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Issue 98, Jun 2020
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Lumateperone: A new treatment for schizophrenia

Correll CU et al.  JAMA Psychiatry. 2020 Jan 8. doi: 10.1001/jamapsychiatry.2019. 4379 [E pub ahead of print]

PMID 31913424

Background

There remains an unmet need to develop newer medications for the treatment of schizophrenia because of the metabolic burden and extrapyramidal side-effects of the current agents. This study investigated the efficacy and side-effect profile of lumateperone which is a serotonin, dopamine, and glutamate modulator.

Methods

This was a randomized, double-blind, placebo-controlled phase three trial conducted in the United States in patients with schizophrenia (18-60 years old) who were experiencing an acute exacerbation. This trial was conducted at 12 sites. Patients were randomized 1:1:1 (150 patients in each arm) to receive lumateperone tosylate, 60 mg: lumateperone tosylate, 40 mg (equivalent to 42 mg or 28 mg, respectively of the active moiety lumateperone); or placebo once daily for 4 weeks.

Results

The study comprised 450 patients (mean age 42 years; 77% male) who were moderate to severely ill with baseline Positive and Negative Symptoms Scale (PANSS) score of 90 (the primary efficacy measure). The Clinical Global Impression-Severity of Illness Score (CGI-S) was a secondary efficacy measure. The lumateperone 42 mg demonstrated statistically significant improvement compared to placebo on the primary (p=0.02) and secondary efficacy measures (p=0.003). The 28 mg only separated from placebo on the CGI-S measure. Both doses were well tolerated without clinically significant changes in EPS, metabolic or endocrine factors.

Conclusions

Lumateperone demonstrated efficacy for improving the symptoms of schizophrenia and had a favorable safety profile in this study.     

Clinical Commentary

Lumateperone is a novel agent for the treatment of schizophrenia. It has a unique mechanism of action through the modulation of serotonin, norepinephrine, glutamate, and dopamine neurotransmission. This drug is a potent 5HT2A receptor antagonist, dopamine D2 receptor presynaptic partial agonist and postsynaptic antagonist, D1 receptor-dependent modulator of glutamate, and a serotonin reuptake inhibitor.

In this clinical trial, the 42 mg dose revealed a statistically significant difference in both the primary and secondary efficacy measures. The 28 mg dose separated from placebo only on the secondary efficacy measure (CGI-S). 

The response was noted to begin by week one for the 42 mg dose,

The 42 mg dose has a D2 receptor occupancy of 40% which suggests a favorable EPS profile, and low hyperprolactinemia liability of this drug. Most of the other available antipsychotics have a 60-80 percent occupancy at the dopamine receptor. Because of this low D2 receptor occupancy, we could theorize that this drug may have low tardive dyskinesia risk though there is currently no supportive data.

There were no significant changes in weight, metabolic parameters, or EKG. These are the current advantages of this drug.

Summary: In my professional opinion a new agent is welcome for our patients. Lumateperone can be dosed once daily and has a 42 mg starting as well as therapeutic dose for patients with schizophrenia. It is dosed with food and once daily. The metabolic, weight, cardiac profile is favorable even in a long term 1 year study.  

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The Z drugs and dementia in patients with affective disorders: A contrarian view

Osler M et al. Am J Psychiatry.2020Apr7; appi/ajp 201919030315.doi:10.1170/ appi.ajp.19030315 [E Pub ahead of print]

PMID:32252539

Background

Benzodiazepines and Z-drugs are two of the most prescribed agents worldwide. Previous studies have attributed these agents to have increased risk of dementia because of the cognitive side-effects of these agents. The authors examined the association of benzodiazepines, Z-drugs, and other anxiolytics with incident dementia in patients with affective disorders.

Methods

The authors conducted a cohort and nested case-control study of 235,465 patients over age 20 who were identified in the Danish National Patient Registry as having had a first-time hospital contact for an affective disorder between 1996 and 2015. From the Danish National Prescription Registry, information was obtained on all prescriptions for benzodiazepines, Z-drugs, and other anxiolytics, and patients were followed for incident dementia (defined by hospital discharge diagnosis or acetylcholinesterase inhibitor use). The hazard ratios and odds ratios were calculated with adjustment for sociodemographic and clinical variables.

