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GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry.  Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.

ISSUE 4, July 2012 — Guest Commentator: Oliver Freudenreich, MD, Harvard Medical School

Early Detection and Intervention Evaluation for People at Risk of Psychosis: 
Multi-site Randomized Controlled Trial

Morrison AP, French P, Stewart SLK, et al
BMJ. 2012;344:e2233.

Objective: To determine whether cognitive therapy is effective in preventing the worsening of emerging psychotic symptoms experienced by help-seeking young people deemed to be at risk for serious conditions such as schizophrenia.

: A multi-site single blind randomized controlled trial involved diverse services at five UK sites. Participants (N=288) were aged 14-35 years (mean 20.74, SD 4.34 years) at high risk of psychosis: 144 were assigned to cognitive therapy plus monitoring of mental state and 144 to monitoring of mental state only. Participants were followed-up for a minimum of 12 months and a maximum of 24 months. Cognitive therapy (up to 26 [mean 9.1] sessions over six months) plus monitoring of mental state was compared with monitoring of mental state only. Primary outcome was scores on the comprehensive assessment of at risk mental states (CAARMS), which provides a dichotomous transition to psychosis score and ordinal scores for severity of psychotic symptoms and distress. Secondary outcomes included emotional dysfunction and quality of life.

: Transition to psychosis based on intention to treat was analyzed using discrete time survival models. Overall, the prevalence of transition was lower than expected (23/288; 8%), with no significant difference between the two groups (proportional odds ratio 0.73, 95% confidence interval 0.32 to 1.68). Changes in severity of symptoms and distress, as well as secondary outcomes, were analyzed using random effects regression (analysis of covariance) adjusted for site and baseline symptoms. Distress from psychotic symptoms did not differ (estimated difference at 12 months -3.00, 95% confidence interval -6.95 to 0.94) but their severity was significantly reduced in the group assigned to cognitive therapy (estimated between group effect size at 12 months -3.67, -6.71 to -0.64, P=0.018).
Conclusions: Cognitive therapy plus monitoring did not significantly reduce transition to psychosis or symptom-related distress, but reduced the severity of psychotic symptoms in young people at high risk. Most participants in both groups improved over time. The results have important implications for the at-risk mental state concept.

Clinical Commentary

Most patients with schizophrenia experience a prodrome before the onset of full-blown psychosis. Unfortunately, the prodrome of schizophrenia is unspecific (eg, depressive symptoms, academic difficulties in school) and can only be diagnosed in hindsight. However, in the past decades researchers have identified clinical variables that allow for a prospective “at risk mental state” determination, intended to predict if a patient is at very or “ultra” high risk of developing schizophrenia. Patients with high-risk mental states are those with attenuated subclinical psychotic symptoms, brief and short-lived psychotic symptoms, or family history of schizophrenia and declining function. It is hoped that some of the disability associated with schizophrenia can be reduced by intervening earlier in the prodromal phase rather than in the full syndromal stage. Moreover, it is hoped that early intervention might prevent the use of antipsychotics and allow for treatment with more benign interventions such as cognitive-behavioral therapy (CBT). This multi-site trial is the largest trial attempting to prevent the development of schizophrenia by intervening with CBT in 288 patients considered to be at high risk. CBT indeed reduced the severity of positive symptoms but not transition to psychosis in the 2-year follow-up. However, power to detect a difference was limited, as only 8% of patients in this cohort made the transition from an at-risk mental state to psychosis, consistent with low transition rates in other high-risk samples.(1) One has to wonder if a re-definition of “ultra high-risk” is in order, to better capture this collection of help-seeking patients. Many improve over time and only a minority develops schizophrenia – a relevant observation for the DSM-V work group contemplating inclusion of an “attenuated psychosis syndrome.” Clinically, it is reassuring that CBT-based approaches and clinical monitoring alone seems to be enough for many patients presenting with an “at risk mental state.”


Group Art Therapy as an Adjunctive Treatment for People with Schizophrenia: Multi-centre Pragmatic Randomized Trial

Crawford MJ, Killaspy H, Barnes TR, et al

BMJ. 2012;344:e846.

Objective: To evaluate the clinical effectiveness of group art therapy for people with schizophrenia and to test whether any benefits exceed those of an active control treatment.

