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Treatment of Depression in Schizophrenia: A Systematic Review and Meta-Analysis

Dr Rachel Upthegrove, Senior Clinical Lecturer, Department of Psychiatry, College of Medical and Dental Sciences. Angharad Gregory, Medical Student University of Birmingham Keywords: Schizophrenia, Psychosis, Depression, Antidepressant, Quality of life and Suicide. Background Co-morbid depression in schizophrenia is common, with prevalence rates reported from 25%(1) to 83%(2). The variation in prevalence is partly due to the challenge in distinguishing symptoms of a mood disorder from core negative symptoms in schizophrenia, for example, blunted affect and difficulty expressing emotion. The discrepancy is further attributed to insufficiency of current classification systems in diagnosing concurrent depression in schizophrenia. However, following results of recent epidemiological studies, the overall consensus is that depressive syndromes are present in 50% of individuals with schizophrenia.(3) Depressive symptoms in schizophrenia can occur in all phases of the illness and cause significant distress. The consequences of depression in schizophrenia are serious and include more frequent relapses(4), increased duration of illness (5) and high rate of substance abuse(6). Suicide is 13 times more likely in people with schizophrenia than in the general population(7). It has also been found that of those that commit suicide, 57% had also been depressed(8). In order to improve quality of life and reduce rates of suicide, effective treatment of depressive symptoms is needed. The optimal treatment approach for depression in schizophrenia is disputed. Guidelines on treatment recommendations from National Institute of Clinical Excellence (NICE)(9) and British Association for Psychopharmacology(10) are brief and without conclusion. NICE recommends Cognitive Behavioural Therapy to all people with schizophrenia or related psychoses but not specifically for concurrent depression(9). The literature on psychological intervention is modest. Most studies on psychological treatments have not investigated depression as a primary outcome or with well-validated scales(11). In terms of pharmacological therapy, in the early 2000’s there was hope that some of the newer atypical may be effective in ameliorating co-morbid depressive symptomatology(12, 13), particularly (14, 15) and (16, 17). However, a Cochrane review in 2008 (18) found no evidence to support atypical antipsychotics are any better than typical antipsychotics for treating depression in people with schizophrenia. The review was based on three extremely small, poorly reported, short studies, vulnerable to bias. The authors suggested practice at that time should be guided by evidence other than that derived from randomised trials.(18) The potential benefit of for co-morbid depression has not received the attention it warrants.(19) Early studies in the 90’s investigating the use of antidepressants, mainly , showed some significance in treating co-morbid depressive features (20, 21). However, there has since been minimal advancement. Whitehead et al (5) conducted a systematic review in 2002 identifying just 11 appropriate trials. The majority used tricyclic antidepressants, with one study investigating a selective .(22) In general, studies were small and of poor quality, with multiple methodological flaws including small sample size, inadequate description of allocation concealment, absent power calculations and multiple trials did not use an intention-to-treat analysis. (5) Although a subgroup analysis indicated some clinical benefit of antidepressants, drawing results from a small number of small trials is unreliable. Furthermore, it was impossible to investigate the likelihood of publication bias as another consequence of the limited trials in the review. To conclude, Whitehead (5) reported although the evidence suggests some clinical benefit of co-prescribing antidepressants in schizophrenia a fairer conclusion would be evidence at that time remains “unproven”. The review is now out of date and the need for a definitive answer regarding the use of antidepressant therapy persists. A substantial body of evidence suggests the use of antidepressant in schizophrenia is increasing.(23) It has been reported, antidepressants are prescribed for 11 to 43% of patients with schizophrenia (4). Notably, alongside depressive symptoms, they are also used to treat anxiety and negative symptoms. However, polypharmacy increases interactions and side effects. A number of case reports have shown concurrent use of selective serotonin reuptake inhibitors and new antipsychotics is associated with arrhythmias, prolonged QTc interval on electrocardiogram and orthostatic hypotension in patients with otherwise normal cardiovascular systems (24). Therefore, it is essential to determine if the use of antidepressants for depression is therapeutic or futile in order to prevent unnecessary harm. In summary, the evidence base for the regular co-pharmacy of antidepressants alongside antipsychotics in clinical practice is weak. Considering how frequently depression occurs as a discrete syndrome in schizophrenia, as well as being a significant mediator of disability and potentially leading to suicide, research into the role of antidepressant therapy is essential to establish adequately informed guidelines.(3) Aim The aim of the study is to conduct a systematic review and meta-analysis of the use of antidepressants as an adjunct to medication to treat depression in people with schizophrenia.

