What Happens to First-Episode Patients After 5 Years?

Following a first episode of psychosis, patients always want to know when they can stop taking medication. Adverse effect such as weight gain or sedation may play a role, but the need to take a daily pill or receive an injection may be inconvenient or stigmatizing no matter the side effects. Existing evidence suggests a high risk of relapse during the first 5 years if medication is discontinued, up to a 5-fold compared to continuous medication treatment, although longer-term outcomes remain uncertain. Two new studies provide further evidence about outcomes longer than 5 years.

In 2003, Drs. Eric Chen, Bill Honer and collaborators in Hong Kong initiated a randomized trial with 178 first-episode patients in several clinics. To be eligible, patients had to be free of positive symptoms during at least 12 months on medication; the mean was 21.9 months. They then received either quetiapine 400 mg daily or placebo for a year or until relapse. Following the RCT, the patients returned to the community for usual clinical care.

Ten years later, the research team followed up the 178 patients; they performed a chart review on all and interviewed 142 of them. A poor outcome was defined as death by suicide, need for clozapine treatment, or persistent positive symptoms measured by the Positive and Negative Syndrome Scale (PANSS). Of 138 patients with adequate follow-up data, 110 were taking antipsychotic medication; the mean dose was 355 chlorpromazine equivalents.

Of those subjects assigned to a year of quetiapine treatment in the RCT 10 years before follow-up, 21% had a poor outcome; of those assigned to placebo in the RCT, 39% had a poor outcome. The relative risk was 1.84 (P = 0.012). Six patients died by suicide and 11 required clozapine; the incidence of these outcomes individually did not significantly differ between the groups. The investigators also found that among subjects originally assigned to medication discontinuation, i.e. placebo, relapse of psychosis during the first 2-3 years of diagnosis seemed to mediate the elevated risk of poor outcomes.

In Finland, Dr. Jari Tiihonen and his group performed a 20-year follow up on all persons hospitalized for schizophrenia for the first time during 1972–2014. Given that everyone in Finland has health and pharmacy services recorded in a national data registry, it was possible to determine who was readmitted to hospital and who filled prescriptions for antipsychotics. Based on this data, the researchers looked at whether subjects were taking medication or had been rehospitalized at various time points and then classified them as either antipsychotic users or nonusers. I suggest readers go to the original article to gain a full understanding of the methods.

Treatment failure was defined as rehospitalization or death. The table below shows the interesting finding that patients who continued antipsychotic treatment throughout the follow-up period had the lowest risk of relapse or death, but those risks rose as a function of the duration of treatment preceding discontinuation. In other words, stopping medication after several years of stability may be more associated with poor outcome than stopping it very soon after the first episode. However, compared to those who were treated continuously, the groups that discontinued treatment at any interval had a higher rate of poor outcome.

Adjusted Hazard Ratio chart

FIGURE: Adjusted hazard ratios as a function of duration of antipsychotic use prior to discontinuation.

The number of deaths was relatively small, but available data allowed the calculation of hazard ratios in 3 matched groups: those who discontinued antipsychotic treatment within the first year, those who remained on antipsychotics throughout, and those who did not use antipsychotics.  In 3057 subjects, 91 deaths occurred; compared with continuous antipsychotic users, nonusers had a 214% higher risk of death (hazard ratio, 3.14; 95% CI, 1.29–7.68), and those who discontinued within a year had a 174% higher risk of death (hazard ratio, 2.74; 95% CI,1.09–6.89).

These studies have important limitations, given their retrospective nature and the lack of details about important outcomes related to function and comorbidities. Nonetheless, they bring new understandings to the role of antipsychotic therapy after the first few years of psychotic illness: patients who go untreated have a higher risk of remaining psychotic and of dying. But the finding that discontinuation after 5 or more years of antipsychotic therapy is highly associated with relapse suggests that stopping medication in chronic patients is risky.


Hui CLM, Honer WG, Lee EHM, Chang WC, et al. Long-term effects of discontinuation from antipsychotic maintenance following first-episode schizophrenia and related disorders: a 10 year follow-up of a randomised, double-blind trial. Lancet Psychiatry. 2018;5(5):432-442.

