Bipolar Disorder: Goodwin GM

Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Moller HJ, Kasper S. · Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK. · World J Biol Psychiatry. · Pubmed #19347775 No free full text.

Abstract: 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.

Goodwin GM, Anonymous00428. · University Department of Psychiatry, Warneford Hospital, Oxford, UK. · J Psychopharmacol. · Pubmed #12870562 No free full text.

Abstract: 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.

Malhi GS, Goodwin GM. · No affiliation provided · Aust N Z J Psychiatry. · Pubmed #17828650 No free full text.

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Goodwin GM, Geddes JR. · No affiliation provided · Br J Psychiatry. · Pubmed #17766755 links to  free full text

Abstract: Psychiatry has long identified schizophrenia as its defining disorder, its heartland as it has been called. In the past 20 years, this has had a number of negative consequences for psychiatry as a medical specialty, which result from the uncertainty of diagnosis and an increasing emphasis on demedicalising services in an attempt to provide social care outside hospital. These changes have probably increased the stigma attached to psychiatric practice and threaten to deskill doctors. They have also meant that services for other disorders do not meet the needs of patients. To continue to allow schizophrenia to be the paradigm condition is against the interests of psychiatrists and their patients.

Chengappa KR, Goodwin GM. · No affiliation provided · Bipolar Disord. · Pubmed #15762863 No free full text.

This publication has no abstract.

Geddes JR, Calabrese JR, Goodwin GM. · Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK. · Br J Psychiatry. · Pubmed #19118318 No free full text.

Abstract: 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.

Goodwin GM, Anderson I, Arango C, Bowden CL, Henry C, Mitchell PB, Nolen WA, Vieta E, Wittchen HU. · University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, UK. · Eur Neuropsychopharmacol. · Pubmed #18501566 No free full text.

