Dopamine sudden depletion as a model for mixed depression

Up to date research on Bipolar Disorders' phenomenology is in keeping with early descriptions made by E. Kraëpelin regarding the overlap in clinical presentation of both manic and depressive symptoms, namely, mixed states. The latter constitute a highly prevalent and characteristic clinical presentation of Bipolar Disorders' and entail therapeutic difficulties, prognostic implications and increased suicidal risk. Notwithstanding, mixed states', more specifically mixed depression, have been underestimated and bypassed to the point where currently neither diagnostic criteria nor specific therapeutic recommendations are provided. In addition to the lack of agreement on nosography and diagnostic criteria, mixed depression is usually excluded from Bipolar Disorders' neurobiological models. Furthermore, renewed interest in the role of dopamine in Bipolar Disorders' physiopathology has left aside hypothesis that may account for the aforementioned clinical presentation. Interestingly enough, other syndromes arising from sudden dopamine depletion such as neuroleptic dysphoria or withdrawal syndromes from dopaminergic drugs, bear remarkable clinical similarities with mixed depression. These syndromes have been subject of further research and may thus provide a model for mixed states' physiopathology.Indeed, this article accounts for clinical similarities between mixed depression, neuroleptic induced dysphoria, and other behavioural syndromes arising from sudden dopamine depletion. After reviewing neurochemical basis of such syndromes we present, to the best of our knowledge, the first neurobiological hypothesis for mixed depression. Specifically, such hypothesis regards over activation symptoms as auto regulatory attempts to compensate for sudden dopaminergic depletion. This hypothesis provides with a beginning step for the neglected problem of mixed depression, a non-antithetic link between the dopaminergic hypothesis for both manic and depressive symptoms, a plausible explanation regarding inter individual variability to mixed depression susceptibility, and suggests new approaches for the development of novel treatments in which dopamine dysregulation should be targeted.Fil: Strejilevich, Sergio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; ArgentinaFil: Teitelbaum, J.. Instituto de Neurología Cognitiva; ArgentinaFil: Martino, Diego Javier. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Quiroz, D.. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; ArgentinaFil: Kapczinski, F.. No especifíca

Bipolar disorder and age-related functional impairment

OBJECTIVE: Although bipolar disorder is a major contributor to functional impairment worldwide, an independent impact of bipolar disorder and ageing on functioning has yet to be demonstrated. The objective of the present study was to evaluate the effect of bipolar disorder on age-related functional status using matched controls as a standard. METHOD: One-hundred patients with bipolar disorder and matched controls were evaluated for disability. Age-related effects controlled for confounders were cross-sectionally evaluated. RESULTS: Patients were significantly more impaired than controls. Regression showed effects for aging in both groups. The effect, size, however, was significantly stronger in patients. CONCLUSION: Bipolar disorder was an important effect modifier of the age impact on functioning. While a longitudinal design is needed to effectively demonstrate this different impact, this study further depicts bipolar disorder as a chronic and progressively impairing illness

Staging Bipolar Disorder.

The purpose of this study was to analyze the evidence supporting a staging model for bipolar disorder. The authors conducted an extensive Medline and Pubmed search of the published literature using a variety of search terms (staging, bipolar disorder, early intervention) to find relevant articles, which were reviewed in detail. Only recently specific proposals have been made to apply clinical staging to bipolar disorder. The staging model in bipolar disorder suggests a progression from prodromal (at-risk) to more severe and refractory presentations (Stage IV). A staging model implies a longitudinal appraisal of different aspects: clinical variables, such as number of episodes and subsyndromal symptoms, functional and cognitive impairment, comorbidity, biomarkers, and neuroanatomical changes. Staging models are based on the fact that response to treatment is generally better when it is introduced early in the course of the illness. It assumes that earlier stages have better prognosis and require simpler therapeutic regimens. Staging may assist in bipolar disorder treatment planning and prognosis, and emphasize the importance of early intervention. Further research is required in this exciting and novel area

Olanzapine plus fluoxetine treatment increases Nt-3 protein levels in the rat prefrontal cortex

AbstractEvidence is emerging for a role for neurotrophins in the treatment of mood disorders. In this study, we evaluated the effects of chronic administration of fluoxetine, olanzapine and the combination of fluoxetine/olanzapine on the brain-derived-neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) in the rat brain. Wistar rats received daily injections of olanzapine (3 or 6mg/kg) and/or fluoxetine (12.5 or 25mg/kg) for 28 days, and we evaluated for BDNF, NGF and NT-3 protein levels in the prefrontal cortex, hippocampus and amygdala. Our results showed that treatment with fluoxetine and olanzapine alone or in combination did not alter BDNF in the prefrontal cortex (p=0.37), hippocampus (p=0.98) and amygdala (p=0.57) or NGF protein levels in the prefrontal cortex (p=0.72), hippocampus (p=0.23) and amygdala (p=0.64), but NT-3 protein levels were increased by olanzapine 6mg/kg/fluoxetine 25mg/kg combination in the prefrontal cortex (p=0.03), in the hippocampus (p=0.83) and amygdala (p=0.88) NT-3 protein levels did not alter. Finally, these findings further support the hypothesis that NT-3 could be involved in the effect of treatment with antipsychotic and antidepressant combination in mood disorders

The prevalence of bipolar disorders in the general population - a growing trending topic?

Bipolar disorder prevalence: a systematic review and meta-analysis of the literature. [Rev Bras Psiquiatr. 2015

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 (\u270-weeks\u27 group) or (ii) at 24 weeks after entry (\u2724-weeks\u27 group) or (iii) continuation of risperidone or olanzapine for the full duration of the study (\u2752-weeks\u27 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

Benzodiazepine prescribing behaviour and attitudes: a survey among general practitioners practicing in northern Thailand

BACKGROUND: Over-prescribing of benzodiazepines appears common in many countries, a better understanding of prescribing practices and attitudes may help develop strategies to reduce prescribing. This study aimed to evaluate benzodiazepine prescribing behaviour and attitudes in general practitioners practising in Chiang Mai and Lampoon, Thailand. METHODS: Questionnaire survey of general practitioners in community hospitals, to estimate: i) use of benzodiazepines for anxiety/insomnia, panic disorder, depression, essential hypertension, and uncomplicated low back pain and ii) views on the optimal duration of benzodiazepine use. RESULTS: Fifty-five of 100 general practitioners returned the completed questionnaires. They reported use of benzodiazepines for anxiety/insomnia (n = 51, 93%), panic disorder (n = 43, 78%), depression (n = 26, 43%), essential hypertension (n = 15, 27 %) and uncomplicated low back pain (n = 10, 18%). Twenty-eight general practitioners would prescribe benzodiazepines for non-psychiatric conditions, 17 for use as muscle relaxants. Seventy-five per cent, 62% and 29% of the general practitioners agreed or totally agreed with the use of benzodiazepines for insomnia, anxiety and depression, respectively. Practitioners agreed that prescribing should be less than one week (80%); or from 1 week to 1 month (47%); or 1 to 4 months (16%); or 4 to 6 months (5%) or more than 6 months (2%). Twenty-five general practitioners (45%) accepted that they used benzodiazepines excessively in the past year. CONCLUSION: A considerable proportion of general practitioners in Chiang Mai and Lampoon, Thailand inappropriately use benzodiazepines for physical illnesses, especially essential hypertension and uncomplicated low back pain. However, almost half of them thought that they overused benzodiazepines. General practitioner's lack of time, knowledge and skills should be taken into account in improving prescribing behaviour and attitudes

Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers