Antidepressants for people with epilepsy and depression

Melissa J Maguire; Anthony G Marson; Sarah J Nevitt

doi:10.1002/14651858.CD010682.pub3

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Figure 1

Study flow diagram

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Analysis 1.1

Comparison 1: RCT: paroxetine versus doxepin, Outcome 1: > 50% reduction in depressive symptoms

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Analysis 1.2

Comparison 1: RCT: paroxetine versus doxepin, Outcome 2: Mean depression scores

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Analysis 1.3

Comparison 1: RCT: paroxetine versus doxepin, Outcome 3: Withdrawals (any reason)

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Analysis 1.4

Comparison 1: RCT: paroxetine versus doxepin, Outcome 4: Adverse effects

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Analysis 2.1

Comparison 2: RCT: amitriptyline versus nomifensine, Outcome 1: > 50% reduction in depressive symptoms

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Analysis 3.1

Comparison 3: RCT: venlafaxine versus no treatment controls, Outcome 1: > 50% reduction in depressive symptoms

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Analysis 3.2

Comparison 3: RCT: venlafaxine versus no treatment controls, Outcome 2: Mean depression scores ‐ HAMD

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Analysis 4.1

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 1: Mean depression scores (BDI)

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Analysis 4.2

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 2: Remission in depressive symptoms

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Analysis 4.3

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 3: Seizure frequency

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Analysis 4.4

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 4: Seizure recurrence

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Analysis 4.5

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 5: Withdrawals (any reason)

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Analysis 4.6

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 6: Quality of life (QOLIE‐89)

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Analysis 4.7

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 7: Adverse events profile

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Analysis 4.8

Comparison 4: RCT: sertraline versus cognitive behavioural therapy (CBT), Outcome 8: Adverse events

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Analysis 5.1

Comparison 5: NRSI: citalopram (before and after), Outcome 1: Mean depression scores HAMD‐21

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Analysis 5.2

Comparison 5: NRSI: citalopram (before and after), Outcome 2: Mean monthly seizure frequency

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Analysis 6.1

Comparison 6: NRSI: SSRIs (sertraline or citalopram) versus CBT, Outcome 1: Mean depression scores (BDI)

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Analysis 6.2

Comparison 6: NRSI: SSRIs (sertraline or citalopram) versus CBT, Outcome 2: Remission in depressive symptoms

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Analysis 6.3

Comparison 6: NRSI: SSRIs (sertraline or citalopram) versus CBT, Outcome 3: Seizure frequency per month at 12 weeks

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Analysis 6.4

Comparison 6: NRSI: SSRIs (sertraline or citalopram) versus CBT, Outcome 4: Withdrawals (any reason)

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Analysis 6.5

Comparison 6: NRSI: SSRIs (sertraline or citalopram) versus CBT, Outcome 5: Quality of life (QOLIE‐31 overall score)

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Summary of findings 1. Paroxetine compared to doxepin for people with epilepsy and depression

Paroxetine compared to doxepin for people with epilepsy and depression
Patient or population: people with epilepsy and depression Settings: outpatients Intervention: paroxetine Comparison: doxepin
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	doxepin	paroxetine
> 50% reduction in depressive symptoms Follow‐up: 8 weeks	706 per 1000	819 per 1000 (621 to 1000)	RR 1.16 (0.88 to 1.52)	67 (1 RCT)	⊕⊕⊕⊝ moderate^a
Mean depression scores (HAMD scores; lower = better) Follow‐up: 8 weeks	NA	The mean HAMD depression score in the intervention groups was 0.65 higher (2.15 lower to 3.45 higher)	NA	67 (1 RCT)	⊕⊕⊕⊝ moderate^a
Seizure frequency Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Withdrawals Follow‐up: 8 weeks	88 per 1000	13 per 1000 (1 to 242)	RR 0.15 (0.01 to 2.74)	67 (1 RCT)	⊕⊕⊕⊝ moderate^a	doxepin: 3 withdrew paroxetine: 0 withdrew
Cognitive functioning Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Quality of life Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Adverse effects Follow‐up: 8 weeks	Reported adverse events: blurred vision, dizziness, dry mouth, sleep disorders, and urinary retention	Reported adverse events: blurred vision, dizziness, dry mouth, and sleep disorders	NA	67 (1 RCT)	⊕⊕⊕⊝ moderate^a	There were no significant differences between treatment groups for any reported adverse events
The basis for the assumed risk* is the event rate in the doxepin group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HAMD: Hamilton Rating Scale for Depression; NA: not applicable; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty. Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty, Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty. We are very uncertain about the estimate.
^aCertainty of the evidence downgraded for imprecision, because only one small study contributed to the outcomes.

