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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 22, January 2014 —Guest Commentator: Sanjay Gupta, MD, Clinical Professor of Psychiatry, SUNY Buffalo, Buffalo, NY



Psychotic Symptoms and Population Risk for Suicide Attempt: A Prospective Cohort Study

Kelleher I, Corcoran P, Keely H, et al
JAMA Psychiatry. 2013;70(9):940-948.


Objective: Up to 1 million persons die by suicide annually. However, a lack of risk markers makes suicide risk assessment one of the most difficult areas of clinical practice. This study aimed to assess psychotic symptoms (attenuated or frank) as a clinical marker of risk for suicide attempt.


  • Prospective cohort study of 1,112 school-based adolescents (13–16 years of age)
  • Participants were assessed at baseline, 3 months, and 12 months for self-reported psychopathology, psychotic symptoms, and suicide attempts.
  • Outcomes included suicide attempts at the 3- and 12-month follow-up and acute suicide attempts (defined as those occurring in the 2 weeks before an assessment).

: Of the total sample, 7% reported psychotic symptoms at baseline. Of that subsample, 7% reported a suicide attempt by the 3-month follow-up compared with 1% of the rest of the sample; 20% reported a suicide attempt by the 12-month follow-up compared with 2.5% of the rest of the sample (Table). Among adolescents with baseline psychopathology who reported psychotic symptoms, 14% reported a suicide attempt by 3 months and 34% reported a suicide attempt by 12 months. Adolescents with psychopathology who reported psychotic symptoms had a nearly 70-fold increased odds of acute suicide attempts (OR, 67.50; 95% CI, 11.41-399.21). Differences were not explained by nonpsychotic psychiatric symptom burden, multimorbidity, or substance use. In a causative model, the population-attributable fraction of suicide attempts would be 56% to 75% for psychotic symptoms.








With Baseline Psychotic Symptoms


Without Baseline Psychotic Symptoms








With Baseline Psychopathology and Psychosis






Suicide attempt by 3 months



OR 10.01; 95% CI, 2.24-45.49


OR 17.91; 95% CI, 3.61-88.82

Suicide attempt by 12 months



OR 11.27; 95% CI, 4.44-28.62


OR 32.67; 95% CI, 10.42-102.31

Conclusion: Adolescents with psychopathology who report psychotic symptoms are at clinical high risk for suicide attempts. More careful clinical assessment of psychotic symptoms (attenuated or frank) in mental health services and better understanding of their pathological significance are urgently needed.

Clinical Commentary
Early detection of adolescents at risk for suicide has been a major clinical challenge, partly due to lack of consistently validated risk markers. As part of the lethality assessment, clinicians should carefully probe the patient and family for presence of psychotic symptoms especially in those with underlying psychopathology. Early detection of psychosis could prevent potential suicides in at-risk adolescents and have important implications in evaluation and treatment. This could be very helpful in the prevention of violent suicides. The level of risk of suicide attempt predicted by psychotic symptoms is higher than other prominent risk syndromes in medicine. For example, 10% of those with pre-diabetes progress to diabetes in 1 year. Adolescents who develop psychosis should be considered high risk for a suicide attempt.



Association of Depression with Accelerated Cognitive Decline Among Patients with Type 2 Diabetes in the ACCORD-MIND Trial

Sullivan MD, Katon WJ, Lovato LC, et al 
JAMA Psychiatry. 2013;70(9):1041-1047.


Objective: Depression has been identified as a risk factor for dementia among patients with type 2 diabetes mellitus, but the cognitive domains and patient groups most affected have not been identified. This study aimed to determine whether comorbid depression in patients with type 2 diabetes accelerates cognitive decline.


  • A 40-month cohort study of participants in the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial.
  • 52 clinics were organized into 6 clinical networks across the US and Canada.
  • Participants included 2,977 individuals with type 2 diabetes at high risk for cardiovascular events.
  • The Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and the modified Stroop test were used to assess cognition.
  • The 9-item Patient Health Questionnaire was used to assess depression.
  • Mixed-effects statistical models were used to analyze cognitive test outcomes incorporating depression as a time-dependent covariate.

: Participants with scores indicative of depression (9-item Patient Health Questionnaire, ≥10) showed greater cognitive decline during 40-month follow-up on all tests. Differences in estimated least squares means are listed in the Table. This effect of depression on risk of cognitive decline did not differ according to previous cardiovascular disease; baseline cognition or age; or intensive vs standard glucose-lowering treatment, blood pressure treatment, lipid treatment, or insulin treatment. Addition of demographic and clinical covariates to models did not significantly change the cognitive decline associated with depression.

Cognitive Assessments

Estimated Least Squares Means

Digit Symbol Substitution Test

0.72 (95% CI, 0.25 to 1.19; P=.003)

Rey Auditory Verbal Learning Test

0.18 (95% CI, 0.07 to 0.29; P=.001)

Stroop Interference

-1.06 (95% CI, -1.93 to -0.18; P=.02)

Conclusions: Depression in patients with type 2 diabetes was associated with greater cognitive decline in all domains, across all treatment arms, and in all participant subgroups assessed. Future randomized trials will be necessary to determine if depression treatment can lower the risk of cognitive decline in patients with diabetes.

