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Evidence suggests a remarkable shared genetic susceptibility between psychiatric disorders. However, sex-dependent differences have been less studied. We explored the contribution of schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) polygenic scores (PGSs) on the risk for psychotic disorders and whether sex-dependent differences exist (CIBERSAM sample: 1826 patients and 1372 controls). All PGSs were significantly associated with psychosis. Sex-stratified analyses showed that the variance explained in psychotic disorders risk was significantly higher in males than in females for all PGSs. Our results confirm the shared genetic architecture across psychotic disorders and demonstrate sex-dependent differences in the vulnerability to psychotic disorders., Competing Interests: Author disclosures CA has been a consultant to or has received honoraria or grants from Abbot, Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion, Takeda and Teva. JB received consulting fees from Takeda as members of the Advisory Board. JB received research grants and served as consultant, advisor, or speaker within the last 3 years for: AB-Biotics, Acadia Pharmaceuticals, Alkermes, Angelini, Ambrosetti-Angelini, Biogen, Casen Recordati, D&A Pharma, Exeltis, Gilead, Indivior, GW Pharmaceuticals, Janssen-Cilag, Jazz Pharmaceuticals, Lundbeck, Otsuka, Pfizer, Roche, Sage Therapeutics, Servier, Shire, Takeda. In addition, JB received research funding from the Spanish Ministry of Economy and Competitiveness—Centro de Investigación Biomedica en Red area de Salud Mental (CIBERSAM), and Instituto de Salud Carlos III, Spanish Ministry of Health. AG-P has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen-Cilag, Lundbeck, Otsuka, Alter, Angelini, Novartis, Rovi, Takeda, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute), the Basque Government, and the European Framework Program of Research. The rest of the authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium's therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi + Gen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD., (© 2021. The Author(s).)

