BACKGROUND: Major depression and other depressive conditions are common in people with cancer. These conditions are not easily detectable in clinical practice, due to the overlap between medical and psychiatric symptoms, as described by diagnostic manuals such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD). Moreover, it is particularly challenging to distinguish between pathological and normal reactions to such a severe illness. Depressive symptoms, even in subthreshold manifestations, have a negative impact in terms of quality of life, compliance with anticancer treatment, suicide risk and possibly the mortality rate for the cancer itself. Randomised controlled trials (RCTs) on the efficacy, tolerability and acceptability of antidepressants in this population are few and often report conflicting results.
OBJECTIVES: To evaluate the efficacy, tolerability and acceptability of antidepressants for treating depressive symptoms in adults (aged 18 years or older) with cancer (any site and stage).
SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was November 2022.
SELECTION CRITERIA: We included RCTs comparing antidepressants versus placebo, or antidepressants versus other antidepressants, in adults (aged 18 years or above) with any primary diagnosis of cancer and depression (including major depressive disorder, adjustment disorder, dysthymic disorder or depressive symptoms in the absence of a formal diagnosis).
DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was 1. efficacy as a continuous outcome. Our secondary outcomes were 2. efficacy as a dichotomous outcome, 3. Social adjustment, 4. health-related quality of life and 5. dropouts. We used GRADE to assess certainty of evidence for each outcome.
MAIN RESULTS: We identified 14 studies (1364 participants), 10 of which contributed to the meta-analysis for the primary outcome. Six of these compared antidepressants and placebo, three compared two antidepressants, and one three-armed study compared two antidepressants and placebo. In this update, we included four additional studies, three of which contributed data for the primary outcome. For acute-phase treatment response (six to 12 weeks), antidepressants may reduce depressive symptoms when compared with placebo, even though the evidence is very uncertain. This was true when depressive symptoms were measured as a continuous outcome (standardised mean difference (SMD) -0.52, 95% confidence interval (CI) -0.92 to -0.12; 7 studies, 511 participants; very low-certainty evidence) and when measured as a proportion of people who had depression at the end of the study (risk ratio (RR) 0.74, 95% CI 0.57 to 0.96; 5 studies, 662 participants; very low-certainty evidence). No studies reported data on follow-up response (more than 12 weeks). In head-to-head comparisons, we retrieved data for selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs) and for mirtazapine versus TCAs. There was no difference between the various classes of antidepressants (continuous outcome: SSRI versus TCA: SMD -0.08, 95% CI -0.34 to 0.18; 3 studies, 237 participants; very low-certainty evidence; mirtazapine versus TCA: SMD -4.80, 95% CI -9.70 to 0.10; 1 study, 25 participants). There was a potential beneficial effect of antidepressants versus placebo for the secondary efficacy outcomes (continuous outcome, response at one to four weeks; very low-certainty evidence). There were no differences for these outcomes when comparing two different classes of antidepressants, even though the evidence was very uncertain. In terms of dropouts due to any cause, we found no difference between antidepressants compared with placebo (RR 0.85, 95% CI 0.52 to 1.38; 9 studies, 889 participants; very low-certainty evidence), and between SSRIs and TCAs (RR 0.83, 95% CI 0.53 to 1.22; 3 studies, 237 participants). We downgraded the certainty of the evidence because of the heterogeneous quality of the studies, imprecision arising from small sample sizes and wide CIs, and inconsistency due to statistical or clinical heterogeneity.
AUTHORS' CONCLUSIONS: Despite the impact of depression on people with cancer, the available studies were few and of low quality. This review found a potential beneficial effect of antidepressants against placebo in depressed participants with cancer. However, the certainty of evidence is very low and, on the basis of these results, it is difficult to draw clear implications for practice. The use of antidepressants in people with cancer should be considered on an individual basis and, considering the lack of head-to-head data, the choice of which drug to prescribe may be based on the data on antidepressant efficacy in the general population of people with major depression, also taking into account that data on people with other serious medical conditions suggest a positive safety profile for the SSRIs. Furthermore, this update shows that the usage of the newly US Food and Drug Administration-approved antidepressant esketamine in its intravenous formulation might represent a potential treatment for this specific population of people, since it can be used both as an anaesthetic and an antidepressant. However, data are too inconclusive and further studies are needed. We conclude that to better inform clinical practice, there is an urgent need for large, simple, randomised, pragmatic trials comparing commonly used antidepressants versus placebo in people with cancer who have depressive symptoms, with or without a formal diagnosis of a depressive disorder.
BACKGROUND: Depression is an important morbidity associated with stroke that impacts on recovery, yet is often undetected or inadequately treated.
