Issue 78, Oct 2018
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Efficacy of Intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial.

Feder A et al. JAMA Psychiatry. 2014 June; 71(6):681-688. doi: 10.1001/jamapsychiatry.2014.62. PMID: 24740528

Background

There are significant limitations to the effectiveness of medication for the treatment of posttraumatic disorder (PTSD) which is a chronic and disabling condition. This study was designed to test the efficacy of intravenous ketamine for the treatment of PTSD and associated depressive symptoms.

Methods

This study was a randomized (N=41), double-blind crossover trial comparing ketamine with an active placebo control, midazolam, in patients with chronic PTSD. The ketamine dosage was 0.5 mg/kg and the midazolam dosage were 0.045 mg/kg. The primary outcome measure was change in PTSD symptom severity and the secondary outcome measures included assessment of improvement in depression using the Montgomery-Asberg Depression Rating Scale (MADRS), and monitoring for side effects using the Clinician-Administered Dissociative States Scale, Brief Psychiatric Rating Scale, and Young Mania Rating Scale.

Results

Ketamine infusion was associated with significant and rapid reduction in PTSD symptom severity, compared with midazolam, 24 hours after the infusion (mean difference in Impact of Event Scale-Revised score, 12.7 [95% CI, 2.5-22.8]; P=0.02). PTSD symptom reduction was noted with ketamine treatment in both crossover and first-period analyses.  Ketamine was also associated with depressive symptoms reduction and overall improvement in clinical presentation. Ketamine was generally well tolerated without clinically significant persistent dissociative symptoms.

Conclusions

This randomized controlled study provides evidence for rapid symptom reduction in patients with PTSD using ketamine infusion.

Clinical Commentary

PTSD is a disabling condition with a 7.8 percent prevalence affecting individuals with severe trauma exposure. There is accumulating evidence regarding the role of glutamate, the most widely distributed neurotransmitter in mediating stress responsivity, formation of traumatic memories, and pathophysiology of PTSD. These individuals often cope with symptoms using substances due to limitations of current pharmacotherapies. This study revealed that intravenous ketamine (sub-anesthetic doses) was effective not only against core PTSD symptoms but also comorbid depression. The findings of this pilot study offer new hope to these individuals. Currently, this treatment is not yet FDA approved and is considered off-label use.

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20-year nationwide follow-up study on discontinuation of antipsychotic treatment in first-episode schizophrenia.

Tiihonen J et al. Am J Psychiatry. 2018 August1; 175(8):765-773. doi: 10.1176/aapi.ajp.2018.17091001. E pub 2018 Apr6. PMID: 29621900

Background

There is clinical lore that after first-episode patients with schizophrenia are stabilized, relapse decreases with time. Treatment guidelines suggest that after clinical stabilization, antipsychotic treatment should be continued for 1-5 years and longer exposure avoided. There was no published data to support this view. This Finnish study used nationwide databases to investigate this issue.

Methods

In this study, prospectively gathered nationwide data was used to study the risk of treatment failure which included psychiatric hospitalization or death after discontinuation of antipsychotic treatment. The sample included N=8,719 subjects hospitalized for the first time with a schizophrenia diagnosis in Finland during the period of 1996-2014.

Results

The lowest risk of rehospitalization or death was observed for patients receiving antipsychotic medication continuously (adjusted hazard ratio=1.00), followed by patients who discontinued antipsychotic use immediately after discharge from the first hospital treatment (hazard ratio=1.63, 95% CI=1.52-1.75), within 1 year (hazard ratio=1.88, 95% CI=1.57-2.24), within 1-2 years (hazard ratio=2.12, 95% CI=1.43-3.14), within 2-5 years (hazard ratio=3.26, 95%CI=2.07-5.13), after 5 years (hazard ratio=7.28, 95% CI=2.78-19.05). Risk of death was 174%-214% higher among nonusers and patients with early discontinuation of antipsychotics compared with patients who received antipsychotic treatment continuously for up to 16.4 years.