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi + Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The identification of bipolar disorder (BD) type II patients has both treatment and prognostic implications. Better understanding of its underlying genetics may yield useful diagnostic tools., Methods: A systematic review on BDII genetics was done using articles published in 2009-2019, following PRISMA recommendations., Results: The most studied polymorphism was BDNF Val66Met with several gene-gene interactions within the dopaminergic system. Associations were reported within the monoaminergic systems (DRD3, ADH1B and SLC6A4), calcium (CACNB2 and CACNG2) and cAMP (PDE1DA, PDE4B and DISC1) signal transduction pathways and the immune system (TNFα, IFNδ and IL-10). Chromosomes 2, 3 and 10 were associated with BDII and polygenic risk scores distinguished between BD subtypes and with major depressive disorder., Conclusions: Research on BDII stems from BDI findings, however with a stronger contribution of gene-gene interactions and low-effect alleles on known neuroplasticity and monoaminergic system genes. Genome studies point to transdiagnostic backgrounds, with wider associations across bipolar spectrum disorders. Findings able to accurately differentiate BDII remain elusive, dependent on better phenotypic characterization and new research methods., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Major depressive disorder (MDD) is a common disease with high morbidity and still unsatisfying treatment response. Both MDD pathogenesis and antidepressant effect are supposed to be strongly affected by genetic polymorphisms. Among promising candidate genes, distrupted in schizophrenia 1 (DISC1), translin-associated factor X (TSNAX) and D-amino acid oxidase activator (DAOA) were suggested since their regulator role in neurodevelopment, neuroplasticity and neurotransmission, and previous evidence of cross-involvement in major psychiatric diseases., Methods: The present paper investigated the role of 13 SNPs within the reported genes in MDD susceptibility through a case-control (n=320 and n=150, respectively) study and in citalopram efficacy (n=157). Measures of citalopram efficacy were response (4th week) and remission (12th week). Pharmacogenetic findings were tested in the STAR(⁎)D genome-wide dataset (n=1892) for replication., Results: Evidence of association among rs3738401 (DISC1), rs1615409 and rs766288 (TSNAX) and MDD was found (p=0.004, p=0.0019, and p=0.008, respectively). A trend of association between remission and DISC1 rs821616 and DAOA rs778294 was detected, and confirmation was found for rs778294 by repeated-measure ANOVA (p=0.0008). In the STAR(⁎)D a cluster of SNPs from 20 to 40Kbp from DISC1 findings in the original sample was associated with citalopram response, as well as rs778330 (12,325bp from rs778294)., Limitations: Relatively small size of the original sample and focus on only three candidate genes., Conclusions: The present study supported a role of DISC1-TSNAX variants in MDD susceptibility. On the other hand, genetic regions around DAOA rs778294 and DISC1 rs6675281-rs1000731 may influence citalopram efficacy., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: To evaluate, in patients affected by an acute major depressive episode, what predictive value certain baseline psychopathological characteristics have with regard to expected therapeutic remission following biological antidepressant treatment (pharmacological/electroconvulsive; non-psychological)., Methods: Six predefined psychopathological characteristics in acute major depressive episode were evaluated using a logistic regression model through a protocolised antidepressant treatment to assess their predictive value with regard to expected remission rate., Results: The final study sample consisted of 129 subjects affected by an acute major depressive episode. From the baseline evaluation of the anguish/restlessness, reduced emotional reactivity, reduced attention, reduced motor response, feeling of worthlessness, and mood characteristics items, it was possible to correctly classify 88.1% of the sample as remitter/non-remitter with sensitivity of 0.77 and specificity of 0.96. Addition of the 17-item HRSD baseline variable to the regression model increased the capacity for correct classification of the baseline sample by only 0.09%., Limitations: Protocolised antidepressant treatment was used. The results of this study may not be generalisable to pharmacological treatments not included in this protocol., Conclusions: The results of this study suggest that certain baseline psychopathological characteristics (and perhaps other clinical variables too) of the acute major depressive episode may be of great use in establishing patient subgroups according to expected clinical remission to the administration of biological antidepressant treatment. This could have considerable consequences for individualised therapeutic decision-making and for future researches (clinical trials included)., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: The influence of genetic and/or environmental factors on the volumetric brain changes observed in subjects affected by anxiety and depression disorders remains unclear. The current study aimed to investigate whether genetic and environmental liabilities make different contributions to abnormalities in gray matter volume (GMV) in anxiety and depression using a concordant and discordant MZ twin pairs design., Methods: Fifty-three magnetic resonance imaging (3T) brain scans were obtained from monozygotic (MZ) twins concordant (6 pairs) and discordant (10 pairs) for lifetime anxiety and depression disorders and from healthy twins (21 subjects). We applied voxel-based morphometry to analyse GMV differences. Concordant affected twins were compared to healthy twins and within-pairs comparisons were performed in the discordant group., Results: GMV reductions in bilateral fusiform gyrus and amygdala were observed in concordant affected twins for anxiety and depression compared to healthy twins. No intrapair differences were found in GMV between discordant affected twins and their healthy co-twins., Limitations: The sample size was modest. This might explain why no intrapair differences were found in the discordant MZ twin group., Conclusions: As concordant affected MZ twins are believed to have a particularly high genetic liability for the disorder, our findings suggest that fusiform gyrus and amygdala gray matter reductions are related to a genetic risk for anxiety and depression. Discrepancies in regard to brain abnormalities in anxiety and depression may be related to the admixture of patients with GMV abnormalities mainly accounted for by genetic factors with patients presenting GMV mainly accounted for by environmental factors., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Rationale: The endocannabinoid system has been implicated in the pathogenesis of major depression (MD) as well as in the mediation of antidepressant drug effects., Objectives: To analyze CNR1 gene variants in MD and clinical response to citalopram (selective serotonin re-uptake inhibitors [SSRI])., Methods: The role of CNR1 gene (rs806368, rs1049353, rs806371, rs806377 and rs1535255) was investigated in 319 outpatients with MD and 150 healthy individuals. A subsample of 155 depressive patients were treated with citalopram and evaluated for response (fourth week) and remission (12th week) by the 21-item Hamilton Depression Rating Scale (HDRS)., Results: We observed a higher frequency of rs806371 G carriers in MD patients with both presence of melancholia (p = 0.018) and psychotic symptoms (p = 0.007) than in controls. Haplotype frequency distributions between MD sample and controls showed a significant difference for Block 1 (rs806368-rs1049353-rs806371) (p = 0.008). This haplotype finding was consistent when we compared controls with MD subsample stratified by melancholia (p = 0.0009) and psychotic symptoms (p = 0.014). The TT homozygous of the rs806368 and rs806371 presented more risk of no Remission than the C carriers (p = 0.008 and 0.012, respectively). Haplotype frequency distributions according to Remission status showed a significant difference for Block 1 (p = 0.032). Also, we observed significant effect of time-sex-genotype interaction for the rs806368, showing that the C carrier men presented a better response to antidepressant treatment throughout the follow-up than TT homozygous men and women group (p = 0.026)., Conclusions: These results suggest an effect of CNR1 gene in the etiology of MD and clinical response to citalopram.

