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Issue 95, Mar 2020
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Pimavanserin as an adjunct to antidepressant therapy in major depressive disorder (MDD): Is it effective?

Fava M et al. J Clin Psych. 2019 Sep 24; 80 (6). pii: 19m12928.doi:10.4088/JCP.19m.12928

PMID:31556975

Background

Pimavanserin, a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist, is FDA approved for the treatment of Parkinson’s disease psychosis. This phase 2 study examined the efficacy and safety of pimavanserin as adjunctive therapy in patients with MDD.

Methods

This was a multicenter, randomized, double-blind, placebo-controlled study in patients with DSM-5 defined MDD who had an inadequate response to selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). The patients were randomized 3:1 to placebo or pimavanserin added to SSRI or SNRI therapy. At 5 weeks, placebo non-responders were-randomized to placebo or pimavanserin for an additional 5 weeks. The Key endpoints were changed from baseline to end of each stage in the 17-item Hamilton Depression Rating Scale (HDRS-17) total score and Sheehan Disability Scale (SDS). 

Results

207 patients were randomized. This study had a sequential design. Over the 10 weeks, pimavanserin was significantly better than placebo on the HDRS 17 (p=0.0076; effect size 0.5). With regard to the SDS, pimavanserin was also significantly better than placebo (P=0.0094; effect size 0.47).  The response was more robust during the first stage of blinded sequential treatment. Significant improvements were observed for several secondary endpoints including sexual functioning, daytime sleepiness, and mental health-related quality of life. The most common adverse events were dry mouth, nausea, and headache. No clinically relevant changes noted on vital signs, EKG, and clinical laboratory testing.

Conclusions

Pimavanserin demonstrated robust efficacy in patients with MDD and an inadequate response to an SSRI or SNRI. Tolerability was consistent with previous experience.

Clinical Commentary

Pimavanserin is FDA approved for treating Parkinson’s disease psychosis (PDP). In this study, pimavanserin demonstrated early robust effects as an adjunct to an antidepressant in patients with an inadequate response. The study had a small sample size and the duration of the trial could have been longer.

Pimavanserin is a potent 5hydroxytryptamine 2A (5-HT 2A) receptor antagonist/inverse agonist with less 5HT2C antagonist/inverse agonist activity. Pimavanserin does not have any activity on adrenergic, dopaminergic, histaminergic or muscarinic receptors.

This translates into a lack of neuroleptic-induced side-effects such as tremors, stiffness, akathisia, and tardive dyskinesia (TD) (lack of dopaminergic activity).

Lack of weight gain and sedation (no action on histaminergic receptors). This drug also lacked significant metabolic dysregulation and sexual dysfunction which are important side-effects of antipsychotics which we would as clinicians would like to avoid.

 In summary:

Pimavanserin is an attractive alternative to the current atypical antipsychotics we use in mood disorders. It is important because of lack of dopamine receptor-related side effects such as TD, galactorrhea, akathisia, and parkinsonism. Currently, the use is considered off-label. When used in PDP the drug may also help with mood symptoms in addition to psychosis.

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Valproic acid-induced hyperammonemia: significance and management

Baddour E et al. Mental Health Clin. 2018 Mar 26;8 (2): 73-77.doi: 10.9740/mhc.2018.03.073. e: Collection 2018

PMID:29955549

Background

Valproic acid (VPA)-induced hyperammonemia poses several challenges in clinical practice. Practitioners often treat this condition in asymptomatic patients although studies suggest that it is unnecessary. This study was designed to identify if VPA-induced hyperammonemia patients are appropriately identified and treated based on their symptoms as well as the most efficacious strategies used for treatment.

Methods

This was a retrospective study and patients were identified between June 1, 2011, to June 30, 2016. Patients were included if they were admitted to a psychiatric unit, received at least one dose of VPA and had at least one ammonia level drawn during the admission. Hyperammonemia was defined as a greater than 47 μmol/L, and symptomatic hyperammonemia was defined based on specific symptom presentation. The treatment was considered successful if the ammonia level was within the normal range at discharge.

