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Issue 97, May 2020
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Schizophrenia and antipsychotic treatment: Physical morbidity and mortality based on a 20-year follow-up

Taipale H et al. World Psychiatry. 2020 Feb 19 (1), 61-68.doi:10.1002/wps.20699

PMID:31922669

Background

It is well established that antipsychotic drugs help treat and prevent relapse in patients with schizophrenia. It is also believed that there are risks of physical morbidity and mortality associated with the long-term use of these agents. This 20-year study aimed to assess the risk of hospitalization due to physical health problems and for severe physical morbidity. It also assessed the risk of all-cause mortality, including cardiovascular and suicidal death associated with antipsychotic use in patients with schizophrenia.

Methods

This was a Finnish study conducted with inpatients between 1972 and 2014 with up to 20-year follow-up (median:14.1 years). The use of antipsychotic drugs (i.e., use of any antipsychotic agent with non-use) and the use of specific antipsychotics were investigated, and outcomes were somatic and cardiovascular hospitalization, and all-cause, cardiovascular and suicide death. Hospitalization-based outcomes were analyzed by a within-individual design comparing use and non-use periods in the same individual. Adjusted hazard ratios were calculated.

Results

The cumulative mortality rates over 20 years were 46.2% for no antipsychotic use, 25.7% for any antipsychotic use, and 15.6% for clozapine useThe adjusted hazard ratios (aHR) for any somatic hospitalization and cardiovascular hospitalization were 1.00 and 1.00 during the use of antipsychotics compared to non-exposure periods within the same individual. The aHR was 0.48 for all-cause mortality, 0.62 for cardiovascular mortality, and 0.52 for suicide during use versus non-use of any antipsychotic. The most beneficial mortality outcome was for clozapine. The all-cause HR for clozapine was 0.39, cardiovascular was 0.55, and suicide mortality was 0.21.  

Conclusions

These data suggest that long-term antipsychotic use does not increase severe physical morbidity in patients with schizophrenia leading to hospitalization, and is associated with substantially decreased mortality, especially among patients treated with clozapine.

Clinical Commentary

Antipsychotic agents have been known to be associated with weight gain, metabolic syndrome, QTc prolongation, and sudden cardiac death. Many of these side-effects are linked to their pharmacological action. There is a lack of knowledge if these side-effects are associated with long-term physical morbidity and mortality.  There is also another alarming statistic that patients with schizophrenia have a shorter life span compared to the general population by an average of 14.5 years, and this gap has not changed over the last many years. Recent short-term studies suggest a 30%-50% reduction in mortality with antipsychotic use compared to non-use. This long-term cohort study was the first of its kind and had remarkable findings favoring the use of antipsychotics over a long period.

This study revealed no differences in both cardiac and non-cardiac hospitalizations during the use of antipsychotic drugs and non-use in the same patient. 

It is interesting to note that the long-term all-cause mortality was approximately 50% lower, cardiovascular mortality was 60% lower, and suicide mortality was 50% lower during the antipsychotic use versus non-use. The data for clozapine was even better in terms of mortality.  The long-acting injectable (LAI) fluphenazine was associated with the greatest reduction in risk.

Clozapine was associated with the lowest mortality. However, it should also be noted that clozapine is used after the failure of two or more drugs. Mortality may be higher in the earlier phase of the illness resulting in clozapine having a survival bias. Once a sensitivity analysis was conducted it resulted in clozapine being ranked 7th (a lot lower) in the order for mortality amongst 19 commonly used antipsychotics.

In summary:

In my opinion, antipsychotic treatment over an extended period does not increase medical or cardiac hospitalizations and lowers mortality in schizophrenia patients. This study makes a strong case for long-term antipsychotic treatment of schizophrenia. This study also suggests that clozapine should be used more often following the failure of two antipsychotics.

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The interplay between frailty and late-life depression: The implications!

Brown PJ et al. Am J Geriatr Psychiatry. 2020 Feb 28 (2): 145-154.doi: 10.1016/j.agp.2019.08.011

PMID:31519517

Background

Late-life depression is a complex and tough illness to treat. Frailty is characterized by a decrease in strength and energy, slowed motor performance, unintentional weight loss, and has a bidirectional relationship to late-life depression (LLD).   This study investigated the relationship between frailty characteristics and late-life depression.

