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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 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.


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