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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 3, June 2012 — Guest Commentator: Roger S. McIntyre, MD, University of Toronto, Canada


Co-occurrence of Serious or Misdiagnosed Medical Conditions with Bipolar Disorder Preventing Clinical Trial Randomization: A Case Series

 Feldman NS, Gwizdowski IS, Fischer EG, et al
J Clin Psychiatry. 2012; Mar 6. Epub ahead of print.

Background: Studies have shown that patients with bipolar disorder have high rates of serious and/or untreated co-occurring general medical conditions. This case series examined reports of co-occurring medical conditions with bipolar disorder in potential clinical study participants, and in particular the percentage of these individuals who were previously unaware of their conditions.

Method: Patients were potential participants in 1 of 2 medication trials who met DSM-IV criteria for bipolar disorder and were excluded from those studies just prior to randomization from May 2009 through July 2011. Patients were compared with each other on a number of demographic criteria, including age, race, gender, reason for exclusion from the trial, and psychiatric diagnoses.

Results: Of the patients excluded from the studies just prior to randomization, 31% (n=10) were excluded because of medical conditions previously unreported by the patient during screening for these studies. Seventy percent of those excluded patients (n=7) had no prior knowledge of their conditions.

Conclusions: These results suggest that patients with bipolar disorder may not only have high rates of co-occurring medical conditions but also frequently remain unaware of those conditions. These findings indicate that co-occurring general medical conditions may be a more serious problem in the treatment of bipolar disorder than previously appreciated and that more stringent monitoring and guidelines are needed regardless of medication regimen. This case series asserts that, regardless of a patient's claim of having no medical conditions, more general medical screening may be needed in outpatient psychiatric settings.

Clinical Commentary
Individuals with bipolar disorder are differentially affected by disparate, comorbid, medical disorders. The co-occurrence of comorbid medical conditions in many individuals is preventable (e.g. by choosing medications with less weight gain propensity) and has been shown to be associated with a more complex illness presentation, course, and outcome. The findings of Feldman and colleagues extend our knowledge by reporting that the majority of individuals with bipolar disorder (i.e. 70%) do not know they have a comorbid medical problem. This latter observation provides empirical support for routine and systematic screening and surveillance for medical disorder risk factors and their occurrence as part of routine care. 


Psychiatric Disorders with Postpartum Onset: Possible Early Manifestations of Bipolar Affective Disorders

Munk-Olsen T, Laursen TM, Meltzer-Brody S, et al
Arch Gen Psychiatry. 2012;69(4):428-434. 

Background: Childbirth has an important influence on the onset and course of bipolar affective disorder, and it is well established that there may be a delay of many years before receiving a diagnosis of bipolar disorder following an initial episode of psychiatric illness.

Methods: To study to what extent psychiatric disorders with postpartum onset are early manifestations of an underlying bipolar affective disorder. Survival analyses were performed in a register-based cohort study linking information from the Danish Civil Registration System and the Danish Psychiatric Central Register. A total of 120,378 women with a first-time psychiatric inpatient or outpatient contact with any type of mental disorder excluding bipolar affective disorder. Each woman was followed up individually from the day of discharge, with the outcome of interest being an inpatient or outpatient contact during the follow-up period with a first-time diagnosis of bipolar affective disorder.

Results: A total of 3,062 women were readmitted or had an outpatient contact with bipolar affective disorder diagnoses. A postpartum onset of symptoms within 0 to 14 days after delivery predicted subsequent conversion to bipolar disorder (relative risk=4.26; 95% CI 3.11-5.85). Approximately 14% of women with first-time psychiatric contacts during the first postpartum month converted to a bipolar diagnosis within the 15-year follow-up period compared with 4% of women with a first psychiatric contact not related to childbirth. Postpartum inpatient admissions were also associated with higher conversion rates to bipolar disorder than outpatient contacts (relative risk=2.16; 95% CI 1.27-3.66).