Methods

Data was used from the evaluation of N=134 individuals with a depressive diagnosis. Depression, neuropsychological functioning, white matter hyperintense ties, and frailty were assessed. This included assessment of depression, neuropsychological functioning, white matter hyperintensity (WMH) burden via magnetic resonance imaging, and characteristics of frailty.

Results

In this study, 25 % of the sample had at least three or more characteristics on the Fried frailty burden. When using clinically meaningful scores for gait speed and physical activity levels the percentage increased to 45.5%.  Additionally, 62% of the sample exhibited gait slowing or weakness of grip. Greater frailty burden was associated with the greater Hamilton Rating Scale for Depression (HRSD) severity (p=0.02). Association was not detected with neuropsychological dysfunction or WMH.

Conclusions

This study suggests that frailty, specifically physical frailty, deficits in mobility and strength are highly comorbid with LLD. They are associated with greater depressive symptom severity, and do not appear to be associated with vascular depression subtype of LLD. There is a need for future research to examine the relationship between frailty and antidepressant treatment response. There is also a need to investigate whether there are age-related biological processes that result in the manifestation of the frail-depressed subtype of LLD.

Clinical Commentary

The frailty index is used to measure the health status of older adults. It also serves as a proxy measure for aging and vulnerability to poorer outcomes. The eight-core frailty indicators are fatigue, weight loss, low physical activity, decreased walking speed, poor balance, and visual and cognitive impairment. A possible limitation of this study is the overlap of symptoms of frailty and LLD (weight loss, low energy, and decreased physical activity). Despite the overlap, the objectively measured physical deficits in this study demonstrate that the frailty depression relationship is not the result of mere symptom overlap. Other limitations include recruitment from advertisement or local physician referrals.

It is also interesting to note that prior studies have found an association between frailty and neuropsychological functioning as well as WMH which were not found in this study suggesting there are inconsistencies.

It is interesting to note that three frailty characteristics namely weight loss, fatigue, and gait speed were associated with higher HRSD severity.

There is an association between frailty and increased morbidity and mortality. Additionally, LLD and frailty have a bidirectional relationship. The intersection of the two factors has been reported to double the mortality rate.

The clinically meaningful finding is the > 4-point difference on the HRSD between Non-frail and frail individuals.

Summary: In my professional opinion, these findings are extremely important considering the aging population. LLD depression is tough to treat. When examining an older adult with LLD, we should consider the frailty indicators especially significant weight loss, fatigue and reduced gait speed as a marker of a severe degree of depressive symptoms. This may affect prognosis. This is a tough condition to treat, and when a couple of medications trials fail, we need to consider electroconvulsive therapy (ECT) though currently no specific studies in this subgroup are reported. It is also important to look for psychotic symptoms and cognitive impairment as these symptoms can be comorbid and impact prognosis.

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Cyberbullying: Symptoms of early life trauma and psychiatric morbidity

Saltz SB. et al. J Clin Psychiatry. 2020 Jan; 81 (1): 8-14. doi: 10.4088/jcp.18m12170.

PMID:31944065

Background

Cyberbullying has received nationwide attention as there have been multiple adverse consequences including suicides. This study investigated the prevalence of cyberbullying amongst adolescent psychiatric inpatients, and related it to social media usage, the current level of symptoms, and histories of adverse early life experiences.

Methods

Data on the prevalence of social media utilization and cyberbullying victimization were collected from adolescent inpatients (N=50) aged 13-17 years from September 2016 to April 2017. The questionnaires used included the Trauma Symptom Checklist for Children and the Childhood Trauma Questionnaire.

Results

Twenty percent of the participants had been victimized by cyberbullying. Most participants were engaged with at least one form of social media daily or more frequently. Those who had been bullied had scored higher on symptoms of posttraumatic stress disorder (PTSD), depression, anger, and fantasy dissociation than those who were not bullied (all p values <0.05). Victims of cyberbullying endorsed significantly higher levels of lifetime emotional abuse on the Childhood Trauma Questionnaire than those who were not bullied (p=0.013). They did not report significantly higher levels of other trauma (physical or sexual abuse, emotional neglect, or physical neglect). The bullied subjects also had statistically significant elevations in hyper-response, PTSD, and depression scores (P<0.05).

