + against other non-medication interventions as augmentation for unipolar depression, adjunctive exercise was found superior to occupational therapy (Martinsen et al., 1985) and comparable to health education (Mather et al., 2002). Comparisons of aerobic and non-aerobic exercise add-on have had mixed results, with no group differences noted in two RCTs (Martinsen et al., 1989a; Veale omega-3 fatty acids omega-3 fatty acids + Existing psychotropics + Existing psychotropics et al., 1992: Study 2), but aerobic exercise reported superior in a third smaller RCT (Knubben et al., 2007). In bipolar disorder, a small retrospective chart review found that depression and anxiety improved significantly among bipolar 16 weeks Existing psychotropics 52 weeks Existing psychotropics 16 weeks Omega-3 fatty acids 16 weeks Existing psychotropics 16 weeks Omega-3 fatty acids – – – – – inpatients (depressed or manic) who participated voluntarily in an 4 4 4 Duration Agent adjunctive exercise program, though overall clinical improvement did not differ from non-participants (Ng et al., 2007). In addition, fi 7 8 exercise augmentation was found bene cial in a small open trial 3 ¼ ¼

¼ (Dimeo et al., 2001) and in a small RCT (Knubben et al., 2007), both 5 6 5 9 13 8 ¼ 1 0 7 with mixed unipolar and bipolar depressed samples. ¼ ¼ ¼ ¼ ¼ ¼ ¼ ¼ In anxiety disorders, exercise augmentation improved anxiety symptoms during acute treatment (though not sustained at 1-year 13 6 (bipolar depression) 4 5 (bipolar depression) 4 10 13 13 ¼ ¼ ¼ ¼ ¼ ¼ follow-up) in an early open trial described previously (Martinsen et al., 1989a, 1989b), but had no impact on GAD or PD in a later Augmentation Augmentation Unipolar depression Bipolar depression Monotherapy Augmentation Monotherapy Augmentation Unipolar depression Bipolar disorder MDD Monotherapy Augmentation N RCT (Oeland et al., 2010). Another small RCT in GAD with/out co-morbid depression and anxiety disorders found aerobic and 0.05. non-aerobic exercise comparably effective and superior as add-on o p to wait-list control (Herring et al., 2012). In OCD, two small open trials noted significant benefits with exercise augmentation, which Meta-analysis Total Meta-analysis Total Meta-analysis Total Meta-analysis Total Type Meta-analysis Total cant at persisted at follow-up even if the exercise regime was not fi maintained (Brown et al., 2007; Lancer et al., 2007). In PD, exercise and relaxation training were comparably effective as augmentation and superior to either treatment alone in an RCT (Wedekind et al., 2010). Exercise, therefore, has Level 3 evidence for use as augmentation in unipolar and bipolar depression, and in GAD, OCD and PD. In unipolar depression, mixed RCT results and positive data Results statistically signi Richardson, 2008 n coming from only open trials support its use as only a third-line Sarris et al., 2012 Montgomery and Lin and Su, 2007 Kraguljac et al., 2009 Study Depression Bloch and Hannestad, 2012

Table 4 Evidence for Omega-3 fatty acids as augmentation for depressive disorders. add-on agent. The very small patient samples in the bipolar and

Ravindran and Silva 2013

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 8 A.V. Ravindran, T.L. da Silva / Journal of Affective Disorders 150 (2013) 707–719 711

OCD studies negate any recommendation at this time, but exercise meditation-induced mania or psychosis has been reported in may have some utility as a third-line adjunct for GAD and PD. vulnerable patients, as well as single cases of serious adverse Heterogeneity in exercise forms and treatment regimes also limit effects such as artery occlusion or lotus neuropathy (see overview interpretation. However, higher frequency and intensity of exer- in Pilkington et al., 2005), the latter possibly resulting from cise appear more beneficial (Perraton et al., 2010; Stathopoulou excessive or incorrect yoga practice. et al., 2006), Though no significant tolerability issues were noted, possible adverse effects include musculosketal pain and/or injury (Hootman et al., 2002), and risk of cardiovascular events in 3.1.3. Light therapy (LT) susceptible patients (Thompson et al., 2007). Exercise may also LT, also described as bright light therapy (bright LT), involves impact lithium levels in bipolar patients (Wright et al., 2009), and daily exposure to artificial bright light, usually through the use of a temporarily increase anxiety in those with high anxiety sensitivity fluorescent light box or light-emitting diodes (Ravindran et al., (Ströhle, 2009). 2009; Tuunainen et al., 2004). LT is thought to influence mood via impact on the suprachiasmatic nucleus and melatonin production (which are both involved in circadian rhythm regulation), and on 3.1.2. Yoga monoaminergic modulation (Pail et al., 2011). Yoga has three main components (postures, breathing exercises In seasonal depression, a small RCT found no group differences and meditation), which are given variable emphasis in the differ- between add-on with CBT+LT or either treatment alone, but ent yoga forms practiced (da Silva et al., 2009). Its posited role in symptom severity was lowest with CBT+LT and relapse highest reducing sympathetic activity, improving parasympathetic drive, with LT alone at 1-year follow-up (Rohan et al., 2004). Another RCT normalizing HPA axis activity, and influencing monoamine reported similar response to bright LT, dim light and negative-ion changes, may explain its potential effects on mood (Brown and therapy as adjunct in seasonally depressed unipolar and bipolar Gerbarg, 2005; Streeter et al., 2012). As well, controlled breathing, patients, though remission was significantly greater with bright LT considered to be the most therapeutic component of yoga, is proposed (Flory et al., 2010). to activate vagal afferents to autonomic, neuroendocrine, and limbic There have been contradictory findings in non-seasonal circuits, with positive impact on emotion regulation and stress depression, as well, with one systematic review reporting benefits responsivity (Brown and Gerbarg, 2005; Streeter et al., 2012). with adjunctive LT in unipolar and bipolar depression (Even et al., Literature on the use of adjunctive yoga in depressive disorders 2008), while two meta-analyses did not (Golden et al., 2005; is not extensive. A recent medium-size meta-analysis concluded Tuunainen et al., 2004). In more recent publications, RCTs in MDD that yoga was an effective adjunct treatment of major psychiatric noted the superiority of bright LT to dim light as add-on (Lieverse disorders, particularly depression and anxiety (Cabral et al., 2011). et al., 2011; Wirz-Justice et al., 2011). Two other RCTs in unipolar However, most included studies were monotherapy trials, and depression failed to find such difference, but used self-rated several recruited patients based only on self-report, which limit measures and not objective clinical ratings (Lande et al., 2011; these conclusions. Among depression studies, a small RCT in MDD Niederhofer and von Klitzing, 2011). Augmentation with early found that Sahaj yoga augmentation superior to medication alone morning bright LT was reported superior to late morning bright (Sharma et al., 2005). Another RCT, with medicated and unmedi- LT in another RCT in MDD (Dallaspezia et al., 2012). cated unipolar depressed patients, did not report acute treatment In bipolar depression, a small RCT found no groups differences data, but at 9-month follow-up, noted better remission with Hatha between augmentation with bright LT or negative-ion therapy yoga+psychoeducation and a trend to higher rates of relapse with (Dauphinais et al., 2012). Another RCT (described earlier) also psychoeducation alone (Butler et al., 2008). Small open trials also failed to distinguish between adjunctive bright LT, dim light and reported Iyengar yoga (Shapiro et al., 2007) and Vinyasa yoga negative-ion therapy in seasonally depressed unipolar and bipolar (Uebelacker et al., 2010) significantly effective as add-on for patients, though bright LT produced higher remission (Flory et al., unipolar depression. 2010). However, open trials have noted positive findings with LT There is no published data on the use of yoga as augmentation add-on (Benedetti et al., 2009a) or augmentation with total sleep in bipolar disorder. deprivation plus LT (Benedetti et al., 2005, 2007, 2009b), with drug The evidence for yoga as augmentation in anxiety disorders is resistance a possible influence on response to total SD+LT even sparser. In GAD, an open trial found adjunctive Sudarshan (Benedetti et al., 2005, 2007). Kriya Yoga significantly improved anxiety symptoms, but treat- There are no published studies of LT augmentation in anxiety ment was very brief at 5 days (Katzman et al., 2012). In OCD, a disorders. small open trial found Kundalini yoga augmentation beneficial and In summary, LT has Level 3 evidence of benefit as augmentation associated with reduced medication use; interestingly, unmedi- in both seasonal and non-seasonal unipolar depression and bipolar cated patients did not show symptom improvement and dropped depression. However, methodological weaknesses and sparse out early (Shanahoff-Khalsa and Beckett, 1996). In a subsequent long-term efficacy and safety data would suggest its use as RCT by the same group, Kundalini yoga meditation add-on was third-line adjunctive treatment only. Many patients relapse upon superior to relaxation+meditation in OCD (p values not reported); cessation of LT (Benedetti et al., 2005; Martiny et al., 2006), and the merged treatment group received an open course of yoga, other adverse effect include (mild) sleep difficulties, headache, eye resulting in significant improvement and reduced medication use irritation, blurred vision, menstrual irregularities, nausea and (Shannahoff-Khalsa et al., 1999). agitation (Terman and Terman, 2005). However, no ocular changes The above data suggest that yoga has Level 3 evidence of or abnormalities were found after either short-term (2–8 weeks) benefit as an adjunctive treatment for unipolar depression, sug- or extended (3–6 years) LT use (Gallin et al., 1995). Induction of gesting possible third-line use. The evidence of benefit in GAD and manic switch or mixed state in vulnerable individuals has been OCD is too preliminary to support any recommendations. Metho- reported occasionally (e.g. Chan et al., 1994; Sit et al., 2007), and dological weaknesses also limit generalizability, while group worsening of pre-existing suicidal ideation under ineffective dynamics may also have contributed to benefits seen (Ravindran treatment conditions appears to explain the rare instances of et al., 2009). Though long-term safety data is lacking, reported side reported suicidality (Terman and Terman, 2005). LT-medication effects are rare, and have tended to be mild and linked to level of interaction is also a potential concern, as is increased photosensi- physical fitness (Pilkington et al., 2005). Very occasionally, tivity with use of psychotropics (Sohn and Lam, 2004).

Ravindran and Silva 2013

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 9 712 A.V. Ravindran, T.L. da Silva / Journal of Affective Disorders 150 (2013) 707–719

3.1.4. Sleep deprivation (SD) Schwarzler, 2002). Lack of robust evidence and practical limita- In SD, patients are kept awake for extended periods, with tions of applying SD (described below), would suggest its use as total sleep deprivation (total SD) lasting up to 40 h, and partial adjunct only, and as third-line. Although SD may produce rapid sleep deprivation (partial SD) allowing 3–4 h of sleep per night benefit (to (Benedetti and Colombo, 2011). In an SD cycle, an SD period is a degree comparable to medications), quick relapse following followed by a recovery sleep. SD is thought to have multi-modal a recovery sleep and frequent development of tolerance, as well influences on mood, involving impact on HPA axis activity and as patient difficulty with sustaining more than brief treatment, thyroid hormone levels (Parekh et al., 1998; Vgontzas et al., 1999), have been noted (Ravindran et al., 2009). Long-term efficacy and and on metabolic and monoaminergic functioning (Benedetti and safety data is sparse, but common side effects include headache, Colombo, 2011; Giedke and Schwarzler, 2002). sleepiness, fatigue, and occasionally, gastrointestinal symptoms, Over 60 studies have been reported on SD for depression and worsening of depression and elevated mood/(hypo)mania in though no meta-analyses are available, systematic reviews have vulnerable patients (Giedke and Schwarzler, 2002). noted the benefits of SD augmentation in MDD (Morgan and Jorm, 2008; Ravindran et al., 2009). Small RCTs (Caliyurt and Guducu, 2005; Gorgulu and Caliyurt, 2009) and small open trials (Bernier 3.1.5. Acupuncture et al., 2009; Murck et al., 2009; Wiegand et al., 2001) have noted Acupuncture (ACP) is part of Traditional Chinese Medicine the benefits of SD (primarily total SD) augmentation in MDD, but (TCM) and is a treatment in which fine needles are inserted into with frequent drop-out due to non-response noted in two of the skin at specific body points (acupoints) to produce therapeutic the open trials (Bernier et al., 2009; Wiegand et al., 2001). benefits; TCM theory suggests that manual or electrical stimula- No differences between SD augmentation and either treatment tion of these needles helps to normalize ‘qi’ or energy flow within alone noted in another RCT (Reynolds et al., 2005). One RCT found the body and rectify imbalances that may contribute to physical or total SD add-on slightly superior to partial SD in unipolar and mental illness (Gunn, 2005). In current forms of ACP, traditional bipolar depression (Giedke et al., 2003). Among evaluations of SD manual ACP (M-ACP) uses manual manipulation of acupuncture versus non-pharmacological comparators as augmentation, a needles, electroacupuncture (E-ACP) passes mild electric current small RCT found adjunctive partial SD+active rapid transcranial through acupuncture needles, and laser ACP (L-ACP) directs a low magnetic stimulation (rTMS) superior to partial SD+sham rTMS in powered laser on acupoints (Smith et al., 2010). It has been MDD and bipolar depression (Eichhammer et al., 2002). However, suggested that ACP impacts the central nervous system by stimu- a later augmentation RCT in MDD did not distinguish between lating monoamine and endorphin production (Cheng and total SD+rTMS and total SD+sham rTMS (Kreuzer et al., 2002). In Pomeranz, 1981; Han, 2004), and influencing brain activity, parti- evaluations of SD+LT add-on, a large meta-analysis in unipolar and cularly of the limbic region and subcortical structures (Hui et al., bipolar depression found it effective only in SD responders 2000; Napadow et al., 2005). (Tuunainen et al., 2004). Small open trials have also reported Meta-analyses in MDD have reported either no group differ- benefits with total SD combined with sleep phase advance (SPA) ences or inconsistent results for ACP augmentation versus medica- (a technique in which the patient's sleep cycle is advanced by up to tion alone (Mukaino et al., 2005; Smith et al., 2010; Wang et al., 6 h) as add-on in MDD (Berger et al., 1997; Voderholzer et al., 2003), 2008; Zhang et al., 2010). Among more recent trials, RCTs found albeit with noticeable drop-out due to non-response and treatment E-ACP augmentation comparable to medication alone, but associated challenges (Berger et al., 1997). The combination of total SD+bright with faster response (Duan et al., 2009, 2011), while an open trial LT+SPA was also found effective in MDD and bipolar depression in a found M-ACP add-on beneficial (Yeung et al., 2011). However, RCTs small open trial (Echizenya et al., 2013). have also reported active ACP and sham ACP equivalent as adjunct Expert reviews have found SD augmentation effective in (Zhang et al., 2009, 2012b), though response was quicker and bipolar depression, and also suggest that it may elicit stronger larger (Zhang et al., 2012b) and side effects fewer (Zhang et al., response in bipolar than unipolar depression (Dallaspezia and 2009) with active ACP. Meta-analytic comparisons of ACP mod- Benedetti, 2011; Giedke and Schwarzler, 2002). An RCT (described alities have found M-ACP and E-ACP equally effective (Smith et al., earlier) found total SD slightly superior to partial SD in unipolar 2010; Stub et al., 2011). and bipolar depression, though the bipolar sample was very In bipolar disorder, most available studies are published only in small (Giedke et al., 2003). In comparisons of adjunctive SD to Chinese and are not reviewed here. Among English publications, a non-medication augmentors, a small RCT (already reported in small RCT found active or sham ACP add-on comparably effective this section) found partial SD+active rTMS superior to partial in (hypo)mania and bipolar depression (Dennehy et al., 2009). SD+sham rTMS as augmentation in MDD and bipolar depression An early case series found adjunctive E-ACP generally inferior to (Eichhammer et al., 2002). As also noted earlier, a large meta- ECT for bipolar depression and mania, but better tolerated analysis found SD+LT add-on beneficial only in SD responders (Kurland, 1976), while a later case report reported ACP add-on (Tuunainen et al., 2004), but subsequent open trials noted stronger beneficial for mania (Hu, 1996). results (Benedetti et al., 2005, 2007, 2009b). More recently, an RCT In anxiety conditions, an RCT in GAD found M-ACP augmenta- (Wu et al., 2009) and a small open trial (Echizenya et al., 2013) tion superior to medication alone, but inferior to M-ACP alone found augmentation with total SD+bright LT+SPA significantly (Yuan et al., 2007). In OCD, an RCT found M-ACP add-on no effective. Small open trials have also offered support for adjunctive different from medication alone, but better tolerated (Feng et al., total SD+SPA (Benedetti et al., 2001; Voderholzer et al., 2003). 2007). In PTSD, an RCT found M-ACP and CBT comparable as adjunct There are no published data for SD as augmentation in anxiety and superior to wait-list, with gains maintained at 3-month follow-up disorders. (Hollifield et al., 2007). SD, therefore, has Level 2 evidence for use as augmentation in To summarize, the findings are promising but poor quality and MDD and bipolar depression (see Table 2). Support for its use as heterogeneity of published studies preclude definitive recommen- adjunct to medication, when combined with other therapies (LT, dations for the use of ACP augmentation in unipolar depression, SPA, rTMS), is far less robust, though SD+LT shows Level 3 evidence bipolar disorder or anxiety disorders. Notably, sham ACP is in bipolar depression. Also of note, though reviews find both forms thought to produce physiological effects, itself (Zhang et al., of SD comparably effective, total SD dominates research publica- 2009), and may explain its comparable efficacy versus active tions and may thus have clinical preference (Giedke and ACP. Long-term efficacy and safety data are lacking, but ACP

Ravindran and Silva 2013

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 10 A.V. Ravindran, T.L. da Silva / Journal of Affective Disorders 150 (2013) 707–719 713

appears well tolerated. Reported mild side effects include bleed- 3.3.1. Omega-3 fatty acids ing, pain and bruising at needling points, as well as drowsiness, Polyunsaturated omega-3 fatty acids are involved in multiple fatigue and headache (MacPherson and Thomas, 2005). Infection, biological systems, including the nervous system. As supplements, seizures, pneumothorax and temporary neuropathy are rare more they are highly purified estyl esters of eicosapentanoic acid (EPA) serious adverse events, but it has also been noted that risk of or docosahexaenoic acid (DHA) or a combination. Their neurop- serious side effects with acupuncture is far lower than with many sychiatric effects are thought to result from modulation of neuro- conventional medical treatments (White, 2004). nal communication and their impact on monoaminergic neural systems (Ross et al., 2007). Low omega-3 levels have been linked to both depression (Lin et al., 2010) and anxiety (Ross, 2009). 3.2. Herbal remedies Though omega-3 fatty acids appear beneficial as augmentation agents in unipolar depression in individual studies, several meta- Herbal remedies are non-prescription, natural health products analyses have failed to find robust evidence of benefit (e.g. Bloch derived from plants and plant extracts, such as leaves, flowers, and Hannestad, 2012; Kraguljac et al., 2009; Lin and Su, 2007). roots, bark and berries. Available as individual herbal supplements, In bipolar disorder, a systematic review was inconclusive as well as herbal compounds that incorporate several herbs into (Turnbull et al., 2008), but meta-analyses have noted the benefits formulations that are thought to have synergistic benefits, they are of omega-3 fatty acid augmentation in bipolar depression, though not frequently used individually or in combination to support general in mania (Montgomery and Richardson, 2008; Sarris et al., 2012). wellness or resolve symptoms of physical or mental stress. Very These reports noted that effect sizes were larger in smaller studies and few herbal remedies have published evidence as add-on for mood methodological weaknesses were also common. and anxiety disorders. It is of note that St. John's wort (hypericum In anxiety disorders, a small cross-over RCT found no benefit to perforatum), the most studied herbal remedy for depression, does EPA or placebo augmentation, though EPA was well tolerated not have any published data as an adjunctive agent. (Fux et al., 2004). Similarly, EPA augmentation was no different from EPA alone in a small open-label case series in PTSD (Zeev et al., 2005). In conclusion, omega-3 fatty acids have Level 1 evidence of 3.2.1. Free and Easy Wanderer Plus (FEWP) benefit as augmentation in bipolar depression, and Level 2 evi- This 11-ingredient Chinese herbal compound has a long history dence in unipolar depression (see Table 4). However, due to the of use. It is thought to act on multiple monoaminergic and heterogeneity of studies and publication bias noted in both benzodiazepine receptors, as well as neurosteroid and cytokine populations, they may be best used as third-line augmentations function, accounting for its antidepressant and anxiolytic effects for both conditions. Meta-analytic comparisons of omega-3 for- (Liao et al., 1995; Mizowaki et al., 2001; Sugiyama et al., 1996). mulations are suggestive (but not definitive) that EPA may be Large meta-analyses have found FEWP safe and effective as superior to DHA or EPA+DHA for depressive disorders (Martins augmentation in unipolar depression, and better tolerated than et al., 2012; Ross et al., 2007). There is no current evidence for the medication alone (Qin et al., 2011; Zhang et al., 2012a). It is of note benefit of omega-3 fatty acids in anxiety disorders. Omega-3s are that most of the included studies were published only in Chinese. generally well tolerated, and side effects reported, such as nausea In bipolar depression, one meta-analysis reported FEWP effec- and a fishy aftertaste, are mild and rarely lead to discontinuation tive as add-on, but included data from only two bipolar studies (Freeman et al., 2010). Omega-3s have also shown cardioprotective (Qin et al., 2011). Among additional English publications, a 3-arm benefits, but monitoring is recommended when used by patients RCT found adjunctive FEWP superior to placebo add-on and on anticoagulants or anti-platelet medications, due to increased placebo alone for bipolar depression, and also better tolerated, bleeding tendencies (Freeman et al., 2010). Risk of hypomania has implying that FEWP may reduce medication side effects (Zhang been noted in a few cases, but no such incidence has been et al., 2007a). The augmentation treatments also improved mania reported in systematic reviews or meta-analyses in bipolar depres- comparably. In the continuation phase of the study (which sion (e.g. Montgomery and Richardson, 2008; Sarris et al., 2012). included only the augmentation treatments), both groups continued to improve comparably, but drop-out rates were lower with FEWP (Zhang et al., 2007b) 3.3.2. S-adenosylmethionine (SAM-e) There are no published reports of FEWP as augmentation in A naturally occurring body molecule, SAM-e is a derivative of anxiety disorders. the amino acid, methionine and functions as a methyl donor in Based on the available data, FEWP has significant Level 2 many biological processes (Alpert et al., 2008). It is thought to evidence of benefit as augmentation agent in both unipolar and boost monoaminergic neurotransmission as its mechanism of bipolar depression (see Table 3), but due to limited clinical action (Alpert et al., 2008), but a proposed relationship between experience outside its country of origin (as with Jio-zai), and low SAM-e levels and depression has not been conclusively proven methodological weaknesses in many studies, it is recommended as (Bottiglieri and Hyland, 1994). It is available as an over-the-counter only a third-line adjunctive treatment. Side effects reported with product in North America, but requires medical prescription in FEWP include mild headache, dizziness, diarrhea, constipation, dry Europe. mouth and tachycardia (Qin et al., 2011; Zhang et al., 2012a). Long- Most reports of SAM-e in depression are as monotherapy. term efficacy and safety data (in English) is lacking. However, an RCT in treatment-resistant major depression (TRD) found SAM-e as adjunct to antidepressants was significantly superior to placebo; mild side effects and drop-out due to side 3.3. Nutraceuticals effects was similar between groups, but drop-out due to lack of efficacy was higher with placebo (Papakostas et al., 2010). An open Nutraceuticals (also known as dietary supplements) are trial of SAM-e augmentation in TRD reported similar efficacy and concentrated forms of naturally occurring substances, such as tolerability (Alpert et al., 2004). vitamins and minerals. Like herbal remedies, they are categorized No data was found for SAM-e as augmentation in anxiety as natural health products that can be used without prescription. disorders. They are popularly used for nutritional and health support, both The limited Level 3 data above offers only preliminary support individually and in combination. for SAM-e as augmentation in TRD, with recommendation as only

