Neurocognitive intra-individual variability in mood disorders: effects on attentional response time distributions.

BACKGROUND: Attentional impairment is a core cognitive feature of major depressive disorder (MDD) and bipolar disorder (BD). However, little is known of the characteristics of response time (RT) distributions from attentional tasks. This is crucial to furthering our understanding of the profile and extent of cognitive intra-individual variability (IIV) in mood disorders. METHOD: A computerized sustained attention task was administered to 138 healthy controls and 158 patients with a mood disorder: 86 euthymic BD, 33 depressed BD and 39 medication-free MDD patients. Measures of IIV, including individual standard deviation (iSD) and coefficient of variation (CoV), were derived for each participant. Ex-Gaussian (and Vincentile) analyses were used to characterize the RT distributions into three components: mu and sigma (mean and standard deviation of the Gaussian portion of the distribution) and tau (the 'slow tail' of the distribution). RESULTS: Compared with healthy controls, iSD was increased significantly in all patient samples. Due to minimal changes in average RT, CoV was only increased significantly in BD depressed patients. Ex-Gaussian modelling indicated a significant increase in tau in euthymic BD [Cohen's d = 0.39, 95% confidence interval (CI) 0.09-0.69, p = 0.011], and both sigma (d = 0.57, 95% CI 0.07-1.05, p = 0.025) and tau (d = 1.14, 95% CI 0.60-1.64, p < 0.0001) in depressed BD. The mu parameter did not differ from controls. CONCLUSIONS: Increased cognitive variability may be a core feature of mood disorders. This is the first demonstration of differences in attentional RT distribution parameters between MDD and BD, and BD depression and euthymia. These data highlight the utility of applying measures of IIV to characterize neurocognitive variability and the great potential for future application.

Bouncing back: is the bipolar rebound phenomenon peculiar to lithium? A retrospective naturalistic study.

In bipolar disorder the discontinuation of lithium prophylaxis is associated with early episode precipitation. Is this ;rebound' phenomenon peculiar to lithium? This naturalistic retrospective case note review investigated the frequency of immediate recurrence after discontinuation of any prophylactic treatment. Bipolar patients who stopped at least one medication after at least 6 months of remission were studied. A total of 310 case notes were examined in a systematic search. A total of 53 cases of discontinuation in 48 subjects were found. Discontinued medications included lithium, valproate, carbamazepine, typical and atypical antipsychotics and antidepressants. Recurrence occurred within 3 months of medication withdrawal in 39 cases (74%). Over half of the discontinuation episodes involved lithium: recurrence occurred in 86% of these cases. In the groups stopping other prophylactic agents, a majority of subjects suffered recurrence: anticonvulsants (89%), antipsychotics (64%) and antidepressants (58%). However, these groups were small and the clarity of the data was undermined by the simultaneous withdrawal of other agents. Manic and hypomanic episodes were the most common form of recurrences. Depressive episodes occurred proportionately most frequently following antidepressant withdrawal. More than half of recurrences required hospital admission. This study provides preliminary naturalistic evidence that early episode recurrence in bipolar disorder is not peculiar to lithium withdrawal but may occur following withdrawal of medication from all classes recommended in prophylaxis. These findings, if replicated, have important implications for clinical practice and for research.

Does 'rebound mania' occur after stopping carbamazepine? A pilot study.

Withdrawal of lithium prophylaxis in patients with bipolar affective disorder has been shown to precipitate 'rebound mania', an effect which may negate its benefits in the poorly compliant. No studies have looked for similar effects on withdrawal of carbamazepine, an alternative and adjunctive prophylactic treatment. This retrospective study examined the effects of withdrawal of carbamazepine prophylaxis in patients with bipolar disorder. A systematic search for patients with bipolar disorder who stopped carbamazepine therapy whilst in remission was conducted, followed by case note review and interview. In a case series of six patients who stopped carbamazepine, four remained well for at least 3 months, one developed an episode of moderate depression and one remained well before resuming treatment after 1 month. None required admission or suffered a manic episode in the 3 months following cessation. This study does not support the existence of a carbamazepine 'rebound' effect. It raises the possibility that recurrence after stopping carbamazepine may be less severe than the 'rebound mania' seen on lithium withdrawal. If this is the case, it may be a better choice of mood stabilizer in the poorly compliant. To date, there is insufficient evidence on which to base this choice. There is a need to examine this issue further through larger prospective and experimental studies on the effects of anticonvulsant withdrawal.

Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder.

