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Issue 91, Nov 2019
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Early improvement in the first two weeks as a predictor of outcome in patients with major depressive disorder: Meta-analysis including 6562 patients.

Szegedi A et al. J Clin Psych. 2009 Mar; 70 (3):344-353. Doi: 10.4088/jcp.07m03780 PMID: 19254516


Major depression (MDD) is a severely disabling and potentially lethal psychiatric illness. The sooner we can predict the outcome with a particular antidepressant medication, the better it will be for our patients, as the time spent on ineffective medication will be cut short. The aim of this study was to determine if early improvement with antidepressant treatment predicts treatment outcome in patients with MDD.


This study included 41 clinical trials comparing mirtazapine with an active comparator or placebo-in inpatients and outpatients with MDD. The patients were examined for early improvement (>or=20% score reduction from baseline on the 17-item Hamilton Rating Scale for Depression [HAMD-17] within two weeks of treatment) and its relationship to treatment outcome. The data were obtained from antidepressant trials with a treatment duration of 4-8 weeks. Trials were excluded if HAMD-17 ratings were not available, there was no diagnosis of MDD, and if they were not blinded.


This study revealed that early improvement predicted stable response and stable remission with high sensitivity (>or=81% and > or =87%, respectively). The negative predictive value for stable responders and stable remitters were high (range 82%-100%).  


The results indicate that early improvement with antidepressant medication can predict subsequent treatment outcomes with high sensitivity in patients with MDD. The high negative predictive values indicate little chance of stable response or stable remission in the absence of improvement within two weeks. A lack of improvement during the first two weeks of therapy may indicate that changes in depression management should be considered earlier than conventionally thought.   

Clinical Commentary

 This study has important findings relevant to clinicians. Depressed patients remain on antidepressant therapies for extended time frames without a switch of the medication for lack of response and continue to suffer. As a full-time clinician, in my opinion, this is a sound strategy we can adopt in our clinical practice.

This study answers the question, “Can I tell early on if a particular antidepressant will be efficacious for my patient with MDD so I can better serve them?”

  • This study brings up the importance of using a rating scale such as the PHQ-9 to assess the patient at baseline, titrate the antidepressant to the therapeutic dose quickly, and reassess at two weeks.
  • Twenty percent improvement at the two-week time frame indicates continuation of the drug, as well as further titration of the dose as deemed clinically appropriate. Such a strategy could result in a high likelihood of response or remission. However, one must consider that the ongoing full response could take 6-8 weeks.
  • On the other hand, if the medication did not show a 20 percent change in the first two weeks, we need to switch the medication (Negative predictive value). This study had a high negative predictive value suggesting that the patient will not likely respond to the treatment.
  • The findings of this study challenge the notion of “delayed response.”
  • Limitations: This is a meta-analysis and does not account for some of the newer antidepressants that are available now.
  • In summary, we should assess patients objectively using rating scales. In patients with MDD, exclude the likelihood of it being a bipolar illness. Try the two-week 20% percent improvement algorithm for response /remission prediction so as to cut short trial time for an antidepressant with the idea of ultimately reducing suffering. This also means that new patients or those highly symptomatic should be seen every two weeks. Practice evidence-based medicine.  
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Treating depression in the context of dementia: Mirtazapine versus sertraline randomized trial

Zuidersma M et al. Am J Geriatr Psychiatry. 2019 September 19; 29 (9):920-931. Doi: 10.1016/j.jagp.2019.03.021 Epub 2019 Apr 6. PMID:31084994


Depression is common in patients with dementia, with prevalence ranging between 10% and 62%. Depression is associated with reduced quality of life and exacerbation of cognitive and functional impairment. This study was designed to examine antidepressant efficacy in subgroups of depression in dementia with different depressive symptom profiles.  


The design was a secondary analysis conducted on randomized, parallel-group, double-blind, placebo-controlled Health Technology Assessment Study of the Use of Antidepressants in Dementia Trial (HTA-SADD). The study was conducted in geriatric centers in England. The participants met the National Institute of Neurological and Communicative Disorders and Stroke and Stroke/Alzheimer’s Disease and Related Disorders Association probable/possible Alzheimer disease criteria and Cornell Scale for Depression in Dementia (CSDD) score of 8 or more. The intervention groups included placebo (N=111), sertraline (N=107), or mirtazapine (N=108). The participants were clustered into symptom-based groups based on baseline CSDD items. Improvement in CSDD was evaluated at 13 and 39 weeks.


