Summary Suicide is the second leading cause of death, worldwide, for those between the ages of 24 and 44 y old. In 2013, more than 41,000 suicides occurred in the United States. These statistics ...underscore the need to 1) understand why people die by suicide and 2) identify risk factors that are potentially modifiable. While it has been posited that sleep disturbance may represent one such factor, systematic research in this arena did not begin until the 2000s. Since that time, sleep disturbance has been reliably identified as a risk factor for suicidal ideation, suicide attempts, and suicide. While insomnia, nightmares, and other sleep disorders have each been found to contribute to the risk for suicidal ideation and behavior, it is also possible that these factors share some common variance. One possibility is that sleep disturbance results in being awake at night, and being awake at night also confers risk. The hypothesis proffered here is that being awake when one is not biologically prepared to be so results in “hypofrontality” and diminished executive function, and that this represents a common pathway to suicidal ideation and behavior. Such a proposition is highly testable under a variety of possible protocols. The current review summarizes the extant literature on suicide rates by time-of-day, and discusses circadian, psychosocial, and neurocognitive explanations of risk. Such a focus promises to enhance our understanding of how sleep disturbance may confer risk, allows for the identification of future lines of research, and further justifies the need for interventions that promote good sleep continuity among at-risk individuals.
Introduction: Vortioxetine is a structurally novel medication that has recently been approved for treatment of major depressive disorder (MDD). This medication is a serotonin reuptake inhibitor that ...also has a number of other potentially relevant effects on serotoninergic receptors, which may differentiate the drug's effects from those of current first-line antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).
Areas Covered: This article will review the basic clinical pharmacology of vortioxetine, summarize the major clinical trials that were performed prior to approval by the US Food and Drug Administration (FDA), discuss relevant post-marketing studies of this drug, and offer expert commentary on the significance of this new agent in clinical practice. Pre-approval studies were identified as all randomized, placebo-controlled studies of vortioxetine listed on clinicaltrials.gov. Other referenced studies were identified via a MEDLINE database literature search in August 2015 using the key search terms, vortioxetine and Lu AA21004, combined with additional terms that included pharmacological profile, pharmacokinetics, drug interactions, adverse effects, side effects, safety, major depression, and major depressive disorder. We identified relevant systematic reviews, meta-analyses, randomized trials and preclinical studies of importance.
Expert Opinion: Results of placebo-controlled trials suggest efficacy and an overall safety profile comparable to existing first-line antidepressants. The most common side effects are nausea, vomiting and constipation. Results of several studies indicate that vortioxetine may have therapeutic effects on cognition (e.g., memory and executive functioning) that exceed that of standard antidepressants. Disadvantages include cost and the current paucity of long-term efficacy data from large clinical trials. The authors suggest that vortioxetine is currently a good second-line antidepressant option and shows promise, pending additional long-term data, to become a first-line antidepressant option.
Objective:The authors evaluated the efficacy and durability of a therapist-supported method for computer-assisted cognitive-behavioral therapy (CCBT) in comparison to standard cognitive-behavioral ...therapy (CBT).Method:A total of 154 medication-free patients with major depressive disorder seeking treatment at two university clinics were randomly assigned to either 16 weeks of standard CBT (up to 20 sessions of 50 minutes each) or CCBT using the “Good Days Ahead” program. The amount of therapist time in CCBT was planned to be about one-third that in CBT. Outcomes were assessed by independent raters and self-report at baseline, at weeks 8 and 16, and at posttreatment months 3 and 6. The primary test of efficacy was noninferiority on the Hamilton Depression Rating Scale at week 16.Results:Approximately 80% of the participants completed the 16-week protocol (79% in the CBT group and 82% in the CCBT group). CCBT met a priori criteria for noninferiority to conventional CBT at week 16. The groups did not differ significantly on any measure of psychopathology. Remission rates were similar for the two groups (intent-to-treat rates, 41.6% for the CBT group and 42.9% for the CCBT group). Both groups maintained improvements throughout the follow-up.Conclusions:The study findings indicate that a method of CCBT that blends Internet-delivered skill-building modules with about 5 hours of therapeutic contact was noninferior to a conventional course of CBT that provided over 8 additional hours of therapist contact. Future studies should focus on dissemination and optimizing therapist support methods to maximize the public health significance of CCBT.