Abstract: DIAGNOSIS AND EPIDEMIOLOGY: DSM-IV, specifically its text revision DSM-IV-TR, remains the preferred diagnostic system. When employed in general population samples, prevalence estimates of bipolar disorder are relatively consistent across studies in Europe and USA. In community studies, first onset of bipolar mood disorder is usually in the mid-teenage years and twenties, and the occurrence of a major depressive episode or hypomania is usually its first manifestation. Since reliable criteria for delineating unipolar (UP) and bipolar (BI) depression cross-sectionally are currently lacking, there is a longitudinal risk - probably over 10% - that initial UP patients ultimately turn out as BP in the longer run. Its early onset implies a severe potential burden of disease in terms of impaired social and neuropsychological development, most of which is attributable to depression. BIPOLAR DEPRESSION IN CHILDREN: Bipolar I disorder is rare in prepubertal children, when defined according to unmodified DSM-IV-TR criteria. A broad diagnosis of bipolar disorder risks confounding with other childhood psychopathology and has less predictive value for bipolar disorder in adulthood than the conservative definition. Nevertheless, empirical studies of drug and other treatments and longitudinal studies to assess validity of the broadly defined phenotype in children and adolescents are desirable, rather than extrapolation from adult bipolar practice. The need for an increased capacity to conduct reliable trials in children and adolescents is a challenge to Europe, whose healthcare system should allow greater participation and collaboration than other regions, via clinical networks. ECNP will aspire to facilitate such developments. BIPOLAR DEPRESSION IN ADULTS - UNIPOLAR/BIPOLAR CONTRAST: Despite some differences in symptom profiles and severity measures, a cross-sectional categorical distinction between bipolar (BP) and unipolar (UP) depression is currently impossible. For regulatory purposes, a major depressive episode, meeting DSM-IV-TR criteria, remains the same diagnosis, irrespective of the overall course of the disorder. However, in refining diagnosis in future studies and DSM-V, a probabilistical approach to the UP/BP distinction is more likely to be informative as recommended by the International Society for Bipolar Disorders (ISBD). Anxiety is a commonly present, often at syndromal levels, in bipolar populations. Thus, RCT inclusion criteria for trials not targeting anxiety, should accept co-morbid anxiety disorders as part of the history and even current anxiety symptoms, where these are not dominating the mental state at recruitment to a study. Rapid cycling patients defined as those suffering from 4 or more episodes per year, may also be recruited into trials of bipolar depression without impairing assay sensitivity. Illness severity critically affects assay sensitivity. The minimum scores for entry into a bipolar depression trials should be >20 on HAM-D (17 item scale). However, efficacy is best detected in patients with HAM-D >24 at baseline. THE USE OF RATING SCALES IN BIPOLAR DEPRESSION: There is some dissatisfaction with the HAM-D or MADRS as the preferred primary outcome for trials, although they probably capture global severity adequately. Secondary measures to capture so-called atypical symptoms (such as hypersomnia or hyperphagia), or specific psychopathology more common in bipolar participants (such as lability of mood), could be informative as secondary measures. TREATMENT STUDIES IN BIPOLAR DEPRESSION: Monotherapy trials against placebo remain the gold-standard design for determining efficacy in bipolar depression. The confounding effects of co-medication are emerging from the literature on antidepressant studies in bipolar depression, often conducted in combination with antimanic agents to avoid possible switch to mood elevation. Three arm trials, including the compound to be tested, placebo, and a standard comparator, are generally preferred in order to ensure assay sensitivity and a better picture of benefit-risk ratio. However, in the absence of any gold-standard, two-arm trials may be enough. If efficacy happens to be proven as monotherapy, new compounds may be tested in adjunctive-medication placebo-controlled designs. Younger adults, without an established need for long-term medication, may be particularly suitable for clinical trials requiring placebo controls. The conversion rate of initial UP depression, converting to become BP in the long run is estimated to be 10%. Switch to mania or hypomania may be the consequence of active treatment for bipolar depression. Some medicines such as the tricyclic antidepressants and venlafaxine may be more likely to provoke switch than others, but this increased rate of switch may not be seen until about 10 weeks of treatment. Twelve week trials against placebo are necessary to determine the risk of switch and to establish continuing effects. Careful assessment at 6-8 weeks is required to ensure that patients who are failing to respond do not continue in a study for unacceptable periods of time. To capture a switch event, studies should include scales to define the phenomenology of the event (e.g. hypomania or mania) and its severity. These may be best applied shortly after the clinical decision that switch is occurring. Long-term treatment is commonly required in bipolar disorder. Trials to detect maintenance of effect or continued response in bipolar depression should follow a 'relapse prevention' design: i.e. patients are treated in an index episode with the medicine of interest and then randomized to either continue the active treatment or placebo. However, acute withdrawal of active medication after treatment response might artificially enhance effect size due to active drug withdrawal effects. A short taper is usually desirable. Longer periods of stabilisation are also desirable for up to 3 months: protocol compliance may then be difficult to achieve in practice and so will certainly make studies more difficult and expensive to conduct. The addition of a medicine to other agents during or after the resolution of a depressive or manic episode, and its subsequent investigation as monotherapy against placebo to prevent further relapse (as in the lamotrigine maintenance trials) is clinically informative. Assay sensitivity and patient acceptability are enhanced if the outcome in long-term studies is 'time to intervention for a new episode' for discontinuation designs.

Mitchell PB, Goodwin GM, Johnson GF, Hirschfeld RM. · School of Psychiatry, University of New South Wales, Sydney, Australia. · Bipolar Disord. · Pubmed #18199233 No free full text.