There were four symptom-based sub-groups: severe (N=34), psychological (N=86), affective (N=129), and somatic (N=77). Mirtazapine, not sertraline, outperformed placebo at week 13 which was sustained to week 39 (sub-group with core psychological depressive symptoms). Statistical significance did not persist at week 39 due to smaller group size. In the other sub-groups, neither mirtazapine nor sertraline outperformed placebo.


This was an exploratory analysis and the finding should be interpreted in the light of a  small group size. Patients with depression in dementia with psychological symptoms have beneficial effects with mirtazapine. It also suggests that depression in the dementia group is distinct from geriatric patients with depression but without dementia.

Clinical Commentary
  • This study suggests that depressed geriatric patients with dementia are different from those without dementia. The depressed subgroup with dementia may not have a response to antidepressants except mirtazapine. Even in this group, those with psychological symptoms fare better on mirtazapine. This study used up to 150 mg of sertraline and 45 mg of mirtazapine, which are adequate doses in older adults.
  • These findings need replication but do provide clinicians with guidance. Clinicians should be cautious regarding prescribing antidepressants in depressed patients with dementia due to limited efficacy.
  • In geriatric clinics and long-term care, clinicians use mirtazapine. This experience is somewhat validated by this study.
  • The subgroup of core psychological depressive symptoms in patients with dementia benefit from mirtazapine.
  • All three study arms improved considerably as patients were offered a broad range of supportive interventions, including problem-solving interventions by a community psychiatric nurse in the patient’s own home. This is an effective intervention for this age subgroup.
  • In Summary: Clinicians should be careful in considering antidepressant therapy for depressed patients with dementia, as data are not supportive except for those with psychological symptoms such as affective symptoms, pessimism, low self-esteem who respond better to mirtazapine. Do not underestimate a broad range of supportive approaches including problem-solving interventions. Watch for additional studies addressing this issue with a larger sample size.
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Oral contraceptive use in adolescence: Vulnerability to depression in adulthood?

Anderl C. et al. J Child Psychol Psychiatry. 2019 Aug 28. doi: 10.1111/jcpp. 13115 [Epub ahead of print]  PMID:31461541


Oral contraceptives (OC) are widely used today. There is data to suggest that OCs are associated with mood changes. This study was designed to investigate if women who had used OCs as adolescents had increased vulnerability to depression in adulthood.


The sample included 1236 women in the United States National Health and Nutrition Examination Survey for whom information on depression and age of first OC use was publicly available. The women who used OCs in adolescence were compared to women who had never used OCs, and women who had first used OCs in adulthood on the 1-year prevalence of major depressive disorder (MDD) assessed by trained interviewers.


Compared with women who had used OCs during adolescence, women who had never used OCs were less likely to meet the criteria for MDD within the past year in adulthood, and so were women who only started using OCs in adulthood. Factors that have previously been proposed to explain the relationship between OC use and depression risk such as age at sexual debut, and, importantly, current OC use, did not account for the results.


This study revealed a long-term association between adolescent OC use and depression risk in adulthood regardless of current OC use. Adolescence may be a sensitive period during which OC use could increase women’s risk of depression in the future.

Clinical Commentary

The use of OC in today’s society is extensive to avoid unwanted pregnancies in teenagers. There is, however, a cost to every intervention. As puberty occurs at an earlier age now than in past decades these issues came to the forefront. This study suggests that the adolescence period may be a time when the brain is more sensitive to hormonal effects and could lead to depression later.

  • In my opinion, one cannot stop prescribing OCs to teenagers, but shared decision making should be considered, which includes informing them of this possible risk later in adulthood.
  • The pros and cons need to be carefully considered. We do know that depression is a treatable disease, especially if diagnosed early.
  • The patient can decide between the risks of not using OCs and the risk of depression, especially if 18 years and above. Prior to that, it would be the legal guardian.
  • In summary: We should be careful in prescribing OC to teenagers and watch for further research on this topic. In the interim, it may be important to inform teenage OC users of future risk. Other forms of contraception, such as intrauterine device (IUD) and non-hormonal, may be considered.
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Nutritional supplements for treating psychiatric disorders: The data speak!