Conclusions

Cyberbullying was associated with greater psychiatric symptom severity and was correlated with histories of emotional abuse. These data suggest that individuals with childhood trauma history were also vulnerable to continued adverse experiences during adolescence.

Clinical Commentary

This cross-sectional study suggests that cyberbullying is not uncommon in this population and increases psychiatric comorbidities and suffering. This study has limitations of a small sample size and a selection bias using inpatients from one institution. This study is also not prospective. It excluded early adolescents (12-year-olds) and late adolescents (17-19-year-olds). The majority of the sample was female. Ten inpatients reported cyberbullying in this sample which limits statistical analysis. It would also help to know to what extent cyber bullying contributed to the hospitalization. The strengths included the utilization of rating instruments for symptoms. Studies with a larger sample would be beneficial.

Cyberbullying is a modern-day problem affecting a significant group of individuals as they negotiate adolescence. Screening and addressing this issue may impact outcomes. These individuals would be key candidates for psychotherapy.

In summary:  We should be asking questions relating to cyberbullying during history taking in addition to bullying. It should be noted that those with emotional abuse (less resilient) may have greater susceptibility to cyberbullying. This group of individuals may be tougher to treat due to a diverse group of symptoms including PTSD, depression, and fantasy dissociation.

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Efficacy of gabapentin for alcohol withdrawal symptoms: A randomized clinical trial

Anton RF. et al.  JAMA Intern Med. 2020 March 9th. doi:10.1001/jamainternmed 2020.0249 [Epub ahead of print]

PMID 32150232

Background

Alcohol use disorder (AUD) is common and affects an estimated 30 million people. There is an unmet need for therapies to treat withdrawal symptoms. This study was designed to investigate the usefulness of gabapentin to treat alcohol withdrawal symptoms in those with AUD.

Methods

This is a double-blind randomized clinical trial (RCT) conducted between November 2014 and June 2018. Gabapentin was compared to placebo in community-recruited participants screened and treated in an academic outpatient setting over a16-week treatment period. One hundred and forty five individuals who met DSM-5 criteria for AUD were screened. Ninety-six subjects met the criteria for alcohol withdrawal and were randomized to treatment after three abstinent days. Daily drinking was recorded, and the percentage of disialo carbohydrate-deficient transferrin in the blood, a heavy drinking marker, was collected at baseline and monthly during treatment. The intervention included gabapentin up to 1200 mg/day orally, vs placebo along with nine medical management visits (20 minutes each).

Main outcomes: The percentage of individuals with no heavy drinking days and those with total abstinence were compared between the treatment groups and further evaluated based on pre-study alcohol withdrawal symptoms.

Results

Ninety out of 96 individuals were evaluable. 77% of the sample included males and 94% were white. 83% of the participants had heavy baseline drinking days (4 or more drinks per day for women and 5 or more for men). More gabapentin treated patients (27%) had no heavy drinking days compared with placebo (9%), a difference of 18 % (p=0.02). The number needed to treat (NNT) was 5.4. Total abstinence was 18% compared with placebo (4%), a difference of 13.8% (p=0.04; NNT 6.2). The pre-study alcohol withdrawal group had positive gabapentin effects on no heavy drinking days (p<0.02; NNT, 3.1) and total abstinence (p=0.003); NNT, 2.7) compared with placebo. There were no significant differences in the low alcohol withdrawal group. Dizziness was associated with gabapentin but this did not affect efficacy.

Conclusions

These data suggest that gabapentin may be efficacious in individuals with AUD and a history of alcohol withdrawal symptoms. Future studies should evaluate sleep changes and mood during early recovery as mediators of gabapentin efficacy.

Clinical Commentary

This study is an RCT adding to the evidence that gabapentin has efficacy in treating alcohol withdrawal. In the past, there was supportive data as well as negative data. Also, a meta-analysis has been weakly positive in the past. This study has a drop-out rate similar to other studies. Limitations include, the gabapentin group had a drop-out rate of 30% while the placebo group had a drop-out rate of 39%.  Perhaps adding other therapies like Alcoholics Anonymous (AA) may reduce the drop-out rate.  Using a self-report scale for alcohol withdrawal symptoms for entry into the trial might not capture the extent of the withdrawal state. Also, patients with high medical and psychiatric comorbidities were excluded as were those with a history of alcohol withdrawal seizures. Hence despite being a well-designed study, it may not be considered a practical clinical trial (PCT).