Tiihonen J, Tanskanen A, Taipale H. 20-Year nationwide follow-up study on discontinuation of antipsychotic treatment in first-episode schizophrenia. Am J Psychiatry. Published online Apr 6, 2018:

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.


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.  

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.


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! 

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.


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


Benzodiazepines may increase the risk of death in people with schizophrenia

Patients with psychosis often accumulate medications during hospitalizations and changes in prescribers. The use of multiple medications, often with uncertain benefit, is called polypharmacy. The use of more than one antipsychotic is considered problematic and may increase the risk of adverse effects such as weight gain and diabetes, but other kinds of psychiatric medications often accumulate as well, including antidepressants and benzodiazepines. The latter are used for a variety of reasons, often for acute agitation in an emergency setting, but also for insomnia or chronic anxiety. They may be associated with tolerance, escalating dosage and dependence, although overall are considered safe medications.

Population-based studies from Finland and Denmark have revealed that patients with schizophrenia, however, may be at elevated risk for death when treated with a benzodiazepine.  Now the same has been found in a US cohort. Researchers from Ohio State University examined outpatients covered by US Medicaid, age 18 to 58 years old, who had received a diagnosis of schizophrenia during 2007 to 2009. They looked at prescription claims for benzodiazepines, antipsychotics, antidepressants and mood stabilizers from time of diagnosis through 2013. They then examined death certificate files for deaths among the 18,953 identified subjects and calculated hazard ratios for all-cause mortality, death from suicide and accidental poisoning, and death by natural causes.

Of 18,953 patients with schizophrenia, 3,476 received a benzodiazepine, and those subjects were more often Caucasian females who were separated or divorced. The top 3 benzodiazepines prescribed were, in order, lorazepam, clonazepam and alprazolam. In patients taking an antipsychotic, in comparison with those who had no added benzodiazepine, the adjusted hazard ratio after initiating a benzodiazepine was 1.48, i.e. a 48% increased risk of death during the time of cotreatment. For patients who received only a benzodiazepine and no antipsychotic or other medication, the adjusted hazard ratio was 3.08. The calculated mortality rate per 1000 person-years was significantly elevated in every examined combination of medications, e.g. for a mood stabilizer alone, or for an antidepressant plus an antipsychotic, when a benzodiazepine was added. Furthermore, the risks of death from suicide, accidental poisoning and natural causes were all elevated.

The investigators caution that this is an association, and that benzodiazepines cannot yet be implicated as a definite cause of premature mortality in people with schizophrenia. However, this evidence adds to existing epidemiologic findings to make the risk-benefit ratio of benzodiazepine prescription less favorable. The possible mechanisms behind the risk could be multiple, and the researchers mention lower mood and impulsiveness which may occur during benzodiazepine use along with withdrawal-related anxiety as factors that could elevate risk of suicide. As for natural causes, some evidence exists for heightened incidence of infectious diseases concomitant with benzodiazepine use. Prospective studies and larger epidemiologic investigations are required to understand this association, but prescribers should always keep in mind the maxim “do no harm” and attempt to eliminate unnecessary medications.


Fontanella CA, Campo JV, Phillips GS, Hiance-Steelesmith DL, Sweeney HA, Tam K, Lehrer D, Klein R, Hurst M. Benzodiazepine use and risk of mortality among patients with schizophrenia: a retrospective longitudinal study. J Clin Psychiatry. 2016;77(5):661-667. Abstract

Topirimate as augmentation for antipsychotic treatment

With modulating dopamine as the primary pharmacotherapeutic option to treat schizophrenia, we are left unable to adequately treat at least 30% of our patients, Dr. Christoph Correll told the audience at the 2016 Pacific Psychopharmacology Conference in Vancouver. The evidence for combining dopamine antagonists, whether first- or second-generation antipsychotics, is not favorable according to a meta-analysis he described which is in review for publication. When only high-quality studies were included, which involved 14 trials with 938 subjects, the evidence for combining antipsychotics melted to nothing. Although it makes sense that using two medications with the essentially the same mechanism of action would not be synergistic, many practitioners nevertheless do just that.

