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Issue 108, Apr 2021
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Rapid Mood Screener (RMS): Novel and pragmatic screening tool for bipolar disorder

McIntyre RS et al. Curr Med Res Opin 2021 Jan;37 (1): 135-144. doi:10.1080/03007995.2020.1860358. [Epub 2021 Jan 6]

Background

Depressive episodes and symptoms of bipolar I disorder are commonly misdiagnosed as major depressive disorder (MDD) in primary care as well as amongst mental health practitioners. The novel and pragmatic Rapid Mood Screener (RMS) was developed to screen for manic symptoms and bipolar I disorder features (e.g., age of depression onset).

Methods

A targeted literature search was conducted to select concepts thought to differentiate bipolar I from MDD and screener tool items were drafted. Items were tested and refined in cognitive debriefing interviews with individuals with self-reported bipolar I or MDD (n = 12). An observational study was conducted to evaluate predictive validity. Participants with clinical interview-confirmed bipolar I or MDD diagnoses (n = 139) completed a draft 10-item screening tool and other questionnaires. Data were analyzed to identify the smallest possible subset of items with optimized sensitivity and specificity.

Results

Adults with confirmed bipolar I (n =67) or MDD (n = 72) participated in the observational study. Ten draft screening tool items were reduced to 6 final RMS items based on the item-level analysis. When 4 or more items of the RMS were endorsed ("yes"), sensitivity was 0.88 and specificity was 0.80; positive and negative predictive values were 0.80 and 0.88, respectively. These properties were an improvement over the Mood Disorder Questionnaire in the same analysis sample while using 60% fewer items.

Conclusions

The pragmatic 6-item RMS differentiates bipolar I disorder from MDD in patients with depressive symptoms, providing real-world guidance to primary care practitioners on whether a more comprehensive assessment for bipolar I disorder is warranted.

Clinical Commentary

Bipolar disorder is a difficult illness to accurately diagnose as most patients seek treatment for a depressive episode while not having any memory of a prior manic/hypomanic episode as patients primarily suffer during a depressive episode. It is the family/significant other who suffer during the manic episode. Also, state-dependent memory impairment during a depressive episode impairs the patient's recall of a manic episode. In a busy practice, we may often not elicit a history of mania and hence miss the bipolar diagnosis. The use of the RMS which is clinician-friendly with impressive metrics helps us extract manic symptoms in a patient presenting in a depressive episode (jogs the memory of the patient/significant other). Please note that the time to accurate diagnosis may be up to 10 years and during this time the illness most commonly treated as an MDD episode progresses with increased cycling of mood and substance abuse. The use of the RMS could help shorten the time to accurate diagnosis and hence prevent delays of accurate treatment. The RMS is clinician-friendly and serves this purpose.

The items in the RMS are different than the MDQ (Mood Disorder Questionnaire)

Clinical Insights:

  • Despite the effort placed on educating psychiatrists and mental health clinicians in the early diagnosis of bipolar disorder, it is still misdiagnosed as major depression. This points to “what the mind does not know the eyes will not see”
  • There is still a need for a clinician-friendly tool and the void can be filled by the RPS which is short, easy to use, and can be done in 2 mins. Time is a key factor in busy overburdened clinics.  4/6 yes answers are a positive on the RMS clues a clinician to bipolar disorder possibility.
  • T his is a screener and not a diagnostic instrument. In the case of a positive RMS, we need to still do a longitudinal diagnostic evaluation.
  • Bipolar disorder has multiple comorbidities commonest being anxiety disorders, substance abuse, and ADHD and hence it should be administered to these groups of patients.
  •  The RMS includes depressive items which are not part of the MDQ.

Summary:

In my professional opinion, the RMS is clinician-friendly and should be used along with a PHQ-9 and GAD-7 as part of the initial evaluation of patients presenting with mood and anxiety disorders. This would help psychiatrists, mental health clinicians, and primary care physicians shorten the time to accurate diagnosis and result in the patients getting disease appropriate treatment.

