G M Goodwin

Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy

Studies of psychiatric disorders have traditionally focused on emotional symptoms such as depression, anxiety and hallucinations. However, poorly controlled cognitive deficits are equally prominent and severely compromise quality of life, including social and professional integration. Consequently, intensive efforts are being made to characterize the cellular and cerebral circuits underpinning cognitive function, define the nature and causes of cognitive impairment in psychiatric disorders and identify more effective treatments. Successful development will depend on rigorous validation in animal models as well as in patients, including measures of real-world cognitive functioning. This article critically discusses these issues, highlighting the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders.

Lithium toxicity profile: a systematic review and meta-analysis

BACKGROUND Lithium is a widely used and effective treatment for mood disorders. There has been concern about its safety but no adequate synthesis of the evidence for adverse effects. We aimed to undertake a clinically informative, systematic toxicity profile of lithium. METHODS We undertook a systematic review and meta-analysis of randomised controlled trials and observational studies. We searched electronic databases, specialist journals, reference lists, textbooks, and conference abstracts. We used a hierarchy of evidence which considered randomised controlled trials, cohort studies, case-control studies, and case reports that included patients with mood disorders given lithium. Outcome measures were renal, thyroid, and parathyroid function; weight change; skin disorders; hair disorders; and teratogenicity. FINDINGS We screened 5988 abstracts for eligibility and included 385 studies in the analysis. On average, glomerular filtration rate was reduced by -6·22 mL/min (95% CI -14·65 to 2·20, p=0·148) and urinary concentrating ability by 15% of normal maximum (weighted mean difference -158·43 mOsm/kg, 95% CI -229·78 to -87·07, p<0·0001). Lithium might increase risk of renal failure, but the absolute risk was small (18 of 3369 [0·5%] patients received renal replacement therapy). The prevalence of clinical hypothyroidism was increased in patients taking lithium compared with those given placebo (odds ratio [OR] 5·78, 95% CI 2·00-16·67; p=0·001), and thyroid stimulating hormone was increased on average by 4·00 iU/mL (95% CI 3·90-4·10, p<0·0001). Lithium treatment was associated with increased blood calcium (+0·09 mmol/L, 95% CI 0·02-0·17, p=0·009), and parathyroid hormone (+7·32 pg/mL, 3·42-11·23, p<0·0001). Patients receiving lithium gained more weight than did those receiving placebo (OR 1·89, 1·27-2·82, p=0·002), but not those receiving olanzapine (0·32, 0·21-0·49, p<0·0001). We recorded no significant increased risk of congenital malformations, alopecia, or skin disorders. INTERPRETATION Lithium is associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. There is little evidence for a clinically significant reduction in renal function in most patients, and the risk of end-stage renal failure is low. The risk of congenital malformations is uncertain; the balance of risks should be considered before lithium is withdrawn during pregnancy. Because of the consistent finding of a high prevalence of hyperparathyroidism, calcium concentrations should be checked before and during treatment. FUNDING National Institute for Health Research Programme Grant for Applied Research.

Evidence-based guidelines for treating bipolar disorder: recommendations from the British Association for Psychopharmacology.

The British Association for Psychopharmacology guidelines specify the scope and target of treatment for bipolar disorder. They are based explicitly on the available evidence and presented, similar to previous Clinical Practice guidelines, as recommendations to aid clinical decision-making for practitioners. They may also serve as a source of information for patients and carers. The recommendations are presented together with a more detailed review of the available evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from participants and interested parties. The strength of supporting evidence was rated. The guidelines cover the diagnosis of bipolar disorder, clinical management and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment.

Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials

BACKGROUND There is uncertainty about the efficacy of lamotrigine in bipolar depressive episodes. AIMS To synthesise the evidence for the efficacy of lamotrigine in bipolar depressive episodes. METHOD Systematic review and meta-analysis of individual patient data from randomised controlled trials comparing lamotrigine with placebo. RESULTS Individual data from 1072 participants from five randomised controlled trials were obtained. More individuals treated with lamotrigine than placebo responded to treatment on both the Hamilton Rating Scale for Depression (HRSD) (relative risk (RR)=1.27, 95% CI 1.09-1.47, P=0.002) and Montgomery-Asberg Depression Rating Scale (MADRS) (RR=1.22, 95% CI 1.06-1.41, P=0.005). There was an interaction (P=0.04) by baseline severity of depression: lamotrigine was superior to placebo in people with HRSD score >24 (RR=1.47, 95% CI 1.16-1.87, P=0.001) but not in people with HRSD score < or =24 (RR=1.07, 95% CI 0.90-1.27, P=0.445). CONCLUSIONS There is consistent evidence that lamotrigine has a beneficial effect on depressive symptoms in the depressed phase of bipolar disorder. The overall pool effect was modest, although the advantage over placebo was larger in more severely depressed participants.

The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: Update 2009 on the Treatment of Acute Mania

These updated guidelines are based on a first edition that was published in 2003, and have been edited and updated with the available scientific evidence until end of 2008. Their purpose is to supply a systematic overview of all scientific evidence pertaining to the treatment of acute mania in adults. The data used for these guidelines have been extracted from a MEDLINE and EMBASE search, from the clinical trial database clinicaltrials.gov, from recent proceedings of key conferences, and from various national and international treatment guidelines. Their scientific rigor was categorised into six levels of evidence (A–F). As these guidelines are intended for clinical use, the scientific evidence was finally asigned different grades of recommendation to ensure practicability.

The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: Update 2010 on the treatment of acute bipolar depression.