Summary of findings 1. Paroxetine compared to doxepin for people with epilepsy and depression

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Summary of findings 2. Amitriptyline compared to nomifensine for people with epilepsy and depression

Amitriptyline compared to nomifensine for people with epilepsy and depression
Patient or population: people with epilepsy and depression Settings: outpatients Intervention: amitriptyline Comparison: nomifensine
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	nomifensine	amitriptyline
> 50% reduction in depressive symptoms Follow‐up: 12 weeks	786 per 1000	432 per 1000 (220 to 833)	RR 0.55 (0.28 to 1.06)	28 (1 RCT)	⊕⊕⊝⊝ low^a
Mean depression scores Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Seizure frequency Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Withdrawals Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Cognitive functioning Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Quality of life Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Adverse effects Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
The basis for the assumed risk* is the event rate in the nomifensine group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; NA: not applicable; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty. Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty, Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty. We are very uncertain about the estimate.
^aCertainty of the evidence downgraded twice for imprecision, because only very small study contributed limited outcome data.

Summary of findings 2. Amitriptyline compared to nomifensine for people with epilepsy and depression

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Summary of findings 3. Venlafaxine compared to no treatment for people with epilepsy and depression

Venlafaxine compared to no treatment for people with epilepsy and depression
Patient or population: people with epilepsy and depression Settings: outpatients Intervention: venlafaxine Comparison: no treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	no treatment	venlafaxine
> 50% reduction in depressive symptoms Follow‐up: 8 weeks	125 per 1000	406 per 1000 (149 to 1000)	RR 3.25 (1.19 to 8.9)	64 (1 RCT)	⊕⊕⊝⊝ low^a^,b
Mean depression scores (HAMD scores; lower = better) Follow‐up: 8 weeks	NA	The mean HAMD depression score in the intervention group was 7.59 lower (11.52 lower to 3.66 lower)	NA	64 (1 RCT)	⊕⊕⊝⊝ low^a^,b
Seizure frequency Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Withdrawals Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Cognitive functioning Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Quality of life Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Adverse effects Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
The basis for the assumed risk* is the event rate in the no treatment group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; HAMD: Hamilton Rating Scale for Depression; NA: not applicable; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty. Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty, Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty. We are very uncertain about the estimate.
^aCertainty of the evidence downgraded for imprecision, because only one small study contributed to the outcomes. ^bCertainty of the evidence downgraded once due to risk of bias; unclear methodological information provided regarding randomisation and allocation concealment.

Summary of findings 3. Venlafaxine compared to no treatment for people with epilepsy and depression

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Summary of findings 4. Sertraline compared to cognitive behavioural therapy for people with epilepsy and depression