1 Objectives

 To synthesise evidence of the effectiveness of antidepressants for treatment of depression in people with schizophrenia  To estimate the aggregate effectiveness of antidepressants for treatment of depression in people with schizophrenia Setting This project is a systematic review therefore will be using published data, not specific to any location. Methods/Design A systematic review and meta-analysis will be conducted with outcomes reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (25). A PRISMA flow diagram will create a graphical representation of citations reviewed in the course of the systematic review (see Appendix 2). Data will be extrapolated and assessed using Cochrane tools for data extraction (26) and risk of bias (27), respectively. Selection Criteria (See Appendix 3 for inclusion criteria table/screening tool) 1. Types of Participants Participants will include any individual aged 18 years or older with schizophrenia or related psychosis; including schizoaffective disorder and psychotic disorder not otherwise specified (as diagnosed using International Classification Diseases-10) with a depressive episode (as assessed using a standardised rating scale or clinical interview). Studies including participants under 18 years old or with a primary diagnosis of organic brain disorder or bipolar disorder will be excluded from the systematic review. This is justified on the basis that depression experienced in these disorders would have a very different aetiology and would be managed differently to the focus of this review. 2. Types of Intervention Interventions used in included trials will take an antidepressant versus usual care or placebo approach. Any class of antidepressant: ; monoamine oxidase inhibitor; selective serotonin reuptake inhibitor or other type will be valid as per those published in the BNF (section 4.3).(28) Agents with only theoretical antidepressant properties never approved in any country for depression will be excluded. It is anticipated that all people in the study will be receiving antipsychotic medication and possibly an . All participants receive throughout the trial duration should be charted, monitored and reported. 3. Types of Outcome Primary Outcome: The primary outcome will be recovery from depression using dichotomous outcomes (depressed/ not depressed) provided by the authors. Continuous outcomes, showing change on standardised scales will also be included. Secondary Outcomes: These will include positive and negative symptoms of schizophrenia and quality of life, using any psychometrically validated scale both self-reported and clinician administered. Timing of Outcome Measures: It is anticipated the time points of measuring outcomes will vary. It may be necessary to group outcome measures into short-term, medium-term and long-term outcomes. For example, as guided by results of Whitehead et al (5), <6 weeks, <12 weeks and >12 weeks, respectively. 4. Types of Studies All appropriate randomised controlled trials or quasi-experimental studies will be included. Observational or qualitative studies will not be included. Search Methods and Identification of Studies The search strategy aims to find both published and unpublished studies to minimise chance of publication bias. 1. Electronic searches The following electronic bibliographic databases will be searched: The Cochrane Central Register of Controlled Trials; MEDLINE (1948 to present); EMBASE (1980 to present); CINAHL (1982 to present); PsycINFO (1967 to present) and Web of Science (1990 to present). The final search update will be 29th February 2015. (See Appendix 1 for MEDLINE search). The following limits will be set: 1. Randomised controlled trials (RCTs) or quasi-experimental studies, 2. English language studies only, 3. Any country, 4.Human studies only. Date restrictions will not be applied.

2 2. Citation Searching The reference lists of relevant papers for which the full text is obtained will be inspected for additional studies. All selected studies will be sought as citations on the Institute for Scientific Information database in order to identify more trials. 3. Gray Literature On going research will be identified using International Standardised Randomised Controlled Trial Number registry and the Turning Research Into Practice database until 29th February 2015. 4. Personal Contact Key authors in the field will be contacted to identify on going research and other potential sources of information. Search terms

See Appendix 1 for full search strategy. As example, keywords will include: [«Schizophreni*» OR «Schizoaffective» OR «Psychosis» OR «Psychoses»] AND [«Depress*» OR «Depressive disorder»] AND [«Antidepressant*» OR «Antidepressive*» OR «Tricyclic*» OR «Serotonin reuptake inhibitor» OR « Monoamine oxidase inhibitors»] Search strategies will be trialled and a search diary will be maintained listing combinations of terms used in each database. Data collection Selection of studies Once records have been identified through electronic databases and supplemented by hand searching, duplicates will be removed and titles and abstracts retrieved. A two stage screening process will be adopted. Initially, based upon titles and abstracts, researchers will exclude those not pertinent to the review. Two reviewers will complete this independently and in duplicate. An Excel spreadsheet will be used to record inclusion/ exclusion decisions, this will enable discrepancies between independent reviewers to be clearly documented. In the second stage, paper copies of relevant full publications will be obtained. Inclusion and exclusion criteria will be applied to the full articles to eliminate those studies that do not fulfil pre-specified criteria. (See Appendix 3 for selection tool). Discrepancies at any stage will be resolved in discussion between researchers with involvement of a third reviewer (RU) if necessary. Endnote X7 will be used to manage references. Data extraction The Cochrane Effective Practice and Organisation of Care Group’s data extraction form will be used to extract data from relevant studies (26) (See Appendix 4), following piloting and reviewing of at least two studies. Extracted information will include: study population, participant demographics and baseline characteristics, details of intervention and control conditions, study methodology, recruitment and drop out rates, outcomes and times of measurement, information for assessment of the risk of bias and variables related to study quality. The use of a standardised form ensures consistency in the style and order used to describe information for each included study. Should additional information be required for clarification, main authors will be contacted. Information on missing data and dropouts will be assessed and discussed. Extracting data before quality assessment ensures the researcher is blind to study quality and reporting is not biased.(29) Assessment of risk of bias in included studies The methodological quality of randomised studies will be assessed using the Cochrane’s Collaboration tool for assessing risk of bias(27) (See Appendix 5). After piloting the tool, the assessment will cover sequence generation, allocation concealment, baseline characteristics, blinding, completeness of outcome data, selective outcome reporting and other potential sources of bias. Each of these will be explicitly rated and graded as being low, high or uncertain risk of bias. Results of assessment of risk of bias will be presented in a table in which judgements for each element of bias are presented alongside descriptive justification. In the main review document this will be summarised in figure format (see Appendix 6). The risk of bias for non-randomised studies will be evaluated using the Cochrane Risk Of Bias Assessment Tool: for Non-Randomized Studies of Interventions(30). Two researchers will independently rate risk of bias of each paper and discrepancies resolved by consensus. Data analysis Before satisfying the assumption of homogeneity, it will be important to discern if participant characteristics, interventions and reporting of outcomes are similar across all trials and treatment effects are generally in the same direction. The heterogeneity of included studies will be assessed by visually inspecting forest plots and the use of Chi-squared and I2 statistics, then, if appropriate, results will be combined in a meta-analysis. If, however, significant heterogeneity is observed a narrative summary will be produced. An I2 value of >50% indicates significant heterogeneity.

