Meta-Analysis Conundrums

For patients whose psychosis doesn’t adequately respond to antipsychotics, especially clozapine, treatment options include electroconvulsive therapy, cognitive-behavior therapy, and augmentation with another medication. Investigators have done cotreatment trials with other antipsychotics, anticonvulsant/mood stabilizers, and even the antibiotic minocycline and anti-inflammatory agents such as aspirin. The trials are small in many cases, so meta-analyses allow various trials to be pooled. Two recent publications give some new guidance but also may sow confusion.

One team examined clinical trials of the anticonvulsants lamotrigine, topirimate and valproate added to clozapine. They included 22 randomized controlled trials (RCTs) comprising 1227 subjects; 613 received clozapine alone, whereas the others received, in order of frequency, valproate, lamotrigine or topirimate. The primary outcome was change in Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) total score. The analysis showed no significant effect for lamotrigine, confirming a previous meta-analysis, but also confirming a prior analysis, topirimate was superior to clozapine alone for reduction in total, positive and negative psychotic symptoms ratings. Sodium valproate, but not magnesium valproate, was superior to clozapine alone in reducing total and positive psychotic symptom scores; it was not effective for negative symptoms. In terms of tolerability, topirimate but not valproate had a significant all-cause discontinuation rate compared to clozapine monotherapy.

One of the limitations of this pooled data set was that many of the patients were not clearly designated as having clozapine resistance; for instance, clozapine serum levels were not recorded. Another concern was that all the trials for valproate augmentation were done in China, and the generalizability to other settings and ethnic groups is uncertain.

The anticonvulsant meta-analysis is one of many that has examined antipsychotic augmentation, which prompted a group led by Christoph Correll to do a meta-meta-analysis. Summarizing this article will not do it justice, so I recommend reading it in its entirety. The investigators looked at 29 existing meta-analyses of trials of augmentation of any antipsychotic with any of 42 medications including, mood stabilizers, anticonvulsants, antidepressants, minocycline, a second antipsychotic, or various hormones such as estrogenic agents. They applied a novel method to assess the quality of the meta-analyses, AMSTAR-Plus Content. Five of the meta-analyses looked at augmentation of clozapine.

In combination with clozapine for positive symptoms of psychosis, only glycine, an amino acid which modulates the NMDA glutamate receptor, had a significant effect size. No treatments showed efficacy in combination with clozapine for total psychopathology or negative symptom scores. In combination with non-clozapine antipsychotics, lamotrigine, estrogenic agents, mirtazapine and a few others showed efficacy.

An important finding is buried in the discussion: “When all this metanalytic literature was compared regarding the quality of its meta-analyzed content, the effect sizes were inversely correlated with the study quality, reducing confidence in these affirmative recommendations.” In other words, many of the studies in this uber-study were small or contained biases, and those studies tended to overrate the effects of the adjunctive treatments. They point out that individual patients may benefit from specific interventions, but the evidence to guide treatment selection is lacking. This leaves the clinician without clear direction for the most difficult-to-treat patients. In an accompanying editorial, however, Wolfgang Fleishhacker suggests that this meta-analysis does not necessarily invalidate all preceding analyses.

References

Zheng W, Xiang YT, Yang XH, Xiang YQ, de Leon J. Clozapine Augmentation with Antiepileptic Drugs for Treatment-Resistant Schizophrenia: A Meta-Analysis of Randomized Controlled Trials. J Clin Psychiatry. 2017;78(5):e498-e505. Abstract

Correll CU, Rubio JM, Inczedy-Farkas G, Birnbaum ML, Kane JM, Leucht S. Efficacy of 42 Pharmacologic Cotreatment Strategies Added to Antipsychotic Monotherapy in Schizophrenia: Systematic Overview and Quality Appraisal of the Meta-Analytic Evidence. JAMA Psychiatry. 2017;74(7):675-684. Astract

The B.C. Mental Health Act Protects My Daughter

The author of the original article, Susan Inman, wrote this piece for the Huffington Post from personal experience. Susan’s daughter has suffered from schizophrenia for the past 16 years, and Susan has seen first hand how involuntary hospitalization and medication have helped her daughter have years of stability.

Susan discusses how provisions in B.C’s Mental Health Act which protect people with severe mental illnesses are currently under attack. This came when a challenge was filed with B.C’s Supreme Court which states both inpatient and outpatient involuntary treatment are violations of people’s human rights. The challenge does not deal with involuntary hospitalisations, rather it proposes changes that would mean people can avoid involuntary treatment no matter how ill they are. Two of the plaintiffs themselves have received involuntary treatment.