Results

357 patients were screened of which 347 met all inclusion criteria for analysis. The reported incidence of hyperammonemia was found to be 36% with 43.2 % of those patients presenting with symptoms. Lactulose initiation was the most common treatment modality chosen (48.7%). Discontinuation of VPA was the most effective treatment (56.3% success rate).

Conclusions

This study suggests that patients with elevated ammonia levels are asymptomatic and therefore, based on the literature, may not require treatment. Although lactulose was the most commonly used treatment, the most effective was the discontinuation of VPA. It is important to note that 60% of the patients in the study had dementia so there could be an overlap of symptoms.

Clinical Commentary

This study has tried to address a clinical problem as VPA is commonly used in psychiatric practice. Hyperammonemia was defined as an ammonia level greater than 47 micromol/L.

Symptomatic hyperammonemia should be addressed. The symptoms include drowsiness, nausea and vomiting, lethargy, cognitive changes as well as neurological signs with higher ammonia levels. The condition is referred to as valproate-induced hyperammonemic encephalopathy (VHE).

If hyperammonemia is detected the ammonia level should first be repeated along with liver function tests to exclude false positives. If asymptomatic hyperammonemia is detected and VPA has been therapeutically efficacious one should probably continue therapy and monitor the condition.

There are known risk factors such as alcoholism, high protein intake, the combination of topiramate and valproate, urea cycle disorders, carnitine deficiency, and nutritional deficiency. Other conditions such as medications, smoking, and gastrointestinal bleeding can also cause hyperammonemia in a patient on VPA and should be considered. (simple and practical.com)

This study suggests that lactulose may be tried for treating hyperammonemia. The  literature suggests that levocarnitine is also effective but stopping VPA has the best effects. A thorough risk-benefit analysis needs to be conducted before stopping VPA. This entire process should include shared decision making (consent from patient/health care proxy)

Summary: In my professional opinion ammonia levels need to be drawn along with LFTs in a patient having symptoms of hyperammonemia. If asymptomatic hyperammonemia is detected we should monitor and continue VPA. Look for other causes of hyperammonemia. If the patient has had an excellent response to VPA we may continue the drug and add lactulose (dose: 20-30 g three to four times a day) or levocarnitine (dose:330 mg three times daily). If these strategies do not work then stop VPA and try another medication. In some patients, carbamazepine can also cause this condition.  If VHE is detected then stop VPA and treat the underlying condition.

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Cannabis concentration and psychosis: The European experience.

Di Forti M. et al. Lancet Psychiatry. 2019 May; 6 (5): 427-436. doi: 10.1016/S2215-0366 (19) 30048-3Epub 2019 Mar 19.

PMID:30902669

Background

Legal use of cannabis for medical purposes is increasing and many states in the USA allow recreation use too. Cannabis use is also associated with an increased risk of psychotic disorder. This study aimed to identify patterns of cannabis use with the strongest effect on the odds of psychotic disorder across Europe.  In addition, they aimed to assess, if differences in such patterns contribute to variations in incidence rates of psychotic disorder.

Methods

This study included patients aged 18-64 years who presented to psychiatric services in 11 sites across Europe and Brazil with first-episode psychosis. Controls representative of the local populations were recruited. Logistic regression was used to estimate which pattern of cannabis use carried the highest odds for a psychotic disorder. The cannabis was divided into high potency (>10% THC) and low potency (<10% THC) based on the concentration of tetrahydrocannabinol. The patterns of cannabis use associated with the highest odds of psychosis and the correlation between such patterns and the incidence rates for psychotic disorder across study sites was calculated.

Results

The study included 901 patients with first-episode psychosis and 1237 controls from the same sites. Daily cannabis use was associated with increased odds of a psychotic disorder compared with never users (adjusted odds ratio 3.2). The odds were 5 times higher for the daily use of high potency cannabis. The calculations also suggested that if high potency cannabis was no longer available 12.2% of the cases of first-episode psychosis could be prevented across the 11 sites. This number increased to 30.3 % in London and 50.3 % in Amsterdam. The incident rate of psychotic disorder was directly correlated with the use of high potency cannabis and daily use.

