Friday, December 11, 2015

December 2015

Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder 


The American Journal of Psychiatry

Abstract

Objective:
Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder.

Method:
The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder.

Results:
Forty studies involving 10,039 participants were included. Longitudinal modeling (dose-by-time interaction=0.0007, 95% CI=0.0001–0.0013) and endpoint analysis (meta-regression: β=0.00053, 95% CI=0.00018–0.00088, z=2.98) demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects (meta-regression: β=0.00207, 95% CI=0.00071–0.00342, z=2.98) and decreased likelihood of all-cause dropout (meta-regression: β=–0.00093, 95% CI=–0.00165 to −0.00021, z=−2.54).

Conclusions:
Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.




Asenapine for the Acute Treatment of Pediatric Manic or Mixed Episode of Bipolar I Disorder


Journal of the American Academy of Child and Adolescent Psychiatry 

Abstract

Objective
To evaluate asenapine versus placebo in 403 patients aged 10 to 17 years with bipolar I disorder currently in manic or mixed episodes.

Method
In this double-blind, placebo-controlled, international trial, patients were randomized 1:1:1:1 to placebo, asenapine 2.5, 5, or 10 mg b.i.d. (twice daily). Primary efficacy measure was change from baseline in Young-Mania Rating Scale (YMRS) total score at day 21. Analyses of patients with/without attention-deficit/hyperactivity disorder (ADHD) and with/without stimulant use were performed.

Results
The mean difference in asenapine versus placebo in YMRS was –3.2 (p = .0008), –5.3 (p < .001), and –6.2 (p < .001) for asenapine 2.5, 5, and 10 mg b.i.d., respectively. Treatment-emergent adverse events with an incidence ≥5% and at least twice placebo were somnolence, sedation, hypoesthesia oral, paresthesia oral, and increased appetite. The asenapine groups had a higher incidence of ≥7% weight gain (range, 8.0%–12.0%) versus placebo (1.1%; p < .05). The mean change from baseline in fasting insulin was larger for patients treated with asenapine than those with placebo (asenapine 2.5 mg b.i.d.: 73.375 pmol/L; asenapine 5 mg b.i.d.: 114.042 pmol/L; asenapine 10 mg b.i.d.: 59.846 pmol/L; placebo: 3.690 pmol/L). The mean changes from baseline for lipid parameters and glucose were also larger in asenapine groups than in the placebo group. No safety differences were observed with respect to ADHD and stimulant use.

Conclusion
All asenapine doses versus placebo were superior based on change in YMRS at day 21. Asenapine was generally well tolerated in patients aged 10 to 17 years with bipolar I disorder in manic or mixed states. Increases in weight and fasting insulin were associated with asenapine.




Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode


Molecular Psychiatry

Abstract 

Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (n=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry (‘0-weeks’ group) or (ii) at 24 weeks after entry (‘24-weeks’ group) or (iii) continuation of risperidone or olanzapine for the full duration of the study (‘52-weeks’ group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, sub-group analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2 kg in the 52-weeks group compared with a weight loss of 0.2 kg in the 0-weeks and 0.1 kg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.



US FDA approveD easy-to-use nasal spray (NALOXONE) to treat opioid overdose


FDA News Release
  
The U.S. Food and Drug Administration approved Narcan nasal spray, the first FDA-approved nasal spray version of naloxone hydrochloride, a life-saving medication that can stop or reverse the effects of an opioid overdose. Opioids are a class of drugs that include prescription medications such as oxycodone, hydrocodone, and morphine, as well as the illegal drug heroin.

Drug overdose deaths, driven largely by prescription drug overdoses, are now the leading cause of injury death in the United States – surpassing motor vehicle crashes. In 2013, the Centers for Disease Control and Prevention reported the number of drug overdose deaths had steadily increased for more than a decade. When someone overdoses on an opioid, it can be difficult to awaken the person, and breathing may become shallow or stop – leading to death if there is no medical intervention. If naloxone is administered quickly, it can counter the overdose effects, usually within two minutes.