Results

A total of 75.9% (N=171,287) of patients used of benzodiazepines or Z-drugs during the median follow-up of 6.1 years when patients were diagnosed with dementia. Any use of benzodiazepines or Z-drugs showed no association with dementia after multiple adjustments in either the cohort analysis or a nested case-control design. In the cohort analysis, the number of prescriptions and the cumulated dose of benzodiazepines or Z-drugs at baseline were not associated with dementia. In the nested case-control study, where prescriptions were counted from 1995 until 2 years before the index date, there was a slightly higher odds ratio of dementia in patients with the lowest use of benzodiazepines or Z-drugs (odds ratio=1.08) compared with no lifetime use. However, patients with the highest use had the lowest odds of developing dementia (odds ratio=0.83).

Conclusions

This large cohort study did not reveal any associations between the use of benzodiazepines or Z-drugs use and subsequent development of dementia, even when exposures were cumulated or divided into long- and short-acting drugs. Some results were compatible with a protective effect.

Clinical Commentary

There have been previous studies suggesting an increased risk of dementia in older adults who are prescribed benzodiazepines. There have been 13 studies in the past investigating this link. Eight studies have found a positive association between benzodiazepine use and risk of dementia. .Two studies found no such association, two had mixed results, and one found that benzodiazepines reduced the risk of dementia (Tampi et al. Future Neurol 2018). None of these were controlled prospective studies hence it is difficult to ascertain causality. Please note that this study was limited to patients with affective disorders and hence the applicability of the findings is also limited to some extent.

This current study controlled for the possibility that benzodiazepines were prescribed for early dementia. It was also prospective with a six-year follow-up. A possible reason for reduced risk has been stated as decreased anxiety and insomnia both of which are linked to an elevated risk of dementia.

Summary:

As a clinician, I am also interested in reviewing studies portraying the pro and con position on any topic. The benzodiazepines do help older adults with anxiety which is often associated with depression and insomnia. Hence, in my opinion, they should be used judiciously in minimal doses and for a short duration of time. Other risk factors such as falls, the risk of hip fracture, and interactions with other medications should be considered before the prescription of these agents. Each situation involves consideration of the risks and benefits along with close monitoring. In my opinion lorazepam in low doses would be the preferable benzodiazepine to use because of lack of active metabolites and an intermediate half-life.

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Electroconvulsive therapy and the risk of dementia in patients with affective disorders

Osler M et al. Lancet Psychiatry. 2018 Apr;5(4): 348-356 doi: 10.1016/S2215-30056-70366 (18) [ E pub 2018 March 6]

PMID:29523431

Background

Electroconvulsive therapy (ECT) is the most effective treatment for severe episodes of mood disorders. Temporary memory loss is a common side-effect, but ongoing debates exist regarding potential long-term adverse cognitive outcomes. This study aimed to examine the association between ECT and the risk of subsequent dementia in patients with a first-time hospital diagnosis of affective disorder.

Methods

This study included a cohort of patients aged 10 years and older in Denmark with a first-time hospital contact for an affective disorder from Jan 1, 2005, through Dec 31, 2015, identified in the Danish National Patient Registry with ICD-10 codes F30.0 to F39.9. From the registry, the authors retrieved information on all ECTs registered for patients and followed up patients for incidental dementia (defined by hospital discharge diagnoses or acetylcholinesterase inhibitor use) until Oct 31, 2016. The association between ECT and dementia was examined.

Results

Of 168, 015 patients included in the study, 5901 (3.5%) patients had at least one ECT. During the median follow-up of 4.9 years (IQR 2.4-7.8) and 872 874 person-years, the number of patients who developed dementia was 111 (0.1%) of 99 045 patients aged 10-49 years, 965 (2.7%) of    35 945 aged 50-69 years, and 4128 (12.5%) of 33 025 aged 70-108 years. 217 (3.6%) of the 5901 patients treated with ECT developed dementia, whereas of the 16 114 patients not treated with ECT 4987 (3.1%) developed dementia. In patients younger than 50 years and 50-69 years, ECT was not associated with a risk of dementia compared with age-matched patients who were not given ECT (p=0.32; and p=0.22, respectively). In patients aged 70 years and older, ECT was associated with a decreased rate of dementia (p<0.0001).

Conclusions

ECT was not associated with an increased risk of dementia in patients with affective disorders after correcting for the potential effect of patient selection or competing mortality. The findings from this study support the continued use of ECT in patients with severe episodes of mood disorders, including those who are elderly.

Clinical Commentary

This study had an interesting finding that revealed that in those over age 70 years ECT decreased the risk of dementia (first study to show this finding). It is well established that depression in older adults is a risk factor for dementia. There were two prior studies an Australian and a Swedish study with small sample sizes both revealing the increased risk of dementia with ECT treatments. This was noted in a third of patients above the age of 65 years over five years. These studies failed to factor in the fact that depression is an independent risk factor for dementia. This study has a large sample and had different findings from the previous two studies. When depression was factored in comparing individuals with affective disorders (those receiving ECT versus those not getting ECT), a decrease in the rate of dementia was noted.  