Conclusions

This study suggests that differences in the frequency of daily cannabis use and also the use of high-potency cannabis contributed to a striking variation in the incidence of psychotic disorder across the 11 sites. The increasing availability of high potency cannabis has important implications for public health.

Clinical Commentary

This is an important study that was conducted in Europe and had a large sample. This is also a case-control study.  Daily use of cannabis was associated with an increased incidence of psychosis as was the use of high potency cannabis. This study also revealed a higher incidence of psychosis in geographical areas with the availability of high potency cannabis compared to areas with the availability of low potency cannabis.

The liberalization of cannabis will increase the risk of psychotic disorder for multiple reasons. These include the fact that the cannabis available is the high potency type. The risk will be increased especially in those around the age of 15 years and those using daily.

The psychosis can be confused with schizophrenia as this illness occurs in the late teenage years and the use of cannabis is a risk factor for schizophrenia.

Teenagers using cannabis have an increased risk of cognitive impairment as the brain has not matured yet.

In summary: It is important for us clinicians to be aware that daily use of, especially high potency cannabis can result in an increased risk of psychosis. We should also expect to see more patients presenting with schizophrenia creating a dilemma, whether the cause is schizophrenia or cannabis or a combination of all of the above factors. We should continue to consider it as a drug of abuse in the interest of our patients and not legitimize cannabis for recreational purposes. We should also be actively screening patients for cannabis abuse. Today’s cannabis is not the same as that of the 1960s.

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Physician depressive symptoms and medical errors. What is the relationship?

Pereira-Lima K. et al. JAMA Netw Open. 2019 Nov1;2(11): e1916097.doi:10.1001/jamanetworkopen. 2019.16097

PMID 31774520

Background

Depression is highly prevalent amongst physicians and has been associated with an increased risk of medical errors. This study aimed to answer questions regarding the magnitude and temporal direction of these associations which remain open in the literature. This study aimed to provide relative risk (RR) estimates for the associations between physician depressive symptoms and medical errors.

Methods

This study was a meta-analysis. A systematic search of standard databases such as PubMed, PsychINFO was performed from database inception to December 31, 2018. Peer-reviewed empirical studies that reported on a valid measure of physician depressive symptoms associated with perceived or observed medical errors were included. The study characteristics and RR estimates were extracted from each article. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline was followed.

The primary outcome measures were the relative risk estimates for the associations between physician depressive symptoms and medical errors.

Results

There were a total of 11 studies involving 21517 physicians. The studies included 7 longitudinal studies (64% with 5595 individuals) and 4 cross-sectional studies (36% with 15922 individuals). The overall RR for medical errors among physicians with positive screening for depression was 1.95 with a high heterogeneity across studies. There were lower RR estimates associated with medical errors in longitudinal studies and higher RR estimates in cross-sectional studies. The association between physician depressive symptoms and medical errors is bidirectional.

Conclusions

The results of this study suggest that physicians with a positive screening for depressive symptoms are at a higher risk for medical errors. Further research is needed to evaluate whether the intervention to reduce physician depressive symptoms could play a role in mitigating medical errors and thus improving physician well-being and patient care.

Clinical Commentary

This large meta-analysis suggests that physicians with positive screening for depression are at a higher risk for medical errors and that this relationship may be bidirectional. There are certain limitations such as 10 out of the 11 studies relied on self-report of medical errors which may have introduced bias into the results. It is important to note that these were perceived medical errors noted through a lens of depression. The questions also were related to the major, and harmful medical errors relying on the depressed physicians' judgment. Hence acts of omission with potential harm might not have been considered harmful as a medical error by the reporting depressed physician. Most studies were related to US physicians and hence the results may not apply to other countries. It is important to note that 8 of the 11 studies exclusively assessed training physicians.  Physicians in training may have greater depression and medical errors due to the added stress in training.

It is important to note that physicians with depression often may not seek help as they may perceive a notification to the licensing board that may occur and affect their license. Training physicians (resident physicians) do not want to seek help as it may discriminate against them and affect training completion. Hence physicians with depression suffer in silence and may remain untreated or inadequately treated. Some may self-treat because of these perceived fears.

