Association study of the serotonin transporter promoter polymorphism and mirtazapine antidepressant response in major depressive disorder

Modulations of serotonergic and noradrenergic systems are thought to be critical to the therapeutic effect of most antidepressants, and their efficacies have been shown to depend on a functional polymorphism within the promoter region of the serotonin transporter gene (5-HTTLPR). Mirtazapine has a dual-action profile, combining the enhancement of the noradrenergic neurotransmitter system with specific actions on particular serotonergic receptor subtypes. The goal of this study was to elucidate whether the 5-HTTLPR polymorphism is associated with the mirtazapine antidepressant response in subjects with major depressive disorder (MDD). One hundred and one MDD patients were evaluated during 4 weeks of mirtazapine treatment. The severity of depression was assessed with the 21-item Hamilton Depression Rating scale, and the 5-HTTLPR genotypes in the patients were determined using the polymerase chain reaction. Our results showed that responses at the 2nd and 4th weeks were significantly better for the s/s genotype of the 5-HTTLPR polymorphism than for l-allele carriers. These results support our hypothesis that the response to noradrenergic and specific serotonergic antidepressants is significantly associated with the 5-HTTLPR polymorphism.     

Association of serotonin transporter gene polymorphisms and major depressive disorder in Chinese Han population

BACKGROUND： Serotonin transporter （5-HTT） polymorphisms comprise 5-HTT gene-linked polymorphism region （5-HTTLPR） and variable number of tandem repeats （VNTR）. Studies have revealed an association between 5-HTT polymorphism and major depressive disorder, which suggests that the ＂S＂ allele of 5-HTTLPR and Stin2.9 of 5-HTTVNTR are associated with major depressive disorder. However, there are a number of studies that do not support the 5-HTT polymorphism effect in major depressive disorder. OBJECTIVE： To study the relationship between 5-HTT gene polymorphism and major depressive disorder in Chinese Han population. DESIGN, TIME AND SETTING： Case-controlled study of 5-HTT gene polymorphism. The experiment was performed at the Central Laboratory, Third Affiliated Hospital of Sun Yat-sen University, China from March 2005 to January 2006. PARTICIPANTS： A total of 99 depressive patients of Chinese Han nationality were recruited for this study. All patients met DSM-IV diagnostic criteria for major depressive disorder and had a total score of Hamilton Depression Scale （24 items） ≥21 points. In addition, 101 healthy subjects, matched for age and gender, served as the control group. METHODS： Venous blood was collected from all subjects. 5-HTT genotypes and alleles were determined by polymerase chain reaction. Consistent with the Hardy-Weinberg equilibrium, the association between 5-HTT gene polymorphism and major depressive disorder were analyzed by Chi-square test. MAIN OUTCOME MEASURES： 5-HTTLPR and 5-HTTVNTR genotypes and allele frequencies were measured. RESULTS： No significant differences in 5-HTTLPR genotypes and allele frequencies were determined between patients and controls （P 〉 0.05）. However, significant differences in 5-HTTVNTR genotypes and allele frequencies were detected （P 〈 0.01 ）. The Stin2.10 allele and 10/10 genotype associated with major depressive disorder （OR = 2.61,7.7, P 〈 0.05; analysis of dose-response relationships Х^2 = 12.35, P 〈 0.01）. CONCLUSION： Results from the present study revealed no association between 5-HTTLPR and major depressive disorder. However, a significant association between 5-HTTVNTR and major depressive disorder existed in a population of Chinese Han. The presence of Stin2.10 and 10/10 genotypes increased the risk for major depressive disorder in a dose-dependent manner.     

Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder.

BACKGROUND: Recent evidence has suggested that the short allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR of the human serotonin gene [SLC6A4]) is associated with increased risk of depressive disorder but only among individuals exposed to social adversity. We report an investigation designed to replicate this finding. METHODS: Data were available from a non-clinical sample of 4,175 adult men and women, ages 41-80 years, selected from participants in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk, United Kingdom) study. Evidence of past-year prevalent episodic major depressive disorder (MDD), defined by restricted DSM-IV diagnostic criteria, was assessed through questionnaire. Adverse experiences in childhood and in adulthood (during the five years preceding assessment) were also assessed through self-report. The 5-HTTLPR variant was genotyped according to published protocols. RESULTS: One-year prevalent MDD criteria were met by 298 study participants. The experience of social adversity (both in childhood and adulthood) was strongly associated with increased rates of past-year prevalent MDD. No gene by environment (GxE) interactions between the 5-HTTLPR genotype, social adversity, and MDD were observed. CONCLUSIONS: This study has not replicated a previous finding of a GxE interaction between the 5-HTTLPR genotype, social adversity, and depression.     

Association between obsessive-compulsive disorder and a variable number of tandem repeats polymorphism in intron 2 of the serotonin transporter gene

BACKGROUND: Pharmacological studies indicate a dysregulation of the serotonergic system in obsessive-compulsive disorder (OCD). A variable number tandem repeats (VNTR) polymorphism with three alleles (Stin2.9, Stin2.10, Stin2.12) has been described in intron 2 of the serotonin transporter (5-HTT) gene. This polymorphism has been associated with unipolar depression, bipolar disorder, schizophrenia, and anxiety disorders including OCD. METHODS: The association between OCD and the polymorphism is examined in 97 OCD patients, 578 psychiatric controls and 406 healthy controls, all Spanish Caucasians. RESULTS: Genotype frequencies for the polymorphism were significantly different in OCD patients, psychiatric patients and controls. There was a significant excess of 12/12 and 12/10 genotypes in OCD patients compared to psychiatric patients and controls. CONCLUSIONS: Our results indicate a possible association between the Stin2.12 allele of the VNTR polymorphism and OCD.     

The symptomatic profile of panic disorder is shaped by the 5-HTTLPR polymorphism

The short allele of a functional polymorphism (5-HTTLPR) in the serotonin transporter (5-HTT) promoter is associated with reduced serotonin transporter expression, lower in vivo 5-HTT binding, higher neuroticism and amygdala reactivity as well as facilitated fear conditioning and is a candidate variant for panic disorder. However, case–control studies have consistently failed to show an association between 5-HTTLPR and panic disorder. As psychiatric disorders are broadly defined phenotypes merging different symptoms to syndromes, they may not be very well suited for genetic association studies. An alternative approach is to measure symptoms along continuous symptom dimensions which may more appropriately reflect their biological underpinnings and may reveal subpopulations within clinical diagnostic groups. We recorded the symptomatic profile in 73 in panic disorder patients using observer-rated instruments (Panic Disorder Severity Scale, PDSS; Montgomery–Åsberg Depression Rating Scale, MADRS) and hypothesized more severe symptoms in patients carrying the 5-HTTLPR s-allele. We observed a strong association between bi- and triallelic 5-HTTLPR polymorphisms and the symptomatic profile. Carriers of the 5-HTTLPR s-allele suffered from most severe panic and depressive symptoms. Our data highlight the importance of defining appropriate phenotypes for psychiatric genetic studies and demonstrate that the 5-HTTLPR genotype may be related to the symptomatic profiles rather than to the vulnerability to develop panic disorder.     

Meta-analysis of the association of serotonin transporter gene polymorphism with obsessive-compulsive disorder

Evidence has supported a role for serotonin system dysfunction in the pathogenesis of the obsessive-compulsive disorder (OCD). Many studies examined the association between OCD and a functional polymorphism of the serotonin transporter gene promoter (5-HTTLPR) but yielded inconsistent results. Current study aimed to determine conclusively whether there is an association by using a meta-analytic method. Over 3000 subjects from 13 independent case-control association studies were included in the analysis. By using random effects model, data from these studies were pooled to compare the genotypes and allelic distribution of the 5-HTTLPR polymorphism between OCD patients and control subjects. In the analysis, OCD was found to be associated with the SS homozygous genotype (OR=1.21, p=0.04), but was inversely associated with the LS heterozygous genotype (OR=0.79, p=0.03). No association with the LL homozygous genotype or the allelic distribution was found. These results suggest that variations of the serotonin transporter gene influence the risk of OCD, but their functional roles in the pathogenesis of OCD need to be elucidated.     

Comparison of the efficacy between paroxetine and sertraline augmented with aripiprazole in patients with refractory major depressive disorder

Objective

Only two-thirds of depressive patients respond to antidepressant treatment. In recent years, addition of an atypical antipsychotic drug to ongoing treatment with an antidepressant has been considered effective and well-tolerated. In the present study, we compared the efficacy between paroxetine and sertraline augmented with aripiprazole in patients with refractory major depression.