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Psychiatric Disorders, Mortality, and COVID-19

Katlyn N et al. JAMA Psychiatry. 2021. Jan 27;(3):27 e204442. doi:10.1001/jamapsychiatry.2020.4442. Online ahead of print.

PMID:33502436

Background

The association of psychiatric diagnoses with mortality in patients infected with coronavirus disease 2019 (COVID-19) has not been evaluated. This study was designed to assess whether a diagnosis of a schizophrenia spectrum disorder, mood disorder, or anxiety disorder is associated with mortality in patients with COVID-19.

Methods

This retrospective cohort study assessed 7348 consecutive adult patients for 45 days following laboratory-confirmed COVID-19 between March 3 and May 31, 2020, in a large New York hospital system. The final date of follow-up was July 15, 2020. Patients without available medical records before testing were excluded.

Patients were categorized based on the following: International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnoses before their testing date: (1) schizophrenia spectrum disorders, (2) mood disorders, and (3) anxiety disorders. Patients with these diagnoses were compared with a reference group without psychiatric disorders.

Main outcome and measures: Mortality, defined as death or discharge to hospice within 45 days following a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test result.

Results

Of the 26540 patients tested, 7348 tested positive for SARS-CoV-2 (mean age, 54 years; 3891 53.0% women). Of eligible patients with positive test results, 75 patients (1.0%) had a history of a schizophrenia spectrum illness, 564 (7.7%) had a history of a mood disorder, and 360 (4.9%) had a history of anxiety disorder. After adjusting for demographic and medical risk factors, a premorbid diagnosis of a schizophrenia spectrum disorder was significantly associated with mortality. Diagnoses of mood disorders and anxiety disorders were not associated with mortality after adjustment. In comparison with other risk factors, a diagnosis of schizophrenia ranked behind only age in the strength of an association with mortality.

Conclusions

In this study of adults with SARS-CoV-2-positive test results, those with a schizophrenia spectrum disorder diagnosis were associated with an increased risk for mortality. Those with mood and anxiety disorders were not associated with a risk of mortality. These results suggest that schizophrenia spectrum disorders may be a risk factor for mortality in patients with COVID-19.

Clinical Commentary

The coronavirus pandemic continues to challenge the medical field. The ongoing aim has been to identify populations predisposed to a worse outcome. In this search the mentally ill have been left behind. Current risk factors have been age, male sex, cardiovascular disease, and diabetes. This study uniquely identified the association between psychiatric disorders and 45-day mortality in adults with COVID-19.

Clinical insights

  • This is the first study to report mortality by diagnostic group indicting a 2.5- fold higher mortality in patients with schizophrenia after adjusting for the COVID-19 risk factors including diabetes and cardiovascular disease. Yet schizophrenia itself is not in the comorbid list of conditions for early vaccination. These findings did not bear out with mood and anxiety disorders.
  • Schizophrenia spectrum diagnosis-related mortality ranks second behind the age in the strength of association of all demographic and medical risk factors.
  • We also know the implications for getting patients with schizophrenia to adhere to treatment let alone come forward for much-needed vaccination.

Summary

In my professional opinion based on this large study patients with schizophrenia spectrum disorder have a higher risk of COVID-19 mortality second only to age begs the need for getting them vaccinated preferentially in the comorbid condition category via community mental health clinics and day treatment programs. Psychiatrists should lead the advocacy for this purpose. Keep in mind paranoia may need to be addressed with this diagnostic population. 

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Psychotropic medications and cannabis: drug-drug interactions

Rong C et al. Expert Opinion on Drug Safety. 2018 Jan;17(1):51-54. doi: 10.1080/14740338.2017.1397128.

PMID:29082802

Background

Cannabis is frequently being prescribed along with other medications including psychiatric medications. This study aimed to determine whether the effect of cannabis on hepatic biotransformation pathways would be predictive of clinically significant drug-drug interactions (DDIs) with commonly prescribed psychotropic agents.

