Faculty Bibliography

BACKGROUND: A retrospective chart review was undertaken in a private clinic to examine the clinical outcomes for patients with an eating disorder comorbid with depression or bipolar illness who underwent a referenced electroencephalographic (EEG) database analysis to help guide medication selection. METHOD: We examined 33 charts for patients with the primary psychiatric diagnosis of an eating disorder and comorbid major depressive disorder or bipolar disorder who underwent a quantitative EEG database assessment to provide additional information for choices of medication. The current analysis includes data from 22 subjects who accepted treatments based on information from the referenced-EEG medication database. Hamilton Depression Rating Scale, Clinical Global Impression-Severity, Clinical Global Impression-Improvement, and hospitalization data were examined for these patients. RESULTS: Patients whose EEG data was used for clinical treatment reported significant decreases in associated depressive symptoms (HDRS scores), overall severity of illness (Clinical Global Impression-Severity), and overall clinical global improvement (Clinical Global Impression- Improvement). This cohort also reported fewer inpatient, residential, and partial hospitalization program days following referenced-EEG compared with the two-year period prior to treatment. CONCLUSION: These findings are consistent with previously reported data for patients with eating disorders and suggest the need for future studies using EEG data correlated with those from other patients with similar quantitative EEG features.

There has been a rapid increase in the use of polypharmacy in psychiatry possibly due to the introduction of newer drugs, greater availability of these newer drugs, excessive confidence in clinical trial results, widespread prescribing of psychotropic medications by primary care, and pressure to augment with additional medications for unresolved side effects or greater efficacy. Even the new generation of medications may not hold significant advantages over older drugs. In fact, there may be additional safety risks with polypharmacy being so widespread. Washout, as a clinical tool, is rarely done in medication management today. Studies have shown that augmenting therapy with additional medications resulted in 9.1%-34.1% dropouts due to intolerance of the augmentation, whereas studies of medication washout demonstrated only 5.9%-7.8% intolerance to the washout procedure. These perils justify reconsideration of medication washout before deciding on augmentation. There are unwarranted fears and resistance in the medical community toward medication washout, especially at the moment a physician is trying to decide whether to washout or add more medications to the treatment regimen. However, medication washout provides unique benefits to the physician: it establishes a new baseline of the disorder, helps identify medication efficacy from their adverse effects, and provides clarity of diagnosis and potential reduction of drug treatments, drug interactions, and costs. It may also reduce overall adverse events, not to mention a potential to reduce liability. After washout, physicians may be able to select the appropriate polypharmacy more effectively and safely, if necessary. Washout, while not for every patient, may be an effective tool for physicians who need to decide on whether to add potentially risky polypharmacy for a given patient. The risks of washout may, in some cases, be lower and the benefits may be clearly helpful for diagnosis, understanding medication effects, the doctor/patient relationship, and safer use of polypharmacy if indicated.

BACKGROUND: Previous studies of major depressive disorder (MDD) have focused on abnormalities in the prefrontal cortex and medial temporal regions. There has been little investigation in MDD of midbrain and subcortical regions central to reward/aversion function, such as the ventral tegmental area/substantia nigra (VTA/SN), and medial forebrain bundle (MFB). METHODOLOGY/PRINCIPAL FINDINGS: We investigated the microstructural integrity of this circuitry using diffusion tensor imaging (DTI) in 22 MDD subjects and compared them with 22 matched healthy control subjects. Fractional anisotropy (FA) values were increased in the right VT and reduced in dorsolateral prefrontal white matter in MDD subjects. Follow-up analysis suggested two distinct subgroups of MDD patients, which exhibited non-overlapping abnormalities in reward/aversion circuitry. The MDD subgroup with abnormal FA values in VT exhibited significantly greater trait anxiety than the subgroup with normal FA values in VT, but the subgroups did not differ in levels of anhedonia, sadness, or overall depression severity. CONCLUSIONS/SIGNIFICANCE: These findings suggest that MDD may be associated with abnormal microstructure in brain reward/aversion regions, and that there may be at least two subtypes of microstructural abnormalities which each impact core symptoms of depression.