Subjects and methods

Twenty-four patients who met the DSM-IV criteria for major depressive disorder who did not at least two different classes of antidepressants were enrolled in the study. Nine were male and thirteen were female, and their ages ranged from 28 to 66 (mean ± SD = 39 ± 12) years. Patients were prescribed paroxetine (n = 11) or sertraline (n = 13) for 4 weeks. Then, those whose scores on the 17-item Hamilton Rating Scale for Depression (HAMD17) decreased below 50% received adjunctive therapy of aripiprazole for 4 weeks.

Results

Although the use of either combination treatment decreased the HAMD17 scores compared to the respective monotherapy, there was no significant difference in HAMD17 scores between the paroxetine plus aripiprazole group and sertraline plus aripiprazole group.

Conclusion

Aripiprazole augmentation therapy with paroxetine or sertraline was equally effective and tolerated in patients with refractory major depressive order.     

No association of serotonin transporter polymorphism (5-HTTVNTR and 5-HTTLPR) with characteristics and treatment response to atypical antipsychotic agents in schizophrenic patients

Background

Serotonin transporter is a candidate gene for the pathogenesis of some psychiatric disorders. The aim of this study was to examine the role of the serotonin transporter gene polymorphism in the clinical aspects of schizophrenia including symptomatology and therapeutic response.

Methods

This study comprised 141 unrelated patients who strictly met the DSM-IV criteria for schizophrenia and 115 control subjects. All subjects were of Korean ethnicity. Serotonin transporter intron 2 VNTR polymorphism (5-HTTVNTR) and serotonin transporter linked polymorphic region polymorphism (5-HTTLPR) were analyzed in schizophrenia patients and control subjects. The Positive and Negative Symptom Scale (PANSS) was used at baseline and 6 weeks after atypical antipsychotic treatment to evaluate the clinical symptoms. Body mass index (BMI), the Barnes Akathisia Rating Scale (BARS), the Simpson–Angus Rating Scale (EPS) for adverse effect and the Calgary Depression rating Scale for Schizophrenia (CDSS) were measured.

Results

There were no significant differences in the frequency of genotypes between schizophrenia patients and control subjects. There were no significant differences in PANSS scores before treatment according to the serotonin transporter genotypes. Treatment response after atypical antipsychotics did not differ among the genotypes. No difference was shown among the genotypes for the scales in adverse effects and depression (BMI, BARS, EPS, CDSS).

Conclusions

Our results suggest that the serotonin transporter polymorphism does not seem to be a susceptibility factor for schizophrenia. Similarly, the serotonin transporter polymorphism might not affect the therapeutic response and adverse effect to atypical antipsychotics in Korean patients with schizophrenia. Further studies with a larger number of subjects are required to better understand the role of the serotonin transporter polymorphism in schizophrenia.     

The norepinephrine transporter gene is associated with the retardation symptoms of major depressive disorder in the Han Chinese population

The norepinephrine transporter plays an important role in the pathophysiology and pharmacological treatment of major depressive disorder.Consequently,the norepinephrine transporter gene is an attractive candidate in major depressive disorder research.In the present study,we evaluated the depression symptoms of subjects with major depressive disorder,who were all from the North of China and of Han Chinese origin,using the Hamilton Depression Scale.We examined the rela-tionship between two single nucleotide polymorphisms in the norepinephrine transporter,rs2242446 and rs5569,and the retardation symptoms of major depressive disorder using quantitative trait testing with the UNPHASED program.rs5569 was associated with depressed mood,and the GG genotype may be a risk factor for this;rs2242446 was associated with work and interest,and the TT genotype may be a risk factor for loss of interest.Our findings suggest that rs2242446 and rs5569 in the norepinephrine transporter gene are associated with the retardation symptoms of depression in the Han Chinese population.     

Topiramate augmentation in patients with resistant major depressive disorder: a double-blind placebo-controlled clinical trial

Background

Despite evolution of new antidepressant treatment, clinicians still encounter challenges in the treatment of depressed patients. Looking for new medications that can potentiate the effects of current antidepressants seems to be necessary. Our objective is to survey the efficacy of topiramate augmentation in resistant major depressive disorder (MDD).

