Schizophrenia and Impaired Cardiovascular Fitness

Schizophrenia and Impaired Cardiovascular Fitness

We’re pleased to announce Randall’s work has been released in a recent publication in the journal Psychiatric Research:

Studies show that individuals with schizophrenia have impaired cardiovascular fitness (i.e., low peak aerobic power (VO2peak)). It is speculated that antipsychotics with adverse cardiovascular and metabolic profiles, in particular clozapine, have a significant impact on VO2peak. In this cross-sectional study, we examined whether exposure to clozapine was associated with further reduced VO2peak compared with non-clozapine antipsychotics. Thirty participants with chronic schizophrenia or schizoaffective disorder were divided into clozapine and non-clozapine groups. Mean daily doses of antipsychotics were standardized to chlorpromazine equivalents and haloperidol equivalents for antagonism of alpha1– and alpha2-adrenergic receptors. Participants completed an incremental-to-maximal symptom-limited exercise test on a cycle ergometer for the assessment of VO2peak. The clozapine group demonstrated significantly lower VO2peak than the non-clozapine group. Haloperidol equivalents for alpha-adrenergic receptor antagonism, but not chlorpromazine equivalents, demonstrated significant inverse associations with VO2peak. The clozapine group had a significantly higher amount of antagonistic activity at alpha-adrenergic receptors than the non-clozapine group. In conclusion, exposure to clozapine was associated with further reduced cardiovascular fitness, which may be explained by the drug’s greater antagonistic activity at alpha-adrenergic receptors. Cardiovascular fitness needs to be promoted in individuals treated with antipsychotics, particularly clozapine, to prevent the risk of cardiovascular disease and mortality.

Kim DD, Lang DJ, Procyshyn RM, Woodward ML, Kaufman K, White RF, Honer WG and Warburton DER. Reduced cardiovascular fitness associated with exposure to clozapine in individuals with chronic schizophrenia. Psychiat Res. 2018;262:28-33.

Orphan Patients: A Case Series of Patients With Treatment-Resistant Psychosis Requiring Alternatives to Clozapine

Dr. Randall White at the APA IPS in Chicago

Dr. Simon Bow presented a research poster at the The Canadian Psychiatric Association’s 68th Annual Conference, September 27-29, 2018 in Toronto, and Dr Randall White presented it at the American Psychiatric Association Institute on Psychiatric Services, October 4-7, 2018 in Chicago. Here is the research represented on the poster:

Abstract:

Background: Clozapine is the gold standard for managing treatment-resistant psychosis (TRP). Despite superior efficacy, some patients do not tolerate or stop it, and research on this population is scarce. Here we describe inpatients with TRP, treated at the British Columbia Psychosis Program (BCPP) from 2012 to 2017, who required alternative interventions to clozapine.

Methods:

In a retrospective analysis of 275 patient records, 78 with TRP were not receiving clozapine at discharge. Data collected included demographics, standardized ratings (Positive and Negative Syndrome Scale [PANSS], Social and Occupational Functioning Assessment Scale [SOFAS], Gut and Psychology Syndrome [GAPS], Clinical Global Impression [CGI]), comorbidities, reasons for clozapine discontinuation, and alternative treatments.

Results:

A total of 85% of patients had previously taken clozapine; the remainder were not offered or refused it. Reasons patients could not have a clozapine trial at BCPP included a history of myocarditis (13%), agranulocytosis (5%) or neutropenia (8%), refusal (18%), poor compliance (12%), poor response (6%), or other severe side effects [JT1]. Antipsychotics at discharge included oral monotherapy (40%), injectable monotherapy (15%), oral polypharmacy (19%), or oral-injectable combination (23%). Additional medications included mood stabilizers (45%), antidepressants (26%), and/or sedative hypnotics (26%). Electroconvulsive therapy (ECT) was used in 13%. Psychotherapy showed benefit in 17%. Mean PANSS total score reduction was 18% and CGI scale score reduction, 1.3, with 32% and 5% of patients achieving response and remission, respectively.