Abstract: OBJECTIVES: There are currently no accepted diagnostic criteria for bipolar depression for either research or clinical purposes. This paper aimed to develop recommendations for diagnostic criteria for bipolar I depression. METHODS: Studies on the clinical characteristics of bipolar and unipolar depression were reviewed. To identify relevant papers, literature searches using PubMed and Medline were undertaken. RESULTS: There are no pathognomonic characteristics of bipolar I depression compared to unipolar depressive disorder. There are, however, replicated findings of clinical characteristics that are more common in both bipolar I depression and unipolar depressive disorder, respectively, or which are observed in unipolar-depressed patients who 'convert' (i.e., who later develop hypo/manic symptoms) to bipolar disorder over time. The following features are more common in bipolar I depression (or in unipolar 'converters' to bipolar disorder): 'atypical' depressive features such as hypersomnia, hyperphagia, and leaden paralysis; psychomotor retardation; psychotic features, and/or pathological guilt; and lability of mood. Furthermore, bipolar-depressed patients are more likely to have an earlier age of onset of their first depressive episode, to have more prior episodes of depression, to have shorter depressive episodes, and to have a family history of bipolar disorder. The following features are more common in unipolar depressive disorder: initial insomnia/reduced sleep; appetite, and/or weight loss; normal or increased activity levels; somatic complaints; later age of onset of first depressive episode; prolonged episodes; and no family history of bipolar disorder. CONCLUSIONS: Rather than proposing a categorical diagnostic distinction between bipolar depression and major depressive disorder, we would recommend a 'probabilistic' (or likelihood) approach. While there is no 'point of rarity' between the two presentations, there is, rather, a differential likelihood of experiencing the above symptoms and signs of depression. A table outlining draft proposed operationalized criteria for such an approach is provided. The specific details of such a probabilistic approach need to be further explored. For example, to be useful, any diagnostic innovation should inform treatment choices.

Taylor MJ, Goodwin GM. · Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK. · CNS Drugs. · Pubmed #16599648 No free full text.

Abstract: Bipolar disorder is a major cause of disability, and the prevention of relapse is a key management goal. Pharmacological interventions, effectively delivered through enhanced clinical care, are central to long-term management.This article summarises the available evidence for a range of pharmacological options, and provides guidance on common issues in clinical management in line with current practice guidelines. The use of medications for long-term prophylaxis should be considered in all patients meeting criteria for bipolar I disorder. Increasing high-quality evidence from randomised trials informs management decisions relating to both novel agents, such as lamotrigine and olanzapine, and longer-established therapies, such as lithium and valproate, in monotherapy. Medications taken long-term in bipolar disorder differ in the extent to which they protect against manic and depressive relapse. Consequently, the emerging challenge is to understand how combination treatments can enhance efficacy and effectiveness based on data from controlled trials rather than random polypharmacy.Clinical care can be enhanced with effective education about the illness, and the use of strategies to improve treatment adherence and the recognition and management of stressors or prodromal symptoms. Where available, a range of specific psychological interventions can be effective as an adjunct to medication.When discontinuation of prophylaxis is necessary, gradual tapering of dose over weeks or months is recommended.

Rendell JM, Gijsman HJ, Bauer MS, Goodwin GM, Geddes GR. · No affiliation provided · Cochrane Database Syst Rev. · Pubmed #16437472 No free full text.

