João Quevedo

Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: A CANMAT randomized double-blind trial.

Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (n=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry (‘0-weeks’ group) or (ii) at 24 weeks after entry (‘24-weeks’ group) or (iii) continuation of risperidone or olanzapine for the full duration of the study (‘52-weeks’ group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, sub-group analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2 kg in the 52-weeks group compared with a weight loss of 0.2 kg in the 0-weeks and 0.1 kg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

Bipolar disorder (BD) is a major health problem. It causes significant morbidity and imposes a burden on the society. Available treatments help a substantial proportion of patients but are not beneficial for an estimated 40-50%. Thus, there is a great need to further our understanding the pathophysiology of BD to identify new therapeutic avenues. The preponderance of evidence pointed towards a role of protein kinase C (PKC) in BD. We reviewed the literature pertinent to the role of PKC in BD. We present recent advances from preclinical and clinical studies that further support the role of PKC. Moreover, we discuss the role of PKC on synaptogenesis and neuroplasticity in the context of BD. The recent development of animal models of BD, such as stimulant-treated and paradoxical sleep deprivation, and the ability to intervene pharmacologically provide further insights into the involvement of PKC in BD. In addition, the effect of PKC inhibitors, such as tamoxifen, in the resolution of manic symptoms in patients with BD further points in that direction. Furthermore, a wide variety of growth factors influence neurotransmission through several molecular pathways that involve downstream effects of PKC. Our current understanding identifies the PKC pathway as a potential therapeutic avenue for BD.

Pathophysiological Mechanisms of Huntington’s Disease

Huntington’s disease (HD) is a dominant autosomal monogenic disease whose pathophysiological basis comes from a mutation in the huntingtin (HTT) protein. HTT is one of the proteins whose gene has a polymorphic CAG trinucleotide repeat tract, leading to the formation of polyglutamine tract in the N-terminal region of the protein. The expansion of CAG repeat is the basic characteristic of mutated huntingtin (mHTT). HD is therefore characterized as one of the polyglutamine diseases (PolyQ). The initially apparent main symptoms are motor changes, with choreic movements, progressive loss of motor coordination, cognitive decline, and psychiatric disorders. The pathophysiology of this disease involves a wide range of biological mechanisms, whose alterations culminate in gliosis, with loss of astrocytes and oligodendrocytes, and in neuronal death and atrophy of brain tissues, with the most affected regions starting with the striatum, which integrates circuit of the basal ganglia and the cerebral cortex. Medium-sized spiny projecting neurons which release inhibitory γ-aminobutyric acid (GABA) neurotransmitter are the most affected, but many other neurons and neurotransmitters are involved in the circuit dysfunction. Among biological alterations inherent or consequent to the dysfunctions in the neurotransmission system are cellular inclusions of protein aggregates, changes in cellular signaling pathways, energy metabolism, oxidative balance, and inflammatory mechanisms. This chapter discourse some well-defined basic pathophysiological features and some mechanisms that are the most recent study objects in HD.

Staging models and neuroprogression in bipolar disorder

Abstract Several studies have suggested that bipolar disorder has progressive characteristics. The term “neuroprogression” has been used to define the disease process acceleration and its underlying factors, such as changes in peripheral biomarkers, cognitive functions, neuroimaging, and functionality, which appear to varying degrees depending on disorder evolution stage. The long-term course of bipolar disorder patients commonly presents with high degrees of impairment, progressive decrease in duration of euthymic periods and inversely increased mood episodes, as well as poor response to psychosocial and pharmacological treatments. The mechanisms underlying the pathophysiological alterations observed in the late stages of neuroprogression are still unknown. The most described theories are “Kindling,” Allostatic Load (AL), and Accelerated Aging (AA). Clinical staging is widely used in many medical specialties, for determining the stage of development of a disease. Several divisions of bipolar disorder phases arise from staging models. The use of staging models in bipolar disorder may lead to early detection, possible prevention, and adoption of social and functional assistance strategies for patients. However, primary prevention has been relatively understudied in bipolar disorder, thus reinforcing the need for consolidation of this field of study.

Perturbed mitochondrial dynamics and apoptosis: insights into bipolar disorder pathophysiology

Comparative risks of treatment failure in bipolar 1 disorder : a population based study of lithium, valproate, olanzapine, quetiapine and aripiprazole in post mania relapse prevention

mTOR signaling in the neuropathophysiology of depression: Current evidence

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Journal of Receptor, Ligand and Channel Research 2015:8 65–74 Journal of Receptor, Ligand and Channel Research Dovepress

Brain uptake of iomazenil in cirrhotic patients: a single photon emission tomography study.

Brain uptake of 123I-iomazenil was studied in seven cirrhotic patients and eight normal controls using single photon emission computerized tomography. The highest concentration of the ligand was found in the occipital cortex, which corresponds to the brain region with the highest concentration of benzodiazepine receptors.The peak uptake was delayed in patients across all brain regions. The uptake in occipital cortex was higher in low albumin cirrhotics. Patients with low albumin also presented a more delayed peak uptake in occipital cortex and a higher volume of distribution of iomazenil in plasma, compared to patients with normal albumin levels and controls. The changes in brain uptake (delayed peak uptake and increased maximal uptake in occipital cortex) appears to reflect changes in the pharmacokinetics of the ligand, particularly in cirrhotics with low levels of plasma albumin. The curve of brain uptake of the tracer was modelled into a two compartments equation, which seems to provide a practical and reliable method to calculate the slopes of acquisition and decay, time to peak and maximal acquisition.