Some may feel that the most morally responsible position is to allow people to choose whether they want to be treated, but Susan highlights how this ignores some vital information about psychotic orders. In psychosis, a person loses the ability to differentiate between what is real and what isn’t. Even as some of its symptoms begin to subside, people can be left with anosognosia, a brain-based inability to understand that they are or have been ill.

As Susan argues, mental illness policy changes can be dangerous when they ignore the impact of the most severe mental disorders, such as suicide, aggression or neglect of one’s most basic personal needs. In their challenge, the plaintiffs fail to address the consequences of the changes they propose on people with profound or life-threatening illness. Any policy changes of this nature must be looked at in depth, looking not only at the change itself but also the consequences that will follow.

Let us know your thoughts on the proposed changes to B.C’s Mental Health Act, join the discussion on our twitter page. Click here to read the full article.

This article previously appeared in Huffington Post Canada.  

Evidence for accelerated aging in severe mental illness

A panel of five investigators discussed an emerging concept in psychiatry which integrates findings in epidemiology, pathophysiology  and cell biology. Dilip V. Jeste, Distinguished Professor of Psychiatry and Neurosciences at the University of California at San Diego, described “inflammaging” as the low-level inflammatory tissue derangement that accompanies aging and which seems to be accelerated in people with chronic mental illness, whether major mood disorders or schizophrenia. Inflammaging can be measured by biomarkers such as C-reactive protein (CRP), tumor necrosis factor-alpha, F2-isoprostanes, chemokines, and leukocyte telomere length. The latter, which refers to the tips of chromosomes which slowly shorten over the lifespan, is a well-recognized measure of cellular senescence.

Although psychiatrists seldom examine these biomarkers in their patients, they know that on a population basis, people with schizophrenia have a high prevalence of metabolic disorder, diabetes, and atherosclerotic vascular disease. Compared to age-matched controls, people with schizophrenia and bipolar disorder have a high rate of morbidity and mortality from these disorders, which are partially inflammatory in nature and age-related.

Dr. Jeste and his research team have studied 140 patients with schizophrenia, ages 26-65 with a mean age of 49, half women, and they confirmed the higher prevalence of metabolic and vascular disorders in this cohort. Moreover, in comparison to a group of 120 non-mentally-ill age-matched subjects, they found elevations in six inflammation-related biomarkers including CRP and the chemokine eotaxin-1. In patients and control subjects, telomere length inversely correlated with age, but only in women with schizophrenia was telomere length significantly reduced compared to controls. According to Dr. Jeste, younger women seemed most at risk for metabolic disturbances: they had the highest rates of obesity, insulin resistance, and elevated inflammatory markers. The researchers will follow the cohort longitudinally to observe what they hypothesize is an accelerated aging process.

References

Jeste DV, Wolkowitz O, Harvey P, Eyler L, Nasrallah H. Accelerated biological aging in serious mental illness: are these disorders of the whole body and not of the brain only? American Psychiatric Association Annual Meeting, San Diego, California, May 20-24, 2017.

Hong S, Lee EE, Martin AS, et al. Abnormalities in chemokine levels in schizophrenia and their clinical correlates. Schizophr Res. 2017;181:63-69. Abstract

American Psychiatric Association 2017 Annual Meeting

American Psychiatric Association 2017

Dr Randall White was presenting a research poster at the American Psychiatric Association 2017 Annual Meeting in San Diego, CA.

Session: New Research Posters 1
Date: Monday, May 22
Time: 10:00 AM–12:00 PM
Poster Number: P5-020
Poster Hall: Exhibit Hall A, Ground Level, San Diego Convention Center

Dr White discussing the BCPP findings with Dr. John Kane, who did the first controlled trial of clozapine in North America.

ABSTRACT

Although clozapine is the standard for treatment-resistant psychosis, 40-60% of those treated with clozapine do not have an adequate response as measured by a 20% or greater reduction in the BPRS, PANSS or other assessments. This condition is known as clozapine resistance, ultra-resistance or refractory psychosis. At the publicly funded BC Psychosis Program, at UBC Hospital in Vancouver, Canada, we have developed criteria to identify clozapine resistance (CR) and an algorithmic approach to treatment based on available evidence. This involves assuring adequate clozapine treatment verified by dose and serum level, including addition of fluvoxamine when appropriate; offering ECT to CR patients, and/or antipsychotic augmentation preferably with sulpiride or aripiprazole. All patients admitted since program inception in February 2012 had failed at least 2 antipsychotic trials. A psychiatrist, social worker, pharmacist, nurse, general physician, and neuropsychologist evaluated each patient. All available summaries of previous psychiatric admissions were reviewed, and medical, pharmacological, social and behavioural histories were recorded.

