Antidepressant Treatment of Depression in Schizophrenia: A ...€¦ · The optimal treatment approach for depression in schizophrenia is disputed. Guidelines on treatment recommendations

1

Antidepressant 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

antipsychotics may be effective in ameliorating co-morbid depressive symptomatology(12, 13)

, particularly olanzapine(14, 15)

and quetiapine

(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 antidepressants for co-morbid depression has not received the attention it warrants.(19)

Early studies in the 90’s investigating the use of tricyclic antidepressants, mainly imipramine, 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 serotonin reuptake inhibitor.

(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 medication 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 drug 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 antipsychotic medication to treat depression in people with schizophrenia.

2

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: tricyclic 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 anticholinergic. All medications 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 29

th 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.

3

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 29

th 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 I

2

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 I

2 value of >50% indicates significant heterogeneity.

4

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).

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.

Week Commencing

18-25/01 01-15/02 22-29/02 07-14/03 21-28/03 04/04 11/04-09/05

Systematic search

Screening papers

Data extraction

Quality Assessment

Data synthesis

Meta Analysis

Write up

5

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 alcohol 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 drugs, 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.

6

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. Clozapine 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 ziprasidone 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 risperidone 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.

7

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 sertraline 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.

8

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

9

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 Amineptine OR Amitryptyline OR Amoxapine OR Benactyzine OR Brofaromine OR

buproprion OR Butriptyline OR Cianopramine OR Citalopram OR Clorgyline OR Clovaxamine OR Demexiptiline OR Desipramine OR Dibenzepin OR Dimetacrine OR Dothiepin OR Doxepin OR ETOPERIDONE OR femoxetine OR fezolamine OR fluoxetine OR fluvoxamine OR ifoextine OR imipramine OR iprindole OR iproniazid OR isocaroxazid OR levoprotiline OR lofepramine OR maprotilne OR medifoxamine OR melitracen OR metapramine OR mainserin OR milnacipran OR minapri OR mirtazapine OR moclobemide OR nefazodone OR nialamide OR nomifensine OR nortriptyline OR oripipramol OR oxaflozane OR oxaprotiline OR oxitriptan OR paroxetine OR phenelzine AND orpirlindole OR propizepine OR protryptyline OR quinupramine OR rolipram OR rubidium OR sertraline OR setiptiline OR sibutramine OR teniloxazine OR tianepine OR tofenacin OR taloxatone OR tranylcypromine OR trazodone OR tripramine OR tryptophan OR venlafaxine OR viloxazine 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]

10

Literature Search Strategy

Search terms (AND, OR, NOT) And truncation

RCT* OR 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 included

Randomised- controlled trials (RCTs) or quasi-experimental studies

11

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.

12

Appendix 2

PRISMA 2009 Flow Diagram

13

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

☐Over 18 years of age + Schizophrenia or related

psychoses (schizoaffective or psychotic disorder not otherwise specified) + depression

Exclude

☐Under 18

☐Bipolar Disorder

☐Organic Brain Disorder

Intervention Include

☐ Antidepressant

Comparator Include

☐Placebo

☐Usual care

Outcomes Must include

☐Depressive symptoms

May include

☐Positive and negative symptoms of schizophrenia

☐Quality of life measure

Exclude

☐No depressive symptoms

Study Design Include

☐Any trial type-RCT, quasi-experimental study

Exclude

☐Not trial design

☐Dissertation/thesis

Overall decision ☐INCLUDED ☐EXCLUDED

Notes

14

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)

15

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

Characteristics

Review Inclusion Criteria

(Insert inclusion criteria for each characteristic as

defined in the Protocol)

Yes/ No /

Unclear

Location in text

(pg & ¶/fig/table)

10. Type of study

Randomised trial ...

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

16

3. Population and setting

Description

Include comparative information for each group (i.e. intervention

and controls) if available

Location in text

(pg & ¶/fig/table)

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:

17

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

Low/ High/Unclear

Support for

judgement

Location in text

(pg & ¶/fig/table)

30. Random sequence generation

(selection bias) ...

31. Allocation concealment (selection bias) ...

32. Blinding of participants and personnel

(performance bias) ...

Outcome group:

All/

(if required) ...

Outcome group:

33. Blinding of outcome assessment

(detection bias) ...

Outcome group:

All/

(if required) ...

Outcome group:

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)

http://www.mrc-bsu.cam.ac.uk/cochrane/handbook/index.htm#chapter_8/8_assessing_risk_of_bias_in_included_studies.htm

18


(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


(pg & ¶/fig/table)

52. Group name

53. No. randomised to group

(specify whether no.

people or clusters)

19


(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


(pg & ¶/fig/table)

63. Outcome name

20


(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


(pg & ¶/fig/table)

74. Comparison

75. Outcome

21


(pg & ¶/fig/table)

76. Subgroup

77. Time point (specify whether from

start or end of

intervention)

78. Results Note whether:

... post-intervention OR

... change from baseline

And whether

... Adjusted OR

...Unadjusted

Intervention Comparison

No.

events

No. participants No.

events

No. participants

79. Baseline data


No.

events

No. participants No.

events

No. participants

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?

