Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis.

BACKGROUND: Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder. METHODS: In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ. FINDINGS: We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36-0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27-0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52-0·99; moderate], 0·70 [0·51-0·95; moderate] and 0·71 [0·52-0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28-3·13; very low]; zolpidem: 1·79 [1·25-2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01-3·33; low]), daridorexant (3·45 [1·41-8·33; low), and suvorexant (3·13 [1·47-6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27-2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36-0·90; very low]; lemborexant: 0·41 [0·04-0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16-1·10; very low]) and zolpidem (0·60 [0·00-1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20-0·93; very low]; zolpidem: 0·43 [0·19-0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11-3·70; very low]). INTERPRETATION: Overall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice. FUNDING: UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Revisiting monoamine oxidase inhibitors for the treatment of depressive disorders: A systematic review and network meta-analysis.

BACKGROUND: Monoamine oxidase inhibitors (MAOIs) were the first class of modern antidepressants; however, they are under-utilized as compared to the newer antidepressants. METHODS: In this systematic review, network meta-analysis was used to investigate the comparative efficacy and acceptability of MAOIs for depressive disorders. Overall, the network meta-analysis included 52 double-blind, randomized controlled trials (RCTs) that compared 14 antidepressants or placebo. Across studies, the mean arm size was n = 58 participants from a total N = 6462 (5309 active drug; 1153 placebo). RESULTS: Except fluvoxamine, all antidepressants demonstrated superior efficacy to placebo, and none demonstrated substantially better or worse all-cause dropout rates. Phenelzine demonstrated superior evidence for efficacy compared to all other treatments, and clomipramine demonstrated superior evidence for acceptability compared to all other treatments. LIMITATIONS: The study is primarily limited by low estimate precision due to a relative paucity of studies for some of the included treatment conditions. Further evidence is required to study the relative efficacy of MAOIs against newer antidepressants. CONCLUSIONS: The results of this analysis largely support the re-evaluation of the use of MAOIs as antidepressant agents in the treatment algorithm of depression.

Lithium modulates striatal reward anticipation and prediction error coding in healthy volunteers.

Lithium is one of the most effective mood-stabilizing medications in bipolar disorder. This study was designed to test whether lithium administration may stabilize mood via effects on reward processing. It was hypothesized that lithium administration would modulate reward processing in the striatum and affect both anticipation and outcome computations. Thirty-seven healthy human participants (18 males, 33 with suitable fMRI data) received 11 (±1) days of lithium carbonate or placebo intervention (double-blind), after which they completed the monetary incentive delay task while fMRI data were collected. The monetary incentive delay task is a robust task with excellent test-retest reliability and is well suited to investigate different phases of reward processing within the caudate and nucleus accumbens. To test for correlations with prediction error signals a Rescorla-Wagner reinforcement-learning model was applied. Lithium administration enhanced activity in the caudate during reward anticipation compared to placebo. In contrast, lithium administration reduced caudate and nucleus accumbens activity during reward outcome. This latter effect seems related to learning as reward prediction errors showed a positive correlation with caudate and nucleus accumbens activity during placebo, which was absent after lithium administration. Lithium differentially modulates the anticipation relative to the learning of rewards. This suggests that lithium might reverse dampened reward anticipation while reducing overactive reward updating in patients with bipolar disorder. This specific effect of lithium suggests that a targeted modulation of reward learning may be a viable approach for novel interventions in bipolar disorder.

Neural effects of a single dose of fluoxetine on resting-state functional connectivity in adolescent depression.

Fluoxetine is commonly prescribed in adolescent depression, but the neural mechanisms underlying its action remain poorly understood. Here, we used resting-state functional magnetic resonance imaging to investigate the effects of a single dose of fluoxetine vs. placebo in adolescents with major depressive disorder. In contrast with previous studies in adults that have demonstrated an acute effect of antidepressants on activity within the default mode network, a single dose of fluoxetine did not alter activity in this network in adolescent depression. There were unexpected group activity differences in the motor network, which should be clarified in future research.

Stress, inflammation and hippocampal subfields in depression: A 7 Tesla MRI Study.