To provide a quantitative meta-analysis of the antidepressant effects of sleep deprivation to complement qualitative reviews addressing response rates.
English-language studies from 1974 to 2016 ...using the keywords sleep deprivation and depression searched through PubMed and PsycINFO databases.
A total of 66 independent studies met criteria for inclusion: conducted experimental sleep deprivation, reported the percentage of the sample that responded to sleep deprivation, provided a priori definition of antidepressant response, and did not seamlessly combine sleep deprivation with other therapies (eg, chronotherapeutics, repetitive transcranial magnetic stimulation).
Data extracted included percentage of responders, type of sample (eg, bipolar, unipolar), type of sleep deprivation (eg, total, partial), demographics, medication use, type of outcome measure used, and definition of response (eg, 30% reduction in depression ratings). Data were analyzed with meta-analysis of proportions and a Poisson mixed-effects regression model.
The overall response rate to sleep deprivation was 45% among studies that utilized a randomized control group and 50% among studies that did not. The response to sleep deprivation was not affected significantly by the type of sleep deprivation performed, the nature of the clinical sample, medication status, the definition of response used, or age and gender of the sample.
These findings support a significant effect of sleep deprivation and suggest the need for future studies on the phenotypic nature of the antidepressant response to sleep deprivation, on the neurobiological mechanisms of action, and on moderators of the sleep deprivation treatment response in depression.
The risk of a manic switch was increased in depressed patients with bipolar disorder who were on antidepressant monotherapy but not in depressed bipolar patients who were treated with an ...antidepressant and concurrent mood stabilizer.
ObjectiveThis study examined the risk of antidepressant-induced manic switch in patients with bipolar disorder treated either with antidepressant monotherapy or with an antidepressant in conjunction with a mood stabilizer.MethodUsing Swedish national registries, the authors identified 3,240 patients with bipolar disorder who started treatment with an antidepressant and had no antidepressant treatment during the previous year. Patients were categorized into those receiving antidepressant monotherapy and those receiving an antidepressant plus a mood stabilizer. A within-individual design was used to control for confounding by disorder severity, genetic makeup, and early environmental factors. Cox regression analyses conditioned on individual were used to compare the rate of mania 0–3 months and 3–9 months after the start of antidepressant treatment with a preceding non-treatment period.ResultsNearly 35% of the patients were treated with antidepressant monotherapy. The increased risk of treatment-emergent mania was confined to patients on antidepressant monotherapy (hazard ratio=2.83, 95% CI=1.12, 7.19). Among patients treated with a concurrent mood stabilizer, no acute change in risk of mania was observed during the 3 months after the start of antidepressant treatment (hazard ratio=0.79, 95% CI=0.54, 1.15), and a decreased risk was observed during the period 3–9 months after treatment initiation (hazard ratio=0.63, 95% CI=0.42, 0.93).ConclusionsIn this national registry study, antidepressant monotherapy was associated with an increased risk of mania. However, no risk of mania was seen in patients receiving an antidepressant while treated with a mood stabilizer. The results highlight the importance of avoiding antidepressant monotherapy in the treatment of bipolar disorder.