Ravindran and Silva 2013

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 11 714 A.V. Ravindran, T.L. da Silva / Journal of Affective Disorders 150 (2013) 707–719

a third-line strategy. It is generally well-tolerated, but reported Levitan et al., 2000) were mild and commonly include sedation, adverse events include nausea, restlessness and diarrhea, and, dry mouth and gastrointestinal distress. more rarely, risk of manic induction in vulnerable patients and serotonin syndrome in patients on antidepressants (Natural 3.3.5. Folate Standard, 2013b). The water-soluble B vitamins, of which folate (B9) is one, are vital to cellular activity and immune and nervous system functioning. Folate is a key to production of homocysteine, a precursor of 3.3.3. Dehydroepiandrosterone (DHEA) methionine and S-adenosyl methionine, the latter being a methyl DHEA, a natural adrenosteroid, is a precursor of the sex donor involved in neurotransmitter function (Farah, 2009). The hormones, estrogen and testosterone, and is also employed in evidence for the association between low folate levels and natural medicine as an anti-aging aid (albeit with undetermined depression is mixed, with no definitive conclusions (e.g. Coppen benefits) (Bhagra et al., 2008). It is thought to modulate monoami- and Bolander-Gouaille, 2005; Kamphuis et al., 2008). nergic and glutaminergic neurotransmission, as well as provide In depressive disorders, small systematic reviews have reported neuroprotective and anti-oxidant benefits (Maninger et al., 2009). folate to be effective and well tolerated as augmentation in Both low DHEA (Markianos et al., 2007; Morsink et al., 2007) and high unipolar depression (Fava and Michoulon, 2009; Morris et al., DHEA (Assies et al., 2004; Goodyer et al., 2003) levels have been linked 2008). Included in the reviews were early RCTs that noted the to depression, but in anxiety, high DHEA levels have been reported benefits of folic acid or methylfolate over placebo as augmentation more consistently (Gill et al., 2008; Hsiao, 2006). in unipolar depression (Coppen et al., 1986; Godfrey et al., 1990), Only one augmentation study in depressive disorders was with the caveat that the patient sample in one study was only found. In a small RCT, DHEA add-on was superior to placebo in marginally symptomatic and no benefits were seen in bipolar improving unipolar and bipolar depression and was also well patients (Coppen et al., 1986). Another RCT found adjunctive folic tolerated (Wolkowitz et al., 1999). Of note, only 2 bipolar patients acid superior to placebo only in female MDD patients (Coppen and participated in the study. Bailey, 2000), while an open trial noted significant improvement No published data was found for DHEA as augmentation in with folinic acid augmentation in TRD, but the reported response anxiety disorders. and remission rates were low (Alpert et al., 2002). More recently, a There is insufficient evidence to recommend DHEA for the small RCT found adjunctive folinic acid superior to placebo in MDD treatment of depression. Though it is well tolerated, potential side (Resler et al., 2008), but a small randomized open trial in MDD effects include acne, hirsuitism, worsening of prostatis and found medication alone superior to folic acid augmentation increased risk of breast cancer, due to its role as a precursor in (Basoglu et al., 2009). Tolerability data were not reported in these hormone production, as well as impact on blood clotting, liver studies. A large retrospective case analysis found l-methylfolate add- damage, manic induction (Natural Standard, 2013a). on superior to medication alone, and with quicker onset of action and lower drop out due to side effects (Ginsberg et al., 2011). In bipolar disorder, an early RCT (described previously) found 3.3.4. Tryptophan no benefit to adjunctive folic acid in marginally depressed bipolar The dietary amino acid, tryptophan, is a precursor of 5-hydroxy patients (Coppen et al., 1986). A more recent RCT in mania found tryptophan (5-HTP) and serotonin (5-HT), and is thus thought to folic acid and placebo comparably effective and tolerable as add- enhance serotonergic neurotransmission through “precursor loading” on, with folic acid separating favorably from placebo only at end of (Shaw et al., 2002). Formulated as both 5-HTP and l-tryptophan, it treatment (Behzadi et al., 2009). requires medical prescription in Canada and Europe, but is available There are no published studies of folate as augmentation in over-the-counter in the U.S. Low mood and cognitive dysfunction have anxiety disorders. been reported with tryptophan depletion in patients vulnerable to Thus, there is only preliminary and inconsistent evidence for depression (Booij et al., 2005; Feder et al., 2011). folate as augmentation in unipolar depression, precluding any Only a few small studies have evaluated tryptophan augmenta- recommendations at this time. Though it appears well tolerated tion in depressive disorders. Two early small RCTs found adjunc- and no drug interactions have been reported, high doses of folate tive 5-HTP superior to placebo in unipolar depression (Aliño et al., increases levels of unmetabolized serum folic acids, possibly 1976; Nardini et al., 1983), with the former noting quicker onset of contributing to depletion of natural killer cells, monoamines and action. A small open trial and a placebo-controlled RCT by one brain l-methylfolate, thus worsening depression (Farah, 2009; Fava group of researchers also found 5-HTP augmentation beneficial in and Michoulon, 2009). Similarly, high folic acid dosage is linked to unipolar and bipolar depression, though the RCT also noted that increased depression, sleep difficulties, irritability, hyperactivity the combination did not differ from l-tryptophan alone, and and discomfort (Farah, 2009; Lazarou and Kapsou, 2010). l-tryptophan was itself no different from placebo (Mendlewicz and Youdim, 1980). Of note, a large review found significant methodological flaws in these early studies (Turner et al., 2006). 3.3.6. Inositol More recently, a small placebo-controlled RCT found adjunctive Inositol is a carboxylic polyol and glucose isomer that is l-tryptophan produced early onset of improvement in MDD, but sometimes included in the B vitamin family (Taylor et al., 2004). which was not sustained to endpoint (Levitan et al., 2000). It is a precursor of the cellular secondary messenger system that There are no published studies of tryptophan as add-on in mediates neurotransmitter receptor activity and intracellular anxiety conditions. functioning (Taylor et al., 2004). Human studies of the links Thus, the evidence for tryptophan augmentation in depression between low inositol levels and depression have had equivocal is only preliminary (Level 3), supporting only third-line recom- results (Coupland et al., 2005; Levine et al., 1996), while animal mendations. Despite its role as a serotonin precursor, serotonin data suggest an association between low inositol and anxiety syndrome has rarely been reported with tryptophan use, and there (Einat and Belmaker, 2001; Kofman et al., 2000). has been no recurrence of Eosinophilia–Myalgia Syndrome, an In depressive disorders, a small meta-analysis in unipolar and outbreak of which was linked to a single manufacturer and a bipolar depression (Taylor et al., 2004) that included two small contaminated batch of tryptophan in the late 1980s (Turner et al., RCTs in MDD (Levine et al., 1999; Nemets et al., 1999) found 2006). Side effects reported in studies (e.g. Aliño et al., 1976; inositol no different from placebo as augmentation for unipolar

Ravindran and Silva 2013

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 12 A.V. Ravindran, T.L. da Silva / Journal of Affective Disorders 150 (2013) 707–719 715

depression, though drop out due to side effects was higher with evidence for augmentation use of acupuncture, folate, inositol inositol in one of the studies (Nemets et al., 1999). and NAC. Similarly, in bipolar depression, two RCTs also failed to differ- Due to the sparse data, frequent methodological weaknesses of entiate between inositol or placebo add-on (Chengappa et al., studies and limited clinical experience, the evidence for the CAM 2000; Eden Evins et al., 2006). With the second RCT, though a therapies reviewed here is generally insufficient evidence to trend favored adjunctive inositol in the double-blind phase, open provide a definitive recommendation. At most, they can be label continuation with inositol also found only non-significant suggested as third-line strategies. As well, as stated previously, benefits (Eden Evins et al., 2006). Interestingly, a small rando- any use of CAM therapies should follow only after a trial of first- mized open label arm of the Systematic Treatment Enhancement line augmenting interventions, such as other antidepressants, Program for Bipolar Disorder (STEP-BD) study, found inositol atypical antipsychotics or mood stabilizers, and evidence-based and psychotropics comparably effective as add-on (Nierenberg psychotherapies. et al., 2006). Inositol was generally well tolerated in these studies However, it is encouraging that the basic physiological mechan- (Chengappa et al., 2000; Nierenberg et al., 2006). isms of action attributed to the CAM therapies reviewed here seem In anxiety disorders, a small placebo-controlled RCT (Fux et al., to mirror those of established pharmacological agents, such as 1999) and a small open trial (Seedat and Stein, 1999) both failed to impact on neuroplasticity, neurogenesis, and monoaminergic, find benefits to inositol augmentation (Seedat and Stein, 1999). glutaminergic and HPA axis activity. It is also noteworthy that In summary, there is insufficient evidence to recommend inositol the published evidence indicates that CAM therapies are generally augmentation in either depressive or anxiety conditions. Though it well tolerated, and that some CAM agents may help to alleviate usually has good tolerability, serotonin syndrome and symptom side effects associated with conventional medications. Thus, this exacerbation requiring hospitalization, including (hypo)manic induc- review provides a rationale for the further exploration of CAM tion, have been reported in some patients (Chengappa et al., 2000; therapies as augmentation to antidepressants in larger, placebo- Eden Evins et al., 2006; Levine et al., 1999; Nemet et al., 1999). controlled RCTs, for both acute and maintenance treatment.

3.3.7. N-acetylcysteine (NAC)

NAC derives from the amino acid, cysteine, which is the Role of funding source precursor of a key brain antioxidant, glutathione (Berk et al., This manuscript was prepared independently without any funding support. 2008). Higher oxidative stress, which is implicated in the patho- physiology of depression, is linked to impaired glutathione metabolism (Berk et al., 2008). Conflict of interest fl In bipolar disorder, a small maintenance RCT found NAC add-on The authors have no actual or potential con icts of interest to disclose. well tolerated and superior to placebo in improving depression, with a trend to improving mania, as well; however, there were no Acknowledgments group differences in time to mood episode (Berk et al., 2008). None. A subsequent two-phase study by the same researchers found adjunctive NAC beneficial as open label for bipolar depression, but no different from placebo in the double-blind phase (Berk et al., References 2011, 2012). In anxiety disorders, only a single case report noted the benefit Aliño, J.J., Gutierrez, J.L., Iglesias, M.L., 1976. 5-Hydroxytryptophan (5-HTP) and a of NAC as augmentation in refractory OCD (Lafleur et al., 2006). MAOI (nialamide) in the treatment of depressions. A double-blind controlled There is only Level 3 evidence of benefit for NAC and EMP+ in study. International Pharmacopsychiatry 11, 8–15. fi depressive disorders, but mixed results preclude recommenda- Alonso, J., Lépine, J.P., 2007. ESEMeD/MHEDEA 2000 Scienti c Committee, 2007. Overview of key data from the European study of the epidemiology of mental tions. It was generally been well tolerated in published studies, but disorders (ESEMeD). Journal of Clinical Psychiatry 68 (Suppl. 2), 3–9. the sparse safety data advises caution in its use. Alpert, J.E., Mischoulon, D., Rubenstein, G.E., Bottonari, K., Nierenberg, A.A., Fava, M., 2002. Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression. Annals of Clinical Psychiatry 14, 33–38. Alpert, J.E., Papakostas, G., Mischoulon, D., Worthington 3rd, J.J., Petersen, T., Mahal, 4. Conclusions and future directions Y., Burns, A., Bottiglieri, T., Nierenberg, A.A., Fava, M., 2004. S-adenosyl-L- methionine (SAMe) as an adjunct for resistant major depressive disorder: an The popularity of CAM therapies among patients with mood open trial following partial or nonresponse to selective serotonin reuptake inhibitors or venlafaxine. Journal of Clinical Psychopharmacology 24, 661–664. and anxiety disorders has stimulated more recent research into Alpert, J.E., Papakostas, G.I., Mischoulon, D., 2008. One-carbon metabolism and the the utility and safety of these agents. However, the overall body of treatment of depression: roles of S-adenosyl-l-methionine and folate. In: research on CAM therapies remains limited. The literature has also Mischoulon, D., Rosenbaum, J. (Eds.), Natural Medications for Psychiatric Disorders: Considering the Alternatives, 2nd ed. Lippincott Williams and tended to focus on depressive disorders over anxiety conditions, Wilkins, PA, pp. 68–83. perhaps reflecting the perceived differential clinical and functional Andreescu, C., Mulsant, B.H., Emanuel, J.E., 2008. Complementary and alternative impact of the disorder categories. The literature on CAM therapies medicine in the treatment of bipolar disorder—a review of the evidence. fi Journal of Affective Disorders 110, 16–26. that evaluates their bene ts as adjunctive agents to antidepres- Assies, J., Visser, I., Nicolson, N.A., Eggelte, T.A., Wekking, E.M., Huyser, J., Lieverse, sants is even sparser, as confirmed by this review. R., Schene, A.H., 2004. Elevated salivary dehydroepiandrosterone-sulfate but In summary, the available evidence would suggest the follow- normal cortisol levels in medicated depressed patients: preliminary findings. ing: As adjunctive treatment in unipolar depression, is the stron- Psychiatry Research 128, 117–122. Babyak, M., Blumenthal, J.A., Herman, S., Khatri, P., Doraiswamy, M., Moore, K., gest evidence (Level 2) is for SD and FEWP, followed by Level Craighead, W.E., Baldewicz, T.T., Krishnan, K.R., 2000. Exercise treatment for 3 evidence for the exercise, yoga, LT, omega-3 fatty acids, SAM-e, major depression: maintenance of therapeutic benefit at 10 months. Psychoso- and tryptophan. LT also has Level 3 evidence as add-on in seasonal matic Medicine 62, 633–638. Basoglu, C., Ates, M.A., Algul, A., Ipcioglu, O.M., Gecici, O., Yilmaz, O., Semiz, U.M., depression. In bipolar depression, the strongest evidence (Level 1) Ebrinc, S., Gulsun, M., Ozcan, O., Kilic, S., Cetin, M., 2009. Adjuvant folate with is for adjunctive omega-3 fatty acids, followed by Level 2 evidence escitalopram treatment and homocystein, folate, vitamin B-12 levels in patients for SD, and very preliminary Level 3 evidence for LT and FEWP. In with major depressive disorder. Bulletin of Clinical Psychopharmacology 19, 135–142. anxiety conditions, only exercise has been found to have some Behzadi, A.H., Omrani, Z., Chalian, M., Asadi, S., Ghadiri, M., 2009. Folic acid efficacy benefit (Level 3) in GAD and PD. There is insufficient or negative as an alternative drug added to sodium valproate in the treatment of acute

Ravindran and Silva 2013

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 13 716 A.V. Ravindran, T.L. da Silva / Journal of Affective Disorders 150 (2013) 707–719