Dr. Christoph Correll at the 2016 Pacific Psychopharmacology Conference

Dr. Christoph Correll at the 2016 Pacific Psychopharmacology Conference

Dr. Correll, who is Professor of Psychiatry at Hofstra Northwell School of Medicine and Medical Director of the Recognition and Prevention Program at the Zucker Hillside Hospital in Queens, New York, said that adding agents with a different mechanism of action may be more promising. Topirimate acts to inhibit activity in the glutamate-NMDA receptor complex and is approved as an anticonvulsant. It also counters the weight gain of psychotropic medications by reducing appetite and enhancing insulin sensitivity. He and six coauthors have recently published a meta-analysis of 16 randomized, controlled trials including a total of 934 patients who received topirimate adjunctive to antipsychotic therapy; outcome data included PANSS or BPRS total scores and body weight, and secondary outcomes included positive and negative symptoms and various metabolic measures including waist circumference and serum glucose.

The benefit for augmentation was significant as measured by total PANSS or BPRS for the entire group, and sensitivity analyses showed it held true with a dose of 150 mg per day or less, in first and multi-episode patients, and either with clozapine or non-clozapine antipsychotics. The effect was independently significant for positive and for negative symptoms. Topirimate was associated with a significant reduction in weight with a mean reduction of 2.75 kg; other metabolic measures were unchanged except for significant reduction in serum triglycerides and fasting insulin. Although discontinuation for adverse effects or inefficacy did not differ with topirimate or placebo, notable adverse effects of topirimate included concentration problems and paresthesias.

These studies were all short-term with a mean duration of 11.8 weeks, a problem with many clinical trials in psychiatry  given that schizophrenia is a chronic disorder and patients remain on  medication for months to years. Cognitive problems including word-finding difficulty are a known effect of topirimate, and in an illness in which cognitive impairment is inherent, this could be a major liability. Longer-term effects on cognition, metabolic outcomes and psychosis are needed. Will topirimate be the NMDA-modulating treatment that makes a difference or end up like lamotrigine, abandoned after a brief dalliance?


Zheng W, Xiang Y-T, Xiang Y-Q, Li X-B, Ungvari GS, Chiu HFK, Correll CU. Efficacy and safety of adjunctive topiramate for schizophrenia: a meta-analysis of randomized controlled trials. Acta Psychiatr Scand. 2016:1–14. Published online 1 Sep 2016. Abstract

Schizophrenia is not a progressive brain disease

DSC_0072 1 (2)Despite Emil Kraepelin’s early characterization of dementia praecox, the disorder or disorders that we now call schizophrenia are not characterized by dementia, or inevitable loss of cognitive ability and function. Dr. Robert B. Zipursky, Professor of Psychiatry and Behavioural Neurosciences at McMaster University in Hamilton, Ontario, said that psychiatrists may share Kraepelin’s impression of a malignant illness because of the clinician’s illusion, which arises from the biased sample of patients that psychiatrists treat, i.e. people with chronic, relapsing illness and multiple co-morbidities who come to hospitals (1). According to Professor Zipursky, who spoke at the 9th Annual Pacific Psychopharmacology Conference in Coquitlam, BC on September 18, 2015, available studies indicate that about 70% of people with first-episode psychosis will achieve remission within a year; he defined remission as having positive symptoms no greater that mild in severity and negative symptoms no greater than moderate in severity.

First-episode psychosis includes patients with various diagnoses including bipolar disorder, schizoaffective disorder, brief psychotic disorder as well as schizophrenia. Patients who achieve functional recovery, however, represent a smaller group, especially in those confirmed to have schizophrenia. In long-term outcome research, 20% or fewer of people with schizophrenia meet criteria for recovery defined as sustained remission of symptoms and success in social relations and competitive employment.
Some psychiatrists have concluded that this long-term functional impairment is due to progressive cognitive deterioration which may occur with untreated or chronic positive psychotic symptoms. A related hypothesis is the “neurotoxicity of psychosis” which posits that persisting psychosis leads to ongoing loss of cerebral tissue as manifested by enlarged ventricles and cortical atrophy on neuroimaging, accompanied by worsening deficits on neuropsychologic testing. Consequently, many clinicians working in first episode psychosis accept that the duration of untreated psychosis is an important determinant of long-term outcome.

