New research is dramatically altering our understanding of the molecular mechanisms underlying neuronal communication.

To elucidate the molecular mechanisms underlying the therapeutic effects of mood stabilisers.

Results from integrated clinical and laboratory studies are reviewed.

Chronic administration of lithium and valproate produced a striking reduction in protein kinase C (PKC) isozymes in rat frontal cortex and hippocampus. In a small study, tamoxifen (also a PKC inhibitor) had marked antimanic efficacy. Both lithium and valproate regulate the DNA binding activity of the activator protein 1 family of transcription factors. Using mRNA differential display, it was also shown that chronic administration of lithium and valproate modulates expression of several genes. An exciting finding is that of a robust elevation in the levels of the cytoprotective protein, bcl-2.

The results suggest that regulation of signalling pathways may play a major part in the long-term actions of mood stabilisers. Additionally, mood stabilisers may exert underappreciated neuroprotective effects.

Although the presence of wide-ranging neuropsychological deficits in individuals with major depression is well established, few studies have investigated the nature of cognitive impairment in patients with bipolar disorder.

To review research of the neuropsychology of bipolar disorder, with special attention to the relationship between mood and cognitive functioning.

Literature review.

Findings generally demonstrate mania-related impairments on conventional neuropsychological tests, with direct comparisons of patients with mania and patients with depression failing to find group differences. More recent work has sought to differentiate these disorders by employing tasks with affective components. This research has demonstrated biases for processing positive and negative stimuli in patients with mania and depression, respectively.

Future studies, employing tasks that require cognitive and emotional processing, should improve our understanding of the deficits observed in depression and mania. Neuroimaging studies of the neural regions that underlie cognitive processing of affective meaning suggest that the medial and orbitofrontal prefrontal cortex may be particularly involved.

A robust body of evidence from family, twin and adoption studies demonstrates the importance of genes in the pathogenesis of bipolar disorder. Recent advances in molecular genetics have made it possible to identify these susceptibility genes.

To present an overview for clinical psychiatrists.

Review of current molecular genetics approaches and emerging findings.

Occasional families may exist in which a single gene plays a major role in determining susceptibility, but the majority of bipolar disorder involves more complex genetic mechanisms such as the interaction of multiple genes and environmental factors. Molecular genetic positional and candidate gene approaches are being used for the genetic dissection of bipolar disorder. No gene has yet been identified but promising findings are emerging. Regions of interest include chromosomes 4p16, 12q23–q24, 16p13, 21q22, and Xq24–q26. Candidate gene association studies are in progress but no robust positive findings have yet emerged.

It is almost certain that over the next few years the identification of bipolar susceptiblity genes will have a major impact on our understanding of disease pathophysiology. This is likely to lead to major improvements and treatment in patient care, but will also raise important ethical issues.

Genetic factors are known to be important in the aetiology of bipolar disorder.

To review linkage studies in extended families multiply affected with bipolar disorder.

Selective review of linkage studies of bipolar disorder emphasising the gains and drawbacks of studying large multiply-affected families and comparing the statistical methods used for data analysis.

Linkage of bipolar disorder to several chromosome regions including 4p, 4q, 10p, 12q, 16p, 18q, 21q and Xq has first been reported in extended families. In other families chromosomal rearrangements associated with affective illnesses provide signposts to the location of disease-related genes. Statistical analyses using variance component methods can be applied to extended families, require no prior knowledge of the disease inheritance, and can test multilocus models.

Studying single large pedigrees combined with variance component analysis is an efficient and effective strategy likely to lead to further insights into the genetic basis of bipolar disorders.

Bipolar disorder is a serious brain disease affecting more than a million individuals living in the USA. Epidemiological studies indicate a role for both genetic and environmental factors in the pathogenesis of this disorder.

To identify RNA transcripts that are up- or down-regulated in the frontal cortex regions of individuals with bipolar disorder.

Serial analysis of gene expression (SAGE) and reverse transcriptase-polymerase chain reaction were used to identify RNA transcripts which are differentially expressed in the frontal cortex of brains obtained postmortem from individuals with bipolar disorder compared with other psychiatric and control conditions.

Levels of RNA transcripts encoding the serotonin transporter protein and components of the NF-κB transcription factor complex are significantly increased in individuals with bipolar disorder compared with unaffected controls. Increased levels of expression of these RNA transcripts were also detected in the brains of some individuals with schizophrenia and unipolar depression.

The SAGE technique offers promise for the characterisation of complex human brain diseases.

Neuroimaging data showing structural and functional brain abnormalities in mood disorders suggest that brain alterations at the neurohistological level may underlie the macropathology seen by imaging in vivo.

To summarise recent post-mortem studies on affective disorders, with a focus on bipolar disorder.

Literature review and discussion of results from volumetric, cyto-architectural and immunohistochemical analyses.

Basal ganglia are smaller in patients with depression irrespective of diagnostic polarity. In addition, higher neuron numbers have been reported in the locus caeruleus of patients with bipolar disorder compared with those with unipolar depression. Patients with bipolar as well as unipolar illness show subtle structural deficits in the dorsal raphe. Histological data are consistent with a regional reduction in the synthesis of noradrenalin and serotonin, which appears to be compensated by antidepressants.

Preliminary results suggest that, aside from functional dysregulation, subtle structural abnormalities in the brain may contribute to the pathogenesis of mood disorders.

Studies highlighting the difficulties associated with lithium suggest that the role of antipsychotic drugs and mood stabilisers in bipolar disorder should be reconsidered.

To review the efficacy and mode of action of antipsychotic drugs in mania, and to consider the differences between official guidelines and routine clinical practice in the use of these agents for mania.

Review of research, guideline- and practice-based literature.

