Adjunctive treatment of acute mania: a clinical overview

OBJECTIVE: To provide an overview of the available high quality evidence-base of studies of adjunctive pharmacologic treatment for acute mania. METHOD: Double-blind controlled trials with adequate samples (n > 100) were identified through search of PubMed/MEDLINE and computerized abstracts from 2004-2006 meetings of the American Psychiatric Association, International Conference on Bipolar Disorder, and Collegium Internationale Neuro-Psychopharmacolium using key words mania, adjunct, and combination. RESULTS: Placebo-controlled studies with positive results support the adjunctive use of five agents including valproate, olanzapine, risperidone, quetiapine, and haloperidol. Agents with only negative or failed placebo-controlled studies included carbamazepine, gabapentin, lamotrigine, topiramate, oxcarbazepine, and ziprasidone. We found no placebo-controlled study of many commonly used agents including lithium, aripiprazole, and clozapine. No studies explicitly excluded subjects, based on prior treatment with the monotherapy being offered and several studies limited randomization to patients with documented inadequate response to the monotherapy arm. CONCLUSION: The available placebo-controlled randomized clinical trials support adjunctive therapy combining lithium or valproate with olanzapine, risperidone, haloperidol or quetiapine. The additional increment of antimanic efficacy of these combinations over monotherapy was similar in magnitude to that seen for the same agents as monotherapy in comparison with placebo. These additive benefits enhanced the tolerability of adverse effects sufficiently to allow a higher proportion of subjects receiving combination therapies to complete the studies than monotherapy treated patients. The available data has several shortcomings and the available studies are inadequate to conclusively determine whether combination treatment is more efficacious than monotherapy when used by subjects naive to both treatments. Nevertheless, adjunctive treatment, which combines agents with proven antimanic efficacy, offers an attractive option for patients with acute mania.     

Outcomes in schizophrenia outpatients treated with amisulpride or olanzapine

INTRODUCTION: We compared stable patients with schizophrenia who were treated with either amisulpride or olanzapine in terms of symptomatic outcome, neurocognitive functioning, functionality, and subjective outcome. METHODS: Sixty outpatients with chronic schizophrenia who had been treated with either amisulpride or olanzapine for at least six months were investigated. RESULTS: The scores of positive, negative, and cognitive symptoms did not differ between the two groups, but patients treated with olanzapine had significantly lower scores on the excitement and depression/anxiety components of the PANSS. With regard to cognitive variables, patients treated with amisulpride showed significantly lower values regarding verbal fluency and significantly better verbal memory than patients treated with olanzapine. Both treatment groups were comparable with respect to functional and subjective outcome variables. DISCUSSION: These observations add to the evidence that continuous treatment with different second-generation antipsychotics with relatively few side effects leads to comparable outcomes in patients with schizophrenia.     

Confocal light absorption and scattering spectroscopic microscopy monitors organelles in live cells with no exogenous labels

This article reports the development of an optical imaging technique, confocal light absorption and scattering spectroscopic (CLASS) microscopy, capable of noninvasively determining the dimensions and other physical properties of single subcellular organelles. CLASS microscopy combines the principles of light-scattering spectroscopy (LSS) with confocal microscopy. LSS is an optical technique that relates the spectroscopic properties of light elastically scattered by small particles to their size, refractive index, and shape. The multispectral nature of LSS enables it to measure internal cell structures much smaller than the diffraction limit without damaging the cell or requiring exogenous markers, which could affect cell function. Scanning the confocal volume across the sample creates an image. CLASS microscopy approaches the accuracy of electron microscopy but is nondestructive and does not require the contrast agents common to optical microscopy. It provides unique capabilities to study functions of viable cells, which are beyond the capabilities of other techniques.     

The effect of estrogen and progesterone on spreading depression in rat neocortical tissues

Although gender differences in the incidence of migraine with aura appear to be related to high circulating levels of ovarian hormones, the underlying mechanisms are not yet fully understood. Several studies have suggested a major role for spreading depression (SD) in the pathogenesis and symptomatology of migraine with aura. To investigate a possible role of SD in the association of high female hormones and attacks of migraine with aura, the effects of beta-estradiol and progesterone on SD were studied in rat neocortical tissues. Application of both hormones enhanced the repetition rate as well as the amplitude of SD in neocortical slices treated with hypotonic artificial cerebrospinal fluid. beta-Estradiol and progesterone also dose dependently increased the amplitude of SD induced by KCl microinjection. Both hormones exhibited a pronounced, persisting, and significant enhancement of long-term potentiation of the field excitatory postsynaptic potential in the neocortical tissues. The changes in SD characteristics in the presence of estrogen and progesterone may responsible for increased migraine with aura attacks associated by high female hormones. These hormones may exert their effects on SD via facilitation of synaptic transmission.     