While he acknowledged that deficits in grey matter volumes observed with MRI are more prominent in chronic patients, Dr. Zipursky asserted that many factors may contribute to this such as sampling bias; concurrent substance use including cannabis, tobacco and alcohol; lack of physical activity; and chronic antipsychotic therapy. The latter is controversial, but he cited a meta-analysis of longitudinal MRI studies in which change in grey matter volumes was correlated with antipsychotic exposure but not illness duration or severity (2). However, he emphasized that relieving suffering and improving function are the goals of treatment, not specifically increasing cerebral volume, which is affected by various factors mentioned before. Furthermore, Dr. Zipursky showed compelling evidence that following a first episode of schizophrenia, antipsychotic discontinuation is by far the most important cause of relapse.

Duration of untreated psychosis (DUP) has a small correlation with treatment outcome, likely accounting for less than 5% of the variance in clinical outcome measures, and questionable association with cognitive functioning and structural brain measures, according to Dr. Zipursky. He presented evidence that it is a risk marker for poor outcome in schizophrenia as opposed to a causative risk factor. “It’s not certain that it relates to improving outcomes, but it does relate to reducing suffering,” Zipursky said.
He concluded that to improve outcomes and promote functional recovery, antipsychotic medication is crucial but so are psychosocial interventions to manage substance use, educate families, provide adequate housing and income support when needed, and engage patients in vocational rehabilitation and supported employment.


Zipursky RB, Reilly TJ, Murray RM. The myth of schizophrenia as a progressive brain disease. Schizophr Bull. 2013;39:1363-1372. Full text

Fusar-Poli P, Smieskova R, Kempton MJ, Ho BC, Andreasen NC, Borgwardt S. Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies. Neurosci Biobehav Rev. 2013;37:1680-1691. Full text

Could grey matter loss in the superior temporal gyrus contribute to treatment resistance?

The DSM 5 abandoned classifying schizophrenia by psychopathology subtype, but the heterogeneity of the disorder still requires explanation. A more pragmatic approach advocated by some researchers is classification according to treatment response: antipsychotic responsive, clozapine responsive, and clozapine non-responsive. Investigators are looking at the biologic correlates of these subtypes, and a group from New Zealand recently examined differences in brain volume. Using a 3-Tesla scanner, they obtained T1-weighted images of the brains of 18 antipsychotic responders, 19 clozapine responders (for whom other antipsychotics failed), 15 clozapine nonresponders, and 20 controls. All subjects were 18 to 45 years old, and patients with neurologic or active addictive disorders were excluded. The clozapine responsive and non-responsive patients had failed to respond to at least two trials of other antipsychotics, and the PANSS was used to assess symptoms.

The groups of patients did not differ by mean age, PANSS scores or illness duration. The groups had some differences in substance use history; the clozapine-resistant patients had more use of hallucinogens, and the antipsychotic responsive group had more use of cannabis, but the groups did not differ in stimulant use history.

Compared with controls, all patient groups had a reduction in whole-brain and white-matter volumes, and the clozapine-resistant group had a significant increase in ventricular volume. The treatment-resistant and clozapine-resistant patients had smaller grey matter volumes compared with controls and antipsychotic-responsive patients. In analysis using voxel-based morphometry, a technique to examine the volume of specific brain regions, the clozapine-resistant patients, compared with controls, showed bilateral grey matter reductions in the superior and middle temporal gyri, ventromedial prefrontal cortex, anterior cingulate gyrus, and postcentral gyrus. The left cerebellum and right occipital cortex also showed grey matter reduction. Compared with controls, the treatment-resistant group had a similar magnitude of grey matter volume reduction which especially affected the right perisylvian region.