Conclusions: A psychiatric episode in the immediate postpartum period significantly predicted conversion to bipolar affective disorder during the follow-up period. Results indicate that the presentation of mental illness in the early postpartum period is a marker of possible underlying bipolarity.

Clinical Commentary
The postpartum period is the most vulnerable time for a woman to present with new onset and recurrent mental illness, with depressive symptomatology being the most often encountered presentation. The results of Munk-Olsen et al. indicate that the probability of a female having bipolar disorder is four times higher if her first psychiatric contact occurs during the first postpartum month when compared to women whose first psychiatric contact is unrelated to childbirth. These results underscore the importance of careful screening (i.e. with the MDQ) for mental illness during the postpartum period, with careful attention to the possibility of bipolar disorder. 


Association of Depression with Increased Risk of Dementia in Patients with Type 2 Diabetes

Katon W, Lyles CR, Parker MM, et al
Arch Gen Psychiatry. 2012;69(4):410-417. 

Background: Although depression is a risk factor for dementia in the general population, its association with dementia among patients with diabetes mellitus has not been well studied. To determine whether comorbid depression in patients with type 2 diabetes increases the risk of development of dementia. 

Method: The Diabetes and Aging Study was a cohort investigation that surveyed a racially/ethnically stratified random sample of patients with type 2 diabetes. A large, integrated, nonprofit managed care setting in Northern California. A sample of 19 239 diabetes registry members 30 to 75 years of age. The Patient Health Questionnaire 8, International Classification of Diseases, Ninth Revision (ICD-9) diagnoses of depression, and/or antidepressant prescriptions in the 12 months prior to baseline were used to identify prevalent cases of depression. Clinically recognized dementia was identified among subjects with no prior ICD-9 Clinical Modification (ICD-9-CM) diagnoses of dementia. To exclude the possibility that depression was a prodrome of dementia, dementia diagnoses were only based on ICD-9-CM diagnoses identified in years 3 to 5 post baseline. The risk of dementia for patients with depression and diabetes relative to patients with diabetes alone was estimated using Cox proportional hazard regression models that adjusted for sociodemographic, clinical, and health risk factors and health use.

Results: During the 3- to 5-year period, 80 of 3,766 patients (2.1%) with comorbid depression and diabetes (incidence rate of 5.5 per 1,000 person-years) vs 158 of 15,473 patients (1.0%) with diabetes alone (incidence rate of 2.6 per 1,000 person-years) had 1 or more ICD-9-CM diagnoses of dementia. Patients with comorbid depression had a 100% increased risk of dementia during the 3 to 5 years post baseline (adjusted hazard ratio, 2.02; 95% confidence interval, 1.73-2.35).

Conclusions: Depression in patients with diabetes was associated with a substantively increased risk for development of dementia compared with those with diabetes alone.

Clinical Commentary
Replicated evidence indicates that mood disorders and diabetes mellitus are frequently comorbid and highly associated with new-onset dementing disorders (e.g. Alzheimer’s disease, vascular dementia). The results of Katon and colleagues indicate that the risk of all-cause dementia is significantly higher in adults who have both depression and diabetes mellitus when compared to diabetes mellitus or depression alone. These findings are a reminder to routinely screen for diabetes mellitus in all patients with mood disorders and vice versa. It is also a reminder that a consequence of both mood disorders and diabetes mellitus are dementing conditions, raising the intriguing and possible scenario that effective treatment and prevention of both conditions may forestall and possibly prevent the onset of dementia. 


Efficacy of Dose Increase Among Non-responders to Low-Dose Aripiprazole Augmentation in Patients with Inadequate Response to Antidepressant Treatment: A Randomized, Double-Blind, Placebo-Controlled, Efficacy Trials

Mischoulon D, Witte J, Levy M, et al
J Clin Psychiatry. 2012;73(3):353-366. 

