Issue 80, Dec 2018
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Lithium-associated hypercalcemia: What we need to know?

Meehan AD et al. World J Surg. 2018 Feb; 42 (2): 415-424. Doi:10. 1007/s00268-017-4328-5. PMID: 29260296

Background

We are all familiar with lithium associated hypothyroidism and monitor TSH in patients on lithium.  Lithium-associated hypercalcemia (LAH) as a result of hyperparathyroidism (also caused by lithium) is a little studied entity. We do not monitor calcium levels on a regular basis in patients taking lithium. The aim of this study was to explore the prevalence of hypercalcemia in bipolar patients (BP) with and without lithium treatment and also to assess the outcomes of surgical treatment of lithium associated hyperparathyroidism

Methods

This clinical retrospective study included laboratory data, medications, and surgical outcomes collected from 313 BP patients treated with lithium from two psychiatric outpatient clinics in Sweden. Data were also collected from 148 BP patients not on lithium. There was a randomly selected control population of 102 subjects. The prevalence of hypercalcemia was assessed in these populations.

Results

The prevalence of lithium associated hypercalcemia was 26%. The BP patients on lithium were 13 times more likely to have hypercalcemia compared to BP patients unexposed to lithium. There were no significant differences between the BP group without lithium and control population. In seven lithium treated BP patients the hyperparathyroidism required surgery.

Conclusions

The high prevalence of LAH suggests the need for calcium monitoring in lithium treated patients. Prospective studies are needed to further address this issue.

Clinical Commentary

It was not standard practice for me to measure calcium levels in BP patients on lithium as I would TSH, lithium levels, and kidney function.

  • The symptoms of LAH may be non-specific and missed and hence monitoring is important.
  •  Serum calcium should be measured before starting lithium and at least once a year thereafter. If abnormalities occur additional testing is done determined by the clinical situation and specialist opinion obtained.
  • Even though serum calcium may be normal in those on lithium but on the higher side of the normal range, the actual calcium level may be higher in those individuals with low plasma albumin.
  • Lithium is an important drug in psychiatry besides treating bipolar disorder and being an augmentation strategy for major depression it also reduces suicide attempts.
  • Bottom line we should be monitoring calcium in BP patients on lithium. This is also recommended by the CANMAT guidelines.
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Augmentation of antipsychotic medication for symptom exacerbation in schizophrenia: Does Withania somnifera (Ashwagandha) work?

Chengappa KNR et al. J Clin Psychiatry. 2018 Jul 10 ;79(5). Pii17m11826. doi:10.4088/JCP.17m11826. PMID:29995356

Background

There has been an increased focus on the use of complementary and alternative medicine (CAM) to treat psychiatric conditions. Antipsychotic medications are the mainstay of treatment of patients with schizophrenia. These medications have several limitations including tardive dyskinesia and metabolic issues. There is little data if any to support the use of two antipsychotic drugs in these patients. Patients often have symptom exacerbations after doing well on a particular antipsychotic medication. The immune-inflammatory dysregulation theory in schizophrenia posits an imbalance between pro and anti-inflammatory cytokines and elevated levels of inflammatory proteins such as C-reactive protein. Withania somnifera (WSE) is known to have anti-inflammatory and immunomodulating properties. This study assessed the role of WSE as an augmentation strategy to ongoing antipsychotic drug therapy in schizophrenia / schizoaffective disorder patients experiencing symptom exacerbation.

Methods

This 12-week study (N=66) was conducted between April 2013 to July 2016. Patients experiencing symptom exacerbation were randomized to WSE (1000 mg/day) or placebo for 12 weeks in a double-blind randomized controlled trial in addition to the antipsychotic drug they were taking. The positive and negative symptom scale was used to assess the symptoms at baseline to end of study. Stress and inflammatory indices were also assessed. This included C-reactive protein (CRP) and S100 calcium binding protein B(S100B).

Results

The study group and the control group both included 33 subjects each.