All information is presented at a case conference and a DSM-IV or -5 multiaxial diagnosis reflects agreement among at least 2 psychiatrists and a psychologist. Symptom ratings included the Positive and Negative Syndrome Scale (PANSS), the Global Assessment of Psychopathology (GAPS), and the Clinical Global Impression-Severity and Improvement scales (CGI). Clozapine resistance is defined by an adequate trial, that is, at least 500 mg daily dose for ≥60 days; and continued symptoms manifested by PANSS with 2 positive scale items rated ≥ 4 (moderate) OR 1 item ≥ 6 (severe).

Of 114 patients with schizoaffective disorder or schizophrenia on clozapine at admission, 89 had received it for≥ 60 days; 23 were on at least 500 mg; and 20 met criteria for clozapine resistance (i.e., 17 men and 3 women). Of these, 17 had schizophrenia and 3 schizoaffective disorder; the mean age was 39.6 years. The mean PANSS scores at admission were Positive=28.3, Negative=26.2, General=50.0, Total=104.4; the mean CGI-S was 6.3. Of 16 patients with complete data, 8 were offered ECT and 3 accepted a course; the number of ECT treatments ranged 19-46. Of 19 patients discharged to date, 17 remained on clozapine with a mean dose of 463.2 mg; to obtain a therapeutic clozapine level, 6 received fluvoxamine, dose range 37.5-200 mg. Seven patients received adjunctive antipsychotics: 3 sulpiride, 2 aripiprazole, 4 first-generation agents. At discharge, the mean PANSS were Positive=20.8, Negative=22.1, General=40.0, Total=82.9; the mean CGI-S was 5.1.

Find full info on the American Psychiatric Association 2017 Annual Meeting here! 

Long-term benzodiazepine use is associated with increased mortality in people with schizophrenia

What I did before

When psychiatric patients are treated in an emergency department, they are often hypervigilant, manic, or otherwise in an excited, agitated state. The current standard of care to manage acute agitation in adults is using an antipsychotic medication and a benzodiazepine, often loxapine or haloperidol and lorazepam. For patients who have schizophrenia, antipsychotic medication alone often treats such symptoms in the longer term, yet many patients are discharged with a benzodiazepine prescription continue long-term benzodiazepine use possibly because the community clinician hopes to avoid triggering a relapse in discontinuing the medication. As a psychiatrist who has worked on acute and tertiary inpatient units, I have discharged patients on benzodiazepines with the expectation it would eventually be discontinued, but I have also seen many patients for whom it never was.

What changed my practice

Then, in 2013 while at the 7th Annual Pacific Psychopharmacology Conference, I was introduced to research showing that people with schizophrenia on chronic benzodiazepine therapy have an increased risk for suicide and all-cause mortality. I kept these observations in the back of my mind and was further alarmed in 2016 when another article from the same researchers found high-dose benzodiazepine use, but not lesser doses, was associated with increased suicide and cardiovascular mortality.

What I do now

Based upon these studies, I find the evidence compelling that benzodiazepines are contraindicated for long-term use in people with schizophrenia. When appropriate, I continue to use lorazepam for acute agitation amongst other reasons, I also educate patients about the risk of long-term use, including dependence and cognitive impairment in addition to mortality.To raise awareness of this issue among my colleagues, I mention the rationale and include recommendations for tapering benzodiazepines in consultation reports and discharge summaries.

Find the full article here!

Raloxifene as adjunctive treatment for chronic psychosis

Psychosis and mood symptoms are sometimes exacerbated  during times of hormonal flux in women such as postpartum and during menopause. Research from Australia has suggested that estradiol may ameliorate psychosis in women with schizoaffective disorder or schizophrenia. The same Australian team has recently published a randomized controlled trial of raloxifene in postmenopausal women with those diagnoses; raloxifene is an estrogen receptor modulator that may be safer than estradiol as it is less likely to provoke hormone-influenced cancers. However, it does entail an increased risk of thromboembolism.

The 56 subjects had a mean age of 53 years and a mean illness duration of 24 years, all were on antipsychotic therapy, and none was deemed at baseline to have elevated risk for thrombotic disease or evidence of reproductive cancers. They were randomly assigned to receive 120 mg of raloxifene or placebo for 12 weeks as cotreatment with their psychiatric medications; 8 patients were taking clozapine, 5 in the active treatment group. The primary outcome measure was the Positive and Negative Syndrome Scale (PANSS); the investigators also monitored depression, movement disorder, cognitive function, and safety measures.