Experiencing stressful events throughout one's life, particularly childhood trauma, increases the likelihood of being diagnosed with Major Depressive Disorder (MDD). Raised levels of cortisol, and markers of inflammation such as Interleukin (IL-6) and C-reactive protein (CRP), have been linked to both early life stress and MDD. We aimed to explore the biological stress signatures of early stress and MDD on hippocampal sub regional volumes using 7 Tesla MRI imaging. A cohort of 71 MDD patients was compared against 46 age and sex-matched healthy volunteers. MDD subjects had higher averages of IL-6 and CRP levels. These differences were significant for IL-6 levels and trended for CRP. There were no significant group differences in any of the hippocampal subfields or global hippocampal volumes; further, there were no hippocampal subfield differences between MDD subjects with high levels of our biological stress measures and MDDs with normal levels.

Comparative efficacy and acceptability of pharmacological treatments for post-traumatic stress disorder in adults: a network meta-analysis.

BACKGROUND: Guidelines about post-traumatic stress disorder (PTSD) recommend broad categories of drugs, but uncertainty remains about what pharmacological treatment to select among all available compounds. METHODS: Cochrane Central Register of Controlled Trials register, MEDLINE, PsycINFO, National PTSD Center Pilots database, PubMed, trial registries, and databases of pharmaceutical companies were searched until February 2016 for double-blind randomised trials comparing any pharmacological intervention or placebo as oral therapy in adults with PTSD. Initially, we performed standard pairwise meta-analyses using a random effects model. We then carried out a network meta-analysis. The main outcome measures were mean change on a standardised scale and all-cause dropout rate. Acute treatment was defined as 8-week follow up. RESULTS: Desipramine, fluoxetine, paroxetine, phenelzine, risperidone, sertraline, and venlafaxine were more effective than placebo; phenelzine was better than many other active treatments and was the only drug, which was significantly better than placebo in terms of dropouts (odds ratio 7.50, 95% CI 1.72-32.80). Mirtazapine yielded a relatively high rank for efficacy, but the respective value for acceptability was not among the best treatments. Divalproex had overall the worst ranking. CONCLUSIONS: The efficacy and acceptability hierarchies generated by our study were robust against many sources of bias. The differences between drugs and placebo were small, with the only exception of phenelzine. Considering the small amount of available data, these results are probably not robust enough to suggest phenelzine as a drug of choice. However, findings from this review reinforce the idea that phenelzine should be prioritised in future trials in PTSD.

Antiepileptic drugs prescribed in pregnancy and prevalence of major congenital malformations: comparative prevalence studies.

OBJECTIVE: The aim of this study was to examine the prevalence of major congenital malformations associated with antiepileptic drug (AED) treatment in pregnancy. PATIENTS AND METHODS: Using data from The Health Improvement Network, we identified women who have given live birth and their offspring. Four subgroups were selected based on the AED treatment in early pregnancy, valproate, carbamazepine, lamotrigine and women not receiving AED treatment. We compared the prevalence of major congenital malformations within children of these four groups and estimated prevalence ratios (PRs) using Poisson regression adjusted for maternal age, sex of child, quintiles of Townsend deprivation score and indication for treatment. RESULTS: In total, 240,071 women were included in the study. A total of 229 women were prescribed valproate in pregnancy, 357 were prescribed lamotrigine and 334 were prescribed carbamazepine and 239,151 women were not prescribed AEDs. Fifteen out of 229 (6.6%) women prescribed valproate gave birth to a child with a major congenital malformation. The figures for lamotrigine, carbamazepine and women not prescribed AEDs were 2.7%, 3.3% and 2.2%, respectively. The prevalence of major congenital malformation was similar for women prescribed lamotrigine or carbamazepine compared to women with no AED treatment in pregnancy. For women prescribed valproate in polytherapy, the prevalence was fourfold higher. After adjustments, the effect of estimates attenuated, but the prevalence remained two- to threefold higher in women prescribed valproate. CONCLUSION: The results of our study suggest that lamotrigine and carbamazepine are safer treatment options than valproate in pregnancy and should be considered as alternative treatment options for women of childbearing potential and in pregnancy.

Lithium prescribing during pregnancy: a UK primary care database study.

