Estrogen for schizophrenia

Wan Lian LC Chua; Angelica Izquierdo de Santiago; Jayashri Kulkarni; Ann Mortimer

doi:10.1002/14651858.CD004719.pub2

Estrógenos para la esquizofrenia

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Referencias

References to studies included in this review

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estudios excluidos
estudios en curso
otras referencias

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References to studies excluded from this review

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References to ongoing studies

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otras referencias

Kulkarni J. Three month double‐blind, randomized, three arm comparison of the effects of olanzapine plus adjunctive raloxifene, estradiol 2mg plus dyhydroprogesterone or placebo in 60 post‐menopausal women with schizophrenia. http://www.stanleyresearch.org/programs/trialGrants.htm#October20032004.

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos
estudios en curso

Glazer 1985

Methods	Allocation: randomised. Blindness: double blind for week 1‐3, thereafter open label with option to change treatments. Duration: interventions 3 weeks, followed up an additional month. Setting: outpatients tardive dyskinesia clinic. Consent: yes. Loss: described.
Participants	Diagnosis: tardive dyskinesia, 8/10 completers also had diagnosis of schizophrenia or schizoaffective disorder. N=12. Sex: female. Age: >45. Inclusion criteria: post‐menopausal >1 year. Exclusion criteria: received estrogen therapy in last 3 months, medical contraindications to estrogen therapy.
Interventions	1. Conjugated estrogen (Premarin): dose 1.25mg, oral. N=6. 2. Placebo. N=6. All continued with standard treatment including antipsychotic medication.
Outcomes	Adverse effects: AIMS. Leaving study early. Unable to use ‐ Mental state: BPRS (no numbers reported). Acceptability of treatment: (data from only one group reported). Adverse effects: Webster scale (no numbers reported). Physiological outcomes: serum estradiol and prolactin levels (not protocol outcome).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Good 1999

Methods	Allocation: randomised (in blocks of 2 and 4 by site). Blindness: double blind.* Duration: 6 months. Setting: outpatients, multicentre. Consent: yes. Loss: described.
Participants	Diagnosis: schizophrenia. N=14. Age: 40‐60 years. Sex: female. Inclusion criteria: At least 6 months amenorrhoea, serum FSH >40IU/L, currently receiving antipsychotic medication, regularly attending an outpatient psychiatric facility Exclusion criteria: disorders that may interfere with olfactory or cognitive function, baseline hypertension, use of HRT in the last 3 months, contraindications to the use of estrogen or progestin therapy.
Interventions	1. Estradiol (Estrace): dose 1 mg and medroxyprogesterone acetate (Provera): dose 2.5mg, oral. N=5. 2. Placebo. N=5. All continued with standard treatment including antipsychotic medication. Four patients from a single site had no treatment assignment recorded.
Outcomes	Mental state: PANSS. Leaving study early. Cognitive Function: BVRT, AVLT, COWA, design fluency test, UPSIT, finger tapping, grooved pegboard. Unable to use ‐ Global state: CGI and GAF (data incomplete).
Notes	* "Some patients may have been aware of status." ‐ Direct from Dr Good. No testing for double blindness was conducted. Treating gynaecologist and associated nurse not blind, raters were.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Kulkarni 1996

Methods	Allocation: randomised (using a randomly generated list of numbers). Blindness: open label but psychopathology rater was blind. Duration: 8 weeks. Setting: inpatient Consent: yes. Loss: none described.
Participants	Diagnosis: schizophrenia and related psychosis. N=18. Age: childbearing age. Sex: female. Inclusion: acutely psychotic, physically well and not on oral contraceptives. Exclusion: none specified.
Interventions	1. Ethinylestradiol: dose 0.02mg, oral, and antipsychotic medication. N=11. 2. Antipsychotic medication alone. N=7
Outcomes	Mental state: BPRS, SAPS and SANS. Leaving study early. Unable to use ‐ Physiological outcomes: serum hormone levels (not protocol outcome).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Kulkarni 2001