Sertraline compared to cognitive behavioural therapy for people with epilepsy and depression
Patient or population: people with epilepsy and depression Settings: outpatients Intervention: sertraline Comparison: cognitive behavioural therapy (CBT)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	CBT	sertraline
> 50% reduction in depressive symptoms Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Mean depression scores (BDI scores; lower = better) Follow‐up: 16 weeks	NA	The mean BDI depression score in the intervention group was 0.50 lower (4.47 lower to 3.47 higher)	NA	117 (1 RCT)	⊕⊕⊕⊝ moderate^a	At 8 weeks: MD ‐2.50 (95% CI ‐6.28 to 1.28; 104 participants)
Seizure frequency Follow‐up: 16 weeks	NA	The mean frequency of GTCS per month in the intervention group was 0 lower (‐0.10 lower to 0.10 higher) The mean frequency of focal seizures with impaired awareness per month in the intervention group was 3.00 lower (7.81 lower to 1.81 higher)	NA	96 with GTCS plus 75 with focal seizures (1 RCT)	⊕⊕⊝⊝ low^b	At 8 weeks: GTCS per month: MD ‐0.10 (95% CI ‐0.26 to 0.06; 86 participants) focal seizures with impaired awareness per month: MD ‐2.60 (95% CI ‐6.52 to 1.32; 75 participants)
Withdrawals Follow‐up: 16 weeks	176 per 1000	222 per 1000 (113 to 434 per 1000)	RR 1.26 (0.64 to 2.46)	140 (1 RCT)	⊕⊕⊕⊝ moderate^a	CBT: 6 withdrew, 6 lost to follow‐up sertraline: 7 withdrew, 9 lost to follow‐up
Cognitive functioning Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Quality of life (QOLIE‐89 scale; lower = better) Follow‐up: 16 weeks	NA	The mean QOLIE‐89 score in the intervention group was 3.10 higher (3.41 lower to 9.61 higher)	NA	118 (1 RCT)	⊕⊕⊕⊝ moderate^a	at 8 weeks: MD 6.10 (95% CI ‐0.28 to 12.48; 104 participants)
Adverse effects Follow‐up: 16 weeks	NA	The mean adverse event profile score in the intervention group was 2.10 lower (6.21 lower to 2.01 higher)	NA	118 (1 RCT)	⊕⊕⊕⊝ low^a^,c	Sertraline resulted in more cases of tiredness than CBT (RR 3.54, 99% CI 1.40 to 8.96; 140 participants) Sertraline did not result in more cases of any other adverse effects than CBT.
The basis for the assumed risk* is the event rate in the CBT group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BDI: Beck Depression Inventory; CBT: cognitive behavioural therapy; CI: confidence interval; MD: mean difference; NA: not applicable; QOLIE: Quality of life in Epilepsy; RCT: randomised controlled trial; RR: risk ratio; GTCS: generalised tonic‐clonic seizures
GRADE Working Group grades of evidence High certainty. Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty, Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty. We are very uncertain about the estimate.
^aCertainty of the evidence downgraded once due to risk of bias: participants and personnel not blinded, and lack of blinding may have influenced outcome ^bCertainty of the evidence downgraded twice due to risk of bias and imprecision: risk of recall bias as seizure frequency data at baseline was collected retrospectively, and data not available for all participants ^cCertainty of the evidence downgraded once due to imprecision: adverse event data not available for all participants who received an intervention

Summary of findings 4. Sertraline compared to cognitive behavioural therapy for people with epilepsy and depression

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Summary of findings 5. Citalopram (before and after treatment) for people with epilepsy and depression

Citalopram (before and after treatment) for people with epilepsy and depression
Patient or population: people with epilepsy and depression Settings: outpatients Intervention: citalopram Control: before citalopram treatment
Outcomes	*Illustrative comparative risks (95% CI)**	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Citalopram (before and after)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
> 50% reduction in depressive symptoms Follow‐up: 4 months	11 out of 45 participants (24%) showed a 50% or more improvement in depression scores after treatment compared to baseline.	45 (1 NRSI)	⊕⊕⊝⊝ low^a
Mean depression scores (HAMD scores; lower = better) Follow‐up: 8 weeks to 4 months	Improved depression scores were shown after citalopram compared to before (see comment)	88 (2 NRSI)	⊕⊕⊝⊝ low^a^,b,c	SMD in HAMD score was 1.17 (95% CI 0.96 to 1.38), indicating improved outcomes and a large treatment effect.
Seizure frequency Follow‐up: 8 weeks to 4 months	See comment	88 (2 NRSI)	⊕⊝⊝⊝ very low^a^,c	Results were mixed between studies; due to very high heterogeneity (I² = 81%), we did not present the overall effect estimate.
Withdrawals Follow‐up: 8 weeks to 4 months	6/45 participants (13%) withdrew from one study; 0/43 from the other study	88 (2 NRSI)	⊕⊕⊝⊝ low^a
Cognitive functioning Follow‐up: NA	‐	0 (0 studies)	‐
Quality of life Follow‐up: NA	‐	0 (0 studies)	‐
Adverse effects Follow‐up: 8 weeks to 4 months	22/45 participants (56%) experienced adverse events in one study; 5/43 (12%) in the other study	88 (2 NRSI)	⊕⊕⊝⊝ low^a	Specific adverse events reported: nausea, sexual dysfunction, headache, dizziness, drowsiness, and fatigue
CI: confidence interval; HAMD: Hamilton Rating Scale for Depression; NRSI: non‐randomised studies of interventions
GRADE Working Group grades of evidence High certainty. Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty, Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty. We are very uncertain about the estimate.
^aCertainty of the evidence downgraded twice as studies were judged to be at serious risk of bias due to lack of blinding, which may have influenced participant‐recorded outcomes, and lack of adjustment for confounding variables. ^bCertainty of the evidence upgraded once as large effect found. ^cCertainty of the evidence downgraded due to inconsistency: substantial statistical heterogeneity was present (I² > 50%).