Background: Serotonergic genes have been widely investigated regarding antidepressant response in major depressive disorder (MDD) but results are still not univocal., Methods: 159 MDD patients treated with citalopram were genotyped and evaluated by the 21-item Hamilton Depression Rating Scale at the beginning and every 4 weeks during the 12-week follow-up. Four serotonin-related genetic variants were tested for association with treatment outcome: tryptophane hydroxylase 1 (TPH1) rs1800532, monoamine oxidase A µVNTR, serotonin 2A receptor rs6311 and serotonin 2C receptor rs6318. The effect of these polymorphisms was tested both in the whole sample and in depressive subtypes with usually higher clinical severity: psychotic and melancholic MDD., Results: No effect on response, remission and symptom improvement was found for the four polymorphisms. However, rs1800532 was found to affect the outcome depending on the MDD subtype: the A allele predicted worse response both in MDD with psychotic (F₆,₃₇₈ = 2.90; p = 0.009) and melancholic (F₆,₃₈₁ = 2.86; p = 0.0097) features., Conclusions: The A allele at TPH1 rs1800532 may be associated with citalopram efficacy only in melancholic and psychotic MDD. These results suggest the usefulness of investigating the effect of genetic variants in conjunction with specific clinical features., (Copyright © 2012 S. Karger AG, Basel.)

First line treatment of major depression is based on selective serotonin re-uptake inhibitors (SSRIs) that enhance serotonergic neurotransmission by blocking the serotonin transporter. However, clinical response is a complex phenomenon in which other systems such as the endocannabinoid system could be involved. Given the evidence for the role of the endocannabinoid system in the pathogenesis of depression as well as in the mediation of antidepressant drug effects, the aim of this study was to analyze genetic variability in the endocannabinoid system genes (CNR1, CNR2 and FAAH genes) and their role in clinical response (at week 4) and remission (at week 12) in SSRI (citalopram) treatment in a sample of 154 depressive outpatients, all of Spanish origin. All patients were treated with citalopram and followed over 12 weeks. Severity of depressive symptomatology was evaluated by means of the 21-item Hamilton Depression Rating Score (HDRS). No differences were found in any of the genotype distributions according to response or remission. The longitudinal study showed that (i) the CNR1 rs1049353-GG genotype conferred a better response to citalopram treatment in the subgroup of male patients and (ii) G allele carriers (CNR2 rs2501431) presented higher HDRS scores in the follow-up than AA homozygous allele carriers. Our results seem to suggest the involvement of CNR1 and CNR2 genes in clinical responses to citalopram treatment.

Major depressive disorder is a genetically complex disease involving several minor, or susceptibility, genes whose expression may be modulated by many environmental factors. From the classical early linkage studies to the complete genome-wide association (GWA) study methodologies, it is evident that it is difficult to understand the genetic bases of this mental disorder. Many studies have identified one or more gene regions whose variability confers a small risk for developing depressive disorder, explaining a small percentage of the total genetic component of disease with low predictive value. Although the results to date are inconclusive, new approaches based on gene-environment interactions and biological pathway analysis (based on GWA studies) open new and promising perspectives in the investigation of the genetic and biological basis of major depression.

Background: Neuroplastic processes are thought to be involved in the pathophysiology of major depression. It has been reported that serum brain-derived neurotrophic factor (BDNF) is decreased in depressed patients., Objectives: Compare BDNF levels in depressed patients and healthy controls in platelet poor plasma and in washed platelets. Observe the effects of 8- and 24-week treatment with S-citalopram on these levels., Methods: We assessed the levels of BDNF in platelet poor plasma and in washed platelets from 18 major depression patients, and compared them with 14 healthy controls. Blood samples were obtained from patients before and during treatment (8 and 24 weeks) with a selective serotonin reuptake inhibitor, S-citalopram., Results: A significant decrease in severity of depressive symptoms was observed from the first month of treatment with S-citalopram, and symptoms continued decreasing until the 6th month. Plasma BDNF levels in untreated patients appeared significantly increased (p<0.01) but reached values similar to those of controls at the 24th week. In contrast, levels of platelet BDNF appeared significantly decreased (p<0.05), but treatment also normalized levels so that values obtained were equivalent to those of controls., Conclusions: Untreated depressed patients showed increased plasma BDNF levels and decreased platelet BDNF levels, as compared with control subjects, and tend to normalize during treatment with S-citalopram for 24 weeks, with BDNF reaching levels similar to those in healthy controls at the 24th week in both samples. We observed that improvement in depressive symptoms was accompanied by normalization of plasma and platelet BDNF levels.

