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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 6, September 2012 — Guest Commentator: Joseph P. McEvoy, Duke University


Disease-Modifying Properties of Long-Term Lithium Treatment for Amnestic Mild Cognitive Impairment: Randomized Controlled Trial

Forlenza OV, Diniz BS, Radanovic M, et al
Br J Psychiatry. 2011;198(5):351-356.

Objective: Two recent clinical studies support the feasibility of trials to evaluate the disease-modifying properties of lithium in Alzheimer's disease, although no benefits were obtained from short-term treatment.

Aims: To evaluate the effect of long-term lithium treatment on cognitive and biological outcomes in people with amnestic mild cognitive impairment (aMCI).

Methods: Forty-five participants with aMCI were randomized to receive lithium (0.25-0.5 mmol/l) (n=24) or placebo (n=21) in a 12-month, double-blind trial. Primary outcome measures were the modification of cognitive and functional test scores, and concentrations of cerebrospinal fluid (CSF) biomarkers (amyloid-beta peptide (Aβ[42]), total tau (T-tau), phosphorylated-tau (P-tau). Trial registration: NCT01055392.

Results: Lithium treatment was associated with a significant decrease in CSF concentrations of P-tau (P=0.03) and better performance on the cognitive subscale of the Alzheimer's Disease Assessment Scale and in attention tasks. Overall tolerability of lithium was good and the adherence rate was 91%.

Conclusions: The present data support the notion that lithium has disease-modifying properties with potential clinical implications in the prevention of Alzheimer's disease.

Clinical Commentary
This group previously reported a lower prevalence of Alzheimer’s disease (AD) among elderly individuals with bipolar disorder (BD) treated with lithium than among elderly individuals with BD not treated with lithium.(1) Two additional cohort studies reported similar advantages for lithium-treated patients with BD. Lithium inhibits glycogen synthase kinase 3 beta, a tau-kinase in the brain that modulates the cleavage of amyloid precursor protein and contributes to the pathophysiology of AD.(2) However, two prospective studies of lithium in individuals with AD without BD failed to demonstrate any advantage for lithium. The present study, in patients with amnestic mild cognitive impairment, was based on the possibility that earlier intervention with lithium, prior to the presence of diagnosed AD, might be more effective. The investigators targeted lithium levels between 0.2–0.5 mEq/L which were very well tolerated by the participants, and benefits were seen in cognitive performance and on biomarkers for AD. The results offer initial promise that as methods become available to detect individuals at high risk for developing AD, early intervention with lithium may have mitigating potential.


Cortical Thinning in Psychopathy

Ly M, Motzkin JC, Philippi CL, et al
Am j Psychiatry. 2012; May 11. doi: 10.1176/appi.ajp.2012.11111627. [Epub ahead of print]

Objective: Psychopathy is a personality disorder associated with severely antisocial behavior and a host of cognitive and affective deficits. The neuropathological basis of the disorder has not been clearly established. Cortical thickness is a sensitive measure of brain structure that has been used to identify neurobiological abnormalities in a number of psychiatric disorders. The authors assessed cortical thickness and corresponding functional connectivity in psychopathic prison inmates.

Methods: Using T1 MRI data, the authors computed cortical thickness maps in a sample of adult male prison inmates selected on the basis of psychopathy diagnosis (21 psychopathic inmates and 31 nonpsychopathic inmates). Using resting-state functional MRI data from a subset of these inmates (20 psychopathic inmates and 20 nonpsychopathic inmates), the authors then computed functional connectivity within networks exhibiting significant thinning among psychopaths.

Results: Relative to nonpsychopaths, psychopaths had significantly thinner cortex in a number of regions, including the left insula and dorsal anterior cingulate cortex, the left and right precentral gyri, the left and right anterior temporal cortices, and the right inferior frontal gyrus. These neurostructural differences were not due to differences in age, IQ, or substance use. Psychopaths also exhibited a corresponding reduction in functional connectivity between the left insula and the left dorsal anterior cingulate cortex.

Conclusions: Psychopathy is associated with a distinct pattern of cortical thinning and reduced functional connectivity.

Clinical Commentary
Psychopathy is characterized by callous, unemotional traits. Psychopaths fail to resonate with other people’s distress and demonstrate impaired ability to recognize fear stimuli. Only 20% to 50% of individuals with antisocial personality disorder (ASPD) demonstrate psychopathy. However, ASPD with psychopathy is associated with increased likelihood of violence, and the heritability of ASPD with psychopathy is stronger than that for ASPD without psychopathy.(3) Psychopathy (callous unemotional traits) can also be present in children and adults without ASPD. As early as 4–8 years of age, children with callous unemotional traits can be shown to fail to attend to the eyes of attachment figures (e.g. their mothers); this impairment is independent of maternal behaviors but associated with “fearlessness” in their fathers.(4) Children with callous unemotional traits have increased risk for later antisocial behavior, poor peer relationships, and hyperactivity. The present article supports prior work demonstrating anatomical and functional imaging abnormalities in the brains of psychopaths.


Dialectical Behavior Therapy Compared with General Psychiatric Management for Borderline Personality Disorder: Clinical Outcomes and Functioning Over a 2-year Follow-up

McMain SF, Guimond T, Streiner DL, et al
Am J Psychiatry. 2012;169(6):650-661.

Objective: The authors conducted a 2-year prospective naturalistic follow-up study to evaluate posttreatment clinical outcomes in outpatients who were randomly selected to receive 1 year of either dialectical behavior therapy or general psychiatric management for borderline personality disorder.

Methods: Patients were assessed by blind raters 6, 12, 18, and 24 months after treatment. The clinical effectiveness of treatment was assessed on measures of suicidal and nonsuicidal self-injurious behaviors, health care utilization, general symptom distress, depression, anger, quality of life, social adjustment, borderline psychopathology, and diagnostic status. The authors conducted between-group comparisons using generalized estimating equation, mixed-effects models, or chi-square statistics, depending on the distribution and nature of the data.

Results: Both treatment groups showed similar and statistically significant improvements on the majority of outcomes 2 years after discharge. The original effects of treatment did not diminish for any outcome domain, including suicidal and nonsuicidal self-injurious behaviors. Further improvements were seen on measures of depression, interpersonal functioning, and anger. However, even though two-thirds of the participants achieved diagnostic remission and significant increases in quality of life, 53% were neither employed nor in school, and 39% were receiving psychiatric disability support after 36 months.