Abstract Objectives. These guidelines are based on a first edition that was published in 2002, and have been edited and updated with the available scientific evidence until September 2009. Their purpose is to supply a systematic overview of all scientific evidence pertaining to the treatment of acute bipolar depression in adults. Methods. The data used for these guidelines have been extracted from a MEDLINE and EMBASE search, from the clinical trial database clinicaltrials.gov, from recent proceedings of key conferences, and from various national and international treatment guidelines. Their scientific rigor was categorised into six levels of evidence (A–F). As these guidelines are intended for clinical use, the scientific evidence was finally assigned different grades of recommendation to ensure practicability. Results. We identified 10 pharmacological monotherapies or combination treatments with at least limited positive evidence for efficacy in bipolar depression, several of them still experimental and backed up only by a single study. Only one medication was considered to be sufficiently studied to merit full positive evidence. Conclusions. Although major advances have been made since the first edition of this guideline in 2002, there are many areas which still need more intense research to optimize treatment. The majority of treatment recommendations is still based on limited data and leaves considerable areas of uncertainty.

Induction of depressed mood disrupts emotion regulation neurocircuitry and enhances pain unpleasantness.

BACKGROUND Depressed mood alters the pain experience. Yet, despite its clear clinical relevance, little is known about the cognitive and neural mechanisms underlying this phenomenon. We tested an experimental manipulation to unravel the interaction between depressed mood and pain. We hypothesized that dysregulation of the neural circuitry underlying emotion regulation is the mechanism whereby pain processing is affected during depressed mood. METHODS Using functional magnetic resonance imaging, we compared the effects of sad and neutral cognitive mood inductions on affective pain ratings, pain-specific cognitions, and central pain processing of a tonic noxious heat stimulus in 20 healthy volunteers. RESULTS The increase in negative pain-specific cognitions during depressed mood predicted the perceived increase in pain unpleasantness. Following depressed mood induction, brain responses to noxious thermal stimuli were characterized by increased activity in a broad network including prefrontal areas, subgenual anterior cingulate cortex, and hippocampus, as well as significantly less deactivation when compared with pain responses in a neutral mood. The participants who reported the largest increase in pain unpleasantness after the sad mood induction showed greater inferior frontal gyrus and amygdala activation, linking changes in emotion regulation mechanisms with enhancement of pain affect. CONCLUSIONS Our results inform how depressed mood and chronic pain co-occur clinically and may serve to develop and translate effective interventions using pharmacological or psychological treatment.

Sustained attention-deficit confirmed in euthymic bipolar disorder but not in first-degree relatives of bipolar patients or euthymic unipolar depression.

BACKGROUND Cognitive dysfunction persists in the euthymic phase of bipolar disorder and may provide a marker of underlying neuropathology and disease vulnerability. This study aimed to replicate a deficit in sustained attention in euthymic bipolar patients and investigate sustained attention in first-degree relatives of bipolar probands and in remitted patients with major depressive disorder. METHODS The rapid visual information processing (RVIP) task was used to measure sustained attention in 15 euthymic patients with bipolar disorder and 15 control subjects in experiment 1 and in 27 first-degree relatives of bipolar probands, 15 remitted patients with major depressive disorder, and 46 control subjects in experiment 2. RESULTS Sustained attention deficit was confirmed in the euthymic bipolar patients in experiment 1, but the deficit was not statistically significant in remitted major depressed patients or in the relatives of bipolar probands. CONCLUSIONS A deficit of sustained attention is not present in patients with recurrent major depression tested during remission nor is it discriminable in the first-degree relatives of bipolar probands. Thus, the confirmed abnormality in euthymic bipolar patients may be acquired as a consequence of bipolar illness. However, future studies of relatives will require larger sample sizes to exclude or utilize small genetic effects.

Folate for Depressive Disorders: Systematic Review and Meta-Analysis of Randomized Controlled Trials:

The objective of this review was to determine the effectiveness, adverse effects and acceptability of folate in the treatment of depression. Electronic databases (Cochrane Controlled Trials Register and the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register) and reference lists were searched, and authors, experts and pharmaceutical companies contacted to identify randomized controlled trials that compared treatment with folic acid or 5 ′-methyltetrahydrofolic acid to an alternative treatment, for patients with a diagnosis of depressive disorder. Three randomized trials (247 participants) were included. Two studies assessed the use of folate in addition to other treatment, and found that adding folate reduced Hamilton Depression Rating Scale (HDRS) scores on average by a further 2.65 points [95% confidence interval (CI) 0.38-4.93]. Fewer patients treated with folate experienced a reduction in their HDRS score of less than 50% at 10 weeks (relative risk 0.47, 95% CI 0.24-0.92). The remaining study found no statistically significant difference when folate alone was compared with trazodone. The identified trials did not find evidence of any problems with the acceptability or safety of folate. The limited available evidence suggests folate may have a potential role as a supplement to other treatment for depression. It is currently unclear if this is the case both for people with normal folate levels, and for those with folate deficiency.

State- and trait-related deficits in sustained attention in bipolar disorder

Abstract.Investigation of neuropsychological functioning in bipolar disorder provides a potential link from the prominent cognitive symptoms of the disorder to the underlying neural mechanisms. Continuous performance measures of sustained attention have yielded consistent findings in bipolar disorder patients. There are impairments that appear to be both state- and trait-related. Impaired target detection may represent one of the most sensitive markers of illness course in bipolardisorder. It is unrelated to residual mood symptomatology and medication status, and is present in patients with good functional recovery. The impairment in target detection is exacerbated in the manic state, and is accompanied by an increased rate of false responding. Sustained attention deficit is present early in the course of the disorder, but becomes more pronounced with repeated episodes. This cognitive profile, of an early-onset, state-modulated, trait marker, is distinct from the profile of attentional disruption seen in schizophrenia or unipolar depression. The state- and trait-related impairments may be differentially associated with the ascending dopamine and noradrenaline projections.