phase of mania in bipolar disorder: a double-blind randomized controlled trial. Chengappa, K.N., Levine, J., Gershon, S., Mallinger, A.G., Hardan, A., Acta Psychiatrica Scandinavica 120, 441–445. Vagnucci, A., Pollock, B., Luther, J., Buttenfield, J., Verfaille, S., Kupfer, D.J., Benedetti, F., Barbini, B., Campori, E., Fulgosi, M.C., Pontiggia, A., Colombo, C., 2001. 2000. Inositol as an add-on treatment for bipolar depression. Bipolar Disorder Sleep phase advance and lithium to sustain the antidepressant effect of total 2, 47–55. sleep deprivation in bipolar depression: new findings supporting the internal Coppen, A., Bailey, J., 2000. Enhancement of the antidepressant action of fluoxetine coincidence model? Journal of Psychiatric Research 35, 323–329. by folic acid: a randomized, placebo controlled trial. Journal of Affective Benedetti, F., Barbini, B., Fulgosi, M.C., Colombo, C., Dallaspezia, S., Pontiggia, A., Disorder 60, 121–130. Smeraldi, E., 2005. Combined total sleep deprivation and light therapy in the Coppen, A., Bolander-Gouaille, C., 2005. Treatment of depression: time to consider treatment of drug-resistant bipolar depression: acute response and long-term folic acid and vitamin B12. Journal of Psychopharmacology 19, 59–65. remission rates. Journal of Clinical Psychiatry 66, 1535–1540. Coppen, A., Chaudhry, S., Swade, C., 1986. Folic acid enhances lithium prophylaxis. Benedetti, F., Calabrese, G., Bernasconi, A., Cadioli, M., Colombo, C., Dallaspezia, S., Journal of Affective Disorder 10, 9–13. Falini, A., Radaelli, D., Scotti, G., Smeraldi, E., 2009b. Spectroscopic correlates of Coupland, N.J., Ogilvie, C.J., Hegadoren, K.M., Seres, P., Hanstock, C.C., Allen, P.S., antidepressant response to sleep deprivation and light therapy: a 3.0 T study of 2005. Decreased prefrontal myoinositol in major depressive disorder. Biological bipolar depression. Psychiatry Research 173, 238–242. Psychiatry 57, 1526–1534. Benedetti, F., Colombo, C., 2011. Sleep deprivation in mood disorders. Neuropsy- da Silva, T.L., Ravindran, L.N., Ravindran, A.V., 2009. Yoga in the treatment of mood chobiology 64, 141–151. and anxiety disorders. Asian Journal of Psychiatry 2, 6–16. Benedetti, F., Dallaspezia, S., Fulgosi, M.C., Barbini, B., Colombo, C., Smeraldi, E., Dallaspezia, S., Benedetti, F., 2011. Chronobiological therapy for mood disorders. 2007. Phase advance is an actimetric correlate of antidepressant response to Expert Rev. Neurother. 11, 961-970. sleep deprivation and light therapy in bipolar depression. Chronobiology Dallaspezia, S., Benedetti, F., Colombo, C., Barbini, B., Fulgosi, M.C., Gavinelli, C., International 24, 921–937. Smeraldi, E., 2012. Optimized light therapy for non-seasonal major depressive Benedetti, F., Radaelli, D, Bernasconi, A., Dallaspezia, S., Colombo, C., Smeraldi, E., disorder: effects of timing and season. Journal of Affective Disorder 138, 2009a. Changes in medial prefrontal cortex neural responses parallel successful 337–342. antidepressant combination of venlafaxine and light therapy. Archives Ita- Dauphinais, D.R., Rosenthal, J.Z., Terman, M., DiFebo, H.M., Tuggle, C., Rosenthal, N. liennes de Biologie 147, 83–93. E., 2012. Controlled trial of safety and efficacy of bright light therapy vs. Berger, M., Vollmann, J., Hohagen, F, König, A., Lohner, H., Voderholzer, U., Riemann, negative air ions in patients with bipolar depression. Psychiatry Research 196, D., 1997. Sleep deprivation combined with consecutive sleep phase advance as 57–61. a fast-acting therapy in depression: an open pilot trial in medicated and Dennehy, E.B., Schnyer, R., Bernstein, I.H., Gonzalez, R., Shivakumar, G., Kelly, D.I., unmedicated patients. Journal of the American Psychiatric Association 154, Snow, D.E., Sureddi, S., Suppes, T., 2009. The safety, acceptability, and effec- 870–872. tiveness of acupuncture as an adjunctive treatment for acute symptoms in Berk, M., Copolov, D.L., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I., Anderson-Hunt, bipolar disorder. Journal of Clinical Psychiatry 70, 897–905. M., Bush, A.I., 2008. N-acetyl cysteine for depressive symptoms in bipolar Dietrich, A., McDaniel, W.F., 2004. Endocannabinoids and exericse. British Journal of — disorder a double-blind randomized placebo-controlled trial. Biological Psy- Sports Medicine 38, 536–541. – chiatry 64, 468 475. Dimeo, F., Bauer, M., Varahram, I., Proest, G., Halter, U., 2001. Benefits from aerobic Berk, M., Dean, O., Cotton, S.M., Gama, C.S., Kapczinski, F., Fernandes, B.S., exercise in patients with major depression: a pilot study. British Journal of Kohlmann, K., Jeavons, S., Hewitt, K., Allwang, C., Cobb, H., Bush, A.I., Schapkaitz, Sports Medicine 35, 114–117. I., Dodd, S., Malhi, G.S., 2011. The efficacy of N-acetylcysteine as an adjunctive Duan, D.M., Tu, Y., Chen, L.P., Wu, Z.J., 2009. Efficacy evaluation for depression with treatment in bipolar depression: an open label trial. Journal of Affective somatic symptoms treated by electroacupuncture combined with fluoxetine. Disorders 135, 389–394. Journal of Traditional Chinese Medicine 29, 167–173. Berk, M., Dean, O.M., Cotton, S.M., Gama, C.S., Kapczinski, F., Fernandes, B., Duan, D.M., Tu, Y., Jiao, S., Qin, W., 2011. The relevance between symptoms and Kohlmann, K., Jeavons, S., Hewitt, K., Moss, K., Allwang, C., Schapkaitz, I., Cobb, magnetic resonance imaging analysis of the hippocampus of depressed patients H., Bush, A.I., Dodd, S., Malhi, G.S., 2012. Maintenance N-acetyl cysteine given electro-acupuncture combined with fluoxetine intervention—a rando- treatment for bipolar disorder: a double-blind randomized placebo controlled mized, controlled trial. Chinese Journal of Integrative Medicine 17, 190–199. trial. BMC Medicine 10, 91. Echizenya, M., Suda, H., Takeshima, M., Inomata, Y., Shimizu, T., 2013. Total sleep Bernier, D., Bartha, R., Devarajan, S., Macmaster, F.P., Schmidt, M.H., Rusak, B., 2009. deprivation followed by sleep phase advance and bright light therapy in drug- Effects of overnight sleep restrictions on brain chemistry and mood in women resistant mood disorders. Journal of Affective Disorders 144, 28–33. with unipolar depression and healthy controls. Journal of Psychiatry and Eden Evins, A., Demopulos, C., Yovel, I., Culhane, M., Ogutha, J., Grandin, L.D., Neuroscience 34, 352–360. Nierenberg, A.A., Sachs, G.S., 2006. Inositol augmentation of lithium or Bhagra, S., Nippoldt, T.B., Nair, K.S., 2008. Dehydroepiandrosterone in adrenal valproate for bipolar depression. Bipolar Disorder 8, 168–174. insufficiency and ageing. Current Opinion in Endocrinology, Diabetes, and Eichhammer, P., Kharraz, A., Wiegand, R., Langguth, B., Frick, U., Aigner, J.M., Hajak, Obesity 15, 239–243. G., 2002. Sleep deprivation in depression stabilizing antidepressant effects by Bloch, M.H., Hannestad, J., 2012. Omega-3 fatty acids for the treatment of – depression: systematic review and meta-analysis. Molecular Psychiatry 17, repetitive transcranial magnetic stimulation. Life Science 70, 1741 1749. 1272–1282. Einat, H., Belmaker, R.H., 2001. The effects of inositol treatment in animal models of – Blumenthal, J.A., Babyak, M.A., Moore, K.A., Craighead, W.E., Herman, S., Khatri, P., psychiatric disorders. Journal of Affective Disorders 62, 113 121. fi Waugh, R., Napolitano, M.A., Forman, L.M., Appelbaum, M., Doraiswamy, P.M., Even, C., Schröder, C.M., Friedman, S., Rouillon, F., 2008. Ef cacy of light therapy in Krishnan, K.R., 1999. Effects of exercise training on older patients with major nonseasonal depression: a systematic review. Journal of Affective Disorders depression. Archives of Internal Medicine 159, 2349–2356. 108, 11–23. Booij, L., Van der Does, A.J., Haffmans, P.M., Riedel, W.J., Fekkes, D., Blom, M.J., 2005. Eyre, H., Baune, B.T., 2012. Neuroimmunological effects of physical exercise in The effects of high-dose and low-dose tryptophan depletion on mood and depression. Brain, Behavior, and Immunity 26, 251–266. cognitive functions of remitted depressed patients. Journal of Psychopharma- Farah, A., 2009. The role of l-methylfolate in depressive disorders. CNS Spectrums cology 19, 267–275. 14 (Suppl 2), 2–7. fi Bottiglieri, T., Hyland, K., 1994. S-adenosylmethionine levels in psychiatric and Fava, M., Mischoulon, D., 2009. Folate in depression: Ef cacy, safety, differences in neurological disorders: a review. Acta Neurologica Scandinavica Supplemen- formulations, and clinical issues. Journal of Clinical Psychiatry 70 (Suppl 5), tum (154), 19–26. 12–17. Brown, R.A., Abrantes, A.M., Strong, D.R., Mancebo, M.C., Menard, J., Rasmussen, Feder, A., Skipper, J., Blair, J.R., Buchholz, K., Mathew, S.J., Schwarz, M., Doucette, J.T., S.A., Greenberg, B.D., 2007. A pilot study of moderate-intensity aerobic exercise Alonso, A., Collins, K.A., Neumeister, A., Charney, D.S., 2011. Tryptophan for obsessive compulsive disorder. Journal of Nervous and Mental Disorder 195, depletion and emotional processing in healthy volunteers at high risk for 514–520. depression. Biological Psychiatry 69, 804–807. Brown, R.P., Gerbarg, P.L., 2005. Sudarshan Kriya Yoga breathing in the treatment of Feng, B., Liu, L., Fangzhong, X., Chen, J., Wang, P., Chen, W., Yu, E., 2007. Thirty cases stress, anxiety and depression: Part I – Neurophysiologic model. Journal of of obsession treated by point-stimulation and with small dose of chlorimipra- Alternative and Complementary Medicine 11, 189–201. mine. Journal of Traditional Chinese Medicine 27, 3–6. Butler, L.D., Waelde, L.C., Hastings, T.A., Chen, X.H., Symons, B., Marshall, J., Flory, R., Ametepe, J., Bowers, B., 2010. A randomized, placebo-controlled trial of Kaufman, A., Nagy, T.F., Blasey, C.M., Seibert, E.O., Spiegel, D., 2008. Meditation bright light and high-density negative air ions for treatment of seasonal with yoga, group therapy with hypnosis, and psychoeducation for long-term affective disorder. Psychiatry Research 177, 101–108. depressed mood: a randomized pilot trial. Journal of Clinical Psychology 64, Freeman, M.P., Fava, M., Lake, J., Trivedi, M.H., Wisner, K.L., Mischoulon, D., 2010. 806–820. Complementary and alternative medicine in major depressive disorder: the Cabral, P., Meyer, H.B., Ames, D., 2011. Effectiveness of yoga therapy as a American Psychiatric Association Task Force report. Journal of Clinical Psychia- complementary treatment for major depressive disorders: a meta-analysis. try 71, 669–681. Primary Care Companion for CNS Disorders 13, PCC.10r01068. Fux, M., Benjamin, J., Belmaker, R.H., 1999. Inositol versus placebo augmentation of Caliyurt, O., Guducu, F., 2005. Partial sleep deprivation therapy combined with serotonin reuptake inhibitors in the treatment of obsessive-compulsive dis- sertraline induces more rapid improvements in quality of life items in major order: a double-blind cross-over study. International Journal of Neuropsycho- depressive disorder. Journal of Affective Disorders 88, 75–78. pharmacology 2, 193–195. Chan, P.K., Lam, R.W., Perry, K.F., 1994. Mania precipitated by light therapy for Fux, M., Benjamin, J., Nemets, B., 2004. A placebo-controlled cross-over trial of patients with SAD (letter). Journal of Clinical Psychiatry 55, 454. adjunctive EPA in OCD. Journal of Psychiatric Research 38, 323–325. Cheng, R.S., Pomeranz, B., 1981. Monoaminergic mechanism of electroacupuncture Gallin, P.F., Terman, M., Remé, C.E., Rafferty, B., Terman, J.S., Burde, R.M., 1995. analgesia. Brain Research 215, 77–92. Ophthalmologic examination of patients with seasonal affective disorder,

Ravindran and Silva 2013

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 14 A.V. Ravindran, T.L. da Silva / Journal of Affective Disorders 150 (2013) 707–719 717

before and after bright light therapy. American Journal of Ophthalmology 119, Lande, R.G., Williams, L.B., Gragnani, C., Tsai, A., 2011. Effectiveness of light therapy 202–210. for depression among active duty service members: A nonrandomized con- Giedke, H., Klingberg, S., Schwarzler, F., Schweinsberg, M., 2003. Direct comparison trolled pilot trial. Complementary Therapies in Medicine 19, 161–163. of total sleep deprivation and late partial sleep deprivation in the treatment of Lazarou, C., Kapsou, M., 2010. The role of folic acid in prevention and treatment of major depression. Journal of Affective Disorders 76, 85–93. depression: an overview of existing evidence and implications for practice. Giedke, H., Schwarzler, F., 2002. Therapeutic use of sleep deprivation in depression. Complementary Therapies in Clinical Practice 16, 161–166. Sleep Medicine Reviews 6, 361–377. Levine, J., Kurtzman, L., Rapoport, A., Zimmerman, J., Bersudsky, Y., Shapiro, J., Gill, J., Vythilingam, M., Page, G.G., 2008. Low cortisol, high DHEA, and high levels of Belmaker, R.H., Agam, G., 1996. CSF inositol does not predict antidepressant stimulated TNF-alpha, and IL-6 in women with PTSD. Journal of Traumatic response to inositol. Journal of Neural Transmission 103, 1457–1462. Stress 21, 530–539. Levine, J., Mishori, A., Susnosky, M., Martin, M., Belmaker, R.H., 1999. Combination Ginsberg, L.D., Oubre, A.Y., Daoud, Y.A., 2011. L-methylfolate Plus SSRI or SNRI from of inositol and serotonin reuptake inhibitors in the treatment of depression. treatment initiation compared to SSRI or SNRI monotherapy in a major Biological Psychiatry 45, 270–273. depressive episode. Innovations in Clinical Neuroscience 8, 19–28. Levitan, R.D., Shen, J.H., Jindal, R., Driver, H.S., Kennedy, S.H., Shapiro, C.M., 2000. Godfrey, P.S., Toone, B.K., Carney, M.W., Flynn, T.G., Bottiglieri, T., Laundy, M., Preliminary randomized double-blind placebo-controlled trial of tryptophan Chanarin, I., Reynolds, E.H., 1990. Enhancement of recovery from psychiatric combined with fluoxetine to treat major depressive disorder: antidepressant illness by methylfolate. Lancet 336, 392–395. and hypnotic effects. Journal of Psychiatry and Neuroscience 25, 337–346. Golden, R.N., Gaynes, B.N., Ekstrom, R.D., Hamer, R.M., Jacobsen, F.M., Suppes, T., Liao, J.F., Jan, Y.M., Huang, S.Y., Wang, H.H., Yu, L.L., Chen, C.F., 1995. Evaluation with Wisner, K.L., Nemeroff, C.B., 2005. The efficacy of light therapy in the treatment receptor binding assay on the water extracts of ten CNS-active Chinese herbal of mood disorders: a review and meta-analysis of the evidence. The American drugs. Proceedings of the National Science Council, Republic of China 19, Journal of Psychiatry 162, 656–662. 151–158. Goodyer, I.M., Herbert, J., Tamplin, A., 2003. Psychoendocrine antecedents of Lieverse, R., Van Someren, E.J., Nielen, M.M., Uitdehaag, B.M., Smit, J.H., Hoogendijk, persistent first-episode major depression in adolescents: a community-based W.J., 2011. Bright light treatment in elderly patients with nonseasonal major longitudinal enquiry. Psychological Medicine 33, 601–610. depressive disorder: a randomized placebo-controlled trial. Archives of General Gorgulu, Y., Caliyurt, O., 2009. Rapid antidepressant effects of sleep deprivation Psychiatry 68, 61–70. therapy correlates with serum BDNF changes in major depression. Brain Lin, P.Y., Su, K.P., 2007. A meta-analytic review of double-blind, placebo-controlled fi Research Bulletin 80, 158–162. trials of antidepressant ef cacy of omega-3 fatty acids. J. Clin. Psychiatry 68, Gunn, C.C., 2005. Acupuncture in context. In: Filshie, J., White, A. (Eds.), Medical 1056–1061. acupuncture: A Western Scientific Approach. Churchill Livingstone, London, Lucassen, P.J., Meerlo, P., Naylor, A.S., van Dam, A.M., Dayer, A.G., Fuchs, E., Oomen, pp. 11–16. C.A., Czeh, B., 2010. Regulation of adult neurogenesis by stress, sleep disruption, fl Han, J-S., 2004. Acupuncture and endorphins. Neuroscience Letters 361, exercise and in ammation: implications for depression and antidepressant 258–261. action. European Neuropsychopharmacology 20, 1–17. Herring, M.P., Jacob, M.L., Suveg, C., Dishman, R.K., O'Connor, P.J., 2012. Feasibility of MacPherson, H., Thomas, K., 2005. Short term reactions to acupuncture—a cross- exercise training for the short-term treatment of generalized anxiety disorder: sectional survey of patient reports. Acupuncture in Medicine 23, 112–120. a randomized controlled trial. Psychotherapy and Psychosomatics 81, 21–28. Maninger, N., Wolkowitz, O.M., Reus, V.I., Epel, E.S., Mellon, S.H., 2009. Neurobio- Hollifield, M., Sinclair-Lian, N., Warner, T.D., Hammerschlag, R., 2007. Acupuncture logical and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and – for posttraumatic stress disorder: a randomized controlled pilot trial. Journal of DHEA sulfate (DHEAS). Frontiers in Neuroendocrinology 30, 65 91. Markianos, M., Tripodianakis, J., Sarantidis, D., Hatzimanolis, J., 2007. Plasma Nervous and Mental Disease 195, 504–513. testosterone and dehydroepiandrosterone sulfate in male and female patients Hootman, J.M., Macera, C.A., Ainsworth, B.E., Addy, C.L., Martin, M., Blair, S.N., 2002. with dysthymic disorder. Journal of Affective Disorders 101, 255–258. Epidemiology of musculoskeletal injuries among sedentary and physically Martins, J.G., Bentsen, H., Puri, B.K., 2012. Eicosapentaenoic acid appears to be the active adults. Medicine and Science in Sports and Exercise 34, 838–844. key omega-3 fatty acid component associated with efficacy in major depressive Hsiao, C.C., 2006. Positive correlation between anxiety severity and plasma levels of disorder: a critique of Bloch and Hannestad and updated meta-analysis. dehydroepiandrosterone sulfate in medication-free patients experiencing a Molecular Psychiatry 17, 1144–1149. major episode of depression. Psychiatry and Clinical Neurosciences 60, 746–750. Martinsen, E.W., Hoffart, A., Solberg, O., 1989b. Comparing aerobic with nonaerobic Hu, J., 1996. Acupuncture treatment of manic psychosis. Journal of Traditional forms of exercise in the treatment of clinical depression: a randomized trial. Chinese Medicine 16, 238–240. Comprehensive Psychiatry 30, 324–331. Hui, K.K., Liu, J., Makris, N., Gollub, R.L., Chen, A.J., Moore, C.I., Kennedy, D.N., Rosen, Martinsen, E.W., Medhus, A., Sandvik, L., 1985. Effects of aerobic exercise on B.R., Kwong, K.K., 2000. Acupuncture modulates the limbic system and depression: a controlled study. British Medical Journal (Clinical Research subcortical gray structures of the human brain: evidence from fMRI studies Edition) 291, 109. in normal subjects. Human Brain Mapping 9, 13–25. Martinsen, E.W., Sandvik, L., Kolbjornsrud, O-B., 1989a. Aerobic exercise in the Kamphuis, M.H., Geerlings, M.I., Grobbee, D.E., Kromhout, D., 2008. Dietary intake treatment of nonpsychotic mental disorders: an exploratory study. Nordisk of B(6–9-12) vitamins, serum homocysteine levels and their association with Psykiatrisk Tidsskrift 43, 521–529. depressive symptoms: the Zutphen Elderly Study. European Journal of Clinical Martiny, K., Lunde, M., Unden, M., Dam, H., Bech, P., 2006. The lack of sustained Nutrition 62, 939–945. effect of bright light, after discontinuation, in non-seasonal major depression. Katzman, M.A., Vermani, M., Gerbarg, P.L., Brown, R.P., Iorio, C., Davis, M., Cameron, Psychological Medicine 36, 1247–1252. C., Tsirgielis, D., 2012. A multicomponent yoga-based, breath intervention Mather, A.S., Rodriguez, C., Guthrie, M.F., McHarg, A.M., Reid, I.C., McMurdo, M.E., program as an adjunctive treatment in patients suffering from generalized 2002. Effects of exercise on depressive symptoms in older adults with poorly anxiety disorder with or without comorbidities. International Journal of Yoga 5, responsive depressive disorder: randomised controlled trial. British Journal of 57–65. Psychiatry 180, 411–415. Knubben, K., Reischies, F.M., Adli, M., Schlattmann, P., Bauer, M., Dimeo, F., 2007. Mendlewicz, J., Youdim, M.B., 1980. Antidepressant potentiation of 5- A randomised, controlled study on the effects of a short-term endurance hydroxytryptophan by L-deprenil in affective illness. Journal of Affective training programme in patients with major depression. British Journal of Sports Disorders 2, 137–146. Medicine 41, 29–33. Mizowaki, M., Toriizuka, K., Hanawa, T., 2001. Anxiolytic effect of Kami-Shoyo-San Kofman, O., Einat, H., Cohen, H., Tenne, H., Shoshana, C., 2000. The anxiolytic effect (TJ-24) in mice: possible mediation of neurosteroid synthesis. Life Science 69, of chronic inositol depends on the baseline level of anxiety. Journal of Neural 2167–2177. Transmission 107, 241–253. Montgomery, P., Richardson, A.J., 2008. Omega-3 fatty acids for bipolar disorder. Kraguljac, N.V., Montori, V.M., Pavuluri, M., Chai, H.S., Wilson, B.S., Unal, S.S., 2009. Cochrane Database of Systematic Reviews 2, CD005169. fi Ef cacy of omega-3 fatty acids in mood disorders – a systematic review and Morgan, A.J., Jorm, A.J., 2008. Self-help interventions for depressive disorderse metaanalysis. Psychopharmacology Bulletin 42, 39–54. and depressive symptoms: a systematic review. Annals of General Psychiatry 7, Kreuzer, P.M., Langguth, B., Schecklmann, M., Eichhammer, P., Hajak, G., Landgrebe, 13. M., 2002. Can repetitive transcranial magnetic stimulation prolong the anti- Morris, D.W., Madhukar, H.T., Rush, A.J., 2008. Folate and unipolar depression. depressant effects of sleep deprivation? Brain Stimulation 5, 141–147. Journal of Alternative and Complementary Medicine 14, 277–285. Kurland, H.D., 1976. ECT and Acu-EST in the treatment of depression. The American Morsink, L.F., Vogelzangs, N., Nicklas, B.J., Beekman, A.T., Satterfield, S., Rubin, S.M., Journal of Chinese Medicine 4, 289–292. Yaffe, K., Simonsick, E., Newman, A.B., Kritchevsky, S.B., Penninx, B.W., 2007. Lafleur, D.L., Pittenger, C., Kelmendi, B., Gardner, T., Wasylink, S., Malison, R.T., Associations between sex steroid hormone levels and depressive symptoms in Sanacora, G., Krystal, J.H., Coric, V., 2006. N-acetylcysteine augmentation in elderly men and women: results from the Health ABC study. Psychoneuroen- serotonin reuptake inhibitor refractory obsessive-compulsive disorder. Psycho- docrinology 32, 874–883. pharmacology (Berl) 184, 254–256. Mota-Pereira, J., Silverio, J., Carvalho, S., Ribeiro, J.C., Fonte, D., Ramos, J., 2011. Lam, R.W., Kennedy, S.H., Grigoriadis, S., McIntyre, R.S., Milev, R., Ramasubbu, R., Moderate exercise improves depression parameters in treatment-resistant Parikh, S.V., Patten, S.B., Ravindran, A.V., 2009. Canadian Network for Mood and patients with major depressive disorder. Journal of Psychiatric Research 45, Anxiety Treatments (CANMAT) clinical guidelines for the management of major 1005–1011. depressive disorder in adults. III. Pharmacotherapy. Journal of Affective Dis- Mukaino, Y., Park, J., White, A., Ernst, E., 2005. The effectiveness of acupuncture for orders 117 (Suppl. 1), S26–S43. depression—a systematic review of randomised controlled trials. Acupuncture Lancer, R., Motta, R., Lancer, D., 2007. The effect of aerobic exercise on obsessive- Medicine 23, 70–76. compulsive disorder, anxiety, and depression: a preliminary investigation. The Murck, H., Schubert, M.I., Schmid, D., Schüssler, P., Steiger, A., Auer, D.P., 2009. The Behavior Therapist 30, 53–62. glutamatergic system and its relation to the clinical effect of therapeutic-sleep

