Advances towards the understanding of the etiological mechanisms involved in mood disorders provide interesting yet diverse hypotheses and promising models. In this context, molecular genetics has now been widely incorporated into genetic epidemiological research in psychiatry. Affective disorders and, in particular, bipolar affective disorder (BPAD) have been examined in many molecular genetic studies which have covered a large part of the genome, specific hypotheses such as mutations have also been studied. Most recent studies indicate that several chromosomal regions may be involved in the aetiology of BPAD. Other studies have reported the presence of anticipation in BPAD. This phenomenon describes the increase in clinical severity and decrease in age of onset observed in successive generations. This mode of transmission correlates with the presence of specific mutations (Trinucleotide Repeat Sequences) and may represent a genetic factor involved in the transmission of the disorder. In parallel to these new developments in molecular genetics, the classical genetic epidemiology, represented by twin, adoption and family studies, provided additional evidence in favour of the genetic hypothesis in mood disorders. Moreover, these methods have been improved through models to test the gene-environment interactions. While significant advances have been made in this major field of research, it appears that integrative models, taking into account the interactions between biological (genetic) factors and social (psychosocial environment) variables offer the most reliable way to approach the complex mechanisms involved in the etiology and outcome of mood disorders.

Serotonin (5-HT) has been implicated in the pathophysiology of bipolar disorders. Acute tryptophan depletion (ATD), which decreases serotonergic turnover, is an established paradigm to study serotonergic vulnerability in affective disorders. Literature on the application of ATD as a research tool in bipolar patients is limited to three studies, which revealed inconsistent results on mood modification. These inconsistencies may be attributed to differences in methodological procedures and / or characteristics of included patients. Patient selection, methodological aspects and procedures of these studies are critically considered and recommendations given. A research protocol to test the 5-HT vulnerability in bipolar disorder is proposed.

Epidemiological and pathobiological findings in bipolar disorder [BP] have often been limited by selection bias and lack of epidemiological representativeness. In a rural, circumscribed catchment area, ‘all’ patients with BP were identified and assessed. On preliminary analysis, morbid risk [MR] for BP over the area as a whole was 5.0 ± 0.6/1000. The distribution of MR for BP over geographical subregions showed no significant deviation from a statistical model for random occurrences in space by place at birth, in contrast to schizophrenia [SZ], and varied only modestly among males by place at onset. These results imply different etiological factors acting in BP in comparison with SZ, particularly with regard to the role of early versus later life events. In preliminary analyses of psychotic and cognitive features, current severity of positive symptoms was predicted in BP only by increasing dominance of the left hand; negative symptoms by duration of illness and current anticholinergic exposure; poorer general and frontal cognitive function by older age at onset of illness, increasing duration of illness, and current anticholinergic exposure. The finding on handedness suggests disturbance of cerebral asymmetry associated with positive symptoms in BP, while both negative symptoms and cognitive impairment may involve progressive processes. Further analysis of this epidemiologically complete population, including systematic comparisons of BP with schizoaffective disorder and SZ, continues.

The mode of action of serotonin in depression is unclear. We tested the modulation of hippocampal long-term plasticity, a model for learning and memory, by 5-HT and found a selective impairment of long-term depression resulting in a positive modification of synaptic network properties. We hypothetize a role for long-term plasticity in emotional regulation and the pathophysiology of affective disorders.

Bipolar disorder has attracted numerous research from different neurobiological angles. This review will summarize selected findings focusing on the role of disturbed transmem-braneous ion fluxes. Several mood stabilizers exhibit a distinct profile including effects on sodium, calcium and potassium conductance. In summary, some decisive mechanisms of action as calcium antagonism and modulation of potassium currents may play a crucial role in the success of any given mood stabilizer in bipolar disorder.

Introduction: Significant changes in immune function have been found in mood disorders. Controlled studies in bipolar disorder concerning cell-mediated immunity and thyroid autoimmunity are reviewed, and presented together with preliminary findings from our own ongoing study.

Method: Using Medline and other sources, 14 controlled studies as well as some other relevant studies were found.

Results: Bipolar disorder is associated with an acute phase response and activation of the cell-mediated immune system, and with an increased prevalence of antithyroid autoantibodies.

Conclusion: Changes in immune function, in connection with neuroendocrine changes, may provide new hypotheses for the pathophysiology of mood disorders.

Background: Previous studies suggest that brain serotonin neurotransmission may mediate the actions of lithium carbonate. Acute tryptophan depletion (ATD) reduces brain serotonin and allows the study of this neurotransmitter in patient groups. Serotonin modulates electroencephalographic (EEG) activity, which is abnormal in bipolar disorder, and EEG abnormalities persist in euthymic bipolar patients. The EEG may therefore be a sensitive marker of 5-HT function in bipolar disorder.

Aims: This study examined the effects of ATD on mood, suicidal ideation and EEG activity in bipolar patients who were symptomatically stable on lithium.

Methods: 19 subjects satisfying DSM-IV criteria for bipolar I disorder participated in a within-subject, double-blind, placebo-controlled random-order crossover study. Following acute tryptophan depletion (induced by a 100g amino acid drink following an overnight fast) symptoms were evaluated, quantitative power spectrum brain mapping and measurement of auditory evoked potentials were carried out.

Results: ATD produced a significant fall in the amplitude of N1P2 and P300 components of the auditory evoked potential, but no significant changes in the power spectrum. There was an 83% reduction in plasma tryptophan (p<0.05, paired t-test) after the depleting but not the control drink. No significant changes in mood or suicidally scores were recorded after ATD.

Conclusions: ATD attenuates auditory evoked potentials in bipolar disorder but does not reverse lithium's effects on mood and suicidally in bipolar disorder.

The few available neuropathological studies of bipolar disorder are reviewed and placed in the context of structural imaging findings. Candidate pathological processes include cy-toarchitectural abnormalities, particularly in the anterior cingulate cortex and affecting glia, and disruption of white matter connections. The possible neuropathological relationship of bipolar disorder with major depression and with schizophrenia is discussed.

The past 20 years have seen much research into affective disorders, reflecting advances in both pharmacological and psychological treatments. However, there has been little basic epidemiological research into bipolar illness. This is particularly apparent regarding its basic occurrence and possible epigenetic causes. This presentation will attempt to bring together and integrate the available evidence regarding the basic epidemiology of bipolar disorder, define areas where further research is needed, and outline a large epidemiological study including bipolar affective disorder that has been supported by the Stanley Foundation.

Neuropsychological deficits are found in both schizophrenic patients and their relatives, and some studies have shown similar, but less severe, deficits in affective psychotic patients and their relatives. We set out to establish – whether schizophrenia spectrum personality traits are more common in the relatives of schizophrenic patients than relatives of affective psychotic patients; – what is the relationship between spectrum personality traits and neuropsychological deficits in these relatives.

Relatives were interviewed using the International Personality Disorder Examination (IPDE), and also completed the National Adult Reading Test (NART), the Trail Making Test (TMT: Parts A and B) and Thurstone's Verbal Fluency Test (TVFT). Spectrum personality traits were equally common in the 129 relatives of schizophrenic and 106 relatives of affective psychotic patients. Relatives of psychotic patients who themselves had high paranoid traits had lower NART scores than those without such personality traits (p=0.007);similarly, those with high schizoid personality traits took longer to complete the TMT, part B than those without such traits (p=0.0l); and relatives with high schizotypal traits generated significantly fewer words on the verbal fluency test than those without such traits (p=0.04).

Bipolar Disorder is a neglected disease. In the last twenty years fewer than 2,000 articles have been published with mania or bipolar disorder in the title, compared to 11,000 for schizophrenia and 19,000 for depression (data from EMBASE). This relative neglect of bipolar disorder is true both for neurobiological investigations and for investigations of treatment. Interest is reviving, I believe, in no small part because of the consistent support by the Stanley Foundation. Genuine advances in understanding neurobiology and treatment may be now be possible. The presentations made at this meeting are testimony to that.

Registers have been widely used in schizophrenia studies. For bipolar disorder, the use has been more limited and no studies exist concerning accuracy of bipolar I diagnoses in registers. We have collected an unselected twin sample for a study of bipolar I disorder. We report here the diagnostic procedures and accuracy of bipolar I diagnoses in a nation-wide hospital discharge registry. We evaluated also the accuracy of the medical record-based best-estimate diagnoses, comparing these with the SCID interview diagnoses. From the National Hospital Discharge Register we identified all like-sex twins, born 1940-1957, (N=42), and all like- or opposite-sex twins, born 1961-1969, (N=15), who had at least once a diagnosis of bipolar I disorder. The best-estimate diagnoses based on medical records, and were made by two doctors blind to each other, and according to DSM-IV-criteria. Diag-noses were then confirmed by SCID interviews, with the mi-nimum follow-up time after the first admission being 6 years. The accuracy of bipolar diagnoses in the register was 92% and 87%, accordingly. When comparing the best-estimate diagnoses to SCID interview diagnoses, there was one false positive case in the first sample, 3.4% [95% CI 0.1% to 7.8%], and none in the second sample. Our study shows that a diagnosis of bipolar I disorder in the hospital discharge register, or if based only on medical records, is highly reliable and stable. These results strengthen the usefulness of regis-ters also in bipolar disorder.