The low rate of response to antidepressants in treatment resistant depression (TRD) justifies studies of next-step therapies following a treatment failure. In TRD clinical trials, it is important to verify the accurate diagnosis of treatment resistance for all enrolled subjects using a reliable and valid instrument. Self-rated scales can reduce the impact of investigator bias and reduce the time burden for clinical researchers. The Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire (ATRQ) is a self-rated scale used to determine treatment resistance in major depressive disorder (MDD). The ADAPT-A study is a multi-center double-blind, placebo-controlled study of low-dose aripiprazole adjunctive to ADT among outpatients with TRD. At the screening assessment, potential subjects completed the MGH ATRQ. The ADAPT-A medical monitors subsequently performed remote patient interviews and obtained detailed medication histories. The data obtained from the MGH ATRQ and by the medical monitors were compared for congruency. Of the 186 patients enrolled by the local sites, no subjects deemed treatment resistant by the MGH ATRQ were found to be nonresistant by the medical monitors. In 76.3% (n = 142) of the subjects, the number of failed adequate antidepressant trials reported by the MGH ATRQ was concordant with the data collected by medical monitors. In 16.1% (n = 30) of all cases, the medical monitors found a greater number of failed trials; in 7.5% (n = 14) of cases, the medical monitors found fewer failed medication trials. The discrepancy was by more than one medication trial in only 4.0% (n = 7) of cases. We found the MGH ATRQ to be relatively concordant in its assessment of treatment resistance in depression compared with independent clinical researchers. Although the MGH ATRQ tended to underreport the number of unsuccessful treatment trials relative to the clinical interviews, its accuracy in cases it detected was confirmed by raters.

OBJECTIVE: Presymptomatic individuals with the Huntingtin (HTT) CAG expansion mutation that causes Huntington's disease may have higher levels of depressive symptoms than healthy comparison populations. However, the prevalence of HTT CAG repeat expansions among individuals diagnosed with major depressive disorder has not been established. METHOD: This was a case-control genetic association study of HTT CAG allele size in two discovery cohorts of individuals with major depressive disorder and comparison subjects without major depression as well as a replication cohort of individuals with major depression and comparison subjects without major depression. RESULTS: CAG repeat lengths of 36 or greater were observed in six of 3,054 chromosomes from individuals with major depression, compared with none of 4,155 chromosomes from comparison subjects. In a third cohort, one expanded allele was observed among 1,202 chromosomes in the major depression group, compared with none of 2,678 chromosomes in comparison subjects. No clear pattern of clinical features was shared among individuals with the expanded repeats. CONCLUSIONS: In clinical populations of individuals diagnosed with major depression, approximately 3 in 1,000 carried expanded HTT CAG alleles.

Evidence suggests that mitochondria undergo functional and morphological changes with age. This study aimed to investigate the relationship of brain energy metabolism to healthy aging by assessing tissue specific differences in metabolites observable by phosphorus ((31)P) MRS. (31)P MRSI at 4 Tesla (T) was performed on 34 volunteers, aged 21-84, screened to exclude serious medical and psychiatric diagnoses. Linear mixed effects models were used to analyze the effects of age on phosphorus metabolite concentrations, intracellular magnesium and pH estimates in brain tissue. A significant age associated decrease in brain pH (-0.53% per decade), increase in PCr (1.1% per decade) and decrease in PME (1.7% per decade) were found in total tissue, with PCr effects localized to the gray matter. An increase in beta NTP as a function of age (1% per decade) approached significance (p = 0.052). There were no effects demonstrated with increasing age for intracellular magnesium, PDE or inorganic phosphate. This study reports the effects of healthy aging on brain chemistry in the gray matter versus white matter using (31)P MRS measures of high energy phosphates, pH and membrane metabolism. Increased PCr, increased beta NTP (reflecting ATP) and reduced pH may reflect altered energy production with healthy aging. Unlike some previous studies of aging and brain chemistry, this study examined healthy, non-demented and psychiatrically stable older adults and specifically analyzed gray-white matter differences in brain metabolism.

BACKGROUND: Recent data indicate that lithium use for bipolar disorder has declined over the last decade and that lithium largely has been replaced with alternate, commercially promoted medications that may or may not result in better outcomes. PURPOSE: This article describes the rationale and study design of LiTMUS, a multi-site, prospective, randomized clinical trial of outpatients with bipolar disorder. LiTMUS seeks to address whether initiating therapy at lower doses of lithium as part of optimized treatment (OPT, guideline-informed, evidence-based, and personalized pharmacotherapy) improves outcomes and decreases the need for other medication changes across 6 months of therapy. METHODS: LiTMUS will randomize 284 adults with bipolar disorder (Type I or II) across 6 study sites. The co-primary outcomes are overall illness severity on clinical global improvement scale for bipolar disorder and a novel measure, necessary clinical adjustments. This metric provides a composite that reflects both clinical response and tolerability. Other relevant outcomes include full symptomatic recovery, quality of life, suicidal behaviors, and moderators of suicidality. RESULTS: As of August 28th, 2009, we have consented 338 patients and randomized 281 for this study. LIMITATIONS: The potential limitations of the study include an arbitrary definition of 'low, but effective' doses of lithium, lack of a placebo-controlled group, open treatment, and use of a new outcome measure (i.e., necessary clinical adjustments). CONCLUSION: We expect that this study will inform our understanding of the effectiveness of low to moderate doses of lithium therapy for individuals with bipolar disorder.