A Selective Association between Central and Peripheral Lithium Levels in Remitters in Bipolar Depression: A 3T-(7) Li Magnetic Resonance Spectroscopy Study.

OBJECTIVE: The objective of this study was to evaluate brain lithium levels using (7) Li magnetic resonance spectroscopy after 6 weeks of lithium therapy in bipolar depression to test the hypothesis that brain and plasma lithium are correlated. It was also tested whether responders and remitters have different pharmacokinetics, blood and brain lithium levels (ratio) compared with those presenting suboptimal antidepressant improvement. METHOD: Twenty-three patients with bipolar disorder (I and II) during depressive episodes were included and followed up for 6 weeks at the University of Sao Paulo using flexible dose of lithium (450-900 mg/day). Sixteen patients were drug-naïve. At endpoint, patients underwent a (7) Li-MRS scan and brain lithium concentrations were calculated. RESULTS: A significant association between central and peripheral lithium levels was found only in remitters (r = 0.7, P = 0.004) but not in non-remitters (r = -0.12, P = 0.76). Also, brain lithium (but not plasma) was inversely correlated with age (r = -0.46, P = 0.025). Plasma lithium did not correlate with any clinical outcome, lithium dosage or adverse effects. CONCLUSION: These findings suggest that non-remitters may not transport lithium properly to the brain, which may underlie treatment resistance to lithium in BD. Future studies with (7) Li-MRS integrated with the evaluation of blood-brain barrier transport mechanisms and longitudinal clinical outcomes in BD and aging are warranted.

Staging systems in bipolar disorder: an International Society for Bipolar Disorders Task Force Report.

OBJECTIVE: We discuss the rationale behind staging systems described specifically for bipolar disorders. Current applications, future directions and research gaps in clinical staging models for bipolar disorders are outlined. METHOD: We reviewed the literature pertaining to bipolar disorders, focusing on the first episode onwards. We systematically searched data on staging models for bipolar disorders and allied studies that could inform the concept of staging. RESULTS: We report on several dimensions that are relevant to staging concepts in bipolar disorder. We consider whether staging offers a refinement to current diagnoses by reviewing clinical studies of treatment and functioning and the potential utility of neurocognitive, neuroimaging and peripheral biomarkers. CONCLUSION: Most studies to date indicate that globally defined late-stage patients have a worse overall prognosis and poorer response to standard treatment, consistent with patterns for end-stage medical disorders. We believe it is possible at this juncture to speak broadly of 'early'- and 'late'-stage bipolar disorder. Next steps require further collaborative efforts to consider the details of preillness onset and intermediary stages, and how many additional stages are optimal.

Treatment response in type 2 diabetes patients with major depression.

AIMS: Major depression is more prevalent in patients with type 2 diabetes mellitus (T2DM) than in general population. Comparing psychotherapeutic and pharmacological treatment responses could help to inform the choice between available treatment options. METHOD: Thirty-four patients with T2DM and major depression detected by using the Hospital Anxiety-Depression Scale (HADS), the Montgomery-Äsberg Depression Rating Scale (MADRS) and a structured interview (Mini-International Neuropsychiatric Interview) were randomized to undergo Interpersonal Psychotherapy (IPT) or treatment with sertraline in a 3-month acute intervention course in addition to a 3-month continuation format. Provided that the initial MADRS score was not reduced ≥25% at week 6, these early non-responding patients continued treatment in a sequential add-on combined format. Psychological adjustment to diabetes, attachment style, diabetes self-efficacy, quality of life and HbA1c were also evaluated along intervention. RESULTS: Out of 22 early-responding patients (11 for each treatment type), 16 had clinically significant improvements (<50% initial MADRS score) at endpoint with 11 reaching remission (MADRS scores ≤8), and with no significant differences between IPT and sertraline. Within sequential add-on treatment, out of eight patients, only three of them achieved a clinically significant improvement and only one reached remission. CONCLUSIONS: These preliminary results suggested that IPT may be an option to treat major depression in T2DM against medical care with sertraline. Early non-responding patients likely need alternative or longer treatment interventions. Limitations of this study relate to small sample and absence of a control group, which was difficult to implement due to ethical restrictions. KEY PRACTITIONER MESSAGE: Findings suggest that Interpersonal Psychotherapy is a useful tool to treat major depression in type 2 diabetes patients. A significant number of type 2 diabetes patients with major depression do not achieve depression remission irrespective of the type of treatment. Further clinical research should focus on addictive effects of psychotherapy and psychopharmacology in the treatment of depressed patients with chronic somatic diseases.

Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis.

OBJECTIVE: An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta-analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view. METHOD: Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task. RESULTS: Impairments were found for all 11 test-measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26-0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test-measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression. CONCLUSION: This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta-analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.

The CACNA1C risk allele selectively impacts on executive function in bipolar type I disorder.

OBJECTIVE: Calcium channels are important for converting electrical activity into biochemical events. A single nucleotide polymorphism (SNP) (rs1006737) in the CACNA1C gene has been strongly associated with increased risk for Bipolar disorder (BD) in genome-wide association studies. Recently, this same SNP has been reported to influence executive function in schizophrenia and controls, but it remains unclear whether this SNP affects behaviour, especially cognition in subjects with BD. METHOD: A total of 109 BD type I subjects and 96 controls were genotyped for CACNA1C rs1006737 and assessed with an executive function tests battery [Wechsler Adult Intelligence Scale III (WAIS-III) Letter-Number Sequence subtest (WAIS-LNS), digit span (WAISDS), trail making test (TMT), and WCST (Wisconsin Card Sorting Test)]. RESULTS: In patients with BD, the CACNA1C genotype Met/Met was associated with worse performance on all four executive function tests compared to Val/Val. No influence of CACNA1C was observed in the cognitive performance of healthy controls. CONCLUSION: Our data indicate for the first time that the CACNA1C risk allele is likely associated with executive dysfunction as a trait in BD, as this association was found regardless the presence of mood symptoms. Larger studies should evaluate the potential influence of CACNA1C on other cognitive domains in BD.

Efficacy of psychoeducation on symptomatic and functional recovery in bipolar disorder.

OBJECTIVE: To evaluate the efficacy of psychoeducation in the symptomatic and functional recovery, and quality of life (QoL) in a sample of patients with bipolar disorder (BD). METHOD: The sample comprised 55 patients with BD I and II in remission (Young Mania Rating Scale ≤6 and Hamilton Depression Rating Scale ≤7). Out-patients were matched assigned to receive 16 sessions of psychoeducation [experimental group (EG)] or 16 sessions of placebo without psychoeducation [control group (CG)]. Groups were evaluated at study baseline, midpoint, endpoint, and at 6- and 12-month follow-ups. RESULTS: No significant differences between the groups were found for the variables evaluated (mood symptoms, functioning and QoL), except for overall clinical improvement, subjectively perceived by EG subjects. Both groups showed a trend toward improved clinical global impression and QoL (environmental). No reduction in mood symptoms or improvement in psychosocial functioning was observed. Psychosocial treatment compliance was positively correlated with global functioning, social adjustment, sociability, and global clinical impression. CONCLUSION: Sixteen session psychoeducation seems to be ineffective to prevent mood episodes or improve functioning in a sample of bipolar patients.

Pharmacological approaches in bipolar disorders and the impact on cognition: a critical overview.