Methods	Allocation: randomised (allocated by giving each person identification number, this number was put into a computer that generated a "pseudo‐random" code determining group of allocation, only statistician and pharmacist could break code). Blindness: double blind (placebo controlled). Duration: 28 days. Setting: inpatient and outpatient. Consent: yes. Loss: none described.
Participants	Diagnosis: schizophrenia, schizophreniform or schizoaffective. N=36.* Age: childbearing age. Inclusion criteria: active phase of illness. Exclusion criteria: pregnant or lactating, known endocrine abnormalities, currently taking synthetic steroids (including OCP) or using illicit drugs.
Interventions	1. Estradiol: dose 50mcg per 24h, transdermal. N=12. 2. Estradiol: dose 100mcg per 24h, transdermal. N=12.** 3. Placebo. N=12. All continued with standard treatment including antipsychotic medication
Outcomes	Mental State: PANSS. Leaving the study early. Unable to use ‐ Physiological outcomes: serum hormone levels (not protocol outcome).
Notes	* Conference abstract 2001b describes identical trial with N=44. ** We used this group alone in the placebo comparison ‐ so N for results =24.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Louza 2004

Methods	Allocation: randomised. Blindness: double blind. Duration: 28 days (washout period of at least 3 days). Setting: inpatient , single centre. Consent: yes. Loss: described.
Participants	Diagnosis: active phase illness and met DSM IV criteria for schizophrenia. N= 42. Age: childbearing age. Sex: female. Inclusions: minimum score of 18 points in BPRS. Exclusions: estrogen dependent disease.
Interventions	1. Conjugated estrogen: 0.625mg, oral. N=21. 2. Placebo. N=19. All participants received a fixed dose of an antipsychotic, haloperidol 5mg daily. Anticholinergics (biperiden, up to 6mg/day PO) and benzodiazepines (diazepam up to 40mg/day PO) were allowed for extrapyramidal symptoms and agitation or insomnia.
Outcomes	Mental state: BPRS and NSRS. Leaving study early. Adverse effects: SAERS and UKU side effects rating scale. Unable to use ‐ Physiological outcomes: serum hormone levels (not protocol outcome). Simpson Angus Extrapyramidal Rating Scale and UKU side effects rating scale BPRS, Negative Symptoms Rating Scale,
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

AIMS ‐ Abnormal Involuntary Movements.
AVLT ‐ Rey Auditory Verbal Learning Test.
BPRS ‐ Brief Psychiatric Rating Scale.
BVRT ‐ Benton Visual Retention Test.
CGI ‐ Clinical Global Impression.
COWA ‐Controlled Oral Word Association.
GAF ‐ Global Assessment of Function.
PANSS ‐ Positive and Negative Symptom Scores.
SAPS ‐ Scale for Assessment of Positive Symptoms.
SANS ‐ Scale for Assessment of Negative Symptoms.
SAERS ‐ Simpson Angus Extrapyramidal Rating Scale
UKU ‐ side effects rating scale
UPSIT‐ University of Pennsylvania Smell Identification Test

Characteristics of excluded studies [ordered by study ID]

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estudios incluidos
estudios en curso