Compared with the antipsychotic-responsive group, both clozapine-resistant and clozapine-responsive groups had reduction in grey matter volume with somewhat differing patterns. Only the clozapine-resistant patients had a relative reduction in the left cerebellum and left anterior cingulate gyrus. No differences were seen in comparing the clozapine-resistant and clozapine-responsive groups.

A controversy in the field of neuroimaging of schizophrenia is the role of antipsychotic exposure in cerebral volume loss; previous research has shown conflicting results. In this study, the clozapine-resistant group had a higher mean daily dose of antipsychotic compared with the other groups, but the researchers found no overall correlation between daily dose and grey matter volume. The study did not look at lifetime antipsychotic exposure.

The investigators highlight the finding of prominent volume reduction in the superior temporal gyrus in the clozapine-resistant group, which was seen in a number of prior studies including longitudinal investigations and in first-episode patients. This brain structure is crucial for auditory processing and language, which are highly implicated in schizophrenia; perhaps tissue loss in this region contributes to poor medication response. However, as the researchers state, in this kind of observational study we are unable to draw conclusions about cause and effect.

Anderson VM, Goldstein ME, Kydd RR, Russell BR. Extensive grey matter volume reduction in treatment-resistant schizophrenia. Int J Neuropsychopharmacol. Published online Feb 25, 2015. Abstract

Brazil: The Use of Nitrous Prusside for Schizophrenia

nitrous prusside, schizophrenia, mental health

In 2013, Drs. Jaime Hallak, Joao Paulo Maia-de-Oliveira and associates in Ribeirao Preto, Brazil, published results from a randomized controlled trial of intravenous nitroprusside in schizophrenia. Two Canadian researchers from the University of Alberta collaborated on the trial. This study was the first to find that sodium nitroprusside, a treatment for hypertensive crises, has a rapid and prolonged effect on both positive and negative symptoms in patients with acute psychosis. The presumed mechanism is enhancement of nitric oxide in the central nervous system, which may modulate the NMDA receptor-cGMP pathway. In normotensive patients, nitroprusside has minimal effect on blood pressure, and cyanide accumulation is a theoretical concern but occurs only after 72 hours or more of continuous infusion. In treating schizophrenia, the infusion dose is 0.5 mg/kg/minute for four hours.

In the initial trial published in JAMA Psychiatry, Hallak’s team used the Brief Psychiatric Rating Scale and the negative subscale of the Positive and Negative Syndrome Scale (PANSS) as outcome measures. A significant effect on certain components occurred within the first two to three hours of treatment, and improvement endured for four weeks. All the patients were also receiving an antipsychotic other than clozapine.

I met with Jaime, Joao Paulo and their team at the University of Sao Paulo Hospital in Ribeirao Preto and was able to observe a treatment. When I first met the patient, whose infusion had begun 10 minutes before, she appeared anxious and tended to avoid eye contact. When I returned 90 minutes later, she was engaged in an art activity and was eager to show me what she had created. She smiled broadly and even tested her English vocabulary a little. The researchers said that they often see an improvement in the patients’ affect over the course of the infusion, and they are trying to find ways to measure this more objectively. Although data are still limited, the effect in treatment-resistant patients tends to be more delayed.

Further studies of nitrous prusside in Ribeiroa Preto are underway, including for treatment-resistant patients, some on clozapine, and on neurophysiologic effects as detected with fMRI and event-related potential. Because the benefits of the treatment begin to wane after four weeks, they are planning a controlled trial of weekly nitrous prusside infusions for four weeks followed by 60 days of observation.
Hallak JEC, Maia-de-Oliveira JP, Abroa J, et al. Rapid Improvement of Acute Schizophrenia Symptoms After Intravenous Sodium Nitroprusside: A Randomized, Double-blind, Placebo-Controlled Trial. JAMA Psychiatry. 2013;70:668-676. Abstract
Photo: Left to right: Dr. Jaime Hallak, Dr. Joao Paolo Maia-de-Oliveira, Juliana Almeida (audiologist), their patient and her mother