Depression in physicians just as in non-physicians may affect concentration leading to medical errors and compromise patient safety.

A warm and nurturing environment must be created through education and screening so that physicians seek and get adequate professional treatment for depression possibly with a psychiatrist involved. This should be part of the medical error reduction program.

Physicians may also get to treatment later when they are unable to function or have death wishes.  Sadly, there is a high suicide rate as the physicians may not see a way out when depressed.

In summary:

Physicians need to have depression adequately treated and monitored, best by a psychiatrist. Education should be provided indicating that there are no punitive measures for seeking treatment. Once these myths are dispelled more physicians are likely to seek treatment for depression on their own resulting in the reduction of medical errors and suicides.  

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Yoga and depression: A randomized controlled dosing study

Scott TM et al. J Psychiatr Pract. 2019 Nov; 25(6):437: 450. doi; 10.1097/PRA.

PMID 31821220

Background

Evidence suggests that yoga may be an effective treatment for major depressive disorder (MDD). There is a need for evaluating the "dosing" of yoga treatment and efficacy for MDD. This study aimed at combining Iyengar yoga and coherent breathing in participants with MDD and determine the optimal intervention dose.

Methods

This study included N=32 participants (18-65 years of age) diagnosed with MDD who were randomized to a high-dose group (HDG) or a low-dose group (LDG) of yoga and coherent breathing for 12 weeks. The HDG (N=15) involved three 90-minute yoga classes and three 30- minute homework sessions per week. The LDG (N=15) involved two 90-minute yoga classes and three 30-minute homework sessions per week. The evaluations were done at baseline, week 4, week, 8, and week 12 with the following instruments: Positivity Self -Test, Spielberger State Anxiety Inventory, Patient Health Questionnaire-9, Pittsburgh Sleep Quality Index, and Exercise-induced Feeling Inventory. An intent-to-treat analysis was done.

Results

Significant improvements in all outcome measures were found for both groups, with acute and cumulative benefits. The HDG group showed superior improvement on all scales but the between-group differences did not reach significance possibly due to lack of power due to small sample size. Cumulative yoga minutes were correlated with improvement in outcome measures

Conclusions

Improvement in psychological symptoms correlated with cumulative yoga practice. Both interventions reduced symptoms of depression and anxiety and increased feelings of positivity. The time commitment for yoga practice needs to be weighed against benefits when designing yoga interventions.

Clinical Commentary

This study demonstrates that an intervention of yoga postures and coherent breathing over 12 weeks was efficacious in reducing symptoms of depression, anxiety, sleep disturbance, many additional measures. I would view this as a proof of concept study which has a small sample size. Eight psychological domains remained significant after applying the Bonferroni correction for multiple comparisons. These studies are not easy to conduct as it is tough to operationalize. It not like a 100 mg dose of medicine is tested against a placebo. In my opinion, the yoga intervention needs further development under the category of complementary and alternative treatments (CAM).

It is important to note the PHQ-9 measured depressive symptoms decreased by 37% associated with the yoga intervention which was greater than seen in placebo-controlled trials. 

There was an increase in positivity, positive engagement, revitalization, and tranquility. There was a decrease in physical exhaustion, anxiety, depression, and sleep disturbance regardless of LDG or HDG. It is interesting to note that Yoga characterized by dose. Many of these domains are items on the PHQ-9.

The current study did not reveal any significant between-group differences which may be related to the small sample size calling for larger study. Because the intervention was characterized into LDG and HDG there was no placebo arm.

Please note we have several patients suffering from anxiety, depression and negativity who have tried a variety of medications where yoga can be suggested. Having comorbid chronic anxiety results in tougher to treat patients.

Summary: This pilot study suggests that yoga should be considered for our patients with MDD as it alleviates many of the symptoms in depression. Improvement in sleep, anxiety, and positivity to name a few. It is also important to know that even if done less often based on one's schedule there is a significant benefit. We should be recommending this treatment to our anxious depressed patients where medications are having limited benefits.

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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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