Richard M. Bloch, PhD

Here we present brief descriptions of 8 of the top 25 articles we have chosen for their relevance to clinical psychiatric practice, and their clinical applicability. The order in which the articles appear is arbitrary.

This study supports the indication that fluoxetine is more likely to be effective than other antidepressants in treating MDD in children younger than 18 years.

The study used network meta-analysis of 34 randomized controlled trials, which included 5260 participants, to compare the efficacy of 14 different antidepressants for acute MDD in children younger than 18 years. SSRIs, SNRIs, TCAs, and other medications were compared. A network meta-analysis allows for comparisons between different medications: although many have not been compared directly with each other, all have been compared with placebo.

Only fluoxetine was statistically superior to placebo in producing improvement. Fluoxetine was associated with fewer dropouts because of adverse effects than several SSRIs, TCAs, and SNRIs. Venlafaxine was statistically most likely to produce suicidal thoughts or behaviors. More patients were exposed to fluoxetine than to any of the other medications; thus, power may be a potential bias in that disparate numbers of patients have been exposed to the different medications.

Cipriani A, Zhou X, Del Giovane C, et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. 

This article adds to the positive support for omega-3 fatty acid preparations, especially those that are primarily eicosapentaenoic acid (EPA) or ethyl-EPA formulations. In this case, adding omega-3 fatty acids to antidepressant therapies for MDD enhanced the therapeutic effects.

This review of nutraceuticals as adjunctive therapy for depression finds several with repeated positive effects on depression. The nutraceuticals with enough trials to enable meta-analyses were examined. Findings for S-adenosylmethionine (SAMe), methylfolate, omega-3, and vitamin D as adjuncts to SSRI therapy for MDD were more positive than negative.

Creatine and an amino acid combination were studied less often but still showed occasional efficacy. Those that did not show much promise were zinc, vitamin C, tryptophan, and inositol.

Meta-analyses supported omega-3 fatty acids from fish oil as very likely to be effective as adjuncts to antidepressant medications. There was mixed support for folic acid and folate-related compounds, but their effects were not comparable to those of omega-3.

It is not yet clear what the optimal dose is, whether it is the same for all antidepressants, and what the optimal duration of adjunctive treatment would be. While safety remains to be determined, omega-3 fatty acid adjunctive treatment does not appear to increase the adverse effects of antidepressants and offers a relatively safe option compared with supplementation with antipsychotic medications or other nutraceuticals.

Sarris J, Murphy J, Mischoulon D, et al. Adjunctive nutraceuticals for depression: a systematic review and meta-analysis. 

Based on a review of the literature by a consensus panel, this guideline strongly recommends cognitive-behavioral therapy for chronic insomnia (CBT-I) in adults as the first-line treatment.

The quality of evidence supporting this recommendation was judged to be moderate for a wide variety of outcomes from remission to improved sleep quality. In addition, CBT-I was effective with delivery methods ranging from in-person delivery to telephone or Internet delivery.

If CBT-I does not prove successful, the guidelines weakly recommend sleep medications for a suggested maximum duration of 4 or 5 weeks. The evidence of medication efficacy was weak, with a narrower range of positive effects and with considerably greater adverse-effect burdens. There was insufficient evidence of efficacy for complementary and alternative approaches.

Qaseem A, Kansagara D, Forciea MA, et al, for the Clinical Guidelines Committee of the American College of Physicians. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. 

This article supports the greater use of clozapine in general practice when managing treatment-compliant patients who continue to require hospitalizations and medication changes.

Because of the risk of agranulocytosis, clozapine has come to be viewed in general practice as a last resort for treatment-resistant schizophrenia. This, in turn, has led to possible underutilization.

This article reports on the effects in general practice of switching to clozapine after an inadequate response to standard antipsychotics, such as olanzapine or risperidone. A retrospective cohort design employing Medicaid data was used to compare 2 groups of 3123 patients with treatment-resistant schizophrenia. One group had been switched to clozapine after showing signs of treatment resistance. The other group had been switched to a different non-clozapine antipsychotic after showing comparable signs of treatment resistance, such as hospitalization and at least 2 antipsychotic medications prescribed while maintaining medication compliance.