“Combating the opioid abuse epidemic is a top priority for the FDA,” said Stephen Ostroff, M.D., acting commissioner, Food and Drug Administration. “We cannot stand by while Americans are dying. While naloxone will not solve the underlying problems of the opioid epidemic, we are speeding to review new formulations that will ultimately save lives that might otherwise be lost to drug addiction and overdose.”  
Until this approval, naloxone was only approved in injectable forms, most commonly delivered by syringe or auto-injector. Many first responders and primary caregivers, however, feel a nasal spray formulation of naloxone is easier to deliver, and eliminates the risk of a contaminated needle stick. As a result, there has been widespread use of unapproved naloxone kits that combine an injectable formulation of naloxone with an atomizer that can deliver naloxone nasally. Now, people have access to an FDA-approved product for which the drug and its delivery device have met the FDA’s high standards for safety, efficacy and quality.

Narcan nasal spray does not require assembly and delivers a consistent, measured dose when used as directed. This prescription product can be used on adults or children and is easily administered by anyone, even those without medical training. The drug is sprayed into one nostril while the patient is lying on his or her back, and can be repeated if necessary. However, it is important to note that it is not a substitute for immediate medical care, and the person administering Narcan nasal spray should seek further immediate medical attention on the patient’s behalf.

The FDA granted fast-track designation and priority review for Narcan nasal spray. Fast track is a process designed to facilitate development and expedite review of drugs intended to treat serious conditions and that demonstrate the potential to address an unmet medical need. The agency’s priority review program provides for an expedited review of drugs that offer a significant improvement in the safety or effectiveness of the treatment, prevention, or diagnosis of a serious condition. Narcan nasal spray is being approved in less than four months, significantly ahead of the product’s prescription drug user fee goal date of January 20, 2016.

In clinical trials conducted to support the approval of Narcan nasal spray, administering the drug in one nostril delivered approximately the same levels or higher of naloxone as a single dose of an FDA-approved naloxone intramuscular injection, and achieved these levels in approximately the same time frame.

“We heard the public call for this new route of administration, and we are happy to have been able to move so quickly on a product we are confident will deliver consistently adequate levels of the medication – a critical attribute for this emergency life-saving drug,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research.

The National Institute on Drug Abuse played a critical role in the development of Narcan nasal spray as well, forming a public-private partnership by designing and conducting the clinical trials required to determine that the intranasal formulation delivered naloxone as quickly and as effectively as an injection. NIDA then worked with its private sector partners to obtain FDA approval.

“This easy-to-use intranasal formulation will no doubt save many lives,” said Nora Volkow, M.D., director, National Institute on Drug Abuse at the National Institutes of Health. “While prevention is the ultimate goal, the drug’s successful development illustrates how public/private scientific partnerships can play an important role in responding to a national crisis right now.”

Increasing access to and the use of naloxone is part of the targeted strategy that Health and Human Services Secretary Sylvia M. Burwell put forward in March to address the opioid epidemic and save lives. In July, addiction and advocacy groups called for expanded availability of naloxone during an FDA-sponsored public workshop exploring the uptake and use of the drug.

The use of Narcan nasal spray in patients who are opioid dependent may result in severe opioid withdrawal characterized by body aches, diarrhea, increased heart rate (tachycardia), fever, runny nose, sneezing, goose bumps (piloerection), sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure.



Use of Lithium and Anticonvulsants and the Rate of Chronic Kidney Disease


JAMA Psychiatry

Abstract

Importance  
Lithium is the main mood stabilizing drug for bipolar disorder. However, it is controversial whether long-term maintenance treatment with lithium or other drugs for bipolar disorder causes chronic kidney disease (CKD).

Objective  
To compare rates of CKD and in particular rates of end-stage CKD among individuals exposed to successive prescriptions of lithium, anticonvulsants, or other drugs used for bipolar disorder.

