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Issue 93, Jan 2020
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Omega-3 and polyunsaturated fat for prevention of depression and anxiety: Surprising results?

Deane KHO et al. Br J Psychiatry. 2019 Oct 24:1-8. doi: 10.1192/bjp.2019.234. [Epub ahead of print] PMID:31647041

Background

There is an intense public perception that consumption of polyunsaturated fats prevents as well as treats depression and anxiety. This perception fuels a huge industry that manufactures these supplements. There is also advertising to this effect. This study was designed to assess the effects of increasing omega-3, omega-6, and total polyunsaturated fat on the prevention and treatment of depression and anxiety.

Methods

This UK based study was a systematic review and a meta-analysis of randomized trials. The search included large databases (e.g. Central, Medline, and EMBASE), trial registers, omega-3, and ongoing trials. Trials of adults with or without depression or anxiety, randomized to increased omega-3, omega-6 or total polyunsaturated fat for ≥ 24 weeks, excluding multifactorial interventions were reviewed. The authors of these studies were contacted if questions arose. The primary outcomes were as follows: 1) risk of depression or anxiety symptoms assessed by formal diagnosis or an appropriate scale, dichotomized to give risk of depression or anxiety in participants without depression or anxiety at baseline. 2) severity of depression and anxiety as a continuous scale in participants with or without anxiety and depression. 3) relapse in those with depression at baseline. This study used random-effects meta-analysis, sensitivity analyses, and subgrouping and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) assessment.  

Results

This analysis included 31 trials assessing the effects of long-chain omega-3 (N=41470), one of alpha-linolenic acid (N=4837), one of total polyunsaturated fat (N=4997) and none of omega -6.  The meta-analysis suggested that increasing long-chain omega-3 probably has little or no effect on the risk of depressive symptoms or anxiety symptoms. The evidence of effects on depression severity and remission in existing depression patients were unclear (very-low-quality evidence). The results did not differ by risk of bias, omega-3 dose, duration, and nutrients replaced. Increasing alpha-linolenic acid by 2 g/d may increase the risk of depression symptoms very slightly over 40 months (number needed to harm=1000).

Conclusions

The results of this study indicate that long-chain omega-3 supplementation has little or no effect in preventing depression or anxiety symptoms.   

Clinical Commentary

 This focused meta-analysis of the effects of long-chain omega-3 on the prevention of depression and anxiety suggests a lack of efficacy. The strengths include a broad search of trials and contact with the authors. The limitations are a lack of data on the consistent use of omega-3 at baseline. In studies where this data was available, it could not be compared across trials. This study recommends not using omega-3 for depression and anxiety.

  • The patients have a perception of using “natural products” for treating various ailments. Hence the increasing market for the use of omega-3 for depression and anxiety. Patients often prefer these products to medications that have FDA approval based on randomized controlled trials.
  • In the GME RR issue of November 2019, we had reviewed a meta-review of metanalyses (Firth J. et al. World Psychiatry. 2019)  of nutritional supplements which found that adjunctive use of polyunsaturated fatty acids (PUFA), particularly those with high EPA content, was beneficial in treating depression. These are conflicting findings.
  • These are the limitations of reviews and meta-analyses.
  • In summary: As clinicians, there is a dilemma due to conflicting results of meta-analyses. There is an unmet need for a well-designed long-term randomized controlled trial with carefully characterized participants with regard to baseline diagnosis of depression and anxiety and consistent doses being given. In the interim, one could tell patients that the evidence is conflicting, and there are no long-term trials with adequate design to address this issue. The patient can make a decision based on the fact that the data are inconsistent.
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Lifetime smoking and the risk of depression and schizophrenia

Wootton RE et al. Psychol Med. 2019 Nov 6: 1-9. doi: 10.1017/ S0033291719002678. [Epub ahead of print] PMID:31689377

Background

The deleterious effects of smoking on physical health are well established. There is a higher prevalence of smoking in those with schizophrenia and depression. Mendelian randomization (MR) can examine whether this association is causal using genetic variants in a genome-wide association study (GWAS).