Despite these limitations, this study suggests that gabapentin can be used for alcohol withdrawal in clinical practice. It is also attractive being an anticonvulsant as it can potentially prevent alcohol withdrawal seizures (not studied specifically in that population) and is excreted through the kidney. Patients with AUD have alcohol-related liver disease. It is also relatively safe in overdose. 

Given the effect of gabapentin on GABA and glutamate systems, and the role of these systems in alcohol withdrawal supports the use of gabapentin. The gene regulating the voltage-sensitive calcium channel α2δ-1protein is thought to be upregulated by long-term alcohol use as well as withdrawal and is a site of action of gabapentin.

The efficacy is supported by an impressive NNT (5.4) in preventing relapse to heavy drinking and also for promoting abstinence NNT (7.2). In this trial, gabapentin appeared to be more efficacious in those with greater severity of withdrawal symptoms. In this sub-group, the NNT for preventing relapse was 3.1 and for abstinence was 2.7. These are impressive numbers. This study was also done in the outpatient setting which is notable.

In summary: In my opinion, there is  significant evidence to support gabapentin use for alcohol withdrawal. The fact that it is an anticonvulsant lacks addiction potential, and is excreted through the kidney makes it highly attractive. Most individuals with AUD have alcohol-related liver disease. This drug should not be used in those with kidney disease.

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Psychedelics: Clinical application in psychotherapy?

Reiff CM et al. Am J Psychiatry. 2020 Feb 26: appiajp201919010035. doi:10.1176/aapi.ajp.2019.19010035 [Epub ahead of print].

PMID 32098487

Background

There has been active interest and publicity regarding the use of psychedelic drugs in the treatment of psychiatric disorders. This article provides an evidence-based summary of the clinical application of psychedelic drugs to treat psychiatric disorders.

Methods

This study searched the commonly used databases such as PubMed and PsycINFO via Ovid for the English language literature of human studies published in the peer-reviewed journals. The time-frame was between January 1, 2007, and July 1, 2009. A total of 1603 articles were identified. Articles that did not identify the terms “clinical trial”, “therapy”, or “imaging” in the title abstract were excluded. The remaining 161 articles were reviewed by two or more authors. Finally, 14 articles reporting well designed clinical trials investigating the efficacy of lysergic acid diethylamide (LSD), 3,4 methylenedioxymethamphetamine (MDMA), psilocybin, and ayahuasca for the treatment of mood and anxiety disorders, trauma and stress-related disorders, and substance-related and addictive disorders as well as in end-of-life care.

Results

MDMA and psilocybin, which have been designated by the FDA as “breakthrough therapies” for posttraumatic stress disorder (PTSD) and treatment-resistant depression, had the most existing database. The research on LSD and ayahuasca is observational, but available evidence suggests these agents may have therapeutic effects in specific psychiatric disorders.

Conclusions

Randomized clinical trials (RCTs) support the efficacy of MDMA in the treatment of PTSD and psilocybin in the treatment of depression and cancer-related anxiety. The research is preliminary, but promising regarding the use of LSD and ayahuasca in the treatment of psychiatric disorders. Overall, the database is insufficient for FDA approval of any psychedelic compound for routine clinical use in psychiatric disorders at this time. Continued research in this area is warranted.

Clinical Commentary

The first hallucinogen synthesized was LSD (1938) by a Swiss chemist Albert Hoffman. LSD was being marketed as an adjunctive psychotherapy medication as early as 1947 by Sandoz. In 1960, the study of psilocybin began as an adjuvant agent for psychotherapy started by Harvard psychologist Timothy Leary. The concept is an old one but now the studies are better designed. All this investigation came to a halt after the Controlled Substances Act was passed in 1970. The past decade has seen a resurgence in the study of the potential benefits of psychedelic compounds. The DEA currently classifies these agents as Schedule I substances.

