Antidepressants for insomnia in adults Everitt, Hazel; Baldwin, David S; Stuart, Beth ...
Cochrane database of systematic reviews,
05/2018, Letnik:
2018, Številka:
5
Journal Article
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Background
Insomnia disorder is a subjective condition of unsatisfactory sleep (e.g. sleep onset, maintenance, early waking, impairment of daytime functioning). Insomnia disorder impairs quality of ...life and is associated with an increased risk of physical and mental health problems including anxiety, depression, drug and alcohol abuse, and increased health service use. hypnotic medications (e.g. benzodiazepines and 'Z' drugs) are licensed for sleep promotion, but can induce tolerance and dependence, although many people remain on long‐term treatment. Antidepressant use for insomnia is widespread, but none is licensed for insomnia and the evidence for their efficacy is unclear. This use of unlicensed medications may be driven by concern over longer‐term use of hypnotics and the limited availability of psychological treatments.
Objectives
To assess the effectiveness, safety and tolerability of antidepressants for insomnia in adults.
Search methods
This review incorporated the results of searches to July 2015 conducted on electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 6), MEDLINE (1950 to 2015), Embase (1980 to 2015) and PsycINFO (1806 to 2015). We updated the searches to December 2017, but these results have not yet been incorporated into the review.
Selection criteria
Randomised controlled trials (RCTs) of adults (aged 18 years or older) with a primary diagnosis of insomnia and all participant types including people with comorbidities. Any antidepressant as monotherapy at any dose whether compared with placebo, other medications for insomnia (e.g. benzodiazepines and 'Z' drugs), a different antidepressant, waiting list control or treatment as usual.
Data collection and analysis
Two review authors independently assessed trials for eligibility and extracted data using a data extraction form. A third review author resolved disagreements on inclusion or data extraction.
Main results
The search identified 23 RCTs (2806 participants).
Selective serotonin reuptake inhibitors (SSRIs) compared with placebo: three studies (135 participants) compared SSRIs with placebo. Combining results was not possible. Two paroxetine studies showed significant improvements in subjective sleep measures at six (60 participants, P = 0.03) and 12 weeks (27 participants, P < 0.001). There was no difference in the fluoxetine study (low quality evidence).
There were either no adverse events or they were not reported (very low quality evidence).
Tricyclic antidepressants (TCA) compared with placebo: six studies (812 participants) compared TCA with placebo; five used doxepin and one used trimipramine. We found no studies of amitriptyline. Four studies (518 participants) could be pooled, showing a moderate improvement in subjective sleep quality over placebo (standardised mean difference (SMD) ‐0.39, 95% confidence interval (CI) ‐0.56 to ‐0.21) (moderate quality evidence). Moderate quality evidence suggested that TCAs possibly improved sleep efficiency (mean difference (MD) 6.29 percentage points, 95% CI 3.17 to 9.41; 4 studies; 510 participants) and increased sleep time (MD 22.88 minutes, 95% CI 13.17 to 32.59; 4 studies; 510 participants). There may have been little or no impact on sleep latency (MD ‐4.27 minutes, 95% CI ‐9.01 to 0.48; 4 studies; 510 participants).
There may have been little or no difference in adverse events between TCAs and placebo (risk ratio (RR) 1.02, 95% CI 0.86 to 1.21; 6 studies; 812 participants) (low quality evidence).
'Other' antidepressants with placebo: eight studies compared other antidepressants with placebo (one used mianserin and seven used trazodone). Three studies (370 participants) of trazodone could be pooled, indicating a moderate improvement in subjective sleep outcomes over placebo (SMD ‐0.34, 95% CI ‐0.66 to ‐0.02). Two studies of trazodone measured polysomnography and found little or no difference in sleep efficiency (MD 1.38 percentage points, 95% CI ‐2.87 to 5.63; 169 participants) (low quality evidence).
There was low quality evidence from two studies of more adverse effects with trazodone than placebo (i.e. morning grogginess, increased dry mouth and thirst).
Authors' conclusions
We identified relatively few, mostly small studies with short‐term follow‐up and design limitations. The effects of SSRIs compared with placebo are uncertain with too few studies to draw clear conclusions. There may be a small improvement in sleep quality with short‐term use of low‐dose doxepin and trazodone compared with placebo. The tolerability and safety of antidepressants for insomnia is uncertain due to limited reporting of adverse events. There was no evidence for amitriptyline (despite common use in clinical practice) or for long‐term antidepressant use for insomnia. High‐quality trials of antidepressants for insomnia are needed.