Design, Setting, and Participants  
This is a Danish nationwide population-based study of 2 cohorts. Cohort 1 comprised a randomly selected sample of 1.5 million individuals among all persons who were registered in Denmark on January 1, 1995, all patients with a diagnosis of a single manic episode or bipolar disorder between January 1, 1994, and December 31, 2012 (n =10 591), and all patients exposed to either lithium (n = 26 731) or anticonvulsants (n=420 959). Cohort 2 included the subgroup of 10 591 patients diagnosed as having bipolar disorder.

Main Outcomes and Measures  
Possible CKD, definite CKD, and end-stage CKD (defined as long-term dialysis or renal transplantation).

Results  
A total of 14 727 (0.8%), 18 762 (1.0%), and 3407 (0.2%) in cohort 1 and 278 (2.6%), 319 (3.0%), and 62 (0.6%) in cohort 2 were diagnosed as having possible, definite, or end-stage CKD, respectively. Based on the total sample and not considering diagnoses, use of lithium was associated with an increased rate of definite CKD (0 prescriptions: hazard ratio [HR] = 1.09, 95% CI, 0.81-1.45; ≥60 prescriptions: HR = 3.65, 95% CI, 2.64-5.05; P for trend < .001) and possible CKD (0 prescriptions: HR = 1.01, 95% CI, 0.79-1.30; ≥60 prescriptions: HR = 2.88, 95% CI, 2.17-3.81; P for trend < .001), whereas use of anticonvulsants, antipsychotics, or antidepressants was not. Neither use of lithium nor use of any other drug class was associated with increasing rates of end-stage CKD. In patients with bipolar disorder, use of lithium was associated with an increased rate of definite CKD (1-2 prescriptions: HR = 0.89, 95% CI, 0.39-2.06; ≥60 prescriptions: HR = 2.54, 95% CI, 1.81-3.57; P for trend < .001) or possible CKD (1-2 prescriptions: HR = 1.26, 95% CI, 0.65-2.43; ≥60 prescriptions, HR = 2.48, 95% CI, 1.80-3.42; P for trend < .001), as was use of anticonvulsants (definite CKD, 1-2 prescriptions: HR = 1.23, 95% CI, 0.76-1.99; ≥60 prescriptions, HR = 2.30, 95% CI, 1.53-3.44; P for trend < .001; possible CKD, 1-2 prescriptions: HR = 1.11, 95% CI, 0.70-1.76; ≥60 prescriptions: HR = 1.97, 95% CI, 1.34-2.90; P for trend < .001). There was no such association with antipsychotics or antidepressants. Also in patients with bipolar disorder, use of lithium was not significantly associated with an increased rate of end-stage CKD, whereas use of anticonvulsants was (1-2 prescriptions, HR = 0 [95% CI, 0.00-infinity]; 30-39 prescriptions: HR = 3.23, 95% CI, 1.26-8.27; ≥60 prescriptions: HR = 2.06, 95% CI, 0.82-5.16; P for trend = .002).

Conclusions and Relevance  
Maintenance treatment with lithium or anticonvulsants as practiced in modern care is associated with an increased rate of CKD. However, use of lithium is not associated with an increased rate of end-stage CKD. The associations between use of medication and CKD may at least partly be attributed to bias.



Adjuvant pioglitazone for unremitted depression: Clinical correlates of treatment response


Psychiatry Research

Abstract

Previous studies suggest that insulin-sensitizing agents could play a significant role in the treatment of major depression, particularly depression in patients with documented insulin resistance or those who are resistant to standard psychopharmacological approaches. This study aimed to assess the effects on depressive symptoms with adjuvant treatment with the PPARγ-agonist pioglitazone. Patients (N=37) with non-psychotic, non-remitting depression receiving standard psychiatric regimens for depression were randomized across an insulin sensitivity spectrum in a 12-week double blind, randomized controlled trial of pioglitazone or placebo. Improvement in depression was associated with improvement in glucose metabolism but only in patients with insulin resistance. An age effect was also shown in that response to pioglitazone was more beneficial in younger aged patients. Study findings suggest differential improvement in depression severity according to both glucose metabolic status and level of depression at baseline. A greater understanding of the reciprocal links between depression and IR may lead to a dramatic shift in the way in which depression is conceptualized and treated, with a greater focus on treating and/or preventing metabolic dysfunction.