Conclusions: One year of either dialectical behavior therapy or general psychiatric management was associated with long-lasting positive effects across a broad range of outcomes. Despite the benefits of these specific treatments, one important finding that replicates previous research is that participants continued to exhibit high levels of functional impairment. The effectiveness of adjunctive rehabilitation strategies to improve general functioning deserves additional study.

Clinical Commentary
Exploratory, unstructured treatment for borderline personality disorder (BPD) proved to be of limited use, and counter-productive in some patients. Current general psychiatric treatment for patients with BPD is structured and based on manuals with recommendations for addressing common clinical problems. Clinicians providing treatment for patients with BPD should want and choose to do this. They must demonstrate empathy and engagement while providing coherent explanations linking the subjective experience of BPD to a model of pathology. Patients are expected to be active, to become preemptive, and to accept self-agency, in particular to accept links between actions and feelings.(5) With such treatments, most patients with BPD achieve symptomatic remission over 10 or more years of follow-up, although the majority demonstrates persistent functional impairment.(6)


Nocturnal Enuresis with Antipsychotic Medication

Barnes TR, Drake MJ, Paton C.
Br J Psychiatry. 2012;200(1):7-9.

Nocturnal enuresis can be discomfiting and troublesome. There is increasing evidence that as a side effect of second-generation antipsychotics, particularly clozapine, it may be under-recognized. Direct but sensitive questioning may be required to elicit this side effect. We briefly review possible mechanisms of this problem, and management and treatment options.

Clinical Commentary
Estimates of the incidence of nocturnal enuresis among patients taking clozapine have ranged up to 40%; the incidences on risperidone, olanzapine, or quetiapine appears to be lower (5% to 10%).(7) In many individuals enuresis occurs early during treatment and resolves spontaneously, but in some patients the problem persists. It is clear that many patients are deeply embarrassed by this side effect and it is commonly not discovered unless asked about by a trusted clinician. It is likely that this side effect leads to medication noncompliance in some patients, with loss of the therapeutic benefit of the antipsychotic treatment. Effective treatments for enuresis are available. We most commonly use ephedrine 25 mg at bedtime or twice daily(8) or pseudoephedrine if ephedrine is not available. Patients should be told about the possibility of this side effect and that the side effect can be readily and safely corrected should it occur.


Metformin for Treatment of Antipsychotic-Induced Amenorrhea and Weight Gain in Women With First-Episode Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled Study

Wu RR, Jin H, Gao K, et al
Am J Psychiatry. 2012;169(8):813-821.

Objective: Data on the treatment of antipsychotic-induced amenorrhea, particularly when occurring with weight gain, are limited. The authors investigated the efficacy and safety of metformin in the treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia.

Methods: Eighty-four women (ages 18–40 years) with first-episode schizophrenia who suffered from amenorrhea during antipsychotic treatment were randomly assigned, in a double-blind study design, to receive 1,000 mg/day of metformin or placebo in addition to their antipsychotic treatment for 6 months. The primary outcome measures were restoration of menstruation and change in body weight and body mass index (BMI). Secondary outcome measures were changes in levels of prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone; in fasting levels of insulin and glucose; in LH/FSH ratio; and in insulin resistance index. Repeated mixed models with repeated-measures regression analyses and binary logistic regression were used in the analysis.

Results: A total of 76 patients completed the 6-month trial. Significantly more patients in the metformin group (N=28, 66.7%) than in placebo group (N=2, 4.8%) resumed their menstruation. Among patients treated with metformin, BMI decreased by a mean of 0.93 and the insulin resistance index by 2.04. In contrast, patients who received placebo had a mean increase in BMI of 0.85. The prolactin, LH, and testosterone levels and LH/FSH ratio decreased significantly in the metformin group at months 2, 4, and 6, but these levels did not change in the placebo group.

Conclusions: Metformin was effective in reversing antipsychotic-induced adverse events, including restoration of menstruation, promotion of weight loss, and improvement in insulin resistance in female patients with schizophrenia.

Clinical Commentary
Many antipsychotic medications lead to weight gain and insulin resistance, contributing to accelerated cardiovascular risk and the striking disadvantage in mortality that afflicts patients with serious and persistent mental illnesses. The most problematic antipsychotic medications, clozapine and olanzapine, provide additional therapeutic benefit to many patients incompletely responsive to other antipsychotic medications, and they cannot be substituted for. Almost a decade passed after the availability of atypical antipsychotic medications before widespread awareness of these side effects among clinicians occurred, followed by calls to monitor (to what end?). Finally, we have evidence that intervention with metformin is not only effective, but safe, in qualified hands.(9) The value of metformin in diabetes prevention is well established.(10) These authors also call attention to the value of metformin in reducing amenorrhea in antipsychotic-treated women with schizophrenia. We can hope that other potential mitigating agents (e.g. omega-3 fatty acids, statins, aspirin) will be similarly well-studied and ultimately utilized if proven effective and safe.


Comparison of Oral Health Between Inpatients with Schizophrenia and Disabled People or the General Population

Chu KY, Yang NP, Chou P, et al
J Formos Med Assoc. 2012;111(4):214-219.

Objective: There is little comparative research evidence to support the claim that there is disparity in dental care between inpatients with schizophrenia and the disabled people or the general population. This study aimed to investigate whether schizophrenia inpatients had poorer dental care and worse oral health than the disabled people and the general population, respectively.

Methods: An oral health survey was conducted in a specific-psychiatric long-term care institution in Taiwan in 2006. The results of this survey were compared with the findings of oral health investigations of the disabled people or the general population in Taiwan using proportion test and t-test.

Results: This study used decayed, missing, and filled teeth index (DMFT) to describe the condition of dental caries. Compared with the disabled people, schizophrenia inpatients aged 19 to 44 years had a lower subjects' filling rate of DMFT index (FI) and a higher caries experience, but schizophrenia inpatients aged 45 or more had a lower mean number of DMFT. Compared with the general population, schizophrenia inpatients had higher caries experience, mean number of DMFT, percentage edentulous, and community periodontal index and lower FI and number of remaining tooth among various gender or age groups.

Conclusion: In Taiwan, inpatients with schizophrenia have a lower FI than the disabled people and a worse overall oral health status than the general population.