The gastric HK-ATPase: structure, function, and inhibition

The gastric H,K-ATPase, a member of the P₂-type ATPase family, is the integral membrane protein responsible for gastric acid secretion. It is an α,β-heterodimeric enzyme that exchanges cytoplasmic hydronium with extracellular potassium. The catalytic α subunit has ten transmembrane segments with a cluster of intramembranal carboxylic amino acids located in the middle of the transmembrane segments TM4, TM5,TM6, and TM8. Comparison to the known structure of the SERCA pump, mutagenesis, and molecular modeling has identified these as constituents of the ion binding domain. The β subunit has one transmembrane segment with N terminus in cytoplasmic region. The extracellular domain of the β subunit contains six or seven N-linked glycosylation sites. N-glycosylation is important for the enzyme assembly, maturation, and sorting. The enzyme pumps acid by a series of conformational changes from an E₁ (ion site in) to an E₂ (ion site out) configuration following binding of MgATP and phosphorylation. Several experimental observations support the hypothesis that expulsion of the proton at 160 mM (pH 0.8) results from movement of lysine 791 into the ion binding site in the E₂P configuration. Potassium access from the lumen depends on activation of a K and Cl conductance via a KCNQ1/KCNE2 complex and Clic6. K movement through the luminal channel in E₂P is proposed to displace the lysine along with dephosphorylation to return the enzyme to the E₁ configuration. This enzyme is inhibited by the unique proton pump inhibitor class of drug, allowing therapy of acid-related diseases.     

Stability of symptoms across major depressive episodes in bipolar disorder

Objective: Some studies suggest that depressive subtypes, defined by groups of symptoms, have predictive or diagnostic utility. These studies make the implicit assumption of stability of symptoms across episodes in mood disorders, which has rarely been investigated. Methods: We examined prospective data from a cohort of 3,750 individuals with bipolar I or II disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder study, selecting a subset of individuals who experienced two depressive episodes during up to two years of follow‐up. Across‐episode association of individual depressive or hypomanic/mixed symptoms was examined using the weighted kappa measure of agreement as well as logistic regression. Results: A total of 583 subjects experienced two prospectively observed depressive episodes, with 149 of those subjects experiencing a third. Greatest evidence of stability was observed for neurovegetative features, suicidality, and guilt/rumination. Loss of interest and fatigue were not consistent across episodes. Structural equation modeling suggested that the dimensional structure of symptoms was not invariant across episodes. Conclusion: While the overall dimensional structure of depressive symptoms lacks temporal stability, individual symptoms including suicidality, mood, psychomotor, and neurovegetative symptoms are stable across major depressive episodes in bipolar disorder and should be considered in future investigations of course and pathophysiology in bipolar disorder.     

Galantamine-ER For Cognitive Dysfunction In Bipolar Disorder and Correlation with Hippocampal Neuronal Viability: A Proof-of-Concept Study

Background: Many subjects with bipolar disorder experience significant cognitive dysfunction, even when euthymic, but few studies assess biological correlates of or treatment strategies for cognitive dysfunction.
Method: Nineteen subjects with bipolar disorder in remission, who reported subjective cognitive deficits, were treated with open-label galantamine-ER 8–24 mg/day for 4 months. Ten healthy volunteers matched for age and gender were also assessed. Mood and subjective cognitive questionnaires were administered monthly. At the beginning and the end of the trial all subjects were administered neuropsychological tests, including tests of attention (Conners CPT) and episodic memory (CVLT). Bipolar subjects underwent proton magnetic resonance spectroscopy (1H-MRS) measurements before and after treatment, healthy volunteers completed baseline 1H-MRS. We acquired 1H-MRS data at 4.0 T from voxels centered on the left and right hippocampus to measure hippocampal N -acetyl aspartate (NAA, a measure of neuronal viability) and choline containing compounds (Cho, a marker of lipid metabolism and membrane turn-over).
Results: Compared to healthy volunteers, bipolar subjects had higher baseline subjective cognitive deficits and lower scores on objective tests of attention (Conner's CPT) and verbal episodic memory (CVLT). After treatment, bipolar subjects experienced significant improvement of subjective cognitive scores and on objective tests of attention (Conner's CPT) and verbal episodic memory (CVLT). In the left hippocampus NAA increased and choline (Cho) decreased in bipolar subjects during treatment.
Conclusion: Bipolar subjects had cognitive dysfunction; treatment with Galantamine-ER was associated with improved cognition and with increases in neuronal viability and normalization of lipid membrane metabolism in the left hippocampus.
This study was registered on ClinicalTrials.gov (NCT00181636).     

The Central Massachusetts Oral Health Initiative (CMOHI): a successful public–private community health collaboration

Objectives: The Central Massachusetts Oral Health Initiative (CMOHI) aimed to improve access to quality oral health care in central Massachusetts. Methods: A broad‐based public and private organization partnership with local and national funding created a steering committee to organize school administrators, community leaders, and a medical school to collaborate on five goals: advocate for changes in oral health policy, increase oral health care access, provide school‐based dental services for underserved children, establish a Dental General Practice Residency, and educate medical professionals about oral health. Results: A state legislative Oral Health Caucus helped secure sought‐after policy improvements; more regional dentists now accept Medicaid; community health center capacity to provide dental services was expanded; school‐based programs were designed and delivered needed dental services; a dental residency was created; and methods of educating medical professionals were established. Conclusions: Significant sustainable gains in oral health care access were created through our multifaceted approach, ongoing evaluation and communication, coordination of CMOHI partner resources, and collaboration with other involved parties.