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Author(s): Sergey Nejentsev [1, 57]; Joanna M. M. Howson (corresponding author) [1, 57]; Neil M. Walker [1]; Jeffrey Szeszko [1]; Sarah F. Field [1]; Helen E. Stevens [1]; Pamela Reynolds [...]

Abstract: Lithium is the ‘gold standard’ of the many drug treatments used in bipolar disorder. It has efficacy in the treatment of mania, prophylaxis against manic relapses, and, to a lesser extent, prophylaxis against depressive relapses. It decreases suicidal risk. Blood monitoring of lithium is essential. In addition to side effects, problems include rebound mania on abrupt cessation of lithium and teratogenetic risks. Carbamazepine, valproate, and lamotrigine are anticonvulsants with an evidence base in bipolar disorder. Carbamazepine is anti-manic, but is poorly tolerated and associated with many pharmacokinetic interactions. Valproate is also anti-manic and is prophylactic, especially against mania, but its antidepressant effects in bipolar disorder are unclear. It is associated with many problems when used during pregnancy, and should be avoided in women of childbearing potential. Lamotrigine is not licensed for use in bipolar disorder in the UK, but has some evidence for effectiveness in bipolar depression and, more particularly, prophylaxis against depressive relapse. It must be introduced slowly to avoid dangerous skin reactions. Other anticonvulsants have no evidence supporting their use. Antipsychotics, including the atypicals, are effective in treating mania. Olanzapine and aripiprazole are also licensed for continuation treatment in acute responders. Quetiapine has evidence for effectiveness in both bipolar mania and bipolar depression. The efficacy of antidepressants in bipolar disorder is unclear. Tricyclic antidepressants and mono-amine oxidase inhibitors should probably be avoided, owing to a possible risk of switching to mania. In general, antidepressants should be used in conjunction with a mood stabilizer and for the shortest period necessary. [Copyright &y& Elsevier]

Abstract: Unipolar affective disorder, or depression, is the one of the leading causes of disability worldwide and its effective management is a high priority. Treatment is required whether or not the illness is seen as ‘reactive’ to circumstances or understandable. Guidelines for its management have been produced by the National Institute for Health and Clinical Excellence (NICE) and the British Association for Psychopharmacology (BAP). These recommend rating the severity of the illness and using this as a guide for treatment. For less severe depression, antidepressants are recommended only when a patient fails to respond to other interventions or there is a history of more severe depression. For moderate-to-severe depression, antidepressants such as citalopram or fluoxetine are recommended as first-line treatments. The management of treatment-resistant depression (failure to respond to two adequate courses of antidepressants) is complex. NICE includes recommendations to consider augmentation of an antidepressant with cognitive behavioural therapy or lithium, monotherapy with venlafaxine or phenelzine (the latter particularly for atypical depression), and the combination of mirtazapine plus a selective serotonin reuptake inhibitor. BAP guidelines also include consideration of atypical antipsychotic or tri-iodothyronine augmentation of antidepressants. Other strategies have limited data supporting them and are not recommended, or are for use only in specialist centres. [Copyright &y& Elsevier]

Visuospatial working memory theory is used to interpret the cognitive impairment in euthymic bipolar disorder. Such patients show deficits in the Corsi Blocks Test (CBT) and executive control. To understand these deficits, 20 euthymic bipolar patients and controls were administered the CBT, Visual Patterns Test (VPT), and a new visual memory task designed to make minimal demands on executive resources. Initial analyses validated the visual memory task and implicated executive involvement in the CBT and VPT. Subsequent analyses on a number of tests confirmed CBT and executive deficits while performance was normal on the VPT and visual memory test. ANCOVA indicated that impaired executive function underpinned patients’ CBT performance. Implications for the interface between executive and slave systems of working memory are discussed. [ABSTRACT FROM AUTHOR]

Objectives: The notion that sufferers of bipolar disorder achieve complete syndromal and functional recovery between illness episodes has been brought into question by evidence that a large proportion of patients fail to regain premorbid levels of functioning after the resolution of major affective symptoms. A growing body of evidence suggests that bipolar patients exhibit neuropsychological impairment that persists even during the euthymic state, which may be a contributory factor to poor psychosocial outcome. However, the aetiology of such impairment and its relation to progression of illness are not well understood. This review aims to consider evidence from studies investigating both the relationship between cognitive impairment and clinical outcome and studies of neurocognitive function in unaffected first-degree relatives (FDRs) of bipolar sufferers to address issues of the temporal evolution of cognitive impairment in bipolar disorder. Methods: Systematic literature review. Results: The weight of evidence suggests that greater neuropsychological dysfunction in bipolar disorder is associated with a worse prior course of illness, particularly the number of manic episodes, hospitalizations and length of illness. The most consistent finding was a negative relationship between the number of manic episodes and verbal declarative memory performance. Impairment in unaffected FDRs was reported in verbal declarative memory and some facets of executive function. Conclusions: Cognitive impairment may be a trait vulnerability factor for bipolar disorder that is present before illness onset and worsens as the illness progresses. Further investigation into the causal relationship between cognitive impairment and illness course is essential. [ABSTRACT FROM AUTHOR]