Clinical Commentary
When matched against normal control populations, individuals with schizophrenia are 3–4 times more likely to be edentulous, a condition that affects an individual’s ability to eat comfortably and speak clearly, as well as the individual’s appearance (and contributes to stigma). Among those who have teeth, individuals with schizophrenia have significantly higher rates of dental caries than matched normal control populations.(11) Severe periodontal disease as assessed by plaque index and bleeding on probing is also more prevalent among patients with schizophrenia.(12) Untreated caries and periodontal disease are the leading causes of becoming edentulous. Clinicians certainly should urge patients and their caregivers to support dental hygiene practices (e.g. brushing regularly) and to reduce smoking, but the most important action clinicians can take is to avoid prescribing medications that produce dry mouth. Saliva protects teeth through four mechanisms: diluting and eliminating sugars and other substances, buffer capacity, balancing demineralization/remineralization, and antimicrobial action.(13)

1. Nunez PV, Forlenza OV, Gattaz WF. Lithium and risk for Alzheimer disease in elderly patients with bipolar disorder. Br J Psychiatry. 2007;190:359-360.
2. Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer disease. J Neurochem. 2008;104:1433-1439.
3. Rutter M. Psychopathy in childhood: is it a meaningful diagnosis? Br J Psychiatry. 2012;200(3):175-176.
4. Dadds MR, Allen JL, Oliver BR, et al. Love, eye contact and the developmental origins of empathy vs. psychopathy. Br J Psychiatry. 2012;200(3):191-196.
5. Bateman AW. Treating borderline personality disorder in clinical practice. Am J Psychiatry. 2012;169(6):560-563.
6. Paris J. The outcome of borderline personality disorder: good for most but not all patients. Am J Psychiatry. 2012;169:445-446.
7. Harrison-Woolrych M, Skegg K, Ashton J, Herbison P, Skegg DC. Nocturnal enuresis in patients taking clozapine, risperidone, olanzapine and quetiapine: comparative cohort study. Br J Psychiatry. 2011;199(2):140-144.
8. El Hemaly AK. Nocturnal enuresis: pathogenesis and treatment. Int Urogynecol J Pelvic Floor Dysfunct. 1998;9(3):129-131.
9. Smith RC. Metformin as a treatment for Antipsychotic Drug Side Effects: Special focus on Women with schizophrenia. Am J Psychiatry. 2012;169:774-776.
10. Diabetes Prevention Program Research Group. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care. 2012;35(4):731-737.
11. Kisely S, Quek LH, Pais J, Lalloo R, Johnson NW, Lawrence D. Advanced dental disease in people with severe mental illness: systematic review and meta-analysis. Br J Psychiatry. 2011;199(3):187-93.
12. Eltas A, Kartalcı S, Eltas S, Dündar S, Uslu M. An assessment of periodontal health in patients with schizophrenia and taking antipsychotic medication. Int J Dent Hyg. 2012 May 15. doi: 10.1111/j.1601-5037.2012.00558.x. [Epub ahead of print]
13. Llena-Puy C. The rôle of saliva in maintaining oral health and as an aid to diagnosis. Med Oral Patol Oral Cir Bucal. 2006;11(5):E449-55.

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 5, August 2012 — Guest Commentator: Philip R. Muskin, MD, Columbia University


Responsiveness of Hypochondriacal Patients with Chronic Low-Back Pain to Cognitive-Behavioral Therapy

Nakao M, Shinozaki Y, Nolido N, et al

Psychosomatics. 2012;53(2):139-147.

Background: Evidence has suggested that cognitive-behavioral therapy (CBT) is effective in reducing hypochondriacal symptoms, and another line of evidence has suggested that CBT is also effective in reducing pain and the psychological conditions associated with chronic low-back pain (CLBP). The purpose of this study was to examine the effectiveness of CBT among hypochondriacal patients with and without CLBP.

: A total of 182 hypochondriacal patients were randomly assigned to a CBT or control group. The Somatic Symptom Inventory was used to define CLBP, and the Symptom Checklist 90R (SCL90R) was used to assess psychological symptoms. The outcome measures for hypochondriasis, the Whiteley Index (WI), and the Health Anxiety Inventory (HAI) were administered before the intervention and at 6 and 12 months after completion of the intervention.

: In the total sample, both WI and HAI scores were significantly decreased after treatment in the CBT group compared with the control group. Ninety-three (51%) patients had CLBP; the SCL90R scores for somatization, depression, phobic anxiety, paranoid ideation, and general severity were significantly higher in the CLBP(+) group than in the CLBP(-) group at baseline. Although the WI and HAI scores were significantly decreased after treatment in the CLBP(-) group, such significant pre- to post-changes were not found in the CLBP(+) group.

: CBT was certainly effective among hypochondriacal patients without CLBP, but it appeared to be insufficient for hypochondriacal patients with CLBP. The core psychopathology of hypochondriacal CLBP should be clarified to contribute to the adequate management of hypochondriacal symptoms in CLBP patients.

Clinical Commentary
Patients with complaints of CLBP suffer from physical and psychological disability. In this study of CBT treatment, hypochondriacal patients who scored 4 or more on the low back pain item of the Somatic Symptom Inventory were compared to those who did not have that complaint. The patients did not receive medical treatment for CLBP as part of the study. CBT was effective for the hypochondriasis as measured by the Whiteley Index and the Health Anxiety Inventory in CLBP (-) patients but not those who were CLBP (+).  The CLBP (+) group was significantly different from the CLBP (-) group in terms of ethnicity, with a larger proportion of Caucasians in the CLBP (-) group. Controlling for ethnicity, Caucasian CLBP (+) patients did not respond to CBT compared to Caucasian CLBP (-) patients. A major limitation of the study is that a single item on a rating scale defined CLBP arbitrarily. In spite of the limitations, the study raises interesting questions regarding psychological approaches to patients who experience themselves as having low back pain. Their lives may be dramatically impaired by their health beliefs, and psychological treatments typically effective for hypochondriasis may not be beneficial. It is hoped that further research will identify modifications to CBT that will aid these patients.

Fertility Treatment Response: Is It Better to be More Optimistic or Less Pessimistic?

Bleil ME, Pasch LA, Gregorich SE, et al

Psychosom Med. 2012;74(2):193-199.

Objective: To evaluate the prospective relation between dispositional traits of optimism and pessimism and in vitro fertilization (IVF) treatment failure among women seeking medical intervention for infertility.