Methods: A three-arm, rater-blinded, pragmatic, randomized controlled trial of secondary care services across 15 sites in the United Kingdom. Participants included 417 people aged 18 or over, who had a diagnosis of schizophrenia and provided written informed consent to take part in the study. Participants, stratified by site, were randomized to 12 months of weekly group art therapy plus standard care, 12 months of weekly activity groups plus standard care, or standard care alone. Art therapy and activity groups had up to eight members and lasted for 90 minutes. In art therapy, members were given access to a range of art materials and encouraged to use these to express themselves freely. Members of activity groups were offered various activities that did not involve use of art or craft materials and were encouraged to collectively select those they wanted to pursue. The primary outcomes were global functioning, measured using the global assessment of functioning scale, and mental health symptoms, measured using the Positive and Negative Syndrome Scale, 24 months after randomization. Main secondary outcomes were levels of group attendance, social functioning, and satisfaction with care at 12 and 24 months.

Results: 417 participants were assigned to either art therapy (n=140), activity groups (n=140), or standard care alone (n=137). Primary outcomes between the three study arms did not differ. The adjusted mean difference between art therapy and standard care at 24 months on the Global Assessment of Functioning scale was -0.9 (95% confidence interval -3.8 to 2.1), and on the Positive and Negative Syndrome Scale was 0.7 (-3.1 to 4.6). Secondary outcomes did not differ between those referred to art therapy or those referred to standard care at 12 or 24 months.

Conclusions: Referring people with established schizophrenia to group art therapy as delivered in this trial did not improve global functioning, mental health, or other health-related outcomes.

Clinical Commentary
Aptly named the MATISSE (Multi-centre study of Art Therapy in Schizophrenia – Systemic Evaluation) trial, this large (N=417) randomized trial of art therapy for schizophrenia surely must have been a disappointment. Clinicians, patients, and families always hope that benign psychosocial interventions reap clinical benefits. However, in MATISSE, weekly group art therapy offered for one year to unselected patients with schizophrenia did not improve symptoms or function when compared to standard care or standard care enhanced by weekly activity groups. Previously, the National Institute for Clinical Excellence (NICE) had issued a guidance to offer art therapy for patients with schizophrenia ( In light of MATISSE, this recommendation needs to be re-considered, at least with regards to its unqualified character. MATISSE does not argue for impoverishing patients’ lives, but merely points to the limits of what activities with seeming face validity like art groups can contribute over and above good clinical care. Moreover, MATISSE also showed the limits of therapies that require patient motivation: 40% of patients assigned to art therapy failed to make a single group visit. Last, maybe a distinction between treatment and enrichment ought to be made when patients participate in an adjunctive activity. Not all such activities will improve symptoms and functions. Enrichment to increase “only” quality of life is a reasonable goal for families and patients. 


A Randomized, Placebo-Controlled Study of Zonisamide to Prevent Olanzapine-Associated Weight Gain

McElroy SL, Winstanley E, Mori N, et al.

J Clin Psychopharmacol. 2012;32(2):165-172.

Objective: Weight gain is commonly observed with olanzapine treatment. Zonisamide is an antiepileptic drug associated with weight loss. This study examined the effectiveness of zonisamide in preventing weight gain in 42 patients beginning olanzapine for bipolar disorder or schizophrenia.

Method: Each patient had a body mass index of 22 mg/kg or greater and was randomized to olanzapine with either zonisamide (n = 20) or placebo (n = 22) for 16 weeks. The primary outcome measure was change in body weight in kilograms from baseline. In the primary analysis using longitudinal regression, patients who received zonisamide had a significantly slower rate of weight gain and increase in body mass index than those who received placebo.

Results: The patients treated with zonisamide gained a mean (SD) of 0.9 (3.3) kg, whereas those treated with placebo gained a mean (SD) of 5.0 (5.5) kg; P=0.01. None of the patients in the zonisamide group, compared with 7 patients (33%) in the placebo group, gained 7% of body weight or greater from baseline (Fisher exact test, P=0.009). The zonisamide group, however, reported significantly more cognitive impairment as an adverse event than the placebo group (25% vs 0, respectively; P=0.02).

Conclusion: Zonisamide was effective for mitigating weight gain in patients with bipolar disorder or schizophrenia initiating treatment with olanzapine, but was associated with cognitive impairment as an adverse event.