Summary:

This research in a large sample suggests that ECT does not increase the risk of dementia. We should not deprive a patient of this extremely effective treatment because of cognitive impairment. The cognition can be monitored using the Montreal Cognitive Assessment (MOCA) or Mini-Mental Status Examination(MMSE). A good way to start is with high dose right unilateral ECT and switching to bifrontal/ bitemporal ECT if the response is not adequate.  By the time a patient comes for ECT they have suffered a long time and hence we must relieve suffering quickly. At this juncture, the clinician, the patient, and relatives can decide on the best approach. It is extremely important to assess baseline cognition before ECT.

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FDA antipsychotic boxed warnings: Use and outcomes in dementia patients

A Rubino et al. JAMA Netw Open 2020 Apr 1;3 (4): e203630. doi: 10.1001/jamanetworkopen.2020.3630.

PMID: 32343351

Background

Atypical antipsychotics (AAPs) are often used off-label to treat dementia-associated neuropsychiatric symptoms. In 2005, the US Food and Drug Administration (FDA) issued a boxed warning for the use of AAPs in elderly patients. The long-term association of this warning with health outcomes is unknown to date. This study assessed the long-term association of the 2005 FDA boxed warning on AAPs with psychiatric medication and opioid use, health events, and quality of life among elderly individuals with dementia.

Methods

This cross-sectional study analyzed data from the household component of the Medical Expenditure Panel Survey (MEPS), the National Ambulatory Medical Care Survey (NAMCS), and the National Hospital Ambulatory Medical Care Survey (NHAMCS) fielded between January 1, 1996, and December 31, 2014. All survey respondents included in this analysis were 65 years or older and had dementia. Data analysis was performed from December 1, 2017, to March 15, 2018. The exposures included the 2005 FDA boxed warning on AAPs.

Main outcomes and measures: Use of psychiatric medications and opioids, the prevalence of cerebrovascular and cardiovascular events, prevalence of falls and/or fractures, 2-year mortality, and health-related quality of life were assessed by the Medical Outcomes Study 12-Item Short-Form Health Survey scores.

Results

A total of 2430 (MEPS) and 5490 (NAMCS and NHAMCS) respondents were identified, corresponding to weighted populations of 22, 996,526 (MEPS) and 65,502,344 (NAMCS and NHAMCS) noninstitutionalized elderly individuals with dementia (mean [SD] age, 81.06 [1.13] years; 63.1% female). In the MEPS sample, compared with before 2005, AAP use (from an annual slope of 0.99 to -0.18 percentage points), cerebrovascular events (0.75 to -0.50 percentage points), and falls and/or fractures (-1.72 to -0.40 percentage points) decreased and opioid use (0.04 to 1.29 percentage points), antiepileptic use (-0.42 to 1.21 percentage points), cardiovascular events (-0.13 to 1.30 percentage points), and 2-year mortality risk (-0.68 to 0.18 percentage points) increased. Health-related quality of life remained relatively unchanged. The NAMCS and NHAMCS sample yielded similar findings.

Conclusions

These data suggest that the 2005 FDA boxed warning was associated with some unintended negative patient outcomes.

Clinical Commentary

This is a cross-sectional study which is a limitation as this topic would be well served by a difficult to do prospective study over many years. The data is derived from three different surveys and analyzed separately revealing some inconsistencies. The strength is a large sample size. It appears that the sample consists of noninstitutionalized patients. There is a need for a large prospective study.

It is important to note that there was excessive use of antipsychotic drugs to manage neuropsychiatric symptoms in older adults. The FDA warning had its intended effect which was the reduction in the off-label use of AAP drugs.

The FDA warning and reduction in AAP drug use resulted in clinicians using other psychotropics including antidepressants, antiepileptics (valproic acid), and opioids. Essentially the neuropsychiatric symptoms which include psychosis, aggression, agitation, depression, anxiety, and insomnia still need to be managed. Clinicians moved to use these other agents for whom the data is even less convincing. As a clinician in geriatric psychiatry, I see this practice even today and the primary care physicians try all the other agents for a patient with psychosis and ultimately call a psychiatric consultation when they think an antipsychotic is indicated.

Psychosis is one of the commoner neuropsychiatric symptoms and using agents other than antipsychotics is akin to treating diabetes with cholesterol-lowering agents. Once we start an antipsychotic appropriately symptoms are better controlled and many other ineffective psychiatric drugs such as antidepressants and antiepileptics may be stopped.