: Among 198 women (aged 24-45 years, mean [standard deviation]=35.1 [4.1] years; white, 77%), the outcome of each participant's first IVF treatment cycle was examined. Treatment outcome was classified as being successful (versus failed) if the woman either delivered a baby or was pregnant because of the cycle by the end of the 18-month study period. At baseline, optimism and pessimism were measured as a single bipolar dimension and as separate unipolar dimensions according to the Life Orientation Test total score and the optimism and pessimism subscale scores, respectively.

: Optimism/pessimism, measured as a single bipolar dimension, predicted IVF treatment failure initially (B=-0.09, p=.02, odds ratio [OR]=0.917, 95% confidence interval [CI]=0.851-0.988), but this association attenuated after statistical control for trait negative affect (B=-0.06, p=.13, OR=0.938, 95% CI=0.863-1.020). When examined as separate unipolar dimensions, pessimism (B=0.14, p=.04, OR=1.146, 95% CI=1.008-1.303), not optimism (B=-0.09, p=.12, OR=0.912, 95% CI=0.813-1.023), predicted IVF treatment failure independently of risk factors for poor IVF treatment response and trait negative affect.

Conclusions: Being pessimistic may be a risk factor for IVF treatment failure. Future research should attempt to delineate the biological and behavioral mechanisms by which pessimism may negatively affect treatment outcomes.

Clinical Commentary
When a woman is unsuccessful in her attempts to conceive a child, there is often speculation about how psychological issues might have factored into the failure.  Meta-analyses have indicated that depression and anxiety do not predict the outcome of assisted reproductive technologies (ART), but that stress and state/trait anxiety do have an impact. In this study, optimism and pessimism were measured using the Life Orientation Test and, as the authors note, individuals can “embody traits of both optimism and pessimism concurrently.” They also measured negative trait affect using the 23-item neuroticism subscale of the Eysenck Personality Questionnaire.  Pessimism was negatively correlated with positive IVF treatment outcome, independent of negative trait affect and other risk factors for poor fertility treatment response.  Each 1-unit increase in the pessimism score increased the likelihood of IVF treatment failure by 17.8%. Optimism was not related to the IVF outcome. The authors speculate that pessimism reflects an accurate appraisal by women with poor prognosis; however, the women in the study were undergoing IVF for the first time and older age was related to less pessimism. Some data suggest that pessimism may be amenable to change. Results from this study might be incorporated into the evaluation of women in ART programs and into the psychiatric support provided to the patients.

Optimism, Response to Treatment of Depression, and Rehospitalization After Coronary Artery Bypass Graft Surgery

Tindle H, Belnap BH, Houck PR, et al

Psychosom Med. 2012;74(2):200-207.

Objective: Optimism has been associated with a lower risk of rehospitalization after coronary artery bypass graft (CABG) surgery, but little is known about how optimism affects treatment of depression in post-CABG patients.

: Using data from a collaborative care intervention trial for post-CABG depression, we conducted exploratory post hoc analyses of 284 depressed post-CABG patients (2-week posthospitalization score in the 9-item Patient Health Questionnaire ≥10) and 146 controls without depression who completed the Life Orientation Test-Revised (full scale and subscale) to assess dispositional optimism. We classified patients as optimists and pessimists based on the sample-specific Life Orientation Test-Revised distributions in each cohort (full sample, depressed, nondepressed). For 8 months, we assessed health-related quality of life (using the 36-item Short-Form Health Survey) and mood symptoms (using the Hamilton Rating Scale for Depression [HRSD]) and adjudicated all-cause rehospitalization. We defined treatment response as a 50% or higher decline in HRSD score from baseline.

: Compared with pessimists, optimists had lower baseline mean HRSD scores (8 versus 15, p=.001). Among depressed patients, optimists were more likely to respond to treatment at 8 months (58% versus 27%, odds ratio=3.02, 95% confidence interval=1.28-7.13, p=.01), a finding that was not sustained in the intervention group. The optimism subscale, but not the pessimism subscale, predicted treatment response. By 8 months, optimists were less likely to be rehospitalized (odds ratio=0.54, 95% confidence interval=0.32-0.93, p=.03).

: Among depressed post-CABG patients, optimists responded to depression treatment at higher rates. Independent of depression, optimists were less likely to be rehospitalized by 8 months after CABG. Further research should explore the impact of optimism on these and other important long-term post-CABG outcomes.

Clinical Commentary

Data indicate that optimistic postmenopausal women and older men have a lower risk of a first myocardial infarction, and optimistic people are at lower risk for cardiovascular disease progression. This paper investigates the role of optimism in post-CABG patients, suggesting that factors we do not usually measure may be operative in determining patients’ outcomes. The authors note that optimism and pessimism are not necessarily a bipolar trait and may independently contribute to health outcomes. They screened for depression in post-CABG patients using the PHQ-2 in the hospital, followed by the PHQ-9 via telephone 2 weeks after discharge. Those patients with a score of 10 or higher on the PHQ-9 (moderate depression) were included in the study. They were compared to a group of post-CABG patients who screened negative on the PHQ-2 and had a score of <5 on the follow-up questionnaire. Participants completed the Life Orientation Test-Revised (LOT-R) to measure their optimism/pessimism. Depressed patients were randomized to usual care (UC) or to a collaborative care intervention; however, the patients and their physicians in the UC group were informed of their depression status. After adjusting for intervention type, education level, physical functioning, perceived social support, and baseline depression severity, optimists were significantly more likely to respond to depression treatment. In the UC group the optimists were five times more likely to respond to treatment than the pessimists. Risk of rehospitalization was 46% lower in optimists overall (17% lower in the depressed patients and 65% lower in those not depressed). Optimism appeared to operate independently of pessimism in this study and pessimism was not correlated with outcomes, a finding that varies from other research. A limitation of the study is the failure to obtain LOT-R scores after treatment. Thus, we do not know if the LOT-R scores for depressed patients truly represent optimism/pessimism or depression. Nevertheless, this study points clinicians to investigate patients’ outlook as potentially modifiable factors in their health outcomes.

Pregnancy Outcome After Exposure to Antidepressants and the Role of Maternal Depression: Results From the Norwegian Mother and Child Cohort Study

Nordeng H, van Gelder MM, Spigset O, et al

J Clin Psychopharmacol. 2012;32(2):186-194.