Ravindran and Silva 2013

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 15 718 A.V. Ravindran, T.L. da Silva / Journal of Affective Disorders 150 (2013) 707–719

deprivation in depression – an MR spectroscopy study. Journal of Psychiatric treatment alternatives to relieve depression (STAR D): rationale and design. Research 43, 175–180. Controlled Clinical Trials 25, 119–142. Napadow, V., Makris, N., Liu, J., Kettner, N.W., Kwong, K.K., Hui, K.K.S., 2005. Effects Sajatovic, M., Levin, J., Fuentes-Casiano, E., Cassidy, K.A., Tatsuoka, C., Jenkins, J.H., of electroacupuncture versus manual acupuncture on the human brain as 2011. Illness experience and reasons for nonadherence among individuals with measured by fMRI. Human Brain Mapping 24, 193–205. bipolar disorder who are poorly adherent with medication. Comprehensive Nardini, M., De Stefano, R., Iannuccelli, M., Borghesi, R., Battistini, N., 1983. Psychiatry 52, 280–287. Treatment of depression with L-5-hydroxytryptophan combined with chlor- Sarris, J., Mischoulon, D., Schweitzer, I., 2012. Omega-3 for bipolar disorder: meta- imipramine, a double-blind study. International Journal of Clinical Pharmacol- analyses of use in mania and bipolar depression. Journal of Clinical Psychiatry ogy Research 3, 239–250. 73, 81–86. Natural Standard, 2013b. DHEA professional monograph. Available from: 〈http:// Schuch, F.B., Vasconcelos-Moreno, M.P., Borowsky, C., Fleck, M.P., 2011. Exercise and www.naturalstandard.com/index-abstract.asp?create-abstract=flashcard-dhea. severe depression: preliminary results from an add-on study. Journal of asp&title=DHEA〉 (accessed 15.03.13.). Affective Disorders 133, 615–618. Natural Standard, 2013a. SAMe professional monograph. Available from: 〈http:// Seedat, S., Stein, D.J., 1999. Inositol augmentation of serotonin reuptake inhibitors www.naturalstandard.com/index-abstract.asp?create-abstract=same. in treatment-refractory obsessive-compulsive disorder: an open trial. Interna- asp&title=SAMe〉 (accessed 15.03.13.). tional Clinical Psychopharmacology 14, 353–356. Nemets, B., Mishory, A., Levine, J., Belmaker, R.H., 1999. Inositol addition does not Shannahoff-Khalsa, D.S., Beckett, L.R., 1996. Clinical case report: efficacy of yogic improve depression in SSRI treatment failures. Journal of Neural Transmission techniques in the treatment of obsessive compulsive disorders. International 106, 795–798. Journal of Neuroscience 85, 1–17. Ng, F., Dodd, S., Berk, M., 2007. The effects of physical activity in the acute Shannahoff-Khalsa, D.S., Ray, L.E., Levine, S., Gallen, C.C., Schwartz, B.J., Sidorowich, treatment of bipolar disorder: a pilot study. Journal of Affective Disorder 101, J.J., 1999. Randomized controlled trial of yogic meditation techniques for 259–262. patients with obsessive-compulsive disorder. CNS Spectrums 4, 34–47. Niederhofer, H., von Klitzing, K., 2011. Bright light treatment as add-on therapy for Shapiro, D., Cook, I.A., Davydov, D.M., Ottaviani, C., Leuchter, A.F., Abrams, M., 2007. depression in 28 adolescents: a randomized trial, Prim Care Companion CNS Yoga as a complementary treatment of depression: effects of traits and moods Disord 2011;13(6): http://dx.doi.org/10.4088/PCC.11m01194. on treatment outcome. Evidence-Based Complementary and Alternative Med- Nierenberg, A.A., Ostacher, M.J., Calabrese, J.R., Ketter, T.A., Marangell, L.B., Miklo- icine 4, 493–502. witz, D.J., Miyahara, S., Bauer, M.S., Thase, M.E., Wisniewski, S.R., Sachs, G.S., Sharma, V.K., Das, S., Mondal, S., Goswampi, U., Gandhi, A., 2005. Effect of Sahaj 2006. Treatment-resistant bipolar depression: a STEP-BD equipoise rando- Yoga on depressive disorders. Indian Journal of Physiology and Pharmacology mized effectiveness trial of antidepressant augmentation with lamotrigine, 49, 462–468. – inositol, or risperidone. The American Journal of Psychiatry 163, 210 216. Shaw, K., Turner, J., Del Mar, C., 2002. Are tryptophan and 5-hydroxytryptophan Oeland, A-M., Laessoe, U., Olesen, A.V., Munk-Jorgensen, P., 2010. Impact of exercise effective treatments for depression? A meta-analysis. Australian and New on patients with depression and anxiety. Nordic Journal of Psychiatry 64, Zealand Journal of Psychiatry 36, 488–491. – 210 217. Sit, D., Wisner, K.L., Hanusa, B.H., Stull, S., Terman, M., 2007. Light therapy for Pail, G., Huf, W., Pjrek, E., Winkler, D., Willeit, M., Praschak-Rieder, N., Kasper, S., bipolar disorder: a case series in women. Bipolar Disorder 9, 918–927. 2011. Bright-light therapy in the treatment of mood disorders. Neuropsycho- Smith, C.A., Hay, P.P., Macpherson, H., 2010. Acupuncture for depression. Cochrane biology 64, 152–162. Database of Systematic Reviews 1, CD004046. Papakostas, G.I., Mischoulon, D., Shyu, I., Alpert, J.E., Fava, M., 2010. S-adenosyl Sohn, C.H., Lam, R.W., 2004. Treatment of seasonal affective disorder: unipolar methionine (SAMe) augmentation of serotonin reuptake inhibitors for anti- versus bipolar differences. Current Psychiatry Reports 6, 478–485. depressant nonresponders with major depressive disorder: a double-blind, Stathopoulou, G., Powers, M.B., Berry, A.C., Smits, J.A.J., Otto, M.W., 2006. Exercise randomized clinical trial. The American Journal of Psychiatry 167, 942–948. interventions for mental health: a quantitative and qualitative review. Clinical Parekh, P.I., Ketter, T.A., Altshuler, L., Frye, M.A., Callahan, A., Marangell, L., Post, R. Psychology: Science and Practice 13, 179–193. M., 1998. Relationship between thyroid hormone and antidepressant responses Streeter, C.C., Gerbarg, P.L., Saper, R.B., Ciraulo, D.A., Brown, R.P., 2012. Effects of to total sleep deprivation in mood disorder patients. Biological Psychiatry 43, yoga on the autonomic nervous system, gamm-aminobutyric-acid, and allos- 392–394. tasis in epilepsy, depression, and post-traumatic stress disorder. Medical Parikh, S.V., Segal, Z.V., Grigoriadis, S., Ravindran, A.V., Kennedy, S.H., Lam, R.W., Hypotheses 78, 571–579. Patten, S.B., 2009. Canadian Network for Mood and Anxiety Treatments Ströhle, A., 2009. Physical activity, exercise, depression and anxiety disorders. (CANMAT), 2009. Canadian Network for Mood and Anxiety Treatments (CAN- Journal of Neural Transmission 116, 777–784. MAT) clinical guidelines for the management of major depressive disorder in Ströhle, A., Feller, C., Strasburger, C.J., Heinz, A., Dimeo, F., 2006. Anxiety modula- adults. II Psychotherapy alone or in combination with antidepressant medication by the heart? Aerobic exercise and atrial natriuretic peptide. Psychoneur- tion. Journal of Affective Disorders 117 (Suppl. 1), S15–S25. oendocrinology 31, 1127–1130. Perraton, L.G., Kumar, S., Machotka, Z., 2010. Exercise parameters in the treatment Stub, T., Alraek, T., Liu, J., 2011. Acupuncture treatment for depression – a systematic of clinical depression: a systematic review of randomized controlled trials. review and meta-analysis. European Journal of Integrative Medicine 3, Journal of Evaluation in Clinical Practice 16, 597–604. – Pilkington, K., Kirkwood, G., Rampes, H., Richardson, J., 2005. Yoga for depression: e259 e270. ‘ the research evidence. Journal of Affective Disorders 89, 13–24. Sugiyama, K., Muteki, T., Kano, T., 1996. The Japanese herbal medicine saikokeishi- ’ Qin, F., Wu, X.A., Tang, Y., Huang, Q., Zhang, Z.J., Yuan, J.H., 2011. Meta-analysis of to activates GABAA receptors of rat sensory neurons in culture. Neuroscience randomized controlled trials to assess the effectiveness and safety of Free and Letters 216, 147–150. easy wanderer plus, a polyherbal preparation for depressive disorders. Journal Taylor, M.J., Wilder, H., Bhagwagar, Z., Geddes, J., 2004. Inositol for depressive of Psychiatric Research 45, 1518–1524. disorders. Cochrane Database System Reviews 2, CD004049. Ravindran, A.V., Lam, R.W., Filteau, M.J., Lespérance, F., Kennedy, S.H., Parikh, S.V., Terman, M., Terman, J.S., 2005. Light therapy for seasonal and nonseasonal fi Patten, S.B., 2009. Canadian Network for Mood and Anxiety Treatments depression: ef cacy, protocol, safety, and side effects. CNS Spectrums 10, (CANMAT), 2009. Canadian Network for Mood and Anxiety Treatments (CAN- 647–663. MAT) clinical guidelines for the management of major depressive disorder in Thompson, P.D., Franklin, B.A., Balady, G.J., Blair, S.N., Corrado, D., Estes 3rd, N.A., adults. V. Complementary and alternative medicine treatments. Journal of Fulton, J.E., Gordon, N.F., Haskell, W.L., Link, M.S., Maron, B.J., Mittleman, M.A., Affective Disorders 117 (Suppl. 1), S54–S64. Pelliccia, A., Wenger, N.K., Willich, S.N., Costa, F., 2007. American Heart Resler, G., Lavie, R., Campos, J., Mata, S., Urbina, M., Garcia, A., Apitz, R., Lima, L., Association Council on Nutrition, Physical Activity, and Metabolism; American 2008. Effect of folic acid combined with fluoxetine in patients with major Heart Association Council on Clinical Cardiology; American College of Sports depression on plasma homocysteine and vitamin B12, and serotonin levels in Medicine, 2007. Exercise and acute cardiovascular events placing the risks into fi lymphocytes. Neuroimmunomodulation 15, 145–152. perspective: a scienti c statement from the American Heart Association Reynolds, C.F., Smith, G.S., Dew, M.A., Mulsant, B.H., Miller, M.D., Schlernitzauer, M., Council on nutrition, physical activity, and metabolism and the Council on Stack, J.A., Houck, P.R., Pollock, B.G., 2005. Accelerating symptom-reduction clinical cardiology. Circulation 115, 2358–2368. in late-life depression: a double-blind, randomized, placebo-controlled Trivedi, M.H., Greer, T.L., Grannemann, B.D., Chambliss, H.O., Jordan, A.N., 2006. trial of sleep deprivation. The American Journal of Geriatric Psychiatry 13, Exercise as an augmentation strategy for treatment of major depression. 353–358. Journal of Psychiatric Practice 12, 205–213. Rohan, K.J., Lindsey, K.T., Roecklein, K.A., Lacy, T.J., 2004. Cognitive-behavioral Turnbull, T., Cullen-Drill, M., Smaldone, A., 2008. Efficacy of omega-3 fatty acid therapy, light therapy, and their combination in treating seasonal affective supplementation on improvement of bipolar symptoms: A systematic review. disorder. Journal of Affective Disorders 80, 273–283. Archives of Psychiatric Nursing 22, 305–311. Ross, B.M., Seguin, J., Sieswerda, L.E., 2007. Omega-3 fatty acids as treatments for Turner, E.H., Loftis, J.M., Blackwell, A.D., 2006. Serotonin a la carte: supplementa- mental illness: which disorder and which fatty acid? Lipids in Health and tion with the serotonin precursor 5-hydroxytryptophan. Pharmacology & Disease 6, 21. Therapeutics 109, 325–338. Ross, B.M., 2009. Omega-3 polyunsaturated fatty acids and anxiety disorders. Tuunainen, A., Kripke, D.F., Endo, T., 2004. Light therapy for non-seasonal depres- Prostaglandins, Leukotrienes and Essential Fatty Acids 81, 309–312. sion. Cochrane Database System Reviews 21, CD004050. Rush, A.J., Fava, M., Wisniewski, S.R., Lavori, P.W., Trivedi, M.H., Sackeim, H.A., Thase, Uebelacker, L.A., Tremont, G., Epstein-Lubow, G., Gaudiano, B.A., Gillette, T., M.E., Nierenberg, A.A., Quitkin, F.M., Kashner, T.M., Kupfer, D.J., Rosenbaum, J.F., Kalibatseva, Z., Miller, I.W., 2010. Open trial of Vinyasa yoga for persistently Alpert, J., Stewart, J.W., McGrath, P.J., Biggs, M.M., Shores-Wilson, K., Lebowitz, depressed individuals: evidence of feasibility and acceptability. Behavior B.D., Ritz, L., Niederehe, G., 2004. STAR D Investigators Group, 2004. Sequenced Modification 34, 247–264.

Ravindran and Silva 2013

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 16 A.V. Ravindran, T.L. da Silva / Journal of Affective Disorders 150 (2013) 707–719 719

Veale, D., Le Fevre, K., Pantelis, C., deSouza, V., Mann, A., Sargeant, A., 1992. Aerobic with sleep deprivation and chronotherapy in bipolar disorder. Biological exercise in the adjunctive treatment of depression: a randomized controlled Psychiatry 66, 298–301. trial. Journal of the Royal Society of Medicine 85, 541–544. Yeung, A.S., Ameral, V.E., Chuzi, S.E., Fava, M., Mischoulon, D., 2011. A pilot study of Vgontzas, A.N., Mastorakos, G., Bixler, E.O., Kales, A., Gold, P.W., Chrousos, G.P., acupuncture augmentation therapy in antidepressant partial and non- 1999. Sleep deprivation effects on the activity of the hypothalamic-pituitary- responders with major depressive disorder. Journal of Affective Disorders adrenal and growth axes: potential clinical implications. Clinical Endocrinology 130, 285–289. (Oxford) 51, 205–215. Yonkers, K.A., Bruce, S.E., Dyck, I.R., Keller, M.B., 2003. Chronicity, relapse, and Voderholzer, U., Valerius, G., Schaerer, L., Riemann, D., Giedke, H., Schwärzler, F., illness–course of panic disorder, social phobia, and generalized anxiety Berger, M., Wiegand, M., 2003. Is the antidepressive effect of sleep deprivation disorder: findings in men and women from 8 years of follow-up. Depression stabilized by a three day phase advance of the sleep period? A pilot study. and Anxiety 17, 173–179. European Archives of Psychiatry and Clinical Neuroscience 253, 68–72. Yuan, Q., Li, J.N., Liu, B., Wu, Z.F., Jin, R., 2007. Effect of Jin-3-needling therapy on Wahlström, M., Sihvo, S., Haukkala, A., Kiviruusu, O., Pirkola, S., Isometsä, E., 2008. plasma corticosteroid, adrenocorticotrophic hormone and platelet 5-HT levels Use of mental health services and complementary and alternative medicine in in patients with generalized anxiety disorder. Chinese Journal of Integrative persons with common mental disorders. Acta Psychiatrica Scandinavica 118, Medicine 13, 264–268. 73–80. Zeev, K., Michael, M., Ram, K., Hagit, C., 2005. Possible deleterious effects of Wang, H., Qi, H., Wang, B.S., Cui, Y.Y., Zhu, L., Rong, Z.X., Chen, H.Z., 2008. Is adjunctive omega-3 fatty acids in post-traumatic stress disorder patients. fi acupuncture bene cial in depression: a meta-analysis of 8 randomized con- Neuropsychiatric Disease and Treatment 1, 187–190. – trolled trials? Journal of Affective Disorders 111, 125 134. Zhang, W.J., Yang, X.B., Zhong, B.L., 2009. Combination of acupuncture and Wedekind, D., Broocks, A., Weiss, N., Engel, K., Neubert, K., Bandelow, B., 2010. A fluoxetine for depression: a randomized, double-blind, sham-controlled trial. randomized, controlled trial of aerobic exercise in combination with paroxetine Journal of Alternative and Complementary Medicine 15, 837–844. in the treatment of panic disorder. The World Journal of Biological Psychiatry Zhang, Y., Han, M., Liu, Z., Wang, J., He, Q., Liu, J., 2012a. Chinese herbal formula xiao 11, 904–913. yao san for treatment of depression: a systematic review of randomized White, A., 2004. A cumulative review of the range and incidence of significant controlled trials. Evidence-Based Complementary and Alternative Medicine. adverse events associated with acupuncture. Acupuncture in Medicine 22, Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159992/pdf/ 122–133. ECAM2012-931636.pdf. Wiegand, M.H., Lauer, C.J., Schreiber, W., 2001. Patterns of response to repeated Zhang, Z.J., Chen, H.Y., Yip, K.C., Ng, R., Wong, V.T., 2010. The effectiveness and total sleep deprivations in depression. Journal of Affective Disorders 64, 257–260. safety of acupuncture therapy in depressive disorders: systematic review and Wirz-Justice, A., Bader, A., Frisch, U., Stieglitz, R.D., Alder, J., Bitzer, J., Hösli, I., Jazbec, meta-analysis. Journal of Affective Disorders 124, 9–21. fi S., Benedetti, F., Terman, M., Wisner, K.L., Riecher-Rössler, A., 2011. A rando- Zhang, Z.J., Kang, W.H., Li, Q., Tan, Q.R., 2007b. The bene cial effects of the herbal mized, double-blind, placebo-controlled study of light therapy for antepartum medicine free and easy wanderer plus (FEWP) for mood disorders: double- depression. Journal of Clinical Psychiatry 72, 986–993. blind, placebo-controlled studies. Journal of Psychiatric Research 41, 828–836. Wolkowitz, O.M., Reus, V.I., Keebler, A., Nelson, N., Friedland, M., Brizendine, L., Zhang, Z.J., Kang, W.H., Tan, Q.R., Li, Q., Gao, C.G., Zhang, F.G., Wang, H.H., Ma, X.C., Roberts, E., 1999. Double-blind treatment of major depression with dehydroe- Chen, C., Wang, W., Guo, L., Zhang, Y.H., Yang, X.B., Yang, G.D., 2007a. Adjunctive piandrosterone. The American Journal of Psychiatry 156, 646–649. herbal medicine with carbamazepine for bipolar disorders: A double-blind, World Health Organization (WHO), 2000. International Consortium in Psychiatric randomized, placebo-controlled study. Journal of Psychiatric Research 41, Epidemiology, 2000. Cross-national comparisons of the prevalences and 360–369. correlates of mental disorders. Bulletin of the World Health Organization 78, Zhang, Z.J., Ng, R., Man, S.C., Li, T.Y.J., Wong, W., Li, T.Y., Wong, W., Tan, Q.R., Wong, 413–426. H.K., Chung, K.F., Wong, M.T., Tsang, W.K., Yip, K.C., Ziea, E., Wong, V.T., 2012b. Wright, K.A., Everson-Hock, E.S., Taylor, A.H., 2009. The effects of physical activity Dense cranial electroacupuncture stimulation for major depressive disorder—a on physical and mental health among individuals with bipolar disorder: a single-blind, randomized, controlled study. PloS ONE 7, e29651. systematic review. Mental Health and Physical Activity 2, 86–94. Zivin, K., Madden, J.M., Graves, A.J., Zhang, F., Soumerai, S.B., 2009. Cost-related Wu, J.C., Kelsoe, J.R., Schachat, C., Bunney, B.G., DeModena, A., Golshan, S., Gillin, J.C., medication nonadherence among beneficiaries with depression following Potkin, S.G., Bunney, W.E., 2009. Rapid and sustained antidepressant response Medicare Part D. The American Journal of Geriatric Psychiatry 17, 1068–1076.

Ravindran and Silva 2013

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 17

Heart, Lung and Circulation (2015) 24, 149–157 ORIGINAL ARTICLE 1443-9506/04/$36.00

http://dx.doi.org/10.1016/j.hlc.2014.09.001

Interval Training Versus Continuous

Exercise in Patients with Coronary

Artery Disease: A Meta-Analysis

a,b* c

Adrian D. Elliott, Ph.D , Kanchani Rajopadhyaya, Ph.D ,

a c

David J. Bentley, Ph.D , John F. Beltrame, MBBS, Ph.D ,

Edoardo C. Aromataris, Ph.D

School of Medical Sciences, University of Adelaide, Australia

School of Translational Health Science, University of Adelaide, Australia

The Queen Elizabeth Hospital and Discipline of Medicine, University of Adelaide, Australia

Received 30 June 2014; received in revised form 29 August 2014; accepted 2 September 2014; online published-ahead-of-print 16 September 2014

Background High aerobic capacity is inversely related to cardiovascular disease morbidity and mortality. Recent studies

suggest greater improvements in aerobic capacity with high-intensity interval training (interval) compared

to moderate-intensity continuous aerobic exercise (continuous). Therefore we perform a meta-analysis of

randomised controlled trials comparing the effectiveness of INTERVAL versus CONTINUOUS in aerobic

capacity, amongst patients with stable coronary artery disease (CAD) and preserved ejection fraction

Methods We searched PubMed, EMBASE, CINAHL, the Australia and New Zealand Clinical Trials Register, clin-

icaltrials.gov and TROVE for randomised controlled trials comparing INTERVAL with CONTINUOUS in

patients with CAD. Studies published in the English language up to December 2013 were eligible for

inclusion. Aerobic capacity, quantified by peak oxygen consumption (VO2peak) post exercise training was

extracted and compared post-intervention between INTERVAL and CONTINUOUS by way of a fixed

model meta-analysis. Secondary outcomes including anaerobic threshold, blood pressure and high-density

lipoproteins (HDL) were also analysed.