  • WSE group produced significantly greater symptom reduction than the control group.
  • The statistically significant symptom reductions were noted in negative, general, and total symptoms but not positive symptoms when compared to placebo. The inflammatory markers were reduced in the WSE group but did not reach statistical significance compared to the placebo group.
  • Adverse events were somnolence, epigastric discomfort, and loose stools noted to be transient and more common in the WSE group.
  • No significant differences were noted in weight, vital signs or lab measures which remained stable.
Conclusions

This study suggests that early treatment with standardized extract of WSE provides significant benefits with minimal side-effects for exacerbation of symptoms in schizophrenia when added to the antipsychotic medication.

Clinical Commentary

WSE has been studied to treat anxiety and depression in separate clinical trials. Negative symptoms of schizophrenia are usually enduring. As antipsychotic drugs have limitations this seems like a viable augmentation strategy especially due to a milder side-effect profile.  Note that it did not benefit positive symptoms. Replication studies in a larger sample size are needed. Clinicians have commonly used lithium, divalproex, or another antipsychotic to augment in this group of patients but the data is limited. Clozapine is an underutilized option that should be considered but has limitations of side-effects and needs for monitoring.

It would currently be considered off-label as it is not FDA approved. This treatment could complement antipsychotics as they are effective against positive symptoms and WSE is effective against negative symptoms. Clinicians may choose to add WSE as available at amazon (Swanson Sensoril Anti-Stress Nutraceutical 120 mg capsules) as the Ashwagandha standardized extract. There is now an increasing trend to test nutraceuticals using randomized clinical trials.

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Effectiveness of medications for PTSD in routine practice: Is there a difference in efficacy?

Shiner B et al. J Clin Psychiatry 2018 Sep 18; 79(5). Pii 18m-12145. doi: 10.4088/JCP. 18m12145.-0575-4179. PMID:30257081

Background

Posttraumatic stress disorder (PTSD) is a common psychiatric disorder affecting 8% of the US population.  Fluoxetine, paroxetine, sertraline, topiramate, and venlafaxine have been shown to have efficacy for the treatment of PTSD treatment in meta-analyses of randomized controlled trials.  It is important to have data regarding their effectiveness in the clinical setting. There is a dichotomy between the clinical trials and the real world. This retrospective study attempts to address this issue of effectiveness by data mining from the clinical electronic medical record (real world).

Methods

This Veterans Affairs study conducted (N=2,931) in outpatients initiating PTSD (DSM-IV criteria) treatment between the years 2004-2013.  This study included subjects who received one of the above five medications at adequate dose and duration combined with baseline and endpoint PTSD Checklist (PCL) measurements. Comparisons of PCL scores, symptom cluster scores, and sleep items as well as reliable improvement including loss of PTSD diagnosis was conducted.

Results

 Patients improved by a mean of 5-6 points on the PCL over approximately six months of treatment.

  • 50 percent of patients had a reliable improvement of 5-6 points on the PCL but less than a fifth achieved loss of PTSD diagnosis.
  • No differences were observed between medications
  • Evidence based psychotherapy was the only predictor for loss of PTSD diagnosis.
Conclusions

Currently available evidence-based medications are equally effective for PTSD. The importance of adding evidence based psychotherapy should be underscored to have meaningful improvement.

Clinical Commentary

PTSD treatment involves a strong therapeutic alliance between the treating clinician and the patient. This study suggests that the choice of medication may be left to the patient choosing one of the above five medications guided by patient preference, tolerability, or another family member having a successful trial. This study focused on outcomes like loss of PTSD diagnosis akin to remission.

  • The key for a successful outcome (loss of PTSD diagnosis) was evidence-based psychotherapy. Two effective therapies Eye Movement Desensitization and Reprocessing (EMDR) and Stress Inoculation Therapy were not included, as a manual review of the records indicated they were not being practiced. EMDR is one of the most effective therapies for PTSD and should be combined with medication.
  • The study included prolonged exposure and cognitive processing therapy which made the difference in patients who recovered from PTSD.
  • Finally, the message from this study is that medication must be combined with an evidence-based therapy which is the differentiating feature to produce results.
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Donepezil addition in older depressed patients with cognitive impairment: Any added benefit?

Devanand DP et al. Am J Geriatr Psychiatry 2018 Oct;26 (10):1050-1060. doi: 10.1016/j.jagp.2018.05.008. Epub 2018 Jun 28 PMID 30037778

Background

Older adults often have depression associated with cognitive impairment. These individuals are thought to progress to dementia rapidly. The cognitive impairment is often uncovered once the depression is treated. It is believed that depression in older adults is the harbinger of dementia. This study sought to answer the question if addition of donepezil would delay conversion to dementia in this group of individuals.