3 Narrative synthesis Should a narrative synthesis be indicated, information will be additionally presented in tables to summarise characteristics and findings of the included studies. Tables will present information on methods, participants, clinical characteristics, interventions, outcomes and comments on methodological quality. The narrative synthesis will explore the relationship within and between the included studies. Quantitative synthesis If sufficient data are available and are of sufficient quality, a meta-analysis will be performed using Review Manager 5.3. Characteristics of the population, interventions and outcomes will be summarised using descriptive statistics. The risk difference will be used to analyse dichotomous outcomes (i.e. recovery from depression) with corresponding 95% confidence intervals. The number needed to treat will be obtained from the risk difference. For continuous outcomes it is anticipated different rating scales will be used, therefore standardised mean differences will be presented with corresponding 95% confidence intervals. For studies using the same unit of continuous outcome measure a pooled estimate will be presented. A fixed-effects model will be used in the absence of heterogeneity. In the case of significant heterogeneity a random-effects model will be utilised. Subgroup analyses will compare the magnitude of treatment effects based on: a) length of follow up: short follow up period versus long follow up, b) type of outcome reporting: clinician administered versus self-reported measures. Sensitivity analysis will be carried out for the primary outcome to explore the effects of addition or removal of lower quality studies. It is anticipated many issues suitable for sensitivity analysis will only be identified during the review process. However, trials that have not used a randomised controlled design with placebo control will be excluded. Additionally, those studies that did not utilise a core schizophrenia diagnosis in defining their population may be omitted, for example predominant inclusion of patients with schizoaffective disorder. During the course of the review, other influences of study design may be identified for sensitivity analysis. Finally, all studies will be entered into a funnel plot in an attempt to investigate the likelihood of overt publication bias. Following description of the evidence, and balance of benefits and harms, different actions will be highlighted with respect to the use of antidepressants in treating depression in schizophrenia. Ethical approval: A study of this nature does not require formal ethical approval. Procedure and Timetable Initial scoping of existing research supports the likelihood aims and objectives can be met within the specified four-month period. Results of a mock MEDLINE search and Whitehead et al’s (5) systematic review in 2002 demonstrate it is unlikely a burdensome number of studies will be obtained. Moreover, new studies have been identified that will assist achievement of research objectives. The schedule is summarised in the Gantt chart below. (See Appendix 7 for full schedule of review).

Week 18-25/01 01-15/02 22-29/02 07-14/03 21-28/03 04/04 11/04-09/05 Commencing Systematic search Screening papers Data extraction Quality Assessment Data synthesis Meta Analysis Write up

Resources and cost There will be no special resources required to carry out the review. Resources that may be necessary include help for library work, interlibrary loans, printing and photocopying. However, printing and photocopying is available free of cost from the University. A second author is required to assess studies for inclusion, assess risk of bias of included studies and check data entry and analyses. This will not require additional funding. The Review Manager software is also available without cost with the University. Statistical advice and support for synthesising results will be necessary. No further funding is anticipated. Acknowledgements Help and advice with statistics regarding meta-analyses from Dr Derek Kyte and Dr Deidre Lane is also acknowledged. Finally, Anita Phull, librarian at the Barberry Institute, is thanked for her assistance with literature search strategy development.

4 Lay Statement (192 words) Schizophrenia is a mental illness characterised by hallucinations, blunting of mood, disorganised thoughts and impaired attention and memory. Depression in patients with schizophrenia is common and causes great distress. As well as poorer functioning, substantial problems experienced include drug and misuse and increased risk of suicide. Clinicians commonly prescribe antidepressant therapy alongside anti-psychotics to treat depression, however at present research has not shown whether using antidepressants in schizophrenia improves patients’ mood. Previous studies have been small and of poor quality and need to be interpreted with caution. When combined with anti-psychotic medication, antidepressants can also cause serious side effects. Therefore, considering doctors are still prescribing these , further research is needed in this area. This review hopes to systematically identify all relevant studies that compare improvement in mood in patients who are taking antidepressants alongside antipsychotics with patients taking antipsychotics alone or a placebo (a substance that has no active drug) in people with schizophrenia and depression. It will then be possible to examine if antidepressants are effective in improving mood or other measures of quality of life. The studies will be compiled and their quality assessed to better inform guidelines.

5 References

1. Siris G, Bench C. Depression and schizophrenia. 2nd ed. Oxford; Blackwell Publishing (2003), pp. 142-167.

2. Hafner H, Maurer K, Trendler G, an der Heiden W, Schmidt M, Konnecke R. Schizophrenia and depression: challenging the paradigm of two separate diseases--a controlled study of schizophrenia, depression and healthy controls. Schizophrenia research. 2005;77(1):11-24.

3. Buckley PF, Miller BJ, Lehrer DS, Castle DJ. Psychiatric comorbidities and schizophrenia. Schizophrenia bulletin. 2009;35(2):383-402.

4. Lako IM, Taxis K, Bruggeman R, Knegtering H, Burger H, Wiersma D, et al. The course of depressive symptoms and prescribing patterns of antidepressants in schizophrenia in a one-year follow-up study. European psychiatry : the journal of the Association of European Psychiatrists. 2012;27(4):240-4.

