Data from the Genetic Association Information Network (GAIN) genome-wide association study (GWAS) in major depressive disorder (MDD) were used to explore previously reported candidate gene and single-nucleotide polymorphism (SNP) associations in MDD. A systematic literature search of candidate genes associated with MDD in case-control studies was performed before the results of the GAIN MDD study became available. Measured and imputed candidate SNPs and genes were tested in the GAIN MDD study encompassing 1738 cases and 1802 controls. Imputation was used to increase the number of SNPs from the GWAS and to improve coverage of SNPs in the candidate genes selected. Tests were carried out for individual SNPs and the entire gene using different statistical approaches, with permutation analysis as the final arbiter. In all, 78 papers reporting on 57 genes were identified, from which 92 SNPs could be mapped. In the GAIN MDD study, two SNPs were associated with MDD: C5orf20 (rs12520799; P = 0.038; odds ratio (OR) AT = 1.10, 95% CI 0.95-1.29; OR TT = 1.21, 95% confidence interval (CI) 1.01-1.47) and NPY (rs16139; P = 0.034; OR C allele = 0.73, 95% CI 0.55-0.97), constituting a direct replication of previously identified SNPs. At the gene level, TNF (rs76917; OR T = 1.35, 95% CI 1.13-1.63; P = 0.0034) was identified as the only gene for which the association with MDD remained significant after correction for multiple testing. For SLC6A2 (norepinephrine transporter (NET)) significantly more SNPs (19 out of 100; P = 0.039) than expected were associated while accounting for the linkage disequilibrium (LD) structure. Thus, we found support for involvement in MDD for only four genes. However, given the number of candidate SNPs and genes that were tested, even these significant may well be false positives. The poor replication may point to publication bias and false-positive findings in previous candidate gene studies, and may also be related to heterogeneity of the MDD phenotype as well as contextual genetic or environmental factors.

These data suggest that the 9-hydroxy metabolite plays a predominant role in risperidone's effect on prolactin release.

The enhancement of central serotonin system function underlies the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs), which have become the most commonly used class of antidepressant agents. However, many individuals experience depressive episodes that are resistant to SSRI treatment. Homeostatic mechanisms that limit the extent to which SSRIs enhance serotonergic neurotransmission have been implicated in this phenomenon. Here, we report a novel strategy for enhancing the efficacy of SSRIs. Using in vivo microdialysis methods in rats, the nonselective 5-HT 2 receptor antagonist ketanserin was observed to produce a robust augmentation of citalopram-, fluoxetine-, and sertraline-induced elevations of hippocampal extracellular serotonin levels. Similar effects were also observed in cortex. The potentiation of SSRI-induced increases in hippocampal serotonin levels was reproduced by the 5-HT 2C receptor-selective antagonists SB 242084 and RS 102221, but not by the 5-HT 2A receptor-selective antagonist MDL 100 907. Although 5-HT 2C receptor antagonists augmented the actions of SSRIs, they had no effect on extracellular serotonin levels or tail suspension responses when administered alone. These results were in strong accord with independent findings using a line of 5-HT 2C receptor-null mutant mice. Although this mutation did not affect baseline extracellular serotonin levels or tail suspension test (TST) behavior, it enhanced fluoxetine effects on serotonin levels and immobility in the TST. These findings reveal an unanticipated pharmacological action of 5-HT 2C receptors that warrants consideration in the development of novel strategies for the treatment of depression.

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Microdialysis was used to assess the involvement of postsynaptic 5-hydroxytryptamine 1A (5-HT 1A ) receptors in the regulation of extracellular 5-HT in the amygdala. Local infusion of the 5-HT 1A receptor agonist¯esinoxan (0.3, 1, 3 mM) for 30 min into the amygdala maximally decreased 5-HT to 50% of basal level. Systemic administration of citalopram (10 mmol/kg) increased 5-HT to 175% of basal level. Local infusion of 1 mM of the 5-HT 1A receptor antagonist WAY 100.635 into the amygdala augmented the effect of citalopram to more than 500% of basal 5-HT level. 5-HT 1A receptor responsiveness after chronic citalopram treatment was determined in two ways. First, by local infusion of 1 mM esinoxan for 30 min into the amygdala, which showed a signi®cant 63% reduction in response (area under the concentration±time curve; AUC) for the citalopram group compared to the saline group. Second, by systemic administration of citalopram (10 mmol/kg), which increased 5-HT to 350% of basal level. The effect was larger than in untreated animals, but more important, local infusion of 1 mM WAY 100.635 into the amygdala now failed to augment the effect of citalopram. Both the¯esinoxan and WAY 100.635 data suggest an involvement of postsynaptic 5-HT 1A receptormediated feedback in the amygdala, which diminishes following chronic citalopram treatment. et al. 1994, 1996) and 5-HT synthesis (Hutson et al. 1989), while stimulation of 5-HT 1B presynaptic receptors decreases 5-HT release (Sharp et al. 1989;Limberger et al. 1991). These secondary phenomena are believed to limit the effect of re-uptake inhibition on the 5-HT release in the terminal regions.The delayed response to antidepressant treatment may be connected to a gradual loss of responsiveness of 5-HT autoreceptors following chronic treatment (Blier et al. 1987a). Theoretically, the latter condition can be mimicked

Major depressive disorder is a heterogeneous disorder, mostly diagnosed on the basis of symptomatic criteria alone. It would be of great help when specific biomarkers for various subtypes and symptom clusters of depression become available to assist in diagnosis and subtyping of depression, and to enable monitoring and prognosis of treatment response. However, currently known biomarkers do not reach sufficient sensitivity and specificity, and often the relation to underlying pathophysiology is unclear. In this review, we evaluate various biomarker approaches in terms of scientific merit and clinical applicability. Finally, we discuss how combined biomarker approaches in both preclinical and clinical studies can help to make the connection between the clinical manifestations of depression and the underlying pathophysiology.

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