Summary of findings 5. Citalopram (before and after treatment) for people with epilepsy and depression

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Summary of findings 6. Selective serotonin reuptake inhibitors compared to cognitive behavioural therapy for people with epilepsy and depression

Selective serotonin reuptake inhibitorscompared to cognitive behavioural therapy for people with epilepsy and depression
Patient or population: people with epilepsy and depression Settings: outpatients Intervention: selective serotonin reuptake inhibitors (SSRIs; sertraline or citalopram) Comparison: cognitive behavioural therapy (CBT)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	CBT	SSRIs
> 50% reduction in depressive symptoms Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Mean depression scores (BDI scores; lower = better) Follow‐up: 12 weeks	NA	The mean BDI depression score in the intervention group was 4.90 lower (14.90 lower to 4.80 higher)	NA	15 (1 NRSI)	⊕⊝⊝⊝ very low^a^,b	at 6 weeks: MD ‐2.60 (95% CI ‐11.58 to 6.38; 15 participants)
Seizure frequency Follow‐up: 12 weeks	NA	The mean frequency of seizures per month in the intervention group was 1.60 lower (5.63 lower to 2.43 higher)	NA	15 (1 NRSI)	⊕⊝⊝⊝ very low^a^,b
Withdrawals Follow‐up: 12 weeks	286 per 1000	126 per 1000 (14 to 1000 per 1000)	RR 0.44 (0.05 to 3.85)	15 (1 NRSI)	⊕⊝⊝⊝ very low^a^,b	CBT: 2 lost to follow‐up SSRI: 1 lost to follow‐up in the
Cognitive functioning Follow‐up: NA	‐	‐	‐	0 (0 studies)	‐
Quality of life ‐ QOLIE‐31 scale Follow‐up: 12 weeks	NA	The mean QOLIE‐31 score in the intervention group was 0.50 lower (19.67 lower to 18.67 higher)	NA	15 (1 NRSI)	⊕⊝⊝⊝^1,2 very low
Adverse effects ‐ adverse event profile Follow‐up: 16 weeks	‐	‐	‐	0 (0 studies)	‐
The basis for the assumed risk* is the event rate in the CBT group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). BDI: Beck Depression Inventory; CBT: cognitive behavioural therapy; CI: confidence interval; MD: mean difference; NA: not applicable; QOLIE: Quality of life in Epilepsy; RCT: randomised controlled trial; RR: risk ratio; SSRI: selective serotonin reuptake inhibitors
GRADE Working Group grades of evidence High certainty. Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty, Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty. We are very uncertain about the estimate.
1. Certainty of the evidence downgraded twice as the study was judged to be at serious risk of bias with regards to lack of blinding which may have influenced participant recorded outcomes and lack of adjustment for confounding variables. 2. Certainty of the evidence downgraded once due to imprecision: very small study of 15 participants, confidence intervals around effect estimates wide

Summary of findings 6. Selective serotonin reuptake inhibitors compared to cognitive behavioural therapy for people with epilepsy and depression

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Table 1. Criteria for overall risk of bias judgements from ROBINS‐I

Risk of bias judgement	Criteria based on seven risk of bias domains
Low risk of bias: the study is comparable to a well‐performed randomised trial	The study is judged to be at low risk of bias for all domains
Moderate risk of bias: the study appears to provide sound evidence for a non‐randomised study but cannot be considered comparable to a well‐performed randomised trial	The study is judged to be at low or moderate risk of bias for all domains
Serious risk of bias: the study has some important problems	The study is judged to be at serious risk of bias in at least 1 domain, but not at critical risk of bias in any domain
Critical risk of bias: the study is too problematic to provide any useful evidence on the effects of intervention	The study is judged to be at critical risk of bias in at least 1 domain
No information on which to base a judgement about risk of bias	There is no clear indication that the study is at serious or critical risk of bias, and there is a lack of information in 1 or more key domains of bias (a judgement is required for this)

Table 1. Criteria for overall risk of bias judgements from ROBINS‐I

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Table 2. Risk of bias judgements for non‐randomised studies (ROBINS‐I)