Clinical Commentary
This study adds further to the evidence of recognizing the implications of depression with regard to increased risk of cognitive decline in patients with type 2 diabetes. This effect did not differ based on factors such as glucose control, blood pressure treatment, or lipid treatment. It underscores the importance of early screening for depression, which is a prognostic indicator of increased dementia as well as early intervention and treatment to remission and addressing residual symptoms. Both depression and type 2 diabetes have a bidirectional relationship and both increase the risk of a major neurocognitive disorder. The presence of depression doubles the risk. It is a well-known that even today depression is not adequately recognized and treated to remission.



SSRI Versus Bupropion Effects on Symptoms Clusters in Suicidal Depression: Post-Hoc Analysis of a Randomized Clinical Trial

Grunebaum MF, Keilp JG, Ellis SP, et al 
J Clin Psychiatry. 2013;74(9):872-879.


Objective: Identifying the depression symptoms most closely associated with suicidal thoughts and which medications provide the fastest depression relief may help suicide prevention.


  • A post-hoc analysis of data from a randomized, double-blind, 8-week clinical trial of the SSRI paroxetine controlled release (n=36) versus the norepinephrine-dopamine reuptake inhibitor bupropion extended release (n=38) was conducted in patients with DSM-IV major depressive disorder and past suicide attempt or current suicidal thoughts.
  • Data were collected from February 2005 to January 2010.
  • Treatment effects on Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory symptom clusters were compared.
  • We hypothesized that paroxetine would demonstrate a superior effect on nonsuicidal, affective/cognitive depression symptom clusters that our prior work found to be associated with suicidal thoughts and attempts.

Results: There was a treatment main effect on HDRS psychic depression (depressed mood, guilt, retardation, helpless, hopeless, worthless) (estimate=-2.2; 95% CI, -3.2 to -1.1; t67.16=-4.01; P<.001), one of the clusters most strongly correlated to suicidal ideation. The net drug effect demonstrated that mean psychic depression score was 2.2 points lower after 1 week of paroxetine compared to bupropion treatment. The significance level of this effect was P<.001 at weeks 1 and 2, P=.012 at week 3, and P=.051 at week 4. Results for other depression scale factors were nonsignificant (P>.05).

Conclusions: The results require replication but suggest a pathway by which selective serotonin reuptake inhibitor treatment may exert a stronger effect compared with norepinephrine-dopamine reuptake inhibitor treatment on reduction of suicidal thoughts during initial weeks of pharmacotherapy in these higher risk patients.

Clinical Commentary
Suicide remains an important sentinel event in patients with major depression, akin to cardiac arrest in cardiovascular disease. There have been ongoing attempts to identify early warning signs and select targeted treatment. The use of symptoms clusters is one such approach. This study suggests that the use of SSRIs may help target such a cluster (depressed mood, guilt, retardation, hopelessness, worthlessness) better compared with bupropion. Clinicians looking for predictors in choosing medications may consider this approach for patients with the above symptom cluster such as to have a higher probability of success with the first choice when guided by such data. Clinicians should also note the limited value of a secondary analysis such as this one which needs replication in a prospective fashion. This finding fits with the hypothesis that low serotonin levels are associated with suicides as demonstrated by Marie Asberg, a Swedish psychiatrist in 1975 utilizing 5 HIAA (5 hydroxy indole acetic acid), a metabolite of serotonin in CSF fluid. In addition, serotonin depletion studies have demonstrated increased depression in prone individuals with such psychological symptoms.



Comorbidities and Mortality in Bipolar Disorder: A Swedish National Cohort Study

Crump C, Sundquist K, Winkleby MA, et al   
JAMA Psychiatry. 2013;70(9):931-939.


Objective: Bipolar disorder is associated with premature mortality, but the specific causes and underlying pathways are unclear. To examine the physical health effects of bipolar disorder using outpatient and inpatient data for a national population.


 •  National cohort study of 6,587,036 Swedish adults, including 6618 with bipolar disorder.

  • Physical comorbidities diagnosed in any outpatient or inpatient setting nationwide and mortality (January 1, 2003, through December 31, 2009).

: Women and men with bipolar disorder died earlier, and all-cause mortality was increased among women and men with bipolar disorder, compared with the rest of the population (Table). Patients with bipolar disorder had increased mortality from cardiovascular disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), influenza or pneumonia, unintentional injuries, and suicide for both women and men and cancer for women only. Suicide risk was also higher among men and women with bipolar disorder, compared with the rest of the population. Substance use disorders contributed only modestly to these findings. The association between bipolar disorder and mortality from chronic diseases (ischemic heart disease, diabetes, COPD, or cancer) was weaker among persons with a prior diagnosis of these conditions (aHR, 1.40; 95% CI, 1.26-1.56) than among those without a prior diagnosis (aHR, 2.38; 95% CI, 1.95-2.90; P(interaction)=.01).