5. Whitehead C, Moss S, Cardno A, Lewis G. Antidepressants for the treatment of depression in people with schizophrenia: a systematic review. Psychological medicine. 2003;33(4):589-99.

6. Addington J, Duchak V. Reasons for substance use in schizophrenia. Acta psychiatrica Scandinavica. 1997;96(5):329-33.

7. Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry. 2007;64(10):1123-31.

8. Roy A. Depression, attempted suicide, and suicide in patients with chronic schizophrenia. The Psychiatric clinics of North America. 1986;9(1):193-206.

9. National Institute Clinical Excellence. Psychosis and schizophrenia in adults: prevention and management [internet]. 2014 [Accessed 30/11/2015]. Available from: http://www.nice.org.uk/guidance/cg178/chapter/1- recommendations 10. British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology. 2011;0(0). 11. Bosanac P, Castle DJ. Schizophrenia and depression. The Medical journal of Australia. 2013;199(6 Suppl):S36-9.

12. Meltzer HY. Treatment of suicidality in schizophrenia. Annals of the New York Academy of Sciences. 2001;932:44-58; discussion -60.

13. Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A, et al. treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60(1):82-91.

14. Kinon BJ, Lipkovich I, Edwards SB, Adams DH, Ascher-Svanum H, Siris SG. A 24-week randomized study of olanzapine versus in the treatment of schizophrenia or schizoaffective disorder in patients with prominent depressive symptoms. Journal of clinical psychopharmacology. 2006;26(2):157-62.

15. Dollfus S, Olivier V, Chabot B, Deal C, Perrin E. Olanzapine versus in the treatment of post- psychotic depression in schizophrenic patients. Schizophrenia research. 2005;78(2-3):157-9.

16. Kasper S. Quetiapine is effective against anxiety and depressive symptoms in long-term treatment of patients with schizophrenia. Depression and anxiety. 2004;20(1):44-7.

17. Lee KU, Jeon YW, Lee HK, Jun TY. Efficacy and safety of quetiapine for depressive symptoms in patients with schizophrenia. Human psychopharmacology. 2009;24(6):447-52.

18. Furtado VA, Srihari V. Atypical antipsychotics for people with both schizophrenia and depression. The Cochrane database of systematic reviews. 2008(1):Cd005377.

6 19. Barnes TR. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. Journal of psychopharmacology (Oxford, England). 2011;25(5):567-620.

20. Siris S, Pollack S, Bermanzohn P, Stronger R. Adjunctive imipramine for a broader group of post-psychotic depressions in schizophrenia. Schizophrenia research. 2000;44(3):187-92.

21. Siris SG, Mason SE, Bermanzohn PC, Alvir JM, McCorry TA. Adjunctive imipramine maintenance in post- psychotic depression/negative symptoms. Psychopharmacology bulletin. 1990;26(1):91-4.

22. Mulholland C, Lynch G, King DJ, Cooper SJ. A double-blind, placebo-controlled trial of for depressive symptoms in patients with stable, chronic schizophrenia. Journal of psychopharmacology (Oxford, England). 2003;17(1):107-12.

23. Olfson M, Marcus SC, Pincus H, Zito JM, Thompson JW, Zarin DA. Antidepressant prescribing practices of outpatient psychiatrists. Archives of General Psychiatry. 1998;55(4):310-6.

24. Pacher P, Kecskemeti V. Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns? Current pharmaceutical design. 2004;10(20):2463-75.

25. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta- analyses: the PRISMA statement. Bmj. 2009;339:b2535.

26. Effective Practice and Organisation of Care (EPOC). Data Collection Form. EPOC Resources for review authors. Oslo: Norwegian Centre for the Health Services [internet]. 2013. [Accessed 30/11/2015]. Available from: http://epoc.cochrane.org/epoc-specific-resources-review-authors

27. Higgins JP AD, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne J. The Cochrane’s collaboration tool for assessing risk of bias in randomised trials. BMJ. 2011;343(5928).\ 28. Joint Formulary Committee. British National Formulary. 65th ed. London: BMJ Group and Pharmaceutical Press; 2013

29. Boland A, Cherry G and Dickson R. Doing a Systematic Review A Student's Guide. London: SAGE Publications; 2014 30. Sterne JAC, Higgins JPT, Reeves BC on behalf of the development group for ACROBAT-NRSI. A Cochrane Risk Of Bias Assessment Tool: for Non-Randomized Studies of Interventions (ACROBAT-NRSI), Version 1.0.0. [internet] 24 September 2014. [Accessed 03/12/2015]. Available from: http://www.riskofbias.info.

7 Appendices Contents 1. Example of MEDLINE search and literature search strategy Page 9 2. PRISMA Flow Chart Page 12 3. Inclusion criteria/Screening Tool Page 13 4. Cochrane Collaboration Data Extraction Form Page 14 5. Cochrane Collaboration Risk of Bias Tool Page 26 6. Figure Presentation of Risk of Bias Assessment Page 30 7. Gantt Chart Page 31

