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Journal of Affective Disorders Apr 2022To compare the efficacy and discontinuation of augmentation agents in adult patients with treatment-resistant depression (TRD). We conducted a systematic review and... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To compare the efficacy and discontinuation of augmentation agents in adult patients with treatment-resistant depression (TRD). We conducted a systematic review and network meta-analyses (NMA) to combine direct and indirect comparisons of augmentation agents.
METHODS
We included randomized controlled trials comparing one active drug with another or with placebo following a treatment course up to 24 weeks. Nineteen agents were included: stimulants, atypical antipsychotics, thyroid hormones, antidepressants, and mood stabilizers. Data for response/remission and all-cause discontinuation rates were analyzed. We estimated effect-size by relative risk using pairwise and NMA with random-effects model.
RESULTS
A total of 65 studies (N = 12,415) with 19 augmentation agents were included in the NMA. Our findings from the NMA for response rates, compared to placebo, were significant for: liothyronine, nortriptyline, aripiprazole, brexpiprazole, quetiapine, lithium, modafinil, olanzapine (fluoxetine), cariprazine, and lisdexamfetamine. For remission rates, compared to placebo, were significant for: thyroid hormone(T4), aripiprazole, brexpiprazole, risperidone, quetiapine, and olanzapine (fluoxetine). Compared to placebo, ziprasidone, mirtazapine, and cariprazine had statistically significant higher discontinuation rates. Overall, 24% studies were rated as having low risk of bias (RoB), 63% had moderate RoB and 13% had high RoB.
LIMITATIONS
Heterogeneity in TRD definitions, variable trial duration and methodological clinical design of older studies and small number of trials per comparisons.
CONCLUSIONS
This NMA suggests a superiority of the regulatory approved adjunctive atypical antipsychotics, thyroid hormones, dopamine compounds (modafinil and lisdexamfetamine) and lithium. Acceptability was lower with ziprasidone, mirtazapine, and cariprazine. Further research and head-to-head studies should be considered to strengthen the best available options for TRD.
Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Depression; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Humans; Network Meta-Analysis
PubMed: 34986373
DOI: 10.1016/j.jad.2021.12.134 -
Journal of Mid-life Health 2022Women are likely to suffer from sleep disorders more in comparison to men during menopause and with advancing age. The incidence of sleep disorders ranges from 16% to... (Review)
Review
Women are likely to suffer from sleep disorders more in comparison to men during menopause and with advancing age. The incidence of sleep disorders ranges from 16% to 47% at peri-menopause and 35%-60% at postmenopause. Insomnia with or without associated anxiety or low lying depression and Mood disorder is most common associated manifestations. Sleep disorders and insomnia largely remain a clinical diagnosis based on the subjective complaints of patients. Benzodiazepines remain the mainstay of the treatment in majority of the sleep disorders including chronic or acute insomnia. Treatment of associated anxiety, depression, or psychosis is most important. Tricyclic antidepressant, Selective Serotonin Reuptake Inhibitors (SSRI), Melatonin, Duloxetine, Fluoxetine, Imipramine, Nortriptyline or Amitriptyline and other drugs such as Eszopiclone, Escitalopram, Gabapentin, Quiteiapine, Citalopram, Mirtazapine followed by long-acting Melatonin and Ramelteon, also are very useful for the management of various sleep disorders. Hormone replacement therapy presently lacks concrete evidence to be used in menopausal women for sleep disorder. Sleep hygiene practices, self-hypnosis, meditation, and exercise play a very important role.
PubMed: 35707298
DOI: 10.4103/jmh.jmh_18_22 -
The Journal of Clinical Investigation Nov 2021Ferroptosis, an iron-dependent nonapoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA-binding proteins in...
Ferroptosis, an iron-dependent nonapoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA-binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here, we report that the RNA-binding protein RBMS1 participates in lung cancer development via mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 is a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3'- and 5'-UTR of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake, and promoted ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potential and clinical value.
Topics: Amino Acid Transport System y+; Animals; Cell Line, Tumor; DNA-Binding Proteins; Ferroptosis; HEK293 Cells; Humans; Lung Neoplasms; Mice; Protein Biosynthesis; Proto-Oncogene Proteins c-ets; RNA-Binding Proteins; Radiation Tolerance; Transcription Factors
PubMed: 34609966
DOI: 10.1172/JCI152067 -
The New England Journal of Medicine Mar 2023The benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied. (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied.
