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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 1, April 2012 — Guest Commentator: Prakash Masand, MD, Global Medical Education, Inc.

A Randomized Trial Examining the Effectiveness of Switching From Olanzapine, Quetiapine, or Risperidone to Aripiprazole to Reduce Metabolic Risk: Comparison of Antipsychotics for Metabolic Problems (CAMP)
Stroup TS, McEvoy JP, Ring KD, et al
Am J Psychiatry. 2011;168(9):947-956. Epub 2011 Jul 18.

Objective: The authors conducted a multisite randomized controlled trial examining the strategy of switching from olanzapine, quetiapine, or risperidone to aripiprazole to ameliorate metabolic risk factors for cardiovascular disease. 

Method: Patients with schizophrenia or schizoaffective disorder with a body mass index ≥27 and non-high-density lipoprotein (non-HDL) cholesterol ≥130 mg/dl who were on a stable treatment dosage of olanzapine, quetiapine, or risperidone were randomly assigned to switch to aripiprazole (N=109) for 24 weeks or stay on their current medication (N=106). All participants were enrolled in a behaviorally oriented diet and exercise program. Clinical raters were blinded to treatment assignment. The primary and key secondary outcomes were change in non-HDL cholesterol and efficacy failure, respectively. 

Results: The pre-specified primary analysis included 89 switchers and 98 stayers who had at least one post-baseline non-HDL cholesterol measurement. The least squares mean estimates of non-HDL cholesterol decreased more for the switch group than for the stay group (-20.2 mg/dl and -10.8 mg/dl, respectively). Switching was associated with larger weight reductions (least squares mean=2.9 kg) and a net reduction of serum triglycerides of 32.7 mg/dl. Twenty-two switchers (20.6%) and 18 stayers (17.0%) experienced protocol-defined efficacy failure. Forty-seven switchers (43.9%) and 26 stayers (24.5%) discontinued the assigned antipsychotic medication before 24 weeks. 

Conclusions: Switching to aripiprazole led to improvement of non-HDL cholesterol levels and other metabolic parameters. Rates of efficacy failure were similar between groups, but switching to aripiprazole was associated with a higher rate of treatment discontinuation. In the context of close clinical monitoring, switching from an antipsychotic with high metabolic risk to one with lower risk to improve metabolic parameters is an effective strategy.

Clinical Commentary

All atypical antipsychotics can be associated with weight gain and other metabolic problems that increase the risk for cardiovascular disease in psychiatric patients. However as the CATIE trial and other large studies have shown there is a differential risk of metabolic side effects with atypical antipsychotics. Olanzapine, clozapine and quetiapine have the greatest risk, asenapine, risperidone and iloperidone have an intermediate risk whereas ziprasidone, aripiprazole and lurasidone have the lowest risk.  Hence, it is not surprising that patients with metabolic side effects on olanzapine, quetiapine and risperidone who were switched to aripiprazole had a decrease in weight and non-HDL cholesterol. However patients who were switched also had higher rates of discontinuation than stayers making the evaluation of the risk benefit ratio of switching extremely important and discussing it with the patient and their family before switching. Antipsychotics are not interchangeable in terms of efficacy as clinicians are often led to believe making relapse and functional worsening due to switching particularly at important lifepoints for patients potentially hazardous. Clinicians should monitor patients being switched closely for even minimal worsening of symptoms so appropriate actions including increasing dose of new antipsychotic, augmentation or switch to an alternate agent can be considered.


Prevalence and Characteristics of Undiagnosed Bipolar Disorders in Patients With a Major Depressive Episode: The BRIDGE Study
Angst J, Azorin J-M, Bowden CL, et al
Arch Gen Psychiatry. 2011;68(8):791-798.

Context: Major depressive disorder, the most common psychiatric illness, is often chronic and a major cause of disability. Many patients with major depressive episodes who have an underlying but unrecognized bipolar disorder receive pharmacologic treatment with ineffective regimens that do not include mood stabilizers.

Objective: To determine the frequency of bipolar disorder symptoms in patients seeking treatment for a major depressive episode.

Design: Multicenter, multinational, transcultural, cross-sectional, diagnostic study. The study arose from the initiative Bipolar Disorders: Improving Diagnosis, Guidance and Education (BRIDGE).

Setting: Community and hospital psychiatry departments.

Patients: Participants included 5635 adults with an ongoing major depressive episode.