BACKGROUND: Women taking lithium must decide whether to continue the medication if they conceive or plan to conceive. Little is known about the extent of prescribing of lithium during pregnancy. AIMS: To determine: 1) the prevalence of lithium prescribing during pregnancy and 2) to assess whether pregnancy is associated with discontinuation of lithium. METHOD: First, we identified women receiving any lithium prescriptions before and during pregnancy using The Health Improvement Network (THIN) primary care database. Subsequently, we used a Kaplan-Meier plot to compare time to last prescription in women prescribed lithium continuously three months before pregnancy and a comparison group of non-pregnant women. Finally, we described the characteristics of the women prescribed lithium in pregnancy. RESULTS: Very few women were prescribed lithium during pregnancy; out of 458,761 pregnancies, we identified 47 (0.01%) in which lithium was prescribed after the 6th week of pregnancy (when the pregnancy was likely to be known). In our study of discontinuation, we found pregnant women were more likely to stop lithium than those who were not pregnant. Of the 52 women who were being continuously prescribed lithium three months before pregnancy, only 17 (33%) continued receiving prescriptions beyond the 6th week of pregnancy. However, most of these 17 women continued treatment throughout pregnancy. CONCLUSIONS: Pregnancy was strongly associated with discontinuation of lithium. Further evidence on the risks of lithium is needed so that women can weight these against the risk of a deterioration in maternal mental health.

Effects of seven-day diazepam administration on resting-state functional connectivity in healthy volunteers: a randomized, double-blind study.

RATIONALE: Benzodiazepines, such as diazepam, are anxiolytic-sedative drugs, used for the treatment of several different disorders. The pharmacological mechanism of action of benzodiazepines is well understood; however, it remains unclear which neural networks and systems are involved in translating these neurochemical actions into their therapeutic effects. OBJECTIVES: The objective of this study was to investigate the effects of 7-day diazepam administration compared to placebo on resting-state functional connectivity in healthy adults independent of any task. METHODS: Thirty-four healthy participants were randomly assigned to receive either diazepam (N = 17) or placebo (15 mg daily for 7 days) and underwent resting-state functional magnetic resonance acquisition. Model-free data analysis was performed using independent component analysis and dual regression. RESULTS: Consistent with previous research, 11 resting-state networks were identified. Increased connectivity in response to diazepam administration was found in the medial visual network and middle/inferior temporal network. Diazepam did not cause any decreases in functional connectivity. CONCLUSIONS: Diazepam administration increases functional connectivity in areas of emotional processing independent of any task. Diazepam also enhanced functional connectivity in the medial visual system, which is a brain region rich in GABAA receptors, and shows high binding of GABAergic drugs. These increases in functional connectivity are characteristic of CNS depressants.

Discontinuation of antipsychotic medication in pregnancy: a cohort study.

BACKGROUND: Women prescribed antipsychotics face the dilemma on whether to continue medication in pregnancy in terms of balancing risks and benefits. Previous research on other psychotropic medications suggests that many women discontinue treatment in early pregnancy. However, very limited evidence exists on discontinuation of antipsychotic medication. METHODS: We identified 495,953 pregnant women from THIN primary care database. Kaplan-Meier plots were used to examine time to last antipsychotic prescription. Poisson regression was used to examine characteristics of those who stopped treatment during pregnancy. RESULTS: There has been an overall increase in prevalence of antipsychotic prescribing since 2007. However, antipsychotics were more likely to be stopped in pregnant than non-pregnant women. Only 107/279 (38%) of women on atypical antipsychotics and 39/207 (19%) of women on typical antipsychotics before pregnancy still received treatment at the start of third trimester. Older women were more likely to continue typical antipsychotic treatment in pregnancy (35+ versus <25 years risk ratio: 3.09 [95% CI 1.76, 5.44]). Likewise, those who received typical antipsychotics for longer periods before were most likely to continue treatment in pregnancy (12+ versus <6 months: RR: 3.12 [95% CI 1.97, 4.95]). For atypical antipsychotics length and dose of prior prescribing were also associated with continuation in pregnancy. CONCLUSIONS: Pregnancy was a major determinant of cessation of antipsychotics. Only 38% of women on atypical and 19% on typical antipsychotics were still prescribed the drug in the third trimester. Duration of prior treatment, maternal age as well as dose was significantly associated with continued treatment of antipsychotics in pregnancy.

Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic.

BACKGROUND: Ketamine has a rapid antidepressant effect in treatment-resistant depression (TRD). The effects on cognitive function of multiple ketamine infusions and of concurrent antidepressant medication on response rate and duration are not known. METHOD: Twenty-eight patients with uni- or bipolar TRD were treated over three weeks with either three or six ketamine infusions (0.5 mg/kg over 40 minutes) in the recovery room of a routine ECT clinic. Post-treatment memory assessments were conducted on day 21 (4-7 days after the final infusion). Patients were followed up for six months where possible, with severity of depression and side effects monitored throughout. RESULTS: Eight (29%) patients responded of whom four remitted. Only three (11%) patients had responded within six hours after a single infusion, but in all responders, the response had developed before the third infusion. The duration of response from the final infusion was variable (median 70, range 25-168 days). Discontinuations included two (7%) because of acute adverse reactions during the infusion and five (18%) because of failure to benefit and increasing anxiety. Ketamine was not associated with memory impairment. The ECT clinic was rated suitable by patients and offered appropriate levels of monitoring. CONCLUSION: This small, open label naturalistic study shows that up to six low dose ketamine infusions can safely be given within an existing NHS clinical structure to patients who continue their antidepressants. The response rate was comparable to that found in RCTs of single doses of ketamine in antidepressant-free patients but took slightly longer to develop.

Effects of short-term varenicline administration on cortisol in healthy, non-smoking adults: a randomized, double-blind, study.

RATIONALE: Varenicline is the most effective drug for smoking cessation, but its use decreased because of reports of depressogenic side effects. However, because smoking and smoking cessation on their own are associated with depression, it remains unclear whether reported depressogenic effects are attributable to varenicline, or to smoking, and/or smoking cessation themselves. OBJECTIVES: Previously, we observed no depressogenic effects of varenicline on a psychological level. In the present study, we aimed at investigating potential depressogenic effects of the partial nicotinergic acetylcholine receptor agonist varenicline on a biological level. A possible pathway would be an effect of varenicline on the hypothalamic-pituitary-adrenal (HPA) axis, considering the relation between the HPA axis and (1) the cholinergic system and (2) depression. METHODS: In a randomized, double-blind design, we administered varenicline or placebo for 7 days (0.5 mg/day first 3 days, then 1 mg/day) to healthy never-smoking subjects, thereby eliminating bias by (previous) smoking status. We used repeated measures (before and after treatment) of the salivary free cortisol awakening response to measure HPA axis activity and flexibility. RESULTS: Salivary cortisol data of 34 subjects were included in the analysis. Results showed no effect of varenicline on height (F1,32 = 0.405; P = 0.529) or shape (F2,31 = 0.110; P = 0.164) of the cortisol awakening response. CONCLUSIONS: Results do not suggest depressogenic effects of varenicline on the HPA axis. Although this does not preclude other biological depressogenic effects of varenicline, it seems that concerns about effects of varenicline on the HPA axis should not limit its potential to treat nicotine and related addictions.

Early markers of cognitive enhancement: developing an implicit measure of cognitive performance.

There is intense interest in the development of effective cognitive enhancing drugs which would have therapeutic application across a number of neurological and psychological disorders including dementia, schizophrenia and depression. However, development in this area has been limited by the absence of sensitive biomarkers which can be used to detect and refine therapeutic-like action in phase 1 clinical studies. The aim of the present study was therefore to develop a measure of cognition relevant to the action of candidate cognitive enhancers which might be sensitive to pharmacological manipulation in healthy volunteers. Healthy volunteers (n = 34) were randomised to receive a single dose of modafinil (100 mg) or placebo. Five hours post dose, attentional flexibility in learning was assessed using a novel implicit learning task. Volunteers also completed an auditory digit span task and visual analogue scales (VAS). Modafinil increased alertness as measured by the VAS. In the implicit learning task, modafinil enhanced learning rates in terms of both accuracy and reaction time, suggesting an increase in implicit rule learning. These results suggest that the novel learning task should be explored as a biomarker of early cognitive improvement which could be more sensitive than conventional measures.

Effects of short-term varenicline administration on emotional and cognitive processing in healthy, non-smoking adults: a randomized, double-blind, study.