At the end of 12 weeks, the women receiving raloxifene had a significant reduction in the PANSS total and general scores, whether the diagnosis was schizophrenia or schizoaffective disorder; the PANSS positive and negative symptom subscales showed no significant improvement with raloxifene. Significantly more subjects who received raloxifene had a clinical response defined as a 20% reduction in PANSS total score (P = 0.01).  Measures of depression and cognition did not show any difference between the groups and adverse events were minimal; no thromboembolic events occurred in either group.

Raloxifene may help prevent osteoporosis and breast cancer, so it confers benefits beyond ameliorating symptoms of chronic psychosis. It has also been trialed in men cotreated with risperidone during an 8-week study in Iran; compared with placebo, the active treatment resulted in improvement in the PANSS total score and the negative and general subscale scores (2). Adverse effects did not occur more often with raloxifene, although the researchers admit that with longer-term treatment, gynecomastia and infertility would be possible which would greatly limit its utility in men.

References

1.Effect of adjunctive raloxifene therapy on severity of refractory schizophrenia in women: a randomized clinical trial. Kulkarni J, Gavrilidis E, Gwini SM, et al. JAMA Psychiatry. 2016;73(9):947-354. Abstract

2.Khodaie-Ardakani MR, Khosravi M, Zarinfard R, et al. A placebo-controlled study of raloxifene added to risperidone in men with chronic schizophrenia. Acta Med Iran. 2015;53(6):337-345. Full text

 

Twenty percent of schizophrenia may be treatment-resistant from onset

About 30% of people with schizophrenia do not have adequate response to antipsychotic medications other than clozapine. Treatment-resistant psychosis has no well-established predictors although early-onset psychosis and prolonged duration of untreated psychosis may be risk factors. The Genetics and Psychosis study based in South London, UK, enrolled 283 patients with schizophrenia-spectrum disorders in their first episode who underwent assessments including the Positive and Negative Syndrome Scale, Global Assessment of Functioning, and the Weschler Adult Intelligence Scale. The cohort had follow-up investigations 5 years after first assessment by means of the WHO Life Chart Schedule, intended for documenting the longitudinal course of schizophrenia.

Patients were determined to have treatment-resistant schizophrenia (TRS) if they were either treated with clozapine or failed to respond to 2 consecutive, adequate trials of non-clozapine antipsychotics. Remission of psychosis was defined as absence of overt psychotic symptoms for 6 months or more. The investigators classified the TRS as either early-onset or late-onset. Early onset TRS occurred when no remission occurred at any time whereas late-onset occurred when resistance developed after an interval of remission.

Of the original cohort, 246 or 87% had follow-up data. Four patients had died, and their mean age was significantly older than the cohort as a whole. In 33.7%, TRS had developed and their only distinguishing characteristic was a younger age of contact for treatment of psychosis: 25.2 years versus 27.9 years in the non-TRS group. Family history of psychosis, use of alcohol or cannabis, cognitive performance, and duration of untreated psychosis (DUP) did not differ between TRS and non-TRS groups. Those patients who were younger than 20 years at the time of first contact had an odds ratio of 2.49 for developing TRS, and men and Black people were also more likely to have TRS at follow-up.

About 70% of TRS patients had early-onset treatment resistance. Compared to the non-TRS group, those with early-onset TRS had a higher mean total PANSS score at baseline; 74% were male compared to 46% in the late-TRS group.

In the TRS cohort, about half the patients received clozapine, and they had on average a greater burden of total psychopathology and negative symptoms compared to the TRS patients who never received clozapine. The clozapine patients were also more likely to reside with family or friends.

According to the investigators, this is the largest first-episode cohort followed for onset of treatment resistance. They estimate that 23% of their patients had resistance to antipsychotic therapy from the onset of illness, and given the mean DUP of 4.5 weeks, which is quite brief, factors other than delayed treatment seem to be at play. If this study is generalizable, only a third of treatment resistance develops after the  onset of illness, and understanding that process could lead to prevention strategies. Furthermore, availability of biomarkers for TRS in early psychosis populations might help determine which patients would benefit from receiving clozapine immediately.

Lally J et al. Psychol Med. 2016;46(15):3231-3240. Abstract

Partnership: People with schizophrenia, family members and clinicians talk about schizophrenia

Schizophrenia is a long-term but treatable brain condition. 1 in 100 people worldwide live with schizophrenia.

Dr. Diane Fredrickson is a psychiatrist who treats psychosis-related conditions including schizophrenia.

Gerhart Pahl is the father of four sons—three of whom it turns out suffer from schizophrenia.

Bryn Ditmars has a form of schizophrenia known as schizoaffective disorder.