Main Outcome Measures: The frequency of bipolar disorder was determined by applying both DSM-IV-TR criteria and previously described bipolarity specifier criteria. Variables associated with bipolarity were assessed using logistic regression.

Results: A total of 903 patients fulfilled DSM-IV-TR criteria for bipolar disorder (16.0%; 95% confidence interval, 15.1%-17.0%), whereas 2647 (47.0%; 95% confidence interval, 45.7%-48.3%) met the bipolarity specifier criteria. Using both definitions, significant associations (odds ratio > 2; P < .001) with bipolarity were observed for family history of mania/hypomania and multiple past mood episodes. The bipolarity specifier additionally identified significant associations for manic/hypomanic states during antidepressant therapy, current mixed mood symptoms, and comorbid substance use disorder.

Conclusions: The bipolar-specifier criteria in comparison with DSM-IV-TR criteria were valid and identified an additional 31% of patients with major depressive episodes who scored positive on the bipolarity criteria. Family history, illness course, and clinical status, in addition to DSM-IV-TR criteria, may provide useful information for physicians when assessing evidence of bipolarity in patients with major depressive episodes. Such an assessment is recommended before deciding on treatment.

Clinical Commentary

Several studies have demonstrated that bipolar disorder is under-diagnosed and that bipolar patients see an average of 3 physicians and spend 10 years before receiving the correct diagnosis (Lish J 1994, Hirschfield et al. 2003). This study offers us what I often refer to as the “red flags” for bipolar disorder including family history of bipolar illness, multiple episodes of depression (usually at least three), hypomania in response to antidepressants, co-morbid substance use disorder and mixed mood symptoms. Other studies have found adolescent onset of depression, seasonal affective disorder, post partum depression and early and non sustained response to antidepressants as other red flags. Clinicians should look for these red flags in all patients presenting with depressive symptoms. In addition a corroborative history from family members is very valuable in picking up on a bipolar diagnosis since hypomania is an ego-syntonic state. 


Guidelines for Screening and Monitoring of Cardiometabolic Risk in Schizophrenia: Systematic Evaluation
De Hert M, Vancampfort D, Correll CU, et al
Br J Psychiatry. 2011;199(2):99-105.

Background: Metabolic and cardiovascular health problems have become a major focus for clinical care and research in schizophrenia.

Aims: To evaluate the content and quality of screening guidelines for cardiovascular risk in schizophrenia.

Method: Systematic review and quality assessment of guidelines/recommendations for cardiovascular risk in people with schizophrenia published between 2000 and 2010, using the Appraisal of Guidelines for Research and Evaluation (AGREE).

Results: The AGREE domain scores varied between the 18 identified guidelines. Most guidelines scored best on the domains 'scope and purpose' and 'clarity of presentation'. The domain 'rigour of development' was problematic in most guidelines, and the domains 'stakeholder involvement' and 'editorial independence' scored the lowest. The following measurements were recommended (in order of frequency): fasting glucose, body mass index, fasting triglycerides, fasting cholesterol, waist, high-density lipoprotein/low-density lipoprotein, blood pressure and symptoms of diabetes. In terms of interventions, most guidelines recommended advice on physical activity, diet, psychoeducation of the patient, treatment of lipid abnormalities, treatment of diabetes, referral for advice and treatment, psychoeducation of the family and smoking cessation advice. Compared across all domains and content, four European guidelines could be recommended.

Conclusions: Four of the evaluated guidelines are of good quality and should guide clinicians' screening and monitoring practices. Future guideline development could be improved by increasing its rigour and assuring user and patient involvement.

Clinical Commentary

Psychiatric patients have high rates of cardiometabolic disturbances (between 16.7%- 67%), often even prior to treatment. In addition atypical antipsychotics (particularly olanzapine, clozapine, quetiapine and to a lesser extent the others) can cause or worsen cardiometabolic conditions. Clinicians infrequently screen for cardiometabolic risk factors in psychiatric patients despite several guidelines as outlined in this paper. In one study the rate of screening at baseline in the APA/ADA pre-guideline and post-guideline cohorts was 8.4% and 10.5% respectively. At 12 weeks the rates of screening were 6.8% and 9.0% respectively (Haupt et al. 2009). Future efforts should focus on improving the extremely low rates of screening in psychiatric patients rather than the criteria for screening.