Rationale
Cytochrome P450 enzymes are important in the metabolism of antidepressants. The highly polymorphic nature of these enzymes has been linked to variability in antidepressant metabolism rates, ...leading to hope regarding the use of P450 genotyping to guide treatment. However, evidence that P450 genotypic differences underlie the variation in treatment outcomes is inconclusive.
Objectives
We explored the links between both P450 genotype and serum concentrations of antidepressant with antidepressant side effects, using data from the Genome-Based Therapeutic Drugs for Depression Project (GENDEP), which is a large (
n
= 868), pharmacogenetic study of depressed individuals treated with escitalopram or nortriptyline.
Methods
Patients were genotyped for the enzymes CYP2C19 and CYP2D6, and serum concentrations of both antidepressant and primary metabolite were measured after 8 weeks of treatment. Side effects were assessed weekly. We investigated associations between P450 genotypes, serum concentrations of antidepressants and side effects, as well as the relationship between P450 genotype and study discontinuation.
Results
P450 genotype did not predict total side effect burden (nortriptyline:
n
= 251,
p
= 0.5638,
β
= −0.133, standard error (SE) = 0.229; escitalopram:
n
= 340,
p
= 0.9627,
β
= −0.004, SE = 0.085), study discontinuation (nortriptyline
n
= 284, hazard ratio (HR) = 1.300,
p
= 0.174; escitalopram
n
= 376, HR = 0.870,
p
= 0.118) or specific side effects. Serum concentrations of antidepressant were only related to a minority of the specific side effects measured: dry mouth, dizziness and diarrhoea.
Conclusions
In this sample where antidepressant dosage is titrated using clinical judgement, P450 genotypes do not explain differences between patients in side effects with antidepressants. Serum drug concentrations appear to only explain variability in the occurrence of a minority of specific side effects.
In a randomized trial involving 59 selected patients with depression, the change in depression scale scores from baseline to week 6 did not differ significantly between patients who received two ...doses of psilocybin and those who received daily escitalopram. Secondary outcomes generally favored psilocybin over escitalopram.
IMPORTANCE: Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 ...administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression. OBJECTIVE: To investigate the effect of psilocybin therapy in patients with MDD. DESIGN, SETTING, AND PARTICIPANTS: This randomized, waiting list–controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population). INTERVENTIONS: Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay. MAIN OUTCOMES AND MEASURES: The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR). RESULTS: Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 7.1 and 8.5 5.7) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 5.4 and 23.5 6.0) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.5; 95% CI, 1.4-3.5; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.5-3.7; P < .001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 3.5 vs 6.3 4.4; Cohen d = 2.6; 95% CI, 1.8-3.5; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 5.7; Cohen d = 2.3; 95% CI, 1.5-3.0; P < .001). In the overall sample, 17 participants (71%) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score). CONCLUSIONS AND RELEVANCE: Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03181529
Background
Functional Abdominal Pain Disorders (FAPDs) present a considerable burden to paediatric patients, impacting quality of life, school attendance and causing higher rates of anxiety and ...depression disorders. There are no international guidelines for the management of this condition. A previous Cochrane Review in 2011 found no evidence to support the use of antidepressants in this context.
Objectives
To evaluate the current evidence for the efficacy and safety of antidepressants for FAPDs in children and adolescents.
Search methods
In this updated review, we searched The Cochrane Library, PubMed, MEDLINE, EMBASE, PsycINFO and two clinical trial registers from inception until February 3th, 2020. We also updated our search of databases of ongoing research, reference lists and 'grey literature' from inception to February 3th, 2020.
Selection criteria
We included randomised controlled trials (RCTs) comparing antidepressants to placebo, to no treatment or to any other intervention, in children aged 4 to 18 years with a FAPD diagnosis as per the Rome or any other defined criteria (as defined by the authors). The primary outcomes of interest included treatment success (as defined by the authors), pain severity, pain frequency and withdrawal due to adverse events.
Data collection and analysis
All citations were reviewed independently by two authors, with disagreement solved with a third‐party arbiter. All potential studies had full texts reviewed, and once again, independent decisions made, with disagreement solved by consensus. Data extraction and risk of bias assessment was completed independently following Cochrane standards. Where homogenous data was available, meta‐analysis was performed using a random effects model. GRADE assessement of the certainty of the evidence was performed.
Main results
Three studies were eligible for inclusion: two using amitriptyline (AMI) and one using citalopram. The studies recruited 223 children diagnosed with either Rome II or Rome III criteria.