Guidelines recommend lithium or valproate as first-line treatments for mania, and antipsychotic agents only as ‘adjuncts’ for agitation, dangerous behaviour or psychosis. However, in routine practice, antipsychotic drugs are often prescribed. The effectiveness of these agents in mania has been established by several studies; newer atypical compounds demonstrate antimanic efficacy with a reduced incidence of neurological side-effects.

Antipsychotic drugs are important in the treatment of bipolar disorder and mania. Future studies should evaluate the long-term efficacy and safety of newer atypical antipsychotic agents, and the place of anticonvulsants in combination with antipsychotics in bipolar disorder.

During the development of a new treatment for bipolar disorder, maintenance studies are used to evaluate the ability of the putative mood stabiliser to prevent relapse and recurrence of further episodes. Comparisons with the early bipolar disorder maintenance studies indicate that the methodologies of recent trials have evolved substantially.

To review the methods used in the first- and second-generation maintenance studies, highlighting the differences of the various designs.

Literature review.

Methods that have evolved the most include patient enrolment, randomisation schemes and the use of outcome measures and statistical analyses. In addition, regulatory and commercial issues have also influenced study design.

There is little consensus on the methodology of bipolar disorder maintenance studies. As the integration of newer therapies into routine clinical practice is dependent on the evidence from controlled studies, it is essential that future maintenance trials in bipolar disorder achieve adequate methodological rigour without sacrificing overall feasibility.

There is increasing support for the use of cognitive behaviour therapy as an adjunct to medication for patients with bipolar disorder.

To explore current psychological models of bipolar disorder, describing the clinical rationale for using cognitive therapy and providing a brief overview of the approach.

Results from outcome studies are discussed.

Preliminary findings indicate that cognitive therapy may be beneficial for patients with bipolar disorder. The collaborative, educational style of cognitive therapy, the use of a stepwise approach and of guided discovery is particularly suitable for patients who wish to take an equal and active role in their therapy.

Randomised, controlled trials of cognitive therapy in bipolar disorder are required to establish the short-term and long-term benefits of therapy, and whether any reported health gain exceeds that of treatment as usual.

The Stanley Foundation Bipolar Network (SFBN) was created to address the paucity of help studies in bipolar illness.

To describe the rationale and methods of the SFBN.

The SFBN includes five core sites and a number of affiliated sites that have adopted consistent methodology for continuous longitudinal monitoring of patients. Open and controlled studies are performed as patients' symptomatology dictates.

The reliability of SFBN raters and the validity of the rating instruments have been established. More than 500 patients are in continuous daily longitudinal follow-up. More than 125 have been randomised to one of three of the newer antidepressants (bupropion, sertraline and venlafaxine) as adjuncts in a study of mood stabilisers and 93 to omega-3 fatty acids. A number of open clinical case series have been published.

Well-characterised patients are followed in a detailed continuous longitudinal fashion in both opportunistic case series and double-blind, randomised controlled trials with reliable and validated measures.

The Stanley Foundation Bipolar Network (SFBN) evaluates treatments, course and clinical and neurobiological markers of response in bipolar illness.

To give a preliminary summary of emerging findings in these areas.

Studies with established and potentially antimanic, antidepressant and mood-stabilising agents range from open case series to double-blind randomised clinical trials, and use the same core assessment methodology, thereby optimising the comparability of the outcomes. The National Institute of Mental Health Life Chart Method is the core instrument for retrospective and prospective longitudinal illness description.

The first groups of patients enrolled show a considerable degree of past and present symptomatology, psychiatric comorbidity and functional impairment. There are associations of both genetic and early environmental factors with more severe courses of illness. Open case series with add-on olanzapine, lamotrigine, gabapentin or topiramate show a differential spectrum of effectiveness in refractory patients.

The SFBN provides important new data for the understanding and treatment of bipolar disorder.

The effectiveness of lithium is being questioned increasingly and requires clarification.

To assess the effectiveness of lithium treatment in depression and mania, syndromal types I and II, with predominantly mixed or psychotic episodes or rapid cycling, during treatment resumed following discontinuation, and across three decades.

The longitudinal course of 360 patients with bipolar disorder compliant with lithium treatment for at least 1 year and without comorbidity for substance use disorder was reviewed.

Risk of single-episode recurrences, a common index of treatment failure, was similar to that in other reports. Both episode frequency and ‘time ill’ improved more in type II than type I cases. Reduced morbidity during treatment was similar in patients with mixed or psychotic episodes, or rapid cycling, and in less complex cases. Retreatment yielded minor decrements in response, and there was no tendency for lesser responses in more recent years.

Based on overall affective morbidity, long-term lithium treatment in compliant patients without comorbid substance use disorder, though imperfect, remains effective, even in subgroups of supposedly poor prognosis.

The increasing use of the methods of evidence-based medicine to keep up-to-date with the research literature highlights the absence of high-quality evidence in many areas in psychiatry.

To outline current uncertainties in the maintenance treatment of bipolar disorder and to describe some of the decisions involved in designing a large simple trial.

We describe some of the strategies of evidence-based medicine, and how they can be applied in practice, focusing specifically on the area of bipolar disorder.

One of the key clinical uncertainties in the treatment of bipolar disorder is the place of maintenance drug treatments and their relative efficacy. A large-scale study, the Bipolar Affective Disorder: Lithium Anticonvulsant Evaluation (BALANCE) trial, is proposed to compare the effectiveness of lithium, valproate and the combination of lithium and valproate.

Providing reliable answers to key clinical questions in psychiatry will require new approaches to clinical trials. These will need to be far larger than previously appreciated and will therefore need to be collaborative ventures involving front-line clinicians.