BACKGROUND: Although lithium has been the most commonly used maintenance treatment in bipolar disorder for several decades, valproate is being used increasingly - especially in the United States of America. There is a need to clarify whether the increasingly prominent prophylactic role of valproate in bipolar disorder is justified. OBJECTIVES: To review the effectiveness of valproate, relative to placebo, other mood stabilisers and antipsychotics, in the prevention and/or attenuation of acute episodes of bipolar disorder. The effectiveness of valproate was considered in terms of mood symptoms, mortality, general health, social functioning, adverse effects and overall acceptability to patients. SEARCH STRATEGY: The CCDAN group search strategy was used. The following databases were searched: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), The Cochrane Controlled Clinical Trials Register (CCCTR), EMBASE, MEDLINE, LILACS, PsycLIT and Psyndex. Reference lists of relevant papers and major textbooks of mood disorder were examined. Authors, other experts in the field and pharmaceutical companies were contacted for knowledge of suitable published or unpublished trials. SELECTION CRITERIA: Randomised controlled trials which compared valproate with placebo, alternative mood stabilisers (including lithium and carbamazepine) or neuroleptics, where the stated intent of intervention was the maintenance treatment of bipolar disorder. Participants were males and females of all ages with a diagnosis of bipolar disorder however diagnosed, approximating to ICD 10 Code F31 and DSM IV 296, but including patients diagnosed as ICD-9 manic depressive psychosis and DSM-III and DSM-IIIR bipolar disorder. DATA COLLECTION AND ANALYSIS: Data were extracted from the original reports individually by two reviewers. The main outcomes to be assessed were: 1. The effectiveness of valproate treatment in preventing or attenuating further episodes of bipolar disorder, including its effectiveness in rapid cycling disorder. 2. The acceptability of valproate treatment to patients. 3. The prevalence of side-effects. 4. Mortality on valproate treatment. Outcomes concerning relapse/recurrence were analysed excluding data from discontinuation studies, which were to be analysed separately. Sub-group analyses were to be performed to examine the effects of valproate treatment in rapid cycling bipolar disorder and previous mood stabiliser non-responders. Data were analysed using Review Manager version 4.1. MAIN RESULTS: One trial of 12 months duration with 372 participants was identified comparing lithium, divalproex and placebo. It had several methodological limitations. The primary analysis of time to occurrence of mood episode described in the main trial report found no reliable difference between the treatments, although there was a trend for divalproex to be more effective than lithium. In the analysis in this review, patients taking divalproex who left the study because of the occurrence of an mood episode were significantly less in number than those on placebo (RRR 37%; RR 0.63; 95% CI 0.44 to 0.90). There was no significant difference in the numbers of patients in receipt of divalproex compared with those in receipt of lithium who left the study because they suffered any mood episode. (RRR 22%; RR 0.78; 95% C.I. 0.52 to 1.17). There was insufficient information to allow sub-group analyses of rapid-cycling disorder. The divalproex group had significantly more patients suffering tremor (RRI 223%; RR 3.23; 95% C.I. 1.85 to 5.62), weight gain (RRI 187%; RR 2.87; 95% C.I. 1.34 to 6.17) and alopecia (RRI 143%; RR 2.43; 95% C.I. 1.05 to 5.65) than the placebo group. In comparison with the lithium, divalproex was associated with more frequent sedation (RRI 58%; RR 1.58; 95% C.I. 1.08 to 2.32) and infection (RRI 107%; RR 2.07; 95% C.I. 1.16 to 3.68), but less suffered thirst (RRR 62%; RR 0.38; 95% C.I. 0.18 to 0.81) and polyuria (RRR 57%; RR 0.43; 95% C.I. 0.22 to 0.82). REVIEWER'S CONCLUSIONS: In view of the equivocal findings of this review, conclusions about the efficacy and acceptability of valproate compared to placebo and lithium cannot be made with any degree of confidence. With current evidence, patients and clinicians would probably wish to use lithium before valproate for maintenance treatment. At present, the observed shift of prescribing practice to valproate is not based on reliable evidence of efficacy

The evaluation of the rheological properties of lactose/microcrystalline cellulose and water mixtures by controlled stress rheometry and the relationship to the production of spherical pellets by extrusion/spheronization.

The consistency of wet powder masses produced from two ratios (7:3 and 8:2) of alpha-lactose monohydrate (L) and microcrystalline cellulose (MCC) mixed with a range of water contents has been assessed with a parallel plate controlled stress rheometer. The range of water contents, which could be studied, was restricted to those, which could be extruded uniformly by a ram extruder. In the creep mode, the instantaneous compliance increased as the water content increased for both L:MCC ratios illustrating the increasing deformability of the mixtures with increasing water content. The derived apparent viscosity of the mixtures as a function of shear rate, increased as the water content decreased and the values for all the systems fell on a common line. This indicates that the measurements are providing a reliable assessment of the mixtures and that the change in water content and L:MCC ratio provides systems, whose change of viscosity with rate of shear is consistent at low rates of shear. The values of the storage and loss moduli obtained from oscillatory measurements, increased with a decrease in water content but this time the two ratios of L:MCC were not on a common line when related to the water content of the mixtures. There was a range of water levels over which both the values of the storage and loss moduli were approximately constant. This corresponded to the level of water, which produced the pellets of the smallest diameter and range of diameters and were of the most spherical shape when produced by a ram extruder and spheronization. For 8:2 L:MCC ratio, there appeared to be a value for both the storage and the loss moduli above which the wet mass could not produce good pellets. For the 7:3 L:MCC these limiting levels were not achieved before extrusion with steady state conditions could be maintained without the mass being too wet or too dry. Instead, there appeared to be minimum levels of the moduli required to ensure that the mixtures were able to produce good pellets.