Method

This augmentation trial was designed as an 8-week randomized, placebo-controlled, double-blind study. Fifty three patients with DSM-IV diagnosis of MDD who had failed to respond to at least 8 weeks of treatment with an adequate dose of one of the SSRIs (fluoxetine, citalopram or serteraline) were included in the study. Patients were randomized to receive a flexible dose of topiramate (100-200 mg/day) or placebo beside their current antidepressant medication for a period of eight weeks. Outcome measures were Hamilton Depression Scale (HAM-D) and Clinical Global Impression (CGI).

Results

42 patients completed the study and there were 6 and 5 dropouts in topiramate and placebo groups, respectively. The topiramate group demonstrated significant improvement over the study period based on mean HAM-D score at week 8 compared to baseline (P = .000, Z = 3.699). Those receiving topiramate demonstrated to have a mean decrease of 32.0% in HAM-D score, compared to only 5.5% for those receiving placebo. Depressed mood, suicidality, insomnia (early, middle and late), agitation and anxiety symptoms were significantly improved in the topiramate group.

Conclusion

Our double-blind placebo-controlled study demonstrated that topiramate augmentation potentiate the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treatment of resistant major depressive disorder. Of note is that our study is preliminary and larger double-blind studies are needed to confirm the results.     

Association between brain-derived neurotrophic factor gene and a severe form of bipolar disorder, but no interaction with the serotonin transporter gene

Background:  Recent data suggest that brain-derived neurotrophic factor (BDNF) and the serotonergic system are involved and interact in major depressive disorder and suicidal behavior (SB). Several family and population-based studies have reported associations between the BDNF gene and serotonin-related genes, specifically the serotonin transporter (5HTT) gene, with bipolar disorder (BD) and SB. However, despite the fact that gene-by-gene interaction between BDNF and 5HTT has been demonstrated in monoamine deficiencies in animals, this kind of interaction has never been tested in humans. Our hypothesis is that some BDNF and 5HTT polymorphisms might confer increased risk for BD and SB and that both genes may interact with each other.
Methods:  To test this hypothesis, we genotyped the most common BDNF polymorphisms, G196A (Val66Met), A-633T and BDNF-LCPR, as well as 5HTT (5HTT-LPR), in 447 BD patients and 370 controls.
Results:  We replicated the association previously reported between BDNF G196A (Val66Met) polymorphism and BD. We also observed a correlation between the number of G196 alleles and short alleles of 5HTT-LPR and the severity of SB in BD. However, we found no significant interaction between these two markers.
Conclusions:  These results suggest that BDNF G196A as well as 5HTT-LPR polymorphisms confer risk for SB in BD, but we did not observe any evidence for an interaction between them.     

ABCB1 (MDR1) gene polymorphisms are associated with the clinical response to paroxetine in patients with major depressive disorder

Variability in antidepressant response is due to genetic and environmental factors. Among genetic factors, the ones controlling for availability of the drug at the target site are interesting candidates. Multidrug resistance 1 (ABCB1, MDR1) gene encodes a blood-brain barrier transporter P-glycoprotein that plays an important role in controlling the passage of substances between the blood and brain. In the present study, we therefore examined the possible association of 3 functional ABCB1 polymorphisms (C3435T: rs1045642, G2677T/A: rs2032582 and C1236T: rs1128503) with response to paroxetine in a Japanese major depression sample followed for 6 weeks. Analysis of covariance at week 6 with baseline scores included in the model as covariate showed significant association of the non-synonymous SNP G2677T/A with treatment response to paroxetine (p=0.011). Furthermore, the wild variants haplotype (3435C-2677G-1236T) resulted associated with poor response (p=0.006). To our best knowledge, this study is the first suggestion of a possible association of ABCB1 variants with SSRIs response.     