Conclusions

This study provides evidence that the risk of relapse after discontinuation of antipsychotics does not decrease as a function of time during the first eight years of illness and that long-term antipsychotic treatment is associated with increased survival.

Clinical Commentary

We should be practicing evidence-based medicine today. This is an important long-term study suggesting that first-episode patients with schizophrenia need long-term antipsychotics. Multiple issues arise in these individuals and their families ranging from denial of the illness, belief that it won’t happen again, recovery of function causes patients and families to think “they are cured”. Additionally, the stigma of taking medications plays a significant role, placing pressure on the doctor to taper or stop the antipsychotic medication. I educate patients and their families that antipsychotics for patients with schizophrenia are “like insulin for the brain”. There is also evidence to suggest that recurrence of psychosis results in cognitive decline and reduction in gray matter volume. I do recommend Long Acting Injections (LAIs) to these individuals for the very same reason.

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The clinical effectiveness and cost effectiveness of lamotrigine in borderline personality disorder: A randomized placebo-controlled trial

Crawford MJ et al. Am J Psychiatry. 2018 August 1; 175(8)756-764. doi: 10.1176/aapi.ajp.2018.7091006. E pub 2018 Apr 6. PMID: 29621901

Background

Borderline Personality Disorder (BPD) has no FDA approved pharmacotherapies at this time. Despite this, patients with BPD are prescribed multiple medications with limited results. This disorder has a high degree of mood instability and hence mood stabilizers are tried. This study was conducted to evaluate the clinical and cost effectiveness of lamotrigine for patients with BPD.

Methods

This study from the United Kingdom was a multi-center double-blind randomized placebo-controlled trial (N=276) between July 2013-November 2016 which included subjects 18 years and older who met the diagnostic criteria for BPD. The participants were randomized 1:1 to receive placebo or lamotrigine up to 400 mg/day. The primary outcome was rating on the Zanarini rating scale for BPD (ZAN-BPD) at 52 weeks. Secondary outcomes included depression, social functioning, adverse events, health related quality of life and costs.

Results

A total of 195 patients (70.6%) were followed for 52 weeks. This included N=49 (36%) in the lamotrigine group and N=56 (52%) in the placebo group. The mean ZAN-BPD score was 11.3 in the lamotrigine group and 11.5 in the placebo group, revealing no significant differences between lamotrigine and placebo on the primary outcome measure. There was no difference between the two groups in any of the secondary outcome measures.

Conclusions

The results suggest that treating patients with BPD is neither clinically or cost effective.

Clinical Commentary

Affective instability is a key feature of BPD. Lamotrigine is commonly used for this problem in clinical practice as it is well tolerated and because of its use as a mood stabilizer in bipolar patients, with particular benefit against depressive episodes. This negative study provides evidence to the contrary. Lamotrigine is not effective for BPD. Psychotherapies remain the mainstay of treatment for BPD. In my opinion, the diagnosis of BPD should be discussed and the patient educated, which would hopefully prevent medication seeking behavior and result in long-term benefit.

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Impact of SSRI therapy on risk of conversion from mild cognitive impairment to Alzheimer’s Dementia in individuals with previous depression.

Bartels C et al. Am J Psychiatry. 2018 March;175(3): 232-241.doi: 10.1176/aapi.ajp.2017. 17040404. E pub 2017 Nov28. PMID 29179578

Background

The population is aging at a high rate and age is one of the risk factors for Alzheimer’s dementia. Depression in the older adult population is common and is also a risk factor for dementia. Research has shown that the selective serotonin reuptake inhibitor (SSRI) citalopram decreases amyloid-B generation and plaque load. This study evaluated the impact of SSRI treatment on CSF biomarkers and progression from mild cognitive impairment (MCI) to Alzheimer’s dementia.

Methods

This study included N=755 subjects from the longitudinal Alzheimer’s Disease Neuroimaging Initiative (ADNI) who were evaluated by Kaplan-Meier analysis of variance and covariance with ApoE4 status and age as covariate. CSF biomarkers were also available as part of the ADNI study. The subjects were divided into cognitively normal at baseline and those with MCI. They were followed every six months. The subjects were screened for past history of depression and medications were recorded including antidepressants. Initial division was made into two groups: one with no previous depression history (N=532) and the other with depression history (N=223). The 3 groups included those with no antidepressant treatment (N=60), those on SSRI therapy (N=116) and those on other antidepressants (N=47).

