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Issue 101, Sep 2020
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Suicidal ideation and attempts in unipolar versus bipolar depression in adolescents

Patel RS et al. Psychiatry Research. 2020 Jun 15; 291;113231. doi:10.1016/psychres.2020.113231. [E Pub ahead of print] Patel RS et al. Psychiatry Research. 2020 Jun 15; 291;113231. doi:10.1016/psychres.2020.113231. [E Pub ahead of print] 

PMID:32574899

Background

The aim of this study was to assess the risk of suicidal ideation and suicidal attempts in adolescents with unipolar depression (UD) versus bipolar depression (BD).

Methods

This study of 131,740 adolescent inpatients (12-17y), with primary diagnoses of UD (92.6%) and BD (7.4%) from a nationwide inpatient sample. The sample was from hospital discharges between 2012 to 2014. Unipolar or bipolar depression was the principal diagnosis based on the International Classification of Diseases 9th Revision (ICD-9). The odds ratio (OR) for suicidal behaviors using logistic regression adjusted for demographic confounders and comorbidities was calculated. 

Results

Comorbid ADHD, psychotic disorders, and substance abuse were more prevalent in BD and comorbid anxiety disorders were prevalent in UD. After adjusting for demographic confounders and comorbidities, UD had a marginally higher odd of suicidal attempts compared to BD.  There were no statistical differences by age and race across both subtypes. The odds were higher for suicidal ideation in males in the hospital setting. Blacks had higher odds of suicidal ideation compared to whites. After adjusting for confounders UD had 1.2 times higher odds for suicidal ideation compared to bipolar depression.

Conclusions

These findings suggest the importance of early identification of BD, accurate differentiation of UD versus BD in adolescents. This would help reduce suicidal behaviors and treat and manage the patients per treatment guidelines.

Clinical Commentary

This study revealed higher rates of suicidal behavior amongst adolescents with unipolar depression (attempts and ideation) when compared to bipolar depression.  Adolescents with UD had 6% higher odds of suicidal attempts and 20% higher odds of suicide ideation compared to those with BD. Prior adult literature has conflicting findings. Most retrospective studies have shown higher rates of suicide attempts with bipolar depression. This has been refuted by longitudinal prospective studies which have revealed that bipolar depression does not necessarily increase the risk of suicidal behaviors. This study has several limitations such as the sample consisted of a majority of patients with unipolar depression (92.6%) while a small number had bipolar depression (7.4%). The diagnostic accuracy remains a question in the inpatient setting where adolescents with externalizing behaviors may be diagnosed with bipolar depression inaccurately or those with bipolar depression may be misdiagnosed as unipolar depression. Adolescents with major depression and suicidal ideation/attempts are more likely to be admitted to the hospital which may enrich a hospital sample.

It should be noted that suicide is the leading cause of death amongst children and adolescents worldwide and the second leading cause of death of individuals between the ages of 10-24 years.

Suicide correlates strongly with psychopathology and the majority of individuals who have attempted suicide have a mood disorder.

In summary: In my opinion, adolescence is a difficult time for many teenagers to negotiate and diagnosis is difficult to make accurately. The earlier age of experimentation with drugs has modified and made the presentations more complex. Hence careful attempts to differentiate unipolar depression from bipolar depression should be made. We should also pay attention to risk factors for suicide in this age group other than mental illness such as previous suicide attempts, family factors, personality structure and impulsivity, specific life events, availability of means, contagion-limitation (more suggestible), and substance use disorder.

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Intravenous ketamine and intranasal esketamine: A meta-analysis

McIntyre RJ et al. J of Affective Disorders. 2020 July 276: 576-584.doi: 10.1016/j.jad.2020.06.050

PMID:31519517

Background

Ketamine is established as a rapid and effective treatment in adults with treatment-resistant depression (TRD). The availability of intravenous and intranasal ketamine brings up questions of efficacy and tolerability differences. Intranasal esketamine is FDA approved for the treatment of TRD in conjunction with an antidepressant medication while the intravenous infusions are not FDA approved but are also being used clinically with success. This meta-analysis aims to quantify the magnitude of effect (using effect size) of different preparations of ketamine across different routes of administration.

Methods

PubMed/Medline and Google Scholar were searched from inception date to June 24th, 2019 for suitable English language articles.  The articles selected were limited to human studies.  The search included major depression, bipolar disorder, and treatment-resistant depression. Included in the search were also various formulations and routes of ketamine administration. Inclusion and exclusion criteria were applied which included human studies, age 18 years and older, and randomized, double-blind placebo-controlled design with data available at key time points.   Effect size concerning depression symptom reduction for each formulation and route of delivery was compared at discrete time-points (i.e., 24 h, 2–6 days, 7–20 days, 21–28 days) in adults with TRD. A random-effects meta-analysis was conducted to evaluate the effect size across intravenous, intranasal, and oral routes of administration. The analysis was also conducted evaluating the effect size of racemic ketamine to esketamine.