Results Six independent studies with 229 patients (n = 99 randomised to INTERVAL) were included in the meta-

analysis. There was a significantly higher increase in VO2peak following INTERVAL compared to

1 1

CONTINUOUS (Weighted Mean Difference = 1.53 ml kgÀ minÀ , 95% CI 0.84 to 2.23) with homogeneity

displayed between studies (Chi Squared = 2.69; P = 0.7). Significant effects of INTERVAL compared to

CONTINUOUS were also found for anaerobic threshold but not systolic blood pressure.

Conclusion In patients with CAD, INTERVAL appears more effective than CONTINUOUS for the improvement of

aerobic capacity in patients with CAD. However, long-term studies assessing morbidity and mortality

following INTERVAL are required before this approach can be more widely adopted.

Keywords Rehabilitation Myocardial infarction Coronary artery bypass graft Risk factors Oxygen uptake

*Corresponding author at: School of Medical Sciences, University of Adelaide. Tel.: +(0061) 8 8313 3194.,

Email: [email protected]

Elliott et al 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 18

150 A.D. Elliott et al.

Introduction study has been published comparing the two approaches.

Importantly, the meta-analysis by Pattyn et al, included

Exercise-based cardiac rehabilitation is an effective strategy studies in which patients had ischaemic heart failure and

for reducing total and cardiovascular mortality in patients ejection fractions <40% [9]. Additionally, in some studies

with coronary artery disease (CAD) [1]. Furthermore, aerobic analysed, there were no differences in the actual exercise

ﬁtness has been established as a strong predictor of cardiovas- intensity between the two training methods. The aim of

cular [2,3] and all-cause mortality [4]. Deﬁning aerobic ﬁtness the present study was to perform a meta-analysis of all ran-

by way of cardiopulmonary exercise testing has become domised controlled trials studies comparing the effectiveness

increasingly available in many rehabilitation settings, where of INTERVAL with CONTINUOUS on aerobic capacity,

peak oxygen consumption (VO2peak) can be directly measured deﬁned using VO2peak, amongst patients diagnosed with sta-

as the gold standard for aerobic capacity. Increases in ble CAD in the absence of disclosed heart failure.

VO2peak have been shown to relate to improvements in

mortality risk [5], where every 1-metabolic equivalent

1 1

(1-MET = 3.5 ml kgÀ minÀ VO ) increase yields a 13%

2 Methods

improvement in survival. Exercise training-induced increases

in aerobic capacity are therefore highly desirable for the Study Selection

improvement of patient outcomes. The search aimed to ﬁnd both published and unpublished

Optimising exercise rehabilitation to maximise the potential studies. The search was restricted to studies published in the

increase in aerobic capacity is an important factor in the pre- English language prior to December 2013. A three-step search

scription of exercise. In patients with CAD, traditional exercise strategy was employed; an initial limited search of PubMed

prescription has included continuous aerobic exercise, such as and CINAHL was undertaken followed by analysis of text

walking or cycling, at a moderate intensity (40-80% VO2peak) words contained in the title and abstract, and of the index

for 30-60 minutes [6]. However, recent evidence in healthy terms used to describe the article. A second search using all

participants [7,8], heart failure patients [9,10] and patients with identiﬁed keywords and index terms was then undertaken

cardiometabolic disease [11] suggests that high-intensity inter- across PubMed, EMBASE, CINAHL, the Australia and New

val training (INTERVAL) may be a more effective strategy for Zealand Clinical Trials Register, clinicaltrials.gov and TROVE

the improvement of aerobic capacity than continuous, mod- (Fig. 1). Thirdly, the reference lists of all identiﬁed reports and

erate intensity exercise training (CONTINUOUS). articles were searched for additional studies. At this time, one

High-intensity interval training is characterised by brief further study came to the attention of the authors.

intermittent bursts of exercise interspersed by active recov- Keywords used in the search included those relating to the

ery periods, and has shown a number of beneﬁts in patients exercise intervention (e.g. exercise rehabilitation, interval

with CAD, including improvements in aerobic capacity, exercise, high-intensity exercise) combined with those spe-

anaerobic threshold, endothelial function and cardiac func- ciﬁc to the population (e.g. coronary artery disease, ischemic

tion [9,12]. heart disease, myocardial infarction). Full-text articles were

Studies comparing INTERVAL with CONTINUOUS train- retrieved after review of the title and abstract. Criteria for

ing in patients with heart disease typically prescribe intervals inclusion were all of the following; i) randomised controlled

of up to four minutes duration at an intensity of approxi- trials comparing INTERVAL with CONTINUOUS in patients

mately 85-95% peak heart rate (HRpeak) [9,13,14]. Alterna- with stable CAD in the absence of heart failure, ii) studies

tively, shorter durations of one to two minutes have also been prescribing an exercise program for at least four weeks, and iii)

applied with a 1:1 work:rest ratio [15,16]. Likewise, both studies including aerobic capacity as a reported outcome.

shorter [7] and longer intervals [8] have been shown to Secondary outcomes for this study included the cardiovascu-

increase aerobic capacity compared to CONTINUOUS in lar risk factor proﬁle including resting systolic blood pressure,

healthy participants. low-density lipoprotein (LDL) and high-density lipoprotein

In many instances, the beneﬁts on aerobic capacity of (HDL). To be eligible for inclusion, INTERVAL was deﬁned as

INTERVAL appear to exceed the improvements seen with brief (1-4 mins), intermittent bouts of high-intensity (>85%

CONTINUOUS training. Previous meta-analyses of studies HRpeak or equivalent) rhythmic exercise such as cycling, jog-

recruiting heart failure [10] and cardiometabolic disease ging, or walking, interspersed by periods of active recovery.

patients [11] indicate that INTERVAL results in increases Both supervised and home-supervised exercise was consid-

of approximately 2-3 ml/kg/min VO2peak greater than that ered for inclusion. Continuous, moderate-intensity exercise

observed with CONTINUOUS training. was deﬁned as at least 30 minutes of rhythmic aerobic exercise,

Previous systematic reviews have included studies com- such as cycling, walking, running or swimming, performed at

paring INTERVAL with no exercise [17] or patients with a moderate-intensity (<80% HRpeak or equivalent) that is sus-

metabolic and/or other lifestyle diseases in addition to those tainable for the duration of the session.

with CAD [11]. More recently, a meta-analysis revealed

greater improvements in aerobic capacity with INTERVAL Assessment of Methodological Quality

compared with CONTINUOUS in patients with CAD [18]. Studies selected for inclusion were assessed for methodolog-

However, since publication of this meta-analysis, a further ical validity by two independent reviewers (A.D.E and D.J.B)

Elliott et al 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 19

Interval Training Versus Continuous Exercise in Patients with Coronary Artery Disease 151

Study citations identified by search

PubMed: 2889; EMBASE: 2948;

CINAHL: 1161; Cochrane: Trials: 564; ANZCTR: 44; TROVE: 20

TOTAL: 7626

Duplicate citations removed

2073

Scree ning of study titles and abstracts

TOTAL: 5553

Did not match inclusion criteria

5509

Full text papers retrieved

(Includes one additional paper

identified by hand search). Studies excluded after full text

TOTAL: 39 screen due to: No exercise control,

Ineligible exercise program; length

of program; CAD patients with heart failure.

Studies assessed for methodological

quality

TOTAL: 8

Papers excluded after quality appraisa l

Studies included in the meta-

analysis

TOTAL: 6 (After combining

articles refe rring to the same

study = 2)

Figure 1 Flow diagram of the search and study inclusion process.

using standard critical appraisal instruments for random- sample size, details of exercise interventions and outcomes

ised controlled trials from the Joanna Briggs Institute Meta- were extracted. The primary outcome extracted was aerobic

Analysis of Statistics Assessment for Review Instrument capacity, namely VO2peak. Secondary outcomes extracted

(JBI-MAStARI, Joanna Briggs Institute, University of Ade- included anaerobic threshold, lipid proﬁle (LDL and

laide, Australia). For inclusion in the review, both reviewers HDL), and systolic blood pressure.

agreed that a cut-off score of ﬁve out of 10 be used to

determine acceptable quality for inclusion.

Statistical Analysis

The JBI-MAStARI was used to pool results from the included

Data Extraction studies. A ﬁxed effect meta-analysis was used to determine the

All data was extracted by a single investigator (A.D.E) using weighted mean difference (WMD) and 95% conﬁdence inter-

a standardised form. For each study, the citation details, vals of outcomes compared between INTERVAL and

Elliott et al 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 20

152 A.D. Elliott et al.

Table 1 Characteristics of included studies.

Study Sample n INT CONT Duration Mode

Rognmo et al (2004); CAD 17 (INT = 8) 3d/wk - 4x4mins @ 3d/wk – 41 10 weeks TM Walking

Amundsen et al 80-90%VO2peak, mins@50-60%

(2008) 3min recovery. VO2peak.

Warburton et al CAD 14 (INT = 7) 2d/wk - 2mins @ 2d/wk - 16 weeks TM, Stairclimber,

(2005) (previous 90% VO2R, 2min 30 mins@65%VO2R Arm and Leg

CABG or recovery. 30 mins Ergometer

AP) total. Additional 3d/wk

30mins & 65%VO2R

Additional 3d/wk

30mins & 65%VO2R

Moholdt et al Post-CABG 59 (INT = 28) 5d/wk – 4x4mins @ 5d/wk – 46min 4 weeks TM Walking

(2009) 90%HRpeak, walking @ 70%HRmax.

3min recovery.

Moholdt et al Post-MI 89 (INT = 30) 3d/wk - 4x4mins @ 3d/wk – 35min 12 weeks TM Walking

(2011, 2012) 85-95%HRpeak, aerobic group (INT), Aerobic

3min recovery. exercise exercises

(Control)

Currie et al Recent 22 (INT = 11) 2d/wk – 10x1min @ 2d/wk – 30-50min 12 weeks Cycling

(2013) CAD event 89%PPO, 1min @ 58%PPO

recovery

Keteyian et al Post-MI, 28 (INT = 15) 3d/wk - 4x4mins @ 3d/wk - 30mins@ 10 weeks TM

(2014) CABG 80-90% HRR, 60-80% HRR

and/or PCI 3min recovery

CAD Coronary Artery Disease; CABG Coronary artery bypass graft; AP Angioplasty; MI Myocardial infarction; PCI Percutaneous coronary intervention; INT

Interval training; CONT Moderate continuous training; HRpeak Peak heart rate; HRR Heart rate reserve; VO2peak Peak oxygen consumption; VO2R VO2 reserve

determined as difference between resting and peak VO2; PPO peak power output; TM Treadmill.

CONTINUOUS measured upon completion of the relevant frequency of exercise training ranging from two to ﬁve days

exercise program. Statistical heterogeneity was evaluated per week (Table 1). The methodological quality of each study

using chi-squared. is reported in Table 3.

VO2peak

Results Pooling of studies using a ﬁxed-effects meta-analysis

revealed that INTERVAL is signiﬁcantly more effective than

Identiﬁed Studies

CONTINUOUS for increasing VO2peak in CAD patients

Following the initial search, 5553 studies were reviewed by (Fig. 2). Patients in the INTERVAL group improved their

1 1

their title and abstract (Fig. 1). Of these, 39 were retrieved in VO by 1.53 ml kgÀ minÀ (95% CI 0.84 to 2.23) more

2peak

full-text, 32 of which did not match the eligibility criteria than the CONTINUOUS group (Overall Z = 4.33,

for the study. Following assessment of methodological qual- P = 0.0001). Homogeneity was observed between studies

ity, eight articles were included in the meta-analysis. In two (chi squared = 2.69, P = 0.7).

instances, two articles were reporting outcomes from the

same study [12,13,19,20]. In these instances, both articles Anaerobic Threshold

were treated as a single study such that the ﬁnal analysis Three of the six studies [15,16,21] reported the VO2 at anaer-

included six independent research studies. obic threshold post exercise training (Fig. 3). The WMD was

1 1

The characteristics of the included studies are shown in 1.95 ml kgÀ minÀ (95% CI 1.23 to 2.67) in favour of INTER-

Table 1. Three studies were from the same institution in VAL (Overall Z = 5.31, P = 0.0001). Statistical heterogeneity

Norway [13,14,20], with the remaining three studies from was observed between studies (chi-squared = 4.95, P < 0.05).

Canada [15,16] and the United States [21]. A total of 229

patients with CAD were analysed (Table 2), 99 of which Cardiovascular Risk Factors

were randomised to INTERVAL. Sample size in the included Three studies with a combined sample of 67 patients

studies ranged from 14 to 89 patients (Table 1). Exercise [13,16,21] reported systolic blood pressure following exercise

program duration ranged from four to 16 weeks with a training (Fig. 4). The WMD was -3.44 mmHg (95% CI -7.25 to

Elliott et al 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 21

Interval Training Versus Continuous Exercise in Patients with Coronary Artery Disease 153

4 0.36), with an overall Z effect of 1.77 indicating a non-signiﬁ- 9

. cant effect (P = 0.07). Two studies with a combined sample of

9 8

4 148 patients revealed no statistically signiﬁcant difference in

plasma HDL [14,22]; a WMD of 0.04 (95% CI 0.00 to 0.07) was

determined (Z = 1.8; P = 0.1). Only one study [14] reported 4.2 21.8 Not Reported 7 58

LDL following exercise training. Meta-analysis was unable to Æ

; NR

be performed on this outcome. Previous PCI, CABG or MI Keteyian et al 8 11 3

3.7 22.4 Discussion 8 60 Æ

The ﬁndings of this meta-analysis indicate that INTERVAL is

6 8 3

more effective than CONTINUOUS for the improvement of

both VO2peak and the anaerobic threshold in patients with 5.7 19.8

11 68

Æ stable CAD in the absence of heart failure. The greater Æ

Coronary Artery Bypass Graft

improvement in VO2peak following INTERVAL compared Angiographically documented CAD Currie et al 7

6 1 1

to CONTINUOUS (4.6 3.1 versus 2.8 2.4 ml kgÀ minÀ )

Æ Æ

; CABG is important in the context of a 10-25% survival advantage 9.3 62

6.7 18.7 1 1

À À Æ Æ with every 3.5 ml kg min improvement in VO [23].

2peak

These ﬁndings are in agreement with previous meta-analyses

59 47 NR 4 NR NR NR NR NR NR NR NR NR NR

comparing INTERVAL with CONTINUOUS in heart failure

patients [10], and cardiometabolic disease [11] although the

10.4 57.7 5.8 32.2

magnitude of the effect reported here is lower than that seen

Æ Æ

in these other populations. The greater effect seen in studies 1 1

Post-MI (2-12 weeks) Moholdt et al NR

of heart failure ( 2.14 ml kgÀ minÀ ) is likely mediated by

impaired cardiac function at baseline in that population.

5.2 31.6 However, the meta-analysis by Weston et al (2013) in patients Percutaneous Coronary Intervention 7.6 56.7

Æ 1 1

À À

Æ with ‘cardiometabolic’ disease indicated a >3 ml kg min

; PCI

31 increase in VO2peak with INTERVAL compared to CONTIN-

UOUS. Although not widely reported, many of the included

6.9 62 4.5 26.2 studies would have enrolled patients without heart failure,

Æ Æ

thus suggesting that the presence of heart failure may not be

Post-CABG (4-16 weeks) NR NR 30 NR NR 23 28 NR NR NR

NR NRa critical NR factor in determining the magnitude of beneﬁt with

INT. One should note that many of the studies of INTERVAL

Myocardial Infarction

2.3 27.1 in heart failure included studies in which INTERVAL was 8 60.2

Æ ; MI

prescribed intermittent exercise with no difference in exercise

2 3 3 intensity. Therefore, the precise description of high-intensity 3 4

interval training may underlie some of the observed differ-

ences between studies. Nonetheless, these ﬁndings indicate 7.7 29.8 7 57

that INTERVAL may be widely incorporated into exercise-

based cardiac rehabilitation programs where a primary aim is

Previous CABG or AP Warburton et al Moholdt et al 3 3 3 4 3

to increase aerobic capacity. Analysis of the studies reporting

Coronary Artery Disease

blood pressure and HDL, indicate no signiﬁcant effect of

7.3 55 5.3 33.3

Æ Æ

; CAD INTERVAL when compared with CONTINUOUS. However,

these outcomes were reported in only three and two studies

8/1 7/0 7/0 24/4 24/7 25/5 49/10 10/1 10/1 11/4 12/1 4 2 3 6 3

respectively, thus potentially limiting statistical power,

although no trends were apparent for either variable.

11.2 61.2 9.3 32.1

The possible mechanisms underlying the greater improve-

Æ Æ

ments in aerobic capacity with INTERVAL are unclear, Continuous Training

INTdocumented CAD CONT62.9 INT CONT INT CONT INT CONT INT CONT INT CONT 31.8 Rognmo et al. 6/2 4 1 2

although the training intensity-dependence of VO2peak [24]

has been established previously and is evident even in

; CONT

groups performing INTERVAL within the desired range of )

85-95% HRpeak [25]. There is considerable evidence that high- À

2peak

Patient characteristics and disease status for included studies. intensity exercise training yields a number of beneﬁcial adap- min

À tations with regards to cardiac function including improved

stroke volume [8], systolic [9] and diastolic left ventricular

Interval Training

Group Disease StatusAge (Yrs.) Angiographically Study (ml Gender (Male/Female) MI (no.) Baseline VO PCI (no.) CABG (no.) 1-2 Diseased Vessels 6 3+ Diseased Vessels 2 function [12]. Additionally, greater improvements in endo-

Table 2 INT

thelial function have been reported with INTERVAL [9,14,26]

Elliott et al 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 22

154 A.D. Elliott et al.

Table 3 Methodological quality of included studies.

Citation Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10

Warburton et al, 2005 N N N N N Y Y Y Y Y

Rognmo et al, 2004 Y N Y N N Y Y Y Y Y

Moholdt et al, 2009 Y N Y N N Y Y Y Y Y

Moholdt et al, 2012 Y N Y N N Y Y Y Y Y

Currie et al, 2013 U N N N N Y Y Y Y Y

Keteyian et al (2014) Y N Y N Y Y Y Y Y Y

% 67% 0% 67% 0% 17% 100% 100% 100% 100% 100%

Y Represents criteria achieved; N Represents criteria not achieved; U Represents criteria unable to be determined.

1. Was the assignment to treatment groups truly random?

2. Were participants blinded to treatment allocation?

3. Was allocation to treatment groups concealed from the allocator?

4. Were the outcomes of people who withdrew described and included in the analysis?

5. Were those assessing outcomes blind to the treatment allocation?

6. Were the control and treatment groups comparable at entry?

7. Were groups treated identically other than for the named interventions?

8. Were outcomes measured in the same way for all groups?

9. Were outcomes measured in a reliable way?

10. Was appropriate statistical analysis used?

1 1

Figure 2 Effect of interval versus continuous exercise training on VO (ml kgÀ minÀ ). CONT moderate intensity

2peak

continuous training; INT Interval training; WMD weighted mean difference; 95% CI 95% conﬁdence intervals.

most likely due to an increased vascular shear stress associ- unsurprising given recent ﬁndings that have shown either a

ated with greater peripheral blood ﬂow. Previously, greater positive [26,27] or no effect [9] in similar populations. Further-

skeletal muscle oxidative capacity has been reported with more, the systolic BP recorded in the studies by Currie et al [16]

shorter sprint, interval training compared to traditional and Keteyian et al [21] did not exceed 130 mmHg, indicating

endurance training in healthy participants [7], an effect that high BP was not a characteristic in the population sample

which may also be apparent with INTERVAL of longer upon entry. Previously, it has been suggested that despite the

duration (four minute intervals). Together, these ﬁndings beneﬁts of moderate-intensity exercise for the reduction of

indicate that both central and peripheral factors may mediate blood pressure, additional increases in the exercise intensity

the greater VO2peak improvements although no studies have confer little added beneﬁt [28,29].

directly assessed this hypothesis. Despite the role of HDL as a positive risk factor, there

The absence of any signiﬁcant effect of INTERVAL was minimal overall difference between INTERVAL and

compared to CONTINUOUS on blood pressure is perhaps CONTINUOUS following exercise training, despite a

Elliott et al 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 23

Interval Training Versus Continuous Exercise in Patients with Coronary Artery Disease 155

1 1

Figure 3 Effect of interval versus continuous exercise training on the VO (ml kgÀ minÀ ) at anaerobic threshold. CONT

moderate intensity continuous training; INT Interval training; WMD weighted mean difference; 95% CI 95% conﬁdence

intervals.