OBJECTIVE: Historically, pharmacological treatments for bipolar disorders (BD) have been associated with neurocognitive side-effects. We reviewed studies which assessed the impact of several psychopharmacological drugs on the neurocognitive function of BD patients. METHOD: The PubMed database was searched for studies published between January 1980 and February 2011, using the following terms: bipolar, bipolar disorder, mania, manic episode, or bipolar depression, cross-referenced with cognitive, neurocognitive, or neuropsychological, cross-referenced with treatment. RESULTS: Despite methodological flaws in the older studies and insufficient research concerning the newer agents, some consistent findings emerged from the review; lithium appears to have definite, yet subtle, negative effects on psychomotor speed and verbal memory. Among the newer anticonvulsants, lamotrigine appears to have a better cognitive profile than carbamazepine, valproate, topiramate, and zonisamide. More long-term studies are needed to better understand the impact of atypical antipsychotics on BD patients' neurocognitive functioning, both in monotherapy and in association with other drugs. Other agents, like antidepressants and cognitive enhancers, have not been adequately studied in BD so far. CONCLUSION: Pharmacotherapies for BD should be chosen to minimize neurocognitive side-effects, which may already be compromised by the disease process itself. Neurocognitive evaluation should be considered in BD patients to better evaluate treatment impact on neurocognition. A comprehensive neuropsychological evaluation also addressing potential variables and key aspects such as more severe cognitive deficits, comorbidities, differential diagnosis, and evaluation of multiple cognitive domains in longitudinal follow-up studies are warranted.

Translating neurotrophic and cellular plasticity: from pathophysiology to improved therapeutics for bipolar disorder.

OBJECTIVE: Bipolar disorder (BD) likely involves, at a molecular and cellular level, dysfunctions of critical neurotrophic, cellular plasticity and resilience pathways and neuroprotective processes. Therapeutic properties of mood stabilizers are presumed to result from a restoration of the function of these altered pathways and processes through a wide range of biochemical and molecular effects. We aimed to review the altered pathways and processes implicated in BD, such as neurotrophic factors, mitogen-activated protein kinases, Bcl-2, phosphoinositol signaling, intracellular calcium and glycogen synthase kinase-3. METHODS: We undertook a literature search of recent relevant journal articles, book chapter and reviews on neurodegeneration and neuroprotection in BD. Search words entered were 'brain-derived neurotrophic factor,''Bcl-2,''mitogen-activated protein kinases,''neuroprotection,''calcium,''bipolar disorder,''mania,' and 'depression.' RESULTS: The most consistent and replicated findings in the pathophysiology of BD may be classified as follows: i) calcium dysregulation, ii) mitochondrial/endoplasmic reticulum dysfunction, iii) glial and neuronal death/atrophy and iv) loss of neurotrophic/plasticity effects in brain areas critically involved in mood regulation. In addition, the evidence supports that treatment with mood stabilizers; in particular, lithium restores these pathophysiological changes. CONCLUSION: Bipolar disorder is associated with impairments in neurotrophic, cellular plasticity and resilience pathways as well as in neuroprotective processes. The evidence supports that treatment with mood stabilizers, in particular lithium, restores these pathophysiological changes. Studies that attempt to prevent (intervene before the onset of the molecular and cellular changes), treat (minimize severity of these deficits over time), and rectify (reverse molecular and cellular deficits) are promising therapeutic strategies for developing improved treatments for bipolar disorder.

Clinical and neurocognitive correlates of insight in patients with bipolar I disorder in remission.

OBJECTIVE: The relationship between insight and neurocognition in bipolar disorder has not been clearly established. METHOD: A neuropsychological battery assessing attention, mental control, perceptual-motor skills, executive functions, verbal fluency and abstraction, and visuo-spatial attention was administered to 50 bipolar remitted patients and 50 healthy controls. Insight was assessed with the Scale to Assess Unawareness of Mental Disorder. RESULTS: Patients presented significantly worse neurocognitive performance. Insight was impaired in 60% of patients, and age, educational level, manic symptoms, age of disease onset, number of admissions, and performance on several neurocognitive tests correlated significantly with insight. A regression model revealed that age and Trail Making Test part B (TMT-B) performance accounted for 32% of the variance in overall illness awareness, while performance on the TMT-B alone accounted for 28% of the variance. CONCLUSION: Impaired insight and neurocognitive dysfunction seem to be present in euthymic bipolar patients. Insight in bipolar disorder may be partially dependent on intact neurocognition.