Background: To examine the efficacy of a dose increase of aripiprazole to 5 mg/d in subjects with major depressive disorder (MDD) who did not respond to 4 weeks of treatment with aripiprazole 2 mg/d in a randomized, double-blind, placebo-controlled, parent study.

Method: 221 subjects with Structured Clinical Interview for DSM-IV Axis I Disorders-Patient Edition-diagnosed DSM-IV-TR MDD (mean±SD age, 45±11 years; 64% women) with inadequate antidepressant response were recruited from September 2008–July 2009 and randomized to 60 days of double-blind augmentation with either aripiprazole or placebo in two 30-day phases. The study was performed across 8 academic hospital sites and 14 nonacademic (private clinic) sites throughout the United States. Randomization in a 2:3:3 ratio per sequential parallel comparison design was drug/drug (aripiprazole 2 mg/d in phase 1 and 5 mg/d in phase 2), placebo/placebo (placebo in both phases), and placebo/drug (placebo in phase 1 and aripiprazole 2 mg/d in phase 2). In phase 2, we examined efficacy of an aripiprazole dose increase to 5 mg/d in nonresponders to 2 mg/d by assessing response rates (≥ 50% reduction in Montgomery-Asberg Depression Rating Scale [MADRS] score [primary outcome measure]) and score changes in MADRS, Quick Inventory of Depressive Symptomatology-Self-Report, 9-item Patient Health Questionnaire (PHQ-9), the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales, and patient-rated versions of the CGI-I and CGI-S scales.

Results: Response rate for aripiprazole 2 mg/d in phase 1 was 18.5% (n/n = 10/54). Among 39 nonresponders who increased their dose to 5 mg/d, response rate was 12.8% (95% CI, 4.30%-27.43%), with significant overall mean ± SD reductions in MADRS scores (-9.46 ± 7.83 [95% CI, -12.00 to -6.92]; P < .0001), Symptoms Questionnaire Distress scores (19.51 ± 17.73 [95% CI, 13.60 to 25.43]; P < .0001), PHQ-9 scores (-7.92 ± 5.92 [95% CI, -9.89 to -5.94]; P < .0001), and CGI-S scores (-0.86 ± 0.86 [95% CI, -1.15 to -0.58]; P < .0001). Differences in efficacy between drug and placebo groups were nonsignificant, however. Aripiprazole and placebo were well tolerated.

Conclusions: Augmentation with aripiprazole 5 mg/d may provide only a modest additional benefit in patients who do not benefit from lower doses.

Clinical Commentary
Several atypical antipsychotic agents are FDA approved in combination with antidepressants. Identifying the appropriate target dose for an individual patient is an often encountered clinical challenge. Under-dosing remains a modifiable deficiency in the management of depression. The results herein indicate that patients insufficiently responsive to aripiprazole 2 mg as augmentation have a modest increase in remission rates when the dose is increased to 5 mg (without compromised tolerability). Taken together, the results herein indicate that the often employed 2 mg dose of aripiprazole results in low rates of response (18.5%); although a reasonable starting dose, clinicians could start at 2 mg but should aim for between 5 mg and 15 mg as tolerated. 


Depressive Symptoms in Mild Cognitive Impairment Predict Greater Atrophy in Alzheimer’s Disease-Related Regions

Lee GJ, Lu PH, Hua X, et al
Biol Psychiatry. 2012;71(9):814-821.

Background: Depression has been associated with higher conversion rates from mild cognitive impairment (MCI) to Alzheimer's disease (AD) and may be a marker of prodromal AD that can be used to identify individuals with MCI who are most likely to progress to AD. Thus, we examined the neuroanatomical changes associated with depressive symptoms in MCI.