Abstract: BACKGROUND: Risperidone, an atypical antipsychotic, is used to treat mania both alone and in combination with other medicines. OBJECTIVES: To review the efficacy and tolerability of risperidone as treatment for mania. SEARCH STRATEGY: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR-Studies December 2004), The Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE, CINAHL and PsycINFO were searched in December 2004. Reference lists and English language textbooks were searched; researchers in the field and Janssen-Cilag were contacted. SELECTION CRITERIA: Randomised controlled trials comparing risperidone with placebo or other drugs in acute manic or mixed episodes. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data from trial reports. Janssen-Cilag was asked to provide missing information. QUALITY ASSESSMENT: As in other trials of treatment for mania, the high proportion of imputed efficacy data resulting from rates of failure to complete treatment of between 12% and 62% may have biased the results. MAIN RESULTS: Six trials (1343 participants) of risperidone as monotherapy or as adjunctive treatment to lithium, or an anticonvulsant, were identified. Permitted doses were consistent with those recommended by the manufacturers of Haldol (haloperidol) and Risperdal (risperidone) for treatment of mania and trials involving haloperidol allowed antiparkinsonian treatment. Risperidone monotherapy was more effective than placebo in reducing manic symptoms, using the Young Mania Rating Scale (YMRS) (weighted mean difference (WMD) -5.75, 95% confidence interval (CI) -7.46 to -4.04, P<0.00001; 2 trials) and in leading to response, remission and sustained remission. Effect sizes for monotherapy and adjunctive treatment comparisons were similar. Low levels of baseline depression precluded reliable assessment of efficacy for treatment of depressive symptoms. Risperidone as monotherapy and as adjunctive treatment was more acceptable than placebo, with lower incidence of failure to complete treatment (RR 0.66, 95% CI 0.52 to 0.82, P = 0.0003; 5 trials). Overall risperidone caused more weight gain, extrapyramidal disorder, sedation and increase in prolactin level than placebo. There was no evidence of a difference in efficacy between risperidone and haloperidol either as monotherapy or as adjunctive treatment. The acceptability of risperidone and haloperidol in incidence of failure to complete treatment was comparable. Overall risperidone caused more weight gain than haloperidol but less extrapyramidal disorder and comparable sedation. AUTHORS' CONCLUSIONS: Risperidone, as monotherapy and adjunctive treatment, is effective in reducing manic symptoms. The main adverse effects are weight gain, extrapyramidal effects and sedation. Risperidone is comparable in efficacy to haloperidol.Higher quality trials are required to provide more reliable and precise estimates of its costs and benefits.

Bhagwagar Z, Goodwin GM. · Department of Psychiatry Warneford Hospital, University of Oxford, Oxford OX3 7JK, UK. · Expert Opin Pharmacother. · Pubmed #16013989 No free full text.

Abstract: Lamotrigine is a novel anticonvulsant agent that has recently been introduced as a long-term treatment in bipolar disorder. Its role in the treatment of epilepsy is based on its actions to decrease ion channel conductance and antagonise glutamatergic function. Therefore, it has a mode of action unlike other agents used on a long-term basis in mood disorders. The evidence for efficacy is stronger for the prevention of depressive, rather than manic, episodes. The pivotal trials are in bipolar I disorder, but there is interest in its actions in patients with bipolar II and spectrum conditions. Its efficacy in other psychiatric conditions remains to be properly established. It is well tolerated and, with careful prescribing, the incidence of rash occurs no more than with placebo; however this is still a concern. Although usually well tolerated, headache, insomnia and drowsiness are probably the most common side effects.

Carney SM, Goodwin GM. · University Department of Psychiatry, Warnford Hospital, Oxford, UK. · Acta Psychiatr Scand Suppl. · Pubmed #15833095 No free full text.

Abstract: OBJECTIVE: To review the literature on the use of lithium in the treatment of bipolar disorder and highlight the evidence base supporting its efficacy and safety. METHOD: A selective literature review. RESULTS: Lithium is widely believed to be effective against acute mania, acute bipolar depression and in relapse prevention to either mania or depression. In fact, the data supporting efficacy in acute treatment are less impressive than is often claimed, whereas for relapse prevention and suicide prevention no other agent has comparable depth of support. Lithium is best described as the bench mark treatment for bipolar disorder, rather than the gold standard, because only a minority of patients show major clinical benefit. There is a developing need for further trials against new alternatives and in combination studies. CONCLUSION: Lithium has a continuing important role in the clinical management of bipolar disorder. Its under-utilization in North America reflects opinion rather than evidence and the demonstrated anti-suicide effects should help to reignite interest in its use.

Ogilvie AD, Morant N, Goodwin GM. · University Department of Psychiatry, Warneford Hospital, Oxford, UK. · Bipolar Disord. · Pubmed #15762866 No free full text.