OBJECTIVES: To evaluate the benefits and harms of pharmacological intervention, non-invasive brain stimulation, psychological therapy, or combinations of these to treat depression after stroke.
SEARCH METHODS: This is a living systematic review. We search for new evidence every two months and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review. We searched the Specialised Registers of Cochrane Stroke, and Cochrane Depression Anxiety and Neurosis, CENTRAL, MEDLINE, Embase, five other databases, two clinical trials registers, reference lists and conference proceedings (February 2022). We contacted study authors.
SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing: 1) pharmacological interventions with placebo; 2) non-invasive brain stimulation with sham stimulation or usual care; 3) psychological therapy with usual care or attention control; 4) pharmacological intervention and psychological therapy with pharmacological intervention and usual care or attention control; 5) pharmacological intervention and non-invasive brain stimulation with pharmacological intervention and sham stimulation or usual care; 6) non-invasive brain stimulation and psychological therapy versus sham brain stimulation or usual care and psychological therapy; 7) pharmacological intervention and psychological therapy with placebo and psychological therapy; 8) pharmacological intervention and non-invasive brain stimulation with placebo and non-invasive brain stimulation; and 9) non-invasive brain stimulation and psychological therapy versus non-invasive brain stimulation and usual care or attention control, with the intention of treating depression after stroke.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, and extracted data from included studies. We calculated mean difference (MD) or standardised mean difference (SMD) for continuous data, and risk ratio (RR) for dichotomous data, with 95% confidence intervals (CIs). We assessed heterogeneity using the I² statistic and certainty of the evidence according to GRADE.
MAIN RESULTS: We included 65 trials (72 comparisons) with 5831 participants. Data were available for: 1) 20 comparisons; 2) nine comparisons; 3) 25 comparisons; 4) three comparisons; 5) 14 comparisons; and 6) one comparison. We found no trials for comparisons 7 to 9. Comparison 1: Pharmacological interventions Very low-certainty evidence from eight trials suggests pharmacological interventions decreased the number of people meeting the study criteria for depression (RR 0.70, 95% CI 0.55 to 0.88; P = 0.002; 8 RCTs; 1025 participants) at end of treatment and very low-certainty evidence from six trials suggests that pharmacological interventions decreased the number of people with inadequate response to treatment (RR 0.47, 95% CI 0.32 to 0.70; P = 0.0002; 6 RCTs; 511 participants) compared to placebo. More adverse events related to the central nervous system (CNS) (RR 1.55, 95% CI 1.12 to 2.15; P = 0.008; 5 RCTs; 488 participants; very low-certainty evidence) and gastrointestinal system (RR 1.62, 95% CI 1.19 to 2.19; P = 0.002; 4 RCTs; 473 participants; very low-certainty evidence) were noted in the pharmacological intervention than in the placebo group. Comparison 2: Non-invasive brain stimulation Very low-certainty evidence from two trials show that non-invasive brain stimulation had little to no effect on the number of people meeting the study criteria for depression (RR 0.67, 95% CI 0.39 to 1.14; P = 0.14; 2 RCTs; 130 participants) and the number of people with inadequate response to treatment (RR 0.84, 95% CI 0.52, 1.37; P = 0.49; 2 RCTs; 130 participants) compared to sham stimulation. Non-invasive brain stimulation resulted in no deaths. Comparison 3: Psychological therapy Very low-certainty evidence from six trials suggests that psychological therapy decreased the number of people meeting the study criteria for depression at end of treatment (RR 0.77, 95% CI 0.62 to 0.95; P = 0.01; 521 participants) compared to usual care/attention control. No trials of psychological therapy reported on the outcome inadequate response to treatment. No differences in the number of deaths or adverse events were found in the psychological therapy group compared to the usual care/attention control group. Comparison 4: Pharmacological interventions with psychological therapy No trials of this combination reported on the primary outcomes. Combination therapy resulted in no deaths. Comparison 5: Pharmacological interventions with non-invasive brain stimulation Non-invasive brain stimulation with pharmacological intervention reduced the number of people meeting study criteria for depression at end of treatment (RR 0.77, 95% CI 0.64 to 0.91; P = 0.002; 3 RCTs; 392 participants; low-certainty evidence) but not the number of people with inadequate response to treatment (RR 0.95, 95% CI 0.69 to 1.30; P = 0.75; 3 RCTs; 392 participants; very low-certainty evidence) compared to pharmacological therapy alone. Very low-certainty evidence from five trials suggest no difference in deaths between this combination therapy (RR 1.06, 95% CI 0.27 to 4.16; P = 0.93; 487 participants) compared to pharmacological therapy intervention and sham stimulation or usual care. Comparison 6: Non-invasive brain stimulation with psychological therapy No trials of this combination reported on the primary outcomes.