For the primary outcome of treatment success, two studies used report of success on a symptom‐based Likert scale, with either a two‐point reduction or the two lowest levels defined as success. The other study defined success as a 15% improvement in Quality of life (QOL) rating scales, which could not be included in the meta‐analysis due to the heterogeneity of the outcome measure. There is insufficient evidence to determine the effects of antidepressants compared with placebo on treatment success (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.87 ‐ 1.56; 2 studies, 205 participants; low certainty evidence). We downgraded the evidence due to significant imprecision due to extremely sparse data.
We are uncertain whether children were more likely to withdraw due to adverse events with antidepressants or placebo, RR 3.80 (95% CI 0.61 ‐ 23.57, very serious imprecision due to low events and number of participants. Sensitivity analysis using a fixed effect model and analysing just for AMI found no change in this result. Due to heterogeneous and limited reporting, no further meta‐analysis was possible for other outcomes of pain severity or frequency.
Authors' conclusions
There is insufficient evidence to determine the effect of antidepressants on treatment success of FAPDs in childhood when compared with placebo (low certainty evidence). The small number of participants in the studies and low number of withdrawals did not enable us to determine reliably whether children are likely to stop taking medication due to adverse events (low certainty evidence). There is currently very little evidence to support clinical decision‐making regarding the use of these medications. Further studies must consider sample size, homogenous and relevant outcome measures and longer follow up.
Ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists (NMDAR antagonists) recently demonstrated antidepressant efficacy for the treatment of refractory depression, but effect sizes, ...trajectories and possible class effects are unclear.
We searched PubMed/PsycINFO/Web of Science/clinicaltrials.gov until 25 August 2015. Parallel-group or cross-over randomized controlled trials (RCTs) comparing single intravenous infusion of ketamine or a non-ketamine NMDAR antagonist v. placebo/pseudo-placebo in patients with major depressive disorder (MDD) and/or bipolar depression (BD) were included in the analyses. Hedges' g and risk ratios and their 95% confidence intervals (CIs) were calculated using a random-effects model. The primary outcome was depressive symptom change. Secondary outcomes included response, remission, all-cause discontinuation and adverse effects.
A total of 14 RCTs (nine ketamine studies: n = 234; five non-ketamine NMDAR antagonist studies: n = 354; MDD = 554, BD = 34), lasting 10.0 ± 8.8 days, were meta-analysed. Ketamine reduced depression significantly more than placebo/pseudo-placebo beginning at 40 min, peaking at day 1 (Hedges' g = -1.00, 95% CI -1.28 to -0.73, p < 0.001), and loosing superiority by days 10-12. Non-ketamine NMDAR antagonists were superior to placebo only on days 5-8 (Hedges' g = -0.37, 95% CI -0.66 to -0.09, p = 0.01). Compared with placebo/pseudo-placebo, ketamine led to significantly greater response (40 min to day 7) and remission (80 min to days 3-5). Non-ketamine NMDAR antagonists achieved greater response at day 2 and days 3-5. All-cause discontinuation was similar between ketamine (p = 0.34) or non-ketamine NMDAR antagonists (p = 0.94) and placebo. Although some adverse effects were more common with ketamine/NMDAR antagonists than placebo, these were transient and clinically insignificant.
A single infusion of ketamine, but less so of non-ketamine NMDAR antagonists, has ultra-rapid efficacy for MDD and BD, lasting for up to 1 week. Development of easy-to-administer, repeatedly given NMDAR antagonists without risk of brain toxicity is of critical importance.
Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients ...require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-d-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.