8 Appendix 1

Ovid MEDLINE 1980 to October 2015

1. (Schizophrenia OR psychosis OR psychoses).ti 2. PSYCHOTIC DISORDERS/ OR SCHIZOPHRENIA AND DISORDERS WITH PSYCHOTIC FEATURES/ OR exp SCHIZOPHRENIA/ 3. 1 OR 2 4. depress*.ti 5. DEPRESSIVE DISORDER/ OR DEPRESSIVE DISORDER, MAJOR/ OR DEPRESIVE DISORDER, TREATMENT-RESISTANT 6. 4 OR 5 7. exp ANTIDEPRESSIVE AGENTS/ OR exp ANTIDEPRESSIVE AGENTS, SECOND-GENERATION/ OR exp ANTIDEPRESSIVE AGENTS, TRICYCLIC/OR exp MONOAMINE OXIDASE INHIBITORS/ 8. (antidepressant* OR antidepressive* OR ssri* OR selective AND "serotonin reuptake inhibitor*" OR tricyclic*).ti 9. Amersergide OR OR Amitryptyline OR OR OR OR buproprion OR OR OR OR Clorgyline OR Clovaxamine OR OR OR OR OR Dothiepin OR OR OR OR OR OR OR ifoextine OR imipramine OR OR OR isocaroxazid OR levoprotiline OR OR maprotilne OR OR OR OR mainserin OR OR minapri OR OR OR OR OR OR OR oripipramol OR OR OR oxitriptan OR OR AND orpirlindole OR OR protryptyline OR OR rolipram OR rubidium OR sertraline OR OR OR OR tianepine OR OR taloxatone OR OR OR tripramine OR OR OR OR viqualine OR zimeldine).ti 10. 7 OR 8 OR 9 11. 3 AND 6 AND 10 12. (rct* OR (randomi* adj2 trial*) OR (randomi* adj2 stud*) OR (control* adj2 trial*) OR (control* adj2 stud*)).ti,ab 13. 11 AND 13 14. 14 [Limit to: (Language English) and (Age group Young Adult or Adult or Middle aged or Aged or Aged, 80 and over) and Humans]

9 Literature Search Strategy

Search terms (AND, OR, RCT* NOT) OR And truncation Randomi* adj2 trial* OR Randomi* adj2 stud* OR Control* adj2 trial* OR Control* adj2 stud* OR Singl* OR Doubl* OR Tripl* O Trebl* OR Trial OR Placebo)

AND Schizophreni* OR Schizoaffective OR Pyschosis OR Psychoses

AND Depress*

AND Antidepressant* OR Tricyclic* OR SSRI OR Monoamine oxidase inhibitor Databases searched Cochrane Central Register of Controlled Trials CINAHL (Cumulative Index to Nursing and Allied Health Literature) EMBASE MEDLINE Psycinfo Web of Science

Grey literature Clinical Trials: ISRCTN registry and TRIP database Date No date restrictions applied Language English language only Types of studies to be Randomised- controlled trials (RCTs) or quasi-experimental studies included

10 Inclusion criteria Participants 18 years and above With schizophrenia or related psychosis including schizoaffective disorder and psychotic disorder not otherwise specified, as diagnosed using any recognised diagnostic criteria With depression (as diagnosed using any recognised diagnostic criteria).

Exclusion criteria <18 years old Primary diagnosis of organic brain disorder or bipolar disorder

Types of intervention Antidepressant (any class)

Control condition Placebo or no intervention/ usual care

Types of Outcomes Primary Outcome: Depressive symptoms (dichotomised and continuous) Secondary Outcome: Positive and Negative Symptoms of schizophrenia, quality of life. Exclusion criteria Dissertations/thesis, studies not available in full text.

11 Appendix 2 PRISMA 2009 Flow Diagram

12 Appendix 3

Screening/Selection Tool Review question: What is the clinical effectiveness of antidepressants alongside antipsychotics to treat depression in schizophrenia? Inclusion criteria (based on PICOS)

Population= adult patients with schizophrenia and depression Intervention= antidepressant Comparator= placebo or usual care Outcomes= At least one of the following:  Recovery from depression/ change in depression on standardised scale  Positive and negative symptoms of schizophrenia  Quality of life Study design= RCT or quasi-experimental study

Effectiveness of antidepressants screening and selection tool Reviewer: Date: Author name: Year: Title: Journal: Population Include Exclude ☐Over 18 years of age + Schizophrenia or related ☐Under 18 psychoses (schizoaffective or psychotic disorder not ☐Bipolar Disorder otherwise specified) + depression ☐Organic Brain Disorder

Intervention Include ☐ Antidepressant

Comparator Include ☐Placebo ☐Usual care Outcomes Must include Exclude ☐Depressive symptoms ☐No depressive symptoms

May include ☐Positive and negative symptoms of schizophrenia ☐Quality of life measure

Study Design Include Exclude ☐Any trial type-RCT, quasi-experimental study ☐Not trial design ☐Dissertation/thesis

Overall decision ☐INCLUDED ☐EXCLUDED

Notes

13 Appendix 4 EPOC Data Extraction Form

Data collection form Intervention review – RCTs and non-RCTs

This form can be used as a guide for developing your own data extraction form. Sections can be expanded and added, and irrelevant sections can be removed. It is difficult to design a single form that meets the needs of all reviews, so it is important to consider carefully the information you need to collect, and design your form accordingly. Information included on this form should be comprehensive, and may be used in the text of your review, ‘Characteristics of included studies’ table, risk of bias assessment, and statistical analysis.