AUTHORS' CONCLUSIONS: Very low-certainty evidence suggests that pharmacological, psychological and combination therapies can reduce the prevalence of depression while non-invasive brain stimulation had little to no effect on the prevalence of depression. Pharmacological intervention was associated with adverse events related to the CNS and the gastrointestinal tract. More research is required before recommendations can be made about the routine use of such treatments.
Depression is an independent risk factor for coronary artery disease (CAD). Both illnesses contribute significantly to the global burden of disease. This systematic literature review examines treatment interventions for CAD patients with comorbid depression. We systematically reviewed The Cochrane Library, MEDLINE, EMBASE, PsycINFO, PUBMED, CINAHL and the ISRCTN Registry for English language randomised control trials investigating treatment interventions for depression in adults with CAD and comorbid depression. Data extracted included author name(s), year published, number of participants, enrolment criteria, depression definition/measures (standardised interviews, rating scales), description of control arms and interventions (psychotherapy and/or medications), randomisation, blinding, follow-up duration, follow-up loss, depression scores and medical outcome. The database search revealed 4464 articles. The review yielded 19 trials. Antidepressant and/or psychotherapy did not significantly influence CAD outcomes in the overall population. There was no difference between antidepressant use and aerobic exercises. Psychological interventions and pharmacological interventions provide small effect on depression outcomes in CAD patients. Patient autonomy in choice of treatment is associated with greater depression treatment satisfaction, but the majority of studies are underpowered. More research is required to explore the role of neurostimulation treatment, complementary and alternative treatments.
BACKGROUND: Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients' global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis (NMA) examining all antidepressants across all chronic pain conditions.
OBJECTIVES: To assess the comparative efficacy and safety of antidepressants for adults with chronic pain (except headache).
SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, AMED and PsycINFO databases, and clinical trials registries, for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions in January 2022.
SELECTION CRITERIA: We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant, or the same antidepressant at different doses, then we required the study to be double-blind. We included RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) but rated them as high risk of bias. We excluded RCTs where the follow-up was less than two weeks and those with fewer than 10 participants in each arm. DATA COLLECTION AND ANALYSIS: Two review authors separately screened, data extracted, and judged risk of bias. We synthesised the data using Bayesian NMA and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve (SUCRA). We primarily used Confidence in Meta-Analysis (CINeMA) and Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used GRADE to assess the certainty of the evidence. Our primary outcomes were substantial (50%) pain relief, pain intensity, mood, and adverse events. Our secondary outcomes were moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events, and withdrawal.
MAIN RESULTS: This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (83), and parallel-armed (141). The most common pain conditions examined were fibromyalgia (59 studies); neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks. Seven studies provided no useable data and were omitted from the NMA. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine studies, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Primary efficacy outcomes Duloxetine standard dose (60 mg) showed a small to moderate effect for substantial pain relief (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.69 to 2.17; 16 studies, 4490 participants; moderate-certainty evidence) and continuous pain intensity (standardised mean difference (SMD) -0.31, 95% CI -0.39 to -0.24; 18 studies, 4959 participants; moderate-certainty evidence). For pain intensity, milnacipran standard dose (100 mg) also showed a small effect (SMD -0.22, 95% CI -0.39 to 0.06; 4 studies, 1866 participants; moderate-certainty evidence). Mirtazapine (30 mg) had a moderate effect on mood (SMD -0.5, 95% CI -0.78 to -0.22; 1 study, 406 participants; low-certainty evidence), while duloxetine showed a small effect (SMD -0.16, 95% CI -0.22 to -0.1; 26 studies, 7952 participants; moderate-certainty evidence); however it is important to note that most studies excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the 'normal' or 'subclinical' ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life, and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events, and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes.
AUTHORS' CONCLUSIONS: Our review and NMAs show that despite studies investigating 25 different antidepressants, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Evidence for all other antidepressants was low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point.
BACKGROUND: Antidepressants may be useful in the treatment of abnormal crying associated with stroke. This is an update of a Cochrane Review first published in 2004 and last updated in 2019.
OBJECTIVES: To evaluate the benefits and harms of pharmaceutical treatment in people with emotionalism after stroke.
SEARCH METHODS: We searched the Cochrane Stroke Group Register, CENTRAL, MEDLINE, Embase, four other databases, and three trials registers (May 2022).
SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing psychotropic medication to placebo in people with stroke and emotionalism (also known as emotional lability, pathological crying or laughing, emotional incontinence, involuntary emotional expression disorder, and pseudobulbar affect).
DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed risk of bias, extracted data from all included trials, and used GRADE to assess the certainty of the body of evidence. We calculated the mean difference (MD) or standardised mean difference (SMD) for continuous data and the risk ratio (RR) for dichotomous data, with 95% confidence intervals (CIs). We assessed heterogeneity using the I2 statistic. The primary emotionalism measures were the proportion of participants achieving at least a 50% reduction in abnormal emotional behaviour at the end of treatment, improved score on the Center for Neurologic Study - Lability Scale (CNS-LS) or Clinician Interview-Based Impression of Change (CIBIC), or diminished tearfulness.
MAIN RESULTS: We did not identify any new trials for this update. We included seven trials with a total of 239 participants. Two trials had a cross-over design, but outcome data were not available from the first phase (precross-over) in an appropriate format for inclusion as a parallel randomised controlled trial (RCT). Thus, the results of the review are based on five trials with a total of 213 participants. It is uncertain whether fluoxetine increases the number of people who have a 50% reduction in emotionalism when compared to placebo (risk ratio (RR) 0.26, 95% CI 0.09 to 0.77; P = 0.02; 1 trial, 19 participants) because the certainty of evidence is very low. Sertraline may lead to little to no difference in Center for Neurologic Study - Lability Scale (CNS-LS) scores and Clinician Interview-Based Impression of Change (CIBIC) scores when compared to placebo (RR 0.20, 95% CI 0.03 to 1.50; P = 0.12; 1 trial, 28 participants; low-certainty evidence). Antidepressants probably increase the number of people who experience a reduction in tearfulness (RR 0.32, 95% CI 0.12 to 0.86; P = 0.02; 3 trials, 164 participants; moderate-certainty evidence). No trials were found that evaluated the impact of other pharmaceutical interventions. Only two trial authors systematically recorded and reported adverse events, resulting in limited data on the potential harms of treatment. Six trials reported death as an adverse event and found no difference between the groups (antidepressants versus placebo) in the number of deaths reported (RR 0.59, 95% CI 0.08 to 4.50; P = 0.61; 172 participants; moderate-certainty evidence). This review provides very low- to moderate-certainty evidence that antidepressants may reduce the frequency and severity of emotionalism. The included trials were small and had some degree of bias.
AUTHORS' CONCLUSIONS: Antidepressants may reduce the frequency and severity of crying or laughing episodes when compared to placebo, based on very low-certainty evidence. Our conclusions must be qualified by several methodological deficiencies in the trials and interpreted with caution despite the effect being very large. The effect does not seem specific to one drug or class of drugs. More reliable data are required before appropriate conclusions can be made about the treatment of post-stroke emotionalism. Future trialists investigating the effect of antidepressants in people with emotionalism after stroke should consider developing and using a standardised method to diagnose emotionalism, determine severity, and assess change over time; provide treatment for a sufficient duration and follow-up to better assess rates of relapse or maintenance; and include careful assessment and complete reporting of adverse events.
BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) might theoretically reduce post-stroke disability by direct effects on the brain. This Cochrane Review was first published in 2012 and last updated in 2019.
OBJECTIVES: To determine if SSRIs are more effective than placebo or usual care at improving outcomes in people less than 12 months post-stroke, and to determine whether treatment with SSRIs is associated with adverse effects.
SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched 7 January 2021), Cochrane Controlled Trials Register (CENTRAL, Issue 7 of 12, 7 January 2021), MEDLINE (1946 to 7 January 2021), Embase (1974 to 7 January 2021), CINAHL (1982 to 7 January 2021), PsycINFO (1985 to 7 January 2021), and AMED (1985 to 7 January 2021). PsycBITE had previously been searched (16 July 2018). We searched clinical trials registers.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) recruiting stroke survivors within the first year. The intervention was any SSRI, at any dose, for any period, and for any indication. The comparator was usual care or placebo. Studies reporting at least one of our primary (disability score or independence) or secondary outcomes (impairments, depression, anxiety, quality of life, fatigue, cognition, healthcare cost, death, adverse events and leaving the study early) were included in the meta-analysis. The primary analysis included studies at low risk of bias.
DATA COLLECTION AND ANALYSIS: We extracted data on demographics, stroke type and, our pre-specified outcomes, and bias sources. Two review authors independently extracted data. We used mean difference (MD) or standardised mean differences (SMDs) for continuous variables, and risk ratios (RRs) for dichotomous variables, with 95% confidence intervals (CIs). We assessed bias risks and applied GRADE criteria.