A significant clinical issue encountered after a successful acute major depressive disorder (MDD) treatment is the relapse of depressive symptoms. Although continuing maintenance therapy with ...antidepressants is generally recommended, there is no established protocol on whether or not it is necessary to prescribe the antidepressant used to achieve remission. In this meta-analysis, the risk of relapse and treatment failure when either continuing with the same drug used to achieved remission or switching to a placebo was assessed in several clinically significant subgroups. The pooled odds ratio (OR) (±95% confidence intervals (CI)) was calculated using a random effects model. Across 40 studies (n = 8890), the relapse rate was significantly lower in the antidepressant group than the placebo group by about 20% (OR = 0.38, CI: 0.33-0.43, p < 0.00001; 20.9% vs 39.7%). The difference in the relapse rate between the antidepressant and placebo groups was greater for tricyclics (25.3%; OR = 0.30, CI: 0.17-0.50, p < 0.00001), SSRIs (21.8%; OR = 0.33, CI: 0.28-0.38, p < 0.00001), and other newer agents (16.0%; OR = 0.44, CI: 0.36-0.54, p < 0.00001) in that order, while the effect size of acceptability was greater for SSRIs than for other antidepressants. A flexible dose schedule (OR = 0.30, CI: 0.23-0.48, p < 0.00001) had a greater effect size than a fixed dose (OR = 0.41, CI: 0.36-0.48, p < 0.00001) in comparison to placebo. Even in studies assigned after continuous treatment for more than 6 months after remission, the continued use of antidepressants had a lower relapse rate than the use of a placebo (OR = 0.40, CI: 0.29-0.55, p < 0.00001; 20.2% vs 37.2%). The difference in relapse rate was similar from a maintenance period of 6 months (OR = 0.41, CI: 0.35-0.48, p < 0.00001; 19.6% vs 37.6%) to over 1 year (OR = 0.35, CI: 0.29-0.41, p < 0.00001; 19.9% vs 39.8%). The all-cause dropout of antidepressant and placebo groups was 43% and 58%, respectively, (OR = 0.47, CI: 0.40-0.55, p < 0.00001). The tolerability rate was ~4% for both groups. The rate of relapse (OR = 0.32, CI: 0.18-0.64, p = 0.0010, 41.0% vs 66.7%) and all-cause dropout among adolescents was higher than in adults. To prevent relapse and treatment failure, maintenance therapy, and careful attention for at least 6 months after remission is recommended. SSRIs are well-balanced agents, and flexible dose adjustments are more effective for relapse prevention.
Antidepressive agents are one of the fastest-growing classes of prescribed drugs. However, the effects of antidepressive agents on bone density are controversial. The aim of this meta-analysis is to ...evaluate the state of research on the relationship between the use of tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs) and bone mineral density (BMD) in women. The database searched was Pubmed. The meta-analysis included human studies in women fulfilling the following criteria: (i) an assessment of bone mineral density in the lumbar spine, the femoral neck or the total hip; (ii) a comparison of the BMD of depressed individuals using antidepressive agents (SSRIs or TCAs), and a control group that did not use antidepressive agents; (iii) measurement of BMD using dual-energy X-ray absorptiometry (DXA); and (iv) calculations of the mean BMD and standard deviation or standard error. Four studies were identified, which, in total, included 934 women using antidepressive agents and 5767 non-using individuals. The results showed that no significant negative composite weighted mean effect sizes were identified for the comparisons between SSRI users and non-users. Similarly, no significant negative composite weighted mean effect sizes were identified for the comparisons between TCA users and non-users, indicating similar BMD in SSRI or TCA users and non-users. The meta-analysis shows that the association between antidepressant medication and bone mineral density has not been extensively researched. Only four studies fulfilled the inclusion criteria. The global result of the literature review and meta-analysis was that the use of antidepressive agents was not associated with lower or higher BMD. This result applies to both SSRIs and TCAs and to all measurement locations (lumbar spine, femoral neck and total hip).
Background Antidepressants, aiming at monoaminergic neurotransmission, exhibit delayed onset of action, limited efficacy, and poor compliance. Glutamatergic neurotransmission is involved in ...depression. However, it is unclear whether enhancement of the N -methyl- D -aspartate (NMDA) subtype glutamate receptor can be a treatment for depression. Methods We studied sarcosine, a glycine transporter-I inhibitor that potentiates NMDA function, in animal models and in depressed patients. We investigated its effects in forced swim test, tail suspension test, elevated plus maze test, novelty-suppressed feeding test, and chronic unpredictable stress test in rats and conducted a 6-week randomized, double-blinded, citalopram-controlled trial in 40 patients with major depressive disorder. Clinical efficacy and side effects were assessed biweekly, with the main outcomes of Hamilton Depression Rating Scale, Global Assessment of Function, and remission rate. The time course of response and dropout rates was also compared. Results Sarcosine decreased immobility in the forced swim test and tail suspension test, reduced the latency to feed in the novelty-suppressed feeding test, and reversed behavioral deficits caused by chronic unpredictable stress test, which are characteristics for an antidepressant. In the clinical study, sarcosine substantially improved scores of Hamilton Depression Rating Scale, Clinical Global Impression, and Global Assessment of Function more than citalopram treatment. Sarcosine-treated patients were much more likely and quicker to remit and less likely to drop out. Sarcosine was well tolerated without significant side effects. Conclusions Our preliminary findings suggest that enhancing NMDA function can improve depression-like behaviors in rodent models and in human depression. Establishment of glycine transporter-I inhibition as a novel treatment for depression waits for confirmation by further proof-of-principle studies.
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