Objective: Results of previous studies on the safety of antidepressants during pregnancy have been conflicting. The primary objective of this study was to investigate whether first-trimester exposure to antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs), was associated with increased risk of congenital malformations. The secondary objective was to examine the effects of exposure to antidepressants during pregnancy on birth weight and gestational age.

: We included 63,395 women from the Norwegian Mother and Child Cohort Study. The women had completed 2 self-administered questionnaires at gestational weeks 17 and 30 on medication use and medical, sociodemographic, and psychological factors. Data on pregnancy outcome were retrieved from the Medical Birth Registry of Norway.

: Of the 63,395 women, 699 (1.1%) reported using antidepressants during pregnancy, most frequently SSRIs (0.9%). Exposure to SSRIs during the first trimester was not associated with increased risk of congenital malformations in general (adjusted odds ratio [OR], 1.22; 95% confidence interval [CI], 0.81-1.84) or cardiovascular malformations (adjusted OR, 1.51; 95% CI, 0.67-3.43). Exposure to antidepressants during pregnancy was not associated with increased risk of preterm birth (adjusted OR, 1.21; 95% CI, 0.87-1.69) or low birth weight (adjusted OR, 0.62; 95% CI, 0.33-1.16).

: This study does not suggest a strongly increased risk of malformations, preterm birth, or low birth weight following prenatal exposure to antidepressants. Without adjustments for level of maternal depression and various sociodemographic and lifestyle factors, antidepressant use during pregnancy would wrongly have been associated with an increased risk of preterm birth.

Clinical Commentary

Safe treatment for depression during pregnancy remains an unsolved problem. Both treating and not treating a depressed pregnant woman exposes the woman and her fetus to risks. Each study contributes something to our knowledge base. In this large study (N=63,395) from the Norwegian Mother and Child Cohort Study, 1.1% reported antidepressant use, with SSRIs being the most frequently used class of medication. There was no increase in risk of congenital malformations in general or cardiovascular malformations associated with first trimester antidepressant use. Antidepressant use was not associated with preterm birth or low birth weight. Women who used antidepressants were also more likely to use benzodiazepines, opioids, hypnotics, and antipsychotics during pregnancy. A major strength of the study is the prospective collection of data; however, major limitations of the study come from how the data were obtained, i.e., self-report, the low response rate (38%), the lack of data obtained about alcohol use, and the lack of data regarding antidepressant dose or duration of exposure. Nevertheless, this study adds to the information we can share with women who are pregnant and in need of treatment for their depression. Ideally, a study will be performed where women are interviewed to obtain accurate information regarding medication use, adherence to treatment, substance use, and outcome of pregnancy. While such a study will not resolve all of the safety issues, it would solve some of the methodological problems of research done to date.

Myocardial Infarction and Generalized Anxiety Disorder: 10-Year Follow-Up

Roest AM, Zuidersma M, de Jonge P

Br J Psychiatry. 2012;200:324-329.

Background: Few studies have addressed the relationship between generalized anxiety disorder (GAD) and cardiovascular prognosis using a diagnostic interview.

: To assess the association between GAD and adverse outcomes in patients with myocardial infarction.

: Patients with acute myocardial infarction (n=438) were recruited between 1997 and 2000 and were followed up until 2007. Current GAD and post-myocardial infarction depression were assessed with the Composite International Diagnostic Interview. The end-point consisted of all-cause mortality and cardiovascular-related readmissions.

: During the follow-up period, 198 patients had an adverse event. GAD was associated with an increased rate of adverse events after adjustment for age and gender (hazard ratio: 1.94; 95% confidence interval: 1.14-3.30; P=.01). Additional adjustment for measures of cardiac disease severity and depression did not change the results.

: GAD was associated with an almost twofold increased risk of adverse outcomes independent demographic and clinical variables and depression.

Clinical Commentary

Most studies investigating the impact of psychological factors on coronary artery disease (CAD) have looked at the role of depression. Depression is a risk factor for both the development of CAD and morbidity and mortality in patients with CAD. This group looked at the prognostic role of GAD over a 10-year period in patients who experienced a myocardial infarction. GAD was associated with an increased risk of cardiovascular events and mortality. Post-myocardial infarction depression was not a significant predictor of adverse outcome in this study. Patients with GAD were two times more likely to have an adverse prognosis even after adjustment for age, gender, and cardiac disease severity. One strength of this study is that the diagnosis was made by a standardized diagnostic interview. The study is also of long duration. It is not known if the patients were treated for their psychiatric disorders and thus we do not have information as to whether interventions would impact on the outcomes. This study does guide us to both inquire ourselves and teach our colleagues to assess patients for both anxiety and depression after a myocardial infarction.

Coping Flexibility and Complicated Grief: A Comparison of American and Chinese Samples

Burton CL, Yan OH, Pat-Horenczyk R, et al

Depress Anxiety. 2012;29(1):16-22.

Background: The ability to process a death and the ability to remain optimistic and look beyond the loss are both thought to be effective means of coping with loss and other aversive events. Recently, these seemingly contrary dimensions have been integrated into the idea of coping flexibility.

: In this study, we assessed the ability of married and bereaved individuals in the United States and Hong Kong to use both coping approaches as operationalized by the trauma-focused and forward-focused coping scales of a previously validated questionnaire. We also calculated a single flexibility score.

: Bereaved participants reported greater trauma-focused coping ability than did married participants. However, bereaved participants meeting criteria for complicated grief (CG) reported less forward-focused coping than both asymptomatic bereaved and married participants. The CG group also showed less overall coping flexibility than the asymptomatic bereaved and married groups. Country was not a factor.

: Findings suggest that deficits in coping flexibility are indicative of pathology in bereaved individuals, and that this relationship extends across cultures. Limitations of the study and directions for future research are discussed.

Clinical Commentary

Freud wrote that the “work” of mourning involved the intense processing of personal meanings and emotions associated with the loss of a loved one. Avoiding this process has been seen as pathological and putting the individual at risk for delayed grief syndromes. Emerging research suggests that flexibility in coping may be a better predictor of grief outcome. This study used a structured clinical interview for DSM-IV-TR for depression comparing married individuals and a group of conjugally bereaved individuals in the United States and Hong Kong. The bereaved participants were questioned about symptoms of complicated grief. Despite the cultural differences between the countries, the ability of bereaved individuals to use flexible coping strategies was more important in distinguishing pathological grief reactions than using a particular coping strategy. While the asymptomatic bereaved and complicated grief groups reported high trauma-focused coping than the married controls, the complicated grief group used less forward-focused coping. The complicated grief group was less flexible than either of the other groups. These results suggest that individuals who can focus on their loss and also move beyond the loss are less likely to develop complicated grief. The therapeutic implications are interesting and suggest how we might work with patients who have suffered a loss both to treat complicated grief and to possibly prevent the occurrence of this painful state.