Study	Reason for exclusion
Bergemann 1999	Allocation: placebo controlled, double blind, cross‐over design. Participants: 46 pre‐menopausal, hyppoestrogenic women with schizophrenia, in "sufficient remission" ‐ a minimum of 6 weeks post acute episode. Intervention: estrogen and progestegen plus standard care vs standard care. Outcomes: helpful contact with author who provided paper accepted and pending publication, crossover data provided could not be used.
Chakos 1999	Allocation: randomised. Participants: women with schizophrenia. Intervention: estrogen plus standard treatment vs standard treatment alone. Outcomes: unknown, no data available, attempts to contact authors unsuccessful.
Godfrey 2002	Allocation: randomised. Participants: 2 pre‐menopausal women. Intervention: estrogen plus standard treatment vs standard treatment alone. Outcomes: unknown, no data kept, authors kindly replied.
Kim 1998	Allocation: unclear, "controlled trial" patients "divided" into treatment and non‐treatment groups. Participants: women with chronic schizophrenia. Intervention: estrogen plus standard care vs standard care. Outcomes: no usable data, attempted contact with authors unsuccessful.
Koller 1982	Allocation: unclear, "double blind crossover". Participants: people with diagnosis of movement disorder, tardive dyskinesia, Huntington's disease or dystonia. No specific diagnosis of schizophrenia. "Several patients with Huntington's disease and tardive dyskinesia were in receipt of neuroleptic medication". Interventions: estrogen plus standard treatment vs placebo plus standard treatment. Outcomes: abnormal movements and dyskinesia, no data at baseline before crossover, unable to distinguish which order individual participants had recieved the two intervention ‐ estrogen and placebo. Attempt to contact author unsuccessful.
Kulkarni 1999	Allocation: randomised. Participants:25 pre‐menopausal women with schizophrenia. Intervention: estrogen plus standard care vs standard care. Outcomes: conference proceeding, no data available, authors contacted and full publication pending.
Kulkarni 2002	Allocation: randomised. Participants:16 men with schizophrenia. Intervention: estrogen plus standard care vs standard care. Outcomes: conference proceeding, no usable data available, authors contacted and full publication pending.
Kulkarni 2003a	Allocation: randomised. Participants: >62 pre‐menopausal women with schizophrenia. Intervention: estrogen plus standard care vs standard care. Outcomes: conference proceeding, no data available, authors contacted and full publication pending.
O' Connor 1983	Allocation: randomised, crossover. Participants: 3 men with schizophrenia and violent behaviour. Intervention: depo‐medroxyl progesterone acetate vs water, no estrogen.
Purdie 2000	Allocation: randomised. Participants: post‐menopausal women with schizophrenia. Intervention: hormone replacement therapy plus standard care vs standard care. Outcomes: trial abandoned, no people recruited, author contacted and kindly replied.
Sackler 1951	Allocation: people selected at random but unclear how treatments were allocated. Participants: men and women with schizophrenia. Interventions: low dose testosterone plus low dose estrogen vs high dose testosterone plus high does estrogen, unable to distinguish testosterone effects from those of estrogens, unable to contact authors for clarification.
Thompson 2000	Allocation: not randomised, survey.
Villeneuve 1980	Allocation: unclear, unlikely randomised, stratified by age into groups and then divided into two treatment groups. Helpful contact with author. Participants: 20 male "chronic psychiatric patients" with dyskinesia/s (13 schizophrenia). Intervention: estrogen high dose vs estrogen low dose for 6 weeks. Outcomes: rating scales for dyskinetic movements and parkinsonian movements.
Yousef 1974	Allocation: randomised, crossover. Participants: post‐menopausal women with schizophrenia. Intervention: estrogen plus antipsychotics vs placebo plus antipsychotic. Outcomes: serum levels of butaperazine with and without estrogen, no usable data.

Characteristics of ongoing studies [ordered by study ID]

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estudios incluidos
estudios excluidos

Kulkarni 2003b

Trial name or title	Unknown.
Methods
Participants	Diagnosis: schizophrenia. N=60. Age: post‐menopausal. Sex: women.
Interventions	Olanzapine plus: 1. Raloxifene. 2. Estradiol 2mg and dyhydroprogesterone. 3. Placebo.
Outcomes	Psychopathology. Cognition. Adverse effects.
Starting date	Unclear
Contact information	Prof Jayashri Kulkarni The Alfred Hospital/Monash University Victoria, Australia
Notes	Allocation: randomised. Blinding: double. Duration: 3 months.

Data and analyses

Open in table viewer

Comparison 1. ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mental state: 1a. Average endpoint in general mental state scores (PANSS total, high=poor) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

Analysis 1.1

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 1 Mental state: 1a. Average endpoint in general mental state scores (PANSS total, high=poor).

1.1 100 mcg estrogen

1

24

Mean Difference (IV, Fixed, 95% CI)

‐2.26 [‐15.44, 10.92]

1.2 50 mcg estrogen

1

24

Mean Difference (IV, Fixed, 95% CI)

‐4.62 [‐14.60, 5.36]

2 Mental state: 1b. Average endpoint in general mental state scores (BPRS, skewed data, high=poor) Show forest plot

Other data

No numeric data

Analysis 1.2


Study	Intervention	Mean	SD	N	Notes
Louza 2004	Conjugated estrogens	7.95	7.10	21
Louza 2004	Placebo	12.89	9.68	19

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 2 Mental state: 1b. Average endpoint in general mental state scores (BPRS, skewed data, high=poor).