Abstract: Caregivers of people with bipolar disorder may experience a different quality of burden than is seen with other illnesses. A better understanding of their concerns is necessary to improve the training of professionals working with this population. Conceptualizing caregiver burden in a conventional medical framework may not focus enough on issues important to caregivers, or on cultural and social issues. Perceptions of caregivers about bipolar disorder have important effects on levels of burden experienced. It is important to distinguish between caregivers' experience of this subjective burden and objective burden as externally appraised. Caregivers' previous experiences of health services may influence their beliefs about the illness. Caregiver burden is associated with depression, which affects patient recovery by adding stress to the living environment. The objective burden on caregivers of patients with bipolar disorder is significantly higher than for those with unipolar depression. Caregivers of bipolar patients have high levels of expressed emotion, including critical, hostile, or over-involved attitudes. Several measures have been developed to assess the care burden of patients with depressive disorders, but may be inappropriate for patients with bipolar disorder because of its cyclical nature and the stresses arising from manic and hypomanic episodes. Inter-episode symptoms pose another potential of burden in patients with bipolar disorder. Subsyndromal depressive symptoms are common in this phase of the illness, resulting in severe and widespread impairment of function. Despite the importance of assessing caregiver burden in bipolar disorder, relevant literature is scarce. The specific effects of mania and inter-episode symptoms have not been adequately addressed, and there is a lack of existing measures to assess burden adequately, causing uncertainty regarding how best to structure family interventions to optimally alleviate burden. The relatively few studies into caregiver burden in bipolar disorder may largely reflect experiences in the US Veterans Affairs health service, but the findings may be limited in their generalizability. Nevertheless, available data suggest that caregiver burden is high and largely neglected in bipolar disorder. Clinically effective, well-targeted and practically viable interventions are needed. However, services cannot be enhanced on a rational basis without an improved understanding and capacity to measure and target caregiver burden the impact of any change in services be evaluated.

Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM. · Department of Psychiatry, Warneford Hospital, Oxford, UK. · Am J Psychiatry. · Pubmed #15337640 links to  free full text

Abstract: OBJECTIVE: This study reviewed the evidence from randomized, controlled trials on the efficacy and safety of antidepressants in the short-term treatment of bipolar depression. METHOD: The authors performed a systematic review and meta-analysis of randomized, controlled trials. They searched the Cochrane Collaboration Depression, Anxiety, and Neurosis Controlled Trials Register, incorporating results of searches of MEDLINE, EMBASE, CINAHL, PsycLIT, PSYNDEX, and LILACS. The main outcome measures were the proportion of patients who clinically responded to treatment and the rate of switching to mania. RESULTS: Twelve randomized trials were included, with a total of 1,088 randomly assigned patients. Five trials compared one or more antidepressants with placebo: 75% of these patients were receiving a concurrent mood stabilizer or an atypical antipsychotic. Antidepressants were more effective than placebo. Antidepressants did not induce more switching to mania (the event rate for antidepressants was 3.8% and for placebo, it was 4.7%). Six trials allowed comparison between two antidepressants. The rate of switching for tricyclic antidepressants was 10%, and for all other antidepressants combined, it was 3.2%. CONCLUSIONS: Antidepressants are effective in the short-term treatment of bipolar depression. The trial data do not suggest that switching is a common early complication of treatment with antidepressants. It may be prudent to use a selective serotonin reuptake inhibitor or a monoamine oxidase inhibitor rather than a tricyclic antidepressant as first-line treatment. Given the limited evidence, there is a compelling need for further studies with longer follow-up periods and careful definition and follow-up of emerging mania and partial remission.

Clark L, Goodwin GM. · Department of Experimental Psychology, University of Cambridge, UK. · Eur Arch Psychiatry Clin Neurosci. · Pubmed #15146334 No free full text.

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.

Rendell JM, Juszczak E, Hainsworth J, Gucht EV, Healey C, Morriss R, Ferrier N, Young AH, Young H, Goodwin GM, Geddes JR. · Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK. · Bipolar Disord. · Pubmed #14996138 No free full text.