Firth J. et al. World Psychiatry. 2019; Oct 18 (3):308-324. doi:10.1002/wps.20672 . PMID 31496103


There is abundant evidence to suggest that people with psychiatric disorders consume a diet high in fat and sugar. There is an established relationship between poor diet and mental illness. Nutritional supplements are widely used in today’s world to self-treat psychiatric disorders as well as recommended by health care professionals. This study examined the various meta-analyses with respect to credible evidence for various nutrient supplements used to treat psychiatric disorders.


This study included meta-analyses (N=33 meta-analyses) of randomized controlled trials (RCTs) so as to gather top-level evidence. The primary analyses included data from 10,951 individuals. The data synthesis was conducted in line with the PRISMA statement. The search was conducted using the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Health Technology Assessment Database, Allied and Complementary Medicine (AMED), Psych INFO and Ovid MEDLINE (R), from inception until February 1, 2019.


The results indicate the strongest evidence for polyunsaturated fatty acids (PUFA) as an adjunctive treatment of depression. Additional evidence suggests that PUFAs may also be beneficial for attention-deficit-hyperactivity disorder. There was no evidence of beneficial effects in the treatment of schizophrenia. There is also evidence to suggest that high-dose methylfolate is efficacious in major depression. There was emergent evidence to suggest N-acetylcysteine as a useful adjunctive treatment in mood disorders and schizophrenia. All supplements had a good safety profile with no evidence of serious adverse effects or contraindications with psychotropic medications.


Clinicians should be informed about the efficacy of nutrient supplements in treating mental disorders but also, more importantly, be aware of those currently lacking supportive evidence. Future research is needed to enhance our knowledge with regard to evidence-based treatment of psychiatric disorders with nutritional supplements.

Clinical Commentary

This study is a meta-review evaluating all top tier evidence from meta-analyses of RCTs examining the efficacy of nutritional supplements in mental disorders. The findings are limited to PUFAs, high dose methylfolate, and N-acetylcysteine. In the case of omega-3, the formulation with high EPA content is the most beneficial one.

  • Supplements can be expensive, and hence, it is important to use evidence-based supplements.
  • Another important take away was that omega-3 supplementation is not effective in patients with depression as a comorbidity to chronic physical conditions, including cardiometabolic diseases.
  • N-acetyl cysteine at dosages of 2000 mg/day was potentially effective for reducing depressive symptoms and improving functional recovery in mixed psychiatric samples. N-acetyl cysteine also has efficacy in reducing symptoms of schizophrenia (reduction of total psychotic symptoms but not negative symptoms) as an adjunct. N-acetyl cysteine acts as a precursor of glutathione, the primary endogenous antioxidant. Reducing oxidative stress and glutamatergic dysfunction may help with bipolar disorder, depression, and schizophrenia. The effects may be delayed to about six months.
  • Methylfolate has positive data (15 mg/day dosage) to reduce symptoms of MDD. This formulation is readily absorbed and overcomes genetic predispositions.
  • In summary: It is important for us to use nutritional supplements that have efficacy data and also educate our patients. The below list is all for adjunctive treatments.


Adjunct Omega-3 with high EPA content (>50% EPA formulas providing 2200 mg EPA/day)

Adjunct N-acetylcysteine (2000 mg-3000 mg)

Adjunct methyl folate 15 mg/day

Adjunct Vitamin D 50,000 units/week should monitor level

Small positive effects Adjunct High EPA formulas 2200 mg/day

Bipolar disorder:

Adjunct N-acetylcysteine (2000 mg/day)


Adjunct N-acetylcysteine (2000mg-3000mg).

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Environmental pollution and psychiatric disorders: Increased risk in the US and Denmark.

Khan A et al. PLoS Biol. 2019; Aug 20;17(8):e3000353. doi: 10.1371/journal.pbio.3000353 . PMID 31430271


The search for genetic factors underlying complex neuropsychiatric disorders has proceeded apace in the past decade.  Despite some advances in identifying variants associated with psychiatric disorders, most variants have small individual contributions to risk. There is a disease risk increase from environmental factors that appears to be less subtle. This study was designed to explore the association between environmental pollution and neuropsychiatric disorders.