Clinical Commentary
One of the most vexing clinical problems in taking care of patients with schizophrenia is antipsychotic-induced weight gain. Weight gain is a factor in non-adherence and a factor in the later development of the metabolic syndrome with its associated mortality risk. In this small randomized, placebo-controlled trial, the authors added zonisamide to olanzapine-treated patients to blunt olanzapine-associated weight gain. Zonisamide is an antiepileptic drug in the same class as topiramate, which is well known to cause weight loss in some patients. On average, patients gained 11 pounds over 4 months if given placebo compared to 2 pounds if zonisamide was added. One downside of zonisamide is tolerability with regards to cognitive side effects. Such attempts at secondary prevention (ie, making weight management an important treatment aspect by early detection and intervention) should probably be considered routinely in patients with schizophrenia, particularly early in the course of illness where prevention might have the greatest effect. There is great interest in combining drugs to develop a truly effective anti-obesity agent, not just for patients with schizophrenia. One drug combination under development for obesity is zonisamide plus bupropion, currently in phase II trials ( 

Ziprasidone and the Corrected QT Interval: A Comprehensive Summary of Clinical Data

Camm AJ, Karayal ON, Meltzer H, et al.
CNS Drugs. 2012;26(4):351-365.

Background: Prolongation of the corrected QT interval (QTc) is understood to be a predictor of risk for ventricular arrhythmia; consequently, data on QTc effects of drugs are used by regulatory bodies to evaluate potential safety risks. Clinical pharmacology studies in adults receiving oral ziprasidone demonstrated a dose-dependent mean increase (4.5-19.5 milliseconds [ms]) in QTc over the range of 40-160 mg/d with a small incremental increase (22.5 ms) at 320 mg/d. In a comparative study of ziprasidone versus five antipsychotics, the mean QTc increase at steady state maximum concentration (C(max)) for ziprasidone was 15.9 ms. Accordingly, the effects of ziprasidone on QTc were studied in phase II-IV randomized controlled trials (RCTs).

Objective: The objective of this study was to provide clinicians and clinical researchers with a comprehensive analysis of QTc changes associated with ziprasidone based on data from Pfizer-sponsored phase II-IV RCTs in schizophrenia or bipolar disorder patients, safety reports, and postmarketing surveillance.

Methods: The following analyses of data were conducted to obtain a comprehensive summary of QTc data on ziprasidone: (i) post hoc analyses (using primarily descriptive statistics) of pooled QTc data (Fridericia correction) from more than 40 phase II-IV adult ziprasidone RCTs organized according to the following subgroups: all monotherapy studies in schizophrenia and bipolar disorder, all intramuscular (IM) studies, adjunctive studies in bipolar disorder and fixed-dose oral studies; (ii) post hoc analyses from 36 phase II-IV adult ziprasidone RCTs exploring the relationship between QTc change from baseline and baseline QTc in adults; (iii) post hoc analyses from phase II-IV adult ziprasidone RCTs modelling QTc change as a function of ziprasidone concentration in both adult (17 studies) and pediatric (5 studies) subjects; (iv) cardiac adverse event (AE) reports from all phase II-IV adult ziprasidone RCTs in schizophrenia; (v) a large simple trial entitled Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) in 18-154 subjects with schizophrenia (the only previously reported results included here); and (vi) cardiac-related AEs presented in a ziprasidone postmarketing surveillance report created in 2007.

Results: A total of 4,306 adults received ziprasidone in placebo- and active-comparator phase II-IV RCTs and had evaluable QTc data. One subject reached a QTc ≥480 ms; 33 (0.8%) had a QTc ≥450 ms. QTc prolongation ≥30 ms was observed in 389 subjects (9.0%); ≥60 ms in 30 (0.7%); and ≥75 ms in 12 (0.3%). In the placebo-controlled studies, mean change in QTc from baseline to end of study was 3.6 (±20.8) ms in the ziprasidone group; the corresponding QTc change in the pooled placebo group was -0.3 (±20.6) ms. Data from IM studies, and bipolar studies in which ziprasidone was used adjunctively with lithium, valproate, or lamotrigine, demonstrated similar QTc effects. A scatter-plot of QTc prolongation against baseline QTc showed QTc prolongation ≥60 ms exclusively in adult subjects with a baseline QTc ≤400 ms. The final concentration-response analysis model, comprising 2,966 data points from 1,040 subjects, estimates an increase in QTc of 6 ms for each 100 ng/mL increase in ziprasidone concentration. The large simple trial (ZODIAC) failed to show that ziprasidone is associated with an elevated risk of non-suicidal mortality relative to olanzapine in real-world use. Post-marketing data over a 5-year period did not show a signal of increased cardiac AEs.