Figure 4 Effect of interval versus continuous exercise training on systolic blood pressure (mmHg) CONT moderate intensity

continuous training; INT Interval training; WMD weighted mean difference; 95% CI 95% conﬁdence intervals.

signiﬁcant increase being reported in the study by Moholdt Prescribing high-intensity exercise to patients with CAD

et al. [22] following INTERVAL and a trend for increased warrants careful consideration. Vigorous exercise can acutely

HDL following INTERVAL in the study by Moholdt et al. and transiently increase the risk of sudden cardiac arrest or

[14]. The absence of any change in HDL number following myocardial infarction in susceptible patients [33]. During

exercise training has been reported previously in hypercho- traditional exercise-based cardiac rehabilitation, the risk of

lesterolaemic men [30], although meta-analysis of the HDL a fatal event is approximately one event per every 750,000

response to exercise indicates that modest improvements in training hours. The estimated risks for cardiac arrest and

HDL with exercise may only be apparent with weekly exer- myocardial infarction are one in 116,000 and one in 219,000

cise durations in excess of 120 minutes, with little effect of training hours, respectively. A recent multicentre analysis of

exercise intensity [31]. Additionally, the total length of the cardiovascular risk in CAD patients performing INT, reports

exercise program may be an important factor with changes in only two non-fatal cardiac arrests across a total of 46,000

HDL being previously demonstrated after two years of aer- training hours [13]. Given the beneﬁts of INTERVAL exercise

obic exercise training, but not one [32]. A larger effect may in patients with CAD, it appears that the overall risk of

have eluded the studies reporting HDL number possibly due INTERVAL is low although possibly higher than that seen

to the short exercise program employed by Moholdt et al in traditional cardiac rehabilitation. However, caution

(2009) [14] or the total weekly exercise duration of less than should be taken when interpreting this data given the limited

120 minutes in the study by Moholdt et al (2012) [22]. dataset in which this analysis was performed. Further

Elliott et al 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 24

156 A.D. Elliott et al.

[2] Laukkanen JA, Kurl S, Salonen R, Rauramaa R, Salonen JT. The predictive

evaluation of the safety of INTERVAL is a critical require-

value of cardiorespiratory ﬁtness for cardiovascular events in men with

ment for future large, multicentre studies.

various risk proﬁles: A prospective population-based cohort study. Eur

Despite the evidence presented here and elsewhere [10] Heart J 2004;25 (Aug (16)):1428–37.

[3] Keteyian SJ, Brawner CA, Savage PD, Ehrman JK, Schairer J, Divine G,

favouring INTERVAL compared to CONTINUOUS in

et al. Peak aerobic capacity predicts prognosis in patients with coronary

patients with heart disease, in the course of conducting this

heart disease. Am Heart J 2008;156 (Aug (2)):292–300.

meta analysis, no study was identiﬁed that evaluated the long- [4] Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE.

Exercise capacity and mortality among men referred for exercise testing.

term beneﬁts on cardiovascular morbidity and/or mortality.

N Engl J Med 2002;346 (Mar (11)):793–801.

Systematic reviews conﬁrm the widely held view that exercise

[5] Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M, et al. Cardio-

is highly beneﬁcial to patients with CAD [1], thus making it respiratory ﬁtness as a quantitative predictor of all-cause mortality and

cardiovascular events in healthy men and women: A meta-analysis.

likely that INTERVAL may offer similar advantages. How-

JAMA 2009;301 (May (19)):2024–35.

ever, whether INTERVAL is more effective than CONTINU-

[6] Fletcher GF, Ades PA, Kligﬁeld P, Arena R, Balady GJ, Bittner VA, et al.

OUS in this regard remains to be answered. Future studies Exercise standards for testing and training: A scientiﬁc statement from

the American Heart Association. Circulation 2013;128 (Aug (8)):873–934.

should aim to evaluate not only the short-term physiological

[7] Gibala MJ, Little JP, van Essen M, Wilkin GP, Burgomaster KA, Safdar A,

adaptations with INTERVAL but also the longer-term health

et al. Short-term sprint interval versus traditional endurance training:

beneﬁts that this form of training may offer. Furthermore, Similar initial adaptations in human skeletal muscle and exercise perfor-

mance. J Physiol 2006;575 (Sep (Pt 3)):901–11.

future studies should assess the effect of INTERVAL on car-

[8] Helgerud J, Høydal K, Wang E, Karlsen T, Berg P, Bjerkaas M, et al.

diovascular risk factor proﬁles so that exercise can be individ-

Aerobic high-intensity intervals improve vo2max more than moderate

ualised to cardiovascular risk scores. training. Med Sci Sports Exerc 2007;39 (Apr (4)):665–71.

[9] Wisløff U, Støylen A, Loennechen JP, Bruvold M, Rognmo, Haram PM,

et al. Superior cardiovascular effect of aerobic interval training versus

Study Limitations

moderate continuous training in heart failure patients: A randomized

The conclusions regarding the beneﬁts of INTERVAL are study. Circulation 2007;115 (Jun (24)):3086–94.

constrained by the quality of the trials reported, which typi- [10] Haykowsky MJ, Timmons MP, Kruger C, McNeely M, Taylor DA, Clark

AM. Meta-analysis of aerobic interval training on exercise capacity and

cally include small sample sizes. Few trials adequately

systolic function in patients with heart failure and reduced ejection

reported the randomisation procedure in sufﬁcient detail to fractions. Am J Cardiol 2013;111 (May (10)):1466–9.

determine whether selection bias may have inﬂuenced the [11] Weston KS, Wisløff U, Coombes JS. High-intensity interval training in

patients with lifestyle-induced cardiometabolic disease: A systematic

study outcomes. Blinding of the assessors to treatment alloca-

review and meta-analysis. Br J Sports Med 2013;Oct 10.

tion was also absent or unclear in a number of studies, raising [12] Amundsen BH, Rognmo O, Hatlen-Rebhan G, Slordahl SA. High-

the possibility of performance bias. Finally, intention to treat intensity aerobic exercise improves diastolic function in coronary artery

disease. Scand Cardiovasc J 2008;42 (2):110–7.

analysis was not performed in any of the studies reported,

[13] Rognmo, Moholdt T, Bakken H, Hole T, Mølstad P, Myhr NE, et al.

where data from withdrawn patients was not included, which Cardiovascular risk of high- versus moderate-intensity aerobic exercise

may have resulted in attrition bias. Future studies investigat- in coronary heart disease patients. Circulation 2012;126 (Sep (12)):

1436–40.

ing the effectiveness of INTERVAL versus other treatment

[14] Moholdt TT, Amundsen BH, Rustad LA, Wahba A, Lovo KT, Gullikstad

options should address these matters in their study design. LR, et al. Aerobic interval training versus continuous moderate exercise

after coronary artery bypass surgery: A randomized study of cardiovas-

Conclusions cular effects and quality of life. Am Heart J 2009;158 (6):1031–7.

[15] Warburton DER, McKenzie DC, Haykowsky MJ, Taylor A, Shoemaker P,

When compared to traditional aerobic training, high-inten-

Ignaszewski AP, et al. Effectiveness of high-intensity interval training for

sity INTERVAL appears to be a more effective option than the rehabilitation of patients with coronary artery disease. Am J Cardiol

2005;95 (May (9)):1080–4.

CONTINUOUS for increasing aerobic capacity in patients

[16] Currie KD, Dubberley JB, McKelvie RS, MacDonald MJ. Low-Volume,

with stable CAD in the absence of any disclosed heart failure,

high-intensity interval training in patients with CAD. Med Sci Sports

despite minimal or no effect on other cardiovascular risk Exerc 2013;45 (Aug (8)):1436–42.

[17] Cornish AK, Broadbent S, Cheema BS. Interval training for patients with

factors. For this form of exercise rehabilitation to become

coronary artery disease: A systematic review. Eur J Appl Physiol 2011;111

commonplace in clinical practice, high-quality randomised

(Apr (4)):579–89.

controlled trials are required to elucidate whether INTER- [18] Pattyn N, Coeckelberghs E, Buys R, Cornelissen VA, Vanhees L. Aerobic

interval training vs. Moderate continuous training in coronary artery

VAL confers any additional beneﬁt on cardiovascular mor-

disease patients: A systematic review and meta-analysis. Sports Med

bidity and mortality in this population.

2014;44 (May (5)):687–700.

[19] Moholdt T, Aamot IL, Granøien I, Gjerde L, Myklebust G, Walderhaug L,

et al. Long-term follow-up after cardiac rehabilitation: A randomized

Acknowledgements study of usual care exercise training versus aerobic interval training after

myocardial infarction. Int J Cardiol 2011;152 (Nov (3)):388–90.

No ﬁnancial assistance was provided for this study. The [20] Moholdt T, Aamot IL, Granøien I, Gjerde L, Myklebust G, Walderhaug L,

et al. Aerobic interval training increases peak oxygen uptake more than

authors wish to thank Dr Matthew Stephenson for assistance

usual care exercise training in myocardial infarction patients: A random-

in the preparation of this analysis. ized controlled study. Clin Rehabil 2012;26 (Jan (1)):33–44.

[21] Keteyian SJ, Hibner BA, Bronsteen K, Kerrigan D, Aldred HA, Reasons

LM, et al. Greater improvement in cardiorespiratory ﬁtness using higher-

intensity interval training in the standard cardiac rehabilitation setting. J

References Cardiopulm Rehabil Prev 2014;34 (2):98–105.

[22] Moholdt T, Bekken Vold M, Grimsmo J, Slordahl SA, Wisloff U. PLoS

[1] Heran BS, Chen JM, Ebrahim S, Moxham T, Oldridge N, Rees K, et al. ONE home-based aerobic interval training improves peak oxygen uptake

Exercise-based cardiac rehabilitation for coronary heart disease. equal to residential cardiac rehabilitation: A randomized, controlled trial.

Cochrane Database Syst Rev 2011;Jul (7). PLoS One 2012;7 (7).

Elliott et al 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 25

Interval Training Versus Continuous Exercise in Patients with Coronary Artery Disease 157

[23] Kaminsky LA, Arena R, Beckie TM, Brubaker PH, Church TS, Forman [29] Pescatello LS, Franklin BA, Fagard R, Farquhar WB, Kelley GA, Ray CA.

DE, et al. The importance of cardiorespiratory ﬁtness in the united states: Exercise and hypertension. Med Sci Sports Exerc 2004;36 (Mar (3)):

The need for a national registry: A policy statement from the American 533–53.

Heart Association. Circulation 2013;127 (Feb (5)):652–62. [30] Crouse SF, O’Brien BC, Grandjean PW, Lowe RC, Rohack JJ, Green JS,

[24] Wenger HA, Bell GJ. The interactions of intensity, frequency and dura- et al. Training intensity, blood lipids, and apolipoproteins in men with

tion of exercise training in altering cardiorespiratory ﬁtness. Sports Med high cholesterol. J Appl Physiol (1985) 1997;82 (Jan (1)):270–7.

1986;3 (5):346–56. [31] Kodama S, Tanaka S, Saito K, Shu M, Sone Y, Onitake F, et al. Effect of

[25] Moholdt T, Madssen E, Rognmo O, Aamot IL. The higher the better? aerobic exercise training on serum levels of high-density lipoprotein

Interval training intensity in coronary heart disease. J Sci Med Sport cholesterol: A meta-analysis. Arch Intern Med 2007;167 (May (10)):

2013;Aug 8. 999–1008.

[26] Tjønna AE, Lee SJ, Rognmo, Stølen TO, Bye A, Haram PM, et al. Aerobic [32] King AC, Haskell WL, Young DR, Oka RK, Stefanick ML. Long-term

interval training versus continuous moderate exercise as a treatment for the effects of varying intensities and formats of physical activity on partici-

metabolic syndrome: A pilot study. Circulation 2008;118 (Jul (4)):346–54. pation rates, ﬁtness, and lipoproteins in men and women aged 50 to 65

[27] Molmen-Hansen HE, Stolen T, Tjonna AE, Aamot IL, Ekeberg IS, Tyldum years. Circulation 1995;91 (May (10)):2596–604.

GA, et al. Aerobic interval training reduces blood pressure and improves [33] Thompson PD, Franklin BA, Balady GJ, Blair SN, Corrado D, Estes

myocardial function in hypertensive patients. Eur J Prev Cardiol 2012;19 NAM, et al. Exercise and acute cardiovascular events placing the risks

(Apr (2)):151–60. into perspective: A scientiﬁc statement from the American Heart Asso-

[28] Halbert JA, Silagy CA, Finucane P, Withers RT, Hamdorf PA, Andrews ciation Council on Nutrition, Physical activity, and Metabolism and

GR. The effectiveness of exercise training in lowering blood pressure: A the Council on Clinical Cardiology. Circulation 2007;115 (May (17)):

meta-analysis of randomised controlled trials of 4 weeks or longer. J Hum 2358–68.

Hypertens 1997;11 (Oct (10)):641–9.

Elliott et al 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 26 Activity 2: Question and Inclusion Criteria Development Using the appropriate mnemonic relevant to the type of review you plan to undertake, develop and design a systematic review question and subsequent inclusion/exclusion criteria relevant to your topic of interest. Use the following table as a guide to select the appropriate mnemonic and the subsequent table to describe the components of your question and inclusion criteria.

Review Type Mnemonic

Effectiveness PICO

Qualitative PICo

Costs/Economics PICO

Prevalence or Incidence CoCoPop

Diagnostic Test Accuracy PIRD

Etiology and Risk PEO

Textual Synthesis PICo

Mixed Methods PICO or PICo or PIRD or CoCoPop or PEO or multiple

Umbrella PICO or PICo or PIRD or CoCoPop or PEO or multiple

Scoping PCC

What type of review do you plan to undertake?

What mnemonic/s will you use to guide your review question?

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 27 Pick the applicable components of your mnemonic and consider the following bullet points. Describe the components of your question and inclusion criteria in the applicable boxes on the right side of the table.

Population (P or Pop): ■■ Who is the target population for your question? ■■ Consider gender, ethnicity, socioeconomic class, age etc. ■■ For qualitative reviews what kinds of people will the review question focus on? E.g. exposure to a disease, or intervention, or interaction with health professionals as they relate to the qualitative experiences or meanings individuals associate with them Intervention (I): ■■ What is the intervention you’re looking at? A drug, therapy, equipment, program etc. ■■ Consider variations (dosage, intensity, frequency, mode delivery etc.) ■■ Consider possible co-interventions Phenomena of Interest (I): ■■ What is the ‘thing’ you want to examine? E.g. an experience, event or process occurring that is under study Condition (Co): ■■ What is the variable of interest? E.g. a health condition, disease, symptom, event or factor Index Test (I): ■■ What diagnostic test is being investigated in the review? Exposure of interest (E): ■■ Consider what particular exposure or risk factor/s you’re looking at. What disease/ condition is it associated with? ■■ Consider dose, nature and duration of exposure Concept (C): ■■ The core concept may include details that pertain to elements that would be detailed in a standard systematic review such as the “interventions” and/or “phenomena of interest” ■■ Outcomes may also be a component of a scoping review’s “Concept”

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 28 Comparator/Control (C): ■■ What will the comparison for the intervention be? E.g. standard care, no treatment, placebo, a different variant of the same intervention, a different drug, a different kind of therapy etc. Reference Test (R): ■■ What is the gold standard test which the index test will be compared with? Context (Co or C): ■■ What kind of social context will your review focus on? E.g. cultural factors (geographic, racial, gender) and setting (the clinic, community, hospital, school, aged care facility)

Outcomes (O): ■■ What are the likely meaningful and important outcome measures? ■■ How will the outcomes be measured? ■■ Consider primary and secondary outcomes, the type and timing of outcome measurements ■■ Outcomes should be stated neutrally, covering benefits and adverse effects Diagnosis of Interest (D): ■■ What disease, injury, disability or other pathological condition is being investigated?

Now take a minute to review the above components and develop a draft review question. Remember not all detailed components need to be included in the review question (e.g. timing and dosage of an intervention or detailing each individual outcome that you intend to focus on). Your review question may also consist of a primary question followed by a series of secondary or sub questions.

My review question/s:

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 29 Consider whether there will be any exclusions to your inclusion criteria e.g. if you are looking at the experiences of exercise programs on nursing home residents will you include residents who have dementia or who are immobile? If you are looking at the effectiveness of a particular drug on pain will you include studies that administer that particular drug but deliver it in combination with physical therapy? Your exclusion criteria must reflect sound clinical and scientific reasoning which should be explained in your background.

My exclusion criteria is/are:

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 30 Activity 3: Logging into JBI SUMARI

Login to JBI SUMARI, select your review type and input your review question and inclusion/exclusion criteria that you have developed in Activity 2.

Type in https://sumari.joannabriggs.org in your web browser

Select [Sign Up]

Enter a username, password, your name and email address

Note: There are no limits to the amount of characters/numbers you can include in your username and password. Also remember usernames and passwords are case sensitive.

Select [Create account]

Activate your account by clicking on the URL provided in the email

Once complete you will be redirected to the Log in page where you will enter your username and password and select [Log in]

Select [New Project]

Type the title of your proposed review in the Project title box

Select the appropriate review type checkbox/es

Select [Create]

Select [Protocol] from the top menu bar

Fill in the following sections based on your answers from Activity 2: - Title - Authors/Reviewers - Review Question - Inclusion Criteria (noting any exclusion criteria)

Remember all text is fully editable – the text in yellow acts as a prompt and signifies that you are required to add in text to this section that is specifically relevant to your protocol topic.

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 31 Activity 4: Logic Grid Development A logic grid is a type of visual aid to help you in deciding on the main concepts of your review question/topic which will assist you in organizing your emerging search strategy. In a logic grid, each column represents a discrete concept that is generally aligned with each element of the relevant mnemonic (e.g. PICO). Placing the terms into a logic grid illustrates how the related concepts or synonyms will combine to construct the final search string. It is not always necessary to include each component of your mnemonic in your final search strategy.

The following example is provided: Example Question: What effect does mifamurtide have on event-free survival, overall survival, and quality of life as an adjunct to chemotherapy for high-grade non-metastatic and metastatic osteosarcoma patients?

Example Logic Grid

Population è Intervention è Comparator/Control è Outcomes ê (OR) AND ê (OR) AND ê (OR) AND ê (OR) osteosarcoma mifamurtide chemotherapy survival

osteosarcoma, Acetylmuramyl-Alanyl- event free survival juxtacortical Isoglutamine

osteogenic sarcoma mepact quality of life

bone sarcoma L-MTP-PE adverse events

osteoid sarcoma MTP PE recurrence

muramyl tripeptide

muramyltripeptide

Example from: Jimmy R, White S & Lisy K. Effectiveness of mifamurtide in addition to standard chemotherapy for high-grade osteosarcoma: A systematic review protocol. The JBI Database of Systematic Reviews and Implementation Reports, [S.l.], v. 12, n. 11, p. 61 - 73, dec. 2014. ISSN 2202-4433. Available at: .

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 32 Develop a logic grid for your review question. Use the terms AND/OR/NOT to connect your terms and brackets to preserve the logic of the search.

Population Intervention OR Comparator/Control Outcome OR Phenomena of OR Reference Test OR Diagnosis of Interest Interest OR Condition Context OR Index Test OR Exposure of interest OR Concept

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 33 Activity 5: Uploading Search Results into JBI SUMARI

Logon to JBI SUMARI

Select [New Project]

Type: ‘The effectiveness of probiotics in reducing the incidence of Clostridium difficile associated diarrhea in elderly patients: a systematic review protocol’ in the Project title box

Select the Effectiveness Review checkbox

Select [Create]

Select [Studies] from the top menu bar

Select [Import XML]

Under ‘Computer’ select [Removable disk] then ‘JBI CSR2016_001Act5.xml’ and click [Open]

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 34 Activity 6: Selecting Studies Study selection addresses the question “should the paper be retrieved? It should be conducted independently by two assessors to limit the risk of error and bias. Spilt into pairs. Read the systematic review protocol by Vernaya and McAdam 2015 provided in the subsequent pages of this workbook, specifically noting the criteria for considering studies for this review. Then review the list of titles and abstracts (where available) also provided in the workbook and indicate below which of these papers you would choose to retrieve. In your pair compare results and see if you can come to an agreement about which studies will be retrieved.

Then: Logon to JBI SUMARI

Select [Studies] underneath ‘The effectiveness of probiotics in reducing the incidence of Clostridium difficile associated diarrhea in elderly patients: a systematic review protocol’

Go through each of the 15 records and based on your decisions select [Include] or [Exclude]. Provide a reason in the text box for each exclusion and select [Exclude]

At any time you can change your decision by clicking on [Revert] for the selected study

The papers I will retrieve are (provide reasoning):

The papers I won’t retrieve are (provide reasoning):

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 35 JBI Database of Systematic Reviews & Implementation Reports 2015;13(8) 79 - 91

The effectiveness of probiotics in reducing the incidence of Clostridium difficile associated diarrhea in elderly patients: a systematic review protocol

Marina Vernaya1,2

Jennifer McAdam3

1 Samuel Merritt University

2 UCSF Centre for Evidence-based Healthcare: an Affiliate Center of the Joanna Briggs Institute

3 School of Nursing, Samuel Merritt University, Oakland, USA

Corresponding author:

Marina Vernaya

[email protected]

Review question/objective

The objective of this review is to assess the effectiveness of probiotics in reducing the incidence of Clostridium difficile-associated diarrhea in elderly patients (60 years and older) who are residents of acute- and post-acute care facilities.