METHODS
We conducted a two-step, open-label trial involving adults 60 years of age or older with treatment-resistant depression. In step 1, patients were randomly assigned in a 1:1:1 ratio to augmentation of existing antidepressant medication with aripiprazole, augmentation with bupropion, or a switch from existing antidepressant medication to bupropion. Patients who did not benefit from or were ineligible for step 1 were randomly assigned in step 2 in a 1:1 ratio to augmentation with lithium or a switch to nortriptyline. Each step lasted approximately 10 weeks. The primary outcome was the change from baseline in psychological well-being, assessed with the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales (population mean, 50; higher scores indicate greater well-being). A secondary outcome was remission of depression.
RESULTS
In step 1, a total of 619 patients were enrolled; 211 were assigned to aripiprazole augmentation, 206 to bupropion augmentation, and 202 to a switch to bupropion. Well-being scores improved by 4.83 points, 4.33 points, and 2.04 points, respectively. The difference between the aripiprazole-augmentation group and the switch-to-bupropion group was 2.79 points (95% CI, 0.56 to 5.02; P = 0.014, with a prespecified threshold P value of 0.017); the between-group differences were not significant for aripiprazole augmentation versus bupropion augmentation or for bupropion augmentation versus a switch to bupropion. Remission occurred in 28.9% of patients in the aripiprazole-augmentation group, 28.2% in the bupropion-augmentation group, and 19.3% in the switch-to-bupropion group. The rate of falls was highest with bupropion augmentation. In step 2, a total of 248 patients were enrolled; 127 were assigned to lithium augmentation and 121 to a switch to nortriptyline. Well-being scores improved by 3.17 points and 2.18 points, respectively (difference, 0.99; 95% CI, -1.92 to 3.91). Remission occurred in 18.9% of patients in the lithium-augmentation group and 21.5% in the switch-to-nortriptyline group; rates of falling were similar in the two groups.
CONCLUSIONS
In older adults with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole improved well-being significantly more over 10 weeks than a switch to bupropion and was associated with a numerically higher incidence of remission. Among patients in whom augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar. (Funded by the Patient-Centered Outcomes Research Institute; OPTIMUM ClinicalTrials.gov number, NCT02960763.).
Topics: Aged; Humans; Antidepressive Agents; Aripiprazole; Bupropion; Depression; Drug Therapy, Combination; Nortriptyline; Treatment Switching; Lithium Compounds
PubMed: 36867173
DOI: 10.1056/NEJMoa2204462 -
British Journal of Pharmacology Jul 2007New data on the pharmacology of tricyclic antidepressants (TCAs), their affinities for human cloned CNS receptors and their cytochrome P450 enzyme inhibition profiles,... (Comparative Study)
Comparative Study Review
New data on the pharmacology of tricyclic antidepressants (TCAs), their affinities for human cloned CNS receptors and their cytochrome P450 enzyme inhibition profiles, allow improved deductions concerning their effects and interactions and indicate which of the TCAs are the most useful. The relative toxicity of TCAs continues to be more precisely defined, as do TCA interactions with selective serotonin reuptake inhibitors (SSRIs). TCA interactions with monoamine oxidase inhibitors (MAOIs) have been, historically, an uncertain and difficult question, but are now well understood, although this is not reflected in the literature. The data indicate that nortriptyline and desipramine have the most pharmacologically desirable characteristics as noradrenaline reuptake inhibitors (NRIs), and as drugs with few interactions that are also safe when coadministered with either MAOIs or SSRIs. Clomipramine is the only available antidepressant drug that has good evidence of clinically relevant serotonin and noradrenaline reuptake inhibition (SNRI). These data assist drug selection for monotherapy and combination therapy and predict reliably how and why pharmacodynamic and pharmacokinetic interactions occur. In comparison, two newer drugs proposed to have SNRI properties, duloxetine and venlafaxine, may have insufficient NRI potency to be effective SNRIs. Combinations such as sertraline and nortriptyline may therefore offer advantages over drugs like venlafaxine that have fixed ratios of SRI/NRI effects that are not ideal. However, no TCA/SSRI combination is sufficiently safe to be universally applicable without expert knowledge. Standard texts (e.g. the British National Formulary) and treatment guidelines would benefit by taking account of these new data and understandings.