Cardiac Transplantation in Adult Patients with Mental Retardation: Do Outcomes Support Consensus Guidelines?

Samelson-Jones E, Mancini DM, Shapiro PA

Psychosomatics. 2012;53(2):133-138.

Background: Selection criteria guidelines list mental retardation as a relative contraindication to heart transplantation, but not to kidney transplantation.

: The authors present a case series of adults with mental retardation or comparable acquired intellectual disability who underwent heart transplantation. They discuss the literature on heart and kidney transplantation in people with mental retardation and the ethical reasoning that guides how recipients of solid organ grafts are chosen.

: Literature review and retrospective review of long-term outcomes for five adult patients with mental retardation or comparable disability who received heart transplants.

: Among these cases, survival times to date ranged from 4 to 16 years, with a median survival of greater than 12 years. Medical non-adherence was a significant factor in only 1 of the 5 cases. In that case, the patient's medical non-adherence was due to a functional decline in the primary caretaker.

: People with mental retardation can receive long-term benefit from heart transplantation when they have the cognitive and social support necessary to ensure adherence to post-transplant regimens. There is no ethical or medical reason for guidelines to consider mental retardation, in and of itself, a contraindication to heart transplantation. The totality of the individual patient's circumstances should be considered in assessing transplant candidacy.

Clinical Commentary

Psychosocial factors are assessed as part of a pre-transplantation evaluation. Mental retardation is a relative contraindication to cardiac transplantation and concerns regarding adherence in these patients may limit their ability to be listed for transplantation. The authors reviewed the cases of four patients with mental retardation and one case of acquired intellectual disability (anoxic brain injury) out of the 2,199 heart transplantations performed at New York-Presbyterian hospital from 1978 to 2010.  They note that contraindications for transplantation have been modified over the decades since renal transplantation was first begun. For example, age limitations for transplantation have progressively increased. They note that patients with mental retardation are less frequently referred to transplantation centers and are less frequently listed for transplantation; however, the evidence from renal transplantation indicates that the outcome for these patients is comparable to patients without mental retardation. The survival time in the five patients reviewed ranged from four to fourteen years, with a mean survival time >12 years. Only one case demonstrated medical non-adherence and that was secondary to a functional decline in the patient’s caregiver. As they note, “Patients with mental retardation should not be held to a higher standard than other patients.”  Reviews such as this one inform how we as psychiatrists can contribute with our non-psychiatric colleagues in the decisions regarding this life-saving but extremely limited procedure.  

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.





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 2, May 2012 — Guest Commentator: Sanjay Gupta, MD, S.U.N.Y., Buffalo, NY


The Role of Psychomotor Activation in Discriminating Unipolar from Bipolar Disorders: A Classification-tree Analysis

Cassano GB, Rucci P, Benvenuti A, et al
J Clin Psychiatry. 2012;73(1):22-28.

Objective: Multiple studies indicate that bipolar disorders are often underrecognized, misdiagnosed, and incorrectly treated. The aim of the present report is to determine which combination of clinical, demographic, and psychopathological factors and corresponding cutoff scores best discriminate patients with unipolar disorder from those with bipolar disorders. 

Method: The study sample includes outpatients and inpatients (N = 1,158) participating in 5 studies carried out in the United States and Italy between October 2001 and March 2008, one of which was a randomized clinical trial. Diagnostic assessment was carried out with the SCID, which allows diagnoses to be made according to DSM-IV-TR criteria. Using an exploratory statistical approach based on a classification tree, we employed 5 mania spectrum factors and 6 depression spectrum factors derived from the Mood Spectrum Self-Report Instrument (MOODS-SR) in combination with demographic and clinical characteristics to discriminate participants with unipolar versus bipolar disorders.

Results: The psychomotor activation factor, assessing the presence of thought acceleration, distractibility, hyperactivity, and restlessness for 1 or more periods of at least 3 to 5 days in the lifetime, identified subgroups with an increasing likelihood of bipolar disorder diagnosis. Mixed instability and suicidality contributed to further subtyping the sample into mutually exclusive groups, characterized by a different likelihood of receiving a diagnosis of bipolar disorder. Of the demographic and clinical characteristics included in the analysis, only sex proved to be useful to improve the discrimination.

Conclusions: The psychomotor activation factor proved to be the most potent discriminator of those with unipolar versus bipolar diagnoses. The items that constitute this factor, together with those that constitute the mixed instability, suicidality, and euphoria factors, might be useful in making the differential diagnosis.

Clinical Commentary
Bipolar disorder is often considered the “missed diagnosis” because patients tend to present during the depressed phase of the illness when manic symptoms are not obvious. Resulting prescription of antidepressants may cause the bipolar illness to accelerate. Thus, it is extremely important to discriminate between unipolar and bipolar depression as treatments differ. The items listed in the psychomotor activation factor facilitate this process as in the study and are also part of the 13-item Mood Disorder Questionnaire, which is a helpful clinical tool for this differentiation.

Cell Atrophy and Loss in Depression: Reversal by Antidepressant Treatment

Banasr M, Dwyer JM, Duman RS
Curr Opin Cell Biol. 2011;23(6):730-737. Epub 2011 Oct 11.

Depression is associated with structural alterations in limbic brain regions that control emotion and mood. Studies of chronic stress in animal models and postmortem tissue from depressed subjects demonstrate that these structural alterations result from atrophy and loss of neurons and glial cells. These findings indicate that depression and stress-related mood disorders can be considered mild neurodegenerative disorders. Importantly, there is evidence that these structural alterations can be blocked or even reversed by elimination of stress and by antidepressant treatments. A major focus of current investigations is to characterize the molecular signaling pathways and factors that underlie these effects of stress, depression, and antidepressant treatment. Recent advances in this research area are discussed and potential novel targets for antidepressant development are highlighted.