Background

Penicillin was discovered less than a century ago1 and since then millions of lives have been saved with the use of antibiotics.2 Today, antibiotics are among the most frequently prescribed medications in healthcare.3-5 Even though antibiotics have numerous benefits, they can also have negative consequences that lead to other health related problems. An example of this is Clostridium difficile (C. difficile) infection that leads to Clostridium difficile associated diarrhea (CDAD). Since the first reported case of CDAD in 1978, this antibiotic associated bacteria has become a major public health threat as was identified by the Centers for Disease Control and Prevention (CDC).6,7

According to the CDC, the incidence of CDAD has tripled over the last decade.8 Patients diagnosed with CDAD have an increase in morbidity and mortality, prolonged hospital stays, and higher hospital costs.3 In the United States alone, the estimated treatment cost for patients with CDAD is $3.2 billion annually9 and this infection is associated with 14,000 deaths per year.8 Patients of any age are susceptible to CDAD; however, elderly patients taking antibiotics are at a particularly high risk.3 Patients aged 60 or older have age related changes in the gastrointestinal micro-flora, decreased immune function, and multiple chronic conditions that further increase their risk.10 In addition, the increased risk of CDAD among older adults may be related to defects in immune response, specifically impaired phagocytes activity of neutrophils and failure to develop IgG and IgM in response to toxin A. The capacity of serum

doi: 10.11124/jbisrir-2015-2197 Page 79

Vernaya and McAdam 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 36 JBI Database of Systematic Reviews & Implementation Reports 2015;13(8) 79 - 91

to neutralize these toxins decreases with age.11 Finally, gastric acid secretion decreases with age, allowing harmful bacteria, such as C. difficile to survive.11,12

C. difficle is classified as an anaerobic, gram positive, spore-forming bacteria.4 Transmission of C. difficile is through the fecal-oral route. An infected individual sheds vegetative forms of the bacteria and spores into the environment. Although the bacteria are inactive in the spore form, once ingested the bacteria undergo several phases of pathogenesis to become active in the colon. When the host uses antimicrobial agents, this alters the normal balance of intestinal flora. This imbalance can lead to the proliferation of C. difficile in the colon. Antimicrobials, such as broad-spectrum antibiotics, (e.g. Bactrim, Clindamycin), the second and third generation of cephalosporins, and fluoroquinolones, are particularly associated with C. difficile infection.11

The process of C. difficile infection leading to diarrhea begins when bacterial growth is no longer suppressed by normal intestinal flora or gastric acid.13 The C. difficile bacteria produce two toxins: enterotoxin A and cytotoxin B. Both of these act synergistically14 and are highly virulent and cytotoxic.15 Enterotoxin A activates macrophages and mast cells that cause the production of inflammatory mediators. These mediators disrupt the cell wall junction, resulting in increased permeability of the intestinal wall and reduced water absorption for the gut, resulting in osmotic diarrhea.16 Toxin B leads to cells accumulating purulent and necrotic debris, a wide-spread colon inflammatory response, and the formation of characteristic ulcers called pseudo-membranes.17 The end result of both toxins A and B is the development of CDAD.

Prompt diagnosis and treatment of CDAD are imperative. Standard management of CDAD consists of discontinuing any medication contributing to diarrhea, correcting fluid and electrolytes imbalances, and initiating an antibiotic for treatment of CDAD.15 Metronidazole is considered a first-line of therapy for treatment of mild to moderate disease, whereas vancomycin is the medication of choice for severe cases and relapses.16,17 In addition, infection control measures can significantly decrease the incidence of CDAD.16,17

Alternative therapeutic approaches for prevention and treatment of CDAD include probiotics. The use of probiotics has grown in popularity for maintaining intestinal health and decreasing the risk of CDAD. Today, science is on the verge of understanding the benefits of probiotics and their effect on incredibly complex gastrointestinal micro-flora. Oral probiotics are hypothesized to decrease the incidence and prevalence of CDAD.18-24 They are nonpathogenic live bacteria and yeast microorganisms that are used to replenish and balance colonic micro flora.25 Because of these benefits, recommending probiotics as prevention and treatment in CDAD in elderly patients needs to be explored. To date, there have been several systematic reviews published on probiotic use and CDAD,26,27 but none have specifically focused on their effectiveness in elderly patients.

There have been a variety of studies conducted to evaluate the effectiveness of probiotics in preventing and treating CDAD in the elderly population.18-24 One randomized controlled trial on 138 elderly patients receiving antibiotic therapy identified that the incidence of stool samples positive for C. difficile toxins was significantly lower in the intervention group versus the control group (2.95% versus 7.25%, respectively).23 Statistical analysis of these findings indicated that incidence of CDAD toxins was 4.35% lower in the experimental group (95% CI of -0.132 to 0.038).23 This finding was also replicated in another randomized double blind controlled trial. The researchers in this study identified that consumption of a probiotic drink twice a day during antibiotic treatment and for one week after antibiotic

doi: 10.11124/jbisrir-2015-2197 Page 80

Vernaya and McAdam 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 37 JBI Database of Systematic Reviews & Implementation Reports 2015;13(8) 79 - 91

treatment significantly (P=0.001) decreased morbidity related to CDAD in elderly patients.19 A placebo-controlled trial performed by Klarin, et al.20 reported that colonization with C. difficile in critically ill elderly patients treated with antibiotics and supplemented with Lactobacillus plantarum299v was reduced when compared to the control group (P=0.0485). In support of these findings, Gao, Mubasher, Fang, Reifer, and Miller18 found that a probiotic blend of Lactobacillus had a positive efficacy and lower incidence of CDAD of elderly patients. Zahoroniet al.24 findings also support that probiotics are effective in elderly populations. Using a randomized, double-blind, placebo-controlled trial, these investigators found that the incidence of diarrhea was significantly lower in the treatment group compared with the control group. In another study, Lahtinen, et al.21 identified that probiotics containing Lactobacillus tended to reduce the average level of C. difficile in intestinal microbiota in elderly subjects. Finally, Ouwehand and colleagues,22 in their randomized placebo-controlled study, identified that higher probiotic dosages decreased the number of daily liquid stools in older patients with CDAD.

Elderly patients are at high risk of morbidity and mortality from CDAD. In the literature, the use of probiotics in this population has shown promise, but needs further exploration. Therefore, this systematic review will provide a comprehensive and unbiased summary of the available research on the effectiveness of probiotics in decreasing the incidence and prevalence of CDAD in elderly patients.

Keywords

Clostridium difficile, elderly, probiotics

Inclusion criteria

Types of participants

This review will consider studies that include participants aged 60 years and older who are residents of acute- and post-acute care facilities and are undergoing or planning to undergo antibiotic treatment. Studies that include participants undergoing treatment for CDAD will be excluded.

Types of intervention(s)

This review will consider studies that evaluate the effectiveness of probiotics for prevention of CDAD in elderly patients in acute- and post-acute care settings compared to usual care. Any brand or strength of a probiotic product will be considered for the review. The review will also include studies examining various forms of probiotics, such as yogurt, buttermilk, combination products or capsules.

Types of outcomes

This review will consider studies that include the following outcome measures: incidence or relapse of CDAD. Cases of CDAD will be defined by presence of diarrhea and verified by positive results for stool enzyme immunoassay (EIA) for toxins A and B. Absence of diarrhea verified by negative results for stool EIA for toxins A and B.

Types of studies

This review will consider both experimental and epidemiological study designs including randomized controlled trials, non-randomized controlled trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies, case control studies and analytical cross sectional studies for inclusion.

doi: 10.11124/jbisrir-2015-2197 Page 81

Vernaya and McAdam 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 38 JBI Database of Systematic Reviews & Implementation Reports 2015;13(8) 79 - 91

This review will also consider descriptive epidemiological study designs including case series, individual case reports and descriptive cross sectional studies if randomized-controlled trials are not available for inclusion.

Search strategy

The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of MEDLINE and CINAHL will be undertaken followed by an analysis of the text words contained in the title and abstract, and of the index terms used to describe articles. A second search using all identified keywords and index terms will then be undertaken across all included databases. Thirdly, the reference list of all identified reports and articles will be searched for additional studies. Studies published in English will be considered for inclusion in this review. Authors of primary studies will be contacted for missing information or to clarify any unclear data. Introduction of probiotics was first described by Russian Nobel laureate Elia Metchnikoff in the early 1900s.28 However, the timeframe for the search will be limited from 1978 to present, since this is when the first reported case of CDAD was recorded.

The databases to be searched include:

CINAHL

PubMed

EMBASE

ProQuest Nursing & Allied Health Source.

The search for unpublished studies will include:

Google Scholar and conference proceedings.

Initial keywords to be used will be:

C.difficile associated diarrhea, antibiotic associated diarrhea, probiotics, elderly, aged

Assessment of methodological quality

Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer.

Data extraction

Data will be extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives.

doi: 10.11124/jbisrir-2015-2197 Page 82

Vernaya and McAdam 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 39 JBI Database of Systematic Reviews & Implementation Reports 2015;13(8) 79 - 91

Data synthesis

Quantitative data will, where possible be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis to determine if the treatment intervention does provide superior results. Heterogeneity will be assessed statistically using the standard Chi-square and also explored using subgroup analyses based on the different study designs included in this review. Where statistical pooling is not possible the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.

Conflicts of interest

There are no conflicts of interests to declare.

Acknowledgements

We would like to thank Dr. Stannard, an Associate Chief Nurse Researcher at UCSF Medical center, for excellent JBI training course presentation. We would like to thank Debbie Sommer, Librarian, for her extensive knowledge and assistance in the development of search strategies of database systems. We would like to thank Mr Bruce T Abbott, UC Davis, Librarian, for assistance to get access to the EMBASE database. I would like to express my grateful appreciation to Dr Wolf for her encouragement and motivation in research for this topic. I would like to thank Dr Hampton for her extensive knowledge, mentorship and valuable advice to produce quality research.

doi: 10.11124/jbisrir-2015-2197 Page 83

Vernaya and McAdam 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 40 JBI Database of Systematic Reviews & Implementation Reports 2015;13(8) 79 - 91

References

1. American Association of Immunologists. Nobel Laureates of AAI: Sir Alexander Fleming, F.R.C.S. (1881-1955) [Internet]. 2014 [cited 2014 Sep 22]. Available from: http://www.aai.org/About/History/Notable_Members/pdfs/Nobel/AAI-Fleming-Alexander.pdf

2. American Academy of Pediatrics. The History of Antibiotics [Internet]. 2014. [Cited 2014 Sep 23 Available from: http://www.healthychildren.org/English/health-issues/conditiions/treatments/pages/The-History-of- Antibiotics.aspx

3. Centers for Disease Control and Prevention. Core elements of hospital antibiotic stewardship programs [Internet]. 2014 [Cited 2014 Sep 22. Available from: http://stacks.cdc.gov/view/cdc/25302

4. Centers for Disease Control and Prevention. Frequently asked questions about Clostridium difficile for healthcare providers. 2012. Available from: http://www.cdc.gov/HAI/organisms/cdiff/Cdiff_faqs_HCP.html

5. Lim CJ, Kong DC, Stuart RL. Reducing inappropriate antibiotic prescribing in the residential care setting: Current perspectives. ClinInterv Aging.2014; 9: 165-177. doi:10.2147/CIA.S46058.

6. Cecil JA. Clostridium difficile: Changing epidemiology, treatment and infection prevention measures. Curr Infect Dis Rep.2012; 14(6): 612-619. doi:10.1007/s11908-012-0298-9.

7. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, [Internet]. 2013. [Cited on 2014 Sep 20 ]. Available from: http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf.2013

8. Centers for Disease Control and Prevention. Vital Signs. [Internet] 2012. [Cited on 2014 Sep 23??? ]. Available from: http://www.cdc.gov/VitalSigns/Hai/StoppingCdifficile/

9. California Department of Public Health. Brief report: Healthcare-associated Clostridium difficile infections in California hospitals, January 2009 through March 2010. [cited 2010, March]. Available from: http://www.cdph.ca/gov/programs/hai/Documents/HAIReportSB-1058Cdiff-FINAL.pdf

10. Crogan NL, Evans BS. Clostridium difficile: An emerging epidemic in nursing homes. Geriatr Nurs.2007; 28(3): 161-164. doi:10.1016/j.gerinurse.2007.04.005

11. Simor AE, Bradley SF, Strausbaugh LJ, Crossley K, Nicolle LE. Clostridium difficile in long-term-care facilities for the elderly. Infec Cont Hosp Epidemiology [Internet].2002 [cited 2015, February]; 23(11): 696-703. Available from: http://www.shea-online/org/Assets/files/position_papers/SHEA_Cdiff.pdf

12. Feldman M, Cryer B, McArthur KE, Huet BA, Lee E. Effects of aging and gastritis on gastric acid and pepsin secretion in humans: A prospective study. Gastroenterology.1996 [cited 2015 Feb 4]; 110(4): 1043-1052. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8612992

13. Vedantam G, Clark A, Chu M, McQuade R, Mallozzi M, Viswanathan VK. Clostridium difficile infection: Toxins and non-toxin virulence factors, and their contributions to disease establishment and host response. Gut Microbes. 2012; 3(2): 121-134. doi:10.4161/qmic.19399.

doi: 10.11124/jbisrir-2015-2197 Page 84

Vernaya and McAdam 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 41 JBI Database of Systematic Reviews & Implementation Reports 2015;13(8) 79 - 91

14. Lyras D, O'Connor JR, Howarth PM, Sambol SP, Carter GP, Phumoonna T, Poon R, Adams V, Vedantam G, Johnson S, Gerding DN, Rood JI. Toxin B is essential for virulence of Clostridium difficile. Nature.2009; 458(7242): 1176-1179. doi:10.1038/nature07822.

15. Redelings MD, Sorvillo F, Mascola L. Increase in Clostridium difficile-related mortality rates, Unites States 1999-2004. Emerg Infect Diseases [Internet]. 2007 [cited 2015 Feb 4]; 13(9): 1418-1419. Available from: http://wwwnc.cdc.gov/eid/article/13/9/pdfs/06-1116.pdf

16. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepin J, Wilcox MH. Clinical practice guidelines for clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA). Infect Control Hosp Epidemiol [Internet].2010 [cited 2015 Feb 4]; 31(5): 431-455. Available from: http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF_Library/cdiff2010a/pdf

17. Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, McFarland LV, Mellow M, Zuckerbraun BS. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J of Gastroenterol.2013; 108: 478-498. doi: 10.1038/ajg.2013.4.

18. Gao XW, Mubasher M, Fang CY, Reifer C, Miller LE. Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285oR for antibiotic-associated diarrhea and clostridium difficile-associated diarrhea prophylaxis in adult patients. Am J Gastroenterol.2010; 105: 1636-1641. doi:10.1039/qjt.2010.11.

19. Hickson M, D'Souza A, Muthu N, Rogers TR, Want S, Rajkumar C, Bulpitt CJ. Use of probiotics Lactobacillus preparation to prevent diarrhea associated with antibiotics: Randomized double blind placebo controlled trial. BMJ 2007; 335(7610): 1-5. doi:10.1136/bmj/39231.599815.55.

20. Klarin B, Wullt M, Palmquist I, Molin G, Larsson A, Jeppsson B. Lactobacillus plantarum 299v reduces colonization of Clostridium difficile in critically ill patients treated with antibiotics. Acta Anaesthesiol Scand.2008; 52: 1096-1102. doi: 10.1111/j.1399-6576.2008.01748.x.

21. Lahtinen SJ, Forssten S, Aakko J, Granlund L, Rautonen N, Salminen S, Viitanen M, Ouwehand AC. Probiotic cheese containing lactobacillus rhamnosus HN001 and Lactobacillus acidophilus NCFM modifies subpopulations of fecal lactobacilli and Clostridium difficile in the elderly. Age. 2011; 34(1): 133-143. doi: 10.1016/j.vaccine.2013.11.053.

22. Ouwehand AC, DongLian C, Weijian X, Stewart M, Ni J, Stewart T, Miller LE. Probiotics reduce symptoms of antibiotic use in a hospital setting: A randomized dose response study. Vaccine.2014; 32(4): 458-463. doi: 10.1016/j.vaccine.2013.11.053.

23. Plummer S, Weaver MA, Harries JC, Dee P, Hunter J. Clostridium difficile pilot study: Effects of probiotics supplementation on the incidence of C. difficile diarrhoea. Int Microbiol [Internet].2004 [cited 2015, Feb 4]; 7: 59-62. Available from: http://www.im.micorbios.org/25march04/09%20Plummer.pdf

24. Zaharoni H, Rimon E, Vardi H, Friger M, Bolotin A, Sharhar DR. Probiotics improve bowel movements in hospitalized elderly patients - the proage study. J Nutr Health Aging [Internet].2011 [cited 2014, Nov 11]; 15(3): 215-220. Available from: http://download.springer.com/static/pdf/510/art%253A10.1007%252Fs12603-010-0323-3.pdf?auth 66=1407891762_e1690f361794942900abcb4be7c130ae&ext=.pdf

doi: 10.11124/jbisrir-2015-2197 Page 85

Vernaya and McAdam 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 42 JBI Database of Systematic Reviews & Implementation Reports 2015;13(8) 79 - 91

25. Chatterjee S, Kar P, Das T, Ray S, Ganguly S, Rajendiran C, Mitra M. Randomized placebo-controlled double blind multicenter trial on efficacy and safety of Lactobacillus acidophilus LA-5 and Bifidobacterium BB-12 for prevention of antibiotic-associated diarrhoea. J Assoc Physicians India [Internet].2013 [cited 2012, Sep 5]; 61: 708-712. Available from: http://japi.org/october_2013/04_oa_randomised_placebo_controlled.html

26. Goldenberg JZ, Ma SSY, Saxton JD, Martzen MR, Vandvik PO, Thorlund K, Guyatt GH, Johnston BC. Probiotic for the prevention of Clostridium difficile-associated diarrhea in adults and children (Review). Cochrane Database of Systematic Reviews [Internet] 2013 [cited 2014 Dec 16]. Available from: http://onlinelibrary.wiley.com.samuelmerritt.idm.oclc.org/doi/10.1002/14651858.CD006095.pub3/p df

27. Nelson PA. Probiotics for treatment of Clostridium difficile-associated colitis in adults (Review). Cochrane Database of Systematic Reviews [Internet] 2008 [cited 2014, Sep 24]. Available from: http://onlinelibrary.wiley.com.samuelmerritt.idm.oclc.org/doi/10.1002/14651858.CD004611.pub2/p dfIn28. Naik P, Marshall B. Focus: Probiotics for prevention and adjunctive therapy. APUA Newsletter [Internet] 2012 [cited 2015, May 1]. Available from http://www.tufts.edu/med/apua/news/newsletter_29_1655861331.pdf

doi: 10.11124/jbisrir-2015-2197 Page 86

Vernaya and McAdam 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 43 JBI Database of Systematic Reviews & Implementation Reports 2015;13(8) 79 - 91

Appendix I: Appraisal instruments MAStARI appraisal instrument

doi: 10.11124/jbisrir-2015-2197 Page 87

Vernaya and McAdam 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 44 JBI Database of Systematic Reviews & Implementation Reports 2015;13(8) 79 - 91

doi: 10.11124/jbisrir-2015-2197 Page 88

Vernaya and McAdam 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 45 JBI Database of Systematic Reviews & Implementation Reports 2015;13(8) 79 - 91

doi: 10.11124/jbisrir-2015-2197 Page 89

Vernaya and McAdam 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 46 JBI Database of Systematic Reviews & Implementation Reports 2015;13(8) 79 - 91

Appendix II: Data extraction instruments MAStARI data extraction instrument

doi: 10.11124/jbisrir-2015-2197 Page 90

Vernaya and McAdam 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 47 JBI Database of Systematic Reviews & Implementation Reports 2015;13(8) 79 - 91

doi: 10.11124/jbisrir-2015-2197 Page 91

Vernaya and McAdam 2015

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 48 Papers identified from the search

Allen, S. J., et al. (2012). “A multicentre randomised controlled trial evaluating lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea in older people admitted to hospital: the PLACIDE study protocol.” BMC Infect Dis 12: 108. BACKGROUND: Antibiotic associated diarrhoea complicates 5-39% of courses of antibiotic treatment. Major risk factors are increased age and admission to hospital. Of particular importance is C. difficile associated diarrhoea which occurs in about 4% of antibiotic courses and may result in severe illness, death and high healthcare costs. The emergence of the more virulent 027 strain of C. difficile has further heightened concerns. Probiotics may prevent antibiotic associated diarrhoea by several mechanisms including colonization resistance through maintaining a healthy gut flora. METHODS: This study aims to test the hypothesis that administration of a probiotic comprising two strains of lactobacilli and two strains of bifidobacteria alongside antibiotic treatment prevents antibiotic associated diarrhoea. We have designed a prospective, parallel group trial where people aged 65 years or more admitted to hospital and receiving one or more antibiotics are randomly allocated to receive either one capsule of the probiotic or a matching placebo daily for 21 days. The primary outcomes are the frequency of antibiotic associated and C. difficile diarrhoea during 8-12 weeks follow-up. To directly inform routine clinical practice, we will recruit a sufficient number of patients to demonstrate a 50% reduction in the frequency of C. difficile diarrhoea with a power of 80%. To maximize the generalizability of our findings and in view of the well-established safety record of probiotics, we will recruit a broad range of medical and surgical in-patients from two different health regions within the UK. DISCUSSION: Antibiotic associated diarrhoea constitutes a significant health burden. In particular, current measures to prevent and control C. difficile diarrhoea are expensive and disrupt clinical care. This trial may have considerable significance for the prevention of antibiotic associated diarrhoea in hospitals.

Bakken, J. S. (2009). “Resolution of recurrent Clostridium difficile-associated diarrhea using staggered antibiotic withdrawal and kefir.” Minn Med 92(7): 38-40. Eight patients, each of whom experienced recurrent episodes of Clostridium difficile-associated diarrhea, were treated with staggered and tapered oral metronidazole or vancomycin combined with daily intake of kefir, an over-the-counter liquid probiotic dairy product. All eight successfully resolved their infection and did not experience any further diarrhea after completion of treatment. Further studies will be needed to determine whether gradual antibiotic withdrawal combined with kefir is a valuable treatment for recurrent C. difficile- associated diarrhea.