Results

Finally, 25 studies met the criteria. The majority of the studies assessed the efficacy of IV ketamine (N=17), intranasal ketamine (N=5), and oral ketamine (N=3). The pooled effect sizes for IV, IN, and oral ketamine overall recorded time points was 0.53 (moderate to large). Individually the pooled effect size for IV administration was 0.41 to 0.55 (moderate), for IN administration 0.67 (large), and oral administration was 0.56 to 0.88 (large).

24 hours: The IV route had an effect size of 0.39, and IN administration was 1.24. The oral route did not have 24-hour data.

2-6 days: IV administration had an effect size was 0.95, IN route 0.52, and oral route had 0.392.

7-20 days: IV administration had an effect size of 0.28, IN route had an effect size of 1.02, and the oral route 0.66.

21-28 days: IV administration had an effect size of 0.29, IN route had an effect size of 0.42, and the oral route 0.62-63.

The effect size of IV ketamine was greatest at 2-6 days while IN ketamine was greatest at 24 hours.  

Conclusions

The short-term efficacy of intravenous and intranasal ketamine/esketamine for adults with TRD was established. No conclusions regarding the comparative efficacy of the disparate formulations and routes of delivery can be derived from this analysis. Direct prospective randomized comparative studies are needed to answer the comparative efficacy and tolerability question.

Clinical Commentary

This is the first meta-analysis on this specific issue. It is a great first step, but there are several limitations making comparisons difficult. The studies had a majority of IV ketamine studies most of which were single infusion studies while IN studies had repeated dosing. Also, the FDA requires the IN ketamine to be added to an antidepressant medication which was not the case with IV ketamine. The analysis was not able to assess the use of different routes of ketamine in a sequential fashion. An example would be beginning with IV ketamine and switching to IN formulation. The definition of TRD also varied between trials. Tolerability has not been addressed in the studies.

The results support the efficacy of IV ketamine (racemic, esketamine) IN (racemic, esketamine) and oral (racemic) ketamine in adults with TRD. Head to head adequately designed trials are needed to answer the specific comparative efficacy and tolerability questions.

Another question that arises is, can we begin with intranasal ketamine due to efficacy data at 24 hours and then switch to IV ketamine? This is not addressed in this study.

Summary: In my professional opinion, there are currently no clear data to choose either IV or IN administration of ketamine. IN ketamine is FDA approved and covered by insurance which increases access. The IV administration is not FDA approved though efficacious for TRD comes at a high cost to the patient which could be prohibitive. In my opinion both IV and IN administration should follow the Risk Evaluation and Mitigation Strategy (REMS). In a multifaceted discussion, many factors come into play before the patient makes a decision. It should be noted that if a patient decides on IV ketamine the access to treatment may be faster. 

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COVID-19 Survivors: Anxiety depression and the role of inflammatory and clinical predictors.

Mazza MG et al.

Brain Behavior and Immunity. July 2020: doi.org/10./1016/j.bbi.2020.07.037

Background

Infection-triggered perturbation of the immune system could induce psychopathology, and psychiatric sequelae were observed after previous coronavirus outbreaks. The spreading of the Severe Acute Respiratory Syndrome Coronavirus (COVID-19) pandemic could be associated with psychiatric implications. This Italian study investigated the psychopathological impact of COVID-19 in survivors, also considering the effect of clinical and inflammatory predictors.

Methods

402 adults surviving COVID-19 (265 male, mean age 58), at one-month follow-up after hospital treatment were screened for psychiatric disorders. The study interviews and data collection were conducted from April 6th to June 9th, 2020. A clinical interview and a battery of self-report questionnaires were used to assess post-traumatic stress disorder (PTSD), depression, anxiety, insomnia, and obsessive-compulsive (OC) symptomatology. The information collected included sociodemographic information, clinical data, baseline inflammatory markers, and follow-up oxygen saturation levels. 

Results

Psychiatric disorders were widely prevalent. 28% for PTSD, 31% for depression, 42% for anxiety, 20% for OC symptoms, and 40% for insomnia. Overall, 56% scored in the pathological range in at least one clinical dimension. Despite significantly lower levels of baseline inflammatory markers, females suffered more from both anxiety and depression. Patients with a positive previous psychiatric diagnosis showed increased scores on most psychopathological measures, with similar baseline inflammation. Baseline systemic immune-inflammation index (SII), which reflects the immune response and systemic inflammation-based on peripheral lymphocyte, neutrophil, and platelet counts, positively associated with scores of depression and anxiety at follow-up. 