Abstract: OBJECTIVES: The initial design of the BALANCE (Bipolar Affective disorder: Lithium / ANtiConvulsant Comparative Evaluation) Trial of maintenance treatment for bipolar disorder was based on the experience of previous trials in bipolar disorder and psychiatry and on the methods developed for large randomized trials in other areas of medicine. This report describes the adaptations to the initial design and trial procedures following the initial phases of the study. The rationale for the trial and full protocol have been published elsewhere. METHODS: A pilot study and start-up phase were used to check the tolerability of the interventions, refine the trial design and develop trial procedures that are acceptable to both clinicians and patients. RESULTS: Changes to the procedures included: the dropping of masking of allocated treatment from clinicians and participants; introduction of the use of postal delivery to supply medication; and dispensing with the proposed schedule of regular follow up appointments. In addition, support was made available to participating psychiatrists who often had limited experience of participating in randomized trials. CONCLUSIONS: Pilot studies and start-up phases are essential to refine clinical trial design and allow development of procedures that are both methodologically rigorous and flexible and robust enough to promote recruitment and follow up. BALANCE is now actively recruiting in the UK and USA.

Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM. · Department of Psychiatry, University of Oxford, Warneford Hospital, UK. · Am J Psychiatry. · Pubmed #14754766 links to  free full text

Abstract: OBJECTIVE: The authors sought to determine the efficacy and acceptability of lithium for relapse prevention in bipolar disorder. METHOD: A systematic review and meta-analysis of randomized controlled trials comparing lithium with placebo in the long-term treatment of bipolar disorders was conducted. Data were obtained from searching the registers of the Cochrane Collaboration; reviewing reference lists, journals, and conference abstracts; and contacting authors, experts, and pharmaceutical companies. Outcomes investigated included risk of relapse (manic, depressive, and total) as well as risk of specific adverse effects and total withdrawal rates. RESULTS: Five randomized controlled trials (770 participants) were included. Lithium was more effective than placebo in preventing all relapses (random effects relative risk=0.65, 95% CI=0.50 to 0.84) and manic relapses (relative risk=0.62, 95% CI=0.40 to 0.95). The protective effect of lithium on depressive relapses was smaller and was less robust (relative risk=0.72, 95% CI=0.49 to 1.07). CONCLUSIONS: Lithium treatment reduces the risk of relapse in bipolar disorder. The preventive effect is clear for manic episodes, although it is equivocal for depressive episodes.

Goodwin GM, Geddes JR. · Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK. · Eur Neuropsychopharmacol. · Pubmed #12957720 No free full text.

Abstract: Although lithium is generally considered to be the gold standard for maintenance therapy in bipolar disorder, evidence of its efficacy has rested on only a small number of adequately designed studies. Results from the lamotrigine bipolar trials, which included lithium as an active comparator, will substantially increase confidence in long-term lithium treatment. In a meta-analysis of these data, lithium was significantly more effective than placebo in preventing relapse in patients with bipolar disorder (relative risk [RR] 0.65; 95% confidence interval [CI] 0.50, 0.84). Furthermore, lithium had significant efficacy against manic relapse (RR 0.61; 95% CI 0.39, 0.95), with a less substantial, not statistically significant, effect against depressive relapse (RR 0.72; 95% CI 0.49, 1.07). Factors such as disease subtype, likelihood of adherence to treatment regimen, tolerability, and dose uncertainty should be considered in the selection of lithium maintenance therapy.

Rendell JM, Gijsman HJ, Keck P, Goodwin GM, Geddes JR. · No affiliation provided · Cochrane Database Syst Rev. · Pubmed #12918000 No free full text.