Bujanda, L. and A. Cosme (2009). “[Clostridium-difficile-associated diarrhea].” Gastroenterol Hepatol 32(1): 48-56. Clostridium difficile is the most frequent cause of nosocomial diarrhea and is a significant cause of morbidity among hospitalized patients. The inflammation is produced as a result of a non-specific response to toxins. In the last few years, a hypervirulent strain, NAP1/BI/027, has been reported. Symptoms usually consist of abdominal pain and diarrhea. The diagnosis should be suspected in any patient who develops diarrhea during antibiotic therapy or 6-8 weeks after treatment. Diagnosis should be confirmed by the detection of CD toxin in stool and by colonoscopy in special situations. The treatment of choice is metronidazole or vancomycin. In some patients who do not respond to this therapy or who have complications, subtotal colectomy may be required. Relapse is frequent and must be distinguished from reinfection. Prevention and control in healthcare settings requires careful attention.

Calder, P. and V. Hall (2012). “Understanding gut-immune interactions in management of acute infectious diarrhoea.” Nurs Older People 24(9): 29-37; quiz 38-29. This article discusses the role that immunity plays in the risk of diarrhoea and the potential role for probiotics in the management of acute infectious diarrhoea in older people, including antibiotic-associated diarrhoea and Clostridium difficile-associated diarrhoea.

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 49 Cohen-Bucay, A., et al. (2014). “Acute oxalate nephropathy associated with Clostridium difficile colitis.” Am J Kidney Dis 63(1): 113-118. We report the case of a 69-year-old man who presented with acute kidney injury in the setting of community- acquired Clostridium difficile-associated diarrhea and biopsy-proven acute oxalate nephropathy. We discuss potential mechanisms, including increased colonic permeability to oxalate. We conclude that C difficile- associated diarrhea is a potential cause of acute oxalate nephropathy.

Ehrhardt, S., et al. (2016). “Saccharomyces boulardii to Prevent Antibiotic-Associated Diarrhea: A Randomized, Double-Masked, Placebo-Controlled Trial.” Open Forum Infect Dis 3(1): ofw011. Background. Antibiotic-associated diarrhea (AAD) and Clostridium difficile-associated diarrhea (CDAD) are common complications of antibiotic use. Data on the efficacy of probiotics to prevent AAD and CDAD are unclear. We aimed to evaluate the efficacy of Saccharomyces boulardii to prevent AAD and CDAD in hospitalized adult patients. Methods. We conducted a multicenter, phase III, double-masked, randomized, placebo-controlled trial in hospitalized patients who received systemic antibiotic treatment in 15 hospitals in Germany between July 2010 and October 2012. Participants received Perenterol forte 250 mg capsules or matching placebo twice per day within 24 hours of initiating antibiotic treatment, continued treatment for 7 days after antibiotic discontinuation, and were then observed for 6 weeks. Results. Two thousand four hundred forty-four patients were screened. The trial was stopped early for futility after inclusion of 477 participants. Two hundred forty-six patients aged 60.1 +/- 16.5 years and 231 patients aged 56.5 +/- 17.8 were randomized to the S boulardii group and the placebo group, respectively, with 21 and 19 AADs in the respective groups (P = .87). The hazard ratio of AAD in the S boulardii group compared with the placebo group was 1.02 (95% confidence interval, .55-1.90; P = .94). Clostridium difficile-associated diarrhea occurred in 0.8% of participants (4 of 477). Nine serious adverse events were recorded in the S boulardii group, and 3 serious adverse events were recorded in the placebo group. None were related to study participation. Conclusions. We found no evidence for an effect of S boulardii in preventing AAD or CDAD in a population of hospitalized patients without particular risk factors apart from systemic antibiotic treatment. ClinicalTrials.gov Identifier. NCT01143272.

Gao, X. W., et al. (2010). “Dose-response efficacy of a proprietary probiotic formula of Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R for antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea prophylaxis in adult patients.” Am J Gastroenterol 105(7): 1636-1641. OBJECTIVES: Standard therapies for antibiotic-associated diarrhea (AAD) and Clostridium difficile-associated diarrhea (CDAD) have limited efficacy. Probiotic prophylaxis is a promising alternative for reduction of AAD and CDAD incidence. METHODS: In this single-center, randomized, double-blind, placebo-controlled dose-ranging study, we randomized 255 adult inpatients to one of three groups: two probiotic capsules per day (Pro-2, n=86), one probiotic capsule and one placebo capsule per day (Pro-1, n=85), or two placebo capsules per day (n=84). Each probiotic capsule contained 50 billion c.f.u. of live organisms (Lactobacillus acidophilus CL1285 +Lactobacillus casei LBC80R Bio-K+ CL1285). Probiotic prophylaxis began within 36 h of initial antibiotic administration, continued for 5 days after the last antibiotic dose, and patients were followed for an additional 21 days. RESULTS: Pro-2 (15.5%) had a lower AAD incidence vs. Pro-1 (28.2%). Each probiotic group had a lower AAD incidence vs. placebo (44.1%). In patients who acquired AAD, Pro-2 (2.8 days) and Pro-1 (4.1 days) had shorter symptom duration vs. placebo (6.4 days). Similarly, Pro-2 (1.2%) had a lower CDAD incidence vs. Pro-1 (9.4%). Each treatment group had a lower CDAD incidence vs. placebo (23.8%). Gastrointestinal symptoms were less common in the treatment groups vs. placebo and in Pro-2 vs. Pro-1. CONCLUSIONS: The proprietary probiotic blend used in this study was well tolerated and effective for reducing risk of AAD and, in particular, CDAD in hospitalized patients on antibiotics. A dose-ranging effect was shown with 100 billion c.f.u., yielding superior outcomes and fewer gastrointestinal events compared to 50 billion c.f.u. (ClinicalTrials.gov number NCT00958308).

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 50 Guo, B., et al. (2012). “Systematic review: faecal transplantation for the treatment of Clostridium difficile- associated disease.” Aliment Pharmacol Ther 35(8): 865-875. BACKGROUND: Management of recurrent Clostridium difficile-associated disease (CDAD), particularly in elderly patients, remains clinically challenging. Faecal transplantation (FT) may restore normal microbiota and break the cycle of recurrent CDAD. AIM: To critically appraise the clinical research evidence on the safety and effectiveness of FT compared with standard care in the treatment of patients with CDAD. METHODS: A comprehensive literature search was conducted by a research librarian to identify relevant studies published between 2000 and 2011. The Cochrane Library, PubMed, EMBASE, CINAHL, Biological Abstracts, BIOSIS Previews and Web of Science were searched using the following Medical Subject Headings (MeSH) terms and keywords, alone or in combination: Clostridium infections/Clostridium difficile/pseudomembranous/colitis/faeces/rectal/ colon flora/gastrointestinal/nasogastric tube/enema/donor/transplant/infusion/bacteriotherapy/human probiotic infusion. Methodological quality of the included case series studies was assessed in terms of patient selection criteria, consecutive recruitment, prospective data collection, reporting of lost to follow-up, and follow-up rates. RESULTS: No controlled studies were found. Based on the weak evidence from seven full-text case series studies of 124 patients with recurrent/refractory CDAD, FT appears to be a safe and effective procedure. In most cases (83%) symptoms improved immediately after the first FT procedure, and some patients stayed diarrhoea free for several months or years. CONCLUSIONS: Although these results appear to be promising, the treatment effects of faecal transplantation cannot be determined definitively in the absence of a control group. Results from randomised controlled trials that compare faecal transplantation to oral vancomycin without or with a taper regimen will help to better define the role of faecal transplantation in the management of recurrent CDAD.

Hautmann, M. G., et al. (2011). “Clostridium difficile-associated diarrhea in radiooncology: an underestimated problem for the feasibility of the radiooncological treatment?” Radiat Oncol 6: 89. BACKGROUND AND PURPOSE: Over the last years an increasing incidence of Clostridium difficile-associated diarrhea (CDAD) has been reported. Especially haematology-oncology patients are at risk of developing CDAD.The aim of this analysis is to determine the incidence of CDAD in radiooncological patients and to find out what relevance CDAD has for the feasibility of the radiooncological treatment, as well as to detect and describe risk factors. PATIENTS AND METHODS: In a retrospective analysis from 2006 to 2010 34 hospitalized radiooncological patients could be identified having CDAD. The risk factors of these patients were registered, the incidence was calculated and the influence on the feasibility of the radiooncological therapy was evaluated. Induced arrangements for prophylaxis of CDAD were identified and have been correlated with the incidence. RESULTS: The incidence of CDAD in our collective is 1,6%. Most of the patients suffering from a CDAD were treated for carcinoma in the head and neck area. Common risk factors were antibiotics, proton pump inhibitors, cytostatic agents and tube feeding.Beside a high rate of electrolyte imbalance and hypoproteinemia a decrease of general condition was frequent. 12/34 patients had a prolonged hospitalization, in 14/34 patients radiotherapy had to be interrupted due to CDAD. In 21 of 34 patients a concomitant chemotherapy was planned. 4/21 patients could receive all of the planned cycles and only 2/21 patients could receive all of the planned cycles in time.4/34 patients died due to CDAD. In 4/34 patients an initially curative treatment concept has to be changed to a palliative concept.With intensified arrangements for prophylaxis the incidence of CDAD decreased from 4,0% in 2007 to 0,4% in 2010. CONCLUSION: The effect of CDAD on the feasibility of the radiotherapy and a concomitant chemotherapy is remarkable. The morbidity of patients is severe with a high lethality.Reducing of risk factors, an intense screening and the use of probiotics as prophylaxis can reduce the incidence of CDAD.

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 51 Hebuterne, X. (2003). “Gut changes attributed to ageing: effects on intestinal microflora.” Curr Opin Clin Nutr Metab Care 6(1): 49-54. PURPOSE OF REVIEW: There is increased evidence of several impaired gastrointestinal functions with ageing. In the elderly, however, most gastrointestinal functions remain relatively intact because of the large reserve capacity of the intestine and the great secretion capacity of the pancreas. This review will focus on changes in gut microflora observed in the elderly and on the potential benefit of probiotics in this population. RECENT FINDINGS: Recent studies suggest that age affects the intestinal microflora with a decrease in anaerobes and bifidobacteria population and an increase in enterobacteria. These changes and the reduced intestinal immunity of the aged may favour gastrointestinal infections that are frequent in the elderly. Clostridium difficile- associated diarrhoea, one of the most common nosocomial infections in the elderly, has a profound effect on morbidity, mortality and health costs. Probiotics may have interesting positive effects on intestinal function, and the efficacy of treatment with Lactobacilli and Saccharomyces boulardii in Clostridium difficile-associated diarrhoea has been well established in a recent meta-analysis. Studies performed in healthy elderly patients suggest that diet supplementation with probiotics may reduce the impaired immunity associated with ageing. SUMMARY: Important changes in intestinal microflora of the elderly have recently been demonstrated and may have important clinical consequences. Further studies should be conducted to determine if the consumption of probiotics is associated with a lower infection rate and a higher effectiveness of vaccines.

Hickson, M., et al. (2007). “Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial.” BMJ 335(7610): 80. OBJECTIVE: To determine the efficacy of a probiotic drink containing Lactobacillus for the prevention of any diarrhoea associated with antibiotic use and that caused by Clostridium difficile. DESIGN: Randomised double blind placebo controlled study. PARTICIPANTS: 135 hospital patients (mean age 74) taking antibiotics. Exclusions included diarrhoea on admission, bowel pathology that could result in diarrhoea, antibiotic use in the previous four weeks, severe illness, immunosuppression, bowel surgery, artificial heart valves, and history of rheumatic heart disease or infective endocarditis. INTERVENTION: Consumption of a 100 g (97 ml) drink containing Lactobacillus casei, L bulgaricus, and Streptococcus thermophilus twice a day during a course of antibiotics and for one week after the course finished. The placebo group received a longlife sterile milkshake. MAIN OUTCOME MEASURES: PRIMARY OUTCOME: occurrence of antibiotic associated diarrhoea. Secondary outcome: presence of C difficile toxin and diarrhoea. RESULTS: 7/57 (12%) of the probiotic group developed diarrhoea associated with antibiotic use compared with 19/56 (34%) in the placebo group (P=0.007). Logistic regression to control for other factors gave an odds ratio 0.25 (95% confidence interval 0.07 to 0.85) for use of the probiotic, with low albumin and sodium also increasing the risk of diarrhoea. The absolute risk reduction was 21.6% (6.6% to 36.6%), and the number needed to treat was 5 (3 to 15). No one in the probiotic group and 9/53 (17%) in the placebo group had diarrhoea caused by C difficile (P=0.001). The absolute risk reduction was 17% (7% to 27%), and the number needed to treat was 6 (4 to 14). CONCLUSION: Consumption of a probiotic drink containing L casei, L bulgaricus, and S thermophilus can reduce the incidence of antibiotic associated diarrhoea and C difficile associated diarrhoea. This has the potential to decrease morbidity, healthcare costs, and mortality if used routinely in patients aged over 50. TRIAL REGISTRATION: National Research Register N0016106821.

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 52 Hood, K., et al. (2014). “Probiotics for Antibiotic-Associated Diarrhoea (PAAD): a prospective observational study of antibiotic-associated diarrhoea (including Clostridium difficile-associated diarrhoea) in care homes.” Health Technol Assess 18(63): 1-84. BACKGROUND: Antibiotic prescribing rates in care homes are higher than in the general population. Antibiotics disrupt the normal gut flora, sometimes causing antibiotic-associated diarrhoea (AAD). Clostridium difficile (Hall and O’Toole 1935) Prevot 1938 is the most commonly identified cause of AAD. Little is known either about the frequency or type of antibiotics prescribed in care homes or about the incidence and aetiology of AAD in this setting. OBJECTIVES: The Probiotics for Antibiotic-Associated Diarrhoea (PAAD) study was designed as a two-stage study. PAAD stage 1 aimed to (1) prospectively describe antibiotic prescribing in care homes; (2) determine the incidence of C. difficile carriage and AAD (including C. difficile-associated diarrhoea); and (3) to consider implementation challenges and establish the basis for a sample size estimation for a randomised controlled trial (RCT) of probiotic administration with antibiotics to prevent AAD in care homes. If justified by PAAD stage 1, the RCT would be implemented in PAAD stage 2. However, as a result of new evidence regarding the clinical effectiveness of probiotics on the incidence of AAD, a decision was taken not to proceed with PAAD stage 2. DESIGN: PAAD stage 1 was a prospective observational cohort study in care homes in South Wales with up to 12 months’ follow-up for each resident. SETTING: Recruited care homes had management and owner’s agreement to participate and three or more staff willing to take responsibility for implementing the study. PARTICIPANTS: Eleven care homes were recruited, but one withdrew before any residents were recruited. A total of 279 care home residents were recruited to the observational study and 19 withdrew, 16 (84%) because of moving to a non-participating care home. MAIN OUTCOME MEASURES: The primary outcomes were the rate of antibiotic prescribing, incidence of AAD, defined as three or more loose stools (type 5-7 on the Bristol Stool Chart) in a 24-hour period, and C. difficile carriage confirmed on stool culture. RESULTS: Stool samples were obtained at study entry from 81% of participating residents. Over half of the samples contained antibiotic- resistant isolates, with Enterobacteriaceae resistant to ciprofloxacin in 47%. Residents were prescribed an average of 2.16 antibiotic prescriptions per year [95% confidence interval (CI) 1.90 to 2.46]. Antibiotics were less likely to be prescribed to residents from dual-registered homes. The incidence of AAD was 0.57 (95% CI 0.41 to 0.81) episodes per year among those residents who were prescribed antibiotics. AAD was more likely in residents who were prescribed co-amoxiclav than other antibiotics and in those residents who routinely used incontinence pads. AAD was less common in residents from residential homes. CONCLUSIONS: Care home residents, particularly in nursing homes, are frequently prescribed antibiotics and often experience AAD. Antibiotic resistance, including ciprofloxacin resistance, is common in Enterobacteriaceae isolated from the stool of care home residents. Co-amoxiclav is associated with greater risk of AAD than other commonly prescribed antibiotics. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 7954844. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 63. See the NIHR Journals Library website for further project information.

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 53 Hopkins, M. J. and G. T. Macfarlane (2002). “Changes in predominant bacterial populations in human faeces with age and with Clostridium difficile infection.” J Med Microbiol 51(5): 448-454. The bacterial composition of human faeces can vary greatly with factors such as age and disease, although relatively few studies have monitored these events, particularly at species level. In this investigation, bacteria were isolated from faecal samples from healthy young adults and elderly subjects, and elderly patients with Clostridium difficile-associated diarrhoea (CDAD). The organisms were identified to species level on the basis of their cellular fatty acid profiles with the MIDI system. In some groups of bacteria, species diversity was found to change with age despite the overall numbers of organisms being similar at genus level. Bacteroides thetaiotaomicron, B. ovatus and Prevotella tannerae were common gram-negative anaerobes isolated from young adults. Bacteroides species diversity increased in the faeces of healthy elderly people. Bifidobacterial species diversity decreased with age, with Bifidobacterium adolescentis and Bif. angulatum being the most common isolates. CDAD patients were characterised by greater diversity of facultative species, lactobacilli and clostridia, but greatly reduced numbers of bacteroides, prevotella and bifidobacteria. Such bacterial population changes in the normal microbiota could result in metabolic conditions favourable for the establishment of pathogenic micro-organisms, such as clostridia, and would have considerable effects on the biochemical capacity of the large intestine as a whole. Alterations in the community structure of bifidobacteria and lactobacilli have relevance for dietary and therapeutic interventions such as the use of pre- or probiotics that aim to modify the composition or metabolic activities of the intestinal microflora in a beneficial way, particularly in elderly people or individuals at risk of CDAD.

Jia, J. S., et al. (2008). “[Relationship between Clostridium difficile associated diarrhea and intestinal microecosystem disorder in patients received allogeneic hematopoietic stem cell transplantation].” Zhongguo Shi Yan Xue Ye Xue Za Zhi 16(1): 135-139. This study was to investigate the relationship between Clostridium difficile associated diarrhea (CDAD) and intestinal microecosystem in patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to clarify clinical characteristics of intestinal microecosystem disorder. Clostridium difficile (CD) was isolated and identified by enzyme-linked-immunosorbent assay using clostridium difficile Premier toxins A&B Kit and anaerobic culture in 44 cases with diarrhea. Fecal flora (bifidobacteria, lactobacillus, bacteroides, peptostreptococcus, Clostridium perfringens, enterobacteriaceae, enterococcus, and yeasts) of patients were quantitatively and qualitatively analyzed by Mitsuoka’s methods. The results showed that CDAD occurred after using antibiotic or chemotherapy. Clostridium difficile was detected in 12 patients with diarrhea (positive rate was 27.27%). There was marked changes of intestinal microecosystem when patients suffered from CDAD. The number of lactobacillus, bifidobacteria, bacteroides, enterobacteriaceae and so on decreased significantly. It was effective to treat CDAD with vancomycin, metronidazole and probiotic, but the recurrence rate was 16.67%. In conclusion, CDAD complicated by allo-HSCT is related to change of intestinal microecosystem. While treating CDAD with the sensitive antibiotic, the intestinal flora of patients should be supported actively. This treatment contributes to improving disease status and reducing diarrhea recurrence.

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 54 Kamdeu Fansi, A. A., et al. (2012). “Savings from the use of a probiotic formula in the prophylaxis of antibiotic-associated diarrhea.” J Med Econ 15(1): 53-60. OBJECTIVE: Antibiotic-associated diarrhea (AAD) and particularly Clostridium difficile-associated diarrhea (CDAD) are the most common causes of healthcare associated infectious diarrhea. A double-blind, dose response, placebo-controlled trial of the probiotic formula (Bio-K+ Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R formula) for prophylaxis of AAD and CDAD was published in 2010. The Bio-K+ Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R formula is a registered trademark of Bio-K Plus International Inc. (Laval, Quebec, Canada). Results indicated that the incidence of AAD and CDAD were lower for patients assigned to the probiotic formula compared with the placebo option. The present study aims to estimate the savings in direct medical costs that might result from the use of two different doses of the probiotic formula vs placebo. METHODS: A cost-consequence analysis was conducted to compare the two doses of the probiotic formula compared to placebo. The analysis was based upon published data and adjusted to the North American context. RESULTS: Economic analyses showed that the use of the probiotic formula would result in estimated mean per patients savings of US$1968 for the single dose and US$2661 for the double dose compared with the placebo option if used an average of 13 days by all patients at risk of developing AAD and CDAD. LIMITATIONS: Several key parameters considered within the economic model were not captured within the Gao et al. study. Numerous sensitivity analyses were conducted to address this issue. CONCLUSION: The use of the probiotic formula in prophylaxis of AAD and CDAD would lead to estimated savings in direct medical costs that would substantially offset its acquisition cost. Treating 1000 hospitalized patients on antibiotics with the double dose of the product compared to current practice would save a single payer system the sum of $2,661,218.

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 55 Activity 7: Developing a protocol in JBI SUMARI

Logon to JBI SUMARI

Select [Protocol] underneath the title of your proposed review (undertaken in activity 3)

Continue developing your review protocol. The following sections should be completed: - Title - Authors/Reviewers - Background - Review Question - Inclusion Criteria (noting any exclusion criteria) - Study Types - Search Strategy - Study Selection

To add references/citations individually: Select [+] Add in the appropriate citation details

Select [Save]

To add references/citations via a reference management system (e.g. EndNote):

Select (next to the ‘+’ button)

Select the desired file from the designated location. Files need to be in XML format or they will not upload successfully. To do this in EndNote for example go to File->Export and select XML as ‘Save as type’. To add a citation into your protocol: Drag the selected reference to the selected spot within the text. The citation will automatically be numbered in order and will re-number itself if more references are added or removed or if it is moved.

Introduction to Evidence-based Healthcare and the Systematic Review of Evidence - Module 1 – Workbook 56