Notes on using a data extraction form:  Be consistent in the order and style you use to describe the information for each included study.  Record any missing information as unclear or not described, to make it clear that the information was not found in the study report(s), not that you forgot to extract it.  Include any instructions and decision rules on the data collection form, or in an accompanying document. It is important to practice using the form and give training to any other authors using the form.  You will need to protect the document in order to use the form fields (Tools / Protect document)

Review title or ID

Study ID (surname of first author and year first full report of study was published e.g. Smith 2001)

Report IDs of other reports of this study (e.g. duplicate publications, follow-up studies)

Notes:

1. General Information

1. Date form completed (dd/mm/yyyy) 2. Name/ID of person extracting data 3. Report title (title of paper/ abstract/ report that data are extracted from)

4. Report ID (if there are multiple reports of this study)

14 5. Reference details

6. Report author contact details 7. Publication type (e.g. full report, abstract, letter)

8. Study funding source (including role of funders)

Possible conflicts of interest (for study authors)

9. Notes:

2. Eligibility

Study Review Inclusion Criteria Location in text Characteristics (Insert inclusion criteria for each characteristic as Yes/ No / (pg & ¶/fig/table) defined in the Protocol) Unclear

10. Type of Randomised trial ... study

Non-randomised trial ...

Controlled before-after study  Contemporaneous data collection ...  At least 2 intervention and 2 control clusters Interrupted time series OR ... Repeated measures study ...

 At least 3 timepoints before and 3 after the intervention  Clearly defined intervention point Other design (specify): ...

11. Participants ...

12. Types of ... intervention 13. Types of outcome ... measures 14. Decision: ...

15. Reason for exclusion 16. Notes:

DO NOT PROCEED IF STUDY EXCLUDED FROM REVIEW

15 3. Population and setting

Description Location in text

Include comparative information for each group (i.e. intervention (pg & ¶/fig/table) and controls) if available

17. Population description (from which study participants are drawn)

18. Setting (including location and social context)

19. Inclusion criteria

20. Exclusion criteria

21. Method/s of recruitment of participants 22. Notes :

4. Methods

Descriptions as stated in report/paper Location in text

(pg & ¶/fig/table)

23. Aim of study

24. Design (e.g. parallel, crossover, non-RCT)

25. Unit of allocation (by individuals, cluster/ groups or body parts)

26. Start date

27. End date

28. Duration of participation (from recruitment to last follow-up)

29. Notes:

16 5. Risk of Bias assessment

See Chapter 8 of the Cochrane Handbook. Additional domains may be required for non-randomised studies.

Domain Risk of bias Support for Location in text judgement Low/ High/Unclear (pg & ¶/fig/table)

30. Random sequence generation ... (selection bias)

31. Allocation concealment (selection bias) ...

32. Blinding of participants Outcome group: and personnel ... All/ (performance bias)

Outcome group: (if required) ...

33. Blinding of outcome Outcome group: assessment ... All/ (detection bias)

Outcome group: (if required) ...

34. Incomplete outcome data (attrition bias) ...

35. Selective outcome reporting? ... (reporting bias)

36. Other bias ...

37. Notes:

6. Participants

Provide overall data and, if available, comparative data for each intervention or comparison group.

Description as stated in report/paper Location in text

(pg & ¶/fig/table)

38. Total no. randomised (or total pop. at start of study for NRCTs)

17 Description as stated in report/paper Location in text

(pg & ¶/fig/table)

39. Clusters (if applicable, no., type, no. people per cluster)

40. Baseline imbalances

41. Withdrawals and exclusions (if not provided below by outcome)

42. Age

43. Sex

44. Race/Ethnicity

45. Severity of illness

46. Co-morbidities

47. Other treatment received (additional to study intervention)

48. Other relevant sociodemographics 49. Subgroups measured

50. Subgroups reported

51. Notes :

7. Intervention groups

Copy and paste table for each intervention and comparison group

Intervention Group 1 Description as stated in report/paper Location in text

(pg & ¶/fig/table)

52. Group name

53. No. randomised to group (specify whether no. people or clusters)

18 Description as stated in report/paper Location in text

(pg & ¶/fig/table)

54. Description (include sufficient detail for replication, e.g. content, dose, components; if it is a natural experiment, describe the pre- intervention)

55. Duration of treatment period

56. Timing (e.g. frequency, duration of each episode)

57. Delivery (e.g. mechanism, medium, intensity, fidelity)

58. Providers (e.g. no., profession, training, ethnicity etc. if relevant)

59. Co-interventions

60. Economic variables (i.e. intervention cost, changes in other costs as result of intervention)

61. Resource requirements to replicate intervention (e.g. staff numbers, cold chain, equipment)

62. Notes:

8. Outcomes

Copy and paste table for each outcome.

Outcome 1 Description as stated in report/paper Location in text

(pg & ¶/fig/table)

63. Outcome name

19 Description as stated in report/paper Location in text

(pg & ¶/fig/table)

64. Time points measured (specify whether from start or end of intervention)

65. Time points reported

66. Outcome definition (with diagnostic criteria if relevant and note whether the outcome is desirable or undesirable if this is not obvious)

67. Person measuring/ reporting 68. Unit of measurement (if relevant)

69. Scales: upper and lower limits (indicate whether high or low score is good)

70. Is outcome/tool ... validated? Yes/No/Unclear

71. Imputation of missing data (e.g. assumptions made for ITT analysis)

72. Assumed risk estimate (e.g. baseline or population risk noted in Background)

73. Notes :

9. Results

Copy and paste the appropriate table for each outcome, including additional tables for each time point and subgroup as required.