Abstract: BACKGROUND: Olanzapine, an atypical antipsychotic, is used in the treatment of mania both as monotherapy and combined with other medicines. OBJECTIVES: To review the efficacy and tolerability of olanzapine in the treatment of mania SEARCH STRATEGY: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), The Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE, CINAHL and PsycINFO were searched. SELECTION CRITERIA: Randomised trials comparing olanzapine with placebo or other drug in acute manic or mixed episodes. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data from trial reports MAIN RESULTS: Six trials (1422 participants) were included in the review. There was a high rate of failure to complete treatment on all treatments which may have biased the estimates of relative efficacy. Olanzapine was superior to placebo at reducing manic symptoms as monotherapy (Young Mania Rating Scale (YMRS) - weighted mean difference (WMD): -5.94, 95% CI -9.09 to -2.80) and in combination with lithium/valproate (YMRS) (WMD -4.01, 95% confidence interval -6.06 to -1.96). Olanzapine monotherapy was superior at reducing psychotic symptoms (PANSS positive symptoms subscale WMD: -3.54, 95% CI -5.28 to -1.80). Olanzapine was superior to divalproex at reducing manic symptoms (standardised mean difference (SMD): -0.29, 95% CI -0.50 to -0.08). Olanzapine did not lead to a statistically higher rate of clinical response than haloperidol (RR: 1.03, 95% CI 0.77 to 1.38). Fewer patients discontinued treatment on olanzapine than placebo (RR: 0.62, 95% CI 0.48 to 0.80). Olanzapine caused greater weight gain than placebo (WMD 1.91Kg, 95% CI 1.29 to 2.53) and somnolence (RR: 2.13 95% CI 1.62 to 2.79) but not more depressive symptoms (RR: 0.95, 95% CI 0.65 to 1.40) or movement disorder (WMD: -0.33, 95% CI -0.74 to 0.09). Olanzapine caused more prolactin elevation than placebo (RR: 4.35 95%CI 1.77 to 10.70). Olanzapine caused greater weight gain (WMD: 1.54, 95% CI 1.02 to 2.05); somnolence (RR: 1.80 95% CI 1.32 to 2.46) and movement disorders (SAS - WMD: 0.72 95% CI 0.11 to 1.33) than divalproex but less nausea ( RR: 0.36 95% CI 0.20 to 0.65). Olanzapine caused more weight gain than haloperidol (RR: 3.59, 95% CI 1.49 to 8.64) but less movement disorder (EPS RR: 0.10, 95% CI 0.04 to 0.24). REVIEWER'S CONCLUSIONS: Olanzapine is an effective treatment for mania and may be more efficacious than divalproex, though leads to more weight gain. Clinicians should consider both the relative efficacy and the different incidence of specific adverse effects of available drugs.

Macritchie KA, Geddes JR, Scott J, Haslam DR, Goodwin GM. · Department of Psychiatry, University of Oxford, Oxford, UK, OX3 7JX. · Cochrane Database Syst Rev. · Pubmed #11687047 No free full text.

Abstract: 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

Goodwin GM. · Department of Psychiatry, Warneford Hospital, Oxford, UK. · Eur Neuropsychopharmacol. · Pubmed #10524839 No free full text.

Abstract: Bipolar disorder is a devastating and chronic mood disorder, which can require life-long treatment. The vast majority of patients will suffer relapse of symptoms in the absence of effective therapy. Of those patients receiving treatment, compliance to medication regimens is poor. Non-compliance, when associated with lithium treatment in particular, increases the risk of recurrence of illness. Problems associated with withdrawal serve as powerful stimuli to develop alternatives to lithium monotherapy. Conventional placebo-controlled studies of treatments are difficult in patients with bipolar disorder. Large-scale, pragmatic and clinically relevant trials should be employed to assess existing and novel treatments for bipolar disorder. These can only develop out of genuine clinician and patient uncertainty and the creation of a trial culture in everyday practice.

Clark L, Kempton MJ, Scarnà A, Grasby PM, Goodwin GM. · University Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom. · Biol Psychiatry. · Pubmed #15652878 No free full text.

Abstract: 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.

Goodwin GM, Bowden CL, Calabrese JR, Grunze H, Kasper S, White R, Greene P, Leadbetter R. · Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, England, UK. · J Clin Psychiatry. · Pubmed #15096085 No free full text.