Different Brain Regions are Infected with Fungi in Alzheimer’s Disease


Nature Scientific Reports

Abstract

The possibility that Alzheimer’s disease (AD) has a microbial aetiology has been proposed by several researchers. Here, we provide evidence that tissue from the central nervous system (CNS) of AD patients contain fungal cells and hyphae. Fungal material can be detected both intra- and extracellularly using specific antibodies against several fungi. Different brain regions including external frontal cortex, cerebellar hemisphere, entorhinal cortex/hippocampus and choroid plexus contain fungal material, which is absent in brain tissue from control individuals. Analysis of brain sections from ten additional AD patients reveals that all are infected with fungi. Fungal infection is also observed in blood vessels, which may explain the vascular pathology frequently detected in AD patients. Sequencing of fungal DNA extracted from frozen CNS samples identifies several fungal species. Collectively, our findings provide compelling evidence for the existence of fungal infection in the CNS from AD patients, but not in control individuals.




An 8-Week Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar I Depression


The American Journal of Psychiatry

Abstract

Objective:
The authors evaluated the efficacy, safety, and tolerability of cariprazine, an atypical antipsychotic candidate, in adult patients with acute bipolar I depression.

Method:
This was an 8-week multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study in adult patients with bipolar I disorder experiencing a current major depressive episode. Patients were randomly assigned (1:1:1:1) to receive placebo or cariprazine at 0.75, 1.5, or 3.0 mg/day. The primary and secondary efficacy parameters were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impressions severity subscale (CGI-S), respectively, analyzed using a mixed-effects model for repeated measures on the modified intent-to-treat population.

Results:
The intent-to-treat population comprised 571 patients (141 in the placebo group and 140, 145, and 145 in the cariprazine 0.75-, 1.5-, and 3.0-mg/day groups). Cariprazine at 1.5 mg/day showed significantly greater improvement on MADRS total score change from baseline to week 6 compared with placebo; the least squares mean difference was −4.0 (95% CI=−6.3, −1.6; significant after adjustment for multiple comparisons). Cariprazine at 3.0 mg/day showed greater MADRS score reduction than placebo (−2.5, 95% CI=−4.9, −0.1; not significant when adjusted for multiple comparisons). The 0.75 mg/day dosage was similar to placebo. A similar pattern for significance was observed on the CGI-S (1.5 mg/day: least squares mean difference=−0.4, 95% CI=−0.6, −0.1; 3.0 mg/day: −0.3, 95% CI=−0.5, −0.0). The most common adverse events (≥10%) in cariprazine-treated patients were akathisia and insomnia; weight gain was slightly higher with cariprazine than with placebo.

Conclusions:
Cariprazine at 1.5 mg/day demonstrated consistent efficacy compared with placebo across outcomes and was generally well tolerated, suggesting efficacy for the treatment of bipolar I depression.




Premature Mortality Among Adults With Schizophrenia in the United States

JAMA Psychiatry

Abstract

Importance  
Although adults with schizophrenia have a significantly increased risk of premature mortality, sample size limitations of previous research have hindered the identification of the underlying causes.


Objective  
To describe overall and cause-specific mortality rates and standardized mortality ratios (SMRs) for adults with schizophrenia compared with the US general population.