Low HDL cholesterol associates with major depression in a sample with a 7-year history of depressive symptoms

Long-term depression may increase the risk for adverse coronary events. Low levels of high-density lipoprotein cholesterol (HDL-C) have in particular been suggested to underlie this connection. A total of 124 participants with a recorded seven-year history of depressive symptoms (depressed, n=63) or euthymic state (controls, n=61) underwent a Structured Clinical Interview for DSM-IV to confirm their psychiatric diagnosis. Total cholesterol (TC), HDL-C and low-density lipoprotein cholesterol (LDL-C) levels, triglycerides, non-HDL-C and atherogenic indices (LDL-C/HDL-C and TC/HDL-C) were assessed. The HDL-C levels were lower and atherogenic indices higher in the depressed group compared with the controls. Furthermore, those with HDL-C level below the gender-adjusted median (<1.54 mmol/l in women, <1.16 mmol/l in men) were 2.4-fold more likely to be depressed in a model adjusting for age and non-HDL-C (p=0.019). After further adjustment for educational level, marital status, alcohol use, daily smoking and overweight this association remained significant (p=0.049). These findings suggest that compared with the healthy controls, those with long-term depression may have lower HDL-C values and higher atherogenic indices.     

Reduced expression of apolipoprotein E receptor type 2 in peripheral blood lymphocytes from patients with major depressive disorder

We measured the mRNA levels of apolipoprotein E receptor type 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR) in peripheral blood lymphocytes from 43 patients with major depressive disorder (27 drug-free patients and 16 medicated patients) and 43 age-matched healthy controls using a quantitative real-time RT-PCR method. The correlations between mRNA levels of both receptors and clinical variables in patients were also examined. The expression of ApoER2 mRNA, but not VLDLR, was significantly lower in patients as compared to controls, irrespective of the medication status. There was no statistically significant correlation between the reduction of ApoER2 mRNA levels and any of the clinical variables measured in patients. Results from this preliminary study suggest that the expression of ApoER2 may serve as a trait marker for major depressive disorder.     

Evidence for specific cognitive deficits in visual information processing in patients with OCD compared to patients with unipolar depression

Objective

Neuropsychological studies comparing cognitive performance in patients suffering from Obsessive-Compulsive Disorder (OCD) or Major Depressive Disorder (MDD) revealed deficits in the domains of verbal fluency and viso-motor speed/set shifting in both groups. Spatial working memory deficits, however, have been identified as specific markers of OCD. As yet, it has not been substantiated whether deficits in visual organization and complex visual memory are also specific to OCD and are not shared by MDD.

Method

Test performance in seven cognitive domains was assessed in 40 OCD patients, 20 MDD patients, and 40 healthy controls. Patient groups were matched according to severity of depressive symptoms.

Results

Deficits shared by both patient groups, as compared to controls, were found in delayed spatial recall and verbal fluency while verbal memory was normal in both patient groups. Only patients with OCD, but not MDD patients were impaired in the domains visual memory, viso-motor speed/set shifting, visual organization, and problem solving. In addition, OCD patients differed significantly from MDD subjects in visual organization and problem solving. Visual organization scores correlated significantly with severity of current compulsions in the OCD group (r = −.324).

Conclusions

OCD patients demonstrate difficulties in visual organization and mental manipulation of complex visual material, which are not accounted for by depressive symptoms and which constitute a specific cognitive deficit of the disorder.     

Cognitive dysfunctions in patients with obsessive-compulsive disorder compared to the patients with schizophrenia patients: relation to overvalued ideas

OBJECTIVE: The clinical overlaps between schizophrenia and obsessive-compulsive disorder (OCD) seem to be related to thought disorders involving obsessions, overvalued ideas, and delusions. Overvalued ideas are beliefs falling in between obsessions and delusions and are stronger than obsessions but weaker than delusions. The goal of the present study was to compare patients with OCD to those with schizophrenia in terms of cognitive functions and to relate cognition and overvalued ideas in OCD. METHODS: Twenty three patients with OCD (free of depression), 24 patients with schizophrenia, and 22 healthy subjects matched to patients in age, gender, education, and hand dominance were included in the study. All subjects were administered neurocognitive tests assessing verbal learning-memory, executive functions, verbal fluency, attention and verbal working memory. RESULTS: Patients with schizophrenia showed worse performance on cognitive tests than the OCD and control groups. The severity of overvalued ideas was significantly correlated to cognitive functions in the OCD group. There were no significant differences in cognitive functions between schizophrenia group and the OCD patients who had higher scores on the Overvalued Ideas Scale (OVIS). CONCLUSION: Overvalued ideas in OCD may be related to cognitive dysfunctions in OCD and this subtype of OCD may have similar characteristics to schizophrenia in terms of cognition.     