Results

In MCI patients with a history of depression, long-term SSRI treatment (>4 years) was significantly associated with delayed progression to Alzheimer’s dementia by approximately 3 years compared to those with short-term SSRI treatment, treatment with other antidepressants, or no treatment compared with MCI patients without a history of depression. No differences in CSF biomarker levels was observed between treatment groups.

Conclusions

Long-term SSRI treatment may delay progression from MCI to Alzheimer’s dementia.     

Clinical Commentary

Depression in older adults is a harbinger of dementia. Hence older adults should be screened for depression and be treated aggressively. The Geriatric Depression Scale (GDS) and the Patient Health Questionnaire -9 (PHQ-9) are user friendly scales to assess depression and can be easily incorporated into clinical practice. In addition, it should be noted that in this population, the treatment is long-term and comes with considerable benefits. Dementia can be delayed by the use of SSRI medications for treating depression. A three-year delay in cognitive decline can mean a lot for the quality of life of the individual and their family. In my opinion sertraline and citalopram would be preferred first starts based on tolerability and drug interaction profile. Paroxetine is avoidable due to anticholinergic activity which could impair cognition in older adults.

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Reduction of PTSD symptoms with pre-reactivation propranolol therapy: A randomized controlled trial.

Brunet A et al. Am J Psychiatry. 2018 May 1;175 (5): 427-433.doi: 10.1176/appi.ajp.2017. 17050481 E pub 2018 Jan 12 PMID:29325446

Background

PTSD is a chronic relapsing illness that is hard to treat.  The current treatments including exposure therapy and cognitive reprocessing therapy have only partial benefits. Therapies with substantial exposure component and reexperiencing of the traumatic event result in patients dropping out as well as decline in efficacy over time.  SSRI and other therapies also have limitations. In this study, the authors used propranolol as a memory reconsolidation blocker to reduce PTSD symptoms. Pharmacological impairment of memory reconsolidation is currently being developed for PTSD.

Methods

This Canadian double-blind randomized placebo-controlled study included 60 adults with longstanding PTSD. The patients were fluent in French or English. Propranolol or placebo was administered 90 minutes before a brief memory reactivation session, weekly for 6 weeks. The dosing was 0.67 mg/kg of short acting propranolol plus 1.0 mg/kg of long-acting propranolol. Systolic blood pressure < 100 mg Hg, basal heart rate <55  beats/minute and medical conditions such as asthma contraindicating use of propranolol were reasons for exclusion. Patients with current substance dependence including alcohol were also excluded.  Evaluation was done using the Clinician-Administered PTSD Scale (CAPS) and the patient-rated PTSD checklist-Specific (PCL-S)

Results

The participants in both groups were similar in terms of their social-demographic variables and CAPS scores. The participants who actively recalled the traumatic event under propranolol weekly for six weeks showed substantial decrease in symptoms ratings compared with placebo on both scales. The effects were also long lasting. The analyses were done intent-to-treat and per protocol pre-to post treatment effect sizes. The effect sizes were 2.74 and 2.63 in the propranolol group and 0.55 and 0.51 in the placebo group. In the intent to treat analyses the significance level was p= 0.034 using the CAPS scale and P <0.001 using the PCL-S scale. In the Per protocol analyses the significance level was p=0.037 using the CAPS scale and P< 0.001 for the PCL-S scale.

Conclusions

Pre-activation propranolol treatment appears to be a novel and efficacious treatment for PTSD. Replication studies of longer duration are required in various trauma populations.

Clinical Commentary

PTSD is a tough and rather recalcitrant disorder to treat with limited psychopharmacological options.   The use of propranolol pre-reactivation, which was well tolerated, as part of exposure therapy offers new hope to patients with PTSD as well as providers who treat these individuals.

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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]