Background: Dysbindin gene (dystrobrevin-binding-protein 1, DTNBP1) variants have been associated with several psychiatric conditions including mood disorders and antidepressant efficacy. We investigated dysbindin gene (DTNBP1) variants in major depression and clinical response to selective serotonin reuptake inhibitors., Methods: In this study we investigated the role of DTNBP1 gene (rs3213207, rs2005976, rs760761 and rs2619522) in 313 major depressive outpatients and 149 healthy individuals. One hundred and forty-seven depressive patients were treated with citalopram and evaluated for response (4th week) and remission (12th week) by the 1-item Hamilton Depression Rating Scale. Single nucleotide polymorphisms (SNPs) were assayed by using Applied Biosystems TaqMan technology., Results: Genotype and haplotype frequencies for four SNPs within DTNBP1 gene did not significantly differ between patients and controls. Allele distribution of SNP rs760761, however, showed a trend of difference between responders and nonresponders (4th week). Haplotype analyses produced a significant association with response to treatment at week 4. No differences were found in remission (12th week)., Discussion: DTNBP seems to have an effect on short-term clinical response to citalopram. New studies focused on other genes involved in glutamatergic neurotransmission and related proteins could help to elucidate the complex mechanism of clinical response to antidepressants.

Background: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been observed in major depression. Normalization of HPA axis has been suggested to play a role in the mechanisms of action of antidepressants. Our aim was to investigate the influence of genetic variants in CRHR1, CRHR2, CRH-BP and FKBP5 genes on both the vulnerability for depression and the response to antidepressant treatment., Methods: The sample consisted of 159 depressive outpatients and 96 healthy controls of Spanish origin. Patients were assessed for clinical features including, among others, age of onset, seasonality or suicidal behavior. The episode was treated with citalopram and followed along 12 weeks. Severity of symptoms was evaluated at the inclusion and then monthly along the follow-up using a 21-item Hamilton Depression Rating Score (HDRS). SNPs were assayed using Applied Biosystems SNaP-Shot and TaqMan technology., Results: rs110402, in CRHR1 gene, was associated with an increased risk to present a seasonal pattern and an early age of onset of the first depressive episode. Allele G carriers of rs2270007 of CRHR2 gene, showed a worse overall response to citalopram along time of follow-up (Genotype effect F=7.45, P=0.007). G allele carriers showed 2.93 increased risk (95% CI [1.24-6.90]) for non-responding at 4th week to citalopram treatment (chi(2)=7.59, df=1, P=0.006)., Limitations: On the light of the moderate sample size, associations based on the mentioned polymorphisms need to be considered with caution and require further replication studies in other samples., Conclusions: Variability at genes encoding proteins with a pivotal role in HPA axis regulation seems to influence i) the expression of severity variables of the depressive spectrum including early age of onset or a seasonal pattern and ii) the interindividual variation in clinical response to SSRI antidepressants.

Introduction and Objectives: There is convincing evidence of interactions between serotonergic and dopaminergic systems and it seems that an increase of dopamine concentration in the whole brain could be a limiting factor for the antidepressant like effect of antidepressants. The COMT gene might be a good candidate for explaining some aspects of the pharmacological response to SSRIs., Methods: The aim of our study was to analyse the Val 158 Met functional polymorphism on COMT gene and clinical response (4 weeks) and clinical remission (6/8 and 12 weeks) in two samples of depressive patients (DSM-IV) treated with SSRIs of Italian and Spanish origin. Clinical outcome was measured using 21 items Hamilton scale, weekly in the Italian sample (along 6 weeks) and monthly in the Spanish one (along 12 weeks)., Results: No overall effect of genotype or genotypextime interaction was detected. However, we observed a genotypextime interaction on HDRS decrease for citalopram treatment (F((4.6,317.5)) = 3.38, P = 0.007) in the Spanish sample. No clear effect was observed in the Italian sample. The three samples were pooled in order to test if carrying the Met/Met genotype confers an increased risk for non-remission at 6-8 weeks. The results showed that Met/Met carriers have an odds ratio of 2.21 (95% CI [1.20-4.12]) for non-remission (chi(2) = 7.43, df = 2, P = 0.006). The Met/Met effect was not observed in response at 4th week (for all SSRI treatments) or in remission at 12th week (citalopram treatment)., Conclusions: COMT gene could have a small and indirect effect of clinical response to SSRIs by slowing-down the antidepressant action along the follow-up, basically in citalopram treatment.