Topics: Animals; Antidepressive Agents, Tricyclic; Central Nervous System; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Therapy, Combination; Humans; Monoamine Oxidase Inhibitors; Practice Guidelines as Topic; Selective Serotonin Reuptake Inhibitors
PubMed: 17471183
DOI: 10.1038/sj.bjp.0707253 -
Journal of Affective Disorders Jul 2015Dose equivalence of antidepressants is critically important for clinical practice and for research. There are several methods to define and calculate dose equivalence...
BACKGROUND
Dose equivalence of antidepressants is critically important for clinical practice and for research. There are several methods to define and calculate dose equivalence but for antidepressants, only daily defined dose and consensus methods have been applied to date. The purpose of the present study is to examine dose equivalence of antidepressants by a less arbitrary and more systematic method.
METHODS
We used data from all randomized, double-blind, flexible-dose trials comparing fluoxetine or paroxetine as standard drugs with any other active antidepressants as monotherapy in the acute phase treatment of unipolar depression. We calculated the ratio of the mean doses for each study and weighted it by the total sample size to find the weighted mean ratio for each drug, which was then used to define the drug׳s dosage equivalent to fluoxetine 40mg/d.
RESULTS
We included 83 studies (14 131 participants). In the primary analysis, fluoxetine 40mg/day was equivalent to paroxetine dosage of 34.0mg/day, agomelatine 53.2mg/day, amitriptyline, 122.3mg/day, bupropion 348.5mg/day, clomipramine 116.1mg/day, desipramine 196.3mg/day, dothiepin 154.8mg/day, doxepin 140.1mg/day, escitalopram 18.0mg/day, fluvoxamine 143.3mg/day, imipramine 137.2mg/day, lofepramine 250.2mg/day, maprotiline 118.0mg/day, mianserin, 101.1mg/day, mirtazapine 50.9mg/day, moclobemide 575.2mg/day, nefazodone 535.2mg/day, nortriptyline 100.9mg/day, reboxetine 11.5mg/day, sertraline 98.5mg/day, trazodone 401.4mg/day, and venlafaxine 149.4mg/day. Sensitivity analyses corroborated the results except for doxepin.
LIMITATIONS
The number of studies for some drugs was small. The current method assumes dose response relationship of antidepressants.
CONCLUSIONS
Our findings can be useful for clinicians when they switch antidepressants and for researchers when they compare various antidepressants in their research.
Topics: Adult; Amitriptyline; Antidepressive Agents; Bupropion; Citalopram; Depressive Disorder, Major; Dose-Response Relationship, Drug; Double-Blind Method; Evidence-Based Medicine; Female; Fluoxetine; Fluvoxamine; Humans; Male; Middle Aged; Moclobemide; Nortriptyline; Paroxetine; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Sertraline; Treatment Outcome
PubMed: 25911132
DOI: 10.1016/j.jad.2015.03.021 -
The Cochrane Database of Systematic... Apr 2020Whilst the pharmacological profiles and mechanisms of antidepressants are varied, there are common reasons why they might help people to stop smoking tobacco. Firstly,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Whilst the pharmacological profiles and mechanisms of antidepressants are varied, there are common reasons why they might help people to stop smoking tobacco. Firstly, nicotine withdrawal may produce depressive symptoms and antidepressants may relieve these. Additionally, some antidepressants may have a specific effect on neural pathways or receptors that underlie nicotine addiction.
OBJECTIVES
To assess the evidence for the efficacy, safety and tolerability of medications with antidepressant properties in assisting long-term tobacco smoking cessation in people who smoke cigarettes.
SEARCH METHODS
We searched the Cochrane Tobacco Addiction Specialized Register, which includes reports of trials indexed in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO, clinicaltrials.gov, the ICTRP, and other reviews and meeting abstracts, in May 2019.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) that recruited smokers, and compared antidepressant medications with placebo or no treatment, an alternative pharmacotherapy, or the same medication used in a different way. We excluded trials with less than six months follow-up from efficacy analyses. We included trials with any follow-up length in safety analyses.
DATA COLLECTION AND ANALYSIS
We extracted data and assessed risk of bias using standard Cochrane methods. We also used GRADE to assess the certainty of the evidence. The primary outcome measure was smoking cessation after at least six months follow-up, expressed as a risk ratio (RR) and 95% confidence intervals (CIs). We used the most rigorous definition of abstinence available in each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed-effect model. Similarly, we presented incidence of safety and tolerance outcomes, including adverse events (AEs), serious adverse events (SAEs), psychiatric AEs, seizures, overdoses, suicide attempts, death by suicide, all-cause mortality, and trial dropout due to drug, as RRs (95% CIs).