Methods

A randomized, double-blind, placebo-controlled trial was conducted in older adults with depression and cognitive impairment. The patients received open-label antidepressant treatment for 16 weeks, initially with citalopram and then with venlafaxine, if needed. This was followed by a random assignment to add donepezil 5-10 mg daily or placebo for another 62 weeks.  The patients received neuropsychological tests to assess cognition as well tests to assess activities of daily living.

Results

Non-blinded treatment with antidepressant therapy resulted in 64% responders with regard to depression symptoms by week 16. In the randomized phase there were no noted differences between donepezil and placebo on dementia conversion rates. In addition, there were no predictors for donepezil efficacy. There was also no difference in adverse events between the groups.

The results do not support off-label cholinesterase inhibitor treatment in patients with depression and cognitive impairment.

Clinical Commentary

As a field we struggle with depression in older adults. Often there is associated mild cognitive impairment which also needs to be addressed. This blinded study does not support addition of donepezil to antidepressant therapy and risk additional side-effects.  Clinicians may consider adding Theracurmin 90 mg bid which is a curcumin (has inti-inflammatory properties) preparation. This has been shown to have benefit in non-demented older adults in areas of memory and attention. There is a double-blind RCT using psychological tests and PET imaging which revealed benefits of curcumin (Small et al 2018). The paper by Small et al. was reviewed in the GME research review June 2018 issue.

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Smoking behavior and cognition in patients with psychosis: What is the impact?

Vermeulen JM et al. Am J Psychiatry. 2018 Nov;175(11): 1121-1128 doi: 10.1176/appi.ajp 2018. 18010069. EPub Aug 2 2018. PMID30138044

Background

Patients with psychosis are heavy smokers and have prominent nicotine stains on their fingers. Cognitive dysfunction is also well known to occur in this patient group.  There are contradictory findings on the association between smoking and cognitive dysfunction. Longitudinal studies are also lacking. In this study the authors sought to examine the association between smoking behavior and cognitive dysfunction in a prospective design.

Methods

This six year follow up prospective Dutch study included patients with nonaffective psychosis (N=1,094), their siblings (N=1,047), and healthy controls (N=579). Smoking behaviors and cognition was assessed at baseline, and three and six year follow ups. The association between smoking and cognitive status was assessed.

Results

At baseline 67% of patients smoked compared to 38% of siblings, and 25% of the control group. Multiple associations were found between smoking and lower processing speed in the patient and control groups compared with the nonsmoking patient group and the nonsmoking control group. In the siblings smoking also was associated with lower performance on working memory, reasoning, and problem solving compared with the nonsmoking sibling group. The number of cigarettes smoked had a negative association. Patients but not siblings and control subjects who quit smoking had improvement in processing speed.

Conclusions

Smoking is associated with poorer cognitive performance in patients, their siblings, and healthy controls compared with nonsmoking. Smoking cessation may improve processing speed in patients.  

Clinical Commentary

Schizophrenia and non-affective psychosis as terminology have been used interchangeably.  In my opinion as, mental health providers (me included) we do not do enough to help our patients with smoking cessation. Among the potential influences on smoking are the genomic alterations in the alpha-7 nicotinic receptor gene complex and these are shared with first degree relatives and are closely related to susceptibility to schizophrenia.

  • There is a high prevalence of smoking amongst those ill with nonaffective psychosis/schizophrenia and stopping smoking leads to cognitive improvement.
  • The number of cigarettes smoked daily is inversely correlated with cognitive performance. So, the goal of reduction of smoking initially is also helpful.
  • This study does not answer questions why some patients are able to stop smoking while others never start.
  • The powerful argument from this study is to strongly encourage smoking cessation in patients with schizophrenia as it will not only improve cognition but also multiple physical ailments such as COPD, hypertension, stroke risk, reduction of lung cancer risk, and many such maladies
  • Finally, I appeal to all of you to ask the question of smoking and work with patients towards cessation strategies of which there are several such as varenicline, nicotine gum/inhaler/patch, and buproprion. This is to be complemented by behavioral therapy.
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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]