Conclusion:

Clozapine may not be feasible for many reasons, but we have documented several alternatives for managing TRP. We are continuing subgroup analyses, along with a comparator group successfully started on clozapine during admission. These results may inform clinical decision making in this difficult-to-treat population.

Dr. Simon Bow at the CPA meeting in Toronto

Dr. Simon Bow at the CPA meeting in Toronto

Orphan patients research poster

Download the poster here: Dr. Randall White Final 2.

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

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

Fluvoxamine

In some patients, achieving a therapeutic serum clozapine concentration requires a high dose entailing a prolonged series of dose increases. This may be more common among smokers, and people with schizophrenia are more likely to smoke and to smoke more cigarettes per day than the population at large. One short cut to achieving a therapeutic level is adding fluvoxamine, a serotonin reuptake inhibitor used to treat anxiety and depression. Clozapine is converted by cytochrome enzyme 1A2 to the metabolite N-desmethylclozapine, known as norclozapine in clinical settings. Fluvoxamine inhibits this process which shifts the ratio of clozapine to norclozapine upward and prolongs the half life of clozapine. Fluvoxamine also inhibits CYP2C19 and in some people, CYP3A4 as well. The clinical effect is to permit a lower total dose of clozapine, and it may make once-daily dosing more tolerable. Furthermore, fluvoxamine can be used to treat concurrent anxiety and depression while maximizing clozapine serum levels. The evidence for the safety and benefits of these uses of fluvoxamine was reviewed in a recently published article.

The authors identified 24 case reports and series comprising 29 patients, and 9 prospective studies comprising 212 patients; 2 of these were randomized trials. Most patients had a primary diagnosis of schizophrenia, and the rationales for the various studies were diverse.

  • Increasing clozapine plasma level
  • Treating negative symptoms
  • Treating positive symptoms
  • Treating depressive symptoms
  • Treating obsessive-compulsive symptoms
  • Reducing metabolic adverse effects

The available evidence for most of these indications is mediocre or poor except for increasing plasma levels; according to the authors, fluvoxamine increases clozapine, norclozapine, and clozapine N-oxide plasma levels in a dose-dependent manner. The data among smokers is supportive but surprisingly limited. One point they raise is that the effects of changing the ratios of metabolites other than norclozapine is not understood. The evidence for reducing metabolic adverse effects is relatively good as it comes from a 12-week RCT, but long-term efficacy is unknown. As for treating depression or obsessive-compulsive symptoms, the authors conclude that it is safer to use an appropriate antidepressant without the pharmacokinetic complications of fluvoxamine given the risk of toxicity if clozapine levels rise abruptly.

Safety concerns addressed in studies include the risk of agranulocytosis and seizures for which there is no evidence of a protective or facilitative effect; the available evidence correlates increasing clozapine dose and not plasma level with risk of seizures. (2) The reports reviewed mention frequent occurrence of common adverse effects including sedation, sialorrhea with drooling, and constipation in fluvoxamine-treated patients. Clinicians and patients should be aware that prescribing fluvoxamine to enhance clozapine effects is not approved by Health Canada or the US Food and Drug Administration.

References

Polcwiartek C, Nielsen J. The clinical potentials of adjunctive fluvoxamine to clozapine treatment: a systematic review. Psychopharmacology. Published online Dec 2, 2015. Abstract

Remington G, Agid O, Foussias G, et al. Clozapine and therapeutic drug monitoring: is there sufficient evidence for an upper threshold? Psychopharmacology. 2013;225:505–518. Abstract

Cognition in treatment resistance

Patients with treatment-resistant schizophrenia or schizoaffective disorder have the most severe form of the illness at least as determined by persistence of positive symptoms, but the other aspects, including negative and cognitive impairments, are typically not as well assessed clinically or in research. Most clinicians may assume that treatment-resistant patients, who often have profound functional deficits, have worse cognition than patients who respond to non-clozapine antipsychotics. This is an hypothesis that requires investigation, and a team from New Zealand have recently published such a study. They went further and also looked at the cognitive status of a group of clozapine-resistant (ultra-resistant) patients.