(if yes, specify why, e.g.

correlation adjustment)

...

Yes/No/Unclear

86. Reanalysis possible?

...

Yes/No/Unclear

87. Reanalysed results

88. Notes:

22

For randomised or non-randomised trial - Continuous outcome


(pg & ¶/fig/table)

89. Comparison

90. Outcome

91. Subgroup


start or end of

intervention)

93. Post-intervention or change from baseline?

94. Results Note whether:

... post-

intervention OR

... change from

baseline

And whether

... Adjusted OR

...Unadjusted


Mean SD (or

other

variance)

No.

participants

Mean SD No.

participants

95. Baseline data


Mean SD (or

other

variance)

No.

participants

Mean SD No.

participants






practice, hospital,

community)

23


(pg & ¶/fig/table)


(e.g. adjustment for

correlation)


(if yes, specify why)

...

Yes/No/Unclear


...

Yes/No/Unclear


104. Notes:

For randomised or non-randomised trial - Other outcome


(pg & ¶/fig/table)

105. Comparison

106. Outcome

107. Subgroup


start or end of

intervention)

109. Type of outcome

110. Results Intervention

result

SD (or other

variance) Control result SD (or other

variance)

Overall results SE (or other variance)

111. No. participant Intervention Control



24


(pg & ¶/fig/table)




practice, hospital,

community)



(if yes, specify why)

...


...


120. Notes:

10. Applicability

121. Have important populations been excluded from the study?

(consider disadvantaged

populations, and possible

differences in the

intervention effect)

...

Yes/No/Unclear

122. Is the intervention likely to be aimed at disadvantaged groups?

(e.g. lower socioeconomic

groups)

...

Yes/No/Unclear

123. Does the study directly address the review question?

(any issues of partial or

indirect applicability)

...

Yes/No/Unclear

124. Notes:

11. Other information


(pg & ¶/fig/table)

25

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:

26

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 generation

Describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

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

Allocation concealment

Describe the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment.

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment.

Performance bias

Blinding of participants and personnel Assessments should be made for each main outcome (or class of outcomes)

Describe all measures used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. Provide any information relating to whether the intended blinding was effective.

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study.

Detection bias

Blinding of outcome assessment Assessments should be made for each main outcome (or class of outcomes)

Describe all measures used, if any, to blind outcome assessors from knowledge of which intervention a participant received. Provide any information relating to whether the intended blinding was effective.

Detection bias due to knowledge of the allocated interventions by outcome assessors.

Attrition bias

Incomplete outcome data Assessments should be made for each main outcome (or class of outcomes)

Describe the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. State whether attrition and exclusions were reported, the 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.

Attrition bias due to amount, nature or handling of incomplete outcome data.

Reporting bias

Selective reporting State how the possibility of selective outcome reporting was examined by the review authors, and what was found.

Reporting bias due to selective outcome reporting.

Other bias

Other sources of bias State any important concerns about bias not addressed in the other domains in the tool.

If particular questions/entries were pre-specified in the review’s protocol, responses should be provided for each question/entry.

Bias due to problems not covered elsewhere in the table.

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

RANDOM SEQUENCE GENERATION

27

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

Criteria for a judgement of ‘Low risk’ of bias.

The investigators describe a random component in the sequence generation 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 of ‘High risk’ of bias.

The investigators describe a non-random component in the sequence generation 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 of ‘Unclear risk’ of bias.

Insufficient information about the sequence generation process to permit judgement of ‘Low risk’ or ‘High risk’.

ALLOCATION CONCEALMENT

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment.


Participants and investigators enrolling participants could not foresee assignment 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.


Participants or investigators enrolling participants could possibly foresee 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

28

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.


Any one of the following:

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.



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.



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.



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.



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.



Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’;


INCOMPLETE OUTCOME DATA

Attrition bias due to amount, nature or handling of incomplete outcome data.



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.

29



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.



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);


SELECTIVE REPORTING

Reporting bias due to selective outcome reporting.


Any of the following:

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).



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.


Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’. It is likely that the majority of studies will fall into this category.

OTHER BIAS

Bias due to problems not covered elsewhere in the table.


The study appears to be free of other sources of bias.


There is at least one important risk of bias. For example, the study:

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.


There may be a risk of bias, but there is either:

Insufficient information to assess whether an important risk of bias exists; or

Insufficient rationale or evidence that an identified problem will introduce bias.

30

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

31

Appendix 7

GANTT Chart for Review

Week Commencing

Dec January February March April May

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

Documents

Antidepressant Treatment of Depression in Schizophrenia: A ...€¦ · The optimal treatment approach for depression in schizophrenia is disputed. Guidelines on treatment recommendations