Objective: Basal levels of glucocorticoids, such as cortisol, are generally unaltered in bipolar disorder. However, neuroendocrine tests of glucocorticoid receptor (GR) function such as the dexamethasone suppression test (DST) are frequently abnormal. Neuropsychological impairment is well documented in healthy volunteers after administration of glucocorticoids and in patients with bipolar affective disorder. This suggests a potential link between neuropsychological and hypothalamic-pituitary-adrenal axis function. We examined the hypothesis that neuropsychological impairment in bipolar disorder is associated with abnormal GR function. Methods: Seventeen euthymic bipolar patients and 16 controls completed tests of verbal declarative and working memory (WM) tests and the DST. The correlation between neuroendocrine and neuropsychological function was examined. Results: Bipolar patients made significantly more errors of omission and commission on the WM paradigm and demonstrated impaired verbal recognition memory. Patients’ post-dexamethasone cortisol correlated with WM commission errors ( rs = 0.64, p = 0.0006). No such relationship was evident in controls. Conclusion: Deficits in declarative memory and WM are evident in patients with bipolar disorder. The deficit in retrieval accuracy from WM appears to be correlated with abnormal GR function. [ABSTRACT FROM AUTHOR]

Monks PJ, Thompson JM, Bullmore ET, Suckling J, Brammer MJ, Williams SCR, Simmons A, Giles N, Lloyd AJ, Harrison CL, Seal M, Murray RM, Ferrier IN, Young AH, Curtis VA. A functional MRI study of working memory task in euthymic bipolar disorder: evidence for task-specific dysfunction.Bipolar Disord 2004: 6: 550–564.© Blackwell Munksgaard, 2004Even when euthymic bipolar disorder patients can have persistent deficits in working memory, but the neural basis of this deficit remains unclear. We undertook an functional magnetic resonance imaging investigation of euthymic bipolar disorder patients performing two working memory paradigms; the two-back and Sternberg tasks, selected to examine the central executive and the phonological loop respectively. We hypothesized that neuronal dysfunction would be specific to the network underlying the executive rather than the phonological loop component of working memory.Twelve right-handed euthymic bipolar I males receiving lithium carbonate monotherapy were matched with 12 controls. The two-back task comprised a single working memory load contrasted with baseline vigilance condition. The Sternberg paradigm used a parametric design incorporating variable working memory load with fixed delay between presentation of an array of items to be remembered and a target item. Functional activation data were acquired during performance of the tasks and were analysed to produce brain activation maps representing significant group differences in activation (ANOVA). Load–response curves were derived from the Sternberg task data set.There were no significant between-group differences (t-test) in performance of the two-back task, or in 2 × 5 group by memory load ANOVA for the performance data from Sternberg task. In the two-back task, compared with controls bipolar disorder patients showed reductions in bilateral frontal, temporal and parietal activation, and increased activations with the left precentral, right medial frontal and left supramarginal gyri. No between-group differences were observed in the Sternberg task at any working memory load.Our findings support the notion that, in euthymic bipolar disorder, failure to engage fronto-executive function underpins the core neuropsychological deficits. [ABSTRACT FROM AUTHOR]

Ferrier IN, Chowdhury R, Thompson JM, Watson S, Young AH. Neurocognitive function in unaffected first-degree relatives of patients with bipolar disorder: a preliminary report. Bipolar Disord 2004: 6: 319–322. © Blackwell Munksgaard, 2004 Patients with remitted bipolar disorder (BD) have persistent impairments in neuropsychological function, particularly in the domains of executive control and declarative memory [ Br J Psychiatry 180 (2002) 293]. If these were the phenotypic expression of genetic vulnerability to BD, then healthy subjects with a genetic predisposition to BD would be expected to display the same deficits. This study, therefore, examined neuropsychological function in healthy first-degree relatives of patients with BD. A cross-sectional design was employed to compare the performance of 17 unaffected first-degree relatives of BD patients and 17 demographically matched controls on a range of neuropsychological tests. Relatives were significantly impaired on Backward Digit Span, Spatial Span and on tasks of visuospatial declarative memory in comparison with controls. Psychomotor performance and verbal declarative memory were intact, as were non-working memory aspects of executive performance. The selective deficits in executive control and declarative memory exhibited by relatives in this study have previously been reported in euthymic BD patients suggesting they may be useful endophenotypic markers of genetic vulnerability to BD. [ABSTRACT FROM AUTHOR]

Seventy-three elderly patients (38 with Alzheimer-type dementia (ATD) and 35 with major depressive disorder) were followed up 2–5 years after an index admission during which a dexamethasone suppression test (DST) had been performed. Clinical state, cognitive function, neurological status and repeat DST were assessed where possible. The death rate was high in both groups (greater in the ATD group) but was not influence by original DST In either group, but DST non-suppression in the depressed group was associated with significant cognitive rate and abnormal neurological features. Possible mechanisms of the association are discussed. [ABSTRACT FROM AUTHOR]

Background: Magnetic resonance imaging studies have reported that lithium can increase the volume of gray matter in the human brain, a finding that has been ascribed to the established neurotrophic or neuroprotective effects of the drug. Lithium, however, might directly influence the intensity of the magnetic resonance signal so it is possible that the volumetric findings are artifactual, essentially a consequence of altered image contrast. Methods: Anatomical and quantitative magnetic resonance scans were acquired on 31 healthy young men before and after taking either lithium or placebo for 11 days. Brain volume change was derived with two established techniques: voxel-based morphometry (a statistical approach using signal intensity to segment images into tissue types), and Structural Image Evaluation, using Normalization, of Atrophy (a technique that operates by detecting changes in the position of the boundaries of the brain). In a subgroup (n = 12), tissue-specific magnetic resonance relaxation times were compared before and after lithium with quantitative T1-mapping techniques. Results: Voxel-based morphometry revealed that gray matter volume was increased by lithium but not placebo (p = .001), whereas Structural Image Evaluation, using Normalization, of Atrophy showed no difference between lithium and placebo (p = .23). Taking lithium reduced the T1 relaxation of the gray matter only (p = .008). Conclusion: Magnetic resonance images of the brain differ before and after lithium, but this difference might derive from a change in the characteristics of the signal rather than a tangible increase in volume. [ABSTRACT FROM AUTHOR]