MAIN RESULTS: We identified 76 eligible studies (13,029 participants); 75 provided data at end of treatment, and of these two provided data at follow-up. Thirty-eight required participants to have depression to enter. The duration, drug, and dose varied. Six studies were at low risk of bias across all domains; all six studies did not need participants to have depression to enter, and all used fluoxetine. Of these six studies, there was little to no difference in disability between groups SMD -0.0; 95% CI -0.05 to 0.05; 5 studies, 5436 participants, high-quality evidence) or in independence (RR 0.98; 95% CI 0.93 to 1.03; 5 studies, 5926 participants; high-quality evidence) at the end of treatment. In the studies at low risk of bias across all domains, SSRIs slightly reduced the average depression score (SMD 0.14 lower, 95% CI 0.19 lower to 0.08 lower; 4 studies; 5356 participants, high-quality evidence) and there was a slight reduction in the proportion with depression (RR 0.75, 95% CI 0.65 to 0.86; 3 studies, 5907 participants, high-quality evidence). Cognition was slightly better in the control group (MD -1.22, 95% CI -2.37 to -0.07; 4 studies, 5373 participants, moderate-quality evidence). Only one study (n = 30) reported neurological deficit score (SMD -0.39, 95% CI -1.12 to 0.33; low-quality evidence). SSRIs resulted in little to no difference in motor deficit (SMD 0.03, -0.02 to 0.08; 6 studies, 5518 participants, moderate-quality evidence). SSRIs slightly increased the proportion leaving the study early (RR 1.57, 95% CI 1.03 to 2.40; 6 studies, 6090 participants, high-quality evidence). SSRIs slightly increased the outcome of a seizure (RR 1.40, 95% CI 1.00 to 1.98; 6 studies, 6080 participants, moderate-quality evidence) and a bone fracture (RR 2.35, 95% CI 1.62 to 3.41; 6 studies, 6080 participants, high-quality evidence). One study at low risk of bias across all domains reported gastrointestinal side effects (RR 1.71, 95% CI 0.33, to 8.83; 1 study, 30 participants). There was no difference in the total number of deaths between SSRI and placebo (RR 1.01, 95% CI 0.82 to 1.24; 6 studies, 6090 participants, moderate quality evidence). SSRIs probably result in little to no difference in fatigue (MD -0.06; 95% CI -1.24 to 1.11; 4 studies, 5524 participants, moderate-quality of evidence), nor in quality of life (MD 0.00; 95% CI -0.02 to 0.02, 3 studies, 5482 participants, high-quality evidence). When all studies, irrespective of risk of bias, were included, SSRIs reduced disability scores but not the proportion independent. There was insufficient data to perform a meta-analysis of outcomes at end of follow-up. Several small ongoing studies are unlikely to alter conclusions.
AUTHORS' CONCLUSIONS: There is high-quality evidence that SSRIs do not make a difference to disability or independence after stroke compared to placebo or usual care, reduced the risk of future depression, increased bone fractures and probably increased seizure risk.
BACKGROUND: Depressive disorders are the most common psychiatric comorbidity in people with epilepsy, affecting around one-third, with a significant negative impact on quality of life. There is concern that people may not be receiving appropriate treatment for their depression because of uncertainty regarding which antidepressant or class works best, and the perceived risk of exacerbating seizures. This review aimed to address these issues, and inform clinical practice and future research. This is an updated version of the original Cochrane Review published in Issue 12, 2014.
OBJECTIVES: To evaluate the efficacy and safety of antidepressants in treating depressive symptoms and the effect on seizure recurrence, in people with epilepsy and depression.
