Cochrane Database of Systematic Reviews (Reviews) || Testosterone for schizophrenia

Testosterone for schizophrenia (Review)

Elias A, Kumar A

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2007, Issue 3

http://www.thecochranelibrary.com

Testosterone for schizophrenia (Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 DHEA + antipsychotics vs PLACEBO + antipsychotics (all short term), Outcome 1 Global

state: Average endpoint global impression (CGI, high=poor). . . . . . . . . . . . . . . . . . 21

Analysis 1.2. Comparison 1 DHEA + antipsychotics vs PLACEBO + antipsychotics (all short term), Outcome 2 Mental

state: 1a. General symptoms - average endpoint score (PANSS, high=poor). . . . . . . . . . . . . 22


state: 1b. General symptoms - average endpoint score (BPRS, high=poor). . . . . . . . . . . . . . 22


state: 2. Positive symptoms - average pre-crossover score (PANSS, high=poor). . . . . . . . . . . . 23


state: 3a. Negative symptoms not improved (SANS). . . . . . . . . . . . . . . . . . . . . 23


state: 3b. Negative symptoms - average pre-crossover score (PANSS, high=poor). . . . . . . . . . . . 24

Analysis 1.10. Comparison 1 DHEA + antipsychotics vs PLACEBO + antipsychotics (all short term), Outcome 10

Behaviour: Leaving the study early. . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Analysis 1.11. Comparison 1 DHEA + antipsychotics vs PLACEBO + antipsychotics (all short term), Outcome 11 Adverse

effects: 1a. Movement disorder - general symptoms - average score (SHRSEPS, high=poor). . . . . . . . 26


effects: 2a. Movement disorder - specific symptoms (SHRSEPS). . . . . . . . . . . . . . . . . 27


effects: 2b. Movement disorder - specfic symptoms - mean parkinsonism score (UKU, high = poor). . . . . 28

Analysis 1.16. Comparison 1 DHEA + antipsychotics vs PLACEBO + antipsychotics (all short term), Outcome 16 Quality

of life: 1a. Average score as rated by observer (QLS, high=good). . . . . . . . . . . . . . . . . 29

Analysis 1.17. Comparison 1 DHEA + antipsychotics vs PLACEBO + antipsychotics (all short term), Outcome 17 Quality

of life: 1b. Average score as rated by self (Q-LES-Q, high=good). . . . . . . . . . . . . . . . . 29

29ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iTestosterone for schizophrenia (Review)


[Intervention Review]

Testosterone for schizophrenia

Alby Elias1, Ajit Kumar2

1Jubilee Mission Medical College, Kerala, India. 2School of Medicine, University of Leeds, Leeds, UK

Contact address: Alby Elias, Jubilee Mission Medical College, Thrissur, Kerala, India. [email protected].

Editorial group: Cochrane Schizophrenia Group.

Publication status and date: Edited (no change to conclusions), published in Issue 2, 2012.

Review content assessed as up-to-date: 21 May 2007.

Citation: Elias A, Kumar A. Testosterone for schizophrenia. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD006197.

DOI: 10.1002/14651858.CD006197.pub2.


A B S T R A C T

Background

Recently, sex hormones such as estrogens and testosterone or its derivatives have been the focus of interest for treatment of persistent

symptoms associated with schizophrenia.

Objectives

To review the effects of dehydroepiandrosterone (DHEA)/testosterone as adjunctive therapy to standard antipsychotic drugs.

Search methods

We searched the Cochrane Schizophrenia Group Trials Register (January 2007).

Selection criteria

We included all clinical randomised trials comparing DHEA/testosterone plus standard antipsychotic treatment with standard treatment

alone.

Data collection and analysis

We independently selected studies and extracted data. For dichotomous data we calculated the relative risk (RR) and its 95% confidence

interval (CI) on an intention to treat basis, using a fixed effects model. We presented continuous data using the weighted mean difference

statistic, with a 95% confidence interval using a fixed effects model.

Main results

We found three relevant small, short trials (total n=126). Clinical Global Impression data were equivocal (n=27, 1 RCT, WMD -0.43

CI -0.9 to 0.1). Average total PANSS scores were not significantly different between the DHEA plus antipsychotic group and those

given antipsychotic drugs and placebo (n=82, 2 RCTs, WMD -4.16 CI -13.8 to 5.5). PANSS positive scores were equivocal (n=55, 1

RCT, WMD -1.00 CI -3.8 to 1.8). For negative symptoms binary SANS scale data favoured the DHEA plus antipsychotic group (n=

30, 1 RCT, RR 0.23 CI 0.1 to 0.6, NNT 2 CI 2 to 3) but PANSS negative scores were not significantly different between comparison

groups (n=55, 1 RCT, WMD -2.30 CI -6.4 to 1.8). About 17% of people left both groups early (n=64, 2 RCTs, RR 0.80 CI 0.3 to

2.4). St Hans Rating Scale data for extrapyramidal symptoms favoured the DHEA plus antipsychotic group (n=30, 1 RCT, WMD -

5.00 CI -8.8 to -1.2) but akathisia ratings were equivocal (n=34, 1 RCT, RR 2.67 CI 0.3 to 23.1). Ratings of parkinsonian movement

disorder differed within the same trial depending of the outcome scale used. Quality of life seemed unaffected by use of DHEA (n=55,

1 RCT, WMD 6.20 CI -1.4 to 13.8).

1Testosterone for schizophrenia (Review)


mailto:[email protected]

Authors’ conclusions

Results are inconclusive with most outcomes being either non-significant or producing contradictory findings. Currently, adjunctive

DHEA should remain an experimental treatment for people with schizophrenia.

P L A I N L A N G U A G E S U M M A R Y

Testosterone for schizophrenia

About 1% of people suffer from schizophrenia, a serious mental illness found in all societies and cultures. Many treatments options

are available to reduce the dramatic symptoms of this illness such as the false beliefs (delusions) and false or distorted perceptions

(hallucinations). Other symptoms, such as emotional withdrawal and apathy are also often seen with schizophrenia and seem less

responsive to treatment with antipsychotic drugs. In addition, some people continue to experience delusions and hallucinations despite

adequate use of antipsychotic drugs and often supplementary treatments are used. These supplementary treatments include sex hormones

such as estrogen and testosterone.

We reviewed the effects of dehydroepiandrosterone (DHEA)/testosterone as an adjunctive therapy to standard antipsychotic drugs

for people with schizophrenia and found three relevant small, short studies. All trials compared antipsychotic drugs plus DHEA with

antipsychotic drugs and placebo. Results are inconclusive, with most outcomes being either non-significant or contradictory and a

much larger, conclusive study should be undertaken. Currently however, people with schizophrenia should only agree to take this

experimental treatment within the context of a well designed experimental study. We found nothing in these studies to suggest that it

should be used in routine care.

B A C K G R O U N D

Schizophrenia is a serious mental illness found in all societies and

cultures with an almost equal incidence and prevalence of approx-

imately 1%. The definite cause or causes of schizophrenia is/are

not yet established but abnormalities of several neurotransmitters/

neuroreceptors have been implicated. Antipsychotic medication,

acting on these neuroreceptors, help most people with schizophre-

nia attain satisfactory results, especially with regard to the so-called

positive symptoms such as delusions, hallucinations and disor-

dered thinking (Joy 2002, Thornley 2002).

For negative symptoms, such as the poor volition and apathy that

are often are seen with schizophrenia, results produced by medica-

tions are far less evident (Crow 1980, Andreasen 1985, Carpenter

1994). New generation antipsychotic drugs, such as amisulpride,

olanzapine or risperidone, were purported to have changed this

but the evidence is not convincing (Duggan 2002, Kennedy 2002,

Mota Neto 2002). For some people with schizophrenia, even the

positive symptoms seem refractory to drug treatment. The drug

clozapine in particular is suggested as a treatment for problematic

refractory symptoms. However, clozapine is associated with agran-

ulocytosis and cardiac problems (Rivaz-Vasquez 2003). Many peo-

ple with schizophrenia have residual positive or negative symp-

toms, with figures ranging from 20-50% (Dilling 2000).