Conclusions: These analyses provide the first comprehensive summary of QTc changes associated with ziprasidone based on Pfizer-sponsored phase II-IV RCTs, safety reports and post-marketing surveillance. The results of the analyses of pooled data from phase II-IV RCTs in adults demonstrate a modest mean increase in QTc, infrequent QTc prolongation ≥60 ms (<1.0 %) and rare observation of QTc ≥480 ms. These data are consistent with results from ziprasidone clinical pharmacology studies, safety reports and postmarketing surveillance. Taken together, they provide the most comprehensive evidence published to date that ziprasidone appears to be safe when used as indicated in patients with schizophrenia or bipolar disorder.

Clinical Commentary
Ziprasidone’s entry into the market was initially delayed when another drug being developed at the time, sertindole, was found to prolong the QTc interval. As a consequence, ziprasidone’s effects on the QTc interval have been extensively scrutinized over the past decade. This comprehensive summary of clinical trials including the previously published ZODIAC (the Ziprasidone Observational Study of Cardiac Outcomes)(2) as well as unpublished pre-approval and post-marketing studies, finds an average increase of QTc of 6 msec for each 100 ng/mL increase in ziprasidone blood levels and no signal for an increased risk of ziprasidone-associated cardiac death. Since patients with schizophrenia have high rates of medical comorbidity, all patients should have a comprehensive physical exam and laboratory work, including an EKG, irrespective of the antipsychotic they are started on.


A One-Year Prospective Study of the Safety, Tolerability, and Pharmacokinetics of the Highest Available Dose of Paliperidone Palmitate in Patients with Schizophrenia

Coppola D, Liu Y, Gopal S, et al

BMC Psychiatry. 2012;12(1):26.

Background: There are no previous reports of paliperidone palmitate's (PP) long-term tolerability or pharmacokinetics of the highest dose in patients with schizophrenia. This study evaluates safety and tolerability, as well as pharmacokinetics, of the highest marketed dose of PP (150 mg eq. [234 mg]) in stable patients with schizophrenia over a 1-year period.

Methods: In this 1-year prospective study, eligible patients (aged 18-65 years; Positive and Negative Syndrome Scale's total score (<70) received an initial deltoid injection of PP 150 mg eq. The second injection one week later and subsequent once-monthly injections were deltoid or gluteal. All injections were to be PP 150 mg eq. Patients willing to participate in intensive pharmacokinetic sampling were classified as Treatment A. Patients unwilling to undergo intensive pharmacokinetic sampling or unable to tolerate the 150 mg eq. dose (consequently receiving flexible doses of 50, 100 or 150 mg eq.) were classified as Treatment B.

Results: Of the 212 patients (safety analysis set), 73% were men; 45% white; 20% black; 34% Asians; mean (SD) age 41 (10.2) years, and mean (SD) baseline Positive and Negative Syndrome Scale total score 54.9 (9.03). A total of 53% (n = 113) patients completed the study and 104 received PP 150 mg eq. throughout. Mean (SD) mode dose of PP was 144.8 (19.58) mg eq. The dosing initiation regimen resulted in rapidly achieved and maintained therapeutic paliperidone levels over the study (average concentrations during the dosing interval were 34.7, 40.0, and 47.8 ng/mL after the 2nd, 8th, and 14th injection respectively). Most frequent ([greater than or equal to] 10%) treatment-emergent adverse events were nasopharyngitis (n = 37), insomnia (n = 32), injection-site pain (n = 32), headache (n = 28), and tachycardia (n = 27). Akathisia (n = 19) and tremor (n = 11) were the most common extrapyramidal adverse events. 33 patients had an SAE and 27 discontinued due to treatment-emergent adverse events. No deaths were reported. Mean (SD) weight change from baseline was 2.5 (5.41) kg at endpoint. Patients' psychoses remained stable.

Conclusions: Safety results after one-year therapy with the highest available dose of once-monthly paliperidone palmitate were consistent with results from previous studies, with no new concerns noted. Plasma concentrations were within the expected range.