The 51 patients were recruited from outpatient and inpatient settings; 5 had schizoaffective disorder and the rest had schizophrenia. The control group comprised 22 healthy adults matched for age and sex. The mean age of the subjects was about 33 years. The researchers classified the patients into 3 groups based on treatment response: first-line antipsychotic responders (n=16), treatment-resistant but clozapine responders (n=20), and clozapine nonresponders (ultra-resistant; n=15). The latter group had a 8-week trial of monotherapy, and all ended up on at least 2 antipsychotics, most often clozapine and a another second-generation antipsychotic. Despite the designations, the 3 groups had no significant difference in PANSS total or subscale scores at the time of evaluation. The mean antipsychotic dose as measured in chlorpromazine equivalence was significantly greater in the clozapine-resistant group, but the mean duration of illness did not differ among groups. The control group had slightly greater mean educational attainment than the treatment-resistant group.

The cognitive assessments consisted of neuropsychologic tests covering the domains of the MATRICS Consensus Cognitive Battery developed by the U.S. National Institutes of Mental Health, considered the standard in psychosis cognitive evaluation. In this study, the testing was computerized and included such domains as executive function, social recognition, processing speed, and verbal and nonverbal learning and memory. The raw scores were converted to Z-scores normalized for age, sex and education.

The results showed that the patients overall had significant impairment in cognitive performance compared with healthy subjects, but the differences among the 3 patient groups were minimal. The treatment-resistant group, however, had a mean verbal fluency Z-score equal to that of the control group whereas the other patient groups had significantly worse performance in this domain, but subsequent analysis did not support a significant difference in verbal fluency performance in patient groups or controls. The researchers mention that pre-existing work has found that clozapine is associated with improvement in verbal fluency, an intriguing finding especially since in this study, verbal fluency was correlated with the negative-symptoms subscale of the PANSS in patients who responded to clozapine monotherapy.

The study is small, and the equivalent positive symptoms scores in the 3 patient groups raises questions about the distinctions based on treatment response, the findings tend to disconfirm the hypothesis that treatment resistance as defined by antipsychotic response necessarily indicates greater cognitive impairment.

Anderson VM, McIlwain ME, Kydd RR, Russell BR. Does cognitive impairment in treatment-resistant and ultra-treatment-resistant schizophrenia differ from that in treatment responders? Psychiatry Res. 2015; published online Oct 2015; http://dx.doi.org/10.1016/j.psychres.2015.10.036

Norclozapine, the metabolite of clozapine, may be more useful than you think

Although psychiatrists know that long-term disability in schizophrenia is related to negative and cognitive symptoms, our treatment goals often focus on positive symptoms. The unfortunate reason is that we lack good treatments for cognitive and behavioral deficits. Many antipsychotics have anticholinergic properties which we know can dull cognition or even cause delirium in sensitive patients, but we accept this risk in exchange for the benefit of eliminating psychosis.

Clozapine is highly anticholinergic but its metabolite, N-desmethylclozapine or norclozapine, has partial cholinergic agonist activity at muscarinic receptors. Although psychopharmacologists have suspected that this property of norclozapine may have cognitive benefits, most psychiatrists focus on optimizing clozapine serum level which is sometimes achieved by blocking clozapine metabolism with cytochrome enzyme inhibitors such as the antidepressant fluvoxamine. This increases the clozapine/norclozapine ratio; some evidence suggests this may reduce the metabolic burden of clozapine therapy (1). However, new evidence suggests that this may come at the price of worse cognitive performance, in particular working memory.