Methods

A literature search was conducted using the following databases: PubMed, PsycInfo, and Scopus from inception to January 2017. The search term cannabis was cross-referenced with the terms drug interactions, cytochrome, cannabinoids, cannabidiol, and medical marijuana. Pharmacological, molecular, and physiologic studies evaluating the pharmacokinetics of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), both in vitro and in vivo, were included. Bibliographies were also manually searched for additional citations.

Results

Δ9-Tetrahydrocannabinol and CBD are substrates and inhibitors of cytochrome P450 enzymatic pathways relevant to the biotransformation of commonly prescribed psychotropic agents (CYP3A4, 2C9, and CYP3A4, and 2 C19). The preparations of Δ-9 THC and CBD-based products, as well as utilization of marijuana (inhalation and ingestion), are prescribed to potentially result in clinically relevant and specific DDIs. The effects vary based on occasional use and chronic/medicinal use. Enzymatic biotransformation pathways that either directly or indirectly affected by cannabinoids would result in DDIs with relevant psychotropic medications.

Clinical Commentary

The high frequency and increasing use of cannabis invite the need for healthcare providers to familiarize themselves with potential DDIs in persons receiving select psychotropic agents, and additionally consuming medical marijuana and/or recreational marijuana.

Clinical commentary:

A high percentage of individuals being prescribed medical cannabis for various medical purposes invites the need for clarity of related DDIs with psychotropic as well as other medications. The data is limited as this is an emerging field and cannabis remains a Schedule I drug limiting federally funded research.

Clinical Insights

  • Δ-9THC and CBD are substrates and inhibitors of cytochrome P450 enzymatic pathways relevant to biotransformation of commonly prescribed psychotropic agents.
  • There is potential for clinically significant elevations in Δ-9THC and CBD exposure with diminished CYP2C9 and /or CYP 3A4 function. 
  • Patients should be informed that Δ-9THC and CBD consumption may result in DDIs having consequences concerning the efficacy, tolerability, and or safety of their treatment.

Example: Lurasidone is a CYP3A4 substrate and may have tolerability concerns or safety problems due to increased bioavailability of the agent when used with Δ-9THC and CBD.

Summary:

In my professional opinion, we should assess medical cannabis/recreation cannabis use for our patients and discuss DDIs with them. It is also important to mention that driving a motor vehicle/operating machinery may be affected and they need to exercise caution. These discussions need to be documented. As with alcohol they could get picked up for intoxication-related to increased Δ-9THC exposure as a result of a DDI.

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Chronic posttraumatic stress disorder: RCT of repeated ketamine administration

Feder A et al. Am J Psychiatry 2021 Feb1; 178 (2):193-202. doi: 10.1176/appi.ajp.2020.20050596 [E pub2021 Jan 5]

PMID:33397139

Background

Posttraumatic stress disorder (PTSD) is a chronic and disabling condition, for which available pharmacotherapies have limited efficacy. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD.

Methods

Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was the change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures.

Results

The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated.

Conclusions

This randomized controlled trial provides the first evidence of the efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD.

Clinical Commentary

RCT is key to the research process and in the development of new treatments. Clinicians have multiple patients suffering from severe PTSD for which treatment options are limited. This disorder is associated with significant morbidity and leads to drug and alcohol abuse. As the first RCT to study the efficacy of ketamine infusions the findings of this trial are important to clinicians. Noteworthy is the use of objective rating scales and psychoactive placebo midazolam. There was also a repeated infusion design (three infusions per week) over two weeks. In the future, it would be great to see another treatment arm in a trial such as Eye Movement Desensitization and Reprocessing (EMDR) or a combination of ketamine infusion and EMDR therapy

Animal studies suggest that subanesthetic doses of ketamine cause a rapid increase in glutamate release and downstream changes including an increase in brain-derived neurotrophic factor (BDNF) which ultimately correlate with symptom response.