Supplementary treatments, adjuncts to standard care with an-

tipsychotic medication, have been used to help this group of

people. These include the sex hormones such as oestrogen and

testosterone. Recent investigations suggest certain abnormalities

of serum testosterone levels and its derivative dehydroepiandros-

terone (DHEA) in people with schizophrenia. As compared to

matched controls, people suffering from schizophrenia exhibit sig-

nificantly lower serum levels of oestradiol, oestrogen, testosterone

and free testosterone and abnormalities in cortisol/DHEA ratio

(Huber 2005, Taherianfard 2005, Silver 2005, Goyal 2004, Harris

2001, Ritsner 2005). Recent controlled trials suggest an efficacy

of DHEA augmentation for people with schizophrenia displaying

negative, depressive and anxiety symptoms (Strous 2003). There

is also one report that suggests that DHEA administration im-

proves extrapyramidal symptoms in schizophrenic patients being

treated with antipsychotic drugs (Nachshoni 2005). The findings

raise important issues regarding the role of neurosteroids in gen-

eral, and DHEA in particular, in the ongoing pharmacotherapy

of schizophrenia. Oestrogen is the focus of another sister review

but in this analysis we seek to find and assimilate the current best

evidence for the value of testosterone or its derivatives for treating

people with schizophrenia.

Technical background



Dehydroepiandrosterone (DHEA) is a steroid produced by adrenal

glands. It is secreted in small amounts by the testis and ovaries and

can be converted into testosterone. DHEA is available in the USA

as over the counter medication in 50 mg and 100 mg tablets.

O B J E C T I V E S

To review the effects of dehydroepiandrosterone (DHEA)/testos-

terone as an adjunctive therapy to standard antipsychotic drugs.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We included all relevant randomised controlled trials. Where a trial

was described as ’double-blind’, but it was implied that the study

was randomised, we included the trial in a sensitivity analysis. If

there was no substantive difference within primary outcomes (see

’types of outcome measures’) when these ’implied randomisation’

studies were added, then we included these in the final analysis.

If there was a substantive difference, we only analysed clearly ran-

domised trials and described the results of the sensitivity analysis

in the text. We excluded quasi-randomised studies, such as those

allocating by alternate days of the week.

Types of participants

We included people with schizophrenia defined and diagnosed by

the authors of the original studies by any criteria.

Types of interventions

1. Treatment with antipsychotic drugs plus DHEA: any dose and

route of administration.

2. Treatment with antipsychotic drugs plus any other form of

testosterone: any dose and route of administration.

3. Treatment with antipsychotic medication +/- placebo: any dose

and route of administration.

Types of outcome measures

We grouped outcomes into short term (up to 12 weeks), medium

term (13 to 26 weeks) and long term (over 26 weeks).

Primary outcomes

We selected relapse (as defined in the individual studies) as the

primary outcome measure but also highlighted adverse effects as

being of particular interest.

Secondary outcomes

1. Death - suicide and natural causes

2. Global state

2.1 Healthy days

2.2 No clinically important change in global state (as defined by

individual studies)

2.3 Average endpoint global state score

2.4 Average change in global state scores

3. Service outcomes

3.1 Hospitalisation

3.2 Time to hospitalisation

4. Mental state (with particular reference to the positive and neg-

ative symptoms of schizophrenia)

4.1 No clinically important change in general mental state

4.2 Average endpoint general mental state score

4.3 Average change in general mental state scores

4.4 No clinically important change in specific symptoms (positive

symptoms of schizophrenia, negative symptoms of schizophrenia,

depression, mania)

4.5 Average endpoint specific symptom score

4.6 Average change in specific symptom scores

5. General functioning

5.1 No clinically important change in general functioning

5.2 Average endpoint general functioning score

5.3 Average change in general functioning scores

5.4 No clinically important change in specific aspects of function-

ing, such as social or life skills

5.5 Average endpoint specific aspects of functioning, such as social

or life skills

5.6 Average change in specific aspects of functioning, such as social

or life skills

6. Behaviour

6.1 No clinically important change in general behaviour

6.2 Average endpoint general behaviour score

6.3 Average change in general behaviour scores

6.4 No clinically important change in specific aspects of behaviour

6.5 Average endpoint specific aspects of behaviour

6.6 Average change in specific aspects of behaviour

7. Adverse effects - general and specific

7.1 Average endpoint general adverse effect score

7.2 Average change in general adverse effect scores

7.3 Clinically important specific adverse effects

7.4 Average endpoint specific adverse effects

7.5 Average change in specific adverse effects

8. Engagement with services

9. Satisfaction with treatment



9.1 Leaving the studies early

9.2 Recipient of care not satisfied with treatment

9.3 Recipient of care average satisfaction score

9.4 Recipient of care average change in satisfaction scores

9.5 Carer not satisfied with treatment

9.6 Carer average satisfaction score

9.7 Carer average change in satisfaction scores

10. Quality of life

10.1 No clinically important change in quality of life

10.2 Average endpoint quality of life score

10.3 Average change in quality of life scores

10.4 No clinically important change in specific aspects of quality

of life

10.5 Average endpoint specific aspects of quality of life

10.6 Average change in specific aspects of quality of life

11. Economic outcomes

11.1 Direct costs

11.2 Indirect costs

12. Cognitive functioning

12.1 No clinically important change in cognitive functioning

12.2 Average endpoint cognitive functioning score

12.3 Average change in cognitive functioning scores

12.4 No clinically important change in specific aspects of cognitive

functioning

12.5 Average endpoint specific aspects of cognitive functioning

12.6 Average change in specific aspects of cognitive functioning

13. Leaving the study early

Search methods for identification of studies

Electronic searches

We searched The Cochrane Schizophrenia Group Trials Register

(January 2007) using the phrase:

[((*androsten* or dehydroepiand* or dehydroisoand* or DHEA*

or prasteron* or testoster*) in title, abstract and index fields in

REFERENCE) OR ((dehydroepiandrosterone or testosterone) in

interventions field in STUDY]

This register is compiled by systematic searches of major databases,

hand searches and conference proceedings (see Group Module).

Searching other resources

1. Reference lists

We inspected all references of articles selected for inclusion for

further relevant trials.

2. Personal contact

We contacted the first author of each included study for informa-

tion regarding unpublished trials.

3. The US Food and Drugs Administration website - http://

www.fda.gov.

We searched this site using the phrase ’*DHEA* or *dehy-

droepiandrosterone*.

Data collection and analysis

[For definitions of terms used in this and other sections, please

refer to the Glossary]

1. Study selection

We (AE, AK) independently inspected and selected all abstracts

identified by the search. Where disagreement occurred we resolved

this by discussion, or when doubt remained, we obtained the full

article for further inspection. If disagreement remained, we added

the article to the list of those awaiting assessment and contacted

the study authors for clarification.

2. Quality assessment

We assessed methodological quality of included trials using the

criteria described in the Cochrane Handbook (Higgins 2005).

This simple set of criteria is based on the evidence of a strong

association between overestimation of effect and poor concealment

of allocation (Schulz 1995) and is defined as follows:

A. Low risk of bias (adequate allocation concealment)

B. Moderate risk of bias (some doubt about the results)

C. High risk of bias (inadequate allocation concealment)

For the purpose of the analysis in this review, trials had to meet

criterion A or B of the handbook. We excluded trials not described

as randomised by the authors, and with no implication of ran-

domisation, and rated these as category C.

3. Data extraction

We (AE, AK) independently extracted data from selected trials.

Where disagreement occurred, we attempted resolution by discus-

sion. If doubt remained and further information was needed to

resolve the dilemma, we did not enter data, but contacted authors’

of the studies for clarification.

4. Data management

4.1 Intention to treat

For studies that do not specify the reasons for persons leaving the

study early (dropping out), we assumed that these people had no

change in their clinical outcome variables. A problem with in-

creasing drop-out rates in randomised trials on drug treatments

for schizophrenia has been reported (Wahlbeck 2001). Since there

is no evidence as to what degree of attrition makes a reasonable

analysis of the data impossible, all trials were eligible to be in-

cluded in the main analysis. We did not include outcomes if more

than 40% of people were not reported in the final analysis. We

tested, where possible, whether exclusion of outcomes with drop-

out rates higher than 40% significantly changed results of the pri-

mary outcomes in a sensitivity analysis. When insufficient data

were provided to identify the original group size (prior to people

leaving or being withdrawn from the study), we contacted trial au-

thors and, in the interim we assigned those trials to those ’awaiting

assessment’.