Method: Two-hundred forty-three MCI subjects from the Alzheimer's Disease Neuroimaging Initiative who had brain magnetic resonance imaging scans at baseline and 2-year follow-up were classified into depressed (n = 44), nondepressed with other neuropsychiatric symptoms (n = 93), and no-symptom (NOSYMP; n = 106) groups based on the Neuropsychiatric Inventory Questionnaire. Tensor-based morphometry was used to create individual three-dimensional maps of 2-year brain changes that were compared between groups.

Results: Depressed subjects had more frontal (P=.024), parietal (P =.030), and temporal (P=.038) white matter atrophy than NOSYMP subjects. Those whose depressive symptoms persisted over 2 years also had higher conversion to AD and more decline on measures of global cognition, language, and executive functioning compared with stable NOSYMP subjects. Nondepressed with other neuropsychiatric symptoms and NOSYMP groups exhibited no differences in rates of atrophy.

Conclusions: Depressive symptoms were associated with greater atrophy in AD-affected regions, increased cognitive decline, and higher rates of conversion to AD. Depression in individuals with MCI may be associated with underlying neuropathological changes, including prodromal AD, and may be a potentially useful clinical marker in identifying MCI patients who are most likely to progress to AD.

Clinical Commentary
Mild cognitive impairment (MCI) often portends Alzheimer’s disease (AD) with a conversion rate with approximately 10% to 15% annually. The results herein indicate that the presence of depressive symptomatology in an individual with MCI significantly increases the rate of cognitive decline, conversion to AD, as well as white matter atrophy. Mental health care providers are increasingly encountering older patient populations presenting with a confluence of affective and cognitive symptoms. All patients with MCI should be carefully screened for the presence of depressive symptoms and guideline concordant care offered for their mitigation. It is a testable hypothesis that successful elimination of depressive symptoms decreases the conversion rate to AD. 


Severity of Depression and Response to Antidepressants: GENPOD Randomised Controlled Trial

Wiles NJ, Mulligan J, Peters TJ, et al
Br J Psychiatry. 2012;200(2):130-136. 

Background: Antidepressant prescribing is widespread. Nonetheless, response to antidepressants is variable. If it was possible to predict response to medication and thus tailor treatment accordingly, this would not only improve patient outcomes but may also have economic benefits. To test the hypothesis that individuals with more severe depression would benefit more from noradrenaline reuptake inhibitors (NARIs) than selective serotonin reuptake inhibitors (SSRIs) compared with individuals with less severe depression.

Method: Individuals recruited from UK primary care who met ICD-10 criteria for a depressive episode and scored 15 or more on the Beck Depression Inventory (BDI) were randomised to either an SSRI (citalopram 20 mg daily) or a NARI (reboxetine 4 mg twice daily). Randomisation was by means of a remote automated telephone system. The main outcome was depressive symptoms measured by the BDI total score 6 weeks after randomisation. (Trial registration: ISRCTN31345163.)

Results: In total, 601 participants were randomised (citalopram: n=298, reboxetine: n=303). Ninety-one per cent were followed up at 6 weeks (citalopram: n=274, reboxetine: n=272). There was little evidence to support an interaction between treatment and severity of depression (interaction term: 0.02, 95% CI -0.59 to 0.62, P=0.96). Adjustment for potential confounders (age, gender, employment status, history of depression, number of life events and social support) did not affect the findings (interaction term: 0.06, 95% CI -0.54 to 0.66, P=0.85).

Conclusions: Treatment with NARIs does not confer any advantage over SSRI treatment for outcome in those with more severe depressive illness presenting in primary care.

Clinical Commentary
There has been renewed debate regarding the effect size of antidepressants and their appropriate application. The results herein do not support claims of superiority of two mechanistically different antidepressants. The clinical translation is that the pharmacotherapy of “severe” depression does not have a “gold standard” antidepressant; clinicians should use measurement-based care to assess symptom severity and choose antidepressants based on their overall efficacy, tolerability and safety. Clinical experience indicates that most individuals with severe depression require multimodality therapy (e.g. with manual-based psychotherapy). 


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