Clinical insights:

  • The efficacy of the IV ketamine infusion (six infusions) has been established for PTSD, duration of effects lasting about a month based on the results of this study. As IV ketamine infusion is not FDA approved and is off-label this RCT gives us a leg to stand on. We can inform patients about this data when considering treatments.
  • This study excluded suicidal patients due to the design however, we do know from previous trials IV ketamine infusion benefits those with suicidal thinking rapidly.
  • PTSD is often comorbid with depression and this trial did show comorbid depressive symptoms responding to the IV ketamine infusion.
  • The study rightly excluded patients with drug and alcohol abuse. We should not be using IV ketamine infusions in those with active drug and alcohol abuse and addictive personality. https://www.copepsychiatry.com/  for more detailed information regarding ketamine infusions.

Summary:

In my professional opinion, ketamine infusions are increasingly playing a role in therapeutics in psychiatry. Limitations include lack of FDA approval and lack of insurance coverage. Patients who have severe PTSD symptoms with a lack of response to traditional treatments should be considered for ketamine infusions. As clinicians, we still need to study the long-term maintenance effects of ketamine infusion. There is a need for post-infusion treatments to be operationalized. At present, there is no well-established long-term data. Maintenance ketamine infusions need to be available to help patients.

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Muscarinic cholinergic receptor agonist and peripheral antagonist: Treatment of schizophrenia

Brannan SK et al. N Engl J Med. 2021 Feb25;384(8):717-726. doi: 10.1056/NEJMoa2017015.

PMID: 33626254

Background

The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia were the focus of this study.

Methods

In this double-blind, phase 2 controlled trial, patients with schizophrenia were randomized in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary endpoint was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale. Secondary endpoints were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2.

Results

A total of 182 patients with schizophrenia were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive a placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group (moderately to severely impaired). The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo a statistically significant finding. The results for the secondary end-points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups.

Conclusions

In this 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.).

Clinical Commentary

There is an ongoing need to develop new therapeutic options to treat schizophrenia using agents targeting novel receptor systems. The present treatments have multiple limitations including neurological and metabolic side-effects. Besides, current strategies have not treated negative symptoms which are enduring and responsible for long-term debilitation due to this disease state. Our current treatments do not put patients with schizophrenia back to work.

The limitations include a small number of sites (12), and lack of ethnic diversity (70% black population) as the trial was conducted in urban centers. The entire study was done as an inpatient which does not simulate the real world and compliance issues are managed in the inpatient setting. There were only two groups, as the trial which did not include an assay drug group for trial validity. Nevertheless, this trial brings hope to clinicians and patients.

Clinical insights:

  • Xanomeline targets novel receptors M1 and M4 which are implicated in schizophrenia, and its cholinergic side-effects are mitigated by trospium a peripherally restricted muscarinic receptor antagonist. Xanomeline lacks action on the dopamine receptor and hence lacks neurological side-effects.
  • The discontinuation rate from adverse events was similar in the active drug and placebo group suggesting good tolerability.
  • Common adverse events were constipation, nausea, dry mouth, dyspepsia, and vomiting both cholinergic and anticholinergic.
  • Extrapyramidal side-effects, weight gain, QTc prolongation, and metabolic issues were no different than placebo which important from the clinical perspective.
  • The improvement in negative symptoms is an important finding as this group of symptoms is responsible for long-term debilitation in schizophrenia which persists after treating the positive symptoms with the currently available antipsychotics (do not treat negative symptoms).
  • It is a concept of using two drugs xanomeline for acute symptom treatment and trospium for managing the peripheral anticholinergic-side effects. This feels like using a first-generation antipsychotic with benztropine to manage tremors or a second-generation antipsychotic with metformin to manage weight and hyperglycemia issues. In psychiatry, we are familiar with these concepts. The question is how far ahead are patients with this combination in the domain of day-to-day functioning, relationships, quality of life, and gainful employment (functional integration). The answer to this issue will only be known once there is FDA approval and we have had a chance to try the drug in the real world.

Summary:

I suggest that the readership stay tuned to more research-related news regarding this novel compound a potential treatment for schizophrenia. This trial shows efficacy not only against positive but also negative symptoms. The negative symptoms have been enduring, tough to treat, and responsible for the significant dysfunction caused by this illness. The side effect profile is also highly favorable in regard to metabolic issues, weight, and cardiac issues such as QTc (no different than placebo).

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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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