4.2 Crossover design



We expected that some trials would use a crossover design and, in

order to exclude the potential additive effect on these trials in the

second or subsequent stages, only data from the first stage were to

have been used.

4.3 Data types

Outcomes are assessed using continuous measures (for example

changes on a behaviour scale), categorical measures (for example,

one of three categories on a behaviour scale, such as ’little change’,

’moderate change’ or ’much change’) or dichotomous measures

(for example, either ’no important changes’ or ’important changes’

in a person’s behaviour). Currently RevMan does not support data

from more than two categories, so these data would only have been

presented in a table and not analysed.

4.3.1 Dichotomous data: Where possible, we made efforts to con-

vert outcome measures to dichotomous data. This may be done

by identifying cut off points on rating scales and dividing people

accordingly into ’clinically improved’ or ’not clinically improved’.

If authors of a study had used a predefined cut off point for de-

termining clinical effectiveness we accepted this. Otherwise it was

generally assumed that a 50% reduction of a scale (e.g. the Brief

Psychiatric Rating Scale - Overall 1962) or a rating of ’at least

much improved’ according to the Clinical Global Impression Scale

(Guy 1976) could be considered as a clinically significant response

(Leucht 2005a, Leucht 2005b).

For dichotomous outcomes, we estimated a relative risk (RR) with

the 95% confidence interval (CI) based on a fixed effects model. It

has been shown that RR is more intuitive (Boissel 1999) than odds

ratios and that odds ratios tend to be interpreted as RR by clinicians

(Deeks 2000). This misinterpretation then leads to an overestimate

of the effect. When data were statistically significant we calculated

the Number Needed to Treat (NNT) and/or the Number Needed

to Harm (NNH) as the inverse of the risk reduction.

4.3.2 Continuous data

Continuous data on outcomes in trials relevant to mental health

issues are often not normally distributed. To avoid the pitfall of

applying parametric tests to non-parametric data we applied the

following standards to continuous final value endpoint data before

inclusion: (a) standard deviations and means were reported in the

paper or were obtainable from the authors; (b) when a scale started

from zero, the standard deviation, when multiplied by two, should

be less than the mean (otherwise the mean is unlikely to be an

appropriate measure of the centre of the distribution - Altman

1996); In cases with data that are greater than the mean they were

entered into ’Other data’ table as skewed data. If a scale starts from

a positive value (such as PANSS, which can have values from 30 to

210) the calculation described above in (b) should be modified to

take the scale starting point into account. In these cases skewness

is present if 2SD>(S-Smin), where S is the mean score and Smin

is the minimum score.

For change data (mean change from baseline on a rating scale)

it is impossible to tell whether data are non-normally distributed

(skewed) or not, unless individual patient data are available. Af-

ter consulting the ALLSTAT electronic statistics mailing list, we

presented change data in RevMan graphs to summarise available

information. In doing this, we assumed either that data were not

skewed or that the analysis could cope with the unknown degree

of skew.

4.3.3 Final endpoint value versus change data

Where both final endpoint data and change data were available

for the same outcome category, we only presented final endpoint

data. We acknowledge that by doing this much of the published

change data may be excluded, but argue that endpoint data is more

clinically relevant and that if change data were to be presented

along with endpoint data, it would be given undeserved equal

prominence. We are contacting authors of studies reporting only

change data for endpoint figures.

4.3.4 Summary statistics: for continuous outcomes, we estimated

a weighted mean difference (WMD) between groups, again, using

a fixed effects model. Whenever possible we took the opportunity

to make direct comparisons between trials that had used the same

measurement instrument to quantify specific outcomes. Where

continuous data were presented from different scales rating the

same effect, we presented the data but did not attempt synthesis.

Intention-to-treat versus completer analyses: in the case of con-

tinuous data we assumed that often an intention-to-treat analysis

was not possible so we analysed data as they were presented in the

original publications.

4.4 Rating scales

A wide range of instruments are available to measure mental health

outcomes. These instruments vary in quality and many are not

valid, and are known to be subject to bias in trials of treatments

for schizophrenia (Marshall 2000). Therefore we only included

continuous data from rating scales if the measuring instrument

had been described in a peer-reviewed journal.

4.5 Cluster trials

Studies increasingly employ “cluster randomisation” (such as ran-

domisation by clinician or practice) but analysis and pooling of

clustered data poses problems. Firstly, authors often fail to account

for intra class correlation in clustered studies, leading to a “unit

of analysis” error (Divine 1992) whereby p values are spuriously

low, confidence intervals unduly narrow and statistical significance

overestimated. This causes type 1 errors (Bland 1997, Gulliford

1999).

Should clustering have not been accounted for in primary studies,

we would have presented the data in a table, with a (*) symbol

to indicate the presence of a probable unit of analysis error in

subsequent versions of this review we would have not sought to

contact first authors of studies to obtain intra-class correlation

co-efficients of their clustered data and to adjust for this using

accepted methods (Gulliford 1999). Where clustering could have

been incorporated into the analysis of primary studies, we would

have also presented these data as if from a non-cluster randomised

study, but adjusted for the clustering effect.

We would have sought statistical advice and would have been ad-



vised that the binary data as presented in a report should have

been divided by a “design effect”. This would have been calcu-

lated using the mean number of participants per cluster (m) and

the intraclass correlation co-efficient (ICC) [Design effect=1+(m-

1)*ICC] (Donner 2002). If the ICC would not have been reported

it would have assumed to be 0.1 (Ukoumunne 1999).

If cluster studies had been appropriately analysed taking into ac-

count intra-class correlation coefficients and relevant data docu-

mented in the report, synthesis with other studies would have been

possible using the generic inverse variance technique.

5. Heterogeneity

First of all, we considered all included studies within any compar-

ison to estimate clinical heterogeneity. Then we visually inspected

graphs to investigate the possibility of statistical heterogeneity. We

supplemented this, with, primarily, the I-squared statistic. This

provides an estimate of the percentage of inconsistency thought

to be due to chance. Where the I-squared estimate was greater

than or equal to 75% we interpreted this as evidence of high levels

of heterogeneity (Higgins 2003). On such occasions, reasons for

heterogeneity were sought, and if we found any clear reasons, we

excluded studies contributing to the heterogeneity and presented

their results separately. If we found no clear reasons we presented

all data together and commented on the heterogeneity within the

discussion.

6. Publication bias

Data from all included trials were entered into a funnel graph (trial

effect versus trial size or ’precision’) in an attempt to investigate

overt small study bias. We did not undertake a formal test of funnel

plot asymmetry (suggesting potential publication bias).

7. Sensitivity analysis

We hoped to examine whether exclusion of trials with attrition

rates higher than 40% led to a significant change in the primary

outcomes.

8. General

Where possible, we entered data in such a way that the area to

the left of the line of no effect indicated a favourable outcome for

DHEA/testosterone.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

For substantive descriptions of the studies, please see Included and

Excluded Studies tables.

1. Excluded studies

We excluded 15 studies. Two of these were not randomised (Shen

2001, Song 2002), and another two because they involved healthy

volunteers (Ishigooka 1991, von Bahr 1991). We excluded eight

studies because they did not use either DHEA or any other

form of testosterone (Brambilla 1979, Cotes 1978, Kinon 2006,

Knegtering 2004, Kulkarni 2002, Kulkarni 2005, Poyurovsky

2003, Rinieris 1988). Another study, Sackler 1951, used different

doses of testosterone and oestradiol but there was no concomitant

use of antipsychotic medication as required by the protocol. Ko

2006 and Strous 2006 did seem relevant but reported no usable

data.

2. Awaiting assessment

No studies are awaiting assessment.

3. Ongoing studies

We did not identify any ongoing trials.

4. Included studies

We identified three studies (six reports) that could be included. All

three were described as randomised. Ritsner 2006 was a crossover

trial. All three studies were also stated to be double blind.

4.1 Length of trials

All studies reported data for short-term follow-up (up to 12 weeks).

4.2 Participants

In total 126 people were involved in these trials, all of them com-

paring antipsychotic drugs and DHEA versus antipsychotic drugs

and placebo. Strous 2002 included people with a diagnosis of

schizophrenia. Nachshoni 2005 and Ritsner 2006 included peo-

ple with the diagnosis of either schizophrenia or schizoaffective

disorder. All three trials used DSM-IV as operational diagnostic

criteria. There were more men in these studies than women (81

men vs 35 women). Ritsner 2006 and Strous 2002 did not specify

sex distribution of seven and three participants respectively. The

age ranges across studies were between 19-64 years. None of the

three studies described participant’s severity of illness.