For randomised or non-randomised trial - Dichotomous outcome Description as stated in report/paper Location in text

(pg & ¶/fig/table)

74. Comparison

75. Outcome

20 Description as stated in report/paper Location in text

(pg & ¶/fig/table)

76. Subgroup

77. Time point (specify whether from start or end of intervention)

78. Results Intervention Comparison Note whether: No. No. participants No. No. participants ... post-intervention OR events events

... change from baseline And whether

... Adjusted OR

...Unadjusted

79. Baseline data Intervention Comparison

No. No. participants No. No. participants events events

80. No. missing participants and reasons 81. No. participants moved from other group and reasons 82. Any other results reported 83. Unit of analysis (e.g. by individuals, health professional, practice, hospital, community)

84. Statistical methods used and appropriateness of these methods (e.g. adjustment for correlation)

85. Reanalysis ... required? Yes/No/Unclear (if yes, specify why, e.g. correlation adjustment)

86. Reanalysis ... possible? Yes/No/Unclear

87. Reanalysed results

88. Notes:

21 For randomised or non-randomised trial - Continuous outcome Description as stated in report/paper Location in text

(pg & ¶/fig/table)

89. Comparison

90. Outcome

91. Subgroup

92. Time point (specify whether from start or end of intervention)

93. Post-intervention or change from baseline? 94. Results Intervention Comparison Note whether: Mean SD (or No. Mean SD No. ... post- other participants participants intervention OR variance)

... change from baseline

And whether

... Adjusted OR

...Unadjusted

95. Baseline Intervention Comparison data Mean SD (or No. Mean SD No. other participants participants variance)

96. No. missing participants and reasons 97. No. participants moved from other group and reasons 98. Any other results reported 99. Unit of analysis (e.g. by individuals, health professional, practice, hospital, community)

22 Description as stated in report/paper Location in text

(pg & ¶/fig/table)

100. Statistical methods used and appropriateness of these methods (e.g. adjustment for correlation)

101. Reanalysis ... required? Yes/No/Unclear (if yes, specify why)

102. Reanalysis ... possible? Yes/No/Unclear

103. Reanalysed results 104. Notes :

For randomised or non-randomised trial - Other outcome Description as stated in report/paper Location in text

(pg & ¶/fig/table)

105. Comparison

106. Outcome

107. Subgroup

108. Time point (specify whether from start or end of intervention)

109. Type of outcome 110. Results Intervention SD (or other Control result SD (or other result variance) variance)

Overall results SE (or other variance)

111. No. participant Intervention Control

112. No. missing participants and reasons 113. No. participants moved from other group and reasons

23 Description as stated in report/paper Location in text

(pg & ¶/fig/table)

114. Any other results reported 115. Unit of analysis (e.g. by individuals, health professional, practice, hospital, community)

116. Statistical methods used and appropriateness of these methods 117. Reanalysis ... required? (if yes, specify why)

118. Reanalysis ... possible? 119. Reanalysed results 120. Notes :

10. Applicability

121. Have important ... populations been Yes/No/Unclear excluded from the study? (consider disadvantaged populations, and possible differences in the intervention effect)

122. Is the intervention ... likely to be aimed at Yes/No/Unclear disadvantaged groups? (e.g. lower socioeconomic groups)

123. Does the study ... directly address the Yes/No/Unclear review question? (any issues of partial or indirect applicability)

124. Notes :

11. Other information

Description as stated in report/paper Location in text

(pg & ¶/fig/table)

24 125. Key conclusions of study authors 126. References to other relevant studies 127. Correspondence required for further study information (what and from whom)

128. Further study information requested (from whom, what and when)

129. Correspondence received (from whom, what and when)

130. Notes :

25 Appendix 5 Cochrane Risk of Bias Tool

1 – Cochrane Collaboration’s Risk of Bias Tool Domain Support for judgement Review authors’ judgement

Selection bias Random sequence Describe the method used to generate the Selection bias (biased allocation generation allocation sequence in sufficient detail to allow to interventions) due to an assessment of whether it should produce inadequate generation of a comparable groups. randomised sequence. Allocation Describe the method used to conceal the Selection bias (biased allocation concealment allocation sequence in sufficient detail to to interventions) due to determine whether intervention allocations inadequate concealment of could have been foreseen in advance of, or allocations prior to assignment. during, enrolment. Performance bias Blinding of Describe all measures used, if any, to blind Performance bias due to participants and study participants and personnel from knowledge of the allocated personnel knowledge of which intervention a participant interventions by participants and Assessments should received. Provide any information relating to personnel during the study. be made for each main whether the intended blinding was effective. outcome (or class of outcomes) Detection bias Blinding of outcome Describe all measures used, if any, to blind Detection bias due to knowledge assessment outcome assessors from knowledge of which of the allocated interventions by Assessments should intervention a participant received. Provide any outcome assessors. be made for each main information relating to whether the intended outcome (or class of blinding was effective. outcomes) Attrition bias Incomplete outcome Describe the completeness of outcome data Attrition bias due to amount, data Assessments for each main outcome, including attrition and nature or handling of incomplete should be made for exclusions from the analysis. State whether outcome data. each main outcome (or attrition and exclusions were reported, the class of outcomes) numbers in each intervention group (compared with total randomized participants), reasons for attrition/exclusions where reported, and any re-inclusions in analyses performed by the review authors. Reporting bias Selective reporting State how the possibility of selective outcome Reporting bias due to selective reporting was examined by the review authors, outcome reporting. and what was found. Other bias Other sources of bias State any important concerns about bias not Bias due to problems not covered addressed in the other domains in the tool. elsewhere in the table. If particular questions/entries were pre- specified in the review’s protocol, responses should be provided for each question/entry.

2 – Criteria for judging risk of bias in the ‘Risk of bias’ tool RANDOM SEQUENCE GENERATION

26 Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence.