Methods

This study included a two-sample MR to explore the bi-directional effects of smoking on schizophrenia and depression. For smoking behavior, the study used (1) smoking initiation GWAS from the GSACN consortium (genetic sequencing consortium of alcohol and nicotine use) and (2) the investigators conducted their own GWAS of lifetime smoking behavior (which captures smoking duration, heaviness and cessation) in a sample of 462690 individuals from the UK Biobank. The instrument was validated using positive control outcomes (e.g. lung cancer). For schizophrenia and depression, the study used GWAS from PGC consortium.

Results

There was strong evidence to suggest that smoking was a risk factor for both schizophrenia and depression. The results remained consistent across both lifetime smoking and smoking initiation. There was significant evidence that genetic liability to depression increases smoking but the evidence is mixed for schizophrenia with very weak evidence for an effect on smoking initiation.

Conclusions

This study suggests that the association between smoking, schizophrenia, and depression is due, at least in part, to a causal effect of smoking, providing further evidence for the detrimental consequences of smoking on mental health.  

Clinical Commentary
  • This study provides further evidence that smoking is deleterious for mental health and incriminated as a risk factor for both depression and schizophrenia.
  • These findings suggest that there is approximately a two-fold increase in the risk of depression and schizophrenia associated with smoking.
  • The relationship between smoking and mental illnesses like depression and schizophrenia is bidirectional.
  • Biologically speaking the dopamine and serotonergic systems are implicated in depression and schizophrenia. Nicotine stimulates the nicotinic cholinergic receptors causing the release of dopamine and serotonin. It is plausible that the disruption of these pathways has a causal effect on these disorders.
  • This study has limitations such as a selection bias in the UK Biobank. Compared to the general UK population, the enrollees from the UK Biobank are highly educated, less likely to be a smoker, and generally healthier.
  • In Summary: In addition to having a strong linkage to multiple physical health problems such as lung cancer, cardiovascular disease, stroke, and COPD, smoking also has a strong bidirectional relationship with depression and schizophrenia. There should be in school education to prevent children from beginning smoking. Smoking cessation should be discussed with patients to encourage them to quit which may better help their mental and physical health. As mental health clinicians we should do more to get patients to stop smoking.    
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Olfactory ability and dementia prediction: Does it have added value?

Devanand DP. et al. Alzheimers Dement. 2019 Oct 23. piiS1552-5260 (19)35374-9. doi: 10.1016/j.jalz 2019.08.200 [Epub ahead of print] PMID:31676234

Background

As the baby boomers are aging there will be an increased need to predict those who are not likely to transition to Alzheimer’s dementia (AD) to avoid unnecessary diagnostic testing. In the early stages of Alzheimer's disease, neurofibrillary tangles develop in the olfactory bulb and central odor processing regions manifesting as impairment in tests of olfaction. This study was designed to predict a lack of transition to dementia in participants who had intact odor identification and brief cognitive tests.

Methods

This study was conducted in an urban community. The sample consisted of 1037 older adults without dementia who completed the 40-item University of Pennsylvania Smell Identification Test which also includes the 12-item Brief Smell Identification Test (B-SIT). The data from 749 participants were followed for four years and analyzed.

Results

Impairment on the Blessed Orientation Memory Concentration Test and B-SIT each predicted dementia (N=109), primarily Alzheimer’s disease (N=101). Amongst participants who had intact olfactory (on B-SIT) and cognitive (Blessed Orientation Memory Concentration Test) ability, 3.4 % (4/117) transitioned to dementia during follow-up. There were no transitions to dementia in the 70-75 and 81-83 years, age group quartiles.

Conclusions

This study suggests that odor identification testing adds value to global cognitive testing, and together can identify individuals who rarely transition to dementia, thereby avoiding unnecessary diagnostic investigation.