Abstract Introduction Serotonin-1A receptor (5-HT1A R) function appears to be decreased in major depressive disorder (MDD) based on physiological responses to 5-HT1A R agonists in vivo and to 5-HT1A ...R binding in brain tissues postmortem or antemortem. We have previously assessed 5-HT1A R binding potential (BP) in depression using positron emission tomography (PET) and carbonyl-11 CWAY-100635, and we have demonstrated reduced 5-HT1A R BP in the mesiotemporal cortex (MTC) and raphe in depressives with primary recurrent familial mood disorders ( n =12) versus controls ( n =8) Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Huang Y, Gautier C, Mathis C. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999;46(10):1375–87. These findings were replicated by some, but not other, studies performed in depressed samples that were more generally selected using criteria for MDD. In the current study, we attempted to replicate our previous findings in an independent sample of subjects selected according to the criteria for primary recurrent depression applied in our prior study. Methods Using PET and carbonyl-11 CWAY-100635, 5-HT1A R BP was assessed in 16 depressed subjects and 8 healthy controls. Results Mean 5-HT1A R BP was reduced by 26% in the MTC ( P < .005) and by 43% in the raphe ( P < .001) in depressives versus controls. Conclusions These data replicate our original findings, which showed that BP was reduced by 27% in the MTC ( P < .025) and by 42% in the raphe ( P < .02) in depression. The magnitudes of these reductions in 5-HT1A R binding were similar to those found postmortem in 5-HT1A R mRNA concentrations in the hippocampus in MDD López JF, Chalmers DT, Little KY, Watson SJ. Regulation of serotonin 1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for neurobiology of depression. Biol Psychiatry 1998;43:547–73 and in 5-HT1A R-binding capacity in the raphe in depressed suicide victims Arango V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung S, Chen JJ, Mann JJ. Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology 2001;25(6):892–903. There exists disagreement within the literature, however, regarding the presence and direction of 5-HT1A R-binding abnormalities in depression, which may be explained in some cases by differences in anatomical location (e.g., Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G. Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression — postmortem evidence for decreased serotonin activity. J Neurosci 1998;18(18):7394–401) and in other cases by pathophysiological heterogeneity within MDD (e.g., some depressives hypersecrete cortisol, which would be expected to down-regulate 5-HT1A R expression López JF, Chalmers DT, Little KY, Watson SJ. Regulation of serotonin 1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for neurobiology of depression. Biol Psychiatry 1998;43:547–73). Antidepressant drug treatment does not alter these abnormalities in 5-HT1A R binding Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J, Gunn RN, Grasby PM, Cowen PJ. Brain serotonin1A receptor binding measured by positron emission tomography with 11 CWAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 2000;57(2):174–80; Moses-Kolko EL, Price JC, Thase ME, Meltzer CC, Kupfer DJ, Mathis CA, Bogers WD, Berman SR, Houck PR, Schneider TN, Drevets WC. Measurement of 5-HT(1A) receptor binding in depressed adults before and after antidepressant drug treatment using positron emission tomography and 11 CWAY-100635. Synapse 2007;61(7):523–30 but may compensate for blunted 5-HT1A R function by increasing post-synaptic 5-HT1A R transmission Chaput Y, de Montigny C, Blier P. Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments. An in vivo electrophysiologic study in the rat. Neuropsychopharmacology 1991;5(4):219–29.
To assess the efficacy, tolerability, and safety of brexpiprazole as adjunctive therapy to antidepressant treatments (ADTs) in adults with major depressive disorder (as defined by DSM-IV-TR criteria) ...and inadequate response to ADTs.
Patients with historical inadequate response to 1-3 ADTs were enrolled. All patients entered a prospective 8-week phase on physician-determined, open-label ADT. Those with inadequate response were randomized to ADT + brexpiprazole 2 mg/d or ADT + placebo for 6 weeks. The study was conducted between July 2011 and May 2013. The primary efficacy end point was change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The key secondary end point was change from baseline to week 6 in Sheehan Disability Scale (SDS) mean score. The efficacy population comprised all patients who had ≥ 1 dose of study drug in the double-blind phase and both baseline and ≥ 1 postrandomization MADRS scores. The efficacy population per final protocol included patients from the efficacy population who met amended randomization criteria of inadequate response throughout prospective treatment.