4.3 Setting

All studies were undertaken in Israel. Nachshoni 2005 and Strous

2002 were described as taking place in inpatient settings, whilst

Ritsner 2006 used both inpatient and outpatient settings.

4.4 Study size

Ritsner 2006 is the largest study with 62 people and Nachshoni

2005 34, and Strous 2002 only 30.

4.5 Interventions

The trialists administered DHEA in range of doses from 25 mg to

200 mg per day. None of the studies gave dose ranges for the an-

tipsychotic drugs used. Strous 2002 mentioned that haloperidol,

fluphenazine, zuclopenthixol, risperidone, olanzapine and cloza-

pine were used.

4.6 Outcomes

Despite having been undertaken in the same country and within a

few years of each other, all three trials used several scales, but there

did not seem to be much co-ordination of effort. Strous 2002 for

example, reported on global outcomes using several scales (CGI,

PANSS, SANS, HAM-A, HAM-D) to measure global clinical im-

provement in the short term. On the other hand, Ritsner 2006

used PANSS, ESRS, AIMS and Quality of Life scale. Nachshoni



2005 used BPRS scale to measure mental state. Data were reported

as continuous. All three studies reported usable data on adverse

effects. Both Nachshoni 2005 and Strous 2002 reported usable

data on participants leaving the study early.

4.6.1 Outcome scales: details of only the scales that provided usable

data are shown below. Reasons for exclusions of data are given

under ’Outcomes’ in the ’Included studies’ section.

4.6.1.1 Global state

4.6.1.1.1 Clinical Global Impression Scale - CGI Scale (Guy

1976)

Trialists used this to assess both severity of illness and clinical im-

provement. The CGI is a seven-point scoring system is usually

used with low scores showing decreased severity and/or overall im-

provement. Nachshoni 2005 and Strous 2002 reported data from

this scale for both severity of illness and improvement subscales.

4.6.1.2 Mental state scales

4.6.1.2.1 Brief Psychiatric Rating Scale - BPRS (Overall 1962)

This is used to assess the severity of abnormal mental state. The

original scale has 16 items, but a revised 18-item scale is commonly

used. Each item is defined on a seven-point scale varying from

’not present’ to ’extremely severe’, scoring from 0-6 or 1-7. Scores

can range from 0-126, with high scores indicating more severe

symptoms. Nachshoni 2005 reported data from this scale.

4.6.1.2.2 Positive and Negative Syndrome Scale - PANSS (Kay

1987)

This schizophrenia scale has 30 items, each of which can be de-

fined on a seven-point scoring system varying from 1 - absent to

7 - extreme. This scale can be divided into 3 sub-scales for mea-

suring the severity of general psychopathology, positive symptoms

(PANSS-P), and negative symptoms (PANSS-N). A low score in-

dicates lesser severity. Ritsner 2006 and Strous 2002 reported data

from this scale.

4.6.1.3 Adverse effects scales

4.6.1.3.1 Extrapyramidal Symptom Rating Scale - ESRS (

Chouinard 1980)

This consists of a questionnaire relating to parkinsonian symp-

toms (nine items), a physician’s examination for parkinsonism and

dyskinetic movements (eight items), and a clinical global impres-

sion of tardive dyskinesia. Ritsner 2006 reported data from this

scale.

4.6.1.3.2 UKU Side Effects Rating Scale - UKU-SERS (Lingjaerde

1987)

The UKU rates four major topics: psychological adverse effects (10

items), neurological adverse effects (8 items), autonomic adverse

effects (11 items) and other adverse effects (19 items). Each item

is defined by means of a four-point scale where zero means-not

or doubtfully present. Scoring range is 0-144. Nachshoni 2005

reported data from this scale.

4.6.1.3.3 The Sanct Hans rating scale - SHRS (Gerlach 1993)

The St. Hans Rating Scale (SHRS) is a multidimensional rat-

ing scale for the evaluation of neuroleptic-induced hyperkinesia,

parkinsonism, akathisia and dystonia. Nachshoni 2005 reported

data from this scale.

4.6.1.3.4 Abnormal Involuntary Movement Scale - AIMS (Guy

1976)

The Abnormal Involuntary Movement Scale has been used to

assess abnormal involuntary movements associated with antipsy-

chotic drugs, such as tardive dyskinesia and chronic akathisia, as

well as ’spontaneous’ motor disturbance related to the illness itself.

Tardive dyskinesia is a long-term, drug-induced movement disor-

der. However, using this scale in short-term trials may also be help-

ful to assess some rapidly occurring abnormal movement disorders

such as tremor. Scoring consists of rating movement severity in

the anatomical areas (facial/oral, extremities, and trunk) on a five

point scale (0-4). A low score indicates low levels of dyskinetic

movements. Ritsner 2006 reported data from this scale.

4.6.2 Redundant data

Enormous efforts were invested in studies rating and recording

data that are then reported in such a way as to render them of

no use to reviews such as this. Trialists often report continuous

measures of global, or mental state but without any variances.

4.6.3 Missing outcomes

We found no usable outcomes for the following categories: service

outcomes, engagement with services and satisfaction with treat-

ment. It is possible that there is a systematic bias in which data,

such as the simple binary outcome of death, are not reported con-

sistently or well.

4.6.4 Primary outcomes

Not one study reported our pre-stated primary outcome of relapse.

All other outcomes in this review were felt at the time of writing

the protocol, to be of secondary importance but we recognise that

they may be of primary interest to others.

Risk of bias in included studies

Three studies met the inclusion criteria for this review.

1. Randomisation

All three included studies were described as randomised.

Nachshoni 2005 and Strous 2002 reported using “random num-

ber generation”. None of the studies stated how allocation con-

cealment was conducted or ensured.

2. Blinding

All the included studies were described as “double blind” but fur-

ther information on blindness of raters was not available in any

trial.

3. Leaving the study early

Four participants in Nachshoni 2005 failed to complete the study.

Similarly seven patients were withdrawn from Strous 2002. The

reasons for leaving the studies early are inadequately reported. The

studies also did not clearly describe how they used data for people

who were lost to follow up. We found no reporting of attempts to

validate any assumptions by following up those who dropped out

early.

4. Data reporting



Overall, due to poor reporting we were unable to use all outcome

data. Findings presented as graphs, whether as percentiles or as

inexact p-values, are often of little use to a reviewer. Studies some-

times failed to provide standard deviations when reporting mean

changes. We are seeking further data from the first authors of rel-

evant trials.

4.1 Outcome measures.

They varied considerably across the studies. One study assessed

Clinical Global Impression (both severity and improvement)

(Strous 2002). For assessment of symptoms of schizophrenia

PANSS was the most common instrument that was used (Ritsner

2006, Strous 2002) but Nachshoni 2005 used BPRS for the same

purpose. Strous 2002 assessed negative symptoms of schizophre-

nia with SANS and depressive symptoms by HAM-D and anxiety

symptoms by HAM-A. Two studies reported data on leaving the

study early and the reasons for it (Nachshoni 2005, Strous 2002).

All three studies assessed adverse effects due to antipsychotic treat-

ment. However the instruments varied from study to study. They

included UKU scale for the side effect profile and St Hans Rating

Scale for extrapyramidal symptoms (SHRS) (Nachshoni 2005),

Extrapyramidal Symptom Rating Scale (ESRS) and AIMS (Ritsner

2006). Quality of life was examined in one study by the use of

Quality of Life Scale and self reported QOL and Satisfaction Ques-

tionnaire (Ritsner 2006).

5. Overall

All three studies were categorised as being prone to at least a mod-

erate degree of bias due to the poor reporting of allocation con-

cealment at the point of randomisation.

Effects of interventions

1. The search

We identified 21 citations from the search strategy, six of which

were relevant to the three trials we could include.