MAIN RESULTS
We included 115 studies (33 new to this update) in this review; most recruited adult participants from the community or from smoking cessation clinics. We judged 28 of the studies to be at high risk of bias; however, restricting analyses only to studies at low or unclear risk did not change clinical interpretation of the results. There was high-certainty evidence that bupropion increased long-term smoking cessation rates (RR 1.64, 95% CI 1.52 to 1.77; I = 15%; 45 studies, 17,866 participants). There was insufficient evidence to establish whether participants taking bupropion were more likely to report SAEs compared to those taking placebo. Results were imprecise and CIs encompassed no difference (RR 1.16, 95% CI 0.90 to 1.48; I = 0%; 21 studies, 10,625 participants; moderate-certainty evidence, downgraded one level due to imprecision). We found high-certainty evidence that use of bupropion resulted in more trial dropouts due to adverse events of the drug than placebo (RR 1.37, 95% CI 1.21 to 1.56; I = 19%; 25 studies, 12,340 participants). Participants randomized to bupropion were also more likely to report psychiatric AEs compared with those randomized to placebo (RR 1.25, 95% CI 1.15 to 1.37; I = 15%; 6 studies, 4439 participants). We also looked at the safety and efficacy of bupropion when combined with other non-antidepressant smoking cessation therapies. There was insufficient evidence to establish whether combination bupropion and nicotine replacement therapy (NRT) resulted in superior quit rates to NRT alone (RR 1.19, 95% CI 0.94 to 1.51; I = 52%; 12 studies, 3487 participants), or whether combination bupropion and varenicline resulted in superior quit rates to varenicline alone (RR 1.21, 95% CI 0.95 to 1.55; I = 15%; 3 studies, 1057 participants). We judged the certainty of evidence to be low and moderate, respectively; in both cases due to imprecision, and also due to inconsistency in the former. Safety data were sparse for these comparisons, making it difficult to draw clear conclusions. A meta-analysis of six studies provided evidence that bupropion resulted in inferior smoking cessation rates to varenicline (RR 0.71, 95% CI 0.64 to 0.79; I = 0%; 6 studies, 6286 participants), whilst there was no evidence of a difference in efficacy between bupropion and NRT (RR 0.99, 95% CI 0.91 to 1.09; I = 18%; 10 studies, 8230 participants). We also found some evidence that nortriptyline aided smoking cessation when compared with placebo (RR 2.03, 95% CI 1.48 to 2.78; I = 16%; 6 studies, 975 participants), whilst there was insufficient evidence to determine whether bupropion or nortriptyline were more effective when compared with one another (RR 1.30 (favouring bupropion), 95% CI 0.93 to 1.82; I = 0%; 3 studies, 417 participants). There was no evidence that any of the other antidepressants tested (including St John's Wort, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs)) had a beneficial effect on smoking cessation. Findings were sparse and inconsistent as to whether antidepressants, primarily bupropion and nortriptyline, had a particular benefit for people with current or previous depression.
AUTHORS' CONCLUSIONS
There is high-certainty evidence that bupropion can aid long-term smoking cessation. However, bupropion also increases the number of adverse events, including psychiatric AEs, and there is high-certainty evidence that people taking bupropion are more likely to discontinue treatment compared with placebo. However, there is no clear evidence to suggest whether people taking bupropion experience more or fewer SAEs than those taking placebo (moderate certainty). Nortriptyline also appears to have a beneficial effect on smoking quit rates relative to placebo. Evidence suggests that bupropion may be as successful as NRT and nortriptyline in helping people to quit smoking, but that it is less effective than varenicline. There is insufficient evidence to determine whether the other antidepressants tested, such as SSRIs, aid smoking cessation, and when looking at safety and tolerance outcomes, in most cases, paucity of data made it difficult to draw conclusions. Due to the high-certainty evidence, further studies investigating the efficacy of bupropion versus placebo are unlikely to change our interpretation of the effect, providing no clear justification for pursuing bupropion for smoking cessation over front-line smoking cessation aids already available. However, it is important that where studies of antidepressants for smoking cessation are carried out they measure and report safety and tolerability clearly.
Topics: Anti-Anxiety Agents; Antidepressive Agents; Bupropion; Humans; Nortriptyline; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Smoking; Smoking Cessation; Tobacco Use Cessation Devices; Varenicline
PubMed: 32319681
DOI: 10.1002/14651858.CD000031.pub5