Conclusions

PTSD, major depression, and anxiety, are all high-burden non-communicable conditions associated with years of life lived with disability. Considering the alarming impact of COVID-19 infection on mental health, the current insights on inflammation in psychiatry, and the present observation of worse inflammation leading to worse depression, it is recommended to screen COVID-19 survivors for psychiatric disorders. Further research on inflammatory biomarkers is needed to diagnose and treat emergent psychiatric conditions.

Clinical Commentary

This study included a wide range age of participants from 18-87 years, mean age 58 years, and was a cross-sectional study. While rapidly done on patients who had suffered from COVID-19 this study also included inflammatory markers. The primary limitation of the study is its cross-sectional nature that does not allow interpretation for causality.

Psychiatric consequences of SARS-COV-2 infection can be caused by the immune response to the virus as well as by psychological stressors such as isolation, the impact of the unknown nature of the illness, knowing the medical system is not fully equipped to handle this new disease yet, concerns about infecting others, the potential of dying, and stigma.

The immune response includes local as well as systemic production of cytokines, chemokines, and other inflammatory mediators, and higher concentrations of these suggest a more severe clinical course as well as psychological issues. 

Females and those with prior psychopathology suffered more in all psychological dimensions. 

In summary: In my opinion COVID-19 results in a wide range of psychiatric disorders. Those with preexisting psychiatric conditions are at risk for both exacerbation of their illness as well as the onset of other psychiatric disorders. We should use the PHQ-9 and GAD-7 to screen COVID-19 survivors and treat them. Immunological markers need prospective study and further research and are not ready for primetime. We must reinforce recurrently the importance of social distancing, correct hand washing technique, use of masks, and avoiding crowds. It is also important for them to know common symptoms like fever, cough, breathlessness, headaches, muscle and body aches. This can be provided in a single page handout. This would be especially helpful for a second wave.

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Obesity and cancer: Relation to 13 anatomic sites

Luaby-Secretan B. et al.  N Engl J Med. 2016 August 25th. doi:10.1056/NEJMsr1606602 

PMID 27557308

Background

In the general population, the rates of obesity are 30 percent and higher. Patients with psychiatric illness have an even higher prevalence of obesity. Obesity is linked to multiple ailments including heart disease, elevated cholesterol, arthritis, diabetes, and mood disorders particularly, unipolar depression and bipolar depression. It has also been linked with anxiety disorders and the link between obesity and mental illness is probably bidirectional. 

It is important to note that obesity is linked to cancer at 13 anatomical sites. The International Agency for Research on Cancer (IARC) has published a viewpoint on this important issue.

Methods

The IARC is based in Lyon France and for this report, more than 1000 epidemiological studies on cancer risk and body fatness were reviewed. The studies were observational as clinical trials of weight -loss or weight control interventions were sparse. Most studies provided risk estimates for increased Body Mass Index (BMI). The studies included meta-analyses. Most of the relative risks were provided relative to a BMI of 18.5 to 24.9. In adults, overweight is classified as BMI between 25 to 29.9 and obesity is a BMI of 30 or higher. 

Results

The IARC found that results based on waist circumference measurements were consistent with BMI. The evidence was divided into three major categories. Sufficient evidence indicates that a preventive relationship has been established between the absence of excess body fatness and the risk of cancer in humans. Limited evidence indicates that a reduced risk of cancer is associated with the intervention for a preventive effect is considered credible by the group. Inadequate evidence indicates current studies are not of sufficient quality, consistency, statistical power, or there is no relevant data.   

Sufficient evidence: adenocarcinoma of esophagus relative risk (RR) 4.8, gastric cardia (1.8), colon and rectum (1.3), liver (1.8), gall bladder (1.3), pancreas (1.5), breast: postmenopausal (1.5), corpus uteri (7.1), ovary (1.1), kidney (renal cell) (1.8), meningioma (1.5), thyroid (1.1), multiple myeloma (1.5). 

Limited evidence: male breast cancer, fatal prostate cancer, diffuse large B-cell lymphoma

Inadequate evidence: esophagus squamous cell cancer, gastric noncardia, extrahepatic biliary tract, lung, skin cutaneous melanoma, testis, urinary bladder, brain, and spinal cord glioma.

The data on body weight loss from observational studies or follow up of patients undergoing bariatric surgery suggested intentional weight loss may reduce cancer risk notably for breast and endometrial cancer. The quality and number of these studies were insufficient for formal evaluation. 