Women with Bipolar Disorder

Men with Bipolar Disorder

Age of death

9 years earlier

8.5 years earlier

All-cause mortality

2-fold increase (aHR 2.34; 95% CI, 2.16-2.53)

2-fold increase (aHR 2.03; 95% CI, 1.85-2.23)

Suicide risk

10-fold increase (aHR 10.37; 95% CI, 7.36-14.60)

8-fold increase (aHR 8.09; 95% CI, 5.98-10.95)

aHR=adjusted hazard ratio.

Conclusions: In this large national cohort study, patients with bipolar disorder died prematurely from multiple causes, including cardiovascular disease, diabetes, COPD, influenza or pneumonia, unintentional injuries, and suicide. However, chronic disease mortality among those with more timely medical diagnosis approached that of the general population, suggesting that better provision of primary medical care may effectively reduce premature mortality among persons with bipolar disorder.

Clinical Commentary
This Swedish Cohort Study with a large sample informs us clinicians about a couple of important aspects of mortality in bipolar disorder. It replicates the shorter life span by 8–9 years, common causes of mortality being cardiovascular illness, diabetes, and chronic obstructive pulmonary disease. The study also suggests that the higher mortality is likely due to lack of early diagnosis and treatment of chronic illness and possibly the lifestyle. In those with early diagnosis and adequate management of medical comorbidity, the risk of death approaches that of the general population. It is extremely important for us clinicians to screen for medical comorbidities just as we look for psychiatric ones such as anxiety and substance abuse. Such patients should be gotten in to medical treatment early as that would improve the prognosis. In addition, psychological stability of the bipolar illness is extremely important for managing the medical comorbidities. The selection of medication treatments should also be based on reducing long-term treatment related risk. We should constantly focus on lifestyle issues (weight, exercise, and smoking) that impact cardiovascular disease and diabetes in patients with bipolar illness.



Antipsychotics and the Risk of Type 2 Diabetes  Mellitus in Children and Youth
WV Bubo
JAMA Psychiatry. 2013;70(10):1067-1075.


Objective: The increased prescribing of antipsychotics for children and youth has heightened concerns that this practice increases the risk of type 2 diabetes mellitus. To compare the risk of type 2 diabetes in children and youth 6 to 24 years of age for recent initiators of antipsychotic drugs vs propensity score-matched controls who had recently initiated another psychotropic medication.


• Retrospective cohort study of the Tennessee Medicaid program with 28,858 recent initiators of antipsychotic drugs and 14 429 matched controls.

• The cohort excluded patients with a previous diagnosis of diabetes, schizophrenia, or some other condition for which antipsychotics are the only generally recognized therapy.

• Outcomes included newly diagnosed diabetes during follow-up, as identified from diagnoses and diabetes medication prescriptions.

Results: Users of antipsychotics had a 3-fold increased risk for type 2 diabetes (HR=3.03 [95% CI=1.73-5.32]), which was apparent within the first year of follow-up (HR=2.49 [95% CI=1.27-4.88]). The risk increased with cumulative doses during follow-up (Table; gram equivalents of chlorpromazine). The risk remained elevated for up to 1 year following discontinuation of antipsychotic use (HR=2.57 [95% CI=1.34-4.91]). When the cohort was restricted to children 6 to 17 years of age, antipsychotic users had more than a 3-fold increased risk of type 2 diabetes (HR=3.14 [95% CI=1.50-6.56]), and the risk increased significantly with increasing cumulative dose (P<.03). The risk was increased for use restricted to atypical antipsychotics (HR=2.89 [95% CI=1.64-5.10]) or to risperidone (HR=2.20 [95% CI=1.14-4.26]).


Antipsychotic dose >5 g

Antipsychotic dose 5–99 g

Antipsychotic dose >100 g

Risk of diabetes

HR 2.13 (95% CI, 1.06-4.27)

HR 3.42 (95% CI, 1.88-6.24)

HR 5.43 (95% CI, 2.34-12.61)

Conclusion: Children and youth prescribed antipsychotics had an increased risk of type 2 diabetes that increased with cumulative dose.

Clinical Commentary
This study in children and youth (6–17 years) highlights the three-fold increased risk of type II diabetes in this age group within the first year of follow up. As the risk includes both usage and cumulative dosage it is important that clinicians use these agents judiciously with appropriate monitoring, taking careful family history and ensuring the accuracy of the diagnoses for use. This applies especially when used for a mood disorder or conduct disorder. Nonpharmacologic interventions and family evaluations are important as often the child “may be the symptom of a family”. Early interventions for metabolic problems, including prevention, are important. This is important in light of the fact that obesity and metabolic issues have increased in this age group even in those not mentally ill. Dietary, exercise, and other interventions have increasing importance. Please note that enrollment was between 1996 and 2007. Majority atypical drug usage was risperidone. The other atypicals including olanzapine and quetiapine were not extensively used in this sample, which may have a minimizing effect.




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