Differential Effectiveness of Antipsychotics in Borderline Personality Disorder: Meta-Analyses of Placebo-Controlled, Randomized Clinical Trials on Symptomatic Outcome Domains
Ingehoven TJ, Duivenoorden HJ
J Clin Psychopharmacol. 2011;31(4):489-496.

Objective: In clinical practice, antipsychotic drugs are widely used in borderline personality disorder (BPD). To evaluate current pharmacological treatment algorithms and guidelines for BPD, the authors reviewed and meta-analyzed studies on the effectiveness of antipsychotics on specific symptom domains in BPD.

Methods: The literature was searched for placebo-controlled, randomized clinical trials (PC-RCTs) on the effectiveness of antipsychotics regarding cognitive perceptual symptoms, impulsive behavioral dyscontrol, and affective dysregulation (with subdomains depressed mood, anxiety, anger, and mood lability) in BPD. Studies whose primary emphasis was on the treatment of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition schizotypal personality disorder or Axis I disorders were excluded.

Results: Meta-analyses were conducted using 11 retrieved studies including 1152 borderline patients. Antipsychotics have a significant effect on cognitive perceptual symptoms (9 PC-RCTs; standardized mean difference [SMD], 0.23) and mood lability (5 PC-RCTs; SMD, 0.20) as well as on global functioning (8 PC-RCTs; SMD, 0.25), but these effects have to be qualified as small. Antipsychotics have a more pronounced effect on anger (9 PC-RCTs; SMD, 0.39). Antipsychotics did not have a significant effect on impulsive behavioral dyscontrol, depressed mood, and anxiety in BPD.

Conclusion: Drug therapy tailored to well-defined symptom domains can have beneficial effects in BPD. At short term, antipsychotics can have significant effects on cognitive-perceptual symptoms, anger, and mood lability, but the wide and long-term use of antipsychotics in these patients remains controversial. The findings from this study raise questions on current pharmacological algorithms and clinical guidelines.

Clinical Commentary

The effect sizes of the antipsychotics were small. Lamotrigine and topiramate have larger effect sizes in BPD. Studies have also not found any superiority of atypical antipsychotics to conventional neuroleptics or to each other. Pharmacotherapy plays a small but important role in the management of patients with BPD. It may be particularly helpful to make patients better candidates for therapies that are efficacious in this population


Dopamine D2 Receptor Occupancy and Clinical Effects: A Systematic Review and Pooled Analysis
Uchida H, Takeuchi H, Graff-Guerrero A, Suzuki T, Watanabe K, Mamo DC
J Clin Psychopharmacol. 2011;31(4):497-502.

Positron emission tomography (PET) studies proposed a therapeutic window of D2 receptor occupancy (65%-80%) of antipsychotics for the treatment of schizophrenia in young adults. However, this conclusion has been drawn from clinical PET studies using small sample sizes (<20). Prospective PET studies that measured D2 occupancy levels and assessed extrapyramidal side effects (EPS) and/or treatment response induced by antipsychotics (excluding partial agonists) were identified, using MEDLINE and EMBASE (last search: March 2010). Individual subjects were divided into 2 groups based on EPS status (ie, presence or lack of newly emergent EPS) and treatment response (ie, a ≥ 25% or ≥ 50% reduction in the Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale). To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cutoff points in the D2 occupancy were calculated: Accuracy = (True Positive + True Negative) / Total N. Twelve studies, including a total of 82 subjects, were included in our analyses. The cutoff points associated with 0.5 or greater in both sensitivity and specificity with the greatest accuracy were 77% to 78% for EPS, 60% for a 25% or greater symptom reduction, and 72% for a 50% or greater symptom reduction. These findings support the presence of a therapeutic window of 60% to 78% D2 occupancy of antipsychotics in young adults with schizophrenia and may suggest the presence of a continuum of effectiveness with increasing occupancy within this therapeutic window.

Clinical Commentary

With the conventional neuroleptics clinicians often used the “ neuroleptic threshold dose, “(McEvoy et al. 1991) to determine optimum dosing for treating psychosis. With the atypical antipsychotics by definition efficacy occurs at doses that do not cause EPS. However the present analysis argues for a dose range to achieve efficacy based on occupancy of D2 receptors on PET scans (60%-78%) even among the atypical antipsychotics. This may explain the clinical observation that some patients with schizophrenia need doses at the higher end of the dose range and others at the lower end. This may also account for the observed efficacy of combining low doses of two atypical antipsychotics that clinicians often use in their practice.



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