Inhibition of serotonergic raphe neurons is mediated by somatodendritic 5-HT1A autoreceptors, which may be increased in depressed patients. We report an association of the C(-1019)G 5-HT1A promoter polymorphism with major depression and suicide in separate cohorts. In depressed patients, the homozygous G(-1019) allele was enriched twofold versus controls (p = 0.0017 and 0.0006 for G/G genotype and G allele distribution, respectively), and in completed suicide cases the G(-1019) allele was enriched fourfold (p = 0.002 and 0.00008 for G/G genotype and G allele distribution, respectively). The C(-1019) allele was part of a 26 bp imperfect palindrome that bound transcription factors nuclear NUDR [nuclear deformed epidermal autoregulatory factor (DEAF-1)]/suppressin and Hairy/Enhancer-of-split-5 (Drosophila) (Hes5) to repress 5-HT1A or heterologous promoters, whereas the G(-1019) allele abolished repression by NUDR, but only partially impaired Hes5-mediated repression. Recombinant NUDR bound specifically to the 26 bp palindrome, and endogenous NUDR was present in the major protein-DNA complex from raphe nuclear extracts. Stable expression of NUDR in raphe cells reduced levels of endogenous 5-HT1A protein and binding. NUDR protein was colocalized with 5-HT1A receptors in serotonergic raphe cells, hippocampal and cortical neurons, and adult brain regions including raphe nuclei, indicating a role in regulating 5-HT1A autoreceptor expression. Our data indicate that NUDR is a repressor of the 5-HT1A receptor in raphe cells the function of which is abrogated by a promoter polymorphism. We suggest a novel transcriptional model in which the G(-1019) allele derepresses 5-HT1A autoreceptor expression to reduce serotonergic neurotransmission, predisposing to depression and suicide.

There is evidence indicating that density of 5-HT2A receptors is altered in brain regions of depressed suicide victims and in platelets of suicidal subjects with major depression or schizophrenia. Recent studies have also shown an association between the allele C of 102T/C polymorphism in the 5-HT2A receptor gene and schizophrenia. The present investigation tested the hypothesis that the observed changes in 5-HT2A receptor density in platelets of patients with major depression are a trait rather than state phenomenon and are associated with the 102 C allele in 5-HT2A receptor gene in a sample of 120 patients with major depression and a group of 131 control subjects comparable with respect to age, sex, and ethnic background. The allele and genotype frequencies of 102T/C polymorphism in 5-HT2A receptor gene were compared between patients and control subjects and between suicidal and non-suicidal patient groups. The major finding of this study was a significant association between the 102 C allele in 5-HT2A receptor gene and major depression, chi(2) = 4.5, df = 1, P = 0.03, particularly in patients with suicidal ideation, chi(2) = 8.5, df = 1, P < 0.005. Furthermore, we found that patients with a 102 C/C genotype had a significantly higher mean HAMD item 3 score (indication of suicidal ideation) than T/C or T/T genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:56-60, 2000.

Antidepressants, such as serotonin or noradrenaline reuptake inhibitors (e.g. fluoxetine, nefadozone) or 5-HT1A agonists (flibanserin), desensitize the 5-HT1A autoreceptor, which may contribute to their clinical efficacy. The 5-HT1A receptor gene is repressed by NUDR/DEAF-1 in raphe cells at the C-, but not at the G-allele of the C(-1019)G polymorphism that is associated with major depression and suicide. Depressed patients (n=118) were treated with antidepressants including fluoxetine or nefadozone combined with pindolol or flibanserin alone. The severity of depression was assesssed using the Hamilton Rating Scale for Depression. Although patients had similar severity initially, those with the homozygous G(-1019) genotype responded significantly less to flibanserin (p=0.039) and in pooled antidepressant treatment groups (p=0.0497) and were approximately twice as likely to be non-responders as those with the C(-1019)C genotype. These results implicate the C(-1019)G 5-HT1A gene polymorphism as a potential marker for antidepressant response, suggesting a role for repression of the 5-HT1A gene.

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O ptimal management of major depressive disorders is enhanced by applying a chronic illnessmanagement model with precise and measurable therapeutic endpoints. 1 In contradistinction to several other chronic medical disorders, biological markers of illness activity in depression do not currently exist. In the interim, therapeutic progress is monitored by evaluating changes in the severity of depressive symptoms and in functional domains. This concatenation of findings is particularly disconcerting in view of the fact that most depressed patients in either primary care or psychiatric settings are not systematically evaluated with objective quantifiable measures -a modifiable deficiency in patient management. [2][3][4][5][6] The most frequently reported symptomatic outcome measure in clinical trials of antidepressants has been response to treatment, arbitrarily defined as a reduction of 50% or more in total symptom severity from a pretreatment assessment of the patient's depression. 7 A categorical response to therapy that fails to achieve a fully asympomatic remitted state furnishes an unsatisfactory outcome, in that it includes patients with ongoing disease activity that is clinically significant. Patients who show improvement in symptom severity but are not asymptomatic are at risk for developing chronic depression, and continue to be vulnerable to poor outcomes and comorbid medical disorders. [8][9][10] Remission is an objective outcome indicated by a quantifiable score with a depressive symptom measurement tool. In antidepressant clinical trials, the 17-item Hamilton Depression Rating Scale (HAMD-17) has been the "gold standard" for use. HAMD-17, however, has not been accepted by clinicians for many reasons, 11,12 notably psychometric deficiencies and the length of time needed to administer it.Although several brief rating scales for depression that attempt to improve upon the limitations of HAMD-17 have recently been validated and reviewed, [11][12][13][14][15][16][17][18] none that are brief, currently available and use a remission cut-off score that correlates with the most frequently cited definition of remission (a HAMD-17 score ≤ 7) 7 have been validated in both tertiary mental health and primary care settings.Our broad objective in using HAMD-7 was to improve upon the conceptual and pragmatic deficiencies ascribed to HAMD-17. HAMD-7 was originally derived from analyses of a natural practice database at a tertiary care centre composed of patients diagnosed with a major depressive disorder (n = 248). 14 The HAMD-17 items that were endorsed in a previous study 14 by 70% of depressed patients and were most sensi- Background: Symptomatic remission is the optimal outcome in depression. A brief, validated tool for symptom measurement that can indicate when remission has occurred in mental health and primary care settings is unavailable. We evaluated a 7-item abbreviated version (HAMD-7) of the 17-item Hamilton Depression Rating Scale (HAMD-17) in a randomized controlled clinical trial of patients with major de...

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