Domain and risk of bias judgement	Study
Domain and risk of bias judgement	Hovorka 2000	Kanner 2000	Kuhn 2003	Orjuela‐Rojas 2015	Specchio 2004	Thome‐Souza 2007
Bias due to confounding	Serious	Moderate	Serious	Moderate	Serious	Serious
Bias in selection of participants into the study	Moderate	Low	Moderate	Low	Serious	Moderate
Bias in classification of interventions	Low	Low	Moderate	Low	Low	Low
Bias due to deviations from intended interventions	Low	Low	Moderate	Moderate	Moderate	Low
Bias due to missing data	Low	Low	Serious	Serious	Serious	Low
Bias in measurement of outcomes	Moderate	Serious	Moderate	Moderate	Moderate	Moderate
Bias in selection of the reported result	Low	Moderate	Low	Moderate	Low	Low
Overall judgement	Serious	Serious	Serious	Serious	Serious	Serious
Support for judgement	No adjustment for confounding; unclear if participants were recruited consecutively; and by design, blinding was not possible, which may have influenced subjectively‐assessed outcomes	Some analyses to investigate prognostic variables, but not a complete analysis of confounders; unclear which variables were of interest in advance, and if other characteristics were tested and analysed; and by design, blinding was not possible, which may have influenced subjectively‐assessed outcomes. The measure of depression was not an accurate or reliable measure	No adjustment for confounding; many discontinuations due to adverse events and non‐compliance, with outcome data analysed by last observation carried forward; unclear if participants were already receiving the intervention on entry into the study, and exactly how groups were assigned. Lack of blinding may have influenced some participant‐reported outcomes.	Some analyses to investigate prognostic variables, but not a complete analysis of confounders; unclear which variables were of interest in advance, and if other characteristics were tested and analysed; small groups and dropouts, with outcome data analysed by last observation carried forward, Lack of blinding may have influenced some participant‐reported outcomes.	No adjustment for confounding; outcome data included only for those who completed analysis (6 participants excluded); and by design, blinding was not possible, which may have influenced subjectively‐assessed outcomes	No adjustment for confounding; unclear if participants were recruited consecutively; and by design, blinding was not possible, which may have influenced subjectively‐assessed outcomes.

Table 2. Risk of bias judgements for non‐randomised studies (ROBINS‐I)

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Comparison 1. RCT: paroxetine versus doxepin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 > 50% reduction in depressive symptoms Show forest plot	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.88, 1.52]

1.2 Mean depression scores Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.2.1 HAMD scores	1	67	Mean Difference (IV, Fixed, 95% CI)	0.65 [‐2.15, 3.45]
1.3 Withdrawals (any reason) Show forest plot	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 2.74]

1.4 Adverse effects Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

1.4.1 Blurred vision	1	67	Risk Ratio (M‐H, Fixed, 99% CI)	0.34 [0.09, 1.32]
1.4.2 Dizziness	1	67	Risk Ratio (M‐H, Fixed, 99% CI)	0.21 [0.03, 1.37]
1.4.3 Dry mouth	1	67	Risk Ratio (M‐H, Fixed, 99% CI)	0.26 [0.06, 1.20]
1.4.4 Sleep disorders	1	67	Risk Ratio (M‐H, Fixed, 99% CI)	0.32 [0.08, 1.20]
1.4.5 Urinary retention	1	67	Risk Ratio (M‐H, Fixed, 99% CI)	0.34 [0.01, 21.99]

Comparison 1. RCT: paroxetine versus doxepin

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Comparison 2. RCT: amitriptyline versus nomifensine

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 > 50% reduction in depressive symptoms Show forest plot	1	28	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.28, 1.06]

Comparison 2. RCT: amitriptyline versus nomifensine

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Comparison 3. RCT: venlafaxine versus no treatment controls

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 > 50% reduction in depressive symptoms Show forest plot	1	64	Risk Ratio (M‐H, Fixed, 95% CI)	3.25 [1.19, 8.90]

3.2 Mean depression scores ‐ HAMD Show forest plot	1	64	Mean Difference (IV, Fixed, 95% CI)	‐7.59 [‐11.52, ‐3.66]

Comparison 3. RCT: venlafaxine versus no treatment controls

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Comparison 4. RCT: sertraline versus cognitive behavioural therapy (CBT)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Mean depression scores (BDI) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.1.1 BDI‐II scores at 8 weeks	1	104	Mean Difference (IV, Fixed, 95% CI)	‐2.50 [‐6.28, 1.28]
4.1.2 BDI‐II scores at 16 weeks	1	117	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐4.47, 3.47]
4.2 Remission in depressive symptoms Show forest plot	1	140	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.65, 1.17]