There were molecular and cellular mechanisms known to be altered during carcinogenesis that could be causally linked with obesity. Obesity is associated with substantial metabolic and endocrine abnormalities which include alterations in sex hormone metabolism, insulin, and insulin-like growth factor (IGF) signaling, and adipokines or inflammatory pathways. The evidence for chronic inflammation and the role of sex hormone metabolism in mediating the obesity-cancer link is significant. The evidence for insulin and IGF signaling is moderate.  

Conclusions

The IARC study group concluded that the absence of body fatness lowers the risk of most cancers. Animal data suggest that intentional weight loss has a cancer-preventive effect although evidence from human trials is needed.   

Clinical Commentary

This report should be an eye-opener to those of us in the mental health field. Obesity has sufficient evidence linking it to cancer at 13 anatomical sites. The lifestyle of our patients and multiple psychotropic medications promote obesity.

There is a bidirectional link between obesity and psychiatric disorders especially of mood via adipokines.

Chronic inflammation is also associated with psychiatric disorders and cancer.

It should be noted that mental health patients are also less likely to have cancer screening done such as mammograms, PSA, and colonoscopy. Just as psychiatry has included metabolic screening so should cancer screening be encouraged by psychiatrists. We are sometimes the only physicians the chronically mentally ill see.

In summary: In my opinion, obesity and particularly morbid obesity is highly prevalent in chronically psychiatrically ill patients. We need to be more aggressive in discussing weight control/loss interventions, cancer screening, and use medications that have a lower weight burden preferentially. This includes paying attention to diet and lifestyle to lower chronic inflammation.

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Adherence to antidepressants associated with decreased premature mortality in cancer patients: Nationwide cohort study

Shoval G et al. Depress Anxiety. 2019 Oct; 36 (10): 921-929. doi: 10.1002/da.22938.Epub 2019 Jul22.

PMID 31332883

Background

Cancer patients have an increased prevalence of depression and anxiety and antidepressant (AD) medications are efficacious treatment. Adherence to medication is a key factor. This retrospective study aimed to evaluate the association between adherence to AD and all-cause mortality in a population-based cohort of patients with cancer.

Methods

This is a 4-year retrospective historical Israeli cohort study including 42,075 patients with cancer who purchased AD at least once during the study period. Adherence to AD was modeled as nonadherence (<20%), poor (20-50%), moderate (50-80%), and good (>80%) adherence. Multivariable survival analyses adjusted for demographic and clinical variables that may affect mortality were conducted.

Results

The sample comprised 64.7% women and 97% were over the age of 40 years. The unadjusted mortality rates were higher for men (22.5%) than women (16.2%). The mean follow-up for patients at risk was 25 months. The survivors were followed for a mean of 27.5 months while the meantime to death among those who died was 14.6 months. 

37% of the sample discontinued AD within a month of the first prescription while 69% discontinued drugs after less than six months. The lowest hazard ratio (HR) for mortality was 0.77 at a 50-80% adherence compared to adherence below 20%. All levels of adherence above 20% were associated with significantly reduced HR for mortality. The HR for mortality for men was 1.48 compared to women. Other predictors were increasing age (age 40-64; HR0.21, age 75-84;0.51), current and past smoking status (HR1.1), lower socioeconomic status (HR 1.1), and more physical comorbidities. 

Analysis of the entire sample and a subgroup with depression, for cancer subtypes, revealed similar patterns for breast, colon, lung, and prostate cancers, but not for melanoma patients.

Conclusions

The present study is the first to demonstrate that higher adherence to AD is associated with a decrease of all-cause mortality in a large nationwide cohort of cancer patients. These data add to the pressing need to encourage adherence to AD among cancer patients. 

Clinical Commentary

The primary finding of this novel large population-based cohort study of patients with cancer treated with AD (N=42,075) is greater adherence was associated with decreased risk of all-cause mortality during the four years follow up. This study is the first to demonstrate an inverse relationship between AD adherence and all-cause mortality. Limitations include retrospective design, lack of clearly identified psychiatric diagnosis, AD medications used, and lack of use of psychometric assessment of depression. 

It is interesting to note the findings were significant for breast, lung, prostate cancer, and colon cancer but not for melanoma. There is no clear explanation for this result though some animal studies suggest certain AD may be effective in inhibiting tumor growth in a murine model, have in-vitro cytotoxic activity against human melanoma cells or possess antioxidant activity in mice. Other studies indicate that selective serotonin reuptake inhibitors may increase mice brain metastases. 

In Summary: In my opinion, this study would strengthen my resolve to check for antidepressant medication adherence in cancer patients with comorbid mood disorders. The evidence is compelling and we should also screen cancer patients for depression and anxiety using rating scales. Educating and even providing a literature reference would be a step I would take. 

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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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