The 2 groups were selected to enable tight matching on gender, race, and age. Medical and psychiatric symptoms were also matched using a scoring system to reduce the likelihood that the clozapine group had more severe symptoms.

Intent-to-treat analysis demonstrated that the group switched to clozapine had significantly fewer hospitalizations, medication discontinuations, or new antipsychotics initiated, while showing no differences from the non-clozapine group in mortality. The clozapine group had higher rates of diabetes, bowel obstruction, and hyperlipidemia. However, the rates of these adverse effects were relatively low. Other medical adverse effects were not different between groups.

Stroup TS, Gerhard T, Crystal S, et al. Comparative effectiveness of clozapine and standard antipsychotic treatment in adults with schizophrenia. 

The study shows that it is likely that tDCS is superior to placebo and that the higher the tDCS dose, the better the response.

The data that support the efficacy of transcranial direct current stimulation (tDCS) for MDD have been mixed Most studies show positive trends toward better responsiveness and remission rates with tDCS than with sham controls. However, meta-analytic attempts to combine trials have led to mixed results because of the low numbers of randomized trials and participants.

This article presents a different meta-analytic approach that emphasizes individual patient data over group comparisons. One issue with this approach, however, is that not all randomized clinical trials (RCTs) allow for the inclusion of individual patient data, so some caution is appropriate.

Six RCTs were included in the meta-analysis. The results indicated that the response to tDCS was more positive than to sham procedures. The overall efficacy of tDCS was comparable to that seen in response to repetitive transcranial stimulation, and perhaps even to SSRI antidepressants.

This study was not a comparison between tDCS and a validated antidepressant treatment, so comparability has to be assumed. In those circumstances in which access to tDCS is available and patients have a poor response to antidepressant medications or prefer nonmedication treatment, tDCS could reasonably be considered.

Brunoni AR, Moffa AH, Fregni F, et al. Transcranial direct current stimulation for acute major depressive episodes: meta-analysis of individual patient data. 

Clinicians who are considering omega-3 fatty acids for their patients with MDD should ensure that EPA-predominant PUFAs are used. Similarly, when PUFAs are being considered as adjunctive treatment to antidepressants, EPA-predominant preparations should be recommended.

Meta-analyses in multiple steps were used to assess several hypotheses regarding the potential antidepressant effects of omega-3 polyunsaturated fatty acids (PUFAs), either alone or as an adjunct to antidepressant medications. Previous meta-analyses had yielded mixed results with no clear positive effects of omega-3 PUFAs on depression symptoms.

In this article, results of separate meta-analyses on EPA-predominant
PUFAs versus docosahexaenoic acid (DHA)-predominant PUFAs were reported. In addition, results of separate meta-analyses for the effects of omega-3 on patients with clinically diagnosed MDD versus depressed persons who did not meet clinical diagnostic criteria were reported. As hypothesized, omega-3 PUFAs that were predominantly EPA significantly reduced depressive symptoms in patients who had received a clinical diagnosis. Neither EPA- nor DHA-predominant omega-3s produced significant improvement in depressed patients who did not have clinically diagnosed MDD.

Hallahan B, Ryan T, Hibbeln JR, et al. Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression. 

The efficacy of interpersonal psychotherapy (IPT) increases the range of evidence-based psychotherapies that can reasonably be recommended for depression, anxiety disorders, and eating disorders, perhaps making referral for psychotherapy easier.

This study compared IPT with other forms of therapy or with some form of placebo for a range of clinical disorders ranging from MDD to eating disorders. The efficacy of IPT in combination with antidepressant medications, IPT for prevention of depression in patients at risk, and IPT for prevention of relapse were also examined. The efficacy of IPT for the treatment of depression has been long recognized, although its relative efficacy compared with CBT or antidepressant medications was less certain.

Meta-analysis of 90 studies including over 11,000 patients again showed that IPT was more effective than placebo or waiting list controls for the treatment of MDD. The results also showed that IPT was comparable in efficacy to CBT and to pharmacotherapies. The combination of IPT with antidepressant medications produced greater improvement in depression than IPT alone. Moreover, IPT was efficacious for anxiety disorders and for eating disorders.

There were no important differences in the efficacy of IPT and CBT or pharmacotherapies for depression, anxiety, or eating disorders. The lack of availability of therapists and evidence-based psychotherapies can be a significant problem, however.