The study revealed that opioid use increased and there is now a body of literature for using analgesics for the management of agitation in patients with dementia (Tampi R et al. Drugs in context 2017) This line of thinking assumes that pain produces agitation in dementia patients.

It is also interesting to note that the cerebrovascular events decreased as was also highlighted by the FDA warning. The decreased falls and fractures is also an additional benefit. There was an increase in the cardiovascular events which may be an unintended consequence of the 2005 FDA warning for which there is no clear reason.

Summary:

In my professional opinion the AAP drug use should be for the right reason in dementia patients who have psychosis, aggression, sexual acting out, and such symptoms. They should be used judiciously after off-label consent has been obtained from the health care proxy. The titration should start at low doses such as 0.25 mg risperidone bid maximum dose being 2 mg in divided doses. I use risperidone as the first choice as we have the maximum number of studies with this agent to manage neuropsychiatric symptoms. We should monitor for side-effects such as sedation and tardive dyskinesia (increased risk in the elderly).

should be used when behavioral interventions have failed. The data for the use of other psychiatric drug categories such as antiepileptics and antidepressants is soft compared to AAPs. I would like to stress that psychotic symptoms associated with dementia are extremely disruptive to the milieu and distressing to caregivers.

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Treatment utilization by children with ADHD: Do parental attitudes and perception of treatment response play a role?

Breaux R et al. Evid Based Pract Child Adolesc Ment Health. 2020;5(1):102-114. doi:10.1080/23794925.2020.1727797. [Epub 2020 March 24]

PMID 32355891

Background

ADHD is a neurodevelopmental disorder.  This is treated with a combination of medication therapy (MED) and behavior therapy (BT). Some families are less likely to utilize MED compared to others. This is thought to have an impact on the child. The present study examined the impact of parental knowledge and attitudes about attention-deficit/hyperactivity disorder (ADHD), and parental perceptions of treatment response on the utilization of behavioral and pharmacological ADHD treatments

Methods

This study used data from a longitudinal treatment study designed to assess physical growth in children with ADHD. It also explored if these relations were moderated by race/ethnicity. 230 (74% Hispanic) families of treatment naïve children with ADHD (M age = 7.56, SD  73% male) were included. Families were randomly assigned to receive behavior therapy (BT) or stimulant medication (MED; which also included low dose BT). After 6 months, families whose children still showed at least moderate impairment had access to either treatment for a total of 30 months. Utilization was measured using the number of BT sessions attended and total mg of MED taken over the study period. The ADHD symptoms were assessed using the parent IOWA Connors Rating Scale

Results

Families who reported more willingness to use medication for their child's ADHD at baseline were more likely to use MED and less likely to use BT, regardless of race/ethnicity. Parental. knowledge about ADHD was only important in predicting BT utilization for White non-Hispanic families. Greater reduction in ADHD symptoms and impairment significantly predicted more MED utilization for Hispanic families.

Conclusions

Results highlight the need to explore multiple parental (e.g., medication willingness) and child (e.g., symptom severity) factors when considering treatment utilization. Results also highlight ethnic factors which affect treatment utilization.

Clinical Commentary

This is an interesting study the first of its kind looking at parental attitudes, knowledge about ADHD, finances, and intact family systems in determining treatment choices. This study consisted of four racial/ethnic groups:1) non-Spanish -speaking Hispanic families referred to as Hispanic (N=144); 2) Spanish-speaking Hispanic families (N=26); 3) White non-Hispanic families referred to as White (N=40); 4) Black non-Hispanic families referred to as Black (N=21). The larger sample size of the Hispanic group (N=144) compared with the other three groups lowered the analytic power. This explains may differences are meaningful but do not achieve statistical significance. Other limitations included a chosen order for treatments administered. Additionally, the parent sex was not examined as a relevant factor, and sex differences are known to occur.

The study findings can be confusing, so for clinicians they can be distilled into the following practical take-home points.

Clinicians working with families of children with ADHD should assess parental knowledge and attitudes about ADHD and its treatment as part of a standard intake procedure. 1) Parents who are having a high willingness for medication, but for whom BT may be more beneficial for their child, it may be important to have a discussion about the benefits of BT alone or in combination with medication. 2) Clinicians need to know that for racial/ethnic minorities solely providing psychoeducation about ADHD will not have much impact. 3) Providing ongoing feedback to parents about the benefits of treatment is a lot more impacting.

Summary:

As a clinician, this has been an extremely educational study in determining the approach to ADHD treatment. The data highlights the importance of education, parental attitude, an ethnic group of the parent in determining the approach to be taken. We as clinicians need to take a step back and think through these issues before we prescribe our favorite stimulant.

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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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