Clinical Commentary
The optimal dose of long-acting injectable antipsychotics (LAIs) for relapse prevention might be one of the higher marketed doses. In a randomized study of four doses of haloperidol decanoate for example, rates of symptomatic exacerbation were 15% in the 200 mg group, 23% with 100 mg, 25% with 50 mg, but a much higher rate of 60% with 25 mg with no significantly higher side effects in the patients taking higher doses.(3) Underdosing LAI for fear of intolerability (and to use the “lowest possible dose”) is problematic as one of its main benefits, relapse prevention, can be lost. In this phase I trial conducted by the manufacturer, patients received two 234 mg injection loading doses one week apart, followed by monthly 234 mg injections. This schedule is different from the final officially recommended second loading dose of 156 mg. No new safety concerns emerged that would not be expected from a strongly D2-binding drug (eg, prolactin elevation). There is value in publishing phase I trials such as this one. For example, it reassures  clinicians who might otherwise hesitate to use the highest FDA-approved dose of the LAI paliperidone palmitate (ie, 234 mg) in patients who might relapse on a lower dose. Treatment-experienced patients with long illness duration are likely to fall into this category during a switch. Note that 234 mg of paliperidone palmitate is equivalent to about 12 mg oral paliperidone.          

Eicosapentaenoic Acid Interventions in Schizophrenia: Meta-analysis of Randomized, Placebo-Controlled Studies

Fusar-Poli P, Berger G.

J Clin Psychopharmacol. 2012;32(2):179-85.

Background: Omega-3 fatty acids, in particular, eicosapentaenoic acid (EPA) have been suggested as augmentation strategies in the treatment of schizophrenia and related psychosis. Published results are conflicting, and the antipsychotic efficacy of such augmentation strategies is not well established.

Methods: Double-blind, randomized, placebo-controlled studies using purified or EPA-enriched oils in established schizophrenia were included in a meta-analysis. The effect size of EPA on psychotic symptoms was measured using Hedges' g. Publication bias was assessed with funnel plots and Egger's intercept. Heterogeneity was assessed with Q statistic and I index. Influence of moderators was assessed with meta-regression analyses in Comprehensive Meta-analysis Software version 2.

Results: The database included 167 schizophrenic subjects under the placebo arm (mean age, 37 [SD, 9.7] years; 37% females) matched with 168 schizophrenic subjects under the EPA arm (mean age, 37 [SD, 7.9] years; 36% females) (t tests P > 0.05). Meta-analysis showed no consistent significant effect for the EPA augmentation on psychotic symptoms (Hedges' g = 0.242; 95% confidence interval, 0.028-0.512, Z = 1.7531, P>0.05). There were no significant effects for moderator variables such as age, sex, and EPA dose used in the trials. Heterogeneity across studies was small and statistically non significant (Q=9.06; P=0.170; I=33.81).

Conclusions: Meta-analysis of randomized controlled trials on symptomatic outcome revealed no beneficial effect of EPA augmentation in established schizophrenia. However, no conclusion can be made for medium- to long-term effects of EPA in schizophrenia, in particular on relapse prevention in the early course of psychotic disorders.

Clinical Commentary
The “membrane hypothesis of schizophrenia” proposes that some aspects of schizophrenia are explained by cell membrane lipid abnormalities. This line of pathophysiological reasoning has led to treatment attempts with cell membrane-affecting agents, particularly polyunsaturated omega-3 fatty acids (PUFAs). Unfortunately, this meta-analysis of 7 studies found little benefit from an augmentation strategy with eicosapentaenoic acid (EPA) for psychotic symptoms in patients with chronic and first-episode psychosis. EPA is one of the two essential omega-3 fatty acids, with docosahexaenoic acid (DHA) being the second one. However, this is unlikely to be the last word on EPA and schizophrenia as EPA’s benefit might be for affective and not psychotic symptoms. EPA could also be beneficial for other aspects of treatment such as reducing triglyceride levels in patients treated with clozapine, which reliably causes an increase in tricglycerides. Further, issues of optimal dose (more might not be better if there is a bell-shaped dose-response curve) and optimal admixtures of EPA plus DHA still need to be resolved. Last, EPA might have preventive efficacy in an earlier illness phase but not in established schizophrenia.(4)


1. Yung AR, Yuen HP, Berger G, et al. Declining transition rate in ultra high risk (prodromal) services: dilution or reduction of risk? Schizophrenia Bulletin. 2007;33(3):673-81.

2. Strom BL, Eng SM, Faich G, et al. Comparative mortality associated with ziprasidone and olanzapine in real-world use among 18,154 patients with schizophrenia: The Ziprasidone Observational Study of Cardiac Outcomes [ZODIAC]. Am J Psychiatry. 2011;168(2):193-201.

3. Kane JM, Davis JM, Schooler N, et al. A multidose study of haloperidol decanoate in the maintenance treatment of schizophrenia. Am J Psychiatry. 2002;159(4):554-560.

4. Amminger GP, Schafer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67(2):146-154.





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