3 Mental state: 2a. Average endpoint in positive symptom scores (PANSS positive, high=poor) Show forest plot

Other data

No numeric data

Analysis 1.3


Study	Intervention	N	Mean	SD
Kulkarni 2001	Estrogen 100mcg	12	14.45	7.4
Kulkarni 2001	Placebo	12	15.37	5.5

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 3 Mental state: 2a. Average endpoint in positive symptom scores (PANSS positive, high=poor).

4 Mental state: 2b. Average endpoint in positive symptom scores ‐ 50mcg estrogen (PANSS positive, high=poor) Show forest plot

1

24

Mean Difference (IV, Fixed, 95% CI)

‐0.37 [‐5.36, 4.62]

Analysis 1.4

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 4 Mental state: 2b. Average endpoint in positive symptom scores ‐ 50mcg estrogen (PANSS positive, high=poor).

5 Mental state: 2c. Average endpoint in positive symptom scores (SAPS, skewed data, high=poor) Show forest plot

Other data

No numeric data

Analysis 1.5


Study	Intervention	Mean	SD	N
Kulkarni 1996	Estrogen	22.20	23.91	11
Kulkarni 1996	Placebo	25.90	16.24	7

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 5 Mental state: 2c. Average endpoint in positive symptom scores (SAPS, skewed data, high=poor).

6 Mental state: 3a. Average endpoint in negative symptom scores (PANSS negative, high=poor) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

Analysis 1.6

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 6 Mental state: 3a. Average endpoint in negative symptom scores (PANSS negative, high=poor).

6.1 100 mcg estrogen

1

24

Mean Difference (IV, Fixed, 95% CI)

‐0.51 [‐3.65, 2.63]

6.2 50 mcg estrogen

1

24

Mean Difference (IV, Fixed, 95% CI)

‐2.21 [‐4.73, 0.31]

7 Mental state: 3b. Average endpoint in negative symptom scores (NSRS,skewed data, high=poor) Show forest plot

Other data

No numeric data

Analysis 1.7


Study	Intervention	Mean	SD	N
Louza 2004	Conjugated estrogen	13.24	8048	21
Louza 2004	Placebo	15.79	9.46	19

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 7 Mental state: 3b. Average endpoint in negative symptom scores (NSRS,skewed data, high=poor).

8 Mental state: 4a. Average endpoint in psychopathology scores (PANSS general symptoms subscale, high=poor) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

Analysis 1.8

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 8 Mental state: 4a. Average endpoint in psychopathology scores (PANSS general symptoms subscale, high=poor).

8.1 100 mcg estrogen

1

24

Mean Difference (IV, Fixed, 95% CI)

‐0.83 [‐7.88, 6.22]

8.2 50 mcg estrogen

1

24

Mean Difference (IV, Fixed, 95% CI)

‐2.04 [‐7.01, 2.93]

9 Leaving the study early: up to 8 weeks Show forest plot

4

96

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.15, 6.07]

Analysis 1.9

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 9 Leaving the study early: up to 8 weeks.

10 Adverse effects: 1. Average endpoint movement disorder scores (skewed data, high=poor) Show forest plot

Other data

No numeric data

Analysis 1.10


Study	Intervention	Mean	SD	N
Abnormal Involuntary Movements Scale
Glazer 1985	Conjugated estrogens	4.60	0.55	5
Glazer 1985	Placebo	5.80	3.35	5
Simpson & Angus Extrapyramidal Rating Scale
Louza 2004	Conjugated estrogens	1.29	2.05	21
Louza 2004	Placebo	1.89	3.31	19

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 10 Adverse effects: 1. Average endpoint movement disorder scores (skewed data, high=poor).

10.1 Abnormal Involuntary Movements Scale

Other data

No numeric data

10.2 Simpson & Angus Extrapyramidal Rating Scale

Other data

No numeric data

11 Adverse effects: 2. Average endpoint adverse side‐effect scores (UKU, skewed data, high=poor) Show forest plot

Other data

No numeric data

Analysis 1.11


Study	Intervention	Mean	SD	N
Louza 2004	Conjugated estrogens	1.09	2.30	21
Louza 2004	Placebo	3.05	4.08	19

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 11 Adverse effects: 2. Average endpoint adverse side‐effect scores (UKU, skewed data, high=poor).

Open in table viewer

Comparison 2. ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mental state: Average endpoint general mental state scores (PANSS, high= poor) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

Analysis 2.1

Comparison 2 ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 1 Mental state: Average endpoint general mental state scores (PANSS, high= poor).