The psychedelics are currently classified into four classes based on their pharmacological profiles and chemical structures.

Classic psychedelics: Serotonin 2A (5-HT2A) receptor agonists (LSD, psilocybin, and ayahuasca) covered in this article

Empathogens or entactogens: mixed serotonin and dopamine reuptake inhibitors and releasers (MDMA).

Dissociative anesthetic agents: (N-methyl-D-aspartate [NMDA] antagonists e.g. ketamine

Atypical hallucinogens: affecting multiple neurotransmitter systems

Psilocybin: is derived from tryptamine precursors and found in a variety of mushroom species natively used in Central and South America to facilitate spiritual experiences. Psilocybin is metabolized to psilocin which inhibits the serotonin transporter. It also has binding affinities to multiple serotonin receptors (5-HT2A, 5-HT2C, 5-HT1A, and 5-HT1B). It has been investigated in the treatment of refractory mood disorders and obsessive-compulsive disorder, anxiety at end-of-life, and alcohol and tobacco use disorders. In the past RCT has shown positive effects in improvement of mood and even with a six-month follow-up. It has been studied with comorbid cancer-related anxiety using RCTs suggesting lasting efficacy. It was designated “breakthrough therapy” status by the FDA in 2018 for treatment-resistant depression. Multiple trials are ongoing at this time without enough data to support use in clinical practice currently. It can cause increased fear, anxiety, depression, and paranoia.

LSD: This is an ergot derivative that is known for its ability to induce powerful psychedelic and spiritual experiences. The effects of LSD are mediated via partial agonism at the 5-HT2A receptor, binding to the 5-HT2C, 5-HT1A, and 5-HT2 B receptors and binding at D2 receptors. It also causes glutamate release in the frontal cortex. LSD has been studied for pain syndromes, mood disorders, anxiety, and alcohol use disorder. This agent has been studied outside of the United States by Swiss and German researchers using RCTs. The results are less impressive than psilocybin. The evidence is currently limited and needs further study.

Ayahuasca: This is a decoction of two different plants in the amazon basin (Banisreriopsis caapi and Psychotria viridis). It is used for traditional practices by indigenous groups in the north-western Amazon region. The preparation simultaneously inhibits monoamine oxidase A (MAO-A), preventing degradation of a serotonin and a norepinephrine transporter. It also serves as an agonist of the 5-HT1A, 5-HT2A, 5-HT2C, and 5-HT2B. This agent is associated with auditory and visual hallucinations, altered spatial orientation, altered sensorium, and euphoria. This is agent is being studied outside the United States for antidepressant refractory depression. In small samples, it has been found to been shown to improve mood with impressive statistical significance (p<0.0005). The studies are limited by small samples, lack of standardization of the concoction administered, and lack of placebo.

MDMA: This agent has structural similarities to amphetamine and mescaline. Despite a lack of evidence, some psychotherapists began using MDMA to enhance the outcome of psychotherapy sessions. It was associated with feelings of emotional well-being and called “penicillin of the soul”. It subsequently became a street drug being illicitly produced and called “ecstasy”.

The effects are mediated by multiple mechanisms including monoamine release, serotonin, and norepinephrine transporter reuptake inhibition, monoamine oxidase inhibition, a partial agonist of the serotonin receptors (5-HT2A, 5-HT1A, and 5-HT2C receptors.). This agent has been studied in healthy volunteers as well as PTSD patients using RCTs for MDMA assisted psychotherapy. There were statistically significant changes in the MDMA treated group revealing a decline in symptoms (p=0.0005). The studies used and the Clinician-Administered PTSD Scale (CAPS) a gold standard for this disease state. The FDA has approved clinical trials in 2016 for PTSD. In 2017 MDMA also was given “breakthrough therapy” status by the FDA.

In Summary:  The psychedelic drugs are in various stages of investigation currently. The number of sites doing research is limited by these drugs being classified as Schedule I. These agents are currently not ready for prime time. They need further study, and if approved by the FDA may come under the Risk Evaluation and Mitigation Strategy (REMS). With the FDA approval of intranasal esketamine for depression and the off-label use of intravenous ketamine infusions this group of agents may offer hope in the future to relieve the suffering of our patients.

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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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