While one major need for improved therapeutic approaches in bipolar disease is the development of long-term treatment strategies, a systematic approach during the acute phase of bipolar disorder is also required. In our own studies we have arbitrarily divided the initial treatment of subjects by the predominant polarity for which they are treated acutely: manic, depressed, or mixed/cycling.1 In this larger investigation of over 150 patients with bipolar disorder, we now demonstrated again that the time to initial stabilization is generally the shortest with a manic episode and the longest with a mixed/cycling episode with the depressed episode in the middle (although almost as long as the mixed/cycling episode). These findings indicate the difficulty of treating both the depressed phase and mixed/cycling episodes in bipolar disorder. It is also noteworthy that gender does not have a significant effect on time to stabilization. Such findings in the acute phase have profound implications in designing and carrying out long-term therapeutic strategies for this disorder.

Background: In clinical practice, typical antipsychotics are widely used in the treatment of bipolar disorder, albeit in treatment guidelines often considered as adjunctive agents only. Recently, focus has shifted towards the use of atypical antipsychotics. This paper reviews the advantages and disadvantages associated with the use of antipsychotics in bipolar disorder.

Methods: Randomised controlled trials (RCTs) were selected for review. A few review articles were also cited.

Results: Typical antipsychotics, at least some of them, are powerful antimanics, beneficial for severe agitation in particular. However, in the long term treatment, typical antipsychics may precipitate depression. Among the atypical antipsychotics, both risperidone and olanzapine are clearly antimanic alternatives, although olanzapine is the best studied. Clozapine seems to be useful when other treatments fail to work.

Conclusions: Antipsychotics are beneficial for some clinical presentations of mania. To minimize side effets, atypical agents should be preferred before typical agents, unless parenteral administration is needed. Despite the lack of RCTs, antipsychotics also seem to be useful as adjunctive agents in the treatment of psychotic bipolar depression. For the long term treatment of bipolar disorder, typical antipsychotics should be used only under certain circumstances. The place of atypical antipsychotics in the long term treatment of bipolar disorder remains to be studied.

Lithium is considered first choice in the prevention of prospective episodes in patients with bipolar disorder. However, efficacy is not satisfactory in all patients and side effects sometimes prevent the use of lithium. It is argued that efficacy in clinical practice may be less impressive than anticipated from clinical trials, and alternative treatments are beinu advocated increasingly for that reason, such as the anticonvulsants, carbamazepine and valproate.

Aims: The efficacy of the anticonvulsants valproate, lamotrigine and gabapentin in bipolar disorder is reviewed.

Method: Using Medline ® and other sources of information, 12 double-blind controlled studies with either of these compounds were identified.

Results: None of the compounds has been proven effective in the prophylaxis of bipolar disorder. Valproate has been found an effective drug in acute mania, while in continuation treatment after acute mania it proved to be save, i.e. not causing switches into depression. Lamotrigine is the only anticonvulsant with proven efficacy in acute bipolar depression. So far gabapentin has not been found effective.

Conclusion: For the prophylaxis of bipolar disorder, lithium is still the treatment of choice. Carbamazepine and valproate are good alternatives, especially for patients not responding to lithium or not tolerating it. Lamotrigine may be a good alternative in bipolar depression.

Objective This study explored the utility of the Health Belief Models (HBM) in explaining medication adherence in subjects with severe affective disorders.

Method Well established measuring instruments, with confirmed reliability and validity, were used to assess each component of two HBMs and adherence with mood stabilising medication in 104 subjects with bipolar (n=82), unipolar (n=18) or schizo-affective (n=4) disorders.

Results Highly adherent and partially adherent subjects differed significantly in the stability of the level and the overall serum level of drug acheived. Subject's beliefs about themselves and their illness and their control over the disorder were more important than side-effects in predicting medication adherence. There were marked differences in the primary reasons for non-adherence identified by patients and their clinicians.

Conclusion Although the study has a number of methodological limitations, the results suggest that clinical assessment of components of HBMs may improve the detection of patients at risk of non-adherence with mood stabilising medication.

Despite ongoing controversy, the view that pediatric mania is rare or non-existent has been increasingly challenged not only by case reports but also by systematic research. This research strongly suggests that pediatric mania may not be rare but that it may be difficult to diagnose. Since children with mania are likely to become adults with bipolar disorder, the recognition and characterization of childhood-onset mania may help identify a meaningful developmental subtype of bipolar disorder worthy of further investigation. The major difficulties that complicate the diagnosis of pediatric mania include:

• - its pattern of comorbidity may be unique by adult standards, especially its overlap with ADHD, aggression and conduct disorder;

• - its overlap with substance use disorders;

• - its association with trauma and adversity;

• - its response to treatment is atypical by adult standards.

These issues will be reviewed in the presentation.

The appearance, the differential diagnosis and the prevalence of bipolar disorder in children and adolescents is discussed. Among adolescents bipolar disorder appears to have a similar prevalence in the US and The Netherlands. However, among children it is frequently diagnosed in the US and hardly in The Netherlands. It is concluded that bipolar disorder tends to start earlier in the US than in the Netherlands. It is hypothesized that this may be related to a higher use of stimulants and antidepressants by US children diagnosed as ADHD or depression, respectively.