2. COMPARISON: DHEA + ANTIPSYCHOTIC versus

PLACEBO + ANTIPSYCHOTIC (only short term)

2.1 Global state

We found continuous Clinical Global Impression scale data

(Strous 2002) were equivocal for the outcomes of ’improvement’

(n=27, WMD -0.43 CI -0.9 to 0.1) and ’severity of illness’ (n=

27, WMD -0.33 CI -0.9 to 0.3) between those given the DHEA

antipsychotic combination and the control group given antipsy-

chotic and placebo. No other global state data were available for

analyses.

2.2 Mental state

2.2.1 General

We found average total PANSS data were not significantly differ-

ent between the DHEA plus antipsychotic group (n=82, 2 RCTs,

WMD -4.16 CI -13.8 to 5.5) and those given antipsychotic drugs

and placebo. Similarly we found BPRS total endpoint scores were

not significantly different between treatment groups (Nachshoni

2005, n=30, WMD -1.20 CI -8.8 to 6.4).

2.2.2 Specific symptoms

PANSS positive scores were equivocal (1 RCT, n=55, WMD -

1.00 CI -3.8 to 1.8). For negative symptoms we found more data.

Dichotomised SANS scale data from one small study (n=30) did

favour the DHEA plus antipsychotic group compared with the

antipsychotic plus placebo group (RR 0.23 CI 0.1 to 0.6, NNT 2

CI 2 to 3). PANSS negative scores, however, were not significantly

different between comparison groups (1 RCT, n=55, WMD -2.30

CI -6.4 to 1.8).

Authors of Strous 2002 kindly supplied scale-derived pre-crossover

data for depression and anxiety scores. Standard deviations are

wide, indicating skewed data, so we included these in ’other data

tables’. There are no clear differences between groups.

2.3 Leaving the study early

The number of people leaving the study early for any reason were

not significantly different between treatment groups (2 RCTs, n=

64, RR 0.80 CI 0.3 to 2.4). One of the studies reported attrition

due to uncooperativeness or getting worse (Strous 2002, n=30,

RR 0.20 CI 0.03 to 1.5).

2.4 Adverse events

2.4.1 General movement disorders

We found general movement disorders reported by Nachshoni

2005 using St Hans rating scale for extrapyramidal side effects

favoured the DHEA plus antipsychotic group (n=30, WMD -5.00

CI -8.8 to -1.2) compared with the antipsychotic plus placebo

group. Ritsner 2006 reported movement disorders by Abnormal

Involuntary Movements and Extrapyramidal Symptom Rating

Scales. These data were reported under ’other data’ table as vari-

ances were very wide. Nevertheless they show no difference be-

tween two treatment groups.

2.4.2 Specific movement disorders

2.4.2.1 Akathisia

We found no statistically significant differences between the

DHEA plus antipsychotic group and those given antipsychotic

and placebo (Nachshoni 2005, n=34, RR 2.67 CI 0.3 to 23.1).

Continuous data reported by Nachshoni 2005 were too skewed to

present graphically, although they did not indicate any difference

between groups.

2.4.2.2 Parkinsonism

We found no significant difference for the occurrence of parkin-

sonian movement disorder between treatment groups (Nachshoni

2005, n=34, RR 2.67 CI 0.3 to 23.1) when measured using the

Sanct Hans Rating Scale. However, Nachshoni 2005 also used the

UKU side effects rating scale, and we found measures of parkin-

sonism were significantly lower in the DHEA and antipsychotic

group (n=30, WMD -4.00 CI -7.5 to -0.6).

2.5 Quality of life

Ritsner 2006 (n=55) reported continuous data for the outcome

observer rated (n=55, WMD 6.20 CI -1.4 to 13.8) and self re-

ported quality of life scale (n=55, WMD 0.20 CI -0.2 to 0.6) but



we found no statistically significant differences between groups.

D I S C U S S I O N

1. The studies

Given the therapeutic interest in androgens as a treatment strategy

for schizophrenia is quite recent, the number of studies is limited.

It appears that almost all of these studies have been reported from

the same centre and by mostly by the same authors. We realise

that this is a new area and there may be a process of evolution of

the best way of undertaking trials and measuring outcomes, but it

was disappointing that the methods, especially the outcome scales,

were not more consistent.

1.1 Applicability of findings

All three studies were conducted in Israel. It is even feasible that

participants of these trials were the same.

All trials involved participants with little in the way of physical

and psychiatric co-morbidity and with well-defined schizophrenia

or schizoaffective disorder. Such people are important but are a

minority in everyday care, where the norm is to find people who

suffer from less well defined illnesses combined with problems

such as depression and substance misuse. This does not mean

that the data are impossible to apply to routine care but just that

the differences between the trial populations and those seen in

everyday practice should be acknowledged and the implications

of those differences on outcomes considered.

1.2 Limited data, confusing data

All included studies reported data only for the short term (less

than 12 weeks) but even then, the collection and quality of the

data reported was variable. For example, often mean figures were

reported without variances and in this way it was difficult to even

present the data. Outcomes were commonly reported using graphs

and p-values instead of tables and confidence intervals. The exces-

sive use of graphs did not allow us to acquire sufficient numbers

to calculate many measures of effectiveness.

Among the 13 groups of defined outcomes in our protocol, only

five were addressed by the studies. We found no data on relapse,

hospital and services outcomes, engagement with services, satis-

faction with treatment and economic outcomes. There was a lack

of information on outcomes that are clinically important such as

death, general functioning, behaviour, treatment and hospitalisa-

tion.

1.3 Quality of studies

We appreciate that studies in this population group bring unique

difficulties. However there were important methodological diffi-

culties with the trials and therefore any conclusions must be viewed

with caution.

2. COMPARISON: DHEA + ANTIPSYCHOTIC versus

PLACEBO + ANTIPSYCHOTIC (only short term)

The overall results after DHEA administration are variable de-

pending upon the particular outcome studied.

2.1 Global and mental state

We were only able to report Clinical Global Impression (CGI)

data (Strous 2002), from a single study with a sample of just 27

of the 30 participants. The results were non-significant and gave

no impression that they were likely to reach statistical significance

with a larger sample.

More results were available for mental state, but this was again

hampered by small sample sizes. The negative symptom score as-

sessed from the SANS scale produced a large treatment effect,

(NNT) of only two. This finding was not supported however,

when negative symptoms were assessed using the PANSS nega-

tive symptom score. Other mental state measures, PANSS total,

PANSS positive and BPRS total were not significantly different.

Overall, these limited results are insufficient to enable us to make

any firm conclusions.

2.2 Leaving the study early

Study attrition from two trials (n=64) did not reveal that DHEA

plus antipsychotic treatment was either more or less acceptable

to participants than antipsychotic drugs alone. When attrition

was categorised due to uncooperativeness or not improving this

also revealed no significant differences. Until larger studies are

conducted we cannot know if this outcome is reliable.

2.3 Adverse effects

These outcomes were also inconclusive. General movement disor-

ders, as reported by Nachshoni 2005 (n=30) favoured the DHEA

plus antipsychotic group but with such limited numbers of partici-

pants more robust data are needed. Parkinsonism measured by two

different scales show contradictory results. The dichotomous data

measured by St. Hans Rating Scale revealed no statistically signif-

icant difference between treatment groups. However, continuous

data for the same outcome recorded using UKU side effects rating

scale did favour the concomitant use of DHEA with antipsychotic

drugs. When it came to specific symptoms such as akathisia, no

significant differences were found. Other ratings of adverse effects

reported by Nachshoni 2005 and Ritsner 2006 were skewed and

problematic to interpret.

2.4 Quality of life

Only Ritsner 2006 reported continuous data for the outcome of

observer-rated and self-reported quality of life scale but did not

show any difference between DHEA and placebo groups. Use of

DHEA does not clearly hinder quality of life.



A U T H O R S ’ C O N C L U S I O N S

Implications for practice

1. For people with schizophrenia

There is insufficient evidence that use of DHEA with antipsy-

chotic drugs is associated with improvement in mental or global

functioning. Use of DHEA should only be agreed to in the context

of a randomised trial.

2. For clinicians

There is no evidence that DHEA use with antipsychotic drugs is

any better than use of antipsychotic drugs alone. Currently, this

treatment is experimental.

3. For managers/policy makers

There are no data on service outcomes and no medium or long

term data. Until these data become available it would be under-

standable if managers and policy makers continue to consider ad-

junctive DHEA to be supportable only within the context of an

evaluative study.