Brexpiprazole (n = 175) reduced mean MADRS total score versus placebo (n = 178) at week 6 in the efficacy population per final protocol (-8.36 vs -5.15, P = .0002). Brexpiprazole improved SDS mean score versus placebo (-1.35 vs -0.89, P = .0349). The most common treatment-related adverse events were weight gain (brexpiprazole, 8.0%; placebo, 3.1%) and akathisia (7.4% vs 1.0%).
Adjunctive brexpiprazole therapy demonstrated efficacy and was well tolerated in patients with major depressive disorder and inadequate response to ADTs.
ClinicalTrials.gov identifier: NCT01360645.
Clinicians should weigh potential adverse effects of antidepressant medications when treating patients with medical comorbidities. Consider an example of the choices that sometimes must be made ...through the case of Tony, a 64-year-old man whose current diagnosis of hypertension and increased risk of diabetes influence his treatment for depression.
To evaluate efficacy, safety, and tolerability of brexpiprazole adjunctive to antidepressant treatments (ADTs) in patients with major depressive disorder (as defined by DSM-IV-TR criteria) with ...inadequate response to ADTs.
Patients still depressed despite 1-3 prior ADTs followed by 8 weeks of prospective physician-determined, open-label ADT were randomized (1:1:1) to double-blind brexpiprazole 3 mg/d, brexpiprazole 1 mg/d, or placebo for 6 weeks. The primary efficacy end point was change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to week 6. The key secondary efficacy end point was change in Sheehan Disability Scale mean score. The Hochberg procedure corrected for multiplicity. The efficacy population comprised all patients who had ≥ 1 dose of study drug with baseline and ≥ 1 postrandomization MADRS scores; the efficacy population per final protocol consisted of efficacy population patients meeting amended criteria for inadequate response throughout the 8-week prospective ADT. The study was conducted between June 2011 and September 2013.
In the efficacy population per final protocol, brexpiprazole 3 mg (n = 213) showed a greater improvement in MADRS total score versus placebo (n = 203; -8.29 vs -6.33; P = .0079), whereas brexpiprazole 1 mg did not (n = 211; -7.64 vs -6.33; P = .0737). The brexpiprazole groups showed comparable improvement in SDS mean score versus placebo (least squares LS mean difference: 1 mg -0.49, P = .0158; 3 mg -0.48, P = .0191). The most frequent adverse events were akathisia (4.4%, 13.5%, 2.3%), headache (9.3%, 6.1%, 7.7%), and weight increase (6.6%, 5.7%, 0.9%) in brexpiprazole 1-mg, 3-mg, and placebo groups, respectively. Mean changes from baseline in Abnormal Involuntary Movement Scale (LS mean difference = 0.08, P = .0141) and Barnes Akathisia Rating Scale (LS mean difference = 0.17, P = .0001) total scores were significantly greater with brexpiprazole 3 mg versus placebo.
Brexpiprazole 3 mg demonstrated efficacy versus placebo in the efficacy population per final protocol. Both doses of brexpiprazole were well tolerated.
ClinicalTrials.gov identifier: NCT01360632.
Objective: Symptoms of bipolar disorder are increasingly recognized among children and adolescents, but little is known about the course of bipolar disorder among adults who experience childhood ...onset of symptoms.
Methods: We examined prospective outcomes during up to two years of naturalistic treatment among 3,658 adult bipolar I and II outpatients participating in a multicenter clinical effectiveness study, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP‐BD). Age at illness onset was identified retrospectively by clinician assessment at study entry.
Results: Compared to patients with onset of mood symptoms after age 18 years (n = 1,187), those with onset before age 13 years (n = 1,068) experienced earlier recurrence of mood episodes after initial remission, fewer days of euthymia, and greater impairment in functioning and quality of life over the two‐year follow‐up. Outcomes for those with onset between age 13 and 18 years (n = 1,403) were generally intermediate between these two groups.
Conclusion: Consistent with previous reports in smaller cohorts, adults with retrospectively obtained early‐onset bipolar disorder appear to be at greater risk for recurrence, chronicity of mood symptoms, and functional impairment during prospective observation.
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