4.3 Seizure frequency Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.3.1 Generalised tonic‐clonic seizures per month at 8 weeks	1	86	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐0.26, 0.06]
4.3.2 Generalised tonic‐clonic seizures per month at 16 weeks	1	96	Mean Difference (IV, Fixed, 95% CI)	0.00 [‐0.10, 0.10]
4.3.3 Focal seizures with impaired awareness per month at 8 weeks	1	75	Mean Difference (IV, Fixed, 95% CI)	‐2.60 [‐6.52, 1.32]
4.3.4 Focal seizures with impaired awareness per month at 16 weeks	1	73	Mean Difference (IV, Fixed, 95% CI)	‐3.00 [‐7.81, 1.81]
4.4 Seizure recurrence Show forest plot	1	104	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.27, 3.94]

4.5 Withdrawals (any reason) Show forest plot	1	140	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.64, 2.46]

4.6 Quality of life (QOLIE‐89) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.6.1 QOLIE‐89 score at 8 weeks	1	104	Mean Difference (IV, Fixed, 95% CI)	6.10 [‐0.28, 12.48]
4.6.2 QOLIE‐89 score at 16 weeks	1	118	Mean Difference (IV, Fixed, 95% CI)	3.10 [‐3.41, 9.61]
4.7 Adverse events profile Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.7.1 Adverse event profile at 8 weeks	1	106	Mean Difference (IV, Fixed, 95% CI)	‐2.70 [‐6.62, 1.22]
4.7.2 Adverse event profile at 16 weeks	1	118	Mean Difference (IV, Fixed, 95% CI)	‐2.10 [‐6.21, 2.01]
4.8 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 99% CI)	Subtotals only

4.8.1 Anxiety	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	8.51 [0.19, 386.16]
4.8.2 Chest pain	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	0.47 [0.05, 4.21]
4.8.3 Cold	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	0.63 [0.13, 3.13]
4.8.4 Diarrhoea	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	19.85 [0.49, 805.53]
4.8.5 Dizziness	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	1.51 [0.37, 6.14]
4.8.6 Dry mouth	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	3.78 [0.22, 65.10]
4.8.7 Headache	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	1.48 [0.69, 3.19]
4.8.8 Insomnia	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	2.16 [0.73, 6.38]
4.8.9 Memory difficulty	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	0.71 [0.10, 4.82]
4.8.10 Muscle strain or pain	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	1.21 [0.36, 4.12]
4.8.11 Nausea	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	2.60 [0.62, 10.96]
4.8.12 Rash	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	4.72 [0.29, 76.72]
4.8.13 Sexual dysfunction	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	8.51 [0.19, 386.16]
4.8.14 Shakiness	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	12.28 [0.88, 171.59]
4.8.15 Tiredness	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	3.54 [1.40, 8.96]
4.8.16 Unsteadiness	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	1.57 [0.25, 9.81]
4.8.17 Worsening depression	1	140	Risk Ratio (M‐H, Fixed, 99% CI)	1.13 [0.25, 5.07]

Comparison 4. RCT: sertraline versus cognitive behavioural therapy (CBT)

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Comparison 5. NRSI: citalopram (before and after)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Mean depression scores HAMD‐21 Show forest plot	2	176	Std. Mean Difference (IV, Fixed, 95% CI)	1.17 [0.96, 1.38]

5.2 Mean monthly seizure frequency Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

Comparison 5. NRSI: citalopram (before and after)

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Comparison 6. NRSI: SSRIs (sertraline or citalopram) versus CBT

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Mean depression scores (BDI) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.1.1 BDI at 6 weeks	1	15	Mean Difference (IV, Fixed, 95% CI)	‐2.60 [‐11.58, 6.38]
6.1.2 BDI at 12 weeks	1	15	Mean Difference (IV, Fixed, 95% CI)	‐4.90 [‐14.60, 4.80]
6.2 Remission in depressive symptoms Show forest plot	1	15	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.77, 3.06]

6.3 Seizure frequency per month at 12 weeks Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	‐1.60 [‐5.63, 2.43]

6.4 Withdrawals (any reason) Show forest plot	1	15	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.05, 3.85]

6.5 Quality of life (QOLIE‐31 overall score) Show forest plot	1	15	Mean Difference (IV, Fixed, 95% CI)	‐0.50 [‐19.67, 18.67]

Comparison 6. NRSI: SSRIs (sertraline or citalopram) versus CBT

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