Implications for research

1. General

If the CONSORT recommendations (Moher 2001) had been

complied with much more data would have been available. Allo-

cation concealment is essential for the result of a trial to be con-

sidered valid and gives the assurance that selection bias is kept

to the minimum. Well-described and tested blinding could have

encouraged confidence in the control of performance and detec-

tion bias. It is also important to know how many, and from which

groups, people were withdrawn, in order to evaluate exclusion

bias. It would have been helpful if authors had presented data in

a useful manner which reflects association between intervention

and outcome, for example, relative risk, odds-ratio, risk or mean

differences, as well as raw numbers. Binary outcomes should be

calculated in preference to continuous results, as they are easier to

interpret. If p-values are used, the exact value should be reported.

2. Specific

If future trials are conducted these should not only be adequately

powered and long, but in our opinion should also adhere to a prag-

matic design in order to increase applicability. Methods should

involve adequate concealment of allocation and follow up. Par-

ticipants should be people recognisable in everyday life and not

those who are so strictly diagnosed as to render them unrecognis-

able to routine care. Interventions should involve standard doses

of DHEA and a control drug that is a real choice in the context of

the study. Outcomes should be measured over months rather than

weeks as this is the usual period a person would be asked to take

the drug. Rating scales need to be validated, clinically meaning-

ful, and outcomes pre-defined. Routine outcomes such as relapse,

employment, living independently, satisfaction with care, serious

or troubling adverse effects can all be easily recorded without the

use of scales. We have outlined such a design in Table 1.

A C K N O W L E D G E M E N T S

With thanks to Judy Wright, Jun Xia, Tessa Grant, John Rathbone

and Clive Adams of the Cochrane Schizophrenia Group, Univer-

sity of Leeds, Leeds, UK for their kind help.

R E F E R E N C E S

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Nachshoni 2005

Methods Allocation: randomised.

Blindness: double.

Duration: 1 week.

Design: single centre.

Country: Israel.

Participants Diagnosis: schizophrenia, paranoid, disorganised, residual, undifferentiated and schizoaffective disorder

(DSM-IV).

N=34.

Age: range 19-64 years.

Sex: 9 females, 25 males.

Inclusion criteria: aged 18-65 years; patients with any form of extrapyramidal symptoms.

Exclusion criteria: patients receiving steroids, pregnant, engaged in any substance abuse or with any

significant medical or neurological illness.

Setting: inpatient.

Interventions 1. DHEA + antipsychotic: dose DHEA 100 mg (50 mg 8 am & 8 pm). N=18.

2. Placebo + antipsychotic.N=16.

Outcomes Leaving the study early.

Mental state: BPRS.

Adverse effects: SHRSEPS.

Unable to use -

Blood DHEA level (no usable data).

Global state: CGI (no usable data).

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment? Unclear risk B - Unclear

Ritsner 2006


Blindness: double.

Duration: 12 weeks (6 weeks before crossover).

Design: crossover, multicentre.

Country: Israel.



Ritsner 2006 (Continued)

Participants Diagnosis: schizophrenia, paranoid, disorganised, catatonic and undifferentiated, schizoaffective disorder

(DSM-IV).

N=62.

Age: mean 36.4 years, range 20-53 years.

Sex: 14 female, 41 male, others not reported.

Inclusion criteria: aged 18-55 years, having DSM-IV criteria for chronic schizophrenia or schizoaffective

disorder, and ability and willingness to sign informed consent.

Exclusion criteria: any evidence of organic brain damage, mental retardation, major medical illness, alcohol

or drug abuse, prostate nodules or cancer, symptoms of benign prostatic hypertrophy, pregnancy, or any

history of breast or uterine illness.

Setting: inpatient and outpatient.

Interventions 1. DHEA + antipsychotic: dose DHEA 200 mg/day. N=31.

2. Placebo + antipsychotic. N=31.

Outcomes Before crossover.

Mental state: PANSS.

Adverse effects: ESRS, AIMS.

Quality of Life Scale.

Unable to use -

Visual & movement skills, attention & memory and executive function test (no usable data).

Serum hormone levels (no usable data).

Notes

Risk of bias



Strous 2002


Blindness: double.

Duration: 6 week.

Design: single centre.

Country: Israel.

Participants Diagnosis: schizophrenia, paranoid, disorganised, residual, undifferentiated. disorder (DSM-IV).

History: duration of illness more than two years.

N=30.

Age: mean 37.4 years, range 19-64 years.

Sex: 12 females, 15 males, others not reported.

Inclusion criteria: aged 18-70 years; duration of illness longer than 2 years; negative symptoms, a score of

at least 25 on the scale for the assessment of negative symptoms (SANS).

Exclusion criteria: patients with any significant (including prostate illness) or neurological illness, preg-

nant.



Strous 2002 (Continued)

Setting: inpatient.

Interventions 1. DHEA + antipsychotics*: dose DHEA 25 mg/day (8am) - 2 weeks, 50 mg/day, equally divided doses

(8 am & 8 pm) - next 2 weeks, 100 mg/day, equally divided doses (8 am & 8 pm) - next 2 weeks. N=15.

2. Placebo + antipsychotics*. N=15.

Outcomes Leaving the study early.

Global state: CGI.

Mental state: PANSS, SANS, HAM-D, HAM-A.

Adverse effects.

Unable to use -

Blood DHEA and DHEA-S level (no usable data).

Blood cortisol (no usable data).

Notes * clozapine, fluphenazine, haloperidol, olanzapine, risperidone, zuclopenthixol

Risk of bias



DHEA - Dehyroepiandrosterone

DHEA-S - Dehyroepiandrosterone-sulfated

Global state -

CGI - Clinical Global Impression

Mental state -

BPRS - Brief Psychiatric Rating Scale

HAM-D - Hamilton Scale for Depression

HAM-A - Hamilton Scale for Anxiety

PANSS - Positive and Negative Syndrome Scale

SANS - Scale for the Assessment of Negative Symptoms

Adverse events -

AIMS - Abnormal Involuntary Movement Scale

ESRS - Extrapyramidal Symptom Rating Scale

SHRSEPS - Sanct Hans rating scale for extra pyramidal syndromes

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Brambilla 1979 Allocation: randomisation not clear.

Participants: males with chronic hebephrenic schizophrenia.

Interventions: L-dopa, carbodopa including placebo versus L-dopa, carbodopa, imipramine including placebo

versus apomorphine including placebo versus L-dopa, carbodopa, apomorphine including placebo, no interven-



(Continued)

tion with DHEA or any other form of testosterone

Cotes 1978 Allocation: randomised.

Participants: people with acute schizophrenia.

Interventions: alpha flupenthixol versus beta flupenthixol versus placebo, no use of DHEA or any other form of

testosterone

Ishigooka 1991 Allocation: randomisation not clear.

Participants: healthy volunteers.

Kinon 2006 Allocation: randomised.

Participants: people with schizophrenia, schizophreniform disorder, or schizoaffective disorder.

Interventions: switching to olanzapine from conventional antipsychotics or risperidone, no use of DHEA or any

other form of testosterone

Knegtering 2004 Allocation: randomised.

Participants: people with psychotic disorder, schizophreniform disorder, schizophrenia, schizoaffective disorder.

Interventions: quetiapine versus risperidone, no use of DHEA or any other form of testosterone

Ko 2006 Allocation: randomised.

Participants: people with chronic schizophrenia.

Interventions: antipsychotics & testosterone versus antipsychotics & placebo.

Outcome: PANSS, SANS, Calgary depression scale for schizophrenia, extrapyramidal symptoms scale, serum

hormone levels, no usable data given

Kulkarni 2002 Allocation: randomised.

Participants: men with acute schizophrenia.

Intervention: antipsychotic and estradiol versus antipsychotic and placebo, no use of DHEA or any other form

of testosterone

Kulkarni 2005 Allocation: randomisation not clear.

Participants: women with schizophrenia.

Intervention: antipsychotic and transdermal estradiol versus antipsychotic and transdermal placebo, no use of

DHEA or any other form of testosterone

Poyurovsky 2003 Allocation: randomised.

Participants: people with schizophrenia.

Intervention: olanzapine and reboxetine versus olanzapine and placebo, no use of DHEA or any other form of

testosterone

Rinieris 1988 Allocation: randomised.

Participants: people with chronic (subchronic) paranoid schizophrenia.

