Brain Ca 1.2 and Ca 1.3 L-type Ca channels play key physiological roles in various neuronal processes that contribute to brain function. Genetic studies have recently identified CACNA1C as a candidate risk gene for bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder (MDD) and autism spectrum disorder (ASD), and CACNA1D for BD and ASD, suggesting a contribution of Ca 1.2 and Ca 1.3 Ca signalling to the pathophysiology of neuropsychiatric disorders. Once considered sole clinical entities, it is now clear that BD, SCZ, MDD and ASD share common phenotypic features, most likely due to overlapping neurocircuitry and common molecular mechanisms. A major future challenge lies in translating the human genetic findings to pathological mechanisms that are translatable back to the patient. One approach for tackling such a daunting scientific endeavour for complex behaviour-based neuropsychiatric disorders is to examine intermediate biological phenotypes in the context of endophenotypes within distinct behavioural domains. This will better allow us to integrate findings from genes to behaviour across species, and improve the chances of translating preclinical findings to clinical practice.

SynopsisA series of depressed probands and their first-degree relatives were categorized as follows: (a) currently depressed; (b) recovered depressed; and (c) never-ill relatives. Their scores on a subscaled version of the Dysfunctional Attitude Scale (the DAS-24) were compared. The DAS total scores mirrored previous findings in that the total scores for recovered individuals returned to normal or near-normal levels. However, the dependency subscale scores remained elevated for the recovered depressed group. It is proposed that these results support the conclusion that self-report measures of cognitive vulnerability should focus on specific rather than global effects, if progress is to be made in the search for true vulnerability factors.