Cuijpers P, Donker T, Weissman MM, et al. Interpersonal psychotherapy for mental health problems: a comprehensive meta-analysis. 

This study strongly suggests that less caution is needed in first-term use of sertraline, but increased caution is needed for fluoxetine in pregnant women. Continued caution should be used when considering paroxetine.

This case-control study is based on a very large multistate US dataset. It allowed individual birth defect risk to be associated with 5 SSRI exposures. The odds found in the dataset were used to modify the odds that already existed in other studies. The authors conducted a meta-analysis to determine the a priori odds and then in conjunction with the dataset determined the posterior odds.

A group of almost 18,000 women who gave birth to infants with birth defects were compared with almost 10,000 women whose infants had no birth defects. All women were asked about their SSRI use in the month before pregnancy and during the first trimester of their pregnancy.

Because of the study design, the odds of each SSRI exposure were associated with specific defect identification, rather than the other way around. In addition, no causal conclusions could be made. Despite these limitations, the large number of defects and exposures allowed for more precise estimates of the associations between defects and first-trimester exposure to each SSRI. The large dataset found that most previously reported associations were not supported. Perhaps most importantly, no birth defects were associated with sertraline exposures.

Many of the previously reported associations of defects with paroxetine were replicated. Two defects were associated with fluoxetine exposure.
Defects were not associated with citalopram, escitalopram, or sertraline.

Reefhuis J, Devine O, Friedman JM, et al, on behalf of the National Birth Defects Prevention Study. Specific SSRIs and birth defects: bayesian analysis to interpret new data in the context of previous reports. 

Dr. Saeed is Professor and Chairman of the Department of Psychiatry and Behavioral Medicine at the Brody School of Medicine at East Carolina University, Director of the ECU Center for Telepsychiatry and e-Behavioral Health as well as of the North Carolina Statewide Telepsychiatry Program (NC-STeP), and Chief of Psychiatry at Vidant Health in Greenville, NC. Dr. Bloch is Professor and Director of Research in the Department of Psychiatry and Behavioral Medicine at Brody School of Medicine at East Carolina University.

Articles

The psychiatric literature is overwhelming. So these authors have culled 25 "top" articles based on their relevance to clinical practice. Here's a quick synopsis of 8 top articles. 

Top Papers That Can Change Your Practice

Psychiatrists and other clinicians are under increasing pressure to stay up to date with the medical literature. With the rapid growth of knowledge, the challenge to keep up with the ever-growing body of information is greater than ever.

There is now an emerging realization that, as clinical providers, we need an efficient and effective system to help us sort and evaluate the quality of information before we can apply it to clinical care. Without such a system, when faced with an overload of information, most of us tend to take the first or the most easily accessed information-without consideration of the quality of such information. As a result, such poor-quality information affects the quality of care we provide and costs billions of dollars annually because of underuse, overuse, and misuse.

To sort and evaluate published research that is ready for clinical utilization, we used the following 3-step methodology:

 Search literature for research findings published between July 1, 2015, and June 30, 2016, that suggest readiness for clinical use.

 Members of the American Association of Chairs of Departments of Psychiatry; the American Association of Community Psychiatrists; the American Association of Psychiatric Administrators; the North Carolina Psychiatric Association; and the Group for the Advancement of Psychiatry (GAP), as well as colleagues, were asked: Among the articles published from July 1, 2015, to June 30, 2016, which ones in your opinion have (or are likely to have or should have) affected/changed the clinical practice of psychiatry?

 Look for appraisals in post-publication reviews, such as 

Faculty of 1000 Factor, Evidence-Based Mental Health

, and commentaries in peer-reviewed journals.

The top 25 articles were selected based on their clinical relevance/applicability. Here, we present brief descriptions of the first 8 papers chosen by this methodology-the order in which the articles appear in the list is arbitrary. We will present descriptions of the remaining papers in upcoming issues. Abstracts are available on PubMed.

Amminger GP, SchÃ¤fer MR, SchlÃ¶gelhofer M, et al. Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study. 

» This follow-up of a randomized clinical trial (RCT) demonstrated that omega-3 fatty acids were effective in preventing new-onset psychotic disorders in high-risk individuals. The current study compared oral administration of daily fish oil capsules containing 700 mg of eicosapentaenoic acid and 480 mg of docosahexaenoic acid with placebo for 12 weeks in individuals at similar risk for a new-onset psychotic disorder. Follow-up was extended to 7 years.

