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ABSTRACTIntroduction: Individuals with bipolar disorder (BD) have higher rates of unhealthy lifestyles and risk for medical comorbidities Research currently suggests that dietary factors may play a role in the development of depression and anxiety. Therefore, nutritional approaches are potential strategies for the treatment of BD. The aim of this review is to summarize the available evidence on nutrition and BD. Materials and Methods: The paper was developed based on PRISMA 2020 guidelines. The search was conducted in Sep-2021 using PubMed and Cochrane Library, augmented by manually checked references lists. The search found 986 studies, of which 47 were included, combined with 13 from reference lists, totaling 60 studies. Results: There were 33 observational trials, of which 15 focused on fatty acids, 9 on micronutrients, 5 on specific foods, 4 on macro and micronutrients. The 27 interventional studies mainly focused on fatty acids, micronutrients and N-acetylcysteine (NAC). Discussion: Dietary intake or supplementation of unsaturated fatty acids, mainly Omega-3 seems to be associated with improved BD symptoms, along with seafood, folic acid and zinc. Studies found variable, mainly non-significant impacts of creatine, carnitine, vitamin D, inositol or NAC supplementation on BD. There are promising results associated with Coenzyme Q10 (Coq10) and probiotics. Taken together, these preliminary findings suggest that dietetic approaches might be included as part of BD treatment. Also considering the high risk of metabolic disorders in individuals with BD, they should be encouraged to choose healthy dietary lifestyles, including daily intake of fruits, vegetables, seafood and whole grains.

Objective: Bipolar disorder (BD) is associated with premature mortality. All-cause and specific mortality risks in this population remain unclear, and more studies are still needed to further understand this issue and guide individual and public strategies to prevent mortality in bipolar disorder Thus, a systematic review and meta‐analysis of studies assessing mortality risk in people with BD versus the general population was conducted. The primary outcome was all‐cause mortality, whilst secondary outcomes were mortality due to suicide, natural, unnatural, and specific‐causes mortality. Results: Fifty-seven studies were included (BD; n= 678,353). All‐cause mortality was increased in people with BD (RR = 2.02, 95% CI: 1.89–2.16, k = 39). Specific‐cause mortality was highest for suicide (RR = 11.69, 95% CI: 9.22–14.81, k = 25). Risk of death due to unnatural causes (RR = 7.29, 95% CI: 6.41–8.28, k = 17) and natural causes (RR = 1.90, 95% CI: 1.75–2.06, k = 17) were also increased. Among specific natural causes analyzed, infectious causes had the higher RR (RR = 4,38, 95%CI: 1.5–12.69, k = 3), but the analysis was limited by the inclusion of few studies. Mortality risk due to respiratory (RR = 3.18, 95% CI: 2.55–3.96, k = 6), cardiovascular (RR = 1.76, 95% CI: 1.53–2.01, k = 27), and cerebrovascular (RR = 1.57, 95% CI: 1.34–1.84, k = 13) causes were increased as well. No difference was identified in mortality by cancer (RR = 0.99, 95% CI: 0.88–1.11, k = 16). Subgroup analyses and meta-regression did not affect the findings. Conclusion: Results presented in this meta-analysis show that risk of premature death in BD is not only due to suicide and unnatural causes, but somatic comorbidities are also implicated. Not only the prevention of suicide, but also the promotion of physical health and the prevention of physical conditions in individuals with BD may mitigate the premature mortality in this population. Notwithstanding this is to our knowledge the largest synthesis of evidence on BD-related mortality, further well-designed studies are still warranted to inform this field.

Objective: Growing evidence suggests that abrupt lithium discontinuation increases the risk of recurrence for patients with bipolar disorder. To assess the effect of abrupt change in lithium dose, the authors reanalyzed data from a previously reported, randomized, double-blind trial of standard- versus low-dose lithium for maintenance therapy in bipolar disorder. Method: In the original study, serum lithium levels were obtained during a 2-month open stabilization period for 94 patients with bipolar disorder who were then randomly assigned to be maintained on a low (serum level=0.4-0.6 meq/liter) or a standard (0.8-1.0 meq/liter) level of lithium therapy. Patients were then followed for up to 182 weeks. This reanalysis examined the potential confounding influence of prerandomization lithium level and change in lithium level on the outcome of subjects assigned to a standard or low maintenance dose of lithium. Results: In a Cox proportional hazards model incorporating pre- and postrandomization lithium levels and the interaction of these factors, only the interaction term remained significantly associated with time to recurrence. Conclusions: The findings indicate that change in serum lithium level may be a more powerful predictor of recurrence of bipolar disorder than the absolute assignment to a low or a standard dose of lithium and suggest that an abrupt decrease in lithium level should be avoided. This reanalysis did not directly address optimal maintenance lithium levels but raises questions about the original study's finding of superiority for lithium levels [greater than or equal to] 0.8 meq/liter. The results underscore the importance of accounting for the possible confounding effects of changes in the intensity of pharmacotherapy in studies of maintenance therapies for bipolar disorder. (Am J Psychiatry 2002; 159:1155-1159)

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18–75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen’s d= 0.14, 95% CI: 0.08–0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

Objective: The purpose of this study was to evaluate whether the concentration of [Beta]-nucleoside triphosphate is lower in the basal ganglia of depressed subjects. Method: In vivo 31P magnetic resonance spectra were acquired from a 45-[cm.sup.3] region surrounding the basal ganglia of 35 unmedicated depressed subjects and 18 comparison subjects. Results: [Beta]-Nucleoside triphosphate, which arises primarily from [Beta]-ATP, was 16% lower in the depressed subjects than in the comparison subjects. Conclusions: The low level of [Beta]-nucleoside triphosphate is consistent with an abnormality of high-energy phosphate metabolism in the basal ganglia of subjects with major depression.