Criteria for a judgement of The investigators describe a random component in the sequence generation ‘Low risk’ of bias. process such as: Referring to a random number table; Using a computer random number generator; Coin tossing; Shuffling cards or envelopes; Throwing dice; Drawing of lots; Minimization*.

*Minimization may be implemented without a random element, and this is considered to be equivalent to being random. Criteria for the judgement The investigators describe a non-random component in the sequence generation of ‘High risk’ of bias. process. Usually, the description would involve some systematic, non-random approach, for example: Sequence generated by odd or even date of birth; Sequence generated by some rule based on date (or day) of admission; Sequence generated by some rule based on hospital or clinic record number.

Other non-random approaches happen much less frequently than the systematic approaches mentioned above and tend to be obvious. They usually involve judgement or some method of non-random categorization of participants, for example: Allocation by judgement of the clinician; Allocation by preference of the participant; Allocation based on the results of a laboratory test or a series of tests; Allocation by availability of the intervention. Criteria for the judgement Insufficient information about the sequence generation process to permit of ‘Unclear risk’ of bias. judgement of ‘Low risk’ or ‘High risk’. ALLOCATION CONCEALMENT Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment. Criteria for a judgement of Participants and investigators enrolling participants could not foresee assignment ‘Low risk’ of bias. because one of the following, or an equivalent method, was used to conceal allocation: Central allocation (including telephone, web-based and pharmacy-controlled randomization); Sequentially numbered drug containers of identical appearance; Sequentially numbered, opaque, sealed envelopes. Criteria for the judgement Participants or investigators enrolling participants could possibly foresee of ‘High risk’ of bias. assignments and thus introduce selection bias, such as allocation based on: Using an open random allocation schedule (e.g. a list of random numbers); Assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or nonopaque or not sequentially numbered); Alternation or rotation; Date of birth; Case record number; Any other explicitly unconcealed procedure. Criteria for the judgement Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’. This is

27 of ‘Unclear risk’ of bias. usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement – for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque and sealed. BLINDING OF PARTICIPANTS AND PERSONNEL Performance bias due to knowledge of the allocated interventions by participants and personnel during the study. Criteria for a judgement of Any one of the following: ‘Low risk’ of bias. No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken. Criteria for the judgement Any one of the following: of ‘High risk’ of bias. No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding. Criteria for the judgement Any one of the following: of ‘Unclear risk’ of bias. Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’; The study did not address this outcome. BLINDING OF OUTCOME ASSESSMENT Detection bias due to knowledge of the allocated interventions by outcome assessors. Criteria for a judgement of Any one of the following: ‘Low risk’ of bias. No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken. Criteria for the judgement Any one of the following: of ‘High risk’ of bias. No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; Blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding. Criteria for the judgement Any one of the following: of ‘Unclear risk’ of bias. Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’; The study did not address this outcome. INCOMPLETE OUTCOME DATA Attrition bias due to amount, nature or handling of incomplete outcome data. Criteria for a judgement of Any one of the following: ‘Low risk’ of bias. No missing outcome data; Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; Missing data have been imputed using appropriate methods.

28 Criteria for the judgement Any one of the following: of ‘High risk’ of bias. Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘As-treated’ analysis done with substantial departure of the intervention received from that assigned at randomization; Potentially inappropriate application of simple imputation. Criteria for the judgement Any one of the following: of ‘Unclear risk’ of bias. Insufficient reporting of attrition/exclusions to permit judgement of ‘Low risk’ or ‘High risk’ (e.g. number randomized not stated, no reasons for missing data provided); The study did not address this outcome. SELECTIVE REPORTING Reporting bias due to selective outcome reporting. Criteria for a judgement of Any of the following: ‘Low risk’ of bias. The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon). Criteria for the judgement Any one of the following: of ‘High risk’ of bias. Not all of the study’s pre-specified primary outcomes have been reported; One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; One or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; The study report fails to include results for a key outcome that would be expected to have been reported for such a study. Criteria for the judgement Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’. It is likely of ‘Unclear risk’ of bias. that the majority of studies will fall into this category. OTHER BIAS Bias due to problems not covered elsewhere in the table. Criteria for a judgement of The study appears to be free of other sources of bias. ‘Low risk’ of bias. Criteria for the judgement There is at least one important risk of bias. For example, the study: of ‘High risk’ of bias. Had a potential source of bias related to the specific study design used; or Has been claimed to have been fraudulent; or Had some other problem. Criteria for the judgement There may be a risk of bias, but there is either: of ‘Unclear risk’ of bias. Insufficient information to assess whether an important risk of bias exists; or Insufficient rationale or evidence that an identified problem will introduce bias.

29 Appendix 6 Example of ‘Risk of Bias Summary’ Figure

Example of a 'Risk of bias summary' Figure [internet]. 2015 Cited [28/11/2015]. Available from http://handbook.cochrane.org/chapter_8/figure_8_6_c_example_of_a_risk_of_bias_summary_figure.htm

30 Appendix 7

GANTT Chart for Review

Week Dec January February March April May Commencing Task: 7th 18th 25th 1st 8th 15th 22nd 29th 7th 14th 21st 28th 4th 11th 18th 25th 2nd 9th Protocol Submission Conduct search for published & unpublished studies Screening of abstracts and titles Screening full text articles

Searching citation list of full studies Final update of systematic search Data extraction Risk of bias assessment Synthesis and collation of results Statistical analysis- meta analysis Drafting write up Poster production Final draft and hand in

31