1.1 PANSS postive symptom scores

1

9

Mean Difference (IV, Fixed, 95% CI)

‐2.0 [‐10.52, 6.52]

1.2 PANSS negative symptom scores

1

9

Mean Difference (IV, Fixed, 95% CI)

‐9.0 [‐17.11, ‐0.89]

1.3 PANSS psychopathology scores

1

9

Mean Difference (IV, Fixed, 95% CI)

‐14.30 [‐29.31, 0.71]

1.4 PANSS total scores

1

9

Mean Difference (IV, Fixed, 95% CI)

‐25.30 [‐50.74, 0.14]

2 Leaving the study early ‐ up to 6 months Show forest plot

1

10

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.02, 6.65]

Analysis 2.2

Comparison 2 ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 2 Leaving the study early ‐ up to 6 months.

3 Cognitive functioning: Average endpoint specific aspects of cognitive functioning Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

Analysis 2.3

Comparison 2 ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 3 Cognitive functioning: Average endpoint specific aspects of cognitive functioning.

3.1 Visual Retention Test (BVRT total, high=good)

1

8

Mean Difference (IV, Fixed, 95% CI)

‐3.5 [‐5.73, ‐1.27]

3.2 Visual Retention Test (BVRT errors, high=poor)

1

8

Mean Difference (IV, Fixed, 95% CI)

‐12.0 [‐17.62, ‐6.38]

3.3 Motor speed (Finger tapping dominant hand, high=good)

1

9

Mean Difference (IV, Fixed, 95% CI)

‐5.10 [‐19.22, 9.02]

3.4 Motor speed (Finger tapping non‐dominant hand, high=good)

1

9

Mean Difference (IV, Fixed, 95% CI)

‐7.70 [‐23.72, 8.32]

4 Cognitive functioning: Average endpoint specific aspects of cognitive functioning Show forest plot

Other data

No numeric data

Analysis 2.4


Study	Component tests	Interventions	Mean	SD	N
Motor dexterity (Grooved Pegboard, high=good)
Good 1999	Dominant hand	Estrogen plus progesterone	149.6	167.2	5
Good 1999		Placebo	189.0	96.8	3
Good 1999	Non‐dominant hand	estrogen plus progesterone	144.4	127.7	5
Good 1999		Placebo	184.7	99.9	3
Good 1999
Good 1999
Design fluency (Design Fluency Test, high=good)
Good 1999	Design fluency free	Estrogen plus progesterone	15.8	8.2	5
Good 1999		Placebo	11.3	9.0	4
Good 1999	Design fluency fixed	Estrogen plus placebo	11.4	6.1	5
Good 1999		Placebo	7.0	2.9	4
Good 1999
Good 1999
Verbal Fluency (COWA,high=good)
Good 1999		Estrogen plus progesterone	33.6	6.9	5
Good 1999		Placebo	16.8	11.0	4
Good 1999
Good 1999
Good 1999
Good 1999
Auditory‐Verbal Learning Test (AVLT trial, high=good)
Good 1999	AVLT trial 1	Estrogen plus progesterone	7.2	5.0	5
Good 1999		Placebo	2.8	2.2	4
Good 1999	AVLT trial 1‐5	Estrogen plus progesterone	45.4	24.8	5
Good 1999		Placebo	24.5	15.0	4
Good 1999	AVLT delayed	Estrogen plus placebo	8.6	5.9	5
Good 1999		Placebo	3.8	2.9	4
Smell identification (UPSIT, high=good)
Good 1999		Estrogen plus progesterone	31.2	7.2	5
Good 1999		Placebo	16.3	11.7	4
Good 1999
Good 1999
Good 1999
Good 1999
Smell sensitivity (Acuity, high=good)
Good 1999		Estrogen plus progesterone	8.4	1.9	5
Good 1999		Placebo	5.8	3.8	4
Good 1999
Good 1999
Good 1999
Good 1999

Comparison 2 ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 4 Cognitive functioning: Average endpoint specific aspects of cognitive functioning.