Serotonin transporter gene promoter polymorphism affects the severity of binge eating in general population

Objective

The s-allele of the 5-HTTLPR has been suggested to lead to the development of less efficient and less flexible 5-HT system and has been associated to different forms of psychopathology. It has also been shown that alterations in serotonergic activity contribute to the pathophysiology of binge eating but it is not clear which changes in 5-HT function observed in eating disorder patients represent trait vs state effect. We investigated the association between the 5-HTTLPR and binge eating in a population-representative sample of women, and tested whether the 5-HTTLPR genotype influences the severity of binge eating.

Methods

The sample was based on women participating in the third wave of the Estonian Children Personality, Behaviour and Health Study. EDI-2 subscales – drive for thinness and bulimia – were used to assess eating behaviour and attitudes. Barratt Impulsiveness Scale (BIS-11) and State and Trait Anxiety Inventory (STAI) were used to measure impulsivity and anxiety. Participants were genotyped for the 5-HTTLPR.

Results

There was no 5-HTTLPR genotype effect on binge eating even after the covarying effect of impulsivity and anxiety was controlled for. However, women prone to binge eating and carrying the s-allele showed significantly higher levels of bulimia scores, and among them, women with s/s genotype had also higher levels of state anxiety and tendency for higher impulsivity.

Conclusions

While the 5-HTTLPR genotype does not predict symptoms of eating disorder in general population, the s-allele, and especially the s/s genotype increases the risk for affective instability and symptom severity.     

Autonomic modulation in healthy first-degree relatives of patients with major depressive disorder

Background

Cardiac mortality is known to be increased in patients with major depression. Several studies have reported an imbalance within the autonomic nervous system (ANS) of patients with major depressive disorder (MDD) as one putative cause. Since a heritability of autonomic modulation was demonstrated in healthy subjects, we aimed to investigate autonomic modulation in first-degree relatives of patients with MDD to find potential autonomic imbalances.

Methods

We included 30 patients with MDD, 30 of their first-degree relatives (siblings or offspring) and 30 matched healthy controls in our study. We obtained a high resolution electrocardiogram and beat to beat blood pressure measurements for 30 min at rest. Linear and nonlinear parameters of heart rate variability (HRV) and baroreflex sensitivity (BRS) were calculated.

Results

Parameters of HRV and BRS did not differ significantly between relatives and controls. We found significant differences between patients and controls for some HRV and BRS parameters confirming results of previous studies.

Discussion

Findings of our study suggest that an imbalance of autonomic function is related to patients with depression and not to first-degree relatives. Thus, a genetic background for autonomic dysfunction is rather unlikely.     

Prediction of relapse in melancholic depressive patients in a 2-year follow-up study with corticotropin releasing factor test

Purpose

To study the power of CRF stimulation test to predict relapse in a sample of melancholic depressive patients in depressed phase, followed-up over a two-year period from the moment they achieved complete remission of depressive symptoms.

Methods

Fifty-one outpatients diagnosed with unipolar depressive disorder with melancholic features according to DSM-IV were assessed with the CRF test. The Structured Clinical Interview for DSM-IV (SCID-IV) was used for diagnosis. Monthly follow-up visits were held over a two-year period after remission; relapse was established using HDRS according to Frank's criteria [Frank E, Prien RF, Jarret RB, Keller MB, Kupfer DJ, Lavori PW, et al. Conceptualization and rationale for consensus definitions of terms in major depressive disorder: remission, recovery, relapse, and recurrence. Arch Gen Psychiatry 1991;48:851–5]. Forty-three patients completed the study. Non-controlled antidepressant treatment protocols were used. Predictive statistical analysis was performed through logistic regression.

Findings

The final predictive model included three variables: net area under cortisol curve (NAUCC), previous suicide attempt, and stress during follow-up. Sensitivity was of 89%, and specificity was of 92%. NAUCC has shown a predictive power of 80%, with an optimal cut-off point of 251.24 μg/ml/min.

Conclusions

Cortisol is the hormone of the HPA axis which shows the highest power to predict relapse. NAUCC is the most relevant variable. The complete predictive model is a complex combination of biological, clinical and psychoenvironmental variables (NAUCC, previous suicide attempts, and stress during follow-up). Further studies with better control of the psychoenvironmental variables are required to obtain more precise neuroendocrine findings.