SEARCH METHODS: For this update, we searched CRS Web, MEDLINE, SCOPUS, PsycINFO, and ClinicalTrials.gov (February 2021). We searched the World Health Organization Clinical Trials Registry in October 2019, but were unable to update it because it was inaccessible. There were no language restrictions.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) and prospective non-randomised studies of interventions (NRSIs), investigating children or adults with epilepsy, who were treated with an antidepressant and compared to placebo, comparative antidepressant, psychotherapy, or no treatment for depressive symptoms. DATA COLLECTION AND ANALYSIS: The primary outcomes were changes in depression scores (proportion with a greater than 50% improvement, mean difference, and proportion who achieved complete remission) and change in seizure frequency (mean difference, proportion with a seizure recurrence, or episode of status epilepticus). Secondary outcomes included the number of participants who withdrew from the study and reasons for withdrawal, quality of life, cognitive functioning, and adverse events. Two review authors independently extracted data for each included study. We then cross-checked the data extraction. We assessed risk of bias using the Cochrane tool for RCTs, and the ROBINS-I for NRSIs. We presented binary outcomes as risk ratios (RRs) with 95% confidence intervals (CIs) or 99% CIs for specific adverse events. We presented continuous outcomes as standardised mean differences (SMDs) with 95% CIs, and mean differences (MDs) with 95% CIs. MAIN RESULTS: We included 10 studies in the review (four RCTs and six NRSIs), with 626 participants with epilepsy and depression, examining the effects of antidepressants. One RCT was a multi-centre study comparing an antidepressant with cognitive behavioural therapy (CBT). The other three RCTs were single-centre studies comparing an antidepressant with an active control, placebo, or no treatment. The NRSIs reported on outcomes mainly in participants with focal epilepsy before and after treatment for depression with a selective serotonin reuptake inhibitor (SSRI); one NRSI compared SSRIs to CBT. We rated one RCT at low risk of bias, three RCTs at unclear risk of bias, and all six NRSIs at serious risk of bias. We were unable to conduct any meta-analysis of RCT data due to heterogeneity of treatment comparisons. We judged the certainty of evidence to be moderate to very low across comparisons, because single studies contributed limited outcome data, and because of risk of bias, particularly for NRSIs, which did not adjust for confounding variables. More than 50% improvement in depressive symptoms ranged from 43% to 82% in RCTs, and from 24% to 97% in NRSIs, depending on the antidepressant given. Venlafaxine improved depressive symptoms by more than 50% compared to no treatment (mean difference (MD) -7.59 (95% confidence interval (CI) -11.52 to -3.66; 1 study, 64 participants; low-certainty evidence); the results between other comparisons were inconclusive. Two studies comparing SSRIs to CBT reported inconclusive results for the proportion of participants who achieved complete remission of depressive symptoms. Seizure frequency data did not suggest an increased risk of seizures with antidepressants compared to control treatments or baseline. Two studies measured quality of life; antidepressants did not appear to improve quality of life over control. No studies reported on cognitive functioning. Two RCTs and one NRSI reported comparative data on adverse events; antidepressants did not appear to increase the severity or number of adverse events compared to controls. The NSRIs reported higher rates of withdrawals due to adverse events than lack of efficacy. Reported adverse events for antidepressants included nausea, dizziness, sedation, headache, gastrointestinal disturbance, insomnia, and sexual dysfunction. AUTHORS' CONCLUSIONS: Existing evidence on the effectiveness of antidepressants in treating depressive symptoms associated with epilepsy is still very limited. Rates of response to antidepressants were highly variable. There is low certainty evidence from one small RCT (64 participants) that venlafaxine may improve depressive symptoms more than no treatment; this evidence is limited to treatment between 8 and 16 weeks, and does not inform longer-term effects. Moderate to low evidence suggests neither an increase nor exacerbation of seizures with SSRIs. There are no available comparative data to inform the choice of antidepressant drug or classes of drug for efficacy or safety for treating people with epilepsy and depression. RCTs of antidepressants utilising interventions from other treatment classes besides SSRIs, in large samples of patients with epilepsy and depression, are needed to better inform treatment policy. Future studies should assess interventions across a longer treatment duration to account for delayed onset of action, sustainability of treatment responses, and to provide a better understanding of the impact on seizure control.
BACKGROUND: Depression is an important consequence of stroke that influences recovery yet often is not detected, or is inadequately treated. This is an update and expansion of a Cochrane Review first published in 2004 and previously updated in 2008.
OBJECTIVES: The primary objective is to test the hypothesis that pharmacological, psychological therapy, non-invasive brain stimulation, or combinations of these interventions reduce the incidence of diagnosable depression after stroke. Secondary objectives are to test the hypothesis that pharmacological, psychological therapy, non-invasive brain stimulation or combinations of these interventions reduce levels of depressive symptoms and dependency, and improve physical functioning after stroke. We also aim to determine the safety of, and adherence to, the interventions.
SEARCH METHODS: We searched the Specialised Register of Cochrane Stroke and the Cochrane Depression Anxiety and Neurosis (last searched August 2018). In addition, we searched the following databases; Cochrane Central Register of Controlled Trials, CENTRAL (the Cochrane Library, 2018, Issue 8), MEDLINE (1966 to August 2018), Embase (1980 to August 2018), PsycINFO (1967 to August 2018), CINAHL (1982 to August 2018) and three Web of Science indexes (2002 to August 2018). We also searched reference lists, clinical trial registers (World Health Organization International Clinical Trials Registry Platform (WHO ICTRP); to August 2018 and ClinicalTrials.gov; to August 2018), conference proceedings; we also contacted study authors.
SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing: 1) pharmacological interventions with placebo; 2) one of various forms of psychological therapy with usual care and/or attention control; 3) one of various forms of non-invasive brain stimulation with sham stimulation or usual care; 4) a pharmacological intervention and one of various forms of psychological therapy with a pharmacological intervention and usual care and/or attention control; 5) non-invasive brain stimulation and pharmacological intervention with a pharmacological intervention and sham stimulation or usual care; 6) pharmacological intervention and one of various forms of psychological therapy with placebo and psychological therapy; 7) pharmacological intervention and non-invasive brain stimulation with placebo plus non-invasive brain stimulation; 8) non-invasive brain stimulation and one of various forms of psychological therapy versus non-invasive brain stimulation plus usual care and/or attention control; and 9) non-invasive brain stimulation and one of various forms of psychological therapy versus sham brain stimulation or usual care plus psychological therapy, with the intention of preventing depression after stroke.
DATA COLLECTION AND ANALYSIS: Review authors independently selected studies, assessed risk of bias, and extracted data from all included studies. We calculated mean difference (MD) or standardised mean difference (SMD) for continuous data and risk ratio (RR) for dichotomous data with 95% confidence intervals (CIs). We assessed heterogeneity using the I2 statistic and assessed the certainty of evidence using GRADE.
MAIN RESULTS: We included 19 RCTs (21 interventions), with 1771 participants in the review. Data were available for 12 pharmacological trials (14 interventions) and seven psychological trials. There were no trials of non-invasive brain stimulation compared with sham stimulation or usual care, a combination of pharmacological intervention and one of various forms of psychological therapy with placebo and psychological therapy, or a combination of non-invasive brain stimulation and a pharmacological intervention with a pharmacological intervention and sham stimulation or usual care to prevent depression after stroke. Treatment effects were observed on the primary outcome of meeting the study criteria for depression at the end of treatment: there is very low-certainty evidence from eight trials (nine interventions) that pharmacological interventions decrease the number of people meeting the study criteria for depression (RR 0.50, 95% CI 0.37 to 0.68; 734 participants) compared to placebo. There is very low-certainty evidence from two trials that psychological interventions reduce the proportion of people meeting the study criteria for depression (RR 0.68, 95% CI 0.49 to 0.94, 607 participants) compared to usual care and/or attention control. Eight trials (nine interventions) found no difference in death and other adverse events between pharmacological intervention and placebo groups (RR 1.25, 95% CI 0.32 to 4.91; 496 participants) based on very low-certainty evidence. Five trials found no difference in psychological intervention and usual care and/or attention control groups for death and other adverse events (RR 1.18, 95% CI 0.73 to 1.91; 975 participants) based on very low-certainty evidence.
AUTHORS' CONCLUSIONS: The available evidence suggests that pharmacological interventions and psychological therapy may prevent depression and improve mood after stroke. However, there is very low certainty in these conclusions because of the very low-certainty evidence. More trials are required before reliable recommendations can be made about the routine use of such treatments after stroke.
OBJECTIVE: To systematically review and analyze the efficacy and tolerability of different antidepressant pharmacologic treatments for depressive symptoms in Parkinson's disease (PD) METHODS: We searched PubMed, EMBASE, Cochrane database (CENTRAL), clinicaltrials.gov, and bibliographies for randomized controlled trials investigating the efficacy of antidepressant medications versus a non‐treatment, placebo, or active treatment groups for depressive symptoms in PD. Twenty of 3191 retrieved studies (1893 patients) were included, but not all could be meta-analyzed. We used a random‐effects model meta‐analysis to compare depression scores between an active drug and placebo or control group then used a network meta‐analysis to compare the effectiveness of different antidepressant classes. The primary outcome was the efficacy of different classes of antidepressant medications in PD patients with depressive symptoms, measured by standardized mean difference (SMD) in depression score from baseline compared with control. RESULTS: Pairwise meta‐analysis suggested that type B‐selective monoamine oxidase inhibitors (SMD = −1.28, CI = −1.68, −0.88), selective serotonin reuptake inhibitors (SMD = −0.49, CI = −0.93, −0.05), and tricyclics (SMD = −0.83, CI = −1.53, −0.13) are effective antidepressants in PD. Network meta‐analysis showed that monoamine oxidase inhibitors had the largest effect on depression in PD (SMD (vs selective serotonin reuptake inhibitors) = −0.78, CI = −1.55, −0.01), but these might not be considered traditional antidepressants given their type B selectivity. CONCLUSIONS: Although limited by few data, this review suggests that multiple antidepressant classes are potentially efficacious in the treatment of depression in PD, but that further comparative efficacy and tolerability research is needed. (PsycInfo Database Record (c) 2021 APA, all rights reserved)
Major depression and other depressive conditions are common in people with cancer. These conditions are not easily detectable in clinical practice, due to the overlap between medical and psychiatric symptoms, as described by diagnostic manuals such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD). Moreover, it is particularly challenging to distinguish between pathological and normal reactions to such a severe illness. Depressive symptoms, even in subthreshold manifestations, have a negative impact in terms of quality of life, compliance with anticancer treatment, suicide risk and possibly the mortality rate for the cancer itself. Randomised controlled trials (RCTs) on the efficacy, tolerability and acceptability of antidepressants in this population are few and often report conflicting results.