Varenicline is an effective and increasingly prescribed drug for smoking cessation, but has been associated with depressive symptoms and suicidal behavior. However, it remains unclear whether those changes in mood and behavior are directly related to varenicline use, or caused by smoking cessation itself or reflects depression and suicidality rates in smokers, independent of treatment. To investigate the influence of varenicline on mood and behavior independent of smoking and smoking cessation, we assessed the effects of varenicline on emotional processing (a biomarker of depressogenic effects), emotion-potentiated startle reactivity, impulsivity (linked with suicidal behavior), and cognitive performance in non-smoking subjects. We used a randomized, double-blind design, in which we administered varenicline or placebo to healthy subjects over 7 days (0.5 mg/day first 3 days, then 1 mg/day). Cognitive and emotional processing was assessed by a battery of computerized tasks and recording of emotion-potentiated startle response. A total of 41 subjects were randomized, with 38 subjects included in the analysis. The varenicline group did not differ from placebo in terms of negative biases in emotional processing or mood. However, compared with placebo, the varenicline group scored higher on working and declarative memory. In conclusion, short-term varenicline use did not influence negative biases in emotional processing or impulsivity in non-smoking subjects, thereby not supporting direct depressogenic or suicidal risk behavior-inducing effects. In contrast, varenicline may have cognitive-enhancing effects.

Short-term NK1 receptor antagonism and emotional processing in healthy volunteers.

BACKGROUND: Despite early promise in phase II, the performance of the NK1 receptor antagonist aprepitant in subsequent clinical trials has been disappointing. Healthy volunteer models of emotional processing offer a potential means by which novel drugs can be screened prior to clinical trials. Here, we consider the effect of 7 days of treatment with aprepitant in such a model. METHOD: Healthy volunteers (n = 32) were randomised to receive 7-day treatment with aprepitant (125 mg) or placebo. On the seventh day, participants completed a battery of tasks measuring emotional processing previously demonstrated to be sensitive to conventional antidepressant drugs. The tasks included facial expression recognition, emotional categorisation and memory, attentional dot-probe and emotion potentiated startle task. RESULTS: Aprepitant abolished the emotionally potentiated startle effect and increased recognition memory for emotionally positive versus negative stimuli. In addition, the drug decreased attention to negative relative to positive emotional stimuli on the masked version of the dot-probe task. These effects were seen in the absence of any change in subjective mood. There were no effects on emotional categorisation, recall or on facial expression recognition. CONCLUSION: These results suggest that NK1 receptor antagonism does affect some aspects of emotional processing and, in particular, that it has anxiolytic-like effects. The profile of effects reported here is, however, more limited than that found in response to conventional antidepressant treatment, and this may explain disappointing results at clinical trial. Healthy volunteer models of emotional processing may be useful in closing the gap between preclinical and clinical trials.

Low-dose tryptophan depletion in recovered depressed patients induces changes in cognitive processing without depressive symptoms.

BACKGROUND: Acute tryptophan depletion can induce a transient reappearance of depressive symptoms in recovered depressed patients. The neurochemical mechanism is thought to be impairment of brain serotonin neurotransmission, but the neuropsychologic mechanisms underlying the effect are unclear. METHODS: To assess whether low-dose tryptophan depletion can tease out the psychological mechanisms sensitive to substrate depletion in vulnerable subjects without inducing mood changes, a between-subjects randomized design was used. Recovered depressed patients (n = 24) and healthy volunteers (n = 24) were administered while fasting either a tryptophan-free or a control mixture, containing 31.2 and 33.2 g of amino acids, respectively. Objective and subjective ratings of mood were made before and 5 hours after ingestion; at the latter time point, cognitive and emotional processing were also assessed. RESULTS: Low-dose tryptophan depletion did not affect mood. Significant changes in emotional and cognitive processing occurred in the recovered depressed group, however, and to a lesser extent in the healthy volunteers. The profile of effects seen in the recovered patients suggested a return of the impairments seen in acute depression. CONCLUSIONS: Our data suggest that low-dose tryptophan depletion permits investigation of the cognitive correlates of acute reductions in brain serotonin in populations vulnerable to depression and in healthy volunteers, without causing depressive symptoms.