Participants (N = 81) between the ages of 13 and 25 who sought treatment for attenuated psychotic behaviors, transient psychosis, or decreased functioning in the presence of genetic risk for psychotic disorders were randomly assigned to omega-3 and placebo. At the 7-year follow-up, patients in the omega-3 group were 32% less likely to have converted to a psychotic diagnosis or to have been treated with antipsychotic medications.

Omega-3 polyunsaturated fatty acids have negligible adverse effects and are relatively inexpensive. This study replicated and extended the duration of positive effects of a 12-week course of polyunsaturated fatty acids on preventing psychotic disorders and improving symptomatic behaviors to 7 years.

Samara MT, Leucht C, Leeflang MM, et al. Early improvement as a predictor of later response to antipsychotics in schizophrenia: a diagnostic test review. 

» This systematic review used positive predictive value to test the hypothesis that a poor response to antipsychotic medication by week 2 would predict poor treatment effects by the end of the trial. Studies in which antipsychotics were used for 4 to 12 weeks to treat schizophrenia, schizophreniform psychosis, or schizoaffective psychosis were combined.

Less than a 20% improvement on the Positive and Negative Syndrome Scale by 2 weeks was used as the measure of lack of early responsiveness; endpoint lack of response was less than 50% improvement. The primary result was an overall positive predictive value of 0.90 or 90%. Patients who exhibited less than 20% improvement by 2 weeks were 90% likely to show less than 50% improvement by the end of their medication trial.

The primary clinical conclusion is that patients who have had at least 1 previous schizophrenia episode and who show at least 20% improvement after 2 weeks of targeted antipsychotic dose treatment should not have their medication changed early.

Kane JM, Robinson DG, Schooler NR, et al. Comprehensive versus usual community care for first-episode psychosis: 2-year outcomes from the NIMH RAISE early treatment program. 

» An RCT utilized the outcome data at the end of a 2-year intervention to compare quality of life and psychopathology scores for a multimodal multidisciplinary team approach (Navigate) versus usual community care for the treatment of first-episode psychosis. The team approach included personalized medication management, family psychoeducation, resilience-focused psychotherapy, and supported employment and education.

First-episode psychotic patients (N = 404), aged 15 to 40 years, were randomized to either treatment approach. Affective psychosis and medically related psychoses were not included. Participants in the Navigate team approach showed greater improvement in quality of life and reduction of psychopathology than those in the treatment as usual group. These differences were greater for participants whose untreated psychotic disorders were of shorter duration.

It is not clear whether the benefits of the intensive team approach will last beyond the 2-year treatment interval. Follow-up studies will tell whether outcome benefits of the intensive team approach persist after the end of the trial.

Jarde A, Morais M, Kingston D, et al. Neonatal outcomes in women with untreated antenatal depression compared with women without depression: a systematic review and meta-analysis. 

» This meta-analysis combined 23 observational studies, 22 prospective cohort studies, and 1 retrospective cohort study to examine the association of untreated prenatal depression with low birth weight, premature birth, and admission to neonatal intensive care units. Increased odds of both low birth weight (odds ratio [OR] = 1.96; 95% confidence interval [CI], 1.24-3.10) and preterm birth (OR = 1.56; 95% CI, 1.25-1.94) were seen in studies that reported conflicts of interest. More clinically relevant, the preterm birth rate OR when there were no conflicts of interest was 1.34 (95% CI, 1.08-1.66).

This study is important for decision-making discussions between clinicians and their depressed pregnant patients. Findings suggest that untreated depression during pregnancy is associated with an increased risk of low birth weight as well as preterm birth.

D’Onofrio G, O’Connor PG, Pantalon MV, et al. Emergency department- initiated buprenorphine/naloxone treatment for opioid dependence: a randomized clinical trial. 

» Patients (N = 329) with opioid dependence who presented to the ED were randomized into 3 treatment groups: referral only, brief intervention and referral, brief intervention and referral plus buprenorphine. Enrollment and participation in addiction treatment 30 days after randomization was the primary outcome.