In the context of a long-term follow-up study, we analysed the possible implication of the 5-HT(1A) receptor gene (HTR1A) -1018C/G polymorphism in the clinical outcome of major depressive patients treated with citalopram. We had previously reported an association between variation on the SERT gene (SLC6A4) and clinical remission after citalopram treatment. In the present 12-week follow-up study, the combined effect of HTR1A and SLC6A4 genes in clinical outcome and response to citalopram was also evaluated. The sample consisted of 130 patients, all of Spanish origin, who were diagnosed as having a current major depressive episode according to DSM-IV criteria. A 21-item Hamilton Depression Rating Scale was used to assess severity of symptoms at the beginning and during the follow-up to determine the outcome and remission status at week 12. Patients were genotyped for HTR1A gene and, in addition, for two polymorphisms at the CYP2C19 gene, which together account for the 87% of the Caucasian poor metabolizer phenotype. Data were analysed adjusting for the effect of poor metabolizers in clinical response. No independent effect was found for the 5-HT(1A) receptor gene in relation to clinical outcome or remission after citalopram treatment. However, a combined genetic effect of HTR1A and SLC6A4 genes was found to influence the clinical outcome of patients [F(4,102) = 2.89, p= 0.02]. When considering the remission status, an increase of patients carrying the risk genotype combination (S/S-G/G) was found among those subjects who did not reach remission (Fisher's exact test = 0.009). Our results suggest that the combined effect of the serotonin transporter and the 5-HT(1A) receptor genes could be related to the clinical outcome of depressive patients treated with citalopram.

In the context of a long term follow-up study, we analysed the possible implication of the 5-HTTLPR polymorphism at the serotonin transporter gene in clinical response and remission of major depressive patients treated with citalopram. The sample consisted of 131 patients, all of Spanish origin, diagnosed according to DSM-IV criteria. A 21-item Hamilton Depression Rating Scale (HDRS) was used to evaluate severity of the symptoms during the follow-up and to determine clinical response and remission condition of the patients at 4th and 12th week, respectively. Our results showed that S/S genotype of the 5-HTTLPR polymorphism was associated with the non-Remission condition at 12th week (chi2 = 8.7, P = 0.013). Moreover, homozygous for the allele S presented three times more risk for non reaching remission of depressive episode after citalopram treatment than patients with any other 5-HTTLPR genotype combination (chi2: 7.29, P = 0.006; OR = 3.23 [95%CI: 1.24-8.5]). In conclusion, our results show that genetic variation of serotonin transporter is involved in clinical remission of major depressive episodes after twelve weeks of citalopram treatment.

In the present study, genetic variation of the 5-HT5A receptor was analyzed in patients affected by affective disorders and healthy controls. The sample consisted of 181 patients with major depression, 88 patients with bipolar affective disorder (BP) and 157 unrelated controls (C), all of Spanish origin. Two polymorphisms (-19G/C and 12A/T) in the 5-HT5A receptor gene were analyzed by polymerase chain reaction amplification and subsequent enzyme digestion. No genotype, allele or haplotype differences were found when we compared patients and controls. When clinical variables were considered as possible tools for detecting genetic heterogeneity, no differences were found. Our results suggest that the polymorphisms analyzed in the 5-HT5A receptor gene do not play a major role in the pathogenesis of affective disorders.

The 102-T/C polymorphism of the 5-HT(2A) receptor gene was analysed in 159 patients with major depression and 164 unrelated and healthy controls using a case-control design. Allele and genotype frequencies did not differ between cases and controls. No differences according to sex, age of onset, melancholia, suicidal behaviour or family history of psychiatric illness were found. However, genotype distributions significantly differed between patients with seasonal pattern in their episodes (MDS) and patients with no seasonal pattern (N-MDS) (chi(2) = 10.63; P = 0.004). A seasonal pattern was 7.57 times more frequent in 102C-allele carriers than in 102T homozygous (95.1% of patients MDS carried 102C-allele vs 72% of patients N-MDS (chi(2) = 9.45, df=1, P = 0.002; OR = 7.57 (95% CI: 1.65--48.08)). These results suggest that variation in the 5-HT2A receptor gene may play a role in the development of major depression with seasonal pattern and support the existence of a genetic and etiological heterogeneity underlying the diagnosis of major depression.