A functional MRI study of working memory task in euthymic bipolar disorder: evidence for task-specific dysfunction.

OBJECTIVES: Even 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. METHODS: 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. RESULTS: There were no significant between-group differences (t-test) in performance of the two-back task, or in 2 x 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. CONCLUSIONS: Our findings support the notion that, in euthymic bipolar disorder, failure to engage fronto-executive function underpins the core neuropsychological deficits.

Tolerability of high-dose venlafaxine in depressed patients.

High doses of antidepressants are often used for treatment-resistant depression. Venlafaxine, a dual serotonin and noradrenaline reuptake inhibitor, has been shown to have a tolerable side-effect profile in previous studies using doses of up to 375 mg/day. We investigated the tolerability of higher than currently recommended doses of venlafaxine using the UKU side-effect rating scale. Seventy outpatients fulfilling DSM-IV criteria for major depressive disorder were recruited into two demographically matched groups according to their daily dosage of venlafaxine: high dose n = 35 (> or = 375 mg/day, range 375-600 mg, average 437 mg/day) or standard dose n = 35 (< 375 mg/day, range 75-300 mg, average 195 mg/day. Clinical characteristics were noted and the UKU side-effect rating scale was administered to a subsample of patients. The most frequently reported complaints in both groups were increased fatigue (48%), concentration difficulties (48%), sleepiness/sedation (37%), failing memory (44.4%) and weight gain (29.6%). Apart from weight gain, the complaints were found to be experienced significantly more severely by the high-dose group. Six patients discontinued venlafaxine due to intolerable side-effects but only two of these patients were on a high dose. There was a tendency for mildly raised blood pressure in 10% of patients on an average dose of 342 mg/day. However, no difference between the two groups was found. This preliminary open study demonstrates that venlafaxine is tolerated at higher than British National Formulary recommended doses (i.e. up to 600 mg daily). However, increased frequency and severity of reported side-effects in the high-dose group are not associated with increased rates of discontinuation.

The pharmacological treatment of bipolar affective disorder: practice is improving but could still be better.

Pharmacological treatment of bipolar affective disorder was examined by case note review of 120 subjects under the care of four hospitals in the North-East of England and compared with that recommended in published consensus opinions and also with the findings of previous surveys. Although the only comparison available is with other geographical regions, it appears that lithium use has remained relatively constant in recent years (53% in this sample). The use of anticonvulsants (62%) was greater than in previous studies, as was use of mood stabilizers in combination (37% overall, 53% in rapid cycling subjects). Antidepressant use was found in 23% of subjects. Eleven percent of subjects taking antidepressants were not prescribed a mood stabilizer and 43% of antidepressants prescribed were tricyclics, possibly increasing the risk of switching to mania. Fifteen percent had no mood stabilizer and antipsychotic use was almost equally split between typical and atypical drugs. Practice in the population studied is nearer than treatment described in previous work to that suggested in the literature. This may result from either, or most probably a combination of, the local availability of a specialist mood disorder service and evolution of overall prescribing practice. However, it still falls short in a number of respects of such recommendations as exist and this requires further examination and monitoring.