Clinical Commentary
This study affirms that stress has an impact on brain structure over time, resulting in atrophy and loss of neurons and glial cells through various complex mechanisms. This article provocatively suggests that mood disorder may be a mildly degenerative problem. Eliminating stress may reverse the changes. Clinicians should realize the importance of a holistic approach in the management of a patient with major depression, which includes pharmacotherapy and psychotherapy as well as lifestyle changes to reduce stress and overall improvement of the individual patient. The relationships between continued stress, brain derived neurotrophic factor, cell loss, and cognitive impairment are complex and are becoming better understood.

Incidence of Tardive Dyskinesia with Risperidone or Olanzapine in the Elderly: Results From a 2-year, Prospective Study in Antipsychotic-naïve Patients

Woerner MG, Correll CU, Alvir JM, et al
Neuropsychopharmacology. 2011;36(8):1738-1746. Epub 2011 Apr 20.

Objective: Tardive dyskinesia (TD) rates with second-generation antipsychotics (SGAs) are considered to be low relative to first-generation antipsychotics (FGAs), even in the particularly vulnerable elderly population. However, risk estimates are unavailable for patients naïve to FGAs. Therefore, we aimed to determine the TD incidence in particularly vulnerable, antipsychotic-naïve elderly patients treated with the SGA risperidone or olanzapine.

Method: The present work describes a prospective inception cohort study of antipsychotic-naïve elderly patients aged >55 years identified at New York Metropolitan area in-patient and out-patient geriatric psychiatry facilities and nursing homes at the time of risperidone or olanzapine initiation. At baseline, 4 weeks, and at quarterly periods, patients underwent assessments of medical and medication history, abnormal involuntary movements, and extra-pyramidal signs. TD was classified using Schooler-Kane criteria. Included in the analyses were 207 subjects (age: 79.8 years, 70.0% female, 86.5% White), predominantly diagnosed with dementia (58.9%) or a major mood disorder (30.9%), although the principal treatment target was psychosis (78.7%), with (59.4%) or without (19.3%) agitation.

Results: With risperidone (n=159) the cumulative TD rate was 5.3% (95% confidence interval (CI): 0.7, 9.9%) after 1 year (mean dose: 1.0±0.76 mg/day) and 7.2% (CI: 1.4, 12.9%) after 2 years. With olanzapine (n=48) the cumulative TD rate was 6.7% (CI: 0, 15.6%) after 1 year (mean dose: 4.3±1.9 mg/day) and 11.1% (CI: 0, 23.1%) after 2 years. TD risk was higher in females, African Americans, and patients without past antidepressant treatment or with FGA co-treatment.

Conclusions: The TD rates for geriatric patients treated with risperidone and olanzapine were comparable and substantially lower than previously reported for similar patients in direct observation studies using FGAs. This information is relevant for all patients receiving antipsychotics, not just the especially sensitive elderly.

Clinical Commentary
Clinicians may have become complacent about monitoring for tardive dyskinesia (TD) in antipsychotic-exposed patients, partly due to the widespread use of second-generation antipsychotics. Despite much lower risk of TD than with first-generation agents (SGAs), it is still necessary to monitor elderly patients for early signs of TD every 3 months using the Abnormal Involuntary Movement Scale (AIMS), as indicated in the study. The risk may be higher in females and African Americans. Despite the fact that SGAs risperidone and olanzapine are commonly used in the elderly when an antipsychotic is indicated, judicious use is indicated due to boxed warnings, especially when used off-label for dementia-related psychosis.


Proinflammatory and "Resiliency" Proteins in the CSF of Patients with Major Depression

Martinez JM, Garakani A, Yehuda R, Gorman JM
Depress Anxiety. 2012;29(1):32-8. Epub 2011 Sep 2

Objective: A number of studies have shown that elevated levels of inflammatory cytokines may promote depression and suicidal ideation and that neuroprotective peptides may decrease the response to stress and depression. In this study, cerebrospinal fluid (CSF) levels of three inflammatory cytokines (IL-1, IL-6, and tumor necrosis factor α (TNFα)) and two putative "resiliency" neuropeptides (brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY)) were compared between patients with depression and healthy controls

Method: Eighteen patients with major depression and 25 healthy controls underwent a lumbar puncture; CSF samples were withdrawn and assayed for IL-1, IL-6, TNFα, BDNF, and NPY levels. Patients with depression were then entered into an 8-week treatment protocol and had repeated lumbar puncture procedures post-treatment.

Results: Contrary to prediction, we found that at baseline depressed patients had higher CSF NPY concentration compared to the normal comparison group. Within the depressed patients, we found several statistically significant correlations between elevated CSF cytokine levels and clinical severity.

Conclusions: Despite the small sample size, given the challenges in obtaining CSF from patients with depression these data are of interest in confirming some aspects of the inflammatory hypothesis of depression.

Clinical Commentary
There continues to be a quest for biomarkers of depression akin to blood sugar in diabetes. This study conducted cerebrospinal fluid (CSF) measurements of various cytokines, brain derived neurotrophic factor (BDNF), and neuropeptide Y. Some of the findings, such as those related to BDNF and neuropeptide Y, were not expected, while there was good replication of cytokine elevation in the CSF in this disease state. In addition, the study suggests that high levels of TNF-alpha predicts poorer response to medication. Currently, this research suggests that some robust biomarkers for antidepressant response are being replicated while others are not. While this finding does not yet have much clinical implication, it is a research finding that clinicians should be aware of. More widespread use of these tests is currently limited by their invasive nature and a simpler way of measuring cytokines in the blood/CSF is warranted.

Serum Levels of Brain-Derived Neurotrophic Factor in Major Depressive Disorder: State-trait Issues, Clinical Features and Pharmacological Treatment

Molendijk ML, Bus BA, Spinhoven P, et al
Mol Psychiatry. 2011 Nov;16(11):1088-1095. Epub 2010 Sep 21.

Objective: Recent evidence supports 'the neurotrophin hypothesis of depression' in its prediction that brain-derived neurotrophic factor (BDNF) is involved in depression. However, some key questions remain unanswered, including whether abnormalities in BDNF persist beyond the clinical state of depression, whether BDNF levels are related to the clinical features of depression and whether distinct antidepressants affect BDNF levels equally.

Method: We addressed these questions and investigated serum BDNF levels in 962 depressed patients, 700 fully remitted persons (≥6 months) and 382 healthy controls.