Design, Setting, and Participants
We identified a national retrospective longitudinal cohort of patients with schizophrenia 20 to 64 years old in the Medicaid program (January 1, 2001, to December 31, 2007). The cohort included 1 138 853 individuals, 4 807 121 years of follow-up, and 74 003 deaths, of which 65 553 had a known cause.


Main Outcomes and Measures  
Mortality ratios for the schizophrenia cohort standardized to the general population with respect to age, sex, race/ethnicity, and geographic region were estimated for all-cause and cause-specific mortality. Mortality rates per 100 000 person-years and the mean years of potential life lost per death were also determined. Death record information was obtained from the National Death Index.


Results
Adults with schizophrenia were more than 3.5 times (all-cause SMR, 3.7; 95% CI, 3.7-3.7) as likely to die in the follow-up period as were adults in the general population. Cardiovascular disease had the highest mortality rate (403.2 per 100 000 person-years) and an SMR of 3.6 (95% CI, 3.5-3.6). Among 6 selected cancers, lung cancer had the highest mortality rate (74.8 per 100 000 person-years) and an SMR of 2.4 (95% CI, 2.4-2.5). Particularly elevated SMRs were observed for chronic obstructive pulmonary disease (9.9; 95% CI, 9.6-10.2) and influenza and pneumonia (7.0; 95% CI, 6.7-7.4). Accidental deaths (119.7 per 100 000 person-years) accounted for more than twice as many deaths as suicide (52.0 per 100 000 person-years). Nonsuicidal substance-induced death, mostly from alcohol or other drugs, was also a leading cause of death (95.2 per 100 000 person-years).


Conclusions and Relevance
In a US national cohort of adults with schizophrenia, excess deaths from cardiovascular and respiratory diseases implicate modifiable cardiovascular risk factors, including especially tobacco use. Excess deaths directly attributable to alcohol or other drugs highlight threats posed by substance abuse. More aggressive identification and management of cardiovascular risk factors, as well as reducing tobacco use and substance abuse, should be leading priorities in the medical care of adults with schizophrenia.


Source: http://archpsyc.jamanetwork.com/


The Roles of Maternal Depression, Serotonin Reuptake Inhibitor Treatment, and Concomitant Benzodiazepine Use on Infant Neurobehavioral Functioning Over the First Postnatal Month


The American Journal of Psychiatry

Abstract

Objective:
The purpose of this article was to systematically compare the developmental trajectory of neurobehavior over the first postnatal month for infants with prenatal exposure to pharmacologically untreated maternal depression, selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors (collectively: SSRIs), SSRIs with concomitant benzodiazepines (SSRI plus benzodiazepine), and no maternal depression or drug treatment (no exposure).

Method:
Women (N=184) were assessed at two prenatal time points to determine psychiatric diagnoses, symptom severity, and prenatal medication usage. Infants were examined with a structured neurobehavioral assessment (Neonatal Intensive Care Unit Network Neurobehavioral Scale) at multiple time points across the first postnatal month. SSRI exposure was confirmed in a subset of participants with plasma SSRI levels. General linear-mixed models were used to examine group differences in neurobehavioral scores over time with adjustment for demographic variables and depression severity.

Results:
Infants in the SSRI and SSRI plus benzodiazepine groups had lower motor scores and more CNS stress signs across the first postnatal month, as well as lower self-regulation and higher arousal at day 14. Infants in the depression group had low arousal throughout the newborn period. Infants in all three clinical groups had a widening gap in scores from the no-exposure group at day 30 in their response to visual and auditory stimuli while asleep and awake. Infants in the SSRI plus benzodiazepine group had the least favorable scores on the Neonatal Intensive Care Unit Network Neurobehavioral Scale.

Conclusions:
Neonatal adaptation syndrome was not limited to the first 2 weeks postbirth. The profile of neurobehavioral development was different for SSRI exposure than depression alone. Concomitant benzodiazepine use may exacerbate adverse behavioral effects.



Online Journals:




Biological Psychiatry - Volume 79, Issue 2, January 2016



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