A team of researchers at the Centre for Mental Health and Addictions in Toronto examined the hypothesis that a greater ratio of clozapine to norclozapine would correlate with worse cognitive performance as measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MATRICS battery) (2).  They recruited 30 adults, mean age 38.6 years, on clozapine monotherapy for schizophrenia or schizoaffective disorder whose dose had been unchanged for at least 4 weeks. The subjects had blood taken for clozapine and norclozapine concentrations on the same day that they underwent PANSS rating and the MATRICS battery, which comprises 10 tests in 7 cognitive domains such as verbal learning, visual learning, working memory and processing speed.

In multiple regression analyses, the clozapine/norclozapine ratio was negatively correlated with performance on working memory but not with the other 6 cognitive domains. Working memory performance was not correlated with demographic variables or PANSS score, nor with either clozapine or norclozapine serum concentrations independently of each other.

The investigators suggest that the significance of the clozapine/norclozapine ratio reflects the opposing effects of the two molecules on muscarinic type 1 receptors, given that the cholinergic system is crucial for complex attentional processes as tested by working memory measures. They acknowledge that the MATRICS battery may not be sensitive enough to detect effects on other domains, and also that this is a cross-sectional study that cannot establish causation. Serial measurements in individuals as the clozapine/norclozapine ratio changes would be more conclusive.

References

1. Lu ML, Lane HY, Lin SK, Chen KP, Chang WH. Adjunctive fluvoxamine inhibits clozapine-related weight gain and metabolic disturbances. J Clin Psychiatry. 2004;65:766-771. Abstract

2. Rajji TK, Mulsant BH, Davies S, et al. Prediction of working memory performance in schizophrenia by plasma ratio of clozapine to N-desmethylclozapine. Am J Psychiatry. 2015;172:579-585. Abstract

Riverview Refractory Psychosis Data Presented at International Psychiatry Congress

WIN_20150329_113434

 

View the poster in a PDF file here

Abstract

Treatment-resistant psychosis is a challenge to psychiatry and a substantial burden to health-care systems. The province of British Columbia in Canada has publicly funded, universal health care, and patients with treatment-resistant psychosis may receive care in a specialized residential program. Between 1993 and 2011, 663 patients were admitted to this program; this cohort contains one of the largest known series of patients with treatment-resistant schizoaffective disorder.

All patients were evaluated by a psychiatrist, social worker, pharmacist, nurse, general physician, and neuropsychologist. Records from previous hospital admissions were reviewed and all information was presented at a multidisciplinary conference. This resulted in a consensus DSM-III or -IV multiaxial diagnosis and a detailed treatment plan. Ratings of symptoms and functioning at admission and discharge included the Positive and Negative Syndrome Scale (PANSS), the Global Assessment of Functioning Scale, the Social and Occupational Functioning Scale, and the Clinical Global Impression of Severity. A research psychologist compiled all data at the time of each patient’s hospitalization.

Patients who did not complete treatment or had a diagnosis other than schizophrenia (SZ), schizoaffective (SZA) or mood disorder (MD) were excluded; the following describes 551 included patients (SZ = 63%, SZA = 29%, MD = 8%). More than half were male (59%), and the mean duration of hospitalization was 30 weeks. The proportion receiving clozapine increased from 21% at admission to 61% at discharge. Those with a MD were less likely to receive clozapine than either SZ or SZA (SZ = 64%, SZA = 61%, MD = 41%). In each diagnostic group, both antipsychotic polypharmacy and the ratio of prescribed daily dose to defined daily dose (PDD/DDD) of antipsychotic medication decreased during hospital stay (polypharmacy: SZ: 52% to 16%, SZA: 52% to 14%, MD: 43% to 0%; PDD/DDD: SZ: 2.1 to 1.6, SZA: 2.1 to 1.4, MD: 1.6 to 1.1). The use of mood stabilizers declined in all groups, but antidepressant use declined only in SZ and SZA. Mean total PANSS score declined in all diagnostic groups, but most in MD, least in SZ, and intermediate in SZA.

In an intensive inpatient program for treatment-resistant psychosis, aggregate improvement occurred despite global reduction in medications while clozapine use nearly tripled. Lower total antipsychotic dose correlated with greater improvement at discharge.

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