Results: We found serum BDNF levels to be low in antidepressant-free depressed patients relative to controls (P=0.007) and to depressed patients who were treated with an antidepressant (P=0.001). BDNF levels of fully remitted persons (whether unmedicated or treated with an antidepressant) were comparable to those of controls. Analyzing the sample of antidepressant-free depressed patients showed that BDNF levels were unrelated to the core clinical features of depression such as its severity or first versus a recurrent episode. The antidepressant associated upregulation of serum BDNF in depressed patients was confined to selective serotonin reuptake inhibitors (SSRIs) (P=0.003) and St John's wort (P=0.03).

Conclusions: Our results suggest that low serum levels of BDNF are a state abnormality that is evident during depression and normalizes during remission. Increases in serum levels of BDNF during antidepressant treatment appear to be confined to some antidepressants and do not parallel clinical characteristics, such as the severity of depressive symptoms.

Clinical Commentary
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is linked to the viability of neurons in brain circuits regulating emotion. It is akin to “fertilizer for the brain.” The study’s findings, revealing that BDNF levels were low in patients with major depressive disorder, are of significance. BDNF may be an important biomarker for depression—a finding that needs to be further explored. In addition, the study found that depressed patients in remission and off antidepressant therapy had levels similar to normal controls. In comparison, there were lower levels in depressed patients who were not on antidepressant therapy, suggesting that normalization of BDNF levels may indicate remission. This also establishes low levels of BDNF as a state characteristic of depression. The BDNF levels were low in the early phase of remission, suggesting it may take time to normalize as other brain changes occur. Interestingly, the increase in serum levels of BDNF was specific to SSRIs and St. John’s wort. It is unclear why SSRIs and St. John’s wort (efficacy trials for major depression were negative) specifically increase BDNF levels.  Clinicians should take into account that these are early biomarkers and continue to follow the research. Currently, data do not suggest that BDNF be measured in day-to-day clinical practice. SSRIs remain the first-line treatment for depression. St. John’s Wort still cannot be recommended as it is not FDA approved and does not have good supportive clinical trials and standardized production as a medication.


Differential Risk of Death in Older Residents in Nursing Homes Prescribed Specific Antipsychotic Drugs: Population-Based Cohort Study

Huybrechts KF, Gerhard T, Crystal S, et al.
BMJ. 2012;344:e977.

Objective: To assess risks of mortality associated with use of individual antipsychotic drugs in elderly residents in nursing homes.

Method: Population based cohort study with linked data from Medicaid, Medicare, the Minimum Data Set, the National Death Index, and a national assessment of nursing home quality. Participants: 75 445 new users of antipsychotic drugs (haloperidol, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone). All participants were aged ≥65, were eligible for Medicaid, and lived in a nursing home in 2001-5. Main outcome measures Cox proportional hazards models were used to compare 180 day risks of all cause and cause specific mortality by individual drug, with propensity score adjustment to control for potential confounders.

Results: Compared with risperidone, users of haloperidol had an increased risk of mortality (hazard ratio 2.07, 95% confidence interval 1.89 to 2.26) and users of quetiapine a decreased risk (0.81, 0.75 to 0.88). The effects were strongest shortly after the start of treatment, remained after adjustment for dose, and were seen for all causes of death examined. No clinically meaningful differences were observed for the other drugs. There was no evidence that the effect measure modification in those with dementia or behavioural disturbances. There was a dose-response relation for all drugs except quetiapine.

Conclusions: Though these findings cannot prove causality, and we cannot rule out the possibility of residual confounding, they provide more evidence of the risk of using these drugs in older patients, reinforcing the concept that they should not be used in the absence of clear need. The data suggest that the risk of mortality with these drugs is generally increased with higher doses and seems to be highest for haloperidol and least for quetiapine.

Clinical Commentary
This study involved a large sample of residents in skilled nursing facilities (SNF) who were typical of patients treated by physicians in this type of setting. Atypical antipsychotics should be preferred in the SNF setting due to the lower risk of movement disorders, especially tardive dyskinesia, compared to the conventional antipsychotics. In an area where the usage of atypical antipsychotics is mostly off-label, risperidone has the advantage of being the best studied. However, this study suggests that quetiapine may be safer, although the efficacy of this agent is not as good as risperidone. Of note, the haloperidol group in the study had more preexisting cardiovascular problems and other comorbid conditions which should be taken into account. In rare instances where rapid control of an agitated patient is needed, haloperidol intramuscular (IM) may be used, though lorazepam IM can be tried first. There is also a separate body of literature attesting to the safety of haloperidol IV in high dosages given to delirious patients, though they were typically not SNF patients. In a compromised population, antipsychotics should be used judiciously, and the utilization and documentation of informed consent from healthcare proxies is important. The discussion should weigh in on a risk-benefit analysis, including the boxed warnings, and specific target symptoms for which the treatment is aimed should be clearly stated. Clinicians should be aware that the maximum dosages for these agents is much lower in the SNF population; for example, 2 mg for risperidone and 200 mg for quetiapine in divided doses. The most data for use is with risperidone, olanzapine, and quetiapine, respectively. Several studies suggest a higher risk of mortality in patients given haloperidol and lower risk in patients prescribed quetiapine. There is a likelihood that these effects are dose related. Data for divalproex are very limited. Also note that prescribing antidepressants as an alternative for dementia-related psychosis will not be helpful. In addition, periodic gradual dosage reduction (GDR) should be tried after a 3–4 month period of stabilization. If GDR fails, then documentation to that effect needs to be done by a psychiatrist, preferably a geriatric psychiatrist, and the patient should be continued on the medication. It is important to keep the family informed of the clinical situation.



Mon, 01/09/2012 - 19:59 -- admin

Prakash Masand, M.D., is Founder, Chairman, and CEO of Global Medical Education (GME) and also serves as Adjunct Professor at the Academic Medicine Education Institute, Duke-National University of Singapore Medical School (Duke-NUS). He is also the Co-founder, Chairman, and CEO of Centers of Psychiatric Excellence (COPE). He was also Consulting Professor of Psychiatry and Behavioral Sciences at Duke University Medical Center in Durham, NC. He previously served as Director of Therapeutic Area Development, Neurosciences Medicine at the Duke Clinical Research Institute. Dr. Masand was also the Founder of psychCME, Inc., a leading program for continuing medical education in the United States, which was acquired by United Health Group, in 2006.

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.




Tue, 12/27/2011 - 22:40 -- admin

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