Intervention: chlorpromazine versus chlorpromazine and trihexyphenidyl versus trihexyphenidyl, no use of

DHEA or any other form of testosterone

Sackler 1951 Allocation: randomised.

Participants: people with schizophrenia, psychosis, depression and manic-depressive disorder.

Intervention: different doses of testosterone + estradiol described as massive and submassive dosages for two

groups, no concomitant use of antipsychotics



(Continued)

Shen 2001 Allocation: not randomised.

Song 2002 Allocation: not randomised.

Strous 2006 Allocation: randomised.

Participants: people with chronic schizophrenia.

Interventions: olanzapine & DHEA versus olanzapine & placebo.

Outcome: PANSS, SANS, extrapyramidal symptoms scale, blood biochemistry, no useable data given

von Bahr 1991 Allocation: randomised.

Participants: healthy volunteers.

DHEA - dehydroepiandrosterone



D A T A A N D A N A L Y S E S

Comparison 1. DHEA + antipsychotics vs PLACEBO + antipsychotics (all short term)

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Global state: Average endpoint

global impression (CGI,

high=poor)

1 Mean Difference (IV, Fixed, 95% CI) Subtotals only

1.1 improvement 1 27 Mean Difference (IV, Fixed, 95% CI) -0.43 [-0.92, 0.06]

1.2 severity of illness 1 27 Mean Difference (IV, Fixed, 95% CI) -0.33 [-0.92, 0.26]

2 Mental state: 1a. General

symptoms - average endpoint

score (PANSS, high=poor)

2 82 Mean Difference (IV, Fixed, 95% CI) -4.16 [-13.78, 5.46]

3 Mental state: 1b. General


score (BPRS, high=poor)


4 Mental state: 2. Positive

symptoms - average

pre-crossover score (PANSS,

high=poor)


5 Mental state: 3a. Negative

symptoms not improved

(SANS)

1 30 Risk Ratio (M-H, Fixed, 95% CI) 0.23 [0.09, 0.57]

6 Mental state: 3b. Negative

symptoms - average

pre-crossover score (PANSS,

high=poor)


7 Mental state: 3c. Negative


score (SANS, high=poor,

skewed data)

Other data No numeric data

8 Mental state: 4. Depression

- average endpoint score

(HAM-D, high=poor, skewed

data)


9 Mental state: 5. Anxiety - average

endpoint score (HAM-A,

high=poor, skewed data)


10 Behaviour: Leaving the study

early

2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

10.1 reason not specified 2 64 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.26, 2.41]

10.2 due to uncooperativeness

or getting worse

1 30 Risk Ratio (M-H, Fixed, 95% CI) 0.2 [0.03, 1.51]

11 Adverse effects: 1a. Movement

disorder - general symptoms

- average score (SHRSEPS,

high=poor)

1 30 Mean Difference (IV, Fixed, 95% CI) -5.0 [-8.85, -1.15]



12 Adverse effects: 1b. Movement

disorder - general symptoms -

average scores (data skewed,

high=poor)


12.1 Abnormal Involuntary

Movement Scale - AIMS


12.2 Extrapyramidal

Symptom Rating Scale - ESRS


13 Adverse effects: 2a. Movement

disorder - specific symptoms

(SHRSEPS)

1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

13.1 akathisia 1 34 Risk Ratio (M-H, Fixed, 95% CI) 2.67 [0.31, 23.14]

13.2 parkinsonism 1 34 Risk Ratio (M-H, Fixed, 95% CI) 2.67 [0.31, 23.14]

14 Adverse effects: 2b. Movement

disorder - specfic symptoms

- mean parkinsonism score

(UKU, high = poor)

1 30 Mean Difference (IV, Fixed, 95% CI) -4.0 [-7.45, -0.55]

15 Adverse effects: 2c. Movement

disorder - specfic symptoms -

mean akathisia score (UKU,

data skewed, high=poor)


16 Quality of life: 1a. Average

score as rated by observer

(QLS, high=good)

1 55 Mean Difference (IV, Fixed, 95% CI) 6.20 [-1.37, 13.77]

17 Quality of life: 1b. Average

score as rated by self (Q-LES-Q,

high=good)

1 55 Mean Difference (IV, Fixed, 95% CI) 0.20 [-0.18, 0.58]



Analysis 1.1. Comparison 1 DHEA + antipsychotics vs PLACEBO + antipsychotics (all short term),

Outcome 1 Global state: Average endpoint global impression (CGI, high=poor).

Review: Testosterone for schizophrenia

Comparison: 1 DHEA + antipsychotics vs PLACEBO + antipsychotics (all short term)

Outcome: 1 Global state: Average endpoint global impression (CGI, high=poor)

Study or subgroup Treatment ControlMean

Difference WeightMean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

1 improvement

Strous 2002 15 3.4 (0.74) 12 3.83 (0.57) 100.0 % -0.43 [ -0.92, 0.06 ]

Subtotal (95% CI) 15 12 100.0 % -0.43 [ -0.92, 0.06 ]

Heterogeneity: not applicable

Test for overall effect: Z = 1.71 (P = 0.088)

2 severity of illness

Strous 2002 15 4.33 (0.61) 12 4.66 (0.88) 100.0 % -0.33 [ -0.92, 0.26 ]

Subtotal (95% CI) 15 12 100.0 % -0.33 [ -0.92, 0.26 ]



Test for subgroup differences: Chi2 = 0.07, df = 1 (P = 0.80), I2 =0.0%

-4 -2 0 2 4

Favours treatment Favours control




Outcome 2 Mental state: 1a. General symptoms - average endpoint score (PANSS, high=poor).



Outcome: 2 Mental state: 1a. General symptoms - average endpoint score (PANSS, high=poor)



Difference


Ritsner 2006 29 84.2 (20.7) 26 89.9 (21.9) 72.5 % -5.70 [ -17.00, 5.60 ]

Strous 2002 15 52.2 (21.8) 12 52.29 (25.9) 27.5 % -0.09 [ -18.43, 18.25 ]

Total (95% CI) 44 38 100.0 % -4.16 [ -13.78, 5.46 ]

Heterogeneity: Chi2 = 0.26, df = 1 (P = 0.61); I2 =0.0%


Test for subgroup differences: Not applicable

-100 -50 0 50 100



Outcome 3 Mental state: 1b. General symptoms - average endpoint score (BPRS, high=poor).



Outcome: 3 Mental state: 1b. General symptoms - average endpoint score (BPRS, high=poor)



Difference


Nachshoni 2005 15 21 (12.5) 15 22.2 (8.3) 100.0 % -1.20 [ -8.79, 6.39 ]

Total (95% CI) 15 15 100.0 % -1.20 [ -8.79, 6.39 ]




-100 -50 0 50 100





Outcome 4 Mental state: 2. Positive symptoms - average pre-crossover score (PANSS, high=poor).



Outcome: 4 Mental state: 2. Positive symptoms - average pre-crossover score (PANSS, high=poor)

Study or subgroup Treatment controlMean


Difference


Ritsner 2006 29 13 (4.9) 26 14 (5.5) 100.0 % -1.00 [ -3.77, 1.77 ]

Total (95% CI) 29 26 100.0 % -1.00 [ -3.77, 1.77 ]




-10 -5 0 5 10



Outcome 5 Mental state: 3a. Negative symptoms not improved (SANS).



Outcome: 5 Mental state: 3a. Negative symptoms not improved (SANS)

Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Strous 2002 3/15 15/15 100.0 % 0.23 [ 0.09, 0.57 ]

Total (95% CI) 15 15 100.0 % 0.23 [ 0.09, 0.57 ]

Total events: 3 (Treatment), 15 (Control)



0.01 0.1 1 10 100





Outcome 6 Mental state: 3b. Negative symptoms - average pre-crossover score (PANSS, high=poor).



Outcome: 6 Mental state: 3b. Negative symptoms - average pre-crossover score (PANSS, high=poor)

Study or subgroup treatment controlMean


Difference


Ritsner 2006 29 27.4 (7) 26 29.7 (8.3) 100.0 % -2.30 [ -6.38, 1.78 ]

Total (95% CI) 29 26 100.0 % -2.30 [ -6.38, 1.78 ]




-10 -5 0 5 10



Outcome 7 Mental state: 3c. Negative symptoms - average endpoint score (SANS, high=poor, skewed data).