OBJECTIVES:
To evaluate the efficacy, tolerability and acceptability of antidepressants for treating depressive symptoms in adults (aged 18 years or older) with cancer (any site and stage).
SEARCH METHODS:
We used standard, extensive Cochrane search methods. The latest search date was November 2022.
SELECTION CRITERIA:
We included RCTs comparing antidepressants versus placebo, or antidepressants versus other antidepressants, in adults (aged 18 years or above) with any primary diagnosis of cancer and depression (including major depressive disorder, adjustment disorder, dysthymic disorder or depressive symptoms in the absence of a formal diagnosis).
DATA COLLECTION AND ANALYSIS:
We used standard Cochrane methods. Our primary outcome was 1. efficacy as a continuous outcome. Our secondary outcomes were 2. efficacy as a dichotomous outcome, 3. Social adjustment, 4. health-related quality of life and 5. dropouts. We used GRADE to assess certainty of evidence for each outcome.
MAIN RESULTS:
We identified 14 studies (1364 participants), 10 of which contributed to the meta-analysis for the primary outcome. Six of these compared antidepressants and placebo, three compared two antidepressants, and one three-armed study compared two antidepressants and placebo. In this update, we included four additional studies, three of which contributed data for the primary outcome. For acute-phase treatment response (six to 12 weeks), antidepressants may reduce depressive symptoms when compared with placebo, even though the evidence is very uncertain. This was true when depressive symptoms were measured as a continuous outcome (standardised mean difference (SMD) -0.52, 95% confidence interval (CI) -0.92 to -0.12; 7 studies, 511 participants; very low-certainty evidence) and when measured as a proportion of people who had depression at the end of the study (risk ratio (RR) 0.74, 95% CI 0.57 to 0.96; 5 studies, 662 participants; very low-certainty evidence). No studies reported data on follow-up response (more than 12 weeks). In head-to-head comparisons, we retrieved data for selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs) and for mirtazapine versus TCAs. There was no difference between the various classes of antidepressants (continuous outcome: SSRI versus
TCA:
SMD -0.08, 95% CI -0.34 to 0.18; 3 studies, 237 participants; very low-certainty evidence; mirtazapine versus
TCA:
SMD -4.80, 95% CI -9.70 to 0.10; 1 study, 25 participants). There was a potential beneficial effect of antidepressants versus placebo for the secondary efficacy outcomes (continuous outcome, response at one to four weeks; very low-certainty evidence). There were no differences for these outcomes when comparing two different classes of antidepressants, even though the evidence was very uncertain. In terms of dropouts due to any cause, we found no difference between antidepressants compared with placebo (RR 0.85, 95% CI 0.52 to 1.38; 9 studies, 889 participants; very low-certainty evidence), and between SSRIs and TCAs (RR 0.83, 95% CI 0.53 to 1.22; 3 studies, 237 participants). We downgraded the certainty of the evidence because of the heterogeneous quality of the studies, imprecision arising from small sample sizes and wide CIs, and inconsistency due to statistical or clinical heterogeneity.
AUTHORS' CONCLUSIONS:
Despite the impact of depression on people with cancer, the available studies were few and of low quality. This review found a potential beneficial effect of antidepressants against placebo in depressed participants with cancer. However, the certainty of evidence is very low and, on the basis of these results, it is difficult to draw clear implications for practice. The use of antidepressants in people with cancer should be considered on an individual basis and, considering the lack of head-to-head data, the choice of which drug to prescribe may be based on the data on antidepressant efficacy in the general population of people with major depression, also taking into account that data on people with other serious medical conditions suggest a positive safety profile for the SSRIs. Furthermore, this update shows that the usage of the newly US Food and Drug Administration-approved antidepressant esketamine in its intravenous formulation might represent a potential treatment for this specific population of people, since it can be used both as an anaesthetic and an antidepressant. However, data are too inconclusive and further studies are needed. We conclude that to better inform clinical practice, there is an urgent need for large, simple, randomised, pragmatic trials comparing commonly used antidepressants versus placebo in people with cancer who have depressive symptoms, with or without a formal diagnosis of a depressive disorder.