Clinical Commentary

The impairment of odor identification is a well-established predictor of Alzheimer’s disease.  This prospective study has an important negative predictive value as it identified those with intact cognition and smell identification as not transitioning to dementia (transition rate only 3.4%).

  • Olfactory deficits have high sensitivity but low specificity in differentiating AD from other dementias. High olfactory ability likely indicates non-transition to dementia.
  • There is a threshold olfactory function level, above which there is a low likelihood of transition to dementia.
  • In summary: These results are interesting for us clinicians as well as for payors, as adequate olfaction and brief cognitive testing predict a low likelihood of transition to dementia. These findings from a community cohort need to be tested in the clinical setting where patients present with cognitive complaints. Brief cognitive tests need to be compared with brief odor identification tests to determine their comparative and added utility in the diagnosis, as well as for estimation of prognosis for cognitive decline and dementia in older adults.

Currently, olfaction and cognitive testing as predictors for non-transition to dementia is not ready (but close) for prime time but needs clinical testing in the trenches.  

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Excess significance bias in Transcranial magnetic resonance (rTMS) imaging literature in neuropsychiatric disorders: Reason for introspection

Amad A. et al. Psychother Psychosom. 2019; Oct 7:1-8. doi:10.1159/000502805 [Epub ahead of print] PMID 31590171

Background

TMS has been widely tested and promoted for the treatment of multiple neuropsychiatric disorders. It is also being promoted aggressively by the equipment manufactures. The efficacy of rTMS remains under debate. This study aimed to test for an excess number of statistically significant results in the literature on the therapeutic efficacy of rTMS across a wide range of meta-analyses and to characterize the power of studies included.  

Methods

The study investigators, based on power calculations, computed the expected number of    “positive” datasets for a medium effect size (standardized mean difference, SMD=0.30) and compared it with the number of observed “positive” data sets. The sensitivity analyses considered small (SMD=0.20), medium (SMD=0.50), and large (SMD=0.80) effect sizes.

Results

There was a total of 14 meta-analyses with 228 datasets (110 for neurological disorders and 118 for psychiatric disorders) that were assessed. For SMD=0.3, the number of observed “positive” studies (N=94) was larger than expected (N=35). This study found evidence for statistically significant excess of significant findings. This was noted in 8/14 meta-analyses. Evidence for an excess of significant findings was also observed for SMD=0.5 for neurological disorders. Most of the data sets were underpowered.

Conclusions

The majority of studies in the rTMS literature are underpowered. This results in fragmentation and waste of research efforts. The high frequency of “positive” results seems spurious and reflects bias. Caution is warranted in widely accepting rTMS as an established treatment for neuropsychiatric conditions.

Clinical Commentary

The utilization of rTMS is growing rapidly for the treatment of depression and other psychiatric disorders such as OCD. rTMS uses magnetic fields to stimulate nerve cells in the brain. Currently, insurance coverage for rTMS is limited but growing.

  • rTMS is a noninvasive treatment that, unlike ECT, does not cause memory loss. It is not as effective as ECT for major depression.  
  • The depression indication from the FDA came first in 2008 for mild to moderate depression not responding to one to two trials of antidepressant therapy. The indication was expanded to certain types of migraines headaches in 2013, and in 2018 the Brainsway machine was approved for Obsessive-Compulsive Disorder.
  • rTMS is oversold in light of these findings. The excessive significance in the literature leads to desperate patients undergoing a not so beneficial therapy. This may delay patients getting an appropriate and more aggressive therapy that they are more likely to respond to.  Please note that the significance was nominal in 13/14 of the meta-analyses studied.
  • In summary: The important question remains as to when to suggest rTMS for the treatment of depression. As a clinician, I suggest rTMS based on a failure of two antidepressant medication trials of adequate dose and duration (Insurance may want to see more antidepressant trials). I suggest rTMS before ECT provided the patient is not acute and highly symptomatic. I have also suggested rTMS for individuals who had improvement of their depressive symptoms with ECT but are having cognitive issues. Some of these individuals could be continued on maintenance rTMS therapy to prevent the recurrence of depression.
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Stellate ganglion block (SGB) for the treatment of posttraumatic stress disorder: Randomized clinical trial.