Schizophrenia occurs most commonly between people between the ages of 15-25. It is the result of physical and biochemical changes in the brain. Symptoms may include:

  • Disordered thinking
  • Changes in emotion
  • Bizarre behaviour
  • Catatonia
  • Paranoia
  • Hallucinations
  • Delusions

60% of people with schizophrenia live with their families. Recovery takes time, a team, medication, and a healthy lifestyle.

Research has improved with brain imagery, but a cause and cure are still unknown.

Statistics about schizophrenia and suicide:

  • 50% attempt suicide.
  • 10-15% of people commit suicide.
  • Self-harm is more common than harm to others.

50% of people with schizophrenia have anosognosis, a condition in which they don’t know they’re ill. Early psychosis intervention (EPI), early diagnosis and treatment improve outcomes.

Stigma contributes to discrimination, which limits access to education, housing and employment. The media contribute to perpetuating myths that create skewed perceptions and unfounded fears.

The B.C. Schizophrenia Society (BCSS) Partnership Program provides mental health literacy. To increase your knowledge, book a presentation.
Call 604-270-7841
Toll Free: 1-888-888-0029
Email: community@bcss.org

Dr. Xavier Amador Talk on Helping People with Mental Illness at Cambridge, MA

Dr. Xavier Amador
President and Founder
The LEAP Instititute
(Listen, Empathize, Agree, Partner)

Dr. Amador lays out pathways to build trust, heal relationships and partner with someone who is suffering from mental illness but is resisting help.

“I’m going to tell you a little bit about something that is very important to me from a professional perspective… but is also very personal. I have a brother with schizophrenia who really is the one who gave me the title for this talk and book by the same name: I’m not sick. I don’t need help.

“This is a very very common problem. I will talk about just how common it is”


Dr. Xavier Amador, founder of The LEAP Institute giving a public talk on how to help people with mental illness who don’t realize they are sick. Sponsored by the NAMI (National Alliance on Mental Illness) Cambridge Chapter. The lecture was given on the evening of October 2, 2012 at the Cambridge Public Library in Cambridge, Massachusetts.

For more information, visit leapinstitute.org.

Anosognosia

Anosognosia

“I think that’s exactly what he had. I believe that my son Chris, over the course of repeated breakdowns, lost his capacity to understand his illness so he went off his meds. That’s when we lost him for good. He never took meds again. He ultimately chose to take his life rather than take medication.” — Cathy Weaver, Austin, Texas

People with anosognosia have a real neurological condition caused by damage to the brain, most likely in the frontal and parietal lobes.

Because of this condition, they can’t recognize that they are sick.

Anosognosia is associated with many diseases.

Some people with strokes, brain tumours, Alzheimer’s disease, and Huntington’s disease suffer from this same lack of insight.

It’s very clear that about half the people with schizophrenia and roughly 40% of people with bipolar disorder have some degree of anosognosia. In other words, they don’t recognize their own illness. We recognize this for Alzheimer’s disease but we seem to have trouble recognizing that this is also common for people with schizophrenia and bipolar disorder.

Russell Weston is one tragic example. Mr. Weston came to Washington D.C. to “save the world from cannibals” and killed two Capitol Police officers while in this delusional state.

Weston was not taking medication because he did not believe he was sick.

County judge, Polly Jackson Spencer developed the first-of-its-kind outpatient commitment program in Texas. She saw the devastation caused when the severely mentally ill are too sick to seek treatment and end up trapped in a revolving door of incarceration, homelessness, hospitalization and victimization.

“You can’t simply tell someone who has a mental illness and is disorganized in their thinking, ‘Hey, you’ve got a doctor’s appointment in three weeks and it’s ten miles from here, these are the different buses you need to take to get there, and don’t forget to go’ and assume that they’re going to make that. That’s just not going to happen.” —Polly Jackson Spencer, County Judge

Judge Oscar Kazen supervises the day-to-day operations of Bexar County’s court-ordered outpatient treatment program. He meets regularly with patients, psychiatrists, and staff.

“When I sit in that little courtroom, down in the basement of that abandoned hospital, the guy who sits at the end of the chair—that mentally ill patient—didn’t have a choice. He didn’t wake up one morning and say ‘I want to lose my life, I want to lose my sanity.’ These people had no choice in the matter and it’s our responsibility to bring them back to sanity.” — Oscar Kazen, Judge

Anosognosia is the number one reason why people fail to seek treatment.

It’s up to the rest of us to make sure that they are able to get treatment.

Learn more about anosognosia at treatmentadvocacycenter.org

Video by the Treatment Advocacy Center.