Abstract: BACKGROUND: Two clinical trials, prospectively designed for combined analysis, compared placebo, lithium, and lamotrigine for treatment of bipolar I disorder in recently depressed or manic patients. METHOD: 1315 bipolar I patients (DSM-IV) enrolled in the initial open-label phase, and 638 were stabilized and randomly assigned to 18 months of double-blind monotherapy with lamotrigine (N = 280; 50-400 mg/day fixed dose or 100-400 mg/day flexible dose), lithium (N = 167; serum level of 0.8-1.1 mEq/L), or placebo (N = 191). The primary endpoint was time from randomization to intervention for a mood episode. Data were gathered from August 1997 to August 2001. RESULTS: Lamotrigine and lithium were superior to placebo for time to intervention for any mood episode (median survival: placebo, 86 days [95% CI = 58 to 121]; lithium, 184 days [95% CI = 119 to not calculable]; lamotrigine, 197 days [95% CI = 144 to 388]). Lamotrigine was superior to placebo for time to intervention for depression (median survival: placebo, 270 days [95% CI = 138 to not calculable]; lithium, median not calculable; lamotrigine, median not calculable). Lithium and lamotrigine were superior to placebo for time to intervention for mania (median survival not calculable for any group). Results of additional analyses adjusted for index mood were similar; however, only lithium was superior to placebo for intervention for mania. There was no evidence that either active treatment caused affective switch. Adverse event analysis indicated more diarrhea (19% vs. 7%, p <.05) and tremor (15% vs. 4%, p <.05) in lithium-treated patients compared with lamotrigine-treated patients. CONCLUSIONS: Lamotrigine and lithium stabilized mood by delaying the time to treatment for a mood episode. Lamotrigine was effective against depression and mania, with more robust activity against depression. Lithium was effective against mania.

Scarna A, Gijsman HJ, McTavish SF, Harmer CJ, Cowen PJ, Goodwin GM. · University of Oxford, Warneford Hospital, UK. · Br J Psychiatry. · Pubmed #12611783 links to  free full text

Abstract: BACKGROUND: Administration of a complex tyrosine-free amino acid drink acutely decreases manic symptoms. Although a nutrient-based approach to illness management is attractive, complex amino acid drinks are too unpalatable for repeated administration. AIMS: To assess whether a simple, branched-chain amino acid (BCAA) drink diminishes manic symptoms acutely and following repeated administration. METHOD: Twenty-five patients with mania were randomly and blindly allocated to treatment with BCAA (60 g) or placebo daily for 7 days. RESULTS: Relative to placebo, the BCAA drink lowered mania ratings acutely over the first 6 h of treatment. In protocol completers there was a persistent advantage to the BCAA group 1 week after the end of treatment. CONCLUSIONS: A nutritional intervention that decreases tyrosine availability to the brain acutely ameliorates manic symptoms. Further studies are required to assess whether this approach has longer-term efficacy.

McTavish SF, McPherson MH, Harmer CJ, Clark L, Sharp T, Goodwin GM, Cowen PJ. · University Department of Psychiatry, Neurosciences Building, Warneford Hospital, Oxford OX3 7JX, UK. · Br J Psychiatry. · Pubmed #11581118 links to  free full text

Abstract: BACKGROUND: In rats, amino acid mixtures lacking tyrosine and its precursor phenylalanine decrease the release of dopamine produced by the psychostimulant drug amphetamine. Amphetamine has been proposed as a model for clinical mania. AIMS: To assess whether dietary tyrosine depletion attenuates the psychostimulant effects of methamphetamine in healthy volunteers and diminishes the severity of mania in acutely ill patients. METHOD: Sixteen healthy volunteers received a tyrosine-free amino acid mixture and a control mixture in a double-blind crossover design 4 h before methamphetamine (0.15 mg/kg). Twenty in-patients meeting DSM-IV criteria for mania were allocated blindly and randomly to receive either the tyrosine-free mixture or the control mixture. RESULTS: The tyrosine-free mixture lowered both subjective and objective measures of the psychostimulant effects of methamphetamine. Ratings of mania were lower in the patients who received the tyrosine-free mixture. CONCLUSIONS; Decreased tyrosine availability to the brain attenuates pathological increases in dopamine neurotransmission following methamphetamine administration and putatively in mania.