 The study conducted exploratory analyses of two large independent datasets. This included 151 million individuals represented in a United States insurance claims dataset and 1.4 million individuals documented in Danish national treatment registers. Environmental Protection Agency (EPA) county-level environmental quality indices (EQIs) in the US and individual-level exposure to air pollution in Denmark were used to assess the association between pollution exposure and neuropsychiatric disorders.  In the US sample, the study included schizophrenia, bipolar disorder, major depression, personality disorder, epilepsy, and Parkinson’s disease. The Danish sample studied schizophrenia, bipolar disorder, major depression, and personality disorder.


Air quality was predictably worse near larger cities on both the US East and West Coasts. Water quality was consistent but noted to be worse in the western states,  Wyoming and Illinois. Land quality was worse in the northern continental US as well as the west. The central US counties have a greater number of poorer weather days, whereas the coastal areas are enriched with more fair-weather days.

Areas of the country away from large bodies of water are most enriched for neuropsychiatric disorders. This was particularly evident for bipolar disorder and major depression in Kentucky and Missouri. Alaska showed more psychiatric disorders for the overall population size, particularly personality disorders and schizophrenia. Hawaii had higher than expected rates of Parkinson’s disease and schizophrenia. The state of Michigan had a higher rate across all psychiatric disorders, and Parkinson’s disease possibly thought to be due to reporting bias. In general, the US east coast had a greater prevalence of phenotypes compared to the west coast. The strongest predictor of mood disorders (MDD and bipolar disorder) was the percentage of white residents. A higher percentage of black non-Hispanic residents predicted higher schizophrenia and epilepsy. Air quality was the strongest predictor of bipolar disorder. Regions with worse air quality had a 27% increase in bipolar disorder. There was a six percent increase in the diagnosis rate of MDD. Personality disorder was best predicted by land pollution leading to a 19.2% increase in the diagnosis of personality disorders.

Pleasant weather was protective for all disorders, particularly bipolar disorder. Counties with the highest number of pleasant weather days showed a 21.8 % decrease in the diagnosis of bipolar disorder.

The Danish sample was structured differently, comprising individuals born between January 1, 1979, and December 31st, 2002, who were residing in Denmark on their 10th birthday. Childhood air pollution and association of psychiatric disorders (MDD, Bipolar disorder, Personality disorder, and schizophrenia). The rates of all four psychiatric disorders increased with air pollution.The rate increase in the highest exposure to the lowest exposure group was bipolar disorder (29.4%), schizophrenia (148%), personality disorder (162%), and MDD (50.5%), which is alarming.


This study suggests that air pollution is significantly associated with an increased risk of psychiatric disorders. The pollutants likely affect the human brain via neuroinflammatory pathways that have also been shown to cause depression-like phenotypes in animal studies.

Clinical Commentary

This is an extremely thoughtful study that has important findings. Air quality is an important issue and poor air quality results in an increased prevalence of neuropsychiatric disorders. The US study is more cross-sectional, while the Danish study takes into account the cumulative exposure to pollutants in early ten years of life. It is important to note that there is a strong association between poor air quality and increase in the four psychiatric disorders, mainly MDD, bipolar disorder, schizophrenia, and personality disorder in both US and Danish populations.

  • Traditionally we have thought that there is an interaction between genetic and environmental components in the case of neuropsychiatric disorders. This study provides significant evidence regarding the contribution of the environmental component towards the “G and E interaction.”
  • The air quality is determined by the variable mixture of particulate matter, gases, metals, and organic contaminants generated by transport vehicles, industrial activity, and fires. These environmental factors cause neuroinflammation to which these psychiatric disorders are linked.
  • We need to expand our thinking not only to the emotional environment which may be toxic but also the physical air quality, land quality, weather our patients live in currently, or were exposed to in the early years of life.
  • The psychiatric disorders still need to be treated, but environmental education can also be provided. It is not possible for all people to move to places with better air quality or fair weather; however, having the information, a choice can be made by patients.
  • Long-term action is needed to which the world is awakening with reduction in carbon dioxide emissions, use of renewable energy and cutting pollution. “Reduce, Reuse, Repair, and Recycle” will make a difference in the long-term
  • In Summary: The importance of clean air cannot be emphasized enough. There is an ongoing global debate currently, however, the effect of air quality and other such factors as noted in this sample of US and Danish citizens hits close to home.
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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]

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