4.1 Motor dexterity (Grooved Pegboard, high=good)

Other data

No numeric data

4.2 Design fluency (Design Fluency Test, high=good)

Other data

No numeric data

4.3 Verbal Fluency (COWA,high=good)

Other data

No numeric data

4.4 Auditory‐Verbal Learning Test (AVLT trial, high=good)

Other data

No numeric data

4.5 Smell identification (UPSIT, high=good)

Other data

No numeric data

4.6 Smell sensitivity (Acuity, high=good)

Other data

No numeric data

Analysis 1.1

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 1 Mental state: 1a. Average endpoint in general mental state scores (PANSS total, high=poor).

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Study	Intervention	Mean	SD	N	Notes
Louza 2004	Conjugated estrogens	7.95	7.10	21
Louza 2004	Placebo	12.89	9.68	19

Analysis 1.2

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 2 Mental state: 1b. Average endpoint in general mental state scores (BPRS, skewed data, high=poor).

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Study	Intervention	N	Mean	SD
Kulkarni 2001	Estrogen 100mcg	12	14.45	7.4
Kulkarni 2001	Placebo	12	15.37	5.5

Analysis 1.3

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 3 Mental state: 2a. Average endpoint in positive symptom scores (PANSS positive, high=poor).

Ir a la figura de la revisión

Analysis 1.4

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 4 Mental state: 2b. Average endpoint in positive symptom scores ‐ 50mcg estrogen (PANSS positive, high=poor).

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Study	Intervention	Mean	SD	N
Kulkarni 1996	Estrogen	22.20	23.91	11
Kulkarni 1996	Placebo	25.90	16.24	7

Analysis 1.5

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 5 Mental state: 2c. Average endpoint in positive symptom scores (SAPS, skewed data, high=poor).

Ir a la figura de la revisión

Analysis 1.6

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 6 Mental state: 3a. Average endpoint in negative symptom scores (PANSS negative, high=poor).

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Study	Intervention	Mean	SD	N
Louza 2004	Conjugated estrogen	13.24	8048	21
Louza 2004	Placebo	15.79	9.46	19

Analysis 1.7

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 7 Mental state: 3b. Average endpoint in negative symptom scores (NSRS,skewed data, high=poor).

Ir a la figura de la revisión

Analysis 1.8

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 8 Mental state: 4a. Average endpoint in psychopathology scores (PANSS general symptoms subscale, high=poor).

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Analysis 1.9

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 9 Leaving the study early: up to 8 weeks.

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Study	Intervention	Mean	SD	N
Abnormal Involuntary Movements Scale
Glazer 1985	Conjugated estrogens	4.60	0.55	5
Glazer 1985	Placebo	5.80	3.35	5
Simpson & Angus Extrapyramidal Rating Scale
Louza 2004	Conjugated estrogens	1.29	2.05	21
Louza 2004	Placebo	1.89	3.31	19

Analysis 1.10

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 10 Adverse effects: 1. Average endpoint movement disorder scores (skewed data, high=poor).

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Study	Intervention	Mean	SD	N
Louza 2004	Conjugated estrogens	1.09	2.30	21
Louza 2004	Placebo	3.05	4.08	19

Analysis 1.11

Comparison 1 ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 11 Adverse effects: 2. Average endpoint adverse side‐effect scores (UKU, skewed data, high=poor).

Ir a la figura de la revisión

Analysis 2.1

Comparison 2 ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 1 Mental state: Average endpoint general mental state scores (PANSS, high= poor).

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Analysis 2.2

Comparison 2 ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 2 Leaving the study early ‐ up to 6 months.

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Analysis 2.3

Comparison 2 ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 3 Cognitive functioning: Average endpoint specific aspects of cognitive functioning.