Mental state: 3c. Negative symptoms - average endpoint score (SANS, high=poor, skewed data)

Study Treatment mean SD N

Strous 2002 DHEA 29.9 25.0 15

Strous 2002 Placebo 35.7 24.0 12


Outcome 8 Mental state: 4. Depression - average endpoint score (HAM-D, high=poor, skewed data).

Mental state: 4. Depression - average endpoint score (HAM-D, high=poor, skewed data)

Study Treatment Mean SD N

Strous 2002 DHEA 4.13 4.47 15





Outcome 9 Mental state: 5. Anxiety - average endpoint score (HAM-A, high=poor, skewed data).

Mental state: 5. Anxiety - average endpoint score (HAM-A, high=poor, skewed data)

Study Treatment Mean SD N

Strous 2002 DHEA 2.13 2.26 15



Outcome 10 Behaviour: Leaving the study early.



Outcome: 10 Behaviour: Leaving the study early



1 reason not specified

Nachshoni 2005 3/18 1/16 17.5 % 2.67 [ 0.31, 23.14 ]

Strous 2002 2/15 5/15 82.5 % 0.40 [ 0.09, 1.75 ]

Subtotal (95% CI) 33 31 100.0 % 0.80 [ 0.26, 2.41 ]


Heterogeneity: Chi2 = 2.04, df = 1 (P = 0.15); I2 =51%


2 due to uncooperativeness or getting worse

Strous 2002 1/15 5/15 100.0 % 0.20 [ 0.03, 1.51 ]

Subtotal (95% CI) 15 15 100.0 % 0.20 [ 0.03, 1.51 ]




0.01 0.1 1 10 100





Outcome 11 Adverse effects: 1a. Movement disorder - general symptoms - average score (SHRSEPS,

high=poor).



Outcome: 11 Adverse effects: 1a. Movement disorder - general symptoms - average score (SHRSEPS, high=poor)



Difference


Nachshoni 2005 15 21.5 (4.4) 15 26.5 (6.2) 100.0 % -5.00 [ -8.85, -1.15 ]

Total (95% CI) 15 15 100.0 % -5.00 [ -8.85, -1.15 ]




-10 -5 0 5 10



Outcome 12 Adverse effects: 1b. Movement disorder - general symptoms - average scores (data skewed,

high=poor).

Adverse effects: 1b. Movement disorder - general symptoms - average scores (data skewed, high=poor)

Study Group N Mean SD

Abnormal Involuntary Movement Scale - AIMS

Ritsner 2006 Treatment 29 1.1 2.8

Ritsner 2006 Control 26 0.8 2.3

Extrapyramidal Symptom Rating Scale - ESRS

Ritsner 2006 Treatment 29 4.0 6.8

Ritsner 2006 Control 26 5.5 8.5




Outcome 13 Adverse effects: 2a. Movement disorder - specific symptoms (SHRSEPS).



Outcome: 13 Adverse effects: 2a. Movement disorder - specific symptoms (SHRSEPS)



1 akathisia

Nachshoni 2005 3/18 1/16 100.0 % 2.67 [ 0.31, 23.14 ]

Subtotal (95% CI) 18 16 100.0 % 2.67 [ 0.31, 23.14 ]




2 parkinsonism

Nachshoni 2005 3/18 1/16 100.0 % 2.67 [ 0.31, 23.14 ]

Subtotal (95% CI) 18 16 100.0 % 2.67 [ 0.31, 23.14 ]




0.01 0.1 1 10 100





Outcome 14 Adverse effects: 2b. Movement disorder - specfic symptoms - mean parkinsonism score (UKU,

high = poor).



Outcome: 14 Adverse effects: 2b. Movement disorder - specfic symptoms - mean parkinsonism score (UKU, high = poor)



Difference


Nachshoni 2005 15 20.2 (4.4) 15 24.2 (5.2) 100.0 % -4.00 [ -7.45, -0.55 ]

Total (95% CI) 15 15 100.0 % -4.00 [ -7.45, -0.55 ]




-10 -5 0 5 10



Outcome 15 Adverse effects: 2c. Movement disorder - specfic symptoms - mean akathisia score (UKU, data

skewed, high=poor).

Adverse effects: 2c. Movement disorder - specfic symptoms - mean akathisia score (UKU, data skewed, high=poor)

Study Treatment N Mean SD

Nachshoni 2005 DHEA 15 1.1 2.6

Nachshoni 2005 Placebo 15 1.2 2.3




Outcome 16 Quality of life: 1a. Average score as rated by observer (QLS, high=good).



Outcome: 16 Quality of life: 1a. Average score as rated by observer (QLS, high=good)



Difference


Ritsner 2006 29 68.5 (13.1) 26 62.3 (15.3) 100.0 % 6.20 [ -1.37, 13.77 ]

Total (95% CI) 29 26 100.0 % 6.20 [ -1.37, 13.77 ]




-100 -50 0 50 100



Outcome 17 Quality of life: 1b. Average score as rated by self (Q-LES-Q, high=good).



Outcome: 17 Quality of life: 1b. Average score as rated by self (Q-LES-Q, high=good)



Difference


Ritsner 2006 29 3.5 (0.6) 26 3.3 (0.8) 100.0 % 0.20 [ -0.18, 0.58 ]

Total (95% CI) 29 26 100.0 % 0.20 [ -0.18, 0.58 ]




-1 -0.5 0 0.5 1




A D D I T I O N A L T A B L E S

Table 1. Suggested design of study

Type of study Patients Interventions Outcomes Notes

Allocation: ran-

domised, process clearly

described.

Blindness: double, and

tested.

Analyses: intention-to-

treat

Duration: 1 year follow-

up.

Design: parallel group.

Diagnosis: people with

schizophrenia or related

disorders with persis-

tant postive or negative

symptoms.

N=300.

Age: over 16 years of age.

Sex: men & women.

1. DHEA + antipsy-

chotic: dose DHEA 200

mg/day.

2. Placebo + antipsy-

chotic.

1. Service utilisation (e.g.

hospital admission, days

in hospital).

2. Mental state and be-

haviour (use appropri-

ate scales, and report

endpoint scores and val-

idated subscale scores

only).

3. Clinical global re-

sponse (e.g. relapse, leav-

ing the study early, end-

point score in global state

improvement).

4. Social functioning (e.

g. social impairment,

employment status, in-

dependent living; report

endpoint scores of scales

used).

5. Quality of life (e.

g. clinically inportant

change, report endpoint

scores of scale used).

6. Family outcome (e.g.

family burden, satisfac-

tion with care, ecomonic

outcomes/cost of care).

7. Satisfaction with treat-

ment

8. Adverse effects (e.g

clinically important gen-

eral adverse effects, mor-

tality, if scales are used re-

port endpoint scores)

Outcomes could be

grouped into

short term (up to 12

weeks)

medium term (13 to 26

weeks)

long term (over 26

weeks)



W H A T ’ S N E W

Last assessed as up-to-date: 21 May 2007.

Date Event Description

18 January 2012 Amended Contact details updated.

H I S T O R Y

Protocol first published: Issue 4, 2006

Review first published: Issue 3, 2007

Date Event Description

11 November 2009 Amended Contact details updated.

5 November 2008 Amended Converted to new review format.

21 May 2007 New citation required and conclusions have changed Substantive amendment

C O N T R I B U T I O N S O F A U T H O R S

Alby Elias - developed the protocol, selected studies, data extracted, analysed data and wrote the report.

Ajit Kumar - helped with the protocol, selected studies, data extracted, analysed data and wrote the report.

D E C L A R A T I O N S O F I N T E R E S T

Ajit Kumar - none known.

Alby Elias - none known.

S O U R C E S O F S U P P O R T



Internal sources

• Jubille Mission Medical College, Thrissur, Kerala, India.

External sources

• South Asian Cochrane Network, India.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Antipsychotic Agents [∗therapeutic use]; Chemotherapy, Adjuvant; Dehydroepiandrosterone [∗therapeutic use]; Randomized Con-

trolled Trials as Topic; Schizophrenia [∗drug therapy]; Testosterone [∗therapeutic use]

MeSH check words

Humans



Documents

Cochrane Database of Systematic Reviews (Reviews) || Testosterone for schizophrenia