Patients in the buprenorphine group (78%) who met the primary outcome far exceeded those in the referral-only group (37%) as well as those in the brief treatment and referral group (45%). This finding strongly suggests that active referral, a link to outpatient services, and buprenorphine treatment are far more successful in motivating patients to participate in longer-term addiction care. ED physicians and consultants should recognize the value of initiating treatment in the ED that is actively linked with ongoing outpatient services. The role of buprenorphine is not clear. Although several benefits were seen for buprenorphine treatment, no significant decreases were observed in the rates of urine samples that tested positive for opioids or in the risk of HIV infection.

Phillips KA, Keshaviah A, Dougherty DD, et al. Pharmacotherapy relapse prevention in body dysmorphic disorder: a double-blind placebo- controlled trial. 

» Adults (N = 100) with body dysmorphic disorder were given open-label escitalopram for 14 weeks, followed by random assignment of 58 responders to either a 6-month continuation of escitalopram or placebo. During the blinded continuation phase, the primary outcome was the comparison of relapse rates in patients who were receiving active treatment and those in the placebo group. Relapse during the 6-month continuation phase was greater in the placebo group. Continuing improvements were seen during the additional 6 months of escitalopram treatment: time to relapse increased, and compared with those who received placebo, fewer patients relapsed.

Guo T, Xiang YT, Xiao L, et al. Measurement-based care versus standard care for major depression: a randomized controlled trial with blind raters. 

» In this 24-week trial, 120 moderately to severely depressed patients were randomly assigned to either measurement-based care or standard treatment. With measurement-based care, antidepressant titration decisions were based on each patient’s Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) score and on the adverse effects the patient experienced. Standard treatment was guided by psychiatrist evaluations without access to scale scores. Both groups were limited to either paroxetine or mirtazapine.

The 2 primary outcome measures were time to response and to remission measured by Hamilton Depression Scale (HAM-D) scores. Response was a decrease of 50% or more on the HAM-D; remission was 7 or lower on the HAM-D. If the QIDS-SR score was not below 9 by week 8, medications were switched. Medications could be switched earlier based on psychiatrist decisions about adverse effects and efficacy.

The measurement-based care group showed higher rates of improvement (86.9%) and remission (73.8%) than the standard care group (62.7% and 28.8%, respectively). Average times to achieve these levels was almost twice as long with standard care. The measurement-care group received more dosage adjustments and ended at higher doses than the standard care group.

The results strongly suggest that better, quicker, and more frequent responses and remission are obtained with measurement-based treatment.

Leonpacher AK, Peters ME, Drye LT, et al. Effects of citalopram on neuropsychiatric symptoms in Alzheimer dementia: evidence from the Cit AD study. 

» The Citalopram for Agitation in Alzheimer’s Disease study (Cit AD) examined the efficacy of citalopram in reducing the incidence and intensity of aggressive behavior in patients with Alzheimer disease. Patients (N = 189) with Alzheimer disease and aggression were randomized to citalopram or placebo. Primary outcome variable was the aggression subscale score on the Neuropsychiatric Inventory (NPI).

After an earlier trial, no statistically significance difference was seen between citalopram and placebo. The current study is a secondary analysis of caregiver reports and other NPI subscales at 9 weeks to gauge whether citalopram reduced other neuropsychiatric symptoms besides aggression.

Citalopram lowered levels of reported delusions, anxiety, and irritability but may have increased sleep/night time behavior disorders. It is not clear whether the strongly serotonergic effects of citalopram offered any benefits compared with other SSRIs, but compared with placebo, neuropsychiatric benefits were seen.

Dr. Saeed is Professor and Chairman of the Department of Psychiatry and Behavioral Medicine at the Brody School of Medicine at East Carolina University, Director of the ECU Center for Telepsychiatry and e-Behavioral Health as well as of the North Carolina Statewide Telepsychiatry Program (NC-STeP), and Chief of Psychiatry at Vidant Health in Greenville, NC. Dr. Bloch is Professor and Director of Research in the Department of Psychiatry and Behavioral Medicine at Brody School of Medicine at East Carolina University. 

Can't keep up with the literature? Here's some help.

Richard M. Bloch, PhD

Articles

Top Papers That Can Change Your Practice

Research Findings That Can Change Clinical Practice: Part 1