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Study	Component tests	Interventions	Mean	SD	N
Motor dexterity (Grooved Pegboard, high=good)
Good 1999	Dominant hand	Estrogen plus progesterone	149.6	167.2	5
Good 1999		Placebo	189.0	96.8	3
Good 1999	Non‐dominant hand	estrogen plus progesterone	144.4	127.7	5
Good 1999		Placebo	184.7	99.9	3
Good 1999
Good 1999
Design fluency (Design Fluency Test, high=good)
Good 1999	Design fluency free	Estrogen plus progesterone	15.8	8.2	5
Good 1999		Placebo	11.3	9.0	4
Good 1999	Design fluency fixed	Estrogen plus placebo	11.4	6.1	5
Good 1999		Placebo	7.0	2.9	4
Good 1999
Good 1999
Verbal Fluency (COWA,high=good)
Good 1999		Estrogen plus progesterone	33.6	6.9	5
Good 1999		Placebo	16.8	11.0	4
Good 1999
Good 1999
Good 1999
Good 1999
Auditory‐Verbal Learning Test (AVLT trial, high=good)
Good 1999	AVLT trial 1	Estrogen plus progesterone	7.2	5.0	5
Good 1999		Placebo	2.8	2.2	4
Good 1999	AVLT trial 1‐5	Estrogen plus progesterone	45.4	24.8	5
Good 1999		Placebo	24.5	15.0	4
Good 1999	AVLT delayed	Estrogen plus placebo	8.6	5.9	5
Good 1999		Placebo	3.8	2.9	4
Smell identification (UPSIT, high=good)
Good 1999		Estrogen plus progesterone	31.2	7.2	5
Good 1999		Placebo	16.3	11.7	4
Good 1999
Good 1999
Good 1999
Good 1999
Smell sensitivity (Acuity, high=good)
Good 1999		Estrogen plus progesterone	8.4	1.9	5
Good 1999		Placebo	5.8	3.8	4
Good 1999
Good 1999
Good 1999
Good 1999

Analysis 2.4

Comparison 2 ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT, Outcome 4 Cognitive functioning: Average endpoint specific aspects of cognitive functioning.

Ir a la figura de la revisión

Comparison 1. ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mental state: 1a. Average endpoint in general mental state scores (PANSS total, high=poor) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 100 mcg estrogen	1	24	Mean Difference (IV, Fixed, 95% CI)	‐2.26 [‐15.44, 10.92]
1.2 50 mcg estrogen	1	24	Mean Difference (IV, Fixed, 95% CI)	‐4.62 [‐14.60, 5.36]
2 Mental state: 1b. Average endpoint in general mental state scores (BPRS, skewed data, high=poor) Show forest plot			Other data	No numeric data

3 Mental state: 2a. Average endpoint in positive symptom scores (PANSS positive, high=poor) Show forest plot			Other data	No numeric data

4 Mental state: 2b. Average endpoint in positive symptom scores ‐ 50mcg estrogen (PANSS positive, high=poor) Show forest plot	1	24	Mean Difference (IV, Fixed, 95% CI)	‐0.37 [‐5.36, 4.62]

5 Mental state: 2c. Average endpoint in positive symptom scores (SAPS, skewed data, high=poor) Show forest plot			Other data	No numeric data

6 Mental state: 3a. Average endpoint in negative symptom scores (PANSS negative, high=poor) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.1 100 mcg estrogen	1	24	Mean Difference (IV, Fixed, 95% CI)	‐0.51 [‐3.65, 2.63]
6.2 50 mcg estrogen	1	24	Mean Difference (IV, Fixed, 95% CI)	‐2.21 [‐4.73, 0.31]
7 Mental state: 3b. Average endpoint in negative symptom scores (NSRS,skewed data, high=poor) Show forest plot			Other data	No numeric data

8 Mental state: 4a. Average endpoint in psychopathology scores (PANSS general symptoms subscale, high=poor) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

8.1 100 mcg estrogen	1	24	Mean Difference (IV, Fixed, 95% CI)	‐0.83 [‐7.88, 6.22]
8.2 50 mcg estrogen	1	24	Mean Difference (IV, Fixed, 95% CI)	‐2.04 [‐7.01, 2.93]
9 Leaving the study early: up to 8 weeks Show forest plot	4	96	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.15, 6.07]

10 Adverse effects: 1. Average endpoint movement disorder scores (skewed data, high=poor) Show forest plot			Other data	No numeric data

10.1 Abnormal Involuntary Movements Scale			Other data	No numeric data
10.2 Simpson & Angus Extrapyramidal Rating Scale			Other data	No numeric data
11 Adverse effects: 2. Average endpoint adverse side‐effect scores (UKU, skewed data, high=poor) Show forest plot			Other data	No numeric data

Comparison 1. ESTROGEN (mostly 100 mcg) + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT

Ir a la tabla de la revisión

Comparison 2. ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mental state: Average endpoint general mental state scores (PANSS, high= poor) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 PANSS postive symptom scores	1	9	Mean Difference (IV, Fixed, 95% CI)	‐2.0 [‐10.52, 6.52]
1.2 PANSS negative symptom scores	1	9	Mean Difference (IV, Fixed, 95% CI)	‐9.0 [‐17.11, ‐0.89]
1.3 PANSS psychopathology scores	1	9	Mean Difference (IV, Fixed, 95% CI)	‐14.30 [‐29.31, 0.71]
1.4 PANSS total scores	1	9	Mean Difference (IV, Fixed, 95% CI)	‐25.30 [‐50.74, 0.14]
2 Leaving the study early ‐ up to 6 months Show forest plot	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.02, 6.65]

3 Cognitive functioning: Average endpoint specific aspects of cognitive functioning Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

3.1 Visual Retention Test (BVRT total, high=good)	1	8	Mean Difference (IV, Fixed, 95% CI)	‐3.5 [‐5.73, ‐1.27]
3.2 Visual Retention Test (BVRT errors, high=poor)	1	8	Mean Difference (IV, Fixed, 95% CI)	‐12.0 [‐17.62, ‐6.38]
3.3 Motor speed (Finger tapping dominant hand, high=good)	1	9	Mean Difference (IV, Fixed, 95% CI)	‐5.10 [‐19.22, 9.02]
3.4 Motor speed (Finger tapping non‐dominant hand, high=good)	1	9	Mean Difference (IV, Fixed, 95% CI)	‐7.70 [‐23.72, 8.32]
4 Cognitive functioning: Average endpoint specific aspects of cognitive functioning Show forest plot			Other data	No numeric data

4.1 Motor dexterity (Grooved Pegboard, high=good)			Other data	No numeric data
4.2 Design fluency (Design Fluency Test, high=good)			Other data	No numeric data
4.3 Verbal Fluency (COWA,high=good)			Other data	No numeric data
4.4 Auditory‐Verbal Learning Test (AVLT trial, high=good)			Other data	No numeric data
4.5 Smell identification (UPSIT, high=good)			Other data	No numeric data
4.6 Smell sensitivity (Acuity, high=good)			Other data	No numeric data

Comparison 2. ESTROGEN + PROGESTERONE + STANDARD TREATMENT vs PLACEBO + STANDARD TREATMENT

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Referencias

References to studies included in this review

Glazer 1985 {published data only}

Good 1999 {published and unpublished data}

Kulkarni 1996 {published data only}

Kulkarni 2001 {published and unpublished data}

Louza 2004 {published and unpublished data}

References to studies excluded from this review

Bergemann 1999 {published data only}

Chakos 1999 {published data only}

Godfrey 2002 {published data only}

Kim 1998 {published data only}

Koller 1982 {published data only}

Kulkarni 1999 {published data only}

Kulkarni 2002 {published data only}

Kulkarni 2003a {published data only}

O' Connor 1983 {published data only}

Purdie 2000 {published data only (unpublished sought but not used)}

Sackler 1951 {published data only}

Thompson 2000 {published data only}

Villeneuve 1980 {published data only}

Yousef 1974 {published data only}

References to ongoing studies

Kulkarni 2003b {published data only}

Additional references

Alderson 2004

Altman 1996

Andreasen 1983

Angermeyer 1988

Baptista 2002

Benton 1963

Benton 1974

Benton 1983

Bland 1997

BNF 2003

Castle 1991

CSM 2004

Cyr 2002

Divine 1992

Donner 2002

Doty 1984

Egger 1997

Felthous 1980

Genazzani 2002

Goldstein 1992

Gulliford 1999

Guy 1976

Hafner 1997

Hafner 2003

Higgins 2003

Iager 1985

Jablensky 1997

Jones‐Gotman 1977

Jones‐Gotman 1991

Kay 1987

Kendell 1987

Lezak 1976

Lezak 1995

Lingjaerd 1987

Mahe 2001

Marshall 2000

Matthews 1964

McKenna 1997

Moher 2001

Overall 1962

Reitan 1969

Rey 1958

Richens 2001

Riecher‐Rossler 1993

Riecher‐Rossler 2003

Schulz 1995

Seeman 1983

Senn 1999

Simpson 1970

Taylor 1959

Tunde‐Ayinmode 2002

Ukoumunne 1999

Characteristics of studies