The authors investigated the outcome of an alternating time schedule versus two fixed schedules (either morning or evening) of bright light treatment for seasonal affective disorder. The subjects were 31 patients who met DSM-III-R criteria for major depression with a seasonal pattern. No statistically significant difference was observed among patients in the three groups for response criteria after 1 week of treatment. These results support the use of more flexible phototherapy schedules.

Bipolar disorder is a chronic and recurrent illness characterized by depressive and manic episodes. Proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated glutamate (Glu) system abnormalities in BD, but it is unclear how Glu varies among mood states and how medications modulate it. The objective of this study was to investigate the influence of mood stabilizers on anterior cingulate cortex Glu levels using 1H-MRS during euthymia.

Bipolar depression (BD) is a highly prevalent condition with limited therapeutic options. Deep (H1-coil) transcranial magnetic stimulation (dTMS) is a novel TMS modality with established efficacy for unipolar depression. We conducted a randomized sham-controlled trial to evaluate the efficacy and safety of dTMS in treatment-resistant BD patients. Patients received 20 sessions of active or sham dTMS over the left dorsolateral prefrontal cortex (H1-coil, 55 18 Hz 2 s 120% MT trains). The primary outcome was changes in the 17-item Hamilton Depression Rating Scale (HDRS-17) from baseline to endpoint (week 4). Secondary outcomes were changes from baseline to the end of the follow-up phase (week 8), and response and remission rates. Safety was assessed using a dTMS adverse effects questionnaire and the Young Mania Rating Scale to assess treatment-emergent mania switch (TEMS). Out of 50 patients, 43 finished the trial. There were 2 and 5 dropouts in the sham and active groups, respectively. Active dTMS was superior to sham at end point (difference favoring dTMS=4.88; 95% CI 0.43 to 9.32, p=0.03) but not at follow-up. There was also a trend for greater response rates in the active (48%) vs sham (24%) groups (OR=2.92; 95% CI=0.87 to 9.78, p=0.08). Remission rates were not statistically different. No TEMS episodes were observed. Deep TMS is a potentially effective and well-tolerated add-on therapy in resistant bipolar depressed patients receiving adequate pharmacotherapy.

Decreased levels of brain derived neurotrophic factor (BDNF) have been found in adult patients with bipolar disorder (BD) compared with a comparison group, yet there are no data specifically examining this in geriatric patients. The objective of this study was to examine whether euthymic late-life BD patients have lower BDNF levels than healthy comparators.

AbstractAn emerging body of evidence points to impairments in neuroplasticity, cell resilience, and neuronal survival as major pathophysiological mechanisms in bipolar disorder. Neuronal survival is influenced by several factors including an orchestrated action of neurotransmitters, hormones, and neurotrophins. Patients with bipolar disorder exhibit increased peripheral level of inflammatory mediators such as cytokines, mainly during acute mood episodes. These mediators interact in several pathways involved in regulation of mood and energy including hypothalamic-pituitary-adrenal axis and monoamine metabolism. Importantly, inflammatory cytokines have a potential role in controlling neuronal and glial cell loss that occurs during mood episodes, especially during mania, as they are the most powerful extracellular stimuli to apoptosis. Bipolar patients have been reported to show imbalanced peripheral production of cytokines both at the mRNA and protein levels, associated signal transduction machinery, as well as to have specific functional polymorphisms in the genes that encode these cytokines. Interestingly, lithium, valproate, and several antidepressants have demonstrated to have immunomodulatory properties. Growing evidence supports the involvement of inflammatory mechanisms in bipolar disorder, opening new paths of investigation using immunomodulatory medications. These findings can offer not only an opportunity of treating mood symptoms but also understanding and reverting neurobiological changes associated with the disorder.

The response to electroconvulsive therapy for six bipolar patients after pharmacotherapy failure is discussed.

It has been suggested that the serotonin transporter (5-hydroxytryptamine-transporter or 5-HTT) may be involved in the pathogenesis of affective disorders. Recently, Collier et al. (1996) found that the frequency of the low-activity short variant (s) of the 5-HTT-linked poly*morphic region (5-HTTLPR) was higher among patients with affective disorders than in normal controls. However, since the observed level of significance was not high, they suggest that these findings should be replicated in independent samples. We have analyzed 86 unrelated patients (47 with bipolar disorder and 39 with schizophrenia) and 98 normal controls from the Brazilian population for the 5-HTTLPR. Statistical analysis revealed that the genotypes (LL, Ls, ss) as well as the estimated allele frequencies (L,s) did not differ significantly among the three studied groups or between bipolar and normal controls. In addition, although not statistically significant, the genotype ss in our sample was less frequent among our bipolar patients than in our normal controls (12.8% versus 16.3%) which is the opposite of what was found by Collier et al. (24% versus 18%) in the European study. Although it will be important to extend the present analysis in a larger sample, our preliminary results suggest that the 5-HTTLPR does not seem to play a major role in the genetics of bipolar and schizophrenic disorders at least in this group of Brazilian psychiatric patients. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:225–227, 1998. © 1998 Wiley-Liss, Inc.