Rae Olmsted KL et al. JAMA Psychiatry. 2019; Nov 6: 1-9. doi: 10.1001/jamapsychiatry.2019.3474. [Epub ahead of print] PMID 31693083

Background

PTSD is an extremely distressing disorder for which effective treatments are limited. This is the first randomized clinical trial of SGB outcomes on PTSD symptoms. The aim was to determine whether paired SGB treatments at 0 and 2 weeks would result in a mean Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total symptom severity scores reduction from baseline to eight weeks.

Methods

This was the first multisite, blinded, sham-procedure, randomized clinical trial using a 2:1 SGB: sham ratio conducted over two years. This study was conducted at three US Army Interdisciplinary Pain Management Centers. The procedures were performed only by anesthesiologists. The participants and assessors were blinded to the intervention (SGB/Sham).  Active duty service members with PTSD on stable dosages of psychotropic medication and PTSD Checklist-Civilian Version (PCL-C) score of 32 or more were included. Prior SGB treatment, selected psychiatric disorders, substance abuse, and moderate to severe traumatic brain injury, and suicidal ideation in the prior two months were reasons for exclusion.

Intervention: Paired right-sided SGB or sham procedures at weeks 0 and 2.

The primary outcome measure was improvement of 10 or more points on mean CAPS-5 total symptom severity scores from baseline to eight weeks.

Results

190 individuals were screened and 113 (mean age 37 years 100 male and 13 were female) were eligible and randomized (N=74 to SGB and N=39 to sham treatment). 108 participants completed the study. The SGB and sham groups were matched for symptoms and demographics with 80% meeting CAPS-5 PTSD criteria. There was a 12.6 points symptom score drop in the SGB group compared with 6.1 points drop in the sham treatment group. There was a 50% greater drop in symptom scores in the active SGB group.

Conclusions

In this trial of active-duty service members with PTSD symptoms, two SGB treatments two weeks apart were effective in reducing CAPS-5 total symptom severity scores over eight weeks. The mild-moderate baseline level of PTSD symptom severity and short follow-up time limit the generalizability of these findings. SGB merits further trials as an adjunct treatment for PTSD.

Clinical Commentary

PTSD has a 12 months prevalence amongst US adults of 3.5 percent. The high-risk groups include combat deployed veterans, sexual assault victims and survivors of motor vehicle accidents. The prominent symptoms include reliving the event, avoidance, hyperarousal, negative cognitions and nightmares. The established treatments are limited and there is an unmet need to research new treatments to relieve suffering.

  • This study sample consisted of active duty fit combat veterans who were not looking for disability. This was a relatively healthier group.
  • At this point, it is not clear if the treatment can be helpful for non-veterans unless tried in these populations. 
  • The SGB blocks the cervical sympathetic chain, most improvement occurring in hyperarousal, avoidance, and numbing. Reexperiencing did not respond as favorably.
  • In summary: In my opinion, FDA approved treatments should be tried first. SGB would be considered an off-label treatment. The findings are robust and SGB should be tested in civilian populations using a similar study design.
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Sanjay Gupta, MD
Clinical Professor of Psychiatry, SUNY Buffalo

GME Research Review is a monthly newsletter edited by Sanjay Gupta, MD, Clinical Professor of Psychiatry, SUNY Buffalo. Dr. Gupta selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry. 

We are always carefully evaluating which research papers to discuss in GME Research Review. Have come across a research paper published in the last 6 months that you thought is clinically relevant? Do you want me to analyze it for you and for the benefit of others? Please email Dr. Gupta the citation at [email protected]

To contact GME, email us at [email protected]


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